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'India can't be indifferent on any global issue'
Not surprisingly, for an admiral known for speaking his mind, it was a speech marked by characteristic candour:
We often hear that our rise to global prominence is inevitable. It is an incontestable fact that the significance of India as a rising power is being widely acknowledged, as has been witnessed by several events in the recent past, the most defining of which has perhaps been the inking of the agreement on civil nuclear cooperation with the United States.
Our growing economic status fuelled by a 300 million strong middle class, the demographic advantage of a burgeoning 'young population', our increasing ventures into high technology areas such as space, and future projections of national growth peg us amongst the world's top five economies by 2020. That is just 11 years away.
The professionalism and military might of the armed forces of India are respected the world over. The very recent launch of our very own nuclear submarine 'Arihant' has also sent out a strong signal of our desire to acquire the appropriate strategic military technology and capability.
Despite our several internal challenges and diversities, we are 'rock solid' as a democratic country, surrounded by an extended periphery of varying instability.
It is therefore not surprising that the role of a 'natural' regional power is expected of us. Our aspirations for inclusion as a permanent member of the UN Security Council and for a greater voice in international diplomacy are a result of these developments.
However, there is a sense that we may not have done adequately rigorous thinking on how to 'manage' our pre-ordained rise to global prominence. With the realisation of our aspirations and greater international recognition will come many more additional responsibilities.
The country cannot afford to be indifferent and non-committal on any regional or global issue -- we must have an objective 'national interest assessment' on all questions of importance.
As military forces of India, we would be expected to function as instruments of peace and stability in this rather fragile environment of the Indian Ocean region. We have to get our 'hands dirty' in addressing common concerns in our respective domains. This will call for increased participation in peace operations, efforts such as anti-piracy as also capacity-building and capability-enhancement of smaller and economically weaker nations which look up to us, for support and security.
We must also be seen far away from our shores, working with friendly nations and shaping perceptions, in furtherance of India's foreign policy. Quite evidently, the navy would lead efforts of military diplomacy, given the medium in which it operates and the distinctive characteristics of its platforms. If we pursue a meaningful foreign policy to advance national objectives -- as we do -- then the military instrument can complement this collective endeavour.
Image: Admiral Sureesh Mehta reviews a ceremonial parade at the Southern Naval Command in Kochi.
Photographs: Sivaram V/Reuters
Coping with China
Once that is done, China is likely to be more assertive on its claims, especially in its immediate neighbourhood. Our 'trust deficit' with China can never be liquidated unless our boundary problems are resolved. China's known propensity for 'intervention in space' and 'cyber-warfare' would also be major planning considerations in our strategic and operational thinking.
Common sense dictates that cooperation with China would be preferable to competition or conflict, as it would be foolhardy to compare India and China as equals. China's GDP is more than thrice that of ours and its per capita GDP is 2.2 times our own. China's early steps to liberalise its economy and invest heavily to modernise its physical infrastructure gave it a substantial edge over India, and made China a more preferred destination for FDI.
India's annual defence expenditure (approximately $30 billion for 2008-2009) is less than half of what China spends on defence. China's official figure is under $40 billion, but it is widely believed that China actually spends more than twice as much. Studies by US think-tanks peg China's defence spending to be anything between $70 billion to $200 billion.
Whether in terms of GDP, defence spending or any other economic, social or development parameters, the gap between the two is just too wide to bridge (and getting wider by the day). In military terms, both conventional and non-conventional, we neither have the capability nor the intention to match China, force for force. These are indeed sobering thoughts and therefore our strategy to deal with China would need to be in consonance with these realities.
The economic penalties resulting from a military conflict would have grave consequences for both nations. It would therefore, undoubtedly be in both our interests, to cooperate with each other in mutually beneficial endeavours, and ensure that the potential for conflict is minimised. This would require pro-active economic, diplomatic, cultural and people-to-people engagement. Our relations with other major powers, notably the USA, Russia, Japan and other East Asian nations need to be nurtured and leveraged to this end.
Our growing relations with South East and East Asian countries would increase opportunities for cooperative engagement with China as well. Since resolution of the border problems, autonomy of Tibet, the China-Pakistan connection, competition for strategic space in the Indian Ocean and management of water resources would be the prime causative factors for any potential tension with China, our diplomatic focus on these issues would have to be maintained.
On the military front, our strategy to deal with China must include reducing the military gap and countering the growing Chinese footprint in the Indian Ocean region. The traditional or 'attritionist' approach of matching 'division for division' must give way to harnessing modern technology for developing high situational awareness and creating a reliable stand-off deterrent.
Image: Chinese People's Liberation Army troops celebrate the PLA's 82nd anniversary.
The non-State actors
We have witnessed an even more worrying phenomenon of the occasional coalescing of the 'State' with some 'non-State' entities which has created an evil-hybrid. This hybrid, to my mind, has been at the very root of the tragic events in Mumbai in November 2008.
.Where should we direct our security efforts? Towards the State-sponsor or the non-State entity? How do we expose the linkages, if any? We have been grappling with this problem for some time now with no satisfactory solution emerging.
Asia today, is witnessing the historical and simultaneous rise of at least four major powers namely, India, China, Japan and the ten countries of ASEAN. Even in these recessionary times, the economic performances of India, China and Indonesia are quite impressive.
On the other hand, Asia is also the ideological crucible of some of the world's ominous non-State forces. Maintaining economic growth, social development and harmony in the face of such disruptive forces will be a thorny problem for many years to come.
Responses to threats
This is a formidable challenge and no country, however large or powerful, has the wherewithal to insulate itself from such omnipresent threats, of which terrorism stoked by distorted religious radicalism is the latest and most grotesque manifestation.
Other universal concerns include threats from traffickers of drugs, arms, human beings, organised poachers, ships that clandestinely discharge oil and toxic cargo into the sea or onto the shores of unsuspecting and ill-informed States, mercenaries and modern-day pirates. In addition, there are several 'non-traditional security threats' as well.
These common challenges can only be faced through the common resolve of like-minded States, facilitated through multilateral structure as well as opportunities and mechanisms for constructive engagement. It will need a transformation in the way we think, and in the way we look at one another. It would also require those nations which have the necessary resources and wherewithal to take the lead in ensuring all forms of security to life, trade and property.
Concerted efforts at capability-enhancement and capacity-building of the smaller countries of the region, through active assistance of larger neighbours would be crucial to such efforts in the long term.
Image: Association of Southeast Asian Nations ministers and officials at the ASEAN Regional Forum in Phuket
Photographs: Sukree Sukplang/Reuters
Shaping our immediate neighbourhood
I am convinced that as India grows in economic and military stature, it would have to take upon itself, the role of further enabling its neighbours in ways that would not only enhance their own security, but contribute positively to regional stability as well.
On the navy-to-navy level, the Indian Ocean Naval Symposium or IONS, which was launched in February last year, is a significant military maritime construct to bring together regional navies and aimed at addressing common concerns. Our diplomatic utterances with regard to our maritime neighbours must be backed by cohesive engagement.
This requires much greater integration of thought and action between the ministries of external affairs, defence and the Indian armed forces. Our maritime neighbours are the gateways to our strategic frontiers. We need to engage them as much as they need our presence and support. It would be imprudent of us to leave voids in this strategic neighbourhood and watch others extend their influence in our backyard.
Securing our maritime borders
A word on coordination of maritime security closer to our coast. Preventing ingress of terrorists from the sea is an abiding challenge. Our long and porous coastline and several island territories, many of which are uninhabited, offer avenues for infiltration of men and material into our heartland, as well as safe havens for clandestine activities.
Intrusions via the sea are extremely difficult to prevent with our current state of material and organisational preparedness, as we were rudely shocked to realise, when the perpetrators of the Mumbai terror attacks breached the shores with impunity.
With a host of ministries and agencies being stake holders in the maritime arena, any attempt at coastal security will warrant a serious 'whole-of-government' approach, and robust coordination.
The entire sequence of surveillance extending out well beyond our Exclusive Economic Zone, suspicion indication, risk and threat assessments and finally investigation and prosecution is a very complex process, demanding a high level of situational awareness, rapid response and total synergy between all concerned enforcement agencies.
This kind of a capability is also technology-intensive, and obviously very expensive to set up and maintain. However, it must be done in the interest of national security, if we are to prevent intrusions and attacks through the sea route.
Our acute consciousness of 'turf guarding' must give way to a more synergistic way of functioning. A modest beginning has been made, which has to be sustained through concerted efforts of all stake holders, adequate funding and most of all, public awareness.
Image: The North Korean ship MV Musan, which was detained by the Indian Coast Guard after a six-hour chase, anchored near Port Blair. The ship had entered Indian waters without the requisite permission or documents.
Photographs: Sanjib Kumar Roy/Reuters
The addressing of these causes and maintenance of order are, nearly in all cases, a matter of internal governance and therefore, squarely within the purview of the civil administration and the police forces.
The rampant spread of left-wing extremism is particularly worrying and tackling the problem requires a well-thought out strategy.
However, the increasing demand on the armed forces to assume 'law and order' responsibilities is clearly an undesirable trend. While 'aid to civil authority' is a mandated role of the armed forces and they will deliver whenever ordered, this must always be a 'last resort' and 'temporary' measure to be expeditiously withdrawn when the critical need is met.
The armed forces must never be seen as being used 'against' our own population -- the irreversible damage of such action is there for all of us to see in our neighbourhood.
Much has also been reported about our handling of intelligence in the past and also in the aftermath of the 1999 Kargil war and more recently, the Mumbai terror attacks. Our intelligence agencies need to be more focussed towards long term intelligence forecasting and therefore, must direct efforts towards anticipatory security planning -- predicated on actionable intelligence inputs, in addition to immediate and short-term requirements.
Cohesion amongst intelligence agencies and sharing of intelligence in a far more integrated manner is an operational necessity. Integration between all organs of government dealing with intelligence and seamless acquisition, processing of strategic, operational and tactical intelligence and its timely dissemination is of essence.
Information exchange mechanisms with other friendly countries also need to be facilitated to enhance domain awareness in different arenas.
Image: An Indian Air Force Mi-8 helicopter participates in a war exercise.
Photographs: Amit Dave/Reuters
Cyber Warfare and Web Espionage
Primary targets include critical national infrastructure network systems with electricity, air traffic control, financial markets and government computer networks taking centre-stage. Reports suggest that the USA, Russia and China have acquired considerable capability in this domain.
The Indian armed forces are increasingly investing in networked operations, both singly and a joint fashion. We cannot, therefore, afford to be vulnerable to cyber attacks.
Information Technology is our country's known strength and it would be in our interest to leverage this strength in developing a formidable 'offensive' and 'defensive' cyber warfare capability. Harnessing the gene pool available in academia, private industry and the younger generation of talented individuals is imperative.
Image: Chinese troops learn to use computers at a military base in Tianjin.
Photographs: Andrew Wong/Reuters
We have had a well-thought our nuclear policy from the 1980s. India is committed to building a capability that will serve her interests and despite several attempts to 'isolate' us in the field of nuclear technology, especially post-1998, we have walked the path alone and created a capability that is recognised today, albeit grudgingly.
We have a draft nuclear doctrine in place, which is restrained, in keeping with our traditional national culture.
Our efforts at achieving credible deterrence are not just about weapons and platforms but also include well-thought out strategies, policies, targetting plans, command and control structures as well as an occasional demonstration of capability.
Our increasing forays in the nuclear field, both military and civilian, would require the highest assurances of nuclear surety and security within the country. This calls for substantial investments in safety and security procedures, testing of environmental parameters, accident prevention and disaster control as well as management.
It also requires a very high degree of awareness and public transparency in proving that our nuclear assets and establishments do not pose a hazard in any way to the population at large.
Image: An activist protests the India-US nuclear deal in Mumbai.
Photographs: Arko Datta/Reuters
The culture of strategic thinking
Strategic decision-making cannot be guided by 'opinion' but by serious 'thought' -- but the reverse is sometimes true. It is unfortunate that discussions on national security in our country have been left largely to think-tanks and academics, and whilst they may do some valuable work in this direction, they lack the executive powers to put thought into action.
For a country of our size and stature, institutionalised strategic thinking mechanism within and outside government is woefully inadequate.
In several established democracies, specialist think-tanks have access to government information on a graded basis. They are often given contracts for studies to be done for the government departments.
In India, we often, jealously guard information, even if it may be required by other government agencies in the execution of their legitimate official duties. Our media too, barring honourable exceptions, has very few people who specialise in defence, though of late a welcome start has been made.
We have to develop much greater mutual interaction between think-tanks, the government, its agencies and the media. In a democracy, the media must be critical -- it is intrinsic to the profession -- but not needlessly adversarial, which is often the case in our country.
Image: Soldiers with the navy's Landing Craft Mechanised vehicle during a war exercise.
Photographs: Amit Dave/Reuters |
Mumbai Mantra Media Ltd. and White Feather Films Pvt. Ltd. are happy to announce the completion of their film ACID FACTORY. All the exploitable rights of the film rest with Mumbai Mantra. The release date of the film will be announced at the forthcoming IIFA Awards. Presented by Mumbai Mantra and produced by White Feather Films, ACID FACTORY is one of the most awaited films of 2009 and is slated for a post monsoon release this year.
''White Feather Films is one of the most consistently successful production companies in the industry today. From KAANTE to SHOOTOUT AT LOKHANDWALA and now, ACID FACTORY, Sanjay Gupta & his team have created a label that attracts the best talent in the business & stands for unparalleled quality. We believe that ACID FACTORY will be the most kick ass movie of the year and we are collectively working towards making it a path breaker in the thriller genre.'' says Andrey Purushottam, CEO Mumbai Mantra.
Commenting on the association with Mumbai Mantra, producer Sanjay Gupta says, ''I am particularly excited about the synergy of the two companies with similar cerebral associations. White Feather Films has always been associated with machismo and style - from KAANTE to our latest offering ACID FACTORY. We are proud to begin this exciting new association with ACID FACTORY - the mother of all thrillers. We are glad to push the envelope and challenge the limits with this film and our new partnership.''.
The film promises to be an outstanding exhilarating suspense thriller. Mumbai Mantra & White Feather films Pvt. Ltd. are planning and looking forward to a release post monsoons. |
Gangplank Build Guide by Drumsloot
Not Updated For Current Season
This guide has not yet been updated for the current season. Please keep this in mind while reading. You can see the most recently updated guides on the browse guides page.
Not Updated For Current Season
The masteries shown here are not yet updated for the current season, the guide author needs to set up the new masteries. As such, they will be different than the masteries you see in-game.
If you're like me, you like playing Gangplank in ARAM.
If you're a bit more like me, you like getting to the point.
Let's get started.
This guide focuses on dropping your opponents hard by applying massive AOE damage on Parrrley.
In other words, press Q to win.
MURAMANA: Essential. Take Tear of the Goddess first and get stacking it. Rush a Manamune early; the earlier you buy it, the better chance you'll get at finishing it into a Muramana for silly on-hit damage on your Q.
COOLDOWN BOOTS: You need these for the extra bit of CDR you'll need to keep pumping out the Parrrleys whenever they're available. No other boots will be as useful as these, except Merc Treads, but take those situationally.
INFINITY EDGE: I don't even think I need to explain why for this one.
RAVENOUS HYDRA: A beast of an item that is severely underrated on GP. Let me explain why.
AOE Lifesteal; press Q and proc hundreds of hp in healing by level 18.
Active: Much more useful than you'd think. It only has a 10 second cooldown, so spam it in teamfights with your Ulti going, and you're going to be dropping insane AOE damage.
Damage: Comes with a juicy +75 AD to help your Parrrleys do even more damage.
Synergy: Perhaps the most important reason; it synergises with the items in this kit. Read on.
ICEBORN GAUNTLET: Another nice "on-hit" item that procs when your Q lands. Do AOE damage in a radius around your target and slows, which works nicely with your Ravenous Hydra and your Ultimate.
STATIKK SHIV: Another item that's quite overlooked on GP. Take the Avarice Blade somewhat early in the game if you're falling behind on money. If you kill a minion with a level 5 Parrrley and an Avarice Blade in your pocket, you'll be racking up the $$$$$$ in no time. Additionally, this item is yet another AOE On-Hit item, which syngerises perfectly with Iceborn Gauntlet and Ravenous Hydra.
That's all you need to know about the items.
Don't be an idiot. You're going to be squishy as hell, so stand back, and throw in your Q whenever you can. That's what the CDR is there for.
You're all about Parrrley, so seriously, stand back and keep shooting.
Use E and W to get away from those in pursuit, Ult if necessary to slow them, but you should be able to kite with Iceborn Gauntlet on your Q.
When an enemy champion is about to die, press E. Automatic Assist.
Focus on towers. You'll have enough AD to take them down, especially when you're full build.
Don't try to take anyone down on your own. Kite them, fight them at a distance. Keep melee champs off you, and ask for help against mages, because unfortunately, champs like Orianna and Veigar will still turn you to mush.
That's it. Enjoy the build. |
San Miguel’s growth and development
By Javier Mojarro
El Colegio de Arquitectos de San Miguel de Allende Guanajuato A.C., preoccupied about the growth, image and urban development of our town, thanks Atención for the opportunity, once a fortnight, to share with its readers our opinions on current issues and activities that concern us. Our organization is made up of more than 70 professionals, specializing in various branches of architecture, urban planning, construction, conservation and restoration.
In existence for 25 years, and characterized by our dedication to service, we have made a significant contribution to San Miguel, which for a number of years has had the eyes of the world upon it because of its beauty, state of conservation and the architectural grandeur of its buildings, both historic and modern.
At this moment San Miguel is considered one of the best towns in the world, and it is a matter of pride that our sector has, over the years, contributed its small part to this, through being the designers, builders and restorers of spaces, which help create the town’s magical atmosphere. Together, of course, with the force and energy of a deep-rooted population determined to preserve our town, each sector giving of themselves 100 percent.
San Miguel today faces major challenges, like other World Heritage sites, which demand a balance in terms of planning and urban development. Conservation is obviously a core priority and demands the direct intervention of our authorities and civil society. The sensitivity of this subject is not just of personal interest but is in the interest of all. The state of preservation of our historic city center, the urban image and the architectural language of new buildings on the town’s periphery becomes the best ground to generate a positive synergy and growth. This is why we share a great interest in building a better San Miguel de Allende and an exemplary municipality within our state.
The professional members of the college have been actively participating in the improvement of San Miguel. We feel an enormous sympathy with the fundamental cornerstone of the government’s vision, both of the city and the state, to have a better San Miguel in all aspects. We recognize the achievements but also consider that it is necessary to squeeze in a lot of different things to consolidate those achievements. Like other civic organizations in our town, we want to be able to face these questions, offer alternative solutions, be heard, and thus have a road forward to achievement. We find ourselves facing big changes in matters of legislation, regulations and codes not only at the municipal level but also at state level and we have many concerns and challenges. Follow us in our next column, when we will address issues that will surely be of as much interest to you as they are to us. San Miguel is all of us and together we can secure for it the heritage that we all desire. |
Like their customers, label printers are working in a fast-moving world. Information gets exchanged as fast as one can click, and customers expect quotes to be given and orders to be filled faster than ever. And, of course, with competition fierce, quality demands have never been higher.
Successful label converters are more proactive than reactive. Many are using technology to quickly turnaround orders, and to effectively communicate with customers on job status. A theme has emerged that revolves around speed. Brand owners are looking to partner to with label companies that move quickly, at a lower cost.
For the annual Label and Narrow Web Mid-year Economic Report, we have invited leaders from four label companies of varying sizes, with different business models. The following is a view from the president’s desk of each company’s performance and the strategies they’re deploying in today’s diverse label market.
Rex Lane, CEO, WS Packaging Group, Green Bay, WI, USA
Challenges: Among our biggest challenges is how the recovering economy is creating a commodity-type environment. As an industry, we have to fight to keep cost-cutting from diluting the value proposition of our collective capabilities. At WS Packaging, we consistently demonstrate a solutions-based approach that assesses every opportunity to develop long-term partnerships focused on helping our customers succeed.
Our goal is to surround CPGs with a full complement of products – automation equipment, consumables, POS and promotions, couponing, games and sweepstakes, decoration alternatives, labeling options, etc.
Innovation: This is why we see innovation providing our biggest opportunities. Our ability to seek solutions and bring them to brand owners with a keen eye focused down-channel towards end users/consumers creates a competitive advantage for everyone.
A key driver of our success today, as well as in the future, is how we go to market. The cornerstone of our business model is our trademarked IMPACT Business System, which drives decision-making and touches literally everything we do. IMPACT is the force behind our commitment to offering innovation and developing partnerships that create significant opportunities to help our customers succeed.
To me personally, and to WS Packaging as a whole, innovation is delivering solutions our customers value. We do that by understanding their business and the pain points they face daily. Seeking innovation in everything we do as part of our IMPACT Business System defines the culture we embrace and deploy to the benefit of our customers throughout the entire supply chain. Innovation doesn’t have to be product related. It can also be process related and we’re focusing a lot of attention in both areas.
On the equipment side, suppliers must get ahead of the industry and produce equipment that drives the initiatives, from sustainability to overall efficiency, lean to end-product quality, and beyond.
Technology: We see digital printing increasingly becoming a key print medium. Through the combination of imaging technologies, press operator capabilities and material science, brand owners can cost-effectively execute marketing strategies that are extremely proactive instead of reactive. It’s a capabilities environment where speed-to-market is a full reality.
Doing business globally offers tremendous opportunities for converters, especially where you have an established relationship with a brand owner looking to expand globally. The ability of converters to respond to the geographic needs of CPGs, regardless of their market locations, will be greatly enhanced by material suppliers with the requisite supply channels. In order to take advantage of these opportunities and effectively compete, I see deeper partnerships developing between converters and material suppliers as a way to make this happen.
Industry Consolidation: Consolidation in the US converter industry will continue. As the economy improves, investment capital will become more readily available. In that environment, I think we’ll start to see the trend to consolidate accelerate a bit. At WS Packaging, we’ve been busy due to our ability to generate excess cash through our IMPACT initiatives. Opportunities continue to remain strong, so I see conversion continuing into the coming years.
Sustainability: Operationally, the industry as a whole has to embrace sustainability. It is here and a key component of doing business. So in that context, it’s a constant factor in the equation. You cannot effectively compete without being committed to it. We have a responsibility to ensure our manufacturing processes are as green as possible and our waste streams are clean. Those efforts are directly related to how we manage our overall operations. All converters must take this position.
Material suppliers are a key factor in the equation and therefore must be as equally committed in order to make sustainability economically viable. For example, the down-gauging of materials shows great promise. Combining that material science with what we do on the converting side is critical if we’re going to continue to deliver value to our packaging customers.
Suppliers have to not only keep our CPG customers in mind, they also must focus on consumers and the impact their products have on them. Suppliers should focus on their costs as strictly as the rest of the supply chain does. In that context, suppliers should look to converters as a stronger resource for CPG and end user insight. And that’s possible only if we have the opportunity to have a seat at the table when the planning starts.
Fulfilling Customer Expectations: From the customer side of the table, customer expectations for service and quality haven’t changed, so they’re always top of mind. The expectations are high. We have to get the job done right the first time. Customer volatility continues to be a significant opportunity for improvement. Suppliers who can solve those volatilities without cost risk to those customers have some key advantages.
The growth opportunities in the industry – through technology, organic growth, acquisitions, etc. – are exceptional and obtainable when customer expectations for service and quality are met. We’re as good as our last run. These are the things that make us want to go to work and do a good job.
Steve Stong, President and CEO, Steven Label/Gold Coast, Santa Fe Springs, CA, USA
Like our peers, we face margin pressure on both sides of the equation, compression of lead times and the never-ending search for growth. In the midst of all this, we remain optimistic, while we work hard to sustain and develop competitive advantages to counteract the trend toward commoditization.
In the short run, our growth is tied to the performance of our key customers, and the dynamics of their vertical segment. In Industrial Durable Goods, certain segments are soft, like TV. However, we are encouraged by the return of manufacturing from China. Our experience correlates with widely reported trends: China’s costs (labor, freight, exchange rate, reduction in export subsidies) are increasing, in some cases dramatically. This combines with other trends, like shorter product life cycles and mass customization, which favor local manufacturing.
We see more caution than normal in our Medical Products customers, related to uncertainties over taxes imposed by the health care bill. There is a fair amount of acquisition and divestiture activity that sometimes favors us, and sometimes does not. The landscape is always changing.
On the packaging side, our Gold Coast division benefits from the proliferation of brands in food, health and beauty, wine and the significant growth of microbrewed beer. We consider ourselves a middle-market supplier, not able to serve the largest users (yet), but offering small-company responsiveness to medium-sized customers. In this area, we at Steven Label/Gold Coast feel it’s important to offer a full range of packaging products, not just labels, along with design services to support them.
In general, buyers prefer to deal with fewer competent suppliers, rather than distribute their requirements (all with similar graphics) out to a variety of unrelated suppliers. We expect to make acquisitions in this area to supplement organic growth and extend our capabilities.
Our approach to sales and marketing continues to evolve. Cold calling and its cousin “quote and hope” is essentially dead. Consequently, we are investing in marketing tools (read: lead generation) to leverage the name recognition that comes from 50+ years of work in the industry. Buyers are more sophisticated and technically competent, and our sales force needs to keep pace. More than ever, our salespeople are selling either value added approaches, or managing new product qualifications to take cost out. In either case, the sales task requires harder work, superior selling skills and in-depth product knowledge.
Press technology plays an important role in our ability to drive down costs and offer new services. Improvements in flexo are driving “economic order sizes” down, just as improvements in digital are moving them up. We are very interested in how this crossover point gets pushed around over the next few years. HP Indigo is a great process, which adds flexibility and the ability to print things that simply can’t be done using any other process. We also are using high-speed inkjet, and are interested in how the many high-speed inkjet technologies will match up in overall cost, resolution, color gamut, etc.
We are constantly developing product extensions related to brand security, extended content, variable data processing and others. On the process side, we are developing technologies for web-based tracking systems, QC systems that drive down defect rates, measurement systems that help us improve our performance. In the end, our ability to do a superior job for our customer is what keeps them with us, motivates them to bring us with them when they move to a new company, and to refer us to a peer that is struggling with their current supplier.
John Abbott, president, Abbott Label, Dallas, TX, USA
Last year was an incredible year for Abbott Label, Inc. The first two quarters of 2013 have continued to prove that domestic production is on the rise and we have certainly been the beneficiary of good-old-fashioned American manufacturing. We’re glad to see movement in the right direction.
I know as the President of Abbott Label, Inc. one of our biggest priorities has been to provide insurance benefits to our employees. They are the company’s strongest assets and therefore can get us through so much, and, like they say, “tough times don’t last, tough people do,” and Abbott Label, Inc. has held and will continue to hold true to this statement.
Our strong commitment to being a performance-driven company has led to some other challenges in 2013. Distributors have grown accustomed to our ability to respond quickly, so synergy among our four plants has been critical in providing desired results. Food packaging, mobile “hipster” printer requirements along with drum labeling needs, to name a few, have seen extensive growth over the past year. We face challenges each day in our planning and strategizing how to keep up with growing demands of our re-sellers.
Pressure on profit margins is something we always face head-on with Lean Manufacturing practices and effective negotiating with our material vendors. Raw materials have been relatively stable, which has allowed us to focus our energy on improving efficiencies rather than combating price increases. Freight is and will always be a major factor but we are able to save our customers on freight due to our strategic locations. We have not seen any major challenges pertaining to labor costs, foreign threats or consolidations. Fortunately, we are not affected much by this. We support one of the few industries where many products that have been specified by our customers cannot be replicated in foreign countries. This gives us the benefit of only having domestic competition.
As a trade-only manufacturer with a strong national footprint, opportunities for growth seem endless moving in to 2014. We are given new opportunities daily. Based on requests from our dealers we’ve invested significant capital in our ability to effectively produce premium prime labels, 1" core items, along with warehouse space to support JIT “run/hold” programs. As an example, we were blessed to have recently opened our fourth manufacturing plant in Chicago which allows us to better provide impeccable service to our customers in the Midwest and Northeast. We have also just closed on our purchase of an 86,000 sq. ft. building to house our new national corporate headquarters in Dallas, Texas. This provides additional capacity to allocate warehouse space for customers.
The calling for digital label manufacturing is being answered by our two new digital units in Dallas. We’re facing stumbling blocks just like every other digital house but suitable production will be under way in no time.
Tara Halpin, President, and Trevor Steinhauser, vice president, Steinhauser Inc., Newport, KY, USA
Today’s consumers have evolving expectations that are driving demands on products at a fast rate and the effects of these quickly changing needs can be felt throughout the supply chain – from the big-box stores all the way down to the label converters. With the complete saturation of the internet and social media, consumers now expect the same rate of change and response in their consumer goods. Choices in flavors, sizes and applications are now expected to change almost overnight. In order to keep up with demands and stay relevant in competitive markets, each piece of the supply chain must do what it takes to rise to the challenge of evolving with the market.
For a medium sized converter, we are most challenged with the delicate balance of setting scheduling boundaries based on our thresholds for maintaining a healthy profit while still meeting our customer’s needs. In today’s quickly changing world and the speed in which information is exchanged and processed, most everyone in the supply chain is expecting their requests “just-in-time.” Long lead times and inventory are becoming non-existent and have been replaced with hourly communications via emails and phone calls to fillers, bottlers and brand owners. As a result of so many changing demands from all facets of the supply chain and constant communications, our customer service representatives have become a vital part of our seamless customer experience.
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Although the challenge of finding balance can seem unattainable at times, being a medium sized converter has given us the opportunity to be nimble and change with our customers. This is something which we feel has allowed us to become an essential part of their supply chain and helps maintain a successful relationship. |
40 responses Add your response
Since your Bryston and Meridian equipment is balanced, take a look at the Bat Preamps. They have SS and tubes. The tubes should last years...why not stick with tubes? The BAT VK50Se is one of the best preamps around, you can get them for just over 5k used. The tubes are supposed to last 5 years. I've had mine for over a year, you'd never know there are tubes inside unless you take the cover off. Very low maintenance. If you want to go new, try the VK30SE I think it lists for $4500. You paid for balanced operation with your CD player and amp, might as well get the full benefits with your preamp!
It's my opinion that any attempts to mimmick valves in ss devices is doomed to failure.
In every instance that I am aware ,the approach has been to capture the "warmth" and "romance" by manipulation of the components frequency response characteristics by rolling the upper octaves or to slow and roll rise/response time leaving an highly altered signal shape which is,in the long haul unsatisfactory at capturing the emotion,spirit and intent of the performance.
I think it better to find a warmish SS amp with low levels of grain and capitalise on what SS does well(ex-speed,attack and rhythmic qualities).
Another approach that imo yields better results is to tailor the presentation by using a SS pre and couple it to an authoratative and dynamic valve amplifier.
To my ears,Valve pre's coupled to SS ampification(hybrid pre's as well)exhibit the worst of both worlds.
As Caterham, I also had a happy experience (yrs ago) using a fast pre coupled w/ valve powers. The set up was a DNM 6 driving EAR 519 cap modofied monos, driving Apogee Stage speakers. Felt like the DNM kept the EARs rocking.
But that was back then, with THAT equipment... you could give the alternative set-up a try, though. Otherwise, the BATs Jfrech suggests are an option (if available in yr area).
With the Bryston amp I would go tube pre-amp. Had a 4B and played around for a while with half a dozen pre-amps before I went SET. Tube pres and SS amps can sound very well together. Have to get the synergy right. This can be attested to by quite a few of my friends who run an assortment of systems. A good bet is join an audio club. Best thing I ever did. If you are determined to stay SS, try the BAT SS gear. It has a coloration that appears to identify with "tube like." It doesnt quite make it in my opinion, but I guess to a degree it could be system dependent. Maybe a good consideration for you would be a hybrid pre. See some Lamm gear time to time at your price point. Best of luck and let your own ears decide......
Argent, why spend any money at all? Your Conrad Johnson is a fine preamp. While it may not be the creme de la creme of preamps don't sell your PV12 short, especially with your Bryston 4B. If you feel the absolute need to change the BAT SS pre and some of the Audio Research LS pre's are nice. Good luck with your choice. PS: If you nixt the PV-12, could I have it? :-)
I would definately recommend CJ solid state, particularly the MF-2500. Personally I think it's the closest to tubes as solid state can get. It has this wonderful rich midrange to die for which is very close in character to CJ's tube amps. You'll also like its excellent imaging capabilities, but that's were the similarities to tube gear end; the dynamics and bass extention and slam are like in a really good ss design. Add to it its high current delivery that will drive the toughest loads and you don't have to ask for more.
I recently did a showroom comparison between Sonic Frontiers Line 2 and Bryston BP-25, using SS Classe power amp and Martin Logan electrostatics. SF pre was slightly more 3D, but Bryston had better tonality, sounded far more musical and less analytical. Even on mid's, for which tube gear is always more acclaimed, Bryston exhibited more musical tones. I wanted to buy the SF going in to the audition, but I left without being certain of which was better. BP-25 is very nice. SF is slightly more open, with good detail and depth to soundstage.
You could make a substantial improvement in your system by changing speakers and speaker cables. A used pair of Dunlavy SC-III will run approx $2500 (more or less) and use a 4 awg speaker cable (assemble them yourself for approx $1.50 a foot including terminals). The difference in sound quality will more than compensate for the tube effect you want to achieve. The 4 awg cable will provide a warm, detailed sound emulating tubes.
Hi Argent, never heard a SS pre that sounded like tubes. IMO if you want the sound of tubes then ya gotta use tubes. Most tube pre-amps today are very reliable. Trying to emulate tubes with SS could be frustating because SS is SS and tubes are tubes. Kind of like a man trying to look like a woman. Ya get a bit closer and somethin aint right.
Thanks, everyone, for all the input. I do agree that to get tube sound you have to have tubes, but I was just curious if any SS came close. Anyone own the CJ Premier 17LS (back to tube again). I read the review in Stereophile. Curious what a realistic price on this piece is (Stereophile quotes list).
I digress, but good to know Ken that I am not the only one to believe that solid state pre with valve power is a better combination than the other way around. The High End took a wrong turn when it went the way of "difficult to drive" speakers, demanding "big brute" power amps that never sound musical (unless you spend mega-bucks). And then to fix this people have used a band-aid approach by employing warm and lush tube preamps. Fortunately the High End has made the U-turn and we are getting speakers that are easier to drive.
Check out the Bat, you won't be disappointed. A used Bat vk3i should run you under 1,500 with remote(this is a tube preamp). I've seen them as low as 1,000. When new they were about 3,500. Great surenergy with the bat vk200 used about 1,700 new they are 3,500. I own the bat vk200 and it is rated at 100 watts, what a joke. My old bryston 3bst was rated at 125 and the bat blew it away. Sounds closer to 200 watts. Good luck.
I musta bin a bad Audiogon citizen when I made that last post, coz I have negative votes. Having seen the error of my ways and being truly remorseful (but not offering reparations), I will refrain from posting opinions that do not conform to conventional wisdom, thereby making this site more comfortable for those that only want to hear what they already believe. Yeah right! Whoever gave me the negative votes... you are a poxy moron! Put up or shut up!
redkiwi, i also have gotten negative wotes, sometimes not even for expressing an opinion, but yust cuz it's *me*! ;~)
i can honestly say that i completely disagree w/your position - i tink it's the synergy betwen the specific amp & pre & speakers that makes a system work, & many, myself included, have found a tube pre to work great w/solid-state amps. of course, the electrocompaniet amps i use *have* been accused of having a toob-like quality... ;~)
regards, doug *the negative wotes weren't from me* sedon
Why give a hoot what people vote.I could care less if I was Negative 5000000.I am going to tell it like it is.The real issue is most people can hanle only so much truth.Give them the real story they cant handle it.
Want tube sound use tubes.Want sand grating on glass use sound use SOLID STATE.SOLID STATE MAY DISTORT LESS BUT ITS DISTORTION SOUNDS LIKE NAILS ON THE CHALK BOARD.Tube distortion sounds like music and is not fatiguing to the ear.
Now you proxy morons flame me.I dont care I stated the truth and if your way of dealing with it is to post negative votes vote away.
c'mon leafs - i tink yure generalizing a bit here. i've heard equipment that made nice music, both toobed *and* s/s. i've also heard equipment that i thought *dint* make nice music, also both toobed & s/s.
for me, personally, i've come to realize that, in order to get sound i like from a solid-state preamp, it's outta my price-range. for me to get sound i like from a toobed amp it's outta my price-range. so, for me, my retail $4600 toob pre & my retail $6k s/s amps work yust fine. of course, if i bought 'em brand-gnu, i couldn't afford *them* either... :>)
re: wotin', i agree it's a yoke - in fact, i find it quite amusing that my prewious post got +2 for delivery, -2 for content. especially ironic, since the point of my post was that i tink it's rediculous to wote negative yust cuz ewe may disagree w/someone... glad some geek disagreed w/me, but liked the way i said it! ;~)
regards, doug s.
I'm currently running a Bryston 4B ST with a Pass Labs Aleph P and the unbalanced Meridian 506.24. It is essentially a balanced setup as I have an RCA out to XLR cable from the CD to the Pass. As for sound, the Pass totally blew away the Cary tube pre amp I had-quieter background, no hiss at idle, more gain, taller & deeper soundstage, tighter bass and more detail. In fact, I'm so impressed with Nelson Pass gear that I'm selling my Bryston, which is only 7 months old, to get either a Pass or Threshold amp. Also, I'd like to mention Stealth cables. Serguei, who runs the place, is an extremely helpful individual who not only has a tremendous product, but is quite knowledgeable. Plus his cables are very reasonable. Cost wise I paid $1,100.00 (used) for my Aleph P and had it completely reworked/retrofitted by Pass Labs for $500.00. The Meridian 506.24 (used) cost $1,000.00. Bryston was $1,700.00 (used). Stealth cables (both silver, one balanced, one RCA to XLR) were $312.00 (new). Speaker cable $13.75 per foot (new, AQ Crystal single bi-wire). The speakers I have I stole for $665.00 (retail $3,400.00) I consider myself a true budget audiophile & there are deals to be had. Full retail price of my system around $12k, but I have under half that invested. My system has great detail & a very nice soundstage with plenty of headroom & presence.
Pcc: It must have been because you stuck your neck out by actually voicing an opinion. Try being more wishy-washy in the future and see if it garners more positive votes for your tally. Just remember "It's all about the VOTES" now, so forget about the hobby and/or actually spending any money at this site and just "Go for the VOTES".
I am looking solely at tubes again. What convinced me?--actually I turned on my present system and just listened. I've decided that I just really love the CJ tube sound. Never harsh, never bright, always warm (at least in my system), and that is the sound I want. Probably this year I'll upgrade to newer CJ stuff (still looking to audition 17LS), then next year will be the fun part...speakers. :)
I've tried tube pre and tube amp together, it was just to tubey for me(kelly if your out there can you check the spelling on tubey, not sure if I got it right.LOL) I and I state I prefer tube pre and solid state. I still get the tube sound with the power of ss. Like to try one of the big boyes but the big tube amps are way out of my price range. Last time I asked the wife if I could sell here truck to buy one, she threated to put a cart in the garage for me. The bat pre tube and ss amp I fell work great together and are in my range. pete
I replaced the Bryston 4B NRB that I used to have with an Audio Research 100.2 solid state amp and never looked back. I compared the 100.2 with the VT100mk2 tube amp amp the 100.2 sounded so good that I bought it. I am not saying that it sounded any better than the VT100mk2, but for much less money it came very very close. If you want the beauty of tubes without hassles, this is the amp for you. Be warned that this amp does not sound overly warm and tubey like some tube amps, but more neutral with great resolution like Audio Researches tube amps do. Good Luck!
I'll mirror mbognar, Stan Klyne makes one of the finest preamps available, ss or tube. It doesn't sound like tube or ss, just music. It's truly one of the best bangs for the buck out there. I've been auditioning pre amps for some time, looking to upgrade, and listened to everything I could including the high priced tube pre often praised on A'gon, reference preamps, etc and nothing bested the Klyne. I ultimately had to go off the deep end and get a CTC Blowtorch to upgrade.
Tubes are not that difficult, and the cool part about it is that you can upgrade (roll) your tubes and custom tailor the sounds to meet your audio needs. Some tubes provide more bass, some are warmer, and others have sweeet highs, but the greatest thing about tubes is the full body sound that I've never heard in solid state pre amps. But, I've also gone back to vinyl so I may not be the best person to ask in regards to maintenance free audio. |
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Law & Kenneth Delhi has bagged the creative duties for the Italian jeans brand Rifle Jeans. In India, Indus Clothing Ltd has got the license to manufacture and market the denim brand. The size of the business is pegged to be in the region of Rs 3 crore.
Vishal Gupta, GM, Sales and Marketing, Indus Clothing Ltd, said, “The denim’s USP is its place of origin, Italy, which is known for high fashion. We are now in the process of launching our Fall/Winter collection.”
Aiming at youth, the brand is looking at primarily print and outdoor as the media mix initially. Several ground activities have also been planned and understanding the synergy between youth and music, plans are also afoot to associate the brand with some music concert some time in December.
Charu Bakshi, Branch Head, Law & Kenneth, said, “It is an exciting win for us and we are taking the communication line of ‘the Great Italian Classic’ and using its origin, that is Italy, as the key differentiator for the brand. The advertising would take the 360-degree approach while besides traditional we believe that non-traditional ways of communication has to be used to engage the youth in the environment that they are familiar with.”
There was no pitch involved and the agency had approached the client when they heard of their plans to launch in India. |
The Brooklyn Academy of Music kicks off its 2013 Next Wave Festival launches with a BAM/New York City Opera co-production of Anna Nicole, the opera by composer Mark-Anthony Turnage and librettist Richard Thomas based on the flamboyant life and tragic death of Anna Nicole Smith. Performances are September 17 to 28 at the BAM Howard Gilman Opera House. The complete season press release follows the jump.
New York City Opera is on track to have its second consecutive balanced budget in a decade, and is receiving overwhelming acclaim for its current season. Today the Company announces its 2013-14 season, which includes two U.S. premieres, two new productions of landmark operas, and multiple opportunities to witness the artistry of Jayce Ogren, New York City Opera’s newly appointed Music Director.
Ogren’s term as Music Director will begin September 1. He will conduct at least two productions per season as well as concerts, galas and other projects. Ogren will work directly with General Manager and Artistic Director George Steel on programming and casting.
New York City Opera opens its 2013–14 season with the U.S. premiere of Anna Nicole (2010), a colossal co-production with the Brooklyn Academy of Music (BAM) that launches the 2013 Next Wave Festival. Running for seven performances (September 17–28) in BAM’s 2,100-seat Howard Gilman Opera House, where New York City Opera has presented two critically acclaimed chamber operas this spring, Anna Nicolewill provide a sensational beginning to the Company’s 2013–14 season.
Composed by Mark-Anthony Turnage with a libretto by Richard Thomas, the opera is based on the flamboyant life and tragic death of Anna Nicole Smith. Reviewing the world premiere at Covent Garden, The New York Times called Anna Nicole a “musically rich, audacious and inexplicably poignant work.” Building upon New York City Opera’s history of integrating opera and popular music, Richard Jones will direct a large cast featuring veterans of Broadway as well as highly accomplished opera singers, including Sarah Joy Miller as Anna Nicole, along with Susan Bickley, Robert Brubaker, Rod Gilfry, John Easterlin,Joshua Jeremiah, Mary Testa, Stephen Wallem, Christina Sajous, James Barbour and Ben Davis.Steven Sloane will conduct 66 members of the New York City Opera Orchestra.
The second production of the season culminates a seed sown in 2001. Having seen and loved So Long Ago I Can’t Remember, from Michael Counts’ theater company GAle GAtes (April 2001), Steel met with Counts to discuss the latter directing an opera for the first time. Steel suggested Endimione (1772), a little known and rarely staged opera by Johann Christian Bach, the only Bach to compose operas. When New York City Opera presents the work (February 8–16, 2014, at El Museo del Barrio), with Counts at the helm, it will be the third new production the Company has created with the director. (Next month (April 14–20), Counts will direct Rossini’s Moses in Egypt at New York City Center, New York City Opera’s original home, having previously directed Monodramas to acclaim in 2011.) El Museo del Barrio was Steel’s first choice of venue for Endimione, a mythological story for which the fairy tale murals that line the walls of El Museo’s Heckscher Theater will provide apt environs.
From February 28 through March 15, 2014, New York City Opera will co-present Béla Bartók’s Bluebeard’s Castle (1911) with St. Ann’s Warehouse. The opera will provide a showcase for Jayce Ogren, the Company’s new Music Director, and the New York City Opera Orchestra. The production will use all 13,000 square-feet of the cavernous warehouse space. Having presented the first fully staged U.S. production ofBluebeard’s Castle in 1952, New York City Opera will now join with St. Ann’s in offering the first American presentation of director Daniel Kramer’s staging, originally produced by ENO in 2009. George Steel is thrilled to welcome Kramer to the Company for the first time. Kramer previously worked at St. Ann’s Warehouse when his unforgettable Woyzeck made its U.S. premiere there in 2006.
New York City Opera will complete a trilogy of Christopher Alden–directed Mozart / Da Ponte operas when the Company presents The Marriage of Figaro, April 19–26, 2014 at New York City Center. The Company previously presented Alden’s critically acclaimed stagings of Don Giovanni (2009) and Così Fan Tutte(2012), and will present his new production of Offenbach’s La Périchole this April at City Center. Conducted by Ogren, The Marriage of Figaro will feature New York City Opera regulars Rod Gilfry as Count Almaviva and Keri Alkema as Countess Rosina Almaviva.
George Steel said, “I am thrilled to welcome conductor Jayce Ogren to role of Music Director. He already has an extraordinary track record with this wonderful orchestra, and he will bring electricity and artistic insight to our music-making. 2013-14 promises to be another powerhouse season for the Company: the climax of our Mozart / Da Ponte project with Christopher Alden, and three other landmark projects.”
Speaking on behalf of New York City Opera’s Board, Chairman Charles Wall remarked, “We take great pride in George Steel’s leadership of the Company, which has resulted in financial health and productions that bring new audiences to opera while electrifying our longtime supporters. The Board and I would also like to extend a warm welcome to Jayce Ogren, whose work in A Quiet Place, Prima Donna, and our new production of The Turn of the Screw last month, makes clear his place among his generation’s greatest young conductors. I can’t wait to see the four operas we will present next season.”
Jayce Ogren said, “Over the past four years, New York City Opera has been my closest collaborator, and our work together has provided many of the most rewarding artistic experiences of my career. I knew from my very first hour of rehearsal with the NYC Opera Orchestra in 2009 that we had a synergy that doesn’t come along every day. Making music with these fine players has continued to be a joy. No other company in the United States is more dedicated to mounting courageous and timely productions than New York City Opera, and the same goes for its commitment to young American singers. There is nowhere I would rather be Music Director.”
Subscriptions to the 2013-14 season, which include a 20% discount, are currently on sale. The on sale date for individual tickets, which are priced $25–$235, will be announced at a later date. To purchase tickets, visit nycopera.com or call 212.870.5600 (Mon-Fri, 10am-6pm). Tickets to Bluebeard’s Castle are also available to St. Ann’s Warehouse members at stannswarehouse.org and 718.254.8779 (Tue–Sat, 1–7pm). Tickets to Anna Nicole are available to BAM Season Ticket buyers on June 17 (June 10 for Friends of BAM) at BAM.org and 718.636.4100.
Since 1999, New York City Opera has presented VOX: Contemporary American Opera Lab, the Company’s annual workshop for new American operas. On January 14 as a central part of OPERA America’s New Works Forum, VOX returns for its 14th season at the NYU Skirball Center.
VOX solidifies the Company’s commitment to producing new works by American artists. Composers are invited to submit works-in-progress or completed, previously unproduced works, and the selected composers will have their work produced by NYC Opera. Since 1999, composers including Mark Adamo, Charles Wuorinen, Richard Danielpour, John Zorn, and Stephen Schwartz have had pieces presented in VOX that have gone on to redefine American opera. Described by The New York Times as an “invaluable showcase,” VOX offers excerpts of new operatic works in professional unstaged performances by members of the New York City Opera orchestra and soloists. As the only program in the country that gives composers the opportunity to hear their new works and works-in-progress with full instrumental ensembles and professional soloists, VOX continues to play a vital part in the fabric of American opera.
New York City Opera has been a pioneer in the field of arts education for more than 40 years. Drawing upon the company’s adventurous and contemporary approach to opera, NYC Opera Education provides students with a three-dimensional introduction to the art form, from page, to stage, to backstage. Students meet with NYC Opera Teaching Artists and other theater professionals in their classrooms, go behind the scenes to see how productions come together, and watch world-class performances during the season.
In classrooms around the City of New York, NYC Opera Teaching Artists collaborate with school teachers to introduce young children to the world of opera through the study of an age-appropriate opera based on a fairy tale or myth. After extensive professional development with school teachers, NYC Opera introduces students to the basics of music and drama, and then encourages students to create their own interpretations of the story through original poems, songs, or art projects. The focus of this year’s Opera is Elementary program, designed for 2nd-5th graders, will be the chamber opera version of Tobias Picker’sFantastic Mr. Fox. This classic story by Roald Dahl will be a wonderful starting point for thousands of NYC children as they have their first encounter with opera. The project will feature costumes designed and constructed in partnership with students from the High School for Fashion Industries. An English teacher at LaGuardia High School says of the program, “NYC City Opera Education is a necessity. It is definitely one of the greatest additions to classroom education in New York City. Opera relates the themes of life and brings together and presents all of the arts in a way that engages young people.”
NEW YORK CITY OPERA 2013-14 PRODUCTIONS
Anna Nicole (2010)
Co-produced with BAM for the 2013 Next Wave Festival
Composed by Mark-Anthony Turnage
Libretto by Richard Thomas
Conducted by Steven Sloane
Directed by Richard Jones
BAM Howard Gilman Opera House (30 Lafayette Avenue, Brooklyn)
September 17, 19, 21, 24, 25, 27, and 28 at 7:30pm
Composed by Mark-Anthony Turnage to a libretto by Richard Thomas, Anna Nicole tells the story of Anna Nicole Smith, a small-town Texas waitress (and, later, exotic dancer) in pursuit of the American Dream. Smith weds an octogenarian billionaire and becomes a Playboy model and tabloid celebrity, living a life of excess and substance abuse under the constant glare of the media until her death at the age of 39. The opera mixes comedy and tragedy and boldly confronts issues of modern celebrity, greed and exploitation.
Richard Jones directs this U.S. premiere, a co-production with BAM that kicks off the 2013 Next Wave Festival. The diverse cast for Anna Nicole includes Sarah Joy Miller as Anna Nicole, Susan Bickley as Virgie, Robert Brubaker as Old Man Marshall, Rod Gilfry as Stern, John Easterlin as Larry King, Stephen Wallem as Trucker, Mary Testa as Aunt Kaye, Christina Sajous as Blossom, James Barbour as Daddy Hogan, Ben Davis as Billy and Joshua Jeremiah as Deputy Mayor. Steven Sloane will conduct the New York City Opera Orchestra.
Commissioned by London’s Royal Opera House, Anna Nicole premiered at Covent Garden in February 2011 under the direction of Richard Jones. The Times (UK) called it “jazzy, bitter-sweet, fizzing, moody and often touchingly tender.” The Independent (UK) said “Richard Thomas’ libretto would carry the day even if the score weren’t as terrific as it is: varied, acidic, lyrical and occasionally heartbreaking.” Turnage’s dynamic score draws on jazz, blues, musical theater and traditional operatic structures; Thomas (co-creator, Jerry Springer: the Opera) provides a razor-sharp and darkly humorous libretto.
Anna Nicole will be sung in English with English subtitles.
Composed by Johann Christian Bach
Libretto by Pietro Metastasio
Directed by Michael Counts
El Museo del Barrio (1230 5th Avenue, Manhattan)
February 8, 12 and 14, 2014 at 7:30pm; February 16, 2014 at 1:30pm
Presenting a very rare, perhaps first-ever staging of a Johann Christian Bach opera in New York, New York City Opera returns to El Museo del Barrio, where the Company presented Telemann’s Orpheus in 2012 to great acclaim. Michael Counts (Moses in Egypt, 2013; Monodramas, 2011) will direct.
The story of Endimione centers on the characters of Diana and Nice. Through the mischief of Amore (Cupid), both fall madly in love with Endimione, a local shepherd. Pastoral mayhem ensues.
J.C. Bach’s ravishing score to Metastasio’s libretto makes crystal clear his enormous influence on Mozart. J.C. Bach, known as “the London Bach,” befriended Mozart when the eight-year-old and his family visited London.
This production, which Steel believes to be the U.S. premiere, culminates his longstanding desire to stage the opera. Endimione will be sung in Italian with English subtitles.
Bluebeard’s Castle (1911)
Co-produced by St. Ann’s Warehouse
Composed by Béla Bartók
Libretto by Béla Balázs
Conducted by Jayce Ogren
Directed by Daniel Kramer
St. Ann’s Warehouse (29 Jay Street, Brooklyn)
February 28, March 4, 7, 11, 13 and 15, 2014 at 7:30PM
March 2 and 9 at 1:30PM
Béla Bartók’s only opera, the fantastical one-act masterpiece Bluebeard’s Castle is a mysterious encounter between two characters, Duke Bluebeard and his new wife, Judith. In the castle, Judith not only discovers great riches, but also bloodstained weapons, lakes of tears and, finally, the bodies of former wives. The opera, based on Charles Perrault’s chilling 1697 fairytale, was written in 1911 and first produced in 1918. New York City Opera presented the first fully staged American production in 1952.
In his Company debut, director Daniel Kramer presents a vision that is brutally dark and full of shocking surprises, as Judith descends deeper within the castle and, perhaps, into Bluebeard’s soul. Reviewing the first presentation of Kramer’s staging, by English National Opera, at the London Coliseum in 2009, The Telegraph (UK) said it was “refreshing to encounter a director who has dug deep into the resonances of a masterpiece… an interpretation that will unsettle any idea you may have had as to what this weird fable signifies.” The Arts Desk (UK) said Kramer “has ripped from the pages of modern newspapers one of the most vital questions of today, which is just how far and appallingly men will go to define and license their own desires.”
Bluebeard’s Castle is a collaboration between New York City Opera, St. Ann’s Warehouse and English National Opera. New York City Opera’s new Music Director, Jayce Ogren, will conduct the Company’s orchestra in this site-specific staging at St. Ann’s Warehouse, which will stand in for Bluebeard’s haunted castle. Bluebeard’s Castle will be sung in Hungarian with English subtitles.
The first performance of the original production took place at English National Opera on November 6, 2009.
The Marriage of Figaro (1786)
Composed by Wolfgang Amadeus Mozart
Libretto by Lorenzo Da Ponte
Conducted by Jayce Ogren
Directed by Christopher Alden
New York City Center (131 W 55th Street, Manhattan)
April 19 and 22, 2014 at 7:30pm; April 24, 2014 at 7pm; April 26, 2014 at 1:30pm
New York City Opera presents a new staging, by Christopher Alden, of the Mozart landmark The Marriage of Figaro. The production completes the Company’s trilogy of Mozart / Da Ponte operas directed by Alden, including Don Giovanni (2009) and Così Fan Tutte (2012), Jayce Ogren will conduct, and the cast will include Company regulars Rod Gilfry (baritone) as the Count Almaviva and Keri Alkema (soprano) as the Countess Rosina.
Mozart’s most popular opera, The Marriage of Figaro takes place in one single day inside the palace of the Count Almaviva. Figaro, the Count’s valet, is set to marry Susanna, the Countess’s maid, who is also a favorite of the Count. But before Figaro can finally be united with his bride, he must first overcome every obstacle put in his way by the philandering Count, who is aiming to bed Susanna first.
The Marriage of Figaro will be sung in Italian with English subtitles. |
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Financial experts say economic recovery is just around the corner.
The difference between stumbling short of the finish line, and making it across, lies in a firm’s ability to maintain cash flow, according to IT industry insiders.
“Canadian businesses should position themselves for growth during the next six to nine months so they can stay ahead of the competition when the tide finally turns,” says Rob Koturbash, managing director of Maple Leaf Angels, a Toronto-based group of private investors focusing on the tech industry.
10 new ways to get more money from your customers
Tips on saving crucial projects from the scrap heap
Expert off beat tactics to keep your small business on track
Koturbash was part of a panel of Canadian entrepreneurs and financial advisers who spoke during the half-day business conference titled Money Chase: Bootstrapping for Growth organized by the Innovation Synergy Centre in Markham (ISCM) in Markham, Ont. last Thursday.
The in-your-face message from the current downturn is that cash is king, said Koturbash whose group, typically, provides viable IT ventures with seed capital ranging from $250,000 to $500,000.
So what steps may Canadian small businesses take to protect their cash flow … a pre-requisite for their very survival?
The first absolutely crucial step for firms in tech sector would be to carefully monitor every expense, according to Brian Brennan, principal partner at Max Potential, a business consulting firm based in Aurora, Ont.
“To stay alive until recovery come you have to cut down on unnecessary expenses,” he said.
But he cautioned against knee-jerk reactions such as “thoughtlessly gutting the workforce just to save on payroll.” Such a move could backfire especially when productive personnel are given the pink slip.
While many large enterprises can afford to lay off 10 per cent of their staff, such a move would be catastrophic for most SMBs, he said. It could decimate the organization.
Even during an economic downturn, it’s vital to keep production and sales in full throttle to ensure that revenues are generated.
Go for the low hanging fruit by exploiting easy-to-access tools and use technology to boost productivity, are a couple of other strategies that have paid off big time for eDev Technologies Ltd. a Toronto-based software company.
Among the company’s portfolio of products is the InteGREAT –an integrated requirements development and management tool that helps administrators manage and maintain application requirements
Company president Asif Sharif tells how – rather than cut their sales force – the firm took advantage of Web 2.0 collaboration tools to double staff productivity.
“We made extensive use of targeted keywords and Google Adwords for online advertising. We cultivated a presence on social networking sites such as Facebook and LinkedIn.”
Trade show appearances used to be a traditional marketing approach used by eDev Technologies. This used to cost anywhere from $10,000 to $15,000 per engagement, and tied many staff members to the trade floor for nearly a week.
The firm gave up these trade show appearances and instead developed a Webinar to reach out to potential and existing clients. The Webinar provided subscribers with industry information, but also highlighted eDev’s products and services.
And the costs were a small fraction of what would typically be expended on a trade show.
The Webinar cost only $500 to develop and market and nearly 500 people registered for the event. “To get the same amount of registrants we would have had to attend two trade shows, be on the road for two weeks and spend about $30,000.” Sharif said.
Here are a few more expert tips to help you manage your cash flow:
Hunt for bargains – Negotiate payment terms and prices with your suppliers. Remember, just like you, your suppliers could be desperate for business. Ask them for discounts or better payment terms. An extension on an upcoming bill or a reduction when you pay on time could provide your business vital breathing space. Don’t be afraid to ask. The worst thing your supplier can say is no.
Lobby your landlord – Ask your landlord if he or she can give you’re a break. Perhaps rent or maintenance fees can be reduced if certain perks in the contract are temporarily given up. Some landlords, Brennan said, might even agree to give up a portion of the rent if the lease is extended.
Collaborate with customers – Work with your customers on reaching a mutually beneficial payment scheme. For instance, if you need cash right away you can offer customers discounts if they pay their invoice within a certain period. Or if customers want to stretch out payments you can introduce installment terms that have a small interest included in the bill.
Spend wisely – Set up a committee to audit company expenses and procedures. Find out which areas are money pits and what operations do not contribute anything to the company. Obtain consensus on what aspects of the business should be changed, maintained or eliminated.
Think strategically – Don’t go for short term gains when thinking about expenses. Always look out for the big picture. For instance, don’t immediately consider layoffs.
“In many instances people will readily accept austerity measures rather than drastic measures like layoffs,” said Brennan.
There are other cost cutting alternatives such as temporary compensation reductions, shortened work weeks, selective outsourcing and the use of technology to bump up production.
An ill-advised staff reduction can throw a wrench at the company’s ability to generate cash flow, Brennan explained. |
A reviewer at gaming site GamePlasma was evaluating recently released point-and-click PC adventure Limbo of the Lost. Something started to look a little familiar to the guy. Check it out:
This screen is from Limbo of the Lost:
This is from Xbox 360 RPG Elder Scrolls: Oblivion:
Do they look similar to you?
Eager message board posters on the internet have cited these sources as further "inspiration" for the game: Diablo II, Silent Hill 4, Painkiller, Unreal Tournament 2003, Black & White, Unreal Tournament 2004, Thief: Deadly Shadows, The Elder Scrolls III: Morrowind, Vampire: The Masquerade - Bloodlines, Crysis, Return to Castle Wolfenstein, World of Warcraft, scenes from the 1997 film Spawn, and Pirates of the Caribbean: At World's End. Well, at least they were thorough!
In response to the controversy, the game's publisher, Tri Synergy, pulled the game and issued this statement:
Tri Synergy is just as shocked as everyone else is by the recent screenshot comparisons. At no point during our dealings with Majestic Studios up until the point that the comparison was first publicly made by a third party did we have any knowledge of these similarities. Additionally, Tri Synergy will discontinue distribution of Limbo of the Lost in both retail and online outlets.
Bethesda, creators of Oblivion, say their legal department is looking into the matter.
GamePlasma: Limbo of the Lost or Oblivion? |
Mass Tab Causes Stroke in 17-Year-Old Football Player
- 10-20-2009, 08:58 AM
Mass Tab Causes Stroke in 17-Year-Old Football Player
Mass Tab is a prohormone supplement marketed to help users gain size and strength. Unfortunately, the makers of this product are in a heap of controversy after the product was linked to allegedly causing a stroke in a 17-year-old football player who used the product and then fell ill!
“The manufacturers of Mass Tab have engaged in what appears to be fraud and reckless and negligent marketing of a bogus bulking supplement that contained a steroid,” said Greg Davis, attorney for the young football player, who filed a lawsuit in state court today. “The manufacturers failed to test and to warn the public of the known risks of its product, insidiously marketing it as having ‘low side-effects.’”
So Here Goes The Story
According to the complaint, Jacob Bray, a 17 year old athlete, purchased Mass Tab from the Supplement Shak in Oklahoma. He used the “supplement” over the course of several weeks. On January 31, 2008, he was weightlifting and immediately after doing a lift had a severe headache, which he terms as “an instant migraine,” and was disoriented. He was driven home by a friend and was still disoriented so he placed an icepack on his head, and took some Tylenol. When the headache seemed to intensify, his mother made an appointment with a neurologist and an MRI/MRA was ordered, at which time it was discovered that he son had suffered a stroke!
“My heart sank when I was told my son had suffered a stroke,” said Mrs. Bray. “The profiteers who sell hidden steroids in unhealthful ‘health’ supplements must be held accountable for their irresponsible conduct. For heaven’s sake, my son is just a teenager with his entire life before him.” Her attorney added, “Jacob was never informed about the extremely dangerous and sometimes lethal effects of steroids contained in dietary supplement products like Mass Tab.“
Mass Tab is a supplement marketed by IDS Sports, Supplement Synergy and Challenger Holdings. Mass Tab appears to have been pulled recently from the market but could be sold and marketed under a new name. Mass Tab contains, as one of its active ingredients, Stenbolone, which is a steroid launched in 1963 by Syntex, a pharmaceutical company no longer in business that was based in Mexico City. For more information check out
Mass Tab Causes Stroke in 17-Year-Old Football Player? | SupplementGenius.com
- 10-20-2009, 09:59 AM
Anotherexample of people not taking responsibility for their actions. Rather than questioning why a 17 yr old was running a potent PH 'over the course of several weeks' they sue the manufacturer when there are health issues.
As for his mother saying IDS 'must be held accountable for their irresponsible conduct', where the hell was she during the last several weeks when her 17 yr old son was taking a steroid?!?!?
10-20-2009, 10:03 AM
Why are kids under the age of 18 being sold these products. Supplement shops should make it policy not to sell PH products to people under 18. This would protect them and the rest of us that use these products responsibily and not have to worry about another congressional hearing on banning supplements.
10-20-2009, 10:09 AM
What's more likely to happen (medically speaking): a steroid causing a bloodclot in a matter of weeks or a clot occurring due to injury from football? Trauma is one of the main causes of a thrombosis, but that's being completely ignored.
M.Ed. Ex Phys
10-20-2009, 10:10 AM
Agreed. The kid probably knew exactly what he was taking but did not care about the sides or thought that he couldn't be adversely effected by them. At 17 he should have been taking creatine and protein if he wanted to take anything.
10-20-2009, 10:26 AM
10-20-2009, 11:42 AM
Nobody needs to be held accountable for their irresposibility except for that kid. You need to do a lot of research before you take any sort of supplement, especially a prohormone, and I'm sure he didn't do that. There's also no reason for him to be taking something like that at 17-years-old. That's just retarded.
10-20-2009, 11:48 AM
damn , thats another thing against the ph companies.
dumb store and kid, he should of known and the store should of told him, kid this stuff aint candy they're steroids.
10-20-2009, 12:11 PM
supp shops need to stop selling this stuff to kids...get them some cell-tech if they wanna get hyyyooge
10-20-2009, 12:50 PM
Lets all jump to conclusions again media.
This is dumb, it annoys me to see how the smart understanding people suffer for the idiots.
Heres comes another raid!
10-20-2009, 12:53 PM
10-20-2009, 12:59 PM
10-20-2009, 12:59 PM
I love how no one can take responsibility for their own actions. The store that sold it to him is at fault not the manufacturer. Ruins it yet again for the rest of us.
10-20-2009, 02:10 PM
Lets pretend that he didn't know what he was taking-READ WHAT YOU'RE PUTTING INTO YOUR BODY!
The retailer should be sued for not giving him the proper information and for selling it to a 17yr old.
MEANWHILE IN THE REAL WORLD:
He more than likely knew exactly what he was taking and didn't take the right support supps b/c he didn't want to spend the extra money and then this happens to him and it turns into "Mommy I had no idea there was a steroid in there, I thought it was magic creatine."
This is getting frustrating.
I'm still waiting for some major news network to have an open discussion on a evening show so that I can call in and talk about this to vent.
10-20-2009, 03:48 PM
My first thought too... The second being the kid and his mom are complete toolsWhat's more likely to happen (medically speaking): a steroid causing a bloodclot in a matter of weeks or a clot occurring due to injury from football? Trauma is one of the main causes of a thrombosis, but that's being completely ignored.
10-20-2009, 04:27 PM
10-20-2009, 06:18 PM
The bulk of the fault lies with the 17 year old kid, but considering he is a minor it would be transferred to his guardian (correct?), who through ignorance allowed her kid to use PH's. No one forced him to take Mass Tabs and I guarantee the kid knew exactly what was going on. Not to mention the label specifically states not for use by anyone under the age of 18.really who do u guys thinks at fault????
The supplement store shouldn't of sold it to the kid for one. I used to work at a GNC. There are a lot of negative aspects about that corporation, but they require ID for their few hormonals (even AI's), and require you to be at least 21 to purchase. Effective enforcement depends on the management, obviously. However they don't give employees any education about hormonals so the majority are ignorant and don't know better when they try to push the product.
10-20-2009, 09:00 PM
Very true,i work at GNC right now and everything i know about hormonal products i have learned through my own research.i work with a few guys who don't have a clue what they're selling to people, just how much comish they get and now because of all of this, last week GNC had us pull all of the hormonals we had left off the shelves. funny thing is my coworkers had no idea why.
10-20-2009, 09:10 PM
10-20-2009, 09:29 PM
You ever check out the label on that product? 30 herbal ingredients with "Stenbolone" stuck in the middle. In this case I just completely disagree. How is someone to know what the hell "stenbolone" is and it is easy to miss in that list. I didn't see the warnings on the box, but I hope at least they had clear over 21 on their supplement. I am all for responsible adults to use these products, but they need to be clearly labeled and have an over 21 warning on them IMHO.
10-20-2009, 10:38 PM
Haha GNC is quite the joke, the only thing i liked was the employee discounts on the post-dated goodies. It helped that my manager didn't make us dispose returns (which we kept ), and that he'd let us put stuff in the back room until it dropped down to 50% or 33% of the list price. Otherwise that company sucks, they create irresponsible salespeople by stressing numbers and commissions instead of creating a knowledgeable salesperson who isn't trying to rip the customer off.Very true,i work at GNC right now and everything i know about hormonal products i have learned through my own research.i work with a few guys who don't have a clue what they're selling to people, just how much comish they get and now because of all of this, last week GNC had us pull all of the hormonals we had left off the shelves. funny thing is my coworkers had no idea why.
Anyways, I was in the same situation as you are. I was the most knowledgeable employee at our store about hormonals (which isn't saying much) and idk how many times i had to talk idiot kids out of buying PH's. Most of them would just blow me off and try to buy one anyways, which worked out great because the majority of the kids weren't even out of highschool so I gladly refused the sale.
I remember one time I got called in by my friend working closing shift to *talk* to this kid about some things he was wanting to buy. I gave the kid a no BS five minute education about why he didn't need to buy 2 different PH's, which he didn't know anything about, and an AI. I could tell he was just blowing me off because he wanted to be right, so I finally just told him to go ahead with it but not to be surprised if he was in worse shape then when he started. My friend managed to somehow talk him out of the sale after I got tired of wasting my time. Funny thing was this kid was talking smack about how i didn't know what i was talking about and i was just a d-bag.
Whatever. Kids who consider a PH cycle are either 1) not educated enough to know (minority) 2) know enough to realize they shouldn't take it but want to cheat instead of putting in hard work and discipline. I think its a damn shame that the responsible educated users have to suffer because of their stupidity, but IMO they deserve every ounce of health problems. Choosing to be ignorant about the truth doesn't hide the fact that its still there.
EDIT: Forgot to add my reply to this-
I googled the product label and the warnings weren't well written. Nothing about checking with a physician outside medical problems, recommended minimum age was 18. They messed up quite majorly there, but in this case the kid is 17 so you could say they scraped past that one.You ever check out the label on that product? 30 herbal ingredients with "Stenbolone" stuck in the middle. In this case I just completely disagree. How is someone to know what the hell "stenbolone" is and it is easy to miss in that list. I didn't see the warnings on the box, but I hope at least they had clear over 21 on their supplement. I am all for responsible adults to use these products, but they need to be clearly labeled and have an over 21 warning on them IMHO.
I agree that someone won't know what the hell stenbolone is and that it is easy to miss, but at the same time they alone are responsible for what they put in their body even if they choose not to realize it.
10-21-2009, 03:00 AM
Sounds like we worked at the same GNC.ive got quite the selection of returns that fill up my kitchen.friends dont complain either when i give them a more than half full tub of creatine or protein cus i simply have too much already at my house to take before its all expired haha its a good way to try stuff i never want to spend money on so i cant complain.
back on topic tho, i fully agree the ingredients weren't very telling.probly a bad call on IDS' part.if anything id say thats what any lawsuit will be based upon.the shady/lack of labeling.definitely shoulda been 21 and over too not 18 on there.
10-21-2009, 06:27 AM
Yes we should all be responsible for our own actions. INCLUDING IDS-MASS TABS! They intentionally mislead an very little warnings on this lable. I am pissed with ban, but here is a classic example of why it's good.
10-21-2009, 07:53 AM
Well it didn't say anything about him using cycle support, maybe would have prevented that... I mean Mass tabs are shady imo anyway.
10-21-2009, 12:44 PM
It is a classic example of why the ban is reasonable. There are synthetic and natural compounds out there and also anything hormonal should have an over 21 label in my opinion. Over 21 lets people know that this stuff is serious and needs to be respected.
10-21-2009, 12:46 PM
10-21-2009, 12:48 PM
10-21-2009, 01:21 PM
Instead of a ban why not make it legal for 21 and over and keep the products on the market. Was tobacco banned? No. Just made it 21 and up. And beer, also not banned, but how many people have been killed by under age drinking and driving? People will find a way to get what they want weather of age or not, true. But why punish an entire group of people using a product responsibily? Punishment should be on the ones that avert the law and use when not allowed to.
10-21-2009, 01:27 PM
10-21-2009, 01:35 PM
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Synthetic optical structures are classified as members of a
hierarchy of electromagnetic materials and diffractive elements.
Innovations on a system level are strongly related to the
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we focus our attention on the synergy of diffractive optics and
optical thin film technology. To this end properties and potential
applications of diffractive optical elements coated with
nonuniform thin films are investigated. Paraxial and non-paraxial
diffraction models based on the Kirchhoff approximation are used
to understand the response of these elements. As an important tool
to provide an intuitive understanding we employ a reciprocal space
representation. Three design problems are discussed, namely the
shaping of the spectral response of harmonic diffractive optical
elements, the design of color separation gratings, and the
implementation of computer generated volume holograms.© (2004) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only. |
On Friday, October 14, The Greek Orthodox Archdiocese of America announced an agreement with the Port Authority of New York and New Jersey regarding the rebuilding of St. Nicholas Greek Orthodox Church, which was destroyed in the terrorist attacks of September 11, 2001. John Maddex talks with Fr. Mark Arey about that agreement and where we go from here.
Fr. Thomas Hopko delivers two lectures at Orthodox Christian Synergy's 2011 Symposium on "Orthodox Christianity and Homosexuality." Listen below to the first lecture: "Theological Vision: Orthodox Christian Faith and Human Sexuality." The gathering took place at St. George Antiochian Orthodox Church in Cicero, Illinois, on Saturday, October 15, 2011.
When we are silently aware of the presence of Christ, the whisper of His name will bring healing to us and spill out to others. Don't miss the latest episode of Dr. Al Rossi's new podcast - Becoming a Healing Presence.
Fr. Lawrence Farley, priest at Saint Herman of Alaska Orthodox Church in Langley, British Columbia, and the host of the AFR podcast "Coffee Cup Commentaries," offers this reflection on the famous British writer and Christian C. S. Lewis.
On a new "Frederica Here and Now," Frederica Mathewes-Green examines the relatively recent phenomenon of men and women expecting their spouses to also be their best friends. Is this how things were meant to be?
St. Issac of Nineveh tells us that “a small but always persistent discipline is a great force; for a soft drop falling persistently hollows out hard rock.” In this episode of "Food, Faith, and Fasting," Rita Madden discusses ways to set realistic goals for healthy behavior change.
Fr. John Oliver, priest at St. Elizabeth Orthodox Christian Church in Murfreesboro, Tennessee, reminds us that "we are not God," and that it is better to use discernment in situations where we do not know the whole story than to leap to judgment.
The West identifies seven sacraments, but how does the Orthodox Church view such things? On a new Worship in Spirit and Truth, Fr. Thomas Hopko, Dean Emeritus of St. Vladimir's Seminary, teaches on the place of the Eucharist in the sacramental life of the Church.
If Christians are to be the salt of the earth, who will be the salt of Christians? Molly Sabourin begins a series of reflections on her weekend experience at a monastery.
As Christians, how do we explain tragedy, earthquakes, floods, and evil? Fr. Tom Hopko takes an in depth look at the nature of God's dealing with the world through His Son, Jesus Christ. |
Summary: CAREER OBJECTIVE: To work with a reputed organization, where I would get ample opportunities to grow and utilize my skills & knowledge gained so far for mutual benefit.
Current: Assistant Manager at Reliance communication Ltd Assistant Manager at Reliance Communication Ltd
Past: Finance Executive at IND Synergy Ltd. Finance Executive at IND Synergy Ltd. Finance Executive at Ind Synergy, Mumbai see less...
Education: Shivaji University Finance (2004-2006)
Shivaji University, Kolhapur Advanced Accountancy Completed a Summer Project on Ratio Analysis in Kisanveer Sugar Factory at Bhuinj,Satara
Shivaji University, Kolhapur in 2006 Finance
Skills: accountancy, accounts payable, balance, bank reconciliation, basic, broadband, budgeting, c, cash flow, credit, customer relations, design, english, equities, finance, financial, fixed assets, forecasting, forms, hindi, immigration and nationality directorate, internet software, microsoft excel, microsoft office, microsoft word, mis, payables, payroll processing, process engineering, requirements, sales, sales forecasting, settlements, visual basic 6.0, wise,
Experience: Reliance communication Ltd (Telecommunications industry): Assistant Manager, (March 2008-Present)
Reliance Communication Ltd (Telecommunications industry): Assistant Manager, (March 2008-Present)
IND Synergy Ltd. (Mining & Metals industry): Finance Executive, (July 2006-February 2008)
IND Synergy Ltd. (Mining...
Interests: career opportunities, consulting offers, new ventures, job inquiries, expertise requests, business deals, reference requests, getting back in touch
API Dattatray Bhilare of the Vinoba Bhave Nagar police station said on Thursday that ... Consultations on Andhra Pradesh cabinet to end tomorrow: Kiran Kumar Reddy
[Oct 8, 2010] I had to tell the passengers to go ahead on their own, said Shankar Bhilare, an ... Kiran Jagdale of Siddheshwar Auto Garage said, We closed our garage at 8.30 pm.
Name: ADITYA KIRAN TEJA Country: India Comment: MY bith day ON 15 MAY . ... Name: aruna bhilare Country: India Comment: i am celebrating my son's 1st birthday on 15 ...
No Name of Candidate Sub GroupPattern of Candidate Merit No. 76.73% YADAV KIRAN SAMPAT Male ... 76.13% BANKAR NAGESH RAJARAM Male Semester 11269 DSE1038632 401 13 76.13% BHILARE BABU ANANDRAO ...
... National B player Rajan Rajadhyaksha, Vakil Akhtar, AN Iyer (Bank of India), Prakash Patole, Kiran Kamble, Devkaran Bhatty and school-boy Akash Khalwadekar. Bhilare, who ...
Ganesh Bhilare 7.5; 3-4. Vaibhav Saxena, Amol Wagle 7; 5-7. Rajan Rajadhayakshya, Kiran Kamble, Abhijit Bhurke 6.5; 8-12. DB Pulekar, Anant Iyer, Raj Parakh, Vakil Akhtar ...
Bhilare Kiran Dasrath: 61%: Appeared: Open: Mumbai: Maharashtra: B.Pharm : 12: MU 5: 120: 1423: Ghadawale Shalaka Ramesh: 32.67%: 847/1200: Open: Mumbai: Maharashtra
bhilare kiran dashrath: gen: 478: 190028: bhuptani ronak subodhkumar: gen: 479: 190042: darade sharad balnath: obc: 480: 190056: gune uma satish: gen: 481: 190062: indulkar anura suresh
5 of 96 104. 140424 shweta sharma gen 105. 151085 y krishnaveni gen 106. 140443 sumit arora gen 107. 190175 thakkar janak shrikant gen 108. 190024 bhilare kiran dashrath gen 109 ...
Bhilare Kiran Dashrath: 61.00%: Appeared: Open: Mumbai: Maharashtra : 87: MU 79: 136: 121: Ghadawale Shalaka Ramesh: 32.67%: 847/1200: Open: Mumbai: Maharashtra : 88 |
Of course, our true passion is the real animals and the real joy in the Brahman breed, both red and gray Brahman cattle.
Venus, FL (PRWEB) September 29, 2016
Moreno Ranches, a leading producer of Brahman Cattle for sale, is proud to announce a significant blog milestone: fifteen blog posts on 'Brahman Cattle' issues posted to its blog since January, 2016. The Ranch's lively blog has proven popular among not only ranchers but also Brahman Juniors, young people interested in participating in the vibrant Brahman cattle industry. Of particular interest has been its dominance of red and gray Brahman cattle, the two 'color varieties' popular in the breed.
“Of course, our true passion is the real animals and the real joy in the Brahman breed, both red and gray Brahman cattle," commented Kelvin Moreno, head of Moreno Ranches. “However, the Internet enables both serious ranchers and young people to keep up to date on industry issues with respect to Brahman cattle and even view the animals online, as during our upcoming 'Cyber Monday' sale. Hitting fifteen blogs on 'Brahman Cattle' since January is truly a significant online achievement.”
To view posts on the topic of 'Brahman cattle,' visit http://www.morenoranches.com/tag/brahman-cattle-for-sale/. There, one can scroll down post-by-post up to and including January. In addition, one can view champion Brahman show cattle from the ranch at http://www.morenoranches.com/champions/. The firm is known as a leader, in particular, with respect to red Brahman cattle.
Blogging on Brahman Cattle: Supporting Ranch Sales
Moreno Ranches is unique in its commitment to the Brahman industry. First and foremost, the Ranch has a unique program supporting Brahman Juniors, i.e., young people who are interested in Brahman show cattle as well as possibly a career in the Brahman industry. For example, the company has an innovative Brahman Junior scholarship program. Second, the Ranch uses the Internet, not only via blogging but via live, online sales, to reach out to both established Brahman cattle breeders but also to Millennials interested in a synergy between the online, Internet world, and the real world of Brahman cattle. By blogging in a systematic and innovative way, the Ranch is able to reach out to the next generation of cattle breeders. Finally, the Ranch is very excited about social media, with a vibrant Facebook page now topping 109,000 'likes' on the No. 1 social media platform.
About Moreno Ranches
Moreno Ranches is a top producer of Brahman cattle for sale. Customers come to the company for genetically superior Brahman bulls for sale and Brahman semen (seed stock) as well as Brahman embryos. The company produces both Brahman heifers and calves for sale, including for use as show cattle or to produce Brahman F1 hybrids. Visit the company's website to browse stock. The company is a trusted source of Brahman cattle whether a buyer is in Florida, Texas, or Louisiana - Latin America, or anywhere in the world. |
Tea and Biscuits with Lauby and Frontline Gamer: Starting the Hobby, part 2
Frontline Gamer and I are still subbing in for Von while he’s on walkabout. Last Saturday we kicked off a conversation about starting the hobby in this day and age. Our intention was to wrap things up in one post and move onto other important questions like “do red ones really go faster?” or “what’s the deal with airline food?”. Once we were past the first paragraph, it was quickly apparent this was gonna be a multi-parter. So begins part 2 right were we left off last week.
Lauby: Ah good, we’re moving on to a game company that’s worthy of my scorn! Actually, I can’t afford to be quite that flippant. Starting over: I think there are a lot of flaws with Privateer Press on the whole. Obviously, none of them seem to be crippling the game but they’re there. Now, as much fun as it would be rake HoMachine over the coals, it could quickly take over the conversation.
|Get it! hahaha.|
Suffice it to say that there is certainly a lot of traction to your argument and I think Privateer Press is absolutely preaching to the converted. And always has been. During the old days of Mk I, the game’s biggest selling point was that it wasn’t 40k. Hell, all that page 5 nonsense was and still is a clear dig at GW. Even once you get past that, there’s still more. PP consistently has a sustained arms race thing going on and a rule set that is much more complex than makes sense for the size of the games they push for. Add in what many people call a steep learning curve and the single most unforgiving win condition I’ve ever seen and you really do have to stop and say: how could HoMachine be for anyone BUT die-hards. Which means that a great deal of the perceived cheapness of HoMachine doesn’t provide such a clear cut advantage.
FG: Yeah that’s sort of my take on Privateer Press’ games to an extent, certainly on cost you end up wanting a lot of ‘kit’ in your toolbox for whichever faction you play. Plus the scale seems to be getting bigger by the minute. I’ve often argued that HoMachine is pure game as opposed to wargame, and I’m not going to go over that right now. What I will say though is that the game is very complex on the board, and extremely unforgiving to newcomers. By complex on the board I mean the level of synergy between troops, combo’s etc. none of it is difficult to grasp in terms of individual rules really, BUT in terms of tactics on the board I do think it’s aimed at experienced gamers. I happen to like the game as it goes, but I can see its faults and certainly wouldn’t shy away from mentioning them.
In the first article Fiendil mentioned Grind, Bodgers and the Warmachine starter box in the comments. Bodgers is a card game, and as fun as the first editions was (not played the second edition) I’m not so sure it’s a gateway product. Maybe a Trojan horse product in terms of being less scary than miniatures but containing lots of advertising material for them. The Warmachine starter box doesn’t convince me as a gateway product. It’s still the full game as it were, but without the full options and range, it’s a snare product not a gateway product, in the same way Assault on Black Reach and The Island of Blood are.
However, I have taken a step back and looked again at Grind. It could be a gateway product. Simple to learn and a far less daunting amount of miniatures to construct and paint. But, I do feel these an even better Gateway product produced by Privateer Press, Monsterapocalypse. Pre-painted mini’s, easy to learn rules and in comes with a pre-made battlefield and scenery, great product. However, it’s been sold via normal retail channels, and that’s the hobby’s problem we’re facing now isn’t it? What about selling these sorts of self-contained at comic book stores, or supermarkets?
Lauby: I’m not so sure that things are so simple. Existing in the first place and being profitable aren’t even necessarily relevant to this idea of a gateway we’re bouncing around. Assuming that we’re even talking about the same thing… lots of room for local differences to be a factor in our conceptualizations.
Anyways, I took some time to dig out what was left of my Heroquest game and you know what? I couldn’t find a GW logo anywhere on it except the back page of the rulebook. Where’s the path to GW proper there? Moving beyond a specific company and out into the ‘hobby at large’, the connection between a self contained boardgame and the world of the actual wargaming hobby is tenuous at best. It’s a completely different mindset is what I’m saying. We can also certainly lump the related video games in here as well.
And there’s always the problem of making the leap from the gateway to the actual, hard to find specialty shop stuff. At least in the US, the weird store with the strange name is the only, physical, place to get some of this stuff – even the kind of gateway thing that I think you’re on about. You can’t just go into Toys R Us and say “one Super Dungeon Explore, my good man – and make it snappy”.
|Not available at fine toy stores everywhere.|
FG: Ah yes defining what a gateway product is. I guess for me it’s something that exposes someone to the wider hobby in some way. For me it doesn’t necessarily have to be a game or require the painting of miniatures. The THQ computer games for example could be gateway products that introduce people to the 40k universe. If that’s handled correctly by GW I guess that works fine.
The same is true of any board game too I suppose. I think of the hobby as having 3 aspects to it that makes it fun I guess, the games themselves, the collecting and painting of miniatures and the fluff. The Holy trinity if you will. So realistically any product that gets out there and brings new people into contact with one of these three aspects is a major boon. But they’ve got to be out there and be discovered.
You’re absolutely right when you say it’s no good having a great product if that product is still delivered to the same old gamers via the same old channels. So I guess distribution of these product is also of paramount importance. So gateway products, whatever they are, need to be seen in different outlets. They need to be seen in toy stores, supermarkets and anywhere else we wouldn’t normally see them.
On that note I think I’ve just had a slight epiphany… I think GW do have an exceedingly good number of gateway products that maybe I originally overlooked. I often see Black Library books on sale at train stations, bookstores and other more mainstream outlets. I also know of people who have been roped into the hobby via them too. Perhaps GW had a master plan all along?
Lauby: I think you’re on to something with the book idea. While were on the subjects of tie in novels and table top games, I have to say that this is exactly how I got into the hobby in the first place. It was actually a Battletech novel that sucked me into this whole thing in the first place. This book, in fact:
I had just finished it, and was super pumped for giant ass robots. There, in the back pages, was an add for the actual game. Before too long, I had my first copy of Battletech in my hot little hands. BUT – I was able to get that first game in the same bookstore that I got the novel. But beyond that past convenience, I wholeheartedly agree that a Black Library novel is a fantastic gateway. It’s cheap, it’s interesting, it’s available and it has the adds in it! Heck, Prospero Burns was even a New York Times best seller back in 2011. How crazy and how awesome is that for what we’re talking about? |
~ATHLETIC EDGE NUTRITION-IntraXCell-FAQ-The Beta-Alanine Carnosine thread!~
- 03-27-2007, 12:15 AM
~ATHLETIC EDGE NUTRITION-IntraXCell-FAQ-The Beta-Alanine Carnosine thread!~
The World’s First Beta-Alanine, Carnosine Boosting Formula in convenient capsule form.
When You Think of Beta-Alanine, We Dare You Not to Think of IntraXCell!
Boost Strength and Increase Lean Muscle Gains with IntraXCell!
Athletic Edge Nutrition, The Nutrient Timing Specialists, is pleased to introduce IntraXCell, the biggest scientific breakthrough in physique enhancement and athletic performance since creatine. We have scientifically formulated precise doses of four key ingredients to create a product that will work synergistically to increase intramuscular Carnosine and Glutathione levels, which boosts strength, lean muscle mass and fights muscular fatigue at the cellular level.
The Result: Explosive Strength and Endurance, forcing lean muscle gains, physique improvements and muscular GROWTH!
IntraXCell is scientifically formulated to:
• Boost Explosive Muscular Strength and Endurance, Forcing
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• Increase Intracellular Carnosine Levels and Fight Muscular
Fatigue & Metabolic Acidosis.
• Extreme Muscle Fullness and Vascularity.
• Naturally Boost the Power Antioxidant Glutathione and Fight
History is about to be made once again!
Until now, creatine, with numerous research studies to support its effectiveness, was the leading supplement for improving exercise and muscular performance. Since creatine exploded into the sports nutrition world in the early 90’s, our understanding of exercise physiology and sports nutrition has evolved exponentially. Exciting new research has given rise to another breakthrough, one that could change the direction of the industry like creatine did so many years ago..
Hydrogen ions are released during exercise, causing performance to plummet.
When we exercise, especially when it’s high intensity exercise, our bodies accumulate a large amount of hydrogen ions (H+), causing our muscles’ pH to drop (become more acidic). This process is occurring whether you feel a burn or not.
The breakdown of ATP and the subsequent rise in H+ concentrations occur in all of our energy systems but H+ buildup is most prevalent in an energy system called glycolysis, which also produces lactic acid. At physiological pH, lactic acid dissociates H+ and is the primary source of released H+ ions during exercise, causing pH to drop. It is the released H+ from lactic acid that causes muscular performance problems, not the leftover lactate ions as many incorrectly believe. While lactic acid is the primary source of released H+, it is not the only source. H+ ions are also being released at a rapid rate when you break down the high energy compound ATP during exercise. With the presence of many sources during energy production releasing H+, pH quickly drops as does muscular performance, slowing progress and lean muscle gains.
While muscle acidity has certainly proven to decrease strength and contribute to muscular fatigue, new research is now showing that exercise-induced intracellular free radical production is another source of muscular fatigue. The combination of muscular acidity and increased free radical production greatly diminishes your performance during exercise, stopping your workouts cold and interfering with lean muscle gains.
Fortunately, Athletic Edge Nutrition has developed a tool you can use to combat intracellular acidity and free radical production, pushing your performance, physique and results to the next level.
Q: How does IntraXCell combat H+ accumulation and free radical production to boosts my strength, fight cellular fatigue and increase my lean muscle gains?
Much of IntraXCell’s benefits come through its key ingredeint, Beta-Alanine. Beta-Alanine effects are realized through its ability to boost the synthesis of a powerful intramuscular buffer called carnosine. Carnosine is a naturally occurring di-peptide that has been consistently and scientifically proven to DRAMATICALLY affect athletic performance when increased above normal baseline levels. How much, can Beta-Alanine increase carnosine concentraions you ask? Daily supplementation with extra Beta-Alanine, can increase muscle carnosine concentrations by as much as 80% after 10-12 weeks
Due to the dramatic boost in our muscles buffering capacity, through supplementing with IntraXCell, you can expect BIG GAINS in strength, lean muscle and muscular endurance.
- 03-27-2007, 12:19 AM
Q: How does the rest of IntraXCell’s formula fit in with Beta-Alanine?
IntraXCell is more than just a carnosine booster designed to increase strength, lean muscle and endurance. IntraXCell also contains ingredients that work synergistically with each other and with carnosine. These ingredients act as direct precursors to the powerful antioxidant, glutathione.
1. N-Acetyl-L-Cysteine (NAC) - increases glutathione levels inside the cell which is a power antioxidant that fights cellular fatigue. Interestingly Beta-Alanine has now been shown to increase the synthesis of glutathione by increasing the availability of its precursor cysteine. Beta-Alanine and NAC work perfectly together.
2.Vitamin E – Vitamin E has been shown to increase carnosine levels more than carnosine alone. Carnosine has been shown to increases Vitamin E antioxidant ability. These two operate hand in hand.
3. Alpha-Lipoic-Acid – Finalizing this HIGHLY synergistic formula, alpha-lipoic-acid is utilized as a highly versatile antioxidant that boosts other antioxidants like Vitamin E and Glutathione.
These three ingredients combined with Beta-Alanine make IntraXCell an extremely powerful and versatile weapon in your quest for greater strength, lean muscle mass and super-charged endurance.
Q: Who can benefit from IntraXCell?
•Individuals participating in weight training looking to gain lean muscle mass and increase strength.
•Any individual involved in athletic activities where strength, power and muscular endurance are needed.
•Active individuals who have reached a training plateau and are looking for something to take them to the next level.
Q: How long will it take for me to start noticing benefits?
Performance benefits typically start occurring in as little as two weeks, although some individuals will notice benefits within one week. As carnosine levels continue to increase, so will the benefits. The most dramatic results are generally experienced within the 3-4 week range, but they don’t stop there. Recent research is now showing carnosine levels continue to increase up to at least 12 weeks, so the benefits just keep on getting better which is why we recommend to continuously stay on IntraXCell for at least 3 months to optimize your carnosine levels.
Immediate benefits: Many users experience intense vasodilatation/pumps from the very first time they take their first does of IntraXCell. The reason this occurs is because Beta-Alanine increases carnosine and carnosine is a powerful precursor in generating nitric oxide synthase (NOS). NOS are a group of enzymes necessary for making the powerful vasodilator nitric oxide. Take IntraXCell with SteelEdge prior to exercise and let us know your experience. We are confident that you will be very pleased pumps/vasodilatation from your very first workout.
Q: At what point during my set will IntraXCell have its strongest effects?
IntraXCell, unlike creatine, is effective at all points during your set whether you’re lifting heavy or doing endurance work. Your body uses three energy systems to perform work: the ATP-PC system, which is primarily used during heavy lifting and for sets in the 5-6 rep range; the glycolytic system, which is predominantly used roughly within the 7-15 rep range; and the oxidative/fat system which is used primarily in endurance training. Our energy systems are simultaneously utilized but depending on the level of intensity or duration, certain energy system will become more dominant. Anybody that trains with weights will use the first two systems predominantly and, in both cases, the result of the build-up of hydrogen ions will contribute to fatigue in both systems, especially glycolysis. This is where creatine falls a little short. It’s mostly effective in the ATP-PC system which relies on ATP and phosphocreatine (PC) for intense, high-energy contractions. Taking creatine will help your explosive and maximal strength but it won’t help you much in that 7-15 rep range. As anyone trying to build bigger muscles knows, you must train in both heavy and moderate (7-15 reps) ranges to gain lean mass. Only IntraXCell can fight the H+ build-up that occurs in both these ranges, allowing you to train at high levels regardless of your goals or your training intensity.
A recent study, in fact, showed that Beta-Alanine significantly outperformed creatine in decreasing cellular fatigue, giving it yet another advantage over what has been considered the most effective sport supplement of the last decade. With Beta-Alanine yielding impressive results in university-sponsored performance studies, creatine’s days at the top may be numbered.
Q: Does Beta-Alanine replace creatine?
Beta-Alanine does not replace creatine. As shown above, they work differently and creatine is still effective for increasing maximal strength and power. If anything, they should be taken together as the ultimate one-two punch.
03-27-2007, 12:23 AM
Q: How should I take IntraXCell?
Take two servings daily. IntraXCell may be taken with or without food, but we recommend it be taken with food as food may dampen the prickling sensation that some individuals experience from the Beta-Alanine content.
On Training days: Take one serving 15-20 minutes prior to exercise (can be conveniently taken with our Pre-Workout formula SteelEdge) and take one serving post workout. This protocol serves two purposes. One, it takes advantage the pre-workout timing benefits of increased blood flow driving Beta-Alanine into the working muscles. Two, the carbohydrate content in SteelEdge speeds up how quickly Beta-Alanine increases its performance benefits and there may also be synergy with the caffeine content in SteelEdge.
On Non-training days: Continue to take two servings daily with food.
For best results, use IntraXCell daily for a minimum of one month to optimize intracellular muscle carnosine levels. Performance benefits from IntraXCell will become noticeable in your workouts withing 1-2 weeks, and will continue to become stronger for the first three months as intracellualr carnosine levels continue to increase.
Q: How much Beta-Alanine is needed to cause performance increases?
Research has shown that you can take an amount between 3.2 grams and 6.4 grams per day to significantly boost carnosine levels and improve performance. The most recent research, now using 4-5 grams a day, is showing comparable carnosine concentration and performance improvements to those using 6.4 g daily.
Q: How long will a bottle of IntraXCell last me?
There are 60 servings in a bottle of IntraXCell. Two serving daily gives you exactly one month worth of product at 4 grams of Beta-Alanine per day, plus the highly beneficial NAC/ALA and Vitamin E.
Q: If one of the building blocks of carnosine is histidine, wouldn't it be beneficial to include it with beta-alanine to further boost muscle carnosine levels?
No, it wouldn't. Histidine is already present in high concentrations in muscle, while beta-alanine is present only in small amounts. Scientists have determined and demonstrated that it is beta-alanine that drives the intra-muscular synthesis of carnosine, not histidine.
Q: What other supplements do you recommend to maximize the results when taking IntraXCell?
•We recommend our Full Spectrum Pre-Workout Formula, SteelEdge. SteelEdge contains many ingredients that may work synergistically with IntraXCell. On training days, take IntraXCell with SteelEdge to amplify the benefits of each product.
•Creatine is another supplement that may work synergistically with IntraXCell and they can certainly be stacked together.
Q: Are there any methods that may increase Beta-Alanine’s ability to increase Carnosine levels?
Yes. A recent study showed that a group of subjects taking Beta-Alanine with carbohydrates increased performance gains in half the time of the group taking an equal amount of Beta-Alanine without carbohydrates. Carbohydrates spike insulin and one of insulin’s effects is to increase amino acid (such as Beta-Alanine) transport into our cells.
Q: What is the prickling I feel when I first take IntraXCell?
The prickling - called parathesia - is caused by Beta-Alanine binding to nerve receptors, activating them and causing them to discharge/fire. Many of these nerves are below the skin, giving a prickling/pins-and-needles sensation. This sensation begins approximately 15-20 minutes after ingesting Beta-Alanine and usually continues for 1-1.5 hours. The intensity varies depending on dosing, individual sensitivity and potentially from activators of Ca2+ channels, such as caffeine.
This sensation, though generally enjoyed, often subsides over a few weeks of continued use. Carbohydrates/food may also blunt the prickling effect from Beta-Alanine.
Q: Are their any stimulants in IntraXCell that would prevent me from taking it for a late night training session?
03-27-2007, 01:08 AM
Anyone, please feel free to jump in and ask Q's. We really enjoy interacting with enthusiasts and love the opportunity and format to be able to explain our products in full detail.
03-27-2007, 10:56 AM
03-27-2007, 01:51 PM
03-27-2007, 07:12 PM
For the guy in the gym, what this means is, more weight, for more reps, with less rest time between sets= overloading the muscle and Greater lean muscle mass.
Than there is the whole, antioxidant angle of IntraXCell, which is often overlooked. The ingredients in IntraXCell, not only boost carnosine levels, which has antioxidant effects, but IntraXCell also boosts glutathione, which is another powerful way to fight cellular fatigue caused by intracellular free radicals. This is an emerging area of interest in exercise physiology research and just another way IntraXCell boosts performance over just Beta-Alanine.
For athletes,such as strongmen competitors,MMA fighters, hockey, soccer and other sports that are predominantly performed in our energy system, called glycolysis, well there probably isn't a more specific supplement that will help them more than IntraXCell/ Beta-Alanine.
We currently sell through one of AM's board sponsors, Planetary Nutrition,.
03-27-2007, 07:51 PM
03-27-2007, 09:31 PM
03-28-2007, 12:11 AM
This video is of a young gentleman that was in one of our early rounds of IntraXCell/SteelEdge testers.
He is aspiring to become a strongman one day and was kind of enough to make this video for us on his own accord and post it in his log. Everytime I watch it, it gets me motivated.
Turn up the volume and enjoy.
[nomedia="http://youtube.com/watch?v=gJbzyUL8xos"]YouTube - Broadcast Yourself.[/nomedia]
03-29-2007, 01:25 PM
When most of us think about IntraXCell/Beta-Alanine, hopefully at this point we think of much of its performance benefits occurring from increasing CARN concentrations in term increasing our buffering capacity, neutralizing more H+ and controlling ph.
While this is the focus of the current research and most understood mechanism of action on how BA a acts as a performance enhancer, there are other ways it works as well.
Some are related again to increased CARNs concentrations and its effects on pH, while others are working independently of CARNs pH effects.
Some of these include:
1. Quenching intracellular free radicals and their connection to cellular fatigue i.e. potentially interfering with calcium uptake necessary for muscle contraction…ect
2. Regulation/activation of Ca2+ from the sarcoplasmic reticulum(SR)…crucial to the muscular contraction process and also ties in with the potential synergy of CARN and caffeine.
3. An enzyme regulator and activator within the various energy systems, this one I find particularly fascinating.
4. Decreases in pH interfering with ATP production and myosin-actin affinity (contractile components of muscle fibers).
5. CARNS connection with NOS/vasodilatation.
These are just a few of the directions I will try and take this thread in and hope others will jump in with there own input and experiences with Beta-Alanine supplementation!
Hopefully we can compile a solid base of info over here, giving AM readers a much more thorough understanding of IXL/BA’s effects beyond H+ buffering.
03-31-2007, 06:09 PM
As I said before, I hope to take this thread in some interesting directions and get into the nitty gritty of how BA supplementation works as a whole. When I first started seeing random threads on the forums about BA, it was simply looked at as a Lactic acid buffer. For some strange reason, BA was looked at as an aerobic/endurance supplement, eventhough all the research until recently shows BA performance affects work on anaerobic/strength/power/muscular endurance tests.
Only recently, does it seem that people are understanding the H+ connection and how it is the H+ that are causing fatigue through lowering pH, not intact lactic acid. As I've mentioned before, lactic acid does contribute to fatigue, but it contribution comes from the H+ is dissociates, NOT the left over lactate ion.
And even before lactic acid is significantly building up in glycolysis, H+ are getting produced much sooner in the ATP-PC system, causing pH to drop and strength to decrease and fatigue to set in
Aside from all the cool pH related research on Beta-Alanine, there are other potential ways BA may affect fatigue, not related to pH. One of them being Beta-Alanine boosts Carnosine and carnosine is a intracellular antioxidant as well as buffer.
Below is a summery of what I will touch on relating carnosine's antioxidant role and how it may fight fatigue.
• Quenching intracellular free radicals, often referred to as reactive oxygen species (ROS) and their connection to cellular fatigue i.e. potentially interfering with calcium uptake necessary for muscle contraction
The above sentence is one area that CARN is thought, though not proven to effect performance, separate from its buffering of H+. Aside from BA/CARN antioxidant connection, I thought it would also be interesting to look at the overall antioxidant aspect of IntraXCell, as IntraXCell is more than just Beta-Alanine. It contains NAC, ALA and E. All four ingredients in IntraXCell work as antioxidants fighting free radicals that cause cellular fatigue. Beta-Alanine antioxidant effects come through boosting CARN. NAC and ALA through boosting glutathione levels. vitamin E works synergisticly with carnosine antioxidant abilities and ALA comes back into the picture with its ability to boost vitamin E and glutathione levels.
(Some of the below is taken from a paper I wrote a while ago)
One of the main sites where ROS are thought to effect fatigue is the calcium storage sites known as the sarcoplasmic reticulum (SR).
The SR is located within a portion of the cell membrane called the sarcolemma, which surrounds a muscle cell. Once the muscle cell is initially stimulated by acetylcholine, this stimulation or excitation travels deep into the muscle cell and reaches the SR. When the SR is stimulated, it releases calcium ion(Ca2+), allowing the two protein filaments myosin and actin to interact and shorten, causing a muscle contraction. This whole sequence of events, though highly summarized, beginning from the nerve impulse to the actual shortening of the muscle cell, is called “excitation-contraction coupling.”
Research shows that tissue damaging, ROS are increased during exercise. While free radicals are a necessary process of physiology, they also contribute to muscular fatigue. One theory suggests that free radicals contribute to fatigue by damaging the SR, causing less Ca2+ to be released and hindering the muscular contraction process as a result. Low pH from H+ accumulation, may also negatively impact Ca2+ in many other ways, but the end result being, less forceful contractions, hurting performance
IntraXCell's formula of pH buffers and antioxidants, performs double duty in maintaining forceful contractions, by fighting ROS and buffering H+ accumulation.
Anyone feel free to jump in and add your thoughts/idea's..
03-31-2007, 06:38 PM
Looks interesting although I really couldn't read through all your posts. The scientific stuff gets really boring after awhile....You say to take it for at least 12 weeks to evaluate it. Thats a pretty long time, maybe it should be cheaper or some with more servings per bottle so its more cost effective?. I would try it because I just tried Green Mag and it has beta alanine in it. I have got great results from it, so I think it might be something elese in the product besides the Creatine because I don't respond to creatine at all. I like to try new creatine products though and see what happens. So I am thinking maybe I still don't respond to CEE but I do respond to something elese in that product, particulary the beta-alanine because I did get some nice pumps. I really want something that will help increase my endurance while running though.
