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"The Volcanology and Geological Hazard Mitigation Center (PVMBG) has noted that there are 20 volcanoes with above normal levels of activity across the country.",
"\n\n\"One of them has the status of awas [danger], two are on siaga [watch] and the remaining 17 mountains are on waspada [caution]. ",
"The awas is Mount Sinabung [North Sumatra], and the siaga are Mount Agung [Bali] and Mount Soputan [North Sulawesi],\" said Kristianto, PVMBG's head of the western region volcanic mitigation subsector, as quoted by tempo.co.",
"\n\nKristianto said a number of volcanoes were popular tourist destinations during the Christmas and New Year holiday period. ",
"The PVMBG has coordinated with the respective tourist area managers, he added.",
"\n\n\"For Mount Tangkubanparahu [West Java], Dieng [Central Java], Papandayan [West Java], Gede [West Java] and Bromo [East Java], we have given the direction to remain cautious and coordinate with us at the PVMBG or with the Volcano Observation Post, which is on stand-by to provide information,\" Kristianto said.",
"\n\nRead also: Mount Krakatau tops Volcano Cup poll on Twitter\n\nHe also cautioned that volcanoes could erupt with little or no warning. \"",
"It's not that there are no signs, but they are short, and not obvious,\" he said.",
"\n\nA number of volcanoes have such characteristics, including Mount Tangkubanparahu and Mount Papandayan. \"",
"Mount Tangkubanparahu in 2013, for example, issued several phreatic eruptions that were not preceded by obvious signs,\" he said.",
"\n\nKristianto said the phreatic eruptions produced a burst of material that fell around the crater of Mount Tangkubanparahu. \"",
"It is imaginable that if it happened during daytime, it could cause a panic, and maybe someone could get hit. ",
"In general, the material thrown out by phreatic eruptions is not hot, but it's the aspect of panic that could actually cause new problems. ",
"This is what needs to be watched out for,\" he said.",
"\n\nHe added that the PVMBG had already established intensive communication to anticipate such events, especially during this holiday season. \"",
"Communication between our managers and us from the PVMBG, as well as officials in the Volcano Observation Post, has been intensified. ",
"Especially at Tangkubanparahu, we have arranged for information to be disseminated,\" he said. (",
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"though back then it seems I was planning on a bright blue strip to join them)\n\nIt's a Leaders & Enders project.",
"\n\nI sew 2 21/2\" squares together, then 2 sets of 2 and 2 sets of 4...etc...\n\nand total them up to 30 squares.",
"\n\nThen join that to a plain strip - mostly 21/2\" but that bit is flexible...\n\ndepending in what I have lying around.",
"\n\nI used 21/2\" binding strips too so that the left over can go into the next project.",
"\n\nIt's fun to re-visit some of the fabrics.",
"I am planning one that will have at least one row of fabrics from each quilt that I make in the future - or if I can do it - that I have already made.",
"\n\nThis is destined for a nursing home or similar.",
"\n\nBluebird Lane\n\nThree of us at Sunday Stitchers have been working on Natalie Bird's Bluebird Lane.",
"\n\nThis month's deadline was to have all the blocks finished,\n\nand we all managed that (nothing like a bit of peer pressure!!!)",
"\n\nHere is mine\n\nI used a fat quarter bundle I bought a while back - a Helen Stubbings range and added some beiges and the teal green.",
"As usual (for me) I changed the layout and used birds in a block that was originally rabbits.",
"\n\nHere is Inca's\n\n(had to use her instagram photo as she wasn't there on Sunday)\n\nInca and I are still pondering the borders - the original has stars all around.",
"\n\nand here is Sandi'sSandi is thinking of making a table runner\n\nand some mini quilts, so she hasn't put her blocks together\n\nIt's been great to have a team project...wonder if we will do one next year???",
"\n\nYour Leaders and Enders quilt will be loved by a special person.. It's nice and bright.",
"All the Birdlane flimsys look fabulous but I like the idea of birds instead of rabbits, they fir in better with the theme..."
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"WASHINGTON -- President Trump argued in favor of his controversial travel ban as London authorities responded to reports of a string of attacks Saturday night.",
"\n\nOne tweet read: \"We need to be smart, vigilant and tough. ",
"We need the courts to give us back our rights. ",
"We need the Travel Ban as an extra level of safety!\"",
"\n\nWe need to be smart, vigilant and tough. ",
"We need the courts to give us back our rights. ",
"We need the Travel Ban as an extra level of safety! — ",
"Donald J. Trump (@realDonaldTrump) June 3, 2017\n\nLondon authorities were investigating reports that a vehicle had hit pedestrians on London Bridge and of reports of an incident at nearby Borough Market. ",
"There were initial reports of a third incident in the South London neighborhood of Vauxhall, but Metropolitan Police said they did not believe that stabbing was related.",
"\n\nGet Breaking News Delivered to Your Inbox\n\nIn what Metropolitan Police called a \"protracted incident,\" seven people were killed and the three male suspects were shot dead. ",
"London Ambulance Service said 48 people were injured.",
"\n\nMr. Trump began tweeting about the incidents an hour or so after initial news reports. ",
"First, he retweeted a Drudge Report item about the attacks, then provided his own message about the travel ban.",
"\n\nA few minutes later Mr. Trump tweeted a message of support for Londoners: \"Whatever the United States can do to help out in London and the U. K., we will be there - WE ARE WITH YOU. ",
"GOD BLESS!\"",
"\n\nWhatever the United States can do to help out in London and the U. K., we will be there - WE ARE WITH YOU. ",
"GOD BLESS! — ",
"Donald J. Trump (@realDonaldTrump) June 3, 2017\n\n\n\nEarlier this week, the Trump administration asked the Supreme Court to immediately reinstate its ban on travelers from six mostly Muslim countries and refugees from anywhere in the world. ",
"The administration argues that the U.S. will be safer if the policy is put in place.",
"\n\nLower courts have blocked the Trump policy, citing various reasons including statements Trump made during the 2016 campaign. ",
"The legal fight pits the president's authority over immigration against what lower courts have said is a policy that purported to be about national security but was intended to target Muslims.",
"\n\nMr. Trump later called Prime Minister Theresa May to offer condolences. ",
"The White House said the president \"praised the heroic response of police and other first responders and offered the full support of the United States government in investigating and bringing those responsible for these heinous acts to justice.\"",
"\n\nThe State Department issued a statement condemning them as \"cowardly.\"",
"\n\n\"The United States stands ready to provide any assistance authorities in the United Kingdom may request,\" State Department spokeswoman Heather Nauert said.",
"\n\n\"Our hearts are with the families and loved ones of the victims. ",
"We wish a full and quick recovery to those injured in the attacks. ",
"All Americans stand in solidarity with the people of the United Kingdom,\" she said."
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"Cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV genotype 1 NS3/4A protease inhibitor.",
"\nThe present study describes the cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV protease inhibitor currently in phase III clinical trials. ",
"BI 201335 showed a good Caco-II permeability (8.7 × 10(-6) cm/sec) and in vitro metabolic stability (predicted hepatic clearence (CL(hep)) <19% Q(h) in all species tested). ",
"Single dose PK revealed a clearance of 17, 3.0 and 2.6 mL/min/kg in rat, monkey and dog respectively, with a corresponding oral bioavailability of 29.1, 25.5 and 35.6%. ",
"Comparative plasma and liver PK profile in rodents showed a high liver Kp in the rat (42-fold), suggesting high target tissue distribution. ",
"Simple allometry based on animal PK predicted a human oral CL/F of 168 mL/min, within two-fold of the observed value (118 mL/min) at 240 mg in healthy volunteers. ",
"Allometry of volume of distribution generated a low exponent of 0.59, and a much lower predicted Vss/F (5-fold less than observed). ",
"Several different approaches of Vss/F prediction were evaluated and compared with the value observed in human. ",
"The averaged Vss/F from preclinical animals provides the best estimation of the observed human value (169 L vs. 175 L). ",
"Corresponding human \"effective\" t(1/2) values were also compared. ",
"The predicted human t(1/2) based on the CL from allometry with metabolic corrections and the averaged animal Vss represented the best estimation of the clinical data (12.1 vs. 17.2 hr). ",
"The present study demonstrated that the good preclinical ADMEPK profile of BI 201335 is consistent with that observed in the clinic. ",
"While preclinical data accurately predicted the human CL, the prediction of human Vss seems to be more challenging. ",
"The averaged Vss/F from all tested preclinical animals provided the best prediction of human Vss and the resulting \"effective\" t(1/2)."
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"\n\nI’ve been waiting all night for you to tell me what you want\nTell me, tell me that you need me\nI’ve been waiting all night for you to,\nOh, oh, tell me what you want yeah\nI’ve been waiting all night for you to tell me what you want\nTell me, tell me that you need me\nI’ve been waiting all night for you to,\nOh, oh, tell me what you want yeah\n\nI’ve been waiting all night for you to tell me,\nTell me that you need me\nTell me that you want me\nI’ve been waiting all night for you to tell me,\nTell me that you need me\nTell me that you want me\n\nTell me that you need me\nTell me that you want me\nTell me that you need me\nTell me that you want me\n\nTell me that you need me\nTell me that you want me\nTell me that you need me\nTell me that you want me\nOh!",
"\n\nUh, yeah, tell me right now\nTell me, tell me right now\nTell me, tell me right now\nTell me, tell me right now\nTell me, tell me right now\nTell me, tell me right now\nTell me, tell me right now\nTell me, tell me right now\nTell me, tell me right now\n\nTell me that you need me\nTell me that you want me\nTell me that you need me\nTell me that you want me\n\nTell me that you need me\nTell me that you want me\nTell me that you need me\nTell me that you want me\nOh!"
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"The enzymatic synthesis of 5-amino-4-imidazolecarboxamide riboside triphosphate (ZTP).",
"\n5-Amino-4-imidazolecarboxamide riboside triphosphate (ZTP) is thought to play a regulatory role in cellular metabolism. ",
"Unlike other nucleoside triphosphates, ZTP is synthesized in a one-step reaction in which the pyrophosphate group of 5-phosphoribosyl-l-pyrophosphate is transferred to the riboside monophosphate (ZMP) in a reaction catalyzed by 5-phosphoribosyl-l-pyrophosphate synthetase; reversal of this reaction leads to dephosphorylation of ZTP to ZMP. ",
"This unusual route of synthesis (and catabolism) of ZTP may be important in defining its metabolic effects in the cell."
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"Dimity Douglas\n\nDimity Douglas (born 3 July 1970) is an Australian swimmer. ",
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"Double-shot molding is another one of the most sought-after methods of keycap printing. ",
"As its name implies, double-shot molding is a two-step process, and it results in a couple of different benefits. ",
"For one, legends will never fade from double-shot keycaps. ",
"They’re also bolder and more vibrant, and they can be colored a distinctive hue different from the keycap itself. ",
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"FIND A FERTILITY SPECIALIST\n\nIVF doctors promoted by Select Surrogacy India are selected after a thorough research and selection procedure. ",
"You are here : Home Fertility / IUI IUI Intrauterine insemination has a higher success rate than intravaginal insemination or intra-cervical insemination as it places the good motile sperm near the Fallopian tubes where there will be one or more eggs available for insemination.",
"\n\n\n\nIUIs can be performed either with the partner's sperm or with donor sperm. ",
"It is recommended that the patient abstain from sexual intercourse for two to three days before the procedure. ",
"The male partner is asked to produce a semen sample by masturbation, one to two hours before the procedure is to be performed or a prior collected frozen semen sample is thawed. ",
"Only washed and prepared sperm are used for intrauterine insemination because untreated semen may cause severe uterine contractions, pain, cramps and may even faint or collapse.",
"\n\n\n\nThis insemination procedure is simple and takes about 5-10 minutes, usually being painless. ",
"It involves insertion of a speculum into the vagina to visualize the cervix. ",
"The cervix is then cleaned with a little culture medium. ",
"The prepared sperm is then injected into the cavity of the womb using a fine plastic catheter. ",
"After insemination, the patient may be asked to rest for a short period of time, approx 10 mins. ",
"There are no restrictions thereafter.",
"\n\nIndications for IUI - Cervical hostility : - when the mucus in the mouth of the uterus is not permeable to the sperm confirmed by the post coital test. ",
"IUI can be performed in a spontaneous ovulatory cycle. ",
"In a cycle where drugs are being used for ovarian stimulation for unexplained infertility and male subfertility. ",
"Every clinic has different cut off values for sperm count after preparation, which they will use to perform an IUI. ",
"Inability for vaginal ejaculation as in men with retrograde ejaculation or spinal cord injury. ",
"Donor Sperm insemination\n\nWho Can Use This Treatment? ",
"IUI is usually suggested for those couples who have been trying to conceive for a year or more without success and have been found to have infertility issues. ",
"It is always recommended to perform a complete infertility examination before undergoing this process.",
"\n\n\n\nIn general, artificial insemination is used when: A woman's cervical mucus is scant or hostile to sperm. ",
"Through IUI, sperm directly reaches the uterus, bypassing the cervix and the cervical mucus.",
"\n\nThe man has a low sperm count, though the sperm should be healthy.",
"\n\nMale infertility due to antibodies to his own sperm. ",
"Sperm not damaged by the antibodies will be separated and used in the IUI process.",
"\n\nEjaculation issues due to vaginal muscle contractions or psychological problems.",
"\n\nRetrograde ejaculation, a condition where the semen goes back into the bladder rather than being expelled from the body.",
"\n\nCouples who cannot naturally have intercourse due to disability, injury or premature ejaculation. ",
"In the process of iui, the fertilisation of the egg and sperm occurs naturally, although the sperm is given a kind of \"push\" into the uterus. ",
"For this reason, both partners must meet certain criteria in order to have the best chances at success with IUI.",
"\n\n\n\nTop ▲\n\nMale Partner Requirements Tests down on sperm prior to IUI must reveal normal functioning in terms of : - Sperm count\n\nMobility (movement of sperm)\n\nSperm morphology (shape of sperm) If sperm are naturally not healthy or they are misshaped, even the use of artificial insemination cannot induce fertilisation. ",
"Under some circumstances, the treatment may also be done using donor sperms. ",
"This is called AID (Artificial Insemination by Donor) or TDI (Therapeutic Donor Insemination). ",
"If using donor sperm, make sure it is tested for mobility, shape as well as quarantined for 180 days before use. ",
"Tests for infectious diseases and disorders, including HIV, must be performed on the semen sample before it can be used.",
"\n\n\n\n\n\nFemale Partner Requirements Because fertilisation and conception are still expected to take place as normal, the female partner will be tested to ensure that she has : - A normal ovulation cycle\n\nOpen fallopian tubes\n\nA normal uterine cavity Sometimes, woman with ovulatory disorders or those who ovulate irregularly can undergo IUI with the help of fertility drugs. ",
"These drugs stimulate the brain to produce hormones that in turn induce the ovary follicles to mature into eggs. ",
"Once the eggs mature, IUI can be used to introduce the sperm inside the uterus. ",
"The timing of this particular procedure is important, as it is only when the egg and sperm are both present that fertilisation will occur.",
"\n\n\n\nWoman suffering from endometriosis but who have a healthy pelvic structure may also benefit from IUI. ",
"Unfortunately, those with damaged fallopian tubes, poor egg quality, are over the age of 40, or who are menopausal are not candidates for IUI, as the chances of conceiving are too low.",
"\n\n\n\nTop ▲\n\nThe Procedure Intrauterine insemination can be performed with or without the use of fertility drugs. ",
"However, using fertility drugs does increase the number of eggs your body matures and therefore increases the likelihood of conception. ",
"On the other hand, your risk of a multiple pregnancy is also increased. ",
"Discuss the pros and cons of using fertility drugs with your partner and your fertility specialist before deciding whether you would like to use fertility medications.",
"\n\nIUI begins with an ultrasound check-up of the female to determine the size of the follicles that can mature into eggs. ",
"She is then given oral fertility drugs, if she has decided to use these, to help stimulate a greater number of egg follicles to mature. ",
"Next, with the help of ultrasound scanning and blood tests to check for oestrogen levels (estrogen is the hormone released by the female body to help the growth of the eggs), follicular growth is monitored. ",
"In women who have taken fertility medications, this also helps in individualising drug doses, keeping track of potential side effects and reducing the risk of multiple pregnancy. ",
"In some cases, women undergoing IUI may receive an injection of human chorionic gonadotropin (hCG) hormone to stimulate egg growth and cause ovulation. ",
"Administering this hormone causes eggs to be released within 30 to 40 hours and provides a better assurance of an egg being present in the ovary when IUI takes place. ",
"Timing is very crucial when dealing with IUI, as sperm has to be injected at the precise time when ovulation has occurred or is about to occur. ",
"Around the time of expected ovulation, a sample of fresh semen is collected from the male partner and processed in the lab by washing in a culture medium or using a density gradient column. ",
"This is done to obtain good quality sperm while minimizing the number of unhealthy, poor quality sperm. ",
"A prompt insemination after the processing is important to increase the success rate. ",
"Sometimes a sperm sample taken at an earlier date may also be frozen and later used for IUI. ",
"Sperm is then inserted into the cervix and placed high inside the uterus by using a catheter. ",
"It is a painless procedure and does not take more than 20 to 30 minutes. ",
"Once insemination is done, regular ultrasound monitoring and pregnancy tests are performed to find out whether the process was successful. ",
"Top ▲\n\nRisk Factors While IUI is a relatively straight forward process, there are risks involved. ",
"This can include infection, brief cramping of uterus, or transmission of venereal disease from donor sperms. ",
"However, the strict quarantine applied nowadays by sperm banks has decreased the risk of viral transmissions dramatically.",
"\n\n\n\nThe use of fertility drugs brings with it the risk of a multiple pregnancy. ",
"In order to reduce this risk, your doctor may stop your cycle midway. ",
"The chance of a miscarriage occurring and having a low birth weight baby is high in the case of multiple pregnancies.",
"\n\n\n\nFertility medications may also cause a rare condition called ovarian hyperstimulation syndrome. ",
"Women affected by this will experience an enlarging of their ovaries and a collection of fluid in the abdomen. ",
"If this occurs, the IUI process may be stopped before insemination.",
"\n\n\n\n\n\nSuccess Rate In a given cycle, the possibility of conception is 15% to 30% provided the sperm count is good and the female has a healthy fallopian tube. ",
"The woman's age is also a deciding factor on the success rate, since advanced maternal age results in fewer follicles maturing into eggs.",
"\n\n\n\nDoctors usually recommend trying two to three IUI cycles before opting for another fertility treatment, such as IVF.",
"\n\n\n\n\n\n\n\nTop ▲ For more information, medical assessment and medical quote\n\nsend your detailed medical history and medical reports\n\nas email attachment to\n\nEmail : - info@selectsurrogacyindia.com\n\n\n\nSend Message Now Your Message : Name : Gender : Age : Select Gender Male Female Select Age 01 02 03 03 04 05 06 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 Email Id : Telephone(Mobile Preferred): Intl Code Mobile No Country : Select a Country.. Afghanistan Albania Algeria American Samoa Andorra Angola Anguilla Antarctica Antigua Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia Bosnia Botswana Bouvet Island Brazil Brunei Darussalam Bulgaria Burkina Faso Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Chad Chile China Christmas Island Colombia Comoros Congo Congo Cook Islands Costa Rica Cote D'ivoire Croatia Cuba Cyprus Czech Republic Denmark Djibouti Dominica Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands Faroe Islands Fiji Finland France French Guiana French Polynesia Gabon Gambia Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guam Guatemala Guinea Guinea-bissau Guyana Haiti Heard Island Holy See Honduras Hong Kong Hungary Iceland India Indonesia Iran Iraq Ireland Israel Italy Jamaica Japan Jordan Kazakhstan Kenya Kiribati Korea Korea,Republic Kuwait Kyrgyzstan Latvia Lebanon Lesotho Liberia Libyan Jamahiriya Liechtenstein Lithuania Luxembourg Macao Macedonia Madagascar Malawi Malaysia Maldives Mali Malta Marshall Islands Martinique Mauritania Mauritius Mayotte Mexico Micronesia Moldova Monaco Mongolia Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands Nether- Antilles New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island Norway Oman Pakistan Palau Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Poland Portugal Puerto Rico Qatar Reunion Romania Rwanda Saint Helena Saint Lucia Saint Vincent Samoa San Marino Saudi Arabia Senegal Seychelles Sierra Leone Singapore Slovakia Slovenia Solomon Islands Somalia South Africa South Georgia Spain Sri Lanka Sudan Suriname Svalbard Swaziland Sweden Switzerland Taiwan Tajikistan Tanzania Thailand Timor-leste Togo Tokelau Tonga Trinidad Tunisia Turkey Turkmenistan Turks Tuvalu Uganda Ukraine United Arab Emirates United Kingdom United States Uruguay Uzbekistan Vanuatu Venezuela Viet Nam Virgin Islands, U.S. Wallis and Futuna Western Sahara Yemen Zambia Zimbabwe Security Question * Select one... what is 5 +(plus) 5 what is 4 +(plus) 4 what is 8 +(plus) 8\n\n\n\nWant to Know More? ",
"Receive a free copy of the In The Know booklet from Select Surrogacy India.",
"\n\nRegister now\n\n\n\n\n\nSay What ? ",
"With so many unfamiliar new terms, learning about fertility can feel like you're learning another language.",
"\n\nGet the translation by using our glossary.",
"\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n"
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"We've had so many of them over the last fifteen years or so, when another one is announced I just shrug and think, \"We'll see how it goes.\" ",
"As horror fans, we've seen nearly every one of our sacred classics get remade, rebooted, or turned into a television series. ",
"What remake could come down the pike that could possibly be as rattling and shocking as what we've already seen?",
"\n\nI never would have thought that it would be a reboot of GHOSTBUSTERS that would get people all riled up again. ",
"The way I've seen some fans complain about it, it's like they've never had a beloved film get remade before. ",
"A lot of the grievances I see expressed online are exactly the sort of thing I would have been saying about something like the DAWN OF THE DEAD or THE TEXAS CHAINSAW MASSACRE remakes more than ten years ago. ",
"I thought we were past those gripes, having figured out how little it actually matters.",
"\n\nWell, one person who's not complaining about the new GHOSTBUSTERS is original Ghostbuster Dan Aykroyd, who came up with the concept of the series and co-wrote the 1984 GHOSTBUSTERS and its 1989 sequel. ",
"Aykroyd has long been dreaming of getting a new GHOSTBUSTERS film off the ground and he has received an executive producer credit on the reboot, in addition to making a cameo in it.",
"\n\nAykroyd has now seen the new film in its entirety, and he took to his social media accounts to rave about it:\n\nAs originator of the original: Saw test screening of new movie. ",
"Apart from brilliant, genuine performances from the cast both female and male, it has more laughs and more scares than the first 2 films plus Bill Murray is in it! ",
"As one of millions of man-fans and Ray Stantz, I'm paying to see that and bringing all my friends!",
"\n\nSo GHOSTBUSTERS 2016 has met the approval of the guy who came up with the idea in the first place. ",
"Will that do anything to quell the indignation of fans? ",
"I wouldn't count on it."
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"Background\n==========\n\nExternal radiotherapy has now become standard following breast conservative surgery. ",
"Despite this, the occurrence of radiation-induced sarcoma is still reported as a rare complication, with incidence ranging from 0.008% to 0.48% \\[[@B1]-[@B4]\\]. ",
"Radio-induced breast sarcoma has a poor prognosis with a 68% recurrence rate after resection, and mean recurrence period of 12.8 months (median = 7.5 months) \\[[@B5]\\]. ",
"Regarding survival, reported mortality rate is 67.6% at a mean of 61.4-month follow-up \\[[@B5]\\], with a five-year survival rate ranging from 27.7% to 36% \\[[@B4],[@B6],[@B7]\\].",
"\n\nAngiosarcoma, malignant fibrous histiocytoma and oesteosarcoma are the most frequent histopathogical types of radiation-induced breast sarcoma published in the English-language literature \\[[@B4]-[@B6],[@B8],[@B9]\\].",
"\n\nCase report\n===========\n\nA 44-year-old woman was admitted in May 2002 at our unit with a fast growing tumour in her left breast. ",
"Clinical evaluation revealed a lesion more than 10 cm in its maximum diameter, occupying the whole breast. ",
"The tumour had grossly infiltrated the skin and was fixed to the chest wall (figure [1](#F1){ref-type=\"fig\"} and [2](#F2){ref-type=\"fig\"}). ",
"Incisional biopsy revealed the tumour to have high-grade spindle cell morphology and negative epithelial immunohistochemical markers, compatible with sarcoma (figure [3](#F3){ref-type=\"fig\"}).",
"\n\n{#F1}\n\n{#F2}\n\n{#F3}\n\nSubsequent thoracic magnetic resonance imaging (MRI) revealed an expansive lesion of left breast and chest wall origin, infiltrating the skin and invading the pectoralis major and minor muscles, and the 7^th^-- 9^th^ribs (figures [4](#F4){ref-type=\"fig\"} and [5](#F5){ref-type=\"fig\"}). ",
"Thoracic and abdominal Computed Tomography did not identify any metastases.",
"\n\n{#F4}\n\n{#F5}\n\nThe patient had been treated seven years earlier for a left breast ductal carcinoma T1N0M0 invasive, and well differentiated. ",
"The treatment had consisted of a local 1.5 cm tumour excision in the left superior quadrant of the left breast with ipsilateral axillary lymph node dissection. ",
"Histological examination of the 29 lymph nodes excised was negative for malignant cells. ",
"Post-operative external beam radiotherapy was initiated 27 days after the surgery. ",
"It was applied to the remaining left breast, left axilla, supraclavicular fossa and internal mammary chain lymph nodes. ",
"The total 55 Gy radiation dose was delivered in 25 fractions, during a 5-week period, using a 3-field technique, in a Cobalt unit. ",
"The treatment ended in August 1994 with no adjuvant chemotherapy, and she had remained disease-free.",
"\n\nNeoadjuvant treatment for the high-grade sarcoma was initiated in June 2002, together with intravenous epirubicin, in a bolus dose of 60 mg/m^2^from day D1 to D2, and ifosfamide, intravenous dose of 1800 mg/m^2^from day D1 to D5 \\[[@B9],[@B10]\\]. ",
"Anaemia, leucopoenia, nausea, vomiting and diarrhoea were the main adverse effects, with decreased leukocyte counts to 400 per mm^3^. Four sessions of chemotherapy were taken with 21-day intervals. ",
"At the end of the second session, clinical evidences of approximately 20% decrease in tumour diameter and resolution of the adjacent satellite lesions were observed.",
"\n\nSurgery was performed in October 31^st^, 2002, according to oncological standards. ",
"Total radical mastectomy with chest wall en bloc resection was carried out. ",
"The oncological principle was to totally excise the tumour-infiltrated tissue with cancer cell-free margins of at least 2 cm. ",
"A large portion of the skin extending from the sternum to the left axilla and from the left clavicle to the 10^th^left rib was resected. ",
"As the dissection was taken deep, the breast, pectoralis major and minor muscles, part of the serratus anterior muscle and the 7^th^to 9^th^ribs and pleura were removed en bloc (figure [6](#F6){ref-type=\"fig\"} and [7](#F7){ref-type=\"fig\"}). ",
"A large soft tissue and chest wall defect required surgical reconstruction.",
"\n\n{#F6}\n\n{#F7}\n\nThe principles of chest wall reconstruction were to provide obliteration of intra-thoracic dead space, skeletal stabilization and adequate soft tissue coverage. ",
"A 20 × 10 cm prolene mesh, covered by transposition and rotation of well vascularized regional muscle flaps, was used for skeletal stabilization. ",
"The mobilized muscles were the contralateral pectoralis major, keeping free the serratus anterior and the ipsilateral latissimus dorsi muscles. ",
"Adequate soft tissue coverage was achieved advancing and rotating an extensive thoracic-abdominal fasciocutaneous flap (figure [8](#F8){ref-type=\"fig\"}). ",
"The reconstruction maintained normal respiration physiology, protected thoracic viscera and provided soft tissue coverage.",
"\n\n{#F8}\n\nHistopathological examination of the surgical specimen confirmed a 9.5 × 9.0 × 8.5 cm high-grade breast and chest wall sarcoma invading the skin anteriorly and three ribs, pectoralis muscles and portion of the serratus muscle posteriorly. ",
"Histological evaluation revealed marked cytological and nuclear pleomorphism, often with bizarre tumour giant cells, occasionally multinuclear, combined with spindle cells and necrosis. ",
"Immunohistochemical examination showed tumour cells were reactive for vimentin. ",
"Stains were negative for cytokeratin (AE1/AE3), actin (HHF-35, IA4), calponin, myo-D1, S100 protein, CD34 and CD31. ",
"These immunohistochemical and histopathological findings allowed a diagnosis of undifferentiated high-grade pleomorphic sarcoma (pleomorphic malignant fibrous histiocytoma).",
"\n\nPresence of 20% of necrosis in the surgical specimen was an important finding of the histological examination, which had not been observed at incisional biopsy performed prior to neoadjuvant chemotherapy (figure [9](#F9){ref-type=\"fig\"}).",
"\n\n{#F9}\n\nThe patient is currently in good health with no recurrence and breast reconstruction is being planned.",
"\n\nDiscussion\n==========\n\nIt is well known that ionizing radiation can induce sarcoma \\[[@B1],[@B8]\\]. ",
"Cahan et al in 1948 defined the criteria for post-radiation bone sarcoma \\[[@B12]\\]. ",
"The requirements are: (a) evidence of an initial distinct malignant tumour different from the subsequent sarcoma, (b) development of the second malignant tumour in an irradiated field, (c) long interval between irradiation and development of sarcoma, and (d) histological confirmation of sarcoma \\[[@B9]\\]. ",
"This case report fulfils all these criteria.",
"\n\nPrognostic factors leading to poor outcome in breast radio-induced sarcomas are large and high-grade tumours, as described previously. ",
"In a study with 34 individuals with localized disease at the time of the surgery, tumour mean diameters of 7.9 cm ± 0.9 (n = 11) had malignant recurrences, with 12.8-month ± 10.6 (median = 7.5 months) mean recurrence period, while those with mean diameters of 3.3 cm ± 1.5 (n = 4) did not (p = 0,021) \\[[@B5]\\]. ",
"Patients who were alive without evidence of cancer had a mean tumour size of 4.2 cm ± 0.77, whereas those who died of the disease had mean tumour size 8.1 cm ± 1.2 tumours (p = 0.030) \\[[@B5]\\]. ",
"In a series of 80 radio-induced sarcoma patients, composed of 42% of breast treated patients, histological grade 2 sarcomas had a 5-year survival rate of 62%, compared to 19% survival rate in grade 3 (high grade) sarcomas (p \\< 0.01) \\[[@B8]\\].",
"\n\nThe unsatisfactory results of recurrence and mortality rates of large and high grade radio-induced breast and chest wall sarcomas may have led oncologists worldwide not to consider extended surgical resection. ",
"Reasons include literature evidence of unfavourable prognosis, patient morbidity caused by the amount of removed surgical tissue. ",
"Palliative chemotherapy has been the mainstay of management in these situations. ",
"This case report indicates that patients with large and high-grade radiation-induced breast sarcomas can be offered a curative treatment. ",
"The reported patient has already survived 44 months of follow-up without evidence of malignancy, despite the presence of bad prognostic features, surpassing the recurrence range period described in the literature for patients with high-grade and large (9.5 cm) tumours \\[[@B5]\\].",
"\n"
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"The four remaining militants at Oregon’s Malheur National Wildlife Refuge are currently engaged in a direct confrontation with the FBI agents that have surrounded the federal compound since one of the gunmen was killed two weeks ago. ",
"They’re broadcasting live, right now.",
"\n\nMilitia-sympathetic radio host Gavin Seim is streaming the audio from a phone call placed to him by militia member David Fry, one of the final radicals still present at Malheur. ",
"The militiamen appear to be on the line with militia-sympathetic Nevada state assemblywoman Michele Fiore, who is currently in Portland and trying to convince the holdouts to stand down and surrender to the FBI.",
"\n\nDavid: \"You guys killed LaVoy. ",
"You let Hillary continue to run for President. ",
"You let terrorists into our country.\" — ",
"JJ MacNab (@jjmacnab) February 11, 2016\n\nThe audio is hard to understand—almost uninterrupted shouting and screaming—but the gunmen seem convinced that they will die soon, and appear ready to engage in a firefight with the FBI.",
"\n\nSandy: \"If they tear gas us, that's the same as firing on us. ",
"If they fire on us, we will fire on them.\" — ",
"JJ MacNab (@jjmacnab) February 11, 2016\n\nWe will update this post as the livestream continues. ",
"The FBI has provided the following release confirming the situation:\n\nAt approximately 4:30 pm (Pacific) on Wednesday, February 10, 2016, one of the occupiers rode an ATV outside the barricades established by the militia at the Malheur National Wildlife Refuge. ",
"FBI Agents attempted to approach the driver, and he returned to the encampment at the refuge at a high rate of speed. ",
"At this time, the FBI has moved to contain the remaining occupiers by placing agents at barricades both immediately ahead of and behind the area where the occupiers are camping. ",
"Negotiations between the occupiers and the FBI continue. ",
"No shots have been fired. “",
"It has never been the FBI’s desire to engage these armed occupiers in any way other than through dialogue, and to that end, the FBI has negotiated with patience and restraint in an effort to resolve the situation peacefully. ",
"However, we reached a point where it became necessary to take action in a way that best ensured the safety of those on the refuge, the law enforcement officers who are on scene, and the people of Harney County who live and work in this area,” said Greg Bretzing, Special Agent in Charge of the FBI in Oregon.",
"\n\nUpdate, 9:47 PM: Assemblywoman Fiore continues to try to dial down tensions:\n\nMichele: \"There has been one martyr too many.\" — ",
"JJ MacNab (@jjmacnab) February 11, 2016\n\nUpdate, 9:54 PM: The Facebook page associated with the Bundy family has listed phone numbers for a variety of Oregon law enforcement agencies and is encouraging people to call to let authorities know that the remaining occupiers want to negotiate a peaceful surrender.",
"\n\nPer NBC, those occupiers are David Fry, Jeff Banta, Sean Anderson and Sandy Anderson. ",
"Some 33,000 people are listening to the livestream. ",
"The occupiers are praying.",
"\n\nUpdate, 9:58 PM: Militia gunman Sandy Anderson just said “We’re not leaving without our weapons” as the FBI blares over megaphones in the background.",
"\n\nUpdate, 10:02 PM: Craig LaFollette, the mayor of Burns, Oregon, is now on the line and says a negotiator is en route.",
"\n\nUpdate, 10:10 PM: OPB has confirmed with Michele Fiore, still at the Portland airport, that the stream is authentic. ",
"Occupier Sandy Anderson is insisting that she will not go to prison. ",
"Apparently, a helicopter is circling the compound.",
"\n\n.@OPB has confirmed the stream from the camp is accurate. ",
"pic.twitter.com/KwveRxkyYx — John Sepulvado (@JohnLGC) February 11, 2016\n\nUpdate, 10:25 PM: Reportedly, the FBI told the evangelist Franklin Graham that he would be allowed to walk the militants out in the morning. ",
"There’s been no external confirmation of that claim. ",
"According to the Bundy Ranch Facebook page, Cliven Bundy, who was already planning on traveling to Oregon to support his son, is on his way to the refuge. “",
"My weapon is in reach,” one militant says. “",
"If they fire first, I’m going to take someone with me.”",
"\n\nAn ambulance pulled into the RV park just outside the FBI blockade. #",
"OregonStandoff — Amanda Peacher (@amandapeacher) February 11, 2016\n\nFBI repeats instructions to occupiers to come out without weapons and surrender — Wanda Moore (@WandaKTVZ) February 11, 2016\n\nUpdate, 10:55 PM: OPB’s Ryan Haas reports that Ammon Bundy’s lawyer is telling the militants that the FBI won’t move on their occupation if the live stream drops. ",
"One of the occupiers is citing the movie Braveheart as inspiration.",
"\n\nA neighbor adjacent to the refuge told me that the FBI told them to stay in their house. — ",
"Amanda Peacher (@amandapeacher) February 11, 2016\n\nFiore being asked how far away they are from Burns? \"",
"It ain't gonna last for four hours, they're getting pretty antsy,\" replies militant. — ",
"Kirk Siegler (@KirkSiegler) February 11, 2016\n\nUpdate, 11:11 PM: The occupiers want to fire up a heater. ",
"The temperature in Burns has dipped below freezing.",
"\n\n.@thomasboyd photo from outside Malheur National Wildlife Refuge tonight. ",
"Lights are seen from the Narrows roadblock pic.twitter.com/9kiuIPDZi8 — Maxine Bernstein (@maxoregonian) February 11, 2016\n\nUpdate, 11:40 PM: Fiore is very deliberately and explicitly telling the occupiers that the FBI has told her that they will not make a move tonight, and that she and Graham will be allowed to enter the refuge tomorrow morning.",
"\n\nUpdate, 12:35 PM: Things seem to have settled down. ",
"Fiore reiterates that the FBI is standing down for the night."
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"Land in Front Games has announced an upcoming Magic: The Gathering Pioneer event with a $2,000 cash prize pool, and the best thing about it is that it's free to register!",
"\n\nPower in the Cornfields #3 is happening at Holiday Inn Lancaster in Lancaster, Pennsylvania on April 25, 2020 (10AM to 9PM).",
"\n\nTop 8 players will receive their share of the $2,000 prize pool, with other prizes for the top-16. ",
"Land in Front notes that full-day prize support will exceed $5,000! ",
"These days, it's hard to find a free Magic tournament with a decent amount of cash prize support, so hundreds will probably show up at this event. ",
"You can pre-register here.",
"\n\nIn addition to the main event, the venue will also have side Magic events, an SCG Invitational Qualifier at their partner, Store Six Feet Under Games, cards for sale, a trading area, and a raffle where you can win booster packs, swag, and an uncut sheet.",
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"1st: $600\n\n2. ",
"2nd: $400\n\n3. ",
"3rd-4th: $200\n\n4. ",
"5-8th: $150\n\n5. ",
"9-16th: LIFG Player Packages valued at approx. ",
"$40\n\nHere's the address for the event: 26 E Chestnut St, Lancaster, PA 17602.",
"\n\nRelated: First MTG 2020 Mythic Point Challenge Details Revealed"
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" Opinions of the United\n2008 Decisions States Court of Appeals\n for the Third Circuit\n\n\n12-5-2008\n\nRozzelle v. Rossi\nPrecedential or Non-Precedential: Non-Precedential\n\nDocket No. ",
"07-4192\n\n\n\n\nFollow this and additional works at: http://digitalcommons.law.villanova.edu/thirdcircuit_2008\n\nRecommended Citation\n\"Rozzelle v. Rossi\" (2008). ",
"2008 Decisions. ",
"Paper 154.",
"\nhttp://digitalcommons.law.villanova.edu/thirdcircuit_2008/154\n\n\nThis decision is brought to you for free and open access by the Opinions of the United States Court of Appeals for the Third Circuit at Villanova\nUniversity School of Law Digital Repository. ",
"It has been accepted for inclusion in 2008 Decisions by an authorized administrator of Villanova\nUniversity School of Law Digital Repository. ",
"For more information, please contact Benjamin.Carlson@law.villanova.edu.",
"\n\f NOT PRECEDENTIAL\n\n\n UNITED STATES COURT OF APPEALS\n FOR THE THIRD CIRCUIT\n\n __________\n\n No. ",
"07-4192\n __________\n\n\n KEITH ROZZELLE,\n Appellant,\n\n v.\n\n CHARLES ROSSI, Health Care Administrator;\n DR. ",
"FALOR; EMSA and/or PRISON HEALTH SERVICES;\n RAYMOND RAMSEY\n __________\n\n Appeal from the United States\n District Court for the Western District of Pennsylvania\n (Civ. ",
"No. ",
"98-1738)\n District Court Judge: Honorable Gary L. Lancaster\n ___________\n\n Submitted Under Third Circuit L.A.R. 34.1(a)\n November 21, 2008\n ___________\n\n\nBefore: FUENTES, HARDIMAN and GARTH, Circuit Judges,\n (Opinion Filed: December 5, 2008)\n\n\n __________\n\n OPINION\n\n ___________\n\fGARTH, Circuit Judge:\n\n Appellant Keith Rozzelle (“Rozzelle”) sued Appellees herein, Charles Rossi\n\n(“Rossi”), healthcare administrator for Pennsylvania Department of Corrections (“DOC”)\n\ncorrectional institute SCI-Greene; Stanley Falor, M.D. (“Dr. Falor”), one of Rozzelle’s\n\ntreating physicians; Emergency Medical Services Associates (“EMSA”), an independent\n\ncontractor that provided health care to inmates at SCI-Greene; and Raymond Ramsey\n\n(“Ramsey”), who worked for EMSA (collectively “Defendants”). ",
"Rozzelle claims the\n\nDefendants violated his Eighth and Fourteenth Amendment rights while he was\n\nincarcerated.",
"\n\n Rozzelle suffers from severe cystic acne and alleges that Defendants were\n\ndeliberately indifferent to his medical needs when they denied him the acne drug\n\nAccutane. ",
"He claims this resulted in painful, open lesions and permanent acne scarring.",
"\n\n Rozzelle was successfully treated with Accutane at various prison facilities until\n\nhis transfer to SCI-Greene in September, 1996. ",
"Within a short time, Accutane was no\n\nlonger prescribed or provided to Rozzelle due to Rozzelle’s increased liver enzymes.1\n\nAppx. ",
"51a. ",
"After Defendant Dr. Falor tried other drugs, Dr. Falor requested a\n\ndermatology consult.",
"\n\n On July 21, 1998, Dr. Small, the outside dermatologist, concluded that Rozzelle\n\n\n\n\n 1\n Potential side effects of Accutane include elevation of liver enzymes and\nclinical hepatitis. ",
"Appx. ",
"52a.",
"\n\n -2-\n\fcould be considered for Accutane pending blood analysis. ",
"The tests were normal, so on\n\nJuly 26, 1998, Dr. Falor ordered a non-formulary2 request for Accutane from EMSA; this\n\nrequest was denied, as was a subsequent request. ",
"Appx. ",
"53a. ",
"EMSA suggested that Dr.\n\nFalor prescribe Retin-A cream. ",
"Rozzelle used the cream until November 9, 1998, when\n\nDr. Falor noted that Rozzelle’s acne was “controlled.” ",
"Id. Rozzelle was then given\n\nmedicated soap and shampoo and Benadryl. ",
"Rozzelle still requested Accutane.",
"\n\n Rozzelle filed two prison grievances, neither of which were appealed.3 They were\n\ndenied and Rozzelle filed suit on October 21, 1998.",
"\n\n On April 22, 2000, the District Court granted summary judgment to\n\nSuperintendent Johnson but denied summary judgment to Rossi and Dr. Falor. ",
"The\n\nDistrict Court also denied a motion to dismiss filed by Dr. Falor. ",
"Rozzelle amended his\n\ncomplaint to add claims against EMSA and Ramsey.",
"\n\n On April 3, 2003, the District Court sua sponte dismissed Rozzelle’s complaint for\n\n\n 2\n A “formulary” is a predetermined list of economical medications that doctors at\nan institution may prescribe; non-formulary drugs are drugs that do not appear on the\napproved list of medications. ",
"Appx. ",
"40a.",
"\n 3\n Pursuant to Pennsylvania DC-ADM 804, the Inmate Grievance Review System,\nthere is a three-step grievance process. ",
"First, an inmate files a grievance with a grievance\ncoordinator, who forwards it to an officer for initial review. ",
"Supp. ",
"Appx. ",
"17a. ",
"This\nreview must occur before any appeal can be sought. ",
"Second, after receiving a written\nresponse, the inmate may appeal the initial decision to the superintendent; this first-level\nappeal can only address issues which were raised in the grievance, and the inmate “must\nappeal in this manner prior to seeking Final Review.” ",
"Id. The facility manager notifies\nthe inmate of the resolution of the first-level appeal, and if the inmate is dissatisfied, he\nmay pursue step three – final review (by sending a request to the Chief Hearing\nExaminer). ",
"Supp. ",
"Appx. ",
"18a; 10a.",
"\n\n -3-\n\ffailure to state a claim under 28 U.S.C. § 1915(e)(2)(B). ",
"Rozzelle appealed.",
"\n\n We issued an unpublished per curiam opinion on October 14, 2004, affirming the\n\ngrant of summary judgment to Johnson. ",
"However, we found sufficient evidence for\n\nRozzelle to state a cause of action against Dr. Falor, Rossi, EMSA, and Ramsey, and we\n\nremanded for further proceedings.",
"\n\n Dr. Falor, Rossi, EMSA, and Ramsey jointly moved for summary judgment on\n\nJanuary 30, 2007. ",
"The Magistrate Judge’s report and recommendation (“R&R”)\n\nconcluded that the Defendants’ motions for summary judgment should be granted for\n\nfailure to exhaust administrative remedies and because Rozzelle’s claims were meritless.",
"\n\nOn September 28, 2007, the District Court adopted the R&R. Rozzelle timely appealed.",
"\n\nWe have jurisdiction under 28 U.S.C. § 1291. ",
"The District Court had jurisdiction under\n\n28 U.S.C. §§ 1331 and 1343.",
"\n\n I.\n\n We review an order granting summary judgment de novo. ",
"Sutton v. Rasheed,\n\n323 F.3d 236, 248 (3d Cir. ",
"2003). ",
"In order to bring a Section 1983 action challenging\n\nprison conditions, a prisoner must exhaust all administrative remedies, which means no\n\nremedies remain available, and the prisoner has not procedurally defaulted. ",
"42 U.S.C. §\n\n1997e(a); Porter v. Nussle, 534 U.S. 516, 524 (2002); Spruill v. Gillis, 372 F.3d 218, 227-\n\n31 (3d Cir. ",
"2004).",
"\n\n The record includes an affidavit by Cindy Watson, grievance review officer in\n\n\n\n -4-\n\fcharge of records of appeals for the Pennsylvania DOC. ",
"Supp. ",
"Appx. ",
"1a. ",
"As custodian\n\nof DOC records, Watson reviewed the documents and found that Rozzelle “has not\n\ncompleted all of the necessary steps in the grievance procedure relative to those\n\ngrievances.” ",
"Supp. ",
"Appx. ",
"2a. ",
"As stated, “[h]e did not file for final appeal concerning\n\neither one of those grievances.” ",
"Id.\n\n We affirm the District Court’s granting of summary judgment to Dr. Falor, Rossi,\n\nEMSA, and Ramsey on lack of exhaustion grounds.",
"\n\n II.",
"\n\n In any event we find no Eighth Amendment violation. ",
"An Eighth Amendment\n\nanalysis is two-pronged: (1) the person inflicting the injury was deliberately indifferent,\n\nand (2) the medical needs were objectively serious.4 Reynolds v. Wagner, 128 F.3d 166,\n\n172 (3d Cir. ",
"1997).",
"\n\n “[W]here ‘knowledge of the need for medical care [is accompanied by the] . . .",
"\n\nintentional refusal to provide that care,’ the deliberate indifference standard has been\n\nmet.” ",
"Monmouth County Corr. ",
"Inst. ",
"Inmates v. Lanzaro, 834 F.2d 326, 346 (3d Cir.",
"\n\n1987)(internal citations omitted). “",
"Medical malpractice does not become a constitutional\n\nviolation merely because the victim is a prisoner.” ",
"Estelle v. Gamble, 429 U.S. 97, 106\n\n(1976). ",
"Here, there was no intentional refusal to provide care for Rozzelle’s acne, and a\n\n\n\n\n 4\n Rozzelle contends his condition is serious enough to satisfy the second prong of\nour inquiry. ",
"This contention does not appear to be disputed.",
"\n\n -5-\n\fmere allegation of malpractice does not raise an issue of constitutional import.",
"\n\n There is no evidence that Dr. Falor was deliberately indifferent. ",
"To the contrary,\n\nDr. Falor treated Rozzelle numerous times, and he attempted to acquire Accutane and\n\nthen treated Rozzelle with substitute medications until Rozzelle’s acne was controlled.",
"\n\nAs we have noted, Rozzelle was kept off Accutane for safety reasons. ",
"According to Dr.\n\nFalor’s notes, Dr. Falor thought the alternative treatments were successful. ",
"Appx. ",
"53a,\n\n54a. ",
"Even if Dr. Falor had erred, such an error would merely amount to malpractice.",
"\n\n Furthermore, Rozzelle offers no new evidence to show deliberate indifference by\n\nRossi, EMSA, and Ramsey. ",
"We agree with the District Court that Rozzelle’s complaint\n\ndoes not meet the standard of deliberate indifference to his medical needs.",
"\n\n\n\n\n -6-\n\f"
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[
"Background\n\nMany systems for routine public health surveillance rely on centralized collection of potentially identifiable, individual, identifiable personal health information (PHI) records. ",
"Although individual, identifiable patient records are essential for conditions for which there is mandated reporting, such as tuberculosis or sexually transmitted diseases, they are not routinely required for effective syndromic surveillance. ",
"Public concern about the routine collection of large quantities of PHI to support non-traditional public health functions may make alternative surveillance methods that do not rely on centralized identifiable PHI databases increasingly desirable.",
"\n\nMethods\n\nThe National Bioterrorism Syndromic Surveillance Demonstration Program (NDP) is an example of one alternative model. ",
"All PHI in this system is initially processed within the secured infrastructure of the health care provider that collects and holds the data, using uniform software distributed and supported by the NDP. ",
"Only highly aggregated count data is transferred to the datacenter for statistical processing and display.",
"\n\nResults\n\nDetailed, patient level information is readily available to the health care provider to elucidate signals observed in the aggregated data, or for ad hoc queries. ",
"We briefly describe the benefits and disadvantages associated with this distributed processing model for routine automated syndromic surveillance.",
"\n\nConclusion\n\nFor well-defined surveillance requirements, the model can be successfully deployed with very low risk of inadvertent disclosure of PHI – a feature that may make participation in surveillance systems more feasible for organizations and more appealing to the individuals whose PHI they hold. ",
"It is possible to design and implement distributed systems to support non-routine public health needs if required.",
"\n\nTimely identification and subsequent reaction to a public health emergency requires routine collection of appropriate and accurate data about the occurrence and location of cases of illness. ",
"There is substantial interest in using routinely collected electronic health records to support both the detection of unusual clusters of public health events and the response to public health threats detected by other means. ",
"Such data are also useful to reduce an initial alert level, if it is clear that no unusual illness clusters exist in a community. ",
"Ideally, such systems operate automatically and include sensitive and specific statistical surveillance software and alerting systems. ",
"These are often referred to as syndromic surveillance systems [1, 2], because they typically rely on the non-specific signs and symptoms that may provide the earliest evidence of a serious public health threat, such as anthrax or SARS.",
"\n\nMany syndromic surveillance systems gather potentially identifiable, individual patient-level encounter records. ",
"These records are typically collected without name or address, but they do contain enough identifiers to allow re-identification in some circumstances. ",
"The potential for re-identification is greatest when records are collected from ambulatory settings or health systems that supply a unique identifier that allows the very useful identification of repeated visits over time. ",
"The risk of disclosing sensitive information that can be linked to the individual also increases when the health care facility provides more than occasional care.",
"\n\nIn the United States, the Health Insurance Portability and Accountability Act [3] (HIPAA) specifically exempts transfer, use and retention of identifiable electronic personal health information (PHI) to support public health activities. ",
"This exemption also applies to syndromic surveillance activities, although HIPAA was developed before large volumes of such data concerning individuals who are not suspected of having a reportable condition were being used for public health purposes in the absence of any known public health emergency. ",
"Despite the exemption, data providers may be unwilling to offer identifiable data for surveillance purposes in the face of increasing awareness of the potential costs of inadvertent disclosure or inappropriate use of PHI. ",
"Additionally, their patients may object to their providing it. ",
"These concerns are common to many developed countries and under these circumstances, designs that minimise the risk of inadvertent disclosure may be needed in order to gain the cooperation of data custodians, for surveillance systems to be feasible. ",
"The focus of this paper is on one such design, in which initial data aggregation is performed to decrease the risk of any PHI being inadvertently disclosed, before the aggregate data is centralised for subsequent statistical analysis. ",
"Although the system we describe is currently operating in the United States and many of the implementation details are specific to that context, some of the conceptual issues we describe and some of the lessons we have learned may be directly relevant to public health practice in other countries.",
"\n\nWhile it is possible to centrally collate and process de-identified records, there is a potential problem with statistical inference if multiple records from the same individual are not distinguished. ",
"This problem arises because many statistical analysis techniques applicable to surveillance, such as Generalised Linear Mixed Models [4] (GLMM), depend on the assumption that observations are statistically independent. ",
"Inference based on this assumption using ambulatory care encounter data will likely be biased if the model cannot distinguish observations from multiple encounters during a single course of illness from a single individual patient. ",
"Although the extent of this bias has not been quantified, the problem is clearly illustrated by real data. ",
"In more than half of the individuals with multiple lower respiratory syndrome encounters over a four year period from one large ambulatory care practice, a second encounter with the same syndrome was noted less than 21 days after the first encounter [1]. ",
"Our approach to this problem of statistical independence is to aggregate multiple encounters from a single individual into \"episodes\" of illness, and is described in more detail below. ",
"Reliably automating this aggregation requires that every patient's records be uniquely identifiable.",
"\n\nTo support the National Demonstration Bioterrorism Surveillance Program (NDP), we developed a system in which no PHI leaves the immediate control of the data provider, and only aggregate data is transferred to the datacenter [2, 5]. ",
"Each data provider performs initial aggregation of the PHI within their own existing, secured data processing environment, producing data that is aggregated beyond the point where any individual patient is identifiable. ",
"Since data processing is distributed to the site of data collection rather than being performed at one central location, we describe this as a distributed processing surveillance system. ",
"Although this particular aspect of our work has briefly been mentioned in previous publications [1, 2, 4–6], we present it in greater detail here, because we believe that it represents a potentially valuable alternative surveillance system design option that deserves more explanation and wider debate than it has received to date.",
"\n\nThe basic principle of distributed processing is simple. ",
"Rather than collecting all needed identifiable, individual PHI records centrally for statistical processing, all PHI is pre-processed remotely, and remains secured, under the direct control of the data provider. ",
"Only aggregate data are transferred to the central datacenter for additional statistical processing, signal detection, display and distribution. ",
"At an appropriate level of aggregation, the risk of inadvertent PHI disclosure becomes very small, and may prove acceptable to data custodians and to individual patients. ",
"Although this risk is never completely absent, it is certainly decreased in aggregate data, making this approach far more acceptable to data providers in our experience, than the more traditional approach of centralized collection of directly identifiable PHI.",
"\n\nCentralized processing models for public health surveillance\n\nBefore describing our distributed system, we briefly review the more familiar model of centralized aggregation and processing of PHI for surveillance. ",
"In the more traditional type of system, individual patient records, often containing potentially identifiable information, such as date of birth and exact or approximate home address, are transferred, usually in electronic form, preferably through some secured method, to a central secured repository, where statistical tools can be used to develop and refine surveillance procedures. ",
"One of the main benefits of this data-processing model is that the software and statistical methods can be changed relatively easily to accommodate changes in requirements, because they only need to be changed at the one central location where analysis is taking place. ",
"As long as appropriate details have been captured for each individual encounter of interest, the raw data can be re-coded or manipulated in different ways. ",
"Only one suite of analysis code is needed, and because it is maintained at a single, central location, costs for upgrading and maintenance are small. ",
"Inadvertent disclosure of PHI is always a potential risk with centralized systems. ",
"Even where minimally identifiable data are stored in each record, the probability of being able to unambiguously identify an individual increases as multiple, potentially linkable records for that individual accrue over time.",
"\n\nDistributed data processing by the NDP\n\nRather than gathering identifiable PHI information into a central repository for analysis, a distributed system moves some of the initial data processing, such as counting aggregated episodes of care (see below), to the site where the data is being collected. ",
"This aggregation minimizes the number of individuals who have access to PHI and diminishes the risk of inadvertent PHI disclosure from the surveillance system, while still allowing effective use of the information of interest. ",
"The focus of this report is on the model used to collect surveillance data while providing maximum protection for PHI, so the statistical methods we use in the NDP, which have been described elsewhere [4] are not discussed further here.",
"\n\nData flows for the NDP are illustrated in Figure 1. ",
"Data pre-processing, detection of repeated visits by the same patient for the same syndrome, and data aggregation is performed using a custom software package, written, maintained, and distributed by the NDP datacenter. ",
"Data providers maintain complete control of the security of their own PHI and also maintain control over the operation of the data processing software, which runs on one of their secured workstations. ",
"Since the pre-processing takes place within a secured environment under the control of the data provider, there is no need for the individual patient identifiers to be divulged to the datacenter. ",
"In the case of the NDP [5], the only data that is centrally collated consists of counts of the number of new episodes of specific syndromes over a defined time period (currently set at each 24 hour period ending at midnight), by geographic area (currently, 5-digit zip code area). ",
"More detailed definitions of \"syndromes\" and \"new episodes\" are provided below. ",
"Table 1 illustrates the data transferred from each data provider each day to the datacenter for statistical processing, reporting and alerting. ",
"Note that the although this data does not contain any obvious identifiers such as date of birth or gender, there is always a risk that a specific individual might be identifiable using additional data, and that this risk is greatest in zip codes with very small populations.",
"\n\nFigure 1\n\nDistributed processing model and data flow.",
"\n\nTable 1\n\nExample of data elements transferred to the datacenter (synthetic data)\n\nSyndrome\n\nEncounter date\n\nOrganization\n\nZip code\n\nTown\n\nDate of receipt\n\nCount\n\nGI:lower\n\n2/1/2006\n\nKPNC\n\n94565\n\nPittsburg CA\n\n2/2/2006\n\n7\n\nGI:lower\n\n2/1/2006\n\nKPNC\n\n95209\n\nStockton CA\n\n2/2/2006\n\n3\n\nGI:lower\n\n2/1/2006\n\nKPNC\n\n95632\n\nGalt CA\n\n2/2/2006\n\n2\n\nGI:lower\n\n2/1/2006\n\nKPNC\n\n94509\n\nAntioch CA\n\n2/2/2006\n\n6\n\nGI:lower\n\n2/1/2006\n\nKPNC\n\n94112\n\nSan Francisco CA\n\n2/2/2006\n\n3\n\nGI:lower\n\n2/1/2006\n\nKPNC\n\n95219\n\nStockton CA\n\n2/2/2006\n\n2\n\nGI:lower\n\n2/1/2006\n\nKPNC\n\n95122\n\nSan Jose CA\n\n2/2/2006\n\n3\n\nGI:lower\n\n2/1/2006\n\nKPNC\n\n94545\n\nHayward CA\n\n2/2/2006\n\n6\n\nGI:lower\n\n2/1/2006\n\nKPNC\n\n95825\n\nSacramento CA\n\n2/2/2006\n\n1\n\nGI:lower\n\n2/1/2006\n\nKPNC\n\n94806\n\nSan Pablo CA\n\n2/2/2006\n\n3\n\nAll source code required to build the data processing software is provided to the data provider at installation and whenever the software is updated, so that the local information services staff can check that there are no \"backdoors\" or other ways the distributed software could compromise the security of their systems. ",
"All information transferred to the datacenter is stored in text files (in XML format) and can be readily accessed by local staff to ensure that no PHI is being transmitted.",
"\n\nAggregation – definition of syndromes of interest\n\nParticipating data providers have near real-time ICD9 codes for every encounter, usually assigned by clinicians at the time of the encounter. ",
"Since much acute infectious disease manifests as broad suites of nonspecific symptoms, we monitor 13 syndromes – Respiratory, Lower gastro-intestinal (GI), Upper GI, Neurological, Botulism-like, Fever, Hemorrhagic, Skin lesions, Lymphatic, Rash, Shock-death, Influenza-like illness and SARS-like illness. ",
"All syndromes except Influenza-like illness and SARS-like illness were defined by a working group led by CDC and Department of Defense [7]. ",
"Individual ICD9 codes are used to aggregate encounters into one of these 13 syndromes. ",
"The definitions (ICD9 code lists) of 11 of these syndromes are available [7]. ",
"The definitions comprising the other two syndromes were developed in consultation with both CDC and the Massachusetts Department of Public Health.",
"\n\nEncounters and episodes of a syndrome\n\nOur surveillance algorithms [4] require statistically independent observations and are based on new episodes of syndromes. ",
"Our goal was to distinguish health care encounters that were related to ongoing care for any given episode of acute illness from the initial encounter that indicated the start of a new episode of a syndrome of interest. ",
"The derivation of the specific method for identifying first encounters for an episode of illness has been described in more detail elsewhere [1]. ",
"We define a new episode to begin at the first encounter after at least a 42-day encounter-free interval for that specific patient and that specific syndrome. ",
"If there has been any encounter for that specific syndrome for the same individual patient within the previous 42 days, the current encounter is regarded as part of the usual ongoing care for the original encounter that signalled the start of an episode of illness of that syndrome. ",
"The start of a new episode for a different syndrome can occur during ongoing encounters for any given specific syndrome – ongoing encounters during an episode are counted as new episodes only if they are outside (i.e. at least 42 days since the last encounter)of an existing episode of the matching syndrome. ",
"As will be described later, all ongoing encounters within any syndrome are recorded, and are visible through reports under the control of the data provider, but they do not contribute to the counts that are sent to the datacentre for analysis. ",
"All of this processing requires consistent and unique patient identifiers for all encounters. ",
"We use the local patient master index record number for this purpose in the software that we provide, but these identifiers are not required once the processing is complete, and they remain under the complete control of the providers.",
"\n\nStandard input file formats\n\nThe distributed software requires the data providers to extract information about encounters of interest (daily, in our case) and convert it into the uniform format used by our distributed software. ",
"This kind of uniform representation is required for any multi-source surveillance system and is not peculiar to the distributed model we have adopted. ",
"In practice, we found that data providers could easily produce text files containing data as comma separated values in the format which we specified, and which the distributed software has been written to process. ",
"However, this requires dedicated programming effort that was supported with resources from the NDP grant.",
"\n\nData transfer\n\nOur project receives support from the CDC, so we are required to comply with relevant CDC standards. ",
"Although the data being transferred to the datacenter is arguably not identifiable PHI because of the high level of aggregation, we use the Public Health Information Network Messaging System [8] (PHINMS), a freely available, secure, data transfer software suite developed by the CDC, to transfer aggregate data. ",
"A PHINMS server operates at the datacenter and each data provider operates a PHINMS client, using a security certificate supplied by the datacenter for encryption and authentication. ",
"PHINMS allows fully automated operation at both the datacenter and at each data provider. ",
"PHINMS communicates over an encrypted channel and usually requires no special modification to the data provider firewall, since it is only ever initiated by an outgoing request (the data provider always initiates the transfer of new data) and uses the same firewall port and protocol (SSL on port 443) as commercially encrypted services such as internet banking. ",
"PHINMS is reasonably robust to temporary connectivity problems, as it will try to resend all messages in the queue until they are delivered. ",
"Data transmission is one of the least problematic aspects of maintaining this system. ",
"We provide automatic installation software and it runs more or less instantaneously and transparently, without intervention in our experience. ",
"No training is needed as the process is fully automated.",
"\n\nData representation and application development language\n\nAll data is transferred to the datacenter in the form of eXtensible Markup Language (XML) since this is a flexible machine-readable representation and is easy to integrate with PHINMS. ",
"We used the Python [9] language for the development of the distributed software package. ",
"This choice was partially motivated by the fact that Python is an open-source language and thus freely distributable, partly by our very positive experience with Python as a general purpose application development language, and partially because in our experience, Python can be installed, and applications reliably run without any change to source code, on all common operating systems (including Linux, Unix, Macintosh and Windows), making it easy for the datacenter to provide support for systems other than Windows PC's. ",
"It is also a language with extensive support for standards such as XML, and securely encrypted internet connections. ",
"In addition, our existing web infrastructure has been built with the open-source Zope [10] web application framework, which is written mostly in Python.",
"\n\nReports available and benefits to data providers\n\nA major design goal for our distributed software was that it should offer potentially useful functions for the data provider. ",
"This was motivated by our desire to encourage data providers to look at their own data in different ways that might not only help them manage the data more efficiently, but might also help them to more easily identify errors. ",
"In our experience, the task of maintaining a system like the one we have developed is far more attractive and interesting to the staff responsible at each participating institution if they gain some tangible, useful and immediate benefits. ",
"In addition, easy access to data flowing through our software is useful for ensuring transparency and to facilitate security auditing by each data provider.",
"\n\nThe distributed software optionally creates reports that show one line of detailed information about each of the patient encounters that was counted for the aggregate data for each day's processing. ",
"These reports are termed \"line lists\" and were designed to support detailed reporting of encounter level data, so that a data provider can quickly make this information available in response to a public health need. ",
"Two versions are available, one with and one without the most specific identifying details, such as patient name and address. ",
"These standard line lists are used most often to support requests by public health agencies for additional information about the individual cases that contribute to clusters identified in the aggregate data. ",
"These lists are never transmitted to the datacenter but may be used to support public health officials investigating a potential event.",
"\n\nCurrent capacity of the NDP to respond to public health needs\n\nWhen unexpectedly high counts of particular syndromes are detected in geographically defined areas, the datacenter automatically generates electronic alerts, which are automatically routed to appropriate public health authorities. ",
"For example, in Massachusetts, electronic messages are automatically sent to the Massachusetts Alert Network within minutes of detection, where they are automatically and immediately forwarded to the appropriate Public Health personnel for follow up. ",
"Available alert delivery methods in the Massachusetts system range from email through to an automated telephone text-to-speech delivery system. ",
"Responders can configure the alert delivery method for each type of alert they have subscribed to. ",
"This alerting system is independent of our distributed system, but in practice, the ready availability of reports in electronic format containing both fully and partially identifiable clinical data for all cases comprising any particular period or syndrome makes the task of the clinical responder much simpler whenever a query is received from a public health official. ",
"Electronic reports, containing clinical information and optionally, full identifiers for all encounters can be generated as required, at the provider's site, from where they can immediately be made available to public health agencies. ",
"In the NDP's current operational mode (see Figure 1), a public health official calls a designated clinical responder to obtain this information.",
"\n\nThe reports have one line per encounter and can be sorted and culled to create subset lists of only the cases contributing to a particular alert. ",
"The original, full line lists are created in two forms. ",
"The fully identified version contains all elements deemed of possible utility to the responder, namely: syndrome; date of encounter; whether the encounter was new or a follow-up to one occurring within the previous 6 weeks; date of the previous encounter, if any; date of birth; sex; town and zip code of residence; type of encounter (regular office visit, urgent care visit, phone call); temperature, if recorded; text corresponding to diagnostic codes assigned by the clinician; tests ordered, in broad categories; physician ID; and medical record number (Table 2). ",
"The \"narrow\" version, which contains fewer identifiers, provides each patient's five-year age group instead of date of birth and does not include the physician ID or medical record number (Table 3). ",
"At the provider's discretion, the clinical responder can provide the \"narrow\" list corresponding to the cases of interest to the public health department. ",
"If on this basis public health officials decide that further investigation is warranted, they can call the clinical provider and request a review of medical records, identifying the cases of interest by date and an index number (unique within date) in the narrow line list. ",
"The clinician finds the medical record number by looking up the date and index number in the wide line list and then accesses the record itself through the usual HMO-specific means. ",
"Resources to support clinical responders were provided through our NDP grant to participating data providers.",
"\n\nNote: This report is kept by the health-care organization. ",
"Some or all records can be shared with the health department when a cluster requires follow-up of individual cases. ",
"Temp = patient temperature if recorded.",
"\n\nNote: These can be shared with a health department to determine whether it is worthwhile to follow up individual cases, in which case full identifiers can also be provided. ",
"Temp = patient temperature if recorded\n\nIt would be straightforward to send detailed lists of encounters that are part of clusters directly to the relevant health department whenever the datacenter detects an event and sends an automated alert to a health department. ",
"We have not implemented this feature because all the participating health plans prefer to have an on-site clinical responder participate in the initial case evaluation with the public health agency. ",
"It would also be simple to allow designated public health personnel to initiate requests for specific line lists, even when no alert has occurred. ",
"Public health officials may, on occasion, wish to inspect the line lists to search for specific diagnoses that do not occur frequently enough to trigger an alert for their syndrome, but may be meaningful in the context of information that arises from other sources.",
"\n\nEnhancing the utility of distributed data-processing for public health surveillance\n\nAlthough not currently implemented in the NDP, it would be feasible to allow a remote user to perform ad-hoc queries on the encounter data maintained by the health plan. ",
"Examples of these queries include focused assessment of disease conditions affecting subsets of the population or specific diagnoses. ",
"This type of direct query capability is currently used at some of the same participating health plans to support the CDC's Vaccine Safety Datalink project [11], a surveillance system that supports post-marketing surveillance of vaccine safety [12].",
"\n\nCurrent status, feasibility, advantages and generalisability\n\nThis distributed data model supports active surveillance and alerting of public health agencies in five states with 7 participating data providers. ",
"The system has proven to be workable, and it supports the syndromic surveillance needs of the participating health departments. ",
"There are fixed costs such as programming to produce the standard input files, installation and training, associated with adding each new data provider, so we have focussed our efforts on large group practices providing ambulatory care with substantial daily volumes of encounters, completely paperless electronic medical record systems, and substantial technical resources, since these enable us to capture large volumes of transactions with each installation. ",
"Relatively large numbers of encounters are needed to ensure that estimates from statistical modelling are robust. ",
"Applying a distributed architecture to surveillance from multiple smaller practices may enable appropriately large numbers of encounters to be gathered, but may prove infeasible because of costs and lack of appropriate internal technical support and because of heterogeneity in the way ICD9 codes are recorded and assigned by each data provider. ",
"Once the programming for standard input files is completed, installation and training take approximately one day total, usually spread out over the first two weeks. ",
"Nearly all problems are related to providers getting the standard file format contents exactly right, and to transferring these to the\n\nThe distributed architecture currently in use by the NDP allows clinical facilities to provide the aggregated information needed to support rapid and efficient syndromic surveillance, while maintaining control over the identifiable PHI and clinical data that supports this surveillance. ",
"The system provides support for the clinical providers to respond quickly to public health requests for detailed information when this is needed. ",
"In our experience, such requests involve only a tiny fraction of the data that would be transferred in a centralized surveillance model, providing adequate support for public health with minimal risk of inadvertent disclosure of identifiable PHI.",
"\n\nWe believe this design, in which patients' clinical data remains with their own provider under most circumstances, while public health needs are still effectively met, conforms to the public's expectations, and so will be easier to justify if these surveillance systems come under public scrutiny. ",
"Many of the details of our approach are specific to the United States context, but the general principle of using distributed processing to minimise the risk of inadvertent PHI disclosure is of potential utility in other developed countries, although the specifics of our implementation may be less useful.",
"\n\nDisadvantages compared with traditional approaches\n\nThe benefit of decreased risk of inadvertent PHI disclosure from our approach entails three principal disadvantages compared with routine, centralized collection of identifiable data. ",
"First, a clinical responder with access to the locally stored PHI data must be available to provide case level information when a cluster is detected. ",
"It would be technically straightforward to provide detailed information for relevant cases automatically when signals are detected. ",
"We deliberately did not implement this feature in the current system, since the participating health plans expressed a strong preference for direct involvement in this process.",
"\n\nThe second disadvantage is the need to pre-specify the syndromes, age groups, and other data aggregation parameters in advance, since changing these requires the distribution of a new release of the aggregation software. ",
"In practice, we have addressed this by means of configuration data for syndrome categories read from a text file as the application loads, so the application code itself does not need alteration. ",
"This limitation could be largely overcome by creating a remote query capability to support ad hoc queries on identifiable data that remains in the control of the provider.",
"\n\nThe third disadvantage is the technical challenge of maintaining distributed software that must reliably process data that the programmers are not permitted to examine. ",
"While the software can be exhaustively tested on synthesized data, we have occasionally encountered subtle problems arising from previously unnoticed errors in the input data. ",
"Our experience suggests that when writing this kind of distributed application, extensive effort must be devoted to detecting and clearly reporting errors in the input data before any processing takes place.",
"\n\nSource code availability\n\nAn archive of Python source code for the distributed software will be made available by the corresponding author upon request. ",
"Unfortunately no resources are available to provide technical or other support outside the NDP.",
"\n\nIn summary, we have implemented a near real-time syndromic surveillance system that includes automated detection and reporting to public health agencies of clusters of illness that meet pre-specified criteria for unusualness [5]. ",
"This system uses a distributed architecture that allows the participating health care provider to maintain full control over potentially identifiable PHI and health encounter data. ",
"The distributed software loads simple text files that can be created from the data stored in virtually any proprietary EMR system. ",
"It sends summary data suitable for signal detection algorithms via a freely available messaging system, to a datacenter that can manipulate the aggregated information and combine it with data from other providers serving the same geographic region, and which automatically generates and sends alerts when unusual clusters of syndromes are identified. ",
"The distributed software also facilitates efficient access to fully identified patient information when needed for following up a potential event.",
"\n\nAcknowledgements\n\nSupported by U90/CCU116997 from the Centers for Disease Control and Prevention/Massachusetts Department of Public Health Public Cooperative Agreement for Health Preparedness and Response for Bioterrorism and RFA-CD-05-109, Center of Excellence in Public Health Informatics, from the Centers for Disease Control and Prevention. ",
"Figure 2 originally appeared in an article in the MMWR supplement [2]\n\nAuthors' original submitted files for images\n\nBelow are the links to the authors’ original submitted files for images.",
"\n\nCompeting interests\n\nThe author(s) declare that they have no competing interests.",
"\n\nAuthors' contributions\n\nRL wrote the first draft of the manuscript after extensive discussions with KY and RP. ",
"KY and RP both made substantial intellectual contributions during the evolution of the submitted manuscript. ",
"KY prepared Figure 1 and all of the tables.",
"\n\nPre-publication history\n\nThis 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."