03-31-2007, 06:48 PM
No, 1-2 weeks is when you start to get benefits from IntraXCell/Beta-Alanine. I talk about the studies going up to 12 showing performance benefits keep on getting better as BA continues to increase CARN levels.
You do NOT need 12 weeks to evaluate it. One bottle of IntraXCell which is a month, gives users strong gains and is all the time someone needs to know if they like it. Judging by all the MONTH long logs, everyone so far has been VERY pleased with IntraXCell.
GreenMAG does NOT have Beta-Alanine in it, but it does have taurine which has cell volumizing effects which is why you may be experiencing the pumps, aside from the creatines. GreenMAG stacks VERY well with IntraXCell.
03-31-2007, 06:58 PM
Well maybe CEE does actually work for me than. I have no idea. I know Green Mag worked but I stoped taking it because it gave me the runs. I only used it for about two weeks. I just dealt with the sides of running to the bathroom. I tried half dosing it and that didn't work, tried it with solid food and that didn't work. I must have been mistaken about the ingredients, I knew it had something in it that started with a b! - Betaine Anhydrous, I just checked. Anyway, all that aside will this product help with my endurance while doing steady state cardio?. I'm trying to get my endurance up and "train my breathing" so I'm not out of breath so fast. I'm starting to like endurance training a lot more lately.
03-31-2007, 07:03 PM
Yes, IntraXCell will help with your endurance, as a recent aerobic study recently showed. It may also help slow down your breathing rate, though if you were bored with my above explanations, my explanation IXL's effects on breathing rate might put you in the loony bin.
03-31-2007, 07:31 PM
Im looking forward to how intraXcell aids a rugby player like myself. Endurance is important in rugby but theres still plenty of pushing pulling lifting and pain.
03-31-2007, 07:37 PM
04-01-2007, 03:24 PM
Regardless, the players are loving our products and greatly benefiting.
04-01-2007, 03:27 PM
04-01-2007, 11:33 PM
04-01-2007, 11:40 PM
Lots of places to purchase our products, AM's very own sponsor Planetary Nutrition is one such place.
«Discount Bodybuilding Supplements – Discount Nutritional Supplements – Planetary Nutrition
Also, they can check our retailers listing here.
Athletic Edge Nutrition, Inc.
04-04-2007, 06:27 PM
For the most part, people seem to know that the NAC/ALA components of IntraXCell are not only safe, but extremely healthy for you, through boosting the powerful antioxidant glutathione. Both NAC/ALA of course have many other benefits most of us are familiar with by now, so we wont go into them at this time.
However,we do get asked this question very often, as many people are just starting to learn about Beta-Alanine as well as much of the performance/safety studies didn't come out until 2005-06.
Is Beta-Alanine Safe?
The answer to the safety question is a resounding YES. Studies, going up to 12 weeks of continued Beta-Alanine use, have looked at a large array of blood biochemical, hematological and hormonal markers and no negative changes have occurred whatsoever. While it is impossible to say Beta-Alanine is one hundred percent safe until longer term studies are complete, we do know that up to 12 weeks of continued Beta-Alanine supplementation is indeed safe.
04-10-2007, 05:35 PM
04-12-2007, 04:16 PM
04-12-2007, 07:50 PM
04-12-2007, 09:04 PM
04-21-2007, 08:42 PM
04-25-2007, 01:57 PM
04-30-2007, 09:42 PM
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This week, we heard the news that Rupert Murdoch will be splitting News Corp. into two separate entities: a publishing company and an entertainment firm. I have several reactions:
1. The News Corp split follows a familiar pattern. In the 1990s, we saw a number of media companies engaging a great deal of both horizontal and vertical integration (Viacom merges with CBS, AOL mergers with Time Warner, Disney buys ABC, etc) Now, we have seen the reversal of many of these strategies. I'm not surprised. Disney always had the strongest case for horizontal integration, because they leverage a highly valuable resource (the characters) across many business units. Other entertainment firms had far less synergy across their businesses.
2. One might argue that the media conglomerate phase of the past was a case of herd behavior. They all imitated one another in strategies of horizontal and vertical integration, without necessarily questioning the merits closely enough.
3. News Corp may not have a great deal of difficulty breaking up into two firms because of how they manage the business units. Murdoch always ran the units in a fairly decentralized manner. That always puzzled me, because it meant that they really weren't pursuing major synergies. On the other hand, that unit autonomy makes breaking up much easier, given the lack of strong interconnections.
4. One wonders how much cross-subsidization occurred in the past, with cash flow from the profitable, but mature publishing businesses to the higher growth entertainment businesses that needed cash to grow. If a great deal occurred, then it will be interesting to see how the entertainment business funds its growth moving forward. Meanwhile, investors may be very happy to see the cash flow from the publishing business returned directly to them (perhaps via strong dividends), for people to invest as they choose. |
Presenting security on the fair stand: Sebastiaan de Vries, Sales Manager Insulating Glass.
For us, security occupies a lot of space, promises Sebastiaan de Vries, Sales Manager Insulating Glass. This is to be understood quite literally. At the fair alone this is equivalent to the 120 m² that Stand A 19 in Hall 17 measures. The fact that this area is definitely necessary to present the cur-rent novelties in the field of the safe sealing of insulating glazing makes clear: A visit to Henkels fair stand is a must for the specialised visitor who intends to take home really advanced solutions from glasstec 2004. This means innovative products and manufacturing know-how in line with high quality and environmental standards such as the silicon system Terostat 1991 / 1996 / 1997 or the PS-based Terostat 998 R, a sag-resistant product even at high temperatures whose adherence has been further improved. Or synergy effects resulting from the R&D of the globally operating Henkel Group, such as the Macroplast technology used in the manufacture of photovoltaic modules or sandwich elements.
On the insulating glass market, the Teroson® brand is a synonym for inno-vation and continuity, says Sebastiaan de Vries. We are looking forward to convincing you personally at our fair stand. HS
Henkel Assembly Kleb- und Dichtstoffe Europa
Henkel Teroson-Straße 57, 69123 Heidelberg
Henkel is a leading company offering brands and technologies that make peoples lives easier, better and more beautiful. The division Henkel Tech-nologies is one of the worlds leading suppliers of systems, services and products in the areas of adhesives and sealants as well as surface technol-ogy for industrial applications. Strong brands, such as Loctite, Teroson, P3, Hysol and Liofol, are at the basis of the success of this division. Among the users of Henkel Technologies are globally the following industries: automobile, electronics, aeronautics & aerospace, metals, assembly, main-tenance/repair, consumer goods and packaging.
Henkel A Brand like a Friend. The Henkel Groups operations are di-rected through three strategic market fields Detergents/Household Cleansers, Cosmetics/Toiletries, Adhesives/Sealants and Surface Technol-ogy. In the financial year 2003, Henkel Groups sales amounted to 9.436 billion euros, and its operating result (EBIT) was 706 million euros. The Group has 50,000 employees worldwide. People in 125 countries of the world rely on brands and technologies from Henkel. |
Romeo and Juliet
A long-standing feud between two powerful rival clans, the Capulets and the Montagues, erupts into fresh violence on the city streets. The Prince arrives, furious, and declares if either of these families ever disturbs the peace again, the crime will be punishable by death.
As the streets clear, Romeo, the melancholy son and heir of the Montagues, arrives. His good friend Benvolio asks him what the cause of his sadness is. Romeo admits he is suffering from unrequited love for a girl named Rosaline.
Meanwhile, the noble Count Paris asks Lord Capulet for the hand of his only daughter, Juliet. Capulet hesitates, but invites Paris to a grand party at his house that very night, where he will introduce Paris to Juliet. Romeo and Benvolio learn of the party from a servant. Benvolio, hoping to cheer up his friend, convinces Romeo to crash the party with him. Later, Lady Capulet broaches the subject of marriage with her daughter, Juliet, and their beloved Nurse. The three women look forward to that night's festivities when Juliet will meet Count Paris, the man who hopes to make Juliet his wife.
Disguised in masks, Romeo, Benvolio, and their impulsive friend Mercutio do crash the Capulets' party. There, Romeo sees Juliet and is overwhelmed by her beauty. He summons the courage to approach her, and as they meet, they are both instantly love-struck. In the process, Romeo is spotted by Juliet's cousin, Tybalt, who is furious at the intrusion and vows revenge.
On the way home, Romeo eludes his friends and sneaks into the Capulets' orchard. He happens upon Juliet standing at her balcony and calls to her. Heedless of their families' hatred, they confess their love for each other and vow to be married. Romeo runs to tell his friend and spiritual mentor, Laurence, the news. Shocked that Romeo would fall for the daughter of his foe, Laurence nonetheless agrees to help his young friend, hoping the union will unite the warring families.
The next day, Juliet sends her Nurse to find Romeo. Through the Nurse, the two arrange to meet and are married.
On the way back from this secret marriage, Romeo and his friends are confronted by the angry Tybalt, who challenges Romeo to a duel. Unwilling to fight his new cousin-in-law, Romeo backs down without explaining why. Confused and humiliated, Mercutio challenges Tybalt on Romeo's behalf. Romeo tries to come between them, but in the confusion, Mercutio is killed. Overcome with emotion, Romeo rushes at Tybalt, killing him. Horrified, Romeo flees. The Prince arrives and, as punishment, banishes Romeo forever.
The Nurse takes the news to Juliet while Laurence tells Romeo. The two are utterly heartbroken, but arrange to spend their wedding night together before Romeo is exiled. Unaware of Juliet's marriage, Capulet agrees to marry her to Paris in two days' time. When Juliet objects, Capulet becomes enraged, threatening to expel her from his house forever.
Desperate to the point of suicide, Juliet begs Laurence's help. He agrees and offers a desperate plan. Juliet will take a sleeping potion that mimics death. Her family, thinking her dead, will entomb her. In two days, she will awaken. Laurence will come to the tomb, free her, and take her to Romeo, who will know of the plot via a letter. Juliet agrees, and everything goes according to plan.
Except the letter never reaches Romeo. Instead, he hears that Juliet has died. Suicidal with grief, he obtains a deadly poison and goes to Juliet's tomb. Seeing her motionless form and not realizing she only sleeps, he drinks the poison and collapses, dead.
Juliet awakens, sees her dead husband, and stricken with grief, kills herself with a dagger. Laurence, the Montagues, Capulets, and the Prince arrive at the tomb too late and can only gaze in horror at the fallen children. Laurence reveals the couple's secret love. The families finally agree to end their blood feud.
This summer, Romeo and Juliet are doing some traveling. From Shakespeare's Renaissance Italy, they're headed a thousand miles southwest and a hundred years into the past, as we relocate the beloved tragedy to 15th century Spain. The year is 1492 and the place, the city of Granada, jewel of the medieval Muslim world. Just months before Columbus set sail on his history-changing voyage to the New World, he stood on the plain outside Granada and watched its last Moorish King surrender the city to King Ferdinand and Queen Isabella. Thus ended more than seven centuries of Muslim rule in southern Iberia.
It was the end of the Reconquista, and the Catholic Monarchs had completed the unification of Spain under Christian rule with a bloodless conquest of Granada. In exchange for a peaceful transfer of power, the Treaty of Granada, signed by both parties, granted the city's Muslims a range of personal and religious freedoms – very generous terms by ancient standards. By law, Muslims would be free to practice their faith openly and without harassment. They would retain their houses of worship, style of dress, and personal property. They could even keep and bear arms. The two communities that had glowered at each other across the frontier for centuries were now entering a new era of cooperation – at least on paper. The reality in the streets was not so sanguine. Just a few months after the signing of the Treaty, the Catholic Monarchs expelled all the Jews from the Iberian Peninsula. Within a decade, the Inquisition would come to Granada, Muslims, too, would be forced to convert or be expelled, and the freedom and tolerance promised by the treaty would seem like a distant memory.
It is in the heart of this uneasy and precarious truce of 1492, on the borderlands of Christendom and Islam, that our young Romeo and his love Juliet "take their lives." Romeo's family, the Montagues, are Muslims, Juliet's Capulets are Catholics. Here, Shakespeare's "ancient grudge" between the two families becomes the troubled coexistence of these two great world religions, whose conflict predated Shakespeare by nearly a thousand years and whose challenges remain very much with us half a millennium after his death.
It was a fascinating historical singularity – one whose possibilities and perils, dreams and disillusions, live in wonderful synergy with the crests and valleys of Shakespeare's story: the uncomplicated rapture of new love, the seductive evil of prejudice, and the ability of each new generation either to rehash or to transcend the sins of their elders. I hope this production will offer audiences a window through which to view the nuances of this classic with fresh eyes and fresh minds. May it for you, as it has for me, be an opportunity to consider with fresh insight our own bloody history, this most precarious present, and the as-yet-unwritten future.
Brett Elliott, Director for Romeo and Juliet |
VIT∆MIN CODE RAW Calcium
– July 2009
Why is calcium important?
A: Calcium is the most abundant mineral in the human
body and has numerous important functions.
It accounts for 1 to 2 % of adult human body weight and more than 99% of
total body calcium is stored in the bones and teeth for structural
2. Why is bone health important?
A: Bone Health means a lot more than simply preventing
osteoporosis. Healthy bones manufacture red blood cells, immune cells,
secrete hormones and much more. Bone loss is associated with increased
inflammation, which then accelerates more bone loss and becomes a
vicious cycle. There is an Osteo-Immune relationship, as well as a link
between bone loss and obesity. Because osteoporosis is often the first
sign of degenerating bone health (often in the form of a fracture due to
weak bone) we consider good bone health to be one of the most overlooked
components of extraordinary health - everyone needs to think about their
3. Why should I question if my calcium supplement
A: Calcium supplements taken in the absence of other
vitamins and minerals and without proper diet and exercise, have not
been proven in clinical studies to help strengthen bones. The best that
can be said is that calcium supplementation helps slow down or stop bone
loss.†† While slowing bone loss is good, increasing bone mineral density
should be the goal. The majority of calcium supplements are made from
ground-up rock and most of them are in tablet form and have solubility
problems. The USA is the country that purchases the most calcium
supplements, but it is also one of the countries with higher incidence
4. What is VIT∆MIN CODE RAW Calcium?
A: VIT∆MIN CODE RAW Calcium is the first raw, vegan
calcium formula, composed of AlgaeCal RAW, a certified organic plant
source of calcium derived from the marine algae Algas calcareas rich in
naturally occurring minerals and trace minerals. The RAW Calcium formula
provides all the necessary cofactors such as 100mcg of Vitamin K2 in the
form of MK-7, 1,600 IU of RAW Food-Created vitamin D3 and other
bone-building† Code Factors, magnesium, boron, silica and vanadium. RAW
Calcium is completely free of commonly-used limestone rock, chalk or
animal bone sources of calcium and is suitable for even the most
dedicated raw food vegan. RAW Calcium May Reduce the Risk of
Osteoporosis,†† Increase Bone Strength, Increase Bone Mineral Density
and Slow Bone Loss.†
5. Who can benefit form taking RAW Calcium?
A: Anyone can benefit from calcium supplementation.
RAW Calcium is the best choice for individuals searching for a RAW,
vegan, whole food calcium supplement; anyone already using a calcium
supplement; those who wish to reduce the risk of developing Osteoporosis
later in life,†† and adults seeking to build better, stronger bones by
increasing bone density.† RAW Calcium is completely free of
commonly-used limestone rock, chalk or animal bone sources of calcium
and is suitable for even the most dedicated raw food vegan.
6. What is the Dietary Reference Intake (DRI) for
A: According to the Institute of Medicine (2003), the
Dietary Reference Intake (DRI) for desirable calcium retention and
balance in people between the ages of 19 and 50 is 1000mg per day; for
people aged 51 improving changes in bone mineral density.
7. How much calcium does RAW Calcium provide and
what is the source?
A: RAW Calcium delivers 756mg (76% DV) of plant-based
calcium from AlgaeCal RAW.
8. What is AlgaeCal RAW?
A: AlgaeCal RAW is the first raw, vegan, certified
organic whole food plant source of Calcium. As
opposed to single element calcium supplements, AlgaeCal RAW is powdered
Marine Algae (Algas
calcareas) containing an entire spectrum of plant nutrients, large
quantities of Calcium and Magnesium
and naturally rich in 73 trace mineral bone-building Code Factors such
as Boron, Strontium, Vanadium,
Silica as well as other naturally-occurring trace minerals. Your body
was designed to accept plant
minerals better than rock because plants pre-digest the minerals for us.
AlgaeCal RAW washes up on the pristine shores of South America where it
is harvested live, just like vegetables from a garden, then cold
processed to retain nutritional value. The porous nature of AlgaeCal RAW
dramatically increases surface area which lends itself to better
9. Is AlgaeCal RAW USDA certified organic?
A: We are very proud to say that Algas calcareas, the
plant source calcium mineral complex that is
AlgaeCal has been certified organic by the USDA, IBD (Organic
Certification for Brazil and other Latin
American Countries) and IFOAM (International Federation of Organic
Agriculture Movements). However,
the RAW Calcium formula as a whole are not certified organic.
10. Is the calcium in AlgaeCal RAW absorbable and
A: The body’s ability to absorb calcium depends on the
body’s need for calcium, the last calcium containing meal consumed, the
presence of co-factors, among many other factors. The body best
absorbs calcium when divided into multiple servings throughout the day
because studies suggest that the body can only utilize a limited amount
of calcium at once. AlgaeCal RAW besides being a plant sourced calcium,
has a unique porous nature, like a sponge so it has a lot more surface
area than an ordinary calcium carbonate. More surface area means more
opportunity for stomach acid to come in contact with the calcium and
dissolve it. Beyond solubility in the stomach, AlgaeCal RAW has been
shown to be bioavailable in the rest of the digestive process. The
calcium that actually goes into the bloodstream varies among
individuals, depending on need for calcium, calcium source, amount
taken, co-factors, etc. Another reason for low calcium absorption is the
poor dissolution of some tablet forms. It has been found that some
tablets are so closely bound with glues that they could take hours to
dissolve. Capsules are a preferable delivery form to tablets for this
reason. The contents of vegetable capsules is a loose powder which has
greater dissolution potential than a tightly bound tablet. RAW Calcium
delivers AlgaeCal RAW, a whole food source of calcium, in a vegan
UltraZorbe capsule for rapid dissolution and better bioavailability.
According to the National Academy of Sciences, most supplement forms of
calcium such as calcium carbonate and calcium citrate are absorbed
typically in a range of 25% to 35%. Foods however have better absorption
and values differ greatly from food to food, but are usually higher. The
key point is that plant based calcium is absorbed better than calcium
from rock. AlgaeCal RAW is a whole food algae naturally rich in calcium
and other minerals which facilitate absorption.
11. Why is vitamin D3 important to bone health?
A: To help the body absorb calcium it is also
important to get enough vitamin D. Vitamin D can be obtained through
sunlight exposure and foods. Recent studies show the need for much more
vitamin D than was previously recommended. Vitamin D functions as an
important hormone by sending a message to the intestines to increase the
absorption of calcium up to 80% depending on individual need. Vitamin D
is well known for maintaining normal calcium levels, but new research
shows it plays an important role in a host of other important functions
such as strengthening the immune system.† Vitamin D3 or cholecalciferol
is the natural form of vitamin D and is much more effective at raising
serum 25 hydroxyvitamin D as opposed to the synthetic D2 or
ergocalciferol form. RAW Calcium delivers 1,600 IU of RAW Food-Created
12. What are the benefits of vitamin K2 in the form
of MK-7 in a calcium formula?
A: Strong scientific evidence now suggests that
vitamin K2 is an important piece of the bone health
puzzle.† Vitamin K2 is derived from Natto, the richest natural source of
vitamin K2. Natto is an ancient
Japanese food made from fermented soybeans, and significant amounts of
vitamin K2 are produced
during the fermentation process. Vitamin K2 is classified into MK-4 and
MK-7 primarily. More recently the attention of scientists is focused on
the MK-7 version which is natural and stays in the blood stream longer
than MK-4 creating bone health benefits. MK-7 stimulates protein
synthesis in osteoblastic cells and enhances osteocalcin production, a
calcium-binding protein in the cells, which stimulates the
mineralization in bone tissues. MK-7 has been found to have a
stimulatory effect on calcification and an inhibitory effect on bone
reabsorption in bone tissue, thereby increasing bone mass.† RAW Calcium
provides 100mcg of RAW Food-Created vitamin K2 in the form of MK-7.
13. Why is magnesium important to bone health?
A: As the fourth most abundant mineral in the body,
magnesium is essential to good health.
Approximately half of the total body magnesium is found in bones and the
other half is distributed
throughout cells of tissues and organs. This critical mineral is needed
for more than 300 biochemical
reactions. It helps maintain normal muscle and nerve function, keeps
heart rhythm steady, supports a
healthy immune system, and keeps bones strong. Magnesium deficiency may
be a risk factor in cases of extensive bone loss because magnesium
deficiency alters calcium metabolism and the hormones that regulate
calcium. Several human studies have suggested that supplementing with
improve bone mineral density.† Magnesium and calcium work together to
keep calcium in bones and out of soft tissues.† RAW Calcium includes
380mg of Magnesium from AlgaeCal RAW.
14. Are there other minerals crucial to bone
A: The consumption of other trace minerals such as
silica, boron, vanadium and strontium have all been linked to healthy
bones.† All of these minerals and many others are naturally occurring in
the Algas calcareas included in RAW Calcium.
15. What are RAW Food-Created Nutrients?
A: The RAW Food-Created Nutrients in Vitamin Code
formulas are individually cultivated with their
unique Code Factors intact, enabling targeted delivery and natural
recognition of nutrients by the body.
Imagine growing a plant in the garden, and adding extra vitamin D to the
soil to yield a plant rich in
vitamin D. The yeast or bacteria is cultivated in water and “fed” a
vitamin to yield a food-based yeast or
probiotic matrix that is rich in that particular vitamin. Raw
Food-Created Nutrients are grown in both S.
cerevisiae (baker’s yeast) and the probiotic Lactobacillus bulgaricus to
provide a broader spectrum of
16. What is a Code Factor?
A: Code Factors are the known, and yet to be
discovered, synergistic compounds found in food and
necessary for proper nutrient delivery. Providing these Code Factors
infuses the essential elements of
whole foods that the body thrives upon.
17. What are RAW Food-Chelated Minerals?
A: Chelation is a naturally occurring process in the
body for transporting minerals across the intestinal
wall during digestion. Common inorganic forms of trace minerals may
interact with lipids, proteins, fiber or other minerals, inhibiting
absorption. When minerals are bound to chelating agents such as amino
acids, they become more stable and are much less reactive in the
digestive tract. RAW Food-Chelated
Minerals are minerals that have been bound to raw rice amino acids
making their structure more akin to
food, designed to enhance mineral absorption and improve
18. What is the difference between RAW Food-Chelated
Minerals and other mineral chelates?
A: The primary difference between RAW Food-Chelated
Minerals and regular amino acid chelates is that the amino acids we use
are derived from raw rice protein and not from a synthetic form. This
means they have a full spectrum of naturally occurring amino acids that
are found in proportions similar to what they would be in foods. All 20
amino acids are present and include both branch chain aminos as well as
all the essential aminos, which can’t be produced by the body. Other
amino acid chelated minerals most times only utilize a dipeptide or
tripeptide (two or three amino acids). Scientific data also shows RAW
Food-Chelated Minerals to have better bioavailability and shelf
19. What is the suggested use for RAW Calcium?
A: Adults take 5 capsules daily. For best results take
3 capsules with breakfast and 2 capsules with lunch. Capsules may be
opened and contents added to water or raw juice.
20. Does RAW Calcium interact with medications?
A: It's important to discuss with a doctor possible
interactions between calcium supplements and overthe-counter and
prescription medications. Any medication that needs to be taken on an
empty stomach should not be taken with calcium supplements. The RAW
Calcium recommended usage can be rearranged to accommodate medications.
Please discuss the appropriate intake schedule with your doctor. RAW
Calcium also includes vitamin K2 which is usually not recommended while
taking blood thinners.
21. Are there any contraindications or warnings for
A: Caution: As with any dietary supplement, consult
your healthcare practitioner before using this product, especially if
you are pregnant, nursing or under medical supervision. Not intended for
22. Can I take RAW Calcium if I am pregnant or
A: Calcium plays a critical role during pregnancy and
lactation. Pease discuss RAW Calcium with your
doctor to decide if it’s appropriate for you.
23. Is RAW Calcium Vegan, Gluten Free, Dairy Free,
and does it contain Soy?
A: The ingredients in RAW Calcium are vegan, gluten
free, dairy free and do not contain soy allergens.
24. Does RAW Calcium contain any binders or
A: There are no fillers or binders in RAW Calcium.
25. Does RAW Calcium contain any artificial colors,
flavors or preservatives?
A: No, there are no artificial ingredients in RAW
26. What are RAW Calcium capsules made of?
A: The capsule used is made of cellulose, the
structural component of the primary cell wall of plants.
Although the content of the capsule is entirely raw, the capsule itself
cannot be made raw. Raw foodist
may open the capsule and pour the contents into water or raw juices. The
capsules are labeled Vegan.
27. Does RAW Calcium require refrigeration?
A: No, RAW Calcium should be stored in a cool dry
place both before and after opening.
28. What is the shelf life of RAW Calcium?
A: RAW Calcium has a shelf life of 3 years.
29. Can RAW Calcium be taken with other Garden of
A: Yes, RAW Calcium can be taken in conjunction with
other Garden of Life products. It is important that you discuss ALL
supplement use with your health care practitioner, particularly if you
have any kind of medical condition.
30. How is VIT∆MIN CODE RAW Calcium different from
other calcium supplements?
A: RAW Calcium is the first ever RAW vegan calcium
from AlgaeCal RAW with 73 minerals and trace
minerals, including the necessary bone-building† Code Factors, vitamins
D3 and K2, magnesium, boron, silica and vanadium. It also contains RAW
Food–Created Nutrients and follows all Vitamin Code quality standards:
- RAW – uncooked, untreated, and unadulterated
- RAW – contain live enzymes and probiotics
- RAW – 100% Active Ingredients– No Binders or
- Contain Nutrient Specific Peptides for Targeted
Delivery and Utilization
- Contain Code Factors for Extreme Nutrient Synergy
31. What is the Suggested Retail Price of VIT∆MIN
CODE® RAW Calcium?
A: RAW Calcium is available in both 75ct (15-day
supply) and 150ct (30-day supply) amber glass
containers and have a Suggested Retail Price of $25.95 and $44.95
32. What does the Vitamin Angels logo on the RAW
Calcium carton mean?
A: For every Vitamin Code® RAW Calcium sold, a
donation will be made to Vitamin Angels and their
Operation 20/20 program to eliminate Vitamin A deficiency in the world
by the year 2020.
††Regular exercise and a healthy diet with enough
Calcium and Vitamin D helps maintain good bone health and may reduce the
risk of osteoporosis later in life.
† These statements have not been evaluated by the Food
and Drug Administration. This product is not intended to diagnose,
treat, cure or prevent any disease. |
SCMP Discloses H.K. Media Talks After Stock SurgeLulu Yilun Chen
SCMP Group Ltd., publisher of the South China Morning Post, said it was in talks to buy “a group of media companies” in Hong Kong after its shares surged the most in more than 15 years.
The company so far has only entered a non-binding preliminary agreement, it said in a statement yesterday, without naming the potential target. The Hong Kong-based publisher will resume trading today. It was halted at lunchtime yesterday following a jump of as much as 31 percent.
SCMP, controlled by Malaysian billionaire Robert Kuok, could buy a Chinese-language publisher or a TV broadcaster, said Doug Young, a journalism professor at Fudan University in Shanghai. The company's sales have fallen more than 50 percent since 1997 as its flagship title struggles to compete with free newspapers and online publications.
“Buying a broadcaster could generate synergy,” said Young, the author of “The Party Line: How The Media Dictates Public Opinion in Modern China.” “Advertisers like it if they can buy deals in one place to get ads in print, online and on TV.”
SCMP, the publisher of Hong Kong’s only paid-for daily English-language newspaper, also faces a possible delisting because its publicly traded shares are set to fall below an exchange-imposed minimum.
Kuok’s Kerry Media Ltd. is due to buy stock from three banks, which will cut SCMP’s free float to about 11 percent. SCMP has said its shares could be suspended Feb. 26 until the proportion of stock held by minority investors returns to above 25 percent.
SCMP was up 23 percent in Hong Kong trading at HK$2.15 when it was suspended. The publisher’s other titles include recruitment publications and Chinese-language versions of Cosmopolitan and Harper’s Bazaar magazines. It doesn’t own a Chinese-language newspaper.
Kuok, 89, bought a controlling stake in SCMP from Rupert Murdoch in 1993. He bought a further 30 percent for HK$1.1 billion ($142 million) in 2008 through Kerry Group Ltd. The publisher’s sales declined to HK$946 million in 2011 from HK$2.4 billion in 1997.
Kuok is ranked 38th in the Bloomberg Billionaires Index with a net worth of $18.8 billion. He also has interests in property, hotels, palm oil and logistics.
The South China Morning Post, first published in 1903, has an audited weekday circulation of 108,047, according to a marketing brochure on its website. The newspaper’s local rival, the Standard, stopped charging readers in 2007 to boost circulation after the government ended a requirement for companies to publish stock-exchange announcements. |
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Last edited by alwaysbelieve1; 01-18-2008 at 01:19 PM.
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Field Reports1 Nov, 2006 By: Thomas Haire, Courtney Beth Pugatch Response
West Corp. Buys InPulse for $44.5M
By Thomas Haire (firstname.lastname@example.org)
OMAHA, Neb. and PHOENIX — West Corp. acquired InPulse Response Group Inc. on Oct. 2 for approximately $44.5 million. InPulse, a leading provider of outsourced sales to direct response (DR) marketers, will operate as part of West's Communications Services segment.
The acquisition was funded with a combination of cash on-hand and West's existing bank credit facility. West expects the transaction to have no impact on 2006 earnings per share and to be slightly accretive to net income in 2007.
"We are now officially part of West, but we will maintain our brand sales and soft offer approach under the InPulse brand," said Steve Pittendrigh, founder/CEO of InPulse in an exclusive interview with Response Magazine. "This partnership, though, will catapult us operationally. Our definition of success remains the same: are our clients making more money by using our services? With this deal, we know the answer will be yes."
The InPulse brand and management team will remain intact, but will use West's varied technology platforms, allowing for growth the two companies couldn't expect on their own.
"We are extremely excited about the synergy of complementary services and the great integrity of these two companies coming together," said Rod Kempkes, executive vice president of West Corp., in an exclusive interview with Response Magazine.
Pittendrigh adds that the timing for such a move was "perfect."
"The industry has been changing, and one of the biggest changes was the expansion of the importance of data," he contends. "While our data was good, to get where we wanted it to be would have been an incredible investment. When we asked ourselves, 'Should we do this alone or should we look for a partner?' the answer was clear. In West, we've found the best partner we could have hoped for."
At the same time,Kempkes says it would have also taken great investments in both time and money for West to replicate the specialties offered by InPulse. "InPulse is all about sales, stewardship and performance," Kempkes adds. "Why should we try to replicate their platform when we respect their brand and can align with it?"
Both leaders say the new partnership also offers services that "extend beyond those of other telemarketers," according to Kempkes. "With this partnership, we can now offer every tech and sales platform imaginable to our customers," he adds.
Pittendrigh agrees, citing West and InPulse's first combined client conference call in mid-October. "The array of solutions we can now offer truly shocked one of our long-term clients," Pittendrigh contends.
Google Buys YouTube As 'Net Video Company Makes Other Deals
By Courtney Beth Pugatch (email@example.com)
NEW YORK — YouTube Inc. continues to make news as Google has agreed to purchase YouTube.com while CBS and two major music labels joined in a partnership with the video-sharing Web site. The new arrangements allow YouTube to continue to promote video sharing with no copyright infringements. |
[This post was conceived and co-authored by Andrew Ruef, Ph.D. student at the University of Maryland, working with me. –Mike]
As researchers, we are often asked to look into a crystal ball. We try to anticipate future problems so that work we begin now will help address those problems before they become acute. Sometimes, a researcher guesses the problem and its possible solution, but chooses not to pursue it. In a sense, she has found, and discarded, an idea ahead of its time.
Recently, a friend of Andrew’s pointed him to a 20-year-old email exchange on the “firewalls” mailing list that blithely suggests, and discards, problems and solutions that are now quite relevant, and on the cutting edge of software security research. The situation is both entertaining and instructive, especially in that the ideas are quite squarely in the domain of programming languages research, but were not considered by PL researchers at the time (as far as we know).
Problem: Exploits via buffer overflow
This 1995 e-mail exchange on the “firewalls” mailing list identifies the problem presented by buffer overflow-based exploits:
Someone can spend hours to develop an exploit for a particular target
platform, OS version, and CPU type. That exploit might need to use different
offsets on other versions or machine types, and it is clearly just a
It is almost getting boring or something.
Note this statement of boredom is being made just one year before the publication of Smashing the Stack for Fun and Profit, a watershed publication that systematizes the construction of stack smashing attacks. This statement also anticipates research that automates the discovery and construction of exploits. The author continues:
I just decided it would be pretty funny if we had a C compiler which would
randomize the location of variables on the stack for each compile. It
would also be nice if it could randomly stick in some unused short ints
into the stack in various places (especially around big strings used
by sprintf, strcpy, and friends 🙂 ).
This would offer some protection against the next 10 years of cloned
stack-o-rama exploits. Raise the level of effort and all that. 🙂
It doesn’t change the price of the first exploit but it might prevent
anybody from making a profit on the volume!
Offhand solutions: 20 years of research
The amazing thing about this email exchange is the number of ideas that are offered almost tongue-in-cheek, but which in the 20 years since have turned into serious topics of study and, in some cases, mainstream deployment.
Stack randomization (2010 – active research)
The initial post quoted above suggests one possible defense — randomizing stack layouts. Some on the email list dismiss the idea (more on this below), but by 2010, Michael Franz makes the case that the idea should be revisited. In the last five years, his group and others have made a compelling case for automated software diversity, which includes the randomization of stack layouts.
Safe Stacks (2006 – now a compiler extension)
Others on the list respond with their own crazy ideas, such as the use of two stacks:
As long as we’re talking ‘blue sky’ solutions, why not do it _right_??
It’s well-known that the way you insure the integrity of code is keep it
separate from data. A single stack, containing both user-data, *and*
program ‘state’ information (function return addresses, etc.), fails to
maintain this separation. Solution: _two_ stacks. One for return-
addresses and processor ‘context’ info *only*, the other for all user-data.
Running with two stacks was seriously explored by the XFI system (which provided other protections, too) in 2006. The idea has matured to the point that it is now in clang, the production-quality front-end of LLVM, as SafeStack
Bounds Checking (1995 – going mainstream)
The author who proposed separate stacks also proposed preventing out-of-bounds accesses in the first place:
Another solution is to add ‘run-time array bounds checking’ to the compiler,
a la Pascal. Of course, then you have to deal with what happens when a
‘array bounds exception’ occurs. Default procedure, in Pascal for example,
is to announce it and _abort_ the program (wouldn’t *this* make for wonderful
‘denial-of-service’ attacks?!!). The way you prevent those aborts is to do
your _own_ checking *first*, and never reference past the end of an array.
Thus, you have _double_ checks on everything.
Jones and Kelly proposed backward compatible bounds checking for C that same year (1995), which also saw the release of the type-safe (and bounds-checked) Java programming language. Jones and Kelly’s solution was far too slow to be practical, but the benefits were deemed promising enough that a long line of research on type-safe (or memory-safe) C followed, including languages such as CCured and Cyclone in the early 2000s, and Softbound/CETS in 2009-2010. Hardware support for runtime bounds checking (based on work by Nagarakatte and others involved with Softbound) is slated to be released as an Intel ISA extension called MPX.
Stack Canaries (1998 – now mainstream)
Another author further riffs on these ideas, proposing what is now known as stack canaries:
I’ll do you one better on that. How about an integer or similiar type
allocated immediately after the buffer, whose value is set by the compiler
(“randomly”) and which is checked after the reads. If the buffer’s been over
written, it’s unlikely that the value will match what is put in. Note
that this doesn’t stop people on the machine from recompiling and noting
differences in the binaries to determine what value is being used, but it
will protect against most external attacks.
The paper that fleshes out the idea of stack canaries was published in 1998 by Cowan et al. Support for stack canaries would be added to mainstream compilers soon afterward (the original paper presented a gcc patch), with some small improvements such as a dynamically allocated integer as opposed to a static one.
Ideas not mentioned
While incredibly prescient, the authors of firewalls thread missed some important defenses against buffer overflow exploits. They did not identify the idea of Address Space Layout Randomization (ASLR), first proposed in 2001, though their idea of stack randomization gets at the same underlying concept. 1 They also did not identify Control Flow Integrity (CFI), first proposed in 2005, 2 which (like the other ideas proposed) compiles the program differently to limit the possible effects of an attack. Finding the right balance of precision and performance is still a research question for CFI, but it is making its way into the mainstream. More ideas explored in the last 20 years are nicely described in Szekeres et al’s 2013 paper, SOK: Eternal War in Memory.
How and why?
Seeing this email exchange, we were led to wonder: What has changed since 1995 that has upgraded what seemed at the time (to the authors) to be impractical ideas?
But when someone suggests fixing the problem by opening up and
hacking *another* large code-generating program, my worry alarm goes off.
Perhaps I’m too paranoid or too cranky, but I’m certainly not going to
accept on faith that hacking a compiler in the way described is a safe and
reliable way to proceed, without a lot of respected people walking through
the compiler and pronouncing it sane and safe on all applicable platforms.
This is a reasonable concern. In the last 20 years, the state of both the art and the practice of compiler construction has advanced quite a bit. There is now production-quality compiler, called CompCert, 3 that has been formally verified to be correct; extensions to this compiler should cause fewer concerns. Also, the emergence of LLVM, which provides a robust, modular infrastructure on which we can create exciting compiler extensions, gives greater confidence that those extensions are correct, and creates a quicker path to adoption. The Vellvm project looks to add verifiability to aspects of LLVM, which should also address “worry alarms.”
It also seems like there is an undercurrent in this discussion of “these runtime checks are expensive and wacky, why don’t we just get the code right the first time?” (which is part of the punchline of some CS stand-up comedy). Maybe it took a long time before the idea of “just write the C code right the first time” started to be replaced with some brutal realism about how hard it is to write C code right the first time. Maybe that realism is what we needed to start thinking about runtime defenses as something more than jokes told on a mailing list.
Another question that may come to mind is: Why were these ideas occurring on the “firewalls” list, and not within the programming languages community? The proposals are germane to language and compiler design, after all. The author closing out the email thread wondered the same thing:
All this said, methinks this is getting a bit far afield from _firewalls_.
and further discussion is probably more appropriate in one of the ‘comp.lang.*’
One possibility is that the firewalls community was closer to the exploits in the wild than the language community: they could identify the properties of the systems that the exploits relied on, and could conceive, at a high level, how those systems could be changed to break those dependencies while preserving the original semantics of the system.
Today, many of the developers of the next generation of runtime security systems either are also, or closely collaborate with, leading security experts that understand how modern exploits work. Indeed, as Mike has written before, there can be great synergy when applying programming languages ideas to problems identified by other fields, such as cryptography and machine learning.
Reading this, you might be inspired to ponder what technologies today seem like impossible long shots but actually could become relevant in 20 years. We’d love to see them, in the comments!
Here are some our off-the-tops-our-heads predictions:
Verification for the rest of us. Verification has existed as, charitably, a pipe dream, for many reasons: verification tools are slow and hard to use, it can be difficult to think about how to phrase properties you want to prove, and there always seems to be a gap between the proof and the implementation. However, systems like frama-c, F*, bedrock, and dafny seem to be closing gaps both in terms of usability and by strongly connecting the proof with the implementation. Projects like IronClad and Sel4, and funding efforts like HACMS, are pushing the state of the art.
Code injection will end. We have been plagued with low level security vulnerabilities that allow an adversary to inject a whole new program into a vulnerable program, usually abbreviated in the literature as buffer overflows. Technologies like those mentioned here have been closing the door on code injection attacks, e.g., the prevalence of stack-based attacks has greatly diminished in recent years. This trend will continue. This does not end the security story, but the concerns 20 years in the future should very different from the concerns of today.
Information disclosure will remain. Much more difficult than proving basic safety properties about C programs is proving properties about how the programs control and release the information they are charged with, such as (variants of) non-interference. Timing or resource usage based information leaks have received little attention in research (which motivated the recent DARPA STAC program). Perhaps if cloud computing continues to be adopted, disclosures of small secrets or keys are all that attackers will really need.
- While ASLR is of questionable value for 32-bit address spaces, it is now in common use and seems effective on modern (64-bit) processors. ↩
- Techniques for restricting a program’s control flow were also proposed prior to 2005, e.g., program shepherding in 2002. CFI is implemented via (re)compilation and defines its policy in terms of a control-flow graph, rather than (say) in terms of legal entry points to libraries. ↩
- Xavier Leroy, the leader of the CompCert project, just won the POPL 2006 Most Influential Paper Award for authoring the first paper on the work. ↩ |
A5tek Corp's ieHIP - Home Infotainment Platform and Syllax AVES, Media-Centric styled console products will be sold to consumers and custom home system installers, through the Syllax e-Commerce web site.
Sunnyvale, Calif., October, 29th, 2003 - Calrad Electronics and E -commerce business partner Syllax, Inc. have partnered with A5tek Corp, to begin selling A5tek Corp's ieHIP product. ieHIP or Home Infotainment Platform as it is also known, is a single console for providing features that include, a CD/DVD player, a Digital Video Recorder (DVR), Music -Jukebox, Digital Photo Album, Karaoke Machine, Television, Internet, and Computer functionality, combined into one simple easy to use device. Syllax already manufactures a similar product called the AVES, (Audio -Video Entertainment -System) the unit is similar to the ieHIP product line but is more directed to the installer OEM markets for expandability. The combined strengths of these units will offer a more complete product line to meet our customers needs, further promoting this new innovative technology for everyone.
A5tek Corp has pioneered the development of an all -in -one platform that encompasses today's need for convergence solutions into one device for a little over a thousand dollars. A5tek's on -screen user interface, smart card technologies, and innovative multimedia system designed architecture, place it head and shoulders above recent entries into the retail Media Center consumer product market. A5tek leverages its expertise in digital to analog, and analog to digital video conversion technologies, and the ability to converge the best functionalities of related consumer devices, and the computer, into this truly state -of -the -art device.
ieHIP is innovated with its unique Numbering Menu System that allows even novice users to operate as an entertainment device, and an information hub that connects to various types of TV's or display mediums throughout the home. The ieHIP can display previously stored content internal to the console and can call up content from other audio -video equipment or computers via its home networking capability.
"When the average consumer takes into consideration the costs associated with purchasing all of these other devices, ieHIP makes a lot of sense" says Lawrence McGeorge, Sales Manager for A5tek Corp. "We've also determined that having a stack of devices with multiple remote controls, isn't exactly a benefit to the average consumer. In fact, the ability to have one device to control from a centralized location in the living room is actually desired by many households in the U.S. and around the world."
ieHIP seeks to take advantage of its easy installation, simple design, and affordable price point, to help consumers do what they want, when they want to do it.
"We combine the best technologies available, integrate their functionality and feature sets with our own ieHIP 1,2,3…software interfaces, and voila, "The most easy to use affordable entertainment -information console available" states McGeorge.
"With ieHIP you already receive the ability to access many different types of entertainment and information at the touch of a button, without all those nasty subscription fees. We feel that the average consumer already pays for an Internet connection and some type of TV subscription service, why should they have to subscribe to another service?
That's why our A5 Studio in the Philippines were created to provide updated content links for on -going product upgrading to allow users to have new IP -Games to play, new IP -TV to watch, or new IP -Radio to listen to."
ieHIP has received widespread industry attention in articles appearing in the Comdex Daily News (November 2002), CEPro Magazine (March 2003, "The Best of CES 2003"), and more recently in Electronic House Magazine (August 2003, "Media Marvels")
Automatic product upgrades for the ieHIP, will be made available through the www.ieHIP.com website. Additional information on ieHIP or A5tek Corp. can be found at: www.a5tek.com To purchase an ieHIP Infotainment Console, please go to the www.syllax.com web site for ordering information and product pricing.
"We are confident that Calrad Electronics and its new e -Commerce business partner Syllax, Inc. will bring over fifty years of solid experience in the home installation and home cabling products market to the table, and provide us with a high profile presence among Calrad's national network of home systems installers," adds McGeorge. "Syllax will provide us with market presence in both the consumer and home system installer markets, giving us the opportunity to penetrate two markets, and a best of both worlds synergy."
About A5tek Corp.
A5tek is the amalgamation of various industry technology experts who came together 4 years ago, in May of 1999, to form the company and set it on its current path of designing the flagship product the ieHIP. Four years later, A5tek is getting strong and growing. The A5 Studio was created as an additional resource for engineering research and development, living room e -Commerce portal software, and content development. The office is strategically located n Cebu City, Philippines, the country's IT hub in the south. A5tek pioneers the convergence of analog and digital technologies for entertainment and information provision to the consumer home.
A5tek Corp's world wide headquarters are located in Sunnyvale California, with a third office located in Taipei, Taiwan, which coordinates the production and manufacturing of ieHIP units. For additional information on ieHIP, A5tek or other company information, please go to the company web site at: www.a5tek.com
Lawrence W. McGeorge
World Wide Product Sales Manager
About Calrad Electronics / Syllax, Inc.
Since the inception of Calrad in the early 1950's the company has been involved in the consumer and hi -end audio -video component and accessory business. With offices and product manufacturing plants located in Japan and Taiwan. Distribution of packaged products under the Calrad brand started with general line electronic distributors thru out the U.S.
Over the years, Calrad's growth to over 4,500 line items has expanded into other markets including broadcast, pro -audio, medical, aerospace, home theater and the development of OEM products and accessories for other well know companies in the industry. In recent years, Calrad has gained recognition for its increased market share and their continued support to customers' needs. With its most recent partnership with Syllax, Inc. one of its OEM, e -Commerce distribution partners in new technologies and products, Calrad's product line with Syllax's strong Internet presence will provide further expansion of product support and awareness to a wider range of customers.
Calrad's corporate offices are located Los Angeles, California, with offices and manufacturing factories located in Taiwan and China.
For additional information on the AVES product or other company information, please go to the company web site at: www.calrad.com
V.P., R & D
323 -465 -2131
Copyright 1999 - 2003, A5tek Corp. All rights reserved. The A5tek Corp. and ieHIP, and ieHIP logo are trademarks of A5tek Corp. |
Whether you're hopping around throwing fireballs in Super Mario Bros or World of Warcraft, skills and abilities are at the core of gameplay. They define what we can do within the game, and how we do it.
Skills can take on a number of forms. Determining how successful they are is difficult, because the task is both subjective and case-sensitive. However, I believe that gameplay can be related to language. In a previous article, I suggest that since they are both forms of communication, they rely on clarity to be effective. This has led me to discover an objective metric which I believe is applicable to skills in most types of IDEs (Interactive Digital Entertainment): demarcation.
Demarcation: the clarity with which a skill's effects are separated from other elements of the game.
Good demarcation will increase the perceived effectiveness of a skill and make the gameplay far easier for the player to learn and master. As stated, this does not necessarily apply to every type of IDE or genre. For instance, the effects of "skills" in a simulation may not be immediately clear to the player if it will better resemble reality.
How to Achieve Clear Demarcation
There are primarily three qualities of a skill which determine its demarcation. They are time, multimedia feedback, and potency.
Timing is a key factor of demarcation. For single action skills, this can be as simple as a clear point of execution.
Things become more complicated, however, when duration is introduced. Duration is typical of skills such as "buffs" and area of effect attacks. A single skill may include several phases. For instance, a spell that summons a meteor may have a warning phase in which the targeted ground pulses red, a point of impact which deals direct, area of effect damage, and a burning phase, during which the struck ground continues to burn, dealing damage to any units who pass over it. Regardless of the number of phases in a skill, each phase should have a clear beginning and end.
A skill does not need to be executed the moment the player selects to trigger it, but the time of its execution must be easily predictable. In other words, it must happen when the player expects it to happen. This will increase the perceived responsiveness of the skill.
A good way to bridge the gap between selection and activation is through a cadence or rhythm, which can be established by audio and visual cues.
Players need some sort of feedback to even realize they're playing a game. The simplest form is likely text. But every word, sound, image, and haptic cue within a game is capable of conveying information to the player.
In order for a skill's cue to work well, it must be easily distinguished from other sounds and images contained within the game. It must be clear and identifiable. But most importantly, it should coincide with the phase of the skill that it represents as closely as possible. Cues can accentuate good beginning and end points or mask fuzzy ones, as may be required when dealing with net code
In addition to a skill's execution, sounds and visual cues may also represent the results of a skill. For instance, whenever a player scores a headshot in an FPS, it can trigger a sound to let them know they've hit their mark. This is typically a higher pitched tone to separate it from the lower pitched noise of a gun.
For the purposes of demarcation, graphics serve primarily as a form of communication. Developing a symbolic language within a game is important. Generally, games will adhere to established paradigms within their genres. Perhaps the simplest example of this is the color-coding of elemental spells in an RPG. Players should not only be able to identify skills with which they are familiar, they should be able to decipher a great deal of information about newly encountered skills from the way they look and sound. This level of order is essential for demarcation to be achieved when things get cluttered in a busy game.
A skill can have a clear beginning and end with excellent cues to represent each of its phases, but what does it do? You can achieve clear demarcation with just timing and feedback. For instance, you can create a skill that displays the damage generated by the next attack in much larger, bolder numbers. Players know they've used the skill, and yet it may do nothing relevant to the gameplay. However, if the attack were also to do extra damage, it would be set even further apart from the normal flow of the game. Therefore, potency is also a quality of demarcation -- and one which becomes increasingly important as the capacity for audio and visual cues diminishes.
How much potency is sufficient? If a player has to check for a little icon by their name to make sure a buff is active, it's probably not potent enough. Or another classic example: Power Swing adds 5 points of damage to a player's next attack, but her normal attack damage can vary from 10 - 20. She swing once, deals 18 damage, and use Power Swing, and deals 12 + 5 = 17 damage. Unless the skill is backed by strong multimedia feedback, the timing could be flawless, yet the skill would have very poor demarcation. And yet if it is accompanied by loud sounds and flashy graphics while proving ineffectual, the iconography in the game loses credibility.
Perhaps it would be more effective to slow a player's attack by a percentage and ensure they deal maximum damage so that Power Swing will always deal more than their normal attacks. If done correctly, this wouldn't affect the mathematical potency of the skill, yet it could increase its perceived potency.
A Gray Area
Unfortunately, in order to determine the pure "potency" of a skill, it must be compared to other similar skills and effects within the context of the game. Trying to determine the potency of a skill without a point of reference is typically not possible. Even then, there is more to potency than big numbers, as not all abilities simply deal damage. The more complex the skill, the harder its effectiveness is to judge.
Often times, creating a successful skill can become a balancing act between applicability and uniqueness. A skill will stand out more if it is unlike any other in the game and/or is not used often. Yet the effectiveness of the skill will seem greater if it is applicable in nearly any situation. How potent is a skill that holds an opponent in place? It's powerful in a race, but it's useless if the opponent wasn't planning on moving. Not only is this subjective, it's extremely case-sensitive.
Other Facets of Successful Skills
Clearly there's more that goes into making a successful skill than just demarcation.
Applicability - How often is the skill useful?
Creating highly specific skills may give the player too much to worry about and insufficient exposure to their given abilities.
Expediency - Does the skill fit the game and is the reasoning behind it sound?
It may seem crazy that an Italian plumber is suddenly spitting fireballs, but it fits the tone of the game and introduces a new dimension to gameplay.
Uniqueness - Is the skill different enough to stand out from others, and how often is it used?
The uniqueness of a skill can enhance its demarcation, but often comes at the expense of applicability. Still, it is quite possible to have a commonly used skill that is unlike any other in the game, particularly if the game only features a small set of skills.
Balance - Is the skill proportionately useful in comparison to other skills in the game?
This is particularly important in competitive games, whether they be multiplayer or single-player. For all the work you may put into a game, it can be eclipsed by a single skill or strategy if it unequivocally proves the most fruitful, as players are forced to employ it in order to maximize their efficiency.
Synergy - How does the skill interact and affect other skills?
This is a crucial question for developing complex gameplay. The synergy between two skills doesn't have to be explicitly stated by the game. For instance, simply jumping and spitting a fireball in Super Mario Bros. can be considered a form of a combo-skill. Without the cooperation between these two abilities, it may have been impossible for players to defeat certain enemies over obstacles.
I find that these are all fine questions to ask when creating skills, but I always consider its demarcation. What approach do you take to guarantee the quality of skills in your games? Or by what criteria do you judge skills to be successful? I would love to gain insight into other people's processes. |
Kits and Plans Synthesizers and Samplers Electronic Instruments
Top: Arts: Music: Instruments: Electronic: Synthesizers and Samplers: Kits and Plans
- Synthaholic's Electronic Music Site - PAiA Fatman mods, part substitution information, OTA tutorial.
- Littleman - A custom synth drawing from EFM and Paia synthesizers and samplers synthesizers and samplers designs.
- Magnus Danielson - Offers resources (books, schematics, companies, links) for the electronic DIY enthusiast.
- Jim Patchell's DIY Synth Page - A site dedicated to those who enjoy building their own electronic electronic musical instruments.
- Synthesizer Projects - Analog synthesizer DIY projects and modifications to vintage kits and plans kits and plans synthesizers.
- Juergen Haible - Home-built synthesizers, effects, schematics, and CDs of Juergen\'s music.
- Synthesis Technology - Source for CEM chips, MOTM modular sythesizer kits (and mods), electronic tips for DIYers, and Synergy refurb information.
- Ken Stone's Modular Synthesizer - Many unusual circuits for a modular synth. PCBs electronic for sale.
- Dave's Hot Rod MOTM Shop - Offers a source of mods for SynthTech MOTM modules.
- Synth'r'us - Original analog synthesizer schematics.
- SynthDIY.com - SynthDIY.com has been put online to gather ALL synthesizers and samplers kits and plans information about making your own musical instruments. The synthesizers and samplers kits and plans goal is to have all DIY / Mods synthesizers and samplers kits and plans / profit / nonprofit products on this site.
- DIY Freak - Synthesizer modules and some DSP stuff. Interesting MIDI controller using synthesizers and samplers a PIC.
- Bergfotron - Analog modular synthesizer plans and pictures in great kits and plans kits and plans detail.
- Grant Richters Synth-DIY page - Unusual signal modifiers/shapers with schematics.
- DIY Oakley Modular Synthesiser - Site dedicated to construction of a synthesiser based kits and plans synthesizers and samplers on Oakleysound modules
- Blacet Research - Analog synth kit manufacturer; many odd and useful synthesizers and samplers synthesizers and samplers FracRak-compatible modules.
- Chris's Synth DIY Page - Home of the Evenfall Minimodular and Chris\\' other kits and plans synth circuits.
MySQL - Cache Direct |
Out of what you listed I would chose the XP-10 for the ss choice nothing like system synergy IMO. Then either the ARC ref 3 or 17ls series II cj for the tubed units. The ARC has balanced outputs so that may present an advantage over the cj unit if that matters to you.
Nelson Pass has commented that either cj or ARC work well with his power amps; so take it from there. The ARC will be more analytical (ss) in its presentation whereas the cj will sound more like a tubed unit at least in my experience; both are great pre-amps.
Good Luck and Great Amp Choice by the way.
far not too many tube amps will be good with your amp and definitely not ARC of any model
you can try BAT VK51 or VK31SE, but using solid state preamp is encouraged. I'd choose Wyred4Sound for clarity and transperency.
I’m looking for a good synergy between pre-amp and power with correct output/input impedance matching.
How could anything be better than a Pass preamp?
Directly from the mouth of Nelson Pass.
"Our experience is no problems at all with the ARC or CJ products with regard to interface. The amp doesn't care about source impedance. It's actual input impedance is close to 0 ohms, and the input impedance spec comes from the resistors we put in series with that input. Adding a little more from the source doesn't create issues."
Tls49 I agree and the one I would go with if it were my decision.
If Mr Pass himself says the ARC and the CJ will be fine, thats good
information. Based on the criteria you list as desirable I'd select the CJ line
stage or the Leben(from your stated choices) as most likely to provide the
full body/tone you want(as well as excellent vocals and
soundstaging).Tube rolling will fine tune to your preference. I believe these
two will be more musically engaging and less analytical and dry.
I would guess the Pass preamp should be the best match, although there should be no problems with the others.
It might come down to what kind of sound you prefer. I would think the Pass will be accurate and clear, while the tube preamps would lend a more tube-like sound. Given that the XA 30.5 may already have a bit of this, you might not want to overdo it. Can you try them out in your system before deciding?
Given the somewhat low input impedance of the Pass amp, specified
as 20K single-ended and 30K balanced (those numbers having been essentially confirmed in John Atkinson's measurements
), I took a look at the output impedances of the tube preamps listed in the OP for potential incompatibilities.
It should be kept in mind that it is very common for tube preamps to have output impedances at deep bass frequencies that are much higher than their specified output impedances (which are typically at mid-range frequencies). That low frequency rise will occur due to the output coupling capacitor that is used in most (but not all) tube preamps, and will reach a maximum (within the audible range) at 20 Hz.
Chances are that with nearly all tube preamps that will not be of significance to you with your present speakers, because of their somewhat limited deep bass extension. However, it may become a significant factor if you later change speakers, or add a sub that is driven from the preamp's outputs.
Based on my research, I would rule out the Premier 17. From JA's measurements
The output impedance was below a lowish 800 ohms in the midband and above, but rose to 1.6k ohms at 20Hz, due to the presence of a finite-sized output coupling capacitor. The C-J should therefore be used with a power amplifier having an input impedance of at least 22k ohms if the bass is not to sound a little lean.
Also, the Leben preamp models shown at their website (RS38CX, RS-100, and RS-100U) all have specified output impedances in the vicinity of 600 ohms. I couldn't find any data indicating their 20 Hz output impedance, but the 600 ohm figure is high enough to suggest caution. If you want to consider those models, I would ask the manufacturer what their output impedance is at 20 Hz.
Also, the ARC datasheets for all of their models which are listed in the OP recommend a minimum load of 20K (although without indicating whether that applies to their unbalanced outputs, their balanced outputs, or both). So you should be ok with any of those models, but without a great deal of margin.
Regarding the statement by Mr. Pass that is quoted above, while I certainly would not question any statement he might make, when he says "the amp doesn't care about source impedance" I would point out that that does not necessarily mean that the preamp doesn't care about load impedance.
Again it was a direct quote form the designer (Nelson
Pass)concerning tubed pre-amp choices and their ability to
work well with his XA series of amps. I am sure he knows a
fair amount about the amps he designs and their ability to
mate up with other manufacturers tubed pre-amps.
And as far as system synergy goes the best match with a Pass
amp is a Pass Pre-Amp. I suspect any designer is going to
use his own products to optimize their synergies together.
When you say you have "settled" on a 30.5, do you already have it or are you going to be getting it?
In any event, I have a 30.5 and 100.5's and use CJ tube preamps with them. Perfect for me. I didn't feel that they "needed" a tube pre, just that those gave me the sound I enjoy the most.
I did audition a XP20 and liked it a bunch. I don't see how you could go wrong with the 10 especially if you have to buy blind (is "deaf" a better word? smile).
If you do go tube, the length and capacitance of the interconnects should be taken into account.
Tube or ss, I think you're going to have a great system. Good luck.
Did you prefer the Pass preamp over your CJ pre? There's really no guarantee the OP will like the Pass pre more simply because it is the same brand as the amplifier. Depending on the listener's taste and goals,another brand could be a better fit sonically. There's only one way to determine which is preferable and that requires listening.
Thanks everyone for your feedbacks and suggestions. It's been very educational and informative. I'll surely consider the impedance matching when I search the pre-amp.
Meanwhile, for those who have experience listening the various pre-amps (i.e. XP10, Audio Research, CJ, Leben, etc)with Pass Labs XA30.5 or other XA.5, how would you characterize the different sound each pre-amp presents?
As Al stated, impedance matching is always a concern when connecting tube preamps to solid state amps. Thanks to JA for providing the real output impedance for the preamps reviewed in Stereophile.
For comparison consider the input impedance of Pass solid state amps and Balanced Audio Technology solid state amps. Note that BAT makes tubed preamps.
It'll take an atypical tube preamp to work well with Pass amps.
Here's a review for the Pass XP-10 and XA60.5. It gives you an excellent description of their sound, separately and together.http://enjoythemusic.com/superioraudio/equipment/0712/pass_labs_xp_10_xa_60_5.htm
It's very easy to understand why the reviewer says what he does, just from my experience with other Pass equipment.
What is an atypical preamp?
And gives credence to the fact that designers design their
equipment to work together and why for best performance and
system synergy it is best to stay within the same brand.
Hence pass labs amp with pass labs preamp. Especially if
buying deaf; so eloquently stated above. Reno hi-fi offers a
free 10 day trial, all you pay is shipping to and fro if you
don't like it; can't beat that.
I have been using a Thor TA-1000 mk2 with my XA30.5 (upgraded from Aleph 5) for over three years now and I am very happy with the combination. The Thor is 400 ohm and I connect single ended. Highly recommend this combination. I also have a passive preamp that I also substitute at times. My experience concurs with Nelson that any reasonable preamp will probably work.
I'm using a Modwright LS36.5 with my XA30.5 and have enjoyed it greatly. I had the Modwright 9.0SE prior...something about that MW tube preamp sound that does it for me. Might be worth a listen if possible.
The Reno Audio trial option of the Pass seems a good move, you may or may not necessarily prefer this same brand sound.I know people who have ARC amps but prefer non ARC line stages. People use Shindo preamps with non Shindo power amps.It all about what sound you want and this could certainly differ from what the designer voiced to his own taste.What if you simply hear differently?
Chuck, An atypical *tube* preamp is one that has a low worst case output impedance so it can be used effectively with either tubed or solid state amps.
Understand Thanks just never heard it described that way .
I preferred my CJ (ART 2). I did tell Mark at Reno "If tubes ever start giving more trouble than their worth, I will just send you a check". Haven't heard the XP30 since it debuted but would imagine it could close the gap even more.
Agree with you, no guarantees. My rec was if he had to buy "deaf", as I so eloquently put it (thanks Czbbcl). It's just a comfort zone being from the same brand especially if that brand has Nelson Pass behind it.
I think most philes will end up with different brands. You have done extremely well with your same brand pair. It's not often a manufacturer makes a world class amp AND preamp. They seem to excel at one or the other even though they may make a decent attempt at the other.
RO817, to your last question:
My particular tube pres (CJ ARTs and ACT 2.2) seem to give me more harmonics and in their natural order than the different ss ones I've tried but the XP20 was certainly one of the better ones. Gather as much info as you can but it will eventually come down to your ears and preferences.
Your success with and preference for the CJ over the Pass line stage makes my simple point, at some point you just have to listen.
The value I do see in forum advice (if it's not agenda driven or heavily biased) is that sometimes you can't listen before you buy so you gather as much info as you can (hopefully from people like yourself) and take your best shot.
I've used this phrase/formula before but I think it's time to mention it again:
Hypothetically: If 100 people heard my system while alternating between a ss and tube preamp, 95% may prefer the tube pre but you might be one of the 5% that prefer the ss.
95% doesn't make it right, your ears make it right. BUT if you can't listen first it's probably safest to go with the odds.
Onemug have you heard the ET-5 ? I also enjoy the sound of cj pre-amps and feel they make one of the best sounding pre amps in the business. I would go with one of their tube amps but not sure I want to deal with power tubes especially given how good the Pass XA series sound.
Haven't heard the ET-5. I would guess it's pretty nice. I sure like mine paired with the XA's.
What amp do you have ?
I have been looking at a pair of LP140M's .
ET-5 vs ET-3SE vs CT-5
Anyone has experience comparing the ET-5 with ET-3 SE? The ET-3SE uses only one tube.
How about the ET-5 vs CT-5? Fundamentally different in sound? Thanks.
I believe the ET-5 uses one vacuum tube as well. Tone audio did a nice review of the ET-5. Basically saying it had 90% of the sound of the GAT for half the price.
Sorry I think you have have the XA 100.5's correct? Great amps by the way. I am looking at the Pass XP-20 pre-amp or the cj ET-5 to pait with a pair of XA100.5 or 60.5's. I am sure they will both sound very good. The Pass would fit in my Rack better .
I owned the XA30.5 for a short time. Just for sale. I used it with the XP-20. I was amazed how good this combo could play togheter. I owned the XA-100.5 before. With the XP-20 had the same stunning stage. I tested some Ayre in the past. There is a big difference in depth and stage wide as well. Pass labs makes the stage wider and deeper. I would not even want a pre-amp for free when my stage would become less wide and deep. Ayre had a less deep and wide stage. For the people who want a big and deep stage this would be a no go. With Tube you also will have a wide and deep stage. Wenn you prefer a more warm sound you can choose for tube. Wenn you want more precision I would go for a XP-10.
Correct on the 100.5. I got the 30.5 first and still use it in another system from time to time.
ET-5 or XP20...that would be a tough call. Is there something in the sound of your system that you want more of (or less of)?
First post here, hope it works.
I use a Pass X1 with my XA30.5, the combination was awesome. I'm sure the XP10 would sound even better.
I need a pre-amp as I sold my Cary Tubed Integrated and it looks like I am going with either the 100.5's or 60,5's. How does the 30.5 compare to the 100.5's. I am sure the 100's are better but how much better.
I even thought of trying an XA30.5 paired with an XP-20 as my speakers Focal 1007 Monitors are pretty efficient. Although I did try an INT30A and thought it was a bit light on power but it did sound great.
I don't know why the larger Pass amplifier should sound any better.It has more power to drive speakers with a difficult load and are more demanding of current. With the appropriate speakers the smaller Pass should sound as good at the very least.
I had the 30.5, 60.5 and 100.5. Even with the same speaker you will hear the difference with ease. There is a big difference in quality. The 100.5 has a lot more drive and resolution. Even with a small speaker you can hear the difference with ease. It is more precise. Cause of the precision you will get a more 3D image. There is even a difference in musicallity. To be honest the 100.5 I found a lot better than the 60.5. The difference between the 60.5 and 30.5 is noticeble easilly. But the 100.5 is more musical in sound and more precise. I prefer the 250.5 over the 60.5 as well. The integrated amps Pass makes I found not that convincing as there Poweramps and pre-amps.
I have read and talked to Pass and I understand there is an improvement as you move up the line and just not more power.
hi, I own a xa-30.5 and wondered if there are other users that could comment on the banana plug binding posts...although the connections are snug and secure, there is just not enough depth for the plugs to be completely inserted...sounds great, but it's the only amp I've ever owned where the banana plugs are not 100% inserted
I just checked my 30.5. The tips of my bananas are 3/4" long and I can insert them all the way. They possibly could go in even farther. I also tried some old Monster Cable bananas and a Radio Shack dual banana and they all went in all the way.
How long are the ones you are trying to insert?
btw, the 30.5 comes new with plastic inserts to keep people in "some' foreign countries from plugging their a/c into them. Did you get your 30.5 new and are you in the USA?
I've tried both SS and tube preamps with my X250.5 and I believe I prefer the solid state for the better bass quality. The x250.5 does bass so well that it's a shame to not have a preamp that can do it justice in this department. Depends on your musical preferences however.
And about speaker binding posts on the Pass Labs amps: use spades not banana plugs. Pass amps are not really designed to be used with bananas.
I owned the XP-20 for 2 years. I did a lot of tests in the last 2,5 years with Audyssey Pro. Now with a Onkyo PR-SC5509 with my way of Audyssey Pro measurement it is a lot better with my Pass Labs x250.5 in every aspect. Even wenn I play extrem loud the needle is less moving then witht the XP-20. The stage is wider and deeper. Individual focus is superior to the XP-20. articulation of voices is also superior to what I had with the XP-20. I have to admitt that my way of measurement is totally different than what Audyssey does. Without this, it would be inferior to the XP-20.
Happy Thanksgiving! I just want to report back what I settled with for pre-amp.
I picked up a Ayre K-1xe, which has a separate power supply. It's very natrual and neutral sounding pre-amp with excellent resolution and detail. Great synergy with my Pass Labs XA30.5 as well. Another advantage is that I use balanced XLR between them. Recently, I acquired a Audio Research CD7 tube CD player - a very musical and involving player indeed.
Now I'm re-discovering every and each of my CD collections. Let me tell you this - the front end, both the CD player and pre-amp made a tremendous difference in performance in my system.
Thanks for again for your input. |
Don’t Expect a Disney Animated Movie Set in the Marvel Cinematic Universe Any Time Soon
When it was first announced that Disney was purchasing Marvel, the minds of many fans leapt immediately to the possibility of a Disney-Pixar animated Marvel movie. We’re sorta getting that in November with ‘Big Hero 6‘ but as that movie approaches, it’s become very clear that it’s not really much of Marvel movie at all, other than being loosely based on the obscure 90s comic. What fans really want to know is if we’ll ever see a Disney or Pixar animated movie in the Marvel Cinematic Universe. John Lasseter, who runs both Disney Animation and Pixar, has your answer: no.
When asked by Vulture if he or anyone on his team had ever had talks with Marvel about collaborating on a project, Lasseter answered bluntly, “No, we haven’t.” And, it’s this next quote that makes us think those talks will never happen either. “If we went directly into the Marvel Universe, that would mean we’d work more directly with Marvel,” as if that were a bad thing.
Now, Lasseter didn’t expressly say that would be a bad thing, but let’s be honest: Marvel had a hard time collaborating with Edgar Wright on ‘Ant-Man’. We can’t imagine they’d be willing to give themselves over creatively to Disney Animation or Pixar just because they’re owned by the same parent corporation. Feige recently told AICN, “We’d never give a director final cut, just as a matter of policy…The whole purpose of becoming our own studio was to be able to make the decisions; this studio was founded on having creative say.” If they’re not going to give an outside director final cut, we can’t imagine they’d afford that level of control over to Pixar either.
And, frankly, that’s the way Disney wants it to. Lasseter was quick to add that ‘Big Hero 6′, while being “inspired” by a Marvel comic, “without question, was made 100 percent here.”
Pixar and Marvel are both strong creative forces, neither of which would be willing to budge much to the others whims. And, frankly, that’s OK. Corporate synergy is great, but not everything needs to crossover with everything else. |
Synergy:PANIC! is the oldest image manipulation project on SITO. So old, in fact, that it pre-dates the web!
PANIC! is a spontaneous, free-form, free-for-all image jam. PANIC is driven by the players, they make the rules, they trade images and babble and bicker. PANIC! is chaos.
In a nutshell, PANIC! gives players a place to exchange images, and not much more. File naming rules are basically this: tack your name to the end of the file name you modified. This should be done automatically if you are a logged in SITO user. That's about it!
Traditionally, PANICers used IRC (Internet Relay Chat) to provide a real-time forum to talk while panicing. We encourage exploring other communication methods including (but not limited to): video chat, cell phones, tin cans with strings, shouting really loud across cubicles and/or cities, etc. |
HighVolMusic is pleased to announce that RADIO EXILE has signed on with the label for release of their self titled debut.
In the post era of the FM dominated airwaves comes a new generation of classic rock, RADIO EXILE.
On rare occasions, some magical-artistic vibe goes out calling up a unique set of musicians to create groundbreaking music. When truly great musicians come together, the resulting brotherhood/sisterhood embraces their diversity, enabling them to collaborate so as to push through otherwise insurmountable boundaries. Collaboratively, they each pour the very best of what makes them cutting edge individually, into one dynamic presentation. For the rest of us, we are compelled to listen over and over.
RADIO EXILE features Chandler Mogel / Lead and Backing Vocals, Charlie Calv / Piano, Keyboards, Jimmy Leahey / Guitars, Backing Vocals, Kenny Aaronson / Bass, and Dave Anthony / Drums, Percussion, Backing Vocals. Individually, these musicians that come together to form RADIO EXILE have perform on stage or in the studio with the greatest artists of our time. This list includes Paul McCartney, Bob Dylan, Hall and Oates, Allison Krauss, Billy Idol, John Waite, members of Pink Floyd, Styx, Journey, Van Halen, the Rolling Stones, and Black Sabbath. This talent pool has been tapped, used, and appreciated over the years. Now, together as one, five brilliantly successful, creative worlds collide in a panoramic musical explosion.
Enlisting Grammy-nominated engineer/producer Steve DeAcutis (Vanilla Fudge, Cyndi Lauper, Corey Glover) and veteran producer/A&R man Steve Lunt (Britney Spears, ‘NSync , Joan Jett), the guys checked into the SPA (Sound Spa Recording) and an immediate synergy took hold. The finishing touches were then added by top mastering engineer Alan Douches (Fleetwood Mac, Yes, Train, Pete Townsend) at his West West Side Music facility.
The RADIO EXILE debut is set for a November release via HighVolMusic and will be available as a special-limited edition E.P. combo package. Additionally, HVM is putting a deal together with a Japanese partner to make the full length release available as an import. A European version will also be available via AOR Heaven/Cargo.
“Charlie Calv and I go back a ways to the old Chavis Records days. We had not seen each other for years and wouldn’t you know it, we run into each other at last years Rock N’ Skull festival. Naturally we stayed in touch and when he presented the RE project to me I was blown away! It’s fresh, new, not outdated and I am a big fan of Chandler Mogul’s work. Every musician in this project is magnificent! Of course I said let’s make it happen! I am honored to have been asked and to be part of the Radio Exile team. We’ve added another component of real rock music to continue the diverse portfolio of artists we have at HighVolMusic.” – Bill Chavis, CEO, HighVolMusic
LONG LIVE RADIO EXILE. |
Some of the comments your readers had after our first set of questions were great and I feel they deserve a proper response. I wish I could respond to everyone but you have such a great following on Raptors Republic that I think I’d be writing until well after the draft
Keep in mind I was trying to issue a relatively short answer to a specific question regarding the Raptors drafting a SG or SF at the #9 spot in the draft. Perhaps I should have started the conversation by saying the first thing that needs to be done is a compilation of the pre-draft assets the Raps have to work with this year. For example, the Portland Trail Blazers have these tools to work with: 5 draft picks (24, 32, 38, 55, and 56), approximately $6.5 Million under the salary cap (which is a number that won’t be exact until the NBA calculates the exact cap figure based on this year’s revenue), a $3 Million Trade Exception (from a trade at the deadline), plus they own the rights to a couple young guys playing in Europe right now.
Secondly, the Raptors need to decide what they’ll do in Free-Agency, how much money they have to work with and who they’ll try to resign off their current roster. Finally, a decision should be made (and probably has been) as to the direction of the team. One of your readers commented that he wanted to take DeMar DeRozan because in the long run he’d be the best player and one argument I had made was to trade down and take a more mature player who could contribute now (Sam Young, Terrance Williams, Gerald Henderson). There are a few things to consider here, first, rookie contracts usually only last 3-4 years so to wait for a guy to come along means the direction you are taking is ‘player development and cost saving’ in that you most likely won’t spend a lot in free agency trying to make a run for the playoffs. If you are like the Blazers coming off 50 plus wins, you are seeing your window of opportunity now and thus feel spending money gives you a chance to win. Aiming for the achievement of your goals now rather than player development for future success. Veteran FA’s worth any considerable value are not going to sign with a club that is developing a young roster. Look at Memphis and Oklahoma City, young talent that is not winning regularly versus the Boston Celtics who went out and got veteran FA’s by working the cap and draft picks to come up with assets to win now.
Finally, another reader mentioned the idea of trading up. I also mentioned this with respect to James Harden if he is your guy. I don’t have any problems with this either IF you feel strongly that Harden is your guy and you have the ability (assets) to make it happen such as multiple 2nd Rd. picks to unload. There have been considerable rumors that 2, 3, 4 could move because after Blake Griffin it is somewhat wide open. Perhaps the Raps see that window and make a move. However, until we know what assets the Raptors have to work with and the direction they want to take the franchise then it’s going to be difficult to get a good gauge on what they will do.
A few random notes from the combine and recent team workouts:
- One Raptor fan liked Tyreke Evans for his length and thus his ‘potential defensive ability’, which is outstanding. But potential is a scary word sometimes and it should be noted that he had the slowest feet in the agility test which is a good measurable for defensive potential as well. Can you see now why I’m not a huge fan of these ‘combine stats’?
- A lot has been made of DeRozan’s superior athleticism but if you look at those infamous ‘combine stats’ you’ll see that he has one great mark when compared to the Small Forwards, his max vertical leap (with steps = 38.5″ the same as Chase Budinger). However, because he has short arms he falls to 9th of 11 SF’s in jump reach nearly 5 inches below James Johnson or Damion James. Worse yet, the only player he beat in the footwork and speed tests was 6’11 Austin Daye. And if he had been compared to the SG group, DeRozan would have been dead last in both categories out of 16 guys. His 11.88 agility score would have been .3 tenths of a second slower than 15 other SG’s and 1.4 seconds slower than the fastest SG. Short arms and slow feet, who will he be guarding? Just some food for thought.
- Sam Young participated in a recent NBA group workout and dominated according to sources.
- Another guy I mentioned in the last post was Ohio State big man BJ Mullens. Apparently both he and Austin Daye (Gonzaga) looked great in ‘camp drills’ in Chicago because they didn’t have to play 5-on-5, but both have struggled in workouts against physical defense. Mullens just played in Minnesota and was abused by Luke Neville (an Aussie from the University of Utah) who many say won’t be drafted. And yet Mullens is coming out of school early and a projected lottery pick? On a positive note, the 7’1 260 big man did post a ‘quicker’ time than DeRozan in the agility drill.
Q. Are there any differences from scouting via Video/TV as opposed to live?
A. Pro’s and con’s to both I’m sure. In live situations you definitely get a good feel for the guy physically, what his body is like, his true height and so forth. You can also see his attitude and leadership abilities up close. How he reacts to calls, opposing fans, his coaches, and his teammates. On film, such as Synergy Video, you can see so much footage that you can really get a feel for what the guy does best, what his favorite moves are, and also what some of his weaknesses are because you could potentially watch every shot he took this season. One thing you always have to be careful of, especially in a combine style workout or a closed workout session is falling in love with a prospect based on that one day. See him live as much as possible and then study as much video as you can.
Q. Who will be available at 9? Who will be the best available player at 9?
A. It’s still too early to tell at this point but I think there will be some good players available at this spot. Keep in mind, last year some guys made very late surges into the lottery such as Russell Westbrook climbing to the 4th spot (OKC), Joe Alexander went 8th (Bucks), and Jason Thompson from Rider 12th (Kings). Anthony Randolph went 14th to the Warriors after being rumored in the top 5 then slipping on some boards to late-first. The point being, decisions are still being made and there are a lot of young guys on the draft board as well as the possibility of guys returning to school. We’ll also learn more about the international guys after the upcoming Euro Camp in Treviso, Italy. Remember that Danilo Gallinari shot up to 6th last year to the NY Knicks. This is something we’ll cover more in the coming weeks.
Q. Is Blake Griffin more a Beasley or Duncan?
A. I don’t think he’s like either one to be honest. He’s 2 inches and 12 pounds bigger than Beasley but not as long or skilled (at least now) as Tim Duncan. He is a true Power Forward in the ‘power’ sense. He is strong, explosive, aggressive, and very quick for his size. He is much more athletic than Duncan but will he develop the head for the game that Duncan has? Beasley is more of a face-up guy and I think Griffin will be a solid post-up option as well as a good pick & roll guy and he can run the floor well also. I’m not putting him in the Hall of Fame just yet but he does have some Karl Malone like features.
Q. Who is the next best player in the Draft?
A. The million dollar question, literally. Again, based on results or potential? I like Ricky Rubio and James Harden a lot. I get why people like Hasheem Thabeet with his obvious size and length, but I’m not a huge fan. So if you are the Memphis Grizzlies and you have Mike Conley and OJ Mayo, do you pick Rubio or Harden or trade down? Perhaps they like Thabeet and go that route. I’m a proponent of picking a guy if you feel strongly about him at that spot, if not, trade down and stockpile players and picks. This may the year to do just that.
Q. Who’s your favorite (sentimental) player in the Draft?
A. As you know, I like international players and REALLY like what the Colangelo’s did in Phoenix bringing in Mike D’Antoni, Steve Nash, and that style of play. So needless to say I’m a Rubio fan and look forward to seeing how that situation plays out. You’ve probably read some of the latest rumblings that he’s willing to stay another year in Spain if he’s not a top 3 pick and I think a lot of that is the negotiations taking place with his Agent and Club (Joventut).
From a basketball standpoint I like his leadership skills for such a young guy, he’s very competitive, has good hand skills and vision and is better athletically than he gets credit for. He is a very good defender and has long arms. He does need to work on his shooting and range, but that should develop with time. A lot of guys from that Spanish team have come to the NBA and done well so I see no reason why he wouldn’t do the same.
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Get your Morning Coffee |
By: Garin Kilpatrick
Successful social networking on Twitter involves actively creating stronger connections with your followers, and avoid networking mistakes so you can sidestep pointless conflicts.
Of course it’s important to grow your Twitter network and actively apply tips that help you get more Twitter followers but once you have those followers it’s important to be cool with them and share valuable stuff.
If you don’t plan on recognizing and communicating with your followers then there is a good chance they won’t stick around.
In this article I dive into ways to create deeper ties within your Twitter network. These tips have helped my network strengthen significantly since I started on Twitter in 2008.
(1) Recognize People who Share Your Content
It gets harder to recognize everyone who re-tweets you as your network grows but the more you can do it the better.
A simple “thanks!” goes a long way.
Another smart Twitter networking strategy is to return the RT favor by retweeting the people who re-tweet you.
The more you encourage and appreciate people who help you, the more likely they will be to help you again!
(2) Introduce People
Recognize a synergy in your network? Introduce your followers to each other when it makes sense to do so and if a friendship grows from the introduction then you are the person to thank.
When trying to decide who you want to introduce on Twitter consider the following things your followers may have in common:
- Location (ie: they live in the same city)
- Industry (ie: they have similar jobs)
- Interests (ie: they all like pie, for example).
(3) RT Influencers to Get on Their Radar
A great way to get on the radar of influential people you want to associate with is by re-tweeting their content.
If the influencer you are trying to reach has a sizable network then they will be getting RT’s all of the time and it might take several tweets to make an impression.
Be persistent and there is a good chance it will pay off!
(4) Follow up With People who Follow You
This one gets harder to stay on top of as your network grows more rapidly.
Nonetheless if you make a habit of going through your list of followers and following back relevant people this can be a smart way to retain your followers since many people only follow in hopes of creating a mutual connection.
(5) Don’t Use a Canned Message for New Twitter Followers
Quite often I get mentions from people thanking me for connecting and when I find that the person has sent the same message to 20 other people it evaporates any meaning that message might of had for me.
Here are some ideas of what not to tweet:
“Hi thanks for following!”
“#Shoutout to my new follower…”
Personally I never respond to tweets like these, and often unfollow people who send them. Maybe that’s rude but it’s the truth. I’m not a “follower” and I take offence to the term, even though there is probably none intended. I’m guessing there are other people out there who have a problem with being called a follower too so I recommend finding another method of introduction instead.
If you want to thank someone for connecting the best way to do this is with a RT or a personalized message. A personalized custom response that speaks to a persons interests will be far more effective than any insincere “copy and paste” canned message.
(6) Open Another Twitter Account
If you have a business or brand Twitter account and that is all you use it makes sense to create a second account so you can build your personal brand.
(7) Use Lists
Check out the Twitter lists directory Listorious to discover Twitter Lists that interest you.
The best way to create a list that interests you is to create your own lists and include the accounts you want to hear from the most.
If you follow lists you create, rather than your main news feed, you can still create beneficial connections with others, even when their tweets do not interest you.
(8) Use Old Style RTs
An old style RT is when you type “RT @Username:” before the tweet.
— Keren Lerner (@topleftdesign) January 21, 2013
These can get you better results than the new style one click RT since they show up in the mentions inbox of the person you RT so there is a better chance they will realize you retweeted them and show appreciation.
(9) Don’t Bleed the Feed
The more often you post the more this dilutes the meaning of each post.
There are millions of tweets a day so if you do post several times that’s alright, but if you are spamming the news feed with constant posts there is a good chance that this will cause several people to unfollow you.
Keep your tweet content quality high. If you have high quality content then it is more acceptable to post more often.
(10) Don’t be a Robot – Use a friendly, conversational tone.
You are not a robot – so don’t tweet like one.
If all you do is post links and quotes you’re doing it wrong.
Spark conversations. Ask and answer questions. Get to know new people.
There is no limit to the value you can create with your connections and conversations.
(11) Recommend People to Follow on #FollowFriday
On Friday what I do when I have time to make #FollowFriday recommendations is scroll back through the mentions I got throughout the week and pick out people who left the best impression.
Quite often people you recommend for #FollowFriday will return the favor by recommending you or re-tweeting you in the future.
(12) Use Social Networking Software
There are two Twitter apps that I use on a daily basis. The first is Hootsuite, which I use to send the majority of my tweets since I can send them to multiple networks on Twitter, Facebook, and LinkedIn plus I can schedule my messages to go out at the optimal time.
Another piece of Twitter software I use daily is TweetAdder. TweetAdder is software that enables you to initiate hundreds of targeted Twitter connections daily. Using TweetAdder you can connect with people based on keywords in their bio, lists they are on, keywords they have recently tweeted, and several other methods. If you want to a continually growing Twitter network TweetAdder is a must.
(13) Hack Your Bio
The most visible elements of your Twitter profile are your bio and profile pic.
An interesting fact about Twitter bios is that if you include a second (or third) link in the description section of your bio that link will be active as well!
Every so often I re-write my bio to keep things interesting and for now I have 2 extra active links in my bio.
Optimize Your Profile Pic
Your profile picture sends a strong message about you since this is the image people see beside all your tweets.
The best way to go in my opinion is with a smiling head shot. This will help the people you tweet with recognize you if you meet up in person.
Personalize your profile as much as possible. There are plenty of robotic accounts and personalization shows that you are real.
Logos do make the most sense in some situations and if you manage one of these accounts I recommend you mention your personal account in the bio. When a Twitter account is mentioned in a bio this creates an active link.
Below you can see the bio strategy I use for my social media marketing news feed @social_focus.
(14) Lead Before You Follow
Social proof is a powerful element of online influence and on Twitter it is demonstrated by being followed by more people than you follow.
If you have plenty of followers then no matter what niche you are in you will be seen as an expert.
Due to the social proof that I have because of my followers I have been able to create many great business connections and get sales on a daily basis.
The first few thousand followers you get on Twitter are the hardest to get, and once you have them growing your Twitter network becomes much easier. For this reason I recommend using the service Grow my Twitter Network to turbo-boost your social proof out of the gate!
(15) Tweet on the Regular
When someone discovers your Twitter profile page if you have not tweeted in a week there is a good chance that they will not follow you. If you are inactive for 30 days or more free tools like Manage Twitter make it very easy for people to unfollow inactive accounts.
Tweeting every day shows that you are alive and actively communicating with your network. If someone comes across your Twitter profile and you have already tweeted that day there that much greater chance they will follow you!
Keep it Real
Everyone is different so different strategies will work for different people. Keep tweeting and testing new tactics and I’m sure you’ll discover what works best for you!
Can you think of a social networking Twitter tip not mentioned in this article? Let us know in the comments below!
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In a perfect synergy of British pomp and majestic heritage, prestige, and tarmac-tearing muscle, the 2013 Jaguar XKR-S is one of those automobiles that everybody loves. It literally has the ability to make you new friends.
The Jag XK is a nameplate that has been etched into the fabric of Jaguar’s – and Britain’s – genes for over 60 years. Stemming from the original XK 120 of 1949, the model has a rich and much-loved history not only in automotive craftsmanship, but also in performance motoring and motorsport pedigree.
For Jaguar, the XK 120 was its first ever ‘mainstream’ production sports car. It set various high speed records in its day, including holding 130mph (209km/h) for an hour at a banked oval circuit in France in 1951.
The XK is still the company’s main sports car, but these days it’s more of a grand touring model, leaving room for the just-launched, smaller and lighter F-Type.
There are four main iterations of the current XK, including the coupe and convertible versions, and the XKR, which is like a Red Savana habanero chilli on the Scoville scale. And then you have this, the XKR-S, which is the full two-million heat-unit Trinidad Moruga Scorpion chilli – you tend to need a sit down and a drink of water after sampling it.
Prices start at the serious end of the super sports car market segment, kicking off at $299,000, without options or on-road costs.
2013 Jaguar XKR-S – THE SPECS
Engine: 5.0-litre supercharged V8
Output: 405kW@6000-6500rpm / 680Nm@2500-5500rpm
Transmission: Six-speed automatic
Drive type: Rear-wheel drive, active LSD
Wheels: F: 20×9.0, 255/35 R: 20×10.5, 295/30 (optional)
ANCAP: Not tested
Kerb weight: 1753kg
Power-to-weight: 4.3:1 (kg:kw)
Official fuel economy: 12.3L/100km
Economy during test: 15.2L/100km
Fuel capacity/Type: 71L/91 RON minimum
Power efficiency: 32.9kW:L/100km
0-100km/h as tested: 4.1 seconds
Priced from: $299,000 ($309,310 as tested)
2013 Jaguar XKR-S – THE PACKAGE
The cabin is relaxed yet dramatic enough to instantly reassure you that you’ve just bought a very special and potentially heart-palpitating piece of machinery.
You sit very low and long in the luscious sports bucket seat, which can be adjusted in what seems like an infinite number of ways, with the dash perched up and flat and the steering wheel right at your chest. It’s a spot-on driving position and one that makes you feel at ease and comforted, even as you anticipate firing up that crackling V8 engine.
There’s no point in trying to squeeze individuals into the rear seats. You’re best off simply calling them a taxi. There’s no other way to put it, they’re shelves. Soft shelves with seat belts. Part of the reason they are there is likely down to legislative and factory design privileges given to four-seat cars.
As you look out over the long lustrous bonnet, with its real bonnet vents ready to let out the spine-chilling sounds of the supercharger, you’ll probably want to get back out again to take another look at the sexy exterior.
It’s as steamy as Chris Isaak’s Wicked Game film clip, with mouth-watering carbon fibre flares and spoilers front and rear, and amorously curvacious rear haunches, not to mention the big bulging 20-inch optional gloss black Vulcan alloy wheels which are wrapped in 295/30s on the rear, and 255/35s on the front.
If you’re planning a weekend away, in the back the cargo space is capacious enough to swallow a couple of large luggage bags and a set of golf sticks. The flat floor features metal strips, which not only give the boot some theatre, they also protect the floor from being carved up over years of wear and tear.
Standard infotainment for the XKR-S consists of Jaguar’s touch-screen LCD multimedia interface which is paired with a powerful 16-speaker stereo system. Audio is clear and loud, and supports MP3, USB and Bluetooth playback, of course.
The interface itself does seem a bit clunky to operate, sometimes requiring multiple touches to navigate around to various common menus. It would be nicer with a remote joystick-type controller on the centre console. Having this though would ruin the clean surfaces and clutter-free approach that Jags are renowned for.
It’s all really well made, with lots of chrome and stainless steel, including that gear lever which rises up from within the console like something out of a James Bond flick. It’s spectacular, and adds a real sense of occasion to the whole interior during ignition.
This test vehicle is fitted with a number of tantalising, and not-so tantalising options. We get the heated suedecloth steering wheel, although quite expensive at $1710, it’s lovely to grasp and especially comforting during cold early morning starts. Adaptive headlights which bend with corners are also very handy ($2100), but really should come standard on a vehicle of this stature.
The 20-inch alloy wheels are a must, setting you back $1700, while the carbon fibre engine cover ($3700) is perfect for impressing your friends, but unless you’re running out of things to spend money on, it doesn’t actually do anything. Lastly, a tyre pressure monitor ($1100) is great if you’re planning on spending some time on the track.
As for safety, ANCAP, thankfully, hasn’t crashed one of these pristine beasts into a wall for testing purposes, so a rating hasn’t been given. It does come with an active electronic differential which does a wonderful job of sorting out the torque between the rear wheels, as well as four airbags, and switchable stability and traction control.
2013 Jaguar XKR-S – THE DRIVE
If you’re not used to high-powered vehicles, you’re likely to wet your pants if you flippantly nail the throttle in this. It’s one of those cars that requires dedication and a certain level of delicacy, not to mention determination, if you want to get the most out of it. It can be touchy, relentless, and mind-blowingly quick if you want it to be. Ideally, a racing circuit is the place to be.
The power comes on very strong, and if you have it in the sportiest ‘Dynamic’ mode setting, very loud. It sounds like a NASCAR on the outside, yet, somehow, Jaguar has done a fantastic job of keeping the cabin well-insulated so you can still enjoy a highway cruise.
It’s refined and rigid on the highway, and gathers speed with the slightest of throttle input. Thanks to the supercharger system, there is zero lag, with instant, savage acceleration available at your right foot.
The driveline is well-matched to cope with the onslaught of that mighty engine too. It feels connected and engaged, directly transferring torque to the rear wheels. It’s then divided up by an electronic active differential.
We know what you’re thinking, ‘one of those electro diffs that brakes the inside wheel’. Fortunately, it’s not one of those diffs. To us, it behaves just like a proper limited-slip differential, with no inside wheelspin slipping through, and plenty of opposite-lock foolery on offer.
Through the gears, on a private road we timed 0-200km/h in 13.1 seconds, which is astonishingly quick and a compliment to the XK heritage. 0-100km/h comes up in just 4.1 seconds.
Handling the big cat does require some getting used to, simply taking in the sheer size of the thing. Nonetheless, the steering is extremely quick off centre. It darts down twisty mountain roads like a much smaller and much more agile sports car, despite feeling a bit heavy, and it changes direction with minimal body roll. On the highway, the steering remains weighted and planted.
In Dynamic mode, the suspension is at its firmest. It can become fidgety in the city, especially on poor roads, however, it does well to soak up undulating surfaces and dips and bumps when you’re out on your favourite winding road. It’s reassuring and confident, despite all of the bells and whistles under the bonnet making a frantic scene.
It’s a fairly heavy car, at 1753kg, even so, the taught suspension does manage to eliminate any sign of ‘boatiness’ that might otherwise be existent.
Jumping onto the brakes at speed is like being on a theme park ride. Massive g-force is sent through your body as the huge discs and multi-piston calipers bite the wheels. They withstand repeated abuse, stopping the big cat time and time again even with a lack of the more visually appealing cross-drilled discs that you might expect on a vehicle like this.
Overall, the XKR-S is a very naughty proposition. It loves to yell out its 405kW worth of anger in loud and forceful bursts, often with the rear tyres scrambling for traction – in all of first and most of second gear (with the traction control off). It’s a mighty machine.
2013 Jaguar XKR-S – THE VIDEO
Exhaust sound – extended cut:
2013 Jaguar XKR-S – THE VERDICT
When we said at the start that everybody loves it, we meant it. Of all the vehicles we’ve tested over the past year or so, since the beginning of PD, we’ve never encountered so many strangers that just had to personally greet us and let us know what a beautiful car it is. We made friends with every petrol station attendant, and if there was a human nearby when we parked, they made smiley contact too.
The Jaguar XKR-S is a companion in that it’s warm and fuzzy on the inside, yet, it also provides the one thing that only a true friendship often embraces; fun. It’s an absolute larrikin. It’s the life of a party. If we had the money, one would be in our garage.
– Diabolical power and speed
– Instant throttle response
– Jaw-dropping exterior, more than turns heads
– Awesome brakes, well matched to the speed
– Exquisite interior
– Throttle response too sensitive at times
– Firm ride
– Fiddly multimedia interface
2013 Jaguar XKR-S – THE COMPETITORS
4.2-litre V8 – 316kW-430Nm – 14.2L/100km – 1635kg – from $279,500 (manual)
BMW M6 Coupe
4.4-litre twin-turbo V8 – 412kW-680Nm – 9.9L/100km – 1850kg – from $292,145
Maserati Gran Turismo Sport MC
4.7-litre V8 – 338kW-520Nm – 15.5L/100km – 1880kg – from $345,000
Mercedes-Benz SLS AMG
6.2-litre V8 – 420kW-650Nm – 13.3L/100km – 1736kg – from $468,320
Porsche 911 Carrera S
3.8-litre flat six – 294kW-440Nm – 9.5L/100km – 1470kg – from $243,100 (manual) |
Physics and astronomy alumni
Our newest alumni!
The class of 2016 included 4 physics majors plus one minor. Above: graduate Karl Meinema (Physics minor), Professor Molnar, graduate Nate McReynolds, Professor Smolinski, graduate Jonathan Shomsky, Professor Balili, graduate Chris Spedden, Professor Walhout, adjunct Katie Shomsky, Professor Haarsma and Professor Harper. (Graduate Aaron Abma not pictured.)
Our alumni have gone on to a great variety of careers in science, technology and teaching. Many hold prestigious positions at universities, national laboratories and observatories, and in industry.
Shaun Alsum ('13) is a Physics graduate student at the University of Wisconsin at Madison.
Tim Atallah ('11) is a fifth year PhD candidate in chemical physics at the Columbia University.
Lane (formerly Jennafer) Banister ('10) is getting a masters in Education at Drexel University. He is currently teaching high school physics at the Science Leadership Academy in Philadelphia. Lane remarks that his masters work in Education has given him a lot of appreciation for the excellent educational philosophy of our Physics department.
Rachel Boerner ('11) is a graduate student in medical physics at East Carolina University.
Kyle Bussis ('13) is at MSU, Wayne State University's school of medicine
Margeaux Carter ('14) is a graduate student at New Mexico Tech, working towards an MS in Hydrology.
Erica Chan ('14) plans to work for a couple years before possibly attending grad school.
Nathan Danks ('11) is employed by Intertek in Grand Rapids, Michigan as an engineer.
Anna DeKievit Boorsma (minor '10) is teaching conceptual physics and chemistry at Holland Christian High School.
Josue Diaz ('14) is a software engineer for Big Data and Security at IBM in the Boston area and working on a Masters in Computer Science at U Mass, Lowell.
Charlotte DuLaney Stahl ('11) was accepted in the UNC-Charlotte Optical Science and Engineering PhD program. She hopes to eventually do research in the field of biomedical optics.
Melissa Haegert Dykhuis ('10) is a PhD candidate at the University of Arizona's Lunar and Planetary Laboratory, with an anticipated graduation date in August 2015. Her research interests include solar system dynamics of small bodies (asteroids, comets, KBOs), both theoretical modeling and observation.
Nathan Harkema ('13) is a Physics graduate student at the University of Arizona.
Andrew Hess ('13) is a graduate student in Physics at the University of Colorado Boulder.
Evan Jensen ('13) will attend GVSU in the summer and fall of 2013 for minors in Geology and Computer Science. He has been accepted at Western Michigan University for a Master's degree in Geophysics.
Carolyn Johnson ('10) planned to start TRS Alternative Designs, to design and market solar power systems.
Jacob Lampen ('14) plans to attend grad school for a PhD in Physics.
Luke Leisman ('11) is a graduate student in the astronomy PhD program at Cornell.
Rick McWhirter ('15) is a graduate student at San Francisco State University, in the Physics MS program.
Nathan Meyers ('10) is a graduate student at Boston University in the Physics PhD program.
Hannah Pagel ('14) After working on the ChemCam team at Los Alamos National Lab in the summer of 2014, Hannah is in the astronomy PhD program at Indiana University.
Nicolas Schuck ('11) works for Optec, an optics and electronics company in Lowell, MI. He also works on the side at the Grand Rapids Public Museum in the Roger B. Chaffee Planetarium where he helps to produce planetarium shows as well as present shows about science and the universe to the public.
Jonathan Shomsky ('16) entered the Marine Corps and is attending officer candidate school in Quantico, Virginia.
Katie Shomsky ('11) received her Physics Master's degree from Eastern Michigan University and was an adjunct lab instructor at Calvin in the 2015-2016 academic year.
Josiah Sinclair ('13) is a Physics graduate student at the University of Toronto.
Samuel Van Kooten ('14) is a grad student at University of Colorado Boulder in the Astronomy PhD program.
Simon Veldkamp (minor '13) is teaching at West Michigan Aviation Academy. He will be teaching physics, intro engineering and possibly some math.
Tom Wilhelm ('11) is working on a Masters of Engineering in Mechanical Engineering at Lehigh University in Bethlehem, Pennsylvania and is employed as a Project Engineer at Market Technologies, Inc. in Charlevoix, Michigan.
Christian Woolley ('13) has returned to Calvin to earn a degree in Computer Science.
Philip Ammar ('04) completed a law degree in 2010 at Case Western Reserve University School of Law following two years in Dushanbe, Tajikistan working with the aid organization Shelter for Life and a year in northern Iraq managing the construction of an aquaduct to supply water to a city of 150,000. Phil is working in patent law for Turocy & Watson in Cleveland. He is willing to talk to current students about careers in law.
Chris Beaumont ('07) is a fifth year Ph.D. student at the University of Hawaii's Institute for Astronomy. Since September 2010,he has been conducting his dissertation at the Harvard-Smithsonian Center for Astrophysics. In June 2011, he was awarded a Smithsonian Predoctoral Fellowship to continue his study in Boston.
Anthony Bouvette ('05) works for L-3 Communications in their Electromagnetic Interference/Compliance lab in Cincinnati. He is primarily involved with electrical performance testing on the jet engine for the F-35 Joint Strike Fighter.
Llian Breen ('05) worked for the National Oceanic and Atmospheric Administration in the NOAA commissioned Corps for two years and is now a student at the University of Alaska Fairbanks.
Kristin Bush Bolkema (minor '05) In 2010 Kristin completed a masters in English education at the University of Illinois. She married Derek Bolkema in June 2012. They live in Lansing, Illinois, and in the fall of 2013 she took over the Physics department at Illiana Christian High School. She still teaches a few English classes as well.
Andrew Butler ('07) is a graduate student in astronomy at Swinburne University in Melbourne, Australia.
Alexis Reynolds Cook ('06) is working at Epic, a medical software company in Wisconsin. She provides technical support to several hospitals across the country for their operating room management product.
Peter Cook ('05) is an assistant professor of physics at the University of Wisconsin-Superior. Peter received his doctorate degree in Experimental Condensed Matter Physics in 2011 from University of Wisconsin-Madison. Peter has received an Applied Research Grant Award from UW System to conduct solar cell research.
Elise Crull ('05, Ph.D. Philosophy of Physics, Notre Dame, '11) Elise spent a year in Jerusalem as a postdoctoral research fellow at Hebrew University, working with the Einstein Papers (which are housed there) and finishing two book projects. This followed a 2 year post-doc at the University of Aberdeen in Scotland where she did full time research, collaborating on a book with a professor there. In the fall of 2014 she will be joining City College CUNY as an assistant professor of philosophy, tenure track. She spoke at Calvin in spring 2010 on "Quantum Decoherence" and in spring 2008 on "Should Christians be Structural Realists?"
J. Clark Cully ('03, Ph.D. Michigan) works for the U.S. Department of Defense on national security policy and arms control & nonproliferation. He previously worked at the Department of Energy on sensors to monitor foreign nuclear programs and detect nuclear smuggling. After graduate work in high energy particle physics at Fermilab (see his 2007 Calvin seminar), he made the transition to Washington in 2008 via a fellowship in science public policy with the National Academy of Sciences, a program he highly recommends to other grad students.
Kristin Datema ('06) teaches Physics and Math at Western Christian High School in Muskegon, Michigan.
James Deterding ('07 minor) teaches physics and math at Chapelgate Christian Academy in Maryland.
Shannon Fogwell Hoogerheide ('05) completed her PhD from Harvard in physics and was awarded a post-doctorate position with the National Institute of Standards and Technology in Maryland. She spoke on campus on April 28, 2011.
Mark Gordon ('03, Ph.D. in Mech. Eng.) is a mechanical engineering
professor at California Baptist University. Mark worked at Innotec for
two years before attending graduate school at the University of
Michigan where he studied the effect of muscle activation level on
steadiness in the Biomechanics Research Lab.
Matt Gritter ('05) is a Software Engineer at IBM in Poughkeepsie, NY.
Jacci Guikema Busch ('01, MDiv, Calvin Seminary 2005) is pastor of McBain Christian Reformed Church in McBain, Michigan (near Cadillac).
Kathy Hoogeboom Pot ('08) received her Ph.D. in physics at the University of Colorado in Boulder in May 2015 and is now a development engineer for Intel in Hillsboro, OR. Her doctoral research made use of tabletop ultrafast coherent x-rays to study thermal and acoustic dynamics in materials at the nanoscale. In addition to receiving several awards for technical presentations about this work, she also created an award-winning short video about this research.
Andrew Jordan ('05, Ph.D.Astronomy, Boston University '10) is now a research scientist at the University of New Hampshire in the Institute for the Study of Earth, Oceans, and Space.He is studying how the Sun's magnetic field affects cosmic rays. To do that, he uses the Cosmic Ray Telescope for the Effects of Radiation (CRaTER) onboard the Lunar Reconnaissance Orbiter (LRO), which is a NASA spacecraft currently orbiting the moon.
Armin Karim ('08) is a graduate student in musicology at Case Western Reserve University.
Mason Klein ('02, Ph.D. Physics, Harvard) is doing a post-doc in biophysics. He stopped back for a visit in Spring 2004 and gave a talk on Shaking Sand: Separation, Pattern Formation, and the Gas between the Grains.
Casey Koopmans ('04 minor) teaches high school physics in St. Joseph, MI.
Kristin Kuzera Palacios ('04, MDiv, Calvin Seminary, '10) was called (and ordained) by Holland Heights CRC to continue her education. She has been accepted for a Ph.D. program at Notre Dame in Old Testament Studies. She wrote a 2008 column on young adults and church involvement.
D. Lee Miller ('05, Ph.D. Georgia Tech) is a post-doc in Boulder, Colorado.
Jon Niehof ('00, Ph.D. Astronomy, Boston University '10) is currently a postdoctoral researcher at Los Alamos National Lab. Among other projects he is working on the ECT suite for NASA's Radiation Belt Storm Probe mission, scheduled for launch in 2012.
Ross Norman ('08) is a process engineer at Electro-Optics Technology in Traverse City, Michigan, which develops Faraday rotators, photodetectors, and other high-tech optical equipment.
Jeff Olivero ('07) teaches physics at Liberty High School in Colorado Springs.
David Pastoor ('04) is a systems engineer at Raytheon in Denver, designing ground control systems for satellites.
Michael Scholten ('03) has a masters degree in physics from the University of Maryland, and works at GE Aviation in the Analytics
Group of Vehicle Health and Data Management. The projects are roughly centered around data mining and anomaly detection.
Zachary Smith ('09) is a graduate student at the University of Maryland.
Jessie Taylor ('08) completed a masters in Biblical studies at Notre Dame University. In the fall of 2010 she became a PhD graduate student in the physics department at the University of Pennsylvania.
Sam Terfa ('08 minor) teaches high school science and math at Minnehaha Academy in Minnesota.
Andrew Vache ('05) was a Mission Assurance Engineer at NASA Goddard Space Flight Center, working on the Joint Polar Satellite System (JPSS). Andrew died tragically in the summer of 2016 in a boating accident on Lake Michigan.
Andrew Vanden Heuvel ('04, M.S. U Florida) After earning a masters degree in astronomy, Andrew obtained a high school teaching certificate. He taught high school for several years, involving his students in Calvin collaborations to discover asteroids. Andrew is now engaged in numerous education projects at the state and national level through his work with Michigan Virtual School and USA TODAY Education. Andrew has returned to Calvin to teach in the physics department and develop education and outreach programs. Read about his experience testing Google Glass.
Jake Vander Plas ('03, Ph.D. University of Washington '12) Jake is the director of research in the physical sciences at the University of Washington's eScience institute, an interdisciplinary program focused on data-drive research and discovery across scientific disciplines.
John Vander Weide ('05) has completed a dual Masters degree in Mechanical Engineering at the Georgia Institute of Technology and the French engineering school Ecole Nationale Supérieure d'Arts et Métiers (ENSAM). He is currently working as an engineer with Areva, a nuclear power and renewable energy company.
Josh Vanderhill ('09) is a graduate student in the PhD program in Physics at the University of Texas, Dallas.
John Van Dyke ('08) is a graduate student in philosophy at the University of Illinois at Chicago, planning to specialize in philosophy of science.
David Van Norstrand ('03) is in the joint MD/PhD graduate program at the Mayo Clinic. In summer 2010 he defended his PhD thesis entitled "The Cardiac Sodium Channel Macromolecular Complex and Sudden Infant Death Syndrome", and will be starting residency in fall of 2012.
Matt Voorman ('05, M.D. University of Southern California '10) completed a General Surgery internship at the University of California. In July of 2011 will be starting a residency in Otolaryngology-Head and Neck Surgery at Geisinger Medical Center, in Danville, Pennsylvania.
Jess Vriesema ('09) has received a three-year NASA Earth and Space Science Fellowship. He is working toward his PhD in lunar and planetary sciences at the University of Arizona in Tucson, Arizona.
Chris Walker ('05) works as a Project Manager in the Design and Integration of Machine Vision Systems and Factory Automation for EPIC Systems, Inc. in St. Louis, Missouri.
David Young ('02 minor) works as an instructional designer for Michigan Virtual School.
Michael Dekker ('98, Ph.D. Notre Dame) is a professor in the mathematics department of Ferris State University and studies topology.
Jason English ('99) teaches physics at William Fremd High School in Palatine, IL (northwest suburbs of Chicago). He earned National Board Certification in 2005 and a Masters Degree in Physics Education from Roosevelt University the same year. He has also been teaching courses to new physics teachers or teachers teaching out of field at Fermilab during the summer.
Matthew Falk ('97) teaches at West Side Christian Middle School in Grand Rapids, Michigan.
Sarah Bowen Fay ('98) teaches high school physics and math at Chicago Christian School.
Christopher Hartemink ('96; Ph.D., Mechanical and Medical Engineering, MIT and Harvard Medical School, 2004) is a research scientist in heart failure at Guidant where he studies biventricular resynchronization therapy. Chris holds a patent for a heart valve prostheses. He completed majors in both physics and engineering at Calvin.
Ben Langdon (minor, Ph.D. Physical Chemistry) is a post-doctoral researcher in the NSF Engineering Research Center for Extreme Ultraviolet (EUV) Science and Technology at Colorado State University. He studies table-top ultra-high power EUV lasers. Research on lasers is truly interdisciplinary, at the intersection of chemistry, physics, and electrical engineering.
Geoff Lenters ('93, Ph.D.) studies the astrophysics of x-ray burst sources and is a professor in the Grand Valley State University physics department.
Hugh Nymeyer ('94, Ph.D. biophysics U.C. San Diego) does computational studies of protein folding and membrane-protein interactions. He is assistant professor of Chemistry and Biochemistry at Florida State University.
Phil Polstra ('90, M.S., Purdue) is Professor of Aviation at University of Dubuque, in Dubuque, IA.
Lewis Reynolds ('93, Ph.D '02) lives in Denver and works in the area of signal processing, specifically aerial spectroscopy for ground surveys.
Harold Schnyders ('91, Ph.D.) studies solid state physics and is a professor in the Grand Valley State University physics department.
Bob Steen ('93, Ph.D. in physics Rice University) received his Ph.D. from the Department of Physics and Astronomy at Rice University. He is now a management consultant at Princeton Consultants in New Jersey.
David Steensma ('92, M.D. University of Chicago) is Associate Professor of Medicine at Harvard Medical School. His research area is hematology (studying diseases of the blood, such as leukemia). Before starting at Harvard in 2009, Dave was a professor at the Mayo Clinic.
David Streutker ('97, Ph.D. Physics and Astronomy, Rice University) is a project scientist at the National Geospatial-Intelligence Agency (NGA) in Washington D. C., which geospatial intelligence in support of national security.
David Tong ('99) received his Ph.D. in physics at the University of Connecticut in 2010 and has done work at Westminster Seminary.
Angela Van Woerkom Portenga ('98) teaches physics at Providence Christian High School in Fremont, Michigan.
Dwight You ('96) completed his MS at DePaul University. He is the head of production at AqVida GmbH, located in Hamburg Germany. The company focuses on the development, manufacturing registration and sales of oncology drugs.
Marvin Bolt ('84; Ph.D. History and Philosophy of Science, Notre Dame) is a curator at Adler Planetarium and Astronomy Museum in Chicago. He recently found two telescopes from the 1600s that had been "lost" in museum storerooms (and gave a seminar at Calvin about it).
Howard Bushouse (`80; Ph.D., Astronomy, U. Illinois) is a Scientist and Senior Scientific Programmer at the Space Telescope Science Institute in Baltimore, MD (science headquarters for the Hubble Space Telescope). His time there is split between research and software development in the Space Telescope Science Data Analysis System (STSDAS) group.
David Cole ('85; Ph.D. Astronomy, University of Chicago) is a scientist at the Jet Propulsion Laboratory working on the Spitzer Space Telescope, studying the universe at infrared wavelengths.
Mike Evele ('88) teaches physics at Grandville High School.
Ron Geerlings ('80) and his wife Sue have served with Christian Reformed World Missions since graduating from Calvin in 1980. For the last several years, Sue has joined Ron as a volunteer in the regional office where he supports and oversees CRWM ministry in West Africa.
Eric Hessels ('84, Ph.D., Physics, Notre Dame) is an Associate Professor in the Department of Physics at York University, doing experimental atomic physics, including studies of anti-hydrogen with Gerry Gabrielse.
Phillip Keegstra ('82) works for the National Ocean and Atmospheric Administration (NOAA) doing ocean remote sensing. This is interdisciplinary work, as they try to sense ocean biological processes using atmospheric and water physics and chemistry.
Alison Kuipers ('83) is a senior engineer at Goodrich Avionics.
W. Ted Masselink ('81) is a physics professor at Humboldt University of Berlin.
Pam Naber Knox ('80; M.S., Meteorology, University of Wisconsin) is a University of Georgia climatologist in Bio and Ag Engineering. She served in state climatology offices in Wisconsin and in Georgia for nearly 20 years. Knox is also a Certified Consulting Meteorologist and for the past decade has worked on numerous court cases; in August 2011 she was the subject of a live interview on The Weather
Channel regarding her work in forensic meteorology. Read a transcript of a December 6, 2011, Georgia radio station interview.
Steve Remillard ('88, Ph.D., The College of William and Mary, 1993) is a professor in the Hope College physics department. Steve studies microwave measurement and microwave induced phenomena, such as microwave superconductivity, microwave photonic bandgap structures, and microwave induced discharges in gases. Before his teaching career, he did research at Los Alamos National Lab, the University of Wuppertal (Germany), the Naval Research Lab. He worked in industry for several years doing research and product development, including as Director of Engineering at Illinois Superconductor Corporation.
Jon Seerveld ('83) is an optical engineer, living in Hawaii and working at the Canada-France-Hawaii Telescope.
James TenCate ('80; Ph.D., Mechanical Engineering, University of Texas at Austin, 1992) is a geophysicist studying seismo-acoustics at Los Alamos National Laboratory. His group models the non-linear elasticity of rocks, a topic which is clearly important for understanding earthquakes, and has broader applications in other materials (such as damaged solids and compressed powdered metals). Jim is also Technical Editor for The Vintage Triumph, the national magazine of the Vintage Triumph Register, the club for Triumph motorcar enthusiasts.
Tom Van Baak ('80, brother of Prof David Van Baak) collects vintage and atomic clocks (see his website leapsecond.com). He recently involved his kids in perhaps the first homemade relativity experiment, reported in a letter to Physics Today and an article in Wired Magazine.
Bill Zeilstra ('82) is an avid amateur astronomer. He wrote astronomy-themed devotionals for the June 2001 issue of Today (download the PDF file).
Tom Ackerman ('70; Ph.D.) is Chief Scientist in the Atmospheric Radiation Measurement Program of the Department of Energy, studying global warming and public policy. In 2005, he was on campus to give a lecture in the January series (audio available at that link).
David Cok ('75; Ph.D. Harvard) is Chief Technologist at Eastman Kodak Research Laboratories, studying the science & technology of digital imaging.
Marten den Boer ('73, Ph.D.) was elected provost of DePaul University in Chicago by its board of trustees and became the chief academic officer July 1, 2015. For the past seven years he has served as provost and vice president for academic affairs at California State Polytechnic University, Pomona.
Shirley Fleischman ('73, Ph.D) is a Professor of Mechanical Engineering at Grand Valley State University and was the Carnegie Foundation Michigan Professor of the Year in 1998.
Gerald Gabrielse ('73; Ph.D., Physics, Chicago, 1980) is the 2011 Julius Edgar Lilienfeld Prize recipient. He is the George Vasmer Leverett Professor of Physics at Harvard University. He recently won the George Ledlie Prize for his research on anti-matter and in 2007 was elected to the National Academy of Sciences. His high-precision measurement of the electron magnetic moment was named the 2006 AIP Physics Story of the Year. On a lighter note, one of his papers was used in a February 2007 sketch by comedian Conan O'Brien with guest Jim Carrey (watch it here).
Keith Griffioen ('79; Ph.D., Physics, Stanford 1984) does accelerator experiments on elementary particles and serves as Chair and Professor of Physics at the College of William and Mary. In 2006, he was named a Fellow of the American Physical Society "for definitive experimental studies of the spin structure of the proton and neutron, both in the perturbative, deep-inelastic regime, and in the non-perturbative resonance region." In the fall of 2010 he spoke to the department on the topic "How does the Proton Spin?"
Steve Haan ('73; Ph.D., Physics, Maryland, 1977) studies nuclear fusion as Group Leader at the National Ignition Facility at Lawrence Livermore National Labs.
Todd Hoeksema ('78, Ph.D.) is a Senior Scientist in the Solar Observatories Group at Stanford. His team designed the Michelson Doppler Imager instrument on the Solar and Heliospheric Observatory (SOHO). He recently was awarded the NASA Distinguished Public Service Medal for his leadership in crafting a 30-year road map for NASA heliophysics research. His work was featured in an April 2012 episode of Nova "Secrets of the Sun." Calvin's alumni magazine Spark profiledTodd and his work in the Winter 2006 issue.
Robert Hollebeek ('70, Ph.D.) is an expert in using supercomputers in physics and medicine. He serves as Director of the National Scalable Cluster Project, Chief Architect for the National Digital Mamography Archive, and Professor of Physics at the University of Pennsylvania.
James Huffman ('79, Ph.D. Michigan State) is Director of Sales and Manufacturing at the Lawrence Semiconductor Research Laboratory.
James Katerberg ('75, PhD, Physics, University of Illinois at Urbana-Champaign, '80) works for the Kodak Graphic Communication Group. James has 20 patents in the field of inkjet. James is the intellectual property coordinator for Dayton Ohio based inkjet group.
Harold Reitsema ('72, Ph.D. Astronomy, New Mexico State) leads the Advanced Systems group at Ball Aerospace, which is responsible for developing new mission concepts for NASA, such as Deep Impact and the Kepler mission to discover Earth-like planets around nearby stars. His past work includes building Hubble Space Telescope instruments, the Submillimeter Wave Astronomy Satellite, and the GIOTTO mission to Comet Halley.
Lyle Roelofs ('75, Ph.D., Physics, Maryland) On June 30, 2012, Lyle will become the ninth president of Berea College in Berea, Ky. Founded in 1855 by abolitionist preacher John G. Fee, Berea is a Christian liberal arts college committed to the Appalachian region and to interracial education. Lyle currently serves as Provost and Dean of the Faculty and as professor of physics at Colgate University. Besides teaching, Lyle has held a number of administrataive posts, visiting appointments and research fellowships in his 35-plus years of academic service. His research area is computational condensed matter physics; he spoke on campus in spring 2011.
Stuart Rupke ('71, M.D.) is a physician and assistant program director of a medical residency program at Synergy Medical Education Alliance.
Tom Strikwerda ('71, Ph.D) supervises the Mission Concept and Analysis group at the Applied Physics Lab of John Hopkins University, which worked on the NEAR mission to the asteroid Eros. Read the Fall 2014 Spark alumni profile "Space Protector."
Joe VanAndel ('78, Masters in Computer Science, U.C.Berkeley) works in the Earth Observing Laboratory at the National Center for Atmospheric Research, writing data acquisition and control software for weather radar systems.
James VanDam ('70, Ph.D.) is the research division director of the Office of Fusion Energy Sciences, part of the U.S. Department of Energy. Previously Jim was professor and director at the Institute for Fusion Studies at the University of Texas, Austin.
Hugh Vander Plas ('72, Ph.D. '76 from Stanford in Materials Science) worked at Hewlett Packard for 22 years, filing several patents for devices that include components for high-speed ink-jet printers. He began a second career as the Science Program Director at the M.J. Murdock Charitable Trust before his death in 2012.
John Zwart ('77, Ph.D. Michigan State) is a physics professor at Dordt College in Sioux Center Iowa.
Alvin Compaan ('65; Ph.D., 1971 Chicago) develops technologies for solar power cells as Professor in the Department of Physics and Astronomy and Director of the Center for Materials Science and Engineering at the University of Toledo.
After 19 years, Ryan Doezema ('64; Ph.D., Physics, U. Maryland) recently stepped down as Chair of the University of Oklahoma Department of Physics and Astronomy. "[Doezema] has secured a place in history as one of the most oustanding department chairs ever," said Paul B. Bell Jr., dean of the College of Arts and Sciences at the University. (more)
Ken Klaasen ('68, M.S. Aerospace Science, University of Michigan) is Supervisor of the Imaging Science Group at the Jet Propulsion Laboratory. He has been involved in the imaging experiments on many solar system exploration missions including Mariner 10, Viking Orbiter, and the Galileo mission to Jupiter, and most recently coordinated all aspects of scientific mission planning and flight operation for the Deep Impact mission to Comet Tempel 1. Read an interview with Ken about the Stardust-NEXT mission he is currently involved in.
Rick Shoemaker ('66, Ph.D.) is professor and director at the Optical Sciences Center at the University of Arizona. He hosted the Astronomy in the Southwest interim class on the day they visited Tucson in January 2009.
Paul Vanden Bout ('61, Ph.D. U. C. Berkeley) recently completed 18 years as Director of the National Radio Astronomy Observatory. He won Calvin's Distinguished Alumni Award in 2003. He was featured in an article in the Sparc alumni magazine.
Terry Van Kalker ('64) teaches at Grand Rapids Christian High School.
Alex Dragt ('58; Ph.D. Physics U. C. Berkeley) studies mathematical physics, is a Professor of Physics and former department chair at the University of Maryland, and won Calvin's Distinguished Alumni Award in 1985.
The Honorable Vernon J. Ehlers ( '56; Ph.D. U. C. Berkeley) served as a United States Congressmen, representing western Michigan, from 1993 until 2011. A former Calvin Physics professor, he won Calvin's Distinguished Alumni Award in 1996.
Henk Van Andel ('59, Ph.D.) is past president of The King's University College in Edmonton Alberta. |
|In 2006 Sami Jämsén of infamous Studio Perkele (Deathchain, Barathrum) took a break from studio work and channelled his producer's anger to found Survivors Zero. A band whose main goal is to deliver quality brutal modern death metal with a melodic edge. After long and tedious demoing sessions and song structuring for a full year the Survivors Zero style was starting to take shape musically.
Then in 2007 a phone call to unexpecting Tommi "Rotten" Virranta (ex-Deathchain) secured him as lead singer and main lyricist. The guys hooked up instantly with the exact same vision and musical direction. Having worked together many times previously the synergy was there right from the start. After this the ball started rolling. Quickly Tapio Wilska (ex-Finntroll) joined the ranks and to take on the lead guitars J-V Hintikka (Machine Men) enrolled. Drumming battery duties were taken by Reima Kellokoski (Impaled Nazarene).
In 2008 the guys rushed into Jive Studio in Helsinki to record drum tracks with Jukka Varmo. Few weeks later in Studio Perkele all the other tracks were hammered down. Jonas Kjellgren, owner of Black Lounge Studio (Carnal Forge, The Absence) in Sweden and of Scar Symmetry fame mixed Survivors Zero's first official "demotape" codenamed "Extinction". It was unleashed with 2 killer songs ("Embrace the Inferno" & "Fortress of Lies") and sonic supremacy delivered by Kjellgren.
In October 2008 lead guitarist J-V Hintikka was replaced by another talented shredder Jani Luttinen also known from the ranks of The Scourger.
Late 2008 Survivors Zero secured a recording deal with Cobra Records (with labelmates Sotajumala & Deathchain) and united again with Jonas Kjellgren for a full album. Entitled 'CMXCIX' the album was to be done & finished during February - March 2009. Recording began 02.02.09 at Seawolf Studios, Finland. Mixing was then to be done with Jonas Kjellgren at Black Lounge Studio, Sweden and mastering with Pelle Henricsson at Tonteknik Recording, Sweden.
'CMXCIX' came out with a blast. Single "Reclaim My Heritage" entered the Finnish charts at position 14 and the album peaked at number 28. The album gathered praising reviews and accolades worldwide. On top of this Survivors Zero made a successful tour in Finland with Sotajumala and Deathchain. In the end of the tour Reima Kellokoski gave way for a new killer drummer Seppo Tarvainen.
Next up their sleeve is the European tour with death-metal legends Hypocrisy in January - February 2010 and a North American tour in April 2010 with Finntroll, Swallow The Sun and Moonsorrow.
Expect some fucking furious mayhem from Survivors Zero for the year 2010! |
|Publication number||US6972322 B2|
|Application number||US 10/237,866|
|Publication date||6 Dec 2005|
|Filing date||10 Sep 2002|
|Priority date||31 Jan 1992|
|Also published as||CA2126091A1, CA2126091C, DE69333622D1, DE69333622T2, EP0624195A1, EP0624195B1, EP1449921A2, EP1449921A3, US5876969, US6686179, US6987006, US6989365, US7041478, US7056701, US7081354, US7094577, US7410779, US7435410, US7833521, US20020151011, US20030022308, US20030036170, US20030036171, US20030036172, US20030082747, US20040086976, US20040086977, US20050239167, US20060105429, US20090176276, WO1993015199A1|
|Publication number||10237866, 237866, US 6972322 B2, US 6972322B2, US-B2-6972322, US6972322 B2, US6972322B2|
|Inventors||Reinhard Fleer, Alain Fournier, Jean-Dominique Guitton, Gérard Jung, Patrice Yeh|
|Original Assignee||Aventis Behring L.L.C.|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (101), Non-Patent Citations (102), Referenced by (49), Classifications (65), Legal Events (6)|
|External Links: USPTO, USPTO Assignment, Espacenet|
This Application is a divisional of Ser. No. 09/984,186, filed Oct. 29, 2001, now U.S. Pat. No. 6,686,179, which is a continuation of Ser. No. 09/258,532, filed Feb. 26, 1999, now Abandoned, which is a divisional of Ser. No. 08/797,689 filed Jan. 31, 1997, now U.S. Pat. No. 5,876,969, which is a continuation of Ser. No. 08/256,927 filed Jul. 28, 1994, now Abandoned, which is a U.S. National Stage of international application PCT/FR93/00085 filed Jan. 28, 1993, which claims priority to French application FR92-01064 filed Jan. 31, 1992.
The present invention relates to new biologically active polypeptides, their preparation and pharmaceutical compositions containing them.
More particularly, the present invention relates to essentially recombinant polypeptides composed of an active part derived from a natural or artificial polypeptide having a therapeutic activity and coupled to an albumin or to a variant of albumin. It is understood that the therapeutic activity of the polypeptides of the invention can be either direct (treatment of diseases), or indirect (and for example capable of being used in the prevention of diseases, in the design of vaccines, in medical imaging techniques and the like).
It is understood in the following text that the albumin variants designate any protein with a high plasma half-life which is obtained by modification (mutation, deletion and/or addition), by genetic engineering techniques, of a gene encoding a given isomorph of human serum albumin, as well as any macromolecule with a high plasma half-life obtained by in vitro modification of the protein encoded by such genes. Albumin being highly polymorphic, numerous natural variants have been identified and classified [Weitkamp L. R. et al., Ann. Hum. Genet. 37 (1973) 219].
The aim of the present invention is to prepare artificial proteins which are biologically active and can be used pharmaceutically. Indeed, numerous polypeptides possessing one or more potential therapeutic activities cannot be exploited pharmaceutically. This may have various reasons, such as especially their low stability in vivo, their complex or fragile structure, the difficulty of producing them on an industrially acceptable scale and the like. Likewise, some polypeptides do not give the expected results in vivo because of problems of administration, of packaging, of pharmacokinetics and the like.
The present invention makes it possible to overcome these disadvantages. The present invention indeed provides new molecules which permit an optimal therapeutic exploitation of the biological properties of these polypeptides. The present invention results especially from the demonstration that it is possible to couple genetically any active structure derived from a biologically active polypeptide to another protein structure consisting of albumin, without impairing the said biological properties thereof. It also results from the demonstration by the Applicant that human serum albumin makes it possible efficiently to present the active structure to its sites for interaction, and that it provides a high plasma stability for the polypeptide of the invention. The polypeptides of the invention thus make it possible to maintain, in the body, a given biological activity for a prolonged period. They thus make it possible to reduce the administered doses and, in some cases, to potentiate the therapeutic effect, for example by reducing the side effects following a higher administration. The polypeptides of the invention make it possible, in addition, to generate and to use structures derived from biologically active polypeptides which are very small and therefore very specific for a desired effect. It is understood that the peptides having a biological activity, which are of therapeutic interest, may also correspond to non-natural peptide sequences isolated for example from random peptide libraries. The polypeptides of the invention possess, moreover, a particularly advantageous distribution in the body, which modifies their pharmacokinetic properties and favours the development of their biological activity and their use. In addition, they also have the advantage of being weakly or non-immunogenic for the organism in which they are used. Finally, the polypeptides of the invention can be expressed (and preferentially secreted) by recombinant organisms, at levels permitting their industrial exploitation.
One subject of the present invention therefore relates to polypeptides containing an active part derived from a polypeptide having a therapeutic activity, coupled to an albumin or a variant of albumin.
In a specific embodiment, the peptides possessing a therapeutic activity are not of human origin. For example, there may be mentioned peptides, or their derivatives, possessing properties which are potentially useful in the pathologies of the blood and interstitial compartments, such as hirudin, trigramine, antistatine, tick anticoagulant peptides (TAP), arictin, applagin and the like.
More particularly, in the molecules of the invention, the polypeptide having a therapeutic activity is a polypeptide of human origin or a molecular variant. For example, this may be all or part of an enzyme, an enzyme inhibitor, an antigen, an antibody, a hormone, a factor involved in the control of coagulation, an interferon, a cytokine [the interleukins, but also their variants which are natural antagonists of their binding to the receptor(s), the SIS (small induced secreted) type cytokines and for example the macrophage inflammatory proteins (MIPs), and the like], of a growth factor and/or of differentiation [and for example the transformant growth factors (TGFs), the blood cell differentiation factors (erythropoietin, M-CSF, G-CSF, GM-CSF and the like), insulin and the growth factors resembling it (IGFs), or alternatively cell permeability factors (VPF/VEGF), and the like], of a factor involved in the genesis/resorption of bone tissues (OIF and osteospontin for example), of a factor involved in cellular motility or migration [and for example autocrine motility factor (AMF), migration stimulating factor (MSF), or alternatively the scatter factor (scatter factor/hepatocyte growth factor)], of a bactericidal or antifungal factor, of a chemotactic factor [and for example platelet factor 4 (PF4), or alternatively the monocyte chemoattracting peptides (MCP/MCAF) or neutrophil chemoattracting peptides (NCAF), and the like], of a cytostatic factor (and for example the proteins which bind to galactosides), of a plasma (and for example von Willebrand factor, fibrinogen and the like) or interstitial (laminin, tenascin, vitronectin and the like) adhesive molecule or extracellular matrices, or alternatively any peptide sequence which is an antagonist or agonist of molecular and/or intercellular interactions involved in the pathologies of the circulatory and interstitial compartments and for example the formation of arterial and venous thrombi, cancerous metastases, tumour angiogenesis, inflammatory shock, autoimmune diseases, bone and osteoarticular pathologies and the like.
The active part of the polypeptides of the invention may consist for example of the polypeptide having a whole therapeutic activity, or of a structure derived therefrom, or alternatively of a non-natural polypeptide isolated from a peptide library. For the purposes of the present invention, a derived structure is understood to mean any polypeptide obtained by modification and preserving a therapeutic activity. Modification should be understood to mean any mutation, substitution, deletion, addition or modification of genetic and/or chemical nature. Such derivatives may be generated for various reasons, such as especially that of increasing the affinity of the molecule for its binding sites, that of improving its levels of production, that of increasing its resistance to proteases, that of increasing its therapeutic efficacy or alternatively of reducing its side effects, or that of conferring on it new biological properties. As an example, the chimeric polypeptides of the invention possess pharmacokinetic properties and a biological activity which can be used for the prevention or treatment of diseases.
Particularly advantageous polypeptides of the invention are those in which the active part has:
(a) the whole peptide structure or,
(b) a structure derived from (a) by structural modification (mutation, substitution addition and/or deletion of one or more residues) and possessing a therapeutic activity.
Among the structures of the (b) type, there may be mentioned more particularly the molecules in which certain N— or O-glycosylation sites have been modified or suppressed, the molecules in which one or more residues have been substituted, or the molecules in which all the cystein residues have been substituted. There may also be mentioned molecules obtained from (a) by deletion of regions not involved or not highly involved in the interaction with the binding sites considered, or expressing an undesirable activity, and molecules containing, compared to (a), additional residues such as for example an N-terminal methioninc and/or a signal for secretion and/or a joining peptide.
The active part of the molecules of the invention can be coupled either directly or via an artificial peptide to albumin. Furthermore, it may constitute the N-terminal end as well as the C-terminal end of the molecule. Preferably, in the molecules of the invention, the active part constitutes the C-terminal part of the chimera. It is also understood that the biologically active part may be repetitive within the chimera. A schematic representation of the molecules of the invention is given in FIG. 1.
Another subject of the invention relates to a process for preparing the chimeric molecules described above. More specifically, this process consists in causing a eukaryotic or prokaryotic cellular host to express a nucleotide sequence encoding the desired polypeptide, and then in harvesting the polypeptide produced.
Among the eukaryotic hosts which can be used within the framework of the present invention, there may be mentioned animal cells, yeasts or fungi. In particular, as regards yeasts, there may be mentioned yeasts of the genus Saccharomyces, Kluyveromyces, Pichia, Schwanniomyces, or Hansenula. As regards animal cells, there may be mentioned COS, CHO and C127 cells and the like. Among the fungi capable of being used in the present invention, there may be mentioned more particularly Aspergillus ssp, or Trichoderma ssp. As prokaryotic hosts, the use of bacteria such as Escherichia coli, or belonging to the genera Corynebacterium, Bacillus, or Streptomyces is preferred.
The nucleotide sequences which can be used within the framework of the present invention can be prepared in various ways. Generally, they are obtained by assembling, in reading phase, the sequences encoding each of the functional parts of the polypeptide. The latter may be isolated by the techniques of persons skilled in the art, and for example directly from cellular messenger RNAs (mRNAs), or by recloning from a complementary DNA (cDNA) library, or alternatively they may be completely synthetic nucleotide sequences. It is understood, furthermore, that the nucleotide sequences may also be subsequently modified, for example by the techniques of genetic engineering, in order to obtain derivatives or variants of the said sequences.
More preferably, in the process of the invention, the nucleotide sequence is part of an expression cassette comprising a region for initiation of transcription (promoter region) permitting, in the host cells, the expression of the nucleotide sequence placed under its control and encoding the polypeptides of the invention. This region may come from promoter regions of genes which are highly expressed in the host cell used, the expression being constitutive or regulatable. As regards yeasts, it may be the promoter of the gene for phosphoglycerate kinase (PGK), glyceraldehyde-3-phosphate dehydrogenase (GPD), lactase (LAC4), enolases (ENO), alcohol dehydrogenases (ADH), and the like. As regards bacteria, it may be the promoter of the right-hand or left-hand genes from the lambda bacteriophage (PL, PR), or alternatively the promoters of the genes for the tryptophan (Ptrp) or lactose (Plac) operons. In addition, this control region can be modified, for example by in vitro mutagenesis, by the introduction of additional control elements or of synthetic sequences, or by deletions or substitutions of the original control elements. The expression cassette may also comprise a region for termination of transcription which is functional in the host envisaged, positioned immediately downstream of the nucleotide sequence encoding a polypeptide of the invention.
In a preferred mode, the polypeptides of the invention result from the expression, in a eukaryotic or prokaryotic host, of a nucleotide sequence and from the secretion of the product of expression of the said sequence into the culture medium. It is indeed particularly advantageous to be able to obtain, by the recombinant route, molecules directly in the culture medium. In this case, the nucleotide sequence encoding a polypeptide of the invention is preceded by a “leader” sequence (or signal sequence) directing the nascent polypeptide in the secretory pathways of the host used. This “leader” sequence may be the natural signal sequcnce of the biologically active polypeptide in the case where the latter is a naturally secreted protein, or that of the stabilizing structure, but it may also be any other functional “leader” sequence, or an artificial “leader” sequence. The choice of one or the other of these sequences is especially guided by the host used. Examples of functional signal sequences include those of the genes for the sexual pheromones or the “killer” toxins of yeasts.
In addition to the expression cassette, one or several markers which make it possible to select the recombinant host may be added, such as for example the URA3 gene from the yeast S. cerevisiae, or genes conferring the resistance to antibiotics such as geneticin (G418) or to any other toxic compound such as certain metal ions.
The unit formed by the expression cassette and by the selectable marker can be introduced directly into the considered host cells, or previously inserted in a functional self-replicating vector. In the first case, sequences homologous to regions present in the genome of the host cells are preferably added to this unit; the said sequences then being positioned on each side of the expression cassette and of the selectable gene so as to increase the frequency of integration of the unit into the genome of the host by targetting the integration of the sequences by homologous recombination. In the case where the expression cassette is inserted in a replicative system, a preferred replication system for yeasts of the genus Kluyveromyces is derived from the plasmid pKD1 originally isolated from K. drosophilarum; a preferred replication system for yeasts of the genus Saccharomyces is derived from the 2 μplasmid from S. cerevisiae. Furthermore, this expression plasmid may contain all or part of the said replication systems, or may combine elements derived both from the plasmid pKD1 and the 2 μplasmid.
In addition, the expression plasmids may be shuttle vectors between a bacterial host such as Escherichia coli and the chosen host cell. In this case, a replication origin and a selectable marker functioning in the bacterial host are required. It is also possible to position restriction sites surrounding the bacterial and unique sequences on the expression vector: this makes it possible to suppress these sequences by cutting and religation in vitro of the truncated vector before transformation of the host cells, which may result in an increase in the number of copies and in an increased stability of the expression plasmids in the said hosts. For example, such restriction sites may correspond to sequences such as 5′-GGCCNNNNNGGCC-3′ SEQ ID NO:19 (SfiI) or 5′-GCGGCCGC-3′ (NotI) in so far as these sites are extremely rare and generally absent from an expression vector.
After construction of such vectors or expression cassette, the latter are introduced into the host cells selected according to the conventional techniques described in the literature. In this respect, any method permitting the introduction of a foreign DNA into a cell can be used. This may be especially transformation, electroporation, conjugation, or any other technique known to persons skilled in the art. As an example of yeast-type hosts, the various strains of Kluyveromyces used were transformed by treating the whole cells in the presence of lithium acetate and polyethylene glycol, according to the technique described by Ito et al. [J. Bacteriol. 153 (1983) 163]. The transformation technique described by Durrens et al. [Curr. Genet. 18 (1990) 7] using ethylene glycol and dimethyl sulphoxide was also used. It is also possible to transform the yeasts by electroporation, according to the method described by Karube et al. [FEBS Letters 182 (1985) 90]. An alternative procedure is also described in detail in the examples below.
After selection of the transformed cells, the cells expressing the said polypeptides are inoculated and the recovery of the said polypeptides can be carried out, either during the cell growth for the “continuous” processes, or at the end of growth for the “batch” cultures. The polypeptides which are the subject of the present invention are then purified from the culture supernatant for their molecular, pharmacokinetic and biological characterization.
A preferred expression system for the polypeptides of the invention consists in using yeasts of the genus Kluyveromyces as host cell, transformed by certain vectors derived from the extrachromosomal replicon pKD1 originally isolated from K. marxianus var. drosophilarum. These yeasts, and in particular K. lactis and K. fragilis are generally capable of stably replicating the said vectors and possess, in addition, the advantage of being included in the list of G.R.A.S. (“Generally Recognized As Safe”) organisms. Favoured yeasts are preferably industrial yeasts of the genus Kluyveromyces which are capable of stably replicating the said plasmids derived from the plasmid pKD1 and in which has been inserted a selectable marker as well as an expression cassette permitting the secretion, at high levels, of the polypeptides of the invention.
The present invention also relates to the nucleotide sequences encoding the chimeric polypeptides described above, as well as the eukaryotic or prokaryotic recombinant cells comprising such sequences.
The present invention also relates to the application, as medicinal products, of the polypeptides according to the present invention. More particularly, the subject of the invention is any pharmaceutical composition comprising one or more polypeptides or nucleotide sequences as described above. The nucleotide sequences can indeed be used in gene therapy.
The present invention will be more fully described with the aid of the following examples, which should be considered as illustrative and non-limiting.
The representations of the plasmids indicated in the following figures are not plotted to scale and only the restriction sites important for the understanding of the clonings carried out have been indicated.
FIGS. 2(a)-(c), together, comprise an example of a nucleotide sequence (SEQ ID NO:1) and an amino acid sequence (SEQ ID NO:2) of a HindIII restriction fragment encoding a chimeric protein of the prepro-HSA-PEPTIDE type. The black arrows indicate the end of the “pre” and “pro” regions of HSA. The MstII restriction site is underligned and the codon specifying the termination of translation is in bold characters.
FIG. 3: Restriction map for the plasmid pYG105 and generic strategy for construction of the plasmids for expression of the chimeric proteins of the present invention. Abbreviations used: P, transcriptional promoter; T, transcriptional terminator; IR, inverted repeat sequences of the plasmid pKD1; LP, signal sequence for secretion; Apr and Kmr designate the genes for resistance to ampicillin (E. coli) and to G418 (yeasts), respectively.
FIG. 7: Characterization of the material secreted by K. lactis transformed with the plasmids pKan707 (control plasmid, lane 2), pYG1206 (lane 3), pYG1214 (lane 4) and pYG1223 (lane 5); molecular weight standard (lane 1). The deposits correspond to 50 μl of supernatant from a stationary culture after growing in YPD medium, running on an 8.5% acrylamide gel and staining with coomassie blue.
FIG. 8: Nucleotide sequence (SEQ ID NO:11) and amino acid sequence (SEQ ID NO:12) of the MstII-HindIII restriction fragment of the plasmid pYG1341 (HSA-UK1→135). The limit of the EGF-like domain (UK1→46) present in the MstII-HindIII restriction fragment of the plasmid pYG1340 is indicated. The numbering of the amino acids corresponds to the mature chimeric protein SAU-UK1→135 (720 residues).
FIG. 9: Secretion of the HSA-UK1-46 and HSA-UK1-135 chimeras by the strain CBS 293.91 respectively transformed with the plasmids pYG1343 (HSA-UK1-46) and pYG1345 (HSA-UK1-135), after 4 days of growth (YPL+G418 medium). The deposits (equivalent to 50 μl of culture) are run on an 8.5% PAGE-SDS gel and stained with coomassie blue: supernatant from a clone transformed with the plasmids pKan707 (lane 1), pYG1343 (lane 3) or pYG1345 (lane 4); molecular weight standard (lane 2).
FIG. 10: Nucleotide sequence (SEQ ID NO:13) and amino acid sequence (SEQ ID NO:14) of the MstII-HindIII restriction fragment of the plasmid pYG1259 (HSA-G.CSF). The limit of the G-CSF part (174 residues) is indicated. The ApaI and SstI (SstI) restriction sites are underlined. The numbering of the amino acids corresponds to the mature chimeric protein HSA-G.CSF (759 residues).
FIGS. 11(a)-(d) together comprise the nucleotide sequence (SEQ ID NO:15) and amino acid sequence (SEQ ID NO:16) of the HindIII restriction fragment of the plasmid pYG1301 (chimera G.CSF-Gly4-HSA). The black arrows indicate the end of the “pre” and “pro” regions of HSA. The ApaI, SstI (SacI) and MstII restriction sites are underlined. The G.CSF (174 residues) and HSA (585 residues) domains are separated by the synthetic linker GGGG. The numbering of the amino acids corresponds to the mature chimeric protein G.CSF-Gly4-SAH (763 residues). The nucleotide sequence between the translation termination codon and the HindIII site comes from the HSA complementary DNA (cDNA) as described in Patent Application EP 361 991.
B, immunological characterization of the material secreted after using primary antibodies directed against the human G-CSF: same legend as in A.
FIG. 14: Nucleotide sequence (SEQ ID NO:17) and amino acid sequence (SEQ ID NO:18) of the MstII-HindII restriction fragment of the plasmid pYG1382 (HSA-Fv′). The VH (124 residues) and VL (107 residues) domains of the Fv′ fragment are separated by the synthetic linker (GGGGS)×3. The numbering of the amino acids corresponds to the mature chimeric protein HSA-Fv′ (831 residues).
FIG. 16: Assay of the in vitro antagonistic activity of the agglutination of human platelets fixed with formaldehyde: IC50 of the hybrids HSA-vWF694-708, [HSA-vWF470-713 C471G, C474G] and [HSA-vWF470-704 C471G, C474G] compared with the standard RG12986. The determination of the dose-dependent inhibition of the platelet agglutination is carried out according to the method described by C. Prior et al. [Bio/Technology (1992) 10 66] using an aggregameter recording the variations in optical transmission, with stirring, at 37° C. in the presence of human vWF, botrocetin (8.2 mg/ml) of the test product at various dilutions. The concentration of the product which makes it possible to inhibit the control agglutination (in the absence of product) by half is then determined (IC50).
FIG. 17: Activity on the in vitro cellular proliferation of the murine line NFS60. The radioactivity (3 H-thymidine) incorporated into the cellular nuclei after 6 hours of incubation is represented on the y-axis (cpm); the quantity of product indicated on the x-axis is expressed in molarity (arbitrary units).
FIG. 18: Activity on granulopoiesis in vivo in rats. The number of neutrophils (average for 7 animals) is indicated on the y-axis as a function of time. The products tested are the chimera HSA-G.CSF (pYG1266), 4 or 40 mg/rat/day), the reference G-CSF (10 mg/rat/day), the recombinant HSA purified from Kluyveromyces lactis supernatant (HSA, 30 mg/rat/day, cf. EP 361 991), or physiological saline.
The methods conventionally used in molecular biology, such as the preparative extractions of plasmid DNA, the centrifugation of plasmid DNA in caesium chloride gradient, electrophoresis on agarose or acrylamide gels, purification of DNA fragments by electroclution, extractions of proteins with phenol or phenol-chloroform, DNA precipitation in saline medium with ethanol or isopropanol, transformation in Escherichia coli, and the like are well known to persons skilled in the art and are widely described in the literature [Maniatis T. et al., “Molecular Cloning, a Laboratory Manual”, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., 1982; Ausubel F. M. et al. (eds), “Current Protocols in Molecular Biology”, John Wiley & Sons, New York, 1987].
The restriction enzymes were provided by New England Biolabs (Biolabs), Bethesda Research Laboratories (BRL) or Amersham and are used according to the recommendations of the suppliers.
The pBR322 and pUC type plasmids and the phages of the M13 series are of commercial origin (Bethesda Research Laboratories).
For the ligations, the DNA fragments are separated according to their size by electrophoresis on agarose or acrylamide gels, extracted with phenol or with a phenol/chloroform mixture, precipitated with ethanol and then incubated in the presence of phage T4 DNA ligase (Biolabs) according to the recommendations of the manufacturer.
The filling of the protruding 5′ ends is carried out by the Klenow fragment of DNA polymerase I of E. coli (Biolabs) according to the specifications of the supplier. The destruction of the protruding 3′ ends is carried out in the presence of phage T4 DNA polymerase (Biolabs) used according to the recommendations of the manufacturer. The destruction of the protruding 5′ ends is carried out by a controlled treatment with S1 nuclease.
Site-directed mutagenesis in vitro with synthetic oligodeoxynucleotides is carried out according to the method developed by Taylor et al. [Nucleic Acids Res. 13 (1985) 8749-8764] using the kit distributed by Amersham.
The enzymatic amplification of DNA fragments by the so-called PCR technique [Polymerase-catalyzed Chain Reaction, Saiki R. K. et al., Science 230 (1985) 1350-1354; Mullis K. B. and Faloona F. A., Meth. Enzym. 155 (1987) 335-350] is carried out-using a “DNA thermal cycler” (Perkin Elmer Cetus) according to the specifications of the manufacturer.
The verification of the nucleotide sequences is carried out by the method developed by Sanger et al. [Proc. Natl. Acad. Sci. U.S.A., 74 (1977) 5463-5467] using the kit distributed by Amersham.
The transformations of K. lactis with DNA from the plasmids for expression of the proteins of the present invention are carried out by any technique known to persons skilled in the art, and of which an example is given in the text.
Except where otherwise stated, the bacterial strains used are E. coli MC1060 (lacIPOZYA, X74, galU, galK, strAr), or E. coli TG1 (lac, proA,B, supE, thi, hsdD5/FtraD36, proA+B+, lacIq, lacZ, M15).
The yeast strains used belong to the budding yeasts and more particularly to yeasts of the genus Kluyveromyces. The K. lactis MW98-8C (a, uraA, arg, lys, K+, pKD1o) and K. lactis CBS 293.91 strain were particularly used; a sample of the MW98-8C strain was deposited on 16 Scp. 1988 at Centraalbureau voor Schimmelkulturen (CBS) at Baarn (the Netherlands) where it was registered under the number CBS 579.88.
A bacterial strain (E. coli) transformed with the plasmid pET-8c52K was deposited on 17 Apr. 1990 with the American Type Culture Collection under the number ATCC 68306.
The yeast strains transformed with the expression plasmids encoding the proteins of the present invention are cultured in erlenmeyers or in 21 pilot fermenters (SETRIC, France) at 28° C. in rich medium (YPD: 1% yeast extract, 2% Bactopeptone, 2% glucose; or YPL: 1% yeast extract, 2% Bactopeptone, 2% lactose) with constant stirring.
The plasmid pYG404 is described in Patent Application EP 361 991. This plasmid contains a HindIII restriction fragment encoding the prepro-HSA gene preceded by the 21 nucleotides naturally present immediately upstream of the initiator ATG for translation of the PGK gene of S. cerevisiae. The nucleotide sequence of this restriction fragment is included in that of FIG. 2. The MstII sitc localized in the coding sequence, three residues from the codon specifying the end of translation is particularly useful as site for cloning a biologically active peptide which it is desired to couple in translational phase at the C-terminus of HSA. In a specific embodiment, it is useful to use peptides whose sequence is encoded by an MstII-HindIII restriction fragment of the type: 5′-CCTTAGGCTTA [3×N]p TAAGCTT-3′ (SEQ ID NO:20), the sequence encoding the biologically active peptide (p residues) is [3×N]p). The ligation of this fragment to the HindIII-MstII restriction fragment corresponding to the entire gene encoding HSA, with the exception of the three C-terminalmost amino acids (leucin-glycine-leucin residues) generates a HindIII restriction fragment containing a hybrid gene encoding a chimeric protein of the HSA-PEPTIDE type (
In a specific embodiment, the combined techniques of site-directed mutagenesis and PCR amplification make it possible to construct hybrid genes encoding a chimeric protein resulting from the translational coupling between a signal peptide (and for example the prepro region of HSA), a sequence including the biologically active peptide and the mature form of HSA or one of its molecular variants. These hybrid genes are preferably bordered in 5′ of the translational initiator ATG and in 3′ of the translational stop codon by HindIII restriction sites and encode chimeric proteins of the PEPTIDE-HSA type (
The combined techniques of site-directed mutagenesis and PCR amplification described in Examples 1 and 2 make it possible to construct hybrid genes encoding a chimeric protein resulting from the translational coupling between the mature form of HSA, or one of its molecular variants, and a biologically active peptide coupled to the N- and C-terminal ends of HSA. These hybrid genes are preferably bordered in 5′ of the translational initiator ATG and in 3′ of the translational stop codon by HindIII restriction sites and encode chimeric proteins of the PEPTIDE-HSA-PEPTIDE type (
The chimeric proteins of the preceding examples can be expressed in yeasts using functional, regulatable or constitutive promoters such as, for example, those present in the plasmids pYG105 (LAC4 promoter of Kluyveromyces lactis), pYG106 (PGK promoter of Saccharomyces cerevisiae), pYG536 (PHO5 promoter of S. cerevisiae), or hybrid promoters such as those described in Patent Application EP 361 991. The plasmids pYG105 and pYG106 are particularly useful here because they permit the expression of the genes encoded by the HindIII restriction fragments as described in the preceding examples and cloned into the HindIII site and in the productive orientation (defined as the orientation which places the “prepro” region of albumin proximally relative to the promoter for transcription), using promoters which are functional in K. lactis, regulatable (pYG105) or constitutive (pYG106). The plasmid pYG105 corresponds to the plasmid pKan707 described in Patent Application EP 361 991 in which the HindIII restriction site which is unique and localized in the gene for resistance to geneticin (G418) has been destroyed by site-directed mutagenesis while preserving an unchanged protein (oligodeoxynucleotide 5′-GAAATGCATAAGCTCTTGCCATTCTCACCG-3′)(SEQ ID NO:21). The SalI-SacI fragment encoding the URA3 gene of the mutated plasmid was then replaced with a SalI-SacI restriction fragment containing an expression cassette consisting of the LAC4 promoter of K. lactis (in the form of a SalI-HindIII fragment) and the terminator of the PGK gene of S. cerevisiae (in the form of a HindIII-SacI fragment). The plasmid pYG105 is mitotically very stable in the Kluyveromyces yeasts and a restriction map thereof is given in FIG. 3. The plasmids pYG105 and pYG106 differ from each other only in the nature of the promoter for transcription encoded by the SalI-HindIII fragment.
The transformation of the yeasts belonging to the genus Kluyveromyces, and in particular the strains MW98-8C and CBS 293.91 of K. lactis is carried out for example by the technique for treating whole cells with lithium acetate [Ito H. et al., J. Bacteriol. 153 (1983) 163-168], adapted as follows. The growth of the cells is carried out at 28° C. in 50 ml of YPD medium, with stirring and up to an optical density of 600 nm (OD600) of between 0.6 and 0.8; the cells are harvested by centrifugation at low speed, washed in a sterile solution of TE (10 mM Tris HCl pH 7.4; 1 mM EDTA), resuspended in 3-4 ml of lithium acetate (0.1M in TE) in order to obtain a cellular density of about 2×108 cells/ml, and then incubated at 30° C. for 1 hour with moderate stirring. Aliquots of 0.1 ml of the resulting suspension of competent cells are incubated at 30° C. for 1 hour in the presence of DNA and at a final concentration of 35% polyethylene glycol (PEG4000, Sigma). After a heat shock of 5 minutes at 42° C., the cells are washed twice, resuspended in 0.2 ml of sterile water and incubated for 16 hours at 28° C. in 2 ml of YPD medium in order to permit the phenotypic expression of the gene for resistance to G418 expressed under the control of the Pkl promoter (cf. EP 361 991); 200 μl of the cellular suspension are then plated on selective YPD dishes (G418, 200 μg/ml). The dishes are incubated at 28° C. and the transformants appear after 2 to 3 days of cell growth.
After selection on rich medium supplemented with G418, the recombinant clones are tested for their capacity to secrete the mature form of the chimeric proteins. Few clones, corresponding to the strain CBS 293.91 or MW98-8C transformed by the plasmids for expression of the chimeras between HSA and the biologically active part, are incubated in YPD or YPL medium at 28° C. The cellular supernatants are recovered by centrifugation when the cells reach the stationary growth phase, optionally concentrated 10 times by precipitation for 30 minutes at −20° C. in a final concentration of 60% ethanol, and then tested after electrophoresis on an 8.5% SDS-PAGE gel, either directly by staining the gel with coomassie blue, or after immunoblotting using primary antibodies directed against the biologically active part or a rabbit polyclonal serum directed against HSA. During the experiments for immunological detection, the nitrocellulose filter is first incubated in the presence of specific primary antibodies, washed several times, incubated in the presence of goat antibodies directed against the primary antibodies, and then incubated in the presence of an avidin-peroxidase complex using the “ABC kit” distributed by Vectastain (Biosys S. A., Compiegne, France). The immunological reaction is then revealed by the addition of 3,3′-diamino benzidine tetrahydrochloride (Prolabo) in the presence of hydrogen peroxide, according to the recommendations of the manufacturer.
E.7.1. Fragments Antagonizing the Binding of vWF to the Platelets
E.7.1.1. Thr470-Val713 Residues of vWF
The plasmid pET-8c52K contains a fragment of the vWF CDNA encoding residues 445 to 733 of human vWF and therefore includes several crucial determinants of the interaction between vWF and the platelets on the one hand, and certain elements of the basal membrane and the sub-endothelial tissue on the other, and especially the peptides G10 and D5 which antagonize the interaction between vWF and GP1b [Mori H. et al., J. Biol. Chem. 263 (1988) 17901-17904]. This peptide sequence is identical to the corresponding sequence described by Titani et al. [Biochemistry 25, (1986) 3171-3184]. The amplification of these genetic determinants can be carried out using the plasmid pET-8c52K, for example by the PCR amplification technique, using as primer oligodeoxynucleotides encoding contiguous residues localized on either side of the sequence to be amplified. The amplified fragments are then cloned into vectors of the M13 type for their verification by sequencing using either the universal primers situated on either side of the multiple cloning site, or oligodeoxynucleotides specific for the amplified region of the vWF gene of which the sequence of several isomorphs is known [Sadler J. E. et al., Proc. Natl. Acad. Sci. 82 (1985) 6394-6398; Verweij C. L. et al., EMBO J. 5 (1986) 1839-1847; Shelton-Inloes B. B. et al., Biochemistry 25 (1986) 3164-3171; Bonthron D. et al., Nucleic Acids Res. 17 (1986) 7125-7127]. Thus, the PCR amplification of the plasmid pET-8c52K with the oligodeoxynucleotides 5′-CCCGGGATCCCTTAGGCTTAACCTGTGAAGCCTGC-3′ (SEQ ID NO:22) (Sq 1969, the MstII site is underlined) and 5′-CCCGGGATCCAAGCTTAGACTTGTGCCATGTCG-3′ (SEQ ID NO:23) (Sq2029, the HindIII site is underlined) generates an MstII-HindIII restriction fragment including the Thr470 to Val713 residues of vWF (
E.7.1.2. Molecular Variants:
In another embodiment, the binding site of vWF is a peptide including the Thr470 to Asp498 residues of the mature vWF. This sequence including the peptide G10 (Cys474-Pro488) described by Mori et al. [J. Biol. Chem. 263 (1988) 17901-17904] and capable of antagonizing the interaction of human vWF with the GP1b of the human platelets. The sequence corresponding to the peptide G10 is first included in an MstII-HindIII restriction fragment (
In another embodiment, the site for binding of vWF to GP1b is directly designed with the aid of synthetic oligodeoxynucleotides, and for example the oligodeoxynucleotides 5′-TTAGGCCTCTGTGACCTTGCCCCTGAAGCCCCTCCTCCTACTCTGCCCCCCTAAGCTT A-3′ (SEQ ID NO:26) and 5′-GATCTAAGCTTAGGGGGGCAGAGTAGGAGGAGGGCCTTCAGGGGCAAGGTCACAG AGGCC-3′ (SEQ ID NO:27). These oligodeoxynucleotides form, by pairing, a MstII-BgIII restriction fragment including the MstII-HindIII fragment (
Useful variants of the plasmid pET-8c52K are deleted by site-directed mutagenesis between the peptides G10 and G5, for example sites for binding to collagen, and/or to heparin, and/or to botrocetin, and/or to sulphatides and/or to ristocetin. One example is the plasmid pMMB9 deleted by site-directed mutagenesis between the residues Cys509 and Ile662. The PCR amplification of this plasmid with the oligodeoxynucleotides Sq1969 and Sq2029 generates an MstII-HindIII restriction fragment (
In other embodiments, the use of combined techniques of site-directed mutagenesis and PCR amplification makes it possible to generate at will variants of the MstII-HindIII restriction fragment of panel A of
In other useful variants of the plasmid pET-8c52K, mutations are introduced, for example by site-directed mutagenesis, in order to replace or suppress all or part of the set of cysteincs present at positions 471, 474, 509 and 695 of the human vWF. Specific examples are the plasmids p5E and p7E in which the cysteins present at positions 471 and 474, on the one hand, and at positions 471, 474, 509 and 695, on the other hand, have been respectively replaced by glycine residues. The PCR amplification of these plasmids with the oligodeoxynucleotides Sq2149 (5′-CCCGGGATCCCTTAGGCTTAACCGGTGAAGCCGGC-3′ (SEQ ID NO:28), the MstII site is underlined) and Sq2029 makes it possible to generate MstII-HindIII restriction fragments including the Thr470 to Val713 residues of the natural vWF with the exception that at least the cystein residues at positions 471 and 474 were mutated to glycine residues. The ligation of these fragments to the HindIII-MstII restriction fragment corresponding to the entire gene encoding HSA with the exception of the three C-terminalmost amino acids (cf.
Other particularly useful mutations affect at least one residue involved in vWF-associated type IIB pathologies (increase in the intrinsic affinity of vWF for GP1b), such as the residues Arg543, Arg545, Trp550, Val551, Val553, Pro574 or Arg578 for example. The genetic recombination techniques in vitro also make it possible to introduce at will one or more additional residues into the sequence of vWF and for example a supernumerary methionine between positions Asp539 and Glu542. E.7.2. Fragments Antagonizing the Binding of vWF to the Sub-Endothelium
In a specific embodiment, the sites for binding of vWF to the components of the sub-endothelial tissue, and for example collagen, are generated by PCR amplification of the plasmid pET-8c52K, for example with the oligodeoxynucleotides Sq2258 (5′-GGATCCTTAGGGCTGTGCAGCAGGCTACTGGACCTGGTC-3′ (SEQ ID NO:29), the MstII site is underlined) and Sq2259 (5′-GAATTCAAGCTTAACAGAGGTAGCTAA-CGATCTCGTCCC-3′ (SEQ ID NO:30), the HindIII site is underlined), which generates an MstII-HindIII restriction fragment encoding the Cys509 to Cys695 residues of the natural vWF. Deletion molecular variants or modified variants are also generated which contain any desired combination between the sites for binding of vWF to the sulphatides and/or to botrocetin and/or to heparin and/or to collagen and/or any residue responsible for a modification of the affinity of vWF for GP1b (vWF-associated type II pathologies). In another embodiment, the domain capable of binding to collagen may also come from the vWF fragment which is between the residues 911 and 1114 and described by Pareti et al. [J. Biol. Chem. (1987) 262: 13835-13841]. The ligation of these fragments to the HindIII-MstII restriction fragment corresponding to the entire gene encoding HSA with the exception of the three C-terminalmost amino acids (cf.
The chimeras present in the culture supernatants corresponding to the CBS 293.91 strain transformed, for example with the expression plasmids according to Examples E.7.1. and E.7.2., are characterized in a first instance by means of antibodies specific for the HSA part and for the vWF part. The results of
A fragment corresponding to the amino-terminal fragment of urokinase (ATF: EGF-like domain+ringle domain) can be obtained from the corresponding messenger RNA of cells of certain human carcinoma, for example using the RT-PCR kit distributed by Pharmacia. An MstII-HindIII restriction fragment including the ATF of human urokinase is given in FIG. 8. The ligation of the HindIII-MstII fragment of the plasmid pYG404 to this MstII-HindIII fragment makes it possible to generate the HindIII fragment of the plasmid pYG1341 which encodes a chimeric protein in which the HSA molecule is genetically coupled to the ATF (HSA-UK1→135). Likewise, the plasmid pYG1340 contains a HindIII fragment encoding a chimera composed of HSA immediately followed by the first 46 residues of human urokinase (HSA-UK1→46, cf. FIG. 8). The cloning in the productive orientation, of the HindIII restriction fragment of the plasmid pYG1340 (HSA-UK1→46) into the HindIII site of the plasmids pYG105 (LAC4) and pYG106 (PGK) generates the expression plasmids pYG1343 and pYG1342 respectively. Likewise, the cloning, in the productive orientation, of the HindIII restriction fragment of the plasmid pYG341 (HSA-UK1→135) into the HindIII site of the plasmids pYG105 (LAC4) and pYG106 (PGK) generates the expression plasmids pYG1345 and pYG1344 respectively.
E.8.2. Secretion of the Hybrids
After selection on rich medium supplemented with G418, the recombinant clones are tested for their capacity to secrete the mature form of the chimeric proteins HSA-UK. A few clones corresponding to the strain K. lactis CBS 293.91, which is transformed with the expression plasmids according to Example E.9.1., are incubated in selective complete liquid medium at 28° C. The cellular supernatants are then tested after electrophoresis on an 8.5% acrylamide gel, either directly by staining of the gel with coomassie blue, or after immunoblotting using as primary antibodies a rabbit polyclonal serum directed against human albumin or against human urokinase. The results of
E.8.3 Purification of the Chimeras Between HSA and Urokinase
After centrifugation of a culture of the CBS 293.91 strain transformed with the expression plasmids according to Example E.8. 1., the culture supernatant is passed through a 0.22 mm filter (Millipore) and then concentrated by ultrafiltration (Amicon) using a membrane whose discrimination threshold is situated at 30 kDa. The concentrate obtained is then adjusted to 50 mM Tris-HCl starlting with a stock solution of 1M Tris-HCl (pH 7), and then loaded in 20 ml fractions onto an anion-exchange column (3 ml) (D-Zephyr, Sepracor) equilibrated in the same buffer. The chimeric protein (HSA-UK1→46 or HSA-UK1→135) is then eluted from the column by a gradient (0 to 1M) of NaCl. The fractions containing the chimeric protein are then pooled and dialysed against a 50 mM Tris-HCl solution (pII 6) and reloaded onto a D-Zephyr column equilibrated in the same buffer. After elution of the column, the fractions containing the protein are pooled, dialysed against water and freeze-dried before characterization of their biological activity and especially with respect to their ability to displace urokinase from its cellular receptor.
E.9.1.1. Coupling at the C-terminus of HSA.
An MstII-HindIII restriction fragment including the mature form of human G-CSF is generated, for example according to the following strategy: a KpnI-HindIII restriction fragment is first obtained by the enzymatic PCR amplification technique using the oligodeoxynucleotides Sq2291 (5′-CAAGGATCC-AAGCTTCAGGGCTGCGCAAGGTGGCGTAG-3′ (SEQ ID NO:31), the HindIII site is underlined) and Sq2292 (5′-CGGGGTACCTTAGGCTTAACCCCCCTG-GGCCCTGCCAGC-3′ (SEQ ID NO:32), the KpnI site is underlined) as primer on the plasmid BBG13 serving as template. The plasmid BBG13 contains the gene encoding the B form (174 amino acids) of mature human G-CSF, which is obtained from British Bio-technology Limited, Oxford, England. The enzymatic amplification product of about 550 nucleotides is then digested with the restriction enzymes KpnI and HindIII and cloned into the vector pUC19 cut with the same enzymes, which generates the recombinant plasmid pYG1255. This plasmid is the source of an MstII-HindIII restriction fragment which makes it possible to fuse G-CSF immediately downstream of HSA (chimera HSA-G.CSF) and whose nucleotide sequence is given in FIG. 10.
It may also be desirable to insert a peptide linker between the HSA part and G-CSF, for example in order to permit a better functional presentation of the transducing part. An MstII-HindIII restriction fragment is for example generated by substitution of the MstII-ApaI fragment of the plasmid pYG1255 by the oligodeoxynucleotides Sq2742 (5′-TTAGGCTTAGGTGGTGGCGGT-ACCCCCCTGGGCC-3′ (SEQ ID NO:33), the codons encoding the glycine residues of this particular linker are underlined) and Sq2741 (5′-CAGGGGGGTACCGCCACCACCTAAGCC-3′) (SEQ ID NO:34) which form, by pairing, an MstII-ApaI fragment. The plasmid thus generated therefore contains an MstII-HindIII restriction fragment whose sequence is identical to that of
The ligation of the HindIII-MstII fragment of the plasmid pYG404 to the MstII-HindIII fragment of the plasmid pYG1255 makes it possible to generate the HindIII fragment of the plasmid pYG1259 which encodes a chimeric protein in which the B form of the mature G-CSF is positioned by genetic coupling in translational phase at the C-terminus of the HSA molecule (HSA-G.CSF).
An identical HindIII restriction fragment, with the exception of the MstII-ApaI fragment, may also be easily generated and which encodes a chimeric protein in which the B form of the mature G-CSF is positioned by genetic coupling in translational phase at the C-terminus of the HSA molecule and a specific peptide linker. For example, this linker consists of 4 glycine residues in the HindIII fragment of the plasmid pYG1336 (chimera HSA-Gly4-G.CSF).
The HindIII restriction fragment of the plasmid pYG1259 is cloned in the productive orientation and into the HindIII restriction site of the expression plasmid pYG105, which generates the expression plasmid pYG1266 (HSA-G.CSF). In another exemplification, the cloning of the HindIII restriction fragment of the plasmid pYG1259 in the productive orientation and into the HindIII site of the plasmid pYG106 generates the plasmid pYG1267. The plasmids pYG1266 and pYG1267 are mutually isogenic with the exception of the SalI-HindIII restriction fragment encoding the LAC4 promoter of K. lactis (plasmid pYG1266) or the PGK promoter of S. cerevisiae (plasmid pYG1267).
In another exemplification, the cloning in the productive orientation of the HindIII restriction fragment of the plasmid pYG1336 (chimera HSA-Gly4-G.CSF) into the HindIII site of the plasmids pYG105 (LAC4) and pYG106 (PGK) generates the expression plasmids pYG1351 and pYG1352 respectively.
E.9.1.2. Coupling at the N-terminus of HSA
In a specific embodiment, the combined techniques of site-directed mutagenesis and PCR amplification make it possible to construct hybrid genes encoding a chimeric protein resulting from the translational coupling between a signal peptide (and for example the prepro region of HSA), a sequence including a gene having a G-CSF activity, and the mature form of HSA or one of its molecular variants (cf. chimera of panel B, FIG. 1). These hybrid genes are preferably bordered in 5′ of the translational initiator ATG and in 3′ of the translational stop codon by HindIII restriction sites. For example the oligodeoxynucleotide Sq2369 (5′-GTTCTACGCCACCTTGCGCAGCCCGGTGGAGGCGGTGATGCACACAAGAGTGAGGT TGCTCATCGG-3′ (SEQ ID NO:35) the residues underlined (optional) correspond in this particular chimera to a peptide linker composed of 4 glycine residues) makes it possible, by site-directed mutagenesis, to put in translational phase the mature form of the human G-CSF of the plasmid BBG13 immediately upstream of the mature form of HSA, which generates the intermediate plasmid A. Likewise, the use of the oligodeoxynucleotide Sq2338 [5′-CAGGGAGCTGGCAGGGCCCAGGGGGGTTCGACGAAACACACCCCTGGAATAAGCC GAGCT-3′ (SEQ ID NO:36) (non-coding strand), the nucleotides complementary to the nucleotides encoding the first N-terminal residues of the mature form of the human G-CSF are underlined] makes it possible, by site-directed mutagenesis, to couple in translational reading phase the prepro region of HSA immediately upstream of the mature form of the human G-CSF, which generates the intermediate plasmid B. A HindIII fragment encoding a chimeric protein of the PEPTIDE-HSA type (cf.
E.9.2. Secretion of the Hybrids.
After selection on rich medium supplemented with G418, the recombinant clones are tested for their capacity to secrete the mature form of the chimeric proteins between HSA and G-CSF. A few clones corresponding to the strain K. lactis CBS 293.91 transformed with the plasmids pYG1266 or pYG1267 (HSA-G.CSF), pYG1302 or pYG1303 (G.CSF-Gly4-HSA) or alternatively pYG1351 or pYG1352 (HSA-Gly4-G.CSF) are incubated in selective complete liquid medium at 28° C. The cellular supernatants are then tested after electrophoresis on an 8.5% acrylamide gel, either directly by staining the gel with coomassie blue, or after immunoblotting using as primary antibodies rabbit polyclonal antibodies directed against the human G-CSF or a rabbit polyclonal serum directed against human albumin. The results of
E.9.3. Purification and Molecular Characterization of the Chimeras Between HSA and G-CSF.
After centrifugation of a culture of the CBS 293.91 strain transformed with the expression plasmids according to Example E.9.1., the culture supernatant is passed through a 0.22 mm filter (Millipore) and then concentrated by ultrafiltration (Amicon) using a membrane whose discrimination threshold is situated at 30 kDa. The concentrate obtained is then adjusted to 50 mM Tris-HCl from a 1M stock solution of Tris-HCl (pH 6), and then loaded in 20 ml fractions onto an ion-exchange column (5 ml) (Q Fast Flow, Pharmacia) equilibrated in the same buffer. The chimeric protein is then eluted from the column by a gradient (0 to 1M) of NaCl. The fractions containing the chimeric protein are then pooled and dialysed against a 50 mM Tris-HCl solution (pH 6) and reloaded onto a Q Fast Flow column (1 ml) equilibrated in the same buffer. After elution of the column, the fractions containing the protein are pooled, dialysed against water and freeze-dried before characterization: for example, the sequencing (Applied Biosystem) of the protein HSA-G.CSF secreted by the yeast CBS 293.91 gives the N-terminal sequence expected for HSA (Asp-Ala-His . . . ), demonstrating a correct maturation of the chimera immediately at the C-terminus of the doublet of residues Arg-Arg of the “pro” region of HSA (FIG. 2).
An Fv′ fragment can be constructed by genetic engineering techniques, and which encodes the variable fragments of the heavy and light chains of an immunoglobulin (Ig), linked to each other by a linker peptide [Bird et al., Science (1988) 242: 423; Huston et al., (1988) Proc. Natl. Acad. Sci. 85: 5879]. Schematically, the variable regions (about 120 residues) of the heavy and light chains of a given Ig are cloned from the messenger RNA of the corresponding hybridoma, for example using the RT-PCR kit distributed by Pharmacia (Mouse ScFv module). In a second stage, the variable regions are genetically coupled by genetic engineering via a synthetic linkage peptide and for example the linker (GGGGS)×3. An MstII-HindIII restriction fragment including the Fv′ fragment of an immunoglobulin secreted by a murine hybridoma is given in FIG. 14. The ligation of the HindIII-MstII fragment of the plasmid pYG404 to this MstII-HindIII fragment makes it possible to generate the HindIII fragment of the plasmid pYG1382 which encodes a chimeric protein in which the HSA molecule is genetically coupled to the Fv′ fragment of
E.10.2. Secretion of the Hybrids
After selection on rich medium supplemented with G418, the recombinant clones are tested for their capacity to secrete the mature form of the chimeric protein HSA-Fv′. A few clones corresponding to the strain K. lactis CBS 293.91 transformed with the plasmids pYG1383 or pYG1384 (HSA-Fv′) are incubated in selective complete liquid medium at 28° C. The cellular supernatants are then tested after electrophoresis on an 8.5% acrylamide gel, either directly by staining of the gel with coomassie blue, or after immunoblotting using as primary antibodies a rabbit polyclonal serum directed against human albumin, or directly incubated with biotinylated antibodies directed against the immunoglobulins of murine origin. The results of
E.11.1. Biological Activity In Vitro.
E.11.1.1. Chimeras Between HSA and vWF.
The antagonistic activity of the products is determined by measuring the dose-dependent inhibition of the agglutination of human platelets fixed with paraformaldehyde according to the method described by Prior et al. [Bio/Technology (1992) 10: 66]. The measurements are carried out in an aggregameter (PAP-4, Bio Data, Horsham, Pa., U.S.A.) which records the variations over time of the optical transmission, with stirring, at 37° C. in the presence of vWF, of botrocetin (8.2 mg/ml) and of the test product at various dilutions (concentrations). For each measurement, 400 ml (8×107 platelets) of a suspension of human platelets stabilized with paraformaldehyde (0.5%, and then resuspended in [NaCl (137 mM); MgCl2 (1 mM); NaH2 PO4 (0.36 mM); NaHCO3 (10 mM); KCl (2.7 mM); glucose (5.6 mM); HSA (3.5 mg/ml); HEPES buffer (10 mM, pH 7.35)] are preincubated at 37° C. in the cylindrical tank (8.75×50 mm, Wellcome Distriwell, 159 rue Nationale, Paris) of the aggregameter for 4 min and are then supplemented with 30 ml of the solution of the test product at various dilutions in apyrogenic formulation vehicle [mannitol (50 g/l); citric acid (192 mg/l); L-lysine monohydrochloride (182.6 mg/l); NaCl (88 mg/l); pH adjusted to 3.5 by addition of NaOH (1M)], or formulation vehicle alone (control assay). The resulting suspension is then incubated for 1 min at 37° C. and 12.5 ml of human vWF [American Bioproducts, Parsippany, N.J.; U.S.A.; 11% von Willebrand activity measured according to the recommendations for the use of PAP-4 (Platelet Aggregation Profiler®) with the aid of platelets fixed with formaldehyde (2×105 platelets/ml), human plasma containing 0 to 100% vWF and ristocetin (10 mg/ml, cf. p. 36-45: vW Program™] are added and incubated at 37° C. for 1 min before adding 12.5 ml of botrocetin solution [purified from freeze-dried venom of Bothrops jararaca (Sigma) according to the procedure described by Sugimoto et al., Biochemistry (1991) 266: 18172]. The recording of the reading of the transmission as a function of time is then carried out for 2 min with stirring by means of a magnetic bar (Wellcome Distriwell) placed in the tank and with a magnetic stirring of 1,100 rpm provided by the aggregameter. The mean variation of the optical transmission (n3 5 for each dilution) over time is therefore a measurement of the platelet agglutination due to the presence of vWF and botrocetin, in the absence or in the presence of variable concentrations of the test product. From such recordings, the % inhibition of the platelet agglutination due to each concentration of product is then determined and the straight line giving the % inhibition as a function of the reciprocal of the product dilution in log-log scale is plotted. The IC50 (or concentration of product causing 50% inhibition of the agglutination) is then determined on this straight line. The table of
E.11.1.2. Chimeras Between HSA and G-CSF
The purified chimeras are tested for their capacity to permit the in vitro proliferation of the IL3-dependant murine line NFS60, by measuring the incorporation of tritiated thymidine essentially according to the procedure described by Tsuchiya et al. [Proc. Natl. Acad. Sci. (1986) 83 7633]. For each chimera, the measurements are carried out between 3 and 6 times in a three-point test (three dilutions of the product) in a zone or the relation between the quantity of active product and incorporation of labelled thymidine (Amersham) is linear. In each microtitre plate, the activity of a reference product consisting of recombinant human G-CSF expressed in mammalian cells is also systematically incorporated. The results of
E.11.2. Biological Activity In Vivo
The activity of stimulation of the HSA-G-CSF chimeras on granulopoiesis in vivo is tested after subcutaneous injection in rats (Sprague-Dawley/CD, 250-300 g, 8-9 weeks) and compared to that of the reference G-CSF expressed using mammalian cells. Each product, tested at the rate of 7 animals, is injected subcutaneously into the dorso-scapular region at the rate of 100 ml for 7 consecutive days, (D1-D7). 500 ml of blood are collected on days D-6, D2 (before the 2nd injection). D5 (before the 5th injection) and D8, and a blood count is performed. In this test, the specific activity (neutropoiesis units/mole injected) of the chimera HSA-G.CSF (pYG1266) is identical to that of the reference G-CSF (FIG. 18). Since this specific chimera has in vitro a specific activity 7 times lower than that of the reference G-CSF (FIG. 17), it is therefore demonstrated that the genetic coupling of G-CSF onto HSA favourably modifies the pharmacokinetic properties thereof.
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|U.S. Classification||530/350, 435/252.3, 536/23.5, 435/69.7, 435/325, 435/320.1|
|International Classification||C07K14/53, A61P43/00, C07H21/04, C07K16/00, C12N1/19, A61K39/00, A61K38/22, A61K38/55, A61K47/48, A61K39/44, A61K38/16, A61K38/38, C07K14/47, C12R1/645, C07K19/00, E05B73/00, C07K14/52, C12N1/21, A61K38/21, C12N15/09, A61K38/43, C07K14/535, C12P21/06, C12N15/81, C07K14/745, C12P21/02, C12N15/62, B65B69/00, A61K48/00, C12N15/12, C07K14/76, C12N9/72, C07K14/765, A61K38/00, C07K14/755|
|Cooperative Classification||B65B69/00, C07K14/76, A61K47/48284, C12N9/6456, A61K38/38, C07K14/575, C07K2319/00, A61K38/21, C07K2319/31, C07K2319/02, C07K14/765, C07K14/755, A61K47/48269, C07K2319/33|
|European Classification||C12N9/64F21Q, C07K14/575, A61K47/48R2L, B65B69/00, A61K47/48R2F, A61K38/21, A61K38/38, C07K14/765, C07K14/755, C07K14/76|
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|Recurring tasks.||ScampMichael||5/13/09 5:18 AM|
Love the new 'tasks feature'. Would like to be able to schedule recurring tasks in the same manner as recurring events. As it is now, most of my recurring events are actually reminders of recurring tasks. Great work folks!
|Re: Recurring tasks.||Kitness||5/13/09 7:44 AM|
Would also like the recurring feature!
|Re: Recurring tasks.||Lhia||5/13/09 11:57 AM|
I also love the tasks feature in Gcalendar!
I have two tasks lists, with several itens in each, why can I only see one list at a time? And why does not show all my tasks in the calendar? It only shows either one or the other. Is it a but or is it supposed to be like this?
It would be awsome if it was possible to view all tasks at any moments, independatly of what list we have open.
|Re: Recurring tasks.||wesykema||5/13/09 1:05 PM|
+1 for recurring tasks!
|Re: Recurring tasks.||paulymer||5/13/09 2:34 PM|
I love having tasks in Calendar as well. I look forward to more feature enhancements - recurring tasks is a good one, and viewing all tasks simultaneously, instead of one list at a time, are two that I would love to see.
|Re: Recurring tasks.||bramhubbell||5/13/09 2:40 PM|
Yes, please make it possible to set up recurring tasks. And SMS reminders would be great as well.
|Re: Recurring tasks.||EGittines||5/14/09 6:32 AM|
Add me to the list of people who want the ability to enter recurring tasks.
|Re: Recurring tasks.||mkazzaz||5/20/09 12:07 PM|
Recurring Tasks please!!
Great work! Keep it up.
|Re: Recurring tasks.||dtsadf||5/20/09 9:10 PM|
Speaking for all members of a large family. We definitely need recurring options for tasks.
|Re: Recurring tasks.||ejeaglesct||5/21/09 12:01 PM|
I agree! Reoccuring events would be awesome!
|Re: Recurring tasks.||bdws1975||5/21/09 6:22 PM|
oh yes!!! please recurring tasks. I'm in love with GMAIL and calendar, etc. It's made my life so much easier!!!!!
|Re: Recurring tasks.||mmlambie||5/23/09 4:15 PM|
I just started using Tasks and immediately wanted to set up a recurring task. No such luck...yet, I hope. Recurring tasks PLEASE!!
|Re: Recurring tasks.||m2mayer||5/26/09 11:43 AM|
Recurring tasks should be easy to implement, so I hope it's just a matter of time before they include it.
|Re: Recurring tasks.||shusterlady||5/26/09 11:47 AM|
ditto on recurring tasks!
|Re: Recurring tasks.||CodeBangaa||5/28/09 12:32 PM|
Another for recurring tasks. Also, would like to be able to change events into tasks and vice versa, or spawn a task from a recurring event. How about associating tasks with calendars?
|Re: Recurring tasks.||jeffowentn||5/29/09 9:04 AM|
Ability to see multiple task lists at the same time and on the calendar at the same time
Ability to create tasks from events or events from tasks
|Re: Recurring tasks.||Ed Harriott||5/31/09 11:50 PM|
I talk up google calendar and gmail and blogger and on and on... all the time. A few things I would wish for...
1) recurring tasks.
2) pre-scheduled emails. I would love to pre-write an email and schedule a send for sometime next week, for example. This way I could take care of sending teams timely reminder messages without having to be near a computer when I want the message to go out.
3) SMS reminders of tasks due and/or auto-emailed to-do lists.
Thanks Google... You're awesome!
|Re: Recurring tasks.||rnielsen||6/6/09 2:31 PM|
I agree wholeheartedly on the desire for recurring tasks.
|Re: Recurring tasks.||yukino2002||6/7/09 12:13 PM|
I also agree on the recurring tasks. That would be awesome!
|Re: Recurring tasks.||ndaniell||6/8/09 10:59 AM|
I want recurring task!!!
|Re: Recurring tasks.||warmbers||6/10/09 12:52 AM|
Recurring tasks along with Birthdays from Contacts have be 2 obvious changes but make sure users can choose these options in settings. My Palm Pre will display the birthdays in calendar from contacts (which are sync'd and 'pushed' from my google contacts using the new fab EAS access) - make sure I don't end up with 2 Birthday details - or will this just be another win for Palm 'synergy'
|Re: Recurring tasks.||erangel||6/11/09 3:18 PM|
Please I need recurring tasks!!! and would be great birthday from contacts.
|Re: Recurring tasks.||bamasunshine||6/14/09 2:17 PM|
+1 for recurring tasks plz :)
|Re: Recurring tasks.||sajendra||6/16/09 8:40 AM|
I would also love the recurring tasks feature! It would be great if I could plan out my fitness schedule in advance (i.e. shoulder workout daily, leg workout every other day), and have the satisfaction of clicking the check box when I've done it for one day, and also noticing which days I missed.
|Re: Recurring tasks.||Old Goat||6/20/09 10:18 PM|
I also find that recurring tasks would be an imperative addition in order to make "Tasks" at all useful to me.
Tasks should be able to recur by the same options given for events, plus the option to recur annually by nth day of week in a particular month (e.g. 2nd Tuesday in March).
This additional recurrence option would be welcome for events, as well--not all annual events recur on a date (such as many holidays, change to or from DST, etc.).
|Re: Recurring tasks.||hochgurgler||7/7/09 5:27 PM|
Recurring tasks would be beautiful.
Think of this: Every January 1st a recurring tasks starts going to get me to book with the florist a delivery of flowers for my wife for Valentine's day.
The task should send me an e-mail message every day all the while the task is not completed. (Or, better yet, include its nudge in a daily digest of outstanding tasks e-mailed to me every day.)
I will have quite a few days when I am just too busy all day, but if I keep getting the nudge every day, I will likely get it done in time.
I am not a diary-oriented or task-organiser-oriented person, so I do not look at my diary or task-organiser every day. I do however look at my e-mail every day, pretty much without fail.
If I just get one reminder on January 1st, I might do it, but I might be too busy that day, and then forget about it.
I don't want to have to create a task for myself based upon a calendar reminder --- that is a trivial piece of work which the machine should do for me.
|Re: Recurring tasks.||curtcleancut||7/9/09 10:49 AM|
Please Please add recurring tasks!!!!
|Re: Recurring tasks.||PaulSchliep||7/9/09 3:38 PM|
I will drop RTM the instant that Google Tasks can create a recurring task as easily as a recurring calendar item.
|Re: Recurring tasks.||sammyboy405||7/14/09 11:14 PM|
Recurring Tasks is a Must have. I have Daily things I Do, and If I can put that in as a recurring that sure would save me time from having to hand enter current tasks that are repetitive.
|Re: Recurring tasks.||BrookeBook||7/29/09 9:18 AM|
I need this feature for Tasks to be the real replacement for other to-dos.
Also, please allow users to set a time for a task to be due, similar to events.
|Re: Recurring tasks.||Melissa92901||7/31/09 7:51 AM|
I WANT TASKS TO BE INCLUDED ON THE DAILY EMAIL AGENDA..........WHAT'S THE POINT OF HAVING THEM IF I DON'T GET REMINDERS THAT THEY'RE THERE?!?!?!?!?!?!
|Re: Recurring tasks.||Jackson Berry||8/10/09 12:47 PM|
I agree, please add a recurring task function.
|Re: Recurring tasks.||ifieatturkey||8/18/09 12:27 PM|
Recurring tasks woot!! Customizability always a plus!
(Well, up to a certain point...)
|Re: Recurring tasks.||xarophti||8/24/09 6:14 PM|
recurring tasks is definately a must. I like to set up a weekly reminder for a certain task that I like to "check off" so I'd really rather not make it an appointment. Would be especially helpful for things like medication reminders, etc.
|Re: Recurring tasks.||chimerical||9/1/09 4:03 PM|
+1 recurring tasks
|Re: Recurring tasks.||nitaj||9/2/09 7:05 AM|
+1 recurring tasks
|Re: Recurring tasks.||scotglen||9/9/09 12:27 PM|
Another vote for recurring tasks. :)
|Re: Recurring tasks.||jmadosky||9/9/09 7:03 PM|
Another vote for recurring tasks!
|Re: Recurring tasks.||Belsevy||9/14/09 11:35 AM|
Add my name to the petition for recurring tasks
|Re: Recurring tasks.||luckymojo||9/14/09 5:29 PM|
+1 recurring tasks
+1 tasks on daily emailed agenda
+1 all tasks from all lists visible
|Re: Recurring tasks.||hadasreich1||9/17/09 9:01 AM|
Yes please recurring tasks!
|Re: Recurring tasks.||jdavidgiese||9/20/09 8:23 AM|
I agree, it would be really, really useful to have recurring tasks.
|Re: Recurring tasks.||hwkns||9/25/09 9:25 PM|
Recurring tasks would be great! Also, mapping tasks to a specific time of day, not just an entire day - that would be wonderful. I like to keep track of my school assignments and when they're due, and I can't really do that with the current features of Gcal. Also, this does seem pretty easy to implement... why has it been more than four months since this was suggested?
|Re: Recurring tasks.||enobayram||9/29/09 5:54 AM|
|Re: Recurring tasks.||S_R||10/1/09 3:40 AM|
Yes PLEAAAASE Recurring Tasks.
|Re: Recurring tasks.||robfin||10/3/09 11:56 AM|
Add me to those who would appreciate a recurring task feature.
|Re: Recurring tasks.||dabbo65||10/13/09 4:59 AM|
Yes, recurring task and SMS reminder would be great.
|Re: Recurring tasks.||akchadwick||10/19/09 2:57 PM|
Definitely need recurring tasks, and I'm glad to see that so many others want this feature as well.
|Re: Recurring tasks.||Jenn Ogle||10/20/09 7:49 AM|
Add me to the list needing recurring events! I made a separate calendar for all my weekly/monthly recurring tasks, but it doesn't allow me to check things off as they are done.
|Re: Recurring tasks.||Acert93||10/26/09 7:53 PM|
Like Jenn Ogle above me, recurring events is a must! I, too, need the ability to mark off tasks on my daily/weekly lists. Would be a great addition!
|Re: Recurring tasks.||jrummell||10/27/09 8:04 PM|
+1 for recurring tasks!
|Re: Recurring tasks.||amandaw33||10/28/09 10:44 AM|
recurring events - please - this has been requested over and over!
|Re: Recurring tasks.||rick wintomac||11/1/09 5:06 PM|
recurring tasks is 'industry standard' . . . do it now. :)
|Re: Recurring tasks.||ataferner||11/9/09 11:04 AM|
Recurring Tasks is a must have feature!
|Re: Recurring tasks.||jenbeast1||11/20/09 3:34 AM|
yes recurring tasks!
|Re: Recurring tasks.||Splatter||11/23/09 9:09 PM|
Gotta agree with the above posters. I really need recurring tasks.
|Re: Recurring tasks.||jonralph1||11/29/09 1:35 AM|
Recurring tasks please
|Re: Recurring tasks.||leeep||11/29/09 3:49 AM|
recurring tasks is a pretty HUGE oversight on the design team... this is a necessity if this app is meant for prime time. please implement this asap.
|Re: Recurring tasks.||LadySlipper||12/5/09 5:06 AM|
Please, please recurring tasks......
|Re: Recurring tasks.||Avlor||12/7/09 5:09 PM|
Yes please recurring tasks!
|Re: Recurring tasks.||Suzeee||12/8/09 9:01 AM|
Yet another vote for a recurring task :o)
|Re: Recurring tasks.||rvasquez||12/11/09 1:40 PM|
YES!!!! Would also like the recurring feature!
|Re: Recurring tasks.||loribug26||12/15/09 9:45 AM|
Need to be able to be set as recurring AND have a reminder option!!! Please????
|Re: Recurring tasks.||petevaughan||12/17/09 11:22 AM|
|Re: Recurring tasks.||JorgeRocha||12/21/09 9:15 AM|
|Re: Recurring tasks.||zz74uty||12/21/09 7:28 PM|
Yes, please put in recurring tasks.
|Re: Recurring tasks.||neelsmalan||12/29/09 2:32 AM|
What beats me is that there is no answer from anybody from Google on this issue. Do you read this, Google?
|Re: Recurring tasks.||bonniefaust||1/4/10 10:42 AM|
i don't think google reads these threads...similar issues on the 'synch tasks' forum.
|Re: Recurring tasks.||Peednas||1/7/10 9:12 PM|
Someone from Google please implement this very easy feature!!
|Re: Recurring tasks.||D-M-C||1/8/10 10:46 AM|
Yet another request for the same feature.
|Re: Recurring tasks.||mysteryg45||1/9/10 1:27 PM|
|Re: Recurring tasks.||bryns||1/10/10 7:43 AM|
Me too ... I would also like this feature.
|Re: Recurring tasks.||Yodelaidan||1/12/10 8:30 AM|
1+ Recurring tasks feature!
|Re: Recurring tasks.||jtbbb||1/14/10 9:49 AM|
yep recurring tasks please
and a way to associate tasks to a calendar
|Re: Recurring tasks.||lubirdy||1/16/10 3:30 PM|
Need recurring tasks!!!! Using regular calendar for bills and tried to pay one twice. Sadly, not the first time it's happened. Please add them!!
|Re: Recurring tasks.||_Dutch||1/19/10 1:57 PM|
|Re: Recurring tasks.||Codemonkey85||1/22/10 7:12 AM|
I am also wanting a task due time, as well as recurrence options.
|Re: Recurring tasks.||flape||1/22/10 7:54 AM|
|Re: Recurring tasks.||chimezien||1/22/10 8:01 AM|
We need the Recurring Tasks feature and alter also
|Re: Recurring tasks.||Devin||1/22/10 9:36 AM|
Yes, recurring tasks please.
|Re: Recurring tasks.||kylejwisniewski||1/26/10 1:40 PM|
Yes, recurring tasks please.
|Re: Recurring tasks.||pama64||2/2/10 10:36 AM|
Would like recurring tasks and to see more than one task list sync to calendar-to have one place for everything would be ideal
|Re: Recurring tasks.||bravozula||2/2/10 1:44 PM|
Yes, yes, yes............please add "recurring" tasks as an option.
|Re: Recurring tasks.||bbfrog||2/5/10 7:41 AM|
Please, dear Google, make my tasks recurring! I need all the help I can get!
|Re: Recurring tasks.||smolina||2/11/10 6:52 PM|
I totally agree with this.
|Re: Recurring tasks.||BradJones||2/12/10 8:47 AM|
|Re: Recurring tasks.||shiznitz345||2/14/10 12:06 PM|
Would like recurring tasks and to see more than one task list sync to calendar-to have one place for everything would be ideal.That would be most helpful.
|Re: Recurring tasks.||blrose1228||2/22/10 2:31 PM|
Add me in too. Would love to see recurring task! Does anyone have any knowledge of when this might happen? Is Google hearing us??????? The first post about recurring task was way back in May of 2009. Come on Google....I know you have bigger stuff on your plate but this is important to us!!!!
|Re: Recurring tasks.||Futchy||2/25/10 6:26 AM|
Please add this feature google. Would make a great product even better.
|Re: Recurring tasks.||Gremlin||2/27/10 9:15 PM|
Me too please - recurring tasks!
|Re: Recurring tasks.||VioletGray||2/28/10 9:23 AM|
It's been quite some time since this issue was posed. Sorry to see no reply.
I subscribe to a need for recurring tasks.
|Re: Recurring tasks.||ElleRust||3/1/10 7:45 AM|
+1 Recurring Tasks
+1 all tasks from all lists option
+1 able to display multiple task lists at the same time
Would like to be able to prioritize by means other than date or order in the column (ideally two characters like A1, B3)
Would LOVE the ability to mark a task as "in progress" then change it to "done"
|Re: Recurring tasks.||denise.vajdak||3/6/10 6:22 AM|
We NEED recurring tasks-it's not an option. If we had Recurring tasks and alerts that we could set to go off at a specific time, then we wouldn't have to use external apps such as Remember the Milk. These should not be that difficult to program. It's the same as Calendar appointments except that they move forward if they are not completed.
Is anyone from Google out there? An acknowledgement would be nice.
|Re: Recurring tasks.||bushveld||3/18/10 4:44 AM|
One more vote for reocurring tasks !
|Re: Recurring tasks.||d.trapasso||3/18/10 11:39 AM|
One more vote for recurring tasks!
|Re: Recurring tasks.||tml12||3/19/10 11:06 AM|
PLEASE add me to the list of people requesting the following:
+1 Recurring Tasks, with options similar to recurring events in calendar (this is a BIG ONE ... PLEASE ADD ASAP!!)
+1 Option to select which task lists (or all task lists) are displayed in calendar, ** with sync to phone **
+1 Option to view all items on task lists simultaneously
+1 Option to prioritize by means other than date or order in the column (by some nifty prioritization system)
+1 Option to mark a task as "in progress" then change it to "done"
It would be much appreciated if someone from Google could address the status of this request? Are these ideas being considered or worked on? If so, is there an estimated date for completion?
The calendar & tasks applications are great, but would be so much more effective w/ these enhancements!!
Thanks so much!!
|Re: Recurring tasks.||ThePimento||3/19/10 11:35 AM|
Tasks needs to be made into Tasks as it's done in Outlook.
NotificationsShow days instead of Tasks Lists:
For instance, I have certain tasks to do on the 25th of the month, then the last day of the month, etc. Why not have a Task list view where it shows what's due Today, Tomorrow, Next Week, etc. so they all aren't grouped into one list. I'd like some separation so I know what day things need to be done.
My company is looking at switching to Google Apps, but this is the biggest drawback so far. People need tasks!
|Re: Recurring tasks.||windnwillows||3/28/10 6:14 AM|
Yet another vote for recurring task feature.
|Re: Recurring tasks.||ellegitimate||4/4/10 5:48 PM|
yes! recurring tasks! please!
|Re: Recurring tasks.||forgot2panic||4/7/10 10:06 PM|
Please add recurring tasks!
|Re: Recurring tasks.||smolina||4/11/10 4:07 PM|
Somebody of Google is reading this?
I also need recurring tasks. It's a must have feature.
There is another thread about the same thing: http://www.google.com/support/forum/p/Calendar/thread?tid=5d904904edb884c5&hl=en
|Re: Recurring tasks.||lifer||4/11/10 11:41 PM|
It appears that all agree that recurring tasks is a must have. The other must have is Tasks that rollover to the next day when they are not completed on the "due" date.
|Re: Recurring tasks.||Jtgates||4/27/10 9:30 AM|
sign me up, this would be very helpful.
|Re: Recurring tasks.||Rt_Bower||4/30/10 10:54 AM|
You would think that a useful calendar app would provide this without asking. What really bothers me, this damn request has gone unanswered and unfulfilled for about a year now. The same shit is happening with Google Docs feature requests. Google seems to have abandoned "Google Apps". Zoho doesn't provide this functionality either; but, at least they respond to requests with some answer and provide a road map with schedule for planned updates. Get on the stick Google. It can't be because you don't have enough money or staff!!!!!!!!!!
|Re: Recurring tasks.||foneguy||4/30/10 2:25 PM|
I'm a new GCal user. I just imported all my Outlook calendar items, went to lots of trouble re-creating all the recurring items, then discovered to my great disappointment that the recurring calendar items don't stick in a reminder list waiting to be checked off ("Dismissed" in Outlook).
A recurring tasks feature would fix this problem. Or, implement a Reminder List like in Outlook that requires each item to be manually checked off.
Without this capability, GCal (IMHO) is useless. Bummer I wasted so much time configuring it...
|Re: Recurring tasks.||forgot2panic||5/9/10 11:24 AM|
I love cal, gmail, reader, docs and all the google apps. I also love the simplicity of tasks. BUT we need recurring tasks asap! Please don't force me to use a third party solution. I want the same integration.
|Re: Recurring tasks.||smervincle||5/20/10 8:08 PM|
i cant believe it would be so complicated to create some a simple feature. this is a basic must have. wtf guys?
|Re: Recurring tasks.||weigelmom||5/27/10 7:09 PM|
Google, I love your gmail, gcalander and gcontacts...I've told a ton of people about it and I've switched to all paperless because Google is so great...make it a little bit better and add recurring tasks that will appear on my calander on the due date...This way I can keep track of when my bills are due...From a busy mom with a full time job and an ill husband, I beg you, please do this!
|Re: Recurring tasks.||Quincifari||6/1/10 1:45 PM|
Would like reoccurring tasks option/feature. Would also be nice to have the option to print the tasks with the calendar :-)
|Re: Recurring tasks.||essentiae||6/9/10 6:01 AM|
+1 for recurring tasks
|Re: Recurring tasks.||gaidigt||6/10/10 2:36 PM|
+1 for recurring tasks
|Re: Recurring tasks.||Rayynn||6/21/10 1:49 PM|
Would also like Reoccuring Tasks... and a comprehensive list view that shows ALL lists. It's nice to have in the calendar as well.. but I'd like to ONLY see tasks.
|Re: Recurring tasks.||wakabra||6/28/10 12:30 PM|
It would be sooooo nice to have recurring tasks!!!!
|Re: Recurring tasks.||ScampMichael||6/28/10 12:40 PM|
How do I unsubscribe from this post. I am currently receiving an email every time someone replies to this post and it is getting somewhat ridiculous.
I have tried clicking on '
unsubscribeUnsubscribe from answers to this question' from the individual emails and unchecking 'Email me when people reply' on the post. I've been doing this for months now and am still receiving the emails.
Anyone know how to get them to stop?
|Re: Recurring tasks.||EdFF||7/10/10 7:22 PM|
Can't understand why it isn't there yet
|Re: Recurring tasks.||LGeorge||7/16/10 8:13 AM|
I also need this feature!!!! Please make it happen!!!!
|Re: Recurring tasks.||ric3bowl||7/26/10 9:00 AM|
I use recurring tasks almost exclusively on my PIM. It's used for medication and they're usually the most important items that I need to check off (instead of set up recurring appointments, not a good work-around). I'd like recurring tasks as well, especially since it is these recurring tasks that I probably don't remember to do on the day they're due as compared to the tasks I set up either a few days in advance or even on the day of.
|Re: Recurring tasks.||a.brent.richards||7/29/10 10:49 AM|
I'll add my request for recurring tasks to the pile.
|Re: Recurring tasks.||EvelynWenzel||7/30/10 7:52 PM|
+1 on recurring tasks especially with the ability to recur at an interval after the previous was completed.
Daily e-mailed agenda sounds awesome too!
|Re: Recurring tasks.||leeep||8/5/10 1:49 PM|
why is this feature not implemented yet? this is a vital feature of any PIM software.
|Re: Recurring tasks.||foneguy||8/9/10 3:56 PM|
To all those who have asked "Why isn't this feature implemented yet?" :
The reason is simple: Google has an established track record of developing new web applications with just enough features to get you to start using them. Then they redirect their developers onto other projects leaving most of their users begging for fine-tuning and "finishing" that would actually make their apps 100% usable. My guess on Google Calendar is that there are NO actual developers 100% working on it now.
Google is only interested in implementing the bare minimum to allow them to data mine your life and communications, all for the purpose of selling more targeted ad clicks via the apps you use that are linked in your master Google account. In effect Google has become a one trick pony, which their CEO has openly admitted last week.
They know once you invest your time to set things up and start using their apps, it will be much harder for you to switch to something else. This is something they obviously count on since they feel they have no competition. Why jump through hoops if they don't have to?
I have personally witnessed this pattern with Google Voice, Google Calendar, and the Android apps for Gmail, etc. Until Google faces stiffer competition with their web apps, expect more of the same. However, history does repeat itself and eventually I think Google will regret their "just enough" strategy.
|Re: Recurring tasks.||nvsblmnstr||8/23/10 5:23 AM|
How, foneguy, do you explain the Data Liberation Front, then?
|Re: Recurring tasks.||clarke.pauley||8/30/10 11:55 PM|
+1 Recurring tasks. Is the task feature turned off on the calendar?
|Re: Recurring tasks.||Risket||9/2/10 9:35 PM|
I would love to see this feature also! I use my calendar to keep track of bills I need to pay. It would be much easier to keep track of what I have paid by being able to check them off and once they are checked the next occurrence of that task is added to the end of the tasks list.
Example: Cell Phone Bill due on September 3rd. Once I pay the bill I check it off. Cell Phone Bill due on October 3rd now appears on the Tasks list.
|Re: Recurring tasks.||mejpark||9/16/10 4:14 AM|
Love Google Tasks, love Google Calendar. This feature would be very useful. Thanks!
|Re: Recurring tasks.||skdfication||9/20/10 8:41 AM|
+1 Recurring tasks
|Re: Recurring tasks.||avb1005||9/20/10 11:56 AM|
Please, please, please add recurring tasks!
|Re: Recurring tasks.||djvaresi||10/1/10 11:36 AM|
+1 recurring tasks
+1 task reminders that operate exactly like the calendar reminders (or very similar, i.e. customizable reminder time, option of SMS, pop-up, or email).
Another suggestion that would be super-sweet to see would be some sort of "Task Priority/Importance" and variable reminder types based on that importance. For example, you could "star" important tasks the way you star emails in Gmail, and those starred tasks get the special privilege of all three reminder types because I'm a busy man and need to be harassed sometimes.
|Re: Recurring tasks.||091787||10/3/10 9:29 AM|
Fully agree with foneguy..
We are where we are because people are simply addicted to "free". Firefox is about to lose it's fabulous Xmarks service.. Why? No enough voluntary donations to keep it going! If Xmarks were to require paid subscriptions you know what will happen? People will move to the next free competing add-on. So people get what they deserve.. WHAT DO YOU EXPECT FOR FREE!!?? If you pay for a service then you can complain of the delay in improvements.. With Gmail we DO pay with our data though..
I would pay for something that competes with Gmail in a heartbeat.. and I just may do that.. But then I hope the vendor has enough support or I may get left high and dry someday.
|Re: Recurring tasks.||091787||10/3/10 9:50 AM|
Also, every additional feature is more server load for Google..
|Re: Recurring tasks.||lowspeed||10/5/10 12:56 PM|
This is a must feature!!!
|Re: Recurring tasks.||marketwizard74||10/12/10 4:02 PM|
Recurring Tasks would be a dream come true!!!
|Re: Recurring tasks.||Aleria||10/14/10 6:02 PM|
For those that are tired of waiting around for them to add the whole recurring tasks option I found a temporary work around that suits me just fine.
In the calendar settings under labs there is one called "Add any gadget by URL" http://code.google.com/apis/calendar/gadgets/sidebar/
If you enable this feature you can now use another gadget called "todoist" http://todoist.com/static/todoist_gadget/index_large.xml
Just enter that as the url of the gadget you'd like to add and you can setup your todoist account with as many different to do lists and very customizable recurring tasks right there in a side bar just as the normal "tasks" bar would be.
I started using it a few weeks ago and have fallen in love with it for managing my bill payment reminders. So much easier than going back through my bank account to try to remember what has been paid and what hasn't.
|Re: Recurring tasks.||mndt||10/15/10 5:35 AM|
Yes, I would like to set up a task to regenerate 1 day/week/month/year after the task is completed.
|Re: Recurring tasks.||eliyak||10/20/10 6:37 AM|
+1 for recurring tasks!
|Re: Recurring tasks.||Adrienne121||10/21/10 11:20 AM|
Hey Tasks Users!
Thanks for continuing to let us know which tasks features you'd like us to improve, we really appreciate your feedback. We'd also really appreciate it if you'd take a few minutes and vote on the Tasks ideas in this poll (or add new ones):
We're always working on bettering the experience with our products, so your feedback is very valuable in this process.
I'll be leaving the Poll up until Friday, November 19th. It'll become inactive in the early evening.