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"Introduction\n============\n\nLorenzo Tomatis was a towering figure in the study of cancer and cancer epidemiology: not just because from 1982 to 1993 he was the Director of the *International Agency for Research against Cancer* (IARC), but even more because he commanded immense international respect as a scientist ahead of his time in the understanding of the environmental causes of cancer. ",
"Tomatis' major influence in this area spanned some four decades\\[[@B1],[@B2]\\] (see Figs. [",
"1a](#F1){ref-type=\"fig\"} and [1b](#F1){ref-type=\"fig\"}). ",
"I never worked with Renzo, but I have vivid memories of many encounters and discussions I had with him, both about science and about research policies: and I am forever grateful for what I learnt from him.",
"\n\n{#F1}\n\nMy job today is to discuss the role of somatic mutations in oncogenesis. ",
"In a nutshell, and using a time-honoured terminology of medicine, if heredity and environment are the aetiology of cancer, somatic mutations are the essence of its pathogenesis. ",
"With respect to heredity, it is abundantly clear that one never does inherit cancer, but rather one may inherit an increased risk of cancer\\[[@B3]\\]. ",
"In first approximation, some mutant genes entail a very high risk of cancer, so much so that they behave as Mendelian dominants (see Fig. [",
"2](#F2){ref-type=\"fig\"}), and they are therefore called high penetrance (cancer susceptibility) genes. ",
"These include (i) tumor suppressors (*e.g. p53*, *APC*, *GPC3*, *VHL*, *CDKN2A*, *MEN1*), (ii) oncogenes (*e.g. PDGFRA*, *KIT*, *MET*, *RET*), and (iii) genes required for genome stability (*e.g. ATM*, *BLM*, *FANCA*, *BRCA2*, *MSH2*, *XPA*). ",
"Known high penetrance genes number by now several dozens\\[[@B4]\\]: they may have tumor (site) specificity (*e.g. BRCA2*) or they may not (*e.g. p53*). ",
"In addition, numerous clinical observations (see for instance Fig. [",
"3](#F3){ref-type=\"fig\"}\\[[@B5]\\]) indicate that cancer susceptibility may 'run in families' in a more subtle way, and this has led to the notion of low penetrance (cancer susceptibility) genes\\[[@B6]\\]. ",
"These are important because they may contribute significantly to the cancer burden in a population (see Figure [4](#F4){ref-type=\"fig\"}). ",
"Until recently, candidate low penetrance genes have been chased through (i) tests on first degree relatives\\[[@B7]\\], (ii) kinship analysis\\[[@B8]\\], (iii) studies on twins\\[[@B9]\\], and (iv) linkage disequilibrium analysis in appropriate populations\\[[@B10]-[@B12]\\] It must be admitted that until recently the yield has been limited, although individual examples have turned up, for instance among genes involved in signal transduction pathways (*e.g.* the TGFβ receptor: see Fig. [",
"5](#F5){ref-type=\"fig\"}), and numerous genes involved in DNA repair (Figure [6](#F6){ref-type=\"fig\"}). ",
"Over the past 4 years, however, genome-wide association studies (GWAS) have become very popular: this is not a conceptually new approach, as it is merely an updated version of (iv), but it is made much more powerful through the availability of some millions single nucleotide polymorphisms (SNPs). ",
"Thanks to this increased power, many low penetrance genes or loci have been now identified, that affect the risk of individual types (or several types) of cancer -- mostly by less than +/- 30% -- in one or another population (see 40 references in webappendix of recent paper by Hartman et al.\\[[@B13]\\] .",
"\n\n{#F2}\n\n{#F3}\n\n{#F4}\n\n{#F5}\n\n{#F6}\n\nWith respect to the environment, I think the most lasting monumental memorial to Lorenzo is the series of IARC publications on carcinogenic agents which, in the jargon of the *cognoscentes*, are known simply as *The Monographs*. ",
"Rarely has an international agency been able to generate publications (each one the product of a collegial effort) with so much scientific content; even more rarely has this taken place consistently in dozens of volumes over some thirty years, to the extent that the Monographs are universally regarded as the ultimate authority on their individual topics; and probably never has a single person -- namely Tomatis himself -- through his scientific rigor, his incredible dedication, and his unique ability to catalyze consensus whenever possible, contributed so much to a successful venture of this nature.",
"\n\nThe model of oncogenesis pioneered by John Cairns\\[[@B14]\\] contained already the key for reconciling aetiology and pathogenesis. ",
"The transformation of a normal cell into a cancer cell takes place through a sequence of a small number of discrete genetic events, somatic mutations (Figure [7](#F7){ref-type=\"fig\"}): thus, cancer can be regarded properly as a genetic disease of somatic cells\\[[@B3],[@B15]\\]. ",
"The analogy between evolution of organisms and evolution of cell populations is compelling (Figure [8](#F8){ref-type=\"fig\"}): in both cases what drives change is mutation, but it is Darwinian selection that enables clones that have a growth advantage to expand, thus providing a larger target size for the next mutation to hit\\[[@B14],[@B16],[@B17]\\] (Figure [7](#F7){ref-type=\"fig\"}). ",
"This model offers a simple interpretation to the mechanism of action of the aetiological factors we have mentioned. ",
"An environmental agent can increase the rate of somatic mutation (*i.e.*, it may be mutagenic, like ionizing radiation), or it can increase the rate of cell proliferation (as when *Helicobacter pylori* causes gastritis), or it may do both things (this is probably the case with the hepatitis B virus causing hepatoma). ",
"As for heredity, in the majority of cases it acts probably by increasing the mutation rate, and this may apply to both high penetrance genes and to low penetrance genes; on the other hand, sometimes an oncogene with a germ-line mutation appears to be in lieu of the first somatic mutation, for instance in the case of *RET* in Multiple Endocrine Neoplasia type 2, thus decreasing by one the number of mutations required for the development of cancer (see Figure [9](#F9){ref-type=\"fig\"}).",
"\n\n{#F7}\n\n![](",
"1476-069X-10-S1-S12-8){#F8}\n\n{ref-type=\"fig\"}. ",
"The middle section illustrates how an increased rate of somatic mutations can produce an accelerated rate of the oncogenic pathway: this is the case for instance for patients with Fanconi anemia, who have a serious defect in DNA repair and often develop cancer at a young age. ",
"The bottom section illustrate that the number of steps for a normal cell to become a cancer cell is cut by one if the first mutation is an inherited (germ-line) mutation rather than an acquired somatic mutation: this is the case for instance for patients who have an APC mutation and present with familial adenomatous polyposis.](1476-069X-10-S1-S12-9){#F9}\n\nIn order to understand the pathogenesis of tumors we must consider their very extensive variety: not only can they arise in virtually every possible cell type in the body, but even within the set of tumors arising from a specific type of cell there is marked heterogeneity, some of it well explored and some yet to be unravelled. ",
"The somatic mutation-Darwinian selection model of cancer is appropriately versatile: we can presume, and we know in specific cases that different genes are involved: some 400 have been already identified\\[[@B18]\\]. ",
"To this end, the methodology that has given the highest returns has been cytogenetic analysis, which has spotted (i) chromosomal translocations harbouring fusion genes or rearrangements that dysregulate gene expression, as well as (ii) loss of heterozigosity betraying deletions. ",
"In other cases somatic mutations have been discovered in genes already known to have germ-line mutations in cancer-prone families, or by deliberately testing for somatic mutations in candidate genes. ",
"Not surprisingly, many of the genes involved belong to sets that are relevant to broad functions within the cell (the buzz-term today is *gene ontology*): particularly the cell cycle, signalling, regulation of transcription, apoptosis and, once again, genome stability (DNA repair)\\[[@B19],[@B20]\\].",
"\n\nThe search for molecular lesions in tumors has taken on a new dimension thanks to two powerful technologies: the micro-arrays for quantitative analysis of global gene expression\\[[@B21]-[@B25]\\] (the *transcriptome*); and 'deep' sequencing for the global analysis of the entire genome (or at least the *exome*). ",
"The former offers the most complete phenotypic characterization of a tumor we could ever hope for -- we could call this the *ultimate phenotype*; the latter can identify all the somatic mutations in an individual tumor -- we could call this the *somatic genotype* (see Figure [10](#F10){ref-type=\"fig\"}). ",
"The ground-breaking paper\\[[@B26]\\] on the latter was published in 2006; and already it has been followed by a flurry of similar work on different types of tumors\\[[@B27]-[@B30]\\]. ",
"The somatic genotype of the tumor can be fully characterized by sequencing in parallel (from non-tumor DNA) also the inherited genome of the patient: thus, the issue of inherited variation versus acquired somatic mutation can be rigorously circumvented. ",
"A more difficult issue has to do with the fact that somatic mutations can occur (indeed are relatively common) in any normal cell: therefore a somatic mutation found in a tumor does non automatically qualify as being causative of that tumor; therefore we must improve algorithms aiming to disentangle *driver mutations* (*i.e.* pathogenic mutations) from *passenger mutations*. ",
"At any rate, by this approach not only are new genes being identified; also, patterns of mutations are emerging (Figure [11](#F11){ref-type=\"fig\"}) that may be signatures of exposure to individual environmental mutagens \\[[@B26]\\]: an unexpected bonus of molecular studies that is highly relevant to the focus of this meeting.",
"\n\n{#F10}\n\n{#F11}\n\nSomatic mutations are central to the process of oncogenesis, because almost certainly no tumor can arise without them (although epigenetic phenomena are important \\[[@B31]-[@B33]\\], I think it is highly unlikely that gene silencing by promoter methylation alone can do the job). ",
"The rate of somatic mutations -- and thus the risk of cancer -- can be increased by inherited genes or by environmental agents, as we have outlined; however, somatic mutations occur all the time as spontaneous stochastic events, because the replication of DNA is extremely faithful but nor perfect: this means that there is always an element of chance in oncogenesis (Figure [12](#F12){ref-type=\"fig\"}). ",
"In this respect, we know surprisingly little about the normal baseline somatic mutation rate (*μ*). ",
"Over the past several years, by using the X-linked gene *PIG-A* as a sentinel gene, we have developed a relatively simple methodology to measure *μ* in any individual\\[[@B34]-[@B36]\\]: we have determined the normal range of *μ*, and we have shown that it is higher in severak groups of cancer-prone subjects. ",
"It will be important to determine whether *μ* correlates with the risk of sporadic cancer, and whether we can measure changes in *μ* in subjects who are exposed to environmental carcinogens. ",
"It is also not unconceivable that *μ* could be decresed by pharmacological agents.",
"\n\n{ref-type=\"fig\"}) can modulate the process, but they somatic mutations are still needed for the onset of cancer; and environmental factors work in large measure by increasing either the mutation rate (mutagenic agents) or the number of cell divisions (*e.g.* with an inflammatory process, such as one caused for instance by *Helicobacter pylori*).](1476-069X-10-S1-S12-12){#F12}\n\nThe progress of contemporary biology has led us within thirty years from a multitude of theories about oncogenesis to the established fact that cancer is a genetic disorder of somatic cells. ",
"On the other hand, much recent literature gives the impression that there is a surplus of information, from gene expression profiles to proteomics to metabolomics, with the risk that while we are truly 'drowned by data, we remain thirsty for knowledge'. ",
"If we want to heed the teachings of Lorenzo Tomatis, I think the message is clear: we ought to take advantage of the new powerful technologies -- not by becoming their slaves, but remaining their masters. ",
"Identifying somatic mutations in a tumor is important not because it qualifies for 'oncogenomics', but because through a deeper understanding of the nature of that particular tumor it can help us to optimize therapy or to design new therapeutic approaches. ",
"Figure [13](#F13){ref-type=\"fig\"}.",
"\n\n{#F13}\n\nCompeting interests\n===================\n\nThe author declare that has no competing financial or non-financial interests.",
"\n\nAcknowledgements\n================\n\nThis article has been published as part of *Environmental Health* Volume 10 Supplement 1, 2011: Proceedings of the First Lorenzo Tomatis Conference on Environment and Cancer. ",
"The full contents of the supplement are available online at <http://www.ehjournal.net/supplements/10/S1>.",
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"Ailanthus vilmoriniana\n\nAilanthus vilmoriniana, commonly known as downy tree of heaven, is a tree in the quassia family. ",
"It is native to western China, but is occasionally encountered in northern European gardens.",
"\n\nDescription\nAilanthus vilmoriniana is a tree that often attains heights of 20 metres or more with a crown spread of 15 metres. ",
"The new shoots occasionally have small green spines. ",
"The leaves are quite similar to those of A. altissima, but they are darker in colour and pendulous. ",
"The rachis is finely pubescent and is a consistent deep red in colour. ",
"It is also longer, being up to 1 metre long on pollards, and with more leaflets, usually numbering 23 to 35, though they have sometimes as few as 20. ",
"The leaves are pubescent beneath. ",
"The bole itself occasionally will have sprouts emerging from it.",
"\n\nCultivation\nThe downy tree of heaven was first grown in the United Kingdom in 1897, but it is rarely found in gardens within the British Isles. ",
"It is occasionally encountered in plant collections as well as gardens in the south of England. ",
"Specimens are also present as far north as the Royal Botanic Gardens in Edinburgh.",
"\n\nReferences\n\nvilmoriniana\nCategory:Trees of China"
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"Special Offer\n\nCosmos\n\nNew Bitcoin Payment Option!",
"\nCurrently, we offer a new convenient and modern payment method – Bitcoin!",
"\nBuying cigarettes with Bitcoin is easy and absolutely safe – it's a direct transaction with no huge fee.",
"\nMoreover, while using Bitcoin you don't disclose any of your personal or Credit Card details.",
"\nHow to place an order using Bitcoin:\n1. ",
"You need to open a Bitcoin wallet (for example at coinbase.com)\n2. ",
"You can buy Bitcoins at any Bitcoin exchange of your preference (for example btc-e.com)\n3. ",
"Then you can place the order on our website, choosing \"Pay with Bitcoin\"...\n\nMore, Marlboro, Pall Mall, Capri, Parliament, Captain Black – all your favorite brands are back in stock. ",
"If you love one of these brands – it's time to rejoice, as we are adding all of them back in stock!",
"\nMore 120s Menthol and More 120s Filters were out of stock for quite a while, but not anymore. ",
"This awesome menthol cigarettes brand is back in stock.",
"\nMaybe you're a fan of Parliament's quality and splendor – not to worry – we're adding 3 more types of this elite cigarette brand: Parliament Pearl Blue, Parliament Carat Sapphire, Parliament Carat Topaz.",
"\nWe did not forget...\n\nA California official presented enactment on Thursday that expects to raise the lawful smoking age to 21 from 18, his office said in an announcement, just over a week after a comparative move by Washington state's top legal advisor.",
"\nThe bill additionally comes a day after California's top wellbeing authority said electronic cigarettes are undermining to disentangle the state's decades-long push to diminish tobacco utilization.",
"\nFair State Senator Ed Hernandez of West Covina, who seats the chamber's wellbeing board of trustees, brought the bill with expectations of keeping more high...\n\nA conclusion by the Paris City Council in March to ban smoking in public areas, including restaurants, angered Brent McKee. ",
"Some sort of restaurant owner, Mr. McKee was taking into consideration the customers who enjoyed a cigarette or two while nursing their own morning coffee.",
"\n“I built that with my blood and perspire, and then they come in and in addition they tell me what I may and cannot do? ",
"That angry me, ” he said with the ban.",
"\nNow, Mr. McKee reluctantly acknowledges a big difference of heart.",
"\n“I’m glad the idea happened, I guess, ” he said a week ago....\n\nWe decided to surprise our beloved customers with special offers. ",
"We have special offer for people who like to smoke famous and excellent Camel cigarette products.",
"\nEvery customer can buy 6 cartons of Camel Blue, Camel Filters or Camel Silver for special reduced price of $15.80 per carton. ",
"Also you can buy special pack that includes 7 cartons of Vogue or 8 cartons of Marlboro Micro. ",
"We appreciate our customers and always ready to surprise you with our special offers.",
"\nAll special offers are available here.",
"\nOffers\nPrice, $...\n\nNo New Casinos If Smoking Ban Succeeds\n\nThe Navajo Nation Gaming Enterprise is threatening to halt its planned $100 million development of new casinos near Flagstaff and Farmington because of President Ben Shelly's push to include casinos in a ban on smoking cigarettes in public facilities throughout the reservation. ",
"Bob Winter, CEO of the gaming enterprise, said if Shelly succeeds, it would drive away high-stakes players, sharply reducing revenue and leading to job cuts at the tribe's two existing casinos.",
"\n\nWhile he's willing to work with the current administration on its concerns, Winter said the proposed ban would undo plans to have the casinos pay for themselves. ",
"He is convinced that a smoking cigarettes ban would reduce casino profits to the point that \"there would be no way that we would be able to service that debt.\"",
"\n\nThe dispute stems from efforts now underway by Shelly to overcome Shirley's veto of 2008 legislation banning the use of commercial cheap cigarettes in public places on the Navajo Nation. ",
"The Council attempted but was not able to override the veto. ",
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"\n\nThe executive order, however, did not take effect because Attorney General Harrison Tsosie issued an opinion that a reservation-wide ban would exceed the president's authority. ",
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"Since then, Shelly has said he will submit legislation to the Navajo Nation Council during its upcoming summer session that would impose the ban.",
"\n\nThree years ago when the tribe was planning to build its first casino, Fire Rock, health advocates urged a discount cigarettes ban but the council voted to allow smoking cigarettes in certain areas at the casino. ",
"The Council backed a full ban in 2008, but Shirley derailed it at the behest of the gaming enterprise.",
"\n\nWinter said the ban would create a competitive disadvantage for Navajo gaming because smoking cigarettes is allowed at other tribal casinos near the Navajo Reservation. \"",
"We wouldn't mind it if the smoking cigarettes ban applied to all casinos in New Mexico and Arizona, but it would affect only us,\" he said.",
"\n\nWhen Navajo Nation got into gaming, other casinos saw their business drop off by as much as 50 percent - much of it from Navajos who could now gamble closer to home. ",
"Winter fears that \"if the smoking cigarettes ban is imposed, those people would go back to the other casinos.\"",
"\n\nOnly one casino in New Mexico currently bans smoking cigarettes, Taos Mountain Casino. ",
"However, casino manager Bob Brooker said it's difficult to say how much the ban has affected business because it's been in place since the casino opened 14 years ago. ",
"Brooker assumes it has affected business \"a little,\" noting that he was working at the casino in Cripple Creek, Colo., when a smoking cigarettes ban was imposed there and it resulted in a loss of about 30 percent of its customers.",
"\n\nThe Blackfeet Indian Nation recently imposed a smoking cigarettes ban at its casino near Browning, Mont., but officials there said it will take a couple of more months to determine what effect it will have on business. ",
"A recent study of Illinois casinos, where a smoking cigarettes ban took effect three years ago, found that 24 percent of the state's gamblers are avoiding casinos because of the ban.",
"\n\nThe study, performed by the University of Massachusetts Dartmouth Center for Policy Analysis, found that fuel cost seems to be a bigger issue, with 40 percent of gamblers reporting that they've skipped a visit to the casino because of the cost of gas. ",
"Winter estimates that 20 percent of visitors to Fire Rock Navajo Casino smoke, but he predicted that the loss of these customers would decrease profits by 40 percent, based on studies showing that people who smoke cigarettes tend to gamble more.",
"\n\nWinter said if the enterprise calls off its plans for additional casinos, it would cost the tribe more than $100 million annually in gaming profits, 1,000 permanent jobs and 1,500 construction jobs. ",
"He estimated the loss in potential wages and benefits at $37.4 million. ",
"But for Shelly, the health threat overshadows the money argument.",
"\n\nIn a statement he released when first proposing the ban, Shelly said the ban was needed to save Navajo lives. \"",
"As leaders we must create safer environments for our people,\" he said. \"",
"We do not want to expose our Navajo people to further unnecessary, health-related illnesses that can be caused by secondhand smoke.\"",
"\n\nSince then Shelly has received recognition from national and local public health advocates, and was praised by former U.S. Surgeon General Richard Carmona, who released a landmark study in 2006 on the health impact of secondhand smoke.",
"\n\nWinter cited the use of advanced ventilation technology at Fire Rock and Flowing Waters casinos, although claims that it would eliminate cigarettes online smoke cigarettes outside the gaming area have proven to be overstated.",
"\n\nAnd Shelly has emphasized his concern for Navajos who work in the gaming areas, who are breathing secondhand smoke cigarettes throughout their shifts, and non-smoking cigarettes players. ",
"Nationally, around 50,000 deaths per year are attributed to secondhand smoke cigarettes exposure."
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"Neuron-selective toxicity of tau peptide in a cell culture model of neurodegenerative tauopathy: essential role for aggregation in neurotoxicity.",
"\nIntracellular aggregation of tau is a pathological hallmark in Alzheimer's disease and other tauopathies. ",
"The mechanisms underlying tau aggregation and the role that these aggregates play in neuronal death have remained controversial. ",
"To study these issues, we established a cell culture model of tauopathy using a hexameric peptide with the sequence (306)VQIVYK(311) located within the third microtubule-binding repeat of tau, rendered cell-permeable by a tag of nine arginine residues (R(9)). ",
"This peptide (VQIVYK-R(9)), designated as T-peptide, self-assembles in vitro into paired helical filament-like aggregates. ",
"Primary neuronal cells treated with T-peptide die within 24 hr. ",
"Neurodegeneration correlates with the ability of the peptide to aggregate. ",
"Two peptides with mutations in the hexameric core, K-peptide (VQIVKK) and VV-peptide (VQVVVK), that are incapable of aggregating are not toxic, whereas two other mutant peptides, V-peptide (VQVVYK) and F-peptide (VQIVFK), which aggregate, are also neurotoxic. ",
"Two other peptides that aggregate in vitro, but are not derived from tau, are not neurotoxic suggesting sequence dependence. ",
"Although localizing to the nucleus, T-peptide induces aggregation of cellular proteins in the cytoplasm. ",
"These aggregates are not caused by disruption of endogenous tau localization, although endogenous tau is reduced in neurons exposed to T-peptide. ",
"Interestingly, nonneuronal cells are less sensitive to T-peptide toxicity, recapitulating in part the selective loss of neurons in tauopathies. ",
"Moreover, T-peptide treatment leads to mitochondrial dysfunction, a common feature of neurodegenerative disorders. ",
"The model system described here represents a convenient paradigm for studying the mechanisms underlying tau aggregation and neurotoxicity and for identifying compounds that can prevent these effects."
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"Main factors that determine business prices decisions\n\n\"Whoever has bought or sold something knows that in reality prices are established by customers and sellers and this it costs time and money to analyze the right price of any product, or to workout how prices should react to a change in the market\" (Hall et al. ",
"1997, p. 7). ",
"Price-setting decisions may seem rather simple for small bargaining trades including two or few functions. ",
"However, lots of influencing factors can lead to the perseverance of any price. ",
"These factors are more relevant and perhaps more easily observable on a larger, business range, where there are a lot more parties involved and usually more products to price. . ",
"The aim of this article is to go over the key factors which determine costs decisions in businesses, and assess the relative importance of these factors.",
"\n\nFirstly, it pays to to format why price setting is important. ",
"There are several different reasons. ",
"Around the macroeconomic opportunity, price setting is important because it determines the consequences of monetary insurance policy decisions (regarding money, inflation and interest levels) on the market (Hall et al. ",
"1997). ",
"This is because of price rigidities (or 'sticky' prices), which occur therefore of some of the factors determining business costing decisions which is mentioned. ",
"With price rigidities, monetary insurance plan has real results on the macroeconomy, at least in the short- to medium-term. ",
"Also, nominal changes in prices can have effects on real result and career in the short-term (Hall et al. ",
"1997). ",
"Over the microeconomic scope, price setting behaviour is of critical importance for businesses to meet their goals. ",
"These objectives may differ depending on individual firm's strategy, but tend towards long-run profit maximisation - therefore business pricing decisions are also important for businesses to maximise gains. ",
"And changes in prices affect profitability by a larger proportion than another variable which a company can change straight (BusinessWeek 2006).",
"\n\nSo how do firms actually determine what prices to demand because of their products? ",
"This may largely rely upon the market composition where the organization is functioning. ",
"Perfect competition is a theoretical market structure in which there's a very large volume of buyers and sellers, who produce a homogeneous product and count up with perfect information and perfect factor mobility. ",
"Given these situations, each individual company serves as a price-taker, without price-setting ability. ",
"Therefore, under perfect competition, business pricing decisions do not can be found, and prices are arranged by the industry pushes of source and demand. ",
"The nearest real examples of perfect competition industries are certain agricultural companies, where suppliers, or farmers, haven't any say over the price tag on their product. ",
"Moving towards imperfect market constructions, monopolistic competition is a structure in which there is also a large quantity of buyers and sellers, but they create a differentiated product, nor rely with perfect information or perfect factor flexibility. ",
"Further down the imperfect competition road is oligopoly, an industry composition characterised by a little number of retailers and high market awareness (or high market electricity). ",
"Finally you can find monopoly, a structure with one seller and multiple buyers, so that the individual company dominates the market entirely and it is the only real price-setter. ",
"Economic theory points out that a monopolist produce a quantity where marginal earnings, MR, equals marginal cost, MC (the profit-maximising condition), and will charge a price where the demand curve matches this variety, as illustrated below\n\nFigure 1 - Monopoly price-setting:\n\nMonopolistic competition and oligopoly price environment are generally predicted to fall somewhere between the perfect competition and the monopoly final results. ",
"That is, businesses in monopolistic competition and oligopoly have some, but not absolute, price-setting power. ",
"You will see factors affecting rates decisions that happen to be beyond your firm's control, at least during setting up or changing prices. ",
"Then there will be certain internal factors including the firm's cost framework, and there will be the firm's rates strategy, which is basically a means of responding to the previously mentioned factors. ",
"First why don't we go through the firm's exterior factors. ",
"This consists of, of course, the market structure where the firm manages, and there can be important dissimilarities even within the same theoretical structure. ",
"For instance, some oligopolies can behave as a monopoly while others can have the same result as perfect competition. ",
"Focusing on imperfect competition, a primary external factor impacting on business rates decisions is, broadly, your competition. ",
"This can be divided into several important factors: the availability of substitutes and level of product differentiation, cross-price elasticity of demand, market stocks, and undoubtedly the rivals' prices. ",
"The option of substitutes is important because a high availability means that if a company raises its prices, its customers can more easily transition to a rival product. ",
"That is partly dependant on the amount of product differentiation which is captured by the cross-price elasticity of demand. ",
"Competitors' prices need to be considered, as customers will make price comparisons on the market. ",
"High product differentiation gives firms more power to demand price mark-ups above the cost of production, thereby making a supernormal earnings (Tucker 2008).",
"\n\nAnother exterior factor is the regulatory framework and any possible government interventions in the price-setting behavior, such as price ceilings and subsidies. ",
"They are artificially imposed factors and, where present, can be of high relative importance because they feature direct bonuses or barriers for a firm to undertake certain rates decisions. ",
"For example, a subsidy may allow a firm to fee lower prices where it would be usually impossible without incurring a damage. ",
"An example is the common development of biofuel from corn in the US (FT 2007). ",
"And a price ceiling makes it impossible for a company to charge a price above a certain government-imposed level. ",
"Typically, price-ceilings have been enforced on basic requirement products and especially those where the seller would in any other case have a higher talk about of bargaining vitality - such as personal rent.",
"\n\nMoreover, characteristics related to the customer-base of the business enterprise are an important exterior factor. ",
"The income level of customers will partly determine the demand curve encountered by\nthe maker, which is central to determining prices and is thus of high importance in accordance with other factors. ",
"Certain psychological features are also taken into account, such as customers' perceptions of prices. ",
"For instance, many businesses may charge a cost of 9. ",
"99 alternatively than 10. ",
"00, because, although the true difference is minimal, customers may understand a large difference between one integer and the next (Teacher2u 2010). ",
"However, since this type of factor only establishes such a minor difference in actual prices, it is of very low importance relative to other factors.",
"\n\nThe main inner factor affecting business pricing decisions is the firm's cost framework. ",
"Given the income motive, the organization will seek to go beyond its costs to produce a profit, and costing is central to reaching this goal. ",
"Inside the long-run, firms are required to produce on the profit-maximising condition where MC=MR, so the condition of the marginal cost curve will be very important to the costs decisions. ",
"If a firm is experiencing economies of size, it might be able to benefit from lowering prices to achieve an increased market show and exploit the common cost reductions. ",
"Hall et al. (",
"1997) make a distinction between two important cost-related factors for business rates decisions: immediate cost plus changing mark-up and direct cost plus set mark-up. ",
"This simply identifies how some companies specify a set, or target, percentage mark-up over costs.",
"\n\nOverall, the analysis by Hall et al. (",
"1997) finds, from a review of 659 UK businesses, that market conditions (an exterior factor) were the most crucial factor in price-setting behavior, with 40 percent of companies establishing prices at the \"highest level that the marketplace could keep\" (p. 12). ",
"Within market conditions, the main is how the own firm's prices (or potential prices) compares to competition' prices. ",
"This is especially true for retailing and production companies and companies in more concentrated markets. ",
"Internal, or company-specific, factors, were also found to be very important. ",
"20 percent of respondents mentioned that prices were determined by direct costs and also a varying mark-up and 17 percent said they were determined with a fixed mark-up. ",
"In any case, cost is of course an essential factor for price-setting behaviour. ",
"The cost/mark-up rule applies more strongly to small companies, presumably because they cannot afford such considerable market research to obtain information on exterior factors. ",
"Finally, external factors related to customers were the least important as reported by respondents.",
"\n\nGiven these immediate factors, a firm can make pretty much use of each one and can determine its price in another way as a reply to these factors, with respect to the firm's prices strategy. ",
"One costs strategy category is differential pricing, based on consumer heterogeneity in three areas: transfer costs (providing rise to special discounts on second markets), demand which incentivises the use of periodic discounting, and search costs, which incentivise random discounting (Tellis 1986). ",
"In other words, the firm can use a technique of price discrimination, which contains charging different prices for the same product under different circumstances or even to different customers.",
"\n\nAnother kind of price-setting strategy category is competitive rates, which includes a number of costing strategies aimed at improving a firm's competitive position. ",
"Penetration rates is the strategy of charging below-market prices to attract a larger market share and thus exploit economies of size. ",
"That is related to both cost and market factors. ",
"Predatory costing is a technique of charging low prices with the purpose of establishing and/or retaining barriers to entrance and growth, to then down the road increase prices again. ",
"Geographic costs, another form of competitive costing, is a technique between second market discounting and predatory costing (Tellis 1986).",
"\n\nFurthermore, you have the category of product line costing strategies, which are based on taking account of the set (or range) of products when coming up with pricing decisions. ",
"One strategy is price bundling, where the firm faces heterogeneous demand for perishable products which are non-substitutes. ",
"The company may have an incentive to charge the highest price which some consumers are prepared to pay for each product, which means overall the merchandise line could be more expensive. ",
"Firms may use a premium prices strategy when they face heterogeneous demand for replacement products which have joint economies of size. ",
"A typical example is whenever a firm can create a superior version of something but still encounters demand at a lesser price for the substandard version. ",
"The organization would charge a premium on its superior version, even if the costs of production are the same, in order to \"subsidise\" the lower-priced sales of the substandard version. ",
"This plan may often mean that \"relative to its costs, the company takes a high quality on its higher priced version and a reduction on its more affordable version\" (Tellis 1986, p. 155). ",
"Other products rates strategies include image costing, where the organization launches an identical product under a different name and at an increased price to indicate quality, and complementary costs.",
"\n\nThe existence of different pricing plans or strategies shows that business rates decisions can be affected pretty much heavily by the various influencing factors mentioned. ",
"These include external factors, such as market structure and consumer willingness to pay, and internal or firm-specific factors, such as the firm's cost composition and the pricing strategy. ",
"The different types of pricing strategy show how different companies may respond in several ways to the same factors. ",
"This implies it is difficult to objectively determine the relative importance of each factor as it may differ from organization to firm. ",
"However, there is certainly empirical evidence to support that the most important factor are the market conditions where the firm operates, an external factor, accompanied by the firm's cost plus mark-up structure, an internal factor. ",
"Other factors, such as customer willingness to pay and regulatory composition are also considered, but normally aren't as important to firms in their charges decisions. ",
"Still, it is worth due to the fact certain extreme regulatory constructions such as price ceilings and heavy subsidies (or fees) would be very important factors, either immediately or indirectly through effect in the firm's cost composition and/or market structure.",
"\n\nOther services that we offer\n\nIf you don’t see the necessary subject, paper type, or topic in our list of available services and examples, don’t worry! ",
"We have a number of other academic disciplines to suit the needs of anyone who visits this website looking for help."