Thanks again for your time,
|Re: Recurring tasks.||allmoney.ws||10/31/10 8:21 AM|
1,5 year left - and we not have this feature :(
|Re: Recurring tasks.||nsentz||11/3/10 12:38 PM|
Yes, yes, yes for recurring tasks! Then I can give up Outlook.
|Re: Recurring tasks.||rustymaynard||11/19/10 5:58 AM|
i concur with requests above and additionally i would find sending SMS texts to tasks very helpful
|Re: Recurring tasks.||SSwaroop||11/28/10 11:13 AM|
Yes I do want recurring tasks, which work as reminders for credit card/utility payments which turn around every month.
|Re: Recurring tasks.||wakabra||12/2/10 10:28 PM|
Is google working a way to allow us to enter recurring tasks? ;o)
|Re: Recurring tasks.||lnhanna||12/17/10 6:58 AM|
Need the recurring task feature!!
|Re: Recurring tasks.||maltachemlabs||12/29/10 5:18 AM|
Recurring Tasks with alert facility would be awesome. I think the facility for a Gantt Chart for tasks would also be great but I don't want to get greedy. :)
|Re: Recurring tasks.||lusciousluka||1/5/11 9:06 AM|
Yes, tasks is one of the last missing features for me in the Google platform.
|Re: Recurring tasks.||brinlo||1/5/11 9:09 AM|
+1 recurring tasks
|Re: Recurring tasks.||leeep||1/13/11 6:11 PM|
It appears voting for this item on the ProductIdeas site is disabled. This feature really needs to be implemented already... it's been over a year now since the OP...
|Re: Recurring tasks.||srblush||1/14/11 12:32 AM|
If we can't get a recurring task feature how about a check box on events? Right now I have to create an event like "Credit card due" and make it recurring. Then I have to make a Task for the same thing so I can check it off when it is paid.What a hassle.
|Re: Recurring tasks.||Adrienne121||1/31/11 2:19 PM|
Thanks to everyone who participated in the Tasks feature request poll a few months ago! We were overwhelmed by the number of responses we received and are so excited to have everyone involved in the process.
We published a blog post last week with some of our results, I'd recommend checking that out if you have time:
Thanks again for participating and providing your feedback, we're looking forward to an exciting 2011!
|Re: Recurring tasks.||ShabbyX||1/31/11 7:37 PM|
Would also like recurring tasks
|Re: Recurring tasks.||dapneym||1/31/11 8:51 PM|
I'm very glad that Google will be working on adding repeating/recurring tasks to Calendar. I really love using Calendar (the interface is so clean and it's so easily accessed from anywhere), and repeating tasks will definitely make it significantly better.
+1 for repeating tasks :)
|Re: Recurring tasks.||christianguitarfreak||2/2/11 4:20 PM|
Add another to the list for recurring tasks
|Re: Recurring tasks.||Guy W.||2/3/11 9:02 AM|
Pretty pretty please can you work on creating recurring tasks ASAP?
|Re: Recurring tasks.||Quantum Faze||3/1/11 5:50 PM|
+1 Recurring Tasks
+1 Reminder for Task
|Re: Recurring tasks.||JMartinSNL||3/24/11 8:40 AM|
+1 Recurring Tasks
Please get on this! Outlook is running circles around your (our) calendar and task features!!
|Re: Recurring tasks.||ManWithCamera||4/25/11 11:44 AM|
I was just contemplating my needs for time management and I envisioned a tool for managing my time as a number of recurring tasks, which each recur on their own schedule. As the tasks reach their scheduled reminder point they would change color from white to green, and eventually turn to red if they were ignored for too long. This would allow me to balance all of my different priorities by reminding me of lower priority tasks which still need attention now and then. If a higher priority task (like exercise, for instance) has been handled recently, I could read a chapter in one of the four different books I've started but never finished, or read some blogs, change the cat litter, cut the grass, etc. If I know I have a device which will remind me of all the little things, eventually, I could more easily focus I what to do today, instead of being overwhelmed by EVERYTHING.
|Re: Recurring tasks.||sawthompson||6/17/11 1:32 PM|
Recurring tasks please
|Re: Recurring tasks.||ozy1234||7/8/11 9:06 AM|
Please add recurring tasks.
- a system we can use to prioritise tasks - colours/numbering/reordering.
- ability to click and postpone by a day or click and say bring all overdue to current.
|Re: Recurring tasks.||Nao Nozawa||7/8/11 12:03 PM|
Recurring tasks, please!
|Re: Recurring tasks.||WombatZ14||7/12/11 8:30 AM|
The lack of recurring tasks is really the only reason I am still using something other than Google Tasks. I see two years of posts asking for this feature; hopefully Google will add it soon, and finally bring this app in line with the same level of capability and quality that we've all come to know.
|Re: Recurring tasks.||jvandenbroek||7/23/11 7:38 AM|
Count me in, now I'm scheduling recurring events in Calendar, but would make much more sense to put them in Tasks! Now I'm not always sure if I've already done such task / event, which can be confusing.
|Re: Recurring tasks.||foneguy||8/3/11 4:58 PM|
Remember The Milk (http://www.rememberthemilk.com) is a very well-designed, well thought out recurring tasks tool that integrates nicely with Google Calendar.
IMHO, based on the kind of app design and inflexible "child-oriented" UI implementations I have seen out of Google lately, I highly doubt they will come even close to RTM.
If you want recurring tasks, use RTM. I've been using it for several months and it really is a very well designed and production quality utility.
|Re: Recurring tasks.||dhaus111||8/12/11 9:43 AM|
I would love to have recurring tasks. I'm using google calendar as a scheduled maintenance organizer for the boat I work on. Recurring tasks with as many options as possible (Such as "the first monday every six months") would be great. Another option would be to recur on a fixed date or a more dynamic one like 3 months from the time of completion. Also possibly a setting to have "task" be the default type as opposed to "event". Thanks google!
|Re: Recurring tasks.||robyngaylor||9/15/11 1:55 PM|
I notice this post was from 2 years ago, and it looks like recurring tasks is a number one issue...can anyone tell me why it has not been resolved? I would love the ability to create a task linked to a calendar entry as well.
|Re: Recurring tasks.||Spartanplantman||9/19/11 7:49 PM|
|Re: Recurring tasks.||davidagee||9/21/11 4:16 PM|
Is development dead on Google Tasks? This seems like something that should be fairly trivial, and it's been languishing for over two years? I can't find a single solution that allows me to manage a calendar and set up recurring to-dos. Outlook for OSX won't subscribe to my Google Calendar, and both iCal and Google Calendar lack recurring tasks.
|Re: Recurring tasks.||Michael.Fiedeldey||10/26/11 9:56 AM|
I would also greatly appreciate the recurring tasks feature. In fact, I haven't found that I've had any use at all for the current implementation of tasks, but I would use recurring ones all the time. Currently, I just add the task as a calendar entry and delete individual ones as I finish them, but it would be much less cumbersome if the tasks just popped into the task list at the appropriate times.
Change oil every three months
Check furnace filter every 6 months
Flip/rotate mattress every 3 months
Clean leaves out of gutters every November 1st
Pay VISA bill on the 14th of each month
|Re: Recurring tasks.||Elizabeth.L.Baker||11/17/11 10:04 AM|
Any hint anything is happening with this? I'm still waiting for recurring tasks. If they can have recurring events, how hard can it be to make recurring tasks?
|Re: Recurring tasks.||rwgtosu||11/29/11 8:52 AM|
+1 recurring tasks
I agree, this needs to be implemented, otherwise I will be moving to another solution. I am in desparate need to have a recurring weekly task automatically created and shared between myself and other employees that share the same calendar so that we can know when these tasks are completed. Our current helpdesk software has a solution, but it isn't elegant enough for an end user to figure out. I expected Google and their user friendly application would have had this simple solution already in place by this time. Very disappointed it isn't. Please make this possible!
|Re: Recurring tasks.||MaoMao||1/18/12 7:40 PM|
I can set recurring tasks for my Google Calendar using the "Gtasks" App for my Andoid mobile phone. But still cant do it from within the Calandar.
|Re: Recurring tasks.||ochekurishvili||3/11/12 3:49 AM|
Any updates on these improvements?
At least give us an approximate schedule when to expect these features implemented because it's been a whole year since this post and I can't see any of these listed tasks implemented.
|Re: Recurring tasks.||Mike Masi||3/30/12 5:45 PM|
I see that feature of gTasks but I don't see it showing up multiple times on my calendar like I'd like, so I think maybe it's just to remind you about the task at regular intervals. I'd prefer to see separate, check-able items on my calendar.
|Re: Recurring tasks.||edkiefer||4/9/12 4:59 AM|
This is a must for me also. Yes to reccuring tasks.
|Re: Recurring tasks.||ScampMichael||6/6/12 9:06 AM|
Now, we’re preparing to tackle some of your top requests. In no specific order, here are the top five feature requests that emerged from the Tasks product ideas page:
|Re: Recurring tasks.||NickQP||6/8/12 9:48 AM|
Hello! Micheal!! Hello!! In case you're still struggling with YOUR calender, it's actually 2012!!!!
|Re: Recurring tasks.||-=|MisterY|=-||7/20/12 5:14 AM|
|Re: Recurring tasks.||Zero0nee||8/1/12 5:45 AM|
|Re: Recurring tasks.||Fabio Lourenço||10/4/12 11:16 AM| |
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Before we jump into day three of "Camp questions", it's important to note that our first camp question — whether Donte Greene would make the Celtics — has already been answered with a big, fat no. Quick answer from Danny Ainge right there.
Alright, now on to the newest edition. Today, we're focusing on the salary dump in of all salary dump ins..Keith Bogans.
About Keith Bogans:
Bogans is an NBA journeyman. He was drafted by the Bucks in the 2nd round of the 2003 draft but quickly traded to the Magic for cash considerations. Since then he has played for:
- Orlando (2003-04)
- Charlotte (2004-06)
- Houston (2006)
- Orlando again (2006-09)
- Milwaukee (2009)
- San Antonio (2009-10)
- Chicago (2010-11)
- New Jersey (2011-12)
- Brooklyn (2012-13)
Of course, the last two were both with the Nets. But it just goes to show, even in an off-season where he stays put, he still moves. For his career the 33-year-old shooting guard has averaged 6.4 points, 2.7 rebounds and 1.3 assists per game while shooting 39.4% from the field. That low field goal percentage is largely linked to his propensity to shoot threes, as over 53% of his career attempts have been from deep, and he has knocked down a remarkably average 35.3% of those shots.
Bogans was part of the mega-deal with the Nets, and will make $5.06 million this season. He has team options for both 2014-15 and 2015-16.
1. Is Bogans sneakily a good trade chip?
When the Celtics and Nets made the famous "KG/Pierce" deal this summer, they needed more salary from the Nets to balance things out. The solution was to give Bogans, an NBA journeyman who made $1.2 million last season, a major pay raise to over $5 million this season. The contract had nothing to do with Bogans play, and everything to do with NBA trade rules. By signing-and-trading Bogans to Boston, the Nets could acquire Pierce, Garnett and Terry. And by agreeing to sign Bogans, the Celtics could simultaneously do two things:
A. Complete the trade and pick up a valuable $10.3 million trade exception from Brooklyn.
B. Give Bogans the necessary money for 2013-14, but make his future salaries non-guaranteed. This means that Bogans becomes a $5 million expiring contract this summer.
What does that mean for the Celtics? Well, it actually makes Bogans a fairly attractive trade chip. Expiring contracts always have value, and Bogans is actually the 25th largest expiring contract in the NBA this season. The Celtics also have the expiring contracts of Kris Humphries ($12 million) and Jordan Crawford ($2.1 million), giving them just over $19 million in expiring deals. This means that if the Celtics feel like there is a buy low superstar out there, they can package these deals with some of their other assets (namely the nine first round picks they have collected between 2015-2019) and try and make a move. Making Bogans deal even more attractive is that it has no guarantee date for next year, meaning he can actually be traded next summer and immediately waived by a team. This could be a very attractive chip for a team looking to dump a player as they can quickly slash $5 million off their payroll.
So yes, Bogan's deal is a pretty good trade chip. But that doesn't mean he's not incredibly overpaid. Which leads us to..
2. Is Bogans the worst player in basketball to be making over $5 million?
Take a look at this list. There are precisely 136 players making at least $5 million (not counting four retired players with cap holds of over $5 million), yet it is really difficult to find a worse player than Bogans on the list. Again, I'm not saying the most overpaid, or else Amar'e and his $22 million salary run away with the competition. But instead, is he the worst out of the 136 making at least $5 million?
I think he is. Sure Richard Jefferson is now useless, but at least he was still serviceable as recently as two seasons ago. And yea, Jason Richardson is injured, but the man still averaged double-figures last season when healthy.
A few other guys who join Bogans as $5M+ players that may not be in a rotation this season: Landry Fields and Michael Beasley. But both of them have the advantage of being young. Bogans on the other hand is 33. Advantage other guys.
3. Does Bogans have any shot of breaking the Celtics rotation?
Ok enough about Bogans salary. Let's talk about him as a player.
As we discussed a little in the "about" section, Bogans is not a very good offensive player. He can shoot the three a little bit, but that's his only real skill and he's actually slightly below average at it (Bogans career from three: 35.3%, NBA average: 35.9%). Besides that he doesn't bring much to the table.
His career rebounding percentage (% of rebounds that he grabs while on the floor) is only 7.3%. Well below average, even for a SG. His assist percentage (9.3%) is adequate until you look at his turnover percentage (which is 12.2%) and realize he turns it over a higher percentage of the time than he assists on a basket. His career PER is also only 9.6, considerably below league average (which is around 15). And if you've ever watched Bogans play, the eyeball test matches the advanced stats. He's kind of like the guard version of Jason Collins, somehow playing decent minutes without wracking up any tangible stats. You could watch Bogans for 20 minutes and not even notice him out there.
He has been lauded by past coaches, including former Celtics assistant and current Bulls coach Tom Thibodeau, for his defensive acumen and basketball IQ. But last year, the defensive ability appeared to slip big time. Here's a look at his last three full seasons (he only played five games in 2011-12 so we're throwing that one out).
All stats via Synergy Sports
2009-10 - 0.89 points per play (ppp) allowed (189th in the NBA)
2010-11 - 0.87 ppp allowed (173rd in the NBA)
2012-13 - 0.94 ppp allowed (392nd in the NBA)
By the way, NBA average is right around 0.85 ppp allowed, so it's not like Bogans started off as Avery Bradley and then slipped to average. He started off around average, and slipped to terrible.
So he's a veteran known for his smarts and defense, only he's not very good defensively. Not a good combination.
He's also fighting a massive uphill battle for playing time as he is one of five shooting guards on the roster (Bradley, Courtney Lee, MarShon Brooks and Jordan Crawford being the others). Considering all four of those guys are younger with more upside (not to mention better players), Bogans chances of being a contributor this year most likely revolve around at least one, and more than likely two of those guys going down with injuries. Let's hope it doesn't come to that.
Ok, not the rosiest of pictures on our good friend Keith. But remember, he's making $5 million this season to sit on the bench. So don't feel too bad for him.
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Michael Dyer 9/17/2013 04:08:00 PM Tweet Edit |
When tallying up the race to a billion users, I noted that both iOS and Android seem to have the potential to reach that size of user base. However, that raises the question of where those users will come from. We have to note the fact that there aren’t a billion users to be captured today.
If not today, then how soon, and where are they?
The first question is who is addressable. If we stick with mobile cellular subscribers, there seem to be plenty of users (at least 5.3 billion as of October 2010 according to the ITU). However, the number of “mobile broadband” (i.e. 3+G network subs) is about 940 million. The chart to the left shows the difference and adds the subdivision between developed and developing economies.
Over half (51.1%) of developed nations’ populations have signed up for mobile broadband while only 5.4% of developing country populations are on 3G. And whereas developing countries have added 2.6 billion mobile subs in 5 years, they added only 293 million mobile broadband (MB) subs. Developed nations added 574 million MBs in the same time frame.
As a result, two thirds of mobile broadband subscribers reside in developed nations as of 2010. This number will decrease rapidly as MB penetration reaches saturation in developed countries, however the race to a billion is being run in these markets first.
By one estimate (Gartner), about 81% of apps downloaded today are free. The way free apps are able to generate revenue is through advertising. 16 percent of application store markets’ $5.2 billion revenue was generated from advertising.
But advertising what?
Michael DeGusta created beautiful and informative charts on how The Newspaper Business Implodes.
With charts, he also told the story of how the recorded music industry followed a similar path:
Microsoft just declared the Zune end of life. This makes it a good time to look back to some notable episodes in the evolution of digital media distribution. First, an episode from 1997:
During two days on the stand, Tevanian accused Microsoft of seeking to divide the multimedia market and then “sabotaging” QuickTime’s ability to work with Windows computers when Apple declined to go along with Microsoft’s plan. Justice also is accusing Microsoft of attempting to illegally allocate the Internet browser market.
In particularly colorful testimony on Nov. 5, Tevanian described an April, 1997, meeting between two Apple and two Microsoft officials. Tevanian, who was not at the meeting, said Microsoft officials suggested that Apple abandon its business of providing “playback” software that enables users to view multimedia content on the computers. Instead, they offered Apple the much smaller portion of the market for the tools that developers use to create the content. In Apple’s mind, though, the playback software was its baby.
And a lot of folks in this tablet market are rushing in and they’re looking at this as the next PC. The hardware and the software are done by different companies. And they’re talking about speeds and feeds just like they did with PCs
Steve Jobs, iPad 2 launch event March 2011.
I’m not above doing a feeds and speeds comparison.
All the products above have dual core processors, 512 MB of memory. The iPad processor is a bit slower. The iPad also has a slightly smaller resolution screen than a MacBook from mid 2006. However, unlike the others, the iPad has cellular broadband connectivity, loads more sensors, and a battery that will last at least 5 times longer.
It’s also a lot cheaper and a lot smaller.
Although five years old, nobody would question that the MacBook or iMacs shown above are still computers. They still run the latest versions of OS X and are probably still in widespread use.
The new iPad is still not considered a computer by the majority of market analysts. One wonders how long this will go on. The specs of the iPad are just going to keep getting better…
Until very recently, we believed our competitive position in smartphones could be improved with Symbian, as well as MeeGo, and our strategy based on those platforms. We are now of the view, however, that for the longer term our Symbian platform is not sufficiently competitive in leading markets.
Nokia’s SEC Form 20F.
The company’s fiscal year, which ended in June, was one of the worst to date for the mobile space. Although in development since 2008, the Kin was pulled after just over six weeks of sales and amounted to a $240 million write-off before including the $500 million to buy Danger. Windows Mobile’s ramp down is partly intentional as Microsoft is rebooting the platform with Windows Phone 7 and is investing $500 million in marketing to spark new interest.
Microsoft CEO bonus cut for Kin flop, lack of iPad rival | Electronista
I was only half-joking when, on first sight, I tweeted that I will buy a new iPad 2 to go with my new Smart Cover. The new iPad cover is enchanting.
It also seems to be enchanting to many.
I’m estimating that at least 60% of iPad buyers will get one. Based on an estimate of 36 million iPads sold in 2011 and an average price of $48 (70% polyurethane and 30% leather mix), the total revenue for Smart Covers will top $1 billion this year.
I further estimate that with a very modest gross margin of 75% (average cost to produce of $12), the Smart Cover could contribute $777 million to Apple’s gross margins.
The iPad by itself should generate $23 billion in revenue and a contribution of $7.7 billion. That means that the Smart Cover will add 4% to sales and 9% to gross profits. If taken as a bundle, the iPad+SC will increase gross margin over the iPad alone by nearly 200 basis points (taking it from 33% to 35%).
It will be interesting to compare the Smart Cover business with competitor tablet businesses.
The following is a work of fiction.
The combination seemed unthinkable just a few years ago. Nokia envisioned itself as a substantial rival to Redmond, threatening to head off its computing dominance as the power of desktop computing shifted to pocket-size devices. But a series of miscues substantially weakened the company, leaving it little choice but to team up with the world’s largest software maker.
I last looked at the race to a billion in September 2010. I’ve now added a few more data points to the tracked platforms and also added points for the major console game platforms and Symbian.
The chart shows the cumulative number of users (approximated by units sold) for 11 platforms indexed to the same starting date. The horizontal axis is the number of quarters since a platform launched. Every fourth quarter is numbered so each number on the axis represents a new year. The last number on the axis represents 10 years.
The vertical axis is the cumulative number of users on a logarithmic scale. Each number of the vertical axis is 10x more users than the previous number. The top of the graph represents a billion users.
The overall chart shows how quickly a platform has grown and is bounded by a billion users and a decade of usage.
John Siracusa dusted off an interesting quote from a former Microsoft employee.
Spolsky: But synergy…there are also negative synergies. In the case of Microsoft they call it “strategy tax.” Where, like, the Internet Explorer team is not allowed to fix the DHTML editor because it might compete with Word. So they’re forced to make that continue to be bad.
Via: The Apple strategy tax
The notion is an interesting one and is a reframing of the metaphorical expression that those who live by the sword die by the sword: Building a business a certain way will, in the end cause it to perish by that way.
In the case of Microsoft, the focus on their platform lock-in strategy binds them into avoiding compelling opportunities and, even more tellingly, keeps them from improving existing products.
It’s tempting to suggest that this “strategy tax” also applies to a company like Apple when it seems to act irrationally or sub-optimally to some arbitrary definition of optimality.
However, what if Apple’s motives are not “strategic”? What if Apple actually does act in a way to optimize what they perceive to be important: the end user experience or as I like to call it “the product“.
What if “the product” is dogma and nothing is allowed to compromise it? |
Debuting at Cityscape Global 2014, the design of One at Palm is a global effort involving Soma of New York, Super Potato of Japan and Vladimir of Lebanon
[UAE, 31 August 2014] - Omniyat, a leading developer in the Middle East, and Drake & Scull International PJSC (DSI), a major player in the region’s construction industry, have entered into a partnership to build a landmark project strategically located at the entrance of the Palm Jumeirah.
Expected to be one of the most significant projects to make debut at the forthcoming Cityscape Global 2014, One at Palm Jumeirah is jointly developed by both companies and will be managed by Omniyat. The enabling works is due to commence within the next two months.
Khaldoun Al Tabari, CEO and Vice-Chairman of DSI PJSC said: “We are delighted to partner with Omniyat to create a unique landmark on the iconic Palm Jumeirah skyline. Our 48 years’ expertise with high rise tower projects around the world will prove vital to delivering a project worthy of this prestigious location. We are confident that the synergy of our combined experience and Construction capabilities will deliver a new milestone on Dubai’s urban architecture. Omniyat’s track record of developing such high profile projects will complement our regional experience and we hope to enter into similar partnerships in the future.”
Mahdi Amjad, Executive Chairman and CEO of Omniyat, said: “Omniyat is very excited about developing this magnificent, super-luxury real estate project situated at the entrance of The Palm Jumeirah.”
“We believe this plot is the perfect location to build such an iconic development that will be a global collaboration with inputs from Dubai, Japan, New York and Lebanon. It will definitely stand out on the Dubai skyline,” Amjad added.
He elaborated: “We couldn’t have found a more competent partner than DSI to co-develop this landmark project, given their 48 years of excellence in the construction industry. The combination of DSI’s expertise and Omniyat’s multi-disciplinary leading credentials is set to create an outstanding piece of architecture that will add to Dubai’s list of numerous outstanding world projects.”
“The luxury residential building will be designed by internationally renowned architects Soma from New York, Super Potato from Japan and Vladimir from Lebanon. The building will offer 360-degree breathtaking views, with apartment sizes ranging from 2,500 to 20,000 square feet,” Amjad said. “The finishing will be handled by famed interior designers. The combined expertise of these world-class firms is guaranteed to create a unique, high-end extraordinary development.”
Internationally renowned Japanese design firm Super Potato is known for its sophisticated designs for the interiors of restaurants, shops and hotels. Super Potato's work has had a significant impact on interior design in Japan and around the world.
Vladimir Djurovic Landscape Architecture is engaged in the creation of timeless landscapes through its commitment to drawing out the uniqueness of an environment with simplicity of gesture that gives nature the stage. The firm’s expertise extends from escapist retreats and private residences, to the planning and development of boutique hotels, resorts and public urban spaces.
SOMA is a New York-based firm of architects with a portfolio and expertise in refurbishment and sustainability. SOMA’s work, mainly in New York, Dubai, Qatar, Erbil and Lebanon, covers projects across several industries as well.
“Our objective is to maximize shareholders’ value by designing and developing unique and prestigious Real Estate developments,” Amjad concluded. |
Judaism And Health: A Handbook of Practical, Professional and Scholarly Resources
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A Practical Guide to Rabbinic Counseling By Yisrael N. Levitz and Abraham J. Twerski
An integral and important work for every rabbi and community leader. This book puts the essential elements of rabbinic counseling into the hands of those who need it most. Rabbis and leaders often find themselves doing formal and informal counseling--but with little or no experience, opportunities can be lost and damage can be done. Here are practical tools to facilitate better communication and assistance, user-friendly and eminently practical. Dr. Levitz is a clinical psychologist, former pulpit rabbi, and Professor Emeritus of Yeshiva University's Wurzweiler School of Social Work. Rabbi Dr. Twerski is a noted psychiatrist and former pulpit rabbi who has published close to fifty self-help books and specializes in addictions and rehabilitation. This book will be of interest and of essence to every rabbi, rebbe, and spiritual or community leader.
Professional Spiritual & Pastoral Care Edited by Rabbi Stephen B. Roberts, MBA, MHL, BCJC
Edited by Rabbi Stephen B. Roberts, MBA, MHL, BCJC
This essential resource integrates the classic foundations of pastoral care with the latest approaches to spiritual care. It is specifically intended for professionals who work or spend time with congregants in acute care hospitals, behavioral health facilities, rehabilitation centers and long-term care facilities. Offering the latest theological perspectives and tools, along with basic theory and skills from the best pastoral and spiritual care texts, research and concepts, the contributors to this resource are experts in their fields, and include eight current or past presidents of the major chaplaincy organizations.
Purchase at Skylight Paths
Flourishing In the Later Years: Jewish Pastoral Insights on Senior Residential Care Edited by James R. Michaels and Cary Kozberg
Flourishing In the Later Years
was created for anyone who works with Jewish residents living in senior residential facilities, whether under Jewish auspices or otherwise. It addresses issues that are of interest not only to chaplains but also to social workers, nurses, PT/OT specialists, administrators, and interested laity.
Purchase at Mazo Publishing
of Soul, Healing of Body: Spiritual Leaders Unfold the Strength
and Solace in Psalms
Edited by Rabbi Simkha
Y. Weintraub, LCSW
A source of solace for those who are facing
illness, as well as those who care for them. These Psalms and
the inspiring commentaries that accompany them offer an anchor
of spiritual support.
at Jewish Lights
Guide Me Along the Way: A
Jewish Spiritual Companion for Surgery
By Rabbi Simkha Y. Weintraub,
LCSW with Rabbi Aaron M. Lever
A 60-page Jewish guidebook with poetry,
prayers, folktales, personal narratives, practical advice,
healing activities and meditations to help patients, family
members, clergy and health care professionals through the surgery
experience, from leaving home to the year anniversary of an
are inspirational, informational
booklets about challenges to our emotional and spiritual lives
and how to deal with them.
is written by a wise
and caring soul, someone you probably know or know about, someone
who knows the inner territory of grief, doubt, confusion and
longing. Each addresses the reader from a uniquely Jewish spiritual
The National Center for Jewish Healing
(NCJH) helps communities better meet the spiritual needs of
Jews living with illness, loss and other significant life challenges.
Working closely with a network of Jewish healing
centers and programs throughout North America the NCJH offers
consultation, training and referrals to community resources.
Jewish spiritual resource and programmatic materials, publications,
bibliographies, website links and a directory of Jewish healing
centers are available on this website.
The Association for Clinical Pastoral Education,
Inc. (ACPE) is a multicultural, multifaith organization devoted
to providing education and improving the quality of ministry
and pastoral care offered by spiritual caregivers of all faiths
through the clinical educational methods of Clinical Pastoral
Education. This site (
describes the Association, accredited training centers, Prospective
Student Information and Frequently Asked Questionsand applications.
The Jacob and Hilda Blaustein Center for Pastoral
Counseling, established by The Jacob and Hilda Blaustein Foundation
of Baltimore, Maryland provides educational opportunities for
students and alumni in pastoral counseling and chaplaincy at
both the New York and Jerusalem campus. Learn more about pastoral
care training here.
The NAJC mission is to enhance the kedusha
of Jewish Chaplains in order that they may provide quality
Jewish, religious, and spiritual care.
NAJC is a professional organization for Rabbis,
Cantors, and other Jewish professionals functioning as Jewish
Chaplains in hospitals, nursing homes and geriatric centers,
hospice, psychiatric facilities, correctional centers, and the
military. In addition to offering collegial support to and professional
certification of Jewish Chaplains, NAJC provides conferences
and ongoing resources to its members to foster services to and
resources for the Jewish and general community on issues of pastoral
and spiritual care based on Jewish traditions and values. This
site lists information about the Association, membership and |
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Sony Corp Chief Executive Kazuo Hirai has said that the Japanese company was not thinking of splitting off or listing its entertainment business. Hirai was responding to a question at an annual shareholders meeting.
Sony rebuffed a proposal last year by investor Daniel Loeb, chief of hedge fund Third Point, to partially spin off its entertainment business to unlock shareholder value. Hirai has repeatedly said since then that retaining full ownership of the entertainment unit is important for synergy across Sony.
Hirai also acknowledged at the meeting that Sony had not responded quickly enough to tough market conditions in its electronics division, which he has failed to make profitable despite promises to do so when he took the helm two years ago. |
West Hollywood's new Sundance Sunset Cinemas is readying for its formal debut on Aug. 31, but a few days before members of the Redford clan will throw a housewarming party by hosting a movie-themed…
Ted Turner's Superstation TBS marked the start of basic cable, and he pioneered made-for-basic-cable programming. His TBS-Atlanta Braves synergy rewrote the rules of sports broadcasting. His CNN was…
Robert Fitzgerald, an attorney who worked with Lew Wasserman at MCA and later with David Wolper, died Jan. 18 in Santa Barbara, Calif., after a lengthy illness. He was 86.
2016-2017 Oscar Predictions
Joseph Stein, who wrote the book for tuner "Fiddler on the Roof," died Oct. 24 in Manhattan from a fall. He was 98 and had been ailing from prostate cancer.
David L. Wolper, the prolific producer who spearheaded such landmark TV and film productions as "Roots," "The Making of the President 1960" and Jacques Cousteau's early specials, has died. He was 82.
Editor David Blewitt, who cut such 1980s blockbusters as "Ghostbusters," died on July 8. He was 81.
Leading French production outfit Pan Europeenne is developing a $37 million 3D biopic on pioneering French oceanographer and filmmaker Jacques-Yves Cousteau.
As d.p. for "Sin nombre," Adriano Goldman spent a week on top of real moving trains and replicas built for the film, 99% of which was shot using handheld cameras. Working closely with director Cary…
MK2 has obtained the 10 year rights to most of the film catalog of Jacques-Yves Cousteau from Europe Images International. The cinematic collection of one of the pioneers of underwater photography…
German toon distrib BKN Intl. has wrapped its fiscal year ended Sept. 30 with steady growth in revenue and net profit.
The most engaging aspect of David L. Wolper's entertaining, exceedingly informative memoir is the fun he seems to have had during almost every moment of his long and successful career. His enjoyment… |
NEW YORK, NY--(Marketwire - May 03, 2010) - MedLink (OTCBB: MLKNA), a leading healthcare IT provider of Electronic Health Record (EHR), practice management, and clinical integration software to the medical community announced today a partnership with iMedicor (OTCBB: VMCI). The partnership will provide a natural synergy of combined solutions that will enable enhanced information exchange capabilities to increase the efficacy of the RHIO Financial Sustainability Model by integrating the iMedicor information exchange portal and MedLink TotalOffice solution to facilitate secure messaging and CCR/ CCD exchange for its users. In addition, TotalOffice users will have access to iMedicor's ClearLobby platform that will provide informative, product specific content on new drugs and medical devices enabling users to directly communicate electronically with the manufacturers to order samples, ask questions and set up onsite meetings. ClearLobby establishes an additional revenue driver to the RHIO sustainability model, allowing for RHIOs to minimize their reliance on grant funding to provide a comprehensive health information exchange to its members.
iMedicor's pharma marketing platform, "ClearLobby," offers the first of its kind physician / pharma electronic communication system resulting in interactions that are much more meaningful and efficient. ClearLobby changes the dynamic of these relationships by placing control squarely in the hands of the physician. At the same time, the interaction between the physician and the pharma becomes more cost effective because ClearLobby is able to distribute critical product information and samples directly to the targeted user base.
iMedicor is the only HIPAA-compliant solution for interoperable medical information transfer that is offered at no cost to healthcare providers and patients. The iMedicor portal also enables doctors, administrators and other qualified healthcare workers to send and receive medical records, files and images in a secure, HIPAA compliant environment; allows disparate EMR (electronic medical record) systems to communicate, collaborate and exchange records in real time; and allows pharmaceutical companies to deliver customized marketing programs to healthcare providers nationwide in a highly targeted, cost-effective and non-intrusive manner. More information on iMedicor is available at www.imedicor.com.
MedLink is a healthcare IT company that provides the medical community with products and services designed to help create, manage, and share medical information. The company's flagship product, MedLink TotalOffice EHR 3.1, a CCHIT Certified® 08 Ambulatory EHR, provides physicians with full EHR and practice management functionality. For more information regarding MedLink's products and services, please visit www.medlinkus.com.
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This news release may contain forward-looking statements within the meaning of the federal securities laws. Statements regarding future events, developments, the Company's future performance, as well as management's expectations, beliefs, intentions, plans, estimates or projections relating to the future are forward-looking statements within the meaning of these laws. These forward-looking statements are subject to a number of risks and uncertainties, outlined in our 2009 Annual Report on Form 10-K available through www.sec.gov. The Company undertakes no obligation to update publicly any forward-looking statement, whether as a result of new information, future events or otherwise. |
After Booster Draft became the Limited format of choice for professional players, Sealed Deck started to get a bad rap. Many players even started to refer to it as “Sealed Luck”. I embraced Draft and put together a string of strong finishes at Draft Pro Tours and Grands Prix. Fellow Hall of Famer Rob Dougherty continued to feel that Sealed Deck was the better format. While he admitted that there was a lot of luck involved in the contents of the card pool you received, he felt that Draft had its own problem variables.
The big difference he pointed out was that at least in Sealed, your card pool didn’t have to worry about human interference. In a Draft, you might be sitting between random drafters picking unpredictably and making it hard for you to end up with a good Draft pool while others at your table might be sitting in a more favorable position. In addition, there is still randomness in the packs you open and in the packs opened around you. What if the person on your left opens an amazing planeswalker in your colors in pack two and decides to switch into your colors?
Wizards of the Coast doesn’t seem to agree with Rob because they seem to have moved away from using Sealed Deck for their highest levels of events. I finished second in the first Sealed Deck Pro Tour in Atlanta, but it was also the last Sealed Deck Pro Tour. I won the first Massachusetts Sealed Deck State Championship, but it was also the last such event. Whichever you prefer, both formats still matter, though, especially if you’re playing in Limited Grands Prix, where they’re both used in the same event. As I prepared for Grand Prix: Nashville, I built and tested several Sealed Deck pools. This has led me to some strong conclusions about how to approach building Sealed pools in Innistrad block.
The biggest question you have to answer when examining your Sealed pool is which direction your pool is best able to go. There are two main archetypes to consider for Sealed:
- A bomb deck – Typically, the best Sealed decks are ones with multiple expensive bombs and with the ability to keep you alive until you can start playing those bombs.
- An aggressive deck – If your card pool can’t do that, the other exciting option is to try to build an aggressive up-tempo deck designed to kill your opponents before they can start dominating the games with their bombs.
If you can’t build a solid version of one of these two archetypes, you’re probably in for a long day. So, the first step is determining if you can build the bomb deck. If you have too few bombs, your bombs are spread out over too many colors, or you don’t think you can build a deck designed to hold your opponent off while getting ready to play your bombs, you should check out your aggro options.
There are several things you should look for when considering your aggro options:
Having a good mana curve of creatures is way more important in an aggressive deck than in a bomb deck. Aggro also needs to have a lower curve than a bomb deck. A bomb deck is happy to spend early turns on card-draw, removal, or mana development as long as its life total isn’t in too much danger. An aggressive deck needs to bring as much creature pressure as possible to bear as early as possible. A bomb deck will often forgo 1-drops and only have three or four 2-drops. An aggressive deck should have the 1- and 2-mana slots well stocked with aggressive creatures—especially 2-drops.
Small, non-evasive creatures are usually pretty bad in Innistrad Sealed. Your opponent will usually have a deck designed to stall the game until he can start dropping bombs. Your best bet is to just bypass your opponent’s potential blockers with flyers, perhaps an Invisible Stalker, or even some intimidate. The most successful aggressive decks I’ve played in this format have all been W/U decks with a lot of flyers. It makes it hard for my opponent to stall the game and often allows me to win the game even after he plays a bomb.
Pretty much any creature removal is good in any Sealed deck. Having some removal for big creatures can make an aggressive deck a lot better, though. If you’re hitting your opponent with a couple small creatures and he plays a medium-sized creature expecting to stabilize, it can be devastating when you just kill it and keep attacking. It’s also nice if you can kill a bomb creature if your opponent plays one.
While evasion and removal are great in both archetypes, pump is much better suited to an aggressive deck. A bomb deck might not have creatures in play early that need to be pumped, and the deck might not have time to leave mana open for pump. When opponents start dropping bomb creatures, pump should be overkill. Not only is pump better for aggressive decks, it’s almost essential. Having a pump spell like Moment of Heroism or Spidery Grasp in hand can allow you to just keep swinging with everyone when an opponent drops a big creature in hopes of stopping your offense in its tracks.
A really big part of playing aggression in Sealed is making sure you have enough ways to win once your opponent starts to stabilize, thus making evasion, removal, and pump so sexy. Like pump, being able to damage your opponent directly isn’t really part of what makes for a good bomb deck, but it can be great in an aggressive deck. While a card like Bump in the Night is terrible in a deck just trying to stay alive and then play a bomb, it can be a great finisher for an aggressive deck.
Obviously, if you’re playing a bomb deck, you also need to keep these things in mind. One advantage to playing aggression is that by building your deck to be as fast as possible, you’re making yourself prepared for both bomb decks and aggressive decks. Building a bomb deck requires a more delicate balance. While most of the top decks will be bomb decks, you can’t ignore the potential presence of aggressive decks. The reason this is annoying is that the types of cards that will be best for you against aggression will often be weak for you against other bomb decks.
One of the ways I sometimes address this is by making a hybrid deck if my pool allows. If I have the right cards, I’ll make an aggressive deck with a couple bombs at the top of my curve. This can give me some of the benefits of both archetypes. You might ask why I don’t always build hybrid decks . . . or at least, How do I know when to do it? These things are always defined by my card pool—like almost everything else in Sealed.
If I have a lot of expensive bombs, I’m rarely going to try to fit them into an aggressive framework. If I have a lot of expensive cards, I’ll want to play with more mana and mana development than I normally would like to in an aggressive deck. If I’m playing with a lot of mana and a lot of 1- and 2-drops, I’d be creating a recipe for a disastrous mana flood.
Here are some factors to consider:
- The main difference between an aggressive deck and a hybrid deck is that in a hybrid deck you have a couple expensive bombs at the top of your curve in case the game goes long.
- In decks that use an aggressive framework, you should only play two colors. If possible, you should either avoid early-game cards with multiple colored mana symbols in the costs or you should choose one color to be your base color and play significantly more mana of that type.
- In bomb decks, it will often be the right play to splash a third color. What I find works best is to have basically a two-colored deck with mana for a third color just to pay some flashback costs and to play one or two powerful, late-game cards. This will usually allow you play with more bombs than if you just played strictly two colors. How good of an option this is will often depend on how much mana smoothing you have in the form of cards like Evolving Wilds, Shimmering Grotto, and Traveler's Amulet.
- Sometimes it will be the right play to make an aggressive deck even if it seems that you might have the cards to build an okay bomb deck. In order for this to be the case, your aggressive deck needs to seem like a really good Draft deck, and your bomb deck needs to not be particularly special.
Colors and Synergy
There are two other main considerations when deciding what direction to go with your Sealed deck-building: depth of colors and synergy. Once you’ve laid out your cards by color, you should be able to quickly eliminate a color or two from consideration. I usually look at my green first because if it doesn’t have any bombs, I can usually eliminate it immediately. This is because green has little evasion, removal, or direct damage in this format. If I have a lot of pump in green, I might end up using it in an aggressive deck. Typically, at least one or two colors won’t be deep enough to be a base color or even a partner in a straight two-colored deck.
Once you’ve eliminated one or two colors, looking for synergies will often help you narrow down your colors further. If you have a lot of cards that go well with Vampires, you might choose B/R or you might choose U/B for Zombie-related cards. If you have many ways to fill your graveyard, you might look for colors with a lot of flashback and cards that benefit you for having creatures in your graveyard.
And That’s It
So, you may not have any control over what cards are in your card pool, but you can still make sure to build your pool in a way that will give you the best opportunity to win. I’ve lost track of the number of people who have told me their card pool just wasn’t good enough . . . only for me to look at it and see they’ve just built poorly. If you keep in mind the deck construction principles that I’ve discussed here, I hope you can avoid becoming one of these people. |
If you have worked harder for someone else than you have in your own business, you’re not alone. I’ve heard this self-limiting habit from many of my clients. It shows up in many ways, including procrastinating, not following up, or not following through.
So how do you build unstoppable momentum when you just feel like being lazy?
There are two secrets critical to building unstoppable momentum:
The first is clarity. As a small business owner, you are wearing many different hats and it’s impossible, not to mention ineffective, to try to keep it all in your head. Stop trying to remember it all and get clear by outlining your:
- Preferred Client. When you know your client’s habits and are familiar with their hangouts, it makes it simple to know where to network. You’ll immediately notice if where you’re networking is the most effective.
- Goals. Goals are broad and describe a general direction. Establish 3-5 goals each year setting at least one stretch goal each year. Many entrepreneurs set too many goals and end up confused on their direction. Keeping it to 3-5 manageable goals will help keep you clear.
- Objectives. Objectives are more narrow and specific. They support each goal and can be measured.
- Timeframes. Remember to set a timeframe. The more you set a timeframe, the more likely it gets done.
Share your plan with others. When you blog or mention to your clients that you have an event coming up in a few months, it lights a fire and gets you committed to that future action.
The second secret is consistency. If you don’t consistently keep in touch with your client base, you’re missing an important part of building unstoppable momentum.
When you deliver consistent high-value messages, your prospects will see you as the go-to expert in your field. As you consistently provide information-rich topics, your prospects begin to look forward to your messages.
Consistent marketing creates a rhythm. The rhythm leads to an expectation from your clients. When you meet that expectation you’ve created, it cultivates trust over time with your prospects. Creating an ongoing system for staying in touch is a critical component in creative unstoppable momentum in your business.
Notice other areas in your business where you can create cadence. If you belong to a networking group and that networking group meets a certain date of the week, you’ve already started that rhythm. Now, start plugging in your other marketing strategies onto your calendar.
Once you regularly apply your marketing tactics, you’ll notice a synergy start to take place. Before you know it, you are getting your message out in a really harmonious way – on your way to building unstoppable momentum. |
There's a new kid on the social media block that's starting to garner a lot of attention from companies.
Microblogging sites, such as Twitter, are increasingly becoming a companion to an existing blog—or a standalone strategy for businesses that are using social media to connect with their customers.
But many companies aren't sure what the microblogging "rules of the road" are. This is where Connie Reece comes in.
Connie was an early adopter of Twitter and is considered a true microblogging authority. She will be moderating Best Practices in Microblogging session at Marketing Profs Digital Marketing Mixer, and she was kind enough to give us a preview of that session, as well as a primer for companies that want to learn more about Twitter and other microblogging sites.
Q: Microblogging seems to be the hot area of social media recently. What exactly is a microblogging site, and what makes it different from a blog?
A: "Microblogging" is a misleading term, in my opinion. "Micro" is accurate, because the popular services like Twitter strictly limit content to 140 characters, about the length of the average text message. It's the "blogging" aspect of the term that is fuzzy. Even though you can pack a lot of information into 140 characters, the content and format are much less structured than a blog.
Sometimes you'll see these sites referred to as "presence" applications; in other words, they are a quick and easy way of being "present" with friends who are far away. This phenomenon was aptly termed "ambient awareness" in an excellent article by Clive Thompson for the New York Times: "Brave New World of Digital Intimacy."
Each little update—each individual bit of social information—is insignificant on its own, even supremely mundane. But taken together, over time, the little snippets coalesce into a surprisingly sophisticated portrait of your friends' and family members' lives, like thousands of dots making a pointillist painting. This was never before possible, because in the real world, no friend would bother to call you up and detail the sandwiches she was eating.
Q: A lot of companies seem to be creating presences on Twitter. What are some of the ways that companies can utilize Twitter?
A: Twitter is yet another way to put a personal face on an impersonal entity: the corporation. Most companies are initially attracted to Twitter because they perceive it as an additional marketing channel. If that's all they use it for, they will not succeed.
However, if they use Twitter to actively engage with people, then a couple of things will happen. One, they will be able to use Twitter as a means of promotion, by occasionally sharing links to their online content. But most likely they will wind up using Twitter for the sheer enjoyment of interacting with customers.
As far as particular uses are concerned, Twitter is especially suited to promoting an online contest. It can also be used as an additional sales channel: Dell's Twitter account DellOutlet has generated around $500,000 in sales by offering special discounts to Twitter users. And many Twitter users enjoy subscribing to their favorite news channels on Twitter.
Marketing Profs Digital Mixer conference attendees will get to hear from Bryan Person how he looks forward to ESPN tweets' popping up in his timeline. And I will share how our local newspaper, the Austin American Statesman, not only uses Twitter effectively on a daily basis but provided superb coverage of Hurricane Ike through a special account, TrackingIke.
Another panelist, Frank Eliason, who tweets as ComcastCares, provided an immediate answer to someone who lost Internet service during the hurricane, explaining that Comcast could not restore cable service until the power company gave them clearance. (As we're conducting this interview, some 1.5 million homes in the Houston area are still without power, one week after Ike.)
Q: While many companies are beginning to explore using Twitter, some companies are finding that their brands are being "hijacked" by people that are posing as employees of a company, but really aren't. How can a company guard against this?
A: Companies need to reserve their name space now, even if they are not ready to use Twitter—and the same applies for other sites. When they do start to use Twitter, the company should add a link from its Web site to its Twitter account, so the public will know the account is genuine.
Of course, companies should be monitoring Twitter to follow chatter about them, and if they find their brand has been hijacked they should contact Twitter to have the unauthorized user account shut down.
Q: Twitter seems to be the microblogging site that most people have heard of, but are there other microblogging sites that companies should be aware of?
A: My favorite, as you know, is Plurk because of its threaded conversations. I love the informal "plurkshops" we have, which are online discussions around a particular topic. (They are archived at plurkshops.com.) I have not seen business adoption of Plurk yet, and it is unlikely until the API is released and it becomes easier to use.
One of the reasons we know that microblogging is here to stay is the rapid uptick in enterprise adoption. Several applications intended for behind-the-firewall use have been launched recently, including Yammer, which is a domain-specific application with many similarities to Twitter.
Q: Moving forward, do you think that companies will begin to use a microblogging strategy in place of a company blog, or in conjunction with an existing blog? Which approach do you think is more effective?
A: Some companies might start with Twitter as their entry-level implementation of social networking, but it will be more effective long-term in conjunction with a blog. The Twitter-blog combination will provide synergy, with Twitter being used to drive traffic to the blog and vice-versa.
Some limitations are inherent in the 140-character format of Twitter: It's difficult to retrieve tweets, for example, if you have more than a few favorites; the lifespan of a tweet can be less than a minute if you follow many people. And some things, like this interview, simply need a longer format. |
David Bourget (Western Ontario)
David Chalmers (ANU, NYU)
Rafael De Clercq
Ezio Di Nucci
Jonathan Jenkins Ichikawa
Jack Alan Reynolds
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This paper explores the interaction between implicit and explicit processes during skill learning, in terms of top-down learning (that is, learning that goes from explicit to implicit knowledge) versus bottom-up learning (that is, learning that goes from implicit to explicit knowledge). Instead of studying each type of knowledge (implicit or explicit) in isolation, we stress the interaction between the two types, especially in terms of one type giving rise to the other, and its effects on learning. The work presents an integrated model of skill learning that takes into account both implicit and explicit processes and both top-down and bottom-up learning. We examine and simulate human data in the Tower of Hanoi task. The paper shows how the quantitative data in this task may be captured using either top-down or bottom-up approaches, although top-down learning is a more apt explanation of the human data currently available. These results illustrate the two different directions of learning (top-down versus bottom-up), and thereby provide a new perspective on skill learning. Ó 2003 Elsevier B.V. All rights reserved.
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Rineke Verbrugge & Lisette Mol (2008). Learning to Apply Theory of Mind. Journal of Logic, Language and Information 17 (4):489-511.
Jenny R. Saffran & Casey Lew-Williams (2012). All Words Are Not Created Equal: Expectations About Word Length Guide Infant Statistical Learning. Cognition 122 (2):241-246.
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PINKERTON, STEVEN D. PhD*; LAYDE, PETER M. MD, MSc†; FOR THE NIMH MULTISITE HIV PREVENTION TRIAL GROUP
RIGOROUS EVALUATION is needed to assess the effectiveness of sexual risk reduction interventions. The most appropriate measure of effectiveness depends on the goal of the intervention. 1–3 For instance, the goal might be to change intervention participants’ sexual behaviors by increasing condom use or decreasing the number of partners with whom they have sex. This goal acknowledges that particular behaviors, such as having unprotected sex with casual partners, are associated with a host of adverse outcomes, including infection with HIV or other sexually transmitted diseases (STDs) and unplanned pregnancies. Consistent with this goal, behavior change intervention programs can be evaluated by assessing the extent to which participants have reduced their risk behaviors. However, behavior change is seldom promoted for its own sake. Instead, the usual goal of sexual behavior change interventions is to reduce participants’ pregnancy and/or STD risk, often with an emphasis on HIV prevention.
The best way to evaluate an intervention's effectiveness against a particular STD is to examine temporal changes in STD incidence. Unfortunately, this strategy poses considerable difficulties for evaluating HIV prevention interventions. Because the incidence of HIV infection in the United States is relatively low, 4 using HIV seroincidence as a primary intervention outcome is seldom feasible. To achieve adequate statistical power to detect an intervention effect would require recruiting an extremely large sample of high-risk individuals, at substantial cost. Consequently, most interventions aimed at prevention of HIV infection are evaluated by assessment of changes in risk behaviors, 5 sometimes augmented by mathematical modeling to estimate the epidemiologic impact of the interventions. 6
Although the Consensus Development Conference on Interventions to Prevent HIV Risk Behaviors concluded that “the weight of the scientific evidence to date suggests that properly administered self-reports… can yield reasonably accurate [information],”3,5 some researchers remain skeptical about the validity of self-reported measures of sexual behavior change. 7–9 Because many of the behaviors that place individuals at risk of acquiring HIV are the same as those that place them at risk for other STDs, researchers and policymakers have called for the use of non-HIV STDs as surrogate markers for HIV infection. 8,10–12 STD incidence recently has been used as a primary or secondary endpoint in several HIV prevention trials in the United States and United Kingdom. 13–21
However, the relationship between particular sexual behaviors, HIV incidence, and the incidence of other STDs is complex, and thus far no empirical relationship between reductions in the incidence of HIV and any specific STD has been demonstrated. 1,2,5,11 The use of STD incidence as a primary intervention outcome relies on the assumption that “if there is a change in risk behaviors of the population, then the incidence of all STDs will be similarly affected.”7 But under what conditions is this assumption justified?
To examine this issue, we applied a mathematical model of HIV/STD transmission to empirical data from a large intervention to prevent HIV infection (Project Light) to determine the characteristics of an ideal marker STD. The main question we sought to address was, under what conditions are changes in STD incidence associated with changes in HIV incidence?
Description of Sample
The Project Light intervention was conducted at seven United States sites, beginning in 1989. 17,18 A total of 3706 high-risk participants, 74% of whom were self-identified as black, were recruited from STD clinics, primary care clinics, and other health service organizations. Participants were randomized to one of two intervention groups. Those in the main intervention group attended seven 90- to 120-minute small-group risk reduction counseling sessions that emphasized motivation, skills, and self-efficacy related to HIV infection risk reduction. Participants in the control intervention attended a single, one-hour AIDS education session in which they viewed a videotape on HIV prevention and engaged in a question-and-answer exchange.
Sexual behavior surveys were conducted at baseline and at 3, 6, and 12 months after the conclusion of the intervention. Each survey elicited information about participants’ sexual behaviors in the preceding 3-month period, including the number of male and female sex partners and the number of acts of unprotected and condom-protected vaginal and anal intercourse. The results of the main outcome analysis indicated that both intervention groups reduced their sexual risk behaviors, but participants in the seven-session cognitive-behavioral intervention engaged in fewer unprotected sex acts, used condoms more frequently, and were more likely to use condoms consistently over the 12-month follow-up period than were participants in the comparison (video) intervention. 18
The present analysis focuses on the baseline and 12-month follow-up data and includes only individuals for whom 12-month follow-up information was available. The final sample included 1859 women (918 in the seven-session intervention and 941 in the video intervention) and 1162 strictly heterosexual men (583 and 579, respectively). Table 1 summarizes the sexual behavior (number of partners and number of acts of unprotected and protected vaginal and anal intercourse) reported by this sample. Because of the paucity of available estimates of the infectivity of anal intercourse for any STD other than HIV, vaginal and anal intercourse were combined in the present analyses. Overall, anal intercourse accounted for approximately 4% of the total number of acts of intercourse reported by the men and women in the sample.
A Bernoulli mathematical model of STD/HIV transmission was used to translate participants’ self-reported sexual behaviors into estimates of their risk of contracting STDs and the change in STD risk from baseline to the 12-month follow-up. (For this analysis, all intervention participants are assumed to be equally susceptible to infection.) In this model, STD risk is a function of the sexual behavior of the individual (number of acts of unprotected and condom-protected intercourse and number of sex partners); the STD prevalence among intervention participants’ sex partners; the per-act STD transmission probabilities (infectivity) associated with unprotected insertive and receptive vaginal intercourse; and the effectiveness of condoms at preventing STD transmission.
The Bernoulli model is described in detail elsewhere. 22–24 As an example, the cumulative probability of STD infection for a woman who engages in n acts of unprotected vaginal intercourse and k acts of protected vaginal intercourse with each of m partners is approximatelyMATHwhere π is the prevalence of STD infection among her sex partners, α is the per-act transmission probability of unprotected receptive vaginal intercourse, and φ denotes the effectiveness of condoms in preventing STD transmission. The incidence of infection over the 3-month assessment period can be estimated by multiplying the average infection probability by the number of participants. 6
Separate STD risk estimates were calculated on the basis of Project Light participants’ sexual behavior during the previous 3 months, reported at baseline and follow-up. The difference between these estimates is a measure of the extent of risk reduction (or risk increase), and the mean change is an indicator of the expected reduction in STD incidence (infections per 3-month period) among participants.
Estimates of the epidemiologic parameters were obtained from the literature. For the base-case analysis, condom effectiveness was set at 90%. 25 In the sensitivity analyses, condom effectiveness was varied from a low of 67%26,27 to 100%28 to examine the impact of uncertainty in this parameter. The same condom effectiveness value was used for HIV and all other STDs; therefore, these analyses apply only to STDs that are not easily transmitted by skin-to-skin contact. The per-act infectivity of HIV for receptive intercourse was set at 0.001 and the infectivity for insertive intercourse was set at 0.0006. 29–31 Holmberg's synthesis of HIV prevalence estimates suggests that approximately 2% of all high-risk heterosexuals in major United States metropolitan areas are infected with HIV. 4 In the base-case analysis we assumed that 2% of the participants’ sex partners are HIV-infected. Sensitivity analyses were conducted for all main parameters, including HIV prevalence.
Measures of Association
To assess the strength of association between reductions in STD risk and reductions in HIV risk as a result of the intervention, we calculated Pearson product-moment correlations between participants’ HIV risk reduction scores and their STD risk reduction scores. The square of the correlation coefficient, which is known as the coefficient of determination and is denoted R2, indicates the strength of association. The coefficient of determination can be interpreted as the proportion of variance in HIV risk reduction associated with reductions in STD risk.
Estimates of the infectivity of several STDs are available in the literature. These estimates generally were obtained from observational studies of heterosexual couples, and most take the form of per-partnership rather than per-act transmission probabilities. Available estimates of the per-partnership transmission probability for syphilis range from 0.15932 to 0.682. 32 Cates and colleagues 33 summarized the results of five studies 34–38 and arrived at an overall average of 0.413. Because of the variety of sources for syphilis infectivity estimates, it is difficult to convert the per-partnership values to equivalent per-act values. For example, if the 0.413 estimate were the result of 10 acts of intercourse, then the equivalent per-act infectivity would be 0.05, whereas if it arose from 100 acts of intercourse, the per-act infectivity would be closer to 0.005. Unfortunately, no information about the number of acts in these studies is available.
The per-partnership probability of chlamydia transmission has been estimated at 0.323 for female-to-male transmission and 0.395 for male-to-female transmission, on the basis of transmission rates for STD clinic clients and their partners. 39 The per-act infectivity could be much smaller, depending on the number of acts of intercourse on which these estimates were based. It is possible to infer a per-act infectivity value from a study of chlamydia acquisition by prostitutes. 40 Three of 20 susceptible women became infected as a result of a total of 939 acts of intercourse. If a 3.5% prevalence of infection among their male partners is assumed, the per-act transmission probability is approximately 0.1.
If it is assumed that each prostitute had sexual intercourse only once with each man, the cumulative probability of infection isMATHMATHwhere m = 939/20 = 46.95 is the mean number of partners per prostitute, π = 0.035 is the prevalence of chlamydia infection among the men, 40 and α is the unknown per-act transmission probability. There were three incident infections among 20 women, hence P = 3/20 = 0.15. Solving the equation for α implies that the per-act chlamydia infectivity for male-to-female transmission is 0.099.
Gonorrhea appears to be relatively easily transmitted. Estimates of the per-act infectivity range from approximately 0.241 to more than 0.5. 41–43 As with syphilis and HIV, male-to-female transmission of gonorrhea is more efficient than female-to-male transmission. 30,33,44,45
Less is known about the infectivity of the hepatitis B virus. For homosexual anal intercourse, the per-contact transmission probability is estimated to be 10 times greater than the corresponding probability for HIV transmission. 46,47 Applying the same scaling factor to heterosexual transmission routes yields a per-act hepatitis B infectivity of approximately 0.01 for male-to-female intercourse and 0.006 for female-to-male intercourse.
The main analysis focuses on the women in the cognitive-behavioral intervention (the women in the video intervention and the men in both intervention conditions are considered below). Figure 1 illustrates the relationship between reductions in STD risk and reductions in HIV risk for women in the seven-session intervention condition for a highly infectious STD such as gonorrhea and a less infectious one such as hepatitis B. For the analysis presented in Figure 1A, the STD infectivity was set at 0.2 and the STD prevalence was set at 0.05. This figure suggests that this STD would make a relatively poor marker for HIV infection. As shown, some of the women with the largest proportionate reductions in HIV risk experienced almost no change in their STD risk, and vice versa. This can be attributed to the very high infectivity of the STD. We would expect new STD infections in 20% of all women who had a single act of unprotected intercourse with an infected man and in 67% of the women who had unprotected intercourse with an infected man five or more times. Unless condoms are used for nearly ever act of intercourse, women who have sex with infected men are likely to become infected. Conversely, the much smaller infectivity of HIV permits a nearly linear relationship between increases in condom use and decreases in HIV risk. 48,49 Thus, by increasing their use of condoms, some women in the intervention reduced their HIV risk to a much greater (relative) extent than they did their STD risk. Therefore, given its high infectivity, it is not surprising that this gonorrhea-like STD makes a poor marker for HIV infection.
It is logical to assume that the best marker STD would be one that is similar to HIV in transmission characteristics. Figure 1B demonstrates that this assumption is correct. This scatterplot shows the relationship between STD and HIV infection risk reduction for an STD with a per-act infectivity of 0.005 and a prevalence of 5% (the corresponding values for HIV are α = 0.001 and π = 2%). An almost perfect correlation (R2 = 0.98) is obtained for this less infectious, hepatitis B–like STD.
Additional analyses were conducted to examine how the strength of association varies across STD prevalence and infectivity values. Figure 2 shows the degree of association between STD risk reduction and HIV infection risk reduction—as reflected in the R2 value—for the women in the seven-session intervention condition, as a function of the infectivity and prevalence of the STD. As this figure illustrates, the infectivity of the STD is a critical determinant of the strength of the association between HIV infection risk reduction and STD risk reduction. The association is strongest when the per-act STD transmission probability for receptive vaginal intercourse is near 0.001, which is the assumed per-act HIV transmission probability. However, the association falls off as the infectivity increases from 0.001. For an STD with an infectivity of 0.2, R2 is less than approximately 0.30, regardless of the STD prevalence. Thus, for gonorrhea and other highly infectious STDs with infectivities of 0.2 or greater, the variance in the women's STD risk reduction values accounts for less than 30% of the variance in their HIV infection risk reduction values. The association also is stronger when the prevalence of STD infection is close to the HIV prevalence. Indeed, the association is perfect (R2 = 1.0) when the HIV and STD infectivities agree and the STD prevalence equals the HIV prevalence (0.02 in Figure 2).
Notably, the association between STD risk reduction and HIV risk reduction is relatively less affected by differences in HIV and STD prevalence than by differences in HIV and STD infectivity. This point is underscored in Figure 3, which illustrates how the coefficient of determination varies as a function of the per-act STD transmission probability for the women in the seven-session intervention condition. This figure demonstrates that the strength of association is greatest when the STD infectivity equals the HIV infectivity, dropping off sharply for transmission probabilities greater than 0.01. The STD prevalence is essentially immaterial; indeed, the three curves, which correspond to prevalence values of 0.002, 0.02, and 0.2, are nearly indistinguishable.
These results could depend on the particular dataset selected for this analysis or on the values assumed for various HIV-related epidemiologic parameters. Sensitivity analyses, described below, were conducted to address the second of these issues. To examine the first issue, we applied this model to a second subset of the Project Light dataset: men who have sex only with women. For this analysis the HIV infectivity of insertive intercourse was set at 0.0006. 50 As illustrated in Figure 4, the results for the men in the seven-session intervention condition were similar to those for the women, although for men the strength of association declined somewhat more rapidly as the STD infectivity value increased. Again, the infectivity of the STD seems to be much more important than the prevalence of infection in determining the strength of association, except when the STD infectivity is very large.
Although this analysis has focused on participants in the seven-session cognitive–behavioral intervention, qualitatively similar results were obtained for male and female participants in the video intervention (data not shown). As noted elsewhere, this control intervention also was effective at changing participants’ risk behaviors 18; hence, it is not surprising that this intervention produced similar results.
Summary of Base-Case Results
In sum, the general pattern appears to be fairly robust across Project Light populations (heterosexual women and men) and intervention conditions. The first main finding is that the association between HIV and STD risk reduction is strongest for STDs with infectivities that are similar to that of HIV. The association is attenuated for larger infectivity values. Second, STD prevalence influences the strength of association for STDs with very large infectivities but does not substantially affect the strength of association when the STD infection is moderate or small. In particular, for STD infectivity values similar to that of HIV—where the strength of association is strongest—the prevalence of STD is essentially immaterial.
A further question is whether modeling assumptions, or the particular values assumed for the HIV epidemiologic parameters, might have affected the results obtained in the base-case analysis. We conducted sensitivity analyses to examine this issue. These analyses focus on the women who participated in the seven-session intervention.
The results of the base-case analysis and the sensitivity analyses are summarized in Table 2, which lists the R2 value for several different STD infectivity values, under the assumption that the prevalence of the STD equals the prevalence of HIV. As shown, changing the condom effectiveness (from 90% to 67% or 100%) or HIV prevalence (from 0.002 to 0.2) had little effect on the results. The only manipulations that had a substantial effect on the results were doubling the number of acts of intercourse for all participants and doubling the number of partners. Doubling the number of acts of intercourse reduced the strength of association, especially for larger STD infectivity values. (As discussed above, for highly infectious STDs, transmission is likely if the number of acts of intercourse is sufficiently large; hence, increasing condom use and taking other risk reduction steps has relatively less effect on STD incidence than on HIV incidence.) In contrast, doubling the number of sex partners increased the strength of association. However, doubling both the number of acts and the number of partners produced results that were nearly identical to the base-case results. Finally, if the true infectivity of HIV were 10 times larger than the base-case value of 0.001, then the results would be shifted so that the strength of association is greatest when the STD infectivity also is 0.01, but otherwise the pattern is similar to that obtained in the base case (see Figure 5).
As indicated in Table 1, moderate to strong associations were obtained for STDs that have infectivity values of 0.05 or less. Indeed, solely on the basis of these epidemiologic considerations, hepatitis B could be a suitable marker for HIV infection (assuming that its true infectivity is close to 0.005). The association between HIV infection risk reduction and gonorrhea risk reduction is much weaker because of the high infectivity of this STD (α ≥ 0.2).
For changes in STD incidence to serve as a surrogate for changes in HIV incidence, STD risk reduction must be strongly associated with HIV infection risk reduction. The analyses presented here indicate that the strength of association between HIV risk reduction and STD risk reduction critically depends upon the infectivity but not the prevalence of the STD. Strong associations were noted for STDs with infectivities of approximately 0.05 or less, and moderate associations were noted with infectivities of less than approximately 0.2 (Figure 3). In contrast, STDs with infectivities greater than 0.2 produced weak associations.
There is limited evidence about the infectivity of common STDs. 51,52 However, estimates of the infectivity of hepatitis B and (possibly) syphilis and chlamydial infection suggest risk reduction associations in the moderate to strong range. In contrast, easily transmitted STDs such as gonorrhea appear to be unsuitable for use as surrogate markers of HIV infection. More information is needed about the true infectivity of these and other STDs to aid in the identification of potential marker STDs. Information also is needed to characterize interpersonal variability in infectiousness and susceptibility to infection, as well as infectivity differences due to stage of infection (e.g., primary versus secondary syphilis infection).
In these analyses, the prevalence of STD infection among sex partners was not an especially important factor in determining the strength of association. For STDs with suitably low infectivities, the prevalence of infection was essentially immaterial. However, the prevalence of infection is likely to be more important for populations in which the number of partners is greater than it was for the heterosexual participants in Project Light and for homosexual populations, because of the substantially greater infectivity of receptive anal intercourse in comparison with receptive vaginal intercourse.
These analyses indicate that stronger HIV–STD associations will be obtained when the observation period for incident STD infections is kept relatively short. The base case results were with an assumed 3-month clinical follow-up, limiting the potential number of sex acts and partners. The sensitivity analyses show that doubling the number of partners strengthens the association between STD and HIV infection risk reduction, whereas doubling the number of acts diminishes the association by diluting the impact of condom use, which is greater for HIV than for other STDs because of the greater infectivity of the latter. 24 However, doubling both acts and partners produces results that are almost identical to those obtained in the base case. Although many people are likely to engage in twice as many acts of intercourse in 6 months as in 3, few individuals will have twice as many sex partners. Therefore, on balance, we would expect a 6-month follow-up schedule to produce weaker associations than a 3-month schedule.
The simple Bernoulli model used in this analysis is both a strength and a limitation. This transmission model is easily described and manipulated, requires few parameters, has high biologic plausibility, and has been empirically verified in an HIV seroconversion study in Africa. 53,54 However, this simple model omits important STD transmission dynamics, including nonrandom mixing patterns, selective condom use (e.g., with new partners but not with steady partners), sexual contact network characteristics, and concurrent partnerships. 8,55–63 These complexities could introduce unknown errors into the analyses. For example, this analysis might underestimate the utility of a marker STD that “inhabits” the same networks as HIV (this is discussed further below). In addition, there is evidence that the per-act Bernoulli model may underestimate or overestimate risk in some situations. 64,65 These concerns are ameliorated somewhat by the use of the model in the present context, in which changes in HIV risk are compared with changes in STD risk.
The HIV infectivity values used in the current study, which were estimated from transmission rates for long-term HIV-serodiscordant couples, 29–31 may fail to capture the brief period of very high viral load—and presumably highly elevated infectiousness—that occurs soon after initial infection and before the development of an effective immune response. Predictions from mathematical models suggest that a substantial proportion of all HIV transmission occurs during this brief period of primary infection, 66,67 which lasts a few weeks to several months. During this time, HIV acts more like a high-infectivity STD than a low-infectivity STD. Consequently, the utility of highly infectious STDs as markers for HIV will be greater in situations in which there is a nonnegligible probability of encountering a partner who was recently infected with HIV—for example, in populations with high partner-change rates. A related issue concerns the facilitative effect on HIV transmission of infection with non-HIV STDs. 68–70 If the same people who are at risk for HIV infection are also at risk for other STDs, which is a fundamental assumption underlying the use of non-HIV STDs as surrogate markers of HIV, then the “effective” infectivity of HIV is likely to be increased in at-risk populations, because of STD in one partner or the other. However, it is not clear how large this “cofactor effect” is likely to be or to what proportion of the population it applies.
Additional limitations of this study include the use of self-reported behavior in the modeling exercise and uncertainty in the HIV and STD infectivity estimates. 29 Notably, the Project Light intervention data were used here to provide a concrete illustration of the relationship between HIV infection risk reduction and STD risk reduction; therefore, slight distortions of the data due to self-reporting bias are of minimal consequence. Although quantitatively the results of the analysis are sensitive to the infectivity estimates, qualitatively the main finding appears robust: namely, that the best marker STD is one with an infectivity near that of HIV. This result was anticipated by Aral and Peterman, who proposed that “for trends in one STD to serve as a good biomarker for another STD, the two STDs need to be identical or very similar” in terms of epidemiologic and other characteristics. 7
The results of this analysis can be used to guide the selection of STD markers for use in HIV prevention trials. However, they also suggest the need for caution in interpreting the results of trials employing surrogate markers. Transmission of HIV and other STDs is differentially sensitive to such factors as partnership acquisition rates and frequency of condom use. Behavioral changes that affect the incidence of a marker STD might not be the same as those that would reduce the incidence of HIV, and vice-versa. Therefore, the failure to detect a measurable reduction in STD incidence does not necessarily imply that an HIV prevention trial has failed to achieve its stated objective of reducing HIV infection risk. 1 Conversely, interventions that successfully decrease STD incidence could have both direct and indirect HIV prevention benefits: first by reducing participants’ behavioral risk and second by diminishing the facilitative effect of STDs on HIV transmission. 71,72
There also are practical obstacles to the use of STDs as surrogate markers of HIV infection risk. This study assumed perfect diagnosis of incident STDs. Existing diagnostic tests for STDs have imperfect sensitivity and specificity, 11 which would impair the performance of the STD as a surrogate for HIV infection risk. Some STDs are readily curable, so between follow-up visits for a study, a participant might become infected with an STD, experience symptoms, receive treatment, and be cured. If the infection was not detected on the subsequent visit, this would be equivalent to a false-negative test result, which would reduce the performance of the marker STD. Another factor that could influence the performance of an STD as a surrogate for HIV infection risk is the distribution of the STD in the population, compared with the distribution of HIV. If an STD was concentrated in the same subgroups of the population as HIV, its utility as a marker for HIV infection risk would be enhanced, whereas if the STD and HIV had different distributions, the performance of the STD as a surrogate would be diminished. For some STDs, acquired immunity could also affect their performance as markers for HIV.
The current analysis focused on HIV and STD acquisition by individuals rather than on the spread of these pathogens throughout a population. As noted above, dissemination of an STD within a population is affected not only by the behavioral characteristics of the individuals who make up that population but also by such factors as the extent of mixing between different risk strata and nonuniform distribution of infection. Population-level models that take these complexities into account are needed. However, because STDs may be differently affected by various network and population-level factors, caution will be required when interpreting the results of these analyses, just as caution is needed here.
This analysis is a first step toward the goal of identifying a suitable marker STD. Further research is needed to better quantify the infectivity of HIV and other STDs and to develop more sophisticated transmission models to examine the complex relationship between HIV and STD risk reduction.
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Dr S.S. Mantha who has been appointed as the Chairman of AICTE was felicitated by the Forum of the Management Institutions, the Forum of Minorities Institutions and the University of Mumbai College Principal's Association (UMCPA) and Consortium of Management Education (COME) at Welingkar Institute of Management Development and Research, on Sunday, 8 Jan 2012.
Among the dignitaries present on the occasion were Dr SS Mantha, Chairman –AICTE, Dr Rajan Welukar, Vice Chancellor, University of Mumbai, Vijay Khole, former Vice Chancellor of University of Mumbai, SK Mahajan Directorof Technical Education,Dr Ajit Singh, President, and Forum of Minorities Institutions. Dr (Prof) Uday Salunkhe, Group Director, Welingkar Institute, welcomed the distinguished gathering as he congratulated Dr SS Mantha on his taking over the mantle of leadership in higher technical education as Chairman, AICTE. The august audience also included esteemed deans, directors and principals of management institutes, engineering colleges and senior members from the Senate of University of Mumbai.
Dr Salunkhe in his congratulatory address on Dr Mantha’s appointment assured him the support of the entire educational community in his efforts to transform the higher technical education scenario with his stress on an expansive, inclusive and bottom to top approach. Dr Salunkhe said the fraternity looked at his appointment as a seminal step which will leverage upon the strength of the nation in terms of knowledge, technology, colossal youth segment and diversity of population to create thought leadership and a competitive edge for our country. He also expressed the keenness of the educational fraternity tocontribute to the positive transformation under Dr Mantha’s multi- faceted leadership.
Expressing his thanks for the sentiments expressed at his appointment, Mantha mentioned that the canvas of the AICTE was quite large as it included Engg, Architecture, Pharma, B Schools, Hotel Management and many more, adding to the complexity of the task on hand. It would be his endeavour to develop national database of institutions, working with the World Bank mapping facts and figures depicting the current status of the technical education. Also he would try to adapt the best global practices to raise the standards of the same.
Mentioning the transformation higher technical education is going through he said managing changes is really demanding in the face of the given demographic inequity, diversity and disparity. Dr Mantha expressing his concern over the issue of a large number of school drop outs said the Council would work on feasible policies to bring them back to the classrooms. Gross Enrollment Ratio is also a similar concern; India has a sad GER of 15 percent whereas the developed countries have it in the neighbourhood of 65.
The colossal segment of the young population that would be around 400 million by the year 2020 has to be accommodated in terms of their need for higher education as per their aptitude and capabilities to equip them with relevant skill-sets. The inequity in the distribution of the educational institutions has to be worked upon and thus ensuring the rural areas a fair share of institutions for higher education.
Education cannot be totally market- driven considering the prevalent socio-economic disparities in the Indian set up though it cannot be totally free .Vocationalisation of higher education has to be worked upon along with good financial models that would enable aspirants to enroll themselves for higher education with a provision of paying later.
Dr Mantha highlighted the need of striking a judicious balance between research and teaching, to bring out the best in both. On earlier occasions Dr SS Mantha had expressed his thoughts on establishing synergy between various departments of educational institutions with respective industrial sectors which would work to the advantage of both. Under his leadership AICTE is also in the process of setting up incubation centres at the top rung institutions, thus encouraging and supporting research.
In his signature style of humor Mantha wrapped up with the comment that regulatory body is always the target of criticism and scrutiny; and he was ready for the same too while he strove to ring in the required changes in the required domains of higher technical education. |
Cricket is one of the most popular games in India and while most fans are eagerly waiting for the World Cup to begin, others are looking forward to seeing some players on a game show.
Indian cricketers Yuvraj Singh, Harbhajan Singh, Manish Pandey and Robin Uthappa were spotted on the sets of the upcoming game show. The show, "India Poochega Sabse Shaana Kaun", will be hosted by Shah Rukh Khan, who is returning to the small screen after four years.
It will be telecast on the recently-launched Zee Entertainment's &TV, which will go on air from 2 March. The show will be aired every Monday to Friday at 9 pm.
Sources close to the channel reveal that the cricketers enjoyed themselves to the fullest during the shooting of the show.
A few days ago, SRK had tweeted regarding the shooting of the show.
Shooting sabse shaana kaun....meeting so many wonderful ppl with common issues but special grit & determination. So special to be ordinary.
Finished another long shoot but all worthwhile becos ppl on SSK so much more real than the plasticity I encounter everyday. Learning life...
"India Poochega Sabse Shaana Kaun" is an adaptation of the international show, "Who's Asking?". It is a question-answer format game show. The show, produced by Big Synergy, is not just about questions; it's about who asks the questions, be it a cook or a driver or an engineer.
"I like the question and answer format. I do that with my children and family. This show will deal with questions that have been asked by common man and will be answered by the common man himself to win the prize money, Shah Rukh Khan said, according to IANS.
On the acting front, SRK will next be seen in the big-budget films, "Raees" and "Fan". |
A recent interview with a noted researcher, IEEE Fellow Michael I. Jordan, Pehong Chen Distinguished Professor at the University of California, Berkeley, provided a downplayed view of recent AI hype. Jordan was particularly critical of AI metaphors to real brain function and took the air out of the balloon about algorithm advances, pointing out that most current methods have roots that are decades long . In fact, the roots of knowledge-based artificial intelligence (KBAI), the subject of this article, also extend back decades.
Yet the real point, only briefly touched upon by Jordan in his lauding of Amazon’s recommendation service, is that the dynamo in recent AI progress has come from advances in the knowledge and statistical bases driving these algorithms. The improved digital knowledge bases behind KBAI have been the power behind these advances.
Knowledge bases are finally being effectively combined with AI, a dynamic synergy that is only now being recognized, let alone leveraged. As this realization increases, many forms of useful information structure in the wild will begin to be mapped to these knowledge bases, which will further extend the benefits we are are now seeing from KBAI.
Knowledge-based artificial intelligence, or KBAI, is the use of large statistical or knowledge bases to inform feature selection for machine-based learning algorithms used in AI. The use of knowledge bases to train the features of AI algorithms improves the accuracy, recall and precision of these methods. This improvement leads to perceptibly better results to information queries, including pattern recognition. Further, in a virtuous circle, KBAI techniques can also be applied to identify additional possible facts within the knowledge bases themselves, improving them further still for KBAI purposes.
It is thus, in my view, the combination of KB + AI that has led to the notable AI breakthroughs of the past, say, decade. It is in this combination that we gain the seeds for sowing AI benefits in other areas, from tagging and disambiguation to the complete integration of text with conventional data systems. And, oh, by the way, the structure of all of these systems can be made inherently multi-lingual, meaning that context and interpretation across languages can be brought to our understanding of concepts.
Structured Dynamics is working to democratize a vision of KBAI that brings its benefits to any enterprise, using the same approaches that the behemoths of the industry have used to innovate knowledge-based artificial intelligence in the first place. How and where the benefits of such KBAI may apply is the subject of this article.
A Brief History of Knowledge-based Systems
Knowledge-based artificial intelligence is not a new idea. Its roots extend back perhaps to one of the first AI applications, Dendral. In 1965, nearly a half century ago, Edward Feigenbaum initiated Dendral, which became a ten-year effort to develop software to deduce the molecular structure of organic compounds using scientific instrument data. Dendral was the first expert system and used mass spectra or other experimental data together with a knowledge base of chemistry to produce a set of possible chemical structures. This set the outline for what came to be known as knowledge-based systems, which are one or more computer programs that reason and use knowledge bases to solve complex problems.
Indeed, it was in the area of expert systems that AI first came to the attention of most enterprises. According to Wikipedia,
Expert systems spawned the idea of knowledge engineers, whose role was to interview and codify the logic of the chosen experts. But, expert systems proved to be expensive to build and difficult to maintain and tune. As the influence of expert systems waned, another branch emerged, that of knowledge-based engineering and their support for CAD– and CASE-type systems. Still, overall penetration to date of most knowledge-based systems can most charitably be described as disappointing.
The specific identification of “KBAI” was (to my knowledge) first made in a Carnegie-Mellon University report to DARPA in 1975 . The source knowledge bases were broadly construed, including listings of hypotheses. The first known patent citing knowledge-based artificial intelligence is from 1992 . Within the next ten years there were dedicated graduate-level course offerings on KBAI at many universities, including at least Indiana University, SUNY Buffalo, and Georgia Tech.
In 2007, Bossé et al. devoted a chapter to KBAI in their book on information fusion, but still, at that time, the references were more generic . However, by 2013, the situation was changing fast, as this quote from Hovy et al. indicates :
The waxing and waning of knowledge-based systems and its evolution over fifty years have led to a pretty well-defined space, even if not all component areas have achieved their commercial potential. Besides areas already mentioned, knowledge-based systems also include:
- Knowledge models — formalisms for knowledge representation and reasoning, and
- Reasoning systems — software that generates conclusions from available knowledge using logical techniques such as deduction and induction.
We can organize these subdomains as follows. Note particularly that the branch of KBAI (knowledge-based artificial intelligence) has two main denizens: recognized knowledge bases, such as Wikipedia, and statistical corpora. The former are familiar and evident around us; the latter are largely proprietary and not (generally) publicly accessible:
Some prominent knowledge bases and statistical corpora are identified below. Knowledge bases are coherently organized information with instance data for the concepts and relationships covered by the domain at hand, all accessible in some manner electronically. Knowledge bases can extend from the nearly global, such as Wikipedia, to very specific topic-oriented ones, such as restaurant reviews or animal guides. Some electronic knowledge bases are designed explicitly to support digital consumption, in which case they are fairly structured with defined schema and standard data formats and, increasingly, APIs. Others may be electronically accessible and highly relevant, but the data is not staged in a easily-consumable way, thereby requiring extraction and processing prior to use.
The use and role of statistical corpora is harder to discern. Statistical corpora are organized statistical relationships or rankings that facilitate the processing of (mostly) textual information. Uses can range from entity extraction to machine language translation. Extremely large sources, such as search engine indexes or massive crawls of the Web, are most often the sources for these knowledge sets. But, most are applied internally by those Web properties that control this big data.
The Web is the reason these sources — both statistical corpora and knowledge bases — have proliferated, so the major means of consuming them is via Web services with the information defined and linked to URIs.
My major thesis has been that it is the availability of electronically accessible knowledge bases, exemplified and stimulated by Wikipedia , that has been the telling factor in recent artificial intelligence advances. For example, there are at least 500 different papers that cite using Wikipedia for various natural language processing, artificial intelligence, or knowledge base purposes . These papers began to stream into conferences about 2005 to 2006, and have not abated since. In turn, the various techniques innovated for extracting more and more structure and information from Wikipedia are being applied to other semi-structured knowledge bases, resulting in a true renaissance of knowledge-based processing for AI purposes. These knowledge bases are emerging as the information substrate under many recent computational advances.
Knowledge Bases in Relation to Overall Artificial Intelligence
A few months ago I pulled together a bit of an interaction diagram to show the relationships between major branches of artificial intelligence and structures arising from big data, knowledge bases, and other organizational schema for information:
What we are seeing is a system emerging whereby multiple portions of this diagram interact to produce innovations. Take, for example, Apple‘s Siri , or Google’s Google Now or the many similar systems that have emerged on smartphones. Spoken instructions are decoded to text, which is then parsed and evaluated for intent and meaning and then posed to a general knowledge base. The text results are then modulated back to speech with the answer in the smartphone’s speakers. The pattern recognition at the front and back end of this workflow has been made better though statistical datasets derived from phonemes and text. The text understanding is processed via natural language processing and semantic technologies , with the question understanding and answer formulation coming from one or more knowledge bases.
This remarkable chain of processing is now almost taken for granted, though its commercial use is less than five years old. For different purposes with different workflows we see effective question answering and diagnosis with systems like IBM’s Watson and structured search results from Google’s Knowledge Graph . Try posing some questions to Wolfram Alpha and then stand back and be impressed with the data visualization. Behind the scenes, pattern recognition from faces to general images or thumbprints further is eroding the distinction between man and machine. Google Translate now covers language translation between 60 human languages — and pretty damn effectively, too. All major Web players are active in these areas, from Amazon’s recommendation system to Facebook , Microsoft , Twitter or Baidu .
Though not universal, most all recent AI advances leveraging knowledge bases have utilized Wikipedia in one way or another. Even Freebase, the core of Google’s Knowledge Graph, did not really blossom as a separate data crowdsourcing concern until its former owner, Metaweb, decided to bring Wikipedia into its system. Many other knowledge bases, as noted below, are also derivatives or enhancements to Wikipedia in one way or another.
I believe the reasons for Wikipedia’s influence have arisen from its nearly global scope, its mix of semi-structured data and text, its nearly 200 language versions, and its completely open and accessible nature. Regardless, it is also certainly true that techniques honed with Wikipedia are now being applied to a diversity of knowledge bases. We are also seeing an appreciation start to grow in how knowledge bases can enhance the overall AI effort.
Useful Statistical and Knowledge Sources
The diagram on knowledge-based systems above shows two kinds of databases contributing to KBAI: statistical corpora or databases and true knowledge bases. The statistical corpora tend to be hidden behind proprietary curtains, and also more limited in role and usefulness than general knowledge bases.
The statistical corpora or databases tend to be of a very specific nature. While lists of text corpora and many other things may contribute to this category, the ones actually in commercial use tend to be quite focused in scope, very large, and designed for bespoke functionality. A good example, and one that has been contributed for public use, is the Web 1T 5-gram data set . This data set, contributed by Google for public use in 2006, contains English word n-grams and their observed frequency counts. N-grams capture word tokens that often coincide with one another, from single words to phrases. The length of the n-grams ranges from unigrams (single words) to five-grams. The database was generated from approximately 1 trillion word tokens of text from publicly accessible Web pages.
Another example of statistical corpora are what is used in Google’s Translate capabilities . According to Franz Josef Och, who was the lead manager at Google for its translation activities and an articulate spokesperson for statistical machine translation, a solid base for developing a usable language translation system for a new pair of languages should consist of a bilingual text corpus of more than a million words, plus two monolingual corpora each of more than a billion words. Statistical frequencies of word associations form the basis of these reference sets. Google originally seeded its first language translators with multiple language texts from the United Nations .
Such lookup or frequency tables in fact can shade into what may be termed a knowledge base as they gain more structure. NELL, for example (and see below), contains a relatively flat listing of assertions extracted from the Web for various entities; it goes beyond frequency counts or relatedness, but does not have the full structure of a general knowledge base like Wikipedia . We thus can see that statistical corpora and knowledge bases in fact reside on a continuum of structure, with no bright line to demark the two categories.
Nonetheless, most statistical corpora will never be seen publicly. Building them requires large amounts of input information. And, once built, they can offer significant commercial value to their developers to drive various machine learning systems and for general lookup.
There are literally hundreds of knowledge bases useful to artificial intelligence, most of a restricted domain nature. Listed below, partially informed by Suchanek and Weikum’s work , are some of the broadest ones available. Note that many leverage or are derivatives of or extensions to Wikipedia:
- BabelNet — is a multilingual lexicalized semantic network and ontology automatically created by linking Wikipedia to WordNet
- Biperpedia — is an ontology with 1.6M (class, attribute) pairs and 67K distinct attribute names, a totally unique resource, but one that is not publicly available
- ConceptNet — is a semantic network with concepts as nodes and edges that are assertions of common sense about these concepts
- Cyc — is an artificial intelligence project that attempts to assemble a comprehensive ontology and knowledge base of everyday common sense knowledge, with the goal of enabling AI applications to perform human-like reasoning
- DBpedia — extracts structured content from the information created as part of the Wikipedia, principally from its infoboxes
- DeepDive — employs statistical learning and inference to combine diverse data resources and best-of-breed algorithms in order to construct knowledge bases from hundreds of millions of Web pages
- EntityCube — is a knowledge base built from the statistical extraction of structured entities, named entities, entity facts and relations from the Web
- Freebase — is a large collaborative knowledge base consisting of metadata composed mainly by its community members, but centered initially on Wikipedia; Freebase is a key input component to Google’s Knowledge Graph
- GeoNames — is a geographical database that contains over 10,000,000 geographical names corresponding to over 7,500,000 unique features
- ImageNet — is an image database organized according to the WordNet hierarchy (currently only the nouns), in which each node of the hierarchy is depicted by hundreds and thousands of images
- KnowItAll — is a variety of domain-independent systems that extract information from the Web in an autonomous, scalable manner
- Knowledge Vault (Google) — is a Web-scale probabilistic knowledge base that combines extractions from Web content (obtained via analysis of text, tabular data, page structure, and human annotations) with prior knowledge derived from existing knowledge repositories; it is not publicly available
- LEVAN (Learning About Anything) — is a fully-automated approach for learning extensive models for a wide range of variations (e.g., actions, interactions, attributes and beyond) from images for any concept, leveraging the vast resources of online books
- NELL (Never-Ending Language Learning system) — is a semantic machine learning system developed at Carnegie Mellon University that identifies a basic set of fundamental semantic relationships between a few hundred predefined categories of data, such as cities, companies, emotions and sports teams
- Probase — is a universal, probabilistic taxonomy that contains 2.7 million concepts harvested from a corpus of 1.68 billion web pages
- UMBEL — is an upper ontology of about 28,000 reference concepts and a vocabulary for aiding that ontology mapping, including expressions of likelihood relationships
- Wikidata — is a common source of certain data types (for example, birth dates) which can be used by Wikimedia projects such as Wikipedia
- WikiNet — is a multilingual extension of the facts found in the multiple language versions of Wikipedia
- WikiTaxonomy — is a large-scale taxonomy derived from the category relationships in Wikipedia
- Wolfram Alpha — is a computational knowledge engine made available by subscription as an online service that answers factual queries directly by computing the answer from externally sourced “curated data”
- WordNet — is a lexical database for the English language that groups words into sets of synonyms called synsets, provides short definitions and usage examples, and records a number of relations among these synonym sets or their members
- YAGO — is extracted from Wikipedia (e.g., categories, redirects, infoboxes), WordNet (e.g., synsets, hyponymy), and GeoNames .
What Work is Being Done and the Future
It is instructive to inspect what kinds of work or knowledge these bases are contributing to the AI enterprise. The most important contribution, in my mind, is structure. This structure can relate to the subsumption (is-a) or part of (mereology) relationships between concepts. This form of structure contributes most to understanding the taxonomy or schema of a domain; that is, its scaffolding of concepts. This structure helps orient the instance data and other external structures, generally through some form of mapping.
The next rung of contribution from these knowledge bases is in the nature of the relations between concepts and their instances. These form the predicates or nature of the relationships between things. This kind of contribution is also closely related to the attributes of the concepts and the properties of the things that populate the structure. This kind of information tends to be the kind of characteristics that one sees in a data record: a specific thing and the values for the fields by which it is described.
Another contribution from knowledge bases comes from identity and disamgibuation. Identity works in that we can point to authoritative references (with associated Web identifiers) for all of the individual things and properties in our relevant domain. We can use these identities to decide the “canonical” form, which also gives us a common reference for referring to the same things across information sources or data sets. We also gain the means for capturing the various ways that anything can be described, that is the synonyms, jargon, slang, acronyms or insults that might be associated with something. That understanding helps us identify the core item at hand. When we extend these ideas to the concepts or types that populate our relevant domain, we can also begin to establish context and other relationships to individual things. When we encounter the person “John Smith” we can use co-occurring concepts to help distinguish John Smith the plumber from John Smith the politician or John Smith the policeman. As more definition and structure is added, our ability to discriminate and disambiguate goes up.
Some of this work resides in the interface between schema (concepts) and the instances (individuals) that populate that schema, what I elsewhere have described as the work between the T-Box and A-Box of knowledge bases . In any case, with richer understandings of how we describe and discern things, we can now begin to do new work, not possible when these understandings were lacking. We can now, for example, do semantic search where we can relate multiple expressions for the same things or infer relationships or facets that either allow us to find more relevant items or better narrow our search interests.
With true knowledge bases and logical approaches for working with them and their structure, we can begin doing direct question answering. With more structure and more relationships, we can also do so in rather sophisticated ways, such as identifying items with multiple shared characteristics or within certain ranges or combinations of attributes.
Structured information and the means to query it now gives us a powerful, virtuous circle whereby our knowledge bases can drive the feature selection of AI algorithms, while those very same algorithms can help find still more features and structure in our knowledge bases. The interaction between AI and the KBs means we can add still further structure and refinement to the knowledge bases, which then makes them still better sources of features for informing the AI algorithms:
Once this threshold of feature generation is reached, we now have a virtuous dynamo for knowledge discovery and management. We can use our AI techniques to refine and improve our knowledge bases, which then makes it easier to improve our AI algorithms and incorporate still further external information. Effectively utilized KBAI thus becomes a generator of new information and structure.
This virtuous circle has not yet been widely applied beyond the early phases of, say, adding more facts to Wikipedia, as some of our examples above show. But these same basic techniques can be applied to the very infrastructural foundations of KBAI systems in such areas as data integration, mapping to new external structure and information, hypothesis testing, diagnostics and predictions, and the myriad of other uses to which AI has been hoped to contribute for decades. The virtuous circle between knowledge bases and AIs does not require us to make leaps and bounds improvements in our core AI algorithms. Rather, we need only stoke our existing AI engines with more structure and knowledge fuel in order to keep the engine chugging.
The vision of a growing nexus of KBAI should also prove that efficiencies and benefits also increase through a power function of the network effect, similar to what I earlier described in the Viking algorithm . We know how we can extract further structure and benefit from Wikipedia. We can see how such a seed catalyst can also be the means for mapping and relating more specific domain knowledge bases and structure. The beauty of this vision is that we already can see the threshold benefits from a decade of KBAI development. Each new effort — and there are many — will only act to add to these benefits, with each new increment contributing more than the increment that came before. That sounds to me like productivity, and a true basis for wealth creation. |
By turns discombobulating and breathtaking, the last of the Singapore International Festival of Arts' Dance Marathon performances at Tanjong Pagar Railway Station is a double bill of differences.
Simple and elaborate, loud and quiet, unabashed and understated, the programme reveals Japanese contemporary dance as one that straddles the cultures of the East and West.
Chie Ito's The Daily Life of Ms. D is an explosion of manga kitsch, with an inordinate number of props in bubblegum shades, all adorned with red lips. These keep the titular character company at home, going about her daily life as though in a drug-induced dream.
She is perhaps Ms Ditzy, Delusional or Desperate, qualities which she exhibits in this glimpse into her world, or the fantastic mind of her creator.
As a middle-aged performer, Ito's physicality is compelling to watch as her movement, while laced with caution, reaches towards spontaneity. She becomes like a baby all over again, staggering to find her balance.
REVIEW / DANCE
DOUBLE BILL: THE DAILY LIFE OF MS. D, PASSAGE ON BLUR
Chie Ito, Tsuyoshi Shirai
SIFA Dance Marathon: Open With A Punk Spirit
Tanjong Pagar Railway Station / Last Friday
The surprises, including a huge inflatable dinosaur and a Dracula character, grow tiresome after a while and it is unclear if Ito intended for these to be more than surprises. The work also suffers from an indecision about the audience's role - voyeurs feasting on a mad-house spectacle or spectators to an absurd circus.
In stark contrast, Passage On Blur is virtuosic in its simplicity, it captivates almost without warning.
Tsuyoshi Shirai and Yugo Morikawa bring life back to the old railway platform with a suave minimalism, calling to mind the subtlety of the traditional Japanese concept of sabi.
They are like two buskers, two travellers waiting for a train and above all, two bodies connected by music. One is slickly clad in a waistcoat, the other in pyjamas; one plays a fancy electric guitar, and the other a classical one.
Shirai evinces a boyish cheekiness, wielding his guitar like a violin, then as a golf club and a pillow. He dances with fluidity, coolly stringing everyday gestures together like pearls on a necklace. His body is like a puzzle of slinky toys, distending and dislocating to astonishing effect.
Setting a loop machine in play, Morikawa juxtaposes guitar chords with percussive taps. The sound of traffic zooming past serves only to amplify the haunting zither-like sounds his strumming produces.
Shirai's face is not overtly expressive but his body conveys a myriad of emotions. It is heartbreaking to see him recede into the depths of the platform and heartening when he snaps out of his fitful state.
Throughout the piece, there is a gripping synergy that sits on the brink of fragility and tenacity. When dance and music meet in such an organic union, there is a tranquil harmony that arises, transforming them both. |
We write about dual-scientist couples every so often, since scientists do have a knack for pairing off with each other. This month, we’ve published two articles on dual-scientist couples in which both partners work in the same — or a very similar — field.
Today we’ve posted a profile of physician-scientists Deepali Kumar at Atul Humar, transplant infectious disease specialists at the University of
Alberta in Edmonton, Canada. When I spoke to them earlier this month,
they offered this advice on working with your partner: “If you’re going
to work together as a couple, you really, really have
to like each other and get along well,” Atul said. “A lot of people
tell me, ‘oh, if I had to work with my wife all day, I think I’d go
crazy.’ For us it’s just not the case. I think we work really well
Earlier this month in A Husband and Wife Play Science on the Same Team, we noted that Michael Crickmore and Dragana Rogulja had different interests when they started out in science, but their work and research questions now regularly overlap. An excerpt:
Even as their research interests have converged, Crickmore and Rogulja
have tried to keep their careers and professional identities separate.
They decided, for example, not to include each other as co-authors on
their papers even though “we easily could have been,” Crickmore says.
“Dragana reads my manuscripts more than my boss.” It’s not rivalry,
they say: They simply think they can help each other more if they keep
some distance. “My secret weapon is that Dragana is both my adviser and
my postdoc,” Crickmore says. They even have complementary traits, they
say: Crickmore obsesses over the details of problems whereas Rogulja
likes to zoom out to see the big picture.
You might think we planned these stories around Valentine’s Day, but really it just worked out that way. Eric Berger at the Houston Chronicle did plan his Valentine’s Day article: an excellent profile of Wadih Arap and Renata Pasqualini, both based at M.D. Anderson Cancer Center where they study the unique molecular signatures of blood vessels. Medical oncologist Christopher Logothetis had a nice observation about the couple: “They feed off of
each other and it creates a synergy,” he said in the Chronicle article. “Him being a physician, her being a
pure scientist, he’s more pragmatic, and she’s more of a risk-taker.
Together, they’re a perfect match.” |
Based on a Renesas Synergy S7 MCU with 240 MHz ARM Cortex-M4 core, the ARIS board is aimed at IoT operations. A 3-axis accelerometer and 3-axis gyroscope deliver position and motion sensing information; humidity and temperature sensors provide environmental feedback. Communication with other devices and the Cloud is enabled via an Ethernet 10/100 port, Bluetooth Low Energy (BLE 4.1/4.2) and Wi-Fi b/g/n support. NFC tag functionality is also included along with a crypto bootloader and support for over-the-air (OTA) firmware updates.
The Renesas Synergy Platform helps accelerate IoT designs by making it easier and quicker to start development with a fully qualified and optimised combination of hardware and software that encourages innovation and product differentiation. The combination of the Arrow ARIS board and Renesas Synergy software platform elements enables developers. TheSynergy Software platform includes an operating system, a variety of qualified stacks, libraries and APIs that simplify and speed up the development process.
Arrow comments, “Product developers want to devote their resources to the elements of their application that differentiate them from their competitors. The combination of the Arrow ARIS board and Renesas Synergy Platform allows developers to get started quickly and concentrate on their own area of specialism rather than having to recreate the basic building blocks.”
Arrow Electronics; www.arrow.com |
G’day guys, here’s the week two LCK Summer Split Preview. Sorry we’re a bit late to the action this week, missing the first two days of LCK. Luckily, there’s still 7 action packed games over the course of this week. Without further ado, lets jump straight into some analysis, dank memes and cringe worthy puns.
ROX Tigers vs. MVP
MVP’s LCK debut against KT Rolster was a solid effort for a rookie team. That being said, MVP’s summer split is going to be nothing short of an uphill battle. They are without a doubt one of the weakest teams in the LCK. When MVP are against such formidable opponents such as the ROX Tigers, they should think of this as an opportunity to improve their communication, plan out early game strategies and see if they can get a hold of the game within its early phases.
MVP is outclassed in every position, as they go up against a lot of well-known veteran Koreans. Every laner of the ROX Tigers possess a carry threat and it is very easy to snowball the carry nature of their laners into a swift victory.
ROX’s sheer aggression in the early game should be very difficult for MVP to deal with. A lane swap that creates a more ‘open’ map could further lead to very early skirmishers that could potentially come out in ROX’s favour.
Ultimately, ROX is expected to win this matchup and it is very, very unlikely that they will lose in the best of 3.
Prediction: ROX Tigers 75% | MVP 25%
Longzhu Gaming vs. KT Rolster
It’s very sad to see Longzhu having another shaky season. Longzhu fans, league commentators and LCK enthusiasts have time and time again noted that this is a team that is stacked with talent or players that were previously, very good at their job. But sadly, Longzhu have never been able to translate what they appear on paper to actual results.
What I can take away from their games in week 1 is that:
– A very weak early game from extremely avoidable mistakes
– Aggressive lanes that lack vision, jungler support
– Despite losing in the early phases, they still manage to mitigate enemy gold leads
– The gold lead becomes bigger due to their weaker team fighting synergy
Longzhu aren’t all that bad. The problem is that what they can do, other teams can do better. If Longzhu were not able to take a single game off weaker teams like Afreeca, they simply won’t be able to match the calibre of KT’s rolster.
Predictions: Longzhu 35% | KT Rolster 65%
SKTelecom T1 vs. CJ Entus
(Note: CJ have been playing around with their subs Untara, Bdd and Haru)
League of Legends king’s SKTelecom come straight outta another international tournament with an easy victory. SKT demonstrates to us the flexibility of their gameplay, adaptability to the changing meta and ability to pick themselves up from losses and come out as one of the greatest teams in eSports history.
To be fair, it is very difficult to gauge how SKT stands in this summer split. While their roster is exactly the same, and the current meta is relatively similar to what it was a few months ago, SKT have always hiccupped throughout splits and even playoffs.
SKT’s line-up is filled with top tier threats, while still revolving around the play-making potential of Faker. CJ Entus on the other hand, have just come out of week 1 with a loss against ESC Ever. Their gameplay has been very sloppy and they haven’t been able to rely on Kramer to carry.
Overall, SKT is expected to win this game. However, I wouldn’t be surprised if SKT pull off another dud split with a lot of their previous issues resurfacing. Hence, this match-up could present itself as a black swan, against all the odds.
Prediction: SKTelecom 60% | CJ Entus 40%
ESC Ever vs. ROX Tigers
ESC Ever was always the challenger team with the potential to disrupt LCK standings. They proved that in Week 1 with an upset win against CJ Entus. This team loves to skirmish and have those interesting fights down bot lane with members mobilising down or initiating the fight alongside their bot-lane duo. This team executes their plays in a very clean fashion, and is without a doubt competing for a top spot in the LCK ladder.
ROX lost to Samsung Galaxy in Week 1. While ROX is without a doubt a very strong and aggressive team, there are a few notable things that have weighed them down in Week 1. Their top lane picks (Swain and Fizz) while very good at climbing solo queue, offer less utility in competitive games. Smeb was very able to take off, offering only a semi-off-tank Swain and zero damage-tank Fizz.
Overall, ROX is expected to win this match-up, with a lot of veteran players, experience and aggression that Ever may not be able to handle. That being said, this does not entirely rule this LCK dark horse out of the equation. Ever could present some value for you punt heads or at the very least, take a game away from the Tigers.
Prediction: ESC Ever 40% | ROX Tigers 60%
Samsung Galaxy vs. MVP
Samsung beating ROX Tigers was a huge upset, especially considering how ROX cruised through the spring split almost undefeated. Samsung demonstrated very well rounded game-play with very strong team fighting compositions.
While I have labelled MVP as one of the ‘weakest’ teams in the LCK, pity still pulls on my heartstrings to come out and say that they could have a chance at causing an upset since it is too early to make such suggestions of them being bad.
Overall, Samsung have started this season very strongly and is a favourite to win this match-up.
Predictions: Samsung Galaxy 75% | MVP 25%
KT Rolster vs. SKTelecom T1
Oooooo this is a very spicy matchup, pairing two very good teams with great players against each other. Honestly, it could go either way, a (2-0) KT victory, a (0-2) SKT victory or a hard fought three game victory for either team; none would come as a surprise.
While the odds are without a doubt going to be in SKT favours (because everyone is bias and loves champions) KT Rolster have similar calibre players and demonstrate the same, if not more aggressive play style. What I can tell you guys is as follows:
– Ssumday is a more carry orientated top laner than Duke, hence Duke will be looking to mitigating his carry presence.
– Referencing back to the last split, Score is a strong and more assertive jungler than Blank, although Blank can prove me wrong (as he did during the MSI finals).
– Faker is hands down much better than Fly.
– The bottom lane is very close in terms of their play making potential and consistency. I would say that Bang and Wolf could be marginally better.
Predictions: SKTelecom T1 50.50% | KT Rolster 49.50%
CJ Entus vs. Afreeca Freecs
I had a lot of respect for Afreeca, as a team that came out of nowhere and managed to maintain a decent standing in the LCK last split. After their first game against Longzhu this split, I was sure that they had improved and looking to make a few upsets as the rest of this season pans out. But I was wrong.
Afreeca have been testing out some new players (Linderang and SeongHwan in top and jungle) while also subbing in Ikksu and LiRa (the main top and jungle players). This raises a lot of question marks above my head as to why management have decided to recruit new players, rotate them in matches and think it’s OK to play Blitzcrank in competitive play.
Overall, the odds are without a doubt in CJ’s favour. And it should be; as a solid team backed up with good players against weaker team. However, should Afreeca bring their A game into this match-up, like they did in Week1, I have no doubts in them taking this series (2-0).
Prediction: CJ Entus 55% | Afreeca Freecs 45% |
The microcirculation consists of blood vessels with diameters less than 150 µm. It makes up a large part of the circulatory system and plays an important role in maintaining cardiovascular health. The retina is a tissue that lines the interior of the eye and it is the only tissue that allows for a non-invasive analysis of the microvasculature. Nowadays, high-quality fundus images can be acquired using digital cameras. Retinal images can be collected in 5 min or less, even without dilatation of the pupils. This unobtrusive and fast procedure for visualizing the microcirculation is attractive to apply in epidemiological studies and to monitor cardiovascular health from early age up to old age.
Systemic diseases that affect the circulation can result in progressive morphological changes in the retinal vasculature. For example, changes in the vessel calibers of retinal arteries and veins have been associated with hypertension, atherosclerosis, and increased risk of stroke and myocardial infarction. The vessel widths are derived using image analysis software and the width of the six largest arteries and veins are summarized in the Central Retinal Arteriolar Equivalent (CRAE) and the Central Retinal Venular Equivalent (CRVE). The latter features have been shown useful to study the impact of modifiable lifestyle and environmental cardiovascular disease risk factors.
The procedures to acquire fundus images and the analysis steps to obtain CRAE and CRVE are described. Coefficients of variation of repeated measures of CRAE and CRVE are less than 2% and within-rater reliability is very high. Using a panel study, the rapid response of the retinal vessel calibers to short-term changes in particulate air pollution, a known risk factor for cardiovascular mortality and morbidity, is reported. In conclusion, retinal imaging is proposed as a convenient and instrumental tool for epidemiological studies to study microvascular responses to cardiovascular disease risk factors.
21 Related JoVE Articles!
The Goeckerman Regimen for the Treatment of Moderate to Severe Psoriasis
Institutions: University of Southern California, University of California, San Francisco , University of California Irvine School of Medicine, University of Arizona College of Medicine, Chicago College of Osteopathic Medicine.
Psoriasis is a chronic, immune-mediated inflammatory skin disease affecting approximately 2-3% of the population. The Goeckerman regimen consists of exposure to ultraviolet B (UVB) light and application of crude coal tar (CCT). Goeckerman therapy is extremely effective and relatively safe for the treatment of psoriasis and for improving a patient's quality of life. In the following article, we present our protocol for the Goeckerman therapy that is utilized specifically at the University of California, San Francisco. This protocol details the preparation of supplies, administration of phototherapy and application of topical tar. This protocol also describes how to assess the patient daily, monitor for adverse effects (including pruritus and burning), and adjust the treatment based on the patient's response. Though it is one of the oldest therapies available for psoriasis, there is an absence of any published videos demonstrating the process in detail. The video is beneficial for healthcare providers who want to administer the therapy, for trainees who want to learn more about the process, and for prospective patients who want to undergo treatment for their cutaneous disease.
Medicine, Issue 77, Infection, Biomedical Engineering, Anatomy, Physiology, Immunology, Dermatology, Skin, Dermis, Epidermis, Skin Diseases, Skin Diseases, Eczematous, Goeckerman, Crude Coal Tar, phototherapy, psoriasis, Eczema, Goeckerman regimen, clinical techniques
Implantation of the Syncardia Total Artificial Heart
Institutions: Virginia Commonwealth University, Virginia Commonwealth University.
With advances in technology, the use of mechanical circulatory support devices for end stage heart failure has rapidly increased. The vast majority of such patients are generally well served by left ventricular assist devices (LVADs). However, a subset of patients with late stage biventricular failure or other significant anatomic lesions are not adequately treated by isolated left ventricular mechanical support. Examples of concomitant cardiac pathology that may be better treated by resection and TAH replacement includes: post infarction ventricular septal defect, aortic root aneurysm / dissection, cardiac allograft failure, massive ventricular thrombus, refractory malignant arrhythmias (independent of filling pressures), hypertrophic / restrictive cardiomyopathy, and complex congenital heart disease. Patients often present with cardiogenic shock and multi system organ dysfunction. Excision of both ventricles and orthotopic replacement with a total artificial heart (TAH) is an effective, albeit extreme, therapy for rapid restoration of blood flow and resuscitation. Perioperative management is focused on end organ resuscitation and physical rehabilitation. In addition to the usual concerns of infection, bleeding, and thromboembolism common to all mechanically supported patients, TAH patients face unique risks with regard to renal failure and anemia. Supplementation of the abrupt decrease in brain natriuretic peptide following ventriculectomy appears to have protective renal effects. Anemia following TAH implantation can be profound and persistent. Nonetheless, the anemia is generally well tolerated and transfusion are limited to avoid HLA sensitization. Until recently, TAH patients were confined as inpatients tethered to a 500 lb pneumatic console driver. Recent introduction of a backpack sized portable driver (currently under clinical trial) has enabled patients to be discharged home and even return to work. Despite the profound presentation of these sick patients, there is a 79-87% success in bridge to transplantation.
Medicine, Issue 89, mechanical circulatory support, total artificial heart, biventricular failure, operative techniques
Modeling Stroke in Mice: Permanent Coagulation of the Distal Middle Cerebral Artery
Institutions: University Hospital Munich, Munich Cluster for Systems Neurology (SyNergy), University Heidelberg, Charing Cross Hospital.
Stroke is the third most common cause of death and a main cause of acquired adult disability in developed countries. Only very limited therapeutical options are available for a small proportion of stroke patients in the acute phase. Current research is intensively searching for novel therapeutic strategies and is increasingly focusing on the sub-acute and chronic phase after stroke because more patients might be eligible for therapeutic interventions in a prolonged time window. These delayed mechanisms include important pathophysiological pathways such as post-stroke inflammation, angiogenesis, neuronal plasticity and regeneration. In order to analyze these mechanisms and to subsequently evaluate novel drug targets, experimental stroke models with clinical relevance, low mortality and high reproducibility are sought after. Moreover, mice are the smallest mammals in which a focal stroke lesion can be induced and for which a broad spectrum of transgenic models are available. Therefore, we describe here the mouse model of transcranial, permanent coagulation of the middle cerebral artery via electrocoagulation distal of the lenticulostriatal arteries, the so-called “coagulation model”. The resulting infarct in this model is located mainly in the cortex; the relative infarct volume in relation to brain size corresponds to the majority of human strokes. Moreover, the model fulfills the above-mentioned criteria of reproducibility and low mortality. In this video we demonstrate the surgical methods of stroke induction in the “coagulation model” and report histological and functional analysis tools.
Medicine, Issue 89, stroke, brain ischemia, animal model, middle cerebral artery, electrocoagulation
Prehospital Thrombolysis: A Manual from Berlin
Institutions: Charité - Universitätsmedizin Berlin, Charité - Universitätsmedizin Berlin, Universitätsklinikum Hamburg - Eppendorf, Berliner Feuerwehr, STEMO-Consortium.
In acute ischemic stroke, time from symptom onset to intervention is a decisive prognostic factor. In order to reduce this time, prehospital thrombolysis at the emergency site would be preferable. However, apart from neurological expertise and laboratory investigations a computed tomography (CT) scan is necessary to exclude hemorrhagic stroke prior to thrombolysis. Therefore, a specialized ambulance equipped with a CT scanner and point-of-care laboratory was designed and constructed. Further, a new stroke identifying interview algorithm was developed and implemented in the Berlin emergency medical services. Since February 2011 the identification of suspected stroke in the dispatch center of the Berlin Fire Brigade prompts the deployment of this ambulance, a stroke emergency mobile (STEMO). On arrival, a neurologist, experienced in stroke care and with additional training in emergency medicine, takes a neurological examination. If stroke is suspected a CT scan excludes intracranial hemorrhage. The CT-scans are telemetrically transmitted to the neuroradiologist on-call. If coagulation status of the patient is normal and patient's medical history reveals no contraindication, prehospital thrombolysis is applied according to current guidelines (intravenous recombinant tissue plasminogen activator, iv rtPA, alteplase, Actilyse).
Thereafter patients are transported to the nearest hospital with a certified stroke unit for further treatment and assessment of strokeaetiology. After a pilot-phase, weeks were randomized into blocks either with or without STEMO care. Primary end-point of this study is time from alarm to the initiation of thrombolysis. We hypothesized that alarm-to-treatment time can be reduced by at least 20 min compared to regular care.
Medicine, Issue 81, Telemedicine, Emergency Medical Services, Stroke, Tomography, X-Ray Computed, Emergency Treatment,[stroke, thrombolysis, prehospital, emergency medical services, ambulance
Stereotactic Radiosurgery for Gynecologic Cancer
Institutions: University Hospitals Case Medical Center and Case Western Reserve University School of Medicine, University Hospitals Case Medical Center and Case Western Reserve University School of Medicine.
Stereotactic body radiotherapy (SBRT) distinguishes itself by necessitating more rigid patient immobilization, accounting for respiratory motion, intricate treatment planning, on-board imaging, and reduced number of ablative radiation doses to cancer targets usually refractory to chemotherapy and conventional radiation. Steep SBRT radiation dose drop-off permits narrow 'pencil beam' treatment fields to be used for ablative radiation treatment condensed into 1 to 3 treatments.
Treating physicians must appreciate that SBRT comes at a bigger danger of normal tissue injury and chance of geographic tumor miss. Both must be tackled by immobilization of cancer targets and by high-precision treatment delivery. Cancer target immobilization has been achieved through use of indexed customized Styrofoam casts, evacuated bean bags, or body-fix molds with patient-independent abdominal compression.1-3
Intrafraction motion of cancer targets due to breathing now can be reduced by patient-responsive breath hold techniques,4
patient mouthpiece active breathing coordination,5
respiration-correlated computed tomography,6
or image-guided tracking of fiducials implanted within and around a moving tumor.7-9
The Cyberknife system (Accuray [Sunnyvale, CA]) utilizes a radiation linear accelerator mounted on a industrial robotic arm that accurately follows patient respiratory motion by a camera-tracked set of light-emitting diodes (LED) impregnated on a vest fitted to a patient.10
Substantial reductions in radiation therapy margins can be achieved by motion tracking, ultimately rendering a smaller planning target volumes that are irradiated with submillimeter accuracy.11-13
Cancer targets treated by SBRT are irradiated by converging, tightly collimated beams. Resultant radiation dose to cancer target volume histograms have a more pronounced radiation "shoulder" indicating high percentage target coverage and a small high-dose radiation "tail." Thus, increased target conformality comes at the expense of decreased dose uniformity in the SBRT cancer target. This may have implications for both subsequent tumor control in the SBRT target and normal tissue tolerance of organs at-risk. Due to the sharp dose falloff in SBRT, the possibility of occult disease escaping ablative radiation dose occurs when cancer targets are not fully recognized and inadequate SBRT dose margins are applied. Clinical target volume (CTV) expansion by 0.5 cm, resulting in a larger planning target volume (PTV), is associated with increased target control without undue normal tissue injury.7,8
Further reduction in the probability of geographic miss may be achieved by incorporation of 2-[18
F-FDG) positron emission tomography (PET).8
Use of 18
F-FDG PET/CT in SBRT treatment planning is only the beginning of attempts to discover new imaging target molecular signatures for gynecologic cancers.
Medicine, Issue 62, radiosurgery, Cyberknife stereotactic radiosurgery, radiation, ovarian cancer, cervix cancer
The Application Of Permanent Middle Cerebral Artery Ligation in the Mouse
Institutions: University of Rochester, University of Alabama at Birmingham, University of Rochester.
Focal cerebral ischemia is among the most common type of stroke seen in patients. Due to the clinical significance there has been a prolonged effort to develop suitable animal models to study the events that unfold during ischemic insult. These techniques include transient or permanent, focal or global ischemia models using many different animal models, with the most common being rodents.
The permanent MCA ligation method which is also referred as pMCAo in the literature is used extensively as a focal ischemia model in rodents 1-6
. This method was originally described for rats by Tamura et al. in 1981 7
. In this protocol a craniotomy was used to access the MCA and the proximal regions were occluded by electrocoagulation. The infarcts involve mostly cortical and sometimes striatal regions depending on the location of the occlusion. This technique is now well established and used in many laboratories 8-13
. Early use of this technique led to the definition and description of “infarct core” and “penumbra” 14-16
, and it is often used to evaluate potential neuroprotective compounds 10, 12, 13, 17
. Although the initial studies were performed in rats, permanent MCA ligation has been used successfully in mice with slight modifications 18-20
This model yields reproducible infarcts and increased post-survival rates. Approximately 80% of the ischemic strokes in humans happen in the MCA area 21
and thus this is a very relevant model for stroke studies. Currently, there is a paucity of effective treatments available to stroke patients, and thus there is a need for good models to test potential pharmacological compounds and evaluate physiological outcomes. This method can also be used for studying intracellular hypoxia response mechanisms in vivo
Here, we present the MCA ligation surgery in a C57/BL6 mouse. We describe the pre-surgical preparation, MCA ligation surgery and 2,3,5 Triphenyltetrazolium chloride (TTC) staining for quantification of infarct volumes.
Medicine, Issue 53, brain, stroke, mouse, middle cerebral artery ligation
Handwriting Analysis Indicates Spontaneous Dyskinesias in Neuroleptic Naïve Adolescents at High Risk for Psychosis
Institutions: University of Colorado Boulder, NeuroScript LLC, University of California, San Diego.
Growing evidence suggests that movement abnormalities are a core feature of psychosis. One marker of movement abnormality, dyskinesia, is a result of impaired neuromodulation of dopamine in fronto-striatal pathways. The traditional methods for identifying movement abnormalities include observer-based reports and force stability gauges. The drawbacks of these methods are long training times for raters, experimenter bias, large site differences in instrumental apparatus, and suboptimal reliability. Taking these drawbacks into account has guided the development of better standardized and more efficient procedures to examine movement abnormalities through handwriting analysis software and tablet. Individuals at risk for psychosis showed significantly more dysfluent pen movements (a proximal measure for dyskinesia) in a handwriting task. Handwriting kinematics offers a great advance over previous methods of assessing dyskinesia, which could clearly be beneficial for understanding the etiology of psychosis.
Behavior, Issue 81, Schizophrenia, Disorders with Psychotic Features, Psychology, Clinical, Psychopathology, behavioral sciences, Movement abnormalities, Ultra High Risk, psychosis, handwriting, computer tablet, dyskinesia
Tilt Testing with Combined Lower Body Negative Pressure: a "Gold Standard" for Measuring Orthostatic Tolerance
Institutions: Simon Fraser University .
Orthostatic tolerance (OT) refers to the ability to maintain cardiovascular stability when upright, against the hydrostatic effects of gravity, and hence to maintain cerebral perfusion and prevent syncope (fainting). Various techniques are available to assess OT and the effects of gravitational stress upon the circulation, typically by reproducing a presyncopal event (near-fainting episode) in a controlled laboratory environment. The time and/or degree of stress required to provoke this response provides the measure of OT. Any technique used to determine OT should: enable distinction between patients with orthostatic intolerance (of various causes) and asymptomatic control subjects; be highly reproducible, enabling evaluation of therapeutic interventions; avoid invasive procedures, which are known to impair OT1
In the late 1980s head-upright tilt testing was first utilized for diagnosing syncope2
. Since then it has been used to assess OT in patients with syncope of unknown cause, as well as in healthy subjects to study postural cardiovascular reflexes2-6
. Tilting protocols comprise three categories: passive tilt; passive tilt accompanied by pharmacological provocation; and passive tilt with combined lower body negative pressure (LBNP). However, the effects of tilt testing (and other orthostatic stress testing modalities) are often poorly reproducible, with low sensitivity and specificity to diagnose orthostatic intolerance7
Typically, a passive tilt includes 20-60 min of orthostatic stress continued until the onset of presyncope in patients2-6
. However, the main drawback of this procedure is its inability to invoke presyncope in all individuals undergoing the test, and corresponding low sensitivity8,9
. Thus, different methods were explored to increase the orthostatic stress and improve sensitivity.
Pharmacological provocation has been used to increase the orthostatic challenge, for example using isoprenaline4,7,10,11
or sublingual nitrate12,13
. However, the main drawback of these approaches are increases in sensitivity at the cost of unacceptable decreases in specificity10,14
, with a high positive response rate immediately after administration15
. Furthermore, invasive procedures associated with some pharmacological provocations greatly increase the false positive rate1
Another approach is to combine passive tilt testing with LBNP, providing a stronger orthostatic stress without invasive procedures or drug side-effects, using the technique pioneered by Professor Roger Hainsworth in the 1990s16-18
. This approach provokes presyncope in almost all subjects (allowing for symptom recognition in patients with syncope), while discriminating between patients with syncope and healthy controls, with a specificity of 92%, sensitivity of 85%, and repeatability of 1.1±0.6 min16,17
. This allows not only diagnosis and pathophysiological assessment19-22
, but also the evaluation of treatments for orthostatic intolerance due to its high repeatability23-30
. For these reasons, we argue this should be the "gold standard" for orthostatic stress testing, and accordingly this will be the method described in this paper.
Medicine, Issue 73, Anatomy, Physiology, Biomedical Engineering, Neurobiology, Kinesiology, Cardiology, tilt test, lower body negative pressure, orthostatic stress, syncope, orthostatic tolerance, fainting, gravitational stress, head upright, stroke, clinical techniques
Ultrasound Assessment of Endothelial-Dependent Flow-Mediated Vasodilation of the Brachial Artery in Clinical Research
Institutions: University of California, San Francisco, Veterans Affairs Medical Center, San Francisco, Veterans Affairs Medical Center, San Francisco.
The vascular endothelium is a monolayer of cells that cover the interior of blood vessels and provide both structural and functional roles. The endothelium acts as a barrier, preventing leukocyte adhesion and aggregation, as well as controlling permeability to plasma components. Functionally, the endothelium affects vessel tone.
Endothelial dysfunction is an imbalance between the chemical species which regulate vessel tone, thombroresistance, cellular proliferation and mitosis. It is the first step in atherosclerosis and is associated with coronary artery disease, peripheral artery disease, heart failure, hypertension, and hyperlipidemia.
The first demonstration of endothelial dysfunction involved direct infusion of acetylcholine and quantitative coronary angiography. Acetylcholine binds to muscarinic receptors on the endothelial cell surface, leading to an increase of intracellular calcium and increased nitric oxide (NO) production. In subjects with an intact endothelium, vasodilation was observed while subjects with endothelial damage experienced paradoxical vasoconstriction.
There exists a non-invasive, in vivo
method for measuring endothelial function in peripheral arteries using high-resolution B-mode ultrasound. The endothelial function of peripheral arteries is closely related to coronary artery function. This technique measures the percent diameter change in the brachial artery during a period of reactive hyperemia following limb ischemia.
This technique, known as endothelium-dependent, flow-mediated vasodilation (FMD) has value in clinical research settings. However, a number of physiological and technical issues can affect the accuracy of the results and appropriate guidelines for the technique have been published. Despite the guidelines, FMD remains heavily operator dependent and presents a steep learning curve. This article presents a standardized method for measuring FMD in the brachial artery on the upper arm and offers suggestions to reduce intra-operator variability.
Medicine, Issue 92, endothelial function, endothelial dysfunction, brachial artery, peripheral artery disease, ultrasound, vascular, endothelium, cardiovascular disease.
Tumor Treating Field Therapy in Combination with Bevacizumab for the Treatment of Recurrent Glioblastoma
Institutions: Southern Illinois University School of Medicine.
A novel device that employs TTF therapy has recently been developed and is currently in use for the treatment of recurrent glioblastoma (rGBM). It was FDA approved in April 2011 for the treatment of patients 22 years or older with rGBM. The device delivers alternating electric fields and is programmed to ensure maximal tumor cell kill1
Glioblastoma is the most common type of glioma and has an estimated incidence of approximately 10,000 new cases per year in the United States alone2
. This tumor is particularly resistant to treatment and is uniformly fatal especially in the recurrent setting3-5
. Prior to the approval of the TTF System, the only FDA approved treatment for rGBM was bevacizumab6
. Bevacizumab is a humanized monoclonal antibody targeted against the vascular endothelial growth factor (VEGF) protein that drives tumor angiogenesis7
. By blocking the VEGF pathway, bevacizumab can result in a significant radiographic response (pseudoresponse), improve progression free survival and reduce corticosteroid requirements in rGBM patients8,9
. Bevacizumab however failed to prolong overall survival in a recent phase III trial26
. A pivotal phase III trial (EF-11) demonstrated comparable overall survival between physicians’ choice chemotherapy and TTF Therapy but better quality of life were observed in the TTF arm10
There is currently an unmet need to develop novel approaches designed to prolong overall survival and/or improve quality of life in this unfortunate patient population. One appealing approach would be to combine the two currently approved treatment modalities namely bevacizumab and TTF Therapy. These two treatments are currently approved as monotherapy11,12
, but their combination has never been evaluated in a clinical trial. We have developed an approach for combining those two treatment modalities and treated 2 rGBM patients. Here we describe a detailed methodology outlining this novel treatment protocol and present representative data from one of the treated patients.
Medicine, Issue 92, Tumor Treating Fields, TTF System, TTF Therapy, Recurrent Glioblastoma, Bevacizumab, Brain Tumor
A Research Method For Detecting Transient Myocardial Ischemia In Patients With Suspected Acute Coronary Syndrome Using Continuous ST-segment Analysis
Institutions: University of Nevada, Reno, St. Joseph's Medical Center, University of Rochester Medical Center .
Each year, an estimated 785,000 Americans will have a new coronary attack, or acute coronary syndrome (ACS). The pathophysiology of ACS involves rupture of an atherosclerotic plaque; hence, treatment is aimed at plaque stabilization in order to prevent cellular death. However, there is considerable debate among clinicians, about which treatment pathway is best: early invasive using percutaneous coronary intervention (PCI/stent) when indicated or a conservative approach (i.e.
, medication only with PCI/stent if recurrent symptoms occur).
There are three types of ACS: ST elevation myocardial infarction (STEMI), non-ST elevation MI (NSTEMI), and unstable angina (UA). Among the three types, NSTEMI/UA is nearly four times as common as STEMI. Treatment decisions for NSTEMI/UA are based largely on symptoms and resting or exercise electrocardiograms (ECG). However, because of the dynamic and unpredictable nature of the atherosclerotic plaque, these methods often under detect myocardial ischemia because symptoms are unreliable, and/or continuous ECG monitoring was not utilized.
Continuous 12-lead ECG monitoring, which is both inexpensive and non-invasive, can identify transient episodes of myocardial ischemia, a precursor to MI, even when asymptomatic. However, continuous 12-lead ECG monitoring is not usual hospital practice; rather, only two leads are typically monitored. Information obtained with 12-lead ECG monitoring might provide useful information for deciding the best ACS treatment.
Therefore, using 12-lead ECG monitoring, the COMPARE Study (electroC
n of ischeM
sive to phaR
atment) was designed to assess the frequency and clinical consequences of transient myocardial ischemia, in patients with NSTEMI/UA treated with either early invasive PCI/stent or those managed conservatively (medications or PCI/stent following recurrent symptoms). The purpose of this manuscript is to describe the methodology used in the COMPARE Study.
Permission to proceed with this study was obtained from the Institutional Review Board of the hospital and the university. Research nurses identify hospitalized patients from the emergency department and telemetry unit with suspected ACS. Once consented, a 12-lead ECG Holter monitor is applied, and remains in place during the patient's entire hospital stay. Patients are also maintained on the routine bedside ECG monitoring system per hospital protocol. Off-line ECG analysis is done using sophisticated software and careful human oversight.
Medicine, Issue 70, Anatomy, Physiology, Cardiology, Myocardial Ischemia, Cardiovascular Diseases, Health Occupations, Health Care, transient myocardial ischemia, Acute Coronary Syndrome, electrocardiogram, ST-segment monitoring, Holter monitoring, research methodology
The Use of Magnetic Resonance Spectroscopy as a Tool for the Measurement of Bi-hemispheric Transcranial Electric Stimulation Effects on Primary Motor Cortex Metabolism
Institutions: University of Montréal, McGill University, University of Minnesota.
Transcranial direct current stimulation (tDCS) is a neuromodulation technique that has been increasingly used over the past decade in the treatment of neurological and psychiatric disorders such as stroke and depression. Yet, the mechanisms underlying its ability to modulate brain excitability to improve clinical symptoms remains poorly understood 33
. To help improve this understanding, proton magnetic resonance spectroscopy (1
H-MRS) can be used as it allows the in vivo
quantification of brain metabolites such as γ-aminobutyric acid (GABA) and glutamate in a region-specific manner 41
. In fact, a recent study demonstrated that 1
H-MRS is indeed a powerful means to better understand the effects of tDCS on neurotransmitter concentration 34
. This article aims to describe the complete protocol for combining tDCS (NeuroConn MR compatible stimulator) with 1
H-MRS at 3 T using a MEGA-PRESS sequence. We will describe the impact of a protocol that has shown great promise for the treatment of motor dysfunctions after stroke, which consists of bilateral stimulation of primary motor cortices 27,30,31
. Methodological factors to consider and possible modifications to the protocol are also discussed.
Neuroscience, Issue 93, proton magnetic resonance spectroscopy, transcranial direct current stimulation, primary motor cortex, GABA, glutamate, stroke
Permanent Cerebral Vessel Occlusion via Double Ligature and Transection
Institutions: University of California, Irvine, University of California, Irvine, University of California, Irvine, University of California, Irvine.
Stroke is a leading cause of death, disability, and socioeconomic loss worldwide. The majority of all strokes result from an interruption in blood flow (ischemia) 1
. Middle cerebral artery (MCA) delivers a great majority of blood to the lateral surface of the cortex 2
, is the most common site of human stroke 3
, and ischemia within its territory can result in extensive dysfunction or death 1,4,5
. Survivors of ischemic stroke often suffer loss or disruption of motor capabilities, sensory deficits, and infarct. In an effort to capture these key characteristics of stroke, and thereby develop effective treatment, a great deal of emphasis is placed upon animal models of ischemia in MCA.
Here we present a method of permanently occluding a cortical surface blood vessel. We will present this method using an example of a relevant vessel occlusion that models the most common type, location, and outcome of human stroke, permanent middle cerebral artery occlusion (pMCAO). In this model, we surgically expose MCA in the adult rat and subsequently occlude via double ligature and transection of the vessel. This pMCAO blocks the proximal cortical branch of MCA, causing ischemia in all of MCA cortical territory, a large portion of the cortex. This method of occlusion can also be used to occlude more distal portions of cortical vessels in order to achieve more focal ischemia targeting a smaller region of cortex. The primary disadvantages of pMCAO are that the surgical procedure is somewhat invasive as a small craniotomy is required to access MCA, though this results in minimal tissue damage. The primary advantages of this model, however, are: the site of occlusion is well defined, the degree of blood flow reduction is consistent, functional and neurological impairment occurs rapidly, infarct size is consistent, and the high rate of survival allows for long-term chronic assessment.
Medicine, Issue 77, Biomedical Engineering, Anatomy, Physiology, Neurobiology, Neuroscience, Behavior, Surgery, Therapeutics, Surgical Procedures, Operative, Investigative Techniques, Life Sciences (General), Behavioral Sciences, Animal models, Stroke, ischemia, imaging, middle cerebral artery, vessel occlusion, rodent model, surgical techniques, animal model
Assessment of Vascular Function in Patients With Chronic Kidney Disease
Institutions: University of Colorado, Denver, University of Colorado, Boulder.
Patients with chronic kidney disease (CKD) have significantly increased risk of cardiovascular disease (CVD) compared to the general population, and this is only partially explained by traditional CVD risk factors. Vascular dysfunction is an important non-traditional risk factor, characterized by vascular endothelial dysfunction (most commonly assessed as impaired endothelium-dependent dilation [EDD]) and stiffening of the large elastic arteries. While various techniques exist to assess EDD and large elastic artery stiffness, the most commonly used are brachial artery flow-mediated dilation (FMDBA
) and aortic pulse-wave velocity (aPWV), respectively. Both of these noninvasive measures of vascular dysfunction are independent predictors of future cardiovascular events in patients with and without kidney disease. Patients with CKD demonstrate both impaired FMDBA
, and increased aPWV. While the exact mechanisms by which vascular dysfunction develops in CKD are incompletely understood, increased oxidative stress and a subsequent reduction in nitric oxide (NO) bioavailability are important contributors. Cellular changes in oxidative stress can be assessed by collecting vascular endothelial cells from the antecubital vein and measuring protein expression of markers of oxidative stress using immunofluorescence. We provide here a discussion of these methods to measure FMDBA
, aPWV, and vascular endothelial cell protein expression.
Medicine, Issue 88, chronic kidney disease, endothelial cells, flow-mediated dilation, immunofluorescence, oxidative stress, pulse-wave velocity
Measuring Ascending Aortic Stiffness In Vivo in Mice Using Ultrasound
Institutions: Johns Hopkins University, Johns Hopkins University, Johns Hopkins University, Macquarie University.
We present a protocol for measuring in vivo
aortic stiffness in mice using high-resolution ultrasound imaging. Aortic diameter is measured by ultrasound and aortic blood pressure is measured invasively with a solid-state pressure catheter. Blood pressure is raised then lowered incrementally by intravenous infusion of vasoactive drugs phenylephrine and sodium nitroprusside. Aortic diameter is measured for each pressure step to characterize the pressure-diameter relationship of the ascending aorta. Stiffness indices derived from the pressure-diameter relationship can be calculated from the data collected. Calculation of arterial compliance is described in this protocol.
This technique can be used to investigate mechanisms underlying increased aortic stiffness associated with cardiovascular disease and aging. The technique produces a physiologically relevant measure of stiffness compared to ex vivo
approaches because physiological influences on aortic stiffness are incorporated in the measurement. The primary limitation of this technique is the measurement error introduced from the movement of the aorta during the cardiac cycle. This motion can be compensated by adjusting the location of the probe with the aortic movement as well as making multiple measurements of the aortic pressure-diameter relationship and expanding the experimental group size.
Medicine, Issue 94, Aortic stiffness, ultrasound, in vivo, aortic compliance, elastic modulus, mouse model, cardiovascular disease
The WATCHMAN Left Atrial Appendage Closure Device for Atrial Fibrillation
Institutions: University of Leipzig Heart Center.
Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting an estimated 6 million people in the United States 1
. Since AF affects primarily elderly people, its prevalence increases parallel with age. As such, it is expected that 15.9 million Americans will be affected by the year 2050 2
. Ischemic stroke occurs in 5% of non-anticoagulated AF patients each year. Current treatments for AF include rate control, rhythm control and prevention of stroke 3
The American College of Cardiology, American Heart Association, and European Society of Cardiology currently recommended rate control as the first course of therapy for AF 3
. Rate control is achieved by administration of pharmacological agents, such as β-blockers, that lower the heart rate until it reaches a less symptomatic state 3
. Rhythm control aims to return the heart to its normal sinus rhythm and is typically achieved through administration of antiarrhythmic drugs such as amiodarone, electrical cardioversion or ablation therapy. Rhythm control methods, however, have not been demonstrated to be superior to rate-control methods 4-6
. In fact, certain antiarrhythmic drugs have been shown to be associated with higher hospitalization rates, serious adverse effects 3
, or even increases in mortality in patients with structural heart defects 7
. Thus, treatment with antiarrhythmics is more often used when rate-control drugs are ineffective or contraindicated. Rate-control and antiarrhythmic agents relieve the symptoms of AF, including palpitations, shortness of breath, and fatigue 8
, but don't reliably prevent thromboembolic events 6
Treatment with the anticoagulant drug warfarin significantly reduces the rate of stroke or embolism 9,10
. However, because of problems associated with its use, fewer than 50% of patients are treated with it. The therapeutic dose is affected by drug, dietary, and metabolic interactions, and thus requires detailed monitoring. In addition, warfarin has the potential to cause severe, sometimes lethal, bleeding 2
. As an alternative, aspirin is commonly prescribed. While aspirin is typically well tolerated, it is far less effective at preventing stroke 10
. Other alternatives to warfarin, such as dabigatran 11
or rivaroxaban 12
demonstrate non-inferiority to warfarin with respect to thromboembolic events (in fact, dabigatran given as a high dose of 150 mg twice a day has shown superiority). While these drugs have the advantage of eliminating dietary concerns and eliminating the need for regular blood monitoring, major bleeding and associated complications, while somewhat less so than with warfarin, remain an issue 13-15
Since 90% of AF-associated strokes result from emboli that arise from the left atrial appendage (LAA) 2
, one alternative approach to warfarin therapy has been to exclude the LAA using an implanted device to trap blood clots before they exit. Here, we demonstrate a procedure for implanting the WATCHMAN Left Atrial Appendage Closure Device. A transseptal cannula is inserted through the femoral vein, and under fluoroscopic guidance, inter-atrial septum is crossed. Once access to the left atrium has been achieved, a guidewire is placed in the upper pulmonary vein and the WATCHMAN Access Sheath and dilator are advanced over the wire into the left atrium. The guidewire is removed, and the access sheath is carefully advanced into the distal portion of the LAA over a pigtail catheter. The WATCHMAN Delivery System is prepped, inserted into the access sheath, and slowly advanced. The WATCHMAN device is then deployed into the LAA. The device release criteria are confirmed via fluoroscopy and transesophageal echocardiography (TEE) and the device is released.
Medicine, Issue 60, atrial fibrillation, cardiology, cardiac, interventional cardiology, medical procedures, medicine, WATCHMAN, medical device, left atrial appendage
Interview: Glycolipid Antigen Presentation by CD1d and the Therapeutic Potential of NKT cell Activation
Institutions: La Jolla Institute for Allergy and Immunology.
Natural Killer T cells (NKT) are critical determinants of the immune response to cancer, regulation of autioimmune disease, clearance of infectious agents, and the development of artheriosclerotic plaques. In this interview, Mitch Kronenberg discusses his laboratory's efforts to understand the mechanism through which NKT cells are activated by glycolipid antigens. Central to these studies is CD1d - the antigen presenting molecule that presents glycolipids to NKT cells. The advent of CD1d tetramer technology, a technique developed by the Kronenberg lab, is critical for the sorting and identification of subsets of specific glycolipid-reactive T cells. Mitch explains how glycolipid agonists are being used as therapeutic agents to activate NKT cells in cancer patients and how CD1d tetramers can be used to assess the state of the NKT cell population in vivo following glycolipid agonist therapy. Current status of ongoing clinical trials using these agonists are discussed as well as Mitch's prediction for areas in the field of immunology that will have emerging importance in the near future.
Immunology, Issue 10, Natural Killer T cells, NKT cells, CD1 Tetramers, antigen presentation, glycolipid antigens, CD1d, Mucosal Immunity, Translational Research
Assessing Endothelial Vasodilator Function with the Endo-PAT 2000
Institutions: Stanford University .
The endothelium is a delicate monolayer of cells that lines all blood vessels, and which comprises the systemic and lymphatic capillaries. By virtue of the panoply of paracrine factors that it secretes, the endothelium regulates the contractile and proliferative state of the underlying vascular smooth muscle, as well as the interaction of the vessel wall with circulating blood elements. Because of its central role in mediating vessel tone and growth, its position as gateway to circulating immune cells, and its local regulation of hemostasis and coagulation, the the properly functioning endothelium is the key to cardiovascular health. Conversely, the earliest disorder in most vascular diseases is endothelial dysfunction.
In the arterial circulation, the healthy endothelium generally exerts a vasodilator influence on the vascular smooth muscle. There are a number of methods to assess endothelial vasodilator function. The Endo-PAT 2000 is a new device that is used to assess endothelial vasodilator function in a rapid and non-invasive fashion. Unlike the commonly used technique of duplex ultra-sonography to assess flow-mediated vasodilation, it is totally non-operator-dependent, and the equipment is an order of magnitude less expensive. The device records endothelium-mediated changes in the digital pulse waveform known as the PAT ( peripheral Arterial Tone) signal, measured with a pair of novel modified plethysmographic probes situated on the finger index of each hand. Endothelium-mediated changes in the PAT signal are elicited by creating a downstream hyperemic response. Hyperemia is induced by occluding blood flow through the brachial artery for 5 minutes using an inflatable cuff on one hand. The response to reactive hyperemia is calculated automatically by the system. A PAT ratio is created using the post and pre occlusion values. These values are normalized to measurements from the contra-lateral arm, which serves as control for non-endothelial dependent systemic effects. Most notably, this normalization controls for fluctuations in sympathetic nerve outflow that may induce changes in peripheral arterial tone that are superimposed on the hyperemic response.
In this video we demonstrate how to use the Endo-PAT 2000 to perform a clinically relevant assessment of endothelial vasodilator function.
Medicine, Issue 44, endothelium, endothelial dysfunction, Endo-PAT 2000, peripheral arterial tone, reactive hyperemia
Catheter Ablation in Combination With Left Atrial Appendage Closure for Atrial Fibrillation
Institutions: St. Antonius Hospital, The Netherlands.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting millions of individuals worldwide 1-3
. The rapid, irregular, and disordered electrical activity in the atria gives rise to palpitations, fatigue, dyspnea, chest pain and dizziness with or without syncope 4, 5
. Patients with AF have a five-fold higher risk of stroke 6
Oral anticoagulation (OAC) with warfarin is commonly used for stroke prevention in patients with AF and has been shown to reduce the risk of stroke by 64% 7
. Warfarin therapy has several major disadvantages, however, including bleeding, non-tolerance, interactions with other medications and foods, non-compliance and a narrow therapeutic range 8-11
. These issues, together with poor appreciation of the risk-benefit ratio, unawareness of guidelines, or absence of an OAC monitoring outpatient clinic may explain why only 30-60% of patients with AF are prescribed this drug 8
The problems associated with warfarin, combined with the limited efficacy and/or serious side effects associated with other medications used for AF 12,13
, highlight the need for effective non-pharmacological approaches to treatment. One such approach is catheter ablation (CA), a procedure in which a radiofrequency electrical current is applied to regions of the heart to create small ablation lesions that electrically isolate potential AF triggers 4
. CA is a well-established treatment for AF symptoms 14, 15
, that may also decrease the risk of stroke. Recent data showed a significant decrease in the relative risk of stroke and transient ischemic attack events among patients who underwent ablation compared with those undergoing antiarrhythmic drug therapy 16
Since the left atrial appendage (LAA) is the source of thrombi in more than 90% of patients with non-valvular atrial fibrillation 17
, another approach to stroke prevention is to physically block clots from exiting the LAA. One method for occluding the LAA is via percutaneous placement of the WATCHMAN LAA closure device. The WATCHMAN device resembles a small parachute. It consists of a nitinol frame covered by fabric polyethyl terephthalate that prevents emboli, but not blood, from exiting during the healing process. Fixation anchors around the perimeter secure the device in the LAA (Figure 1
). To date, the WATCHMAN is the only implanted percutaneous device for which a randomized clinical trial has been reported. In this study, implantation of the WATCHMAN was found to be at least as effective as warfarin in preventing stroke (all-causes) and death (all-causes) 18
. This device received the Conformité Européenne
(CE) mark for use in the European Union for warfarin eligible patients and in those who have a contraindication to anticoagulation therapy 19
Given the proven effectiveness of CA to alleviate AF symptoms and the promising data with regard to reduction of thromboembolic events with both CA and WATCHMAN implantation, combining the two procedures is hoped to further reduce the incidence of stroke in high-risk patients while simultaneously relieving symptoms. The combined procedure may eventually enable patients to undergo implantation of the WATCHMAN device without subsequent warfarin treatment, since the CA procedure itself reduces thromboembolic events. This would present an avenue of treatment previously unavailable to patients ineligible for warfarin treatment because of recurrent bleeding 20
or other warfarin-associated problems.
The combined procedure is performed under general anesthesia with biplane fluoroscopy and TEE guidance. Catheter ablation is followed by implantation of the WATCHMAN LAA closure device. Data from a non-randomized trial with 10 patients demonstrates that this procedure can be safely performed in patients with a CHADS2
score of greater than 1 21
. Further studies to examine the effectiveness of the combined procedure in reducing symptoms from AF and associated stroke are therefore warranted.
Medicine, Issue 72, Anatomy, Physiology, Biomedical Engineering, Immunology, Cardiology, Surgery, catheter ablation, WATCHMAN, LAA occlusion, atrial fibrillation, left atrial appendage, warfarin, oral anticoagulation alternatives, catheterization, ischemia, stroke, heart, vein, clinical, surgical device, surgical techniques, Vitamin K antagonist
Microsurgical Clip Obliteration of Middle Cerebral Aneurysm Using Intraoperative Flow Assessment
Institutions: Havard Medical School, Massachusetts General Hospital.
Cerebral aneurysms are abnormal widening or ballooning of a localized segment of an intracranial blood vessel. Surgical clipping is an important treatment for aneurysms which attempts to exclude blood from flowing into the aneurysmal segment of the vessel while preserving blood flow in a normal fashion. Improper clip placement may result in residual aneurysm with the potential for subsequent aneurysm rupture or partial or full occlusion of distal arteries resulting in cerebral infarction. Here we describe the use of an ultrasonic flow probe to provide quantitative evaluation of arterial flow before and after microsurgical clip placement at the base of a middle cerebral artery aneurysm. This information helps ensure adequate aneurysm reconstruction with preservation of normal distal blood flow.
Medicine, Issue 31, Aneurysm, intraoperative, brain, surgery, surgical clipping, blood flow, aneurysmal segment, ultrasonic flow probe
A New Single Chamber Implantable Defibrillator with Atrial Sensing: A Practical Demonstration of Sensing and Ease of Implantation
Institutions: University Hospital of Rostock, Germany.
Implantable cardioverter-defibrillators (ICDs) terminate ventricular tachycardia (VT) and ventricular fibrillation (VF) with high efficacy and can protect patients from sudden cardiac death (SCD). However, inappropriate shocks may occur if tachycardias are misdiagnosed. Inappropriate shocks are harmful and impair patient quality of life. The risk of inappropriate therapy increases with lower detection rates programmed in the ICD. Single-chamber detection poses greater risks for misdiagnosis when compared with dual-chamber devices that have the benefit of additional atrial information. However, using a dual-chamber device merely for the sake of detection is generally not accepted, since the risks associated with the second electrode may outweigh the benefits of detection. Therefore, BIOTRONIK developed a ventricular lead called the LinoxSMART
S DX, which allows for the detection of atrial signals from two electrodes positioned at the atrial part of the ventricular electrode. This device contains two ring electrodes; one that contacts the atrial wall at the junction of the superior vena cava (SVC) and one positioned at the free floating part of the electrode in the atrium. The excellent signal quality can only be achieved by a special filter setting in the ICD (Lumax 540 and 740 VR-T DX, BIOTRONIK). Here, the ease of implantation of the system will be demonstrated.
Medicine, Issue 60, Implantable defibrillator, dual chamber, single chamber, tachycardia detection |
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Other Ingredients: Magnesium Stearate, Silicon Dioxide, Titanium Dioxide.
To assess tolerance, begin by taking 1 capsule before breakfast and 1 capsule six to eight hours later. Once tolerance is determined, take 1-2 capsules on an empty stomach before breakfast and an additional 1 capsule six to eight hours later on an empty stomach, if needed. Due to extreme potency, do not use product for longer than 8 weeks followed by a subsequent 4 week break. Do not exceed 3 capsules in any 24 hour period.
This product is only intended to be consumed by healthy adults 18 years of age or older. Pregnant or nursing women should not use this product. Consult with your health care provider before using this product, especially if you are taking any prescription, over the counter medication, dietary supplement product or if you have any pre-existing medical condition including but not limited to: high or low blood pressure, cardiac arrhythmia, stroke, heart, liver, kidney or thyroid disease, seizure disorder, psychiatric disease, diabetes, difficulty urinating due to prostate enlargement or if you are taking a MAO-B inhibitor or any other medication, including but not limited to MAOIs, SSRIs, or any other compounds with serotonergic activity.
Discontinue use 2 weeks prior to surgery. Discontinue use and immediately consult your health care professional if you experience any adverse reaction to this product. Do not exceed recommended serving. Do not use if safety seal is broken or missing.
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These statements have not been evaluated by the Food and Drug Administration (FDA). This product is not intended to diagnose, treat, cure or prevent any disease. |
On Tuesday March 28th I'm giving a talk about postpunk New York and the synergy between the downtown art world and the No Wave/mutant disco scene, as part of The Downtown Show: The New York Art Scene 1974-1984 exhibition which is running at the Grey Gallery and at NYU's Fales Library.
Admission is free, the time is 6-30 PM, and the location for the talk is:
NYU Fales Library (inside Bobst Library)
70 Washington Square South at La Guardia, 3rd Floor
(further information: 212 998 2596)
Another free Downtown Show event worth checking out is Friday 3/31's Nightclubbing: The Original Punk Rock Music Video Series, which is at the Cantor Film Center, 36 East Eighth Street, starts at 6PM, and has live footage of Contortions, DNA, Teenage Jesus & the Jerks, Suicide, Talking Heads, Bush Tetras, Lounge Lizards, the Voidoids, Cramps, Pylon, John Cale, Bad Brains, and many more, and is followed by a discussion between the curators of the event Pat Ivers and Emily Armstrong moderated by Amos Poe.
Aggravatingly I won't get to see this as that very night I'll to be walking in Memphis (youngest brother's getting married) |
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Written by The Caretaker Coach for @Hollywoodbets. Follow them both on Twitter and Facebook now!
By the time the second PSL gameweek kicks off on Tuesday evening, it would have been 25 days since the beginning of the season. The lack of synergy between the league, cup competition, CAF Champions League and internationals means teams not involved in more than one of the above have been battling to keep themselves busy in the month of August. There are obvious positives and negatives to this, with lower league teams still being fresh after only one competitive game, whilst teams like Pirates already have six competitive matches under their belts. This has affected the league to the extent where Ajax Cape Town’s clash with Pirates has been postponed for a second time. Bearing this in mind, as well as some standout performances from the first round of the PSL, means we’re in for some interesting matchups in the midweek.
AmaZulu vs Mpumalanga Black Aces
Usuthu were the upset winners in the first round of fixtures, with an impressive 1-0 away win over Orlando Pirates; the first of its kind in 20 years for the men from Kwa-Zulu Natal. This win, however, highlights my initial concerns. Although Bucs had many chances to draw level and possibly win it, their lack of focus ahead of some big games outside of the league was evident, which dents the value of the feat somewhat. This means that hosting Black Aces in Durban is set to be a tougher task than it first looks. Despite going down at home to the league champions, Aces made Chiefs work hard for their three points. A late appeal against his seemingly ridiculous 12-month ban saw Mabhuti Khenyeza start, and put in a notably passionate performance for Aces. If it weren’t for goalkeeper extraordinaire Itumeleng Khune, he would’ve been on the score sheet that night. Should Aces repeat this performance away on Tuesday night, we could well see the points being shared. AmaZulu have what it takes to win it, but it could well come down to chances being taken and which goalkeeper turns up to save his team. With AmaZulu at 12/10 for the win, I’d rather see myself backing the draw at a very healthy 21/10.
Kaizer Chiefs vs Moroka Swallows
There is no doubt that the AmaKhosi are most definitely back. Their star-studded team are an intimidating bunch for most PSL sides, and with their focus solely on the league for now, I foresee a strong run over the next few weeks. Saturday’s MTN8 Soweto Derby can be neglected in terms of form; I can’t see it being too much of a stumbling block for Chiefs going forward. Moroka Swallows needed an 88th minute winner from Lerato Chabangu to sneak a win at home against a weaker University of Pretoria side earlier this month. Swallows were expected to put in a more dominant display, despite finishing a place lower than AmaTuks last season, and whilst their superior talent shone through in the middle third of the pitch, they lacked the finishing that’s needed to see off a side of Chiefs’ pedigree. You’ll always look to back Chiefs at home, and I don’t see it being any different this time around. The bookies seem to agree, and at 7/10, it looks to be safe a 70% return from your investment. Also look to throw a Chiefs win into multiples as a nice boost to payouts.
Free State Stars vs Maritzburg United
Here are two teams that are capable of anything. That is, unless they’re playing each other. For mid-table sides, their inconsistency always makes a matchup like this a difficult one to call. Free State Stars were at the wrong end of a small hiding from Supersport United on the opening weekend. After taking an early lead, a dominant second half comeback from Matsatsantsa put any early season joys to bed for Stars. Maritzburg, on the other hand, grabbed a regulation win against PSL first timers Polokwane City. Yakubu Mohammed looked good in his first appearance for the club, and is one to watch as the season progresses, but I can’t see them making it two wins from two away in Bethlehem. The Team Of Choice have never beaten FSS in their ten previous meetings, with the total goals tally in favour of the hosts 17-6. Free State Stars are my firm pick for the clash, currently at a healthy 13/10. The draw is at 21/10 for those less confident.
Bidvest Wits vs Golden Arrows
Although both teams are coming off draws in their opening games, last season’s performances could not have been more different. Arrows struggled, eventually escaping relegation, whilst Wits had a stellar run finishing fourth. Wits, however, looked rusty in their opening game. Gavin Hunt has shown his mettle in seasons past and I highly respect his pedigree, but he’s got a lot to prove at Wits. There’s not much in their strongest starting XI to excite me, and I doubt the calibre of players he has can match their showing last season. They did notch up a good 3-0 win in the MTN8 however, albeit to a weak Bloem Celtic side. This was followed on Sunday with a lacklustre semi-final first leg, going down 4-2 to a spirited Platinum Stars side. Golden Arrows are in a similar predicament this season, with no new significant recruitments in place to improve on their poor showing last season. This means this fixture could either be a scrappy affair or an absolute goal fest at both ends. Having said all this, the stats show something more convincing, and really this is what we have to go on in a game of this nature. The last time Arrows beat Wits was back in 2008, and with that in mind you have to look to the home side to keep the unbeaten record going. The draw at 23/10 looks great value, with Wits at 7/10 being too short for my liking.
Mamelodi Sundowns vs Platinum Stars
These are two teams with heaps of potential this season, making this the clash of the gameweek. Downs impressed last time out with a convincing 3-1 win away at Bloem Celtic, never an easy place to play. And with guys like Katlego Mashego and Surprise Moriri not even in the starting XI that day, they seem to have built a great squad during the off-season. Bongani Zungu is also going to be one to watch. With a strike force that strong and guys like Teko Modise controlling the midfield, they’re always going to be a threat. Although Stars played out a tame draw at home, they should bring more to this fixture, and will be looking to Mogakolodi Ngele to get back to last season’s form. They had a convincing 3-0 win against FSS in the MTN8, followed by a come-from-behind 4-2 victory over Wits in the 1st semi final on Sunday. This game will be tighter than the betting suggests, with Downs at evens to win it being the way I’d go, purely based on their opening fixture coupled with the fact that Stars may be a bit fatigued having played a strenuous 90 minutes just three days prior.
Polokwane City vs Bloemfontein Celtic
Celtic have conceded six goals in their opening two fixtures, one in the league against Downs at home, followed by getting knocked out convincingly in the MTN8 to Wits. They’re making their way back to Pretoria to face the newbies, Polokwane City. They lost their opener away to Maritzburg United, but have a great opportunity to assert themselves in top-flight football against what looks like a lacklustre Celtic side this season. A win here would be a huge morale booster, and they’re fortunate to have this fixture so early in the season. The bookies have this just as tight as it suggests, with both sides at 16/10 a win, with the draw at 21/10. Its going to be tough to call this, but I’m putting my neck out and predicting a feverish draw.
Pretoria University vs Supersport United
AmaTuks were a surprise package in their first PSL season, credibly finishing eighth. This snuck them into the MTN8, where they got a rude awakening in the first round, getting overwhelmed by Chiefs 3-0. Supersport United on the other hand had a great preseason, beating a star studded Manchester City followed by a healthy 4-1 win at home to FSS. Although coming short to Pirates on penalties in the MTN8, things could’ve gone either way, and they might well have played in the semi-final last weekend. I can’t see Matsatsantsa struggling in this Pretoria derby. A short bus ride to the game, and there’ll no doubt be enough support there for them to feel almost at home. The bookies agree, pricing them short at 75/100 despite being ‘away’ from home. Look to include in multiples and boost payouts.
The man knows his football, but even he gets it wrong from time to time. Feel free to share your PSL tips and multiples below.
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The coupling of pathways and processes through shared components
© Seaton and Krishnan; licensee BioMed Central Ltd. 2011
Received: 12 January 2011
Accepted: 29 June 2011
Published: 29 June 2011
The coupling of pathways and processes through shared components is being increasingly recognised as a common theme which occurs in many cell signalling contexts, in which it plays highly non-trivial roles.
In this paper we develop a basic modelling and systems framework in a general setting for understanding the coupling of processes and pathways through shared components. Our modelling framework starts with the interaction of two components with a common third component and includes production and degradation of all these components. We analyze the signal processing in our model to elucidate different aspects of the coupling. We show how different kinds of responses, including "ultrasensitive" and adaptive responses, may occur in this setting. We then build on the basic model structure and examine the effects of additional control regulation, switch-like signal processing, and spatial signalling. In the process, we identify a way in which allosteric regulation may contribute to signalling specificity, and how competitive effects may allow an enzyme to robustly coordinate and time the activation of parallel pathways.
We have developed and analyzed a common systems platform for examining the effects of coupling of processes through shared components. This can be the basis for subsequent expansion and understanding the many biologically observed variations on this common theme.
Intracellular signalling networks are characterised by their ability to perceive and integrate a variety of signals in order to make decisions. In order to do this, their components often interact with multiple entities at multiple locations, allowing them to receive and send multiple signals. This property is seen, for example, in proteins capable of multiple allosteric interactions such as n-WASP , WAVE , Cdk-2 , and PLC . There are also many examples of enzymes capable of modifying multiple substrates [5–9], including signalling proteins such as cyclin-dependent kinases [10, 11], and ubiquitin ligases . Similarly, substrates may be modified by multiple enzymes, as is the case for the p53 tumour suppressor and many GTPases. Each of these reactions may take place while bound to various adaptor and scaffold structures, as is common for instance in MAPK cascades . Finally, all of these interactions and reactions may take place in diverse cellular locations, with many proteins having been identified as having multiple subcellular localizations . Commonly known examples of this are cell-cycle proteins such as cyclins, which shuttle between the nucleus and cytoplasm, and a wide variety of membrane-binding signalling proteins, which may also be present in the cytoplasm. The sharing of components between pathways and locations is widespread and one of the most basic ways in which processes may be coupled.
A notable aspect of signalling in biological systems, and one which distinguishes them from many engineered systems, is that it is inherently bidirectional. Whenever a signal is being sent or received, components must interact with one another, and/or change location, and are occupied by those actions for finite periods of time. Therefore a signal is itself modified when it is perceived by a downstream signalling element. The extent of bidirectional signalling has been termed retroactivity . While retroactivity may be low in some cases, and while there may be reasons for systems minimising it in some cases, it is nonetheless likely to have a non-trivial effect in other cases. This is particularly true, and especially significant, in networks containing elements with multiple interactions. Signalling networks involve many proteins with multiple interactions and multispecific enzymes, where many of the elements are similar in concentration. Therefore, proteins may be shared between multiple pathways, and the question arises as to what functional roles these multiple interactions and consequent bidirectionality might play in cellular signal processing in biological systems.
The most important aspect of signalling networks which may be affected by multiple interactions is their ability to perceive and integrate signals, and thereby perform logical operations. Multiple interactions and bidirectional signalling may affect the input-output response of pathways, and may be particularly relevant to investigating signalling crosstalk [17–19]. Crosstalk occurs when multiple pathways share components. Despite this coupling, signalling networks are often seen to allow one input to specifically regulate only one or a few outputs. This is termed signalling specificity. Likewise, it is observed that in some networks particular outputs are regulated by only one or a few inputs, termed signalling fidelity. It is important to understand the role of crosstalk in such networks and how signalling specificity and fidelity may be maintained. Another phenomenon observed in signalling is the temporal coordination of processes with one another. Examples include events such as mitosis and the assembly of large protein complexes involved in flagellar motors . Bidirectional aspects of signalling may affect or even contribute to these properties in a very non-trivial manner, and therefore are of direct biological relevance. Overall our studies provide important insights which help bridge descriptions of networks at local and global levels.
Further to the biological implications discussed above, there are important implications for the ways in which biological signalling circuits are modelled. Mathematical modelling has been used to analyse and understand many signalling networks. Such models frequently consider enzyme-substrate complexes only implicitly, often using Michaelis-Menten kinetics or other simplifications such as the quasi-steady state assumption (QSSA) [22–24]. It has been recognised that these simplifications may have significant effects on the behaviour of models, as seen recently in analyses of ultrasensitive and multistable reaction networks [25–27]. Another implication is that modular decompositions of networks, which may allow rapid simulation and more straightforward analysis, must be undertaken with care. The analysis which we present is relevant to both these aspects.
In order to focus on the essential aspects of coupling of processes through shared components, and hence provide insights into the various issues mentioned above, we develop an appropriate modelling/systems framework. The modelling framework incorporates two components which bind exclusively to a common third component, and are therefore indirectly affected by each other. The model incorporates the production and degradation of all components, thus allowing each component to serve as a "signalling port". Having developed the basic model, we proceed to systematically examine the signal processing through this module, as this sheds direct light on the above issues. It is worth emphasizing that in this minimal general setting, systems analysis provides transparent and important insights which are relevant to a wide range of systems/contexts where the above feature(s) occur. We further build on the study of the basic model to include additional features such as spatial diffusion/localization, and other complexities in signal propagation such as threshold effects. Throughout, we focus on the effects of coupling signalling elements through shared components, revealing different facets of such generic coupling.
This paper is organized as follows. In the next section, we present the basic modelling framework which we employ. Following this, we systematically examine the steady state and temporal signal processing in this module in turn. We illustrate the relevance of the analysis in specific biological contexts. We then examine the effect of the additional elements mentioned above. Finally we conclude with a synthesis and discuss additional applications and extensions.
The basic model of coupling of signalling pathways
Here, we develop a basic model of pathway coupling - the sharing of one component between processes. In its most basic form, the coupling of processes and signalling can be studied via a simplified ordinary differential equation model, which involves the interaction of three species A, B and X. A and B each bind exclusively to X, and thus X serves as a factor which couples the dynamics of A and B. We formulate the model in a general form, so that the essential insights can be extracted in a transparent and generalisable way. Details of additional models used and the parameter values used in simulations are available in Additional File 1.
Here, [X], [A], and [AX] denote the concentrations of each species A, X and the complex AX. In the above equation, ka1 and ka2 denote the binding and unbinding rate constants, kpx, kpa denote the production rates of the species X and A respectively, and kdx, kda denote the degradation rates of these species.
Note that in these simplified equations, the total amounts of A and X are conserved, and hence information about the availability of these species is contained in the initial conditions. These expressions may be condensed by applying conservation conditions using the total quantities of A, and X (denoted [AT] and [XT], respectively).
The above model incorporates the binding of B to X to form a complex BX, as well as the dissociation, and in addition includes the production and degradation of B (rate constants kb1,kb2,kpb, and kdb respectively). While we have described the production and degradation of species, we stress that this need not be taken as protein synthesis and degradation - it includes, for example, the rate of formation of a particular post-translationally modified form of a protein. This is significant because these processes may occur on a much faster timescale than protein synthesis and degradation.
Some of the analysis will be concerned with the steady-state of these models. In this, the equilibrium constants for the complex formation of A and B with X (the ratio of binding to dissociation rate constants) become relevant parameters of interest. We denote these K A (= k a 1/k a 2) and K B (= k b 1/k b 2).
Variation of inputs and outputs
We note at the outset that the model is a general model of components A and B, interacting through competitive binding with the element X. This model allows modulation of the levels of each of these components by external signals through their rates of production and degradation. Throughout the paper, we are primarily interested in two essentially different ways in which the levels of components are modulated by external signals. In the first case, we examine how changes in production of the shared component, X, are propagated to affect the levels of free A and B, and the levels of the complexes AX and BX, and therefore modify both pathways in which X participates. In the second case, we examine how changes in the production of the components A and B affect the levels of all components and complexes. This corresponds to the pathways being controlled while the shared component remains constant. Through this analysis, we hope to understand the range of behaviours available to such systems, and their possible biological significance. In particular, we examine how shared components may coordinate processes, and how processes may remain independent despite sharing components.
At this stage we make very few assumptions about the nature of the downstream processes involving the complexes AX and BX. Later in the paper, we build on the existing modelling framework to examine certain additional features in the downstream processes from our perspective.
Our results involve analyzing the models using simulations (performed in MATLAB using ode15 s) and analytical results. We choose a representative set of parameters, and examine the effect of the change in important parameters as appropriate.
Results and discussion
The results are organized as follows: we use our modelling framework to study how the system responds to different signals from both steady state and temporal perspectives. We then build on our analysis to examine a number of biologically motivated variations to our structure, which include additional components, downstream switching elements and spatial signal transduction, and discuss their possible biological significance. We start by examining the case where a signal modulates the production of the shared component, X, and continue by examining the case where signals modulate the components A and B, both separately and simultaneously.
Modulation of the shared component
We begin by analysing the steady state response of the system to changes in the production of X. From the perspective of signal propagation, this may be regarded as signal processing through "diverging pathways”. Assuming that the rates of degradation of all components are equal, we can write the total quantity of each component in terms of the production and degradation rates ([X T ] = k px / kd , [A T ] = k pa /k d [B T ] = k pb /k d , where [X T ], [A T ], and [B T ] refer to the total concentrations of X, A, and B, respectively). This allows us to analyse the model in terms of its response to [X T ], allowing more transparent explanation of the results.
Note that [A] and [B] are the concentrations of free A and free B and hence implicitly depend on the total X in the system. Assuming that the binding affinity of A is much greater than that of B, we can discern three regimes in the response. These three regimes can be described in terms of the saturation of A and B. Initially, since the binding affinity of A is much greater than B and A and B are present in equal amounts K A [A] + K B [B] + 1 ≈ K A [A], and most of the available X forms complexes with A (this implicitly assumes that the available A and B is in excess of X). Once A is depleted, the quantity K A [A] becomes dwarfed by K B [B], and K B [B] + K B [B] + 1 ≈ K B [B], and most of the available X forms complexes with B. This is what underlies an "ultrasensitive" response in BX as the total concentration of X is increased. This parallels the effects discussed by Buchler et al [28, 29], although we note that the relative sensitivity (the sensitivity scaled by concentrations, see appendix for details) in the complex BX is less than the relative sensitivity observed in the free X (see Figure 2). Once B is depleted, all remaining X is added to the free pool. We note that the "ultrasensitivity" in response of the B pathway depends on suppression of signal at low values of the input (in this case [X T ]) by the A pathway. This requires that K A [A] ≫ K B [B], which is a condition on relative affinities rather than absolute affinities. However, the absolute sensitivity in [BX] also depends upon a high linear response once A is depleted and that suppression is overcome, requiring K B [B] ≫ 1. Therefore, the response observed requires the system to satisfy the condition K A [A] ≫ K B [B] ≫ 1. The results are illustrated in Figure 2.
Other classes of regime may similarly be discerned, depending on the relative amounts of A and B initially and the affinities. For instance suppose KA[A] >> 1 >> KB[B], then we see that as XT is increases, A is largely taken up, but as A depletes, much of the extra X remains free rather than bound to B. The other case where 1 >> KA[A] >> KB[B] throughout is one where most of the X is unbound, and is hence of less interest.
Returning to the above analysis for the case when K A [A] ≫ K B [B] ≫ 1, we note that our analysis and conclusions were based on a steady state analysis and the factors which enter the analysis are the equilibrium constants. We now examine how such a network responds to temporal signals.
In order to do this, we take the full system at steady state and change the production rate of X at t = 0. Note that a slow change in the quantity of X would leave the system in a quasi-steady state, and the results would follow directly from the steady state analysis presented above. Thus, we examine cases where rapid changes in the quantity of X available are induced.
Also shown in Figure 3 is that, in the opposite case, if the relative time scales of the high affinity binding/unbinding are changed (keeping the equilibrium constant fixed) it is possible to saturate the low-affinity component, B, more rapidly than the high-affinity component. In Figure 3, a case where a sufficiently high change in X is considered so that both A and B are essentially saturated at steady state. For intermediate levels of X, what can be observed is that the low affinity component complex is rapidly formed before a gradual redistribution of X between the pathways. Thus if the low affinity component B is the faster responding component, then a step change in X (in this range) will affect B first, before it gradually reduces with the X "leaking" back to the A pathway. Thus in this regime, a step change in X results in a marked but essentially transient response for BX, and a much more gradual response for AX. Thus BX displays a faster but adaptive response, while AX displays a slower but persistent response. We further note that if the total X is increased past a level which ensures saturation of the component A, then BX displays a response which is partially adaptive. This partial adaptation (underadaptation) can be traced to the saturation of the "inhibitory" pathway A.
This can be further understood by analytical studies (see Appendix). This illustrates the importance of kinetics in addition to steady state and quasi-steady state analysis in understanding the temporal order of activation of the pathways.
Overall, the analysis above provides insight into how the coupled pathways process steady and temporal signals through their shared component and propagate them downstream, and the role of other factors in modulating this process.
Modulation of each pathway alone, and together
We now use our modelling framework to examine the case where input signals "converge" on common target. This is done in our model by changing the production of A and B, and keeping the production of X fixed.
The above simulation has relevance for the case of pathways which are costimulated, and which have common downstream targets. Again, in the above case, the simulation studies can be complemented by analytical studies which distil the effects seen above. This is discussed in the Appendix.
We briefly discuss analytical results from a simplified perspective, to complement those in the previous section. We again consider a setting where the affinity of A for X is very high and much greater than that of B (K A >> K B ). For specificity, we assume that under basal conditions, an equal amount of A and B is present. Suppose the production and degradation of all components is ignored, then we have conservation of total A, B and X as discussed in the previous section. Further the fraction of X in a complex with A and B at steady state is in fact given exactly by the expressions in the previous subsection. Now suppose we consider a case, where extra A and B are introduced in equal amounts at t = 0, and the system is allowed to evolve. The response of the system depends on the affinity of B. If B also has sufficiently high affinity for X then initially both A and B are present almost completely as complexes (assuming sufficient X is available). Now when A and B are added, at steady state if enough X is available, they will both be taken up as complex. Therefore from the point of the individual pathways, we see an essentially proportional response. On the other hand if the total amount of A and B in the system exceeds that of X, then at steady state, it is A which is present entirely in complex form, while B is bound to the X which is not taken up by A. Thus here while the A pathway shows output directly reflects the addition of A, the B pathway in fact reflects only a partial complexing, which in turn directly depends on the presence of A. At this stage, any further (concurrent) additions of A and B increase the AX concentration, but decrease the BX concentration. As the level of the input increases, the AX concentration increases till it essentially equals the total X concentration while the BX concentration reduces till it becomes zero.
Similar trends also hold good if the affinity of B for X is at intermediate levels. Here, only a fraction of B is found bound to X and this depends also on the amount of B in the system. If A and B are added, when A and B are at relatively low levels, this results in the complete uptake of A and an increase in complex of B, due to the presence of increased B in the system. However, when the levels of A and B are further increased, the concentration of AX increases, and the concentration of BX decreases, because the effect of additional B is counteracted by the fact that less X is available for binding to B.
Again, we can go beyond steady state responses to examine kinetic effects. We see that if A is the faster responding pathway, then the insights of the steady state analysis are mirrored in the way the concentrations of the complexes AX and BX change. When available X is present, the added A binds to available X, followed by B if some X remains. When the levels of A and B combined exceed that of X, and unbound A exists, the complex BX gradually unbinds to allow for the subsequent rapid binding of A with released X. Thus the kinetics of the complex BX dissociating may limit the rate at which free A is subsequently absorbed (and likewise the concentration of BX is reduced due to this effect). Hence one may observe that the increase of AX occurs in two phases, a fast phase where it binds with free X and a slow phase where it relies on dissociation of BX.
We can also examine the opposite case, where B is the faster component. Here the effect of B on X is faster, but this is gradually eroded by the extra A. When A and B levels are such that their total is less than that of X, we see an increase of BX followed by that of AX. When in a stimulus A and B levels exceed that of X, we see an increase of BX first followed by a gradual unbinding and increase of AX. Depending on the initial concentrations of A and B and the extent of the stimulus, the concentration of BX may temporally increase before decreasing, and end up either above or even below prestimulus levels. These are qualitatively reminiscent of underadaptive and overadaptive responses respectively. Thus overall we see that depending on the basal level and the strength of the added stimulus, the response of the B pathway may be non-adaptive, partially adaptive, or overadaptive, and this behaviour is determined by the coupling to the pathway A.
Summary of results for the basic model
Changing the rate production of the shared Component, X.
At steady state, "ultrasensitivity" may be observed in the response of the lower affinity component, and of free X. When one examines the dynamics of the response of the two pathways, the relative timescales of the interactions are important. Depending on this, the dynamics may mirror the steady state response; alternatively, an adaptive response may be observed in the low affinity component.
Changing the rate of production of A and B.
The two pathways may inhibit one another, with the high affinity component having a greater inhibitory effect. Depending on the timescales of the interactions, the dynamics may either mirror the steady state response, or result in an adaptive response in the lower affinity pathway.
Combinatorial signalling and the influence of complex formation mechanisms and allostery
It was shown above that, in essence, processes which share a component may act to inhibit one another. The above analysis of the mass-action model applies to situations where A and B form complexes with X by simple independent interactions. In many cases a protein may bind cooperatively, and it may be affected by further binding proteins. In this section we show how such mechanisms influence the potential interaction and coupling between processes. We then suggest a role for this effect in insulating pathways against crosstalk. In particular, since these mechanisms allow single proteins to behave as "AND" gates - active only when receiving both input signals - they allow tuning of specificity through combinatorial signalling.
Thus, such a complex formation mechanism can act to increase signalling specificity by effectively combining the cross inhibition and combinatorial signalling methods of reducing crosstalk. In the case of CDK-cyclin complexes mentioned above, given that different cyclins result in different substrate specificities , sequestration provides a mechanism for the presence of substrates for a particular cyclin-CDK complex to favour the formation of that complex rather than other cyclin-CDK complexes. Further, deletion of a cyclin may lead to compensation effects from the binding of substitute cyclins, as many are present at significant levels at the same time .
The other case, where binding of Y to A precedes binding of X to form the active complex AXY, can also be considered within our framework (Figure 7c). In this case, addition of Y allows binding of X, and so performs the same role in modulating B as A alone did in the basic model. Figure 8 shows again that the presence of Y, increases specificity of A and leads to greater inhibition of B. On the other hand, we see that the presence of Y acts to insulate A from the crosstalk through B via the common connection X. Analytical studies of the above two cases are performed in the Appendix. While in both cases an increased Y acts to inhibit BX formation at steady state, there are some differences. In one case (Y binding with A before binding with X) we see that the amount of Y limits the amount of X involved in this pathway. Thus a low level of Y will substantially reduce the amount of X involved in this pathway. This is not the case for the scenario where Y binds to the complex AX. The contrasting effects of the two mechanisms on the uptake of X in response to Y are shown in Figure 8.
Where K A 1 and K A 2 are association constants and α is the cooperativity constant between X and Y. Note that in the above model the same co-operativity constant appears in the last two expressions. This is done for simplicity, and ensures that the steady state of binding in the network corresponds to equilibrium conditions. Again, we see that signalling specificity may be increased through this mechanism. Just as in the previous cases, we find that the presence of Y increases the active output from pathway A but also inhibits pathway B (Figure 8).
It is worth pointing out that allosteric models of complex formation predict that this mechanism of crosstalk inhibition can occur bidirectionally, meaning that Y affects uptake of X and vice versa. This is in contrast to the sequential-binding model discussed above, where the component which binds first can affect uptake of the other, but not the other way round. It should also be noted that, while allosteric mechanisms are often proposed due to observed synergistic activation of a protein, the crosstalk inhibition effect identified here does not require such synergy. In the case considered here, if Y can activate A on its own, then allosteric effects may not appear to be significant. However, they can still allow cross-inhibition of pathways, and therefore signalling specificity.
Taken together we have seen how the presence of an extra element Y to the simple pathway coupling can lead to the activation of the relevant pathway and inhibition of the other (competing) pathway. Thus mechanisms of complex formation provide control settings to determine how pathways and processes may inhibit one another. Overall, additional elements can modulate the pathway structures in highly non-trivial ways, and this provides some insight into how additional elements in cellular signalling systems may act to modulate and control signal splitting between pathways.
Coupling of switches
The basic model presented here made no assumptions about the nature of the pathways in which A and B are involved, and merely represented the binding of species to one another. However, in many cases proteins with multispecificity are also capable of enzymatically modifying the proteins with which they interact [5–9, 11]. In this section we extend our model to examine some of the consequences which reversible multispecific posttranslational modification might have on the signalling properties of the system.
Further to the steady state analysis, we can look at the effects of the system dynamics on signalling. As expected from the dynamic analysis of the response of coupled pathways to modulation of the shared component X, if the timescale of interaction between A and X (the high affinity interaction) is faster than the interaction between B and X, the dynamic pattern is similar to the steady state one - activation of A preceding that of B. Likewise, if the timescale of interaction between B and X is faster than the interaction between A and X, we get the reversed pattern, where at first B is active, followed by A. Again, adaptive behaviour in the low-affinity component, B, can result due if the faster pathway is the lower affinity pathway(results not shown).
Taken together the examples show how it is possible to get sequential spaced switching from the coupling of switches with identical thresholds and also to get coordinated switching of pathways in a striking manner.
This paper thus far has studied the coupling of pathways/processes through shared components and focussed exclusively on temporal signal processing. Many cellular processes involve aspects of spatial signal transduction, and the importance of spatial aspects in signalling is being increasingly recognized. In the context of our analysis, we systematically investigate phenomena introduced purely by differences in the diffusivity and localization of the components.
In order to do this, we assume that all components exist in a spatial domain. For specificity, we take this to be a 1-dimensional periodic domain, although most of the essential results remain valid in other domains. We now include the spatial element, by including spatial variation in one or more elements. Additionally, we examine the effects of one of the components being highly diffusible to see if this changes the effect of the interaction of the pathways in a non-trivial way. In this case, we will assume that A is highly diffusible, and likewise so is the complex AX. We emphasize that while we perform simulations and analysis in a 1-D periodic domain, our analysis and main conclusions are also relevant to other situations, for instance where X is initially present only in the membrane of the cell, while A is present, along with its complex, both in the membrane as well freely diffusible in the cytosol.
We will examine some scenarios which draw a direct contrast with the purely temporal signal processing in the case where the shared component, X, is modulated. We start by examining the situation where X is present only in part of the domain. A concrete example is if X is present at a non-zero level only in a specific region initially (for example having a square-pulse like spatial profile). No species is either produced or degraded. Now if all entities are non-diffusible then we expect that, in the region where X is present, at steady state there exists a balance between the concentrations of free X and complexes AX and BX, and this is determined exactly as above. Overall the conclusion therefore is that the complexes AX and BX are present only in the region where X is present, and the balance between these complexes is determined just as in previous sections.
Now we consider the effect of the high diffusivity of the pathway A. Analysis of the steady state equations reveals a number of points (see Appendix for details). Firstly, the total amount of A and B is constant at every location. Secondly, at steady state, at every location the binding/unbinding reactions between both A and B with X are at equilibrium. Thirdly, the complex AX attains an essentially spatially homogeneous profile. From this, it follows that at steady state both complexes AX and BX as well as X attain a homogeneous profile at steady state. The clear effect of the coupling of the pathways is seen, most directly in contrast to the case where both pathways were non-diffusible. Here the diffusion of one pathway has the effect of homogenizing the profile of both complexes. Thus we see that the regulation of the B pathway by X and the spatial profile of the complex BX is affected by the interaction with the diffusible A pathway.
In the above case, the activating signal was spatially inhomogeneous and this was the source of the spatial aspect of signalling. A slightly different case can be also examined, which fits naturally into our framework. This is the case where the activating signal is spatially homogeneous, but a localized sequestration reaction occurs. Thus in the above case we let the production of X be spatially homogeneous, but we regard the activation of the B pathway as occurring only locally in a restricted region. This can be described either by starting with homogeneous X in the domain, and B present only in a localized region, with no production or degradation of any species or alternatively by having homogeneous production of X (and A) and highly inhomogeneous production of B and having degradation of all species. Both situations provide essentially similar results. The first case is examined analytically in the Appendix.
We see that if both A and B are non-diffusible, the above sequestration effect of B would lead to AX being sharply depleted in this region, with AX showing a pronounced inhomogeneous profile and this being reflected in the profile of X as well. Further the balance between X, AX and BX can be determined exactly as performed in the purely temporal case.
Now, if the A pathway is highly diffusible, at steady state the AX profile becomes homogeneous and an analysis of the X profile reveals that it too becomes homogeneous. The BX profile reflects the pronounced heterogeneity, and now there is a global coupling between the levels of X and AX, and the profile of BX, which arises from a global conservation condition.
In the above, when we have considered the effects of a diffusible pathway, we have assumed that both A and AX are diffusible. One may also examine the case where A is the only diffusible component, and not AX. In this case, the response is similar to non-diffusible case, and AX exhibits a non-trivial spatial profile. The main difference when X is inhomogeneous arises in the fact that X is no longer limited by the local availability of A in contrast to the results in the purely temporal case.
Overall the above cases provide an illustration of the coupling of signalling pathways with shared components, where spatial aspects of signalling are important.
This paper focussed on analyzing the interaction and coupling of pathways through shared components, a ubiquitous phenomenon in cellular networks. In this paper we examined this basic branching structure from a modelling and systems perspective.
We believe that a detailed systems analysis of signal processing in this setting is useful for multiple reasons. Firstly, it allows us to explicitly analyze the different features which affect signal processing, without being distracted by the details of a particular signalling context. Secondly, since such structures are repeatedly encountered biologically, it is only to be expected that different variations around this basic theme will be encountered, and the results here provide a platform and framework for analyzing these subsequently.
We developed a minimal modelling framework where we could examine the interaction of pathways with shared components. Since we include the possibility of production of all components, we were able to examine both dynamic and steady state responses to a variety of signals. More complex cases such as temporally regulated interacting pathways, with buffering of one pathway also form part of the framework. Each of the pathways of necessity interacted with the other, because of the shared component. These results were obtained using simulations and analytical work (see Table 1 for a summary of the main results).
We first examined the case where the common component is regulated by some external signal. Building on the work of Buchler et al [28, 29], our studies reveal how, depending on the affinities of the common activating component to the two pathways, it is possible to obtain "ultrasensitivity" in the response of the component with a weaker affinity. We also showed how depending on the kinetic rates of binding/unbinding, the pathways could get activated in either temporal order or even concurrently. If there is a clear separation of affinities, and the low affinity pathway is the faster pathway, then for certain ranges of the input signal, the response of this pathway to a persistent stimulus is adaptive: this adaptation may be close to being exact if enough quantity of the high affinity component is present. A significant departure from the adaptive response is observed if the high affinity component is consumed. The saturation effect leading to inexact adaptation in this case is the consumption of the additional "inhibitory" high affinity component, and this is qualitatively similar to other saturating mechanisms leading to inexact adaptation (see the discussion in ).
In a similar manner we examined the case where the two other components, A and B, are regulated by external signals. Our framework allowed us to naturally apply and extend our analysis to this case too. We found that at steady state the high affinity pathway dominates. However, temporally, if the low affinity pathway was the faster pathway, then the response of this pathway was (for certain stimulus levels) partially adaptive (either underadaptive or overadaptive) and this was entirely due to the added high affinity component acting as an inhibitory component. If one regards the components A and B to be stimulated externally through some common source, then the signal transduction of the low affinity pathway in this regime is qualitatively similar to a feedforward adaptive signalling module.
Although our analysis was performed for the case of two pathways sharing a common component, the insights naturally generalize to the case where there are multiple pathways sharing a common component. Our results indicate that depending on the relative affinities, kinetics, and amounts of the individual components, different combinations of steady state responses (including possible "ultrasensitivity") and different kinds of temporal responses will be observed for the different complexes. This will be examined in detail subsequently. Our results have natural relevance for the (competitive) binding/activation of different entities by a common factor. Further, it is possible to predict the effect of modulating individual pathways here. Additionally, since many components are subject to temporal modulation (for instance, in concert with the progression with the cell cycle), this framework provides a natural platform for examining such effects systematically.
Summary of results for variations on the basic model
An additional component is involved the uptake of X by one of the two pathways through a complex formation mechanism.
The additional component can control how signalling through X is divided between the two pathways. This may enhance signalling specificity. The degree of control the additional component has depends on the mechanism of complex formation.
The shared component is involved in two downstream pathways which display switching behaviour.
Where uptake of the shared component is significant, the switching behaviour of one pathway may influence that of the other. This can result in either a specific ordering of activation, or coordinated activation, of the two pathways.
One of the downstream components, and its complex with the shared component, is diffusible.
The shared component is spread across the domain. This results in uptake being significant across the domain, with the spatial distribution of the nondiffusible components also affected.
In the first case we examined the effect of an additional component modulating one of the two pathways. It was shown that this could allow for greater specificity in signalling, effectively through inhibition of the one pathway by the other. Different modes of interaction via the extra component were considered, including sequential binding either before or after binding with the target, as well as co-operative binding to the target species. Analysis reveals that many of the relevant conclusions for all these cases were similar. This indicates how cellular systems may have naturally exploited their pre-existing set of molecules to add further layers of control and separation/differentiation between diverging pathways.
We additionally examined the effect of coupling of pathways which are involved nontrivial and highly non-linear signal processing. Thus we built on our existing modelling structure to include switch-like signalling in each pathway. Our analysis reveals that coupling two switches even with identical switching thresholds, can result in a well-defined order in the switching response, and further that under many conditions it is possible to maintain a robust "dosage gap" in the switching of the pathways. In other cases the interaction of two switches can lead to one switch being highly accentuated by coupling to a multiphosphorylation switch which is bistable. This is an example of co-ordinated switching in two pathways which arises from their coupling through shared components, and suggests that in some cases switch-like behaviour in some pathways can arise from their coupling to other pathways rather than their intrinsic switch-like behaviour.
Finally we expanded our model in a natural way to include spatial aspects in signalling and built on our early studies to examine signal processing in coupled pathways in spatial signal transduction. We showed that the coupling of a highly diffusible pathway to a non-diffusible pathway, could lead to effective redistribution, even of the non-diffusible complexes and hence provide a completely different spatial signalling profile. This reveals another facet of the coupling between pathways through shared components.
Our framework and analysis is relevant in a range of cellular settings. The activating of elements involved in controlling multiple pathways is observed in different settings, especially for proteins which interact promiscuously with a range of downstream targets (eg. Cyclin-dependent kinases and ubiquitin ligases ). A special case is that of a protein which interacts with different isoforms of downstream proteins. One example of an effect similar to the response we have analyzed here occurs with anaphase promoting complex (APC)-mediated ubiquitination of cyclin A, securin and geminin: securin and geminin are ubiquitinated, and thus degraded, earlier than cyclin A . Further, the presence of securin and geminin delays the ubiquitination of cyclin A. Other examples include the multiple GEFs (Guanine Exchange Factors) which target RhoGTPases. Our analysis of the is also relevant to competitive exclusive binding of multiple ligands to the same receptor, and is of special interest when the binding of each ligand triggers opposite responses (for e.g. CAMP and 8-CPT CAMP to CAR1 receptors in Dictyostelium )
In the case of the two separate components being modulated together, our framework provides insight into how different elements are targeted by multiple pathways, and how cells may have evolved strategies to reinforce or minimize the concurrence of signals. The presence of a host of additional proteins providing combinatorial control and selective tuning of individual pathways is a key aspect to be investigated to understand signal processing through classes of hub proteins, and is also likely to be highly relevant to selective targeting of pathways intended as drug targets. Our analysis is also relevant to the assessment of the deleterious effects of increased gene dosage (suggested to be the result of the promiscuous interaction of certain proteins, which is suppressed at low copy numbers) as well as their mitigation by selective degradation of unbound proteins which are also promiscuous [38–40].
The spatial aspect of signalling we have considered here is relevant to enzyme regulation of multiple components, all or some of which may shuttle between different compartments (for eg. membrane, cytosol, nucleus, ER) as well as the enzyme regulation of multiple components, some of which may be highly diffusible (eg. cGMP). Likewise the localized sequestration is observed when certain enzymes which are otherwise freely mobile, partially bind to anchor proteins at specific regions on the cell membrane or elsewhere in the cell. An example of this is the case of PKA which may be partially anchored in certain regions by suitable anchor proteins. Analogues of these spatial effects at the tissue level also exist. In developing Drosophila embryos it has been suggested that substrate competition for MAPK (itself present in a spatial pattern) coordinates the anterior and terminal patterning systems .
The presence of a common element between two pathways can serve to couple them. If the signal transduction in either or both pathways is highly non-linear, this can lead to a significant interference between the signal processing and distortion as a result. In which situations this actually happens due to the natural wiring of the cell, and under which conditions this is effectively minimized, is a topic which needs much more thorough investigation. It will be of interest to see how shared components may affect the interaction of other modules (e.g. ) and this is something which will be examined in the future.
Our results and insights have been obtained in a general setting, and thus we expect that many of these insights to be relevant of a wide range of systems. Using this framework, it is possible to build additional features like multiple-component signalling, combined converging and diverging signals as well as coupling of more complex downstream processes. Additionally, the analysis here provides insight into understanding to what extent control or temporal modulation of upstream signals may be propagated through multiple pathways and how this affects the manner in which pathways interact with one another. It is worth pointing out that the analysis here is relevant not only to natural signalling circuits but to synthetic circuits as well. In synthetic circuits a major challenge is to how a synthetically constructed circuit may interact with the host cell. One of the most basic interactions is the possibility of components in the synthetic circuit being also involved in other pathways in the host cell.
The network structure which embodies the diverging/converging pathways we have studied is ubiquitously observed. By examining the signal processing in this "splitter" or "converger" element from a systems perspective we can examine how such elements may be interfaced with other signal transduction elements both upstream and downstream. This will be invaluable both in understanding complex dynamics and control regulation and coupling of signalling in systems biology, but also be vital for starting to build synthetic circuits which usefully and optimally channelize signals for a range of purposes.
Appendix: Analysis of models
We begin as in the text, analysing the case where there is modulation of the shared component, X.
1.1 Modulation of the shared component
As mentioned in the text, the equation A1 includes production and degradation of X, A and B. We first restrict ourselves to the case where no production signal is directly affecting A or B. A production signal affects X and X affects both pathways A and B. Rather than vary every parameter in the model, we examine the model in a number of special cases, gradually increasing in complexity.
Case 1: There is no production or degradation of any entity
The above solution is the limiting case of weak binding of X to A and B, resulting in a situation where (free) A and B are very far from depletion.
It is worth pointing out that if one of the species (e.g. B) satisfies the above condition, analytical solutions can again be obtained. Thus, if the binding of X to B was weak, this would imply that [BX] was essentially directly proportional to [X], and [X] could hence be written as a linear function of [AX], and this results in a quadratic equation for [AX] which can be solved explicitly.
Case 2: There is production and degradation of only X: the production of X serves as an input signal to the model
We see here that clearly the affinity of X for A affects how much A is present in a complex (and likewise for B). In this case we can obtain analytical expressions for the steady state concentrations of the complexes involved in the two pathways. However, in this special case, the level of free X is fixed at a constant value at steady state and this effectively decouples the two pathways. The conclusion therefore is that if X is being produced and degraded, the production/degradation of other species is necessary to achieve non-trivial coupling between the two pathways at steady state.
Case 3: The degradation rates of all species are equal (denoted by kd)
We immediately see from above that at steady state the total amount of A (free and complexed) is set at the level A T = k pa /k d , and likewise the total amount of B (free and complexed) is set at the level B T = k pb /k d and hence the total amounts of each of A and B at steady state may be regarded as conserved, as far as signalling from X is concerned.
We note in passing that while we have assumed all degradation rates to be equal, the above conclusion for the total amount of A actually only requires the degradation rates of free and complexed A to be equal (and likewise for B).
where X T , A T , and B T are as given above. The solution of these equations is formally identical to that of case 1, and the same conclusions hold good here as well.
"Ultrasensitivity" in the steady state response
As mentioned in the text, for our purposes "ultrasensitivity" involves heightened absolute and relative sensitivity to [X T ] along with any concomitant threshold effects. The absolute sensitivity of a concentration to [X T ] is defined as its derivative with respect to [X T ], while the relative sensitivity is this quantity scaled by the ratio of the relevant concentrations. Here, we analyse the steady state response of the complete model in terms of the absolute and relative sensitivities to the total quantity of X, [X T ]. In particular, we look at how these quantities behave in particular limits, when there is a significant difference in the affinities K A and K B .
From these expressions, we can explain the pattern in relative sensitivities shown in Figure 2b. First, when there is very little X present, very little complex is formed, and we have [A] ≈ [A T ], [B] ≈ [B T ], and [X T ] << 1 (the amount of different complexes is proportional to the available X). At this point, noting that the derivatives in the above expressions are bounded, we simply have .
This shows that, before A becomes saturated (i.e. while K A [A] ≫ K B [B] + 1 holds), the relative sensitivities of both [X] and [BX] to [X T ] increase from 1, while that of [AX] decreases from 1. This is observed in simulations, as shown in Figure 2b.
where the numerators approach a constant value. This indicates the asymptotics for [A] and [B] as the total X becomes large (this can be justified carefully).
This result can also be obtained by incorporating the asymptotic expression for [A] and [B] for large [X T ] and evaluating the relevant expressions.
This demonstrates what we expect intuitively - as [X T ] becomes large, the relative sensitivity of free X asymptotes to one, while the relative sensitivities of the complexes AX and BX asymptote to zero.
As in the text, the basic case examined (Case 1 above) reveals that at steady state X is taken up much more by the high affinity component, in the case where the affinities are very different. The discussion in the text showed that X is primarily taken up by the high affinity component A, and so at steady state the complex BX displays an ultrasensitive response as a function of total X in the system.
As mentioned in the text, this focuses only on the steady state, and the information (affinities) rely only on equilibrium constants rather than rate constants. If the individual rate constants of binding/unbinding to A are much faster than that of B, then dynamically too, if X is added, it is taken up by A first, before B.
Here we examine (in a setting analogous to case 1 above) the case that A is the high affinity component, but actually the slower pathway. To illustrate this we consider a case where the binding and unbinding rate constants for the interaction of X with A are changed to εka1, εka2, where ε << 1 is a small parameter. This ensures that the equilibrium constant remains the same.
This quasi-steady state can be obtained by solving the resulting quadratic equation, and reflects the uptake of X only by B. At a slower time scale, there is a very gradual "leaking" of X by its binding to A (described by the first differential equation (equation A15)), resulting in less X available to the B pathway since [X] + [BX] = [X T ] - [AX], and during this long time scale, the X is gradually redistributed to A, with BX being in a quasi-equilibrium with B and free X, equation A16, at every instant. Eventually more X ends up being bound to A than B, reflecting the higher affinity of X for A. Note that this assumes that the amount of X added is not too high (in particular not in excess of A and B in total). If a very high amount of X is added, then both pathways will be eventually saturated.
1.2 Modulation of each pathway alone and together
We now examine our modelling framework for the case where A and B are each modulated alone and together. Here the signalling occurs through the production of A and B, which impinge upon X. The focus is to determine how the signals A and B affect the formation of the complexes AX and BX. We can consider some particular cases:
Case 1: The degradation rates of all species are identical
This is identical to Case 3 of the above subsection, except for the fact that the signals are transmitted through the production of A and B. The steady state analysis otherwise is identical to the above case.
Case 2: The only species being degraded are A and B
1.3 Combinatorial effects in modulating pathways
In the text we examined how an additional element Y could significantly affect the signal processing through the coupled pathways. We now revisit this, and examine the effect of the additional element Y. We examined three cases in the text. Here, we will examine the effect of Y in two of the cases considered.
We noted from our studies that it was not easy to obtain analytical solutions for the coupled pathways, except in the case where X was the only species being externally produced and degraded. However, in this case, at steady state, the complex dynamics are decoupled. We will revisit the basic case where no species is being produced or degraded.
with [AY] obtained from above. The point is that the concentration of [AY] depends on the concentration of Y, and clearly with no Y there is no complex. On the other hand increasing the Y increases the concentration of AY and this acts to inhibit the concentration of BX. This complements the numerical simulation, showing the same effect.
In the second case we have the situation of Y binding to AX, with an equilibrium constant which we will again refer to as kay. In this scenario, X can bind to A and B, but Y binds to the complex AX to give AXY. The analysis of this case follows from our analysis of the simple coupled pathways. Again, for simplicity, we will assume that there is no production or degradation of any quantity. This immediately leads to the conservation of total X, total A and total B (free and complexed). For simplicity we will assume that Y is in excess.
This equation again simply reveals that increasing the concentration of Y tends to increase the concentration of X taken up by A at steady state and decrease the concentration of X taken up by B at steady state. This points to that fact that increasing Y can lead to the inhibition of the B pathway at steady state. Similar conclusions continue to hold good if the complexed A and/or B are substantial fractions of their respective amounts, except that explicit close-form solutions are difficult to obtain.
The case of co-operative binding can again be analyzed in a similar manner, and we do not repeat the analysis here.
1.4 Spatial signalling
In this subsection, we will analyze the coupled pathway structure to include spatial effects. We will analyze the resulting model in a manner which builds on, and complements, the above analysis. As mentioned in the text, A will be assumed to be the diffusible pathway. Both A and AX are assumed to be highly diffusible. The model is formulated on a 1-D periodic domain for simplicity. Thus to start with we will consider the following situation.
Case 1: No production or degradation of any species
X can form complexes with A and B. X is initially present only in a localized region while A and B are present everywhere in the spatial domain. At the outset we note that if A and AX are non-diffusible, this exactly reduces to the case of coupled pathways analyzed earlier and the net result would be an activation of both pathways in the region where X is present. The total amount of X at any location is fixed by the initial condition, and from the equations presented in the earlier subsection (based on the model in equation A1), we see that this affects the steady state concentrations of AX and BX. We also note that if no X is present in particular regions, the concentration of AX and BX are both zero.
This shows that the total amount of A at any location satisfies the diffusion equation, and in particular if the total amount of A is constant at every location initially, then this remains so in the subsequent dynamics. Thus we have [A] + [AX] = A T at every location, exactly as before.
We see that, in this equation, as k d becomes large, the steady state profile of AX approaches a flat profile. This is easily verified by performing a regular perturbation analysis in the small parameter 1/k d as has been performed elsewhere.
Now since the steady state concentration profile of AX is constant (flat), and since we have a conservation of A, from above, it also follows that the steady state concentration profile of free A is also constant.
This is because there is a local equilibrium in the binding/unbinding to B at steady state, and the only contributor in the dynamics is the binding and unbinding to A. Now from above since A and AX have constant steady state profiles, it immediately follows that the steady state profile of X from the previous equation is also constant.
Here 2π is the length of the domain. This determines the total X at any location at steady state. Note that the above assumes that initially X is present only in an uncomplexed form. If it is present partially in complexed forms, then these have to be included in the integral.
Overall the significance of the above analysis is that owing to the diffusivity of the pathway A, at steady state an equidistribution of all species across the domain occurs.
We now examine some other related cases.
Case 2: A uniform amount of X is present initially (and likewise A). X is sequestered by B in a localized region
The sequestration of X by B is modelled by having B present initially in only a localized region. In general the total B need not necessarily be constant in this region.
In the above case we see that if A and AX are non-diffusible, we simply note that outside the region where B is present X and AX are uniform (determined simply by the binding and unbinding of A and X). In the sequestration region the balance between X, AX and BX would be described precisely by the purely temporal model.
We now examine the case when A and AX are highly diffusible. We see that much of the analysis of Case 1 remains relevant. There is a conservation of B so that B + BX = B T , where the total B is now a function of position.
Thus overall we see that the high diffusivity of AX implies a uniform profile of AX and X, but a localized profile of BX in a manner proportional to the total amount of B present at that location. The uniform levels of X and AX are of course coupled to the BX profile through a global conservation law. The main point, however, is that the localized sequestration of X by B does not lead to a localized dip in free X when AX is highly diffusible.
Note that the above conclusion is also true if an inhomogeneous B is created through an inhomogeneous production of B.
Case 3: X is produced in an inhomogeneous manner, and all species are degraded at the same rate
Similarly the total amount of B is fixed at every location at a value k pb /k d .
Now in this equation, we note that the profiles of AX and A are uniform. The only source of explicit heterogeneity arises for the production of X. In fact if the fraction of B in the complexed form BX is small the above equation reduces to a linear equation for X, where the "production" terms involve dissociation from AX, which is spatially uniform, and the production which is spatially non-uniform. However, the concentrations of AX, BX and X are coupled through a global conservation condition. We also note that when the production rate of X, the situation reduces to the cases analyzed previously.
Overall the analysis provides direct insight into the source of the heterogeneity of the X profile (and hence the BX profile).
Case 4: Only free A diffusible
In this subsection we very briefly examine a variation of the above analysis where the free species A is diffusible but the complex is non-diffusible.
If we examine the first case above where X is present inhomogeneously initially, we see from the equations at steady state that A attains a uniform profile. BX is in local equilibrium with X and so is AX. Thus in this case we have a situation where BX and AX are present only where X is present and in local equilibrium with X, and the equations are formally similar to the purely temporal signalling case. However the level of A is determined by a global conservation condition, and depends on the amount of A present as a complex.
In the other case, where a localized sequestration reaction involving B occurs, again at steady state free B in equilibrium with BX and at steady state A has a uniform profile. In this case however, AX is locally depleted in the sequestration region, and the (uniform) level of A reflects the amount of A present as a complex in this region via a global conservation condition.
We gratefully acknowledge funding to DDS through an EPSRC DTA award.
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Condor Travel has expanded its business tourism operations into Brazil
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July 8, 1999
Bullpens: The Last Word
Final thoughts on the importance of relief
Now, more than any time in baseball history, games are won and lost in the bullpen. As such, more attention has focused on the importance of a good bullpen as oen significant difference between a playoff team and an underachieving also-ran. Whether it's explaining the Mariners' inability to contend despite fielding two of the 50 greatest players in history, or defining how the Reds are in first place with Steve Avery in the rotation and Dmitri Young riding the bench, the fortunes of a team's bullpen seem to dictate the fortunes of the team as a whole.
We recently published the results of a study that looked at whether a good bullpen could add some sort of synergy to a team's win-loss record above and beyond the runs that they save, and conversely, whether a collection of pitchers throwing AckerCurves and WengerTaters would snatch more defeats from the jaws of victory than the run totals would suggest. In the study, published at ESPN.com, we looked at two sets of teams--those with the best bullpens in their league and those with the worst--and compared the records for those teams with their expected records, as calculated by the Pythagorean Method.
What we found was that teams with good bullpens actually won more games--about 1.3 more, on average--than would be expected from their totals of runs and runs allowed, while teams with bad bullpens won about 1.6 fewer games than expected. This is, we believe, the first time any study has pinpointed a subset of teams which routinely outperform or underperform their Pythagorean projection.
Having established that having a good bullpen is important, and calculated how important a good bullpen is, let's test the conclusion a bit.
A Control Group
Any statistical study worth its salt has to account for bias. You must show that the results of your study are not skewed by hidden factors. The best way to do that is to use a control group.
What we showed in the earlier study was that teams with the best bullpens, defined as the bullpens which allowed the lowest OPS in the late innings of close games (LICG), won more games--on average--than their Pythagorean projection, and teams with the worst bullpens won fewer games. But does that prove that good bullpens lead to overachievement, or is it possible that the study's design was flawed?
For example, is it possible that the reason the teams overachieved was that they simply had good pitching, period, whether in the first inning or in the eighth? That teams with good opponent's OPS tend to play in pitcher's parks, where runs are more valuable? There are dozens of ways in which the design of the study may have unintentionally skewed the results, giving us a conclusion which may not be warranted.
So we designed a control group to see if we could eliminate that bias as much as possible. The original study compared the three best and three worst bullpens in each league, from 1980 to 1998 (except 1981 and 1994), based on OPS by relievers in LICG. Here are those results again:
Record vs. Avg. Pythagorean Record SO WO WU SU Best Bullpens 34 32 25 11 + 1.28 Games Worst Bullpens 8 32 27 35 - 1.57 Games
SO - Strong Overachiever (won 3 or more games more than expected) WO - Weak Overachiever (won fewer than 3 games more than expected) WU - Weak Underachiever (won fewer than 3 games less than expected) SU - Strong Underachiever (won 3 or more games fewer than expected).
To briefly review the results: 66 of the 102 teams with the best bullpens (65%) won more games than projected. For teams with the worst bullpens, 62 out of 102 (61%) won fewer games than prjoected. On average, teams with excellent bullpens won about 1.3 games more than projected, while teams with poor bullpens won about 1.6 games fewer, a swing of almost three games.
To construct a control group, we ranked the same teams by the effectiveness of their starting pitchers, based on the OPS allowed by all starting pitchers used by that team. Mimicking our original design as much as possible, we took the top three and bottom three rotations in each league from the same years, and compared their won-loss record against their expected performance.
Here are those results:
Record vs. Avg. Pythagorean Record SO WO WU SU Best Rotations 23 34 24 21 + 0.04 Games Worst Rotations 24 35 22 20 + 0.11 Games
(One of the teams with a poor rotation, the 1983 Padres, went 81-81 and also scored and allowed the exact same number of runs (653), which is why the second group only contains 101 teams.)
As you can see, while slightly more than half (56%) of the teams with good rotations overachieved, the overall effect was extremely small, just 0.04 games above expectation. And teams with bad rotations had almost an identical breakdown to the teams with the best rotations. In fact, on average the teams with bad starters did slightly better (0.11 games above expectation) than the first group, although the difference is so slight as to be statistically insignificant.
In summary, it appears that the results of the original study are not due to some hidden bias, and indeed appears to be a true relationship: good bullpens do correlate with better-than-expected records.
Effect on One-Run Games
It stands to reason that a team with a great bullpen should be able to prevent runs at the most crucial times and thus win more games than their ratio of runs scored to runs allowed would predict. It would also make sense that those same teams would win more than their fair share of tight games, with a record in one-run ballgames better than would be expected from their overall record. Actually, it stands to reason that these two factors would be tightly correlated for all teams--that a team which wins more than its share of one-run games should end up with more wins overall than would be expected.
It stands to reason, and it stands up to the facts as well. Here is a chart comparing the two (for all teams from 1980 - Present, save 1981 & 1994):
Record vs. Avg. Pythagorean Record SO WO WU SU SO 30 20 5 1 + 3.09 Games One-Run Record WO 54 64 29 19 + 1.35 Games vs. WU 17 35 46 44 - 1.17 Games Overall Record SU 2 10 21 35 - 3.53 Games
Some explanation is needed on what we are calling a team's "expected" record. As before, for "Record vs. Pythagorean Record", we are comparing a team's overall won-loss record with their record as predicted by the formula (Runs Scored^2) / (Runs Scored^2+ Runs Allowed^2). The use of 2 as the exponent for this formula is traditional, but in fact is not the most accurate number to use. Previous studies have shown that the most accurate value for the exponent is about 1.87 (see a new study by Clay Davenport for more on this), but the difference is quite small, and for purposes of this study we'll use 2 as our exponent to keep this study in line with the previous one at ESPN.com.
In comparing "One-Run Record vs. Overall Record", it is important to realize that a team which plays .600 ball overall is *not* expected to play .600 ball in one-run games. The common perception is that the best teams win the close games, and that a mark of great teams is the ability to pull out one-run games. It's a silly perception.
Here's n example why: when the best team in the league takes on the worst, the better team is probably going to win around three-fourths of the games. If the Indians play the Twins 20 times, Cleveland is probably going to 15-5 or so. Included in those 15 wins are going to be games with scores of 14-1, 12-2 and, in today's game, 18-8. How many of the Twins' victories are going to be blowouts? When the Twins do squeeze out a win, it's likely to be a 7-5 score or something similar.
In reality, one of the marks of a good team is the ability to blow out its opponents. And in fact, what we find is that all teams play towards the center in one-run games: a .600 team will play around .565 ball, while a .400 team will play around .435. So in comparing records, each team's record in one-run games was compared to their expected record in one-run games, based on their overall record.
The results are striking. Among teams that did extremely well in one-run games, 50 out of 56 (89%) also did much better than expected compared to their Pythagorean projection. On the flip side, 56 out of 68 (82%) of teams that played poorly in one-run games had a similar profile in their Pythagorean record. The results among teams that over- or under-achieved by lesser amounts follows the same overall trend.