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"\n788 S.W.2d 632 (1990)\nFIRST VICTORIA NATIONAL BANK, Appellant,\nv.\nGeronimo BRIONES, Appellee.",
"\nNo. ",
"13-89-003-CV.",
"\nCourt of Appeals of Texas, Corpus Christi.",
"\nApril 5, 1990.",
"\nRehearing Overruled May 3, 1990.",
"\nMichael Meier, Kelly, Stephenson & Marr, Victoria, for appellant.",
"\nJohn Griffin, Jr., Houston, Marek & Griffin, Victoria, David C. Griffin, Houston, Marek & Griffin, Port Lavaca, for appellee.",
"\nBefore NYE, C.J., and BENAVIDES and DORSEY, JJ.",
"\n\n\n*633 OPINION\nNYE, Chief Justice.",
"\nThis is an action for breach of contract. ",
"Charles Waters, Jr., and his wife, Pearl, executed a \"MECHANIC'S LIEN NOTE\" in the amount of $20,000.00 to appellee, Geronimo Briones. ",
"This note is secured by a mechanic's lien by virtue of a mechanic's lien contract. ",
"The contract required Briones to construct improvements on the Waters' property. ",
"Pursuant to a \"TRI-PARTY FINANCING AGREEMENT,\" Briones requested appellant, First Victoria National Bank, to purchase the indebtedness owing under the contract together with the lien and security interest securing the payment thereof and to make a purchase money loan to the Waters to finance his cost for the improvements. ",
"The Bank agreed to these requests, subject to certain conditions. ",
"Briones, however, received only $14,000.00 out of the $20,000.00 loan and brought suit against the Bank for the remaining $6,000.00. ",
"The Bank filed a counterclaim, seeking indemnification from Briones for sums to which he may show that he is entitled to under the contract. ",
"After presentation of the evidence, both parties moved for instructed verdicts. ",
"The trial court instructed a verdict favorable to Briones for the $6,000.00. ",
"The Bank appeals.",
"\nBy points of error one through four, six and seven, the Bank complains the trial court erred in instructing a verdict favorable to Briones. ",
"Specifically in point one, the Bank complains that the trial court erred in instructing a verdict favorable to Briones because the \"TRI-PARTY FINANCING AGREEMENT\" did not require the Bank to pay the entire amount of the loan ($20,000.00) to Briones for his work. ",
"We agree.",
"\nIn determining whether the trial court correctly instructed a verdict, we are required to review the evidence most favorable to the losing parties in the trial court, to indulge against the judgment every inference that may be drawn from the evidence and to disregard all contrary evidence thereto. ",
"Seideneck v. Cal Bayreuther Associates, 451 S.W.2d 752, 753 (Tex.1970); In re K.D.R., 590 S.W.2d 176, 177 (Tex.",
"Civ.",
"App.Corpus Christi 1979, writ ref'd n.r.e.). ",
"If, after having viewed the evidence in accordance with this rule, the evidence has any force of probative value, an issue of fact is raised and we must hold that the instructed verdict was improper. ",
"White v. White, 141 Tex. ",
"328, 172 S.W.2d 295, 296 (1943); In re K.D.R., 590 S.W.2d at 177-78.",
"\nThe evidence shows that Charles Waters informed the Bank that he wished to borrow $15,000.00 for a home improvement loan. ",
"He also told the Bank that he owed delinquent taxes on the property to be improved. ",
"The Bank advised Waters to obtain a bid for the improvements, and he acquired one from Briones for $19,817.00. ",
"Waters, however, told the Bank that since he would be assisting Briones with the improvements, a $20,000.00 loan would cover both the cost of the improvements and the delinquent taxes. ",
"Therefore, the Bank loaned Waters $20,000.00 which included sufficient money for the delinquent taxes and for the home improvements. ",
"The Bank prepared the documents needed for the loan, i.e., the \"MECHANIC'S LIEN NOTE,\" the \"MECHANIC'S LIEN CONTRACT WITH POWER OF SALE AND ASSIGNMENT,\" and the \"TRI-PARTY FINANCING AGREEMENT\" (Tri-Party Agreement).",
"\nThe Tri-Party Agreement obligates the Bank to make a loan to its borrowers (the Waters) in the amount of $20,000.00 provided that Briones, as contractor, sells to the bank the indebtedness and lien created by the mechanic's lien contract. ",
"This sale and purchase is to be consummated in installments as Briones earns the right to payment under the mechanic's lien contract and the Bank advances portions of the loan on behalf of the Waters to pay for the work. ",
"The first draw on the loan, a cashier's check for $5,000.00, was made payable to Charles and Pearl Waters and Geronimo Briones. ",
"Gaile Hoad, the Bank's loan officer who handled the loan herein, indicated that a portion of the $5,000.00 ($4,244.02) went to discharge the delinquent taxes on the Waters' property and to pay closing *634 costs. ",
"Briones originally sued Waters and the Bank. ",
"Briones and Waters settled their differences during trial. ",
"Waters is not a party to this appeal. ",
"The only issue remaining is between the Bank and Briones.",
"\nWhen construing a written contract, the primary concern of an appellate court is to ascertain and to give effect to the intentions of the parties as expressed in the instrument. ",
"R & P Enterprises v. LaGuarta, Gavrel & Kirk, Inc., 596 S.W.2d 517, 518 (Tex.1980). ",
"To achieve this goal, courts should examine and consider the entire writing in an effort to harmonize and give effect to all the provisions of the contract so that none will be rendered meaningless. ",
"Coker v. Coker, 650 S.W.2d 391, 393 (Tex.1983). ",
"No single provision taken alone will be given controlling effect; rather, all the provisions must be considered with reference to the entire instrument. ",
"Myers v. Gulf Coast Minerals Management Corp., 361 S.W.2d 193, 196 (Tex.1962).",
"\nSection 1 of the Tri-Party Agreement states, in relevant part, that the \"Bank shall make a loan (the \"Loan\") to Borrower [the Waters] in the principal amount of $20,000.00....\" A typewritten statement at the end of Section 1 states that \"[t]he initial advance on the loan in the amount of $____ shall be paid to discharge existing tax liens on the property.\" ",
"Gaile Hoad testified that this typewritten provision was added to the agreement.",
"\nAlthough the amount of the initial advance needed to discharge the tax liens is not specified, this does not render the meaning of this provision uncertain or ambiguous concerning whether the initial advance is to be applied to discharge the existing tax liens. ",
"Thus, the true intention of the parties was to allocate a portion of the loan proceeds for payment of the taxes. ",
"The exact amount could have been supplied by extrinsic evidence. ",
"Briones signed the agreement along with the Waters and the Bank. ",
"There was no doubt that Briones was aware that a portion of the loan proceeds were to be used to pay the delinquent taxes on the subject property. ",
"Thus, a fact issue was raised concerning whether the bank and Briones agreed that a portion of the loan proceeds would be used to pay the existing tax liens on the Waters' property.",
"\nMoreover, Section 3 of the agreement provides, in relevant part, that:\nBank has no obligation to make the Loan until Contractor [Briones] sells the indebtedness owing under the Contract together with the mechanic's lien and security interest securing the payment thereof and Financing Statement (the \"Contractor's Documents\") to Bank by assignment and endorsement, in form and substance satisfactory to Bank. ",
"The purchase price (the \"Purchase Price\") of the Contractor's Documents shall be the contract price (the \"Contract Price\") set forth in the Contract or so much thereof as may be earned thereunder.... (Emphasis added.)",
"\nAccording to the Tri-Party Agreement, the Bank's duty to make advances on the loan to pay for construction of the improvements is owed to its borrowers (the Waters), and these amounts shall be \"advanced under the loan on behalf of Borrower and shall be delivered directly to Contractor [Briones] as an installment payment owing to Contractor for the purchase of Contractor's Documents as provided in Section 3 hereof.\" ",
"Ownership of these documents becomes \"vested in the Bank at the times Bank makes advances to Borrower under the loan to pay Contractor for the Completed Work.\" ",
"The amount of each advance is the amount which Contractor has earned under the contract.",
"\nThus, if Briones did not fully perform the contract, then the agreement allows the Bank to pay the amount Briones actually earned rather than the contract price of $20,000.00. ",
"This raises a fact issue concerning whether Briones earned the full amount, or earned some amount less than the full amount, i.e., the loan amount of $20,000.00 less $4,244.02 for taxes and closing costs. ",
"If Briones did not earn the full amount, the Bank would be justified in not paying the full $20,000.00.",
"\nWe conclude that the Tri-Party Agreement raises a fact issue regarding whether *635 the Bank has to pay Briones the entire loan amount of $20,000.00 for his work. ",
"The trial court erred in granting an instructed verdict favorable to Briones. ",
"See White, 172 S.W.2d at 296; In re K.D.R., 590 S.W.2d at 178. ",
"Point one is sustained.",
"\nBy point five, the Bank complains the trial court erred in excluding extrinsic evidence of the \"understanding of the parties\" concerning the amount of the \"initial advance\" which was to be paid to discharge existing tax liens on the Waters' property. ",
"In a bill of exceptions, Gaile Hoad, the loan officer who handled the loan herein, testified about what happened during the closing of the loan. ",
"According to Hoad, she, Briones, the Waters and a title company representative discussed the fact that the initial advance would be used to pay the delinquent taxes. ",
"The amount to discharge the existing tax liens, $3,983.02, was supposed to go in the blank contained in Section 1 of the agreement where it states that \"[t]he initial advance on the loan in the amount of $____ shall be paid to discharge existing tax liens on the property.\" ",
"The Bank intended for the amount of taxes to be inserted in the agreement, but the closing agent neglected to write the figure in the blank. ",
"At the closing, Briones signed the Mechanic's Lien Note, the Mechanic's Lien Contract, and the Tri-Party Agreement.",
"\nWhere a writing is incomplete or ambiguous, parol evidence becomes admissible to explain the writing or to assist in the ascertainment of the true intention of the parties insofar as the parol evidence does not alter or contradict any part of the written memorandum in question. ",
"Patterson v. Patterson, 679 S.W.2d 621, 624 (Tex. ",
"App.San Antonio 1984, no writ); Warren Brothers Co. v. A.A.A. Pipe Cleaning Co., 601 S.W.2d 436, 438-39 (Tex.",
"Civ.",
"App. Houston [1st Dist.] ",
"1980, writ ref'd n.r.e.). ",
"Here, the Tri-Party Agreement is incomplete regarding the amount of the initial advance that would be expended to discharge the tax liens. ",
"Thus, the amount to be expended could have been established by parol evidence. ",
"We hold, therefore, that the trial court erred in excluding Gaile Hoad's testimony concerning the amount of the initial advance to be expended to discharge the tax liens. ",
"Point five is sustained.",
"\nBy point eight, the Bank complains that the trial court erred in failing to enter judgment on its counterclaim based on an agreement contained in the \"AFFIDAVIT AS TO DEBTS AND LIENS.\" ",
"On January 23, 1987, in connection with the closing of the permanent loan on the improvements, Briones visited Gaile Hoad's office and executed an \"AFFIDAVIT AS TO DEBTS AND LIENS\" (affidavit). ",
"Charles and Pearl Waters also signed this affidavit. ",
"The notarized affidavit states, in relevant part, that:\nAll labor and materials used in the construction of improvements on the above described property [the Waters' property] have been paid for and there are now no unpaid labor or material claims against the improvements or the property upon which same are situated, and I hereby declare that all sums of money due for the erection of improvements have been fully paid and satisfied. (",
"Emphasis added.)",
"\nThe affidavit also contained an indemnity provision which states as follows:\nI AGREE TO PAY ON DEMAND TO THE PURCHASERS AND/OR LENDER IN THIS TRANSACTION, THEIR SUCCESSORS AND ASSIGNS, ALL AMOUNTS SECURED BY ANY AND ALL LIENS NOT SHOWN ABOVE, TOGETHER WITH ALL COSTS, LOSS AND ATTORNEY'S FEES THAT SAID PARTIES MAY INCUR IN CONNECTION WITH SUCH UNMENTIONED LIENS, PROVIDED SAID LIENS EITHER CURRENTLY APPLY TO SUCH PROPERTY OR A PART THEREOF, OR ARE SUBSEQUENTLY ESTABLISHED AGAINST SAID PROPERTY AND ARE CREATED BY ME, KNOWN TO ME, OR HAVE AN INCEPTION DATE PRIOR TO THE CONSUMATION OF THIS TRANSACTION.",
"\nAccording to Briones, the indemnity provision provides that the Bank shall be indemnified for all costs incurred in connection *636 with liens and cannot be extended to include his suit for breach of contract. ",
"He maintains that the indemnity provision is not an agreement by Briones that the Bank has performed on its obligation to pay him for the note and Mechanic's Lien Contract. ",
"We disagree.",
"\nThe language employed by the parties to a written instrument should be given its plain grammatical meaning unless it definitely appears that the intention of the parties would thereby be defeated. ",
"Fox v. Thoreson, 398 S.W.2d 88, 92 (Tex.1966); Skyland Developers, Inc. v. Sky Harbor Associates, 586 S.W.2d 564, 570 (Tex.",
"Civ. ",
"App.Corpus Christi 1979, no writ). ",
"The language of the affidavit clearly states that \"all sums of money due\" for the construction of the improvements have been fully paid and satisfied. ",
"Thus, the parties' intention is to assure the Bank that all sums owing for the construction of the improvements have been paid. ",
"The affidavit obligates Briones to pay any claims which might thereafter be asserted, including his own. ",
"Moreover, the affidavit is not self-serving because it is totally adverse to Briones' interests. ",
"Based on the affidavit, there is no fact issue for determination between Briones and the Bank. ",
"Therefore, we hold that the trial court should have granted the Bank's motion for instructed verdict based on Briones' certification that all the construction bills have been paid and that he would indemnify the Bank against any claims or liens for any work performed. ",
"Point eight is sustained. ",
"We do not need to address the remaining points of error.",
"\nThe trial court's judgment is hereby REVERSED and judgment is RENDERED that appellee Briones take nothing against the First Victoria National Bank.",
"\n"
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"To terrorists, biological warfare is attractive because bio-weapons have relatively low production cost, it is relatively easy to obtain a wide variety of disease-producing biological agents, bio-weapons are non-detectable by routine security systems, and bio-weapons are easily transportable.",
"\nUnlike relatively mature radiation- and chemical-detection technologies, early-warning technology for biological agents is in its infancy. ",
"Most known bio-detection systems are “flow-through,” wherein individual particles that are contained in a flowing stream (e.g., air, etc.) ",
"are interrogated in an optical cell. ",
"Interrogation is typically performed using high-power lasers. ",
"The flowing stream, and hence the particles, have an extremely low residence time in the optical cell. ",
"As a consequence, the laser samples only a portion of the stream, must be relatively high power to provide an appropriate signal-to-noise ratio, and must be operating constantly to ensure detection.",
"\nFurthermore, some bio-detection systems use consumables, such as buffered saline solutions, antibodies, assay strips, reagent solutions, cleansing solution and antibodies. ",
"Most of these consumables have a specific shelf life, which creates a logistical burden. ",
"Furthermore, these consumables are typically unable to withstand demanding thermal requirements in theater. ",
"Also, many current bio-detection systems are large, heavy, and consume large amounts of power.",
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"Scientists at Columbia University have devised a clever way of converting thoughts into speech using a nifty combination of speech synthesizers and artificial intelligence (AI).",
"\n\nThe technology effectively connects to and \"listens\" to the brain, detecting patterns of activity it can then \"translate\" into words. ",
"As of right now, its abilities are relatively basic but, as the researchers note in Scientific Reports, the possibilities are huge. ",
"Not only could it offer us a way to communicate with computers, it may one day offer potentially life-changing solutions to people with speech-limiting conditions – for example, those who have had a stroke or are living with amyotrophic lateral sclerosis (ALS), like the late great Stephen Hawking.",
"\n\nThe process hinges on the tell-tale patterns of activity that light up our brains when we speak or even just think about speaking. ",
"Similarly, when we listen to someone else speak (or imagine doing so), there are various other patterns that present in the brain.",
"\n\nBut while previous attempts to \"read\" brain activity have relied on spectrogram-analyzing computer models and have been unsuccessful, this new technique uses the technology adopted by Apple for Siri and Amazon for Alexa – an AI-enabled vocoder.",
"\n\nVocoders are a type of computer algorithm that is able to synthesize speech, but first it has to be trained on recordings of people talking. ",
"For this particular study, led by Nima Mesgarani, a principal investigator at Columbia University's Mortimer B. Zuckerman Mind Brain Behavior Institute, the vocoder was trained with the help of five epilepsy patients, chosen because they were already undergoing brain surgery. ",
"While the epilepsy patients were asked to listen to the speech of various different people, the researchers monitored their brain activity.",
"\n\nThen, the experiment really began. ",
"To test whether or not the algorithm was now able to \"read\" the participants' brainwaves, the researchers played recordings of the same speakers reeling off sequences of digits between 0 and 9. ",
"The brain signals of the epilepsy patients were recorded and run through the vocoder. ",
"The results of the vocoder were then checked and \"cleaned up\" with AI (neural networks). ",
"Finally, a robotic-sounding voice repeated the sequence numbers.",
"\n\nTo determine how accurate (or not) the AI-enabled vocoder had been, the researchers asked participants to listen to the recording and say what they heard.",
"\n\n\"We found that people could understand and repeat the sounds about 75 percent of the time, which is well above and beyond any previous attempts,\" Mesgarani said of the result in a statement.",
"\n\n\"The sensitive vocoder and powerful neural networks represented the sounds the patients had originally listened to with surprising accuracy.\"",
"\n\nThe next steps will be to try to work on more complicated sequences – for example, actual sentences such as \"I need a glass of water\". ",
"But while there is clearly some way to go and there are limitations to the technology as it stands at the moment, the implications could be ground-breaking.",
"\n\n\"Our voices help connect us to our friends, family and the world around us, which is why losing the power of one's voice due to injury or disease is so devastating,\" Mesgarani added.",
"\n\n\"With today's study, we have a potential way to restore that power. ",
"We've shown that, with the right technology, these people's thoughts could be decoded and understood by any listener.\""
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"The Chicago Blackhawks season came to an end on Monday night in St Louis, with a Game 7 loss in their opening round series against the Blues. ",
"Now, we wait and see what else ended with it.",
"\n\nAn era? ",
"A dynasty? ",
"Something more? ",
"Or maybe just a chapter in an ongoing story, one that can’t end with a Cup parade every time even if it’s often seemed to.",
"\n\nThe NHL is a far different league than it was before the 2005 lockout that wiped out an entire season and ushered in a new set of rules, and that makes it hard to put what the Blackhawks have done in historical context. ",
"In decades past, an NHL dynasty meant an unstoppable force, like the great Canadiens teams of the 50s and 70s. ",
"It was Al Arbour’s Islanders winning four Cups and an unthinkable 19 straight playoff series. ",
"It was the Gretzky-led Oilers powerhouse that followed them, one that won four titles in five years and only lost when it scored into its own net.",
"\n\nThe Hawks, by comparison, have never even repeated as champions. ",
"They’ve won Cups in 2010, 2013 and 2015, making them the only team to win three titles in the post-2005 salary cap era. ",
"But they’ve also lost in the first-round three times since that first championship. ",
"Is that really a dynasty?",
"\n\nWell, yeah. ",
"In today’s NHL, it is. ",
"Because today’s NHL is designed to make it all-but impossible for the best teams to stay on top. ",
"There’s a hard salary cap in place, one that forces teams to stay under a preset budget. ",
"A good team can keep its core – the four or five players who define its identity – but they’ll become increasingly expensive, squeezing out the supporting cast that’s so crucial. ",
"Like a crab getting yanked back into the bucket, the NHL’s best teams are relentlessly pulled back to the pack. ",
"The system has resulted in an age of unprecedented parity and competitive balance, one that the league relentlessly promotes as a good thing.",
"\n\nDespite that, the Blackhawks have been able to keep winning. ",
"Not all the time, like teams could in the old days, but more than anyone else in the league could manage. ",
"Since emerging as a contender in 2009, Chicago have won 76 playoff games; the next best team have won just 54. ",
"They’ve got three Cups, while only one other team has even won two in the cap era. ",
"Hockey fans don’t argue about the era’s best team anymore, because there’s really no argument to be had. ",
"It’s the Blackhawks by a landslide.",
"\n\nAnd yet there they were on Monday, sent home in the first round by a longtime rival with a reputation for postseason failure. ",
"The title defense was over before it even really began.",
"\n\nSo what happened? ",
"And more importantly, what happens next?",
"\n\nAccording to the standings, the 2015-16 Blackhawks were very good but not great. ",
"They got a career year from winger Patrick Kane, one that earned him the league scoring title and probably MVP honors too. ",
"Captain Jonathan Toews was still among the best even in an off-year, while goaltender Corey Crawford was excellent and newcomer Artemi Panarin ran away with the rookie scoring race.",
"\n\nThe Hawks finished with 103 points, a mark that tied them with two other teams for the fifth best record in the league but was only good for third place in the Central Division. ",
"That isn’t unusual – Chicago have finished third or worse in their division in five of the last six seasons. ",
"They treat the regular season as tune-up time. ",
"This is a team that makes noise in the playoffs.",
"\n\nExcept that this year, they didn’t. ",
"They drew a tough matchup against the 107-point Blues, and fell behind 3-1 in the series through four games. ",
"The Hawks fought back to send the series to a seventh game, one that saw the Blues score a late goal and then survive a Chicago rally that came within a fraction of an inch of tying the game. ",
"A 3-2 final sent the Blues on to round two, and the Hawks back home to pack up their gear.",
"\n\nFor most of the league’s other 29 teams, a 100+ point season and a hard-fought playoff series would feel like some sort of success. ",
"But the Hawks aren’t most teams. ",
"Even factoring in fatigue – Chicago had played 65 playoffs games over the last three years, by far the most in the league – and the quality of their opponent, the Blues series was always winnable. ",
"It felt like the Blackhawks were going to find a way yet again, right up until they didn’t.",
"\n\nAnd so here we are. ",
"In Chicago, at least, this is what failure looks like.",
"\n\nOff the ice, it has to be noted, the Blackhawks’ season was even worse, with their reputation as the league’s model franchise taking several hits. ",
"Kane was accused of rape in the offseason; a lengthy police investigation resulted in no charges being filed, but not before he was paraded in front of cameras for an embarrassing training camp press conference. ",
"A minor league prospect faced felony charges in a revenge porn case, leading to questions over whether management had known about the case (the charges were later dropped). ",
"And just last week, Blackhawks’ forward Andrew Shaw was suspended for a crucial playoff game after being caught on camera using an anti-gay slur.",
"\n\nThree unrelated incidents, but each serving to tarnish the Blackhawks’ image as the team that could do no wrong. ",
"Combine that with a first-round exit, and you’re left with a season that many fans might rather forget.",
"\n\nAnd now, it’s tempting to go ahead and declare the Blackhawks dynasty over. ",
"It’s been a great run, the best we’ve seen in the cap era, but there’s just too many obstacles in the way for it to continue. ",
"Monday’s game seven loss was the last gasp, a proud champion sent home on its shield. ",
"This is the way the dynasty ends; not with a bang, but with two goalposts and a handshake line.",
"\n\nThere’s just one problem: We’ve done all this before.",
"\n\nWe did it back in 2010, when the Blackhawks won their first Cup, then immediately had to dismantle because of salary cap troubles. ",
"They were forced to dump a big chunk of their roster, including both goaltenders and future stars like Dustin Byfuglien and Andrew Ladd, and then they didn’t win another playoff round for two years.",
"\n\nWe did it again in 2013, after the Blackhawks’ second title, when more veterans had to be shipped out. ",
"We did it in 2014, when another cap crunch loomed, and again during the 2015 playoffs, when the Ducks pushed them to the brink in the conference final.",
"\n\nWe’ve all been the self-appointed coroner, pulling the sheet up and declaring the Blackhawks dead for years now. ",
"And every time we turn around, there they are, hopping off the gurney and heading off to go win another Cup.",
"\n\nAnd yes, this may the year that the pessimists are finally right. ",
"The Blackhawks really do seem to be facing a potential roster crisis. ",
"Toews and Kane are signed to long-term deals that carry the highest cap hits in the league, and for now they’re still worth it. ",
"Duncan Keith is about to turn 33, with a back-diving contract (one that would be illegal under current rules) still represents great value. ",
"But Marian Hossa is 37 and slowing down noticeably, and still carries a big cap hit for five more years, while 31-year-old Brent Seabrook’s massive eight-year extension hasn’t even kicked in yet. ",
"The team gave up several draft picks and prospects in an unsuccessful attempt to load up at this year’s trade deadline, so the pipeline of young talent is drying up.",
"\n\nSo this is it. ",
"It has to be. ",
"The dynasty is over.",
"\n\nThat’s the story and we’re sticking to it. ",
"And we’ll stick to it all through the summer, into next season, and maybe even right up until the Blackhawks are skating another Cup around a rink somewhere next June. ",
"And then, chances are, we’ll rewrite the whole story one more time, and start sticking to that one.",
"\n\nWe’ll be right one of these days. ",
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"Early pregnancy: normal and abnormal.",
"\nThe understanding of early pregnancy both normal and abnormal as seen by transvaginal ultrasound is an essential skill of any clinician involved in reproductive medicine and infertility. ",
"The \"sonomicroscopy\" of the vaginal probe results from the high level of magnification and close proximity to the structure being studied. ",
"In addition, the ability to detect minute levels of human chorionic gonadotropin, often by over-the-counter home pregnancy tests, has caused patients to present to clinicians earlier then ever before. ",
"It is essential that the sonologist or sonographer understand what early pregnancy looks like on transvaginal ultrasound and why it looks like that, so that one can distinguish early pregnancies that are normal from those that are absolutely destined to fail. ",
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"This invention relates generally to sawmill equipment and more particularly to an apparatus and method for cutting a log into suitable lengths.",
"\nOne of the first steps in converting a tree into lumber is to first cut the tree into suitable log lengths. ",
"It is important that the tree be bucked or cut into lengths that will produce the highest possible value of lumber for that tree. ",
"During the bucking procedure it is also desirable that defective or excessively crooked wood be cut out of the tree. ",
"Such wood is subsequently sent to a chipper for conversion into chips and later pulped. ",
"Cutting decisions made during bucking have traditionally been exercised by a highly skilled operator, but computer systems have been recently developed which scan the log and advise the operator as to the most appropriate lengths.",
"\nTwo types of bucksaw systems are typically utilized. ",
"The simplest system is known as the cutoff saw system. ",
"In this system the log travels endwise down a conveyer and the operator activates a so-called length stop when he has decided where a cut should be made. ",
"The forward end of the log hits the stop, the conveyer is shut down, and the saw is activated to make the desired cut. ",
"The log stop is then retracted, and conveyer travel is resumed. ",
"Once the cut log has passed the stop, the stop is re-extended, causing the leading end of the remaining part of the tree to run into the stop, and the process is repeated.",
"\nThe cutoff saw system gives the operator a great amount of versatility because he can cut the log at any point by merely stopping the log on the conveyer, and can reject wood to the chipper by cutting out undesirable sections. ",
"However, due to the intermittent nature of the cutoff saw system, it is very slow, resulting in poor productivity. ",
"Bucksaw productivity is extremely important because a bottleneck will usually exist in the sawmill at the bucksaw.",
"\nA second type of bucksaw which is more commonly used is the slasher deck system. ",
"This system is more elaborate than the cutoff saw system and has far greater capabilities. ",
"In this system trees are conveyed laterally on lug transfer chains which pass under a series of saws spaced at predetermined increments. ",
"Using special log loaders, the operator loads individual trees onto each log space of a continuously moving transfer deck. ",
"As each tree is moving toward the saws, the operator is positioning the saws as desired to make the necessary cuts. ",
"When the tree reaches the saws, the saws are displaced into the tree to make all of the required cuts at once.",
"\nA slasher deck system is far more productive than a cutoff saw system. ",
"However, there are a number of drawbacks with a slasher deck system. ",
"The system is very elaborate and is therefore expensive to purchase and maintain. ",
"Moreover, despite the complex construction of this type of system, it is very difficult to precisely space the saws so that the cut is made exactly where desired. ",
"Often the saws are merely placed at commonly required cut points rather than being specifically positioned for each particular log. ",
"This results in crooks and other defects remaining in the logs, which produces lower quality lumber and might even require that a cut log be subsequently passed to a chipper as a result of the failure to identify and remove a defect at an early point in the sawmill cycle.",
"\nA slasher deck system also takes up a great deal of space. ",
"The sheer size of the system also sometimes permits logs to become crossed as they move across the deck on the chains. ",
"To correct such faulty positioning, the operator must pry the logs back into a correct position. ",
"This can at times be a very dangerous procedure both to the equipment and to personnel.",
"\nIt is therefore an object of the present invention to provide a bucksaw apparatus and method which overcomes the drawbacks and limitations of the prior proposals. ",
"More specifically, the invention has as its objects the following:\n(1) to provide a bucking system which gives the operator as much control as possible to cut logs of different lengths while removing defects and damaged portions; PA1 (2) to develop a bucking system which is physically small, simple in construction, and low in initial and operating costs; PA1 (3) the provision of a bucksaw system which may be continuously operated to reduce or eliminate the bottleneck present in existing systems at this point in the system; and PA1 (4) the development of a bucksaw which can be substituted for existing cutoff and slasher deck systems without disrupting or requiring replacement of the remaining portions of the production line."
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"INTRODUCTION {#S0001}\n============\n\nAt present, airway management and respiratory support are of great importance in both ICU (Intensive care Unit) and RCU (Respiratory Care Unit) ([@CIT0001]). ",
"Weaning is a transmission process through which patients resume spontaneous breathing after mechanical ventilation ([@CIT0001], [@CIT0002]). ",
"Accurate weaning time is critically important in ICU and RCU. ",
"Any delay in ventilation removal may lead to ventilator acquired pneumonia and other possible side effects ([@CIT0003], [@CIT0004]). ",
"Premature removal may increase the length of ICU stay or result in patient\\'s death ([@CIT0005]). ",
"On the other hand, increase in number of patients who need ICU hospitalization and high relevant expenses have resulted in using a variety of indices including maximal inspiration pressure (PImax), minute ventilation and vital capacity for successful weaning. ",
"These indices have different specificity and sensitivities ([@CIT0006]). ",
"Rapid Shallow Breathing Index (RSBI) is one of the most commonly used indices which was first introduced by Yang and Tobin ([@CIT0007]). ",
"RSBI is calculated by this formula: $$\\frac{\\textit{Respiratory\\ rate}}{\\textit{Tidal\\ volume}}$$\n\nSeveral medical centers perform weaning if RSBI is less than 105 ([@CIT0008]). ",
"A variety of studies have defined different specificities and sensitivities for RSBI ([@CIT0009]--[@CIT0012]). ",
"The present study was designed to define specificity, sensitivity, negative predictor value and positive predictor value of RSBI in RCU and compare these values with those reported by previous studies.",
"\n\nMATERIALS AND METHODS {#S0002}\n=====================\n\nThis cross-sectional study was performed in Tehran Labbafi Nejad Hospital in 2010 on 70 patients who were clinically stable and had the criteria for weaning from the ventilator. ",
"Subjects were under ventilation for 9.4 ± 2.3 days. ",
"RSBI was calculated when patients were on spontaneous breathing mode with PSV=0 and PEEP=0 for one minute. ",
"Subjects who had RSBI \\> 105 were reventilated and RSBI was calculated on the next day. ",
"Patients with RSBI\\<105 were set on T-peace and extubated within 2 hours by taking into account all the medical conditions of the patient. ",
"If the patient tolerated spontaneous respiration for 48 hours, the weaning would be considered successful. ",
"Failure criteria were as follows: PaCO~2~\\>50 or more than 7mmHg increase in PaCO~2,~ PH\\<7.33, PaO~2~\\<60 with FIO~2,~ cold sweat, tachycardia, arrhythmias, increase in respiration struggle and hypotension. ",
"The local ethics committee approved the study and all subjects gave written informed consent.",
"\n\nData analysis {#S20003}\n-------------\n\nWe used SPSS version 11.5 software for data analysis. ",
"Frequency and proportion were used for numeric variables and mean and standard deviation for string variables. ",
"We used repeated measures ANOVA for comparisons within groups followed by Bonferroni test. ",
"Multivariate ANOVA was used for comparisons between groups. ",
"P \\<0.05 was considered statistically significant.",
"\n\nRESULTS {#S0004}\n=======\n\nA total of 70 patients were included in this study. [",
"Table 1](#T0001){ref-type=\"table\"} summarizes the baseline characteristics of the subjects. ",
"There were 29 females (41.4%) and 41 (58.6%) males. ",
"Age range was 40-91 yrs. ",
"and the mean age was 69.4 ± 13.1 yrs.",
"\n\n###### \n\nBaseline characteristics of study patients\n\n Characteristics Value\n -------------------------- -------------\n **Men/Women** 41/29\n **Age, Years** \n Mean± SD 69.4 ± 13.1\n Range 40-91\n **Concomitant diseases** \n pneumonia 19 (27.1)\n Heart failure 16 (22.9)\n COPD exacerbation 16 (22.9)\n Renal failure 6 (8.6)\n Sepsis 5 (7.1)\n Other 8\n\nData are shown as number (%) or mean± SD\n\nSubjects' concomitant diseases are shown in [Table 2](#T0002){ref-type=\"table\"}; among them pneumonia was the most common (27.1%) and sepsis (7.1%) was the least common concomitant disease. ",
"Duration of mechanical ventilation ranged from 2 to 45 days (mean=17 days).",
"\n\n###### \n\nConcomitant diseases of the patients\n\n Disease Frequency (%)\n ------------------- ---------------\n Pneumonia 27.1\n Heart failure 22.9\n COPD exacerbation 22.9\n Kidney failure 8.6\n Sepsis 8.1\n Other 9.3\n\n[Table 3](#T0003){ref-type=\"table\"} shows mechanical ventilation information and also patients' status. [",
"Figure 1](#F0001){ref-type=\"fig\"} compares frequencies of x-ray findings of patients. ",
"Seven patients never reached RSBI\\<105 and were excluded from the study. ",
"From a total of 63 patients, 49 (77%) subjects had successful weaning, while 14 (23%) patients had unsuccessful weaning. ",
"In patients with successful weaning, the mean RSBI was 65±37.2. ",
"This rate was 76.9±28.1 for unsuccessful weaning group. ",
"In the present study RSBI\\<105 was considered as the threshold and RSBI specificity, sensitivity, negative predictor value and positive predictor value were 77.8%, 71.4%, 96.1% and 26.3%, respectively. ",
"A total of 51 subjects out of 63 had RSBI\\<80 of which 46 (90.2%) patients had successful weaning while 5 (9.8%) had unsuccessful weaning (P=0.001). ",
"If we consider RSBI \\<80 as the threshold, RSBI specificity, sensitivity, negative predictor value and positive predictor value will be 92.25, 73.7%, 90.1% and 73.7%, respectively.",
"\n\n{#F0001}\n\n###### \n\nMechanical ventilation and patients' status.",
"\n\n Variables Mean±SD Range\n ------------------ ------------ -----------\n FIO~2~ 0.44±0.06 0.4-0.6\n Breath/min 20.3±5.7 10-36\n Tidal volume 430±133 300-720\n PEEP 4.9±0.44 4-6\n Pressure support 11.6±3.7 5-12\n PH 7.4±0.09 7.25-7.45\n Pco~2~ 38.9±12.4 30-50\n Hco~3~ 26.08±8.07 18-50\n Sao~2~ 94.3±2.7 89-99\n Weaning Index 69.7±50 20-200\n\nDISCUSSION {#S0005}\n==========\n\nIn this study, we evaluated specificity and sensitivity of RSBI in a medical ICU. ",
"Finding the cause of respiratory failure is the first step in management of patients who are under mechanical ventilation. ",
"The second step is to select patients who can have spontaneous respiration and can breathe without the aid of ventilator ([@CIT0013]). ",
"A standard assessment method for weaning should be simple and safe ([@CIT0013]).",
"\n\nFor the first time Yang and Tobin used RSBI for weaning in 1991. ",
"They reported RSBI as the most specific and most sensitive index for weaning. ",
"For tidal volume measurement they used a special spirometer which was connected to the trachea ([@CIT0007]). ",
"Although some studies have considered RSBI as a useless method ([@CIT0014], [@CIT0015]), many ICUs use RSBI for weaning ([@CIT0013]). ",
"Such differences may be attributed to sample size or absence of a global definition for weaning ([@CIT0016]). ",
"Patel and his colleagues ([@CIT0004]) tried different methods for RSBI measurement. ",
"They proved that CPAP application with 5 CmH~2~O can cause significant decrease in RSBI but method of measurement or time of measurement could not change this index. ",
"Therefore, CPAP application for measurement of RSBI can increase the measured RSBI up to 25% although its role in outcome of the disease is not well studied.",
"\n\nAnother study revealed that CPAP application with 5 CmH2O can increase RSBI up to 49% after heart surgery ([@CIT0009]). ",
"In the present study patients underwent ventilation for 1 minute by PEEP:0 and PSV:0 and then we measured RSBI. ",
"The two mentioned studies measured RSBI after 1 minute of ventilation. ",
"In the primary studies of Tobin and Yang, they measured RSBI when patients inhaled room air. ",
"But in the next studies they used higher FIO~2~ levels. ",
"It seems that Yang and Tobin\\'s method for measurement of RSBI should be modified with current methods. ",
"In our study, from a total of 63 patients, 48 (77%) had successful weaning with mean RSBI =65 but this index was 76.9 in patients who had unsuccessful weaning. ",
"This difference was not statistically significant (P=0.433). ",
"RBSI=105 showed relatively high sensitivity (77.8%) but low specificity (71.4%). ",
"Decreased RSBI can cause an increase in sensitivity and specificity. ",
"For RSBI \\<80 we found sensitivity=90.2% and specificity =73.7%.",
"\n\nCONCLUSION {#S0006}\n==========\n\nAlthough RSBI \\<105 is a helpful index for weaning, it is presumed that application of RSBI alone can be misleading. ",
"General status of the patient, concomitant diseases and duration of ICU stay should all be taken into account for successful weaning.",
"\n\nWe wish to thank the RCU staff of Labbafi Nejad Hospital for their efforts. ",
"The authors declare no conflicts of interest.",
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[
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"\n207\nWhat comes next: 319, 322, 327, 334?",
"\n343\nWhat is next in -46, -44, -42, -40?",
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"\n261\nWhat is next in 211, 405, 599, 793?",
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[
"Q:\n\nConflict between AngularJS and Thymeleaf\n\nam a newbie to angularJS and Thymeleaf and am experiencing some weird conflict.",
"\nThis is what I have below\n <input type=\"text\" th:field=\"*{unit}\" value=\"{{unit.unitID}}\" class=\"unit_value\"/>\n\nWhenever the template is resolved and displayed in the browser, the value is set to empty as in something like this\n<input class=\"unit_value\" type=\"text\" value=\"\" id=\"unit\" name=\"unit\" />\n\nam not having the angularJS expression in the value anymore.",
"\nI know the expression is synonymous to that of thymeleaf, I really dont know how to solve this.",
"\nI have searched everywhere but cant get a solution.",
"\n\nA:\n\nThe Solution I found is to literally bind the tag yourself and releave thymeleaf from binding it that is just put in the expected generated html that thymeleaf will generate \n <input type=\"text\" name=\"unit\" value=\"{{unit.unitID}}\" class=\"unit_value\"/>\n\nAnd everything works fine.",
"\n\n"
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"\n167 N.W.2d 80 (1969)\n184 Neb. 274\nSTATE of Nebraska, Appellee,\nv.\nVictor C. HOWARD, Appellant.",
"\nNo. ",
"37011.",
"\nSupreme Court of Nebraska.",
"\nApril 11, 1969.",
"\n*82 Munro, Parker, Munro & Grossart, Kearney, for appellant.",
"\nClarence A. H. Meyer, Atty. ",
"Gen., Mel Kammerlohr, Asst. ",
"Atty. ",
"Gen., Lincoln, for appellee.",
"\n*83 Heard before WHITE, C.J., SPENCER, BOSLAUGH, SMITH, McCOWN, and NEWTON, JJ., ",
"and COLWELL, District Judge.",
"\nCOLWELL, District Judge.",
"\nVictor C. Howard was found guilty by the district court for Sherman County of the crime of fourth degree arson, a felony, in violation of section 28-504.04, R.R.S. 1943. ",
"Defendant pleaded not guilty and waived jury trial. ",
"Probation was imposed for a term of 2 years. ",
"Motion for a new trial was denied and an appeal perfected to this court.",
"\nDefendant lived and was employed at Poole, Buffalo County, Nebraska; he owned and possessed a small acreage on the edge of Rockville, Sherman County, Nebraska, improved by a vacant house in poor condition, a barn and a chicken house, the area around the improvements was fenced; and he kept some cattle there. ",
"Between 4 and 5 p.m., on August 27, 1967, Laverne Thompsen, accompanied by Samuel Sullivan, went to defendant's acreage to examine the house as an interested buyer. ",
"Thompsen had hearsay information that the defendant wanted to sell the house. ",
"They opened the gate, entered the premises, lifted the latch on a broken screen door, and entered the house. ",
"The door and several windows were open. ",
"After a brief inspection they detected the odor of smoke, which directed them to the basement where they observed two bales of straw on a ledge near the floor joists concealing an electric light bulb connected to a socket and an electrical cord extending out of the basement through a window; and they observed a small pile of ashes near the bales of straw and that the floor joists showed some evidence of burning. ",
"They left the premises and immediately reported their observations to Ruppert Claussen, fire chief for the Rockville volunteer fire department and the Rockville rural fire protection district. ",
"Chief Claussen, Thompsen, and Sullivan immediately returned to the Howard acreage and reentered the premises in the same manner. ",
"Chief Claussen made an inspection and verified the information given him; in addition he determined that the electrical cord reentered the house through a bedroom window and was coiled in a space between the window and the screen; he also determined that there was electrical power \"on\" in the house. ",
"These three men then returned to Rockville about 6 p.m. Chief Claussen contacted Virgil J. Kaminski, county sheriff of Sherman County, Nebraska, who arrived in Rockville at about 10 p.m. Claussen informed Kaminski of the facts known to him; and these officers relayed this information by telephone to the office of the State Fire Marshal, Lincoln, Nebraska. ",
"Between 3 and 4 a.m. on the following morning assistant state fire marshal Wallace Barnett and deputies William Watson and Harley J. Mannier arrived in Rockville and conferred with sheriff Kaminski and chief Claussen. ",
"No surveillance had been maintained of the Howard premises; and there was concern among the officers whether or not a fire might then be burning. ",
"Sheriff Kaminski, fire marshals Barnett, Watson, and Mannier went to the Howard property at about 4 a.m., stepped over the fence, shined flashlights on the house and into the basement, looked into the basement and walked around the house. ",
"They did not enter the house and no fire was observed. ",
"These four officers left the premises and returned to Loup City, county seat of Sherman County, Nebraska. ",
"Later that morning Barnett consulted with county attorney Robert M. Martin, who prepared an affidavit for Barnett to apply for a search warrant. ",
"About 10 a.m. the affidavit was filed by Barnett with P. J. Kowalski, county judge of Sherman County, Nebraska, who issued a search warrant directed to Wally Barnett, assistant state fire marshal, to search defendant's premises and seize property, both being described. ",
"Immediately thereafter Barnett, Watson, Mannier, and Kaminski went to the Howard acreage, entered the premises, and made a search of the house. ",
"Photographs were taken; and the investigation further revealed in a closet *84 on the main floor of the house a pile of paper, feed sacks, and other papers covering another light bulb connected to a socket and electric extension cord. ",
"Two drop cords with recepticles and light bulbs and one gallon jug with oil were seized and inventoried. ",
"Later on in the afternoon defendant was located at Poole, Nebraska; he was taken into custody and Miranda warnings were given; and, after a brief interview, defendant made oral admissions. ",
"Defendant was taken to the sheriff's office in Loup City, Nebraska, where further Miranda warnings were given him, and the defendant on the same day executed a written confession. ",
"At the preliminary hearing before the county judge, P. J. Kowalski, defendant did not testify and he offered no evidence. ",
"Defendant was represented by his own counsel at the preliminary hearing and at the trial.",
"\nPrior to trial, defendant filed a plea in abatement and a motion to suppress evidence. ",
"Upon hearing, the plea in abatement was denied and the motion to suppress granted as to witness Wallace Barnett. ",
"Appeal from this ruling on the motion was taken by the State pursuant to sections 29-824 and 29-826, R.R.S.1943, for ruling by one Judge of the Supreme Court. ",
"Ruling of the trial court was reversed, and defendant's motion to suppress was denied.",
"\nThe main thrust of defendant's argument is that there was an unlawful search and seizure made; that evidence obtained thereby, both physical evidence, instruments of the crime, and the admissions subsequently obtained from the defendant, was unlawfully considered both at the preliminary hearing and at the trial of the case. ",
"We will consider this argument in the several areas covered in defendant's brief, being mindful that both the Fourth Amendment to the United States Constitution and Article I, section 7, of the Nebraska Constitution, relate to the right of the people to be secure against unreasonable searches and seizures, and that search warrants shall issue only upon probable cause supported by oath or affirmation.",
"\nThe original discovery of the property later seized was made by Thompsen and Sullivan who trespassed upon the premises for a purpose unrelated to the crime and they removed no property. ",
"Defendant cites no cases supporting his view that this entry was an unlawful search. ",
"The protection of the Fourth Amendment is a restriction on governmental action only. ",
"Burdeau v. McDowell, 256 U.S. 465, 41 S.Ct. ",
"574, 65 L.Ed. ",
"1048, 13 A.L.R. 1159.",
"\nA search implies some exploratory investigation. ",
"It is not a search to observe that which is open and patent, in either sunlight or artificial light. ",
"State v. Carpenter, 181 Neb. 639, 150 N.W.2d 129.",
"\nFire is a destructive burning involving combustion which manifests itself in heat and flame. ",
"Fire consumes and destroys. ",
"Fires, reports of fires, the existence of incendiary devices, and fire prevention demand the urgent and emergency response and vigilance of all firemen and law inforcement officers to protect the public.",
"\nIn Shypulski v. Waldorf Paper Products Co., 232 Minn. 394, 45 N.W.2d 549, that court said: \"The first thing to be recognized is that firemen, policemen, and similar personnel have a status sui generis. * * * ",
"Firemen make their entry under license of law, * * *. ",
"Firemen are regarded as making their entry primarily for the purpose of performing a duty owed to the public. ",
"Although the benefit of their services may accrue entirely to an individual property owner, that fact is regarded as incidental.\"",
"\nWhen Thompsen and Sullivan reported to chief Claussen, they told him what was there, that there had been a fire, that it smelled like smoke, and it looked like it was set to start again. ",
"Claussen knew that the house was vacant and he made an immediate investigation. ",
"Firemen have a duty to promptly investigate fire reports; and they have the duty and right to enter property to combat fires. ",
"Is their duty and right any less when, after entry, their *85 investigation reveals that there is no fire? ",
"We think not. ",
"Chief Claussen properly performed his duties here; and there was no search and no trespass.",
"\n\"The States are not * * * precluded from developing workable rules governing arrests, searches and seizures to meet `the practical demands of effective criminal investigation and law enforcement' in the States, provided that those rules do not violate the constitutional proscription of unreasonable searches and seizures and the concomitant command that evidence so seized is inadmissible against one who has standing to complain.\" ",
"Ker v. California, 374 U.S. 23, 83 S.Ct. ",
"1623, 10 L.Ed.2d 726.",
"\n\"The right of an individual to be free from unwarranted intrusions on his person and property should be balanced against the need for effective law enforcement which can only exist where an officer's actions are measured objectively against a standard of reasonableness.\" ",
"State v. Harding, 184 Neb. 159, 165 N.W.2d 723.",
"\nGiacona v. United States, 257 F.2d 450 (5th Cir.), ",
"is similar in part to this case. ",
"Federal officers received information that marijuana was concealed in the foundation blocks under a store building; a surveillance was maintained; and one of the officers crawled up to the building, reached underneath it, and removed a paper bag containing marijuana. ",
"The bag was inspected, initialed, and replaced; and thereafter one of the officers filed an affidavit and obtained a search warrant. ",
"The court said: \"When the performance of his duty requires an officer of the law to enter upon private property, his conduct, otherwise a trespass, is justifiable. ",
"52 Am.",
"Jur., ",
"Trespass, § 41. ",
"In any event, evidence is not rendered inadmissible merely because it has been obtained by a simple trespass upon land. ",
"The protection of the Fourth Amendment is not that extensive. * * * ",
"The Fourth Amendment protects against `unreasonable searches and seizures.' ",
"Reasonableness is often a question of degree as to `when the right of privacy must reasonably yield to the right of search.' ",
"Johnson v. United States, 1948, 333 U.S. 10, 14, 68 S.Ct. ",
"367, 369, 92 L.Ed. ",
"436. * * * ",
"`Reasonableness is in the first instance for the District Court to determine.' ",
"United States v. Rabinowitz, 1950, 339 U.S. 56, 63, 70 S.Ct. ",
"430, 434, 94 L.Ed. ",
"653. ",
"See, also, Harris v. United States, 1947, 331 U.S. 145, 150, 67 S.Ct. ",
"1098, 91 L.Ed. ",
"1399. * * * ",
"What may be unreasonable in a search of a man's house, may be entirely reasonable in a search of his place of business. ",
"Harris v. United States, supra. * * ",
"The nature of the search also is an important circumstance in determining reasonableness. (",
"The) preliminary search was not of a general exploratory nature but might more accurately be considered a mere inspection to verify the information which he had received.\"",
"\nSection 81-502, R.S.Supp.1967, provides: \"It shall be the duty of the State Fire Marshal * * * (1) to enforce all laws of the state relating to the suppression of arson and investigation of the cause, origin and circumstances of fires; * * *.\" ",
"Section 81-505, R.R.S.1943, provides: \"The duties of the first assistant and the deputy fire marshals shall be to operate under the direction of and to assist the State Fire Marshal * * *.\" ",
"Section 23-1710, R.R.S.1943, provides: \"It shall be the duty of the sheriff by himself or deputy to preserve the peace in his county, to ferret out crime, to apprehend and arrest all criminals, and insofar as it is within his power, to secure evidence of all crimes committed in his county, * * * and to perform all other duties pertaining to the office of sheriff.\"",
"\nAs to the entry upon the premises by sheriff Kaminski, and fire marshals Barnett, Watson, and Mannier, defendant argues that the entry was a trespass under a pretext of investigating a possible fire, that it was unlawful, and that the evidence obtained by trespass could not be used as a basis for an affidavit to obtain a search warrant, citing United States v. Bush, 6 *86 Cir., ",
"283 F.2d 51. ",
"Although defendant does not claim the entry to be an unreasonable search, the reasonableness of the acts of the officers under the circumstances will be examined. ",
"Defendant cites Camara v. Municipal Court of City and County of San Francisco, 387 U.S. 523, 87 S.Ct. ",
"1727, 18 L.Ed.2d 930, as authority that the inspection was unlawful requiring a search warrant. ",
"Camara is distinguished from the facts here, it prohibits warrantless nonemergency inspections by housing code inspectors. ",
"In the present case, none of these officers had ever been at the Howard property; but they had reliable information about the existence of an incendiary device in the basement of the Howard property which could have been \"triggered\" at any time by connecting the cord to the electrical source available by any so designing person. ",
"A felony had been committed; no surveillance had been maintained at the scene; they had no information whether a fire might be then burning; and they were concerned about the possibility of a fire at the Howard property. ",
"They took the precaution of inspecting the premises to determine whether or not there was a fire; they did not enter the house; their inspection furnished them with no added information; they made no search for either evidence or instruments of the crime; and finding no fire they left the premises to await search warrant process. ",
"We are not persuaded that the officers entered the premises under pretext. ",
"The entry of these officers was not a search; at most, it was a technical trespass, more in the nature of an inspection, made in the proper performance of their duties, reasonable and justified by the circumstances. ",
"Any information gained by them could be lawfully used in an affidavit for a search warrant.",
"\nNext the defendant claims that the search and seizure accomplished by the officers with the use of a search warrant was unlawful because the affidavit was void for the following reasons: (1) No oath was administered, and (2) the stated grounds for probable cause were based on hearsay and observations made by unlawful trespass.",
"\nCounty attorney Martin prepared the affidavit for the signature of Wally Barnett, assistant state fire marshal. ",
"These two men went to the office of county judge Kowalski. ",
"Martin introduced Barnett to judge Kowalski and announced the purpose of their presence. ",
"Barnett was wearing the regular uniform of state fire marshal with badge. ",
"Barnett handed the affidavit to judge Kowalski who read it, and then asked Barnett if he was the affiant. ",
"Barnett acknowledged that he was, the affidavit was returned to Barnett who signed it, and judge Kowalski then signed the jurat and affixed the seal of his office. ",
"The following testimony of Kowalski is pertinent: \"Q Now, at this time that he signed this affidavit you did not at that time ask him specifically, `Do you swear to this'? ",
"A No, that probably is one of my weaknesses, because I feel that a man signs it right in my presence and ishow would I say that?anyhow it is authentic; that's what I mean.\"",
"\nAs to the first claim that Barnett was not placed on oath, the first paragraph of the affidavit recites: \"The Complaint and Affidavit of Wally Barnett of the Office of the State Fire Marshal * * * who being first duly sworn, on oath, says: * * *.\" ",
"The jurat recites: \"Subscribed and sworn to before me this 28th day of August, 1967. ",
"P. J. Kowalski.\" ",
"An affidavit is a written declaration under oath, made without notice to the adverse party. ",
"Section 25-1241, R.R.S.1943. ",
"We have held that an affidavit must bear upon its face by the certificate of the officer before whom it was taken evidence that it was duly sworn to by the party making the same. ",
"Sebesta v. Supreme Court of Honor, 77 Neb. 249, 109 N.W. 166. \"",
"Oaths to affidavits ordinarily are not required to be administered with any particular ceremony, but affiant must perform some corporal act before the officer whereby he consciously takes upon himself the obligation of an oath; but it is not essential that he *87 raise his hand.\" ",
"2 C.J.S. Affidavits s.20, p. 959. \"",
"If the attention of the person making the affidavit is called to the fact that it must be sworn to and, in recognition of this, he is asked to do some corporal act and he does it, the instrument constitutes a statement under oath, irrespective of any other formalities.\" ",
"3 Am.",
"Jur.2d, Affidavits, s. 11, p. 389. ",
"See, also, Dalbey Bros. Lumber Co. v. Crispin, 234 Iowa 151, 12 N.W.2d 277. ",
"The affidavit here meets the requirements of execution under oath.",
"\nAs to the second claim we have disposed of the objection of trespass, and now direct our attention to whether the affidavit stated grounds for probable cause. ",
"Recently in Spinelli v. United States, 393 U.S. 410, 89 S.Ct. ",
"584, 21 L.Ed.2d 637, the court stated: \"In holding as we have done, we do not retreat from the established propositions that only the probability, and not a prima facie showing, of criminal activity is the standard of probable cause, Beck v. Ohio, 379 U.S. 89, 96, 85 S.Ct. ",
"223, 228, 13 L.Ed.2d 142 (1964); that affidavits of probable cause are tested by much less rigorous standards than those governing the admissibility of evidence at trial, McCray v. Illinois, 386 U.S. 300, 311, 87 S.Ct. ",
"1056, 1062 [18 L.Ed.2d 62] (1967); that in judging probable cause issuing magistrates are not to be confined by niggardly limitations or by restrictions on the use of their common sense, United States v. Ventresca, 380 U.S. 102, 108, 85 S.Ct. ",
"741, 745 [13 L.Ed.2d 684] (1964); and that their determination of probable cause should be paid great deference by reviewing courts, Jones v. United States, 362 U.S. 257, 270-271, 80 S.Ct. ",
"725, 735-736 [4 L.Ed.2d 697] (1960).\" ",
"In a concurring opinion in Spinelli, Justice White discusses some further guides: \"An investigator's affidavit that he has seen gambling equipment being moved into a house * * * will support the issuance of a search warrant. * * * ",
"Personal observation attests to the facts asserted * * *. ",
"But if the officer simply avers, without more, that there is gambling paraphernalia * * *, the warrant should not issue, even though the belief of the officer is an honest one, * * * and even though the magistrate knows him to be an experienced, intelligent officer who has been reliable in the past. ",
"This much was settled in Nathanson v. United States, 290 U.S. 41, 54 S.Ct. ",
"11, 78 L.Ed. ",
"159 (1933) * * *. ",
"What is missing in Nathanson and like cases is a statement of the basis for the affiant's believing the facts contained in the affidavitthe good `cause' which the officer in Nathanson said he had. ",
"If an officer swears that there is gambling equipment at a certain address, the possibilities are (1) that he has seen the equipment; (2) that he has observed or perceived facts from which the presence of the equipment may reasonably be inferred; and (3) that he has obtained the information from someone else. ",
"If (1) is true, the affidavit is good. ",
"But in (2), the affidavit is insufficient unless the perceived facts are given, for it is the magistrate, not the officer, who is to judge the existence of probable cause. ",
"Aguilar v. Texas, 378 U.S. 108, 84 S.Ct. ",
"1509, 12 L.Ed.2d 723 (1964); Giordenello v. United States, 357 U.S. 480, 486, 78 S.Ct. ",
"1245, 1250, 2 L.Ed.2d 1503 (1958); Johnson v. United States, 333 U.S. 10, 14, 68 S.Ct. ",
"367, 369, 92 L.Ed. ",
"436 (1947). ",
"With respect to (3), where the officer's information is hearsay, no warrant should issue absent good cause for crediting that hearsay.\"",
"\nIn United States v. Ventresca, 380 U.S. 102, 85 S.Ct. ",
"741, 13 L.Ed.2d 684, the court stated: \"Observations of fellow officers of the Government engaged in a common investigation are plainly a reliable basis for a warrant applied for by one of their number.\" ",
"In Giacona v. United States, supra, the court stated: \"Whether or not the information * * * received `from a reliable source' would have sufficed need not be decided. ",
"Certainly, after that information had been verified by * * * personal inspection, it constituted `probable cause'.\"",
"\n*88 Defendant urges that the affidavit is void because it recites the conclusion of the sheriff, \"* * * that the Sheriff had reason to believe that an act of arson might be committed or might have been committed.\" ",
"This is a conclusion and hearsay; however, this recitation can be disregarded in considering this issue here since the affidavit also recites an inspection made of the premises, which defendant concedes was an inspection made by the affiant, deputy fire marshals Watson and Mannier and sheriff Kaminski. ",
"The inspection relates a personal observation and that is sufficient. ",
"For the same reason we disregard defendant's argument that State v. McCreary, 179 Neb. 589, 139 N.W.2d 362, controls here. ",
"In McCreary, a part of the information related in the affidavit was attributed to a \"reliable informant\"; here the information is personal observation.",
"\nFrom reading the affidavit in its entirety, the county judge had a substantial basis for finding probable cause by independent judgment. ",
"We cannot say that the finding of probable cause was improper. ",
"The search warrant was properly issued to Wally Barnett, a law enforcement officer under section 29-814, R.R.S.1943. ",
"The search conducted pursuant to the search warrant was lawful.",
"\nDefendant contends that a preliminary hearing conducted by a county judge not an attorney and not trained in the law is in violation of his equal protection of the laws and due process of law guaranteed under the Fifth and Fourteenth Amendments to the United States Constitution and Article I, section 3, of the Constitution of Nebraska. ",
"Section 291607, R.R.S.1943, provides: \"No information shall be filed against any person for any offense until such person shall have had a preliminary examination therefor * * * before a Justice of the peace or other examining magistrate or officer, * * *.\" (",
"Emphasis supplied.) ",
"In State v. Sheldon, 179 Neb. 377, 138 N.W.2d 428, we said: \"The purpose of a preliminary hearing is to ascertain whether a crime has been committed and whether there is probable cause to believe that the accused committed it. ",
"It is not a trial of the person accused * * *.\" ",
"Defendant had available to him procedures to test the sufficiency of the evidence at the preliminary hearing which he did by plea in abatement. ",
"We find no merit in this contention.",
"\nThe claim of the defendant that the admissions made by him were the \"fruit\" of an unlawful search finds no support in the evidence.",
"\nWe find no prejudicial error in the record. ",
"The motion to suppress and the plea in abatement were properly denied; and the motion for new trial was properly denied.",
"\nThe judgment of the trial court is affirmed.",
"\nAffirmed.",
"\n"
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"Edit This Favorite\n\nLou Holtz has established himself as one of the most successful college football coaches of all time.",
"\n\nBorn Louis Leo Holtz on January 6, 1937, Holtz grew up in East Liverpool, Ohio, just up the Ohio River from his Follansbee, West Virginia, and birthplace. ",
"He graduated from East Liverpool High School, earned a Bachelor of Science degree in history from Kent State in 1959 and a master’s degree from Iowa in arts and education in 1961. ",
"He played linebacker at Kent State for two seasons before an injury ended his career. ",
"He has received 9 honorary doctorate degrees.",
"\n\nCOACH\n\nHoltz is the only coach in the history of college football to: 1) Take 6 different teams to a bowl game. ",
"2) Win 5 bowl games with different teams. ",
"3) To have 4 different college teams ranked in the final Top 20 poll.",
"\n\nDespite never inheriting a winning team, he compiled a 243-127-7 career record that ranked him third in victories among active coaches and eighth in winning percentage. ",
"His 12 career postseason bowl victories ranked him fifth on the all-time list. ",
"Holtz was recently selected for the College Football Hall of Fame, class of 2008, which places him in an elite group of just over 800 individuals in the history of football who have earned this distinction. ",
"Approximate 1 in 5,000 people who played college football or coached it make it into the Hall of Fame. ",
"In April of 2012, Coach Holtz was inducted into the Cotton Bowl Hall of Fame.",
"\n\nThe Follansbee, West Virginia, native became the 27th head coach of Notre Dame following two seasons at Minnesota (1984 to 85), seven at Arkansas (1977 to 83), four at North Carolina State (1972 to 75) and three at William & Mary (1969 to 71). ",
"He spent the 1976 season as head coach of the New York Jets of the National Football League. ",
"Twenty-one of the 26 collegiate teams under his direction have earned post-season bowl invitations—and 14 have finished in the final AP top 20, eight in the top 10 (not including the 1995 finish in that category).",
"\n\nHoltz’s head-coaching career began in 1969 at William & Mary at age 32. ",
"His second team in 1970 won the Southern Conference title and advanced to play 15-ranked Toledo in the Tangerine Bowl in the only postseason appearance in the history of the school. ",
"Holtz’s stab at professional football—between his tenures at North Carolina State and Arkansas produced a 3-10 record. ",
"He resigned the week of the Jets’ final regular season game.",
"\n\nBefore becoming head coach at William & Mary in 1969, Holtz served as an assistant coach at Iowa (freshmen, 1960), William & Mary (offensive backs, 1961 to 63), Connecticut (defensive backs, 1964 to 65), South Carolina (defensive backs, 1966 to 67) and Ohio State (defensive backs, 1968). ",
"The Buckeyes won the national championship in 1968 in his one season on the Ohio State staff. ",
"He worked under such respected coaches as Forest Evashevski at Iowa, Rick Foranzo at Connecticut, Paul Dietzel at South Carolina and Woody Hayes at Ohio State.",
"\n\nWhen Holtz took over as Notre Dame’s 27th head football coach back in November of 1985, he brought with him a well-proven reputation as a fixer of football programs following a series of spectacular repair jobs at William & Mary, North Carolina State, Arkansas and Minnesota.",
"\n\nTwenty-six seasons as a collegiate head coach earned Holtz a sterling reputation for turning pretenders into contenders—for taking football programs and elevating them a level or two on their way to the top 20. ",
"But nowhere has he done this as impressively than at Notre Dame.",
"\n\nHe enhanced that track record quickly, needing only two years to put the Fighting Irish back into a major post-season bowl game for the first time in seven seasons. ",
"Holtz proved he could take the Irish back to the ranks of college football’s elite and keep them there on a consistent basis.",
"\n\nHe also has developed a well-earned reputation as an expert when it comes to knocking off highly ranked opponents. ",
"That ability has been particularly well displayed in bowl games, with his team recording wins on January 1 in five of the last seven seasons against teams with a combined record of 74-4-1, all of them ranked seventh or higher in the Associated Press poll.",
"\n\nIn his 11 seasons at Notre Dame, Holtz chalked up more victories than the number accumulated by Parseghian, Rockne or Leahy in their first 11 years on the job. ",
"Including the consensus national championship in 1988, a record 23-game winning streak that ranks as the longest in Notre Dame history. ",
"An overall 100-30-2 mark during those eleven years—his accomplishments nonetheless have positioned him alongside those Fighting Irish coaching legends. ",
"When the Fighting Irish met Florida in the 1996 Orange Bowl, it was the ninth straight year Holtz had taken Notre Dame to the traditional January post-season bowls (Cotton Bowl following 1987, 1992 and 1993 campaigns, Fiesta in 1988 and 1994, Orange in 1989, 1990 and 1995, Sugar in 1991). ",
"This is something that no other coach in the country has matched. ",
"Holtz is the 2008 recipient of the Notre Dame Monogram Club’s highest honor, the Moose Krause Distinguished Service Award.",
"\n\nAfter his departure from Notre Dame following the 1996 season, he joined CBS Sports’ College Football Today for two seasons as a sports analyst and worked with United States Filter (a global provider of water treatment) as a customer relations spokesman. ",
"From there he went on to be head coach at the University of South Carolina for six seasons from 1999-2004 where he led the Gamecocks to back-to-back January 1 bowl games for the first time in the history of the school and defeated Ohio State in consecutive bowl appearances.",
"\n\nESPN SPORTS ANALYST AND SPEAKER\n\nCurrently, Holtz serves as a college football studio analyst on ESPN. ",
"He appears on ESPNEWS', ESPN College GameDay programs, SportsCenter as well as serves as an on-site analyst for college football games.",
"\n\nFor many years Holtz has been considered among the greatest speaking legends in America today. ",
"He speaks on overcoming seemingly impossible challenges by setting your own goals and working to achieve them.",
"\n\nHe has built a reputation as a motivator, a demanding disciplinarian and someone who relishes challenges and hard work.",
"\n\nAUTHOR\n\nHoltz has authored three New York Times best-selling books The Fighting Spirit that chronicled Notre Dame's 1988 championship season and Winning Everyday:AGame Plan For Success (August 1998), which has been published in several languages. ",
"His latest book which was released August 15, 2006 is Wins, Losses and Lessons, an autobiography of his life and the lessons he has learned, and is also a best seller.",
"\n\nAdditionally, he has produced three highly acclaimed motivational videos: Do Right, Do Right II, and If Enough People Care. ",
"The Lou Holtz Hall of Fame opened in East Liverpool, Ohio in July 1998. ",
"And he recently released his latest video, Do Right 20 Years Later.",
"\n\nThe Walter Camp Football Foundation, an award that is presented annually to an individual who has attained a measure of success and been a leader in his chosen profession, named Lou Holtz 1998’s Man of the Year. ",
"This is the second time Coach Holtz has been saluted by the organization named for the legendary Father of American Football. ",
"In 1977, while in Arkansas, he was named Coach of the Year.",
"\n\nMarried to Beth Barcus of East Liverpool on July 22, 1961, Holtz and his wife are the parents of four children and currently reside in Orlando, Florida."
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"These are 100pcs unpainted model car. ",
"These unpainted model cars are great collectibles. ",
"Your building or train landscape will be more authentic with these items. ",
"These unpainted model cars are perfect for model train set landscape. ",
"You can draw or paint by yourself and have great fun with these model cars!",
"\n\nWe're working hard to make sure our prices are the best around. ",
"If you find a lower price on another qualifying website, please don't hensitate to let us know. ",
"Your feedback will help us to make sure our prices remain competitive.",
"\n\n*Lower Price:US$\n\n*URL:\n\n*Your E-mail:\n\nPrivacy Protection:We will contact you if the price match request is handled."