To make a long story short: the correlation between a team's performance in one-run games and their performance compared to their Pythagorean record is +0.56, indicating a strong if not overwhelming correlation.
So, since we found a high correlation between good bullpens and exceeding a team's pythagorean win total, we should expect that good bullpens would also correlate with a better-than-expected record in one-run games, right? Here's the data:
One-Run Record vs. Avg. Expected Record SO WO WU SU Best Bullpens 12 45 31 14 + 0.22 Games Worst Bullpens 11 39 34 18 - 0.26 Games
While there does appear to be a trend, it's a small one. Just 56% of the teams with great bullpens performed especially well in one-run games, and barely 51% of the teams with bad bullpens did poorly in those situations. On average, the teams with the best bullpens played just a half-game better in one-run contests than teams with the worst pens. That's just one-sixth of the three-game disparity we found in their performance against their Pythagorean record.
So if these teams aren't doing that much better or worse in one-run games, how are they winning more games than their Pythagorean projection? Let's look at their record in two-run games against their expected record. Keep in mind that just as in one-run games, teams play towards the center in two-run games, although the effect is not as significant: a .600 team should play around .580 ball in two-run games.
One-Run Record vs. Avg. Expected Record SO WO WU SU Best Bullpens 13 44 34 10 + 0.21 Games Worst Bullpens 8 33 48 13 - 0.54 Games
The same general trend is followed in two-run games as in one-run games, and in fact the correlation appears to be a little stronger. When we combine the results of both one- and two-run contests, teams with good bullpens win 0.47 games more than expected, while teams with bad bullpens win about 0.80 games less than expected. Together, this still explains less than half of the disparity between actual records and Pythagorean projections.
One possibility that would explain the difference is that teams with strong bullpens-- remember, in this case we're defining "bullpen" as only those relievers used in tight games--may have focused their resources on acquiring good late-inning relievers to the detriment of the rest of the team. This might cause such teams to get blown out of games more often than usual. If a team has two great relievers but a lousy starting rotation, there's going to be a lot of big losses that the bullpen isn't going to bail you out of. Those blowouts would damage the team's runs scored/runs allowed ratio, and hence their Pythagorean record, but would cause only minor damage to their overall win-loss record. However, it's just a theory, and more research may be needed to determine the true source of this dichotomy.
So maybe this isn't the last word after all.
Rany Jazayerli is an author of Baseball Prospectus. |
Based 'stache QC: GP: Overview ######## Great defensive typing lets it check pokemon such as Ice Punch Lucario, Jirachi, Keldeo, and Scizor. Good HP and Special Defense Great ability(s) Access to reliable recovery and useful utility moves such as Will-o-wisp and Taunt Role as a spinblocker is largely downsized due to defog Because spinblocking isn't as valuable, Jellicent faces competition from Rotom-W Is threatened by common offensive Pokemon such as Thundurus, Aegislash, Mega Charizard X. Utility ######## name: Utility move 1: Will-O-Wisp move 2: Scald / Shadow Ball move 3: Recover move 4: Taunt ability: Water Absorb item: Leftovers evs: 248 HP / 172 Def / 88 Spe nature: Bold Moves ======== Will-O-Wisp is excellent for crippling physical attackers and getting nice residual damage on things. It also goes well with Jellicent's naturally good special bulk Scald is a reliable STAB with a high 30% burn chance. Surf is an option for a power increase, but generally inferior Shadow Ball is an option with great neutral coverage if Scald is undesired Recover is mandatory for longevity Taunt shuts down defensive Pokemon who seek to set up entry hazards or use status moves, and allows Jellicent to often beat these Pokemon 1v1. Ice Beam has use to hit Grass-types and Dragons super effectively Set Details ======== Given EV spread minimizes Stealth Rock damage and emphasizes physical bulk. Speed EVs are to outrun CB ttar, Belly Drum Azumarill, Defensive Politoed, CB Scizor, and Skarmory. Water Absorb is the ability of choice for the Water-type immunity, though Cursed Body can be effective against Pokemon who have only one move to damage Jellicent with, such as Starmie or Lucario. Leftovers for handy healing. Bold nature for maximum defense investment. Usage Tips ======== Use this set to check common Physical attackers such as Azumarill, Scizor, and Excadrill Be wary that many of the Pokemon that Jellicent checks can carry moves to severely damage it with. eg Scizor's Knock Off and Azumarill's Play Rough. You should be suitably cautious in these situations. Jellicent is prone to being trapped by Pursuit, especially from Tyranitar. As such, if the opponent has a healthy TTar it is often a good idea to expect it to come in and use Will-O-Wisp, especially if you are not running any Speed EVs. Use Taunt as much as is wise when you face defensive Pokemon to prevent them from setting up entry hazards, and, importantly, stop them from inflicting status. Be wary against certain opponents, however. Taunting a Ferrothorn to block Spikes or Leech Seed is not always a good option, as Power Whip will deal heavy damage. Will-O-Wisp should also be heavily used, especially on expected switches to cripple physical threats and wear down special ones. Team Options ======== Jellicent is best used as a pivot or wall on defensive or balanced teams. Grass-types are great partners to cover Jellicent's Grass- and Electric-type weaknesses. Mega Venusaur and Ferrothorn are excellent choices. In return, Jellicent can take Fire- and Ice-type attacks. Skarmory and Forretress can lay down entry hazards on the opponent's side of the field, and take Grass-type attacks with ease. Jellicent can switch into Fire-type moves for them. They also can clear entry hazards with Defog and Rapid Spin, which Jellicent appreciates. Assault Vest Conkeldurr is a decent partner to check opposing Tyranitar and Thundurus Specially Defensive ######## name: Specially Defensive move 1: Scald move 2: Recover move 3: Will-O-Wisp / Toxic move 4: Shadow Ball / Ice Beam ability: Water Absorb item: Leftovers evs: 248 HP / 172 SpD / 88 Spe nature: Calm Moves ======== Scald is STAB with nice burn chance Recover for longevity Will-O-Wisp works excellently with Jellicent's high Special Defense and cripples physical attackers Toxic is an option for foes that don't fear w-o-w, such as Volcarona and Mega Charizard X Shadow Ball is also STAB and has great neutral coverage while hitting Latios, Aegislash, and Gengar super effectively. Ice Beam is a decent choice to target Grass- and Dragon-types. Taunt works well to cripple defensive Pokemon such as Skarmory Set Details ======== EVs and Calm nature emphasise special bulk. Speed EVs are to outpace the same as prev. set (TTar, Scizor, BellyJet Azumarill, Skarmory, and Politoed) Water Absorb is preferred to provide an immunity, though Cursed Body is viable Leftovers for healing Usage Tips ======== Use specially defensive Jellicent to check specially-oriented threats such as Keldeo, Manaphy, and Latias Be aware that several special attackers carry Psyshock which targets Jellicent's lower special defense. Examples include Latios, Alakazam, and Starmie. Remember that because Jellicent has an average Defense stat and this set runs no Defense investment, Jellicent will struggle to be even somewhat effective against physical threats. Staying in to use will-o-wisp against such Pokemon may not always be wise, as they could get off a heavy hit. It is usually best to try and burn such Pokemon as they switch in. This set is extremely vulnerable to Pursuit users due to the lack of defensive investment. Will-o-Wisp can remedy this to a certain extent, but be aware that even if you cripple the opposing Pursuit user (usually ttar) it can still do a sizeable amount, which means Jellicent will often fall to the special attackers it is meant to be switching into. Team Options ======== Best used on defensive or balanced teams as a special wall. Teammates that can handle physical threats are good partners. Mega Venusaur and Ferrothorn can do this while providing excellent type synergy. Defensive Skarmory and Forretress can lay down entry hazards on the opponent's side of the field, and take Grass-type attacks from the likes of Breloom with ease. Jellicent can switch into Fire-type moves for them. They also can clear entry hazards with Defog and Rapid Spin, which Jellicent appreciates. Pokemon who can deal with Tyranitar and Bisharp are excellent choices. Conkeldurr and Lucario work well on balanced teams, while Hippowdon is a good choice on defensive teams. Other Options ######## Offensive Water Spout Energy Ball for Gastrodon and Quagsire Trick Room Magic Coat Trick Confuse Ray Checks & Counters ######## **Grass-types**: Celebi and Mega Venusaur take little from any move and deal heavy damage in return. Celebi doesn't fear Toxic or Burn thanks to Natural Cure. Breloom can KO with Bullet Seed, though it is ruined by a timely Burn. Ferrothorn easily takes any attack, but hates Scald's burn chance and is crippled by w-o-w. **Electric-types**: Thundurus and Thundurus-T can smash Jellicent with Thunderbolt, though they don't like switching into a potential burn. **Dark-Types and Pursuit**: Ttar fears a burn, but can still do significant damage with Pursuit if Jellicent switches; Scarf sets outrun Jellicent and hit hard with Crunch. Bisharp can also use Pursuit, though generally it will OHKO with Knock Off. **Ghost Types**: Aegislash and Gengar threaten Jellicent with their STAB attacks while not fearing Toxic. They take hefty damage from Shadow Ball, though. **Substitute users**: Pokemon who can set up a Sub that Jellicent cannot break are good checks. Kyurem-B and Gyarados are good examples here. **Status**: Toxic in particular ruins Jellicent. Users that can outrun Taunt such as Poison Heal Gliscor, and Heatran. **Knock Off**: Several Pokemon that Jellicent is called upon to check can deal significant damage and remove Jellicent's leftovers in one stroke. Scizor and Donphan in particular. **Entry hazards**: Jellicent is vulnerable to all forms of hazards, which wear it down and greatly hinder it from doing its job. |
JMB Profit Machine Review: In this review of Jonathan Mark’s JMB Profit Machine cloud processing trading software we will reveal our test results that prove it’s a scam!
Our Official JMB Profit Machine Review
About the JMB Profit Machine Cloud Processing Software:
Product Name: 21 Days To Riches
Niche: Binary Option Trading Software
Product Creator: Jonathan Mark
Product Summary: JMB Profit Machine is a new cloud processing binary trading software by Jonathan Mark. The software is suppose to be a cluster of computers that take advantage of the synergy of networking to use speed and a binary trading software to make money on auto-pilot.
I could waste my time and yours trying to explain what this all means but I know you just have 1 question.
Does The JMB Profit Machine Really Work?
Over the past few years there have been hundreds of different free trading software giving away online and we personally tested 116 of them. Of the 116 free trading software that we have personally tested, only 2 were legit.
Today we are going to test the JMB Profit Machine software to see if it’s one of the few legit trading software or just another scam.
Here our test results for the JMB Profit Machine software:
Number of trades = 100
Number of winning trades = 46
Number of losing trades = 54
Percentage of winning trades = 46%
Note: Due to online broker fees and rate of return you will need to win 75% of your trades to make a consistent income trading binary options online.
As you can see by the above results, the JMB Profit Machine software did not come close to the 75% winning picks that is required to make real money trading binary options.
This really came as no surprise to use because we have tested 113 similar trading software and of those only 1 that is still available for free was able to pass or test.
The software that passed our 100 trade test actually won 88% of it’s trades and made us a profit of $830 in 1 day!
As for Jonathan Mark’s JMB Profit Machine? It looks like just another scam and we do not recommend it. |
By Margaret Yu
It was a hard night where I tossed and turned with a horrible cough and a constricted throat — and I was not even sick! However, upon hearing my alarm, I was afraid that I would have to cancel because I was not sure if I had a voice to speak. (For speakers, that is a NO-NO. I had only canceled once in my life.) So I sought to rest in bed for at least 40 minutes just to be sure that I had some rest and to see what would happen. I prayed and told God that I would get up as if I were headed towards church. I did and lo and behold, I was somehow healed from all the night’s illnesses.
During my message, I had stepped away from the pulpit and felt a bit frustrated that I ran over the given time for my sermon. I was upset and bummed. However, as I sat down, I prayed my usual prayer after speaking or serving others: Lord, I pray that you would have used me in spite of myself and because of myself.
As usual, I was able to walk away with my service being an offering to Him no matter the results.
Driving home from church, I was so grateful that somewhere along the way, I had learned to add the second part of that prayer after each sermon or service. I’m so glad that I no longer just pray that God would humbly use me in spite of my own weaknesses or my failings. Somewhere along the way, God had used people and organizations to help me see that God does indeed use me because of how he has created me. (I thank God for Epic Movement, Synergy Women’s network, APIWLC, and friends for how they have helped alter my view of myself in God and in service!)
Being an Asian American woman leader, it was always easy to believe that I had many failings. Having lived in the culture of saving-face, anything that did not seem perfect was hard for me to swallow. It was also a lot easier to believe that I did not have much to offer as well. As a woman leader, so often our standards for leading, speaking and serving are male figures. As I have served in a predominately White organization, most of my models are White male leaders. Hence, it was easier to subtly believe that my kind of service or speech was not as good as other styles of service. Indeed, it was with much facility that I could pray the first part of that prayer — that God would humbly use me no matter my shortcomings, sometimes even in spite of my cultural or gender identity.
However, it has been a joy to have been with friends, co-workers and organizations that affirm my identity as an Asian American or as a woman. It has been humbling to have served and been affirmed by people or organizations to lead with all of my identity and history. It has been very much a grace-ful blessing to be the recipient of honor for being me in all of my glory…being all that I am. It has been so confirming to have others share with me that the best way to be used is to be myself and that being an Asian American woman is by God’s design. To be affirmed in various aspects of my unique contribution to the Kingdom has freed me to live out my calling in an authentic way.
I am so glad that I now actually believe that God will use me because of me. In his eyes, all of my past, my failings, my cultural background, my gender and my spiritual gifts is a part of his unique calling for me in this world. My highest calling is to be fully myself in all of God’s design for his glory in order to do good in this world. I am to let my life speak for God — and that life includes all the fullness of my spiritual giftings, gender, cultural and racial realities. I don’t have to be used like others are being used. God can use me because of me.
So on that day of speaking at church with only 40 minutes of sleep the night prior, I was aware of the spiritual battle that also came with being God’s servant. I was reminded again that even if I was a bit long, and even if I felt disoriented from some weird illnesses, that God would cover me with his love and care, and that the mystery of it all was that God could use me even when I thought it went horribly. In fact, all of my inabilities to speak well or my jumbled thoughts were still an offering to him for his usage for his kingdom. He in his grace still uses me because I am available. So God does use me in spite of my shortcomings or challenging circumstances, and He uses them so that I can be an example to others that service to God is not about perfection, but about heart.
I am also amazed at the fact that there is an aspect to my ministry that is so unspoken; that is, that I am a role model for other Asian American woman leaders. So what matters most is not just my good preparation or service, but that my heart is open to be used. The results are incidental and some are even positive only because I am an Asian American woman leader….because I am who I am. The most amazing thing again on that day was to see many men and women come up to me to share how God used that sermon that I did not think very highly of. What a privilege that God uses me simply because of myself.
What do you pray after your sermons or service? How do you offer that to God? I praise God that I can pray both parts of this prayer: Lord, use me in spite of myself and because of myself.
Margaret Yu is the National Director of Leadership Development for Epic Movement, the Asian American Ministry of Campus Crusade for Christ. Her passion is to empower Asian American leaders to lead while using their God given design and heritage. |
You clearly have a passion for tapped lands and you like to drop them always at the wrong time.
In game 2 when you counter his Diabolic Edict with Counterspell, you could have protected the Ninja by playing Pestermite and sacrificing it. Doesn’t really matter much, because it’s almost impossible to lose at that point, but I think the Counterspell is more valuable than the Pestermite, so it’s better to save it.
I enjoyed your videos. I can see how this deck would do well against the current metagame.
Nice job. The synergy between all your cards is neat to see, especially all the “comes into play” effects and the ways you exploit them.
Thanks – game 1 in the final was epic, and game 2 was very solid also. Your opponent did not go to any lengths to represent tricks of any kind – so that was nice. Your bold triple block of the golem paid off.
Your last couple videos have had the top chopped off. I’m not sure how easy this is to correct – but because of this it is not always clear what your opponent’s life total is, or how many land they have/have untapped.
How do you play versus an Artifact deck?
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Anti-Aging Beauty Tips Product Review Rosy Peel Supplements Whitening
November 27, 2014
Beauty Product Review: Rosy Peel Herbal Dietary Supplement
What if I tell you that I found the
fountain pill of youth, would you believe me?
A pill that not only makes your skin rosy smooth, but also clears up acne and prevents immature aging.
I have been taking 2 capsules a day, one after breakfast and one before dinner for a week now, (the suggested amount is 1 or 2 before or after a meal), and I can really tell the difference on my skin.
It sounds so cliché, but my skin does feel rosy smooth. No side effects were experienced but the only thing that was noticeable was that my skin is glowing more. Also, some people have been asking me about my weight. I can feel that I have lost some since started taking the pill. It really does work!
So, you’re probably wondering, what makes this different than your facial and body products that you apply? Creams and lotions help fade the signs of aging from the outside but fails to breakthrough within. Rosy Peel is definitely a revolutionary new supplement that is a must if you’re conscious about your skin.
How does Rosy Peel do it? From it’s ingredients of course.
The capsule is all natural is made from dormant saps of young green strawberry, guava, bignay, and kamias fruit. These unique combinations of fruit saps were made to work in synergy, unleashing its great potential in keeping the skin healthy and in enhancing the skin’s capability of reformation.
What’s so special about Strawberries? These little red fruits pack a powerfully healthy punch of Ellagic Acid, which lightens skin and prevents wrinkles by preventing the production of melanin and the break down of collagen. Young green strawberries also contain Resveratrol, which prevents all sorts of diseases from skin cancer to heart disease to diabetes. Strawberries also help in preventing breakouts caused by oils and blockages in pores, which leaves you with clean, rejuvenated, and youthful skin.
The Guava Fruit contributes ultra-high levels of Vitamin C, (5X more than oranges!) which is an antioxidant that is known in many countries to eliminate free radicals that keep your skin from looking the best.
Bignay, a vital player in the Rosy Peel mixture, provides plenty of calcium and co-enzyme Q10, which boost the immune system and stop premature aging.
Last but not least, Kamias rounds out this quartet by offering flavonoids and saponins that act as an antibacterial agent and astringent for treating pimples.
These four fruit combined boosts collagen production, minimizing pockmarks, which is usually the after effect of pimples or acne. It gently exfoliates the skin, leaving it with a whiter and rosier skin. Buying all four would cost a fortune and would be difficult to buy strawberries when it’s off-season. Rosy Peel makes it convenient for you to have all four for the low price of P22 per capsule, a fraction of the cost to have all this year round. Available at your nearest Mercury Drugstore nationwide.
Fountain of youth is no longer a tale that has been passed from our ancestors, it’s within our reach, and it’s called Rosy Peel.
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Herbal therapy associated with antibiotic therapy: potentiation of the antibiotic activity against methicillin – resistant Staphylococcus aureus by Turnera ulmifolia L
© Coutinho et al; licensee BioMed Central Ltd. 2009
Received: 22 January 2009
Accepted: 08 May 2009
Published: 08 May 2009
Staphylococcus genus is widely spread in nature being part of the indigenous microbiota of skin and mucosa of animal and birds. Some Staphylococcus species are frequently recognized as etiological agents of many animal and human opportunistic infections This is the first report testing the antibiotic resistance-modifying activity of Turnera ulmifolia against methicillin-resistant Staphylococcus aureus – MRSA strain.
In this study an ethanol extract of Turnera ulmifolia L. and chlorpromazine were tested for their antimicrobial activity alone or in combination with aminoglycosides against an MRSA strain.
The synergism of the ethanol extract and aminoglycosides were verified using microdillution method. A synergistic effect of this extract on gentamicin and kanamycin was demonstrated. Similarly, a potentiating effect of chlorpromazine on kanamycin, gentamicin and neomycin, indicating the involvement of an efflux system in the resistance to these aminoglycosides.
It is therefore suggested that extracts from Turnera ulmifolia could be used as a source of plant-derived natural products with resistance-modifying activity, constituting a new weapon against the problem of bacterial resistance to antibiotics demonstrated in MRSA strains.
Staphylococcus genus is widely spread in nature being part of the indigenous microbiota of skin and mucosa of animal and birds. Some Staphylococcus species are frequently recognized as etiological agents of many animal and human opportunistic infections . S. aureus, S. epidermidis, S. saprophyticus and S. haemolyticus are the most important species as community and nosocomial human infection causing agents. In addition of causing different kinds of intoxications, S. aureus has been the most common etiological agent of festering infections that attack different tissues and/or organs (e.g. furuncle, carbuncle, abscess, myocarditis, endocarditis, pneumonia, meningitis, bacterial arthritis) [2, 3]. Capsule, peptidoglican, teicoic acids, adesins and synthesis of enzymes and extracelullar toxins are some virulence attributes present in/on S. aureus cell .
Clinicians write millions prescriptions for antimicrobials every year . Clinicians need to apply sound concepts when prescribing antimicrobials to both achieve a good outcome and avoid encouraging resistance. There is convincing evidence that inappropriate use of antibiotics directly leads to the development of resistant organisms . To prevent this, is necessary educate all health worker regarding healthy drug use and regarding the natural history of the infection, emphasizing palliative therapies and infection control measures . Infectious diseases are the major cause of morbidity and mortality and experience has shown that an approach that seeks to 'defeat' infectious diseases will not work. Long-term solutions must acknowledge this, and nurses and other health care professionals must take a proactive part in finding alternative solutions .
With increased incidence of resistance to antibiotics, natural products from plants could be interesting alternatives [8, 9]. Some plant extracts and phytochemicals are known to have antimicrobial properties, and can be of great significance in therapeutic treatments. In the last few years, a number of studies have been conducted in different countries to demonstrate such efficacy [10–12].
Many plants have been evaluated not only for direct antimicrobial activity, but also as a resistance-modifying agent . Several chemical compounds, synthetic or from natural sources, such as the phenothiazines, and natural products, have direct activity against many species of bacteria, enhancing the activity of a specific antibiotic, reversing the natural resistance of specific bacteria to given antibiotics, promoting the elimination of plasmids from bacteria and inhibiting transport functions of the plasma membrane in regard to given antibiotics. The inhibition of plasma membrane-based efflux pumps has been observed as well [14, 15]. The enhancement of antibiotic activity or the reversal of antibiotic resistance by natural or synthetic non-conventional antibiotics affords the classification of these compounds as modifiers of antibiotic activity.
Turnera ulmifolia L. (Turneraceae), a small annual herb, can be found in the north and northeast brazilian regions, where it is considered a weed . It grows preferentially in sandy soils and on hill slopes. T. ulmifolia L. is already known to be of medicinal value, being used popularly as an anti-inflammatory, as an expectorant, and in the treatment of several problems [16–18]. Authors detected flavonoids, alkaloids, tannins and phenolic compounds in preparations from this plant [19–21].
Aminoglycosides are potent bactericidal antibiotics targeting the bacterial ribosome, and the increase in cases of bacterial resistance to aminoglycosides is widely recognized as a serious health threat . The main mechanisms of resistance to aminoglycosides are active efflux and enzymatic inactivation .
In this work, we tested an ethanol extract of Turnera ulmifolia as a resistance modifying agent in an aminoglycoside-resistant strain of S. aureus.
The strain used was the clinical isolate Staphylococcus aureus 358 (SA358), resistant to several aminoglycosides . The SA-ATCC25923 strain of Staphylococcus aureus was used as a positive control. The strains were maintained in heart infusion agar slants (HIA, Difco), and prior to assay, the cells were grown overnight at 37°C in brain heart infusion (BHI, Difco).
Leaves of Turnera ulmifolia were collected in the county of Crato, Ceará State, Brazil. The plant material was identified and a voucher specimen was deposited with the number 1618 at the Herbarium "Dárdano de Andrade Lima" of Universidade Regional do Cariri – URCA.
Preparation of ethanol extract of Turnera ulmifolia (EETU)
A quantity of 200 g of leaves were dried at room temperature and powdered. The powdered material was extracted by maceration using 1 L of 95% ethanol as solvent at room temperature, and the homogenate was allowed to stand for 72 h at room temperature. The extracts were then filtered and concentrated under vacuum in a rotary evaporator . For the tests, the dry extract material was dissolved in DMSO (dimethyl sulfoxide) 0,5%. The DMSO was chosen due its less toxicity than ethanol.
Chlorpromazine, gentamicin, tobramycin, kanamycin, amikacin and neomycin were obtained from Sigma Chemical Co. All drugs were dissolved in sterile water.
Drug susceptibility test
The minimum inhibitory concentration (MIC) of EETU, antibiotics and chlorpromazine (CPZ) were determined in BHI by the microdilution assay using suspensions of 105 CFU/ml and a drug concentration range of 1024 to 1 μg/ml (twofold serial dilutions) . MIC was defined as the lowest concentration at which no growth was observed. For the evaluation of EETU as a modulator of antibiotic resistance, MICs of the antibiotics were determined in the presence of EETU (32 μg/ml) and CPZ (16 μg/ml) at sub-inhibitory concentrations, and the plates were incubated for 24 h at 37°C. CPZ was used as positive control for efflux pump inhibition . Each experiment was undertaken in duplicate.
The EETU did not show a substantial antibacterial activity at 1024 μg/ml against the strains assayed (MIC ≥ 1024 μg/ml). None effect was observed when EETU was combined with the aminoglycosides in the strain SA-ATCC25923.
MIC‡ values (μg/ml) of aminoglycosides in the absence and presence of EETU# and CPZ * in Staphylococcus aureus 358.
EETU (32 μg/ml)
CPZ (16 μg/ml)
A MIC reduction for gentamicin and kanamycin was also observed when CPZ was added to the growth medium at 16 μg/ml, which indicates the involvement of an efflux pump in the resistance to these antibiotics (Table 1).
A potentiating effect of CPZ on amikacin and tobramycin was not observed, which suggests the occurrence of other resistance mechanisms (Table 1).
Only few articles were published focusing pharmacological activities of the genus Turnera. Some species of Turnera are widely used in folk medicine for different types of inflammatory diseases. Fresh leaves of T. guaianensis Aubl. is used to treat inflammatory diseases in general and as an immunomodulator while the decoction of it's dried leaves is employed to treat furunculosis . T. diffusa Willd., in a decoction of the whole plant, is used to treat otitis and nephritis [28, 29], while the leaf infusion is used in diseases related to the gastrointestinal and respiratory systems , reproductive organs in general or specifically for gonorrhoea treatment . T. ulmifolia is used popularly as an anti-inflammatory and as an expectorant [16–18], but as far as we know, natural products of Turnera ulmifolia or of any plants from the genus Turnera having a potentiating effect on any drug, mainly antibiotics (as aminoglycosides) have not been previously reported in human or animals.
Phenothiazines, such as chlorpromazine, probably act on the plasma membrane of bacteria affecting the efflux pumps . This modification of permeability could enhance the activity of antibiotics that act within the cell, such as the aminoglycosides.
Efflux pumps have been associated with resistance mechanisms since the 1980s32, representing one of the main mechanism of multidrug resistance (MDR) evolved in the antibiotic resistance to aminoglycosides . Several studies have been performed to identify drugs interfering with these pumps, called resistance modifying agents . Other plant products, as ethanol extract of Mentha arvensis, affected the efflux system of an Escherichia coli multiresistant to aminoglycosides, inhibitinh these resistance mechanism .
This strategy is named "herbal shotgun" or "Synergistic multi-target effects" and refers to the use of herbals and drugs in a multitargeted approach, due the fact of mono or multi-extract combinations affect not only a single target, but several ones, cooperating in an agonistic-synergistic way. This approach are not exclusive for extract combinations, but combinations between single natural products or extracts with chemosynthetics or antibiotics are possible too [34, 35].
The results obtained indicate that Turnera ulmifolia (and broadly Turneraceae) could serve as a source of plant-derived natural products with antibiotic resistance-modifying activity to be used against multiresistant bacteria as MRSA strains acquired from hospital and community.
This work was supported by the following Brazilian agencies CNPQ and FAPESQ/PB.
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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
PART 5 – HAYWARD VIA SYNERGY SPORTS
Here is Gordon Hayward via Synergy Sports. Synergy Sports labels every possession as a type of play be it a post up, spot up, hand off, etc. The label is based upon how the play ends. If you make a pass to create a play it is not registered under the player who made the pass.
Overall, Gordon had a very good offensive year. As a 2nd year player to rank 96th in ppp (pts per possession) is strong. He struggled early in the year with his shot or these numbers would be considerably higher.
The numbers on his spot up shooting should improve in the coming years. Hitting just 38% of his spot ups and 35% of the spot ups from three.
What jumps out is nothing is elite. He is not a very good isolation player yet (34.6% score rate and 29%) shooting. His pick and roll play is really hampered by the turnovers (30% of possessions on the pick and roll) as well as he didn’t hit any three’s off a pick and roll where he stepped behind the pick and nailed the shot. If he can develop this it would be a game changer. Coming off screens for catch and shots or drives he is only ok. Despite his size he wasn’t used at all as a post up player.
Where Gordon is at his best is in transition where he had 13 and 1’s this year and scored on 68% of the chances.
Without being elite in any area Gordon was still significantly above average offensively and much improved from his rookie year.
Surprisingly, Hayward overall production his 2nd year was not up a great deal from his rookie year. The drop in 3 pt shooting from 47% to 33% hurt his overall performance. Yet, if you dig in a little you see some marked improvement.
Compared to his rookie year he improved from 26% score rate on isolations to 35%. Transition jumped from 54% score rate to 68%.
These are very surprising to me. Everything I have seen tells me Hayward is a strong defender, opposing coaches discuss it and our own coaches believe it. However, the numbers don’t treat him well at all.
My instinct is to dismiss this as Synergy struggling to understand defense, since if a defender stymies someone and he passes out to a shooter it doesn’t get registered. It only gets registered if the player takes the shot. However, it is worth seeing what it says and see if we can learn anything.
Gordon’s big issue is player hit 42% of three’s when he is guarding them. 44% of those on spot ups. He needs to put a focus on this area of his defense.
His size does come into play when players are trying to post him up as he allowed just 33% shooting on post ups. He is also very good when guarding players off the screen.
The areas of struggle are defending the isolations, the ball handler on the pick and roll and protecting the three.
The good news is he is considerably better than a year ago when he allowed 1.06 ppp and this year just .97. He had a similar issue a year ago on the three’s allowing 40% of all three’s.
Hayward’s biggest area of improvement was in the post where a year ago he allowed 53% shooting. |
What do we make of that strange thing, an artist’s life? What do we want from it, other than answers—except that the trouble with our lives, yours, mine, anyone’s really, is that often, always, they lead only to more questions, to spiraling bafflement without conclusions or clear cut take-aways.
Bad biographies truck in the false promise of answers. They want us to believe that after chewing through six hundred or so pages we’ll truly understand the biographee under review, while good biographies instead treat the lives of their subjects as they ought to be treated, as the brief, inexplicable, boring, grotesque miracles that they are.
Deborah Solomon’s Utopia Parkway: The Life and Times of Joseph Cornell is a good biography for a lot of reasons: one of which is that it’s fabulously written; another is that Solomon never tries to convince us of anything other than the fact that Cornell is an artist who we should spend a little more quiet time with. Page by page, we follow the day-to-day ramblings of this humdrum fellow, who lived in Queens with his mother and handicapped brother and who constructed these odd works of wonder, shadow boxes that, in the words of critic Robert Motherwell, force “you to use the word ‘beautiful.’ What more do you want?” He was a funny sort, Joseph Cornell. Dressed in clothes that never quite fit right, he wandered the streets of New York, dragging along his personal movie projector and gathering trinkets, baubles, and bits of colored glasses as he went, objects he’d store in labeled boxes in his basement for decades until finally finding the perfect place for them inside one of his designs. Cornell lived a dull life mostly. He was a pack rat, yes, a human magpie, maybe, a guy with a keen eye whose art evokes the “power of reticence,” where what is concealed takes on more importance than what it is visible.
Throughout the book, Solomon interweaves the two primary genesis stories found in artists’ biographies: #1. That the artist is an independent, isolated inventor, a mad genius alone in some ramshackle Dutch colonial or garret room, creating masterpieces and as ignorant of the outside world as the outside world is of her, and #2. That the artist is a byproduct of a highly specific and unique bubble of time, the member of a movement, whose creativity is unleashed thanks to the synergy of being surrounded by other awesome artists. Because Cornell lived in the far-off borough of Queens and because he was a lonesome eccentric, he definitely fits into Category #1. But then, he was also a background character in some rather happening scenes. Cornell still lived in New York after all, and Julien Levy’s gallery was only a train ride away. It’s here, amidst the confluence of artists and innovation and highbrow trends, that Utopia Parkway booms with life; Solomon writes a lovely history of New York’s avant garde from the 1930s through the 1950s—there’s everybody of note, Saldavor Dali, Max Ernst, Marcel Duchamp and the local surrealists; William de Kooning and Peggy Guggenheim and the mostly forgotten but important at the time “neo-romantics” like Pavel Tchelitchew (“If his name had been easier to pronounce,” said one critic about Tchelitchew, “it might have had more currency”); and then there’s New York itself, with its gaudy streets, cinemas, opera theaters, and endless bustle, “the teeming life of the metropolis,” as Cornell called it in a letter he wrote later on. For him and for his art, the magnificent city was inspiration enough.
Understanding this rambunctious milieu, Solomon contends, is necessary for understanding Cornell. He wasn’t an outsider by any meanings. Cornell might’ve been aloof and early on his work was not taken seriously (considered, as it was, “toys for adults” by the gallery owners and artistic press). However, he had his contemporaries’ respect. While watching Cornell’s short compilation film Rose Hobart in 1936, Salvador Dali even erupted in anger. “My idea for a film is exactly that,” Dali told Levy, at whose gallery the film was screened, “I never wrote it or told anyone, but it is as if he had stolen it.” Orbiting each other’s brilliance, the artists’ were stealing one another’s undisclosed dreams.
Seeing Cornell in his time and place, “as the quintessential New Yorker: the loner who couldn’t stand to be alone, and who looked to the city as a place in which to live out his dream of connectedness,” we are able to situate him in the necessary art-historical context. We come to understand both his influences—from the French symbolists and surrealists to the Victorian ladies’ craftwork to the silent movies, with their montage techniques, where disparate images are quickly juxtaposed to engender new meanings—and his legacy. Solomon argues Cornell’s body of work presaged much of the art of the latter half of the 20th century, with his mixing of “high” and “low” culture like the Pop Artists would later do, and his love for pastiche and collage, a love shared by so many postmodern folks. Still, though, at the core of Cornell’s art and life, there is an oddness, which can’t be attributed to context or milieu. There is a certain dark, compelling strangeness, a trapped and haunted beauty, the “apparition of glamour sealed inside a box.”
Although Solomon delights in describing the house at 37-08 Utopia Parkway, it’s clear she doesn’t always know what to do or make of the man alone in his basement. Cornell’s internal life is poked at, but Solomon refuses to delve into the armchair psychoanalysis found in most biographies. Yet we’re left to wonder: Cornell climbs down the creaky steps and emerges later from “that cramped space overflowing with books and newspaper clippings” with a masterpiece like A Parrot for Juan Gris or Medici Slot Machine in hand, sure, but what else occurs, what other thoughts and desires and impulses floated about that well-organized hovel horde of debris and souvenirs whose orchestration was “a chronicle of infatuations whose meaning was as complicatedly inward as a private journal”? What do we make of Cornell’s creepiness, of how he hired Pat Johanson, an “attractive brunette” forty years his junior, just to look at her, and how even after she quit he kept “court[ing] her with letters and phone calls”? Courting here seems like much too generous a word for Solomon to use, but it’s a word that let’s us avoid that dank, subterranean unpleasantness that lurks in the corners of Cornell’s world.
“The ratio between the material Cornell collected,” Solomon writes, “and the material that ended up in his boxes was probably a thousand to one.” We can see the magic created with that 1/1000th of material, but what do we make of everything else, of everything that’s saved in some way and leftover, of everything that lingers unmentioned? When Cornell told an interviewer in 1967, “I thought, everything can be used in a lifetime, can’t it,” he was being fanciful and perpetuating a falsehood. Most of everything in our lives, the 999/1000ths of material, is never used. It waits and rots and rusts in the scrapheap of memory. And yet what we are we to make of it, still, everything else, all these trinkets and totems and silly scraps of paper (receipts, movie ticket stubs, the post-it notes you left me every morning) that have been imbued with a meaning beyond words? No coffin in the world is large enough to hold all this, no work of art either–and yet we try to make sense of it, still, to see how it all adds up into these strange, monstrous, gorgeous jokes we call our lives. |
Welcome to Walkable Suburbia
Welcome to Walkable Suburbia
Traditional suburban office parks are gray flannel suits in a skinny jeans world. Faced with adapting to change or becoming obsolete, the bland, old-school behemoths are increasingly getting mixed-use makeovers. The result is rave reviews along with a healthy stream of new occupants.
Originally built exclusively for business, office parks are evolving into vibrant villages as investors and developers strive to improve performance and add value through redevelopment. The result is a re-envisioned suburbia where people can dine, shop, and live—all within walking distance of work.
The move toward makeovers is the product of a triple whammy that hit the suburban office market during and after the Great Recession. First came the waves of layoffs that led to permanent corporate downsizing. Next came a shift to more open floor plans in offices requiring less square footage. The clincher is the perspective of a new generation of young professionals in their 20s and early 30s—the millennials—who have no interest in working in the same dull McOffice Park that their parents did.
It all adds up to an excess of suburban office inventory that is pushing developers to hit the reset button because employers no longer have the space needs they once did. “There’s definitely too much suburban office right now—substantially too much,” says Dane Anderson, CCIM, director of appraisal and litigation services with Real Estate Research Corp. in West Des Moines, Iowa. The nationwide vacancy rate for suburban office space was 16 percent as of the fourth quarter of 2013, according to the commercial real estate services firm Newmark Grubb Knight Frank. If over-supply is the problem, mixed-use makeovers are a potential solution in places where job growth is strong and there’s also high demand for multifamily and retail.
Helping Workers Feel at Home
To recruit and retain top talent, employers are eager to give millennials what they want: a walkable live-work-play environment. And suburban office parks can capitalize by giving employers what they seek: diversified environments where offices are surrounded by dining, entertainment, shopping, and housing. “It’s the new norm,” says Anjee Solanki, national director of retail services with Colliers International in San Francisco. “People are expecting it.”
That’s the vision Advance Realty and CrossHarbor Capital Partners LLC have for a vacated biotech campus in Bridgewater, N.J., which they bought for $45 million last year from a global pharmaceutical company. After getting a “good deal” on the campus, they hope to begin redevelopment sometime this year, says Peter Cocoziello, president and CEO of Advance Realty.
The campus, renamed the New Jersey Center of Excellence, contains 1.2 million square feet of offices and labs on 110 acres. While most of the office and lab space will remain, the new owners plan to demolish some of it to make way for multifamily housing (apartments, townhomes, and condos are all being considered), retail, and a hotel, as well as a new corporate headquarters building for an unspecified occupant. When redevelopment is complete, the overall footprint will grow to between 1.5 million and 1.7 million square feet, Cocoziello says.
The new owners found takers for 360,000 square feet of office and lab space in the first few months after buying the mothballed campus. A central location and state-of-the-art labs are big carrots for tenants, but so is the pending addition of apartments, retail, and a hotel.
Advance Realty typically holds properties for a period of time while they gain value, Cocoziello said. Current rents at the New Jersey Center of Excellence vary from $20 to $35 per square foot. “As I keep building out the product, I should be able to get better pricing,” he says.
Retrofitting for the Times Continental Park in El Segundo, Calif., has already traveled the path the New Jersey Center of Excellence is on. The 86-acre office complex once teemed with workers from the aerospace industry, but when defense spending began to shrink in the 1990s, the buildings began to empty. “We had to rethink what to do with the property,” says Alex Rose, senior vice president of Continental Development Corp.
Most of the buildings had been occupied by single large tenants. Continental Development steadily began retrofitting the buildings to fit multiple tenants. Then it began adding restaurants, shopping, hotels, fitness centers, and a movie theater—all served by a light rail stop. “Once you get the cycle going, it feeds on itself,” Rose says. With 3 million square feet of mixed-use space and an office vacancy rate below 5 percent, Continental Park found the right strategy to turn things around. “By taking a mixed-use approach, we think we did a good job of listening to our market,” Rose says. “We’ve been able to keep our rents up, keep occupancy up, and attract tenants that perhaps our competition can’t.”
Invesco Real Estate and SSV Properties of Ontario, Calif., bought four office buildings in Continental Park totaling 540,000 square feet for an undisclosed amount last year. One was fully leased, but the new owners are spending an estimated $75 million to convert the other three to open floor plans that support workplace collaboration.
Continental Park’s mixed-use environment was a key factor in the decision to buy the buildings as a long-term investment, said Peter Cassiano, director of acquisitions for Invesco. “The way officing is going right now, folks want the [mixed-use] environment and amenities,” he says.
Garrick Brown, director of research with Cassidy Turley in Sacramento, Calif., is bullish on mixed-use makeovers. “There are plenty of markets where this would solve an awful lot of problems—especially if you can incorporate multifamily in the mix, because that’s where the strongest demand is,” Brown says. “The only reason we haven’t seen more [mixed-use redevelopment] is cost.”
Many underperforming office parks can’t afford mixed-use makeovers because the owners don’t have the capital. They don’t have the capital because the property is underperforming. The only escape from this Catch-22 is acquisition by new owners with deeper pockets, Brown says.
Investing for the Long Haul
Synergy Business Park in Brentwood, Tenn., wasn’t necessarily underperforming when Boyle Investment Co. bought it for $62.8 million in 2012 with an eye on giving it a mixed-use makeover and holding it as a long-term investment. The 500,000-square-foot complex—since renamed CityPark—was at 90 percent occupancy at the time of the sale and climbed to 96 percent occupancy with a bump in rents before the makeover even began earlier this year. “It wasn’t an issue of needing to redevelop the property due to increased vacancy and declining rents, but more an issue of us wanting to enhance the property ... so that it adds value and succeeds both now and 30 years from now,” says Shelby Larkin, a Boyle spokeswoman.
Boyle got good value by purchasing the property in a downturn, Larkin says. Construction is underway on 40,000 square feet of retail and restaurant space, a 126-room Hilton Garden Inn, and a one-acre park—all within a stroll of a 300-unit upscale apartment complex another developer is building nearby. “There really won’t be anything like it in Brentwood,” Larkin says.
North Carolina’s iconic Research Triangle Park will start construction later this year on the first of three planned mixed-use clusters. Phase one consists of 1,000 apartment units, 200,000 square feet of retail, and 700,000 square feet of new office and research space.
The triangle in Research Triangle Park refers to three surrounding universities: the University of North Carolina in Chapel Hill, North Carolina State University in Raleigh, and Duke University in Durham. The vast park, founded in 1959 and now home to 170 companies with more than 38,000 employees, created an identity for the region as a center for innovation, but the park is a laggard when it comes to urban amenities. “Research Triangle Park is 7,000 acres—that’s half of the size of Manhattan—and you can’t buy a latte anywhere,” says Bob Geolas, president and CEO of the Research Triangle Foundation, which manages the campus. “We want to make sure the park stays at the forefront. If the park was viewed as a dinosaur, that would impact the Research Triangle brand.”
The overall vacancy rate in the 21 million square foot park is 3.34 percent, but most buildings are owner-occupied. The vacancy rate is 18.9 percent in the 4.3 million square feet of space that is under lease. Lee Clyburn, sior, principal with Avison Young, a commercial real estate firm in Raleigh, N.C., says adding a live-work-play flavor should help Research Triangle Park improve occupancy. “I think adding amenities to the park will help all of us attract more tenants and lease more space out there,” Clyburn says.
Transportation Game Changers
Some suburban office parks are better positioned for redevelopment than others. The presence of transit options and support from local government for any needed zoning changes are game changers. Redevelopment was a nonstarter in Tysons Corner, Va., until the Washington, D.C., Metro decided to extend light rail service to the unincorporated suburb—four new stations will open this spring—and Fairfax County approved greater density.
With 26 million square feet of office space and a workforce of 110,000 people, Tysons Corner is a “tremendous employment and economic engine,” says Eric Maggio, vice president and chief financial officer at CityLine Partners, a leading developer and owner of office and commercial property in Tysons Corner. “The problem is it’s just a collection of office parks and a large shopping center. It’s not a livable place.”
CityLine is in the opening stages of a sweeping live-work-play makeover that could total up to 8.5 million square feet of residential, retail, and office space over the next decade and beyond. Construction is underway on 1,575 apartment units. “You can continue to operate old office parks, but you’re chasing falling revenue,” Maggio says. “Corporations are no longer in the mode of wanting office buildings where all their employees have to drive to work.” |
I was a Kickstarter backer for the game Darkest Dungeon, which I'm sure /tg/ knows all about. Long story short I have one week to create a character and have him or her added to the game as one of the heroes who will descend into the depths. I asked /vg/ but they don't give a fuck anymore, so you guys get to be the silver medal. Darkest Dungeon is pretty fuckin' close to being /tg/ related anyway, so that's why I'm letting you guys in on the process.
We will get to choose things such as class/gender, name, skills, mental illnesses, and so on. We'll use straw poll and do this diplomatically. I'll check each result every 24 hours and come back to make a new poll.
Remember, we only have one week, so if you want to be a part of this then you gotta VOTE. The first vote for class/gender is here: http://strawpoll.me/6461645/
Wait, so you get to make a character, as in not a custom class or enemy or anything, just a character (as in a preset name that will get changed anyway and some arbitrary stats that will get overridden with sanitarium and items)?
Not as exciting as I thought it would be, 6/10 got me excited for nothing.
What it boils down to is if you want to be able to say "hey, I helped design that poor faggot who just got axe-raped" or not.
Yes. The game does come out later this month... hence why the character needs to be PROCESSED by the 12th.
Plague Doctor the most popular with the early voters it seems. I wonder why.
I thought they already designed the kickstarter backer character?
Better tell devs to buff Grave Robber and Jester camp skills. They are shit. GR needs skills like "5-6 respite for +25% increase in loot drops with drawback of getting surprised more often". Jester needs "Sharpen his Sickle for +10% Crit" at least.
Big Boss, man at arms
>Every 24 hours
Nigga you a fool, also I haven't evun begun to play DD so sorry if I make bad choices optimization wise
Nigga, what you on? All we're doing is naming a character, selecting it's palate and choosing how insane it is. How's that any different from what's already there? Hell, it doesn't even have a custom sprite.
I suppose I should blame myself for not realizing the obvious fan-sway that Plague Doctor has as one of... what, four females in the cast?
I just put Bounty Hunter because he was my fave, utility-wise.
Do they all have a quick storyboard like that?
Its sorta slowed down to a crawl. Then again release is right around the corner and theyre missing features theyve promised like town events. The release patch is probably going to be huge.
Or a disappointment.
>reynauld is on deaths door!
Man I sure love darkest dungeon, tiny inpersistant dungeons free of difficult exploration, perks that don't matter so all I lose is gold when a hero dies and combat with as much depth as a glass of water so it's nice and easy for me, and lots of rng to trick me into thinking it's a hard game!
>plague doctor gets rid of them for free and i find your almost guaranteed to remove multiples at the sanitorium
Madmans just a new enemy type, i have no opinion of him other than hes just something to target first like any other stress inducer
prophet was totally doable a hard boss but then again i fucked up the fight so thats on me, despite that i still managed to beat him, i highly doubt his level 6 incarnation is suddenly impossible, i havent gotten to him on my new save, dont want to go through everything until release
madmans too squishy to be overpowered, just kill the man, hell didnt they nerf him?
>abom is 4/10
abom is literally the best front liner in the game
>like any other stress inducer
That's the point, he just a bunch. There's nothing interesting about him, he's annoying to deal with, and does nothing new.
>Abom best frontliner
yeah ok, just driving the rest of the party nuts, no biggie. Plus he stresses himself to death in transform form.
Prophet fight, the pews are pointless. If you take the time to kill them to get cash he rapes you to death with the insane damage of falling rubble and stuns.
I tried it a couple of times with a Crusader, Leper, Vestal, and Man At Arms. My plan was to have the MaA tank the damage with his prot stack and trinkets, while the Leper and Crusader chopped their way to him and healed htemselves as needed. Unfortunately, due tot he way the MaA works, if two targets are hit by falling rubble, he blocks one and the other takes a 40 damage smack to the face. Between crazy high damage, blights, and stuns, they just couldn't keep up. I've tried it about a dozen times with different trinket loadouts, different party members, etc. Nothing works. It's hard enough killing him, the pews are utterly pointless.
thirded, why does it have such a hold on me
Instead of trying to make a genderbent version of a character, try to make a original character.
Maybe a scientific guy who is the scientist gentleman adventurer to the Occultist's mystic and the Plague Doctor's medical scientist?
Bounty Hunter has the best synergy with Arbalest, Hound Master and Occultist in a team.
The Occultist uses the Vulnerability Hex, and everyone else uses their attacks that become more lethal against Marked Targets.
Its a decently strong party wide stress heal, like the jesters only not on the shitty jester.
Dodge tanks seem extremely unreliable, especially with how accurate monsters are in the level 6 dungeons. Hound master to me will always be a better support because his mark is the best mark in the game
Yeah. Man-At-Arms is actually not only tanky, but the buffs he has do the job.
So that's that. Gonna try it out.
Also they should buff up the Jester. Like give him ridiculously high speed.
You cant actually lose darkest dungeon though, youll always have an infinite supply of fresh meat off the cart to send to their dooms. Apparently NG+ will have a failstate though
>let's tank falling rocks
>let's waste turns chopping at benchs
>let's forget about Holy Lance or ranged skills
I actually used exactly the same composition on my first run when I didn't know how the fight works and expected to endure some damage and heal tough guys
> If you take the time to kill them to get cash he rapes you to death with the insane damage of falling rubble and stuns.
..... then don't attack the pews?
>while the Leper and Crusader chopped their way to him and healed themselves as needed
First.... why the fuck are you bringing a Leper to a Boss that sits in the fucking backrow.
Second..... you do realize Crusader's best attack hits the backrow right? (Holy Lance)
Third, I ran a somewhat similar party (Except you know, I had Highwayman with Unholy Ring instead of Leper because I wanted to still deliver decent damage consistently) and it's pretty easy to tank damage. Just use both the Crusader's and MaA's Protect Buffs and have them shuffle to wherever those rocks are falling to. It wasn't even that hard to get mixed up since I had my MaA at the back to buff the party so things didn't get lost and I had both the Highwayman's move skill so I didn't even have to waste a turn not attacking the Prophet.
Anon you misunderstand.
I'm accusing it of being an incredibly simple and easy game with an added layer of artificial difficulty to trick people into thinking it's hard, all coated in a very nice atmosphere so that it takes people longer to notice the actual game beneath it is shit tier.
>why the fuck are you bringing a Leper to a Boss
Actually why bring a Leper to a Boss fight at all? He isn't great against any of them, kinda good versus pig bosses but those aren't too hard.
What? Did you misquote or something? Youre continuing to not make sense from my perspective
The game is tedious, not actually hard. It's grindy and boring, and the "difficulty" is about resource dwindling, not actually about encounters that will quickly fuck you up if you make mistakes or similar. And after you learn what works, it turns even more repetive as you simply repeat that over and over again, since this is what the game promotes. Endless grindy fun-vampiric bullshit.
I've never finished the content Darkest Dungeon has, because I get bored way before. There's no actual challenge to it, just tedium. The game ain't hard, it's just stingy with resources, and every new change by the devs simply promotes more tedious, boring gameplay.
But it's flawed as a resource management game, as well. I don't need to make any hard decisions about where to spend my resources or stuff like that. I don't feel there's actual pressure on me when I play. It's a simplistic game with a very tedious playstyle.
>The game's not hard, it's just about tedious resource management, anon
>Well maybe you just don't like resource management
>But the resource management part is flawed and sucks as well, and doesn't promote the kind of hard and punishing gameplay the game says it does
>Herp derp it's just not for you
Good argument there, buddy.
No exploration, dungeons are 4 flavors of tiny on rails experiences you enter with near omniscient knowledge, rather than 4 dungeons you explore on your own accord.
All attempts at emergent characterisation fail. Characters have no personality, one of the primary advertised goals during early development.
Light stress and quirks are all poorly realized mechanics.
Light could be intresting if it was something other than a mild rng influencer and was say an obstruction to exploration, but exploration dosent exist.
Stress is just a second health bar.
Quirks are all insignificant and reprogrammable.
Combat is incredibly shallow, the skill cap of which is "learn the target priority of the small number of guys per dungeon" and "make a mildly balanced team comp" all of which is pretty self evident.
Character advancment is completely linear and near exclusively gold based.
Missions are limited to "walk around this near linear track until you kill everything of visit all but two of the rooms." "look for the dead end and make a beeline for it because the boss is there" or if your lucky "visit 3 specific rooms"
Enviormental interaction is "randomly lose or gain stress, get bled or blighted, roll on the entire quirk table or pointless things or get gold" the shamblers alter is a step in the right direction though, I'll give it that.
All difficulty is artificial.
It's a really good looking smd sounding piece of garbage
The way I see it, you can absolutely grind your brains out in Darkest Dungeon to play in the safest way possible, but that alone isn't really indicative of anything because you can do that with a ton of RPGs, but you won't end up doing it with all of them.
In a very punishing game, you'll obviously want to play more safe, so I can definitely see why people grind like mad in Darkest Dungeon. But to me personally it's balanced out by possibilities to play it greedy at virtually any corner. Just ooone more room battle until the quest is done. Hey I'm not doing so bad, maybe there's something good in this container. Maybe I don't need to buy a second shovel, it'll be fine. Maybe I'll clear whatever's left of the dungeon with low torchlight for extra gear. Hmm my dude is on Death's Door, but I'm sooo close to wiping that last enemy party...
Stuff like that. I can see how long-term players may get burnt so often they'll avoid any risk period, but for me personally Darkest Dungeon has plenty of lures to prevent me from using the Dominant Strategies. Tho, considering how often I hear grind complaints, they should probably put in more possibilities to play greedy, or maybe they should take a note from The Swindle and put you on a timer. Doesn't need to be a strict one, it'll still have a psychological effect just by existing.
Playing risky is exactly as grindy as playing safe anon. You just lose your gold and time Invested in your guys instesd of the gold you would have earned completing the mission. The game isn't punishing. Punishing means you make mistakes and you get raped. In DD you are just get periodically raped.
Resources are hardly something that needs managing. Gold is abundant and food is basically free. Its just a "run dungeons and get experience, immediately upgrade everything at the blacksmith and guild because you have so much gold, periodically lose a dude and repeat.
Anon the issue is that making the best of miserable situations is supposed to be a series of challanging decisions. In darkest dungeon "a misblerable situation" is getting your party killed by unlucky crits. The way you make the best of that is by...sending out another party and hoping that dosent occur again.
See sunless sea for a game that pulls this off correctly.
Not the anon you replied to but
I bought DD and SS during the wintersales
I refunded SS because it was after about 12 hours in of doing the same thing just trying to make money, I did a few of the events and thought the combat was fun but it just got so tedious.
I am having fun with DD though.
It is not flawed just doesn't live up to its reputation. Once your get past the starting difficulty and explored most things a quiet tediousness sets in. The game rarely deviates from the basic formula.
Also people claim that DD is VERY HARD and VERY PUNISHING but it is not, once you start know what you are doing it just gets randomly punishing.
The start is hard I give it that but only because your options are extremely limited but it quickly looses the starting steam. |
Friday, January 6, 2012
THE LAKE 1 & 2 DOWNLOAD
VGM MIX STREAM
Thursday, January 5, 2012
Sunday, December 25, 2011
GO F A BURD is a unique, 3 part release, which includes a mashup album, a video game, and a dj mix of video game music. Every part of the GO F A BURD bundle is it's own handmade physical release, all of which you can get for free with the price of shipping.
GO F A BURD (15 copies, various formats)
Made from around 2009-2011, we pieced this this together using HLDJ on our respective computers, trolling in goldsrc & source games such as TFC and Synergy. Every copy is totally unique and recycled, some packaged in video game cartridges, others in little handmade pieces of art. The audio is mastered in beautiful 11025 hz for authenticity. First 5 sent off will include a special numbered packet.
"i loved the packaging"
-7u?, aka DJ Rainbow Ejaculation
THE LAKE 1 & 2 (50 copies, CD)
The Lake is a game about a dog. It was made in a few days, includes 7 action packed levels, and lots of midis. The Lake 2 is a game about the same dog, out for revenge. It was made over about a year, includes cutscenes, drama, action, and romance. There are 12 huge levels, filled to the brim with challenges, secrets, and enemies to fight. There are even 3 different endings depending on how you play the game.
"i think a day at the lake 2 is not olny the best gaem i played all night
but the only indy game beter than bubba goes number 2"
-ROCKCOCK64, The Best Gamers
VGM MIX (50 copies, CD)
I made this mix using entirely music and sounds from video games, using about 100 themes and a few sound effects, crammed into a little over 20 minutes. The games used span a wide range, with new and old, and console and PC games. The discs are hand painted and packaged in sleeves individually made from pages of NES era Nintendo Power.
"extremely well done"
-Fluorescent Grey, Record Label Records
TO ORDER "GO F A BURD":
email me at email@example.com, and include which parts of the bundle you want, your address, and the email address for your paypal account. If you are ordering GO F A BURD and you cannot use one of the formats listed, please say so in the email. |
The Quebec Stock Savings Plan is slated to end on December 31, 2014, and Quebec counts for only 7% of the corporations listed on the exchanges of the TMX Group, whereas the province's economic weight in the Canadian economy is 20%. By comparison, 33% of the corporations listed on TMX Group exchanges are from Ontario and 50% are from Western Canada. In 2013, only 5.3% of new listings on those exchanges were by Quebec corporations, versus 11% from abroad. That same year, all of the listed Canadian corporations raised an aggregate of $43.6 billion, versus only $4 billion by corporations from Quebec, and of the 59 new exchange listings of structured products, none was from Quebec.1 Quebec is thus far from fully benefitting from Canadian securities exchanges, which have a solid reputation and are known for supporting SMBs.2
There was a time when Quebec succeeded in listing many SMBs on the stock market, some of which went on to become giants, such as CGI, Québecor, Couche-Tard and Jean Coutu, to name but a few. While their initial public offerings raised only modest amounts, the exercise gave these SMBs a higher valuation than when they were private companies, as well as access to new and less costly sources of financing and, above all, a keystone for expansion, in the form of publicly tradable shares. These corporations, run by visionary builders, became major consolidators through mergers and acquisitions. Thus, improved prospects for future growth can be seen as the primary reason for listing on an exchange.3 The Quebec financial ecosystem has evidently changed significantly since then.
It should first of all be emphasized that for a junior company an exchange listing is not always the best course: it is not within the means of every small business and is not necessarily suited to the personality of the owner of the business. And when listing is a viable option, the environment must be favourable if the exercise is to be successful.
It must also be acknowledged that there has been a decline in exchange listings in Quebec and Canada, as well as in the United States, for a variety of reasons of which some are structural,4 on both the general and local levels. In particular, there is an increasing recourse to pre-IPO private financing, plus a pronounced aversion to reputational risk on the part of the investing financial institutions, and an evolution of sorts in the role of securities brokers, who have gone from investment advisors to asset managers proposing a selection of investments that are often pre-packaged and carefully structured by the brokerages, leaving little room in the market for SMBs aspiring to go public. Another factor that should not be underplayed is the swallowing up of innovative Quebec technology companies by larger corporations, most of which are already listed on an exchange. In addition, Quebec has its own ways of doing things.
Going public is an operation that often must coincide with a favourable stock market cycle for the type of business involved. To seize an opportune moment, the company must be ready and well organized. Unfortunately, Quebec businesses tend not to make their move until the favourable market cycle is peaking, and only a few are successful at listing.5
The dynamic nature of Quebec's financial sector is often vaunted, particularly in connection with its investment sector. And while it is true that there are many high quality firms in Quebec engaged in those activities, in the context of an analysis on contributing to wealth creation it is important to differentiate between the "buy side" and "sell side" of the financial sector.
The firms alluded to above are definitely successful in terms of investing (the buy side). However, the "sell side" of Quebec's financial sector, insofar as it involves SMBs, is not nearly as developed. This situation has far from negligible consequences for our economy and for wealth and job creation. By way of example, the major banking institutions in Quebec provide corporate finance services through their securities brokerages, i.e. their investment bankers, who cater primarily to companies of a certain size. In 2010 at a conference on this issue, Jacques Ménard, the chairman of BMO Nesbitt Burns and president of BMO Financial Group, Quebec, pointed out that in Canada taking SMBs public is the stock-in-trade of small brokerages, often termed "boutiques", and that very few of them are present in Quebec.6
In order to succeed in obtaining an exchange listing, the aspiring issuer must be well prepared and have the support of both key investors and the local public financing milieu. The operation thus requires both specific expertise and a favourable local environment. The sad reality is that both of those aspects are lacking in Quebec.
What's missing in Quebec
The globalization of equity markets necessitates heightened visibility and access to investors in both Canada and abroad, which publicly listed companies often enjoy. They also benefit from an expanded network, greater opportunities for mergers and acquisitions, and access to new types of financing.
Canadian securities exchanges have a reputation for welcoming SMBs as public issuers.7 That being so, why is Quebec not part of this scenario? Whatever the answer may be, this situation has to change.
While many feel that any such change will be slow and protracted,8 Quebec should nonetheless immediately set about establishing a public financing sector for SMBs that is permanent, dynamic and open to a changing economy, and which integrates investment bankers, analysts, retail and institutional brokers and market makers, and is accompanied by fiscal and other incentives.
The lack of this segment in Quebec's financing sector results in the following:
- fewer investment opportunities for Quebec companies and investors;
- departures from Quebec of businesses and entrepreneurs who move to a more propitious investment climate;
- the absence of a means for entrepreneurs to monetize the value they have built up in their businesses when they retire;
- the sale of innovative Quebec companies to foreign corporations – over the last ten years, in Canada and to a lesser degree in Quebec, bulk sales by venture capital firms have predominantly been to foreign buyers;
- fewer opportunities to realize value on the part of Quebec investment funds;
- the absence of the mobilizing and stimulating effects of a public listing for Quebec entrepreneurs;
- a lack of synergy between our businesses and markets outside Quebec.
This situation negatively impacts:
- access to long-term development capital;
- integration with international capital funding networks;
- the ability of certain Quebec companies to realize their full value;
- return of capital from government incentives;
- access to new sources of financing;
- job creation and preservation;
- the vulnerability of Quebec businesses, who are too often gobbled up by public companies instead of becoming consolidators themselves;
- the visibility that some businesses deserve.
Quebec must implement long-term structural measures so that listing on an exchange becomes a viable alternative for Quebec corporations that are willing and able to do so.
Measures to consider for the sustainable structuring of the "sell side" of Quebec's financial sector include the following:
- incentives for the creation of units within Quebec financial services corporations composed of investment bankers dedicated to taking SMBs public. They could, for example, be offered incentives similar to those for international financial centres;
- simplify the financial information reporting rules applicable to public SMBs;
- use the latest information technology in order to adapt to current methods and accelerate the process for listing and maintaining an exchange listing, at the lowest possible cost;
- incentivize brokerages to include stakes in junior issuers in their clients' investment options;
- ensure that universities and professional associations offer relevant continuing education courses;
- make incentives for investing in junior issuers available to Quebec-based and other investment funds;
- better inform Quebec investors on the risk-return ratio of investments in junior issuers;9
- revise the Quebec Stock Savings Plan II to make it more attractive for Quebec corporations and investors;
- amend Quebec's income tax laws so that listing on an exchange by an SMB no longer results in the loss of tax benefits;
- implement measures promoting the emergence of managers specialized in exchange-listed structured products.
The potential for SMBs to list their shares on a stock exchange is an important component of a healthy economy. This is borne out by the reaction of entrepreneurs, professionals and government in the United States when it became apparent that the number of publicly listed American SMBs was stagnating. To remedy this, several economic measures to stimulate that segment of the economy were hurriedly put in place, including the federal Jumpstart our Business Startups Act (Jobs Act).
Let's hope that Quebec follows the same course by adding to its wealth-creation toolbox a series of measures that, through converging incentives and policies, encourages more Quebec corporations to become publicly listed.
1 TMX Group, December 2013.
2 Pandes, J. A., Robinson, M. J., "Is Effective Junior Equity Market Regulation Possible?" (2014) Vol. 70: No. 4 Financial Analysis Journal, 42-54.
3 Celikyurt, U., Sevilir, M., & Shivdasani, A., "How an IPO Helps in M&A" (2010) Vol. 22: No. 2 Journal of Applied Corporate Finance", 94-99.
4 B.C. Tingle, J.A. Pandes et M.J. Robinson, "The IPO Market in Canada: what a comparison with the United-States tells us about a global problem", Canadian Business Law Journal, Vol. 54, 2013, p. 321 et ss.
5 PWC & FMC (now Dentons), "Pour une démocratisation du financement de nos entreprises" (2011).
6 Ménard, J., "A Perspective on the Canadian IPO Marketplace" (breakfast conference organized by Réseau Capital, April 29, 2010).
7 Carpentier, C., Suret, J.-M., "The Canadian Public Venture Capital Market", Report prepared for the Autorité des marchés financiers du Québec, January 21, 2009; Pandes, J. A., Robinson, M. J., "Is Effective Junior Equity Market Regulation Possible?" (2014) Vol. 70: No. 4 Financial Analysis Journal, 42-54.
8 Ragan, C., "What Now? Addressing the
Burden of Canada's Slow-Growth Recovery" (2014) 413
C. D. Howe Institute Commentary.
9 Carpentier, C., Suret, J.-M., « Connaissance financière et rationalité des investisseurs : une étude canadienne » (Autorité des marchés financiers du Québec, September 1, 2011).
The foregoing provides only an overview and does not constitute legal advice. Readers are cautioned against making any decisions based on this material alone. Rather, specific legal advice should be obtained.
© McMillan LLP 2014 |
As I see it, the synergy between Sun and IBM, employees going from Sun to IBM etc., I'm guessing was created by Sun to create a cooperative atmosphere between the two companies and in the end as I see it, it worked.
Now both are great supporters of Open Source. Sun Micro is inventing and then giving away
things like crazy it seems and when you ask yourself why, the answer is most assuredly,
at least in part, to DEFEAT Microsoft.
We are in a WAR! Do you know what it is to for a big company to give things away feverishly
and not even say WHY they are giving things away? IBM appears to me to support all of this and it's as if they are competing with Sun in a friendly manner.
Now could Sun create such a loving cooperation with Microsoft??, that is for people from Microsoft to go over to Sun and vice versa. no Way! It would never work because Microsoft is too
far gone in their mentality.
Now then, O'Reilly wants to create this same kind of communication channel to Microsoft.
O'Reilly wants to work with (and work on) Microsoft so to speak. But what they don't realize
is how strong Microsoft actually is, what an incredibly smooth talker Bill Gates is e.g., and
that they can really have no influence. The only way to defeat Microsoft is to surround them by
creating Innovation in many different places. Then Complexity will soon tire them.
Now I'm not a Microsoft Hater. I believe that Microsoft is excellent in many areas of
Business. But it's their tactics. C# should not even exist because it's purely an attack on
the momentum of Java. This is not true cooperation in the industry. This is not playing
well with others! C#'s innards were constructed to compete with Java so it would be completely heretical for a Java Developer to embrace C#. He would be betraying openness and cooperation and innovation, this special vision, this dream in the industry in a very direct way. Yet O'Reilly
does a piece on the creme de la creme of taboo's for Java Developers??
As I said before, this is a WAR. The 'Open Community' really has no choice but
to be part of it. Now the O'Reilly Network advertises itself as one of these 'Open Communities' that look toward the future. Yet they invite the sworn enemy of open source??
Not even IBM would do such a thing. |
Docosahexaenoic acid (DHA) induces autophagy-associated apoptotic cell death in wild-type p53 cancer cells via regulation of p53. The present study investigated the effects of DHA on PC3 and DU145 prostate cancer cell lines harboring mutant p53. Results show that, in addition to apoptosis, DHA increased the expression levels of lipidated form LC3B and potently stimulated the autophagic flux, suggesting that DHA induces both autophagy and apoptosis in cancer cells expressing mutant p53. DHA led to the generation of mitochondrial reactive oxygen species (ROS), as shown by the mitochondrial ROS-specific probe mitoSOX. Similarly, pretreatment with the antioxidant N-acetyl-cysteine (NAC) markedly inhibited both the autophagy and the apoptosis triggered by DHA, indicating that mitochondrial ROS mediate the cytotoxicity of DHA in mutant p53 cells. Further, DHA reduced the levels of phospho-Akt and phospho-mTOR in a concentration-dependent manner, while NAC almost completely blocked that effect. Collectively, these findings present a novel mechanism of ROS-regulated apoptosis and autophagy that involves Akt-mTOR signaling in prostate cancer cells with mutant p53 exposed to DHA.
The anticancer properties and mechanism of action of omega-3 polyunsaturated fatty acids (ω3-PUFAs) have been demonstrated in several cancers; however, the mechanism in lung cancer remains unclear. Here, we show that docosahexaenoic acid (DHA), a ω3-PUFA, induced apoptosis and autophagy in non-small cell lung cancer (NSCLC) cells. DHA-induced cell death was accompanied by AMP-activated protein kinase (AMPK) activation and inactivated phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling. Knocking down AMPK and overexpressing Akt increased mTOR activity and attenuated DHA-induced cell death, suggesting that DHA induces cell death via AMPK- and Akt-regulated mTOR inactivation. This was confirmed in Fat-1 transgenic mice, which produce ω3-PUFAs. Lewis lung cancer (LLC) tumor cells implanted into Fat-1 mice showed slower growth, lower phospho-Akt levels, and higher levels of apoptosis and autophagy than cells implanted into wild-type mice. Taken together, these data suggest that DHA-induced apoptosis and autophagy in NSCLC cells are associated with AMPK activation and PI3K/Akt inhibition, which in turn lead to suppression of mTOR; thus ω3-PUFAs may be utilized as potential therapeutic agents for NSCLC treatment.
The present study identified that ω-3 long chain polyunsaturated fatty acids (ω-3 PUFAs), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) demonstrate anti-proliferative effects in lung cancer A549 cells. MTS and cytotoxicity assays were conducted to confirm that ω-3 PUFAs induced cell death. Autophagy-associated gene and signaling pathways were also detected. Microtubule-associated protein light chain 3 (LC3) expression was found to be increased subsequent to treatment with DHA and EPA, and the expression of LC3-II was particularly increased. mRFP-GFP-LC3 fluorescence staining and p62 expression levels were used to detect autophagic flux. The present results indicate that DHA and EPA block autophagic flux, suggesting autophagosome accumulation. Subsequent to treatment with DHA and EPA, which interfered with autophagosomes, the expression of Beclin 1 was significantly decreased, while the expression of phosphorylated Akt and phosphorylated mammalian target of rapamycin was significantly increased. Therefore, DHA and EPA exert anti-proliferative effects by inhibiting autophagy in A549 cells, which highlights the potential of DHA and EPA for use in the prevention or treatment of lung cancer.
ω-3 long chain polyunsaturated fatty acids; autophagy; Akt/mammalian target of rapamycin
Despite recent advances in the therapy of non-small cell lung cancer (NSCLC), the chemotherapy efficacy against NSCLC is still unsatisfactory. Previous studies show the herbal antimalarial drug dihydroartemisinin (DHA) displays cytotoxic to multiple human tumors. Here, we showed that DHA decreased cell viability and colony formation, induced apoptosis in A549 and PC-9 cells. Additionally, we first revealed DHA inhibited glucose uptake in NSCLC cells. Moreover, glycolytic metabolism was attenuated by DHA, including inhibition of ATP and lactate production. Consequently, we demonstrated that the phosphorylated forms of both S6 ribosomal protein and mechanistic target of rapamycin (mTOR), and GLUT1 levels were abrogated by DHA treatment in NSCLC cells. Furthermore, the upregulation of mTOR activation by high expressed Rheb increased the level of glycolytic metabolism and cell viability inhibited by DHA. These results suggested that DHA-suppressed glycolytic metabolism might be associated with mTOR activation and GLUT1 expression. Besides, we showed GLUT1 overexpression significantly attenuated DHA-triggered NSCLC cells apoptosis. Notably, DHA synergized with 2-Deoxy-D-glucose (2DG, a glycolysis inhibitor) to reduce cell viability and increase cell apoptosis in A549 and PC-9 cells. However, the combination of the two compounds displayed minimal toxicity to WI-38 cells, a normal lung fibroblast cell line. More importantly, 2DG synergistically potentiated DHA-induced activation of caspase-9, -8 and -3, as well as the levels of both cytochrome c and AIF of cytoplasm. However, 2DG failed to increase the reactive oxygen species (ROS) levels elicited by DHA. Overall, the data shown above indicated DHA plus 2DG induced apoptosis was involved in both extrinsic and intrinsic apoptosis pathways in NSCLC cells.
Artemisinin, a powerful antimalarial medicine, is extracted from the Chinese herb, Artemisia annua L., and has the ability to inhibit the proliferation of cancer cells. Dihydroartemisinin (DHA), the major active metabolite of artemisinin, is able to inhibit the growth of a variety of types of human cancer. However, the effect of DHA on human glioma cells remains unclear. The aim of the present study was to investigate the effect of DHA on the proliferation of glioma cells, and whether DHA was able to enhance temozolomide (TMZ) sensitivity in vitro and in vivo. In total, 10 human glioma cell lines were used to analyze the growth inhibition ability of DHA by MTT assay. The typical autophagic vacuoles were monitored by the application of the autofluorescent agent, monodansylcadaverine. Western blotting was used to detect markers of apoptosis and autophagy, namely Caspase-3, Beclin-1 and LC3-B. The combination efficiency of DHA and TMZ was assessed in vitro and in vivo. The half maximal inhibitory concentration (IC50) of DHA differed among the ten human glioma cell lines. The number of autophagic vacuoles was higher in DHA-treated SKMG-4 cells; this was highest of all cell lines analyzed. The expression of autophagy molecular markers, Beclin-1 and LC3-B, was increased following DHA treatment, while no significant alteration was detected in the expression of apoptotic marker Caspase-3. When combined with DHA, the IC50 of TMZ decreased significantly in the four glioma cell lines analyzed. Furthermore, DHA enhanced the tumor inhibition ability of TMZ in tumor-burdened mice. The results of the present study demonstrated that DHA inhibited the proliferation of glioma cells and enhanced the tumor inhibition efficacy of TMZ in vitro and in vivo through the induction of autophagy.
dihydroartemisinin; temozolomide; glioma; autophagy
Autophagy is a complex “self-eating” process and could be utilized for cell survival under stresses. Statins, which could reduce apoptosis in mesenchymal stem cells (MSCs) during both ischemia and hypoxia/serum deprivation (H/SD), have been proved to induce autophagy in some cell lines. We have previously shown that atorvastatin (ATV) could regulate AMP-activated protein kinase (AMPK), a positive modulator of autophagy, in MSCs. Thus, we hypothesized that autophagy activation through AMPK and its downstream molecule mammalian target of rapamycin (mTOR) may be a novel mechanism of ATV to protect MSCs from apoptosis during H/SD. Here, we demonstrated that H/SD induced autophagy in MSCs significantly as identified by increasing acidic vesicular organelle–positive cells, type II of light chain 3 (LC3-II) expression, and autophagosome formation. The levels of H/SD-induced apoptosis were increased by autophagy inhibitor 3-methyladenine (3-MA) while decreased by rapamycin, an autophagic inducer. ATV further enhanced the autophagic activity observed in MSCs exposed to H/SD. Treatment with 3-MA attenuated ATV-induced autophagy and abrogated the protective effects of ATV on MSC apoptosis, while rapamycin failed to cause additional effects on either autophagy or apoptosis compared with ATV alone. The phosphorylation of AMPK was upregulated whereas the phosphorylation of mTOR was downregulated in ATV-treated MSCs, which were both attenuated by AMPK inhibitor compound C. Further, treatment with compound C reduced the ATV-induced autophagy in MSCs under H/SD. These data suggest that autophagy plays a protective role in H/SD-induced apoptosis of MSCs, and ATV could effectively activate autophagy via AMPK/mTOR pathway to enhance MSC survival during H/SD.
Saturated fatty acids like palmitate contribute to muscle atrophy in a number of conditions (e.g., Type II diabetes) by altering insulin signaling. Akt is a key modulator of protein balance that inhibits the FoxO transcription factors (e.g., FoxO3) which selectively induce the expression of atrophy-inducing genes (atrogenes) in the ubiquitin-proteasome and autophagy-lysosome systems. Conversely, omega-3 polyunsaturated fatty acids have beneficial effects on insulin signaling and may preserve muscle mass. In an earlier report, the omega-3 fatty acid docosahexaenoic acid (DHA) protected myotubes from palmitate-induced atrophy; the mechanisms underlying the alterations in protein metabolism were not identified. This study investigated whether DHA prevents a palmitate-induced increase in proteolysis by restoring Akt/FoxO signaling. Palmitate increased the rate of protein degradation, while co-treatment with DHA prevented the response. Palmitate reduced the activation state of Akt and increased nuclear FoxO3 protein while decreasing its cytosolic level. Palmitate also increased the mRNAs of two FoxO3 atrogene targets, the E3 ubiquitin ligase atrogin-1/MAFbx and the autophagy mediator Bnip3. DHA attenuated the effects of palmitate on Akt activation, FoxO3 localization, and atrogene mRNAs. DHA, alone or in combination with palmitate, decreased the ratio of LC3B-II:LC3B-I protein as well as the rate of autophagosome formation, as indicated by reduced LC3B-II protein in the presence of 10 mmol/L methylamine, suggesting an independent effect of DHA on the macroautophagy pathway. These data indicate that palmitate induces myotube atrophy, at least in part, by activating multiple proteolytic systems and that DHA counters the catabolic effects of palmitate by restoring Akt/FoxO signaling.
palmitate; docosahexaenoic acid; muscle atrophy; proteolysis; macroautophagy; FoxO3
Vitamin E succinate (VES), a potential cancer therapeutic agent, potently induces apoptosis and inhibits the growth of various cancer cells. Autophagy has been supposed to promote cancer cell survival or trigger cell death, depending on particular cancer types and tumor microenvironments. The role of autophagy in the growth suppressive effect of VES on gastric cancer cell is basically unknown. We aimed to determine whether and how autophagy affected the VES-induced inhibition of SGC-7901 human gastric carcinoma cell growth. SGC-7901 cells were treated with VES or pre-treated with autophagy inhibitor, chloroquine (CQ) and 3-methyladenine (3-MA). Electron microscopy, fluorescence microscopy and Western blot were used to study whether VES induced autophagy reaction in SGC-7901 cells. Western blot evaluated the activities of the mammalian target of rapamycin (mTOR) axis. Then we used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry to detect the level of cell viability and apoptosis. Collectively, our data indeed strongly support our hypothesis that VES treatment produced cytological variations that depict autophagy, increased the amount of intracellular green fluorescent protein—microtubule associated protein 1 light chain 3 (GFP-LC3) punctate fluorescence and the number of autophagic vacuoles. It altered the expression of endogenous autophagy marker LC3. VES activated the suppression of mTOR through inhibiting upstream regulators p38 MAPK and Akt. mTOR suppression consequently inhibited the activation of mTOR downstream targets p70S6K and 4E-BP-1. The activation of the upstream mTOR inhibitor AMPK had been up-regulated by VES. The results showed that pre-treatment SGC-7901 with autophagy inhibitors before VES treatment could increase the capacity of VES to reduce cell viability and to provoke apoptosis. In conclusion, VES-induced autophagy participates in SGC-7901 cell protection by inhibiting mTOR axis phosphorylation. Our findings not only strengthen our understanding of the roles of autophagy in cancer biology, but may also be useful for developing new treatments for gastric cancer patients.
Anticancer properties and mechanisms of mimulone (MML), C-geranylflavonoid isolated from the Paulownia tomentosa fruits, were firstly elucidated in this study. MML prevented cell proliferation in a dose- and time-dependent way and triggered apoptosis through the extrinsic pathway in A549 human lung adenocarcinoma cells. Furthermore, MML-treated cells displayed autophagic features, such as the formation of autophagic vacuoles, a primary morphological feature of autophagy, and the accumulation of microtubule-associated protein 1 light chain 3 (LC3) puncta, another typical maker of autophagy, as determined by FITC-conjugated immunostaining and monodansylcadaverine (MDC) staining, respectively. The expression levels of LC3-I and LC3-II, specific markers of autophagy, were also augmented by MML treatment. Autophagy inhibition by 3-methyladenine (3-MA), pharmacological autophagy inhibitor, and shRNA knockdown of Beclin-1 reduced apoptotic cell death induced by MML. Autophagic flux was not significantly affected by MML treatment and lysosomal inhibitor, chloroquine (CQ) suppressed MML-induced autophagy and apoptosis. MML-induced autophagy was promoted by decreases in p53 and p-mTOR levels and increase of p-AMPK. Moreover, inhibition of p53 transactivation by pifithrin-α (PFT-α) and knockdown of p53 enhanced induction of autophagy and finally promoted apoptotic cell death. Overall, the results demonstrate that autophagy contributes to the cytotoxicity of MML in cancer cells harboring wild-type p53. This study strongly suggests that MML is a potential candidate for an anticancer agent targeting both autophagy and apoptotic cell death in human lung cancer. Moreover, co-treatment of MML and p53 inhibitor would be more effective in human lung cancer therapy.
Insulin receptor substrate (IRS)-1 is associated with tumorigenesis; its levels are elevated in several human cancers. IRS-1 protein binds to several oncogene proteins. Oxidative stress and reactive oxygen species (ROS) are involved in the initiation and progression of cancers. Cancer cells produce greater levels of ROS than normal cells do because of increased metabolic stresses. However, excessive production of ROS kills cancer cells. Autophagy usually serves as a survival mechanism in response to stress conditions, but excessive induction of autophagy results in cell death. In addition to inducing necrosis and apoptosis, ROS induces autophagic cell death. ROS inactivates IRS-1 mediated signaling and reduces intracellular IRS-1 concentrations. Thus, there is a complex relationship between IRS-1, ROS, autophagy, and cancer. It is not fully understood how cancer cells grow rapidly and survive in the presence of high ROS levels.
Methods and results
In this study, we established mouse NIH/3T3 cells that overexpressed IRS-1, so mimicking cancers with increased IRS-1 expression levels; we found that the IRS-1 overexpressing cells grow more rapidly than control cells do. Treatment of cells with glucose oxidase (GO) provided a continuous source of ROS; low dosages of GO promoted cell growth, while high doses induced cell death. Evidence for GO induced autophagy includes increased levels of isoform B-II microtubule-associated protein 1 light chain 3 (LC3), aggregation of green fluorescence protein-tagged LC3, and increased numbers of autophagic vacuoles in cells. Overexpression of IRS-1 resulted in inhibition of basal autophagy, and reduced oxidative stress-induced autophagy and cell death. ROS decreased the mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase signaling, while overexpression of IRS-1 attenuated this inhibition. Knockdown of autophagy-related gene 5 inhibited basal autophagy and diminished oxidative stress-induced autophagy and cell death.
Our results suggest that overexpression of IRS-1 promotes cells growth, inhibits basal autophagy, reduces oxidative stress-induced autophagy, and diminishes oxidative stress-mediated autophagy-dependent cell death. ROS-mediated autophagy may occur via inhibition of IRS-1/phosphatidylinositol 3-kinase/mTOR signaling. Our data afford a plausible explanation for IRS-1 involvement in tumor initiation and progression.
Insulin receptor substrate; Oxidative stress; Autophagy; Cell death; Cancer; Mammalian target of rapamycin; p70 ribosomal protein S6 kinase; Reactive oxygen species; Glucose oxidase
c-Jun NH2-terminal kinases (JNKs) are strongly activated by a stressful cellular environment, such as chemotherapy and oxidative stress. Autophagy is a protein-degradation system in which double-membrane vacuoles called autophagosomes are formed. The autophagy-related gene Beclin 1 plays a key role in this process. We previously found that autophagy was induced by dihydroartemisinin (DHA) in pancreatic cancer cells. However, little is known about the complex relationship between ROS, JNK activation, autophagy induction, and Beclin 1 expression.
Cell viability and CCK-8 assays were carried out to determine the cell proliferation; small interfering RNAs (siRNAs) were used to knockdown c-Jun NH2-terminal kinases (JNK1/2) genes; western blot was performed to detect the protein expression of LC3, JNK, Beclin 1, caspase 3 and β-actin; production of intracellular ROS was analyzed using FACS flow cytometry; autophagy induction was confirmed by electron microscopy.
In the present study, we explored the role of DHA and Beclin 1 expression in autophagy. DHA-treated cells showed autophagy characteristics, and DHA also activated the JNK pathway and up-regulated the expression of Beclin 1. Conversely, blocking JNK signaling inhibited Beclin 1 up-regulation. JNK activation was found to primarily depend on reactive oxygen species (ROS) resulting from the DHA treatment. Moreover, JNK pathway inhibition and Beclin 1 silencing prevented the induction of DHA-induced autophagy.
These results suggest that the induction of autophagy by DHA is required for JNK-mediated Beclin 1 expression.
c-Jun NH2-terminal kinase; Beclin 1; Apoptosis; LC3; Autophagy; Pancreatic cancer; Dihydroartemisinin
Autophagy is an indispensable lysosomal self-digestion process involved in the degradation of aggregated proteins and damaged organelles. Autophagy is associated with the several pathological processes, including cancer. Cancer stem cells (CSCs) play significant roles in cancer initiation, progression and drug resistance. Recent studies have demonstrated the antitumor activities of plant-derived chemopreventive agent rottlerin (Rott). However, the molecular mechanism by which Rott induces autophagy in breast CSCs has not been investigated.
The objectives of this study were to examine the molecular mechanism by which Rott induces autophagy which leads to apoptosis in breast CSCs. Treatment of breast CSCs with Rott for 24 h resulted in a concentration dependent induction of autophagy, followed by apoptosis as measured by flow cytometry. Electron microscopy confirmed the presence of autophagosomes in Rott treated breast CSCs. Western blot analysis showed that Rott treatment increased the expression of LC3, Beclin-1 and Atg12 that are accumulated during autophagy. Prolonged exposure of breast CSCs to Rott caused apoptosis which was associated with the suppression of phosphorylated Akt and mTOR, upregulation of phosphorylated AMPK, and downregulation of anti-apoptosis Bcl-2, Bcl-XL, XIAP and cIAP-1. Knock-down of Atg7 or Beclin-1 by shRNA inhibited Rott-induced autophagy at 24 h. Our study also demonstrates that pre-treatment of breast CSCs with autophagosome inhibitors 3-methyladenine and Bafilomycin, as well as protein synthesis inhibitor cycloheximide inhibited Rott-induced autophagy and apoptosis. Rott induces autophagy via extensive cytoplasmic vacuolization in breast CSCs. Molecular docking results between C2-domain of protein kinase C-delta and Rott indicated that both hydrogen bonding and hydrophobic interactions contributed significantly for ligand binding with minimum binding affinity of ≈ 7.5 Kcal/mol. Although, autophagy inhibitors suppress the formation of cytoplasmic vacuolization and autophagy in breast CSCs, the potency of Rott to induce autophagy and apoptosis might be based on its capability to activate several pathways such as AMPK and proteasome inhibition.
A better understanding of the relationship between autophagy and apoptosis would eventually allow us to discover novel drugs for the treatment of breast cancer by eliminating CSCs.
3-methyladenine (3-MA); Autophagy; Bafilomycin (Baf); Beclin-1; Cycloheximide (CHX); LC3; AMPK; Atg12
Proliferation of vascular smooth muscle cells is a characteristic of pathological vascular remodeling and represents a significant therapeutic challenge in several cardiovascular diseases. Docosahexaenoic acid (DHA), a member of the n-3 polyunsaturated fatty acids, was shown to inhibit proliferation of numerous cell types, implicating several different mechanisms. In this study we examined the molecular events underlying the inhibitory effects of DHA on proliferation of primary human smooth muscle cells isolated from small pulmonary artery (hPASMCs). DHA concentration-dependently inhibited hPASMC proliferation, induced G1 cell cycle arrest, and decreased cyclin D1 protein expression. DHA activated the unfolded protein response (UPR), evidenced by increased mRNA expression of HSPA5, increased phosphorylation of eukaryotic initiation factor 2α, and splicing of X-box binding protein 1. DHA altered cellular lipid composition and led to increased reactive oxygen species (ROS) production. DHA-induced ROS were dependent on both intracellular Ca2+ release and entry of extracellular Ca2+. Overall cellular ROS and mitochondrial ROS were decreased by RU360, a specific inhibitor of mitochondrial Ca2+ uptake. DHA-induced mitochondrial dysfunction was evidenced by decreased mitochondrial membrane potential and decreased cellular ATP content. DHA triggered apoptosis as found by increased numbers of cleaved caspase-3- and TUNEL-positive cells. The free radical scavenger Tempol counteracted DHA-induced ROS, cell cycle arrest, induction of UPR, and apoptosis. We conclude that Ca2+-dependent oxidative stress is the central and initial event responsible for induction of UPR, cell cycle arrest, and apoptosis in DHA-treated hPASMCs.
► DHA induces ROS production, cell cycle arrest, UPR and apoptosis in hPASMC. ► Ca2+ and mitochondria are required for DHA-mediated induction of ROS. ► DHA alters cellular lipid composition and decreases ΔΨm and cellular ATP content. ► Free radical scavenger Tempol counteracts DHA effects in hPASMC.
ATF6, activating transcription factor 6; DHA, docosahexaenoic acid; ΔΨm, mitochondrial membrane potential; eIF2α, eukaryotic initiation factor 2α; ER, endoplasmic reticulum; FCS, fetal calf serum; hPASMC, human pulmonary artery smooth muscle cell; HSPA5, heat shock 70-kDa protein 5; IRE1α, inositol-requiring enzyme 1α; n-3 PUFA, n-3 polyunsaturated fatty acid; PERK, protein kinase RNA-like endoplasmic reticulum kinase; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PTP, permeability transition pore; ROS, reactive oxygen species; TG, triglyceride; UPR, unfolded protein response; XBP-1, X-box binding protein 1; Oxidative stress; Unfolded protein response; n-3 polyunsaturated fatty acid; Apoptosis; Mitochondria; Cell cycle; Free radicals
It was previously reported that docosahexanoic acid (DHA) reduces TNF-α-induced necrosis in L929 cells. However, the mechanisms underlying this reduction have not been investigated. The present study was designed to investigate cellular and biochemical mechanisms underlying the attenuation of TNF-α-induced necroptosis by DHA in L929 cells.
L929 cells were pre-treated with DHA prior to exposure to TNF-α, zVAD, or Necrostatin-1 (Nec-1). Cell death and survival were assessed by MTT and caspase activity assays, and microscopic visualization. Reactive oxygen species (ROS) were measured by flow cytometry. C16- and C18-ceramide were measured by mass spectrometry. Lysosomal membrane permeabilization (LMP) was evaluated by fluorescence microscopy and flow cytometry using Acridine Orange. Cathepsin L activation was evaluated by immunoblotting and fluorescence microscopy. Autophagy was assessed by immunoblotting of LC3-II and Beclin.
Exposure of L929 cells to TNF-α alone for 24 h induced necroptosis, as evidenced by inhibition of cell death by Nec-1, absence of caspase-3 activity and lamin B cleavage, and morphological analysis. DHA attenuated multiple biochemical events associated with TNF-α-induced necroptosis, including ROS generation, ceramide production, lysosomal dysfunction, cathepsin L activation, and autophagic features. DHA also attenuated zVAD-induced necroptosis but did not attenuate the enhanced apoptosis and necrosis induced by combination of TNF-α with Actinomycin D or zVAD, respectively, suggesting that its protective effects might be limited by the strength of the cell death insult induced by TNF-α.
DHA effectively attenuates TNF-α-induced necroptosis and autophagy, most likely via its ability to inhibit TNF-α-induced sphingolipid metabolism and oxidative stress. These results highlight the role of this Omega-3 fatty acid in antagonizing inflammatory cell death.
DHA; L929 cells; lysosomes; necroptosis; oxidative stress; inflammation; TNF-α
The apoptotic effects of docosahexaenoic acid (DHA) and other ω-3 polyunsaturated fatty acids (PUFAs) have been documented in cell and animal studies. The molecular mechanism by which DHA induces apoptosis is unclear. Although there is no direct evidence, some studies have suggested that DNA damage generated through lipid peroxidation may be involved. Our previous studies showed that DHA, because it is high degree of unsaturation, can give rise to the acrolein-derived 1,N2-propanodeoxyguanosine (Acr-dG) as a major class of DNA adducts via lipid oxidation. As a first step to investigate the possible role of oxidative DNA damage in apoptosis induced by DHA, we examined the relationships between oxidative DNA damage and apoptosis caused by DHA in human colon cancer HT-29 cells. The apoptosis and oxidative DNA damage, including Acr-dG and 8-oxo-deoxyguanosine (8-oxo-dG) formation, in cells treated with DHA and ω-6 PUFAs, including arachidonic acid (AA) and linoleic acid (LA), were measured. DHA induced apoptosis in a dose- and time-dependent manner with a concentration range from 0 to 300 µM as indicated by increased caspase-3 activity and PARP cleavage. In contrast, AA and LA had little or no effect at these concentrations. The Acr-dG levels were increased in HT-29 cells treated with DHA at 240 and 300µM, and the increases were correlated with the induction of apoptosis at these concentrations, while no significant changes were observed for 8-oxo-dG. Because proteins may compete with DNA to react with Acr, we then examined the effects of BSA on the DHA induced apoptosis and oxidative DNA damage. The addition of BSA to HT-29 cell culture media significantly decreases Acr-dG levels with a concomitant decrease in the apoptosis induced by DHA. The reduced Acr-dG formation is attributed to the reaction of BSA with acrolein as indicated by increased levels of total protein carbonyls. Similar correlations between Acr-dG formation and apoptosis were observed in HT-29 cells directly incubated with 0 to 200µM of acrolein. Additionally, DHA treatment increased level of DNA strand breaks and caused cell cycle arrested at G1 phase. Taken together, these results demonstrate the parallel relationships between the Acr-dG level and apoptosis in HT-29 cells, suggesting that the formation of Acr-dG in cellular DNA may contribute to apoptosis induced by DHA.
polyunsaturated fatty acids; apoptosis; chemoprevention; colon cancer; docosahexaenoic acid (DHA); arachidonic acid (AA); linoleic (LA); acrolein; 4-hydroxy-2-nonenal; cyclic deoxyguanosine adducts; oxidative DNA damage; 32P-postlabeling
On the basis of our previous reports that cardioprotection induced by ischaemic preconditioning induces autophagy and that resveratrol, a polyphenolic antioxidant present in grapes and red wine induces preconditioning-like effects, we sought to determine if resveratrol could induce autophagy.
Methods and results
Resveratrol at lower doses (0.1 and 1 µM in H9c2 cardiac myoblast cells and 2.5 mg/kg/day in rats) induced cardiac autophagy shown by enhanced formation of autophagosomes and its component LC3-II after hypoxia–reoxygenation or ischaemia–reperfusion. The autophagy was attenuated with the higher dose of resveratrol. The induction of autophagy was correlated with enhanced cell survival and decreased apoptosis. Treatment with rapamycin (100 nM), a known inducer of autophagy, did not further increase autophagy compared with resveratrol alone. Autophagic inhibitors, wortmannin (2 µM) and 3-methyladenine (10 mM), significantly attenuated the resveratrol-induced autophagy and induced cell death. The activation of mammalian target of rapamycin (mTOR) was differentially regulated by low-dose resveratrol, i.e. the phosphorylation of mTOR at serine 2448 was inhibited, whereas the phosphorylation of mTOR at serine 2481 was increased, which was attenuated with a higher dose of resveratrol. Although resveratrol attenuated the activation of mTOR complex 1, low-dose resveratrol significantly induced the expression of Rictor, a component of mTOR complex 2, and activated its downstream survival kinase Akt (Ser 473). Resveratrol-induced Rictor was found to bind with mTOR. Furthermore, treatment with Rictor siRNA attenuated the resveratrol-induced autophagy.
Our results indicate that at lower dose, resveratrol-mediated cell survival is, in part, mediated through the induction of autophagy involving the mTOR-Rictor survival pathway.
Autophagy; Cell survival; Rictor; mTOR; Resveratrol; Cardioprotection
Benzyl isothiocyanate (BITC), a constituent of edible cruciferous vegetables, inhibits growth of breast cancer cells but the mechanisms underlying growth inhibitory effect of BITC are not fully understood. Here, we demonstrate that BITC treatment causes FoxO1-mediated autophagic death in cultured human breast cancer cells. The BITC-treated breast cancer cells (MDA-MB-231, MCF-7, MDA-MB-468, BT-474, and BRI-JM04) and MDA-MB-231 xenografts from BITC-treated mice exhibited several features characteristic of autophagy, including appearance of double-membrane vacuoles (transmission electron microscopy) and acidic vesicular organelles (acridine orange staining), cleavage of microtubule-associated protein 1 light chain 3 (LC3), and/or suppression of p62 (p62/SQSTM1 or sequestosome 1) expression. On the other hand, a normal human mammary epithelial cell line (MCF-10A) was resistant to BITC-induced autophagy. BITC-mediated inhibition of MDA-MB-231 and MCF-7 cell viability was partially but statistically significantly attenuated in the presence of autophagy inhibitors 3-methyl adenine and bafilomycin A1. Stable overexpression of Mn-superoxide dismutase, which was fully protective against apoptosis, conferred only partial protection against BITC-induced autophagy. BITC treatment decreased phosphorylation of mTOR and its downstream targets (P70s6k and 4E-BP1) in cultured MDA-MB-231 and MCF-7 cells and MDA-MB-231 xenografts, but activation of mTOR by transient overexpression of its positive regulator Rheb failed to confer protection against BITC-induced autophagy. Autophagy induction by BITC was associated with increased expression and acetylation of FoxO1. Furthermore, autophagy induction and cell growth inhibition resulting from BITC exposure were significantly attenuated by small interfering RNA knockdown of FoxO1. In conclusion, the present study provides novel insights into the molecular circuitry of BITC-induced cell death involving FoxO1-mediated autophagy.
Macro-autophagy is associated with drug resistance in various cancers and can function as an adaptive response to maintain cell survival under metabolic stresses, including androgen deprivation. Androgen deprivation or treatment with androgen receptor (AR) signaling inhibitor (ARSI), Enzalutamide (MDV-3100, ENZA) or bicalutamide induced autophagy in androgen-dependent and in castration-resistant CaP (castration-resistant prostate cancer (CRPC)) cell lines. The autophagic cascade triggered by AR blockage, correlated with the increased light chain 3-II/I ratio and ATG-5 expression. Autophagy was observed in a subpopulation of C4-2B cells that developed insensitivity to ENZA after sustained exposure in culture. Using flow cytometry and clonogenic assays, we showed that inhibiting autophagy with clomipramine (CMI), chloroquine or metformin increased apoptosis and significantly impaired cell viability. This autophagic process was mediated by AMP-dependent protein kinase (AMPK) activation and the suppression of mammalian target of rapamycin (mTOR) through Raptor phosphorylation (Serine 792). Furthermore, small interfering RNA targeting AMPK significantly inhibited autophagy and promoted cell death in CaP cells acutely or chronically exposed to ENZA or androgen deprivation, suggesting that autophagy is an important survival mechanism in CRPC. Lastly, in vivo studies with mice orthotopically implanted with ENZA-resistant cells demonstrated that the combination of ENZA and autophagy modulators, CMI or metformin significantly reduced tumor growth when compared with control groups (P<0.005). In conclusion, autophagy is as an important mechanism of resistance to ARSI in CRPC. Antiandrogen-induced autophagy is mediated through the activation of AMPK pathway and the suppression of mTOR pathway. Blocking autophagy pharmacologically or genetically significantly impairs prostate cancer cell survival in vitro and in vivo, implying the therapeutics potential of autophagy inhibitors in the antiandrogen-resistance setting.
Dietary intake of long-chain n-3 polyunsaturated fatty acids (n-3 PUFA) has been reported to decrease several markers of lymphocyte activation and modulate monocyte susceptibility to apoptosis. However most human studies examined the combined effect of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) using relatively high daily amounts of n-3 PUFA. The present study investigated the effects of increasing doses of DHA added to the regular diet of human healthy volunteers on lymphocyte response to tetradecanoylphorbol acetate (TPA) plus ionomycin activation, and on monocyte apoptosis induced by oxidized LDL (oxLDL). Eight subjects were supplemented with increasing daily doses of DHA (200, 400, 800 and 1600mg) in a triacylglycerol form containing DHA as the only PUFA, for two weeks each dose. DHA intake dose-dependently increased the proportion of DHA in mononuclear cell phospholipids, the augmentation being significant after 400mg DHA/day. The TPA plus ionomycin-stimulated IL-2 mRNA level started to increase after ingestion of 400mg DHA/day, with a maximum after 800mg intake, and was positively correlated (P<0.003) with DHA enrichment in cell phospholipids. The treatment of monocytes by oxLDL before DHA supplementation drastically reduced mitochondrial membrane potential as compared with native LDL treatment. OxLDL apoptotic effect was significantly attenuated after 400mg DHA/day and the protective effect was maintained throughout the experiment, although to a lesser extent at higher doses. The present results show that supplementation of the human diet with low DHA dosages improves lymphocyte activability. It also increases monocyte resistance to oxLDL-induced apoptosis, which may be beneficial in the prevention of atherosclerosis.
DHA enrichment; interleukin-2; mitochondrial membrane potential; oxidized LDL
Breast cancer is a collection of diseases in which molecular phenotypes can act as both indicators and mediators of therapeutic strategy. Therefore, candidate therapeutics must be assessed in the context of multiple cell lines with known molecular phenotypes. Docosahexaenoic acid (DHA) and curcumin (CCM) are dietary compounds known to antagonize breast cancer cell proliferation. We report that these compounds in combination exert a variable antiproliferative effect across multiple breast cell lines, which is synergistic in SK-BR-3 cells and triggers cell signaling events not predicted by the activity of either compound alone.
Dose response curves for CCM and DHA were generated for five breast cell lines. Effects of the DHA+ CCM combination on cell proliferation were evaluated using varying concentrations, at a fixed ratio, of CCM and DHA based on their individual ED50. Detection of synergy was performed using nonlinear regression of a sigmoid dose response model and Combination Index approaches. Cell molecular network responses were investigated through whole genome microarray analysis of transcript level changes. Gene expression results were validated by RT-PCR, and western blot analysis was performed for potential signaling mediators. Cellular curcumin uptake, with and without DHA, was analyzed via flow cytometry and HPLC.
CCM+DHA had an antiproliferative effect in SK-BR-3, MDA-MB-231, MDA-MB-361, MCF7 and MCF10AT cells. The effect was synergistic for SK-BR-3 (ER- PR- Her2+) relative to the two compounds individually. A whole genome microarray approach was used to investigate changes in gene expression for the synergistic effects of CCM+DHA in SK-BR-3 cells lines. CCM+DHA triggered transcript-level responses, in disease-relevant functional categories, that were largely non-overlapping with changes caused by CCM or DHA individually. Genes involved in cell cycle arrest, apoptosis, inhibition of metastasis, and cell adhesion were upregulated, whereas genes involved in cancer development and progression, metastasis, and cell cycle progression were downregulated. Cellular pools of PPARγ and phospho-p53 were increased by CCM+DHA relative to either compound alone. DHA enhanced cellular uptake of CCM in SK-BR-3 cells without significantly enhancing CCM uptake in other cell lines.
The combination of DHA and CCM is potentially a dietary supplemental treatment for some breast cancers, likely dependent upon molecular phenotype. DHA enhancement of cellular curcumin uptake is one potential mechanism for observed synergy in SK-BR-3 cells; however, transcriptomic data show that the antiproliferation synergy accompanies many signaling events unique to the combined presence of the two compounds.
To overcome drug resistance caused by apoptosis deficiency in patients with non-small cell lung carcinoma (NSCLC), there is a need to identify other means of triggering apoptosis-independent cancer cell death. We are the first to report that isogambogenic acid (iso-GNA) can induce apoptosis-independent autophagic cell death in human NSCLC cells. Several features of the iso-GNA-treated NSCLC cells indicated that iso-GNA induced autophagic cell death. First, there was no evidence of apoptosis or cleaved caspase 3 accumulation and activation. Second, iso-GNA treatment induced the formation of autophagic vacuoles, increased LC3 conversion, caused the appearance of autophagosomes and increased the expression of autophagy-related proteins. These findings provide evidence that iso-GNA induces autophagy in NSCLC cells. Third, iso-GNA-induced cell death was inhibited by autophagic inhibitors or by selective ablation of Atg7 and Beclin
1 genes. Furthermore, the mTOR inhibitor rapamycin increased iso-GNA-induced cell death by enhancing autophagy. Finally, a xenograft model provided additional evidence that iso-GNA exhibited anticancer effect through inducing autophagy-dependent cell death in NSCLC cells. Taken together, our results demonstrated that iso-GNA exhibited an anticancer effect by inducing autophagy-dependent cell death in NSCLC cells, which may be an effective chemotherapeutic agent that can be used against NSCLC in a clinical setting.
The role of autophagy in cisplatin anticancer action was investigated using human U251 glioma, rat C6 glioma and mouse L929 fibrosarcoma cell lines. A dose- and time-dependent induction of autophagy was observed in tumour cells following cisplatin treatment, as demonstrated by up-regulation of autophagy-inducing protein beclin-1 and subsequent appearance of acridine orange-stained acidic autophagic vesicles. The presence of autophagosomes in cisplatin-treated cells was also confirmed by electron microscopy. Inhibition of autophagy with lysosomal inhibitors bafilomycin A1 and chloroquine, or a PI3 kinase inhibitor wortmannin, markedly augmented cisplatin-triggered oxidative stress and caspase activation, leading to an increase in DNA fragmentation and apoptotic cell death. The mechanisms underlying the protective effect of autophagy apparently involved the interference with cisplatin-induced modulation of Bcl-2 family proteins, as inhibition of autophagy potentiated cisplatin-mediated up-regulation of proapoptotic Bax and down-regulation of anti-apoptotic Bcl-2. Autophagy induction in cisplatin-treated cells was preceded by activation of adenosine monophosphate-activated protein kinase (AMPK) and concomitant down-regulation of mammalian target of rapamycin (mTOR)-mediated phosphorylation of p70S6 kinase. The ability of cisplatin to trigger autophagy was reduced by small interfering RNA (siRNA)-mediated AMPK silencing, while transfection with mTOR siRNA was sufficient to trigger autophagy in tumour cells. Finally, siRNA-mediated AMPK down-regulation and AMPK inhibitor compound C increased cisplatin-induced tumour cell death, while mTOR siRNA and AMPK activator metformin protected tumour cells from cisplatin. Taken together, these data suggest that cisplatin-triggered activation of AMPK and subsequent suppression of mTOR activity can induce an autophagic response that protects tumour cells from cisplatin-mediated apoptotic death.
cisplatin; cancer; autophagy; apoptosis; AMPK; mTOR
Plumbagin (PLB) has been shown to have anticancer activities in animal models, but the role of PLB in prostate cancer treatment is unclear. This study aimed to investigate the effects of PLB on apoptosis and autophagy and the underlying mechanisms in human prostate cancer cell lines PC-3 and DU145. Our study has shown that PLB had potent pro-apoptotic and pro-autophagic effects on PC-3 and DU145 cells. PLB induced mitochondria-mediated apoptosis and autophagy in concentration- and time-dependent manners in both PC-3 and DU145 cells. PLB induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) pathways and activation of 5′-AMP-dependent kinase (AMPK) as indicated by their altered phosphorylation, contributing to the pro-autophagic activity of PLB. Modulation of autophagy altered basal and PLB-induced apoptosis in both cell lines. Furthermore, PLB downregulated sirtuin 1 (Sirt1), and inhibition of Sirt1 enhanced autophagy, whereas the induction of Sirt1 abolished PLB-induced autophagy in PC-3 and DU145 cells. In addition, PLB downregulated pre-B cell colony-enhancing factor/visfatin, and the inhibition of pre-B cell colony-enhancing factor/visfatin significantly enhanced basal and PLB-induced apoptosis and autophagy in both cell lines. Moreover, reduction of intracellular reactive oxygen species (ROS) level attenuated the apoptosis- and autophagy-inducing effects of PLB on both PC-3 and DU145 cells. These findings indicate that PLB promotes apoptosis and autophagy in prostate cancer cells via Sirt1- and PI3K/Akt/mTOR-mediated pathways with contribution from AMPK-, p38 MAPK-, visfatin-, and ROS-associated pathways.
AMPK; visfatin; PC-3; DU145; ROS
Our previous study has shown that ampelopsin (AMP), a flavonol mainly found in Ampelopsis grossedentata, could induce cell death in human breast cancer cells via reactive oxygen species generation and endoplasmic reticulum (ER) stress pathway. Here, we examined whether autophagy is activated in AMP-treated breast cancer cells and, if so, sought to find the exact role and underlying molecular profile of autophagy in AMP-induced cell death. Our results showed that AMP treatment activated autophagy in MDA-MB-231 and MCF-7 breast cancer cells, as evidenced by the accumulation of autophagosomes, an increase of microtubule-associated protein 1 light chain 3 beta-2 (LC3B-II) and the conversion of LC3B-I to LC3B-II, the degradation of the selective autophagic target p62/SQSTM1, and the formation of green fluorescent protein (GFP)-LC3 puncta. Blockage of autophagy augmented AMP-induced cell death, suggesting that autophagy has cytoprotective effects. Meanwhile, AMP treatment suppressed Akt-mammalian target of rapamycin (mTOR) pathway as evidenced by dose- and time-dependent decrease of the phosphorylation of Akt, mTOR and ribosomal protein S6 kinase (p70S6K), whereas Akt activator insulin-like growth factor-1 (IGF-1) pretreatment partially restored Akt-mTOR pathway inhibited by AMP and decreased AMP-inuduced autophagy, signifying that AMP activated autophagy via inhibition of the Akt-mTOR pathway. Additionally, blocking ER stress not only reduced autophagy induction, but also alleviated inhibition of the Akt-mTOR pathway induced by AMP, suggesting that activation of ER stress was involved in induction of autophagy and inhibition of the Akt-mTOR pathway. Taken together, these findings indicate that AMP induces protective autophagy in human breast cancer cells through Akt-mTOR pathway via ER stress.
Ampelopsin; autophagy; breast cancer; endoplasmic reticulum stress; mammalian target of rapamycin
Background. Accumulation of free fatty acids leads to lipid-toxicity-associated skeletal muscle atrophy. Palmitate treatment reduces myoblast and myotube growth and causes apoptosis in vitro. It is not known if omega-3 fatty acids will protect muscle cells against palmitate toxicity. Therefore, we examined the effects of docosahexaenoic acid (DHA) on skeletal muscle growth. Methods. Mouse myoblasts (C2C12) were differentiated to myotubes, and then treated with 0 or 0.5 mM palmitic acid or 0 or 0.1 mM DHA. Results. Intramyocellular lipid was increased in palmitate-treated cells but was prevented by DHA-palmitate cotreatment. Total AMPK increased in DHA+ palmitate-treated compared to palmitate only cells. RpS6 phosphorylation decreased after palmitate (−55%) and this was blunted by DHA+ palmitate (−35%) treatment. Palmitate treatment decreased PGC1α protein expression by 69%, but was increased 165% with DHA+ palmitate (P = 0.017) versus palmitate alone. While palmitate induced 25% and 90% atrophy in myotubes (after 48 hours and 96 hours, resp.), DHA+ palmitate treatment caused myotube hypertrophy of ~50% and 100% after 48 and 96 hours, respectively. Conclusion. These data show that DHA is protective against palmitate-induced atrophy. Although DHA did not activate the AMPK pathway, DHA treatment restored growth-signaling (i.e., rpS6) and rescued palmitate-induced muscle atrophy. |
52 Super Series in 2014
In just six weeks the US 52 Super Series first regatta sets sail over 20-24 January at Quantum Key West, an early season springboard for a season, that will see the fleet move on to Miami, followed by European events in Capri, for the first time ever, Porto Cervo, Sardinia, Palma Mallorca and Ibiza.
Building on the success of last year’s initiative to take the 52 Super Series to America for the first time, seven 52s will be competing at Quantum Key West, including the 2013 world champions, Niklas Zennström’s Rán Racing and 2013 Key West winners Azzurra.
Of the five US-flagged boats which are expected to compete, three crews will be new to 52 Super Series - Anema & Core (ex-Platoon 2006), Hooligan (ex-2x Med Cup winning ETNZ) – which has just been bought by US owner Gunther Buerman from a very successful period in Australia, and Sled (ex Rio/Synergy), owned by Takashi Okura.
When the US 52 Super Series then moves on to Miami on 5-9 March at least one more American crew will join for the 52 East Coast Championship. Vesper, owned by Jim Swartz, raced there in 2013 with the owner steering and Gavin Brady as tactician. They will be back, reported to be with a new ultra high modulus carbon Hall Spars rig and carbon rigging, so should be quicker than ever. Enquiries from other active owners seeking competitive boats to charter or buy give solid hope that one additional 52 materialises here.
Rob Weiland, TP52 Class Manager commented: “We are really pleased with the increased interest to own and race 52s in the USA and feel like it will be a solid foundation for the 2014 season to build from. This will be the season in which we start the final transition to 2015 which we already know looks very exciting.
“The US 52 Super Series really opens the door to 52 Super Series racing for all. It shows a wide variety of TP52 optimisations, now possible under the Wild Card Invitation scheme to encourage older TP52s to 'speed up' to the performance level of the most recent boats. In the Med a similar trend is visible with boats like Aquila, B2, Paprec and Provezza getting extra pace from upgrades in draft, composite rigging and sail area variations.”
It will be the first time ever that the TP52s, as a class, visit the beautiful surroundings of the Italian island of Capri when the 52 Super Series is hosted over 20-24 May by Rolex Capri Sailing Week and the International Maxi Organization. The 52s will share the event with the Maxi fleet although their schedule is different, the Maxis opening with a 48 hours offshore race. But Thursday’s coastal race will see both fleets race together.
“Capri is possibly going to be a light winds venue, something like 80% of the time less than 10 knots at this time of year, but there is also the chance of getting much more, so it will be a very good challenge for the fleet,” Weiland suggests.
Capri will be the first regatta of the season that the 52s will race in the 2014 ‘transition’ form, that is with longer bowsprits and 10sqm more spinnaker area which should make the boats appreciably quicker downwind, as a precursor to the advent of the 2015 TP52 Rule when all boats will be 200kg lighter and will have composite rigging and the mainsail area will get a few metres larger.
Capri will also be the first 52 Super Series event for the first boat to be built to the 2015 rule, the Botin Partners designed, King Marine built Phoenix for Brazilian owner Eduardo de Souza Ramos. Phoenix is scheduled to race first at Palma Vela.
Weiland anticipates one more new build 2015 rule 52 to be launched and raced later this summer.
A further five teams have already pledged to build new for 2015.
The ciricuit then moves on to the Yacht Club Costa Smeralda, Porto Cervo for the second regatta of four in Europe. Held over 10-14 June, this will also be the 2014 TP52 World Championship, before heading once again to the ever popular week long Copa del Rey in Palma over 4-9 August, Mallorca, which traditionally attracts the biggest 52 fleet of the season in Europe.
And after a very successful first visit to Ibiza in 2013, the final event of the 52 Super Series, will be hosted by MarinaIbiza over 17-21 September.
The format for the 2014 season is the same as 2013. The 52 Super Series comprises four events in Europe, aggregating all scores with no discards. The US 52 Super Series takes total scores over Key West and Miami. And there is, once again, an aggregate series for US and European regattas which is awarded the 52 Super Series Atlantic Cup.
Weiland continues: “Where other traditional development grand prix classes, like the Volvo Race have by necessity chosen to go one-design, the TP52 Class is still solidly behind the fun and energy that developing race boats and their equipment gives its owner and crew. Personally I find it a sad thing is that the demise of traditional development classes reduces the number of people that now get the chance to learn and understand about what makes a boat tick.
“We are confident that as the TP52 boats are now are one of the few options left which are a full scale test of design and construction of boats, sails and equipment in high level real time competition, we will continue to see the ongoing growth of the TP52."
Agustin Zulueta, CEO of the 52 Super Series, concludes: “We begin 2014 with high expectations . The 52 Super Series is more consolidated than ever before. It is the perfect pure performance arena for talented owner drivers and skilled amateur crews to mix with the best professionals.
“In 2013 year we had an average fleet of eight boats. In this coming year we expect the average to go up. Our choice of reliable and beautiful venues produces an incredible sailing platform, making our circuit not only attractive to European owners but also to others further from further afield, like Mr Souza Ramos coming from Brazil, attracted by our competition.
"The venues for 2014 are spectacular with good winds predicted and fun sites. We are working hard to come up with an equally impressive schedule for 2015 based on a mix of new and trusted venues.
“ Many cities and their marinas are already bidding to host 52 Super Series regattas in 2015. In the coming months the owners will be asked for their input to help us choose the 2015 venues from a pre-selection that meets our high location and sailing condition standards to ensure maximum support from competitors and sponsors. We have a big project ahead.” |
With his new quintet recording, Time Lines, the innovative and acclaimed pianist/composer Andrew Hill begins his third tenure with Blue Note Records. In addition to his regular working ensemble of tenor saxophonist/clarinetist Greg Tardy, bassist John Hebert and drummer Eric McPherson, Time Lines reunites Hill with trumpeter Charles Tolliver who twice recorded with him in the 1960s, during his initial stay with Blue Note. Hill refers to Time Lines as his "coming full circle," and just as his music contains layer upon layer, that statement rings true in a number of ways.
Signed by Blue Note’s legendary founder and producer Alfred Lion—who called him "my last great protégé"—Blue Note issued numerous groundbreaking and highly influential albums by Hill between 1963 and 1970. Featuring many of the most provocative, adventurous and important musicians of that incredibly fertile period—including Eric Dolphy, Sam Rivers, Joe Henderson, Bobby Hutcherson, Booker Ervin, Freddie Hubbard, Woody Shaw, Lee Morgan, John Gilmore, Richard Davis and many others—classic sessions such as Black Fire, Judgment!, Point of Departure, Smokestack, Andrew!!!, Grass Roots, Lift Every Voice and Dance With Death earned Hill a well deserved reputation as a brilliant composer, pianist and bandleader, and one of the most compelling and original figures to emerge during that era.
"I was nourished and supported creatively and economically by Alfred Lion," Hill says. "I left ‘home’ to enter the world after his retirement." Hill returned "home" for a brief stay in 1989 after current Blue Note President Bruce Lundvall and producer Michael Cuscuna had revived the dormant label. He recorded two albums, Eternal Spirit and But Not Farewell, both of which featured Greg Osby, introducing the alto saxophonist to the label for which he continues to record.
Hill refers to Time Lines as his "coming full circle,"The turn of the century saw Hill return to the spotlight with two acclaimed recordings for Palmetto, as well as a "new" Blue Note recording, Passing Ships, after Cuscuna discovered the original tapes of a lost 1969 nonet session in the vaults. (The New York Times quipped "The best jazz album of 2003 was recorded in 1969.") But Hill is officially back "home" again with Time Lines, marking Part 1 of the full circle.
Part 2 is the reconnection with Charles Tolliver. When Cuscuna (producer of the Time Lines sessions) issued a 3-disc set of Hill’s previously unreleased Blue Note sessions on his Mosaic Select label, listening to a session that included the trumpeter prompted the pianist to contact his old cohort. (Tolliver was also featured on Dance With Death) "Charles is primarily a straight-ahead player, but he’s very creative and spontaneous. I wanted to see if the blend would still work." Hill invited him to join the quartet for a gig at New York’s Birdland club as the group was preparing for the new recording. "It reminded me of some of my older groups, where the audience would become heavily involved in the music. The response at Birdland was just like that." Hill re-conceived Time Lines for a quintet and Tolliver has joined the ensemble for the group’s upcoming dates.
"At first I’d conceived Time Lines as a retrospective in a sense. But I couldn’t do that. Instead elements of all of the different genres I’ve embraced came out in this music. It encapsulates lyricism and adventurous evolution in a cohesive way."
So another circle closed as Hill re-connected to the source of those rich exploratory years during his first Blue Note period, and the palpably exciting sense of mutual adventure and discovery that would occur between the musicians and the audience. "If musicians are just trying to be different, but don’t have a synergy with the audience, they have nothing," Hill states, making a testament to the essence of evolution and innovation that have always been at the core of the jazz legacy; and offering a convincing argument against those who claim that artists who push the boundaries play for themselves and not the audience.
Another element of the full circle is found in the two versions of "Malachi," the composition that opens and closes the album. It’s a dedication to the great late bassist Malachi Favors Maghostut, who co-founded and performed with the legendary Art Ensemble of Chicago. Malachi was one of Hill’s earliest collaborators, playing with him in their hometown Chicago between 1957 and 1959. "It was actually written before Malachi passed," Hill says, "but in the evolution of playing it with the group, it became an appropriate dedication." The quintet version that opens the album is beautifully wrought, with percussively delicate piano, fluid and mournful clarinet, and mellow bending trumpet. The closing version is solo piano—resonant, deeply moving and eloquent.
Hill re-connected to the source of those rich exploratory years during his first Blue Note period. That same type of creativity and evolutionary development is also evident on another pair of tracks that feature two versions of the same composition. Ry Round 1 is a jagged composition in 4/4 time, built on a spare, almost ominous bass ostinato, featuring a percussive chordal piano solo, stinging trumpet and fluid bass clarinet soaring over the dark liquid mist of the rhythm section. Ry Round 2 was recorded one week later, evoking a totally different mood—playful, more deeply grooved and with a jaunty bounce throughout, alternating 5/4 and 4/4 time. This offers a totally different landscape for the soloists, changing not only the aural textures, but the stories they tell. The two versions provide a vividly powerful expression of the spirit of continuous evolution that is the hallmark of the truly visionary artist. Same musicians, same album, plus one week of time passage equal an entirely new creation.
The remaining four pieces display Hill’s full palette of colors and textures. An unusual time signature, in 11/8, gives the title tune its unique flavor. Interweaving and rhythmically varied tenor and trumpet lines, sometimes elongated, sometimes staccato, interface with each other and the piano over a fractured bass ostinato. "Smooth is a rondo, with piano, trumpet and piano repeating and expanding upon the melody," Hill explains. Hill describes the atmospheric, richly-hued ballad Whitsuntide as named for "an old slave expression dating back to the 18th century; a tradition brought from the Caribbean as a celebration around Christmas. It inspired the famous poem Night Before Christmas." For Emilio was commissioned by Chamber Music America as part of its Doris Duke Foundation Initiative. It’s another dedication to an artist who has passed on, Emilio Cruz. "Emilio was a great painter and a Renaissance man. I had many good moments talking with him and was inspired by his work."
"These magic moments, when the rhythms and harmonies extend themselves and jell together and the people become another instrument. These are things that are priceless and can’t be learned; they can only be felt."This brings us to another part of the full circle, as all of Hill’s creative efforts are being forged under the specter of his battle with cancer.
"I found out that I had cancer in July 2004, which was the end of my world as I knew it. It wasn’t a bad world for I had plotted my return and had upward mobility. I recorded Dusk, a CD that brought me numerous awards and allowed me to perform on the concert stage for packed audiences. So the answer to ‘what does your re-signing with Blue Note for the third time mean is,’ even though I am living with a terminal illness I am able to look forward to my work and the future with enthusiasm."
Rather than using his illness as a stimulus to tell new stories and deliver his message while he still has the opportunity, Hill prefers to use it as a positive influence to add a new perspective to his overall vision, and hoping that his efforts "will overlap to inspire younger musicians" all of whom must ultimately face their own mortality. He has already blessed us with a glorious personal legacy of darkly luminescent beauty and powerfully compelling artistry. Like Hill, we should all look forward to his and our future, and appreciate the gifts he has given us and will continue to offer as the most precious and profoundly valuable contributions that they are, beginning with this extraordinary new album.
Courtesy of Blue Note.com
Bestselling Titles by Andrew Hill |
Tops on the list of items impacting today’s router bits is the substrates to be machined. No longer are woodworking operations cutting strictly solid wood or wood-based panels, and changes in tool composition and geometry are reflecting this.
“The variety of materials machined by our customers has grown significantly over the last few years. Not only do we see changes in the substrates or core materials but also in the variety of laminates and surface treatments themselves,” said John Michel, director of Sales and Technical Services at Leuco Tool Corp. “Some materials are more abrasive, some more brittle, and some are very challenging to machine acceptably. Today’s tooling manufacturers must address the variety of these materials while at the same time not requiring customers to have a special tool for each material type.”
Ron Migedt, CEO of Riverside Tool Corp. commented on the “continual addition of low emission adhesives and other fillers into the material” along with new materials being used by wood products manufacturers. “Both of these material developments are demanding more advanced tooling in order to produce the product with acceptable quality.”
He adds, “Now more than ever we are designing tools with the entire product in mind. We work with customers to find out the machine, material, and all factors involved with producing the product. We have advanced our tool designs by innovating with new geometry, such as shear, to achieve the cut quality and chip evacuation needed to meet the customer’s expectations. We have also advanced universal tool technologies, such as multi-profile insert tools, to help customers meet the demands of quick-delivery and small batch sizes.”
Bob Barone, sales manager at Benz Inc., agreed. “I think the ever-widening arena of ‘Engineered Materials’ is the driving force behind new tool design. More and more materials are crossing over between industries today. Classic woodworking shops are now processing plastics and composites as a result of changing architectural specifications. The dust generated by these materials must be removed from the shop atmosphere in accordance with the regulating agencies. Typical dust hoods on machinery do a fine job for wood particulates, however with engineered materials we are constantly pressured to design tool holders and aggregates that aid in expelling the dust precisely at the source.”
Frank Horvath, marketing manager at FS Tool Corp., also commented on the demand for improved dust extraction on the cutting tools, particularly within the CNC routing cells. “We are responding by investing heavily in the research and development of new technologies.”
Along with FS Tool, a number of companies, including Royce//Ayr and Leitz, also offer dust extraction systems that move dust and chips away from the cutting tool, thereby reducing heat and “secondary collision damage to the tool.” ”Several tool manufacturers have recognized the benefits associated with improved dust extraction and collection, such as reduced heat build-up, reduced tool damage, and reduced machine downtime due to tool changes and machine clean-up,” said Mark Alster, regional manager at Leitz Tooling Systems LP.
Along with dust extraction, the newer substrates also are impacting the actual material composition of the tool itself.
“The biggest change I see is the hardness of the carbide. We are continually working with the carbide companies to improve on and develop harder and more-wear resistant grades of carbide,” said Chuck Hicks, president of Southeast Tool. “But, this has its challenges, with the harder carbide means the customers are going to have to stay on top of feeds and speeds and change those collets regularly. The higher grades of carbide are so hard it’s extremely fragile and breaks very easily so machine maintenance is a must.”
“Tool life and cut quality are sometimes affected negatively when switching to a new material,” said Mike Serwa, vice president at Vortex Tool Co. Inc. “Oftentimes our customers are forced to switch materials either because of cost savings or because of supply issues.”
He added, “Even though the materials look the same they will oftentimes react differently when being machined.” A site visit can also determine if there is another cause for the problem.
Scott Feimster, vice president Sales & Marketing at LMT Onsrud, added, “We analyze the material, identify its challenges and develop a solution with a combination of [tool] substrate, cutting geometry, coatings and cutting technique.”
He continued, “The foundation of tool engineering is understanding the cutting challenges to define the best substrate. Today’s advanced coatings offer heat resistance and protect the cutting edge of the tool to maximize the return of your highly engineered cutting tool.”
Not only is this relevant to woodworking, but other industries as well, said Marc Wijtenburg, T-Tool USA owner. “We have seen an increased demand for tooling used in the aerospace industry with the main focus on nonferrous materials. Several U.S.-based OEM machine builders whose core business segment is primarily woodworking and plastics have ventured into this market segment.”
Karin Deutschler, president of GUHDO USA, added. “Tooling manufacturers have to look at all aspects that affect the performance of a cutting tool. There is a synergy between cutting tool, collet, tool holder, chip evacuation, spindle speed (and accuracy), feed rate and, of course, the material being machined, and all this must be considered when finding solutions.
“New tool geometries, dust removal attachments, hydro, heat-shrink, or even improving the quality of standard tool holders all play a role in the elimination of unnecessary tolerances at the cutting edge, which, not only provides a cleaner surface finish, but equally important, will reduce overall tooling cost. Many folks shy away from upgrading their cutting tools because of initial expense without giving a second thought to the cost savings they will experience over the life of the cutting tool,” she added.
Maximizing Tools with Holders
In today’s competitive marketplace, tool manufacturers are often tasked with increasing the machine performance. Choosing the correct tool holder for the job is integral to achieving this.
“The most advanced cutting tool in the world in a worn and inaccurate tool holder just became the most advanced, worn and inaccurate tool available. Maximizing the accuracy and rigidity of your tool presentation will result in higher productivity, longer tool life and better quality cuts. If you purchased a three flute tool………you want all three flutes providing a finish cut and all three doing an equal share of the work,” Feimster said.
Serwa agreed. “Tool holding and clamping is an extremely important factor in achieving optimal machining results and is often overlooked as a source of increasing machine performance.”
Options are available that can significantly increase clamping force over standard systems and improve production, “By increasing the clamping force and accuracy of the holding system, users will see less tool vibration, which results in the ability to increase feed rates, extend tool life and extend spindle life,” Serwa added.
Wijtenburg also noted that “Spindle suppliers are now offering more HSK-63A taper tooling to the OEM machine builders giving the end user more tooling options,” whether machining wood, metal or other materials.
Tool balance and concentricity are critical to achieve quality products noted a number of manufacturers, including Hicks, Michel and Migedt.
“You have to run balanced tools,” Migedt said simply. “We are seeing an increased need for highly accurate tool-holding technologies that can provide the support that next generation tools demand; for example an extreme-shear tool will require the best tool-holding to reach its potential. There have been innovations in user-friendly tool-holders with high-clamping pressure that have enabled customers to easily achieve the tool-holding needs that today’s tools are requiring.”
Horvath agreed. “The synergy between the cutting action produced by the tooling and the machine has become a much greater focal point in the last two to three years,” he said.
“This is terrific as the quality of tool holding has a direct correlation to surface finish, accuracy, tool life and changeover downtime that will provide cost savings but also and more importantly improved product quality. Balancing requirements, specifically the target of G2.5 at 18-24,000 RPM has become more frequently demanded by machine manufactures and end users alike. This, in conjunction with improved tool holding, is providing dramatic improvements to production and enables our customers to be even more competitive,” Horvath added.
Barone also noted increased requests for “very dedicated CNC aggregate tool holders designed specifically for a single task. This typically is to eliminate an operation off-line from the CNC machine.”
Alster added, “Tool holders provide the critical link between the machine spindle and the cutting tool. Minimizing tool deflection and maximizing tool concentricity divides the workload evenly across all cutting knives, thereby optimizing cut quality and machine throughput by a factor of at least 30%. Tool rigidity and concentricity also improves tool life by a factor of at least 30%.” He continued, “Heat shrink systems can be integrated alongside existing chuck systems, so primary routing activity can be optimized while maintaining flexibility for more obscure applications.”
The use of clamping systems, such as heat shrink, mechanical shrink and hydraulic, was also addressed by many, with Michel stressing their use for high volume tool applications.
Deutschler added, “Heat-shrink or power shrink tool holders are my preferred tool holder option for insert tooling. The tool body will never need to be removed from the holder as the cutting inserts are simply replaced when dull, and therefore, no accessories are needed. The tool is delivered already mounted and balanced on the holder.” For those using standard tool holders, she recommended that the collet be replaced every 500 machine hours.
“Manufacturing the tool correct from the beginning is a must,” added Hicks. “Then we must have the operators keep up the maintenance on the machine.”
“If there ever was a time to say ‘You get what you pay for, this is it,” added Barone. “To my customers I say; ‘Buy good machinery, learn how to use it and all of the features you paid for and most of all, partner with a good tooling supplier.’ One that will work with you to find the best tooling product for your application.” |
Now that we all agree that the consumerization of IT is a reality, the next thing to do is implement a BYOD program. With so many so called solutions available few can offer a complete end-to-end BYOD solution that Citrix can.
One of the key components of this solution is Citrix CloudGateway which can securely deploy and manage all your mobile, web, SaaS and Windows applications and desktops (XenDesktop/XenApp) along with follow-me data (ShareFile) from one simple to use, self-service app store.
What is CloudGateway?
CloudGateway is comprised of the follow components:
Citrix Receiver which can be installed on any device only need a user’s enterprise email address to automatically provision a user for internal and remote access using a auto-discovery service called Account Services. This service eliminates the need for users or IT to download files and manually import them into Receiver.
NetScaler Access Gateway which provides secure remote access from outside the corporate network while maintaining the highest level of protection over sensitive corporate data.
StoreFront (the next-generation version of Web Interface) which provides a set of service interfaces for use by Receiver that enable access to AppController and XenDesktop/XenApp.
AppController which manages and enables access to an organization’s mobile, web and SaaS apps and ShareFile data resources.
ShareFile which enables users to securely store, sync and share data, both within and outside the organization.
To learn more about CloudGateway at Synergy Barcelona be sure to check out the following sessions to learn how to securely deliver enterprise mobility for your BYOD program…enabling the workplace of the future – today.
- SYN207 – Mobilise all your enterprise apps for the cloud
- SYN201 – Making the case for enterprise mobility management
- SYN202 – Architecting your mobile enterprise
- SYN204 – CloudGateway delivers essentials of enterprise mobility management
- SYN203 – Deep dive on CloudGateway
- SYN205 – What’s next for CloudGateway
- SYN612D – Enhancing enterprise mobility with CloudGateway Enterprise
Be sure to stop by the BYOD Showcase to learn how to take advantage of CloudGateway and other Citrix BYOD technologies plus enter for a chance to win one of the latest and coolest mobile devices.
In addition, on Wednesday, 17 October between 4:00 p.m. – 5:00 p.m. “Meet the Expert” Scott Schwarzoff, VP of Product Marketing, as he talks about CloudGateway and Best practices for successful BYOD
Follow me on Twitter Follow @ChrisLCampbell
For the latest Citrix and industry related news regarding Mobility and BYOD, follow us at: |
I will start by stating that I believe e-textbooks are a great opportunity to improve the quality of education. But the players have to start thinking outside the box and stop resisting the new concept. E-textbooks should be a wake-up call to professors and students, publishers, authors and content providers.
I have been championing ebooks and ebook authors for a while how and listening to the educational community’s reasons for not adopting the new technology. Oh I know about the current pilot programs and the studies being conducted. Some schools are even being forced into using them because of their cost savings but the quality of education must be the key here.
I decided to take a look into the resistance to change from a different point of view. Instead of looking at the faults of e-readers and e-textbooks, let’s take a look at what’s wrong with current textbooks and how e-textbooks solve the problems.
Because of the many levels of education, I will focus on higher education for this discussion. Most college students have access to personal computers and to the Internet. By using e-textbooks in combination with e-readers or tablets, PC’s and software, they should be able to get the most ‘bang for their buck’.
Traditional Textbook Shortcomings
What are the shortcomings of traditional textbooks? We can start with the standard issues.
1. Textbooks are expensive.
2. Their useful life is short. They seem to change every year or so.
3. They are heavy. If I have to carry multiple books to class, I have a problem.
4. And of course, there is the bookstore experience. Oh I love those long lines and the beat up used textbooks.
But some way we manage to get by these problems because that is the way we have always done it.
E-textbooks: They cost less. Weight is not a problem. You can have lots of ebooks at our fingertips. They are portable. I can carry them anywhere. On my PC, I can even view multiple ebooks at the same time, each in a different window. Tablets are even adding this feature.
I have the convenience of on-line delivery anywhere and anytime I want to order and they will never be out of stock. Unlike traditional textbooks, ebooks are easy for publishers to update. They can adjust and grow with the changing environment and conditions.
Traditional Textbook Studying Process
1. I hand write in the margin of my books.
2. I highlight passages that I feel are important.
3. I have posits tabbed at the top of some of the pages just to help find something important later.
4. I carry a small dictionary with me and a large notebook to try to keep up.
5. I have manual references to Internet links throughout my textbooks. Hopefully when I key them into my PC the links are still valid.
If I don’t do these things to my textbook, sometimes I have a problem finding information.
I guess I am the typical student. I know this destroys the textbook but I am the one that needs to do this, so that it is easy for me to review come test or report time. I will deal with what I have done to the textbook when I try to resell it at the end of the semester.
E-textbooks: They are a live, digital media. I can key in class notes on my device or with public notes I can key in notes on my PC and view them on my device. I can highlight text and later I can remove the highlights. Using my PC, I can copy and paste information to a Word document and not have to re-key it into my computer.
I can tag or bookmark passages. On some devices I can even color the tags. I can easily search my e-textbook to find information. I have a dictionary and encyclopedia at my fingertips. If they can’t solve the problem, I can go on-line and use a search engine.
On my PC, I can interact with my e-textbook and a host of tools like databases, spreadsheets and a word processor with spellcheck.
But the resistance abounds. We have the standard arguments.
1. E-textbooks are hard to read.
2. There are no page numbers or the numbers don’t match the paper textbook. (This has been resolved my Amazon.)
3. Ereader keyboards are too small.
4. Students will not be paying attention to the lecture.
5. Traditional textbooks have a look and feel that ereaders don’t possess.
I even see a history professor blogging that they have always done it that way so why change. E-textbooks will interrupt the flow of his teaching in the classroom. E-textbooks have no place in the History department. You know “If it is not broke, don’t fix it”.
If I was going to start anywhere, I would start in the history genre. This area has great potential for linking information and companion ebooks. And a history e-textbook is a growing adventure. One that is never ending. As more ebooks are written about history, they can be linked back to the original e-textbook which will enhance the experience.
Because I am an Equal opportunity blogger, I will occasionally highlight the dissenting point of view. I have included a link to the professor’s blog so you can make your own judgment. History e-textbooks: Not worth the trouble?
So what do I do now? What needs to happen?
Professors, Teachers and Administrators
The e-textbook concept must be accepted by professors, teachers and administration. They must understand the new technology and it’s potential and they must adapt their methods of teaching to incorporate the features of the digital textbook.
Publishers and facilitators need to realize the potential and rise to the occasion. Printed textbooks and e-textbooks versions should be in sync, including the teacher’s edition. That should also fall into the administrator’s responsibility above. If you’re going to offer the use of e-textbooks in the classroom, they should match the paper version you’re using.
eBook Authors and Content Providers
E-textbooks present a large opportunity for ebook authors. They can write and develop companion ebooks that relate to a specific topic or a source textbook. For example, if I am studying President Lincoln in my history e-textbook and I want to know about New Salem, a place Lincoln lived in his young adult years, I might be able to get an ebook about his early years immediately on my e-reader written by an ebook author.
Students should start creating their own ebooks. They could put their notes, research and ideas in an ad hoc ebook and have it as a reference during their class or while they are studying for a test. The e-textbook can be right next to it on their e-reader. They can create their own ebook with software like Kindlegen (mobi) and Calibre (epub).
New software must be developed to take advantage of the digital format and authors must step up to plate and start creating e-textbooks directly for that platform. Group software integrated into the class environment using an e-reader or PC should be a must.
For example, one of the new tools released recently is NookStudy from Barnes and Noble. This free software download shows great potential. Available on your PC or Mac, you can read e-textbooks, class material, study aids, test guides and many other items. You can create your own stuff and have it at your fingertips. And, of course, you have all the computer tools you need to manipulate the information.
We need a process that insures that digital links are still valid. For example, a good links process could be maintained by publishers or authors on their website. Actually this could be a good opportunity for both. They could have readers accessing their site to update the link information and that could give them a marketing shot at a companion ebook.
Think outside of the box.
I have included a couple of recent blogs that address thinking outside of the box. Both are right on-spot.
How Kindle’s new Public Notes could change the way we read ebooks by Chris Walters
Chris addresses the large potential of new versions of ebooks using Kindle’s public notes. He sees the great potential of notes and the value they can add to the reading experience.
I think education can be the real winner with Public Notes.
Also Joe Wikert wrote a great blog, Margin notes in ebooks.
Joe discusses how important notes are. He defends the use of notes in ebooks as being an integral part of the reading experience.
Both bloggers are thinking outside of the box. How can notes help the reader to better understand the content of the book?
I even got in on the thinking by suggesting that public notes could add to a study group environment. Working with other students and the professor, the synergy could improve the communication and the thought process.
E-textbooks are a great opportunity to improve the quality of education. I believe the resistance to e-textbooks should be weighed against the traditional textbook shortcomings.
Remember. Here comes the kids. You know the gadget-centric generation that will be right at home with e-readers or tablets. These devices will fall right in with their social networking and their cell phones. As a side note, I am waiting for schools to start offering a class in two thumb typing.
What do you think? Can we improve the quality of education with the use of e-textbooks? Will ebook authors get involved with companion ebooks? |
Atlanta, GA (PRWEB) October 01, 2013
Dr. Taz's Atlanta Center for Holistic and Integrative Medicine is pleased to announce enhanced cancer care programs for its patients. The Center has established partnerships with multiple cancer treatment facilities around the world to assist patients in this difficult journey. The goal of the Atlanta Center for Holistic and Integrative Medicine's Cancer Support Program is to help minimize side effects of therapy, provide support, understand alternative and adjunctive regimens and help patients create a comprehensive care plan to minimize risks of recurrence.
Dr. Taz MD, is a board certified physician, pediatric ER trained specialist, certified nutritionist, prevention/wellness expert and articulate Founder and Medical Director of the nationally recognized Atlanta Center for Holistic and Integrative Medicine.
Dr. Taz MD has the proven expertise, experience and unique sensibility to thoughtfully address all matters dealing with women's and children's health issues and treatments, drawing from both Traditional and Eastern medicine. "As the mother of two young children, I believe the synergy between women and children's health and its ultimate impact on the health of the family is at the core of my Center's mission."
Read the full story at http://www.prweb.com/releases/2013/10/prweb11181644.htm.
Copyright©2012 Vocus, Inc.
All rights reserved |
ERIC Number: ED184184
Record Type: RIE
Publication Date: 1979-Nov
Reference Count: 0
Group Syntality and Parliamentary Procedure.
Winn, Larry James; Kell, Carl L.
The group syntality concept of Raymond B. Cattell furnishes a useful framework for teaching parliamentary procedure. Although there are contrasts between the histories, subject matters, and perspectives of the areas of parliamentary procedure and group dynamics, teachers and students of parliamentary procedure might profitably draw from some of the research and concepts associated with group dynamics. Cattell's theory may be used by parliamentary procedure teachers to provide an understanding of group syntality, which consists in large part of synergy (the total amount of energy that a group brings to bear on its activities), and to offer a perspective on leadership--any behavior that influences group syntality. Teachers can point out such obstacles to effective group decision making as inadequate preparation, hasty decision making, prolonged or imbalanced discussion, insufficient group cohesiveness, and the phenomenon of "groupthink," as discussed by Irving L. Janis, in which groups fail to consider the full range of options available to them in making decisions. The group syntality perspective provides an effective framework for integrating parliamentary rules and relevant principles of group dynamics and also heightens the responsiblity of individual group members. (GT)
Publication Type: Speeches/Meeting Papers; Opinion Papers; Guides - Classroom - Teacher
Education Level: N/A
Authoring Institution: N/A
Identifiers: Cattell (Raymond B)
Note: Paper presented at the Annual Meeting of the Speech Communication Association (65th, San Antonio, TX, November 10-13, 1979). |
The treatment program is best suited for a certain subgroup of people who stutter. The subgroup can be identified by several factors which are not necessarily exclusive. The identification of factors which contribute to a particular person's eligibility for this stuttering treatment program is still a work in progress. That is, they may be modified sometime in the future. For the present (1977), however, the eligibility criteria are as follows:
There are multiple purposes of this program. They are:
For the purposes of this treatment program, and to clarify terms related to this program important to share some restricted definitions pertinent to the program. They are as follows:
NORMAL SPEECH: the generation of a naturally continuous airflow, which is voiced or unvoiced, and which is resonated and articulated upon in such a way that it does not call any personal reaction or negative attention to itself by the speaker or listener.
FLUENT SPEECH: the generation of continuous airflow, voiced or unvoiced, which is resonated and articulated upon but in some way may engender a personal reaction or negative attention by the speaker or listener.
STUTTERED SPEECH: an unnatural disruption in the continuous airflow, voiced or unvoiced, which causes a personal reaction or calls negative attention to itself by the speaker or listener.
Each of these definitions combines mechanical and perceptual properties. The important difference between the first two is that a person can be mechanically fluent, but perceptually speech "different." The speech may draw attention to itself in the mind of the speaker or listener. Normal speech may have disruptions in the mechanics of production but these disruptions generally do not call attention to themselves or are not chronic. Normal speech may be fluent but fluent speech may not necessarily be normal
Once a client is identified as eligible for program participation, a brief description of the treatment program and the processes the client will engage in are provided The client's consent and willingness to participate in the program is also obtained.
THE TREATMENT PROGRAM:
The first item of business is to explore with the client the use of cognitive secondary mannerisms The use of avoidances, substitutions, circumlocutions, and starters are identified and mechanisms to eliminate them initiated. The older the person is, the more likely these kinds of secondary mannerisms may occur. Some people do these behaviors so quickly and with such sophistication that they hardly realize it or are cognizant of it only after the fact. Mechanisms to eliminate them include 1) the clinician's addressing and confronting suspected avoidances, substitutions, circumlocutions, and/or starters, 2) charting particular behaviors, 3) keeping a diary of specific behaviors, and 4) reinforcing client's identification of potential mannerisms and verbalization of initially intended words. Clients are educated that these secondary mannerisms are "tricks" which actually keep the stutter going, quietly confirm the person's inability to manage their speech, and ultimately reinforce the stutter (behaviorally).
When these secondaries are eliminated, the underlying tension and struggle are greatly reduced and an inappropriate strategy is eliminated. In the short run, the elimination of the cognitive secondary mannerisms may result in an increase in observable physical struggle in speaking (with physical secondaries). These physical secondaries are NOT addressed The client is, in fact, told stuttering is quite acceptable, regardless of its observable severity, as long as they are not using the cognitive secondary mannerisms. It is stressed and emphasized that the client is to say what s/he intends to say with the words s/he initially and truly wishes to use. Whenever the clinician observes any of these unwanted mannerisms, it should be addressed immediately-even if it means interrupting the utterance to identify the problem and encourage the statement of the original sound, word, or thought. So the first step is to identify and eliminate cognitive secondary mannerisms. In many cases, this will be a process that is simultaneously addressed with other initial portions of the treatment program.
The second step is to increase the client's awareness of sensory inputs. Typically, the client (and any attending individuals or significant others) is asked to go through a short exercise. The exercise is as follows: The client is asked to close his eyes. He is then asked to extend his right arm out forward in front of him. After 'briefly holding it there, he is asked to swing it out to the side, away from his body. Then he is asked to bend it at the elbow ninety degrees, with the palm facing the ceiling. Then he is asked to raise his hand to the ceiling, hold it there, then make a fist. Then he is directed to place his fist on his head, hold it there, then on his lap. Now he is asked to open his eyes and is asked, "How do you know you did what you were asked to do?" Answers vary from "my brain told me what to do" to "I felt it.". This last answer is the closest: one can feel it. Three different sensory inputs were used: 1) proprioception, which informed the client where a particular body part was in space, 2) kinesthesia, which informed the client direction and how much a body part was moved or stopped, and 3) tactility, which informed the client when, what, and how much one body part came into contact with another body part. It is these sensory inputs which allow us to monitor and manage our motor outputs. That is how the client knew his right arm (not the left) was extended forward, then laterally from his body. This is how the client knew he bent at the elbow (not the wrist or knee) and was able to raise his hand straight up (not some other compass direction). That is how the client knew he made a fist (and how tight a fist), knew he contacted his head, and ultimately placed it in his lap (not to the side of the chair). The proprioceptive, kinesthetic, and tactile information allowed the accurate motor movements requested of him.
The exercise is briefly repeated (with eyes closed) to enhance awareness of sensory parameters in postures and movements underlying respiration (i.e.: depth amounts, inhalation/exhalation, short/rapid or long/slow), phonation (i.e.: voice on/off, sustained/broken, volume or pitch changes), and articulatory posturing (i.e.: jaw open/closed, lips pursed/retracted, tongue up/down or in/out). The client is instructed that the use of these various sensory feedback systems to manage motor (or muscular) events underlying normal speech production is what will be emphasized throughout the treatment process. Auditory feedback is also important but generally plays a much lesser role than these other sensory systems. Many clients are able to express what it "feels like" to stutter but are less able to express what it "feels like" to speak without the stutter (like with a pet).
Muscular events, however, do not occur in a simple "on and off" fashion. There are degrees of muscular tension and change as well as degrees of sensory feedback before, during, and after these changes take place. For example, when holding a rubber ball, one can squeeze it very tight, hold it with average pressure and effort, or barely hold it at all and still keep if from falling to the floor (i.e.: resting it at edge of thumb, middle, and little fingers.) Sensory information is used to determine and monitor the amount of muscular effort desired to hold the ball. The degree of sensory feedback experienced can be rated from "one" (hardly any felt) to "five" (average amount felt) to "ten" (an extreme amount felt.) In the same way, clients are trained to rate the amount of sensory feedback used with various techniques they learn in the treatment process (from one to ten, with "ten" being maximum sensation experienced with use.) Being able to respond to degrees of sensory feedback in the use of specific treatment techniques is very important to develop exaggerated use of techniques, to develop self-monitoring, to aid in "grading" motor events, and to allow successful use of techniques outside the clinic environment. Clients are asked to rate themselves on how much they are using particular techniques throughout the treatment process.
Such assessments are also made by the clinician so some commonality (interjudge reliability) is determined regarding achievement of specific targets. Clients soon learn to make differential assessments of how much a particular target is achieved. Initially, clients will be encouraged to exaggerate targets at "ten" levels to help achieve, reinforce, and habituate the productions of neuromuscular patterns and physiological processes. Productions at these levels across time (different amounts for different people) and increased ability to grade (adjust) amount of technique used helps develop normal patterns and less need to exaggerate techniques.
An understanding of the process of change a client will experience is also presented. Feeling and managing the motor events underlying the mechanics of speaking is not enough. Adjustments to behavioral changes and perceptual changes will also have to occur. To get a "window of understanding" to this process, the following task is presented: The client is asked to hold his hands out in front of him, at shoulder width, with fingers spread and palms facing each other. He is then asked to bring palms together and interlace fingers. After a momentary hold in that position, he is asked to return the hands to the original position (spread apart) then brought back together and interlaced again. The process is repeated a few times. At some point he is asked to hold the posture of interlaced fingers and note if right thumb is over left thumb, right forefinger is over left forefinger, etc. (or the opposite). This posture is labeled "the old way." Then the client is asked to return hands to the original spread position but this time bring the hands together with the fingers laced the opposite way (if formerly right over left, this time digits left over right.) The position is held and labeled "the new way." (Be sure all digits are interlaced.) Often people have a hard time achieving "The new way", struggling to get the finger(s) just right. Most people describe the sensation as "weird" or "strange." The client is then asked to separate his hands to the original start position, then interlace the fingers "the new way". This is repeated several times until the client does it rather smoothly. Eventually the client is asked to hold "The new way" position and asked if it feels less strange or weird Most say it feels more comfortable. The initial awkward feelings and sensations, the trials and adjustments in the motor planning of successfully achieving "the new way", and the course of adaptation experienced before the movements and postures became easier and more natural are reviewed The fingers are still interlaced in "the new way" but it took some time, use of sensory feedback to adjust motor outputs, and repeated experiences before "the new way" became accepted and perceived as "o-kay".
The client is instructed that this is the process of change that will be experienced as new techniques for fluent speech production are learned and implemented. He is directed to how sensory information was needed and used to manage motor movements, how that knowledge was applied over several trials before it became easier and more natural, and that if the sensory-motor loop is not tapped into, then he is likely to revert to "the old way" if asked to interlace his fingers again in fifteen minutes from now. Only after many trials over a period of time of doing it "the new way," will a new muscular pattern and eventual habit be formed and eventually automated so that it is done without thinking. In the same way, various speech techniques taught in this treatment program must be felt, repeatedly done and applied in increasingly longer and complex conditions, accepted and perceived as "o-kay", and eventually habituated before becoming automated in normal conversational speech. Speaking without stuttering will often "feel strange" as the new way of interlacing fingers felt strange. The process of achieving fluent speech and later normal speech is a similar process (albeit more complex and integrated) as the process experienced with interlacing fingers in a new manner.
The client is shown a picture of a "stick person" lying on its back (fig. 1.) The ribcage, spinal column, and pelvic girdle are identified. The client is asked to paint out where the lungs are found (at the site of the ribcage.) Then the client is asked how air gets into the lungs to breathe. Most say "the chest moves", "the ribs go out", or "the diaphragm moves", or something to that effect. It is noted that to inflate the lungs with rib movement only requires a great deal of muscular effort as the respiratory system must push against rigid structures (the ribs and spinal vertebrae). It is also shown that the lung dimensions can be increased by lowering the bottom area below the ribs. A partial ellipse ( "(" ) to represent a diaphragm is drawn pointing towards the ribcage. Then a dotted partial ellipse ( ")" ) (or mirror image) to represent the diaphragm during inspiration is drawn pointing away from the ribcage. It is noted that by lowering the diaphragm muscle (reversing the ellipse shape of the muscle from "pointing up" to "pointing down"), we can increase the volume of the lungs without exerting any chest effort. The lowering of the diaphragm is achieved by extending the abdominal muscles. By extending the abdominal muscles outward (straight out and laterally), one draws the diaphragm down. Hence the term "abdominal-diaphragmatic breathing." As this is a mouthful, the technique is re-named "belly breathing" for our purposes. It is easier to feel and understand the use of the belly muscles when using this than during breathing tasks. When belly breathing, one does not have to push against any fixed structures (like the ribs). Belly breathing also draws muscular tension away from the thorax (chest) and laryngeal (throat) areas. Next, a picture is drawn to help the client imagine an old fashioned bellows beside then as part of the stick person with the handles at the level of the navel (belly button) and the opening around the level of the neck. By pushing on the handles of the bellows, one can drive the airstream with great force and efficiency. If one tries to drive air from the bellows by squeezing the fabric close to the opening of the bellows, then air is collected and expelled quite inefficiently. A lot of effort is expended with little result. Many people who stutter experience tight, inefficient squeezing at the level of the chest during silent blocks. Little or no air is expelled and silence results. So it becomes quite important that the client learns to drive the air from the belly with belly breathing.
Now the client is asked to lie down on his back on the floor. He is asked to quietly lie there and breathe. As soon as he calms down sufficiently, it becomes apparent that the belly is participating in the breathing process. The client is asked to draw his attention to the movement of the abdominal muscles (the belly muscles). As he is doing this, some challenges are proposed: observe an infant sleeping on its back: it is primarily a belly breather. Also, if the client will observe his own breathing just before he nods off to sleep tonight (if he sleeps on his back), have him note the type of breathing he is doing. Most likely, he will be belly breathing as it is the most natural and efficient manner of breathing. The respiratory system works with greatest ease that way. With the client lying on his back he is asked to feel the muscles of the belly stretching and contracting, pulling and letting go, as he naturally breathes. A heavy book is placed on the belly (the center of the book over the site of the navel), and the rise and fall of the book is felt. In all of this the absence of chest breathing is emphasized. If there is some chest breathing, efforts are made at this level to minimize it: let all respiration be under belly breathing control. The book rises on inspiration, falls on expiration. The client is directed to pay attention to the physical feeling accompanying the motions. He is asked to take a slightly deeper belly breath and note greater book excursions with the breath. Slowly and gradually, the amount of belly breath (with abdominal excursions) is increased while maintaining no chest movement. In some cases, it helps to have the client place one hand on the belly (instead of the book) and the other hand on the chest with direction to monitor movement of the lower hand and no movement of the upper hand While focusing on the feel of the muscles working at the belly site, the client continues this awareness of breathing process until volitional smooth, deep, and continuos inspiratory through expiratory cycles are achieved. The easy movements of the belly muscles are contrasted with the loose, relaxed, non-moving muscles of the chest muscles. The lack of feel of the chest muscles is also noted. His attention is directed to the proprioceptive and kinesthetic feedback he is experiencing during the natural ebb and flow of his quiet breathing.
As the client slowly deepens the inspiratory and expiratory cycles of each breath, ask him to compare the feel of the muscular feedback with the baseline feelings established during quiet breathing. Point out and reinforce that the client is volitionally changing the depth of his breathing cycles and volitionally controlling the degree of relaxed muscular posturing through the proprioceptive and kinesthetic feedback he is experiencing. Breathing should be through an open mouth. Be sure the inward and outward airflow is continuous: not turned off at the level of the glottis (vocal folds.) Ask the client to take a deep breath, hold it momentarily with the belly extended (not by closing off the vocal folds), then release it while again monitoring and registering the sensory feedback and volitional control of the muscles he uses during these respiratory cycles. Again, no chest movement. Also ask the client to fully expire air, wait a moment with an open glottis, then inspire normally again while continuing to feel and maintain the loose muscular movements. Maximum use of the belly breath is rated a "10". Engage the client in rating the amount of success he has in sensing and achieving the belly breathing movements. When you are confident the client is fully feeling, volitionally moving, and cognitively registering the muscular actions he is experiencing in these activities, then it is time to move on to variations of belly breathing control.
The client should be encouraged to adjust and develop easy belly breathing in five conditions while lying on the floor. (fig. 2) The client is asked to rate (l - 10) his degree of success with each trial in each condition. The first is simply quiet, passive breathing. In the second, the client is asked to take a very deep breath and slowly let it all out before resuming passive breathing. The third condition is broken into two parts: The first is to take a deep breath then release half the air, hold it momentarily with the belly muscles (not at the throat), then release the second half of air and resume passive breathing. The second part is to take a deep breath and release the airstream in thirds: one third expired, hold, second third expired, hold, and last third expired then resume passive breathing. Again, direction to feel the control of air expulsion and control through belly muscles. The fourth condition is also broken into two parts: the first is to take a deep breath and release a long breath (about 75% or 80% of the airstream), pause, then release a short breath (the last 20% or 25% of air) before resuming passive breathing. The second part is to do the reverse: first let out a short breath, pause, then release a long breath and resume passive breathing. Finally, the fifth condition is to take a series of five deep inspiration-expiration cycles: deeply in, deeply out, deeply in, deeply out, et cetera. Throughout all conditions be sure the client is using only belly breathing, not chest breathing. Once. belly breathing is firmly established lying down, repeat the conditions standing up. Again, self-ratings are encouraged. Once they are established standing up, repeat them with the client sitting down. Be sure the client is FEELING the sensory inputs and adjusting motor outputs accordingly. Reinforce the volitional use and control of these abilities and be sure they are firmly established before moving on to the next step.
Developing an Open Throat posture:
The second major technique to teach is the "open throat." This is where an open, relaxed, pharyngeal structure through which the airstream will flow is emphasized. This posture will initially cause a resonance change, especially in the exaggerated (rating of "10") levels. There is often a breathy quality in the early phases of word and phrase training, but allow this during the process of establishing the "feel" of the open throat. Resonance change and breathiness are not to be components in the final form of speech production but may be experienced in the process of change to that final form. The open throat feeling can be achieved in any one of four methods.
The first method is called the "hot potato." Tell the client to imagine he is eating dinner at the White House with the President. Imagine biting off a hot piece of food and, instead of impolitely spitting it out of his mouth, he gingerly rests it on the back of his tongue. There, with lips slightly parted, back of tongue lowered, and back of throat dilated, he inhales and exhales air forcefully across the back of his tongue in an effort to politely cool the "hot potato." As the client draws the air back and forth across the back of his tongue, ask him to FEEL the throat muscles dilate. FEEL the openness through which he is passing air up and down over the back of the tongue. The awareness of air turbulence should be felt behind the tongue: not mid-mouth or at the level of the lips. Sufficient time should be allowed to feel maximal pharyngeal dilation and the continuous free airflow through the structures.
The second method is called the "cold mirror" approach. In this case the client is asked to imagine fogging up a cold mirror or glass (those who clean their glasses this way get the idea real fast.) In doing so, the client relaxes his jaw in an open posture and drives air from the oral pharynx. As the person does this, ask him to FEEL the dilation of the pharyngeal muscles as he exhales air. FEEL the openness as air is released from the back of the throat. Emphasize how he feels the muscle postures accompanying the open throat sensation.
In the third method the process of a natural yawn is described. The client is directed to the times when he has experienced a natural yawn. During it, he slowly dilated the pharyngeal muscles in an attempt to draw in more air. At some paint there is a "peak experience" of maximally opening the throat, sometimes during which one last small gulp of air is conducted prior to exhalation. A simple graph of this experience (a curve with a bubble at the peak to denote maximum relaxation of throat muscles-the peak experience) is drawn for the client. The client is encouraged to FEEL the peak experience and try to make it occur volitionally. Then, his attention is drawn to the FEEL of increasing the duration of the peak experience. He is asked to use the feeling of exceptional openness to volitionally keep the throat open. All of this is done without making a sound. Just the feeling of air moving in and out through the open throat posture is emphasized. Please note that this particular method is difficult to accomplish from a "fake" or "forced" yawn: it takes a natural and automatic yawn that is NOT stifled (which is often a natural reaction in a non-private moment) to fully appreciate the peak experience. If natural yawns can be stimulated in a treatment session, or if a natural yawn is produced as a reflex to yawning models, then immediately point out what the client is experiencing as the event occurs. Do not allow yawn inhibition. Encourage the client to take the feeling and "use it."
The fourth method to achieve an open throat posture is to simply ask the client to lower his larynx. In all the above examples, the larynx drops as the open throat posture is achieved. Some people have enough conscious muscular control of their larynx that they are easily able to lower it. While keeping the larynx lowered, ask the client to FEEL the dilated pharynx and the air sliding back and forth through it. Encourage increasing time duration (up to one minute) of holding this posture.
All four methods are designed for the same purpose: feeling and volitionally achieving a loose and open pharyngeal structure. Regardless of the method used, the client is encouraged to rate the degree to which he achieves an open throat posture and give the sensation of maximum openness a rating of "10". It does not matter which method is used as some people find one more helpful (or easier to employ) than another. The point is that they develop the feeling of the muscular posture to achieve maximum openness for least restricted airflow. Once the open throat posture is achieved, the client is returned to the floor. While lying on his back, the client is asked to review the five easy belly breathing conditions but this time while simultaneously sustaining an open throat posture. Between this treatment session and the next, the client is given the homework assignment of practicing the integration of open throat posture with belly breathing
Developing the Easy Voice Onset:
As the client practices belly breathing through an open throat posture, lots of emphasis is placed on FEELING the air flow through the throat. The client is asked to note and attend to the feel of the musculature throughout the pharyngeal region as breath moves in and out. The feel of air moving through different degrees of openness in the throat is experienced repeatedly. Then instruction in the two primary aerodynamic events which affect vocal fold vibration is provided.
In many cases of stuttering, too much effort is expended at the level of the larynx to produce vocal fold vibration. Sometimes the excessive effort results in complete blockage (full glottic closure) of the airstream. This may be due to more neuromuscular action than necessary: the client is generating too much neurological energy to the muscles resulting in too much muscular contraction. In vegetative breathing or reflexive sighing only a minimal amount of muscular effort is required to posture the vocal folds. In reflexive sighing, the vocal folds are mainly vibrated by two aerodynamic forces to generate the sound Explanation is provided to the client of how sound vibrations are made by these two aerodynamic forces: The Bernoulli effect and an air pressure differential. Pictures are provided to the client of how in the Bernoulli effect the air molecules draw the vocal folds together. Then, once the folds are closed by the Bernoulli effect, a pressure differential develops where greater pressure builds up below the level of the vocal folds compared to less pressure existing above the level of the vocal folds. Once the pressure below the folds reaches a critical point, h pushes (or blows) the vocal folds apart, completing a close to open cycle. The process is repeated again and again resulting in a series of vocal fold vibrations heard as sound. It does not require as much neuromuscular effort as it does aerodynamic events. It is more a process of physics than of neurology. The movement from quiet airstream to voiced airstream is gradual and continuous. It should be a natural, effortless event. At this point the client is presented a graph contrasting this gradual continuous (aerodynamic) onset condition with a sudden spike-like (neuromuscular) onset condition. The idea of "seamless change" is described as when day becomes night and night becomes day: it is continuous and gradual and not on-off like a lightswitch. Pictures demonstrating this continuous change are also provided (fig. 3). It is then that the clinician should physically demonstrate the integration of belly breathing with an open throat in the achievement of easy voice onset. One can feel and hear the correct versus incorrect production. After multiple demonstrations by the clinician, the client is asked to lie on the floor and practice achieving the smooth transition from voiceless airstream to voiced airstream. Attention is directed to the looseness of the laryngeal and pharyngeal structures as the airstream is driven from the belly. Initially the productions may be excessively breathy and this is permissible at this level of treatment as the client is learning to feel the "seamless change" from voicelessness to voice. A sliding motion is emphasized Immediate feedback is provided by the clinician regarding the smoothness of transitions versus the suddenness of error transitions. Errors are often described as a "click", "small catch", "step", or "speedbump" change. Of the techniques taught, this one is often experienced as the most difficult to master due to its subtlety. In children, the transition for easy voice onset is described as a glider taking off and the hard onset described as a rocket suddenly blasting off. With the airstream driven from the belly, the major focus becomes feeling the voiceless airstream become a voiced airstream, however momentary it may be. It is effortless and nearly spontaneous, much as a natural ''sigh" sound occurs in a yawn or reflexive "huh" of acknowledgment. The focus is on the transition to voice, not on the actual sustainment of voice.
Once awareness of the feel of easy voice onset is achieved, a series of drills are presented where the spoken vowels of speech are practiced one at a time. The feel of exaggerated airflow with "h" followed by the mid-vowel "uh" as one continuous sound production is developed. As skill is developed in feeling easy voice onset in this condition, the "h" is combined with all the spoken vowels in the traditional vowel chart. Once competence is achieved with "h" plus vowels, the process is repeated with feeling the easy voice onset with "w" plus vowels. Once competency is systematically developed with "w" plus vowels, single words are presented which begin with "h", "wh", and "w". After competency is demonstrated with these various words, practice of feeling easy voice onset on words initiated by the various spoken vowels is initiated This includes all vowels in the traditional vowel chart plus the "y'' (phonetically /j/). The client continues to focus on the feel of voice initiation. As greater skill and competency is demonstrated in the production of easy voice onset at the single word level, the use of easy voice onset in short phrases heavily loaded with "h" or "w" is practiced Then a series of short easy voice onset phrases heavily loaded with vowels are presented. Additional awareness of continuous airflow is developed in the production of these phrases. At this point in the treatment, the sound produced may be slightly breathy and resonance slightly fuller (rounded, lower pitched) as the client is asked to exaggerate the production of these phrases with a feel of "10" levels. This is not the ultimate vocal tone which will be achieved. Right now the focus is on the feel of the seamless transition in initiating voice. Once 100% exaggerated productions in 20 consecutive phrases is achieved the client is moved to longer sentences which are also heavily loaded with vowels and glides. In longer sentences more than one breath group may be required, but each breath group should be initiated with the same level of easy voice onset. When competency is demonstrated on the easy voice onset sentences, the client is ready to move to the next technique.
Developing Light Articulatory Contacts:
In the next phase emphasis is placed on experiencing the feeling of very soft touching and limited muscular effort. In one example to demonstrate this feeling, the clinician may rest a hand on a table with the index finger extended fleshy side up. The client is asked to touch the finger, which is typically done with a moderate degree of pressure (finger tip to finger tip.) Then the client is asked to repeat the touch but this time with the slightest amount of contact: almost to the point of a imperceptible tactile contact. This is an exaggeration of light touch. It is pointed out that the contact is made but the slightest amount of pressure or muscular effort is exerted. In the same way, the parts of the mouth used to articulate sounds will be used ever so slightly. This is the light articulatory contact, also referred to as light touch.
Another example of degrees of effort to accomplish a task is demonstrated with a rubber ball. The clinician presents the rubber ball and holds it in his hand, palm downward The ball may be squeezed very tightly (this is demonstrated), be held with a moderate (regular) amount of effort (this is demonstrated), or held so loosely that it is barely supported by the palm and first finger joints (and this is demonstrated) In each case the ball was suspended from the floor and kept in the hand. In the last demonstration the action was accomplished with the least amount of physical effort One may feel the different amounts of effort as well as actually regulate the amount of effort. In the same way, the client is instructed that the least amount of effort possible will be expended to produce consonant sounds through the use of light articulatory contacts. The physical effort will be regulated by the awareness of sensory inputs (touch, pressure, and tension) which tell us how much effort we are expending. Production of consonants at a light articulatory contact touch level of "10" is subsequently practiced in a systematic manner. It is very important that a light articulatory contact as opposed to a no contact is made. This should be noted as some clients become so sophisticated in making light contacts that the actually make no contact yet the actual consonant sound targeted is perceived Light contacts at a "10" level to a point of distortion from insufficient pressure is permitted at this level of training but a "no contact" production is not acceptable.
A list of single words beginning with each targeted consonant is presented. The degree of muscular effort is focused upon with emphasis on using sensory inputs to lessen and make aware of the lack of physical effort required to make the target sound The experiences in holding the rubber ball and feeling finger-to-finger contact is re-emphasized The first sounds introduced are the "h" and "w" sounds to reinforce the easy voice onset concept combined with an awareness of looseness in the jaw and/or lip areas. Noting the degree of absence in muscular tension in those sites is emphasized The same process is repeated with lists of "y" and "r" initiated words, with emphasis on the feeling of limited muscular tension and effort experienced in the tongue. Belly breath, open throat, and easy voice onsets continue to be preliminary elements prior to the production of the light articulatory contact target. Feeling, modifying, and barely approximating the lips during the production of "m"-initiated word lists is then presented The same degrees of feeling, modifying, and slightly approximating the tongue tip to the alveolar ridge for "n"-initiated words is practiced The process is repeated for "t"-initiated word lists. Up to this point, the easy voice onset actually preceded the light articulatory contact.
The next sounds introduced are the "f" and "v" sounds. Not only is the sensory awareness emphasized in the production of light articulatory contacts and easy voice onsets in "f" and "v"-initiated words, but also the timing of the two concepts is illustrated in minimal pair words. For example, compare the words "fine" and "vine. In the word "fine" a light articulation of the upper teeth to the lower lip is made and a slight exhalation of unvoiced air occurs. This air expulsion is the "u" sound which must be followed by an easy voice onset into the "i" of nine. In this way, the light articulatory contact of "f" precedes the easy voice onset of "ine" in the word "fine." However, in the word "vine" the opposite occurs. The voice is already vibrating (initiated with easy voice onset) before the lower lip (which is lightly touched by the upper teeth) is sent into vibration. This occurs in milliseconds and still requires extremely light contact for the "v" production. The voice continues through the "ine" to produce "vine." To further illustrate the point, a series of minimally paired "f" and "v"-initiated words are practiced with awareness directed to the timing of the elements of light articulatory contacts and easy voice onsets. Given this awareness, a series of "f"-initiated words are practiced at a level n 10~. emphasis of the light articulatory contact to competency levels. Then a series of "v"-initiated words are practiced to similar competency levels of light articulatory contact use.
Use of sensory inputs to manage the appropriate articulators in the production of light articulatory contacts for voiceless "th" and voiced "th" is presented next. The tongue should barely be presented between the teeth. The lack of pressure, tension, touch and effort is reinforced with each production of each word in the voiceless "th"- initiated word list and the voiced "th"-initiated word list. The elements of timing light articulatory contact versus easy voice onset is again examined. Minimal pair drill examination of the timing elements involving light articulatory contacts versus easy voice onsets are examined to various degrees in subsequent phoneme cognate pairs, depending upon client needs. The awareness of the timing element is important because later on if a difficulty arises with a particular word some people will misdiagnose where the breakdown may be occurring: for example, thinking the problem may be with a hard articulatory contact when in reality the problem is with lack of easy voice onset. Most importantly, though, is the continuing process of sensory exploration and manipulation of light articulatory contacts (at "10" levels) in single words of "s"-initiated and "z"-initiated word lists, "p"-initiated and "b"-initiated word lists, "t"-initiated and "d"-initiated word lists, and "k"-initiated and "g"-initiated word lists. Additionally, light articulatory contacts with awareness of airflow movement and feeling is practiced in "sh"-initiated words to competency levels. Finally, the affricates "ch" and "j" are practiced last as they require the most pressure for the longest durations of all the consonants . But the same process is repeated using awareness of sensory inputs to modify the degree of contact to the lightest amounts possible. Again, sound distortions at these single word levels is permissible to develop awareness of a "10" level of light articulatory contact. After competency is demonstrated (i.e.: 100% in 20 consecutive productions) with each consonant, the client is ready to apply this new skill at a higher level.
At the next level, the client is given lists of phrases to drill and practice the light articulatory contact. Each phoneme practiced at the single word level is revisited, in the same order, but with multiple use within a given phrase. Emphasis is placed on sustaining use of sensory inputs to keep light articulatory contacts on any targeted phoneme throughout the phrase and to its end Again, level "10" productions are stressed This is done with the glides, fricatives, sibilants, plosives, and affricates. Clients have varying degrees of success in applying light articulatory contacts at these phrases levels. If a client is noted to produce a monotone voice, then he is encourage to vary loudness, pitch, or both in any given phrase while maintaining the light articulatory contact. If rate is abnormally slow, then he is guided to practice the phrases until near normal rates of speaking are achieved The only distortions accepted should be in the precision of articulation of the phonemes, which would naturally be distorted by the extreme imprecision of articulation a level "10" production of light articulatory contact would require. As the phrases are being practiced, the client is also asked to increase his awareness of the continually uninterrupted airflow as he lightly articulates through each phrase. Though there may be breathiness or distortions from imprecise articulation, the client is encourage to develop awareness of an "open speech system" where air is driven from the belly through open respiratory, phonatory, and articulatory sites. Once competency is demonstrated with multiple use of each consonant at phrase levels, the client is ready to move to the next technique.
Developing Continuous Phonation:
By this point in the treatment program, the client has integrated belly breathing with the open throat posture to achieve an easy voice onset. The easy voice onset has been combined with light articulatory attacks in such a manner that the client is able to initiate any word without a stutter. Different individuals will report exerting varying degrees of mental, emotional, and/or physical effort to accomplish this, but it should be occurring with 100 percent reliability at single word levels and short phrase levels. In the phrase levels, the client has begun to experience the sense of continuously moving and uninterrupted airflow in his verbal utterances. Given this and the reliability for initiating sounds in words, the client is ready to develop the awareness and skill of continuous phonation.
In the context of natural speech, the vocal folds are constantly put into and out of a state of vibration creating voiced and voiceless sounds. In both conditions, air is continuously moving, whether vibrated on not. On a larger scale, when one hums there is continuous vibration. When one "breathes heavily" (without vocal sounds), there is no vibration. The client is asked to hum or sustain a vowel and while doing so, feel the vibration occurring in the neck region. The client is then asked to sustain a tone for several seconds (as an eastern monk might sustain a chant) and focus his attention to the sense and feel of vibration in the laryngeal, pharyngeal, oral, and facial sites. Then, while exaggerating the vibration, say a simple sentence such as "how are you." A comparison is made between a non-exaggerated "how are you" and an exaggeratedly vibrated "how are you." The sense of "droning" while talking is noted. The client is also asked to observe television reporters (when he is home) to see if he can notice a "drone" off of which the reporter speaks while reporting the news (most are able to identify this.) The exaggerated droning is the continuous phonation we wish to develop. After practice on some sentences, a level "10" is identified and mutually agreed upon. A sense of sliding across sounds with light contacts and exaggerated continuous phonation is developed. Occasionally, voiceless sounds will be distorted with voice. During the initial phase of continuous phonation development, such distortions are allowed. The main point is to feel the continuing vibrations as sentences are spoken. With the exaggerated drone (or continuous phonation) the client increases awareness of the continuous movement of air through the laryngeal, pharyngeal, and oral cavities.
To develop the feel of continuous phonation at sentence levels, the client conducts lots of drill and practice in a series of sentences heavily loaded with particular phonemes. Sentences come directly from the Voice and Articulation Drillbook (second edition) by Grant Fairbanks. In all sentences, the continuous phonation is added to the previous techniques learned. Rate of production is not important though slower rates allow easier self-monitoring of continuous phonation (as well as integration of other techniques.) In some cases, clients may produce sentences with a monotone, but this is not a requirement and not necessarily desired. In some cases, the client is asked to exaggerate inflection and stress in the sentences to dampen the effects of the monotone. Sometimes changes in pitch only, loudness only, or both parameters together are directed to enhance variability in voicing. Sometimes an exaggerated, almost melodramatic production is encouraged to demonstrate how the voice should stay on over variations in loudness or pitch. Self-rating of amount of continuous phonation is frequently encouraged The client is guided to enhance his awareness of internal control as he keeps the air and voice moving in these sentences. After competency is demonstrated in all the sentences, the client is ready to move to the next level of treatment.
Review and Inclusion of Others:
At this point the client is asked to review what has been learned to this point. As part of the review, a significant other is included in the treatment session (if s/he has not already been a part of the treatment process.) The client is asked to verbalize to the significant other (ie: spouse, friend, parent) what has been learned The process of belly breathing through an open throat to achieve an easy voice onset should be briefly explained and demonstrated (BB + 0T = EVO). The combination of easy voice onset, light articulatory contacts, and continuous phonation lead to mechanically fluent speech (EVO + LAC+ CP=FS). Mechanically, if all components are in place the client will not stutter, as the combined components are incompatible with stuttered speech. The idea of rating the degree of use of the techniques should be illustrated to the significant other. The idea of being one's own therapist with monitoring and manipulating variations in the amount of use of various techniques should be conveyed. If it has not already spontaneously occurred, the idea of "trying out" the new speech style with loved ones should be presented. This means, in those conditions where the client feels comfortable and the listener knows what the client is doing, the client should be applying the speech fluency techniques with significant others in real life environments. These significant others should become discriminative stimuli to help encourage practice outside the clinic situation. It is also at this point that the client should develop a personal list of speaking situations or conditions and hierarchically arrange them from easiest to hardest. A minimum of ten conditions is encouraged
Integration and Expansion of Techniques:
After reinforcing self-monitoring and exaggeration of all techniques in sentences, the client is asked to apply these skills in longer and more complex contexts. Simple reading material (provided by therapist or client) is presented. The client is asked to read a couple of sentences with exaggeration of techniques. After two to five sentences are read with exaggerated hyperfluency, the client is then asked to assess how well he used each component learned thus far: belly breath support, open throat, easy voice onset, light articulatory contacts, and continuous phonation. Those areas which are not noted or underutilized are then emphasized in the reading of the next two to five sentences. The process is repeated until the client reports an ability to feel and "sense" how successfully he is integrating all techniques in the production of hyperfluency (and still abnormally exaggerated speech production.) Although still analyzed separately, there is less emphasis on each particular technique and more emphasis on the synergy or "holistic integration" of the feel in speaking fluently with use of technique. This ability to integrate technique to a "greater whole level" is applied to reading which is timed with a stopwatch. Initially, the clinician will want to reinforce with comments about good application (or the need to increase exaggerated application) of various techniques at various points in the oral reading as the client is reading. If a stutter occurs, an analysis is made of where the breakdown in the system(s) occurred. The target problem is repeated with the appropriate exaggerated technique(s). The clock is reset to zero with reading and timing subsequently resumed. Generally, it is helpful to reinforce technique use at " 10" levels intermittently until ten consecutive minutes of hyperfluent reading is achieved. After that point, verbal reinforcements are faded out and the client is given verbal encouragement to monitor, manage, and sustain the integration of techniques by himself. The hyperfluent reading is conducted until 20 consecutive minutes are achieved After that accomplishment, a new target is set.
The next target is to achieve 20 consecutive minutes of hyperfluent conversation. During the conversation portion, the stopwatch is started when the client is talking and stopped when he is not talking or the clinician is talking. This way approximately 20 minutes of the client's talking (and not the clinician's talking or pause time within conversations) is accumulated Normally, conversational topics are neutral: not intended to stimulate emotive response. Like in the reading condition, the first ten minutes of the client's talking time is reinforced when "10" levels of technique are noted. Additionally, when the client demonstrates an exaggerated and easy general flow of fluent speech (as perceived by the clinician), this is also noted and reinforced by the clinician. Distorted exaggeration is still acceptable though degrees of distortion are explored: instead of a "10" level of easy voice onset the client may use an "8" level of easy voice onset. This may feel more comfortable to the client (though perceptually he may still consider it distorted and for him compared to his history, it is) and also be indiscernible from what is considered "normal" speech. Feedback with a tape recorder helps with the initial adjustment to accepting the new manner of speaking as acceptable and worth continuing. Neutral topics are continued until 20 consecutive minutes of hyperfluent conversation is achieved.
At this point, if it has not already been discussed, a discussion of "normal" speech begins. The type of hyperfluent speech the client just completed is identified as something that does NOT occur in normal speech all the time. In normal speech there are many hesitations, stops in speech flow, part and whole-word repetitions, fumbling around and restructuring of sentences. These disruptions in speech may occur due to various emotional states (surprise, unsureness, sadness, urgency, anxiety, desire to impress, etc.), problems in organizing thoughts, difficulty in articulating unusual sound or word combinations/productions, various physical states (i.e.: during exercise or if ill), problems remembering words, or other states of being. Sometimes they catch the speaker's or listener's attention, sometimes they don't. But neither party has an abnormal reaction to it. Sometimes the speech disruption is unnoticed or ignored, sometimes corrected by either party (i.e.: "what I/you meant to say was...~), sometimes laughed off (spoonerisms or "Freudian slips of the tongue"), and sometimes directly addressed with a remark (ie: "Darn! I can't get my tongue to work!"). In all cases the disruption does not distract the speaker or listener from the flow of communication. The disruptions are easy, natural, and normal. For the stutterer, it becomes important to identify a "naturally occurring" disruption to speech versus a "stuttered" disruption of speech. this may be defined by the client ("it felt like a stutter") or by the clinician ("that looked/sounded like a stutter"). If differences are identified by either person (typically on minute or micro-stutters), each is encouraged to explain why it was identified, what could be done to prevent it from occurring, or how it could be dealt with appropriately.
Breaking Perceptual Barriers:
Up to this point in the treatment program, emphasis has been placed on changing the observable or mechanical characteristics of the stuttering problem. If treatment were to stop at this point, relapse would be assured Although mechanically fluent, the client still knows himself as a stutterer. He still believes, feels, and internalizes his self-concept, in part, as a stutterer. For lasting effects to occur, he must change and accept a new internalized self- concept as a competent and normal speaker. For this to occur, the perception of oneself as a speaker must often radically change. Many perceptual barriers must be broken, over a period of time, before one's self-perception as a speaker can change and remain changed.
First, let us define a perceptual barrier. A perceptual barrier is a mental or emotional construct which filters data or information for assimilation by a person (adapting reality to one's own mental or emotional structures) and thereby affects that person's accommodation to the real world (adapting one's own mental or emotional structure to environmental circumstances.".)
Let us explore this through an example. Let us pretend that as a stutterer, whenever I speak with a stutter I see strange or quizzical looks from my listener and this makes me uncomfortable, self-conscious, and generally feeling "bad". In my mind (mental construct) and heart (emotional construct) I have learned and believe people look at me strangely when I talk. More attention is placed on how I am talking than on what I am saying. That is how I assimilate the world and my perception is based on real-life experiences. But with speech therapy I have learned to have both fluent and normal sounding speech. When I speak to someone with such a speech pattern, and the listener responds to what I am saying and the communication event is eventually concluded, I still leave with the belief that the listener looked at me strangely: I am taking my past mental and/or emotional constructs and applying them (inaccurately and wrongly now) to the communication event. I still believe the listener is paying attention to the "how" instead of the "what" of the communicative event even though there is no real data to support this belief. I am now applying my uncomfortable, self-conscious, or bad feelings to the communicative event. I may even tell myself "whew, I made it through that! (little talking event)" just like the few times I may not have stuttered when my stuttering was REAL bad. In each case, either mentally and/or emotionally, I am experiencing my successful speaking event as a stutterer. That is my perceptual barrier. Until I truly (mentally and/or emotionally) experience my successful speaking event(s) as a successful (regular) speaker (or normal speaking event as a normal speaker), I will always be a stutterer. It will take many repeated successful speaking events to occur in many speaking conditions for me to finally change my "perceptual set" as a normal speaker. The more perceptual barriers I break or cross, the closer I get to the desired perceptual set. There are varying degrees of perceptual sets from "stutterer" to "normal speaker" and where I finally end up will depend on many, many factors. These factors include (but are not limited to) my personality, my need for fluent or normal speech in various situations, my desire to attend to my communicative style, my willingness to apply various degrees of exaggerated use of techniques, the kind of "tapes" (self-talk) I choose to run in my head, the amount of influence or control I give to my listeners regarding my communicative interactions, my comfort levels or moods at any given time, and/or other factors.
The example above is a description of a process of change and various factors that may influence that process of change. Different individuals will require different amounts of guidance in moving through the process of change affecting their self-perception as a communicator. Some are quite independent and require little assistance. Others need to be systematically guided and challenged step-by-step through many speaking experiences. But all must go through it. All clients should be instructed on this process of change, with repeated instruction as needed in transfer and generalization activities. The older an individual is, or the longer the individual has stuttered, the more time may be required to undergo this process of change. For some, the process continues even after formal termination of therapy.
Transfer and Generalization:
With the understanding of "normal speech with normal disruptions" versus "stuttered speech with abnormal disruptions" the client is engaged in conversational topics which have particular relevance to him or may place him under some communicative stress or distress. From this point forward, treatment sessions should be held outside of the formal clinic environment whenever possible. Neutral topics may be extended by the clinician and stressors of inattention, interruption, disagreement, competition, encouragement to rush, antagonism, oppositional behaviors/opinions/beliefs may be introduced, depending upon client needs. Additionally, topics which are more complex and/or personal may be introduced: exploration of beliefs regarding stuttering, discussion of particular anxieties and fears associated with stuttering or communicating generally or specifically, identification of factors affecting confidence and/or acceptance of self as a speaker or person, the role shame or guilt may play in the experience with stuttering, and descriptions of "normal" versus "stuttered" speech, to name a few. Topics may vary with the particular needs of the individual. Attached is a list of some general discussion topics (table 1). It is not an exclusive list and many items may not pertain to many individuals. Additionally, the clinician should engage in discussion of various personal items which arouse a particular client's emotions, allows exploration of any challenging life experiences, or challenges given personal opinions or beliefs. In the latter case, the clinician would do well to be the "devil's advocate" on a particular topic while reinforcing the client's good use of techniques in defense of his verbal arguments or positions. This role playing helps approximate real world situations. However, one should always tell the client at the conclusion of the session if one truly believes what was defended as "the devil's advocate" or not, and the reason in taking the opposite position (i.e.: to develop control of speech fluency in emotional contexts.) This process should continue with the client taking an increasing role in being his own therapist by managing speech fluency in various conversational topics, integrating and modeling techniques while generalizing and "settling into" the feeling of the ongoing flow of air and voice as he speaks. In the process the client should move from "micro-management" of speech fluency to "macro-management" of speech fluency (settling into the general "flow" of easy, ongoing speech experiences.) After several conversational experiences, the client is videotaped when engaged in a clinical conversation. This videotape should be replayed and compared with a videotape taken at the initial evaluation (or audio recording done at this point compared with audio recording done at initial evaluation.) The experience often has a tremendous impact in the client giving himself "license" to use and accommodate to using fluent speech. The experience of seeing and listening to stuttered versus unstuttered speech samples of oneself is a major contributor to breaking perceptual barriers to normalizing speech fluency.
At this point the hierarchy of personal speaking conditions and/or topics the client had previously outlined (after reviewing and instructing significant others in the treatment techniques) is directly addressed. They are ranked from easiest to hardest. The easiest items are addressed first. In some conditions, an item may have to be further broken down into its component parts, practiced in segmented parts, then slowly and gradually increased in level of difficulty until it is addressed in its originally described form. As each part, item, and level is addressed, discussion ensues regarding the speaker's (client's) perception of what occurred, what he thinks about it, and how he feels about it. Discussions may be about comfort levels, what he is telling himself, what he is experiencing emotionally, what he thinks is going on, what he thinks the listener might be responding to ("how" versus "what"), the overall naturalness of the communicative event, and/or other influencing factors. For many clients, it is not only assessment of the client's reactions to his fluent speech events that is important but also the client's assessment of the various listeners' reactions to the fluent speech events. For many clients, increasing awareness of the listener's non-reactions is extremely important and "eye-opening". Goals should be slowly shaped to longer and more complex speaking tasks. The use of tape recorders or video recorders is especially helpful as they give immediate feedback to just experienced real life events. This allows comparison of "just recorded" versus "just experienced" (the same thing) communication events. Clients are directed to identity degrees of successes and failures and WHY successful or not. In some cases, the clinician should demonstrate exaggerated use of techniques and let the client observe reactions/nonreactions of listeners and later comment on and/or analyze the communicative event. Then the client should engage in a similar communicative event. As each speaking event is successfully experienced and reinforced, the ability to accommodate new mental or emotional constructs to communication is made. Another part or whole perceptual barrier is broken. After the client's hierarchies of speaking conditions are addressed, the process is continued with clinician-directed activities. More one-to-one conversations, in public places, with or without significant others, with visits from surprise visitors, and under various conditions of client-centered comfort (or discomfort) are engaged. All slightest of communicative concerns the client may express or imply should be addressed In doing so, more perceptual barriers are broken. Included in table 2a and table 2b are lists of some activities directed at breaking various related perceptual barriers: some related to telephone use, some related to general speaking experiences. The client is also asked to report speaking experiences which occur between formal therapy sessions.
The more the client settles into the new loose and fluent speaking style, under various conditions and circumstances, with revolving attention to conscious use versus no conscious use of various techniques, the more he habituates the motor skills and perceptual constructs that underlie normal speech. With overpractice, a more natural and automatic use of desired speech patterns or processes is achieved. Additionally, he is encourage to "play" with the varying degrees of fluency skills learned. To manage occasional small stutters or undue pressure a client may place upon himself to speak too fluently, the idea of "pseudostuttering" may be introduced. In pseudostuttering there are purposeful interjections, part or whole word repetitions, hesitations, prolongations, and the like that are finally under the speaker's control. They do not have the "feel" of real stuttering and can be expanded or contracted at will. Conversational flow is maintained and the controlled non-fluencies mimic normal nonfluencies. Many individuals report that pseudostuttering not only enhances their fluency and control of their speech (if this is an issue for them), but also "frees-up" the individual to apply fluency shaping techniques with greater exaggeration as learned in the clinic situation. The client is encouraged to assess his perceptions and challenge them in the face of reality. He is encourage to allow himself to "mess up" his communication interactions and note his and other's responses to such "mess ups." In short, he is encouraged to continue being his own therapist. Habituation of successful mechanical skills and changed perceptual constructs occurs with consistent successful communication experiences. Normally sounding speech becomes more automatic when successful communication experiences occur across a period of time. Such a time period will vary from individual to individual. This is a process that must continue beyond the formal termination of treatment.
Termination of Treatment:
Many clients achieve such a high degree of fluency that they become "cocky" or have such feelings of communicative "omnipotence" that they give up or lessen self-monitoring, use of fluency enhancing techniques, or respect of "micro-stutters" as warning signs prematurely. These individuals, if not forewarned of this in the treatment program (usually soon after the 20 minutes of hyperfluent conversation), will experience a stinging (sudden) relapse. This is sometimes a desired experience as it helps reinforce the need for continued monitoring and vigilance of appropriate behaviors. Clients are urged not to prematurely "rest on their laurels" as the years of stuttering usually take months of fluency (and often years) before their belief system or self-image as a normal speaker is fully changed. But most clients, who towards the end of therapy are being seen once every two weeks or once a month, voluntarily recognize the appropriateness of treatment termination.
In a final treatment session, it is recommended that the client and clinician review, discuss, and counsel on the factors which affect the client's continued communicative independence. Topics may include relative strengths/lack of use of techniques used, the sense of "being" a normally speaking person, non-communicative reasons for listener reactions or non-reactions, amount of internal control experienced, amount of self-reinforcement and kinds of self-talk the client uses, not owning other people's problems, and distinguishing normal versus non- normal dysfluencies. Clients become their own therapists and learn to honestly assess and adjust physical, mental, and emotional parameters associated with communicative situations. Although intermittent exaggerated use of techniques may be applied (using it when you don't need to), letting oneself "be" communicative in a natural, non- monitored manner is encouraged The positive feelings and perceptions associated with normal speaking experiences should be noted and reinforced by the clinician and the client. If indicated the clinician should provide references (for independent pursuit) to further enhance the client's positive belief systems of himself. If desired references to classes or organizations which enhance rhetorical or public speaking skills should also be made. And finally, the client should know that the clinician is always available to address special or unexpected needs that may crop up anytime in the future. But in most cases, the client already has the tools to deal with those issues should they even come up. |
Accelerating antimalarial drug discovery through repositioning
, PhD thesis, University of Salford.
Of the plethora of parasitic diseases that afflict mankind, malaria remains the most significant with 100-300 million cases reported annually and 600,000 fatalities. Treatment and control measures have been hampered by the emergence of drug resistance to most antimalarial therapies. Early signs of drug resistance to the current frontline option, the artemisinins, make it imperative that novel drug candidates are discovered. One possible short-term solution is drug repositioning, via screening existing FDA-approved (Food and Drug Administration agency) drug libraries for antimalarial activity. Towards this goal, two, fast, simple, and reliable in vitro SYBR Green-based drug susceptibility assays were optimised. The first, the SYBR Green microplate method offered a medium throughput option that was used to screen two FDA-approved libraries (Z score = 0.68 +0.06), LOPAC and ENZO (~700 compounds). Approximately 60 hits, defined as > 50 % inhibition at 2.5 µM, were identified by the preliminary screen. The SYBR Green flow cytometer method, capable of providing direct parasitaemia estimates and stage-specific information, was used for second-phase characterisation of the hits. From these, antiamoebic compound emetine dihydrochloride hydrate was identified as a potent inhibitor of the multidrug resistant Plasmodium falciparum, strain K1, with an IC50 of 47 nM (95 %
confidence interval 44.92-49.17). Further characterisation of the compound involved analysis of the parasite killing profile, to determine the parasite reduction ratio (PRR) and parasite clearance time (PCT) as well drug interaction analysis with existing antimalarials. Emetine was shown to have a similar killing profile to atovaquone inferring a similar mitochondrial mode of action, corroborated by fluorescence staining with the JC-1 mitochondrial probe. Taken together, emetine’s pharmacokinetic matching and synergy with atovaquone provide an exciting drug combination for further investigation. The relatively high hit rate presented in the study, and in vitro workflow outlined for emetine, also showed drug repositioning to be a promising option for antimalarial drug discovery.
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Image credit: Ham Kakembo (CARE-Kenya).
In October 2014, WACC will send two representatives to ACT Alliance’s general assembly – the first time a communications rights organization has attended the Geneva-based development and relief group’s annual gathering.
It’s the result of WACC’s acceptance in May 2014 as a member of ACT Alliance, the first time a global ecumenical ministry specializing in communication rights has applied and been accepted for membership.
“We applied for membership because we in WACC strongly believe communication rights are essential for sustainability in development, key to effective advocacy, and important in humanitarian crisis situations,” said WACC General Secretary the Rev. Karin Achtelstetter.
ACT Alliance is a coalition of more than 140 churches and affiliated organizations working together in 140 countries to create positive and sustainable change in the lives of poor and marginalized people. Its work takes place regardless of religion, politics, gender, sexual orientation, race or nationality in keeping with the highest international codes and standards. It targets three areas: humanitarian aid; development; and advocacy.
The ACT Assembly is the strategic meeting place of the ACT membership, “the crossroads where we strengthen who we are and unleash all of our potential,” according to a message from General Secretary John Nduna on the organization’s website.
The theme of the 2nd General Assembly is based on John 10:10: “The thief comes only to steal and kill and destroy; I have come that they may have life, and have it to the full.” The assembly dates are Oct. 21-24, 2014 and the location will be Punta Cana, Dominican Republic. The first assembly was held in October, 2010.
“Our intention is to strengthen this work – to make efforts towards development, advocacy and humanitarian response more effective and sustainable through contributing the perspective of communication rights. This holistic approach would strengthen WACC, ACT Alliance, and its members,” said Achtelstetter.
Since WACC is a networking organization, it highly values “being part of a network that addresses and links humanitarian aid, development and advocacy. The learning, partnerships and involvement in different efforts can also impact our themes, programmes and methodologies,” she said.
“We have WACC members who are also ACT members. Through them, we already see that there is a synergy in what each of us is doing. We have been encouraged by these ACT members to further the links, and connect the WACC and ACT networks,” she added. |
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Food importers and wholesaler companies in UAE and Dubai. It consist information about the importers and wholesalers of rice, cakes, coffee and other food products in this region. ...
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We are passionate about hotel online marketing
Let's face it: We can no longer manage our hotels the way we used to for the past 30 years. The landscape has changed drastically. If you need proof, you need to look no further than the explosive growth of OTAs (Online Travel Agencies, such as Expedia and Booking.com) in the recent years. However, too often, we see hotel owners/operators simply not taking any action on their hotels' online marketing strategy. We cringe at the sight of spending 3% of hotel's revenue on print-media marketing, which is only 25% effective as online marketing today! So our goal is simple:
Save Hotels From OTAs
We want to help maximize all online bookings to your direct booking channel.
Make Hotel Websites Affordable
Hotel Website Designs should be affordable. Period.
Make Hotel Online Marketing Approachable
Hotelliant gives you all the tools you need to launch a successful online marketing strategy.
Create Synergy, Not Compete, With Brand.com
We believe having 2 direct channels are better than one.
- 80% of guests search the Internet to find hotels
- Hotel Website is the 2nd most important factor to guests when booking
- OTAs and Search Engines are where guests begin to comparison shop for hotels
- Most hotels don't have an online marketing strategy
- Source: Google Think Insights
Website For Hotels
Hotel Website Designed To Sell Rooms Online
A good hotel website design is not about providing detailed information about your hotel. A good hotel website design is about leveraging the information about your hotel to gain visibility. With Hotelliant, you will instantly be armed with the tools necessary to reach a broader market, gain mind-share of those traveling near you, and ultimately get more people to book directly with your hotel. To begin, ask yourself these four simple questions and find out how you're addressing them today:
Guests looking for a place of interest
How are you marketing to those looking for "a hotel near a Point of Interest"?
Guests looking to stay for an event
What are you doing proactively to capture your fair share of a major event in your area?
Your Hotel's Unique Value Proposition
Is it possible to highlight the uniqueness of your hotel vs the competing hotels online currently?
Hotel Online Marketing Strategy
What are you currently doing about the hotel online marketing at your hotel?
Hotel Website Designed To Generate Demand
Hotelliant is a cloud-based hotel website design solution that allows you to set up your own hotel website for your hotel. Our intuitive hotel website builder allows your hotel to publish a detailed hotel information online, engage your customers with photos and videos, and highlight a variety of packages and events in your area — all with a few clicks of the mouse. With Hotelliant it's easy to create the online presence to jumpstart your online-marketing campaign. Oh, and there's no up-front fee or contract.
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Choose from our growing library of beautiful hotel website templates.
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BLACK STAR RIDERS, the new band formed by THIN LIZZY alumni Ricky Warwick (vocals), Scott Gorham (guitar), Damon Johnson (guitar), Marco Mendoza (bass) with new addition Jimmy DeGrasso (ALICE COOPER, MEGADETH, DAVID LEE ROTH, SUICIDAL TENDENCIES) on drums, will enter a Los Angeles studio next week with producer Kevin Shirley (LED ZEPPELIN, IRON MAIDEN, AEROSMITH, RUSH) to begin recording its debut album for a May 2013 release via Nuclear Blast.In October 2012, THIN LIZZY announced that they would not be recording new material under the THIN LIZZY monicker. The last incarnation of the band — Gorham, Brian Downey, Wharton, Warwick, Johnson and Mendoza — would be looking to form a new project. According to a press release, Brian Downey decided to not become involved with BLACK STAR RIDERS because he didn't want to commit to the touring cycle a new album would entail and Darren Wharton wanted to concentrate on DARE and other music and film projects. The BLACK STAR RIDERS album will feature material the band wrote while touring as THIN LIZZY and the sound retains that classic feel but is very much its own as well. The BLACK STAR RIDERS record is the next step in the evolution of the THIN LIZZY story. "We are all very excited about the music that we have created for BLACK STAR RIDERS. The synergy between the five of us has been phenomenal and I can't wait for the world to hear these songs," says Warwick. BLACK STAR RIDERS was signed to Nuclear Blast by Monte Conner — the former Roadrunner A&R guru who has worked with such acts as SLIPKNOT, MACHINE HEAD, SEPULTURA and RUSH. Conner recently joined Nuclear Blast as the president of Nuclear Blast Entertainment, a new U.S. partnership he co-founded with Nuclear Blast owner Markus Staiger. Says Conner: "As a lifelong THIN LIZZY fan, I was floored by this line-up's new material. Not only do the new songs sound like THIN LIZZY but they sound like CLASSIC THIN LIZZY. BLACK STAR RIDERS totally captures the essence of what was great about the original band while at the same time adding something totally fresh and modern. Even when I heard the band decided to change their name, my interest in signing them did not waver for one second." The band are looking to support their May album release with European festivals shows in the summer of 2013 and follow this up with worldwide touring. The setlist will consist of material from the new album and classic THIN LIZZY material. |
Even though CenturyLink (NYSE:CTL) has always had the lowest dividend yield of the rural telecom trifecta (CenturyLink, Frontier (NYSE:FTR) and Windstream (NASDAQ:WIN), we believe it is the best-in-breed in the rural telecom space. Granted, this sector is dominated by CTL, FTR and WIN. We believe that investors in the rural sector shouldn't mind sacrificing 1-3% current yield to buy CenturyLink instead of Windstream or Frontier because we believe that investors are more likely to see the return of their money, as well as incremental growth on their seed capital by investing in CenturyLink versus Windstream or Frontier. We believe it is of the utmost importance to analyze how a company earns the money to pay us our quarterly dividends rather than merely grabbing the yield off MSN Money. Based on our analysis, we see that CenturyLink's operating performance continues to outpace Frontier and Windstream.
Source: Bloomberg LP
CenturyLink recently reported adjusted Q2 2012 EPS of $.66/share, which beat the $.59/share analyst consensus and was an increase from the $.61 adjusted EPS achieved in Q3 2011. We weren't surprised by CTL beating expectations. We weren't surprised by CTL's continued progress in stabilizing its revenue. We were particularly pleased to see that the company's last blockbuster acquisition was the Savvis deal and that deal closed in early Q3 2011. That means that this is the last quarter and last fiscal year that CTL has to report on a pro forma adjusted basis with regards to its financials. We are most pleased with the fact that the company's adjusted and reported EPS are finally increasing after steady declines since 2007. CenturyLink's reported EPS is influenced by the (non-cash) depreciation and amortization expenses it accrues as part of its blockbuster acquisitions of EMBARQ in 2009, Qwest Communications International (NYSE:Q) in April 2011 and Savvis in July 2011. CenturyLink incurs relatively high depreciation and amortization expenses because the assets it acquired in its trifecta of blockbuster acquisitions were valued at a stepped-up fair market valuation. The depreciation of these assets are accrued on this higher fair market valuation instead of its low cost original cost valuation and causes a depression in CTL's reported EPS.
CTL made a significant improvement in its adjusted pro forma revenue decline by reducing it to -1.3% for Q3 2012 versus the 4.6% decline in Q3 2011. CenturyLink's wireline access lines declined by 5.79% year-over-year in Q3 2012 and reflected an improvement from the 6.05% achieved in the linked quarter as well as the 7.11% achieved in Q3 2011. This decline was also better than the 8.03% year-over-year decline in wireline access lines by Frontier. Unlike Frontier, CTL improved its year-over-year access line decline in Q3 2012 while FTR saw its access line rate of decline creep up. CTL's wireline decline even compared favorably with the 10.7% decline in wireline customers at AT&T (NYSE:T) and the 6.8% wireline decline at Verizon (NYSE:VZ). CTL's wireline declines was mostly offset by a 4.1% year-over-year increase in the number of Broadband Internet customers served, which compared favorably to the 1.56% increase that Frontier saw, the 2.3% growth at Verizon and the 50bp decline at AT&T. We were especially pleased that excluding revenue growth from Savvis, CTL's pro forma revenue decline excluding Savvis improved to -1.4% in Q3 2012 on a year-over-year basis and we are excited that the company is expected to see incremental revenue growth starting next year.
Click to enlarge
Source: CenturyLink's last six Earnings Releases
Evaluation of CenturyLink's Business Segments
Regional Markets Group: We were pleased to see strategic revenues for CTL's RMG segment to continue to make up a larger share of division revenues and to offset in wireline revenue declines. Q2 2012 strategic communication services revenues grew by $18M on a linked-quarter basis and $67M on a pro forma basis (7.9%) versus the prior year's levels and reached $912M in the quarter. Strategic revenues and data integration revenues now make up 39.6% of the division's revenues, versus 35% for pro forma Q1 2011 levels (Q1 2011 was the last quarter before CenturyLink acquired Qwest and Savvis). This helped the division partially offset a 6.75% decline in legacy services (primarily wireline) and resulted in a small 2.1% pro forma revenue decline. RMG's pro forma year-over-year revenue decline of 2.1% had narrowed by 50bp during Q3 2012 versus the 2.6% in Q2 2012. RMG also ended the period with over 104K Prism TV (advanced next generation fiber-optic television) subscribers, an increase from the 44K in Q2 2011. 90% of new Prism TV customers also subscribed to CenturyLink's broadband services and Prism TV is now in 10% of available homes in the CenturyLink service area.
Click to enlarge
Source: CenturyLink's last six earnings releases
Wholesale Markets Group: WMG's strategic services revenues declined by 1% in the quarter versus prior year's quarterly period. This was driven by wireless carrier bandwidth expansion and Ethernet sales and was offset by declines in copper-based revenue. Legacy services revenues declined by 16.7% due to decreased wireline customers served and total revenues declined by 7.6% in the quarter versus the comparable quarter last year. Direct segment expenses excluding depreciation and amortization declined by 11% and this helped keep the segment income decline to less than 6%. Total revenue during the quarter was $908M and strategic communications revenues accounted for over 62.5% of division revenues. CenturyLink's Wholesale Markets revenue declines were narrower than the 9.6% that Windstream saw in Q3 2012. CTL's WMG segment completed approximately 1,335 fiber builds during the second quarter and over 3,300 year-to-date, ending the quarter with about 13,500 fiber-connected towers. WMG currently remains on track to complete 4,000 to 4,500 fiber builds in 2012. This effort is to position CenturyLink WMG to benefit from significant growth in wireless data demand.
Enterprise Markets Group-Network Segment: We were satisfied that strategic revenues for EMG-NS increased by 7.2% pro forma for Q3 2012 and reached a quarterly record of $333M. This division shook off a 92bp pro forma revenue decline in its legacy services revenues and grew its revenues by 5.8%, thanks to a 17% increase in data integration revenues. Excluding the decline in private line services, strategic revenues grew nearly 13%. The segment benefited from positive operating leverage in that total segment expenses declined slightly versus the prior year period and this enabled the segment to post 34% pro forma growth in segment income (excluding depreciation and amortization expenses).
Enterprise Markets Group-Data Hosting (primarily Savvis): We were pleased that operating revenues reached $280M in the quarter and grew by 8.1% versus pro forma Q3 2011 levels. Colocation revenues were $113M and grew by 7.6% while managed data hosting revenues were $107M and grew 9.2% over the same period. The EMG-Data Hosting segment closed the acquisition of certain assets of Ciber's IT Outsourcing business in mid-October, which enhances and expands CenturyLink's capabilities in areas such as application-management services and help-desk support. EMG-Data Hosting also opened a new data center in Singapore and expanded its NY/NJ data center.
Click to enlarge
Source: CenturyLink Q3 2012 Earnings Release
CenturyLink generated over $1.9B in operating cash flows during the quarter ($4.7B YTD) and nearly $1.2B in free cash flows ($2.825B YTD). The company ended the quarter with an annualized operating expense synergy run rate of approximately $450 million from the Qwest acquisition. CenturyLink currently expects to exit 2012 with approximately $480 million in annual run-rate synergies related to the Qwest acquisition as operating expense savings are being achieved earlier than anticipated.
In conclusion, we continue to see our thesis validated with regards to CenturyLink as our top choice in the rural telecom sector. We continue to see the same factors justifying our thesis:
- Although CenturyLink's dividend yield of 7.25% is lower than that of its rural telecom peers, it is still higher than the 5.1% yield from AT&T and the 4.7% yield from Verizon.
- CenturyLink is an investment grade company whereas Frontier and Windstream are high yield companies. That probably explains why CenturyLink's weighted average interest expense of 6.04% is lower than Frontier's 8.3% and Windstream's 7%.