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"pile_set_name": "Pile-CC"
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"Q:\n\nI saw no notification about my answer that was to be deleted\n\nI spotted the deletion only because I forgot to close the browser tab:\nhttps://codereview.stackexchange.com/a/134503/665\nIt's ridiculous that I was not notified that someone saw some issue with my answer and didn't point out what exactly I should do, but just deleted.",
"\nHow many of my answers had the same fate? ",
"Should I continue to review code here while such things are happening? ",
"No way!",
"\n\nA:\n\nIt's very unfortunate that you have not received a notification when the post notice. ",
"We (mods) were under the impression that users receive a notification when we do this, but it seems that's not always the case. ",
"We'll work with the community managers on that.",
"\nIt's also very unfortunate that you have not received a notification about the deletion of the post. ",
"Again, I find that unexpected, a very bad surprise, and we'll work with the CMs on that. ",
"\nUntil the notifications are improved, I propose the following workaround:\n\nWhen adding a post notice, mods should add a helpful comment to make sure the user gets notified. ",
"Even if we have nothing better to say than repeat the post notice, it's important to trigger a notification.",
"\nWhen seeing an answer with a post notice and no comments, users should add a helpful comment to make sure the user gets notified.",
"\nWhen voting to delete an answer with no comments, mods and users alike should add a comment to make sure the user gets notified.",
"\n\nA:\n\nThe answer in question showed up in the low quality queue, and is not a good answer in general for Code Review. ",
"We expect code to go along with explanations and answers to not just be a code dump.",
"\nI don't know why your answer was deleted (or by whom). ",
"Answers are not regularly deleted on this site unless it becomes an issue of moderation and authors are usually given the chance to respond to any warnings (such as the one currently on your post).",
"\nNote that your answer may have been flagged for deletion because it falls under the category of \"Not An Answer\", which users may have elected to do because as mentioned earlier your answer does not meet appropriate standards for Code Review.",
"\nAgain, this doesn't really tend to happen, only in cases of moderation or low quality. ",
"Consider addressing the notice @Jamal has added to your answers and elaborating on your answer, else it may still get flagged for deletion by other users.",
"\n\nA:\n\nYou were already given a post notice, which was also to provide an explanation on the issue with the answer:\n\nWe are looking for answers that provide insightful observations about the code in the question. ",
"Answers that consist of independent solutions with no justification do not constitute a code review, and may be removed.",
"\n\nMost of your answers are very good and of the type that are accepted here, but not this one (and some similarly problematic ones have already been deleted as well). ",
" You have also been here for over five years (and even longer than me!), ",
"so you should already be aware that such answers without explanations aren't accepted. ",
" It doesn't matter how simple they are, either. ",
" Just a simple explanation will make the difference between a review and a non-answer.",
"\nThe solution here should be simple: use your good existing answers as guidance for future answers and remember to provide explanations for answers like the one reported here.",
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"An oral heparin would avoid the inconvenience of subcutaneous injections and adverse events associated with warfarin. ",
"A mild chitosan/PEG/calcium alginate microencapsulation process, as applied to encapsulation of biological macromolecules such as heparin and LMW Hep was investigated. ",
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"It was observed that approximately 70% of the content is being released into Tris-HCl buffer, pH 7.4 within the initial 6 hours and no significant release of LMW Hep was observed from enteric coated microspheres (12%) during treatment with 0.1 M HCl, pH 1.0 for 4 hours. ",
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"To help protect communities from disasters and tackle the adverse effects of climate change, a new IUCN project will show how healthy ecosystems can help reduce the risks and make livelihoods more resilient.",
"\n\nAvalanches and landslides threaten human settlements and transport lines in mountainous regions of countries such as Nepal, Chile and China. ",
"Coastal communities in Thailand are exposed to tropical storms and soil salinization due to the degradation of mangrove forests while droughts, floods and other extremes seriously affect communities in Burkina Faso and Senegal.",
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"\n\n“EPIC will also work with policy makers at national and local levels to promote policies that link the various sectors such as environment, disaster management, land-use planning and public finance, and help in coordinated planning,” she adds.",
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"Why we should stop labelling people climate change deniers\n\nWe are not doing a good job of communicating climate change. ",
"People have diverging interpretations of how climate change fits into their own stories. ",
"Credit: Unsplash, CC BY-SA\n\nIn the westernmost reaches of Nunavut, on the Northwest Passage, Inuit hunters have told me some pithy things about climate change. \"",
"The land is changing. ",
"It isn't climate change. ",
"This is part of cycles. ",
"Our elders saw this coming.\"",
"\n\nSome of the most visible and profound effects of global warming are occurring in the Arctic. ",
"Some Inuit are worried climate change will permanently alter the world. ",
"Others say it will pass, as other times of want and plenty have passed through the Inuit's long cycles of life in the Arctic.",
"\n\nIn Inuit Nunangat, the Inuit homeland in Canada, perceptions about climate change cannot be divided into two camps of \"believers\" and \"deniers.\" ",
"The situation is far more complex.",
"\n\nSome fear climate change, some deny it's real and some don't know what, or whom, to believe. ",
"Many don't want to talk about climate change at all. ",
"Others say we must talk. ",
"The diverse interpretations of how climate change fits into their own stories are beautifully captured in the documentary Qapirangajuq: Inuit Knowledge and Climate Change.",
"\n\nIt's simplistic to divide people into only two opposing camps of climate change: believers or deniers. ",
"The way we have been communicating the science of climate change has not been persuasive.",
"\n\nPlace matters\n\nScientists warn that human activity, industrialization and our dependence on fossil fuels have caused a warming of global temperatures that threatens life on Earth. ",
"By contrast, climate change deniers dismiss such dire premonitions as conspiracy. ",
"The weight of scientific facts is often presented to better inform or inoculate a misinformed public.",
"\n\nYet between those two polarized positions are local populations living with the immediate effects of climate change on the environments they depend upon.",
"\n\nFew people can claim to share the Inuit's experience of climatic variation. ",
"Many process the concept of global warming with facts about climate change, but also by the geographies they occupy. ",
"As University of Cambridge geography professor Mike Hulme suggests, we should conceive of climate change as the cultural evolution of the idea of climate.",
"\n\nLocal experience, traditional knowledge and personal experience may blend in a swill of contradictory impressions about climate change. ",
"People are shaped in part by their place in the diverse physical and social spaces undergoing climate-related events, whether they are marine, mountain, urban or desert regions.",
"\n\nThe history and experience of individuals and communities may influence how they interpret and prioritize climate change. ",
"This diversity of lived experience and worldviews contradicts the divisions between climate change belief and denial.",
"\n\nFacts aren't enough\n\nClimate change science alone is not convincing. ",
"Recent research suggests the public is split into two conflicting groups: those whose views align with the scientific community (believers) and those who do not. ",
"These opinion-based groups have distinct social identities, beliefs and emotional reactions to environmental change; they are set apart by cultural differences and political leanings.",
"\n\nA recent study found that social networks influence people's stance on climate change. ",
"So, how you talk about climate change matters. ",
"An international survey of 24 countries found that personal experiences, beliefs, knowledge, values and worldviews are important factors that shape climate change belief.",
"\n\nThe video was initially swiftly embraced by climate change champions. ",
"For instance, Canada's Environment Minister Catherine McKenna tweeted: \"THIS is what climate change looks like. ",
"Climate change is real. ",
"As are its impacts. ",
"Time to stand up for our polar bears and our planet.\" ",
"But the photographers were later criticized for assuming the polar bear was starving because of climate change, laying the \"believe\" camp open to ridicule.",
"\n\nThe dominant climate change narrative is one of permanent, near-irreversible human-induced changes to the climate accompanied by a rise in global temperatures.",
"\n\nThis is what I thought I heard as an Inuit hunter eloquently described how the land has stayed greener for longer during each of the last 40 seasons he has travelled since his honeymoon.",
"\n\nThen I pondered his words again, and I asked him, \"Do you think climate change is permanent or cyclical?\" ",
"He paused and replied, \"It's cyclical.\"",
"\n\nListen to local people\n\nIn its new report \"Global Warming of 1.5℃,\" the Intergovernmental Panel on Climate Change (IPCC) says the prognosis is dire if we do not contain a rise in global temperatures to 1.5℃.",
"\n\nThe debate over \"1.5 to stay alive\" is not new. ",
"It was central to the 21st Conference of the Parties (COP) to the United Nations Framework Convention on Climate Change (UNFCCC) held in Paris in December 2015.",
"\n\nWill the IPCC's latest message finally convince the climate change confused or their leaders, who failed to make 1.5℃ binding in the Paris text three years ago? ",
"The debate will rage on at the 24th COP in Katowice, Poland in December.",
"\n\nMeanwhile, far from the pomp and formality of COP meetings, do local populations feel engaged in climate change action? ",
"I doubt it.",
"\n\nInuit hunters must increasingly navigate unpredictable sea ice. ",
"One explained their seeming indifference to climate change this way: \"What are we going to do about it? ",
"We Inuit take care of the land.\"",
"\n\nElsewhere, a community leader hinted at his weariness of a problem that has been known to Inuit but ignored by the world for too long: \"What's there to say? ",
"We've said it all before.\"",
"\n\nBe better communicators\n\nAfter attending three COP meetings since Paris, I question the reach of the existing narrative and governance of climate change. ",
"I suggest we move beyond a simplistic division between believers and deniers, and talk to people in local communities to examine how climate change complexity and confusion are hindering effective action on climate change.",
"\n\nWe need to communicate at the local scale where resource-dependent or climate-susceptible populations live with the actual or foreseen threats of climate change.",
"\n\nWe should heed the words of Thai marine scientist Suchana Chavanich, who told delegates at a workshop at COP 23, hosted by Fiji but held in Bonn, last year that to make a difference we need more than scientific knowledge; we need to connect with local people on the ground, in the places they live and work, to learn about the relevance of climate change in their lives.",
"\n\nThat is more effective than theorizing about what might happen in a 1.5℃ or 2℃ world.",
"\n\nFor many, climate facts are not convincing nor do they speak for themselves. ",
"And because people are not necessarily swayed by climate change facts but rather the communicator of facts, the nature of communication, their personal affiliations and networks, and their personal experience, labelling someone who is confused about climate change as a denier does not advance us to a world of collective effort to confront climate change.",
"\n\nWe are not doing a good job of communicating climate change. ",
"Maybe we can do a better job if we recognize that people are not just passive receivers of climate change facts, but actors with their own history and knowledge in place and interpretations of how climate change fits into their own stories.",
"\n\nRelated Stories\n\nPeople are hard-wired to respond to stories, but climate-denial narratives can be just as compelling as those that convey the facts about global warming. ",
"A new collection, \"Confronting Climate Change in the Age of Denial,\" ...\n\nClimate change will have a rapidly increasing effect on the structure of global ecological communities over the next few decades, with amphibians and reptiles being significantly more affected than birds and mammals, a new ...\n\nclimate change discussions on social media are very influential. ",
"A new study in BioScience shows that when it comes to iconic topics such as polar bears and retreating sea ice, climate blogs fall into two distinct camps with ...\n\nRecommended for you\n\nResearchers from the University of Washington and Microsoft have demonstrated the first fully automated system to store and retrieve data in manufactured DNA—a key step in moving the technology out of the research lab and ...\n\nOne of the ocean's little known carnivores has been allocated a new place in the evolutionary tree of life after scientists discovered its unmistakable resemblance with other sea-floor dwelling creatures.",
"\n\nIn research that casts cells as curators of their own history, Dana-Farber Cancer Institute scientists have discovered that adult tissues retain a memory, inscribed on their DNA, of the embryonic cells from which they arose. ...",
"\n\nNew photonic tools for medical imaging can be used to understand the nonlinear behavior of laser light in human blood for theranostic applications. ",
"When light enters biological fluids it is quickly scattered, however, some ...\n\nCan't believe somebody would be so dismissive as to say \"when someone says 'Facts are not enough' I start wondering what their agenda is\".",
"\n\nYes, facts are enough to tell us that we need to take drastic actions to combat climate change. ",
"But here is another fact: carbon dioxide emissions rose to a record high in 2018. ",
"So what that says is, facts aren't enough to combat climate change successfully. ",
"And if you dismiss that then you are denying the facts. ",
"Period."
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"\n\nThis race was won by French driver Jean Behra in a Maserati 250F winning by 30.1 seconds, from British driver Stuart Lewis-Evans in a Vanwall VW5 in second place, and another French driver Maurice Trintignant finishing third in a BRM P25.",
"\n\nThe race coincided with an outbreak of Asian flu amongst the Grand Prix community which explains the absence of Stirling Moss and the lacklustre performance of Fangio.",
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"\n\nThe straight-to-DVD film is a good adaptation of the original series, but does make some changes to the story. ",
"We don’t get Jimmy Olsen / Doomsday story or Superman’s adventure to Bizarro World, and Krypto, sadly, finds himself on the cuttting-room floor as well.",
"\n\nOf the stories we do get Lois Lane’s birthday works the best (even if I did get tired of the annoying demigod figures of Samson and Atlas). ",
"The movie also has a little more life when Lex Luthor is on-screen. ",
"Denton isn’t bad as the voice of the Man of Steel but his delivery is a little too laid back making film’s main character come off as bland at times.",
"\n\nI was less impressed with the story involving Bar-El and Lilo (fellow Kryptonians who have made their way to Earth) which I felt was rushed and a little out of place. ",
"Yes, it provides one of the film’s big battle sequences, but the movie has plenty of others. ",
"I would have preferred the time used here to focus more on Superman himself, his relationships, and the more human scenes of Superman dealing with, and saving, regular people from threats other than aliens and super-villains.",
"\n\nThe film certainly captures Quitely’s style (which is both good and bad) but there are a couple of small gaffes which bothered me. ",
"The first is the crowd sequence at Lex Luthor’s trial which both looks and sounds incredibly cheap, and the second appears near the end of the film when a character appears to be walking up stairs only to be revealed to be flying. ",
"Is it a cool reveal? ",
"That’s arguable, but what’s not is the motion of his legs moving up and down the steps doesn’t make any sense if he was simply floating up from the subway. ",
"Small nitpicks to be sure, but both felt like something that should have been seen and taken care of well before the film hit DVD shelves.",
"\n\nThe DVD extras are scant, but the Blu-ray does include quite a bit worth watching. ",
"And it seems DC is finally listening to me by including extras for the movie they are releasing instead of only extras for their upcoming projects (although we do get a sneak peek at Green Lantern: Emerald Knights). ",
"The best feature is the full-length commentary with Grant Morrison and producer Bruce Timm discussing the film, the graphic novel, Superman, and comics in general.",
"\n\nThere is also a featurette with interviews of Morrison and Dan Didio discussing the creation of the original comic as well as a shorter featurette showcasing some of Morrison’s original artwork. ",
"Also included are a couple episodes of Superman: The Animated Series and a virtual comic of All Star Superman‘s first issue.",
"\n\nIs All-Star Superman a great film? ",
"No. ",
"It’s certainly not in the league with Justice League: New Frontier, but it does capture the feel of the character and the original comic very well. ",
"It’s a solid effort from Warner Premiere and DC Animation that’s worth adding to any comic book fan’s shelf."
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"And, hey, what do you know? ",
"She’s completely nude. ",
"Like downtown nude. ",
"I think these shots not only celebrate the human spirit and fine art of cinema, they also prove that foreign films are wicked awesome. ",
"And not just because of the nudity. ",
"But because of their compelling story and characters – who eventually get nude and do it with all kinds of crazy angles. ",
"Viva la cinema!"
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"after the \\S+. ",
"This makes the + match as few as possible. ",
"\n\n"
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"Secrets of Self-Made Millionaires\n\nMillionaires were once normal people like you and I, except that they now have plenty of cash with them. ",
"How do they create those additional cash streams and turn themselves millionaires over time? ",
"This article presents to you the five secrets of self-made millionaires:\n\nSelf-made millionaires set their sights on what they want to achieve.",
"\nSet yourself clear goals. ",
"Imagine yourself being a millionaire and what you would do to achieve it. ",
"As Robert Collier says, “if you see yourself as prosperous, you will be. ",
"If you see yourself as continually hard up, that is exactly what you will be.” ",
"Everything has to start somewhere, so make your first step and move ahead!",
"\n\nSelf-made millionaires work on their passion.",
"\nAccording to a research conducted by Thomas J. Stanley, author of The Millionaire Mind, more than 80% millionaires admitted they would not have been successful if their vocation was not something they cared about. ",
"Look at the rich people around – Warren Buffet, Bill Gates, Donald Trump. ",
"Don’t they all talk about their work passionately? ",
"The question now is, what is YOUR passion?",
"\n\nSelf-made millionaires educate themselves.",
"\nOne major hurdle to making money is not understanding how money works. ",
"Simple example, do you know how to read your bank statements? ",
"How much do you know about money management and investing in bonds? ",
"If we have zero knowledge on investment and finance management, how do we expect ourselves to earn big money? ",
"As Jim Rohn correctly pointed out, “Formal education will make you a living; self-education will make you a fortune.”!",
"\n\nSelf-made millionaires grow their money.",
"\nLife is a struggle if you live paycheck to paycheck, especially with the forever increasing inflation while your monthly wage stays the same. ",
"Self-made millionaires work hard to make extra money for investing, where their money will in turn “work hard” for them, i.e. they grow them by putting them on a side business, stocks, or real estates. ",
"If you want to get rich, control and manage your income, just like Benjamin Franklin once says, “He does not posses wealth that allows it to possess him.”",
"\n\nSelf-made millionaires are willing to take risks.",
"\nIf you read biographies of self-made millionaires, you would have realised many of them have often gone through countless failures. ",
"What makes them who they are today is their persistence and their never-give-up attitude! ",
"They try and try and try and then, one success push them up to the top!",
"\n\nMonitium’s unique program is leading the global wealth revolution and offers not only multiple ways to create wealth but also training and education to help members grow professionally as well as financially.",
"\n\nIncoming search terms:\n\nmineralsi1h\n\nIf you found the information on this page helpful to you, please comment below and share it on your Social Media.",
"\n\nThank You for reading my post.",
"\n\nHave a Wonderful & Blessed Day,\n\nJimmie Schwinn\n\nIf you want to take you Business to the Next Level then optin to my Mastermind Training Webinars below.",
"\n\nLearn How to Get YOUR Online Business into Multiple 6 Figures a Year with FREE Mastermind Training Webinars."
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"Q:\n\nHow do i change value of variable from another java class?",
"\n\nI am new to java so help is much appreciated.",
"\nI have a few classes. ",
"I want to pass the user input from my GUI class to my Basket class where it will update the value stored in the variable. ",
"Below is what i currently have but it doesn't seem to be updating the variable.",
"\nClass One - GUI Class: I would like to pass the 'seats' to the basket class\nBasket b;\nb = new Basket(); \nString seats = JOptionPane.showInputDialog(\"Enter the number of seats to book\");\ntry {\n int currentValue = Integer.parseInt(seats);\n int newValue = currentValue; \n b.setSeatsBooked(newValue);\n //some code emitted\n}\n\nSecond Class - Basket Class, I would like the 'seats' to be passed into this class and stored in the instance variable.",
"\npublic class Basket {\n private int seatsBooked;\n public int getSeatsBooked() {\n return seatsBooked;\n }\n public void setSeatsBooked(int seatsBooked) {\n this.seatsBooked = seatsBooked;\n }\n}\n\nThis is in another class where i see the result as 0:\nBasket b;\nb = new Basket();\nlblMovieSelection = new JLabel(\"You have booked:\" + b.getSeatsBooked());\n\nA:\n\nThis is the reason of the wrongly behaviour:\nBasket b;\nb = new Basket();\n\nlblMovieSelection = new JLabel(\"You have booked:\" + b.getSeatsBooked());\n\nyou are creating a new object! ",
"so the default value is zero for that\n\nA:\n\nYou need to pass the class object for which you have stored the value. ",
"If you create a new instance of a class, how can you expect that object will contain that value?",
"\nIn the following two cases,\nBasket b;\nb = new Basket(); \nString seats = JOptionPane.showInputDialog(\"Enter the number of seats to book\");\ntry {\n int currentValue = Integer.parseInt(seats);\n int newValue = currentValue; \n b.setSeatsBooked(newValue);\n //some code emitted\n}\n\nand \nBasket b;\nb = new Basket();\nlblMovieSelection = new JLabel(\"You have booked:\" + b.getSeatsBooked());\n\nAre the object b of class Basket same in both blocks? ",
"Answer is No. ",
"So, you are getting zero value when you call b.getSeatsBooked() from the newly created object b of class Basket in the second block of code.",
"\nThere are two way to solve this problem.",
"\n\nBest solution is to pass the class object (as parameter) to the third class where you are calling the getSeatsBooked() method.",
"\n\nExample: Suppose your another class is X and there is a function called method(). ",
"Then you can pass Basket class object as parameter to that function where you can access it to get the updated value. ",
"The code may look like as follows.",
"\nclass X{\n // other code\n public void method(Basket b){\n lblMovieSelection = new JLabel(\"You have booked:\" + b.getSeatsBooked());\n }\n}\n\nIf you want share the variable seatsBooked across all class instances, you can declare the variable as static. (",
"I guess this is not what you are looking for)\n\n"
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"Jack Stalwart: The Secret of the Sacred Temple\n\nThis Book ISBN you have selected is currently not available in any of the Sri Lankan\nwebsite. ",
"Please click\nhere for the same book with different ISBN or other books from the same author\n\nIn case of unavailability in Sri Lanka we can special order the book for you.",
"\n\nDidn’t find the right price? ",
"Set your price\n\nEmail ID\n\nTarget price\n\nLet us know what price you would like to pay for this book.",
"\n\nDescription\nThe keeper of the sacred necklace of Angkor Wat has been kidnapped in the jungles of Cambodia. ",
"Can Secret Agent Jack Stalwart rescue her and prevent a madman from using the power of the necklace for his own wicked plans?"
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"With the Witherstorm on your tail, it's time to act swiftly. ",
"As you make your way out of the town and towards the portal, follow the action commands to make it one piece. ",
"Once you're through the portal, you'll make it back to the temple.",
"\n\nAfter Lucas lets you in, you'll be greeted by either Petra or Gabriel, depending on who you saved in the first episode. ",
"From here on out the role of Petra and Gabriel can be swapped out with little changes to dialogue. ",
"Get to the top area to meet either Magnus or Ellegaard, depending on who you just retrieved. ",
"After some discussion and some bickering, place the amulet on the pedestal to see where the last hero is.",
"\n\nWith Ivor heading to the same area, you'll have to decide whether or not to stay the night in the safety of the temple, or head into the night to try and stop Ivor as soon as possible.",
"\n\nKey Decision(SPOILERS):\n\n- We should go now. - ",
"You'll head into the night and encounter enemies that you need to fight off.- Let's wait til morning. - ??"
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"Q:\n\nFocus all input fields - Jquery\n\nHow to focus all the four input text fields... Need to focus all the fields when there is an error $(\"#sar1\").focus(); $(\"#sar2\").focus(); $(\"#sar3\").focus();\nIts focussing only the last element. ",
"same is the case with below one too. ",
"$(\"#searchSeId\").find(\"input[type=text]\").each(function(){ $(this).focus(); });\n\nA:\n\nYou can't focus more than one input at a time. ",
" Doing so would imply that you could edit the text in all focused fields simultaneously. ",
" If that is really what you want, you would have to edit the other fields using a script onkeyup or onchange.",
"\nInstead, I would recommend adding a class using JavaScript:\n$(\"#showerrors\").click(function(){\n $(\"input[type=text]\").each(function(){\n if ($(this).val() == \"\") {\n $(this).addClass(\"error\");\n }\n else {\n $(this).removeClass(\"error\");\n }\n });\n})\n\nAnd then apply a CSS red border, or something to indicate the fields with errors:\ninput.error {border:1px solid red;}\n\nA very simple example of this can be found here, placing an error class on empty fields: http://jsfiddle.net/b3tnh6c0/\n\n"
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"Meet the Team\n\nNews, Events & Press\n\nInvestors\n\nCareers\n\nCellnex Telecom\n\nCellnex Telecom employed Intralinks Dealspace® to ensure smooth and secure management of the due diligence process ahead of its pending Initial Public Offering (IPO).",
"\n\nCellnex Telecom\n\nPart-owned by infrastructure company Abertis, Barcelona-based Cellnex Telecom is the main independent infrastructure operator for wireless telecommunication in Europe.",
"\n\nIt offers a site-leasing service for telecommunications operators and provides highly advanced audio-visual services to broadcasters at local, regional and national levels.",
"\n\nIn addition, the company is deploying a network of intelligent communication solutions to enable the development of a solid ecosystem for Spain’s Internet of Things.",
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"\n\nThroughout the entire process, Intralinks Dealspace enabled Cellnex to collaborate smoothly and effortlessly with AZ Capital, and allowed both companies to efficiently manage the IPO process between them, saving time and effort while maintaining the high level of security required.",
"\n\nSupport\n\nNews and Press\n\nConnect\n\nCOOKIES\n\nThe cookies which we use on this site record information about your online preferences, remember information about you when you visit our site and compile statistical reports on website activity. ",
"Some of the cookies we use are essential in order for us to provide our services and the website to you."
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"\n\nThe new filing accuses Congress of undertaking an unprecedented attempt “to rifle through the private financial information of a sitting President, his family, and his businesses.”",
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"\n\nYet in the new filing, his attorneys claim that Congress is engaging in a radical expansion of its own power by issuing these “illegal” subpoenas. ",
"They urge the court to take its time in deciding the case.",
"\n\n“This Court would do well to pause, and at least receive full briefing and argument on the merits of these serious constitutional questions, before endorsing the Committees’ unchecked view of congressional subpoena power,” Trump wrote.",
"\n\nHe goes on to say that it is “‘cold comfort’ that only the House—an institution controlled by the other political party and that is currently investigating every nook and cranny of the President’s life,” would receive the requested information.",
"\n\nThe President also suggests that delays by House Democrats in starting their investigations show that there is no urgency to the request and that, therefore, the judge can postpone the subpoena’s enforcement until higher courts rule on the matter."
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"First I wanted to start off by saying that my thoughts and prayers are with the people of Guatemala during this difficult time. ",
"Mother nature sure has been punishing the world lately and I can only hope that it gets better and less extreme as the years go on. ",
"I went to Guatemala to attend… Continue Reading"
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"The contribution of neuroimaging to the study of language and aphasia.",
"\nNew structural and functional imaging methods continue to be developed at a rapid pace. ",
"In the last 25 years, advanced imaging techniques have provided insights into how language is represented and processed in the brain and how it can be disrupted by damage to, or dysfunction of, various parts of the brain. ",
"Imaging studies have also yielded new information regarding how individuals recover language after stroke. ",
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"141 F.3d 439\nThe FAIR HOUSING COUNCIL OF SUBURBAN PHILADELPHIA, Appellant,v.MAIN LINE TIMES; Acme Newspapers, Inc.*No. ",
"97-1169.",
"\nUnited States Court of Appeals,Third Circuit.",
"\nArgued Sept. 9, 1997.Decided March 31, 1998.",
"\n\nClifford A. Boardman (argued), Philadelphia, PA, for Appellant.",
"\nGregory M. Harvey (argued), Lisa A. Mathewson, Lewis & Bockius LLP, Philadelphia, PA, for Appellees.",
"\nElaine R. Jones, Director-Counsel, Norman J. Chachkin, David T. Goldberg, Paul K. Sonn, NAACP Legal Defense and Educational Fund, Inc. New York City, Judith A. Browne, Peter F. Rundlet, NAACP Legal Defense and Educational Fund, Inc., Washington, DC, for Amicus Curiae NAACP Legal Defense & Educational Fund, Inc.\nWilliam G. Scarborough, Stradley, Ronon, Stevens & Young, LLP, Philadelphia, PA, Karen L. Black, Public Interest Law Center of Philadelphia, Philadelphia, PA, for Amicus Curiae Fair Housing Action, Fair Housing Council of Montgomery County, Fair Housing Council of Southern New Jersey, Fair Housing Partnership of Greater Pittsburgh, Housing Consortium for Disabled Individuals, and Housing Council of York.",
"\nJohn P. Relman, Washington Lawyers' Committee for Civil Rights and Urban Affairs, Washington, DC, James R. Bird, Dona J. Martin, Timothy G. Lynch, Shea & Gardner, Washington, DC, for Amicus Curiae the National Fair Housing Alliance.",
"\nBefore: MANSMANN and NYGAARD, Circuit Judges and BLOCH, District Judge.**",
"\nOPINION OF THE COURT\nMANSMANN, Circuit Judge.",
"\n\n\n1\nIn this action brought pursuant to the Fair Housing Act, 42 U.S.C. § 3604, The Fair Housing Council of Suburban Philadelphia (\"FHC\") appeals an order of the district court granting a motion for judgment notwithstanding the verdict filed by Acme Newspapers, Inc. (\"Acme\"), its publication, The Main Line Times, and the paper's publisher. ",
" The district court granted this motion based on its conclusion that the FHC lacked standing under Article III of the United States Constitution to maintain this suit. ",
" Because we agree that the FHC failed to establish any \"perceptible impairment\" to its operation caused by the alleged discrimination and thus failed to satisfy the minimum standing requirements embodied in Article III, we will affirm the order of the district court.",
"\n\nI.\n\n2\nThe FHC, a fair housing group which has operated in the Philadelphia area for more than forty years, describes itself as a non-profit organization whose \"purpose is to educate and promote fair housing and to oppose segregation based on the protected classes found in the Fair Housing Act of 1968, as amended.\"",
"\n\n\n3\nOn February 21, 1996, the FHC filed eleven lawsuits in federal court, nine of which charged various newspaper publishers and related defendants with violations of the Fair Housing Act, 42 U.S.C. § 3604.1 In this suit, the FHC sought damages for injuries alleged to have been caused by real estate advertisements placed in the Main Line Times on a number of occasions during 1994 and 1995. ",
" In its complaint, the FHC alleged that:\n\n\n4\nOn or about December, 1994 through at least November, 1995, defendants approved and published real estate advertisements that stated \"no children,\" \"three persons,\" as well as, upon information and belief, many other advertisements which indicated a preference or limitation on the basis of familial status.",
"\n\n\n5\nThe case was tried before a jury in December, 1996. ",
" At that time, five advertisements were at issue. ",
" These advertisements contained the following allegedly discriminatory phrases 1) \"no children;\" 2) \"3 persons;\" 3) \"ideal for couple or professional single;\" 4) \"(for one person);\" and 5) \"(for one person).\" ",
" At the close of all the evidence, Acme and the other defendants filed a motion for judgment as a matter of law, pursuant to Fed.",
"R.Civ.",
"P. 50. ",
" Acme contended that the FHC had failed to establish injury sufficient to satisfy the standing requirement imposed by Article III of the United States Constitution. ",
" The district court deferred ruling on this motion and submitted the case to the jury.",
"\n\n\n6\nOn December 4, 1996, the jury returned a verdict in favor of the FHC, awarding the FHC $25,000 in compensatory damages. ",
" On December 17, 1996, Acme renewed its Rule 50 motion, again arguing that the FHC lacked standing to pursue its claims under the Fair Housing Act. ",
" The district court granted this renewed motion on January 28, 1997, stating that it had \"acted prematurely in submitting the case to the jury as[the FHC] did not have standing to bring any of the claims asserted in its Complaint.\" ",
" Fair Housing Council of Suburban Philadelphia v. Main Line Times, No. ",
"96-1379, 1997 WL 30642 at * 6 (E.D.Pa. ",
"Jan. 27, 1997). ",
" This timely appeal followed.",
"\n\nII.",
"\n\n7\nThis appeal requires that we revisit, albeit in a different context, the identical issue raised in Fair Housing Council of Suburban Philadelphia v. Montgomery Newspapers, 141 F.3d 71 (3d Cir.1998): whether the FHC has shown \"distinct and palpable\" injury sufficient to satisfy Article III standing requirements under the Fair Housing Act. ",
" Resolution of this question turns on the application of constitutional standing requirements. ",
" We reviewed the parameters of these requirements at length in our opinion in Montgomery Newspapers, and will not repeat that discussion here.",
"\n\n\n8\nWe begin our examination of the issue before us by noting that Article III principles governing standing are by now well-settled. ",
" In Lujan v. Defenders of Wildlife, 504 U.S. 555, 560-61, 112 S.Ct. ",
"2130, 2136, 119 L.Ed.2d 351 (1992), the Supreme Court summarized the law of standing as follows:\n\n\n9\nOver the years, our cases have established that the irreducible constitutional minimum of standing contains three elements. ",
" First the plaintiff must have suffered an \"injury in fact\"--an invasion of a legally protected interest which is a) concrete and particularized, and b) \"actual or imminent, not 'conjectural' or 'hypothetical.' \" ",
" Second, there must be a causal connection between the injury and the conduct complained of--the injury has to be \"fairly ... trace[able] to the challenged action of the defendant and not ... th[e] result [of] the independent action of some third party not before the court.\" ",
" Third, it must be \"likely\" as opposed to merely \"speculative,\" that the injury will be \"redressed by a favorable decision.\"",
"\n\n\n10\n(Citations omitted.) ",
" These requirements--particularly the need for injury in fact--were applied in the fair housing context in Havens Realty Corp. v. Coleman, 455 U.S. 363, 378-79, 102 S.Ct. ",
"1114, 1124, 71 L.Ed.2d 214 (1982). ",
" There, the Supreme Court wrote that:\n\n\n11\nIn determining whether [a fair housing organization] has standing under the Fair Housing Act, we conduct the same inquiry as in the case of an individual: Has the plaintiff \" 'alleged such a personal stake in the outcome of the controversy' as to warrant his invocation of federal court jurisdiction\"? ",
" ... If, as broadly alleged, petitioner's practices have perceptibly impaired [the organization]'s ability to provide counseling and referral services for low- and moderate-income homeseekers, there can be no question that the organization has suffered injury in fact. ",
" Such concrete and demonstrable injury to the organization's activities--with the consequent drain on the organization's resources--constitutes far more than simply a setback to the organization's abstract social interests.",
"\n\n\n12\n455 U.S. at 378-79, 102 S.Ct. ",
"at 1124 (citations omitted) (emphasis added).",
"\n\n\n13\nThe caselaw establishes that in order to defeat the motion for judgment notwithstanding the verdict, the FHC was required to submit \"evidence showing through specific facts ... that ... it [was] 'directly' affected [by the alleged discrimination].\" ",
" Lujan v. Defenders of Wildlife, 504 U.S. at 562, 112 S.Ct. ",
"at 2137-38 (emphasis added). ",
" \"Since [the elements of standing] are not mere pleading requirements but rather an indispensable part of the plaintiff's case, each element must be supported in the same way as any other matter on which the plaintiff bears the burden of proof, i.e. with the manner and degree of evidence required at the successive stages of the litigation.\" ",
" Id. at 561, 112 S.Ct. ",
"at 2136. ",
" Despite the jury verdict in the FHC's favor, the district court concluded that the FHC failed to meet its burden of proof, producing nothing of substance at trial to support the damage allegations set forth in the complaint.2 There was no \"evidence upon which the jury could properly find a verdict for [the FHC].\" ",
"Lightning Lube, Inc. v. Witco Corp., 4 F.3d 1153, 1166 (3d Cir.1993).",
"\n\n\n14\nJudgment as a matter of law is to be granted sparingly. ",
" We will affirm an order granting judgment as a matter of law \"only if, viewing the evidence in the light most favorable to the nonmovant and giving it the advantage of every fair and reasonable inference ... it is apparent that the verdict is not supported by legally sufficient evidence.\" ",
" Id. We have carefully reviewed the FHC's damage allegations and the evidence introduced to support them and are convinced that this is one of those rare cases where, following a jury verdict, judgment as a matter of law was warranted.",
"\n\nIII.",
"\n\n15\nThe FHC alleges that it suffered impairment sufficient to establish Article III standing when it was forced to divert resources from counseling and other activities to: (1) an investigation designed to determine the existence and extent of on-going discrimination in advertising; (2) litigation; and (3) an educational campaign designed to counteract the discriminatory effect of the advertisements. ",
" We considered and rejected identical damage claims based on the need to divert funds to investigation and litigation in Montgomery Newspapers. ",
" As the \"proof\" offered on these issues is virtually identical to that offered and found lacking in Montgomery Newspapers, we need not detail that proof or repeat our analysis here.",
"\n\n\n16\nBecause, however, the evidence regarding the need for an educational campaign to counteract the alleged discrimination differs somewhat from that offered in Montgomery Newspapers, we address it briefly. ",
" At trial, the FHC's Executive Director sought to establish that the FHC had suffered injury sufficient to satisfy Article III by offering the following testimony:\n\n\n17\nFor [forty years, the FHC] educates. ",
" We go out to all kinds of organizations, groups ... and educate them about their rights to obtain housing on a nondiscriminatory basis. ",
" We also spend a tremendous amount of time educating the industry.... So, when these ads appear in the paper and even if it's only one ad, it sort of undoes--not sort of, it definitely undoes all that good work, all that hard work, all that education. ",
" Its back to where we started from. ",
" It's as though we never did this. ",
" It's broadcast to tens of thousands of people. ",
" First of all, people see it and think that they could be turned down for housing. ",
" Other Realtors, landlords, see this, think either the laws don't exist or they're not enforced. ",
" We have filed complaints against people and they've come to us with dozens of ads from the newspaper that say, look, here's ads that say not children, no children, adults only, adults preferred, perfect for single. ",
" And they say, well, what's wrong? ",
" This is in the newspaper.",
"\n\n\n18\nQ. Are you talking about people you've charged?",
"\n\n\n19\nA. Yes.",
"\n\n\n20\nQ. Okay.",
"\n\n\n21\nA. --people that we have filed complaints against.",
"\n\n\n22\nQ. Like who?",
"\n\n\n23\nA. Individual landlords.... So our job is to educate. ",
" And all this education goes down the drain when these ads appear in the paper.",
"\n\n\n24\nWhile we can agree intuitively that continued publication of discriminatory advertising in general could have an adverse effect on public perception, thus making the job of the FHC more difficult, we are convinced that even were we to assume injury, the evidence submitted failed to establish the necessary \"causal connection between the injury and the [particular advertisements].\" ",
" Lujan v. Defenders of Wildlife, 504 U.S. at 560, 112 S.Ct. ",
"at 2136.",
"\n\n\n25\nThe evidence submitted by the FHC did not show that the advertisements at issue created any adverse effects upon families seeking housing or upon public perception of the advertisements' legality. ",
" The evidence offered was probative only as to the effect of discriminatory advertising generally on landlords and realtors. ",
" The testimony offered by the FHC with respect to the five specific advertisements failed to establish that they had been read by anyone outside the FHC or that the FHC was required to modify its operation in any way as a result of these advertisements.3 As Acme correctly observes, \"No injury to the cause of fair housing--or consequent impairment of the Council's programs--could follow from the publication of advertising which was only proven to have been observed by persons who knew that it was illegal, i.e. the Council's staff members.\"",
"\n\nIV.",
"\n\n26\nFaced with the difficulties inherent in its evidence, the FHC takes the position that, because it holds the status of a private attorney general, it need show nothing more than a violation of the Act in order to establish Article III standing. ",
" We disagree. ",
" The fact that a housing organization is able to show that a particular advertisement violates the Act is not sufficient to satisfy the requirements of Article III; a violation of the Act does not automatically confer standing on any plaintiff, even one who holds the status of a private attorney general. ",
" An organization acting as a private attorney general is relieved only of prudential limitations on standing and may bring suit to enforce the rights of others only where the organization itself is able to demonstrate that it has suffered injury in fact. ",
" See Lujan, 504 U.S. at 572-73, 112 S.Ct. ",
"at 2142-43 (requiring that an organization holding status of private attorney general show injury in fact). ",
" The required demonstration of legally cognizable injury is absent in this case. ",
" Although we have given serious consideration to the jury's verdict and award of compensatory damages in favor of the FHC, our analysis of the record compels us, nonetheless, to conclude that the record is devoid of \"evidence upon which the jury could properly [have found a] verdict for [the FHC].\" ",
"Lightning Lube, Inc., 4 F.3d at 1166.",
"\n\nV.\n\n27\nIn concluding that the strictures of Article III bar the FHC from maintaining this suit, we emphasize here, as we did in Montgomery Newspapers, that the goal of \"eliminating discrimination in housing is vitally important.\" ",
" (Slip Opinion at 18.) ",
" Even this laudable objective does not, however, warrant an evisceration of Article III. ",
" As Acme points out:\n\n\n28\n[T]he most impassioned public policy arguments cannot eliminate the case or controversy requirement from the Constitution. ",
" If anything, the appeal to public policy should highlight ... the separation of powers rationale from which the case or controversy doctrine flows. ",
" Adjudicating actual controversies, not legislating social policy, is the province of the judiciary.",
"\n\n\n29\nOur adherence to the requirements of Article III should not impede vigorous enforcement of the Fair Housing Act. ",
" The caselaw is replete with examples of housing organizations which have successfully established injury sufficient to carry them over the Article III threshold. ",
" As we observed in Montgomery Newspapers, \"It should not be insurmountably difficult for these organizations to establish standing either in their own right or on behalf of their members by referring to well-established standing principles and adjusting their pleadings and proof accordingly.\" ",
" (141 F.3d at ----.)",
"\n\nVI.",
"\n\n30\nFor the foregoing reasons, we will affirm the order of the district court.",
"\n\nNYGAARD, Circuit Judge, dissenting\n\n31\nThis appeal raises the identical issue presented in Fair Housing Council of Suburban Philadelphia v. Montgomery Newspapers, 141 F.3d 71 (3d Cir.1998). ",
" Again, I respectfully dissent.",
"\n\n\n32\nThe FHC has standing to sue The Main Line Times under 42 U.S.C. § 3604(c) because it has shown the threshold injury that is required under Article III, Section 2 of the Constitution. ",
" At trial the FHC demonstrated that it must redirect resources to an educational campaign to inform landlords, real estate agents, housing providers, and consumers that discrimination based on family status violates 42 U.S.C. § 3604(c). ",
" The FHC held a press conference to advise, among others, housing providers and consumers that the advertisements in The Main Line Times violated the Fair Housing Act. ",
" The FHC further demonstrated the ignorance of housing providers, who continue to attempt to submit illegal advertisements, and the need for an educational campaign for the housing industry and for the defendant itself, who continued to publish illegal advertisements and to promote misunderstanding about the familial status provisions of the Fair Housing Act. ",
" The majority mistakenly concludes that the FHC has not demonstrated the need for an educational campaign. ",
" In support of its holding, the majority repeats its characterization of the FHC's evidence from the Montgomery Newspapers case. ",
" As I concluded in Montgomery Newspapers, the majority's depiction of the evidence is incorrect. ",
" The district court concluded that the advertisements were not the cause of any programmatic changes the FHC may have made. ",
" Again, I disagree; the FHC is only required to show that its injury is fairly traceable to the actions of the defendant. ",
" Furthermore, the FHC has demonstrated standing for costs incurred investigating and applying legal pressure to The Main Line Times. ",
" The majority does not discuss this as it pertains to the evidence submitted in this case; but because it relies on its conclusion in the Montgomery Newspapers case, I reiterate my disagreement with that conclusion here.",
"\n\nI. Standard of Review\n\n33\nThis is an exceptional case in which the district court granted judgment as a matter of law following a jury verdict of $25,000 in favor of the FHC. ",
"Generally, courts grant judgment as a matter of law sparingly, and give the nonmoving party every fair and reasonable inference before concluding that the verdict was not supported by legally sufficient evidence. ",
" Lightning Lube, Inc. v. Witco Corp., 4 F.3d 1153, 1166 (3d Cir.1993). ",
" The majority misapplies this standard, and credits only one passage of testimony in support of the FHC's position. ",
" We have held that a case is properly submitted to a jury unless it is \"critically deficient of that minimum quantum of evidence from which the jury might reasonably afford relief.\" ",
" Link v. Mercedes-Benz of N. Am., ",
"Inc., 788 F.2d 918, 921 (3d Cir.1986). ",
" A review of the record plainly reveals sufficient evidence to support a verdict in favor of the FHC.",
"\n\nII. ",
"Educational Injury\n\n34\nThe Supreme Court held in Havens Realty Corp. v. Coleman, 455 U.S. 363, 372, 102 S.Ct. ",
"1114, 1121, 71 L.Ed.2d 214 (1982), that the plaintiff organization had standing to sue if the activity that allegedly violated the Fair Housing Act perceptibly impaired counseling and referral services. ",
" This impairment meets the \"injury in fact\" test because a concrete and demonstrable drain on resources is a more plausible injury than a conjectural \"setback\" to an organization's abstract social interests. ",
" Id. at 379, 102 S.Ct. ",
"at 1124-25 (distinguishing Sierra Club v. Morton, 405 U.S. 727, 92 S.Ct. ",
"1361, 31 L.Ed.2d 636 (1972)). ",
" The courts of appeals interpreting Havens agree that diversion of resources to educational programs is sufficient to impart Article III standing. ",
" See, e.g., Fair Employment Council of Greater Washington, Inc. v. BMC Mktg. ",
"Corp., 28 F.3d 1268, 1276-77 (D.C.Cir.1994); Housing Opportunities Made Equal, Inc. v. Cincinnati Enquirer, Inc., 943 F.2d 644 (6th Cir.1991); Spann v. Colonial Village, Inc., 899 F.2d 24, 27 (D.C.Cir.1990). ",
" An \"identifiable trifle\" of this type of injury will suffice to confer standing upon the FHC, even when the proceedings have advanced to trial. ",
" United States v. Students Challenging Regulatory Agency Procedures, 412 U.S. 669, 689 n. 14, 93 S.Ct. ",
"2405, 2417 n. 14 (1973) (rejecting the argument that standing should be limited to those significantly injured, and ruling that any level of injury is sufficient to confer standing). ",
" The FHC has clearly met its burden by showing sufficient evidence of injury.",
"\n\n\n35\nThe FHC held a press conference to inform consumers and the housing industry that the discriminatory advertisements that appeared in The Main Line Times violated the Fair Housing Act. ",
" Jan Chadwick, Assistant Director of the FHC, testified to the detailed plan to educate housing providers and consumers about the Fair Housing Act's family status provisions, and explained a specific proposal for newspaper campaign. ",
" The FHC also presented evidence of the additional costs associated with the newspaper campaign.",
"\n\n\n36\nThe FHC has also shown that its educational plan is a necessary response to the discriminatory advertisements that appeared in The Main Line Times because individuals seeking to place advertisements, as well as those responsible for publishing the ads, misunderstood the family status provisions of the Fair Housing Act. ",
" The illegal advertisements at issue in this lawsuit were accepted into publication by the trained staff of The Main Line Times advertising department. ",
" Frequently, individuals placing housing advertisements insisted on illegal wording, telling newspaper staff members to \"take it or leave it,\" and the paper would sometimes have to reject ads because the individual placing it refused to comply with the Fair Housing Act. ",
" The FHC educational plan, and specifically the press conference the FHC already held, attempted to dispel misconceptions about the Fair Housing Act that housing providers might have developed from reading the illegal advertisements in The Main Line Times.",
"\n\nIII. ",
"Investigation Injury\n\n37\nTime spent reviewing the newspaper for illegal housing advertisements can constitute Article III injury. ",
" Havens found \"injury in fact\" when a fair housing organization had to divert resources to \"identify and counteract\" discriminatory practices. ",
" 455 U.S. at 379, 102 S.Ct. ",
"at 1124. ",
" Like \"educational injury,\" the courts following Havens agree that costs incurred investigating violations of the Fair Housing Act can confer standing. ",
" See, e.g., Hooker v. Weathers, 990 F.2d 913, 915 (6th Cir.1993) (costs incurred in the investigation to confirm the facts and circumstances).",
"\n\n\n38\nViewing the evidence of the two alternative Article III factors, investigation and litigation injury, there is at least a minimum quantum of evidence required to show injury. ",
" Here, the FHC demonstrated that it diverted resources to review The Main Line Times to identify violations of the Fair Housing Act.",
"\n\nIV. ",
"Litigation Injury\n\n39\nI restate my conclusion from my dissent in Montgomery Newspapers that activities falling between investigation and the filing of the lawsuit can constitute Article III injury to an organization under Havens. ",
" My decision to confer standing upon fair housing organizations for enforcement activities, other than the filing of the lawsuit, does not conflict with the Court of Appeals for the D.C. Circuit's cases that the majority finds persuasive. ",
" Those cases only prohibit conferral of standing for the act of filing the lawsuit. ",
" See Fair Employment Council of Greater Washington, Inc. v. BMC Marketing Corp., 28 F.3d 1268 (D.C.Cir.1994); Spann v. Colonial Village, Inc., 899 F.2d 24 (D.C.Cir.1990).",
"\n\n\n40\nThe FHC testified to the activities it had to postpone when it dedicated resources to enforcement activities arising from The Main Line Times advertisements. ",
" (Direct of James Berry, J.A. at 208-209.) ",
" The FHC chose nonlitigation methods to apply legal pressure upon The Main Line Times to enforce the Fair Housing Act, including filing a complaint with the Pennsylvania Human Resources Commission (J.A. at 855) and holding a press conference to publicize the newspaper's violations of the Fair Housing Act.",
"\n\nV. Causation\n\n41\nThe district court held, and the majority agrees, that the FHC could not show that the alleged injury was caused by any illegal advertisements published by the Main Line Times. ",
" I disagree. ",
" For standing purposes, a plaintiff is required to show that its injury is \"fairly traceable\" to the defendant's actions. ",
" Public Interest Research Group of New Jersey, Inc. v. Powell Duffryn, 913 F.2d 64, 71 (3d Cir.1990). ",
" Tort causation is not required by Article III, and a plaintiff, even at the trial stage, does not have to prove injury for standing purposes with scientific certainty. ",
" Id. at 73 n. 10.",
"\n\n\n42\nThe FHC was able to specifically connect the advertisements at issue in this lawsuit to the press conference. ",
" Likewise, the FHC was able to associate its investigation and litigation injuries to the specific advertisements that were the ultimate subject of the lawsuit.",
"\n\nVI. ",
"Conclusion\n\n43\nFor all the foregoing reasons, including the reasons set forth in my Montgomery Newspapers dissent, I conclude that the FHC has standing to advance a claim under 42 U.S.C. § 3604(c). ",
" I would reverse the district court and reinstate the $25,000 verdict in favor of the FHC and against The Main Line Times.",
"\n\n\n\n*\n Amended per Clerk's Order of April 9, 1997\n\n\n**\n Honorable Alan N. Bloch of the United States District Court for the Western District of Pennsylvania, sitting by designation\n\n\n1\n 42 U.S.C. § 3604(c) of the Fair Housing Act makes it unlawful:\nTo make, print, or publish, or cause to be made, printed, or published any notice, statement, or advertisement with respect to the sale or rental of a dwelling that indicates any preference, limitation, or discrimination based on race, color, religion, sex, handicap, familial status, or national origin or an intention to make any such preference, limitation, or discrimination.",
"\nThe Act provides that \"an aggrieved person may commence a civil action in an appropriate United States district court ....\", § 3613(a)(1)(4), and defines an \"aggrieved person\" (including corporations and associations) as:\nAny person who--\n(1) claims to have been injured by a discriminator y housing practice; or\n(2) believes that such person will be injured by a discriminatory housing practice that is about to occur.",
"\nSection 3602(I).",
"\n\n\n2\n The complaint contains the following allegations bearing on injury:\n\n\n9\n [E]ach act of discrimination conducted in the Delaware Valley causes a setback to the good work accomplished by the FHC's educational and outreach efforts and to the development of an integrated housing community. ",
" As a result, the FHC must launch further efforts to undo the damage that the discrimination has caused. ",
" In the case of widespread and broadly disseminated discrimination, such as occurs in the ongoing publication of a landlord's discriminatory advertisements, the further efforts required are a substantial drain on its resources and harms[sic] the FHC\n\n\n18\n As a result of the conduct of the Defendants, persons were injured in their person and property. ",
" Specifically, families with children were barred from housing in violation of the Fair Housing Act of 1968 as amended. ",
" Further, the FHC is now forced to divert funds to counteract the discriminatory message and acts of Defendants, and has had its purpose frustrated by Defendants' discriminatory conduct\nThese damage allegations are identical to those set forth in the complaint filed in Fair Housing Council v. Montgomery Newspapers.",
"\n\n\n3\n The dissent states that activities \"falling between investigation and the filing of a lawsuit can constitute Article III injury....\" (141 F.3d at 446). ",
" The dissent concludes that the FHC suffered such an injury when it devoted resources to holding a press conference \"to publicize the newspaper's violation of the Fair Housing Act.\" ",
" Id. The testimony of an FHC representative establishes that this \"press conference was held to announce the filing of [eleven] lawsuits ... so that we could get the message out ... that the type of ads that appear in the Main Lines Times ... are in violation of the Fair Housing Act.\" ",
" We have not found any case which has held that a press conference announcing the filing of lawsuits might be sufficient to establish Article III injury. ",
" To adopt this radical view of injury would effectively nullify the Article III standing requirement\n\n\n"
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"Gore Endorses Dot Eco Domain Name: But Will the New Domain Be Credible?",
"\n\nA new social venture, Dot Eco LLC, hopes to become the .eco domain registrar through the ICANN application process later this year. ",
"ICANN (the Internet Corporation for Assigned Names and Numbers) coordinates the Internet’s systems of unique identifiers and periodically expands domain names through a formal application process. ",
"Dot Eco’s efforts gained considerable visibility and credibility last week when Al Gore and his Alliance for Climate Protection announced their support. ",
"If granted accreditation as the .eco domain registrar, Dot Eco has pledged to donate more than 50% of registration fees to fund initiatives and research in climate change, ocean analysis, economic policy, and other environmentally related areas.",
"\n\nBut the Goreacle’s detractors are already voicing their skepticism: Will the .eco domain really succeed in attracting registrants and raising awareness, or will it crash and burn like several other seldom used domains (remember .mobi, .biz, .tv and .info)? ",
"By what standards will Dot Eco vet those organizations seeking an .eco domain? ",
"Who decides which environmental causes are worthy of receiving donations? ",
"And how does Dot Eco maintain the integrity of the .eco brand and avoid digital green washing?",
"\n\nIn a recent interview with Earth2Tech, Dot Eco co-founder Minor Childers addressed some of these issues. ",
"Childers, who is based in Los Angeles, has been meeting with marketing agencies, working on celebrity endorsements, and expects the company to launch a $10 million marketing campaign in its early stages to push adoption of the .eco domain. ",
"The company is already talking with VCs about investing opportunities to fund these types of marketing efforts.",
"\n\nOn the question of setting standards and maintaining the integrity of the .eco registration, Childers was a bit fuzzier. ",
"He said domain owners might have to adhere to some environmental criteria to keep their domain registration. ",
"Roy Neel, Gore’s chief of staff, says that The Alliance for Climate Protection fully supports “filters” to make sure dot eco is not exploited. ",
"But how they will define these filters and maintain compliance with a set of performance criteria remains to be seen.",
"\n\nDot Eco LLC is the creation of Internet entrepreneurs Fred Krueger (who founded Tagworld) and Clark Landry, as well as Minor Childers, a Hollywood creative executive and film producer. ",
"Davis Guggenheim, the director of the documentary An Inconvenient Truth, sits on the company’s advisory board. ",
"The company was founded in 2008 to secure, operate and promote the .eco domain through ICANN’s new generic top level domain (gTLD) process. ",
"ICANN is working to launch a new application round for gTLDs in late 2009. ",
"Any public or private-sector organization that meets certain operational and financial criteria can apply to create and operate a new gTLD. ",
"If Dot Eco LLC is granted ICANN accreditation to operate the .eco registry, they collect registration fees from companies wishing to create an .eco domain. ",
"The pledge to donate most of their revenue to environmental research and initiatives may help to attract new registrants. ",
"And if the idea catches on, Childers believes his company could become “one of the largest contributors to environmental causes.” ",
"Gore and the Alliance for Climate Protection are on board:\n\nWe fully support Dot Eco LLC in its efforts to secure the .eco top level domain and look forward to working with Dot Eco LLC to promote .eco. ",
"This is a truly exciting opportunity for the environmental movement and for the internet as a whole.",
"\n\nIf they successfully secure the new domain, Dot Eco LLC will register companies seeking “to promote their environmental initiatives, and environmental organizations to maintain their websites in a namespace that is more relevant to their core missions.”",
"\n\nSounds good, but first ICANN must accept their application, potential registrants must respond positively by buying and renewing .eco domain names, and Dot Eco must demonstrate they can separate the green from the green washed. ",
"Stay tuned.",
"\n\nMy professional experience over the past 20 years has taken me from Madison Avenue to Silicon Valley in various marketing research, marketing, business development and sales roles. ",
"I now work as a freelance environmental writer and researcher while pursuing an MBA in Sustainable Management at the Presidio Graduate School.",
"I'm especially interested in the use of technology to address the issues of education, equality, environment, health, and economic development.",
"You can keep tabs on me at Triple Pundit and the NY Times Green Inc blog, email me at jameswitkin@gmail.com, or find me typing away at the various coffee shops around Palo Alto."
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"For quite a while, a package called MonadRandom by Cale Gibbard has been available on Hackage. ",
"At first it seems like just a little silly convenience module. ",
"But I argue that it should be used instead of System.",
"Random whenever possible, not just when it’s more convenient. ",
"Here’s why:\n\nWhat’s a RandomGen?",
"\n\nclass RandomGen g where next :: g -> (Int, g) split :: g -> (g,g) genRange :: g -> (Int,Int)\n\nIt’s this thing… this thingamajigger, if you prefer, which has a next, a split, and a genRange. ",
"Cool, that’s great. ",
"Um… so, what are those things? ",
"What do they mean? ",
"And what do they have to do with randomness? ",
"next. ",
"NEXT? ",
"That doesn’t seem very random!",
"\n\nMonadRandom is very humble in its self-description:\n\nComputation type: Computations which consume random values. ",
"Binding strategy: The computation proceeds in the same fashion as the identity monad, but it carries a random number generator that may be queried to generate random values.",
"\n\nBut it means much more than it says. ",
"Rand a is not merely an “identity monad carrying a random number generator” (a random number generator being one of those what-the-heck-is-thats above). ",
"Rand a is a probability distribution of a’s! ",
"Which is simple, meaningful and easy to reason about!",
"\n\nWe can model it like so:\n\nRand a = a -> Real fmap f p x = ∑ p[f-1[{x}]] return x = δ(x) (p >>= f) x = ∑ y p(y) f(y)(x)\n\nWith getRandom etc. ",
"being standard distributions on various data types.",
"\n\nAs long as your computations are in Rand (I don’t give a hoot about RandT), you can use this semantics for precise, mathematical reasoning. ",
"What did you have when you were using RandomGen?"
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"Η νέα έρευνα της διαΝΕΟσις σε συνεργασία με το ΙΟΒΕ χαρτογραφεί τα προβλήματα του συστήματος φορολογίας εισοδήματος στην Ελλάδα και προτείνει λύσεις.",
"\n\nΤο φορολογικό σύστημα στην Ελλάδα είναι άδικο και αναποτελεσματικό. ",
"Αποτελεί σημαντικό εμπόδιο για την επιχειρηματικότητα, αποτυγχάνει να αντιμετωπίσει τις οικονομικές ανισότητες, είναι υπερβολικά περίπλοκο, αλλάζει πολύ συχνά και είναι φτιαγμένο με τρόπο που διευκολύνει τη φοροδιαφυγή. ",
"Τι αποτέλεσμα όμως θα είχε μια μείωση των φορολογικών συντελεστών στην Ελλάδα, τόσο ως προς το ύψος τους όσο και ως προς τον αριθμό τους; Θα μπορούσε να λειτουργήσει ένα σύστημα με μόνο ένα, ενιαίο φορολογικό συντελεστή στην Ελλάδα; Αν όχι, ποιος θα ήταν ο καλύτερος συμβιβασμός όσον αφορά την οικονομική αποτελεσματικότητα από τη μια πλευρά και την οικονομική δικαιοσύνη από την άλλη;\n\nΗ νέα έρευνα της διαΝΕΟσις σε συνεργασία με το ΙΟΒΕ περιλαμβάνει μια εκτενή ανάλυση της φορολογίας εισοδήματος στην Ελλάδα, με ένα πλήθος από στοιχεία και δεδομένα, και μια σειρά από αναλυτικές απαντήσεις σε όλα τα παραπάνω ερωτήματα, και σε πολλά άλλα επιπλέον. ",
"Η πολυμελής ερευνητική ομάδα, υπό τον συντονισμό του Γενικού Διευθυντή του ΙΟΒΕ Νίκου Βέττα:\n\nαναλύει τη σημερινή κατάσταση του φορολογικού συστήματος στη χώρα -σύμφωνα και με όσα έχει υπογράψει η ελληνική κυβέρνηση για τα επόμενα χρόνια,\n\n-σύμφωνα και με όσα έχει υπογράψει η ελληνική κυβέρνηση για τα επόμενα χρόνια, καταγράφει τα διαθέσιμα στοιχεία που αναδεικνύουν τα μεγάλα προβλήματα του συστήματος φορολογίας εισοδήματος στην Ελλάδα,\n\nτου συστήματος φορολογίας εισοδήματος στην Ελλάδα, εξετάζει έξι εναλλακτικά σενάρια διαφορετικών συστημάτων για μια απλούστερη και δικαιότερη φορολογία εισοδήματος φυσικών και νομικών προσώπων και,\n\nγια μια απλούστερη και δικαιότερη φορολογία εισοδήματος φυσικών και νομικών προσώπων και, καταλήγει σε συγκεκριμένες προτάσεις πολιτικής για την απλοποίηση και τον εκσυγχρονισμό του ελληνικού φορολογικού συστήματος.",
"\n\nΜπορείτε να διαβάσετε τη σύνοψη της μελέτης εδώ, μια πιο σύντομη παρουσίαση των βασικών στοιχείων της έκθεσης εδώ, και ολόκληρη τη μελέτη εδώ:\n\nΦΟΡΟΛΟΓΙΑ ΕΙΣΟΔΗΜΑΤΟΣ ΣΤΗΝ ΕΛΛΑΔΑ (.PDF)\n\nΠΑΡΟΥΣΙΑΣΗ ΒΑΣΙΚΩΝ ΣΤΟΙΧΕΩΝ ΤΗΣ ΜΕΛΕΤΗΣ (.PDF)\n\nΕξάλλου, η διαΝΕΟσις ασχολείται από την αρχή της λειτουργίας της με τα προβλήματα του φορολογικού συστήματος. ",
"Έχουμε ήδη δημοσιεύσει μια μεγάλη έρευνα για το πρόβλημα της φοροδιαφυγής, καθώς και μια μελέτη για την αναμόρφωση του φορολογικού συστήματος, ενταγμένη σε μια τριπλή πρόταση για την επανεκκίνηση της οικονομίας και ταυτόχρονα την αντιμετώπιση του δημόσιου χρέους και των προβλημάτων του ασφαλιστικού συστήματος, ενώ μέσα από τη μεγάλη δημοσκοπική έρευνα Τι Πιστεύουν οι Έλληνες έχουμε προσπαθήσει να ανιχνεύσουμε τις απόψεις των Ελλήνων σε μια σειρά από θέματα που σχετίζονται με τη φορολογία."
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"Mozilla Making Phone Using Community Ideas\n\nDetermined to prove it does more than make a superb web browser and less popular but still rather nifty email client, Mozilla has announced it plans to make a mobile phone. ",
"Yep, you heard that right.",
"\n\nCurrently dubbed the 'Mozilla Phone' or 'Mozphone' it aims to be all things to all people - by using the input of all people. ",
"In short this means the whole project is an open forum where web users can suggest ideas and input feedback while a partnership with the famed Yanko Design will recreate the proposals feeding off these discussions.",
"\n\nMozilla acknowledges this will initially be chaotic but expects over time for core aspects to be hammered out and certain universal features to be agreed. ",
"Where this will lead, who knows? ",
"To kick things off Yanko has already pushed out the 'OLED BlackBerry' - a BlackBerry 7130 melded with an Optimus keyboard. ",
"It's throwaway concept but represents a starting point to get user debate flowing.",
"\n\nWildly optimistic or truly inspired and utilising the best aspects of its 'open source' mindset? ",
"I guess we'll have a better idea a few months down the line...\n\nUpdate: Doh! ",
"It seems Mozilla is taking a step back here saying it currently has no plans to manufacturer a handset at the end of this process. ",
"It did leave us hope with this statement however:\n\n\"While Mozilla doesn't have plans to produce an OS or phone hardware at the moment — this doesn't mean that either are out of scope for Mozilla Labs and that's the point of the Concept Series. ",
"Everything is on the table.\""
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"Chapter VIIIThe Battle of Keren\n\nThe plan of operations, as outlined in the previous chapter provided for joint attack on Keren by the 4th and 5th Indian Divisions, the former to operate on the north and west of the road and the latter to the east of it. ",
"The initiative was to be taken by the 4th Indian Division, whose objectives included the series of hills from Mt. Sanchil to Mt. Samanna. ",
"The divisional plan was based on a two-brigade attack which was to be launched by the 11th and 5th Indian Infantry Brigades, and the date fixed was 15 March. ",
"In the paragraphs below the operations of the two brigades are narrated separately.",
"\n\nAttack by the 11th Indian Infantry Brigade\n\nThe 11th Indian Infantry Brigade was deployed for the attack with three battalions: on the right 2 Camerons was directed on Mt. Sanchil and Brig's Peak, in the centre 1/6 Rajputana Rifles headed for Hog's Back, and on the left 2/5 Mahratta Light Infantry was directed on Flat Top. ",
"On 14 April stores were carried to the dump. ",
"At 1900 hours, 2/5 Mahratta moved to the assembly area on the left of 1/6 Rajputana Rifles getting into position at 2130 hours. ",
"At this hour, 2 Camerons began its move up from the railway line to its assembly point and 1/6 Rajputana Rifles got into position. ",
"The assembly was carried out without incident or interference by the Italians. ",
"The night passed quietly and by 0600 hours, the next morning, the 11th Indian Infantry Brigade was in position according to plan. ",
"The attack was timed for 0700 hours on 15 March.",
"\n\nThe attack went in as timed. ",
"The artillery bombardment opened at 0700 hours, but as the leading troops went forward the Italian defensive fire caused a number of casualties. ",
"Heavy artillery and machine gun fire from Mt. Sanchil and Brig's Peak was directed against 2 Camerons, which nevertheless continued to advance slowly, with C Company directed on Brig's Peak and B Company on Sanchil. ",
"By 0815 hours, C Company almost got to the top of Brig's Peak but failed to drive out the Italians. ",
"However, B Company encountered very stiff opposition and failed to make much headway in securing Sanchil. ",
"At 0850 hours one company and at 1030 hours another company of the 1st Royal Fusiliers came under command of 2 Camerons. ",
"But, in spite of these reinforcements, 2 Camerons failed to capture Sanchil and Brig's Peak, as\n\n--92--\n\nthe Italian opposition was quite determined. ",
"Savoy Grenadiers poured machine gun fire, mortars and grenades down the slopes. ",
"In consequence, by 1600 hours, 2 Camerons had suffered heavy casualties and was unfit for further fighting. ",
"At that hour at Brig's Peak only a few men of C Company (2 Camerons) had survived from the grim ordeal; the only survivors of the company of 1st Royal Fusiliers were the Commander and eight men. ",
"The Commander of B Company 2 Camerons with about eight men had reached the top of Sanchil but had been driven off. ",
"No further progress was possible with the depleted forces, hence it was decided to use the rest of the 1st Royal Fusiliers to complete the capture of Sanchil. ",
"The attack by the Royal Fusiliers on Sanchil passed the forward company positions of 2 Camerons at 1815 hours. ",
"At 2300 hours, this attack was reported to be going on slowly but little headway could be made against the strong Italian positions. ",
"Thus not much progress was made either at Sanchil or Brig's Peak. ",
"The terrain in this area was very difficult, consisting of boulders and small trees and intersected by small Khors which made observation of movement at times impossible.",
"\n\nOn the left of 2 Camerons, 1/6 Rajputana Rifles was directed on Hog's Back. ",
"Its objective was from excluding Brig's Peak to including Hog's Back. ",
"The plan was for B Company to secure Hog's Back, on the capture of which A Company was to pass through to capture Bich Hill on the right. ",
"C Company was to move approximately 400 yards behind A Company. ",
"It was to be ready to assist A Company on to its objective and to capture Saddle. ",
"D Company was to be in reserve. ",
"One section Mortar Platoon was to assist B Company on to its objective whilst the second detachment was to follow behind B Company and to be prepared to cover A Company on to its objective. ",
"The Carrier Platoon was placed under the command of A Company.",
"\n\nThe battalion came under defensive fire, which the Italians put down when the British guns opened up. ",
"It suffered several casualties even before crossing the start line. ",
"However, by 0830 hours, it was able to capture Hog's Back though not without suffering severe losses. ",
"Three companies had been committed to secure this objective. ",
"At this time the Commander of the 11th Indian Infantry Brigade felt that the battalion was not in a fit state to attack Bich Hill and Saddle. ",
"He, therefore, ordered the battalion to consolidate on Hog's Back. ",
"A rough estimate showed that, of the three forward companies, most of one, half of the second and a good proportion of the third had been knocked out.",
"\n\n--93--\n\nAt 1030 hours, the Italians put in a counter-attack on Hog's Back from the direction of Saddle but it was repulsed. ",
"At 1230 hours, G Company and one platoon of B Company 4/6 Rajputana Rifles were placed under the command of 1/6 Rajputana Rifles, which kept them in reserve and used up its fourth company to strengthen Hog's Back. ",
"Throughout the early part of the night and again at 0430 hours next morning the Italians made repeated counter-attacks against Hog's Back but were driven back by 1/6 Rajputana Rifles.",
"\n\nTo the left of 1/6 Rajputana Rifles, 2/5 Mahratta attacked Italian defences on Flat Top. ",
"The objective of 2/5 Mahratta was from exclusive Hog's Back to inclusive Flat Top. ",
"The plan was for C Company on the left to secure Flat Top (from including prominent tree to including boulder) and D Company on the right to secure Slab Rock (from including prominent tree to including Slab Rock). ",
"A Company was to advance behind D Company, pass Slab Rock on the west and secure the saddle of low ground between Hog's Back and Flat Top (excluding prominent rocks to including prominent tree on the east edge of Flat Top). ",
"B Company in reserve was to move up immediately in the rear of the Battalion Headquarters to the area south of Slab Rock feature. ",
"Its role was to capture Mole Hill, about 400 yards north of Flat Top.1\n\nThe attack was launched in accordance with the plan at 0700 hours. ",
"Heavy defensive fire from the Italian artillery and mortars came down forward of the starting line and caused considerable losses in all companies advancing on the objectives. ",
"The Commander of D Company and some of his headquarters men were wounded but the company continued to advance and seized its objective, the Slab Rock feature, without much difficulty at 0720 hours.2 A Company advancing behind D, passed Slab Rock on the west and moved on towards its objective--the saddle of low ground between Hog's Back and Flat Top. ",
"After hard fighting the company captured its objective by 1030 hours. ",
"It had to cross three belts of wire before it could get into the Italian positions. ",
"C Company, detailed as the left forward company with Flat Top as the objective, advanced at 0700 hours. ",
"It approached Flat Top from the southeast but was held up when only fifty yards from it. ",
"Further efforts were made to get into the position round the west flank but were unsuccessful. ",
"The company suffered heavy casualties in the process.",
"\n\n--94--\n\nThe battalion plan was based on saving the reserve company for the capture of Mole Hill, but when the situation deteriorated around Flat Top, D Company was sent in to attack that feature from the east. ",
"In this the company suffered severe losses, particularly from an Italian medium machine gun which opened up at twenty yards' range as the company advanced towards the crest of Flat Top. ",
"This machine gun was, however, ultimately silenced and by 1440 hours, the objective had been captured. ",
"The casualties sustained by the two companies, engaged on Flat Top, were so heavy that the idea of advancing on to Mole Hill was given up and the companies were ordered to consolidate their position on Flat Top. ",
"At 1600 hours, the total strength of the two companies on Flat Top had been reduced to one British officer, two Viceroy's Commissioned Officers and thirty-four Indian other ranks. ",
"Italian sniping from Mole Hill continued until dark. ",
"At dusk, considerable Italian artillery and mortar fire was opened up and caused more losses to the Indian troops.",
"\n\nAt 1600 hours, the 11th Indian Infantry Brigade was informed that 3 Royal Garhwal Rifles was being put under its command forthwith, but that it could only be used in a static role. ",
"Hence the Brigade Commander ordered 3 Royal Garhwal Rifles to relieve 4/6 Rajputana Rifles which was then to come into brigade reserve. ",
"In addition, it was decided to use all available men from battalion and brigade B Echelons to thicken up the defences. ",
"They were sent up at 1730 hours and formed into two composite platoons (one British and one Indian). ",
"The British platoon was placed under the command of 1/6 Rajputana Rifles and occupied a feature to the south of Hog's Back, called Near Feature. ",
"The Indian platoon came under the command of 2/5 Mahratta for a counter-attack on Flat Top. ",
"Thus at nightfall on 15 March, the 11th Indian Infantry Brigade had made some progress in the teeth of opposition. ",
"Though heavy casualties had been sustained, Hog's Back had been captured and 1st Royal Fusiliers was on the move forward to attack Sanchil. ",
"Flat Top had also been taken and a way opened for further advance.",
"\n\nAttack by the 5th Indian Infantry Brigade\n\nThe 5th Indian Infantry Brigade detailed 4/11 Sikh to capture Mt. Samanna. ",
"The leading company advanced from Pt. ",
"1710 at 0700 hours to capture Left Bump. ",
"This feature was secured without much difficulty for the attack was made before the Italians could recover from the artillery concentration. ",
"Then the other two companies moved on to their respective objectives--Middle\n\n--95--\n\nOperations of 7 Ind Inf Bde North of Keren, 12-27 March 1941\n\n--96--\n\nBump and Right Bump which were held by 1st Alpini Battalion, 10th Savoy Grenadier Regiment. ",
"By about 0830 hours, the second company had reached within 200 yards from the crest of Middle Bump but was held up by determined resistance. ",
"Meanwhile the third company pushed on to Right Bump but was held up about 400 yards from the top. ",
"1st Alpini Battalion, which held these features, offered stubborn resistance and held up the advance of 4/11 Sikh. ",
"Further efforts to capture Middle Bump were unsuccessful, although the reserve company was also committed. ",
"It was then decided to abandon the attack on Right Bump, which had been found to be very strongly held by about four hundred Italians. ",
"The company in front of Right Bump was withdrawn successfully and ordered to assist the attack on Middle Bump. ",
"This attack, supported by artillery, was put in at 1335 hours but failed. ",
"Plans were made to attack during the night using the reserve battalion, 3/1 Punjab. ",
"This proposal was not accepted by the Commander of the 4th Indian Division, owing to the necessity of keeping this flank secure. ",
"It was, therefore, decided to withdraw 4/11 Sikh from the area of Middle Bump. ",
"The situation at nightfall was that 4/11 Sikh had captured Left Bump, 'but had failed to secure Middle Bump and Right Bump. ",
"It had suffered about 120 casualties during the day.",
"\n\nDiversionary Operations of the 7th Indian Infantry Brigade North of Keren\n\nThe leading troops of the 7th Indian Infantry Brigade had arrived south of the Mescelit Pass on 3 March. ",
"After that there lay between the brigade and Keren only the range of formidable hills covering the pass south of Mendad. ",
"At that time the Italians had six battalions in that sector. ",
"They were increased to seven by 12 March. ",
"The role of the brigade was to operate in the north to prevent the Italians from moving troops from that sector for use in the main battle in the south. ",
"Also it was to cut the line of Italian communications east of Keren and to interfere with their movements. ",
"The preliminary operation was the capture by the 1st Royal Sussex of Pt. ",
"2084 ridge as far as the line of the water course running east and west to the south of Vasentet. ",
"This operation was to be completed by the evening of 13 March. ",
"Royal Sussex was then to patrol vigorously in the plain to attract Italian attention and to pay particular attention to the protection of its right flank. ",
"Then the main operation was to be carried out in two phases. ",
"In the first phase, 4/16 Punjab was to capture the line from Pt. ",
"1557 to Pt. ",
"1457 and to consolidate on this line and support further operations by fire. ",
"In the second phase, the Free French units (3rd Chad Battalion and 14th Battalion Foreign Legion) were\n\n--97--\n\nto capture and consolidate the line Mt. Hono (Pt. ",
"1652) Mt. Ebibru, Cerasi. ",
"From this line they were to send patrols to the Keren--Asmara road and prevent the passage of Italian troops and vehicles along it.",
"\n\nOn 12 March, Advanced Brigade Headquarters and 4/16 Punjab moved from the bivouac area at Cogai to an area two miles to the north-east of Mt. Engiahat. ",
"It was hoped to accomplish the task set for 4/16 Punjab by surprise. ",
"The next day, reconnaissance groups spotted from Mt. Gegghiro some Italian troops on Pt. ",
"1967. ",
"An observation post party sent at 1200 hours from 4/16 Punjab to Mt. Gegghiro, ran into an Italian observation post, which had been established there and all the men of the Indian party were killed or captured. ",
"Thus surprise was lost. ",
"On the same day, the 1st Royal Sussex encountered Italians on the Pt. ",
"2084 ridge. ",
"The advance was held up and all efforts to reach their objectives on the ridge during the day failed.",
"\n\nWhen the presence of the Italians on Mt. Gegghiro became known, D Company 4/16 Punjab was detailed to drive them from there. ",
"It reached a spur running north from the feature but could not get any further. ",
"14th Battalion Foreign Legion was, therefore, ordered to capture the feature before first light on 14 March. ",
"After the capture of Mt. Gegghiro, the latter battalion was to continue the operations in the area and capture Engiahat, it was hoped, before the Italians could reinforce it further. ",
"Mt. Gegghiro was captured by 0100 hours on 14 March, but the attack on Engiahat was not successful. ",
"One company of the 14th Battalion Foreign Legion, which was sent round the south-east flank, came under fire from the Italians and suffered very heavy casualties.",
"\n\nA reconnaissance party of 4/16 Punjab found that the Italians were holding the ridge running west of Pt. ",
"1967. ",
"In view of this it became vital for the security of the line of communication to hold Pt. ",
"1967. ",
"A and C Companies of 4/16 Punjab were therefore sent up in the afternoon to occupy it. ",
"They went up the five-thousand-foot climb with good speed. ",
"A party of the Italians, which was trying to occupy a feature to the north-east of Pt. ",
"1967, was surprised and withdrew to Engiahat. ",
"Pt. ",
"1967 was then occupied by the Punjab troops.",
"\n\n15 March was D day for the main attack on Keren. ",
"The role of cutting the Italian line of communication, however, had to be abandoned until the opposition at Engiahat was overcome. ",
"4/16 Punjab sent out a patrol during the day to locate the Italian positions on Engiahat and to ascertain their strength. ",
"It was found to be\n\nAt 1300 hours, on 16 March, A and C Companies 4/16 Punjab attacked Engiahat, preceded by artillery fire. ",
"The Italians put up a strong resistance. ",
"The attacking companies reached the lower slopes of Engiahat, but then ran out of ammunition and had to withdraw. ",
"Meanwhile 1st Royal Sussex had failed to make any progress on the Pt. ",
"2084 ridge.",
"\n\nThe capture of Engiahat became difficult. ",
"On its spurs the Italians had constructed a series of fortified positions nearly a mile in depth. ",
"The only approaches to it were along two narrow ridges not permitting more than six men to pass at a time. ",
"The Commander of the 7th Indian Infantry Brigade made the following appreciation of the situation:--\n\nAs Engiahat dominated the line of communication for the area of intended operations towards the Keren-- Asmara road, its capture was essential before an advance in that direction was undertaken.",
"\n\nIt was necessary to build camel tracks up the hill side to a height of five thousand feet above the valley and to dump supplies, rations and ammunition before starting operations for the capture of Engiahat.",
"\n\nAir photographs were required to enable definite objectives to be allotted to the different units. (",
"This proved to be very difficult as, for many days, the air photos supplied seemed just to miss out the area required).",
"\n\nAll these factors caused delay and further operations were not undertaken until 27 March.",
"\n\n5th Indian Division Operations\n\nThe plan of operations had allotted the capture of Mts. ",
"Dolo-gorodoc and Zeban to the 5th Indian Division which had intended to execute it in four phases with the aid of two brigades, the third being in the reserve till these objectives had been secured. ",
"Accordingly, early in the morning of 15 March, the 9th and 29th Indian Infantry Brigades concentrated behind the lower slopes of Cameron Ridge. ",
"The assault on Fort Dologorodoc was to be carried out by 2nd Highland Light Infantry which was to approach its objective from a south-westerly direction. ",
"The attack was not to start until Mt. Sanchil and Brig's Peak had been secured by the 4th Indian Division. ",
"It was calculated that these objectives would be taken\n\n--99--\n\nby 0900 hours. ",
"The exact time of attack depended on when the artillery supporting the 4th Indian Division might be spared to support the 5th Indian Division. ",
"By 0945 hours the situation on the 4th Indian Division front appeared to be sufficiently satisfactory for the 5th Indian Division to start its attack. ",
"At this time it was not known whether Brig's Peak and Mt. Sanchil had been captured though it seemed that they would be taken shortly.",
"\n\nAttack by the 9th Indian Infantry Brigade\n\nThe 2nd Highland Light Infantry, leading the attack, crossed the start line (west bank of the water course south of bend at 368858) at 1030 hours in order to capture Pinnacle, White Rock Hill and Dologorodoc Fort. ",
"The leading company was unable to cross the road owing to very heavy Italian artillery and mortar concentrations, and also enfilade machine gun fire from the top and the eastern slopes of Sanchil. ",
"The remaining companies tried to capture Pinnacle and Razor Hill from the south. ",
"But no progress was made. ",
"At 1500 hours, it was decided that further progress by daylight was not possible. ",
"The 2nd Highland Light Infantry was ordered to consolidate the ground gained and a new plan was formed. ",
"Preceded by heavy artillery concentrations on Pinnacle, Pimple and Fort Dologorodoc, 3/5 Mahratta was to attack Pinnacle from the south. ",
"3 Royal Frontier Force Regiment was then to pass through and capture Pimple. ",
"Finally, after the first two objectives had been secured 2nd West Yorkshire Regiment, preceded by a further artillery concentration, was to pass through 3 Royal Frontier Force Regiment and capture the Fort. ",
"The first phase of this attack was originally planned to start at 1630 hours, but was later postponed to 1700 hours.",
"\n\nCrossing the start line at 1700 hours, 3/5 Mahratta encountered strong opposition. ",
"Yet by 1800 hours, it had reached Pinnacle, where a dogged fight ensued and the objective was not finally secured until 2000 hours. ",
"3 Royal Frontier Force Regiment, less two companies, then passed through and captured Pimple at 0005 hours on 16 March. ",
"Touch was lost with the two forward battalions at this stage. ",
"The Commander of the 9th Indian Infantry Brigade, however, ordered 2nd West Yorkshire Regiment to move up to the low ground between Pinnacle and Pimple, in preparation for the attack on Fort Dologorodoc. ",
"At 0400 hours, the Italians put in a strong counter-attack on Pinnacle and Pimple. ",
"This met the whole of the 9th Indian Infantry Brigade in line and was beaten off.",
"\n\nThe plan for the final phase of the attack had been for 2nd West Yorkshire Regiment to go through 3/5 Mahratta and 3 Royal\n\n--100--\n\nFrontier Force Regiment and assault the Fort under cover of a timed artillery programme. ",
"In the confusion caused by the counterattack mentioned above, communications broke down and it was not possible to stop the artillery concentrations which came down on the Fort as planned. ",
"In fact, this proved to be most fortunate. ",
"The Italian counter-attacking forces found themselves between the small arms fire of the 9th Indian Infantry Brigade and the artillery fire falling on their own fort behind. ",
"They broke and were pursued by 2nd West Yorkshire Regiment into the Fort, which reached there at 0615 hours and immediately exploited for eight hundred yards beyond.",
"\n\nSubsequent 4th Indian Division Operations\n\nOn 16 March, on the 11th Indian Infantry Brigade front, 1st Royal Fusiliers and 4/6 Rajputana Rifles attacked Sanchil and Brig's Peak respectively while the Italians launched strong counterattacks on 1/6 Rajputana Rifles at Hog's Back and on 2/5 Mahratta at Flat Top. ",
"1/6 Rajputana Rifles and 2/5 Mahratta were counterattacked a number of times during the night of 15/16 March. ",
"The forward positions had only been partially wired and the Italians managed to penetrate them many times and had to be ejected at the point of bayonet. ",
"A large number of high explosive grenades were used in repelling these attacks. ",
"The first counter-attack came simultaneously on both the battalions at 2230 hours on 15 March. ",
"Defensive fire was called for and the attack was repulsed by 2315 hours. ",
"The second counter-attack was on 1/6 Rajputana Rifles only. ",
"It lasted from 2315 hours on 15 March to about 0015 hours on 16 March, when it was driven back. ",
"At 0430 hours, on 16 March, there was a third counter-attack on 2/5 Mahratta and 1/6 Rajputana Rifles. ",
"In the Mahratta area, all the forward posts except one were recaptured by the Italians. ",
"This one post consisting of one officer and seventeen other ranks held on to the south-west edge of the position. ",
"A counter-attack by one Mahratta platoon was put in but was held up. ",
"Then a composite platoon from B Echelon under the command of an adjutant put in another counterattack and, by 0515 hours on 16 March, had cleared the Italians from Flat Top at the point of bayonet.3 The Italian counterattack on 1/6 Rajputana Rifles at Hog's Back was less severe. ",
"The battalion held its ground until first light at 0500 hours on 16 March, when the Italians withdrew.",
"\n\n--101--\n\nWhile 2/5 Mahratta and 1/6 Rajputana Rifles were busy in repelling strong Italian counter-attacks, 1st Royal Fusiliers, reinforced by 4/6 Rajputana Rifles, attacked Italian positions at Sanchil and Brig's Peak. ",
"As mentioned earlier, the attack of 1st Royal Fusiliers on Sanchil had passed the forward company positions of 2 Camerons at 1815 hours on 15 March. ",
"At 2300 hours, on 15 March, this attack was reported to be progressing slowly but little headway could be made against the strong Italian positions. ",
"At 0245 hours, on 16 March, the Fusiliers were about two hundred yards below the top of Sanchil. ",
"At 0430 hours they launched a vigorous attack to drive out the Italians from Sanchil. ",
"The attack progressed slowly against strong opposition. ",
"By 0600 hours, the forward elements of the Fusiliers managed to get through the wire on to the top, but were driven back by superior numbers and mortar fire. ",
"At 0750 hours, the Commander of the Fusiliers was wounded and the second-in-command was sent up to take over and make a final effort for the capture of Sanchil. ",
"At 0015 hours, he reported that the Fusiliers were unfit to put in an attack on Sanchil as they had suffered heavy casualties, and the strength of the battalion at the time had fallen down to less then ninety men. ",
"Thus the Fusiliers had failed to drive out the Italians from Sanchil.",
"\n\n4/6 Rajputana Rifles attack on Brig's Peak was also not successful. ",
"This battalion had been relieved by 3 Royal Garhwal Rifles and had concentrated at Rajputana Hill for an attack on Brig's Peak at 0430 hours on 16 March. ",
"The plan was for B Company less one platoon to capture Brig's Peak. ",
"D Company was to secure Middle Bump and A Company to capture Sugar Loaf (the peak at the north-west end of Brig's Peak). ",
"Advanced Battalion Headquarters with C Company and one platoon B Company in reserve was to follow as soon as possible in the rear of the forward companies. ",
"The artillery support arranged for this attack was defensive fire to be put down on previously registered lines on Brig's Peak and Saddle, at half-hourly intervals from 0300 hours to 0500 hours, by which time it was hoped the leading troops would be nearing the objectives. ",
"However, the attack did not make much progress. ",
"Italian opposition was very strong and the Indian troops suffered heavy casualties. ",
"The leading elements could not get nearer than two hundred yards from the peaks, by 0800 hours. ",
"Another attack was put in at 0830 hours, using the reserves of the forward companies, but was no more successful. ",
"A further attack was arranged to take place at 1015 hours with air, mortar and machine gun. ",
"At 1005 hours, information was received that there would be no air co-operation, but that the attack was to go in at 1030 hours. ",
"It\n\n--102--\n\nDespatch riders in the Amba Alagi area\n\nA truck of a mechanised column of an Indian cavalry regiment about to start on a patrol in the Amba Alagi area<\n\nA Bren-gunner and a rifleman in a stone sangar at an observation post Ethiopia\n\nA squadron section post and observation post beyond Amba Alagi\n\nRoad block partly cleared for the trucks to carry supplies to forward troops in Ethiopia\n\nPanorama of the country on the southern side of the Falaga Pass in Ethiopia\n\nMembers of the Jammu & Kashmir Mountain Battery at work camouflaging their guns\n\nWith bayonets fixed a platoon of Sikhs attack the enemy position up a mountain in Ethiopia\n\nwas, then, too late to change the original orders. ",
"Therefore, the attack was put in at 1015 hours, without support of any kind. ",
"It had not made much progress when it was brought to a halt by machine gun fire.",
"\n\nAt this stage the 10th Indian Infantry Brigade was placed under the command of the 4th Indian Division for exploitation into the plain west of Keren. ",
"This brigade was ordered to move up to Cameron Ridge area in readiness for an attack starting from the line of the col between Sanchil and Brig's Peak. ",
"The attack was to start at 2100 hours. ",
"In view of this the 11th Indian Infantry Brigade was told to hold on to the ground gained and to continue the forward pressure.",
"\n\nOn the 5th Indian Infantry Brigade front, no operations were undertaken on 16 March. ",
"4/11 Sikh consolidated its position on Left Bump. ",
"It was subjected to intermittent mortar and artillery fire.",
"\n\n5th Indian Division Operations\n\nOn the 5th Indian Division front, on 16 March, the 9th Indian Infantry Brigade consolidated the ground gained. ",
"As mentioned earlier, Fort Dologorodoc had been occupied at 0615 hours on 16 March by 2nd West Yorkshire Regiment. ",
"The Italian reaction to this success was violent. ",
"The first counter-attack on the Fort came at 1005 hours. ",
"Defensive fire was called for; artillery engaged the Italian assembly area and the attack was broken up. ",
"The next attack came not long after. ",
"At about 1150 hours, a large number of Italians were observed to be forming up to the east of the Fort, evidently for a counter-attack. ",
"Two field regiments engaged the target and the Italians, estimated at three battalions, were scattered. ",
"In view of the impending counter-attack, air support, in the form of two fighter aircraft for strafing ground targets outside three hundred yards radius from the Fort, was arranged and the guns of both divisions were laid on. ",
"When, after all, the attack did develop at 1330 hours, it was repulsed. ",
"Although there were no further counter-attacks during the day, the troops holding the Fort were constantly shelled and sniped by the Italians who had complete observation of the area from Sanchil, Zeban and Falestoh.",
"\n\nEstimate of the Progress of Operations (15-16 March)\n\nDuring these two days of fighting British and Indian troops had made some important gains. ",
"On the 5th Indian Division front, Fort Dologorodoc had been captured and held against persistent Italian counter-attacks. ",
"The capture of Fort Dologorodoc was\n\n--103--\n\nof great importance since it afforded, for the first time, observation on to the Keren plain. ",
"On the 4th Indian Division front, the British and Indian troops, in spite of strenuous efforts, had failed to drive out the Italians from Sanchil and Brig's Peak. ",
"Further to the west, however, Hog's Back and Flat Top had been captured and held against strong counter-attacks. ",
"On Samanna, the Left Bump had been captured and held, though efforts to capture Middle and Right Bumps had been unsuccessful, and had finally been abandoned. ",
"The Italians still held all the dominating features and, while this state of affairs lasted, the British and Indian troops were exposed to heavy machine gun, mortar and artillery fire.",
"\n\nThe Italians had offered stout resistance and inflicted severe casualties on the British and Indian troops with the result that some of the units were rendered unfit for immediate action. ",
"In addition to the determination shown by the Italians in the fighting, the failure of the British and Indian forces in gaining objectives, was due to the unfavourable weather and physical conditions. ",
"During the two days of the hard fighting, the weather was extremely hot and oppressive. ",
"Speaking of the operations on 15 March General Platt observed \"Some of the efforts of the troops that day were defeated almost as much by heat and heat exhaustion as by hostile opposition\".",
"\n\nOperations on 17 March\n\nAs the British and Indian troops in the forward line had suffered heavy casualties it was necessary to employ fresh troops for launching another attack. ",
"An attack on both the divisional fronts to break through to the Keren plain was now undertaken. ",
"On the 4th Indian Division front, the 10th Indian Infantry Brigade was ordered to break through between Brig's Peak and Mt. Sanchil and advance as far as the line of the water course running west from the railway and water course junction at 378883. ",
"This attack was to start from the line of the col between Sanchil and Brig's Peak at 2100 hours on 16 March. ",
"The Commander of the 10th Indian Infantry Brigade planned to carry out the operation in two phases. ",
"In the first phase, 3 Royal Garhwal Rifles was to capture Sanchil and 4/10 Baluch on the left was to capture Brig's Peak. ",
"In the second phase, 2nd Highland Light Infantry was to attack the col between Sanchil and Brig's Peak and break through on to the Keren plain and secure up to the line of the water course running west from the railway crossing over the water course at 378883.4\n\n--104--\n\nOn the 5th Indian Division front, the 9th Indian Infantry Brigade was to consolidate its position in the Fort area and the 29th Indian Infantry Brigade was to attack forward of the Fort and capture Falestoh Ridge--Pt. ",
"1552-- Zeban--cross roads 402883. ",
"The attack was to start from the Fort and the time for it was to be approximately 2200 hours on 16 March. ",
"The actual time was to be decided by the Commander of the 29th Indian Infantry Brigade, after reconnoitring the approach and considering the state of the moon.5 This operation was also conceived in two phases. ",
"In the first phase, the 1st Worcestershire Regiment on the right was to capture Falestoh Ridge up to Pt. ",
"1552, and 3/2 Punjab on the left was to capture Zeban Minor up to Pt. ",
"1717. ",
"The attack of the 1st Worcestershire Regiment was timed for 2230 hours on 16 March and that of 3/2 Punjab for 2245 hours. ",
"In the second phase, 6 Royal Frontier Force Rifles was to capture the remainder of Zeban and cross roads 402883. ",
"This attack was to start at 0300 hours on 17 March.",
"\n\nAttack by the 29th Indian Infantry Brigade (17 March)\n\nThe concentration of the 29th Indian Infantry Brigade in the area of the Fort prior to the attack was very seriously delayed. ",
"The climb up the Hill was very difficult, the track being narrow and having large quantities of cable laid across and along it. ",
"The last battalion did not reach the Fort area until 0100 hours on 17 March. ",
"The zero hour for the attack was, therefore, changed to 0230 hours. ",
"The artillery fire in support of the attack opened at 0230 hours on 17 March. ",
"The delays in this attack, however, were not yet over; 1st Worcestershire Regiment miscalculated the time needed to get to its start line and was one and a half hours late. ",
"However, once it had crossed the start line, it made good progress and by 0730 hours had established itself on a little feature, a hundred yards to the south of Pt. ",
"1552, on Falestoh Ridge. ",
"All attempts to get to the top of Mt. Falestoh were, however, unsuccessful and the battalion suffered heavy casualties--23 killed, 55 wounded and 7 missing.",
"\n\nOn the left, 3/2 Punjab made some progress. ",
"The plan was for D Company to move north of the Fort track and secure Zeban Minor. ",
"C Company following D Company in the rear was to secure Pt. ",
"1717. ",
"A Company following C Company in the rear was to secure the col north of Pt. ",
"1552 on the left flank of 1st Worcestershire Regiment. ",
"Battalion Headquarters and B Company were to move behind A Company. ",
"The attack took place according\n\n--105--\n\nto plan and D Company crossed the start line at 0230 hours on 17 March. ",
"D Company, not being fired at from M.G. ridge (a small feature immediately below the Fort), moved on towards its objective. ",
"Hardly had it gone 800 yards when it met the Italians in a strong position just east of a small nullah. ",
"This position was attacked at once by D Company from the front and by the two other companies following (C and A Companies) from the right and the left. ",
"Although Italian machine guns on the flanks caused heavy casualties, the attack was pressed home with determination and the position was captured.",
"\n\nAt 0600 hours, the Italians put in a counter-attack on the forward positions. ",
"This was repulsed. ",
"In order to help in repulsing this counter-attack, B Company 6 Royal Frontier Force Rifles was placed under the command of 3/2 Punjab and was ordered to move up on the left flank. ",
"The ground over which it had to pass was swept by machine gun fire from Sanchil and Railway Bumps. ",
"The company, however, rushed across this area and eventually captured forty prisoners. ",
"Its own losses were three killed and five wounded. ",
"At the same time some Italian troops were seen creeping up the northern slopes of the Fort. ",
"They were engaged by fire and forced to withdraw. ",
"The advance of the forward companies was held up by heavy machine gun fire from M.G. ridge. ",
"B Company, in reserve, engaged the Italians in position on M.G. ridge and the machine gun fire from this ridge was neutralised by Bren and mortar fire. ",
"The advance on Zeban was resumed again. ",
"By 0730 hours, the forward troops had reached the bend in the track. ",
"Further advance was held up by heavy fire from Zeban Minor and col. ",
"This situation remained unchanged until 1300 hours. ",
"Then the Brigade Major was sent forward to get exact information about the situation. ",
"The weather continued to be hot and the maintenance of the forward troops with water and ammunition was found difficult. ",
"The forward troops had been moving and fighting for nearly twenty hours, and their positions were very exposed. ",
"The Commander of the 29th Indian Infantry Brigade appreciated that all the above factors had combined to break the impetus 'of the attack. ",
"As no fresh troops were available to carry on it was decided to withdraw the forward troops to less exposed positions after dark.",
"\n\nAt 1600 hours, British aircraft dropped supplies of food and ammunition on the two forward battalions. ",
"A great volume of hostile fire from the ground greeted the aircraft and the supply drop was not a success. ",
"Owing to faulty packing the ammunition was bent and many of the supplies fell so far away from the battalion areas that they could not be recovered.",
"\n\n--106--\n\nAt 1900 hours, B Company 6 Royal Frontier Force Rifles was counter-attacked again. ",
"This was a very strong effort by the Italians, but the Company fought gallantly and held its ground at the cost of over a third of its total strength. ",
"Heavy casualties were inflicted on the Italians also, and the attack was finally repulsed. ",
"During this attack two platoons from C Company 6 Royal Frontier Force Rifles reinforced B Company. ",
"Captain Anat Singh Pathania displayed great courage in this keenly-contested engagement. ",
"Although wounded in the face and both legs he rallied his men to a final charge and pushed out the Italians at the point of the bayonet from his company's position where they had succeeded in penetrating.",
"\n\nThe withdrawal started at 2300 hours on 17 March and the 1st Worcestershire Regiment moved back to a position on the slope south-east of the Fort (Big Rock area). ",
"The movement was covered by 3/2 Punjab, which retired to a position about 800 yards in front of the Fort.",
"\n\nAttack by the 10th Indian Infantry Brigade\n\nTo conform with the 29th Indian Infantry Brigade operations, the attack by the 10th Indian Infantry Brigade was so timed that the leading troops would reach their objectives about 0330 hours on 17 March. ",
"The two leading battalions, 3 Royal Garhwal Rifles and 4/1 OBaluch,therefore, moved from their assembly areas at 0130 hours. ",
"3 Royal Garhwal Rifles was led by guides provided by 1st Royal Fusiliers to within one hundred and fifty yards of the top of Sanchil. ",
"The attack was launched at 0300 hours with D Company on the right and B Company on the left, C Company being in reserve. ",
"Although the troops fought well the advance was held up by heavy machine gun fire from Brig's Peak and by grenades and mortar fire. ",
"A dogged fight continued until 0700 hours but no progress was made. ",
"The Garhwalis suffered heavy casualties.",
"\n\nMeanwhile 4/10 Baluch too had not made much progress. ",
"The battalion moved off from Granite Peak (3585) behind the Garhwal-Rifles, crossed the col and reached the lower slopes of Brig's Peak. ",
"The attack was launched with C Company on the right and B Company on the left, D Company being in reserve. ",
"The attack was met by heavy machine gun and mortar fire and could not get nearer than three hundred yards from the objective. ",
"At 0530 hours, the Italians put down defensive fire, artillery and mortar, and inflicted severe casualties. ",
"Under their accurate fire it became difficult to get the wounded away. ",
"The forward companies were withdrawn to about a third of the way from the Brig's Peak feature at 0700 hours.",
"\n\n--107--\n\nThroughout the day the two forward battalions, 3 Royal Garhwal Rifles and 4/10 Baluch were subjected to heavy fire. ",
"By the evening of 17 March, it was clear to General Platt that the attack had failed and that the 10th Indian Infantry Brigade would have to be withdrawn. ",
"The Italian strength on Sanchil-Brig's Peak had been underestimated. ",
"The forward troops had suffered heavy casualties. ",
"They could also not be maintained due to heavy fire. ",
"Success was not likely to be gained even if the weak 2nd Highland Light Infantry (the only remaining battalion of the 10th Indian Infantry Brigade) was committed to battle. ",
"A further assault, in the face of strong opposition, would have probably resulted in the destruction of the 10th Indian Infantry Brigade, the only reserve force available. ",
"He, therefore, decided to withdraw the 10th Indian Infantry Brigade, leaving the 11th Indian Infantry Brigade to hold on to Hog's Back and Flat Top. ",
"The 10th Indian Infantry Brigade was to be concentrated again as Force Reserve.6 The withdrawal was carried out during the night of 17/18 March without incident (2nd Highland Light Infantry remained on Cameron ridge until withdrawn on the night of 18/19 March). ",
"The 10th Indian Infantry Brigade had suffered heavy casualties in the operations of 16/18 March. ",
"The casualties of 4/10 Baluch were 123--16 killed, 105 wounded and 2 missing. ",
"The casualties of 3 Royal Garhwal Rifles were 193--10 killed, 174 wounded and 9 missing. ",
"These figures are indicative of the intensity of the struggle.",
"\n\nThe attacks on both the divisional fronts had thus spent themselves and the British and Indian troops were still in the hills with a hostile force, severely mauled but unbroken, between them and Keren. ",
"The attack by the 10th Indian Infantry Brigade on Brig's Peak-Sanchil had left no reserves with which to make further advance, once the 29th and the 10th Indian Infantry Brigades had been held up. ",
"A period of reorganisation was therefore necessary. ",
"A week passed during which the British and the Indian troops held the ground gained, while the Italians counter-attacked a number of times to recapture Fort Dologorodoc.",
"\n\n5th Indian Division Front\n\nBetween 18 and 22 March the Italians attacked Fort Dologorodoc no less than seven times. ",
"These attacks were beaten off and the British and Indian troops fought with courage and determination. ",
"On 19 March Italian General Lorenzini was killed on this front.",
"\n\n--108--\n\nHe was respected by his troops and his death was a severe blow to them. ",
"Active patrolling was carried out during this period and efforts were made to start work on the road block to open the road to Keren for the passage of mechanised forces.",
"\n\nThe 29th Indian Infantry Brigade had withdrawn from the area of Falestoh and Zeban early in the morning of 18 March. ",
"At 0230 hours, the Italians made a counter-attack from the direction of Railway Bumps and Falestoh. ",
"It was directed on the Fort and 2nd West Yorkshire Regiment had to bear the brunt of the attack. ",
"By first light, the attack had been beaten off and the Italians suffered several casualties in the fighting.",
"\n\nAgain at 1645 hours, the Italians launched another attack on the Fort. ",
"It was preceded by heavy artillery concentrations, but was repulsed without difficulty.",
"\n\nAt 0400 hours on 19 March, the Italians again made an attack. ",
"It was carried out by 10th Alpini Battalion which had assembled in the depression of the valley to the west of the Fort. ",
"From there, two companies moved direct towards the Fort while one went round the north to the Hill (367860). ",
"They could get to within seventy yards of the Fort and were then driven back. ",
"The Italians reformed and made a more determined effort. ",
"They were repulsed again, and this time pursued with bayonets and grenades. ",
"They abandoned two pack guns, some mortars and machine guns.",
"\n\nA regrouping of British and Indian forces on Mt. Dologorodoc was ordered on 19 March. ",
"It was to be completed by the midnight of 19/20 March. ",
"The various features in the Dologorodoc area were to be held by two brigades. ",
"A forward brigade was to be responsible for holding the Fort and ridges four to six hundred yards north of it. ",
"In the south, its area was to extend as far as, but excluding the features at 382856 and 376860. ",
"It was also to be responsible for the protection of the working parties engaged in clearing a way through the road block. ",
"The 9th Indian Infantry Brigade was to take over this area.",
"\n\nThe rear brigade was to hold the area 382856--376859-Pinnacle 375857. ",
"It was to be responsible for the protection of both flanks. ",
"It also had the role of operating astride the railway in the event of the Italians attacking in force from that direction. ",
"The 29th Indian Infantry Brigade was ordered to pull back and take over this area.",
"\n\nThe relief was completed without incident. ",
"3 Royal Frontier Force Regiment, less one company, relieved 3/2 Punjab on the features to the north of the Fort. ",
"The company of 6 Royal Frontier Force Rifles which was under the command of 3/2 Punjab passed to the\n\n--109--\n\ncommand of 3 Royal Frontier Force Regiment. ",
"3/5 Mahratta took over the Fort and 2nd West Yorkshire Regiment came out of the Fort to the area between the Fort and 376859.",
"\n\nAfter the relief, the dispositions of the 29th Indian Infantry Brigade were as follows:--\n\nBrigade Headquarters\n\n--Pinnacle\n\n1st Worcestershire Regiment\n\n--Area Pinnacle--376859-382856\n\n3/2 Punjab\n\n--Area Pinnacle\n\n6 Royal Frontier Force Rifles\n\n--South of the peak.",
"\n\nThe Italian counter-attacks had not exhausted themselves yet. ",
"On the night of 20/21 March, a patrol from 3 Royal Frontier Force Regiment found a party of Italians collected in a water course preparing for an attack on the left flank of the battalion area. ",
"The patrol attacked this party and dispersed it, capturing thirteen prisoners. ",
"At 2300 hours, a party of the Italians attacked the left forward company of 3 Royal Frontier Force Regiment. ",
"The attack was preceded by a very heavy artillery and mortar concentration. ",
"This attack was beaten off, but was soon followed by a battalion attack on the right forward company of the same unit. ",
"This larger attack was supported by three light tanks and was pushed home in a very determined manner. ",
"After a sharp action lasting about twenty minutes, the Italians were again driven back at the point of the bayonet. ",
"They were pursued with grenades, and artillery fire took a heavy toll of them as they withdrew.",
"\n\nOn 18 March, the 5th Indian Division planned an operation to make a way for 'I' tanks and carriers over the road block. ",
"The plan was to lay explosive charges and blow them up on the night of 18/19 March. ",
"During the night of 19/20 March, the maximum number of working parties was to be used to clear the debris and make a way for the tanks and carriers.7 On the completion of this task a force, consisting of B Squadron 4th Royal Tank Regiment less one section, and with carriers in support, was to pass over the road block and exploit to Keren.",
"\n\nOn 18 March, the sapper demolition party, with an infantry escort, went out after dark to work on the road block. ",
"The party contacted the Italians near the road block and had to withdraw.",
"\n\n--110--\n\nHowever, it was reported that these Italians were only part of a counter-attacking force which was forming up in the area for attacking Fort Dologorodoc. ",
"Therefore, it was decided to repeat the attempt the next night.",
"\n\nDuring the night of 19/20, the Sappers were escorted by a platoon of 6 Royal Frontier Force Rifles. ",
"Some Italians were met with in the area of the road block again and the escort suffered nineteen casualties. ",
"The operation was, therefore, abandoned until such time as an attack could be arranged to clear the Italians from the ground from which small arms fire could be brought to bear on the road block.",
"\n\nAt 1130 hours on 20 March, two \"I\" tanks reconnoitred along the road as far as the road block. ",
"The Italians opened with artillery and mortars, covering the demolition on both sides of the road.",
"\n\nOperations on the 4th Indian Division Front\n\nAfter the withdrawal of the 10th Indian Infantry Brigade during 17/18 and 18/19 March the dispositions of the 4th Indian Division were as follows:--\n\n11th Indian Infantry Brigade\n\nCameron Ridge\n\n4/6 Rajputana Rifles (less two companies)\n\nExcluding Cameron Ridge to Near Feature 353877\n\n2 Camerons\n\nExcluding Near Feature to Hog's Back\n\n1/6 Rajputana Rifles plus two companies 4/6 Rajputana Rifles\n\nExcluding Hog's Back to including Flat Top\n\n2/5 Mahratta\n\nIn reserve\n\n1st Royal Fusiliers\n\n5th Indian Infantry Brigade\n\nLeft Bump\n\n4/11 Sikh\n\nPt. ",
"1710\n\n3/1 Punjab and Brigade Headquarters\n\nAt 0440 hours on 19 March, 4/11 Sikh put in an attack on Middle Bump preceded by an artillery concentration. ",
"The attack was made on a two-company front. ",
"Some of the Italian machine gun posts on top held on in spite of the heavy artillery fire and barred the advance of the infantry when about two hundred yards from the objective. ",
"Italian troops on the feature were then reinforced. ",
"At 0800 hours,\n\n--111--\n\nwhen the failure of the attack was apparent, the Commander of the 5th Indian Infantry Brigade ordered a withdrawal, which was completed by 0910 hours. ",
"4/11 Sikh had eleven men killed and sixty wounded.8\n\nOn 19 March, two men of 3 Royal Garhwal Rifles, who had not received the withdrawal order on the night of 17/18 and had got left behind in the area of Sanchil, were brought in by an officer's patrol of 2 Camerons.",
"\n\nOn 21 March, 3 Royal Garhwal Rifles was ordered to move into Happy Valley to achieve the following purposes:--\n\nto secure the flank of the 5th Indian Division,\n\nto protect the artillery in Happy Valley,\n\nto persuade the Italians to believe that an attack on Acqua Gap was being planned.",
"\n\nNo other major events occurred before 24 March and the Italians continued to enjoy the advantage of complete observation over British and Indian positions held by both the divisions. ",
"The forward troops were shelled, machine gunned and sniped constantly. ",
"On the night of 19/20 March, the 11th Indian Infantry Brigade had arranged a programme of harassing artillery fire to cover the movement of the 5th Indian Division troops in the Dongolaas Gorge, but the Italian fire in return was so intense that the programme had to be cancelled.",
"\n\nAs the time passed the weather warmed up and became very unpleasant for the troops in the valleys. ",
"As a result of preparations, however, during this period the administrative position improved considerably. ",
"There were more mules and more tracks for them\n\n--112--\n\nto use than before; still there was a good deal of manhandling to be done though the problem had ceased to be serious.",
"\n\nAir Situation\n\nDuring this period of reorganisation, the Italian Air Force became active after a long spell of inactivity. ",
"Their fighters carried out a large number of patrols but were unwilling to engage British Hurricanes, unless in superior numbers and when operating from a position of initial advantage. ",
"British aircraft kept up their attacks on Asmara in addition to the standing patrols over the battle area. ",
"These patrols performed offensive, air photo and reconnaissance work.",
"\n\nDuring this period too the Royal Air Force received its first call for artillery reconnaissance. ",
"The first attempts were not successful owing to the lack of experience of pilots and gunners and some equipment difficulties. ",
"But within a few days very successful shoots were conducted.",
"\n\n5th Division Plan to break through the Road Block\n\nFrom Mt. Sanchil a spur ran to the north-east. ",
"The railway ran along the east side of Sanchil and, after going round this spur, it turned west. ",
"At the level of the railway this spur flattened out into small broken hills, which were called Railway Bumps--which ended at the junction of two dry stream beds. ",
"The main stream bed was that of a water course which ran down the Dongolaas Gorge. ",
"A subsidiary one came in from the north-west. ",
"At the junction, the banks of the latter were very steep, the south-west bank being the Railway Bumps and the north-east one Railway Ridge. ",
"Machine guns on Railway Bumps and Railway Ridge commanded Dongolaas Gorge, the east side of Sanchil, the west side of Mt. Do-logorodoc and the road block.",
"\n\nThe attempt to secure protection for the Sappers working on the road block (380868) on the nights of 18 and 19 March had failed because of Italian positions in the area Railway Bumps--Railway Ridge--spur 384871 (East Gate Spur)--Hillock 'A 377863--Hillock 'B' 380866. ",
"An operation was, therefore, planned,\n\nfirst, to secure ground from which close range small arms fire might be brought to bear on the road block area, next to prepare a way across the road block for the passage of tracked vehicles; and finally, to exploit towards Keren.",
"\n\nAll these operations were to be carried out by the 5th Indian Division which had under its command B Squadron 4th Royal Tank Regiment (less one troop), ten carriers of 3/1 Punjab and\n\n--113--\n\none Field Company Royal Indian Engineers. ",
"In addition, the 4th Indian Division artillery was to fire in support of the 5th Indian Division and to distract Italian attention from the latter by sending fighting patrols in Brig's Peak area.",
"\n\nThe divisional plan was to carry out the operation in four phases with some preliminary moves, and finally to exploit with a mobile force. ",
"The preliminary moves were to consist of:--\n\nConcentration of the 10th Indian Infantry Brigade less 3 Royal Garhwal Rifles in the area of Cameron Tunnel on 24 March.",
"\n\nSending of reconnaissance patrols on the night of 23/24 March to the area of Hillocks 'A' and 'B', and East Gate Spur.",
"\n\nDespatch of fighting patrols by 3 Royal Garhwal Rifles on the nights of 23 and 24 March towards Acqua Gap.",
"\n\nThe main operation was to be carried out in four phases. ",
"In the first phase, the 9th Indian Infantry Brigade with 28 Field Regiment in support was to capture Hillock 'A' by 0430 hours on 25 March. ",
"In the second phase at the same time, the 10th Indian Infantry Brigade less 3 Royal Garhwal Rifles was to advance on and capture Railway Bumps. ",
"It was then to exploit to hill 376882, if the situation so demanded. ",
"Simultaneously, the 9th Indian Infantry Brigade was to capture Hillock 'B'.",
"\n\nAt 0445 hours, Sapper working parties were to advance to the area of the road block and commence work on clearing a way through it. ",
"It had been estimated that this task would take thirty-six to forty-eight hours.",
"\n\nIn the third phase, the ground captured was to be consolidated. ",
"If necessary, for the protection of the right flank of the 10th Indian Infantry Brigade, the 9th Indian Infantry Brigade was to be prepared to secure the ridge west of 385876 (Railway Ridge).",
"\n\nIn the fourth phase, the 29th Indian Infantry Brigade was to capture Zeban Minor. ",
"This was not to be executed before 26 March. ",
"Fire programme for this attack was to be arranged mutually between the brigade commander and the commander Royal Artillery.",
"\n\nExploitation by a Mobile Force\n\nA mobile force called Fletcher Force9 was detailed for exploitation. ",
"The task allotted to this force was to advance down the main road to Keren in co-ordination with an attack by the 29th Indian\n\n--114--\n\nKeren--The Final Battle, 15-27 March 1941\n\nInfantry Brigade on Zeban Minor. ",
"It was to cut. ",
"Italian communications and destroy guns, headquarters, rearward services and capture or destroy Italian forces in the Keren area.10 During the exploitation phase, the 10th and 29th Indian Infantry Brigades were to co-operate in accomplishing the above tasks as opportunity offered.",
"\n\nThe 4th Indian Division was to hold its positions and try to distract Italian attention from the operations of the 10th Indian Infantry Brigade by active patrolling and harassing the Italians. ",
"It was also to be prepared to exploit towards Sanchil-Brig's Peak-hill 358880, when ordered.",
"\n\nThe 7th Indian Infantry Brigade was to co-operate, to the full, by exerting pressure on the Italians from the north.",
"\n\nThe Attack\n\nAt 1745 hours on 24 March, 3 Royal Frontier Force Regiment reported that Italian artillery was registering Hillock 'A' (377863). ",
"At 2330 hours that night, a patrol from 2nd West Yorkshire Regiment occupied the feature and by 0430 hours two companies were established on it without the pre-arranged artillery support. ",
"Following this, 3/5 Mahratta advanced at 0430 hours and captured Hillock 'B' (380866) against strong opposition. ",
"By 0655 hours, it had taken a part of East Gate Spur. ",
"This came as a surprise to the Italians who retaliated by heavy and accurate shelling and mortar fire on 3/5 Mahratta and the road block, where the Sappers were already at work.",
"\n\nThe attack by the 10th Indian Infantry Brigade started at 0430 hours on 25 March according to the plan and made good progress. ",
"The Italians had been expecting an attack from the direction of the Dologorodoc Fort, hence they were completely taken by surprise. ",
"Although they fought hard their opposition was overcome easily.",
"\n\nThe objective of Railway Bumps had been divided into six separate points called 'A', 'B', 'G', 'X', 'Y' and 'Z'. ",
"Going from west to east, 'A', 'B' and 'C' were along the southern edge and 'X', 'Y' and 'Z' along the northern edge. ",
"By 0700 hours, 2nd Highland Light Infantry had captured 'A', 'B' and 'C' and 4/10 Baluch 'Y' and 'Z'.",
"\n\n3/2 Punjab had been placed under the command of the 10th Indian Infantry Brigade and was directed to capture Railway Ridge\n\n--115--\n\n(383876), starting at 0945 hours. ",
"By 1025 hours, it had secured that objective.",
"\n\nThe situation on East Gate Spur remained unsatisfactory for some time. ",
"3/5 Mahratta reached its objective but was forced off it by enfilade fire which inflicted heavy casualties. ",
"The battalion put in another attack at 0945 hours, in conjunction with an attack by 3/2 Punjab. ",
"By 1045 hours, the situation had improved with 3/5 Mahratta consolidating on Red Hill, a part of East Gate Spur. ",
"In all, this battalion was counter-attacked four times but held its ground in spite of heavy losses.",
"\n\nWork on the Road Block\n\nThe tasks allotted to the Sappers during this operation were:--\n\nTo clear mines from the road and railway as far as the forward troops might advance.",
"\n\nTo construct anti-tank obstacles and mine the road north of the road block to cover the troops working on the demolition.",
"\n\nTo clear a way for \"I\" tanks and carriers across the road block as soon as possible.",
"\n\nTo send a Sapper party with the mobile force to assist in removing obstacles and mines during the exploitation phase.",
"\n\nThe Sapper plan was for the 2 Field Company to advance at 0445 hours behind the artillery barrage and start work on the block as soon as possible. ",
"The first task on the block was to demolish the large boulders. ",
"At 1830 hours, the 20 Field Company was to relieve the 2 Field Company on the block and carry on work until 2330 hours when it would be relieved by the 21 Field Company. ",
"An officer from B Squadron 4th Royal Tank Regiment was detailed as liaison officer with the commander Royal Engineers 5th Indian Division to advise him on the extent of work required to make a way for \"I\" tanks and carriers to pass.",
"\n\nThe 2 Field Company advanced at the fixed time and commenced work on the road block. ",
"Although the Italians kept up a heavy fire on the road to the south of the block, the work on the actual site proceeded without much interference, and satisfactory progress was made throughout the day. ",
"Italian shelling on the road block increased in the evening, but work continued throughout the night and, by 1430 hours on 26 March, a way for \"I\" tanks and carriers had been cleared.",
"\n\n--116--\n\nThe Operations\n\nAt 1350 hours on 25 March, the Commander 10th Indian Infantry Brigade reported that the Italians were massing for a counterattack at 390877 and asked for artillery to engage them. ",
"Thereupon the artillery engaged the Italian force and dispersed it. ",
"At 1340 hours, white flags were reported on Sanchil. ",
"Forward troops asked for artillery fire to be stopped but the General Officer Commanding 5th Indian Division ordered the fire to continue until the fire from Sanchil on the road block had stopped. ",
"The reports about the white flags, however, did not seem to be correct as the Italians continued to hold out. ",
"There were also reports of white flags on Zeban Minor but they were not confirmed.",
"\n\nDuring the night of 25/26 March, minor counter-attacks were put in by the Italians against 4/10 Baluch, in the Railway Bumps area, but were easily repulsed. ",
"Another counter-attack had been planned by the Italians to take place on the 3/5 Mahratta positions on Red Hill at 0500 hours. ",
"While the counter-attack troops were assembling the Mahrattas got scent of them and the attack was broken up by artillery and machine gun fire.",
"\n\nAlso Italian movement eastward across the Mogareh plain was detected. ",
"All this seemed to indicate that they were preparing to withdraw. ",
"At 0725 hours, a patrol from 4/10 Baluch met a party of Italians who put up their hands. ",
"But on the approach of the patrol, they threw bombs at it and then ran away into the hills.",
"\n\nIn planning for attack on Zeban the Commander of the 29th Indian Infantry Brigade had suggested that it would be best to attack at dawn on 27 March to save the troops from exhaustion from the stiff climb up to the objective. ",
"General Officer Commanding the 5th Indian Division, however, decided that, if the way across the road block was cleared, the 29th Indian Infantry Brigade was to be prepared to move at 1200 hours on 26 March. ",
"In his opinion a delay of several hours was likely to affect the subsequent operations adversely and the mere danger of the troops being exhausted was not enough justification for postponing the attack till the 27th.",
"\n\nIt was however finally decided to start the attack at 0430 hours on 27 March. ",
"3 Royal Garhwal Rifles was placed under the command of the 29th Indian Infantry Brigade for the operation. ",
"3 Royal Garhwal Rifles had been relieved in Happy Valley on 25 March by the Central India Horse, which had, on that date, been placed under the command of the 5th Indian Division. ",
"The Commander of the 29th Indian Infantry Brigade had planned to attack on a two-battalion front. ",
"1st Worcestershire Regiment was to capture\n\n--117--\n\nZeban Minor and 3 Royal Garhwal Rifles, on the left, to capture the cross roads at 402883 and then to secure the line of the road Mission--Mogareh to the west of the main road. ",
"This would allow the main road to the north of the road block to be cleared of the mines. ",
"6 Royal Frontier Force Rifles was to be in reserve.",
"\n\nThe attack started at 0430 hours on 27 March with artillery support. ",
"When the infantry went in, very slight opposition was encountered and both the battalions had captured their objectives by 0600 hours. ",
"6 Royal Frontier Force Rifles was ordered to advance through 1st Worcestershire Regiment and capture Mt. Zeban. ",
"This was done without opposition at 0730 hours.",
"\n\nIt was now clear that the Italians had evacuated Keren. ",
"6 Royal Frontier Force Rifles was ordered to exploit up to Mt. Canabai which was occupied at 1030 hours. ",
"Patrols were then sent out to round up the stragglers.",
"\n\nOn the 4th Indian Division front, patrols, out during the night of 26/27 March, reported that the Italians were still holding their positions. ",
"At 0540 hours, 3/2 Punjab reported white flags on Sanchil. ",
"This was confirmed from more than one source by 0600 hours and arrangements were made to take over the positions. ",
"They had all been taken over by 1000 hours.",
"\n\nOperations of Fletcher Force\n\nFletcher Force was composed of following troops:--\n\nB Squadron 4th Royal Tank Regiment (less one troop)\n\n(eight tanks)\n\nCarrier Squadron Central India Horse\n\n(seventeen carriers)\n\nCarriers 9th Indian Infantry Brigade\n\n(thirteen Brigade carriers)\n\nCarriers 10th Indian Infantry Brigade\n\n(thirteen Brigade carriers)\n\nCarriers 3/1 Punjab\n\n(ten carriers)\n\nAt stated above, the task allotted to this force was to break through in conjunction with the 29th Indian Infantry Brigade attack and destroy all Italian communications, headquarters and guns in the Keren area. ",
"Fletcher Force's plan was to move with an advanced guard of one carrier Central India and one troop \"I\" tanks directed on to cross roads at 402883 as first objective and area 410895 as second objective. ",
"Of the main body, two troops carriers of Central India Horse were to move at the head and join the advanced\n\n--118--\n\nguard on the second objective. ",
"Two \"I\" tanks and one light tank were to go to the Mission. ",
"Two Central India Horse troops carriers were to go to the area 410895 and thence to the Nacfa Road. ",
"The 9th Indian Infantry Brigade carriers were to go to Tantarua in the north-east quarter of the town, while the carriers of 3/1 Punjab were to remain at the cross roads at 402883.",
"\n\nCrossing the start point at the bridge at 377846, at about 0500 hours on 27 March, the advanced guard got as far as the road block. ",
"In trying to cross it the leading carrier got stuck on an incline where the engine failed and it had to be cleared back. ",
"The \"I\" tanks then tried and the leading one got across at about 0600 hours, and the second at 0620 hours, while the third and last of the advanced guard crossed at 0640 hours. ",
"At 0700 hours, orders were issued to Fletcher Force stressing the importance of advancing up the Nacfa road and trying to cut the retreat of Italian troops in that area, opposing the 7th Indian Infantry Brigade. ",
"It was also told to try to advance on Habi Mantel from the north.",
"\n\nThe 10th Indian Infantry Brigade was allotted the responsibility of looking after Keren.",
"\n\nAt 0730 hours, Sudan Defence Force armoured cars were sent forward with orders to follow up the withdrawal of the Italians along the road. ",
"They were to be launched under orders of the General Officer Commanding 5th Indian Division as soon as he could get them across the road block.",
"\n\nBy 1000 hours, the mobile force had got across and was well on the way in pursuit of the Italians. ",
"At 1230 hours, the leading elements of this force were reported to be about one mile*west of Habi Mantel. ",
"All the available aircraft had been put on to harass the Italians in their withdrawal.",
"\n\n7th Indian Infantry Brigade Operations\n\nOwing to repeated delays in obtaining air photos it was not possible for the 7th Indian Infantry Brigade to attack until 27 March. ",
"In the intervening period continuous artillery fire was kept up on the Italian positions on Engiahat. ",
"Finally, an attack on Engiahat was planned in conjunction with the operations of the 5th Indian Division. ",
"Because morning mist prevented artillery observation, this attack could not be timed to start before 0730 hours. ",
"4/16 Punjab pressed this attack with great vigour, the Chad Battalion co-operating on the left flank. ",
"The Italian resistance, however, was slight and it was soon clear that they had withdrawn the bulk of their forces during the night of 26/27 March. ",
"The Foreign Legion\n\n--119--\n\nBattalion was therefore immediately directed to advance into the Anseba valley to cut the retreat of the Italians and to establish contact with the 5th Indian Division. ",
"This was accomplished before dark and many prisoners were taken. ",
"4/16 Punjab was ordered to advance to Mt. Gubcub and join up with 1st Royal Sussex, which was told to open the road to Keren.",
"\n\nThus, after a siege of fifty-three days British and Indian troops entered Keren. ",
"The strategic possibilities of this position had been appreciated by the Italians for many years, and it was here that they had decided to make their main stand. ",
"They had concentrated the bulk of their forces in Eritrea in this area. ",
"From the build up of their forces and the statements of their prisoners it was clear that they were staking a great deal on holding this fortress. ",
"They feared that if Keren fell, Asmara, the capital of Eritrea, would also be lost. ",
"The selection of Fort Dologorodoc as an objective was very sound. ",
"Its capture put British and Indian troops in a strong position. ",
"Although it was overlooked by Sanchil and Falestoh, and was a very difficult position to hold, it was a key position in the system of the Italian defences. ",
"They wanted it back and their keenness was so great that, during the days following its capture, they made repeated efforts to take it and wore themselves out in a series of unsuccessful counter-attacks. ",
"In all, the Italians were estimated to have employed at Keren a total of thirty-nine battalions and thirty-six batteries. ",
"During the whole battle they used over thirty thousand infantry and one hundred and forty-four guns. ",
"Many of these were fresh troops.",
"\n\nGeneral Frusci in his reports, admitted to having lost three thousand men at Keren including General Lorenzini. ",
"The total Italian losses probably were about ten thousand. ",
"He made much of the fact that he had managed to withdraw from Keren the bulk of his infantry and guns; but the fall of Keren had finally shattered the morale of the Italian Army. ",
"At the end of the battle of Keren there were only three battalions and few batteries uncommitted between Keren and Asmara. ",
"Practically all had been staked on holding Keren.",
"\n\nThe British and Indian troops had fought hard and won. ",
"The battle was described by General Platt as \"a ding-dong battle, a soldier's battle, fought against an enemy infinitely superior in numbers, on ground of his own choosing which gave him every bit of observation against the movement of our troops, the positions of our guns and the approaches of our transport\". ",
"And it was won by \"the tenacity and determination of commanders and troops, by\n\n--120--\n\nwhole-hearted cooperation of all ranks, whether forward or back, of whatever race or creed, and by the continuous support given to infantry by the Royal Artillery...\". ",
"The British casualties were not light. ",
"Some 500 officers and 3,000 men had been killed and wounded. ",
"The 4th Indian Division was particularly hard hit. ",
"Yet the determination of the British and Indian troops to fight to victory was to leave its mark upon the Italians and to affect their conduct in the subsequent operations. ",
"They were never really to stand to fight again in the same spirit. ",
"The outcome of the contest in Italian East Africa was no longer in doubt. ",
"There were to be more battles and more victories before Italian East Africa was conquered, but Keren had broken the back of Italian resistance and subsequent operations were easier.",
"\n\nThe conduct of the 4th and 5th Indian Divisions won them ready applause from several quarters. \"",
"The whole Empire\", wrote the British Prime Minister to the Viceroy of India shortly after the victory at Keren, \"has been stirred by the achievement of the Indian forces in Eritrea.........\". ",
"He also congratulated Generals Platt and Cunningham upon \"this timely and brilliant culmination of your memorable and strenuous campaign\".11 Lord Wavell, who had been awaiting the outcome of the battle with anxiety and had flown to the Sudan on 26 March to confer with General Platt, was evidently relieved. ",
"He found the victory \"a fitting climax to the great work in Eritrea of the 4th and 5th Indian Divisions ably commanded by Major-General N. M. de la Beresford-Peirse and Major-General L. M. Heath respectively\". ",
"He could now well think of transferring some of the forces from this theatre to the more important areas of war. ",
"Eritrea had ceased to present a military threat to the Allies."