- While Frontier's reseller agreement with AT&T allows it to generate fees for marketing AT&T Mobility's wireless service to its customer base, we already went into great detail about how CenturyLink is better at promoting its relationship with Verizon Wireless.
- CTL has five key markets that we are attracted to; Denver, Phoenix, Seattle, Portland and Las Vegas. Denver (17.9%), Phoenix (33.1%) and Las Vegas (36.6%) have seen strong population growth. Portland and Seattle have also seen above-average population growth over the last 10 years.
- CenturyLink's wireline declines are narrower than AT&T, Verizon and Frontier and its broadband internet growth exceeds those other three companies.
- We believe that these reasons explain why CenturyLink's stock generated a positive total return for 2012 while its rural telecom peers have seen negative returns. CenturyLink has even seen a slightly higher total return than Verizon.
Disclosure: I am long CTL, S. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.
Additional disclosure: This article was written by an analyst at Saibus Research. Saibus Research has not received compensation directly or indirectly for expressing the recommendation in this article. We have no business relationship with any company whose stock is mentioned in this article. Under no circumstances must this report be considered an offer to buy, sell, subscribe for or trade securities or other instruments. |
Polymeri Online 26.3.13 | Butterflies cluster, Polymer clay knitted masks, Beautiful scrap jewelry and Fusion design team
|Gloria's Butterflies Cluster|
While looking at the ACC 2013 show presenters list, which took place in Atlanta at the same time with Synergy conference, I stumbled upon a polymer clay artist name that was new to me (and I think I know most of them), Gloria Danvers. The piece shown as a thumbnail next to her name was a lovely butterflies canes necklace. According to her she is using link chains to form a bib, and then cover it with butterfly wings. It is her interpretation of the way butterflies clustering on trees during migration.
I have been in the ACC show several times before, when Synergy took place in Baltimore and it is a must show for every artist in any medium.
|Sari's polymer clay masks|
Sari Lin from Israel is a long time friend and polymer clay colleague. I had the pleasure of being her teacher for several technique classes and we continued our polymer clay friendship through the internet and on Facebook. In her recent creations she is playing with faux knitting to create polymer clay masks. Here is another version of masks in a different color/technique.
Sari is mad about pens which are always on demand among her friends, family and customers and loves to play with different techniques. Even though she is dealing with multiple sclerosis for many years, she is choosing the more colorful side of life and found polymer clay to be her best chosen medium. One of her recent creations is a LaserCut bracelet after taking Jana Benzon's workshop recently given in Israel.
Tanya Mayorova is from Russia is only 25 years old. Her flickr gallery is full of goodies, I had a difficult time choosing which picture to show next to her name. She is working with polymer clay and scrap booking, plan to start to learn to draw. Her techniques are mixed - millefiori, beautiful use of scrap and more.
|Fusion in Polymer|
One of Tanya's favorites on Flickr is vix @fusion, mother (jean) and daughter (vix) fusion team playing with materials and techniques. In this photo they are presenting polymer clay rings on twisted copper wire bracelet. Fusion jewelry designs are handcrafted and created from various craft mediums such as polymer clay, semi precious gemstones, wire and kumihimo braiding techniques.
It's passover holiday in Israel right until next week, family time and resting, always a pleasure.
Have a great week!
Have a great week! |
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"26.10.2016 15:29:02" Timeline Photos No shirt? No shoes? We have you covered! Maintain your workout routine on-the-go with our Gear Lending Program. #RunWestin #MoveWell
Photo: @sustainablystylish taken at The Westin Paris - Vendôme @WestinParisVendome
"23.10.2016 03:09:01" Timeline Photos This little travel companion is enjoying her complimentary Heavenly Dog Bed. Sleep better whenever & whoever you travel with. #Westin #SleepWell
Photo: Instagram; seaportdaisy taken at Westin Boston Waterfront Hotel
"18.10.2016 12:00:03" Timeline Photos Escape to tropical paradise and enjoy a leisurely Sunday morning playing a game of love next time you stay at The Westin Resort & Spa, Puerto Vallarta. #PlayWell
"15.10.2016 20:24:01" Timeline Photos Coloring is known to reduce anxiety, help with concentration and bring about more mindfulness. Stay at one of our hotels in Asia Pacific, and color between the lines with complimentary coloring sheets designed by Johanna Basford. #WestinWellness
"14.10.2016 14:00:08" www.huffingtonpost.com The Run of a Lifetime This summer during the Olympic games in Rio, Bill Murray suggested that "every Olympic event should include one average person competing for reference." ... #FitnessFriday inspiration from our National #runWESTIN Concierge, Chris Heuisler. Read more about his run of a lifetime with Champion Runner Meb Keflezighi in his second post with The Huffington Post http://huff.to/2c5N3EZ
"14.10.2016 11:43:51" Marriott Rewards It's Global Travel Day! We polled 6,600 leisure travelers, in 14 international cities, to learn more about travel trends and uncover surprising truths. The results are in.
"14.10.2016 03:31:01" Timeline Photos Step outside to fresh air, a crisp breeze, and mountain views unique to the West Coast when you stay at The Westin La Paloma Resort & Spa. #FeelWell
Photo: Instagram; wineryexplorers
"11.10.2016 18:10:03" Timeline Photos Excited to announce the opening of The Westin Buffalo! A 2 hour bike ride or 6 hour run from to Niagra Falls, if you're feeling ambitious...If not, stroll downtown and visit Ellicott Street for restaurants, entertainment, and historical landmarks. Learn
"11.10.2016 14:07:41" Starwood Preferred Guest® (SPG) Your points can help those affected by Hurricane Matthew. Donate by October 31st and we'll match your contribution.
"05.10.2016 22:14:01" Timeline Photos Pack a light snack and paddle down the Charles River until you reach the Esplanade, the perfect picnic spot in Boston, next time you stay at The Westin Copley Place. #PlayWell
"04.10.2016 17:30:32" Timeline Photos Get your blood flowing and start your day motivated and refreshed with an outdoor yoga session at The Westin Harbour Castle, Toronto #MoveWell
"27.09.2016 21:55:02" Timeline Photos See the sights of Vancouver by bike, like Stanley Park, courtesy of a new bicycle rental program at The Westin Bayshore. #MoveWell Photo: nodestinations
Photo: IG, nodestinations
"25.09.2016 15:44:02" Timeline Photos Visit The Westin Chicago River North and explore the Windy City with a relaxing Wendella Boat Tour on the iconic Chicago River. #FeelWell
"23.09.2016 14:00:27" Starwood Preferred Guest® (SPG) We're linked – join us. Link your SPG & Marriott Rewards accounts.
"23.09.2016 11:44:39" Timeline Photos We are thrilled to announce that today, no matter where you go, you are here. With more than 5,700 hotels in over 110 countries, we are now a part of the world's largest collection of hotels + travel experiences. Join or link your accounts at
"23.09.2016 05:07:55" The new Marriott portfolio of hotels has 30 brands and over 5,700 locations. Today, you have access to the world's largest collection of hotels and travel experiences. Now, no matter where you go, you are here. Explore more at members.marriott.com/brands.
"21.09.2016 17:35:03" Timeline Photos Opportunities for adventure and spaces for quiet retreats...even for our littlest travelers. #WonderAwaits #WestinFamily
"17.09.2016 23:48:02" www.huffingtonpost.com How Social Media Changed Running Social media has changed our sport. With apps like Strava and Instagram, we're seeing more and more "groups" of runners who may never physically meet one... We are excited to announce that our National #runWESTIN Concierge, Chris Heuisler, is now a regular contributer to the The Huffington Post. Read his first article here: http://huff.to/2aGUptK
"15.09.2016 16:08:02" Timeline Photos We are proud to announce the debut of The Westin Dubai, Al Habtoor City. Towering 41 stories above the heart of Dubai and situated on the iconic Sheikh Zayed Road, this hotel offers a true urban oasis. After a busy afternoon in Dubai's Financial Center,
"13.09.2016 22:49:02" Timeline Photos The Westin Kierland Resort & Spa offers a dedicated Golf Concierge, giving golfers personalized instruction as well as a novel fitness option: seven-gear mountain bikes with wide tires designed for turf riding. Each bicycle is also outfitted to carry the
"10.09.2016 17:29:02" Timeline Photos Our idea of breakfast in bed! Plenty to fuel a long weekend of sightseeing around Milan. Head to the Sforzesco Castle or the Pinacoteca of Brera and discover Italian masterpieces. #EatWell #PlayWell
Photo: IG, koentadyy
"07.09.2016 15:27:02" Timeline Photos Like our friends at Partnership for a Healthier America, we're committed to supporting the health of children. You'll find our Eat Well Menu for Kids at every hotel, created with experts from our partners at Superchefs. #EatWell
Photo: The Westin
"04.09.2016 22:28:01" Timeline Photos All of our guests dream big in a Heavenly Bed. Extend your travel experience to your loyal companion with our Heavenly Dog Bed. #SleepWell
Photo: IG; puppies_ella_and_lily taken at The Westin South Coast Plaza
"02.09.2016 16:29:02" Timeline Photos Book your next long weekend getaway refreshing your mind and re-energizing your body with a little seaside sunshine at the Westin St. John Resort & Villas, U.S. Virgin Islands, one of Travel & Leisure's Top Family Resorts. Learn more about them here:
"31.08.2016 16:32:03" Timeline Photos Did you know that adding more color to your plate equals more nutrients for your body? So, add some color to your dinner table for a healthy meal that's fun for the whole family. Read about more fun food facts from EatingWell here: http://bit.ly/1bgaIph
"30.08.2016 14:59:55" Timeline Photos For many of our family travelers around the world, back to school is coming! We, like our friends at Partnership for a Healthier America, want to make healthier choices easier for busy parents and families. So check out these tips we've developed together
"26.08.2016 21:18:01" Timeline Photos Today we debut our fist hotel in Jakarta (and the highest hotel in Indonesia!). Stay ahead of this bustling city with our signature offerings like SuperFoodsRx dishes and Gear Lending. Plan your first stay at: http://west.tn/29PmnTU
"26.08.2016 16:52:03" Timeline Photos Treat yourself to a weekend on one of our award-winning golf courses, located in premier resort destinations. Learn more about them here: http://bit.ly/2a14seD #PlayWell #WestinWeekend
Photo: The Westin Mission Hills Resort & Villas
"23.08.2016 18:26:02" Timeline Photos Head to The Westin Maui Resort and Spa and challenge yourself to a morning kayaking adventure over Maui's magnificent reefs. #MoveWell
"18.08.2016 22:07:01" Timeline Photos Plan a long a weekend and enjoy it with the help of our Out of Office Generator. Better your getaway and stay connected to your body and mind, not your email. #FeelWell http://west.tn/2b3Sazv
"14.08.2016 09:49:23" Timeline Photos Start your day with an early morning tour around your city with our handy #RunWestin Running Maps. What city are you exploring today? #MoveWell
Photo: The Westin Bayshore
"11.08.2016 22:15:01" Timeline Photos Go beyond breathtaking beaches and take an excursion around The Westin Lagunamar Ocean Resort. Swim with dolphins, play a round of golf, and explore the ancient ruins of Cancun. #PlayWell
Photo: IG; edgararana702
"08.08.2016 15:35:01" Timeline Photos We've transformed your hotel room into a destination for exploration. Ignite wonder and spark curiosity in your children with #WestinFamily. #WonderAwaits
Photo: The Westin Excelsior Rome
"06.08.2016 22:46:05" Timeline Photos Not only refreshing, pomegranates are rich in antioxidants and green tea has a kick of natural caffeine. Choose well behind the bar with our Pomegranate Green Tea Cocktail next time you are at The Westin Singapore. #CraftedAtWestin
"04.08.2016 21:37:01" Timeline Photos Dreams can come true. #SleepWell beneath plush Westin Heavenly bedding during your next Delta One @Delta Air Lines flight. Where to next?
"01.08.2016 16:42:01" Timeline Photos Stay active this summer and meet us in the mountains! The Westin Snowmass Resort is waiting for you with 94 hiking trails & 3,300 acres of terrain.
"29.07.2016 14:10:02" Timeline Photos We can help you keep up your wellness routine on the road. Enjoy a complimentary trial to @FitStarlabs Yoga Premium.Visit fitstar.com/westin to download. #FitStarWestinWorkout
"28.07.2016 16:23:02" Timeline Photos #TBT to taking over NYC sweatworking-out with National #RunWestin Concierge, Chris Heuisler. #RunWithAView
"25.07.2016 14:03:02" Timeline Photos Ultimate workout #RoomWithAView. Even if you don't leave The Westin Denver International Airport, you can swim laps and catch glimpses of the city.
Photo: Instagram; SimonKopec
"24.07.2016 14:48:02" Timeline Photos Fuel your day with a fresh squeezed juice from Westin Fresh by The Juicery #EatWell #FeelWell
"21.07.2016 16:24:02" Timeline Photos We want to help you keep up with your health and wellness routine on the road! Enjoy a complimentary trial to FitStar Yoga Premium and get flexibly fit wherever you are. Visit westin.com/fitstar to download. #FitStarWestinWorkout
"19.07.2016 17:10:01" Timeline Photos Whether you #eatwell, #sleepwell or #workwell, Westin has your well-being covered when you travel. Photo: Instagram; reelsplicer
"15.07.2016 15:50:01" Timeline Photos Our littlest travelers waiting at The Westin Abu Dhabi Golf Resort and Spa to taste test locally-inspired recipes for the new #EatWell Menu for Kids #MissionDelicious
"13.07.2016 18:51:02" Timeline Photos The youngest chefs at The Westin Paris - Vendôme are giving their final seals of approval for the Eat Well Menu for Kids. #MissionDelicious
"11.07.2016 12:35:02" Timeline Photos Gather a group of friends together for a fun workout! There is no better way to start your day than with morning rooftop yoga at The Westin Edina Galleria to get your body moving and blood flowing. #MoveWell #FeelWell
"10.07.2016 18:41:01" Timeline Photos Bring your kids into the kitchen! We did to help create recipes for the #EatWell Menu for Kids…coming soon to a Westin near you! #MissionDelicious
Photo: IG; Frenchmomes
"09.07.2016 19:58:01" Timeline Photos Relax and renew with this poolside escape brought to you by The Westin Siray Bay Resort & Spa Phuket #FeelWell
"08.07.2016 16:32:04" Timeline Photos Stay in tonight and challenge yourself on #FitnessFriday with a personalized workout you can do from the comfort of your own home or while traveling with the help of FitStar and Westin. #FitStarWestinWorkout westin.com/fitstar
"06.07.2016 15:41:02" Timeline Photos Bring your business meetings outside and sweat-workout with our Run Concierges around the world. #WorkWell #RunWestin
Photo: The Westin Grand Munich
"01.07.2016 16:37:34" Timeline Photos Bringing yoga to your bedroom at home and beyond, today marks the launch of our partnership with FitStar Yoga. Keeping you fit on the go, visit Westin.com/Fitstar for a chance to win #fitnessfriday essentials.
"30.06.2016 18:11:01" Timeline Photos Revive with an artisanal elixir from our signature cocktail program. #CraftedatWestin
Photo: The Westin Bayshore
"27.06.2016 21:51:02" Timeline Photos Dreaming of your favorite meal? Executive Sous Chef at the The Westin Pune Koregaon Park brainstorms a new dish for the Westin Eat Well Menu for Kids. #MissionDelicious #WonderAwaits
"25.06.2016 18:07:01" Timeline Photos Ride the California waves in between conference calls or business meetings with help from the Surf Concierge at The Westin Los Angeles Airport. #PlayWelll #WorkWell
"21.06.2016 21:20:03" Timeline Photos Celebrating #InternationalYogaDay, visit www.westin.com/fitstar for a #sneakpeek of what we are launching on July 1st.
"20.06.2016 20:33:02" Timeline Photos Extra daylight provides for more time to get outside & be active today. #SummerSolstice #MoveWell
Photo: The Westin Hilton Head Island Resort & Spa
"19.06.2016 18:41:01" Timeline Photos The Westin Princeville, Ocean Resort Villas is fueling up their creations with fresh & local ingredients, gathering inspiration as they experiment & concoct their new Westin Eat Well Menu for Kids recipes. #MissionDelicious
"17.06.2016 20:17:04" Timeline Photos See how The Westin Singapore embraces our new signature cocktail program by bringing fresh and locally sourced ingredients to Happy Hour. #CraftedatWestin #PlayWell
Photo: The Westin Singapore
"15.06.2016 20:33:01" Timeline Photos Take a walk around the Plaza de Canovas and get inspired by the vibrant colors and culture of Madrid.
Photo: The Westin Palace, Madrid
"14.06.2016 14:20:59" Westin Workout Keeping your routine on track...even when there is no track. #FitStar #GearLending #WestinWORKOUT
"13.06.2016 19:55:01" Timeline Photos Trade in your smartphone for a map today and stimulate your senses with a walk around your city.
"11.06.2016 20:14:03" Timeline Photos Happy #GlobalWellnessDay! Whether you want to #MoveWell, #EatWell, #SleepWell, or all 3, Westin has your well-being covered when you travel. Get inspired by The Westin Resort Nusa Dua Bali's monthly well-being program beginning today.
Read more here:
"11.06.2016 01:58:01" Timeline Photos Always inspiring a good night sleep, Westin's Heavenly Bed and #SleepWell menu are sure to relax & restore your body and mind.
"03.06.2016 20:02:38" Westin Hotels & Resorts celebrates #NationalRunningDay, bringing together guests, associates & buzzworthy businesses to "Net-Work Out" #RunWithAView #runWestin #MoveWell National Running Day 2016 Westin Hotels & Resorts celebrates #NationalRunningDay, bringing together guests, associates & buzzworthy businesses to "Net-Work Out" #RunWithAView #runWestin #MoveWell
"01.06.2016 16:34:36" Timeline Photos Our favorite day of the year is here. Lace up and hit the pavement. Happy #NationalRunningDay. #RunWithAView #runWestin
"20.05.2016 14:03:01" Timeline Photos A #SneakPeek of some behind the scenes prep work at Westin Gurgaon for competition #MissionDelicious. What are your favorite ingredients to use in the kitchen?
"19.05.2016 14:54:05" Timeline Photos Our chefs are dreaming up new recipes for our Eat Well Menu for Kids in collaboration with Partnership for a Healthier America. #PHASummit
"13.05.2016 16:02:02" Timeline Photos Revive with an artisanal elixir infused with natural ingredients and local flavors, with our new Crafted at Westin cocktail program. #NationalCocktailDay
"11.05.2016 11:33:02" Timeline Photos Better your morning routine with a dive in the gorgeous pool at The Westin Fort Lauderdale Beach Resort. #MoveWell
"08.05.2016 13:25:02" Timeline Photos Every mom deserves to sleep in and enjoy breakfast in bed on #MothersDay. How will you spend today? #EatWell
"05.05.2016 20:20:03" Timeline Photos We're spending #CincoDeMayo building our own healthy tacos. #PlayWell #EatWell
"04.05.2016 16:55:02" Timeline Photos If you're enjoying a relaxing staycation, take some time to explore the culture around you. A local food market near The Westin Chennai Velachery is the perfect place to get inspired. #EatWell
"03.05.2016 21:20:01" Timeline Photos The beautiful beaches of The Westin Ka'anapali Ocean Resort Villas make for a picturesque view during your afternoon beach walk. #MoveWell
"01.05.2016 10:46:02" Timeline Photos Getting your daily dose of Vitamin D is easy enough with a sunrise this radiant at The Westin Grand Cayman Seven Mile Beach Resort & Spa #FeelWell
"29.04.2016 16:00:03" Timeline Photos Wake up well-rested in the heart of downtown Atlanta at The Westin Peachtree Plaza, just steps away from sights like Atlantic Station and the Georgia Aquarium. http://west.tn/1VQlixq
"27.04.2016 20:32:49" Timeline Photos Surprising #Westin survey says #honeymooners are heading to the mountains to bike, hike, and hit the slopes. Nothing says love like a view from above! http://bit.ly/1riK5ib
"27.04.2016 16:00:02" Timeline Photos Escape your routine and relax along the shores of the Caribbean Sea at The Westin Dawn Beach Resort & Spa, St. Maarten.. Photo: Tineey
"25.04.2016 20:25:06" Timeline Photos Traveling for work can be tiring. End each day with a cup of Herbal Tea from our Sleep Well Menu, designed to promote rest and recovery so you can take on the week ahead. #SleepWell
"23.04.2016 20:47:03" Timeline Photos Playing golf is a great way to stay active on vacation. The Dunes Course at The Westin Resort, Costa Navarino offers an excellent climate for golfers throughout the entire year so you can #MoveWell.
"20.04.2016 17:37:02" Timeline Photos Treat yourself to a Westin Weekend of jazz and barbecue at The Westin Kansas City at Crown Center, and enjoy 3PM late checkout on Sundays to help you relax and recharge.
"18.04.2016 12:00:04" Timeline Photos Sometimes motivation comes from within…your mobile device. We are giving guests premium access to FitStar, with personalized videos and workouts at your fingertips. westin.com/fitstar #MoveWell
"14.04.2016 20:00:02" Timeline Photos The desert climate of The Westin Mission Hills Golf Resort & Spa offers warm, sunny days and cool evenings, making it the ideal setting for daytime adventure and evening relaxation. Photo: Instagram user, @merissasnider
"10.04.2016 12:31:02" Timeline Photos Make your Westin Weekend last longer. A late Sunday check-out gives you extra time by the pool at The Westin La Paloma Resort & Spa.
"08.04.2016 16:52:02" Timeline Photos Revitalize and reset in the extensive 4000 square meter spa at The Westin Resort, Costa Navarino, featuring distinct, specialty treatments that feature the areas's unique, natural products. #FeelWell http://west.tn/1WcSWhb
"06.04.2016 19:10:02" Timeline Photos #EatWell on on the road and enjoy the Ahi Tuna Steak at The Westin Resort & Spa Whistler; a great source of lean protein and packed with B vitamins. #spgcravings
"04.04.2016 14:12:02" Timeline Photos Run the trails at The Westin Hilton Head Island Resort & Spa using our Westin running maps, like 2008 Olympic Qualifier, Kathleen Jobes. #RunWestin #RunWithAView
"02.04.2016 16:47:05" Timeline Photos Just 20 min from Seattle, The Westin Bellevue provides endless possibilities for recreation in the Pacific Northwest.
"31.03.2016 12:00:01" www.forbes.com The 6 Best Running Routes In New York City NEW YORK CITY - Okay, you've had enough summer ice cream. You're inspired by the NYC marathon runners. Time to go for one of six scenic runs around the rivers and bridges around the city. This is the best season for it. NYC is a great city to log a few miles while taking in the scenic views. Take a look at the some of these great running routes for your next trip to the Big Apple. #runWESTIN
"28.03.2016 18:50:02" Timeline Photos Located in the heart of one of California’s most exciting cities, The Westin Pasadena features a relaxing outdoor pool with superb views, and is conveniently located to downtown excitement.
"26.03.2016 13:00:02" Timeline Photos Aloha, adventure. The incredible Moana Surfrider, A Westin Resort & Spa, is situated along the infamous Waikiki beach and offers beautiful views and lots activities to enjoy.
"23.03.2016 15:00:01" Timeline Photos Fuel your body with our delicious SuperFoodsRx™ dishes, packed with nutrients and energy. #EatWell
"20.03.2016 13:00:02" Timeline Photos You have the motivation, and we have the gear. Try our New Balance Gear Lending program and leave your sneakers at home. http://west.tn/1KvkHP6
"19.03.2016 16:09:02" Timeline Photos Eat Well to Sleep Well. We’re making you better in bed with our new Sleep Well Menu for in-room dining, featuring foods packed with vitamins and minerals that promote rest and well-being. #SleepWell #EatWell
"18.03.2016 13:20:15" Happy World Sleep Day #SleepWell We know nothing restores your mind & body like restful sleep. So celebrate World Sleep Day…and Dream Big. #SleepWell
"17.03.2016 18:13:02" Timeline Photos The Westin Dublin Hotel is in the perfect location to explore Ireland’s beautiful capital city. http://west.tn/1mRzqIz
"14.03.2016 13:00:04" Timeline Photos Fitness at your fingertips! We partnered with FitStar by Fitbit to offer another meaningful way to stay connected to your routine, when and where it works for you. http://west.tn/1Lg1yk6
"11.03.2016 20:08:02" Timeline Photos Take your kids on a vacation that’s filled with wonder and exploration with our new Family Program at The Westin Hilton Head Island Resort & Spa. http://west.tn/1mZUo82 #WonderAwaits
"10.03.2016 15:51:33" Westin Hotels & Resorts
"10.03.2016 15:51:09" Westin Hotels & Resorts's cover photo
"08.03.2016 19:36:05" www.spgweekends.com Best Places for a Romantic Getaway Sometimes the destination might be the difference between a weekend trip and a couples getaway you'll always remember. We've gathered a list of ideal retreats to spend with your special someone. Looking for a weekend getaway for two? Starwood Preferred Guest® (SPG) lists the 10 Best Places for Romance. See which Westin Hotels and Resorts made the list.
"06.03.2016 14:00:01" Timeline Photos Wake up and start your day with a nutritious and energy packed breakfast, like a delicious parfait and a berry smoothie. #EatWell
"05.03.2016 13:21:01" Timeline Photos Situated along the Savannah River, The Westin Savannah Harbor Golf Resort & Spa, offers incredible views for a morning run. #runWESTIN #RunWithAView
"02.03.2016 15:00:04" Timeline Photos Introducing one of our newest hotels, The Westin Doha Hotel & Spa. The hotel features a revitalizing Heavenly Spa, and refreshing indoor and outdoor pools. http://west.tn/1Lg9Ok0
"26.02.2016 13:00:06" www.spgweekends.com Whistler Winter Adventures In Whistler, British Columbia, you'll find there's so much more to a ski destination than just skiing. Adventures await off the slopes, like dog sledding an Big winter adventure awaits off the slopes of The Westin Resort & Spa Whistler. http://west.tn/1PS2I0T
"25.02.2016 15:28:11" Timeline Photos One third of people quit their New Year’s resolution after 1 month. We teamed up with FitStar by Fitbit to bring you premium access to great workouts so you can keep your routine while on the road. westin.com/fitstar #MoveWell
"21.02.2016 17:51:02" Timeline Photos No snow here. Enjoy plenty of sunshine at the The Westin Key West Resort & Marina. http://west.tn/1S9wXpa
"20.02.2016 02:48:01" Timeline Photos Energy comes in many colors. Kick-start your day with one of our Westin Fresh juices by The Juicery. #EatWell
"18.02.2016 17:53:02" Timeline Photos Escape for the weekend. The Westin Langkawi Resort and Spa has everything you need for a relaxing getaway. http://west.tn/1OMLVz4
"16.02.2016 13:30:02" Timeline Photos A #RunWithAView doesn't always have to be outside. #runWESTIN
"12.02.2016 16:43:03" Timeline Photos The perfect spot to start your weekend. Take in the views and relax in the sunshine at The Westin Maui Resort and Spa.
"09.02.2016 14:20:05" Timeline Photos Staying motivated can be tough. To help keep your routine on track, we've partnered with FitStar to offer guests free premium access to personalized workouts. Learn more: westin.com/fitstar #MoveWell
"07.02.2016 19:00:02" www.health.com Healthy Super Bowl Snacks Enjoy these 11 delicious and healthy game day recipes. You don't have to eat poorly on game day. Take a look at the these heatlhy alternatives for kick-off. http://west.tn/20bNLhU #EatWell
"06.02.2016 20:00:03" Timeline Photos We engage our youngest guests at every turn, inspiring kids to interact with their environment and try something new. Learn more at westin.com/family. #WonderAwaits
Photo: Travel Babbo
"04.02.2016 15:00:04" Timeline Photos Our new Westin Family program empowers the littlest sous chefs to make the most creative things, like homemade pizza with whole wheat crust and fresh vegetables. westin.com/family #WonderAwaits
Photo: IG user, @foxmeetsbear
"02.02.2016 17:13:02" Timeline Photos Beautifully situated along a peninsula on the Republic of Malta’s largest island, The Westin Dragonara Resort, Malta is an oasis of luxury and tranquility. http://west.tn/1OMGfoM
"30.01.2016 21:09:32" Timeline Photos Experience Southern hospitality with a stay at The Westin Huntsville.
"28.01.2016 14:44:02" Timeline Photos Clear some space in your bag and leave your workout gear at home. New Balance Gear Lending has you covered. #MoveWell
"27.01.2016 19:27:02" Timeline Photos Travel Babbo and his daughter put the Westin Family Travel Journal to use during their trip to NYC. westin.com/family #WonderAwaits
"25.01.2016 18:19:04" runwestin.tumblr.com 5 Tips for Healthy Eating on the Road Matt Fitzgerald's newly published book, "Racing Weight Cookbook" offers recipes as well as tips on how to eat healthy away from home. I spoke with Mr. Fitzgerald to discuss how he, a runner who travels roughly 8 days a month, practices eating healthy Maintaining a healthy diet while traveling isn't easy, but these 5 tips to #EatWell on the road can help.
"22.01.2016 21:13:03" Timeline Photos Located in the heart of Chicago’s theater district, The Westin Chicago River North is just steps from world-class restaurants, museums, art galleries, and upscale boutiques. http://west.tn/1Sa2IOF
"21.01.2016 21:19:04" Timeline Photos You spend about a third of your life asleep, so don't compromise your comfort. #SleepWell
"21.01.2016 00:18:02" Timeline Photos The stressful holidays are over. Now its time for a real vacation, like a relaxing stay at The Westin Jekyll Island. westin.com/HolidayAfterTheHoliday
"19.01.2016 22:20:07" Timeline Photos Adventure is open to all ages, and now our youngest visitors can explore more with our new Westin Family Program. westin.com/family #WonderAwaits
"18.01.2016 01:42:38" Timeline Photos Taking in the view from The Westin Phoenix Downtown after today's Rock 'n' Roll Marathon Series. The hotel is steps away from nearby stadiums, concert venues, museums, and restaurants. http://west.tn/1ncLfu5
"15.01.2016 23:36:03" Timeline Photos Miles and miles of incredible views. The Phoenix Rock 'n' Roll Marathon Series is this weekend, and our #runWESTIN running concierges are on-site for all of the excitement. #MoveWell
"13.01.2016 22:17:04" Timeline Photos The middle of the week is when you need the most energy, so try adding peach to your #WestinFresh juices from The Juicery. #EatWell
"12.01.2016 17:00:34" Timeline Photos Learn how our Family Program was created to help kids embrace and foster their imagination: westin.com/family #WonderAwaits
"10.01.2016 21:44:31" Timeline Photos Take full advantage of Westin Weekends late checkout and get in one more run. http://west.tn/1TO4hkz
"09.01.2016 17:17:38" Timeline Photos Ski season is in full swing in Colorado and across the US. #MoveWell and hit the slopes at The Westin Snowmass Resort. http://west.tn/1ZTGSBD
"07.01.2016 23:11:03" www.nytimes.com 52 Places to Go in 2016 It's a big world out there, so NYT narrowed it down for you. From the temples of Malta to the crystalline waters of the Yucatán, explore the top destinations to visit this year. Take your wellness routine further this year with 52 new places to go in 2016, by The New York Times, including The Westin Harbour Castle, Toronto.
"06.01.2016 15:26:24" Timeline Photos Did you know that several of our hotels produce fresh honey? Learn how we're using honey at our hotels around the world: http://west.tn/1SzN6EK #EatWell
"04.01.2016 20:26:05" Timeline Photos The holiday season may be over, but there's plenty of time for a #HolidayAfterTheHoliday. westin.com/holidayaftertheholiday
"02.01.2016 20:55:58" Timeline Photos Jodi Mockabee Photography showed us that her children have a passion for exploration, which is exactly what our new Westin Family program is all about. westin.com/family. #WonderAwaits
"01.01.2016 20:01:06" Timeline Photos Want to be more fit in the New Year? Regularly practicing yoga can help boost muscle strength and improve flexibility. #MoveWell
"31.12.2015 21:29:32" Timeline Photos Here's to another year filled with Well-Being, wherever your travels might take you in 2016.
"29.12.2015 19:27:31" Timeline Photos Spend the last few days of 2015 in a winter wonderland with a visit to The Westin Riverfront Resort & Spa at Beaver Creek Mountain. http://west.tn/1MFm4Vg
"28.12.2015 18:06:34" Timeline Photos Start your adventure with our Westin Family Package with great perks like 50% off your second room and free meals from our Westin Eat Well Menu for Kids. westin.com/family #WonderAwaits
"27.12.2015 21:37:02" Timeline Photos A daily run can help boost your spirits, fight off fatigue, and lessen the risk of high blood pressure and cardiovascular disease. #RunWestin #MoveWell
"25.12.2015 15:34:29" Timeline Photos Wishing you and your family a very happy holiday season.
"23.12.2015 16:11:05" www.westinooogenerator.com Westin Out Of Office Generator A better vacation deserves a better Out of Office Message. With the help of the humorists at McSweeney's, we've created a new way for you to step up your reply the next time you step away from the office and social media. The holidays are here. Let people know that you're taking some time off with our Westin Out Of Office Generator: www.westinooogenerator.com
"22.12.2015 19:04:34" Timeline Photos Healthy food isn't just for adults. Our Eat Well Menu for Kids features balanced meals for children of all ages. westin.com/family #WonderAwaits
"20.12.2015 23:04:03" Timeline Photos As part of the Westin Family program, when you stay at The The Westin Key West Resort & Marina you''ll receive a Local Activity Guide featuring kid-friendly attractions like the Butterfly Conservatory, Mel Fisher Maritime Museum, and the Conch Tour T
"19.12.2015 22:35:31" www.youtube.com WestinWORKOUT: 5-Minute Full Body Strength Training with Fitness Expert Holly Perkins Move Well with Westin. Check out this 5 minute full body strength training workout video from Certified Strength & Conditioning Specialist, New Balance Fitne... Even when on the road, get a full body workout in just five minutes with Certified Strength & Conditioning Specialist Holly Perkins #MoveWell
"18.12.2015 22:10:04" Timeline Photos The Westin Family Kids Club at The Westin Turtle Bay Resort & Spa, Mauritius is designed to encourage exploration, accomplishment, and wonder. See more more about our new Westin Family Program: westin.com/family #WonderAwaits
"17.12.2015 18:07:20" Westin Hotels & Resorts's cover photo Introducing the new Westin Family program. #WonderAwaits westin.com/family
"16.12.2015 18:57:40" Timeline Photos Make your family bonding more fitness-oriented with one of our kid-friendly active yoga classes at The Westin Hilton Head Island Resort & Spa. westin.com/family #WonderAwaits
"15.12.2015 01:26:35" Timeline Photos Keep yourself fresh and full of energy for the week ahead with a rejuvinating workout #MoveWell
"14.12.2015 21:09:48" We celebrated the launch of the new Westin Family program with a special event in New York City, empowering kids to explore their inner creativity. #WonderAwaits westin.com/family Westin Family Celebration Event #WonderAwaits We celebrated the launch of the new Westin Family program with a special event in New York City, empowering kids to explore their inner creativity. #WonderAwaits westin.com/family
"14.12.2015 01:11:15" Timeline Photos With our New Balance Gear Lending program, you can pack light and still stay active. #MoveWell
"11.12.2015 22:08:32" Timeline Photos Located next to Venice's magnificent Grand Canal, The Westin Europa & Regina, Venice offers amazing views just outside of your window.
"10.12.2015 23:14:59" www.spgweekends.com A Run Through 10 Cities with Chris Heuisler Meet Starwood Hotels & Resorts RunWESTIN Concierge, Christopher Heuisler! As Westin's official running expert, Chris shares training and race advice and a running guide of 10 cities across America. Need some inspiration for your next trip? Check out the RunWestin Concierge running guides for ten cities across the US.
"09.12.2015 22:19:33" Timeline Photos Eating fresh greens regularly can help you feel fuller while cutting down your calorie intake. #EatWell
"08.12.2015 17:24:15" Westin Family Introducing the new Westin Family Program, created to leave children feeling worldlier, happier, and healthier. Learn more and book your trip now: west.tn/family #WonderAwaits
"07.12.2015 21:02:03" Timeline Photos If you're looking to add some healthier options into your diet, berries are filled with folates and fibers, which can help improve your memory and reduce your risk of illness. #EatWell
"07.12.2015 15:43:28" The holidays are great, but a #HolidayAfterTheHoliday is even better. We partnered with @[153743181341677:274:Jaime King], @[188458483938:274:Hilary Rhoda], and @[125472670805257:274:Delta] to surprise unsuspecting New Yorkers and LAX associates wit Westin Holiday After The Holiday The holidays are great, but a #HolidayAfterTheHoliday is even better. We partnered with Jaime King, Hilary Rhoda, and Delta to surprise unsuspecting New Yorkers and LAX associates with Westin getaways. Book your post holiday getaway at westin.com/ho
"06.12.2015 00:33:58" Timeline Photos Join us at The The Westin Riverwalk, San Antonio for tomorrow’s Rock 'n' Roll Marathon Series! Located right alongside the famous San Antonio Riverwalk, the hotel offers instant access to a tranquil boat ride down the barge. http://west.tn/1YR7ZwU #W
"01.12.2015 21:55:02" Timeline Photos Soak in the scenery of the illustrious Gardens By The Bay with a stay at The Westin Singapore. http://west.tn/1Xw5Fhw
"30.11.2015 19:34:05" Westin Holiday After The Holiday Last week, Hilary Rhoda surprised holiday travelers in New York with rejuvenating #HolidayAfterTheHoliday Westin Resort getaways. Book your post-holiday vacation at westin.com/holidayaftertheholiday.
"30.11.2015 01:01:03" Timeline Photos A healthy meal, a cup of tea, and a #HeavenlyBed are what you need for a serene Sunday. #FeelWell
"28.11.2015 23:25:31" Timeline Photos Add some green to your diet with nutritious #WestinFresh juices and smoothies from The Juicery.
"26.11.2015 00:47:46" Timeline Photos Give your vacation the out-of-office message that it deserves with our #WestinOOO Generator. www.westinooogenerator.com
"25.11.2015 00:59:29" www.fitnessmagazine.com Why We Love Running in Cold Weather Does your running motivation wane every winter? It's time for a new workout mindset. Need some motivation for an outdoor workout? Here are RunWESTIN Concierge Chris Heuisler’s 9 reasons to run in cold weather: http://west.tn/1OfjwTv
"22.11.2015 16:52:00" Timeline Photos In addition to offering a world-class travel experience, The Westin Denver International Airport is positioned perpendicularly to the airport’s famous Jeppesen Terminal so guests can enjoy sweeping views of the Rocky Mountains and downtown Denver sky
"22.11.2015 00:33:17" Timeline Photos With more than 500 rooms and a design that emphasizes convenience and accessibility, The The Westin Denver International Airport is perfectly suited to provide travelers with a relaxing destination before and after they take flight.
"20.11.2015 22:11:08" Timeline Photos We are thrilled to introduce the brand new The Westin Denver International Airport! The hotel’s impressive roof, which resembles a bird in flight, was inspired by Denver’s iconic tents, surrounding natural environment, and the city itself. http://wes
"18.11.2015 17:47:35" Timeline Photos Papaya is full of fiber and antioxidants, and low in calories, making it one of the world's healthiest fruits. #EatWell
"17.11.2015 00:07:50" Timeline Photos Discover why Hainan Island is renowned as the 'Hawaii of the East' with a serene visit to The Westin Sanya Haitang Bay Resort 三亞海棠灣威斯汀度假酒店
"15.11.2015 15:25:02" Timeline Photos Whether you’re running a mile or today’s #RNRVegas Marathon, a 10-minute stretch can help you avoid aches & potential injuries. #RunWestin
"13.11.2015 22:08:34" Timeline Photos Follow us as we spend the next few days at The Westin Las Vegas Hotel, Casino & Spa for Sunday's Rock 'n' Roll Marathon Series. #RNRVegas
"12.11.2015 07:00:01" fitnessontoast.com COMPETITION #WESTINONTOAST We’re delighted to announce that Faya Nilsson from Fitness On Toast is our new Well-Being expert in Europe. Together we’ll host a set of special competitions and the first one launches today. Find out more at http://west.tn/westinontoast #westinontoa
"10.11.2015 23:11:07" Timeline Photos Experience Colorado's lush fall foliage firsthand with a trip to The Westin Snowmass Resort.
"09.11.2015 22:40:01" Timeline Photos Unwind beneath the sweeping backdrop of South Africa's fabled Table Mountain at The Westin Cape Town. http://west.tn/1M2ssZL
"08.11.2015 13:30:00" Timeline Photos A visit to The Westin Savannah Harbor Golf Resort & Spa wouldn't be complete without a stroll through the charming Forsyth Park, one of Georgia's largest and most historic parks.
"07.11.2015 12:00:01" starwoodpromos.com Westin VIP Marathon Package | Westin Hotels & Resorts Westin® Hotels and Resorts – the preferred hotel partner of the Rock`n’ Roll Marathon Series, has developed special packages designed to remove the stresses of traveling for a race. Good luck to all the runners in today's Rock 'n' Roll Marathon Series in Savannah! If you opted for the VIP Marathon package at The Westin Savannah Harbor Golf Resort & Spa, be sure to take advantage of our post-race ice bag delivery & late check out
"06.11.2015 21:14:22" westinsavannah.com The Westin Savannah Harbor Golf Resort & Spa Of the Savannah GA hotels in the Savannah River District, this hotel is perfect for your next family vacation or romantic retreat. We're heading to The Westin Savannah Harbor Golf Resort & Spa for the weekend in honor of tomorrow's Rock 'n' Roll Marathon Series. #RunWestin #RNRSav
"05.11.2015 23:21:09" Timeline Photos A daily dose of yoga can help keep your body feeling fresh and your mind alert. #MoveWell
"05.11.2015 00:59:52" Timeline Photos We're thrilled to introduce The Westin Soma Bay, our newest property in Egypt!
"02.11.2015 17:00:00" Timeline Photos Refuel for the week ahead with an energizing #WestinFresh juice blend by The Juicery. #EatWell
"01.11.2015 15:46:32" Timeline Photos Many thanks to Deena Kastor and Dean Karnazes for helping our The Westin New York Grand Central guests tune up for today’s TCS New York City Marathon. Best of luck to all the runners. #RunWestin
"31.10.2015 01:27:53" Photos from Westin Hotels & Resorts's post The Westin Abu Dhabi Golf Resort and Spa celebrated their annual Kilomarathon tonight. Proceeds will support UNICEF WASH projects across Africa and the Middle East, providing clean drinking water and proper sanitation facilities for families. #RunWes
"29.10.2015 20:26:23" Timeline Photos From its full-service spa to its scenic grounds, The Westin Kierland Resort & Spa is ideal for a family retreat.
"27.10.2015 23:09:02" westinchicago.com Downtown Chicago Hotels | The Westin Chicago River North Hotel Recently renovated! As one of the premier downtown Chicago hotels, The Westin Chicago River North is in the heart of the business and theatre districts. There's never a dull moment at The Westin Chicago River North, which is nestled next to the majestic Chicago River in the heart of the Windy City's restaurant & theatre districts. http://west.tn/1GHmlLi
"25.10.2015 15:00:01" Timeline Photos Good luck to all the runners participating in the Rock ‘n’ Roll Vancouver Half Marathon and Cunningham Seawall 10K today, including the Westin team led by our RunWestin Concierge! #RNRVan
"24.10.2015 19:56:02" Timeline Photos The outdoor swimming pool at The Westin Grande Sukhumvit, Bangkok is perfect for a refreshing getaway.
"23.10.2015 21:58:58" Timeline Photos Get centered this weekend with an outdoor adventure like this canoe ride through the lush Mercer Slough Nature Park, located just minutes away from the The Westin Bellevue #PlayWell #westinweekend
"23.10.2015 18:57:38" www.shape.com How to Plan Your Healthiest (and Best!) Vacation Ever You want a vacation that leaves you feeling refreshed, renewed, and reinvigorated. Mission: accomplished. We found the hotels, lodges, retreats, and road trips offering the most dynamic, healthiest, fittest, fun perks imaginable. Pack up, life is abo "A runner's fantasy" is how SHAPE Magazine editors recognize Westin's offerings for runners in their annual 'Healthy Travel Awards'.
"22.10.2015 22:59:51" delta.com Arrive Well-Rested: Heavenly® In-Flight Bedding on Delta One™ Curl up or stretch out beneath plush Westin Heavenly® In-Flight Bedding on 180-degree flat-bed seats. Bedding includes an oversized white comforter and hypoallergenic, down-alternative pillows. Wake even more refreshed with a lumbar pillow on flights From take off to landing, Delta One passenger can relax with our Heavenly In-Flight Bedding. Available on all long-haul flights and all cross-country flights from JFK to LAX or SFO. http://west.tn/delta
"21.10.2015 23:52:05" westinwellbeing.starwoodpromos.com Eat Well: SuperFoodsRx™ Fuel your body with delicious SuperFoodsRx™ dishes packed with nutrients and energy. Antioxidant rich and naturally low in calories, our tempting selections – from whole-wheat blueberry pancakes to all-natural roasted turkey wraps and black bean humm Created together with doctors and nutritionists, our SuperFoodsRx menu cultivates “food synergy,” the pairing of certain foods to increase their nutritional value, to give you the focused energy you need to meet the challenges of your day. http://wes
"20.10.2015 22:07:00" Timeline Photos Explore seven centuries of Florentine culture and history while staying at The Westin Excelsior, Florence.
"20.10.2015 02:32:41" westinooogenerator.com Westin Out Of Office Generator A better vacation deserves a better Out of Office Message. With the help of the humorists at McSweeney's, we've created a new way for you to step up your reply the next time you step away from the office and social media. Step up your Out of Office message this vacation with our #WestinOOO Generator http://west.tn/OOO
"19.10.2015 02:00:01" Timeline Photos Sundays were meant for sleeping late in a #HeavenlyBed. #sleepwell
"17.10.2015 16:59:40" Timeline Photos Stay fresh with a soothing Saturday afternoon in our Heavenly Spa at The Westin Turtle Bay Resort & Spa, Mauritius. #FeelWell
"15.10.2015 23:59:36" Timeline Photos At the end of the most challenging journeys await the most fulfilling views. #MoveWell
"14.10.2015 19:53:53" westinooogenerator.com Westin Out Of Office Generator Westin created a witty new way to step up your reply the next time you step away from the office or social media. A better vacation deserves a better Out of Office message. With the help of the humorists at McSweeney's, we’ve created a new way for you to step up your reply the next time you step away from the office. #WestinOOO http://www.westinooogenerator.com/
"13.10.2015 20:19:39" starwoodhotels.com Westin Resort & Spa Los Cabos | Beach Resort in Los Cabos Exclusive offers. Best rates guaranteed. Experience a Upscale Beach Resort in Los Cabos booking in Westin. Book online or call: (52)(624) 142 9000 The alluring ocean views at the The Westin Resort & Spa, Los Cabos are sure to take your breath away. Reopening July 2016. http://west.tn/1PrEdeW
"11.10.2015 21:50:47" Timeline Photos Forgot to pack your sneakers? Through our gear lending partnership with New Balance, we'll deliver athletic apparel and shoes to your room to get you started. #RunWestin #MoveWell
"09.10.2015 23:05:40" Timeline Photos The Westin Valencia is located only a short stroll away from the City of Arts and Sciences, one of Spain’s most celebrated cultural landmarks. #WestinFinds
"08.10.2015 10:00:02" Timeline Photos Hit the road while on the road. Join a group run with our Run Concierge or grab a running map and take off on your own. http://west.tn/1WOkdFo #RunWestin #movewell. Photo credit: @chrisheuisler
"06.10.2015 22:41:04" Timeline Photos Tap into New England's rich history & lively culture with a visit to the iconic Boston Harbor at Westin Boston Waterfront Hotel. http://west.tn/1QXB5FX
"06.10.2015 02:18:00" nytimes.com Weddings Take Offbeat Turns, With Help From Hotels and Planners Hotels and wedding planners are catering to new trends like informal mixers, after-parties, custom meals, social media concierges and personalized hashtags. Learn how The Westin La Paloma Resort & Spa & The Westin Cape Coral Resort at Marina Village can give you a modern, nontraditional wedding experience. Via The New York Times
"05.10.2015 22:52:59" Timeline Photos Eating well isn't just for adults - our Eat Well Menu for Kids means family meals are healthy, balanced and kid-approved. http://west.tn/superchefs #eatwell
"04.10.2015 13:27:02" Timeline Photos Spend your Sunday testing out your 9 iron and taking in the view at The Westin Resort, Costa Navarino #westinweekend
"03.10.2015 15:00:08" Timeline Photos Rest and relaxation are just as important to well-being as healthy eating and exercise. Treat yourself to a #HeavenlySpa experience this weekend. #feelwell
"02.10.2015 20:33:04" Timeline Photos Take a break from the ordinary with an exhilarating downhill mountain bike tour at The Westin Trillium House Blue Mountain. #playwell
"01.10.2015 02:22:59" Timeline Photos Lavender oil helps you ease the effects of jet lag and travel. It acts as a mild sedative, promoting sleep and leaving you more refreshed the next day. http://west.tn/sleepwell #WestinWellBeing #sleepwell
"29.09.2015 23:59:32" Timeline Photos Runners warm up at the track club during the inaugural Mammoth Running Escape with Olympic medalist and American record holder in the marathon, Deena Kastor . This retreat celebrated wellness through running in the most stunning mountain environment.
"28.09.2015 17:47:49" youtube.com The “Mebsie” RunWESTIN Concierge Chris Heuisler and Runner’s World’s Chief Running Officer Bart Yasso discover the phenomenon known as “The Mebsie” with Meb Keflezighi. What happens when Meb Keflezighi, Runner's World Chief Running Officer Bart Yasso, and our #RunWestin concierge Chris Heuisler team up? Introducing the #Mebsie. #MoveWell https://youtu.be/WZYlmiZRHI0
"24.09.2015 23:31:07" Timeline Photos Stella San Jac, located on the ground floor of the the new The Westin Austin Downtown is serving up fresh savory dishes, like this delectable Pearl Cous Cous with Oil Cured Tomato, Feta and Frisee. #eatwell #WestinWellbeing http://west.tn/1KxYa0j
"23.09.2015 22:20:00" Timeline Photos #FirstDayOfFall means you're one step closer to your yearly running goals. #WestinWellBeing #movewell
"22.09.2015 20:20:07" roadwarriorvoices.com These healthy hotels put fitness first These hotels offer packages ranging from cliffside yoga to boxing classes to in-room workout centers. Road Warrior Voices by USA TODAY Travel lists The Westin Verasa - Napa as a top healthy hotel that puts fitness first, featuring the RunWestin Concierge, gear lending, 24-hour gym saltwater pool, and a Yoga Concierge. Achieve wellness on the road. #W
"20.09.2015 15:26:33" superfoodsrx.com Folate Foods That Can Save Your Life Folate -- we all need it, but what the heck is it? And where do we find folate foods if we’re mostly plant-eating people? Dr. Lindsey Mcilvena breaks it down. Folate is an antioxidant that also goes under the alias vitamin B9 and it's essential to our bodies. Find out about this and other SuperFoodsRx : http://west.tn/1MkkuuO
"18.09.2015 22:29:27" Timeline Photos The weekend is always on the horizon. Fridays at Moana Surfrider, A Westin Resort & Spa start like this. #westinweekend #playwell
"17.09.2015 21:04:01" Timeline Photos A morning run at The Westin Long Beach is more than a workout when it comes with an inspiring view. #runwithaview
"16.09.2015 16:19:03" Timeline Photos Unwind with an afternoon walk and injection of color, like this view of Burano, a short boat ride away from The Westin Europa & Regina, Venice. #feelwell
"15.09.2015 00:14:28" 2015.usopen.org BTB Day 14: On The Road BTB Day 14: On The Road - Video from the 2015 US Open Tennis Championships. Our Global Brand Leader, Brian Povinelli, stopped by #BeyondBaseline set during the final of the U.S. Open Championships and shared his insights for a better you. http://west.tn/1J8O5CW
"09.09.2015 16:41:06" 2015.usopen.org BTB Day 7: On the Road BTB Day 7: On the Road - Video from the 2015 US Open Tennis Championships. A perfect match. Indulge in SuperFoodsRx dishes, live US Open Tennis Championships coverage, cocktails and more during Match Point Hour. Everyday until Sep. 10th at The Westin New York At Times Square. http://west.tn/1EOGHl1
"04.09.2015 18:40:03" Timeline Photos Long weekends are for indulging, renewal and reconnecting. How are you spending your #LaborDayWeekend? #playwell
"31.08.2015 21:10:38" youtube.com US Open Beyond the Baseline Presented By Westin Sneak peek to the US Open Beyond the Baseline presented by Westin Hotels and Resorts. Join us at #BeyondtheBaseline presented by Westin as we explore how players live, play and eat well during the US Open Tennis Championships. Tune in everyday at 7PM on www.usopen.org and ESPN3.
"30.08.2015 17:00:01" westinwellbeing.starwoodpromos.com Late Sunday Checkouts and Extended Breakfast Hours | Westin Weekend Enjoy late checkout on Sundays and extended breakfast hours to help your Westin Weekend last even longer. How to make Monday's better? http://west.tn/weekend
"29.08.2015 19:00:01" afar.com What to Do around The Westin Grande Sukhumvit, Bangkok Once you're in Thailand's capital you'll discover there's more to this vibrant city than meets the eye. While it's known for late nights, warm weather, unique markets, opulent temples, and delicious food, it's the cosmopolitan culture that makes Bang The riverside Buddhist temple Wat Arun main feature is it's central 'prang' or tower, which is encrusted with colorful porcelain. Find great local places in Bangkok with #WestinFinds from AFAR. http://west.tn/1LwTTu0
"28.08.2015 15:51:11" spghotescapes.com Escape with weekly savings Weekly Starwood Hotel discounts. SPG members save more and earn Starpoints. Counting down the rest of your summer weekends? Plan your next getaway with weekly savings. http://west.tn/1VbqhqE
"26.08.2015 21:28:40" westinwellbeing.starwoodpromos.com Westin Heavenly® Dog | Pet Friendly Westin Hotels Program With a plush bed and special amenities, the Heavenly® Dog Program extends the Heavenly experience to guests’ favorite travel companions. Happy #NationalDogDay. Extend the Heavenly experience to your trusted travel companion. http://west.tn/heavenlydog
"24.08.2015 19:10:35" afar.com Being in the Moment After a full day of exploring Warsaw on foot, I decided to take a moment to unwind in Saxon Gardens. To enjoy being in the moment with the locals and travelers alike, as the sun highlighted the scene. The day was then topped off with a Chopin concert Saxon Gardens is an ideal place to relax after a full day of exploring Warsaw. http://west.tn/1Pvu9zD
"22.08.2015 21:22:00" The Westin Harbour Castle, Toronto is located in the heart of downtown with sprawling views of Lake Ontario. http://west.tn/1PvxLl8
"21.08.2015 20:17:00" superfoodsrx.com west.tn Get more broccoli into your diet with these tips from @SuperfoodsRx: http://west.tn/1PvxyhZ
"20.08.2015 19:04:01" Treat yourself to this view of the Andaman Sea at The Westin Langkawi Resort and Spa. http://west.tn/1fsaSSP
"18.08.2015 14:14:21" Game. Set. Match. Stay close to the action at this year's US Open Tennis Championships. http://west.tn/1J8KyJk
"16.08.2015 18:07:13" Sink into the Heavenly Bed and experience a night of restorative sleep that is so divine you’ll never want to get out of bed. http://west.tn/1L2dKE6
"14.08.2015 14:09:14" superfoodsrx.com Healthy Orange Chicken Recipe with Apricot Almond Couscous Yes, there is such a thing as a healthy orange chicken recipe. It looks like a lot of work, but this is easy to make if you assemble everything in advance. Enjoy this delicious and healthy orange chicken with apricot almond couscous recipe from SuperFoodsRx: west.tn/1JRll6N
"12.08.2015 15:30:59" sleep.org Energizing Foods That Perk You Up | Sleep.org It’s natural to reach for a cup of coffee when you are feeling tired, but these five foods can help boost your energy instead. Instead of reaching for coffee, try these 5 foods that can help boost your energy: http://west.tn/1JRePNE
via National Sleep Foundation
"11.08.2015 12:26:51" Planning to run while traveling? Our Move Well amenities will help you stay fit while taking in the city sights. http://west.tn/gearlending
"09.08.2015 15:37:37" luxury-insider.com Lara Dutta, Bollywood actress and former Miss Universe, shares 6 tips on staying active and... Lara Dutta is a Bollywood actress, Miss Universe 2000 and a yoga enthusiast. The newly appointed Westin Well-being brand advocate shares her approaches on how to maintain an active and productive lifestyle while on holiday. Westin Well-Being Advocate Lara Dutta shares her secrets to achieving balance amidst a hectic schedule. http://west.tn/1HYJq9h
"07.08.2015 15:07:30" The perfect workout combination: state-of-the-art equipment and inspiring ocean views.
"05.08.2015 12:15:48" Throughout the summer, guests are taking advantage of a complimentary yoga series hosted at The Westin Edina Galleria. http://west.tn/1HYDDAJ
"03.08.2015 14:36:24" Enjoy the Windy City's must-see places and best-kept secrets, all within easy reach of The Westin Michigan Avenue. http://west.tn/1HYAQYk
"01.08.2015 14:10:07" Find your suite spot. Who would you share this view with?
"31.07.2015 12:56:07" Get up and go. Explore Vancouver with a morning run around the world famous Stanley Park: http://west.tn/1I72hPz
"30.07.2015 16:06:39" Drinking water is one of the easiest things we can do to keep ourselves healthy. Keep a water bottle nearby so you can drink from it all day and stay hydrated.
"28.07.2015 16:23:10" Need a mental break? Float away with us to the Lazy River at Westin Kierland Resort & Spa. www.kierlandresort.com
"27.07.2015 14:05:38" Rise and energize with a blueberry smoothie and granola parfait from SuperFoodsRx.
"25.07.2015 13:15:19" A breath of fresh air from the moment you arrive, this newly-installed Vertical Garden is our largest in the US at four stories tall.
"24.07.2015 14:31:09" Westin Wellness Escape with Waka Nozawa Discover Westin Wellness Escape with top fashion model and acclaimed yogi, Waka Nozawa. Explore holistic approaches to well-being through yoga and Westin signature brand programs like SuperfoodsRx and runWESTIN. http://west.tn/1JCTnHz
"23.07.2015 15:45:02" Need a quick getaway? Take a mental vacation with us to Westin St. John Resort & Villas, U.S. Virgin Islands.
"21.07.2015 16:29:31" superfoodsrx.com Tarragon Turkey Salad Recipe with Walnuts This tarragon turkey salad recipe is full of great flavor. It's also a fantastic way to eat both turkey and walnuts, 2 amazing superfoods. Here's the recipe from SuperFoodsRx.
"20.07.2015 15:08:23" Enjoy your perfect post-workout smoothie from Westin Fresh by The Juicery. www.west.tn/fresh
"19.07.2015 14:27:49" Did you know? Blueberries contain more fiber, vitamins, and minerals per ounce than almost any other fruit.
Eat Well with Westin: www.west.tn/eatwell
"18.07.2015 14:23:56" Wake up to views overlooking the stunning Via Veneto from the breezy terrace of The Westin Excelsior Rome: http://west.tn/1eWQCbS
"17.07.2015 14:45:58" Explore the Live Music Capital of the World from the all new The Westin Austin Downtown: http://west.tn/1faFad0
"16.07.2015 15:16:40" San Francisco is one of the world’s best places to ride a bike. Start planning your perfect summer weekend: http://west.tn/1M2hkgm
"15.07.2015 14:45:43" Experience Costa Rica's 'pura vida' lifestyle at The Westin Golf Resort & Spa, Playa Conchal, an All Inclusive Resort.
Begin your exotic escape: http://west.tn/1eWRNYQ
"14.07.2015 13:38:47" sleep.org How to Improve Your Sleep Quality These tips will help your improve your sleep... staring tonight! Here are six science-backed tips from The National Sleep Foundation that are bound to help you sleep better.
"11.07.2015 15:51:01" westinwellbeing.starwoodpromos.com Westin Wellness Escapes Discover Westin Wellness Escapes, a series of ongoing well-being retreats led by experts in the fields of fitness, mindfulness meditation, nutrition, yoga, running and more. Running a Fall marathon? Join Deena Kastor at The Westin Monache Resort, Mammoth to gain your edge.
"10.07.2015 15:48:21" Soak up the views with stand-up paddle boarding.
"09.07.2015 14:26:24" inc.com 6 Steps to Reenergizing Your Mind During the Workday How to use meditation to rejuvenate and repair the mind. See how to use meditation to rejuvenate and repair the mind during your workday.
"07.07.2015 16:59:27" Studies show that more time outdoors will reduce stress, boost creativity, and improve overall wellness.
"06.07.2015 16:32:10" Start your stay with 18 challenging holes along the stunning coastline of the Ionian Sea at The Dunes or Bay Course.
"05.07.2015 16:27:40" Our 3pm checkout on Sundays means more time to recharge poolside, and a better start to your Monday.
"04.07.2015 14:45:01" Need a fresh and flavorful idea for your July 4th BBQ? Eat Well with these homemade fresh fruit popsicles.
"03.07.2015 16:05:36" What do successful people read in the morning? Here is a quick glimpse: http://west.tn/1CJJRjo
"01.07.2015 19:40:16" Break for a rejuvenating stroll through St. Stephen’s Green Park. It's the perfect spot for a nourishing picnic along the swan-filled lake.
"29.06.2015 19:14:20" Tokyo Tower by night. Be captivated by stunning views of the city from 333 meters high.
"28.06.2015 12:48:25" spgweekends.com Bikeable Weekends - The Best Cities To Explore On Two Wheels SPG Weekends Explore your next city destination by bike.
"27.06.2015 15:53:01" superfoodsrx.com No Cook Vegetable Kabobs These vegetable kabobs can be eaten raw or grilled. A simple marinade makes the veggies delectable by bringing out their natural flavor. Enjoy this delicious SuperFoodsRx recipe for no-cook vegetable kabobs.
"25.06.2015 22:21:01" Enjoy deep, restful sleep for a productive tomorrow.
"23.06.2015 13:36:53" runnersworld.com 26.2 Suprises: A Birthday Party of Marathon Proportions Copyright © 2015 Rodale Inc. No reproduction, transmission or display is permitted without the written permissions of Rodale Inc. Our RunWestin Concierge planned a surprise birthday party of marathon proportions. Here are highlights from the epic race.
"21.06.2015 13:19:03" Today marks the first ever #InternationalDayofYoga. Celebrate a world of well-being along the beach of The Westin Sohna Resort & Spa.
"20.06.2015 14:19:29" afar.com Things to Do in Singapore Photos, Guides, Itineraries Travel deeper in Singapore with stunning photos, personal highlights and travel advice from AFAR's editors and travel community. Embark on a new adventure in Singapore with our curated local guide offering the best-kept secrets of what to see and do.
"19.06.2015 14:21:18" entrepreneur.com The Morning Rituals of 10 of the World's Most Inspirational Entrepreneurs (Infographic) Take a note from Jack Dorsey, who rises every morning at 5:30 for a meditation session followed by a six-mile jog. Start today inspired by the morning routines of the world’s top 10 entrepreneurs.
"18.06.2015 22:33:56" Impeccable greens and fairways matched with inspiring vistas. Play your best round yet at The Westin Mission Hills Resort & Villas: http://west.tn/1B5tMJH
"17.06.2015 12:30:55" Fly through Florence. Accomplish the trip of your dreams with our curated guide to the city’s most exhilarating experiences: http://west.tn/1KZo3oN
"14.06.2015 13:09:57" Reward yourself with a weekend of white-sand beaches along the turquoise Caribbean Sea.
"12.06.2015 22:22:00" sleep.org 5 Things Not to Do Before Going to Sleep | Sleep.org by the National Sleep Foundation Find out what 5 things you should always avoid before bedtime. Texting before bed makes it harder for you to sleep all night. The National Sleep Foundation suggests avoiding these 5 bedtime habits in order to sleep well.
"11.06.2015 13:34:13" superfoodsrx.com Low Fat Yogurt – SuperFood – Overview - SuperFoodsRx There are tons of benefits in low fat yogurt. From the live and active cultures to being a great source of protein. See what other good stuff it contains. Fit fact: A single serving of yogurt improves workout recovery and gives you a healthy boost of Vitamin B12. Discover more benefits from SuperFoodsRx: http://west.tn/1RK3WyN
"10.06.2015 15:59:30" westinwellbeing.starwoodpromos.com Westin Wellness Escapes Discover Westin Wellness Escapes, a series of ongoing well-being retreats led by experts in the fields of fitness, mindfulness meditation, nutrition, yoga, running and more. Escape to stunning views of the Sierra Mountains on a 4-day running retreat led by renowned Olympian Deena Kastor at The Westin Monache Resort, Mammoth.
"09.06.2015 14:23:33" Move Well Tip from Fitness Expert Holly Perkins: Break the Status Quo Westin Wellbeing Council Member Holly Perkins Fitness explains the cause of your fitness plateau and how to beat it.
"05.06.2015 13:55:35" www.active.com Post-Run Stretches Every Runner Should Do Many runners miss an important step when training: stretching. Spend less than five minutes stretching after your run, and you'll notice a world of difference. Performing stretching exercises after a run will help you cool down gradually and improve your flexibility. Here are a few to get you started, and keep you healthy.
"04.06.2015 15:20:26" Reward Yourself. To revive tired muscles after a run, try to swim some easy laps or simply recharge poolside.
"03.06.2015 16:33:53" In celebration of National Running Day, Westin encouraged guests and associates to take their runs outside, while also discovering interesting views and wellness moments along the runWESTIN Running Routes. Run With A View In celebration of National Running Day, Westin encouraged guests and associates to take their runs outside, while also discovering interesting views and wellness moments along the runWESTIN Running Routes.
"03.06.2015 16:33:53" In celebration of National Running Day, Westin encouraged guests and associates to take their runs outside, while also discovering interesting views and wellness moments along the runWESTIN Running Routes. Run With A View In celebration of National Running Day, Westin encouraged guests and associates to take their runs outside, while also discovering interesting views and wellness moments along the runWESTIN Running Routes.
"02.06.2015 14:39:55" medicaldaily.com Runner's High, Explained It's true: a marijuana-like high is possible to experience during endurance exercise. But only recently has science started to understand what exactly causes it. Have you ever achieved a ‘runner’s high’? Science reveals that you produce more feel-good chemicals while running. #NationalRunningDay
"01.06.2015 13:09:40" To help you pack light and stay fit, we offer New Balance shoes and clothes for you to use during your stay.
Shoes come with socks that are brand new and yours to keep.
"31.05.2015 16:10:49" Top off the work week. Refresh with a revitalizing 'Weekender' on Seven Mile Beach.
"30.05.2015 14:53:14" Reconnect in paradise. Who would you share this oceanfront view with?
"29.05.2015 15:49:22" Awe-inspiring views meet state-of-the-art equipment at this WestinWORKOUT Fitness Studio.
"28.05.2015 15:46:24" superfoodsrx.com The Real Fantastic 4: Exploring the Power of Avocados Avocados are rich in nutrients, including magnesium, potassium and folate as well as phytonutrients and phtytosterols. Avocados have four powerful nutrients that make them a SuperFood. Can you guess them all?
SuperFoodsRx has the answers.
"27.05.2015 18:41:39" Combine your workout routine with a tour of the local scenery using our convenient Westin Workout Running Maps.
"26.05.2015 12:59:40" Awaken inspired. Captivating floor-to-ceiling city views fuel you for a day headed towards success.
"24.05.2015 13:41:01" Long Delta trip ahead? Our Westin Heavenly In-Flight bedding gives you soothing comfort so that you can land on your feet, recharged.
"23.05.2015 15:40:00" Fit fact: A well-designed and well-executed cheat meal might help you overcome a weight-loss plateau: http://west.tn/1QXj1N3
"22.05.2015 11:27:31" Rejuvenate with an uplifting swim in Qingshui Bay, or watch the sunset from your oceanfront suite.
"21.05.2015 13:19:09" jamesclear.com Hacking the Workout Journal: How to Track Your Workouts Read this article to learn how to hack your workout journal by using this simple and effective system for tracking your workouts. Improve your workouts over time by logging each workout in a diary. Here’s what you should be tracking.
"20.05.2015 21:43:01" Business or leisure? Unwind from your busy day in the soothing, refreshing sanctuary of The Westin Houston Downtown: http://west.tn/1A4vLxc
"19.05.2015 15:25:37" Fit fact: If you have at least 12 minutes, you have time for a rewarding upper body, lower body, and cardio pool workout.
Dip into one of our refreshing pools, and challenge yourself to one of these invigorating workouts. http://west.tn/1A4tO3U
"18.05.2015 17:03:49" A natural and nurturing atmosphere. Our vertical gardens are designed to help you feel balanced and inspired during your stay.
"14.05.2015 20:41:58" Stick with your routine, even while traveling. Here are seven tips to help you swim in hotel pools. http://west.tn/1FgvpWm
"12.05.2015 16:31:23" Our RunWestin Concierge is traveling to The Westin Jekyll Island and racing in his first triathlon this weekend. After the race, guests will also enjoy a number of carefully selected amenities targeted at the importance of proper recovery following
"11.05.2015 16:08:16" Sight-running through Bangkok's Benjakitti Park.
Designed with New Balance, our pocket-sized running maps help you combine your workout with fresh air and local scenery.
"09.05.2015 14:50:34" Cool-down exercises help to recover your muscles and improve your performance.
Here are a few easy routines: http://west.tn/1ELWxcp
"08.05.2015 17:47:53" Our RunWESTIN Concierge compiled a running guide of 10 cities across America. Did your favorites make the list? http://west.tn/1cvl646
"05.05.2015 14:55:01" Green smoothies are a quick and easy way to get large amounts of fruits and leafy greens into your daily diet.
Today's ingredients: Spinach, Kale, Banana, Mango, Cinnamon, Almond Milk
"03.05.2015 13:48:13" Your weekend lasts longer with 3pm checkout on Sunday. Learn how to Make Monday Better: http://west.tn/1Is5Lxk
"01.05.2015 16:37:09" A SuperFoodsRx power hour.
Find recipes and tips on how to incorporate these foods in your daily diet. http://west.tn/1IsbQtt
"28.04.2015 13:52:06" Who would you enjoy this moment with? Tag them in the comments to share the view!
"25.04.2015 13:48:24" RunWESTIN Combine your workout routine with fresh air and local scenery with our RunWESTIN program. http://west.tn/runwestin
"24.04.2015 15:30:23" Did you know that 95% of the vitamins and enzymes our bodies need are found in the juice of raw fruits and vegetables?
Fuel your day and enhance your wellness with Westin Fresh by The Juicery.
"23.04.2015 14:17:01" self.com 11 Spring Fruits and Veggies to Boost Your Metabolism Spring has officially sprung—just glance around the farmers market for proof of the seasons bounty—and a parade of fresh produce is soon to hit your plate. From fruit-packed breakfasts to veggie side dishes that outshine your mains, were getting gear Spring forward your diet by eating these in-season fruits and vegetables.
"22.04.2015 20:26:02" Celebrate the opening of our newest resort, The Westin Jekyll Island, with an extra 1,000 Starpoints per stay and more: west.tn/1IJkL7L
"21.04.2015 14:30:04" runwestin.tumblr.com A Marathon of Life As the Star Spangled Banner was being sung at the start line of the Rock’n’Roll Raleigh Marathon on Sunday, I was doing my best to keep it together because it was at that moment when I knew we had done it: we kept a secret for nearly a year. The pla Our RunWestin Concierge planned 26 miles of surprises at his most recent marathon. Read more about his memorable day: http://runwestin.tumblr.com/post/116384876282/a-marathon-of-life
"20.04.2015 14:57:50" Clean air helps energize the body and mind. Stay refreshed with our Vertical Gardens.
"16.04.2015 15:04:07" Need a better alternative to cure your sweet-tooth? Raspberries and blackberries are rich in antioxidants and low in calories.
"14.04.2015 14:01:45" Roam around Rome. Find great restaurants and memorable sights during your Westin Weekend: http://west.tn/1FQoakG
"11.04.2015 14:49:40" Kick-off your weekend with Holly Perkins Fitness!
She’s in San Diego hosting the inaugural Westin Wellness Escapes, a new series of expert led well-being experiences that help you stay fit even when you travel.
"08.04.2015 13:27:27" Take your work outdoors.
Enjoy the view while staying productive at Westin Playa Bonita Panamá.
"07.04.2015 14:36:47" Pilates and yoga to start the day. It’s a great way to cleanse the body, as well as peace of mind.
"04.04.2015 11:53:56" Are you running junk miles? Read why our Run Westin Concierge recommends quality over quantity: http://west.tn/1FGZyNK
"02.04.2015 15:55:55" westinfinds.com Westin Finds from AFAR At Westin, everything we do is designed to help you be your best and make the most of your stay. That’s why we’ve partnered with award-winning AFAR magazine to help you find and experience the best-kept secrets near your hotel. Westin Finds from AFAR offers you access to the best-kept secrets on what to see and where to eat, drink and shop during your stay.
"31.03.2015 17:39:11" Thanks to Instagrammer wandererinasia for sharing her view from The Westin Siray Bay Resort & Spa Phuket.
"29.03.2015 14:44:32" Enjoy the views of the The Westin Key West Resort & Marina's 5-mile running route: http://sta.rw/1HtPfx9
"27.03.2015 13:47:12" Pack Light and Stay Fit. We offer New Balance clothing and shoes for you to use during your stay. http://west.tn/gearlending
"25.03.2015 14:37:49" Create lasting memories at The Westin Langkawi Resort and Spa. Book now and save 20% on Suites and Villas: http://west.tn/19PCoaP
"23.03.2015 20:45:37" The Westin Heavenly Bed. Ten layers of pure comfort that add up to one exceptional sleep experience.
"20.03.2015 15:41:26" Experience the magic of Mauritian hospitality in a truly luxurious setting at The Westin Turtle Bay Resort & Spa, Mauritius: http://west.tn/1BA0kJT
"18.03.2015 18:21:42" WestinWORKOUT: 5-Minute Full Body Strength Training with Fitness Expert Holly Perkins Don’t miss out on our first well-being retreat hosted by Holly Perkins Fitness at Westin San Diego Gaslamp Quarter April 10-12!
Reserve a spot: westin.com/wellnessescapes
"16.03.2015 14:47:59" We've teamed up with SuperChefs Cookery for Kids to educate kids on the importance - and the fun - of eating smart.
Learn more: http://west.tn/eatwellmenuforkids
"14.03.2015 15:58:22" Nothing restores your mind and body like restful sleep.
Dream away in the Westin Heavenly Bed so you can meet the challenges of the day head on.
"12.03.2015 16:11:02" Trade in the treadmill for a RunWESTIN self-guided jog or refreshing walk with our custom running maps.
Designed by New Balance, our pocket-sized maps feature 3-mile and 5-mile routes from our hotel so you can combine your workout routine with fresh
"11.03.2015 14:22:36" Uplifting downtime. Experience the very best skiing and snowboarding of Ontario at The Westin Trillium House Blue Mountain. http://west.tn/bluemntn
"10.03.2015 22:08:02" Caffeine may be your daily go-to energy boost, but avoiding it at night will help your body relax & rest. #SleepWell http://west.tn/1Bh8TsA
"07.03.2015 15:19:13" Not only do the Tuileries gardens provide a vast space away from busy Parisian street life, but it's conveniently located next to The Westin Paris - Vendôme.
"05.03.2015 14:12:29" The Westin Resort Nusa Dua Bali provides you with a rejuvenating haven to be at your best. http://west.tn/1M8RMuO
"03.03.2015 15:43:54" Move Well Tip from Fitness Expert Holly Perkins: It Just Takes Three Move Well with #WestinWellBeing Council Member and New Balance Fitness Ambassador Holly Perkins Fitness.
Learn more about Holly's retreat at Westin San Diego Gaslamp Quarter as part of the new Westin Wellness Escapes series. westin.com/wellnessesca
"02.03.2015 12:49:03" westinwellbeing.starwoodpromos.com Westin Wellness Escapes Discover Westin Wellness Escapes, a series of ongoing well-being retreats led by experts in the fields of fitness, mindfulness meditation, nutrition, yoga, running and more. Announcing Westin Wellness Escapes, the latest phase of the Westin Well-Being Movement! Led by wellness experts and designed to inspire as well as empower, our new retreats include interactive workshops like fitness classes, healthy cooking courses,
"28.02.2015 14:02:55" Experience a Suite Ride with Starwood Preferred Guest® (SPG) and Uber today by requesting ‘SPG’ in the Uber app.
See all participating cities: http://west.tn/SPGuber
"25.02.2015 15:49:13" spgpromos.com SPG | Starwood Preferred Guest Now you can earn 1 Starpoint for every U.S. dollar you spend with Uber®, and earn even more Starpoints® during your stays with SPG®. Just sign in and link your SPG and Uber accounts — then sit back and watch your earning accelerate. Ride Uber to more Starpoints. Link your Starwood Preferred Guest® (SPG) account with your Uber account to earn Starpoints for your next Westin stay: http://west.tn/UberSPG
"24.02.2015 17:09:46" Westin Well-being Council Member Arianna Huffington: "Pick an image that ignites the joy in you. And any time you feel contracted, go to it to help you expand."
"23.02.2015 15:18:40" Rise and energize with these SuperFoodsRx kiwi cups filled with yogurt.
"21.02.2015 18:26:52" Feel well with your family and enjoy the ultimate family escape: west.tn/1BSU4sm
"20.02.2015 15:40:48" Build-your-own-breakfast.
The Westin Eat Well Menu For Kids helps our youngest guests discover the importance and fun of eating smart. www.west.tn/superchefs
"18.02.2015 14:17:08" Looking for a new form of exercise? Stand up paddleboarding is a great full-body workout, plus it's fun to get out on the water.
"16.02.2015 14:57:35" The Heavenly Dog Program extends the Heavenly experience to guests’ favorite travel companions.
"14.02.2015 14:53:10" Happy Valentine's Day! Check out these 8 surprising health benefits that come with love: http://west.tn/1zcM7gZ
"12.02.2015 22:07:07" Our Vertical Garden not only improves indoor air quality but also helps to relieve stress. #WestinWellbeing
"11.02.2015 13:55:30" sleepfoundation.org How Much Sleep Do We Really Need? Ever wonder how much sleep you really need? We have done extensive research on this topic, find it all out on National Sleep Foundation website. The National Sleep Foundation has updated its recommendations for how much sleep you really need. Are you getting enough? #SleepWell
"10.02.2015 19:49:57" europe.westinstore.com Westin Hotel Store Nothing restores your mind and body like restful sleep. Dream away in the Westin Heavenly® Bed so you can meet the challenges of the day head-on. Need a gift for your Valentine? Shop now and take 30% off our White Tea collection. http://west.tn/1AhudOr
"08.02.2015 15:17:18" Westin Resorts' Guide to a Better Break Discover a better weekend with Westin Hotels and Resorts.
"05.02.2015 23:12:38" Start your dinner with a stunning view.
"04.02.2015 14:51:06" westinwellbeing.starwoodpromos.com WESTIN WELL-BEING MOVEMENT Experience Headspace firsthand by listening to these meditations developed exclusively for Westin guests. This Headspace exercise will help you feel confident and prepared for a big presentation. www.west.tn/1y5dBrU
"03.02.2015 12:37:02" Experience the thrill of dogsledding through Colorado's spectacular terrain. http://west.tn/1Jfwnyn
"31.01.2015 14:05:33" Enjoying a morning beach run alongside the Caribbean. #WestinWellbeing
"28.01.2015 15:47:41" Fuel the day with a vitamin-filled breakfast from @The Westin Moana Surfrider. west.tn/1y5kyJf
Image captured by tinkisdead
"26.01.2015 12:12:32" Welcome to the SPG family, The Westin Dubai Mina Seyahi Beach Resort & Marina.
Now guests can earn and redeem Starpoints and enjoy member benefits. west.tn/1JfCVgz
"23.01.2015 15:14:31" Soak up sunshine and enjoy the serenity of Hainan, China. west.tn/1Cwl9Dv
"23.01.2015 00:21:33" Traveling to a new time zone can result in jet lag.
Here are some tips for minimizing the effects: west.tn/1rpXD8o
"21.01.2015 14:32:09" Move Well On The Road Our world-class fitness studios, Gear Lending with New Balance and local running maps will help keep you moving. #WestinWellbeing
"15.01.2015 15:07:04" Jumpstart your day with Westin Fresh by The Juicery. Try blending the deepest colors of fruits and vegetables in order to receive the most nutrients. #WestinWellbeing
"13.01.2015 02:01:47" Dinner for two, with a view.
Explore more from The Westin Turtle Bay Resort & Spa, Mauritius. west.tn/1xwhNRi
"11.01.2015 14:25:56" Mornings are better when your breakfast is packed with SuperFoodsRx.
A dose of honey does more than just satisfy your sweet tooth, it also raises levels of antioxidants in the body. #WestinWellbeing
"09.01.2015 15:10:40" www.businessinsider.com The Best Way To Start 2015 The workout is based on the idea of interval training, an exercise style of short, intense periods of exercise broken up by brief periods of rest. This is the quickest and easiest way to uphold your "workout more" resolution. www.west.tn/1BB9d2B
"08.01.2015 15:23:59" Discover a tropical paradise like no other. See why The Westin Resort, Guam is great for both family vacations and romanic retreats. west.tn/1xw3Suv
"07.01.2015 16:30:06" www.fastcompany.com 10 Ways To Improve Your Well-Being (And Productivity) Beginning when your feet hit the floor in the morning, these tips help you get more done without burning out. True productivity happens when you take care of yourself, physically and mentally.
Here are 10 ways you can tap into your best self, and get more done in the process. www.west.tn/1BB7PNs
"06.01.2015 14:53:03" A stroke of genius. Instead of another treadmill session, turn to the pool for a different form of cardio training.
"02.01.2015 16:29:53" Sleep Well from The Westin Qingdao: west.tn/1BqV8EX
"29.12.2014 15:06:48" Turkey Sliders - grilled turkey burger served with carrots, celery sticks and low-fat cranberry mayonnaise.
The Westin Eat Well Menu for Kids is as delicious as it's nutritious, making kids and parents happy. SuperChefs Cookery for Kids
"27.12.2014 13:57:23" Start the morning with Westin Fresh by The Juicery.
This blend of carrot, mango, orange, turmeric, and ginger is great kickstart to the day. #westinwellbeing
"26.12.2014 19:58:31" Here's to the power of positive thinking. Best wishes for well-being during the holidays and the year to come! #WestinWellbeing
"23.12.2014 16:55:14" Start planning your next weekend retreat with The Westin Resort & Spa Cancun: west.tn/13X96El
"22.12.2014 15:25:21" The Westin Hilton Head Island Resort & Spa welcomes you to a renewal of southern luxury.
Take a tour of the recently transformed resort: http://west.tn/1zbTSmA
"21.12.2014 17:26:26" A workout with a view. These floor-to-ceiling windows let in natural daylight and provide a beautiful background to your indoor run.
"20.12.2014 23:09:43" Sightseeing through Piedmont Park, one of Atlanta's most popular running paths.
Keep up with your training routine with our 3-mile and 5-mile running maps designed by New Balance.
"19.12.2014 13:54:31" An uplifting start to the morning. Just a few minutes of yoga can be great for relieving stress. #WestinWellbeing
Thanks to mimiyogagirl for sharing her chin-stand pose from The Westin Galleria.
"18.12.2014 16:06:26" Traveling for the holidays? Save room in your suitcase with the Westin Gear Lending program.
Enjoy New Balance shoes and apparel that's delivered right to your room. #WestinWellbeing
"17.12.2014 14:44:37" Planning your next winter adventure? The Westin Trillium House Blue Mountain, is just steps away from the slopes. www.westinbluemountain.com
"16.12.2014 16:51:12" To celebrate the opening of our new hotel in Mauritius, The Westin Paris - Vendôme transformed their Winter Terrace into a lush and colorful garden.
See more from The Westin Turtle Bay Resort & Spa, Mauritius: http://west.tn/1ACnuf2
"11.12.2014 00:12:45" Eat Well Tip from Ashley Koff Approved:
Make it easier to enjoy a meal out together by eating "family" style. Order several side dishes and appetizers so that everyone can enjoy at least one option. #WestinWellbeing
"07.12.2014 15:30:04" Majestic View and Unique Suites. Escape to a weekend of renewal at The Westin Europa & Regina, Venice. http://west.tn/1yDXx04
"05.12.2014 15:27:45" Westin Well-Being Council Member Arianna Huffington suggests taking a brief walk, especially in green space, to boost productivity and creativity. http://west.tn/workwell
"30.11.2014 22:08:47" www.westinstore.com Win the Westin Heavenly Bed, a Westin stay and More. The Westin Heavenly Bed Celebrates 15 years. For Superior Nights of Sound Slumber. Sleep Well Dreaming of better sleep? Here’s your last chance to win your very own Heavenly Bed: http://west.tn/storepromo
"25.11.2014 19:45:11" #SleepWell from Westin Crystal City.
Visit our recently renovated hotel just minutes away from Washington, D.C. http://west.tn/1vjYucI
"24.11.2014 19:49:18" www.westinwhistler.com Things to do in Whistler | The Westin Resort & Spa, Whistler Check out all of the things to do in Whistler. From winter skiing and snowboarding to summer hiking and biking, there's something for everyone in Whistler. The Westin Resort & Spa Whistler is the perfect mountain retreat for your next adventure.
"23.11.2014 16:24:29" itunes.apple.com Lark - Fitness, Diet, & Sleep Tracker + Text Feedback Get Lark - Fitness, Diet, & Sleep Tracker + Text Feedback on the App Store. See screenshots and ratings, and read customer reviews. Tap into a happier, healthier you with Lark. Their app chats with you about your activity, sleep, and nutritional data to make getting healthier more enjoyable. Download it here: http://west.tn/11OHsZa
"23.11.2014 00:00:38" "Sleep is the best meditation" - The Dalai Lama
"20.11.2014 14:36:04" We offer our youngest guests healthy food options with The Westin Eat Well Menu for Kids, including these Berry & Banana Pancake Lollipops.
"19.11.2014 14:57:34" Which type of view do you prefer from the Heavenly Bed - beach or skyline?
"17.11.2014 20:26:04" Daily exercise can help you sleep at night and is also great for your health. Try out 24-hour fitness studios to keep the routine while traveling. #WestinWellbeing
"16.11.2014 15:26:04" Sound Slumber. Guests at The Westin Palace, Milan are invited to test Lark products during their stay with wearables that track and coach their sleep. #WestinWellbeing
Get the Lark app now: http://west.tn/1uhQcQA
"15.11.2014 16:26:32" The stress of work can negatively effect sleep and relaxation. Spend a Westin Weekend recharging in a Heavenly Bed and make Monday better. www.west.tn/weekend
"14.11.2014 15:29:02" Comfortable sun beds with an 'infinite' view of Turtle Bay and the Indian Ocean.
"13.11.2014 23:18:03" www.huffingtonpost.com A Simple Meditation For Better Sleep There are some specific meditative exercises that can help us nod off when our minds are in overdrive. It’s no secret that meditation can help us sleep better. Here's a 10-Step Mindfulness Practice For Better Sleep by Headspace: http://west.tn/1tLWzPd
"12.11.2014 20:51:03" A sanctuary of peaceful relaxation. Get back to your best self with Heavenly Spa by Westin. http://west.tn/1xyjWuX
"11.11.2014 16:52:12" We've teamed up with Lark to bring our guests enhanced sleep knowledge and guidance through smart tech.
Lark's wearable sleep products are available at 8 select Westin properties throughout November. Learn more by visiting west.tn/lark
"10.11.2014 21:47:04" Can you guess the U.S. city where this Westin is located? Here's a hint: http://west.tn/1xhnhfD
"10.11.2014 14:45:34" weekend.westinwellbeing.com Get insider tips on exploring your chosen city in just one weekend. Explore cities through the eyes of locals- Build your perfect weekend getaway with the Westin Weekend Itinerary Creator. Immerse yourself in Balinese culture with a visit to the local market & cooking class at Bumbu Bali Cooking School.
For more local tips on what to explore during your next getaway, check out our #WestinWeekend Itinerary Creator here: http://bit.ly/
"09.11.2014 23:42:02" Sleep Well tip from the experts at Lark: It’s so easy to find ourselves staying up late at night with work, errands, email, and other activities. Reducing how often we work on late night projects or errands can get you ready for bed earlier.
"07.11.2014 15:43:03" www.westinstore.com Win the Westin Heavenly Bed, a Westin stay and More. CLICK HERE TO ENTER! Celebrate 15 years of restful nights and premium comfort.
Enter our Heavenly Bed Anniversary sweepstakes for the chance to win your very own Heavenly Bed, a Westin hotel stay and more. http://west.tn/storepromo
"06.11.2014 14:50:03" We've transformed traveler's sleep experience in the air ever since partnering with Delta in 2013. #WestinWellbeing
Over 3 million travelers have been able to achieve better sleep during their flight with Heavenly In-Flight bedding!
"05.11.2014 18:00:08" Westin and Lark have partnered to bring you sound sleep through smart tech.
We invite guests to try the Lark Sleep Sensor, Silent Alarm Clock and Personal Sleep Coach this month at 8 hotels around the globe. http://west.tn/lark
"04.11.2014 15:45:05" westinwellbeing.starwoodpromos.com Westin Well-Being Movement At Westin, everything we do is designed to help you feel your best. This year, we're excited to introduce the Westin Well-Being Movement, a global initiative dedicated to inspiring our guests to discover new approaches to well-being at Westin and bey Meet the newest member of the Westin Well-being Council, Julia Hu. Julia is the CEO of Lark and is dedicated to helping people live healthier lives.
Check out tips from Julia and the Lark Health Committee for better sleep: http://west.tn/lark
"03.11.2014 16:00:12" Celebrating the 15th Anniversary of the Heavenly Bed, Westin Hotels & Resorts and Lark have partnered to bring you sound sleep through smart tech. See more ways to Sleep Well: http://west.tn/sleepwell
"01.11.2014 15:14:03" abcnews.go.com 5 Tips to 'Fall Back' From Daylight Saving Time With time, your body will adjust to the time change on its own. But here are a few ways to help it along. These tips will help you 'fall back' from daylight saving time and adjust to the extra hour. http://west.tn/1tLBPXQ #SleepWell
"31.10.2014 20:20:01" weekend.westinwellbeing.com An Insider's Guide to the City Explore cities through the eyes of locals- Build your perfect weekend getaway with the Westin Weekend Itinerary Creator. Ever wish you had a local guide to help you navigate new destinations? Our #WestinWeekend Itinerary Creator will help you make the most of your next getaway. Start planning now: http://bit.ly/1pkgvjM
"30.10.2014 20:43:31" Nothing restores your mind and body like restful sleep.
Dream away in the Westin Heavenly Bed so you can meet the challenges of the day head on. http://west.tn/heavenlybed
"29.10.2014 14:05:15" Did you know? The Westin New York Grand Central incorporates ingredients from their rooftop garden into seasonal menu items. http://west.tn/1tD6IMf
"28.10.2014 16:01:55" www.health.com 7 Tips for the Best Sleep Ever Surprising new tips to help you get the rest you crave. Awaken anew. Try these surprisingly simple tips to help you get the rest you need: http://bit.ly/VnF4Qv
"27.10.2014 18:27:38" The Westin Riverfront Resort & Spa offers multiple outdoor fire pits where guests can roast s’mores and enjoy the stunning Vail Valley views. http://west.tn/1oQU780
"25.10.2014 15:55:03" www.runnersworld.com What to Pack for a Marathon Dear Susan- I'm about to do my first marathon and it's time to pack for my trip! My question is, what do I pack for the race? What should I bring? What should I carry with me during the race and what do I pack in my race gear check bag? As you can pr Traveling for your next marathon? Here are five tips for packing all of your race day essentials.
"24.10.2014 14:45:35" The best way to start the day is waking up to a balanced breakfast.
Image taken by snackfixation at The Westin Washington, D.C. City Center. #EatWell
"23.10.2014 16:57:37" Experience ultimate luxury in the Presidential Suite of The Westin Palace, Milan. http://west.tn/ZP0vRr
"22.10.2014 13:09:00" Stay active at The Westin Indianapolis and explore the city by bike. http://west.tn/1yY6GBO #WestinWellbeing
"21.10.2014 21:10:04" How do you stay active on the road? Join us at The Westin Copley Place on 11/4 for a special Girls Night Out by New Balance celebrating “Fitness on the Go.” #NBGNO
RSVP details here: http://west.tn/1sM9Dk0
"20.10.2014 12:39:36" westinwellbeing.starwoodpromos.com Andy Puddicombe, Feel Well by Westin Council Member BETTER BALANCE. Unwind from your travels with our refreshing amenities, uplifting spa treatments, inspiring designs and innovative partnerships focused on fostering mindfulness. Do you worry you might be turning in to a control freak? Life has a momentum of its own and often the best approach is to watch things unfold rather than forcing a result.
See more #FeelWell tips from Andy Puddicombe and Headspace at http://west.tn
"18.10.2014 15:39:20" Looking to get the most out of your vacation?
Explore local travel experiences and create your perfect getaway with the #WestinWeekend Itinerary Creator:
"17.10.2014 16:01:04" The Westin La Paloma Resort has everything you're seeking in a desert getaway. http://west.tn/1wilsAF
"15.10.2014 14:15:31" Indulge in a rooftop renewal at The Westin Singapore: http://west.tn/1nlUVRv
"12.10.2014 15:13:04" Eat Well with Ashley Koff Approved:
"A better breakfast includes a balance of nutrients providing different kinds of fuel for your body. If you’re eating oatmeal, add fruit, nuts and seeds or peanut butter." #WestinWellbeing
"10.10.2014 14:48:35" www.westinstore.com Westin Hotel Store Dream away every night in the Westin Heavenly Bed. Nothing restores your mind and body like restful sleep. Save 50% on all bedding with the purchase of a Westin Heavenly Bed.
"09.10.2014 21:29:03" End the day with a lap swim and tranquil view. http://west.tn/1sgztgT
"08.10.2014 15:19:04" Create your own personal retreat at The Westin Grande Sukhumvit, Bangkok.
"06.10.2014 12:36:03" Nourish both mind and body with this green goodness from Westin Fresh by The Juicery. #WestinWellbeing
"03.10.2014 16:33:03" Find time to recharge in a private oasis. Instagrammer dcrepatriate shares the calm water view from The Westin Resort & Spa Cancun.
"02.10.2014 13:15:04" Tag a friend you'd share this view with in the comments below.
"30.09.2014 14:09:57" Experience the newly revitalized The Westin San Diego: http://west.tn/1yxUFDN
"27.09.2014 16:29:03" Can you spot The Westin Chongqing Liberation Square from far distance? (Hint: Follow the red lasers to the hotel)
"25.09.2014 16:01:08" www.huffingtonpost.com Everything You Ever Wanted To Know About Running Shoes In One Simple Chart Picking the perfect running shoe is practically an art. Between arch type, weekly mileage and terrain, there's much to take into consideration -- not to mention all the color options! But before you can make an educated decision on a new pair of s... There's so much to take in before deciding on a new pair of sneakers. Here's one simple chart that explains it all. http://west.tn/1muLH4P
"23.09.2014 18:50:39" Announcing the Starwood Preferred Guest® (SPG) More For You global promotion. Register to earn up to triple Starpoints on stays at hotels and resorts worldwide. spg.com/moreforyou
"21.09.2014 12:02:56" There’s nothing like laughter to bring some lightness to life. Andy Puddicombe says that finding a sense of play will lift your overall mood. #WestinWellbeing
"20.09.2014 13:30:44" Pure relaxation on your own private terrace of the Belvedere Suite.
"18.09.2014 13:56:36" A breath of fresh air from the moment you arrive.
"17.09.2014 14:33:22" Eat Well at The Westin Singapore
"17.09.2014 14:33:21" Eat Well at The Westin Singapore
"17.09.2014 14:33:17" Eat Well at The Westin Singapore
"17.09.2014 14:33:15" Eat Well at The Westin Singapore
"17.09.2014 14:33:14" Eat Well at The Westin Singapore
"17.09.2014 14:33:13" Eat Well at The Westin Singapore
"17.09.2014 14:33:11" Eat Well at The Westin Singapore
"17.09.2014 14:33:10" Eat Well at The Westin Singapore
"17.09.2014 14:33:08" Eat Well at The Westin Singapore
"17.09.2014 14:33:07" Eat Well at The Westin Singapore
"17.09.2014 14:33:05" Eat Well at The Westin Singapore
"17.09.2014 14:33:04" Eat Well at The Westin Singapore
"17.09.2014 14:33:03" Eat Well at The Westin Singapore
"15.09.2014 18:01:29" A seaside retreat on Hainan Island. The Westin Blue Bay Resort awaits your arrival. west.tn/WR6YtC
"14.09.2014 14:40:53" Our guests, both young and old, are eating well on the road. Thanks to youngparents_sg for sharing these fish tacos with mango, corn and lettuce.
"13.09.2014 15:38:01" Tee it up on our world-class golf courses. For players of every kind, Westin provides an unforgettable day on the links. Plan your next golf getaway: http://west.tn/1oCsJEO
"10.09.2014 13:37:02" Announcing 30% Off Bedding, Bath and White Tea at the Westin Store.
Make mornings better while wrapped in our down blanket and cotton robes. http://west.tn/1rFreXt
"09.09.2014 17:36:04" Rejuvenate with our newly opened The Westin Zhujiajian Resort, Zhoushan. http://west.tn/1rBAICT
"08.09.2014 13:40:03" www.inc.com 5 Tips to Totally Dominate Your Monday Who kills it on Mondays? You do--starting now. Kick-off your week with positive purpose and dominate your Mondays with these easy steps from Inc. Magazine. #WorkWell
"06.09.2014 16:29:04" Insider Tip: When staying at The Westin Palace, Madrid, make sure you look up.
"03.09.2014 13:44:34" Exercise at any hour of the day, for as long as you like, in the privacy and comfort of your own WestinWORKOUT room.
"31.08.2014 14:20:56" A day in the pool will help you swim with the sharks. Discover how Weekends Last Longer at Westin: west.tn/makemondaybetter
"30.08.2014 14:50:00" Unwind under the stars from the privacy of your own pool. west.tn/costanavarino
"29.08.2014 14:33:31" The Westin Turtle Bay Resort & Spa Mauritius Seasonal Tastes
"29.08.2014 14:33:28" The Westin Turtle Bay Resort & Spa Mauritius Whisper Zone Pool
"29.08.2014 14:33:24" The Westin Turtle Bay Resort & Spa Mauritius Seasonal Tastes Terrace
"29.08.2014 14:33:21" The Westin Turtle Bay Resort & Spa Mauritius Arrival Experience Catwalk
"29.08.2014 14:33:18" The Westin Turtle Bay Resort & Spa Mauritius Ocean Deluxe Family Room
"29.08.2014 14:33:16" The Westin Turtle Bay Resort & Spa Mauritius Ocean Deluxe Family Room
"29.08.2014 14:33:13" The Westin Turtle Bay Resort & Spa Mauritius Bathroom - Ocean Grand Deluxe Room
"29.08.2014 14:33:10" The Westin Turtle Bay Resort & Spa Mauritius Workout Studio
"29.08.2014 14:33:08" The Westin Turtle Bay Resort & Spa Mauritius Beach
"29.08.2014 14:33:04" The Westin Turtle Bay Resort & Spa Mauritius Hotel Exterior
"27.08.2014 22:06:03" Feel like soaking in the view?
"26.08.2014 13:49:19" www.huffingtonpost.com 5 Ways To Decompress From The Stress Of Traveling I recently traveled internationally for a wedding. Although I was excited to arrive at my destination, the journey itself was less than stellar. After traveling overnight and missing my connection flight, much drama ensued and the stress levels surge Vacation is supposed to take us away from stress, but traveling can at times make it challenging. Here are 5 ways to add more calmness to your next trip. http://west.tn/XP7qJW
"25.08.2014 14:48:03" Venice is a city that's filled with culture and entertainment. Discover a curated collection of local experiences with Westin Finds: west.tn/afarvenice
"23.08.2014 16:18:02" Recharge with Paris at your doorstep. The Westin Paris - Vendôme overlooks the Eiffel Tower and Tuileries garden, two of the city's most beautiful and eternal treasures.
"22.08.2014 14:00:20" The Westin Snowmass Resort is built for more than just winter. Enjoy mountain views while unwinding poolside.
"20.08.2014 13:35:32" Fuel your day with Westin Fresh by The Juicery. Each custom blend is packed with nutrients and designed to enhance your wellness. #WestinWellbeing
"19.08.2014 14:51:33" Looking for more ways to work well? Arianna Huffington suggests operating like a sprinter. west.tn/workwell
"The most effective way to operate at work is like a sprinter, working with single-minded focus for periods of no longer than 90 minutes, and
"18.08.2014 14:52:34" The Westin Dawn Beach Resort, Spa & Casino was the first of our hotels to go solar. It's powered solely on the St. Maarten sunshine during daylight hours.
"16.08.2014 13:19:32" Plan your stay at The Westin Maui Resort and Spa and discover what it has to offer with SPG Social Traveler: http://west.tn/1m4ZoBV
"13.08.2014 15:05:41" Breakfast and lunch are crucial for kids, especially as they head back to school. Make the school day healthier with these kid-friendly recipes: http://west.tn/backtoschool #WestinWellbeing
"12.08.2014 14:55:08" A Heavenly Spa experience from the most convenient location, your own guest room. west.tn/hyderabad
"11.08.2014 14:34:47" Collaborate and connect with convenience. Tangent is perfect for impromptu meetings, interviews and brainstorming while on the road.
"09.08.2014 15:39:34" Get back to your best self at The Westin Lagunamar Ocean Resort. west.tn/cancun
"08.08.2014 14:18:45" Our Vertical Gardens are designed to beautify your stay, relieve stress and purify the air we share. #WestinWellbeing
"07.08.2014 14:04:40" Taking time off of work? Here's an exclusive Headspace exercise from Andy Puddicombe to help you effectively recharge and make the most of it. http://west.tn/dayoff
"06.08.2014 15:23:02" SuperFoodsRx tastes better with a side of spectacular scenery.
"05.08.2014 16:07:02" Game. Set. Match. Stay close to the action at this year's US Open. http://west.tn/1zR4ee8
"03.08.2014 14:37:54" The Westin Cleveland Downtown Rock and Roll Hall of Fame
"03.08.2014 14:37:52" The Westin Cleveland Downtown Cleveland Skyline
"03.08.2014 14:37:50" The Westin Cleveland Downtown Cleveland Convention Center
"03.08.2014 14:37:48" The Westin Cleveland Downtown Urban Farmer Lounge
"03.08.2014 14:37:46" The Westin Cleveland Downtown Pickling Station Restaurant
"03.08.2014 14:37:44" The Westin Cleveland Downtown Westin Living Room and Live Plant Wall
"03.08.2014 14:37:42" The Westin Cleveland Downtown Westin Lobby
"03.08.2014 14:37:40" The Westin Cleveland Downtown Traditional Lake view King
"03.08.2014 14:37:37" The Westin Cleveland Downtown Traditional Skyline King
"03.08.2014 14:37:35" The Westin Cleveland Downtown Skyline King Club Level
"01.08.2014 16:54:13" One of the easiest and delicious ways to consume a variety of colors is to sip on a juice blend of vegetables and fruit. The ingredients with the brightest and deepest colors are the ones that provide a big boost of nutrients. #WestinWellbeing
"31.07.2014 16:30:12" We’re dedicated to the well-being of our guests – big and small. The Westin Eat Well Menu for Kids was designed to teach the importance, and the fun of eating smart. See more #EatWell essentials at west.tn/eatwell.
"30.07.2014 12:43:02" Enjoy an exhilarating swim overlooking Bangkok’s spectacular skyline.
"29.07.2014 16:25:56" Westin Fresh by The Juicery was created in tandem with leaders in nutrition, offering juices and smoothies designed for business and leisure travelers seeking healthy options while traveling. The program will be featured at all of our hotels worldwid
"28.07.2014 13:35:42" "When you wake up in the morning, don’t start your day by looking at your smartphone. Take one minute to breathe deeply, or set your intention for the day." - Arianna Huffington
Prioritize your well-being with more Work Well tips: http://west.tn/wor
"26.07.2014 16:18:49" Superchefs Cookery For Kids
"26.07.2014 16:18:45" Superchefs Cookery For Kids
"26.07.2014 16:18:41" Superchefs Cookery For Kids
"26.07.2014 16:18:37" Superchefs Cookery For Kids
"26.07.2014 16:18:33" Superchefs Cookery For Kids
"26.07.2014 16:18:29" Superchefs Cookery For Kids
"26.07.2014 16:18:25" Superchefs Cookery For Kids |