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"You may recognize Felicia Day as Dr. Horrible's red-haired obsession (or maybe from that appliance commercial). ",
"And if you've been reading this blog, you probably have heard of NASA's Spitzer Space Telescope, which was responsible for last month's discovery of a massive ring around Saturn. ",
"Add the two together and you get the latest video about colliding galaxies from IRrelevant astronomy. ",
"If you find this one funny, and if you are geeky enough to recognize names like Sean Astin and George Takei, you'll probably spend the rest of the day giggling as you watch earlier episodes from the series. ",
"They can be found intermingled with more traditional educational videos on the telescope's YouTube site. ",
"Enjoy!"
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"iCloud Goes Live (as Beta - for Developers)\n\nApple let iCloud go live late Monday, but it’s a beta rollout, and it’s open only to developers. ",
"The beta reveals that some of MobileMe’s Web apps will make the transition to iCloud, and the company also unofficially revealed pricing for adding additional online storage to their iCloud accounts.",
"\n\niCloud Beta\n\niCloud is part semi-backup solution, part file sharing-to-yourself service, and part iTunes distribution system, and that’s just for starters. ",
"The company uses iCloud to make iTunes purchases (Music, Apps, iBooks, and TV Shows for now) available to all of your devices, and it will be at the heart of iTunes Match, Apple’s service for scanning your iTunes library, matching it to its own servers, and then making that content available to you anywhere.",
"\n\nIt’s also at the heart of Versions, the company’s cloud-based file storage and versioning solution introduced in July with the release of OS X Lion. ",
"In addition, Apple is using iCloud to allow users to view their iWork documents (Pages, Keynote, Numbers) on the Web.",
"\n\nWhat’s new in the beta is confirmation that some MobileMe Web apps will making the transition to iCloud, including an address book, an e-mail app, and a calendaring app. ",
"Find My iPhone is there, too, as well as the above-mentioned iWork document viewing feature.",
"\n\nThe other major feature of iCloud is Photo Stream, the ability to have all of your photos go straight to iCloud and then straight out to to all of your other devices. ",
"Like MobileMe before it, your contacts, bookmarks, and calendar information will also be pushed to your devices through iCloud.",
"\n\niCoud comes with 5GB of storage, and your Photo Stream doesn’t count against that total. ",
"9to5Macnoted that Apple has revealed pricing for adding additional storage. ",
"As of this writing, an addition 10GB (for 15GB total) is priced at US$20 per year, 20GB (25GB total) is $40 per year, and 50GB (55GB total) is $100 per year.",
"\n\nThat’s $2 per GB after the first free 5GB of online storage, and comparisons are already being made to Amazon’s Cloud Drive, which charges just $1 per GB for additional storage, though Amazon’s service does far less than Apple’s iCloud.",
"\n\nNo official launch data has been set for iCloud but Apple said at June’s World Wide Developer Conference that it would go live sometime this fall.",
"\n\nThe more I hear about iCloud the more certain I am that I won’t be using it.",
"\n5Gb is so far short of what I need for proper backups it’s laughable. ",
"I use a 2TB drive for TimeMachine.",
"\nI do not want all my music and videos automatically pushed out to all my devices.",
"\nI do not want all my photos automatically pushed out to all my devices.",
"\nI do not want my private documents automatically drifting all over the cloud.",
"\nI’m too concerned about security to want any of that and in any event, my libraries are too big for my devices. ",
"I’ll manage them myself\n\nI just hope that like Ping before it, Apple defaults this to off.",
"\n\nEDIT: after further thought a clarification. ",
"I use MobileMe for two things:\nI host my web site but this will be dropped with the transition to iCloud. ",
"I’ll need to find a new host.",
"\nMy e-mail address is through MobileMe. ",
"However I did so because I liked the .mac address and MobileMe was pushing harder and harder to make me use .me Oh well, I’m getting a lot of SPAM on the old addresses so it’s likely time I switched addresses anyway.",
"\nSo with the transition to iCloud I’ll likely be dropping Apple cloud services completely.",
"\n\nBased on my understanding, iCloud is not meant to be a “proper” backup. ",
"To me, the fact that it *acts* as a backup is incidental. ",
"Its real purpose—and value—is in the syncing. ",
"Indeed, if you don’t want your data synced to iCloud (or any cloud) then this presents a problem in and of itself. ",
"Additionally, it’s not (yet) clear if iCloud will offer any sort of user-managable file-storage, or if all of this will be controlled by apps.",
"\n\nAs to file storage. ",
"It is my understanding that iWork files will be backed up to the iCloud. ",
"I don’t know how it would work, if it can be set to auto, or similar to how iDisk works now. ",
"I guess we will have to wait and see."
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"Drive within a hundred miles of Knoxville, and you’ll see Volunteer Orange everywhere: street signs, grocery store displays, porch flags. ",
"The East Tennessee area code 865 even spells out VOL. ",
"On Saturdays, the streets are jammed at sunrise and boats docked near campus are tied 10-deep into the river. ",
"When kickoff rolls around, over 100,000 people crowd into Tennessee’s Neyland Stadium. ",
"To people here, football is a central part of life—a topic of conversation 365 days a year.",
"\n\nBut the past seven years in Knoxville have not gone as planned. ",
"During that stretch, Tennessee has finished above .500 only twice and has shuffled through four different Head Coaches. ",
"One, who left for USC in the middle of the night, is so reviled in town that the locals named a sewage plant in his “honor.” ",
"Win here, and you become a legend. ",
"Lose, and you better start prepping your resume.",
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"As Tennessee’s Offensive Coordinator for the past two seasons, Bajakian is a household name throughout the Southeast. ",
"Since graduating from Williams two decades ago, Bajakian hasn’t lived in one place for more than three years. ",
"He’s coached at every level from high school to the NFL, including coaching a Super Bowl with the Chicago Bears. ",
"Far from a straightforward rise, Bajakian’s up and down journey illustrates the importance of commitment and hard work when pursuing a dream.",
"\n\nLike every teenager, I wanted to go play professional football. ",
"It became evident early on that that wasn’t going to be a part of my future. ",
"I knew that to stay involved in the game I was going to have to take up coaching.",
"\n\nInitially my thought was that I would become a teacher and a coach. ",
"For winter study my senior year I did an independent study with the coaching staff, however, and really got an itch to coach at the college level. ",
"College coaching jobs are hard to come by so to gain experience I went to a high school and taught math and coached football and baseball.",
"\n\nThen I got an opportunity as a graduate assistant at Rutgers. ",
"From there, it’s been a whirlwind. ",
"Every two or three years, I’ve taken on a new opportunity. ",
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"\n\nThe film premieres on-air and online tonight, starting at 10 p.m. EST (check local listings). ",
"You can watch part One of United States of Secrets, FRONTLINE told the inside story of how the U.S. came to spy on millions of ordinary Americans."
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"Related Art\nA cover apparatus is provided above a vehicle luggage space in a sub-cover structure of Japanese Patent Application Laid-Open (JP-A) No. ",
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"One side section of a frame shape frame is supported so as to be able to swing at the rear edge of the sub-cover, and a hook is provided at another side of the frame.",
"\nThe rear edge of the sub-cover is connected to the cover apparatus by inserting the hook into the groove portion of the hook engaging portion and engaging the hook with the removal prevention portion. ",
"The sub-cover is accordingly disposed (deployed) between the cover apparatus and the seatback, and visibility into the luggage room from between the cover apparatus and the seatback is suppressed (blocked) by the sub-cover.",
"\nIn the sub-cover structure here, configuration is made such that when the sub-cover is pulled out towards the front, the frame swings about an axial line of the one side section, and engagement of the hooks with the hook engaging portion is released. ",
"There is therefore the possibility of the sub-cover coming away from the cover apparatus unintentionally.",
"\nIn order to overcome the problem, as shown in FIG. ",
"6, there is provided a sub-cover structure configured such that the sub-cover does not come away from the cover apparatus even if the sub-cover is pulled. ",
"A cover apparatus 100 is provided in this sub-cover structure with a coupling groove 102 open to the outer peripheral side of the cover apparatus 100, and an engaging wall 104 formed at the lower side of the opening portion of the coupling groove 102. ",
"A substantially plate shaped hook 108 is attached to the rear edge of a sub-cover 106, and a claw portion 110 formed with a substantially U-shaped cross-section is integrally provided to the leading end of the hook 108. ",
"The claw portion 110 opens downwards, and the leading end portion of the claw portion 110 is disposed inside the coupling groove 102, thereby coupling the sub-cover 106 to the cover apparatus 100.",
"\nHowever, in this sub-cover structure too, if the sub-cover 106 is pulled in the direction of the arrow in FIG. ",
"6, the leading end portion of the claw portion 110 is pressed by the engaging wall 104, resiliently deforming the opening claw portion 110 such that the opening dimension of the claw portion 110 is made larger, with the possibility arising of the claw portion 110 passing through the opening portion of the coupling groove 102."
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"\n\nA message from the conference stated: \"Thank you to everyone who made their voices heard concerning SB 175. ",
"It was your witness that made it possible to kill this horrible piece of legislation. ",
"It is because of your willingness to engage the public square that we were able to defeat SB 175!! ",
"Your voices matter and are needed in the public square now more than ever; please remember what we were able to accomplish and continue to be involved and make your voices heard!\"",
"\n\nThe legislation threatened to undo pro-life progress in Colorado. ",
"In an open letter to \"supporters of life,\" Archbishop Aquila described it thus: \"This over-reaching piece of legislation would essentially shut down any attempt to pass life-affirming legislation in Colorado ever again. ",
"More than that, it enshrines the 'right to abortion' into Colorado law. ",
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"It enshrines the culture of death into law and ignores science.\""
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"Q:\n\nDigital signature - how secure is it?",
"\n\nI'm new to asymmetric encryption guys, I read about it thoroughly lately and I don't get one thing.",
"\nIf, say, I have a message, I sign it by first hashing the message, then encrypting it with my private key. ",
"After that I publish message and signature together. ",
"Then if anyone wants to check it, they have to decrypt it with my public key and compare the hash. ",
"\nMy question is: how do they know my public key? ",
"\nIf I send it with message - then anyone can forge it by altering the message, replacing the open key and making a new valid signature. ",
"Or maybe it can be requested from me? ",
"If yes, then what if someone interrupts that request and replace my public key in response with theirs fake one? ",
"\nOne more thing: what if the public key is not available? ",
"For example if there is a system were each node can broadcast its public key - what if some of the nodes are offline for weeks - does it mean their signatures can not be verified? ",
"Maybe their public keys are saved on some kind of centralized database, where you could request my public key by, say, my email. ",
"But this database can be hacked and public key will be replaced by a fake one - and nobody will trust my signatures anymore. ",
"\nYou see, maybe I don't get some particular subtle moment here - an issue of how to trust a genuine public key in any given network system, given that hacker may somehow interrupt any connection and replace messages between nodes (or if it's a centralized DB - public keys may be replaced by hacker).",
"\n\nA:\n\nA public key ultimately needs to be securely exchanged out of band to fulfill the commitment part of the signature process. ",
"\nTypically the public key is pre-distributed where it needs to be used. ",
"As an example, your web browser comes pre-installed with the public keys it needs to validate certificates signed by certificate authorities. ",
"This can be used to obtain new public keys that are not pre-installed. ",
"\nYou are probably looking for Public Key Infrastructure (PKI).",
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"NEW DELHI: The National Investigation Agency (NIA), in its first probe involving an act of terror against an Indian citizen on foreign soil, has filed a case in connection with the March 25 bombing on a gurdwara in Kabul Not only was an Indian national — Tian Singh from New Delhi — killed in the attack apart from 26 others, but one of the attackers is also suspected to be an Indian youth from Kasargod, Kerala . ",
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"About 150 people were inside the Sikh shrine when the attack took place. ",
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"This invention relates to a liquid crystal display device suitable for use in a color display such as a color television set.",
"\nA liquid crystal color display device has the following construction. ",
"A plurality of transparent electrodes are formed on each of two transparent substrates and a color filter is provided over the transparent electrodes on either of the two transparent substrates. ",
"The two transparent substrates are faced to each other with the electrodes-formed sides inside. ",
"An orientational film is formed for orientation, covering the entire surface of that side of each transparent substrate facing the other transparent substrate. ",
"TN (Twisted Nematic) liquid crystal is filled in the space between the orientational films. ",
"A deflecting polarizing plate is provided on the other side of each transparent substrate. ",
"In the liquid crystal display device of the above construction, when voltage is applied to transparent electrodes, the optical characteristic of the liquid crystal at the positions where voltage is applied will change. ",
"Specifically, the liquid crystal transmits light or shields it depending upon the combination of the deflecting axis directions of the two deflection plates. ",
"Thus, a color image is presented on the display device as voltage is applied selectively to transparent electrodes.",
"\nTo prevent deviation by parallax, the color filter is normally positioned as close to the liquid crystal layer as possible. ",
"Liquid crystal color display devices are divided into two types according to the position of the color filter: the one with a color filter provided over the transparent electrodes formed on a transparent substrate, and the one with a color filter provided on a transparent substrate and with transparent electrodes formed over the color filter.",
"\nIn a typical liquid crystal display device, a plurality of X-electrodes are formed on one of two transparent substrates and a plurality of Y-electrodes on the other transparent substrate, the X-electrodes and Y-electrodes being orthogonally arranged and being made to face each other to form display picture elements at the intersections thereof. ",
"The liquid crystal display device of this type is driven in a so-called time division drive method, that is, by scanning the X-electrodes sequentially and applying display or non-display voltage to the Y-electrodes corresponding to the picture elements on the selected X-electrodes. ",
"Liquid crystal materials are relatively slow in response, and have a property that the light transmittance becomes constant after being scanned repeatedly. ",
"For a liquid crystal display device designed for high duty cycle operation and expected to provide a wider visual angle and a higher contrast, however, it is desirable that the light transmittance of the liquid crystal change sharply when applied voltage reaches a specified threshold value.",
"\nIn the liquid crystal color display device with the color filter formed over the transparent electrodes, applied voltage is reduced by the color filter, causing slower change in the light transmittance around the threshold value of applied voltage. ",
"As a result, a clear image cannot be obtained on the display device. ",
"For this reason, the liquid crystal color display device with the transparent electrodes formed over the color filter is more preferable. ",
"For the display device of this type, however, because of the thermal resistance limitation of the color filter, it is not possible to raise the substrate temperature high enough to form transparent electrodes of a small resistance which is essential to a liquid crystal display device of a high duty ratio. ",
"To solve this problem, a liquid crystal display device has been proposed in which the resistance of the transparent electrodes is lowered by forming metal electrodes on the transparent electrodes.",
"\nFIG. ",
"5 is a plan view of a transparent substrate 4 with a color filter 1, transparent electrodes 2 and metal electrodes 3 formed thereon, for use in a typical liquid crystal display device by the conventional art. ",
"FIG. ",
"18 is a sectional view of the transparent substrate 4 cut along the line VI--VI of FIG. ",
"5. ",
"In FIG. ",
"5, transparent electrodes 5 formed on another transparent substrate to be arranged as opposed to the transparent substrate 4 are shown by broken lines. ",
"Referring to FIG. ",
"18, the color filter 1 is formed into a pattern of, say, a red color filter 1R, a green color filter 1G, a blue color filter 1B, a red color filter 1R, and so on. ",
"In FIG. ",
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"\n\nThe Girl Rising: ENGAGE INDIA partnership is launching a two-year initiative with a focused goal of getting more girls to pass Class 10 and increasing secondary school completion rates for girls and reduce gender-based discrimination in India. ",
"The announcement was made at a high-powered event in the American Center, hosted by Chargé d’Affaires Ambassador Kathleen Stephens and attended by Indian Film Stars and Girl Rising ambassadors Priyanka Chopra and Freida Pinto, Holly Gordon – co-founder and CEO at Girl Rising, Samantha Wright, VP of Global Programs at Girl Rising, Lloyd Mathias – CMO at HP India, Ashutosh Chadha, – Director of Corporate Affairs at Intel, Debjani Ghosh – VP Sales and Marketing Group and Managing Director South Asia at Intel Corporation, Neeta Broochra – President at FICCI FLO, Vivek Rangachari – Director & Commissioning Producer at DAR Motion Pictures, Priya Naik – Founder and Joint MD at Samhita Social Ventures, amongst others. ",
"Also present at the event were leading Indian business tycoons and industry figureheads.",
"\n\nCommenting on the initiative, Priyanka Chopra said: “I’ve been a part of the Girl Rising campaign since inception and am honoured to be able to bring this powerful idea to India. ",
"I am also extremely humbled by and grateful for the support from my colleagues in the industry. ",
"All it took was one phone call for me to have these amazing 7 ladies to graciously agree to join us on this journey. ",
"If more girls are educated, all of India stands to gain. ",
"The Girl Rising campaign aims to address that through various innovative initiatives that will not only help create awareness but also create a tangible platform to effect change.”",
"\n\n“Too often, it is social and traditional ideas that are holding girls back. ",
"People just can’t imagine a different future for girls. ",
"The time has come where instead of questioning why we should educate girls, we should be asking why not. ",
"When we know that educating a girl can change the world, why wait?",
"\n\nThe Girl Rising: ENGAGE INDIA partnership is launching a two-year storytelling campaign to increase secondary school completion rates for girls and reduce gender-based discrimination in India with an ambition to get more girls to pass Class 10. ",
"Girl Rising: ENGAGE INDIA will be activated by a new Bollywood version of the widely-acclaimed Girl Rising feature film, reviewed by The New York Times as “one of the hottest cause documentaries in years.” ",
"The film spotlights the stories of nine unforgettable girls around the world, striving against difficult circumstance to achieve their dreams. ",
"It shows audiences what change looks like and inspires change-makers to stand up and get involved.",
"\n\n“Educating girls is not only vital to India’s prosperity and stability, but also represents an unprecedented economic opportunity. ",
"Women are the biggest emerging market ever seen. ",
"They influence 65% of the world’s annual consumer spending–and, right now it is estimated that there are 270 million women and girls under age 25 in India. ",
"Furthermore, by not educating girls equally, it is estimated that India misses out on potential economic growth of about $33 billion dollars per year.”",
"\n\nAbout GIRL RISING\n\nGirl Rising is a global campaign for girls’ education that uses storytelling, including a highly acclaimed feature film, to promote the truth about the transformative power of educating girls and to catalyze support for girls’ education and empowerment. ",
"Praised by The New York Times as “one of the hottest cause documentaries in years,” the groundbreaking 2013 feature film has grown into a powerful movement.",
"\n\nOver the last 18 months, Girl Rising has been embraced by leaders around the world: UN Secretary General Ban Ki-moon, World Bank President Jim Kim, UNESCO’s Irina Bokova, Christine LaGarde from the IMF, the presidents of Chile, Costa Rica and Brazil, U.S. Ambassador to India Nancy J. Powell, the First Ladies of Peru and Uganda, Aung San Suu Kyi, the Cypriot Ministers of Education and Foreign Affairs, International ambassadors and consuls from France, Australia, Ireland, Ethiopia, Afghanistan, Nepal, and Sweden, and many, many more.",
"\n\nAbout\n\nDisclaimer\n\nThe content on this website dumkhum.com (“Website”) are edited and administered by Mr. Hemant Sanganee (“the Owner”). ",
"This Website and all other information and content in the Website and otherwise in connection with this Website are provided on “as-is” and “as available”\nView more.."
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"Q:\n\nVisual Studio gets stuck on opening a sql project\n\nWe are trying to setup a sql project, in a new machine with Windows 7, VS 2010 with SP1 & SSDT 2010 (installed SSDT 2010 from iso image). ",
"But getting the below message when I open the sqlproj.",
"\n'Verifying your model is synchronized with your source files. ",
"Your database will be ready in 12734 operations are completed.'",
"\nAnd the number keeps on increasing. ",
"And it keeps on running in the background.",
"\nTried re-installing SSDT, VS 2010 but no help. ",
"\nCreated a new database project for Northwind db, and had the same issue. ",
"Ran procmon and saw it's just going over and over the same files.",
"\nIt works fine in another system with similar configuration.",
"\nEDIT\nThe issue seems to be related to TFS, if we unbind from TFS it works fine. ",
"But not sure about the exact cause.",
"\nAny suggestion would be really helpful.",
"\n\nA:\n\nMy suggestion is if you are using source control such as Git and you have just switched branches and you are hitting this issue is to use git clean which will remove untracked files (which VS and SSDT are choking up on)\ngit clean -fdx\n\nNot sure what to use if you are on TFS or SVN or HG.. but same idea applies\n\nA:\n\nI deleted the .suo file in the .vs folder in the root of solution directory. ",
" This fixed it for me. ",
" I think this is the best and least damaging answer as it preserves your modified files and some of your other settings (of course some settings such as your start up project will be lost)\n\n"
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"The incidence of ARMs in VAD and ETU groups was 64.8% (59/91) and 45.9% (61/133), respectively (P > .05). ",
"Anorectal malformations were not found in the normal group. ",
"Protein gene product 9.5 and S-100 protein expression in the non-ARM rectums of the VAD group was lower than the ETU (P = .0156 vs P = .0105) and normal groups (P = .0091 vs P = .0024). ",
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"Protein gene product 9.5 and S-100 protein expression was also lower in ARM than non-ARM rectums in the VAD and ETU groups (P < .0001, P = .0203, and P = .0122, respectively). ",
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[
"Q:\n\nJava Play Mustache NPE Error\n\nWe are getting a mustache play error in production (amazon linux EC2 AMI) but not in development (MACs) and we have tried upgrading the jvm, using the jdk instead, and changing from a tomcat deploy model to match our development environments as much as possible but nothing is working. ",
" Please any help would be greatly appreciated. ",
" We have lots of shared code in java and javascript using mustache and it would be a big deal to rewrite everything if we had to ditch mustache on the java side.",
"\n20:48:52,403 ERROR ~ \n@6al2dd0po\nInternal Server Error (500) for request GET /mystuff/people\n\nExecution exception (In {module:mustache-0.2}/app/play/modules/mustache/MustacheTags.java around line 32)\nNullPointerException occured : null\n\nplay.exceptions.",
"JavaExecutionException\n at play.templates.",
"BaseTemplate.throwException(BaseTemplate.java:90)\n at play.templates.",
"GroovyTemplate.internalRender(GroovyTemplate.java:257)\n at play.templates.",
"Template.render(Template.java:26)\n at play.templates.",
"GroovyTemplate.render(GroovyTemplate.java:187)\n at play.mvc.results.",
"RenderTemplate.<init>(RenderTemplate.java:24)\n at play.mvc.",
"Controller.renderTemplate(Controller.java:660)\n at play.mvc.",
"Controller.renderTemplate(Controller.java:640)\n at play.mvc.",
"Controller.render(Controller.java:695)\n at controllers.",
"MyStuff.people(MyStuff.java:183)\n at play.mvc.",
"ActionInvoker.invokeWithContinuation(ActionInvoker.java:548)\n at play.mvc.",
"ActionInvoker.invoke(ActionInvoker.java:502)\n at play.mvc.",
"ActionInvoker.invokeControllerMethod(ActionInvoker.java:478)\n at play.mvc.",
"ActionInvoker.invokeControllerMethod(ActionInvoker.java:473)\n at play.mvc.",
"ActionInvoker.invoke(ActionInvoker.java:161)\n at Invocation.",
"HTTP Request(Play!)",
"\nCaused by: java.lang.",
"NullPointerException\n at play.modules.mustache.",
"MustacheTags._template(MustacheTags.java:32)\n at play.modules.mustache.",
"MustacheTags$_template.call(Unknown Source)\n at /app/views/User/people.html.(line:22)\n at play.templates.",
"GroovyTemplate.internalRender(GroovyTemplate.java:232)\n ... 13 more\n\nA:\n\nSeems the issue is with the threadlocal. ",
"In Prod as per my logs, the session gets initialized with the main thread.",
"\n [2012-06-30 18:35:38,102] INFO 10097[**main**] - Mustache module initialized\n\nHowever, MustacheTag tries to access with various thread like this during request.",
"\n [2012-06-30 17:48:44,669] INFO 66048[**play-thread-1**] - [{module:mustache-0.2}/app/play/modules/mustache/MustacheTags.java:46] _meta() :: MustachePlugin.session():null\n\nSo I changed the implementation of MustachePlugin like this.",
"Changed line commented out:\n //private static ThreadLocal<MustacheSession> session_ = new ThreadLocal<MustacheSession>();\n private static MustacheSession _session = null;\n public static MustacheSession session(){\n //return session_.get();\n return _session;\n }\n public void onConfigurationRead(){\n // some code\n _session = new MustacheSession(compiler, root);\n // some code\n }\n\nAnd it is working fine now in prod mode! ",
"I see no reason why it should have been in a ThreadLocal in the first place as the session gets initialized at startup! ",
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"According to the calibration curve, ITA quantified the reference from 0.40 to about 2.4 μg. ",
"The consistency among the abundance of enzyme/mutants through ITA of proteins in cell lysates prepared under the same conditions supported their consistent immunological reactivity to the antisera. ",
"Specific activities of PAAS/mutants or BFU/mutants in cell lysates through ITA of proteins showed excellent proportionality to those carefully determined after purification. ",
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"\n\n“Apoyamos una auditoría electoral completa por parte de entidades creíbles e internacionalmente reconocidas, y el establecimiento de un Consejo Nacional Electoral independiente”, dijo la portavoz del Departamento de Estado, Heather Nauert, en un comunicado.",
"\n\nEE UU condenó además la acción del régimen venezolano al requerir que los gobernadores recién electos el domingo se sometan a la ilegítima asamblea nacional constituyente (ANC), integrada únicamente por oficialistas, para juramentar su cargo, afirmó Nauert.",
"\n\n“Esta maniobra, que llega después de las fraudulentas elecciones del 15 de octubre, es otro ejemplo del autoritarismo del régimen de Nicolás Maduro, y su desdén por la voluntad del pueblo venezolano”, añadió la portavoz.",
"\n\nLos 18 candidatos oficialistas que resultaron ganadores en la elección de gobernadores que se celebró se juramentaron este miércoles ante la ANC, mientras que los cinco opositores que también triunfaron se negaron a acudir a ese acto.",
"\n\nAl solicitar una auditoría de los resultados del domingo, EE UU se sumó a una petición que ya hicieron este martes los 12 países americanos que forman parte del llamado Grupo de Lima.",
"\n\nEsas naciones (Argentina, Brasil, Canadá, Chile, Colombia, Costa Rica, Guatemala, Honduras, México, Panamá, Paraguay y Perú) solicitaron una auditoría independiente de los resultados con el acompañamiento de observadores internacionales especializados y reconocidos.",
"\n\nDonald Trump denunció el lunes que esas elecciones no fueron libres ni justas, y citó, entre otros factores, la falta de observadores independientes y creíbles, los cambios de último minuto a locales de votación sin notificaciones públicas y la manipulación del diseño de las boletas.",
"\n\n“Mientras que el régimen de Maduro siga comportándose como una dictadura autoritaria, trabajaremos con los miembros de la comunidad internacional e impondremos todo el peso del poder económico y diplomático estadounidense a favor del pueblo venezolano en su intento de restaurar la democracia”, alertó Nauert en su comunicado del lunes.",
"\n\nEste miércoles, Trump habló por teléfono sobre la situación en Venezuela con el presidente argentino, Mauricio Macri."
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"[简体中文](./README.md) | English\n\n<p align=\"center\">\n<a href=\" https://www.aliyun.com\"><img src=\"https://aliyunsdk-pages.alicdn.com/icons/AlibabaCloud.svg\"></a>\n</p>\n\n<h1 align=\"center\">Alibaba Cloud Drcloud SDK for PHP</h1>\n\nIf [Alibaba Cloud SDK for PHP][sdk] is installed, there is no need to install the product dependency package. ",
"This product dependency package is only part of the synchronization from [Alibaba Cloud SDK for PHP][sdk], and its namespace and usage are consistent with [Alibaba Cloud SDK for PHP][sdk].",
"\n\nIf you don't care about file size, we recommend that you install [Alibaba Cloud SDK for PHP][sdk] and update it regularly so as to maintain the latest and most complete product support:\n```\ncomposer require alibabacloud/sdk\n```\n\nThe product can also be installed only:\n> The version of this product is always synchronized with [Alibaba Cloud SDK for PHP][sdk] to ensure that it can switch with [Alibaba Cloud SDK for PHP][sdk] at any time without changing the business code, although the code between different versions of this product may not change.",
"\n```\ncomposer require alibabacloud/drcloud\n```\n\n***\nRefer to document [Alibaba Cloud SDK for PHP][sdk] for more SDK usage.",
"\n\n[sdk]: https://github.com/aliyun/openapi-sdk-php\n"
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"Mitch McConnell: Protest at Louisville restaurant didn't ruin my meal\n\nMitch McConnell | Guest Contributor\n\nShow Caption Hide Caption McConnell, Elaine Chao confronted at Louisville restaurant A man is seen confronting Senate Majority Leader Mitch McConnell and Elaine Chao at Havana Rumba in Louisville, Kentucky. (",
"Video has no sound) Oct. 19, 2018\n\nRecently, we’ve seen several examples that when the far left doesn’t get what it wants through the democratic process, it resorts to intimidation and mob tactics. ",
"This tendency was on full display during the debate over the nomination of Justice Brett Kavanaugh to the U.S. Supreme Court. ",
"Republican Senators and their families were targeted by the mob at their homes, at airports, and in their cars. ",
"They received threatening phone calls and letters. ",
"Death threats spiked. ",
"These were not efforts to engage in civil discourse or to persuade peacefully – these were simply efforts to intimidate.",
"\n\nUnfortunately, these antics and incivility did not stop after Justice Kavanaugh was rightly confirmed.",
"\n\nOn Friday evening, my wife and I were once again the target of the aggressive intimidation while eating at a restaurant in Louisville. ",
"You may have read about it in the Courier Journal, but the article and its video didn’t lay out all the facts. ",
"So let me set the story straight.",
"\n\nRelated column: Mitch McConnell does not get to play the victim in restaurant protest\n\nAs Elaine and I sat at a booth and enjoyed our dinner, a man came in off the street and rushed at us. ",
"Acting alone, he began shouting, slamming his fists on our table, and causing a disruption as others tried to eat. ",
"At one point, he even grabbed my wife’s to-go box off of our table and threw it outside onto the ground.",
"\n\nAlmost immediately, the restaurant’s other customers began rejecting his harassment. ",
"They told him to quiet down or leave. ",
"A few men even approached the aggressor and escorted him to the exit. ",
"We are grateful to our fellow diners and the restaurant staff who helped end the disruption.",
"\n\nBackground: Man dumps McConnell's to-go box on Bardstown Road, witness says\n\nI’m not sure exactly what in my career suggests I would be easily swayed by such a spectacle. ",
"The reality is simple: I will not be intimidated. ",
"But this issue is not really about me, or about any individual elected official. ",
"It’s about something larger: The mob mentality that is being systematically fed and encouraged by the far left all across our nation.",
"\n\nThe threats and intimidation are even being cheered on by prominent, leading Democrats. ",
"Former Secretary of State Hillary Clinton said there should be no civility until her party was back in power. ",
"Eric Holder, President Obama’s Attorney General, recently told a group that “when they go low, we kick ‘em. ",
"That’s what this new Democratic Party is about.”",
"\n\nSo the extreme left’s playbook is quite clear. ",
"But even while the far left is forming its mobs, the Senate is continuing our productive work for the American people. ",
"As angry protesters climbed over barricades, disregarded and disrespected the police, and attempted to shout down anyone who disagreed, I was proud to prioritize the passage of landmark opioids legislation. ",
"Similarly, the Senate recently passed important aviation infrastructure legislation. ",
"The president just signed our water infrastructure bill into law. ",
"And we will continue to confirm more of the president’s highly qualified judicial nominees this year. ",
"Our work in the Senate is too important to the country to back down in the face of these mob antics.",
"\n\nWhen the Senate is not in session, I frequently travel across this Commonwealth listening to the men and women who I represent in Washington. ",
"For instance, this week I traveled to Eastern Kentucky to visit with workers at a manufacturing facility, small business owners and community leaders, and opioid treatment professionals at the University of Pikeville. ",
"My office receives thousands of calls, letters and emails every week from Kentuckians. ",
"While we may not always agree, I do appreciate every person who engages in the democratic process in a civil way.",
"\n\nIn fact, while Elaine and I waited for our table, a social worker approached us. ",
"She wanted to talk about the devastating effects of opioid addiction she witnessed firsthand. ",
"We discussed her work and how important this issue is to Kentucky and the country. ",
"That’s how our government is supposed to work – with reasoned judgment and respect, not with intimidation and extreme mob behavior.",
"\n\nColumn: Trashing McConnell's food went too far. ",
"How to protest and not be an idiot.",
"\n\nIt’s time for each of us to decide what kind of country we want. ",
"One side can continue to hurl mud, hatred, and toxic behavior until we reach a breaking point. ",
"Or, those with strong beliefs on both sides of an issue can speak up in a civil way.",
"\n\nI enjoyed my meal in Louisville on Friday night, and I will continue to eat with my friends and family at my favorite Kentucky restaurants. ",
"I appreciate those who spoke up against the shameful behavior. ",
"We hope other customers weren’t too inconvenienced by the extremist left-wing tantrums.",
"\n\nI was not the first senator confronted, and I unfortunately likely won’t be the last. ",
"But the Senate will not be intimidated by the antics of far-left protesters, and we will continue our important work."
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[
"Introduction {#s1}\n============\n\nPlacentation requires the complex regulation of trophoblast proliferation, differentiation and invasion. ",
"This enables the trophoblasts to breach the uterine luminal epithelium and colonize the endometrium and its vasculature in order to sequester a blood supply for the developing placenta. ",
"Impaired placental invasion, development and function have been implicated in several complications of pregnancy, such as unexplained miscarriage ([@DMP046C97]), pre-eclampsia, intrauterine growth restriction (IUGR) ([@DMP046C96]), placental abruption ([@DMP046C34]), pre-term labour with intact membranes ([@DMP046C100]), premature rupture of the membranes ([@DMP046C99]) and stillbirth ([@DMP046C161]).",
"\n\nIn humans, endovascular cytotrophoblasts (CTBs) invade and initially plug the uterine spiral arterioles, so there is little to no maternal blood flow to the intervillous space (IVS). ",
"Paradoxically, despite oxygen being essential for late gestation placental function and fetal growth, the early placenta and embryo differentiate in a relatively low oxygen environment. ",
"However, at about 11 weeks of gestation the arteriole plugs are displaced and maternal blood flow commences ([@DMP046C14]). ",
"Extravillous CTBs (EVTs) replace the maternal endothelium and the spiral arterioles are remodelled, dramatically increasing in diameter and compliance and are no longer responsive to vasoactive molecules in the maternal circulation. ",
"This and expansion of the uterine vascular tree, permit the 12-fold increase in uterine blood flow that occurs from the non-pregnant state to provide for the demands of the growing fetus later in gestation ([@DMP046C116]). ",
"However, if trophoblast differentiation, invasion and/or vascular remodelling are impaired, pregnancy complications can occur. ",
"In pre-eclampsia and some miscarriages, for example, insufficient trophoblast invasion and vascular remodelling in the first trimester paradoxically promote premature blood flow into the IVS leading to reduced maternal blood flow to the placenta later in pregnancy ([@DMP046C97]; [@DMP046C147]; [@DMP046C196]; [@DMP046C87], [@DMP046C88]). ",
"Hypoxia is therefore implicated as a key regulator of placental morphogenesis and function. ",
"In normal pregnancy, a low oxygen environment in the placenta is physiological and necessary in the first trimester but when it occurs later in gestation it is pathological and associated with common complications of pregnancy.",
"\n\nHypoxia inducible factors (HIFs) are key regulators of placental vascularization and invasion as well as trophoblast differentiation and thus are essential to placental development. ",
"It is well known that HIFs mediate the response to hypoxia, however, it is increasingly apparent that this regulation is highly complex and, furthermore, that these transcription factors can be regulated by non-hypoxic stimuli. ",
"Therefore, in addition to being potential mediators of the effects of variation in oxygen supply on placentation, HIFs may also be involved in the regulation of placental development through their interactions with hormones, growth factors and cytokines. ",
"This review will examine what is known about the regulation of placental development and function by oxygen in both normal and abnormal pregnancies. ",
"Furthermore, it will elucidate mechanisms of acute and prolonged hypoxic regulation, as well as non-hypoxic regulation, of HIFs and what role these may play in the control of placental differentiation, growth and function in both normal and pathological pregnancies. ",
"In addition, we will identify novel interactions which may regulate placental development and suggest new areas for research.",
"\n\nMethods {#s2}\n=======\n\nHypoxic regulation of HIF activity in other systems has been extensively reviewed over many years. ",
"Therefore, we provide a brief overview of this area. ",
"An extensive online search of published articles on HIFs and oxygen in the placenta was undertaken. ",
"The Pubmed database was consulted using combinations of the following search terms: placenta, trophoblast, pregnancy, HIF, oxygen, hypoxia, non-hypoxic regulation, angiogenesis, invasion and transport. ",
"Where possible we have limited publications to those involving human placentation. ",
"The articles were then selected based on relevance and quality after discussion between the authors. ",
"References of selected articles were also hand searched for additional relevant citations. ",
"HIF is thought to be regulated at the post-translational level and thus articles reporting HIF nuclear localization or DNA binding were given greater weighting. ",
"However, as reported in this review, emerging evidence suggests that HIF may also be regulated at the transcriptional level and we felt that these reports, although scarce, were highly novel and worth inclusion, despite the lack of data on HIF nuclear localization or DNA binding.",
"\n\nHypoxia inducible factors {#s3}\n=========================\n\nHIFs are a family of basic Helix--Loop--Helix transcription factors that mediate the response to changes in cellular oxygen. ",
"HIF-1 is a heterodimer consisting of a HIF-1α subunit bound to the aryl hydrocarbon nuclear translocator (ARNT), which is also known as HIF-1β ([@DMP046C177]; [@DMP046C155]). ",
"Following hypoxia-induced nuclear translocation and dimerization, HIF is able to bind to the hypoxia response element (HRE) of target genes, which has the core consensus sequence 5′-CGTG-3′, in responsive genes ([@DMP046C137]). ",
"HIFs mediate the expression of a wide variety of genes that play critical roles in erythropoiesis, angiogenesis, glucose transport and glycolysis ([@DMP046C181]; [@DMP046C155]; [@DMP046C149]). ",
"In mammals, three genes have been shown to encode HIF-α subunits. ",
"The expression of HIF-1α is ubiquitous whereas the expression of its paralogs, HIF-2α ([@DMP046C37]; [@DMP046C44]; [@DMP046C170]) and HIF-3α ([@DMP046C64]) are more restricted ([@DMP046C181]; [@DMP046C160]; [@DMP046C32]). ",
"These data indicate that HIF-1 plays a general role in homeostasis whereas HIF-2 and HIF-3 may play more specialized roles ([@DMP046C181]; [@DMP046C160]).",
"\n\nOxygen-regulated HIF stabilization {#s3a}\n----------------------------------\n\nThe process of HIF-1α activation has been studied extensively over the past few years and includes both enhanced protein stability and transcriptional activity. ",
"In well-oxygenated cells, HIF-1α has a half-life of \\<5 min ([@DMP046C178]). ",
"Under normoxic conditions the α subunit is hydroxylated at conserved proline residues (HIF-1α Pro^564^ and Pro^402^) ([@DMP046C81]; [@DMP046C82]; [@DMP046C117]) contained within a unique oxygen-dependent degradation domain that critically controls protein stability ([@DMP046C75]; [@DMP046C164]; [@DMP046C74]; [@DMP046C22]). ",
"The enzymes promoting the hydroxylation of these residues are prolyl-4-hydroxylases (PHDs) of which there are three isoforms, PHD1, PHD2 and PHD3 ([@DMP046C12]; [@DMP046C38]; [@DMP046C82]). ",
"These enzymes have an absolute requirement for Fe(II) as a cofactor, and molecular oxygen as a co-substrate, but do not require ATP or NAD (P) ([@DMP046C82]). ",
"The requirement of the PHD for molecular oxygen means that this reaction can act as an 'oxygen sensor' ([@DMP046C126]).",
"\n\nOnce the proline residues of HIF-1α are hydroxylated, the von Hippel--Lindau (VHL) tumour suppressor gene product (pVHL) is able to bind ([@DMP046C81]; [@DMP046C82]; [@DMP046C126]). ",
"pVHL is then able to regulate HIF-1α proteolysis ([@DMP046C118]) by acting as the recognition component of an E3 ubiquitin protein ligase complex ([@DMP046C109]; [@DMP046C28]; [@DMP046C132]) to mediate polyubiquitination and proteasomal degradation of HIF-1α under normoxic conditions ([@DMP046C156]; [@DMP046C75]; [@DMP046C90]; [@DMP046C166]).",
"\n\nRegulation of HIF activity {#s3b}\n--------------------------\n\nThe second means of HIF inhibition during normoxia involves the hydroxylation of a conserved asparagine residue ([@DMP046C105], [@DMP046C106]) by factor inhibiting HIF-1 (FIH-1), an asparaginyl hydroxylase ([@DMP046C114]; [@DMP046C71]; [@DMP046C105], [@DMP046C106]). ",
"Therefore, the hypoxic regulation of HIF requires firstly the stabilization of the HIF-1α subunit and secondly its activation ([@DMP046C124]). ",
"Like other known hydroxylase enzymes, FIH-1 is an Fe(II)-dependent enzyme that uses molecular oxygen to modify its substrate ([@DMP046C105], [@DMP046C106]). ",
"When oxygen is available, FIH-1 hydroxylates the α subunit, inhibiting the interaction of HIF-1α and HIF-2α with the transcriptional co-activators p300/CBP whereas during hypoxia the non-hydroxylated HIF is free to bind to p300/CBP ([@DMP046C6]; [@DMP046C33]; [@DMP046C49]; [@DMP046C105], [@DMP046C106]).",
"\n\nIn addition to FIH-1, other co-factors can impact on HIF function. ",
"Specifically, p300/CBP interacting transactivator with ED-rich tail 2 (CITED2) is a negative regulator of HIF function. ",
"CITED2 actively competes with HIF-1 for p300/CBP binding ([@DMP046C50]). ",
"Furthermore, *Cited2* expression is activated through a HRE in its promoter under hypoxic conditions ([@DMP046C10]) which suggests a possible negative feedback to HIF transcriptional activity. ",
"CITED2 may play an important role in regulating HIF function during placentation as CITED2 null mice have impaired trophoblast differentiation and fetal vascularization of the placenta ([@DMP046C187]).",
"\n\nPlacental oxygenation {#s4}\n=====================\n\nThere has been much debate in recent years as to whether the term hypoxia should be used when discussing the oxygen tension in the placenta. ",
"Therefore, it is important to outline how we perceive hypoxia and normoxia during placental development. ",
"For the purposes of this review we have used the term hypoxia only when the oxygen concentration is lower than that to which the placenta is normally exposed. ",
"For example, as will be discussed, the first trimester placenta normally develops in a low oxygen environment and so in this case the oxygen tension is physiologically normoxic, even though it is lower than that experienced later in gestation. ",
"This is in contrast to, for example, a term placenta that is experiencing abnormally low oxygen levels and is therefore classified as hypoxic or ischemic.",
"\n\nPhysiologically low oxygen in early placental development {#s4a}\n---------------------------------------------------------\n\nIn 1987, Hustin and Schaaps reported that maternal blood flow to the IVS was not fully established until ∼ 11--12 weeks of gestation ([@DMP046C77]). ",
"The use of Doppler ultrasound during pregnancy confirmed that there is very little blood flow within the IVS until 11--12 weeks of gestation ([@DMP046C46]; [@DMP046C29]) due to CTBs initially plugging the maternal spiral arterioles. ",
"This is consistent with acid-base and respiratory gas values in the fetal circulation and placental tissue during the first trimester ([@DMP046C86]). ",
"At about 11 weeks of gestation the arteriole plugs are displaced and blood flow commences ([@DMP046C77]; [@DMP046C14]). ",
"The onset of maternal blood flow is progressive, it starts at the periphery of the placenta and gradually extends towards the centre ([@DMP046C87], [@DMP046C88]). ",
"As a result, the oxygen tension within the IVS rises from 18 mmHg (2.5%) at 8 weeks to ∼60 mmHg (8.5%) at 12 weeks ([@DMP046C150]; [@DMP046C85]; [@DMP046C13]), resulting in a burst of oxidative stress in the placenta, particularly in the syncytiotrophoblast (STB) ([@DMP046C85]). ",
"This switch to a well-oxygenated environment serves a physiological role in stimulating trophoblast differentiation. ",
"However, early onset of maternal blood flow into the IVS results in a premature increase in placental oxidative stress ([@DMP046C87], [@DMP046C88]) and is associated with early pregnancy loss ([@DMP046C78]; [@DMP046C84]; [@DMP046C87], [@DMP046C88]). ",
"This premature onset of blood flow occurs prior to the establishment of robust mechanisms to ameliorate oxidative stress since the placenta only contains low levels of antioxidant enzymes at 8--10 weeks of gestation ([@DMP046C179]; [@DMP046C180]). ",
"Therefore, adequate trophoblast invasion and 'plugging' of the uterine arterioles resulting in a low oxygen environment in early pregnancy are essential for normal embryonic and placental development.",
"\n\nThe above data suggest that trophoblast invasion early in pregnancy determines placental oxygenation. ",
"The question then is what causes inadequate trophoblast invasion in pathological pregnancies? ",
"Indeed there are many potential regulators of trophoblast invasion including trophoblast genotype, various growth factors and cytokines and interactions with maternal immune cells. ",
"Perhaps to some extent it is also true that the oxygen environment determines optimal trophoblast invasion. ",
"Oxygen concentration is a major influence on the balance between CTB proliferation and invasion in cultured explants of early gestation human placentas.",
"\n\nCulturing 5--8-week-old placental villous explants in a low oxygen environment (2 or 3% O~2~) stimulates EVT outgrowth associated with increased trophoblast proliferation compared with explants in a well-oxygenated environment (20% O~2~) ([@DMP046C56]; [@DMP046C19], [@DMP046C20]). ",
"It has therefore been proposed that early in the first trimester (prior to 8 weeks) a low oxygen environment causes CTBs to proliferate but prevents their differentiation along the invasive pathway ([@DMP046C56]; [@DMP046C19], [@DMP046C20]; [@DMP046C17]). ",
"Similar conclusions were drawn from using villous explants from 8 to 14 weeks gestation cultured at 2--3, 8 or 20% oxygen ([@DMP046C55]; [@DMP046C159]). ",
"In contrast, culture of placental samples from 8--10, 12--14 to 16--18 weeks gestation in 3% O~2~ inhibited EVT invasion, with no change in cell proliferation, and increased apoptosis at 3 and 8% oxygen compared with 20% O~2~ ([@DMP046C107]). ",
"Similarly, culture of 8--12 week villous explants in 1.5% oxygen resulted in fewer explants producing EVT outgrowths than those in 8% O~2~ and a decrease in the area of outgrowth and number of cells that these explants produced ([@DMP046C83]).",
"\n\nUtilizing a different *in vitro* technique involving culture of myometrial spiral arteries with fluorescently labelled EVTs, culture in 3% oxygen suppressed EVT invasion regardless of the route (interstitial or endovascular) compared with those cultured in 17% oxygen ([@DMP046C31]). ",
"However, there was more endovascular EVT invasion than interstitial invasion in 17% oxygen. ",
"These studies demonstrate conflicting data on the role of oxygen in the regulation of trophoblast function particularly regarding trophoblast proliferation, apoptosis and invasion. ",
"This may result from differences in media composition, the substrate the samples are grown on, oxygen levels used in the experiment or the gestational age of the trophoblast. ",
"In the future we would recommend that at a minimum, researchers include a group exposed to 5--10% oxygen in all studies. ",
"This is physiological for the placenta from 10 to 12 weeks onwards and will make results from different studies easier to interpret. ",
"Having only a control group exposed to 20% oxygen, which although a standard culture condition, is actually hyperoxic, and comparing this to a low oxygen tension, such as 2%, is only relevant when comparing results with the literature and makes data much more difficult to interpret and relate to the *in vivo* situation.",
"\n\nFurthermore, some studies suggest that culture of HTR-8/SVneo cells (a human first trimester cytotrophoblast cell line) in low (1%) oxygen conditions promotes invasion of these cells when compared with culture under standard conditions (20% oxygen) ([@DMP046C62]). ",
"In contrast, there has also been a report that culture of HTR-8/SVneo cells in 2% oxygen decreases trophoblast invasion and increases cell proliferation compared with those cultured in 20% oxygen ([@DMP046C98]). ",
"In a similar study, the invasiveness of HTR-8/SVneo cells was increased after 24 h but inhibited by 72 h in culture ([@DMP046C108]). ",
"The presence of serum, the addition of plasminogen or other factors, the reduced oxygen levels, or the use of a different invasion assay in the Graham *et al*. ([",
"@DMP046C62]) study may account for the different results observed. ",
"Microarray and real-time RT--PCR analyses of HTR-8/SVneo cells exposed to either 20 or 1% oxygen have revealed several genes that encode proteins involved in cell migration, angiogenesis and apoptosis, as well as anti-invasive factors which are up-regulated in low oxygen ([@DMP046C103]), suggesting that a low oxygen environment may 'fine-tune' trophoblast differentiation.",
"\n\nImportantly, it is difficult to relate these *in vitro* observations to the situation that occurs *in vivo*, especially when there is such an array of conflicting evidence in the literature. ",
"It is clear that *in vivo*, invading trophoblast cells are exposed to an oxygen gradient as they migrate from the trophoblast cell column into the maternal decidua. ",
"Invading CTBs respond to this increased oxygen availability by altering the expression of various cell adhesion molecules and proteases, promoting further migration. ",
"We suggest that future research efforts are directed toward assessing whether these current *in vitro* models truly reflect the environment *in vivo*, by matching gestational age and oxygen concentration as much as possible. ",
"Additionally, a much more detailed characterization of placental development as it occurs *in vivo* is required (including trophoblast differentiation, invasion, proliferation and vasculogenesis) as well as of the molecules involved in the regulation of these events and their interaction (e.g. growth factors, cytokines, oxygen levels). ",
"Of course this has proven difficult, since there is a lack of early gestation samples for which the pregnancy outcome is known.",
"\n\nPlacental hypoxia late in pregnancy {#s4b}\n-----------------------------------\n\nInsufficient trophoblast invasion and defective vascular remodelling of the uterine spiral arteries in the first trimester can lead to increased rate of blood flow, which damages the villous architecture, and an increased risk of spontaneous vasoconstriction and ischemia-reperfusion injury resulting in oxidative stress ([@DMP046C15]). ",
"This causes impaired placental perfusion and hence has been assumed to result in chronic placental ischemia and hypoxia later in gestation, which is detrimental to pregnancy success and may lead to pre-eclampsia and/or IUGR, and in some cases will result in preterm delivery ([@DMP046C21]; [@DMP046C176]). ",
"Although the preeclamptic and IUGR placentas are thought to be hypoxic, to date there have been no direct measurements to support this assumption. ",
"Interestingly, in pregnancies at high altitude, where placental hypoxia has been considered to be exacerbated, infant birthweight is decreased, primarily due to a slowing of fetal growth in the third trimester (reviewed in [@DMP046C190]; [@DMP046C127]), and these pregnancies have an increased incidence of pre-eclampsia. ",
"Subsequently, there is also an increased incidence of perinatal and infant mortality and morbidity in pregnancies at high altitude. ",
"Importantly, placentas from uncomplicated pregnancies at high altitude show no indication of significant hypoxic stress at term compared with placentas from pregnancies at low altitude and appear to have successfully adapted to the lower oxygen atmosphere ([@DMP046C171]; [@DMP046C192], [@DMP046C193]). ",
"It is unclear then whether these placentas can actually be considered hypoxic and it will be important in future to determine why some placentas apparently adapt to the hypoxic environment and others do not.",
"\n\nThus, oxygen appears to play a critical role in the development of pregnancy complications and is a key mediator of placental development and function. ",
"During pregnancy a low oxygen environment can result in different outcomes depending on the timing of exposure in pregnancy, the severity of the hypoxic exposure and the duration. ",
"The exact mechanism by which trophoblasts sense oxygen tension is currently unclear. ",
"However, several potential pathways have been identified: these pathways often utilize redox-sensitive transcription factors, of which the HIF family is the best characterized in trophoblasts.",
"\n\nExpression and function of HIFs in the placenta {#s5}\n===============================================\n\nBoth HIF-1α and HIF-2α proteins are constitutively expressed in the human placenta. ",
"In the first trimester, HIF-1α and -2α have been localized in the STB, villous CTB and fetoplacental vascular endothelium ([@DMP046C137]; [@DMP046C57]), consistent with the low oxygen environment of the placenta during the first trimester of pregnancy, but their abundance decreases significantly with gestational age ([@DMP046C19], [@DMP046C20]; [@DMP046C137]; [@DMP046C17]). ",
"More specifically [@DMP046C79]) have described in detail the dynamic expression of HIF and HIF regulators during placental development. ",
"HIF-1α and VHL mRNA and protein are present throughout gestation, with levels peaking at 7--10 weeks of gestation, when the oxygen tension is low, and declining thereafter ([@DMP046C79]).",
"\n\nDuring early pregnancy, HIF-1α can be immunolocalized to CTBs and EVTs while VHL is present in STB. ",
"By 10--12 weeks, HIF-1α disappears, coinciding with an increase in expression of VHL in the CTB and an increase in VHL:HIF-1α binding throughout the placenta ([@DMP046C79]). ",
"The expression of ARNT and HIF-2α mRNA and protein are present and stable throughout gestation ([@DMP046C79]). ",
"The PHD enzymes (PHD1, 2, 3) are also dynamically expressed in an oxygen dependent fashion, peaking at 10--12 weeks gestation ([@DMP046C79]). ",
"Previous reports by others have found slightly different results. ",
"In 2000, Rajakumar *et al*. ",
"reported that the levels of *Hif-1α* mRNA in the placenta do not change across gestation, while *Hif-2α* mRNA abundance increases as gestation proceeds ([@DMP046C137]). ",
"However, it would be most pertinent to quantify HIF-1α and HIF-2α proteins and determine their cytoplasmic versus nuclear localization and DNA binding in the placenta across gestation in order to understand HIF-1 activity.",
"\n\nIn a preliminary report examining pregnancies at high altitude, HIF-1 DNA binding (measured by enzyme-linked immunosorbent assay) and HIF-associated proteins were unchanged compared with placentae from low altitude pregnancies ([@DMP046C171]), leading to the conclusion that there was placental adaption to the hypoxic environment. ",
"However, in a more recent and comprehensive study, HIF-1α and VHL mRNA and protein levels were significantly increased in placentae from high altitude pregnancies, whereas *Hif-2α* and *Arnt* levels are unchanged ([@DMP046C192], [@DMP046C193]). ",
"Similarly, HIF-1α and HIF-2α are over-expressed in the villous placenta of women with pre-eclampsia compared with normal term pregnancies ([@DMP046C138]; [@DMP046C140]), with the expression of HIF-1α in villous and extravillous trophoblast cells being similar to the expression in trophoblasts prior to exposure to increased oxygen in first trimester ([@DMP046C17]). ",
"Oxygen-dependent down-regulation of HIF-1α and -2α protein is impaired in pre-eclampsia ([@DMP046C139]), likely a result of both increased formation and decreased degradation owing to proteosome dysfunction ([@DMP046C143]). ",
"Consistent with this, others have reported enhanced placental expression of HIF target genes, including *Vegf*, in pregnancies complicated by pre-eclampsia and IUGR ([@DMP046C70]), which maybe suggestive of a vasculo-adaptative response to chronic hypoxia at the fetoplacental--maternal interface. ",
"Both HIF-1α and HIF-2α are therefore in an ideal position to regulate placental development throughout gestation in both normal and pathological pregnancies.",
"\n\nDifferential regulation of HIF-1α and HIF-2α in acute versus prolonged hypoxia {#s6}\n==============================================================================\n\nThe degradation of the HIF-α protein and its stabilization under hypoxia has been the focus of much research in the last 10 years. ",
"In particular, it is apparent that HIF-1α and HIF-2α may respond differently depending on the length and severity of hypoxic exposure. ",
"HIF-2α is expressed to a higher degree than HIF-1α in a number of endothelial, fibroblast-like and epithelial cell lines in normoxic conditions ([@DMP046C185]). ",
"In addition, HIF-2α is increased to a greater extent than HIF-1α following exposure to mild hypoxia (5% O~2~) ([@DMP046C185]; [@DMP046C73]). ",
"It has now been proposed that HIF-1α stabilization in hypoxia (1% O~2~) is an acute response, which is diminished under prolonged periods of low oxygen exposure (reviewed in [@DMP046C111]). ",
"Conversely, HIF-2α protein levels are increased under mild hypoxia (5% O~2~) and continue to increase with time, thereby playing an important role in mediating effects on gene expression under conditions of prolonged exposure to low oxygen. ",
"In addition, it is likely that a different set of HIF targets are up-regulated in response to acute versus prolonged hypoxia but this phenomenon is yet to be examined in the placenta.",
"\n\nDifferential regulation of the mRNA for the α subunits has been reported in response to acute and chronic hypoxia. ",
"For instance, in rats, *Hif-3α*, but not *Hif-1α* or *Hif-2α*, mRNA levels increase in the cerebral cortex, hippocampus, lung, heart, liver and kidney after 2 h of *in vivo* hypoxic exposure but no change was seen within 30 min ([@DMP046C68]). ",
"In contrast, a previous study had shown that *Hif-1α* mRNA in rat and mouse brain, kidney and lung was up-regulated within 30 min of hypoxia treatment *in vivo*, but returned to baseline after 4 h ([@DMP046C184]). ",
"Similarly, Wang *et al*. ",
"showed that hypoxia induces the expression of *Hif-1* mRNA *in vitro* but this is diminished by longer periods of hypoxia ([@DMP046C178]; [@DMP046C175]). ",
"These studies suggest that *Hif-1α* mRNA is transiently increased in response to hypoxic stimuli. ",
"Consistent with this, others have reported unaltered *Hif-1α* mRNA levels in mice in response to 4 h of hypoxia *in vivo* ([@DMP046C182]).",
"\n\nIn 1999, a naturally occurring antisense transcript of HIF-1α (*asHif-1α*) was discovered in human renal cancer ([@DMP046C169]). ",
"More recently, *asHif-1α* was identified in the kidney, liver, testis, brain, lung, spleen, heart and skeletal muscle of rodents ([@DMP046C154]) and specifically in the mouse decidua and trophoblasts early in gestation ([@DMP046C135]). ",
"It has been suggested that asHIF-1*α* exposes AU rich elements in the 3′untranslated region of *Hif-1α* mRNA which decreases the stability of *Hif-1α* mRNA (Fig.",
" [1](#DMP046F1){ref-type=\"fig\"}), impairing HIF-1α protein translation and expression ([@DMP046C153]). ",
"Conversely, *Hif-2α* mRNA is not destabilized by asHIF-1α owing to the lack of AU rich elements ([@DMP046C175]). ",
"In fact, *Hif-2α* transcription can increase in hypoxia when it increases its own promoter activity ([@DMP046C157]). ",
"Since *asHif-1α* contains a putative HRE it is assumed that both HIF-1 and HIF-2 are involved in the regulation of *asHif-1α* expression thus creating a negative feedback loop of HIF regulation under prolonged hypoxia (Fig.",
" [1](#DMP046F1){ref-type=\"fig\"}) ([@DMP046C153]; [@DMP046C175]).",
"\n\n{#DMP046F1}\n\nIn the placenta, some evidence of differing responses to acute versus prolonged hypoxic exposure can be found but to date no studies have examined this directly. ",
"Human placental villous explants from 5 to 8 weeks gestation, cultured at 3% oxygen demonstrated significantly greater mRNA expression of *Hif-1α* when compared with explants cultured at 20% oxygen, after 24 h of culture ([@DMP046C19], [@DMP046C20]). ",
"First trimester or term villous explants exposed to 2% oxygen for 3--24 h showed increases in HIF-1α and HIF-2α protein expression, with no change in their mRNA levels, and increased HIF-1 DNA binding activity ([@DMP046C137]). ",
"However, in cultured 6--8 week placenta it was HIF-2α protein that dramatically increased following 48 h exposure to 2% oxygen, whereas HIF-1α levels were the same in those explants cultured under hypoxic and normoxic conditions ([@DMP046C57]). ",
"These *in vitro* studies have yielded inconclusive results, which may result from the use of different oxygen tensions, culture conditions or duration of exposure.",
"\n\nIn the future it will be important to investigate the effect of different oxygen concentrations and prolonged versus acute hypoxic exposure on HIF mRNA and protein and their targets throughout placental development in more detail. ",
"In addition, asHIF-1α expression and localization in the human placenta has yet to be elucidated. ",
"In the mouse, we have found that culture of early trophoblasts in 1% oxygen for 3 days significantly decreases *Hif-2α*mRNA abundance whereas *Hif-1α*mRNA levels remain unchanged ([@DMP046C135]). ",
"Furthermore, our data suggest that the differential effects on *Hif-1* and *2α* mRNA levels may be mediated by an increase in *asHif-1α* mRNA in trophoblasts cultured in 1% oxygen. ",
"Research in this area may be of critical importance when considering the role of HIFs in prolonged hypoxic exposure of the placenta, such as occurs in pre-eclampsia and pregnancy at high altitude.",
"\n\nNon-hypoxic induction of HIF-1α {#s7}\n===============================\n\nHIF-1α can also be induced by factors other than hypoxia, including hormones, cytokines and growth factors (Table [I](#DMP046TB1){ref-type=\"table\"}), many of which are expressed in the placenta or are increased in the maternal circulation during pregnancy. ",
"Indeed, HIF-1α protein is up-regulated in a well-oxygenated environment (∼20% oxygen) during Matrigel induced endovascular differentiation in a human EVT cell line ([@DMP046C52]). ",
"The mechanisms, however, are unknown.",
"\n\n###### \n\nNon-hypoxic regulators of HIFs.",
"\n\n Non-hypoxic stimuli Action Proposed mechanism Found in placenta (Yes/No) HIF target gene (Yes/No) References\n -------------------------------- ------------------------------------------------------------ ------------------------------------------------- ---------------------------- -------------------------- -------------------------------------------------------------------------------------\n Progesterone Increased *Hif-1α* mRNA, or HIF-1α and HIF-2α protein ? ",
" Yes No [@DMP046C32]), [@DMP046C162])\n Estrogen Increased *Hif-2α* mRNA ? ",
" Yes No [@DMP046C32])\n Prostaglandin E2 Increased HIF-1α protein ERK, AKT, C-SRC tyrosine kinase activity Yes No [@DMP046C51])\n Angiotensin II Increased HIF-1α mRNA and protein AT1R, PKC, ROS activation Yes No [@DMP046C146]), [@DMP046C134]), [@DMP046C5])\n Thrombin Increased HIF-1α mRNA, protein and activity AT1R, PKC, ROS activation Yes No [@DMP046C146]), [@DMP046C60]), [@DMP046C134])\n Platelet derived growth factor Increased HIF-1α protein and activity Via ROS activation Yes No [@DMP046C146]), [@DMP046C60])\n Transforming growth factor-β1 Increased HIF-1α protein via inhibiting HIF-1α degradation Decreased VHL mRNA and protein via Smad pathway Yes Yes [@DMP046C61]), [@DMP046C121])\n Endothelin-1 Increased HIF-1α protein ? ",
" Yes Yes [@DMP046C163])\n Epidermal Growth Factor Increased HIF-1α protein Via PI3K Yes No [@DMP046C89])\n RhoA Increased HIF-1α protein ? ",
" Yes No [@DMP046C67])\n Mechanical stretch Increased HIF-1α mRNA and protein Via p42/p44 MAPK pathway [@DMP046C23])\n Interleukin-1β Increased HIF-1 protein ERK 1/2 activation Yes Yes [@DMP046C69]), [@DMP046C92]), [@DMP046C136])\n Tumor Necrosis Factor-α Increased HIF-1 DNA binding Activation of HIF co-activators, NFκB pathway Yes No [@DMP046C200], [@DMP046C69]), [@DMP046C76])\n Insulin Increased *Hif-3α* mRNA, HIF-1α and HIF-3α protein Via PI3 and MAPK pathways Yes No [@DMP046C194]), [@DMP046C42]), [@DMP046C89]), [@DMP046C68]), Treins *et al*. (",
"2002)\n Insulin-like Growth Factor-I Increased HIF-1α and HIF-2α protein Via PI3 and MAPK pathways or through PHD2 Yes No [@DMP046C194]), [@DMP046C42]), [@DMP046C25]), Richard *et al*. (",
"2000)\n Insulin-like Growth Factor-II Increased HIF-1α protein, decreased *Hif-2α* mRNA Via Mdm2 and decreased p53 Yes Yes [@DMP046C42]), [@DMP046C199], [@DMP046C135])\n\n*Hif-1α* mRNA can be regulated by progesterone in the mouse uterus whereas estrogen has the ability to regulate *Hif-2α* mRNA ([@DMP046C32]). ",
"In sheep, progesterone treatment increases HIF-1α and HIF-2α protein but not mRNA in endometrial luminal and superficial glandular epithelium ([@DMP046C162]). ",
"Similarly, exposure of colon cancer cells to prostaglandin E2 (PGE2) induces the expression of vascular endothelial growth factor (VEGF) via increased HIF-1α ([@DMP046C51]). ",
"HIF-1α protein levels in vascular smooth muscle cells are strongly increased in normal oxygen conditions when cells are stimulated with angiotensin II (Ang II), thrombin, platelet derived growth factor (PDGF) or Transforming Growth Factor-β1 (TGF-β1) ([@DMP046C146]; [@DMP046C60]; [@DMP046C134]). ",
"More recently, it was found that TGF-β1 decreases mRNA and protein levels of PHD2, through the Smad signalling pathway, thereby inhibiting the degradation of HIF-1α ([@DMP046C121]). ",
"Other non-hypoxic inducers of HIF-1α include Endothelin 1 ([@DMP046C163]), epidermal growth factor ([@DMP046C89]), Rho A which regulates actin stress fibres ([@DMP046C67]) and even cyclical mechanical stretch ([@DMP046C23]).",
"\n\nOf particular interest is a recent study demonstrating that in first trimester placental villous explants Ang II mimics the effects of hypoxia by increasing HIF-1α mRNA and protein ([@DMP046C5]). ",
"In addition, Ang II increased EVT outgrowth and the number of cells in CTB cell columns and increased Ki67 suggesting an increase in proliferation ([@DMP046C5]). ",
"Ang II has also been shown to increase plasminogen activator inhibitor (PAI)-1 synthesis and secretion in human trophoblasts through the type 1 angiotensin receptor (AT~1~R) and is associated with decreased trophoblast invasion ([@DMP046C188]; [@DMP046C5]). ",
"Interestingly, it has been proposed that Ang II and the renin angiotensin system may play a role in the development of pre-eclampsia. ",
"Ang II levels in the placental bed are significantly elevated in women with pre-eclampsia ([@DMP046C4]), and may act on the placental villi, which display an up-regulation of AT~1~Rs ([@DMP046C3]),\n\nCytokines also regulate HIF in normoxia. ",
"For example, interleukin (IL)-1β and tumour necrosis factor (TNF)-α increased HIF-1 DNA binding in human hepatoma cells ([@DMP046C69]). ",
"IL-1β increased HIF-1α nuclear protein, whereas the positive effect of TNF-α on HIF-1 DNA binding was suggested to result from activation of HIF co-activator proteins ([@DMP046C69]). ",
"Similarly, a more recent study found that IL-1β induces HIF-1α-mediated VEGF secretion in normal human trophoblast cells and this may be a result of ERK 1/2 activation ([@DMP046C136]). ",
"Interestingly, matrix metalloproteases (MMP-2, MMP-9) and urokinase plasminogen activator (uPA), which are abundantly expressed by CTBs and degrade the extracellular matrix (ECM), were also up-regulated by IL-1β in human trophoblasts ([@DMP046C92]). ",
"In contrast, HIF-1α protein accumulation induced by TNFα requires the NFκB pathway ([@DMP046C197]). ",
"In addition, TNFα inhibits trophoblast migration through elevation of PAI-1 in first trimester villous explant cultures ([@DMP046C7]; [@DMP046C76]) likely by activation of NFκB ([@DMP046C76]). ",
"Indeed a recent review by Redman and Sargent ([@DMP046C145]) emphasizes the role of inflammatory stimuli in HIF accumulation. ",
"This may be important in both normal pregnancies, where a systemic inflammatory response is evident, and in pathological pregnancies, such as pre-eclampsia, where inflammation is exaggerated. ",
"To date there have been few studies on the role of HIF in the placental inflammatory response but research in this area may provide novel insights in the future.",
"\n\nAlthough insulin-like growth factor (IGF)-II is known to be a target gene of HIF-1 ([@DMP046C42]), insulin, IGF-I and IGF-II are all able to induce HIF-1α protein expression in various cell lines ([@DMP046C194]; [@DMP046C42]; [@DMP046C89]; [@DMP046C25]; [@DMP046C172]; [@DMP046C168]; [@DMP046C2]). ",
"Similarly, both insulin and 2-deoxy-[d]{.smallcaps}-glucose treatment resulted in a widespread increase in HIF-3α mRNA and protein ([@DMP046C198]). ",
"IGF-I can also induce VEGF expression in human osteoblast-like cells through transcriptional activation involving the HIF-2α/ARNT complex ([@DMP046C1]). ",
"However, the magnitude of the increase in HIF protein induced by insulin or IGFs *in vitro* is far less than that caused by hypoxia. ",
"In contrast, IGF-II treatment of mouse trophoblasts *in vitro* has been shown to decrease *Hif-2α*, *asHif-1α*, *Glut-1* and *Vegf* mRNA levels following culture in prolonged hypoxia, but not in well oxygenated cells ([@DMP046C135]). ",
"This suggests that the response to growth factors varies depending on the oxygen availability.",
"\n\nMany, if not all, of the non-hypoxic regulators of HIF protein abundance reported to date are present and active in the placenta (Table [I](#DMP046TB1){ref-type=\"table\"}). ",
"To date, the role of HIF in mediating their effects in the placenta has been little studied. ",
"As an initial step, it will be important in the future to identify which of these non-hypoxic regulators of HIF (outlined in Table [I](#DMP046TB1){ref-type=\"table\"}) are playing a similar role in the placenta. ",
"From there we can start to examine the role of non-hypoxic HIF regulation in placental development and when this may occur. ",
"This would be a novel approach to research on placental HIF and will provide exciting insights into the regulation of placental development. ",
"In addition, it is important to consider possible interactions between hypoxic and non-hypoxic HIF regulators and the effects these may have. ",
"Importantly, it will be essential to also examine the role of both hypoxic and non-hypoxic HIF regulation in pathological pregnancies, such as pre-eclampsia, and whether these interact.",
"\n\nRegulation of placental development and function by HIF target genes {#s8}\n====================================================================\n\nHIF target genes may therefore be regulated by either hypoxic or non-hypoxic stimuli and many of these genes have critical roles in placental development and function. ",
"Interestingly, some HIF target genes, such as IGF-II and TGF-β, are also non-hypoxic regulators of HIF (Table [I](#DMP046TB1){ref-type=\"table\"}) whereas others can feed back to regulate HIF in prolonged hypoxia. ",
"Therefore, these molecules may provide novel co-regulatory responses or feedback pathways in the regulation of placental development. ",
"Many other HIF target genes have not yet been investigated in this way but further research may provide interesting insights into the complexity of interrelationships between HIF and its target genes. ",
"Here, we outline just some of the numerous roles that HIF-regulated genes have in placental development and how they could interact to regulate its differentiation, growth and function through HIF dependent or independent mechanisms.",
"\n\nTrophoblast invasion and migration {#s8a}\n----------------------------------\n\n*Hif1α −/− Hif2α −/−* mice display a 17% reduction in trophoblast invasion compared with wild type placentae ([@DMP046C30]). ",
"Several pro- and anti-invasive factors that are expressed by the trophoblast cells themselves or by the maternal decidua are HIF target genes. ",
"Furthermore, these factors seem to interact in such a way that they are able to tightly coordinate the extent and timing of trophoblast invasion and migration.",
"\n\n### uPA system {#s8a1}\n\nuPA, the uPA receptor (uPAR) and uPA inhibitors play a central role in trophoblast migration and invasion. ",
"EVTs have been shown to exhibit a highly polarised distribution of uPAR-bound uPA at the invasive front ([@DMP046C128]). ",
"uPA is secreted as an inactive proenzyme (pro-uPA) which, upon binding to its specific uPAR on the cell surface, is cleaved to its active form. ",
"Following activation, cell membrane bound uPA can catalyse the conversion of the inactive zymogen plasminogen, to the active proteinase plasmin ([@DMP046C101]) which can then go on to activate MMPs and directly degrade certain ECM components required for invasion and remodelling of the maternal decidua. ",
"This process is modulated by tissue inhibitors of matrix metalloproteinases (TIMPs) and PAI-1 which are predominantly synthesized by the decidua but also by the invading trophoblasts ([@DMP046C189]; [@DMP046C45]). ",
"Interestingly, the uPA:uPAR interaction can stimulate EVT migration independently of uPA catalytic action, via the mitogen activated protein kinase (MAPK) pathway and calcium signalling events that require phosphatidylinositol-3 kinase and phospholipase C ([@DMP046C110]).",
"\n\nCulture of HTR-8/SVneo trophoblasts less than 1% oxygen results in elevated expression of uPAR at the mRNA and cell surface bound protein levels and promotes trophoblast invasion ([@DMP046C62]). ",
"However, a more recent study has shown that culture in 3% oxygen inhibits early gestation EVT invasion, increases uPAR and PAI-2 expression and decreases uPAR activity ([@DMP046C107]). ",
"Although direct experimental evidence for HIF regulation of uPA in placenta is currently lacking, PAI-1 mRNA and protein levels have been shown to increase in HTR-8/SVneo cells in response to hypoxia via HIF-1α or HIF-2α \\[determined by small interfering RNA (siRNA) against HIF-1α and -2α\\] ([@DMP046C43]; [@DMP046C122]) and may provide a mechanism for the control of trophoblast invasion.",
"\n\n### Insulin-like growth factor-II {#s8a2}\n\nIGF-II is regulated by HIF ([@DMP046C42]) among other factors and is thought to play an important role in placental development. ",
"Maternal circulating concentrations of IGF-II increase during early pregnancy in humans ([@DMP046C186]; [@DMP046C54]). ",
"In addition, presumed *in vivo* hypoxia at term has been associated with increased levels of placental *Igf2* mRNA ([@DMP046C173]) whereas placental IGF-II protein is elevated in preeclamptic placenta ([@DMP046C63]). ",
"Direct evidence for HIF regulation of IGF-II in the placenta has not yet been reported but warrants further investigation. ",
"Indeed, IGF-II has been shown to promote migration of human EVT cells ([@DMP046C80]; [@DMP046C65]; [@DMP046C120]), increase proliferation in first trimester villous CTBs *in vitro* ([@DMP046C72]; [@DMP046C47]) and decrease CTB apoptosis ([@DMP046C47]). ",
"IGF-II induced migration of EVT cells *in vitro* is thought to be mediated by the IGF2R using a Gi-coupled receptor and (MAPK) intracellular signalling pathway ([@DMP046C120]).",
"\n\nThe bioavailability and biological actions of the IGFs are regulated by a family of 6 IGF binding proteins (IGFBPs 1-6). ",
"Interestingly, IGFBP-1, -2 and -3 are also HIF regulated genes ([@DMP046C167]; [@DMP046C42]). ",
"In blood, ∼75% of IGFs circulate as a complex with IGFBP-3 or IGFBP-5 and the acid-labile subunit, which acts as a reservoir ([@DMP046C125]). ",
"The remaining IGFs in the circulation bind to one of the remaining IGFBPs enabling them to cross the endothelium, increasing their availability to local tissues. ",
"Binding of IGFs to IGFBPs can result in either inhibition or enhancement of IGF actions. ",
"The affinity of IGFBPs for IGFs is higher than that of the receptors for IGFs, therefore binding of IGFBPs to IGFs prevents interactions with the IGF receptors ([@DMP046C27]; [@DMP046C9]; [@DMP046C125]; [@DMP046C152]; [@DMP046C35]). ",
"Conversely, several studies have also shown that a number of IGFBPs are able to stimulate IGF actions in a variety of cell types. ",
"Indeed, the same IGFBP can act to enhance or inhibit IGF actions depending on the cell type, abundance of IGFBP and post-translational modifications such as glycosylation or phosphorylation, which result in altered affinity for IGFs ([@DMP046C9]; [@DMP046C125]; [@DMP046C35]). ",
"Furthermore, IGF-II can alter the phosphorylation state of IGFBP-1 at the feto-maternal interface promoting its own actions ([@DMP046C183]). ",
"Several IGFBPs are also associated with the cell surface or ECM, reducing their affinity for the IGFs, and hence can also modulate IGF actions ([@DMP046C27]; [@DMP046C9]; [@DMP046C125]).",
"\n\n### Transforming growth factor-β {#s8a3}\n\nThe TGF-β isoforms are believed to be major factors regulating CTB behaviour and are commonly thought to inhibit cell proliferation and invasion ([@DMP046C11]). ",
"TGFβ3 expression is induced by hypoxia both *in vivo* and *in vitro* and is directly regulated by HIF-1 in trophoblast cells (determined by siRNA knockdown of HIF-1α) ([@DMP046C19], [@DMP046C20]; [@DMP046C158]; [@DMP046C130]). ",
"Interestingly, both HIF-1α and TGF-β3 are overexpressed in preeclamptic placentae ([@DMP046C130]). ",
"However, during normal pregnancy, the decidua is the major source of TGF-β. ",
"TGF-β1 inhibits EVT invasion via the RhoA/Rho-associated kinase (ROCK) pathway ([@DMP046C40]) by up-regulating integrin expression ([@DMP046C80]) and reducing uPA activity *in vitro* via decreasing the secretion of uPA and increasing the production and secretion of PAI-1 ([@DMP046C61]; [@DMP046C43]). ",
"Similarly, TGF-β1 can up-regulate TIMP-1 and -2, PAI-1 and -2 ([@DMP046C92]) and deposition of ECM components ([@DMP046C41]) and adhesive cell surface molecules ([@DMP046C123]; [@DMP046C93]) in human trophoblasts *in vitro*. ",
"TGF-β1 is also known to inhibit steroidogenesis in human trophoblasts ([@DMP046C112]) and promotes syncytium formation in isolated first trimester trophoblast primary cultures by increasing surface expression of cadherin-11 ([@DMP046C58]). ",
"In contrast to this, first trimester villous explants, exposed to either antisense TGF-β3 oligonucleotide or TGF-β3 antibody (but not those for TGF-β1 or TGF-β2), displayed prominent EVT outgrowth from the distal end of the villous tip and an increased number of cells migrating into the surrounding matrix ([@DMP046C18]).",
"\n\nTGF-β is secreted in a latent pro-form in complex with a latency associated peptide (LAP) and has the ability to bind the IGF2 receptor (IGF2R) (via M6P residues in the LAP) which interacts with the uPAR on the cell surface ([@DMP046C59]). ",
"uPA binding to uPAR allows uPA to cleave plasminogen into plasmin which can then go on to cleave the LAP, and active TGF-β1 is released. ",
"This provides a novel interaction between the uPA, IGF-II, TGF-β and HIF systems whereby, depending on the relative abundance of IGF-II and/or TGF-β, the uPAR/IGF2R interaction can be utilized to either promote or inhibit trophoblast migration and invasion. ",
"Importantly, hypoxia-induced HIF regulation of IGF-II, TGF-β, PAI-1, uPAR and uPA will also impact on this system and ultimately, trophoblast behaviour. ",
"In addition, non-hypoxic regulation of HIFs by IGF-II and TGF-β may provide additional feedback pathways.",
"\n\nPlacental vascularization {#s8b}\n-------------------------\n\nIt is thought that the low oxygen environment in the placenta controls CTB vascular remodelling and acts as a major regulator of placental angiogenesis. ",
"Indeed, *Hif1α −/− Hif2α −/−* mice have impaired placental vascularization ([@DMP046C30]). ",
"The VEGFs are key molecules involved in angiogenesis. ",
"The VEGF family consists of VEGF (VEGF-A), VEGF-B, VEGF-C, VEGF-D, VEGF-E and placental growth factor (PlGF), the latter of which is closely related to VEGF-A. There are three VEGF family receptors, VEGFR-1 (Flt-1), VEGFR-2 (KDR, called Flk-1 in mice) and VEGFR-3, as well as a soluble form of Flt-1 (sFlt-1) that is generated by alternative splicing and lacks transmembrane and cytoplasmic domains ([@DMP046C94]). ",
"VEGF is thought to act locally via its receptors, VEGFR-1 and VEGFR-2, to establish the fetoplacental circulation. ",
"VEGF is hypoxia inducible and is a well-known HIF target gene ([@DMP046C177]). ",
"Circulating sFlt-1 binds VEGF and PlGF with high affinity thereby decreasing their availability for the transmembrane receptors VEGFR-1 and VEGFR-2. ",
"Although not members of the VEGF family, the angiopoietins are also involved in placental vasculogenesis through their interaction with tyrosine kinase receptor (Tie-2) and are influenced by oxygen availability ([@DMP046C195]). ",
"It appears that rather than solely their concentration at the feto-maternal interface, the ratio and interaction of VEGF family members, angiopoietins and growth factors orchestrate the development of the placental vasculature and all in all, this is influenced by oxygen ([@DMP046C24]).",
"\n\nPlacental villous and extravillous trophoblasts secrete sFlt-1 during pregnancy ([@DMP046C26]) and sFlt-1 levels in the maternal circulation increase with increasing gestational age ([@DMP046C102]). ",
"Interestingly, *sFlt-1* mRNA levels and sFlt-1 secretion into culture media are up-regulated following exposure to a low oxygen environment in villous explants from first trimester and uncomplicated and preeclamptic pregnancies at term ([@DMP046C144]). ",
"HIF-1α knockdown using antisense oligonucleotides has demonstrated that this up-regulation is mediated by HIF-1α in first trimester villous explants ([@DMP046C129]). ",
"In addition, placental sFlt-1 is up-regulated in pre-eclampsia, leading to increased maternal circulating concentrations of sFlt-1 that precede symptoms and fall after delivery ([@DMP046C102]; [@DMP046C119]; [@DMP046C141]; [@DMP046C142]; [@DMP046C144]).",
"\n\nRecently, multiple isoforms of sFlt-1 have been identified in the circulation of women with pre-eclampsia as well as in uncomplicated pregnancies ([@DMP046C144]). *",
"Vegf* and its receptor *Flt-1* mRNA levels are also increased in preeclamptic placenta compared with controls ([@DMP046C174]; [@DMP046C140]; [@DMP046C141]; [@DMP046C142]). ",
"Conversely, membrane bound Flt-1 is decreased in the placental bed of patients with pre-eclampsia ([@DMP046C174]). ",
"Pre-eclampsia is associated with an increase in total circulating VEGF, but decreased free VEGF and PlGF a result of increased sFlt-1 ([@DMP046C119]; [@DMP046C174]) and this is thought to contribute to endothelial dysfunction seen in pre-eclampsia. ",
"Indeed, administration of sFlt-1 to pregnant rats induces hypertension, proteinuria and glomerular endotheliosis ([@DMP046C119]). ",
"Of considerable interest is the observation that experimental induction of utero-placental insufficiency (ischaemia with restricted transport function) by uterine artery ligation in baboons resulted in a pre-eclampsia-like syndrome with hypertension and proteinuria and, notably, elevated placental and maternal circulating monocyte*Flt-1* mRNA and increased sFlt-1 protein in plasma ([@DMP046C115]).",
"\n\nRecently, sFlt-1 was shown to be up-regulated in pregnant mice lacking catechol-*O*-methyltransferase (*Comt* −/− mice) ([@DMP046C91]). ",
"COMT generates 2-methoxyoestradiol (2-ME) from hydroxyoestradiol, a potent inhibitor of angiogenesis ([@DMP046C48]; [@DMP046C113]). ",
"These *Comt* −/− pregnant mice display a pre-eclampsia-like phenotype, including endothelial damage in the decidual arteries and renal glomeruli, gestational hypertension and proteinuria ([@DMP046C91]). ",
"Importantly, this pre-eclampsia-like phenotype is restored by the administration of 2-ME. ",
"This is in accordance with human preeclamptic pregnancies which display decreased levels of 2-ME and COMT ([@DMP046C91]). ",
"Additionally, *Comt* −/− mice display signs of hypoxia (as determined by hypoxyprobe localization), elevated nuclear HIF-1α in the placenta and increased circulating sFlt-1, which was prevented by 2-ME administration. ",
"2-ME is a negative regulator of HIF-1α ([@DMP046C113]) and was further shown to suppress hypoxia-induced HIF-1α and sFlt-1 in HTR-8 trophoblast cells ([@DMP046C91]). ",
"This very elegant study by Kanasaki *et al.* ",
"provides very strong evidence that disruption of COMT/2-ME resulting in elevated HIF-1α and subsequent sFlt-1 leads to angiogenic dysfunction, placental insufficiency and ultimately, the preeclamptic phenotype in mice.",
"\n\nPlacental transport {#s8c}\n-------------------\n\nGlucose transport is up-regulated by hypoxia in a number of cell types and is crucial for fetoplacental growth. ",
"In term placental villous explants, *in vitro* hypoxic exposure increases *Glut1* and *Glut3* mRNA levels and significantly increases glucose consumption ([@DMP046C39]). ",
"It was subsequently shown that hypoxic induction of *Glut1* mRNA and protein in human BeWo and rat Rcho-1 trophoblast cell lines was a result of HIF-1α interacting with a consensus HRE site in the *Glut-1* promoter ([@DMP046C66]). ",
"Furthermore, in human BeWo cells and first trimester explants, hypoxic induction of GLUT1 and GLUT3 was inhibited by asHIF-1α, and culture in 3% oxygen was shown to increase transepithelial glucose transport ([@DMP046C8]). ",
"Paradoxically, expression of placental GLUT1 is decreased in pregnancies at high altitude ([@DMP046C191]).",
"\n\nThe placental barrier is also a site of iron transport and recently hypoxia and HIF have been implicated in this process. ",
"Iron in serum is mainly transported by transferrin ([@DMP046C36]) which interacts with the transferrin receptor (TfR) and this complex is internalized by receptor-mediated endocytosis, enabling iron to enter the cell. ",
"It has been previously shown that transferrin is up-regulated in response to hypoxia and this is mediated by HIF in hepatoma cells ([@DMP046C151]). ",
"Similarly, culture of human Hep3B hepatoma cells increases *TfR* mRNA expression via HIF-1 dependent mechanisms ([@DMP046C165]). ",
"Surprisingly, expression of TfR is decreased in the placentae of pregnancies at high altitude ([@DMP046C191]) and in pregnancies complicated by pre-eclampsia ([@DMP046C95]). ",
"However, there is currently no direct evidence for HIF regulation of tranferrin or TfR in the placenta. ",
"There are very conflicting results between *in vitro* and *in vivo* studies regarding the effect of hypoxia on GLUTs and TfR in the placenta, perhaps, in part, because of the chronic exposure to hypoxia in pregnancies at high altitude compared with the short-term *in vitro* experiments. ",
"Additionally, other factors involved in the regulation of these transporters *in vivo* may be missing from the *in vitro* system, which may warrant further investigation.",
"\n\nThe future of placental HIF research {#s9}\n====================================\n\nWhile oxygen regulation of placental development and function and the role of HIFs in these processes is an area of keen interest, the currently available data are highly confusing. *",
"In vitro* studies examining the effects of oxygen are all diverse in methodology in terms of media composition, cell line versus primary trophoblasts, first trimester versus term placental samples, presence or absence of ECM substrate and timing of exposure. ",
"Most studies use 20% oxygen, which is hyperoxic, as a control or comparison group and is irrelevant when considering the physiology of the placenta and all but a few tissues for that matter: it is only useful in attempts to compare it with previous observations in the literature. ",
"How then can these data be truly interpreted and related to the *in vivo* situation? ",
"It is clear that what is needed is a systematic study looking at the effects of low oxygen (1--3%) compared with physiological control (5--10%) using placental villi from different gestational ages. ",
"In addition, given that the effects of prolonged versus acute hypoxia in the placenta are yet to be explored, it will be of great interest to examine this in the future.",
"\n\nSecondly, publication of articles that only report HIF mRNA or protein levels will no longer be sufficient. ",
"Ideally, studies examining the regulation of HIF should, where possible, include data on mRNA, protein and DNA binding for both HIF-1 and HIF-2. ",
"It is only when more data, such as these for placenta, are available that we will be able to draw accurate conclusions about the role of HIFs in placental biology. ",
"In addition, the regulation of HIFs is complex, and involves factors influencing stability, degradation and transcriptional activity of the HIFs. ",
"Investigation of other components of the HIF regulatory network, such as asHIF-1α, may offer valuable insights into placental HIF regulation in both normal and pathological pregnancies. ",
"Finally, HIF can no longer be considered simply as a transcription factor which is regulated by hypoxia. ",
"Future studies examining the regulation of HIF by oxygen and other factors are essential if we are to move forward in this field.",
"\n\nConclusion {#s10}\n==========\n\nThe HIFs are able to function throughout all aspects of normal and abnormal placental differentiation, growth and function; during the first trimester (physiologically low oxygen), during mid-late gestation (where there is adequate maternal blood supply and placental oxygenation) and in pathological pregnancies complicated by placental hypoxia/ischemia. ",
"The identity of HIFs as simply hypoxia-responsive transcription factors is an oversimplification and very misleading, as they do much more. ",
"During normal pregnancy HIFs respond to complex alterations in oxygen, hormones, cytokines and growth factors to precisely regulate placental invasion, differentiation, transport and vascularization. ",
"In the ever-changing environment created during pregnancy, the HIFs appear to act as key mediators of placental development and function and thereby are likely to be important contributors to both normal and adverse pregnancy outcomes.",
"\n\nAuthors\\' Role {#s11}\n==============\n\nK.G.P., K.L.K., A.N.S.-P., J.G.T. and C.T.R. were all involved in reviewing the literature and the preparation of the manuscript.",
"\n\nFunding {#s12}\n=======\n\nWe acknowledge funding from the National Health and Medical Research Council of Australia. ",
"Funding to pay the Open Access publication charges for this article was provided by the National Health and Medical Research Council, Australia.",
"\n"
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"It must be scary, or a bit sad, for parents to realize that their kids are starting to read on their own, so parents seem to rely on recommendations. ",
"In my experience, parents are often looking for books that children can read themselves, but that are also enjoyable read alouds. ",
"Some publishers have gotten rather smart about this phenomenon, but more on that another time. ",
"For very new readers, let’s say several steps before chapter books, when kids are sounding out words and can read sentences, but not full paragraphs, I highly recommend Mo Willems’s Elephant & Piggie books.",
"\n\nKids who enjoyed his Knufflebunny and Pigeon picture books will love the irreverent humor in this early reader series. ",
"The text is sparse, but Willems plays with words, often delighting in words themselves. ",
"Elephant & Piggie laugh and laugh at the sound of the word ‘banana’. ",
"Say it over and over again; you’ll start laughing, too. ",
"The two characters display a range of emotions and have hilarious conversations, with occasional misunderstandings, but one of the most interesting feature of this series is that they also engage directly with the reader and serve as guides for conceptualizing reading and books. ",
"In We are in a Book! (",
"Hyperion, $8.99) they comment on their own status as characters in a book. ",
"They then discuss what makes up a book, instructing readers about the different pieces. ",
"Anxiety about the “end of the book” is humorously alleviated by the perpetual present tense of books. ",
"Start over and the story is still there. ",
"Willems series is as much about introducing the phenomenon of reading to children as it is about practicing reading. ",
"I find that quite an amazing feat for a book with approximately one sentence on each page.",
"\n\nA few weeks ago, a customer told me that she reads the books out loud with her son, each taking one of the characters, which I thought was a wonderful idea. ",
"The books are primarily dialogue and offer unlimited possibilities for discussion. ",
"Oh, and don’t forget to look for the Pigeon."
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[
"---\nauthor:\n- |\n M. T. Dova$^1$, M. E. Manceñido$^1$, A. G. Mariazzi$^1$, T. P. McCauley$^2$ & A. A. Watson$^3$\\\n [*(1)Department of Physics,Universidad de La Plata,1900,Argentina\\\n (2)Department of Physics,Northeastern University, Boston,MA 02115,USA\\\n (3)Department of Physics and Astronomy,University of Leeds,Leeds LS2 9JT,UK*]{}\n---\n\nAn Estimate Of The Primary Mass Of Cosmic Rays At $10^{18}$ eV As Inferred From Volcano Ranch Data.",
"\n===================================================================================================\n\nAbstract {#abstract .unnumbered}\n--------\n\nAccurate measurements of the lateral distribution of extensive air showers produced by cosmic rays of energy greater than $10^{17}$ eV were made in the 1970s by Linsley. ",
"At the time, the state of knowledge about the best hadronic interaction model to use to describe such data prevented conclusions about the cosmic ray mass from being drawn. ",
"We have used a modern model, [qgsjet98]{}, to infer the primary mass from these data, using the very careful records left by Linsley. ",
"We find that at a median energy of $10^{18}$ eV , the data are well described by an iron-dominated composition (88 $\\pm$ 6(stat) $\\pm$ 18 (syst))%. ",
"We discuss the systematic errors in this estimate that arise from model uncertainties and from the range of energies used in the work of Linsley. ",
"These data are used with the permission of the late John Linsley to whom this work is dedicated.",
"\n\nIntroduction\n------------\n\nDetermining the mass composition above $10^{17}$ eV is an important and challenging measurement and has been tackled by several groups using different techniques. ",
"These results have not all been consistent in their conclusions. ",
"It is important to solve this problem because of its implications for cosmic ray models of origin, acceleration and propagation. ",
"We present a first interpretation of the precise Volcano Ranch measurements of the lateral distribution function using Monte Carlo tools that were not available when the data were recorded in the 1970s. ",
"The pioneering Volcano Ranch instrument was described by Linsley, in his various writings \\[2,3\\], with unusually detailed descriptions of his equipment, together with many shower details and a description of his data reduction methods.",
"\n\n![ ",
"LEFT: Lateral distribution measurements compare with simulations. ",
"RIGHT: Fe fraction from various experiments: Fly’s Eye ($\\blacktriangle$), Agasa A100 ([$\\blacksquare$]{}), Agasa A1 ([$\\square$]{}) using a [sibyll 1.5]{} \\[4\\] and references therein, Haverah Park \\[5\\] using [qgsjet98]{} ([$\\bullet$]{}) and [qgsjet01]{} ([$\\circ$]{}). ",
"Mean composition determined in this paper with the corresponding error for the Volcano Ranch energy range using [qgsjet98]{} (dashed rectangle) and an estimation of what it would result using [qgsjet01]{} following \\[5\\] (solid line rectangle). ](",
"volcanon6e19iron.eps \"fig:\"){width=\"17.pc\" height=\"17.pc\"} ![ ",
"LEFT: Lateral distribution measurements compare with simulations. ",
"RIGHT: Fe fraction from various experiments: Fly’s Eye ($\\blacktriangle$), Agasa A100 ([$\\blacksquare$]{}), Agasa A1 ([$\\square$]{}) using a [sibyll 1.5]{} \\[4\\] and references therein, Haverah Park \\[5\\] using [qgsjet98]{} ([$\\bullet$]{}) and [qgsjet01]{} ([$\\circ$]{}). ",
"Mean composition determined in this paper with the corresponding error for the Volcano Ranch energy range using [qgsjet98]{} (dashed rectangle) and an estimation of what it would result using [qgsjet01]{} following \\[5\\] (solid line rectangle). ](",
"fefraction.eps \"fig:\"){width=\"17.pc\" height=\"17.pc\"}\n\n![",
"The distributions of $\\eta$ for pure iron (left), pure proton (right) and from the fit (bottom). ",
"Histograms: Monte Carlo; points: data.](fig1bfe.eps \"fig:\"){width=\"15.pc\"} ![",
"The distributions of $\\eta$ for pure iron (left), pure proton (right) and from the fit (bottom). ",
"Histograms: Monte Carlo; points: data.](fig1bpr.eps \"fig:\"){width=\"15.pc\"} ![",
"The distributions of $\\eta$ for pure iron (left), pure proton (right) and from the fit (bottom). ",
"Histograms: Monte Carlo; points: data.](fig1b.eps \"fig:\"){width=\"15.pc\"}\n\nDerivation of the primary mass composition\n------------------------------------------\n\nWe have generated 1735 proton and iron showers with $\\sec\\theta=1.0-1.5$, and primary energy between $10^{17}$ eV and $10^{19}$ eV using the [aires]{} code (version 2.4.0), with the hadronic interaction generator [qgsjet98]{}. ",
"The results of the simulated showers were convolved with a simulation of the detector response made using [geant4]{} to obtain the scintillator response \\[1\\]. ",
"As a second step, each simulated shower was thrown up to 100 times on to a simulated Volcano Ranch array with random core positions in the range 0-150 m from the array center. ",
"A comparison between lateral distribution measurements \\[2\\] and average $10^{19.1}$ eV iron showers including the scintillator response of the detectors in the Volcano Ranch array configuration is presented in Fig 1 (left). ",
"The agreement of the lateral distributions is good and gives confidence in the procedures used.",
"\n\nA generalized version of the Nishimura-Kamata-Greisen (NKG) formula was used by Linsley to describe the lateral distribution \\[3\\]:\n\n$$S_{{\\rm VR}}(r) = {\\frac{N}{r_{m}^{2}}} \\frac{\\Gamma(\\eta-\\alpha)}{2\\pi\\Gamma(2-\\alpha)\\Gamma(\\eta-2)} \\left( {\\frac{r}{r_{m}}} \\right)^{-\\alpha} \\left( 1 + {\\frac{r}{r_{m}}} \\right)^{-(\\eta-\\alpha)} \n\\nonumber$$\n\nFrom a subset of 366 showers detected with the array, the form of $\\eta $ as a function of zenith angle $%\n\\theta $ and shower size $N$ was found to be \\[3\\] with $\\alpha =1$: $$\\langle \\eta(\\theta, N) \\rangle = a + b(\\sec \\theta - 1) + c\\:log_{10}({\\frac{N}{10^{8}}})$$ with $a = 3.88 \\pm 0.054$, $b = - 0.64 \\pm 0.07$, and $c = 0.07 \\pm 0.03$.\\\nWe estimate the primary mass by a maximum likelihood fit of the best linear combination of pure iron and proton generated samples to match the data sample assuming a bi-modal composition. ",
"The probability of observing a particular number of events $d_i$ in a particular bin is given by $\\exp^{-f_i}\\,f_i^{d_i}/d_i!$ where $f_i$ is the predicted value for the number of events in this particular bin.\\\nIf we assume a bi-modal composition of proton and iron with proportions $P_{Fe}$ and $P_p$ then, $f_i=C(P_{Fe} + P_p)$ and $C$ is the overall normalization factor between numbers of data and Monte Carlo events. ",
"The estimates of the proportions $P_j$ are found by maximizing the total likelihood or its logarithm, $\\ln(\\pounds)=\\Sigma d_i\\ln(f_i)-\\ln(d_i!)-f_i$.\n\nIn Fig 2 we show the Monte Carlo pure iron sample (left) and pure proton sample (right) with the corresponding Volcano Ranch data points. ",
"As can be seen from Fig 2 (right), the tail at large $\\eta $, in the comparison with iron, indicates that a light component must be included to fit the experimental data. ",
"The best fit gives a mixture with (88 $\\pm $ 6)% of iron and a corresponding amount of protons. ",
"The resulting $\\eta$ distribution is shown in Fig 2 (bottom) together with Volcano Ranch data. ",
"The systematic error arising from our lack of knowledge of the energy distribution of the events is estimated by repeating the fitting procedure with different energy spectra. ",
"From these analyses we estimate a systematic error of 12%. ",
"The systematic error introduced by the choice of hadronic model is estimated to be 14% \\[5\\].",
"\n\nDiscussion and Conclusions\n--------------------------\n\nIn Fig 1 (right) we present the fraction of iron for Fly’s Eye, Agasa and Haverah Park using different hadronic interaction models. ",
"Also shown is the mean composition with the corresponding error we get for the Volcano Ranch energy range using [qgsjet98]{} and an estimation of what we would get using [qgsjet01]{} as it was done in Haverah Park \\[5\\]. ",
"Cosmic rays at Volcano Ranch are found to be compatible with mean fraction (88 $\\pm$ 6(stat) $\\pm$ 18 (syst))% of iron in a bi-modal proton and iron mix, in the energy range $10^{17.7}$ eV to $10^{19}$ eV with mean energy $10^{18}$ eV.\n\nThe inconsistency between measurements of mass composition needs to be addressed in order to make a more solid conclusion on the origin, acceleration or propagation of cosmic rays. ",
"This work attempts to help answer these important questions by re-interpreting the pioneering Volcano Ranch experiment, but in doing so has in some ways deepened the mystery of the origin of these particles. ",
"Qualitatively there are significant differences between the estimates of composition at energies above $10^{17}$ eV. So the questions appear far from being resolved.",
"\n\nReferences\n----------\n\n1.",
" M. T. Dova et al, Proceedings of the XII ISVHECRI, CERN, 15-20 July 2002. ",
"2.",
" J. Linsley, Proc. ",
"13th ICRC, Denver, (1973) 3212. ",
"3.",
" J. Linsley, Proc. ",
"15th ICRC, Plovdiv,(1977) 56-62-89. ",
"4.",
" B. R. Dawson et al, Astropart. ",
"Phys. ",
"9 (1999) 331. ",
"5.",
" M. Ave et al., ",
"Astropart. ",
"Phys. ",
"19 (2003) 61.",
"\n"
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[
"---\nauthor:\n- 'R. Fedriani'\n- 'A. Caratti o Garatti'\n- 'M. Koutoulaki'\n- 'R. Garcia-Lopez'\n- 'A. Natta'\n- 'R. Cesaroni'\n- 'R. Oudmaijer'\n- 'D. Coffey'\n- 'T. Ray'\n- 'B. Stecklum'\nbibliography:\n- 'phd\\_bibliography.bib'\ndate: 'Received month day year / accepted month day year'\nsubtitle: 'Near-infrared CO overtone disc emission of the high-mass YSO IRAS 11101-5829[^1]'\ntitle: 'Mirror, mirror on the outflow cavity wall'\n---\n\n[The inner regions of high-mass protostars are often invisible in the near-infrared, obscured by thick envelopes and discs. ",
"We aim to investigate the inner gaseous disc of IRAS 11101-5829 through scattered light from the outflow cavity walls.]{} [",
"We observed the immediate environment of the high-mass young stellar object IRAS 11101-5829 and the closest knots of its jet, HH135-136, with the integral field unit VLT/SINFONI. ",
"We also retrieved archival data from the high-resolution long-slit spectrograph VLT/X-shooter. ",
"We analysed imaging and spectroscopic observations to discern the nature of the near-infrared CO emission.]{} [",
"We detect the first three bandheads of the $\\upsilon=2-0$ CO vibrational emission for the first time in this object. ",
"It is coincident with continuum and Br$\\gamma$ emission and extends up to $\\sim10\\,000$au to the north-east and $\\sim10\\,000$au to the south-west. ",
"The line profiles have been modelled as a Keplerian rotating disc assuming a single ring in local thermodynamic equilibrium. ",
"The model output gives a temperature of $\\sim3000$K, a CO column density of $\\sim1\\times10^{22}\\mathrm{\\,cm^{-2}}$, and a projected Keplerian velocity $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc} \\sim 25\\mathrm{\\,km\\,s^{-1}}$, which is consistent with previous modelling in other high-mass protostars. ",
"In particular, the low value of $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$ suggests that the disc is observed almost face-on, whereas the well-constrained geometry of the jet imposes that the disc must be close to edge-on. ",
"This apparent discrepancy is interpreted as the CO seen reflected in the mirror of the outflow cavity wall.]{} [",
"From both jet geometry and disc modelling, we conclude that all the CO emission is seen through reflection by the cavity walls and not directly. ",
"This result implies that in the case of highly embedded objects, as for many high-mass protostars, line profile modelling alone might be deceptive and the observed emission could affect the derived physical and geometrical properties; in particular the inclination of the system can be incorrectly interpreted.]{}",
"\n\nIntroduction {#sect:introduction}\n============\n\nTheoretical and observational studies support the idea that high-mass young stellar objects (HMYSOs, $M_{*}>8\\,M_\\odot, L_\\mathrm{bol}>5\\times10^3L_\\odot$) might be born as a scaled-up version of their low-mass counterparts [see e.g. @beuther2007; @tan2014]. ",
"A particularly important piece of the puzzle has been the discovery of accretion discs around HMYSOs [e.g. @patel2005; @kraus2010]. ",
"Structures in Keplerian rotation have been observed in a wide range of massive protostars and they have been associated with accretion discs or toroids [see e.g. @beltran2016 and references therein]. ",
"These structures are mainly composed of gas and dust with a variety of atoms and molecules [see @henning2013 for a review]. ",
"In the sub-millimetre, millimetre, and radio regimes, we can analyse the molecules forming further away in the disc and dust continuum [@cesaroni2005; @cesaroni2006; @cesaroni2007; @motogi2019]. ",
"However, if we want to probe the inner gaseous disc within a few astronomical units from the central source, namely where accretion and ejection take place, we need to observe in the near-infrared (NIR). ",
"An excellent tracer to study the inner gaseous disc is the NIR ${}^{12}$C${}^{16}$O overtone bandhead emission (hereafter CO emission) at $2.29-2.5\\mathrm{\\,\\mu m}$ [@dullemond2010]. ",
"Indeed, this emission has been observed in a number of HMYSOs [@scoville1983; @bik2004; @bik2006; @davies2010; @cooper2013] as well as in intermediate- and low-mass YSOs [see e.g. @connelley2010; @ilee2014; @koutoulaki2019]. ",
"Even though the CO emission has been observed in several YSOs in multiple mass regimes, the detection rate is very low, i.e. around 20% [e.g. @carr1989; @ishii2001; @connelley2010; @cooper2013]. ",
"A plausible reason for this low detection rate, at least in the case of HMYSOs, is that the CO emission seems to be sensitive to the mass accretion rate $(\\dot{M}_\\mathrm{acc})$ of the system; because this rate is a moderate value of $\\dot{M}_\\mathrm{acc}\\sim10^{-5}\\,M_\\odot\\mathrm{\\,yr^{-1}}$ it best produces the most prominent CO emission [@ilee2018]. ",
"Therefore, adding objects with CO detection represents both a challenge and an important contribution. ",
"The CO emitting region is usually modelled as a disc in Keplerian rotation [see e.g. @kraus2000; @ilee2013] and thus can give us important constraints on the physical properties of the inner gaseous disc and the geometry of the system.",
"\n\nIRAS 11101-5829 (also known as G290.3745+01.6615) is a HMYSO of $L_\\mathrm{bol}\\sim10^4\\,L_\\odot$ located in the eastern Carina star-forming region and is driving the Herbig-Haro (HH) objects HH135/136 [@ogura1992; @tamura1997; @ogura1998]. ",
"Unlike many other HMYSOs, this object does not lie in the plane of the Milky Way and consequently has not been observed in major IR or millimetre surveys (Spitzer, Herschel, or Atlasgal), although it was observed in the Midcourse Space Experiment (MSX) and Infrared Astronomical Satellite (IRAS). ",
"The distance to this object has been associated with the distance to the open cluster Stock 13 [@ogura1992], which has a photometric distance of 2.65kpc [@steppe1977]. ",
"There are [GAIA DR2]{} distance measurements for this open cluster. ",
"These measurements have large uncertainties, although they are consistent [$d=2.625^{+2.52}_{-1.40}$kpc; @bailerjones2018] with the photometric distance. ",
"In this work we adopt a distance of 2.7kpc, as in @ogura1992 and @gredel2006. ",
"The parsec-scale bipolar jet has been studied in atomic (\\[\\], \\[\\]) and molecular (H$_2$) tracers [@gredel2006] and a strong helical magnetic field has been revealed through circular polarimetry [@chrysostomou2007]. ",
"The geometry of the jet is well-constrained and its axis lies almost in the plane of the sky [$i_\\mathrm{jet}\\sim5^\\circ{}$; @ogura1998], therefore its disc must be seen close to edge-on ($i_\\mathrm{disc}\\sim85^\\circ{}$). ",
"Notably, no CO bandhead emission nor any evidence of circumstellar disc has been previously reported for this object.",
"\n\nWe report on the spectro-imaging results of the first 20000au of IRAS 11101-5829. ",
"In particular, we investigate the CO emission that is observed for the first time in this object. ",
"The observations and data reduction are presented in Sect.",
" \\[sect:observations\\], results in Sect.",
" \\[sect:results\\], discussion in Sect.",
" \\[sect:discussion\\], and conclusions in Sect.",
" \\[sect:conclusions\\].",
"\n\nObservations and data reduction {#sect:observations}\n===============================\n\nVery Large Telescope/SINFONI data\n---------------------------------\n\nIRAS 11101-5829 was observed with the Very Large Telescope (VLT) spectrograph for integral field observations in the NIR [SINFONI; @sinfoni2003] on 2018 June 15 (Programme ID 0101.C-0317(A)) in the $K$ band ($1.95-2.5\\mu$m). ",
"The field of view (FoV) of $8'' \\times 8''$ was centred on the source, with a position angle (PA) east of north (E of N) of zero degrees. ",
"Spatial sampling was $125\\times250\\mathrm{\\,mas\\,pixel^{-1}}$; the smaller sampling was carried out in the northern direction. ",
"The total exposure time was 360s. ",
"Spatial resolution achieved using adaptive optics + natural guide star (AO+NGS) was $0.3''-0.4''$ and spectral resolution was $\\mathcal{R}\\sim4000$ ($75\\mathrm{\\,km\\,s^{-1}}$). ",
"The NGS used for the AO system was 2MASS J11121780-5846425 ($B = 14.4$, $J = 13.9$ mag and separation of $22''$ from the target). ",
"Data were reduced in the standard way, using dedicated instrument software, [GASGANO]{}, standard IRAF routines, and Python custom scripts. ",
"A wavelength accuracy of $0.11$Å (or $\\sim1.5\\mathrm{\\,km\\,s^{-1}}$) was achieved. ",
"Flux calibration and telluric correction were performed using the photometric standard star Hip053018.",
"\n\nSpectra at various locations of the IRAS11101-5829 system were extracted. ",
"For this purpose, boxes of various sizes and positions were extracted from the data cube (see Fig.",
" \\[fig:cont\\_boxes\\]). ",
"Two different sets of boxes were considered. ",
"One of the sets comprises three $1.75''\\times1.75''$ boxes, which are shown as red (NE), black (central), and blue (SW) rectangles in Figure \\[fig:cont\\_boxes\\]; the spectra are shown in Figure \\[fig:spectra\\_three\\_regions\\]. ",
"The purpose of these boxes is twofold: measure the line fluxes at each position and discern whether or not there is large-scale variation in the line profiles along the red-shifted and blue-shifted cavity walls and on source (NE, SW, and central box, respectively). ",
"The second set consists of a total of 15 boxes, each $0.625''\\times0.625''$ in size, distributed along the system. ",
"The purpose of these boxes is to discern if there is any line profile variation with distance and/or location from the source (see Fig.",
" \\[fig:CO\\_line\\_profile\\_variation\\]).",
"\n\n![",
"Boxes extracted from the cube to generate the spectra shown in Figures \\[fig:spectra\\_three\\_regions\\] and \\[fig:CO\\_line\\_profile\\_variation\\] overlaid in the continuum image at $2.085\\mathrm{\\,\\mu m}$ in arbitrary units. ",
"White boxes are $5\\mathrm{\\,pix}\\times5\\mathrm{\\,pix} =0.625''\\times0.625''$ whereas red, black, and blue boxes are $14\\mathrm{\\,pix}\\times14\\mathrm{\\,pix} =1.75''\\times1.75''$. Brown lines show the X-shooter slit position centred on the NIR peak emission.[]{data-label=\"fig:cont_boxes\"}](figures/cont_boxes_map_IRAS11101_XS_slit.png){width=\"49.00000%\"}\n\nVery Large Telescope/X-shooter archival data\n--------------------------------------------\n\nHigh-resolution long-slit spectra using the VLT/X-shooter [@xshooter2011] were also retrieved (Programme ID 098.C-0636(A), observed on 2017 January 31). ",
"From the full data set, we only used a small portion of the NIR arm and thus only technical details for this arm are given. ",
"The $0.4'' \\times 11''$ long slit was positioned at the brightest point of the NIR nebula with a PA of $-45^\\circ{}$ E of N, perpendicular to the jet (see Fig.",
" \\[fig:cont\\_boxes\\]). ",
"Total exposure time was 560s. ",
"The spectral resolution achieved was $\\mathcal{R}\\sim7000$ ($\\sim43\\mathrm{\\,km\\,s^{-1}}$) and the seeing-limited spatial resolution was $\\sim1.0''$. A wavelength calibration accuracy of $0.3$Å (or $\\sim4.2\\mathrm{\\,km\\,s^{-1}}$) was achieved. ",
"We retrieved the pipeline-calibrated spectra from the ESO Archive Science Portal. ",
"The spectrum was corrected for telluric absorption features using the telluric standard Hip058859. ",
"The X-shooter and SINFONI CO bandhead profiles, extracted from the same region, are consistent with each other (see Fig.",
" \\[fig:CO\\_spectrum\\_xs\\_sin\\]).",
"\n\nResults {#sect:results}\n=======\n\n{width=\"100.00000%\"}\n\nSpectra extracted along the IRAS11101-5829 system {#sect:emission_maps}\n-------------------------------------------------\n\nThe main advantage of integral field unit observations is that we have imaging and spectra for each single pixel in the image, providing us with spectral and spatial information of the system. ",
"In this section, we first present the spectra extracted at various locations and then we show the emission maps of the central source and its immediate environment.",
"\n\nOur data show a plethora of prominent emission lines, namely H$_2$, Br$\\gamma$, , , and CO (see Fig.",
" \\[fig:spectra\\_three\\_regions\\] and Table \\[tab:observed\\_lines\\_IRAS11101\\]). ",
"In this section, we focus on the results related with the CO emission and use the H$_2$ lines only to determine the jet structure and kinematics (see Sect.",
" \\[sect:H2\\_geometry\\]). ",
"For the first time, the NIR CO bandhead emission at $2.29-2.4\\mathrm{\\,\\mu m}$, associated with active accreting discs, is observed in this source. ",
"In particular, the first three bandheads and a hint of the fourth ($\\upsilon=2-0, \\upsilon=3-1, \\upsilon=4-2, \\upsilon=5-3$ transitions) are detected in both X-Shooter and SINFONI spectra. ",
"In the case of SINFONI spectra, the emission is more intense at the centre of the nebula (Fig.",
" \\[fig:spectra\\_three\\_regions\\] central panel, see also Fig.",
" \\[fig:flux\\_density\\_maps\\]), but it is also observed in the north-east (NE) and south-west (SW) outflow cavity walls extending more than 10000au (Fig.",
" \\[fig:spectra\\_three\\_regions\\] top and bottom panels).",
"\n\nSimilarly, the Br$\\gamma$ at $2.1662\\mathrm{\\,\\mu m}$, doublet at $2.2062/2.2089\\mathrm{\\,\\mu m}$, and at $2.2437\\mathrm{\\,\\mu m}$ lines show an analogous behaviour, which is more intense at the central brightest region and weaker in NE and SW. ",
"Interestingly, all these lines are expected to form in the disc or in its proximity [@lorenzetti2011]. ",
"However, the large spatial extent (thousands of au) and its spatial coincidence with the continuum emission from the central source, tracing the outflow cavity walls, indicate that this emission is reflected. ",
"The line profile of the CO bandheads does not change significantly along the emitting area (see Fig.",
" \\[fig:cont\\_boxes\\] and Fig.",
" \\[fig:CO\\_line\\_profile\\_variation\\]) suggesting that the geometry of the outflow cavity walls does not change much [see e.g. @davies2010].",
"\n\n[c c c c c c]{} Species & Transition & $\\lambda_\\mathrm{vac}$ &\\\n& &($\\mu\\mathrm{m}$) &\\\n& & & NE region & SW region & central region\\\nH$_2$ & $1-0$S(3) & 1.95755 & $5.10\\pm0.12$ & $2.69\\pm0.05$ & $\\cdots$\\\nH$_2$ & $1-0$S(2) & 2.03375 & $1.78\\pm0.06$ & $0.89\\pm0.02$ & $\\cdots$\\\nH$_2$ & $2-1$S(3) & 2.07351 & $0.47\\pm0.04$ & $0.18\\pm0.02$ & $\\cdots$\\\nH$_2$ & $1-0$S(1) & 2.12182 & $5.19\\pm0.02$ & $2.71\\pm0.01$ & $3.87\\pm0.14$\\\nH$_2$ & $2-1$S(2) & 2.15422 & $0.17\\pm0.02$ & $0.15\\pm0.01$ & $\\cdots$\\\n& Br$\\gamma$ & 2.16612 & $2.94\\pm0.37$ & $0.77\\pm0.13$ & $17.2\\pm0.31$\\\nH$_2$ & $3-2$S(3) & 2.20139 & $0.22\\pm0.05$ & $0.14\\pm0.03$ & $\\cdots$\\\n& ${}^2S_{3/2}-{}^2Po_{1/2}$ & 2.20624 & $0.37\\pm0.05$ & $\\cdots$ & $1.50\\pm0.02$\\\n& ${}^2S_{1/2}-{}^2Po_{1/2}$ & 2.20897 & $0.44\\pm0.07$ & $\\cdots$ & $1.42\\pm0.02$\\\nH$_2$ & $1-0$S(0) & 2.22330 & $1.24\\pm0.02$ & $0.84\\pm0.01$ & $1.34\\pm0.17$\\\n& ${}^1S_1-{}^1Po_0$& 2.24373 & $0.14\\pm0.01$ & $0.07\\pm0.01$ & $1.03\\pm0.06$\\\nH$_2$ & $2-1$S(1) & 2.24772 & $0.59\\pm0.01$ & $0.32\\pm0.01$ & $1.24\\pm0.04$\\\nCO & $\\upsilon=2-0$ & 2.29320 & $4.48\\pm0.45$ & $2.47\\pm0.25$ & $41.0\\pm4.10$\\\nCO & $\\upsilon=3-1$ & 2.32320 & $4.09\\pm0.41$ & $3.21\\pm0.32$ & $46.5\\pm0.47$\\\nCO & $\\upsilon=4-2$ & 2.35320 & $2.55\\pm0.26$ & $3.60\\pm0.36$ & $41.4\\pm4.14$\\\nCO & $\\upsilon=5-3$ & 2.38350 & $\\cdots$ & $\\cdots$ & $\\cdots$\\\nH$_2$ & $1-0\\,Q(1)$ & 2.40659 & $4.30\\pm0.15$ & $2.49\\pm0.09$ & $\\cdots$\\\nH$_2$ & $1-0\\,Q(2)$ & 2.41343 & $1.61\\pm0.16$ & $1.01\\pm0.08$ & $\\cdots$\\\nH$_2$ & $1-0\\,Q(3)$ & 2.42372 & $3.67\\pm0.14$ & $2.04\\pm0.09$ & $\\cdots$\\\nH$_2$ & $1-0\\,Q(4)$ & 2.43749 & $1.15\\pm0.16$ & $0.64\\pm0.08$ & $\\cdots$\\\n\nEmission maps of the first 10000au of IRAS11101-5829\n----------------------------------------------------\n\nOur SINFONI FoV covers $21\\,600\\mathrm{\\,au}\\times21\\,600\\mathrm{\\,au}$ at a distance of $2.7$kpc. ",
"The top left panel of Figure \\[fig:flux\\_density\\_maps\\] shows the emission map of the first bandhead CO$(\\upsilon=1-0)$ line at $2.2932\\mathrm{\\,\\mu m}$; the contribution of the continuum at $2.0855\\mathrm{\\,\\mu m}$ is represented in black contours. ",
"The continuum emission is very bright at the centre of the image and extends smoothly to the NE and towards the SW, where it becomes weaker. ",
"The continuum is tracing the emission of the central engine and its circumstellar environment being the extended emission reflected light. ",
"The top right panel of Figure \\[fig:flux\\_density\\_maps\\] shows the continuum-subtracted emission map of the CO$(\\upsilon=1-0)$ line extending more than 10000au, mimicking both the shape and distribution of that of the continuum. ",
"This indicates that the CO emission, which comes from the circumstellar disc, is reflected in the outflow cavity walls (as for the continuum), and does not represent real extended emission directly observed from the disc.",
"\n\nIn the middle panels, the emission maps of the Br$\\gamma$ line (line+continuum and continuum-subtracted, left and right, respectively) are presented. ",
"It is clear that the morphology of both CO and Br$\\gamma$ emitting regions is remarkably similar, suggesting that both are reflected in the outflow cavity walls. ",
"This idea is strengthened by the fact that these transitions have different excitation energies and trace different gas conditions. ",
"Indeed, it should be noted that CO and Br$\\gamma$ emission should come from different regions/layers of the disc [see e.g. @dullemond2010]. ",
"In addition, the Br$\\gamma$ could also be emitted from the base of a wind [see e.g. @tambovtseva2016] or from a collimated jet close to the disc [@caratti2016; @fedriani2019].",
"\n\nIn contrast, the continuum-subtracted H$_2$ emission map, corresponding to the $1-0$S(1) transition at $2.1218\\mathrm{\\,\\mu m}$, clearly delineates the molecular jet (bottom panels of Fig.",
" \\[fig:flux\\_density\\_maps\\]), which has an orientation of NE to SW [see Fig.",
" 7 of @gredel2006 to see the full extent of the molecular jet]. ",
"It should be noted that some H$_2$ emission might also represent scattered light in the cavity walls. ",
"Towards the NE (which corresponds to the red-shifted lobe, see Fig.",
" \\[fig:H2\\_vel\\_map\\]) there is an evident bow-shock structure. ",
"Similarly, towards the SW (which corresponds to the blue-shifted lobe) there is also a hint of bow-shock-like structure.",
"\n\n{width=\"45.00000%\"} {width=\"45.00000%\"} {width=\"45.00000%\"} {width=\"45.00000%\"} {width=\"45.00000%\"} {width=\"45.00000%\"}\n\nLine profile variation\n----------------------\n\nThe line profile variations of the first two CO bandheads, the $1-0$S(1), Br$\\gamma,$ and the H$_2$ extracted from the 15 selected regions in SINFONI FoV (see Fig.",
" \\[fig:cont\\_boxes\\]) are shown in the top, middle, and bottom panels of Figure \\[fig:CO\\_line\\_profile\\_variation\\], respectively.",
"\n\nThe CO emission is detected in all the small white boxes with the exception of box13. ",
"Notably, there is no significant change in the line profile, therefore there is no relevant variation in the geometry of the outflow cavity walls. ",
"The same happens for the Br$\\gamma$ line profiles which show radial velocity peaks around 0kms$^{-1}$. This indicates that the bulk of the Br$\\gamma$ emission is seen in scattered light. ",
"There is however an extra blue-shifted component detected in some of the line profiles (e.g. boxes 3, 5, 7, and 10). ",
"This blue-shifted component might possibly trace a wind. ",
"Finally, there is a notable change in the line profile of the molecular hydrogen line $1-0$S(1) (Fig.",
" \\[fig:CO\\_line\\_profile\\_variation\\] bottom panel). ",
"In this figure, we can clearly see that both the FWZI and the line peak vary, depending on where the spectrum was extracted. ",
"On the one hand, the FWZI varies from $\\sim200$ to $400\\mathrm{\\,km\\,s^{-1}}$. On the other hand, the difference between the red- and blue-shifted lobes is also evident. ",
"Namely, the boxes located towards the NE (i.e. boxes $1-10$) show line profiles peaking at red-shifted radial velocities, whereas those located towards the SW (i.e. boxes $11-15$) show lines profiles peaking at blue-shifted radial velocities delineating the jet (see Section \\[sect:H2\\_geometry\\] and Figure \\[fig:H2\\_vel\\_map\\] for more details on the velocity structure of the jet).",
"\n\nCO ![*",
"Top panel:* Spectra from VLT/SINFONI showing the profile variation of the two firsts CO bandhead lines along the cube. *",
"Middle panel:* Same as top panel for the Br$\\gamma$ line at $2.16\\,\\mu$m. *",
"Bottom panel:* Same as top panel for the H$_2$ line $1-0$S(1) at $2.12\\,\\mu$m. ",
"The box numbering corresponds to that given in Figure \\[fig:cont\\_boxes\\]. ",
"Velocities are given with respect to the LSR.[]{data-label=\"fig:CO_line_profile_variation\"}](figures/CO_line_profile_variation_IRAS11101.png \"fig:\"){width=\"49.00000%\"} Br$\\gamma$ ![*",
"Top panel:* Spectra from VLT/SINFONI showing the profile variation of the two firsts CO bandhead lines along the cube. *",
"Middle panel:* Same as top panel for the Br$\\gamma$ line at $2.16\\,\\mu$m. *",
"Bottom panel:* Same as top panel for the H$_2$ line $1-0$S(1) at $2.12\\,\\mu$m. ",
"The box numbering corresponds to that given in Figure \\[fig:cont\\_boxes\\]. ",
"Velocities are given with respect to the LSR.[]{data-label=\"fig:CO_line_profile_variation\"}](figures/BrG_line_profile_variation_IRAS11101.png \"fig:\"){width=\"49.00000%\"} H$_2$ ![*",
"Top panel:* Spectra from VLT/SINFONI showing the profile variation of the two firsts CO bandhead lines along the cube. *",
"Middle panel:* Same as top panel for the Br$\\gamma$ line at $2.16\\,\\mu$m. *",
"Bottom panel:* Same as top panel for the H$_2$ line $1-0$S(1) at $2.12\\,\\mu$m. ",
"The box numbering corresponds to that given in Figure \\[fig:cont\\_boxes\\]. ",
"Velocities are given with respect to the LSR.[]{data-label=\"fig:CO_line_profile_variation\"}](figures/H2_line_profile_variation_IRAS11101.png \"fig:\"){width=\"49.00000%\"}\n\nH$_2$ jet kinematics to probe the geometry of the system {#sect:H2_geometry}\n--------------------------------------------------------\n\nTwelve H$_2$ lines are detected (see Table \\[tab:observed\\_lines\\_IRAS11101\\]). ",
"The brightest line corresponds to the $1-0$S(1) transition exceeding a signal-to-noise ratio of 100. ",
"This emission is a clear tracer of jet shocked material.",
"\n\nFigure \\[fig:H2\\_vel\\_map\\] shows the $1-0$S(1) velocity map tracing the protostellar jet of IRAS11101-5829. ",
"To construct the map, we only considered pixels with signal-to-noise ratios greater than 10 in the H$_2$ line. ",
"The radial velocities shown in Figure \\[fig:H2\\_vel\\_map\\] are with respect to the local standard of rest (LSR) and corrected for the velocity of the parent cloud [$\\varv_\\mathrm{LSR}^\\mathrm{cloud}=-24\\mathrm{\\,km\\,s^{-1}}$, @walsh1997]. ",
"There is a clear distinction between the red-shifted lobe (towards the NE) and the blue-shifted lobe (towards the SW). ",
"In the red-shifted lobe the radial velocities measure up to $30\\mathrm{\\,km\\,s^{-1}}$, whereas in the blue-shifted lobe they reach up to $-30\\mathrm{\\,km\\,s^{-1}}$.\n\n![",
"Velocity map (LSR) of molecular hydrogen obtained from the $1-0$S(1) line at $2.12\\,\\mu$m. ",
"The cyan star denotes the position of the star given by @tamura1997; the circle around it represents the uncertainty $\\sim1.7''$. The grey star indicates our suggested position of the central engine; the circle around it represents the uncertainty $\\sim0.4''$.[]{data-label=\"fig:H2_vel_map\"}](figures/H2_velocity_map_IRAS11101.png){width=\"49.00000%\"}\n\n@hartigan1987 demonstrated that the full width at zero intensity (FWZI) of emission lines tracing jet shocked material is similar to the shock velocity. ",
"From our data, we measured the FWZI of the $1-0$S(1) line at various locations obtaining a shock velocity $(\\varv_\\mathrm{tot})$ of $\\sim200-400\\mathrm{\\,km\\,s^{-1}}$ (see Fig.",
" \\[fig:CO\\_line\\_profile\\_variation\\], bottom panel). ",
"The radial velocity $(\\varv_\\mathrm{rad})$ was also measured to be $\\sim15-30\\mathrm{\\,km\\,s^{-1}}$ (see Fig.",
" \\[fig:H2\\_vel\\_map\\]). ",
"Hence, knowing $(\\varv_\\mathrm{tot})$ and $(\\varv_\\mathrm{rad})$, the inclination angle of the jet can be estimated as $i_\\mathrm{jet}=\\arcsin\\left(\\frac{\\varv_\\mathrm{rad}}{\\varv_\\mathrm{tot}}\\right)$. We obtained a range of values of $i_\\mathrm{jet}\\sim2.1^\\circ{}-8.6^\\circ{}$ at a distance of $1^{\\prime\\prime}-4^{\\prime\\prime}$ ($2700-10\\,800$au) from the central source. ",
"This result is consistent with @ogura1998, who obtained $i_\\mathrm{jet}\\sim5^\\circ{}$ at a distance of $20^{\\prime\\prime}-60^{\\prime\\prime}$ ($54\\,000-162\\,000$au), utilising optical atomic lines (H$\\alpha$$\\lambda\\lambda6562$ and \\[\\]$\\lambda\\lambda6584$).",
"\n\nAs the jet is orthogonal to the disc and its precession is modest (see Fig.",
" \\[fig:flux\\_density\\_maps\\] and Figs. ",
"6 and 7 in @gredel2006 [-@gredel2006]), its geometry allows us to infer that of the disc, and vice versa. ",
"As just shown, HH135/136 is nearly in the plane of the sky and therefore the IRAS11101-5829 disc must be near to edge-on; see for example the case of HH30 or HH111, where the jets lie also almost in the plane of the sky [@ray1996; @reipurth1997].",
"\n\nPhysical conditions of the NIR CO bandhead overtone emitting region {#sect:co_modelling}\n-------------------------------------------------------------------\n\nWe developed a local thermodynamic equilibrium (LTE) model [see @koutoulaki2019] to explain the CO emission. ",
"The details of the model are given in the Appendix\\[sect:appendix\\_CO\\], and the main results are reported below. ",
"We assumed a single ring in LTE at temperature $T$, CO column density $N(\\mathrm{CO})$, turbulence velocity of the molecule $\\Delta \\varv$, and projected Keplerian velocity $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$, where $i_\\mathrm{disc}$ is the inclination of the plane of the disc with respect to the plane of the sky. ",
"That is $i_\\mathrm{disc}=0^\\circ{}$ is face-on and $i_\\mathrm{disc}=90^\\circ{}$ is edge-on; we note that the latter case corresponds to the jet laying in the plane of the sky, i.e. $i_\\mathrm{jet}=0^\\circ{}$. We modelled SINFONI and X-shooter spectra, reproducing both spectra with very similar conditions. ",
"However, given the higher spectral resolution of X-shooter, we only considered this spectrum for our modelling. ",
"We subtracted the contribution of the continuum by fitting a straight line to the left part of the first bandhead and extrapolated over the entire bandheads. ",
"Interestingly, at the spectral resolution of the X-shooter observations, several individual $J-$components of the rotational ladder are spectrally resolved. ",
"This is clearer in the first two bandheads. ",
"This fact, together with the sharp blue part of the spectrum to the left of the peak of the bandheads, allows us to accurately constrain $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$ (see Appendix \\[sect:appendix\\_CO\\]). ",
"Figure \\[fig:CO\\_spectrum\\] shows the first four bandheads of the CO emission overplotted with our best model. ",
"The model parameters giving the best results are $T = 3000^{+500}_{-500}$K, $N(\\mathrm{CO}) = 1^{+0.2}_{-0.4}\\times10^{22}\\mathrm{\\,cm^{-2}}$, $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc} = 25^{+5}_{-10}\\mathrm{\\,km\\,s^{-1}}$, and $\\Delta \\varv = 10^{+2}_{-3}\\mathrm{\\,km\\,s^{-1}}$ (see Table\\[tab:CO\\_model\\_output\\]). ",
"These physical conditions are consistent with previous studies modelling the CO emission around HMYSOs [@ilee2013].",
"\n\n[l c]{} Parameter & Value\\\nTemperature (K) & $3000^{+500}_{-500}$\\\nCO column density $(\\mathrm{cm^{-2}})$ & $1^{+0.2}_{-0.4}\\times10^{22}$\\\n$\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$ $(\\mathrm{km\\,s^{-1}})$ & $25^{+5}_{-10}$\\\n$\\Delta \\varv$ $(\\mathrm{km\\,s^{-1}})$ & $10^{+2}_{-3}$\\\n\n{width=\"100.00000%\"}\n\nDiscussion {#sect:discussion}\n==========\n\nCO disc emission reflected in the outflow cavity wall\n-----------------------------------------------------\n\nOur CO model gives reasonable parameters of a warm $(T=3000\\pm500\\mathrm{\\,K})$ and dense $(N(\\mathrm{CO})=1^{+0.2}_{-0.4}\\times10^{22}\\mathrm{\\,cm^{-2}})$ gas consistent with previous results for other sources [@ilee2013]. ",
"In fact, the high CO column density suggests that this emission possibly originates close to the midplane of the disc. ",
"Indeed, there is a factor of $10^{4}$ between the CO column density and the total gas column density, implying a gas column density of $N_\\mathrm{total}\\sim10^{26}\\mathrm{\\,cm^{-2}}$.\n\nAs suggested by the jet geometry, the circumstellar disc of IRAS11101-5829 should be almost edge-on. ",
"Such geometry should be very evident in our CO line profiles as the projected Keplerian rotation term ($\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$) is expected to be large in edge-on discs and therefore form a prominent “shoulder” to the left of the bandheads; in Figs. ",
"3 and 4 of @ilee2013 the prominent shoulder in a spectrum with large $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$ is shown (see also Appendix \\[sect:appendix\\_CO\\] for an explanation of the formation of the shoulder). ",
"However, no indication of large $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$ ($=25\\pm5\\mathrm{\\,km\\,s^{-1}}$) is evident in our observations (see Figure \\[fig:CO\\_spectrum\\_zoom\\] for a zoom-in in the first bandhead). ",
"This term is well constrained because no shoulder is present and the low-$J$ components are spectrally resolved, which allow us to match the expected wavelength. ",
"There are then two possible explanations for the low value of $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$.\n\nThe first possibility is that we are observing the CO emission from an almost edge-on disc geometry. ",
"Therefore, $\\sin i_\\mathrm{disc}\\sim1$ (hence $i_\\mathrm{disc}\\sim90^\\circ{}$, i.e. edge-on disc) means that $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}\\approx \\varv_\\mathrm{K}\\approx25\\mathrm{\\,km\\,s^{-1}}$. However, this velocity would locate the CO emitting region at more than 10au in a disc in Keplerian rotation ($v_\\mathrm{K}=(GM_*/d)^{0.5}$, where $G$ is the gravitational constant, $M_*$ the mass of the source, and $d$ the distance from source) around a massive protostar of $10-20\\,M_\\odot$ (Fig.",
" \\[fig:disc\\_checks\\] top panel). ",
"However, this scenario can be excluded when considering the gas expected temperature at that distance. ",
"A simple estimate of the temperature in the midplane of the gaseous disc is given by Eq.",
" (\\[eq:T\\_midplane\\]) [i.e. Eq.",
" (15) of @dullemond2010], under the assumption of a dust-free gaseous disc heated by stellar radiation, i.e.\n\n$$T_\\mathrm{disc} = \\left(\\frac{R_*^{3}f}{3\\pi}\\right)^{1/4}T_*R_\\mathrm{disc}^{-3/4}\n \\label{eq:T_midplane}$$\n\nwhere $R_*,R_\\mathrm{disc},T_*, f$ are the radius of the star, the distance from the central source, the temperature of the star, and the factor describing how much of the stellar radiation is longwards of $0.45\\,\\mu$m, which was taken to be one-half, respectively.",
"\n\nAs $L_\\mathrm{bol}\\sim10^4\\,L_\\odot$, we consider two $L_*$ values to cover a wide range of possible luminosities. ",
"Firstly, we assume $L_*\\sim L_\\mathrm{bol}$ as an upper limit (Fig.",
" \\[fig:disc\\_checks\\] bottom panel). ",
"Secondly, we assume $L_*\\sim10^3\\,L_\\odot$ as a lower limit considering that accretion luminosity is comparable to the stellar luminosity. ",
"Stellar parameters were taken from @pecaut2013 assuming the star on the zero age main sequence (ZAMS). ",
"Figure \\[fig:disc\\_checks\\] bottom panel shows that in both cases the gas temperature at more than 10au drops to few hundred Kelvin, which disagrees with our CO modelling (range of values in $T_\\mathrm{disc}$ shown in light blue area). ",
"As the stellar radiation might not be the main source of disc heating, we also investigated the heating effect from viscous accretion [see e.g. Eq. (",
"7.2) from @hartmann2009]. ",
"We find that this effect is not dominant for mass accretion rates equal or below $10^{-4}\\,M_\\odot\\,\\mathrm{yr^{-1}}$. Finally, both the large distance and low temperature of the CO emitting region are also in disagreement with previous studies [@ilee2013]. ",
"Therefore, we can initially exclude the edge-on scenario.",
"\n\nThe second possibility is that we are observing the CO emission from an almost face-on disc geometry. ",
"Our observations suggest that $i_\\mathrm{disc}$ is low ($\\sim10-15^\\circ{}$, almost face-on disc) since the CO bandhead line profile is characterised by a very sharp or non-existent shoulder (see Figs.",
" \\[fig:CO\\_spectrum\\] and \\[fig:CO\\_spectrum\\_zoom\\]). ",
"A low value of $i_\\mathrm{disc}$ implies that $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}\\approx100-150\\mathrm{\\,km\\,s^{-1}}$ (green dotted and blue dash-dotted lines in Fig.",
" \\[fig:disc\\_checks\\], respectively), which agrees better with the expected distance of the CO disc emitting region, i.e. a few astronomical units. ",
"At this distance, the temperature of the disc ($T_\\mathrm{disc}$) is consistent with the results obtained in our modelling (see Fig.",
" \\[fig:disc\\_checks\\]) and with results from literature [@ilee2013]. ",
"Nevertheless, a face-on disc geometry of the disc strongly disagrees with that of the jet, which is well-constrained.",
"\n\nWe suggest a reflection scenario to reconcile the disc-jet geometries. ",
"In the proposed scenario, the disc of IRAS11101-5829 is indeed edge-on (in the plane of the sky), but what we are observing is the reflected light in the mirror of the outflow cavity walls, from which the disc is “seen” close to face-on. ",
"In Figure \\[fig:schematic\\_view\\] we present our proposed reflection scenario highlighting the main components. ",
"Direct observations of the circumstellar disc is blocked by obscuring material, most likely the thick envelope of the system. ",
"This prevents us from observing the characteristic shoulder of edge-on discs. ",
"The light from the disc is then reflected in the outflow cavity wall and observed at a different angle. ",
"The large-scale jet is still visible beyond the envelope and allows us to establish the geometry of the system.",
"\n\nFinally, it is worth mentioning that reflected CO emission has been observed in another HMYSO, W33A, using IFU observations as well [@davies2010]. ",
"The authors observed extended CO and extracted the spectrum at five representative positions. ",
"They were able to observe changes in the CO line profile and discussed the possibility that they were observing the system from different viewing angles. ",
"There, at variance with IRAS11101-5829, the NIR continuum peak matches the real position of the object.",
"\n\nPosition of the central source\n------------------------------\n\nAnother interesting result from our spectroscopic and kinematic analysis is that the position of the driving source in the NIR FoV might be misinterpreted. ",
"It is natural to think that its position coincides with the peak of the NIR continuum emission. ",
"However, our analysis shows that the CO emission at this position can be modelled with the same disc conditions as in other parts of the outflow cavities. ",
"Therefore, the NIR continuum peak is also seen in scattered light. ",
"This is also supported by $JHK$ polarimetric observations [@tamura1997]. ",
"These observations reveal high degree of polarisation ($30-75\\%$) with a centro-symmetric pattern owing to scattered light (see their Fig.",
" 3). ",
"Tamura et al. ",
"proposed that the scattered polarisation originates from the nebulosity associated with the outflow cavity walls. ",
"The authors also proposed a position of the central source from the centro-symmetric pattern of the polarimetric observations in the $K$-band, although with a large uncertainty given by their low spatial resolution ($\\sim1.7^{\\prime\\prime}$; see Figure \\[fig:flux\\_density\\_maps\\]). ",
"With our observations we can narrow down the uncertainty on the position of the central engine using kinematic maps (see Fig.",
" \\[fig:H2\\_vel\\_map\\]). ",
"The driving source of HH135/136 should lay in the geometrical centre between the blue- and red-shifted lobes of the jet. ",
"Therefore, we suggest a position for the driving source of RA(J2000) = 11h12m18.03s, Dec(J2000) = -58d46m21.4s. ",
"We estimate an uncertainty of $0.4^{\\prime\\prime}$ based on our AO-assisted observations (see Fig.",
" \\[fig:H2\\_vel\\_map\\]).",
"\n\n![*",
"Top panel:* Keplerian rotation vs. distance from the central source for a $10\\,M_\\odot$ (blue solid curve) and $20\\,M_\\odot$ (green solid curve) protostar. ",
"Dashed lines show the expected Keplerian velocity for $i$ equals 10$\\degr$, 15$\\degr$, and 90$\\degr$ (blue, green, and red dashed line, respectively). ",
"Vertical lines at 0.4au (dashed) and 2.0au (solid) are drawn for reference where the lines intersect with the plausible inclination values. *",
"Bottom panel:* Disc temperature vs. distance from the central source for $log_{10}L_*=3.10$ (black dashed curve) and $log_{10}L_*=4.13$ (black solid curve). ",
"Observed gas temperature range is indicated in purple. ",
"Vertical lines at 0.9au (dashed) and 2.5au (solid) are drawn for reference where the lines intersect with the plausible values in temperature.[]{data-label=\"fig:disc_checks\"}](figures/vkep_distance.png \"fig:\"){width=\"48.50000%\"} ![*",
"Top panel:* Keplerian rotation vs. distance from the central source for a $10\\,M_\\odot$ (blue solid curve) and $20\\,M_\\odot$ (green solid curve) protostar. ",
"Dashed lines show the expected Keplerian velocity for $i$ equals 10$\\degr$, 15$\\degr$, and 90$\\degr$ (blue, green, and red dashed line, respectively). ",
"Vertical lines at 0.4au (dashed) and 2.0au (solid) are drawn for reference where the lines intersect with the plausible inclination values. *",
"Bottom panel:* Disc temperature vs. distance from the central source for $log_{10}L_*=3.10$ (black dashed curve) and $log_{10}L_*=4.13$ (black solid curve). ",
"Observed gas temperature range is indicated in purple. ",
"Vertical lines at 0.9au (dashed) and 2.5au (solid) are drawn for reference where the lines intersect with the plausible values in temperature.[]{data-label=\"fig:disc_checks\"}](figures/tdisc_distance_Eq15_DandM10.png \"fig:\"){width=\"49.00000%\"}\n\n![",
"Suggested configuration of the first 20000 au of the IRAS11101-5829 system. ",
"There is some obscuring material blocking direct observation of the central source and its immediate environment. ",
"The system is reflected in the outflow cavity walls.[]{data-label=\"fig:schematic_view\"}](figures/schematic_view_IRAS11_first_20k_au_V5.pdf){width=\"45.00000%\"}\n\nConclusions {#sect:conclusions}\n===========\n\nIn conclusion, we argue that the reflection scenario might be more common than previously expected in other HMYSOs, preventing us from retrieving the true geometry and ultimately the right parameters. ",
"Combining simultaneous studies of jet-disc systems can usher us to discern the geometry and nature of these massive protostars better. ",
"Likewise, it is fundamental to observe at both high spatial and spectral resolution at the same time to resolve the immediate environment of the central engine. ",
"Future ALMA observations will reveal the true geometry of the circumstellar disc of IRAS 11101-5829. ",
"At these wavelengths it could be possible to penetrate the obscuring material hindering direct observations of the system in the optical and NIR, reveal the dusty disc, and set strong constraints in its geometry [see e.g. @sanchez-monge2013]. ",
"Our main findings are summarised in the following:\n\n- We observed, for the first time, NIR CO overtone bandhead emission in IRAS11101-5829 indicative of an active accretion disc.",
"\n\n- We modelled the CO emission with an LTE model retrieving relatively warm $(T=3000\\pm500\\mathrm{\\,K})$ and dense $(N(\\mathrm{CO})=1^{+0.2}_{-0.4}\\times10^{22}\\mathrm{\\,cm^{-2}})$ conditions. ",
"The high density indicates that this emission is most likely coming from the midplane of the inner gaseous disc.",
"\n\n- We also observed the protostellar jet close to the source in the form of H$_2$. We estimated the geometry of the jet close to the source, which lies in the plane of the sky (consistent with previous results).",
"\n\n- Both imaging and spectroscopic analysis indicate that the CO (and the bulk of the Br$\\gamma$) emission is reflected in the outflow cavity walls and thus the inner gaseous disc appears to be seen close to face-on.",
"\n\n- The NIR continuum emission is seen through scattered light and as a consequence the position of the central source does not coincide with the NIR peak.",
"\n\nR.F. acknowledges support from Science Foundation Ireland (grant 13/ERC/12907) and from the School of Physics of University College Dublin. ",
"A.C.G. and T.P.R. have received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No.",
" 743029). ",
"R.G.L has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant (agreement No.",
" 706320). ",
"M.K. is funded by the Irish Research Council (IRC), grant GOIPG/2016/769 and Science Foundation Ireland (grant 13/ERC/12907). ",
"A.N. acknowledges the kind hospitality of the DIAS. ",
"We would like to thank the anonymous referee for his/her comments that help to improve the quality of the manuscript. ",
"We would like to thank Devaraj Rangaswamy for fruitful conversations on polarimetric observations.",
"\n\nLTE NIR CO overtone disc model {#sect:appendix_CO}\n==============================\n\nOur CO modelling is based on @kraus2000 and first used in @koutoulaki2019. ",
"We assume that the emission is coming from a single ring undergoing Keplerian rotation in LTE. ",
"In this way, the levels are populated following the Boltzmann distribution, i.e.\n\n$$N_{\\upsilon,J}=\\frac{N}{Z}(2J+1)\\,e^{\\frac{-E_{\\upsilon,J}}{kT}}\n \\label{eq:boltzmann}\n,$$\n\nwhere $N$ is the total column density of the CO molecule, $T$ is the temperature, $J$ is the rotational level (we considered 100 levels), $\\upsilon$ is the vibrational level, and $k$ is the Boltzmann constant.",
" The quantity $E_{\\upsilon,J}$ is the energy of the vibrational-rotational transition given by [@dunham1932a; @dunham1932b]\n\n$$E_{\\upsilon,J} = hc \\sum_{k,l}Y_{k,l}\\left(\\upsilon+\\frac{1}{2}\\right)^k(J^2+J)^l\n \\label{eq:energy_function}\n,$$\n\nwhere $h$ is the Planck constant, $c$ the speed of light, and $Y_{k,l}$ are the Dunham coefficients (where $k$ and $l$ are the power of the vibrational and rotational quantum number, respectively), and $Z$ is the partition function given by the product of the vibrational and rotational partition functions as shown in Eq.\\[eq:partition\\_function\\]\n\n$$Z = Z_\\upsilon \\cdot Z_J = \\sum_\\upsilon e^{\\frac{-E_\\upsilon}{kT}} \\sum_J (2J+1)\\, e^{\\frac{-E_J}{kT}}\n \\label{eq:partition_function}\n.$$\n\nThe intensity of the line is given by\n\n$$I_\\nu = B_\\nu(T)\\left(1-e^{-\\tau_\\nu}\\right)\n,$$\n\nwhere $B_\\nu(T)$ is the Planck function and $\\tau_\\nu$ is the optical depth for a given frequency $\\nu$, which can be written as (but it is actually given by Eq.",
" \\[eq:total\\_tau\\])\n\n$$\\tau_\\nu(\\upsilon,J;\\upsilon',J') = \\frac{c^2A_{\\upsilon,J;\\upsilon',J'}}{8\\pi\\nu^2}\\left(\\frac{2J+1}{2J'+1}\\frac{N_{\\upsilon',J'}}{N_{\\upsilon,J}}-1\\right)N_{\\upsilon,J}\n \\label{eq:optical_depth}\n.$$\n\nWe assume that each $J$ component has a Gaussian profile given by\n\n$$\\Phi(\\nu) = \n \\frac{1}{\\sqrt{2\\pi}\\frac{\\Delta \\varv}{c}\\nu_0}\n \\exp\\left[-\\left(\\frac{\\nu-\\nu_0}{2\\frac{\\Delta \\varv}{c}\\nu_0}\\right)^2\\right]\n \\label{eq:guassian_broadening}\n,$$\n\nwhere $\\nu_0$ is the rest frequency of the $J$ component. ",
"Applying this broadening a total optical depth is obtained given by\n\n$$\\tau(\\nu) = \\sum_{J=0}^{J=100}\\tau_\\nu(\\upsilon,J)\\Phi(\\nu)\n \\label{eq:total_tau}\n.$$\n\nThe way we select the model velocity grid generates a spectrum with a resolution of $\\mathcal{R}_\\mathrm{model}\\sim0.3\\mathrm{\\,km\\,s^{-1}}$. Once the spectrum is generated and before comparing with the observations, we reduced the resolution to the observed one using a Gaussian convolution (in the case of X-shooter to $\\mathcal{R}\\sim 7000$, i.e. $\\sim43\\mathrm{\\,km\\,s^{-1}}$).",
"\n\nExpression $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$ in the CO modelling\n---------------------------------------------------------------------\n\nAssuming that the CO is emitted in a ring in Keplerian rotation, the rotational velocity is\n\n$$\\varv_\\mathrm{K} = \\sqrt{\\frac{GM_*}{r}}\n \\label{eq:keplerian_velocity}\n,$$\n\nwhere $G$ is the gravitational constant, $M_*$ the protostar mass, and $r$ the disc radius or distance from the central source. ",
"For a single element of the ring with azimuthal angle $\\theta\\in[0,2\\pi],$ the projected velocity is given by the expression\n\n$$\\varv_\\mathrm{proj} = \\cos\\theta\\,\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}\n \\label{eq:projected_velocity}\n,$$\n\nwhere $i_\\mathrm{disc}$ is the inclination of the plane of the disc with respect to the plane of the sky, i.e. $i_\\mathrm{disc}=0^\\circ{}$ is a face-on disc and $i_\\mathrm{disc}=90^\\circ{}$ is an edge-on disc. ",
"We note that $\\varv_\\mathrm{proj}$ takes both positive and negative numbers since $\\cos\\theta\\in[-1,1]$. This fact determines the line broadening and is more evident the larger $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$ gets. ",
"Owing to rotation, the frequency is Doppler shifted according to the expression\n\n$$\\nu_\\mathrm{K} = \\nu_\\mathrm{int}\\left(1+\\frac{\\varv_\\mathrm{proj}}{c}\\right)\n \\label{eq:keplerian_frequency}\n,$$\n\nwhere $\\nu_\\mathrm{int}$ is the intrinsic frequency. ",
"This is the term responsible of the characteristic blue shoulder created in systems with large values of $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$ and therefore large $\\varv_\\mathrm{proj}$.\n\nEven though an accurate and fully constrained fit is not possible with the resolution of our observations $(\\mathcal{R}\\sim7000)$, important information can still be retrieved. ",
"Therefore a visual fit was performed to estimate the best parameters. ",
"In particular, the term $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$ can be very well constraint without the high spectral resolution $(\\mathcal{R}\\gtrsim30\\,000)$ needed for an accurate and proper fit [see e.g. @ilee2013; @ilee2014]. ",
"Fixing a set of $T$, $N(\\mathrm{CO})$, and $\\Delta \\varv$, a small variation in $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$ completely changes the shape of the CO emission. ",
"To prove this, we ran our code for the values that best reproduce our observations (Fig.",
" \\[fig:CO\\_spectrum\\_zoom\\], top panel) and for the same conditions, adopting values of $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$, which are large but still reasonable, $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}=100-200\\mathrm{\\,km\\,s^{-1}}$ [see @ilee2013 for observations reproduced with large values of $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$]. ",
"We can see that with a large value of $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$, the characteristic blue shoulder appears (see above). ",
"In addition to that, this term produces a “shift” of the spectrum to the left or to the right, and therefore affects all the $J-$components. ",
"In Figure \\[fig:CO\\_spectrum\\_zoom\\] bottom panel, it is clear that, by applying a large value of $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$, the low-$J$ components and high-$J$ components are missed in the creation of the blue shoulder. ",
"In conclusion, using the shape of the left part of the peak of the bandhead together with the shape of the low-$J$ components in the observations, we are able to estimate $\\varv_\\mathrm{K}\\sin i_\\mathrm{disc}$ in the model. ",
"In this way, we estimated the uncertainty in our parameters, by fixing all variables but one and varying it until the shape of the CO was significantly different. ",
"Observations at higher spectral resolution are needed to accurately and properly fit our observations. ",
"Model output parameters are given in Table \\[tab:CO\\_model\\_output\\].",
"\n\n{width=\"90.00000%\"} {width=\"90.00000%\"}\n\n{width=\"90.00000%\"}\n\n[^1]: Based on observations collected at the European Southern Observatory Paranal, Chile, Programme ID 0101.C-0317(A) and 098.C-0636(A).",
"\n"
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"SAN MARCOS, Texas -- It has been precisely 40 years since the Lone Star State cast its big electoral clout behind a Democrat for president. ",
"Yet suddenly, Texas is closer to doing so again than it has been in all the years since.",
"\n\nWhile much attention has been fixed on the map of traditional battleground states like Virginia and North Carolina, as well as new and unexpected ones like Arizona and Georgia (both traditionally Republican) all of them may be eclipsed over the long term by what is happening in Texas.",
"\n\nLike a big rain at the end of a long dry spell, the political skies over Texas are turning increasingly purple and putting into play the state's 38 electoral votes, more than any state except California. ",
"Texas has been a land of Republican domination by huge margins, and yet the Republican advantage here has consistently dropped this year to as low as a single percentage point.",
"\n\nTim Brinton/NewsArt.com\n\nIt's easy to lay the blame at the shiny Oxford shoes of the Republican nominee, Donald Trump, who has managed to alienate so many people, from Hispanics to white males alike. ",
"Yet, something more fundamental is happening. ",
"Yes, Texas is becoming less white and more diverse. ",
"But even more importantly is the permanent altering of the landscape: Those wide open spaces are finally filling up. ",
"And the rolling landscape around this once sleepy college town is proof positive.",
"\n\nThis election year, Trump has sunk to new lows not seen since Jimmy Carter barely bested Gerald Ford in 1976 by fewer than 60,000 votes. ",
"Ever since, Texas has been a runaway steed for Republicans. ",
"Ronald Reagan won by more than 1 million. ",
"George H.W. Bush won by 700,000. ",
"His son's margin soared to nearly 2 million. ",
"John McCain cleared hundreds of thousands.",
"\n\nPresident George W. Bush speaks to supporters at a campaign rally in Reunion Arena in Dallas, Texas Monday, November 6, 2006.",
"\n\nMitt Romney won Texas by 16 percent. ",
"In contrast, Trump's margin dwelled in the basement of double digits even when he was the clear front-runner in the spring. ",
"Ever since, polls conducted by the University of Texas Polling Project have displayed a candidacy in a slow spiral, down to a seven-point margin among likely voters -- and just a single point among registered voters in a survey for the Texas Lyceum.",
"\n\nIf Trump has been consistent at anything in Texas, it has been in his direction: down. ",
"Other polls track in the same direction. ",
"This is no mere tightening of a race entering the homestretch. ",
"The Washington Post reported a single-digit lead in August among registered voters. ",
"Likely voters tend to turn out at rates of 85 to 90 percent and are a more reliable gauge, so the Morning Consult gave Trump a six-point edge among them.",
"\n\n\"Texas is not a pure red state anymore,\" said Kyle Dropp, the Morning Consult's research director, who now rates Texas as just leaning Republican. \"",
"It's very purple, particularly because of the Hispanic population.\" ",
"Yet there is more than demographics at work. \"",
"The combination of the slow march of demographic change and Trump's rhetoric,\" according to UT's Joshua Blank, \"appears to have made Texas' registered voter pool more Democratic than we have seen in previous presidential races.\"",
"\n\nPolitical analysts love to argue about whether the Hispanic vote will really turn out and, if so, whether it will make a difference. ",
"But in focusing on demographics they're ignoring geography. ",
"The Lone Star State encompasses nearly 269,000 square miles, more than France.",
"\n\nBig stretches are wide open and probably always will be. ",
"Much of the lonesome Trans-Pecos is dotted only by creosote, windmills and little windblown highway towns like Ft. ",
"Hancock and Van Horn. ",
"Out on the high plains of the Panhandle, the only constant companion can still be the wind.",
"\n\nBut the Texas Triangle, 60,000 square miles anchored by Houston, San Antonio, Austin and Dallas-Ft. ",
"Worth, has drawn nearly 7 million people since 2000. ",
"It is filling up with newcomers, with a flow of migrants from California and New York, as well as immigrants from Latin America, Asia and Africa. ",
"Some 70 percent of the population growth of the state is concentrated here.",
"\n\nTo put that into perspective it's like adding another Dallas, a Hong Kong or a Nanchang every 15 years. ",
"The farms of the rolling countryside here are plowed under daily to make way for the relentless march of suburban tract homes.",
"\n\nUp and down Interstate-35, once small, sleepy towns like Georgetown and New Braunfels top the list of fastest-growing small, American cities as their once rural counties turn into bedroom communities for commuters. ",
"More farm and ranch land is plowed under in Texas each year than any other state. ",
"This is where the suburban counties formed a bulwark for Republicans controlling the state's politics; about 13 counties have made the difference between winning and losing statewide. ",
"Some, it's true, are as Republican as ever. ",
"Near Houston, Montgomery County's strong Republican preference is unchanged since 2000.",
"\n\nBut little by little, the map changes hues. ",
"The big cities and metropolitan counties long ago slipped the GOP's grasp. ",
"Among the counties in Central Texas, Hays County is a prime example of the social and political change sweeping aside tall pastures and mesquite thickets. ",
"For decades, San Marcos was just a sleepy little college town on a crystalline river. ",
"The state university's most famous alumnus was Lyndon Johnson and its most common pastime was tubing downriver on beer-soaked, hot summer days.",
"\n\nBut quickly, it grew. ",
"In 2000, George W. Bush won twice as many votes as Al Gore's vote in Hays County, to 20,000 to 10,000. ",
"Four years later, the number of voters had climbed to 40,000, but Bush beat John Kerry by just 7,000 votes. ",
"In 2008, John McCain held off Barack Obama by fewer than four points. ",
"Four years later, San Marcos, the county seat, was the fastest-growing city in America and Mitt Romney improved his margin, but only to 10 points -- far below the heyday.",
"\n\nBy 2014, San Marcos was the fastest-growing city in the nation for the third year in a row, swelling at nearly 40 percent per year. ",
"Today, the university injects $1 billion into the local economy and streets are constantly being ripped up and widened. ",
"Here, people live cheek-by-jowl at nearly 1,700 per square mile. ",
"That's nearly 1,700 times more dense than the state. ",
"It's about the same density as Miami or New York.",
"\n\nTubers and swimmers have fun on the San Marcos River at City Park off of Cheatum Rd just west of I-35 in San Marcos, TX. ",
"The spring-fed river has become increasingly popular with tubers over the last few years and is now becoming more policed to curb under-aged drinking, lewd behavior and litter problems. (",
"Austin American-Statesman)\n\nIn these high-density environments some things do not thrive as they did in the wide open spaces. ",
"One is the fishhook cactus. ",
"Another is conservative politics. ",
"Out of the 100 most populous cities in the country, for example, fewer than a third are run by Republican mayors. ",
"Dense living means more demand for services, public institutions and a greater sense of shared fate than, say, a solitary rancher up in Tom Green County. ",
"For Republicans, the thunderclouds on the horizon must be troubling: some 35 million Texans will crowd into the Triangle by 2050, on par with today's Northeast Corridor from Boston to New York to Washington.",
"\n\nThe smart money says Hillary Clinton loses Texas, despite a University of Houston poll putting her up by 10 points in Harris County, once Bush country. ",
"The cautious money says ad money will go farther in Virginia and North Carolina than Texas' multiple major media markets. ",
"But the long money says the fact that Texas is in play alone is historic; just taking it out of the predictably red Republican column will alter national politics all by itself.",
"\n\nThere's nothing wrong with Republicans governing Texas, but it is inherently unhealthy for any one party to monopolize power in a state of 26 million people and counting; competition is as good for the body politic as the economy.",
"\n\nSo the change is like a big rain after a long drought, a frog strangler. ",
"The clouds build up slowly untill they blot out the bright orange of dusk. ",
"And right before the deluge, right before dark, the sky turns a beautiful and foreboding shade of purple.",
"\n\nRichard Parker is lecturer-of-practice in journalism at Texas State University and author of Lone Star Nation: How Texas Will Transform America. ",
"Twitter@richardparkertx"
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"\nGlycosaminoglycans (GAGs) such as chondroitin sulphate/dermatan sulphate (CS/DS) are complex molecules that are widely expressed on the cell membrane and extracellular matrix (ECM). ",
"They play an important role in wide range of biological activities especially during pathological conditions. ",
"Diabetes, a metabolic disorder characterized by sustained hyperglycemia, is known to affect GAGs in different tissues and affect erythrocyte adhesion. ",
"The present investigation was aimed at exploring the nature of GAGs present in erythrocytes and its role on adhesion of erythrocytes from control and diabetic rats to major extracellular matrix components. ",
"GAGs isolated from erythrocytes were demonstrated to be CS/DS and a 2-fold increase was observed in erythrocytes from diabetic rats. ",
"Disaccharide composition analysis by HPLC after depolymerization by the enzyme, chondroitinase ABC showed the presence of 4-O sulphated disaccharide units with small amounts of non-sulphated disaccharides, in both control and diabetic erythrocytes. ",
"Erythrocytes from diabetic rats, however, showed significantly increased binding to poly-l-ornithine (P-orn), type IV collagen, laminin and fibronectin, which was abrogated on treatment with chondroitinase ABC to various degrees. ",
"This study sheds new light on CS/DS in erythrocytes and its likely biological implications in vivo."
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"Calves born after open pulled straw vitrification of immature bovine oocytes.",
"\nThe aim of this study was to evaluate the developmental capacity of immature bovine oocytes after vitrification with 20% ethylene glycol (EG)+20% dimethyl sulfoxide (Me(2)SO) and 0.5M sucrose (SUC), by open pulled straw (OPS) technology. ",
"The effect of treatment with cytochalasin D before vitrification was also examined. ",
"No differences were observed in cleavage and blastocyst rates among the group vitrified without cytochalasin D treatment (Vitri) (49.0% and 6.1%) and that with cytochalasin D treatment before vitrification (CDVitri) (46.4% and 3.6%), but both were lower (P<0.05) than the unvitrified control group (85.1 and 45.9%). ",
"Calves were obtained after transfer of fresh and vitrified blastocysts from the Vitri group and after transfer of vitrified blastocysts from the CDVitri group. ",
"Cytochalasin D treatment does not improve the development of immature bovine vitrified oocytes. ",
"The results show that a small proportion of immature oocytes vitrified with this technology are fully competent to produce blastocysts, which may be transferred immediately or vitrified before transfer, and go on to develop healthy offspring."
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"\nAblative fractional resurfacing (AFR) is a new modality for photorejuvenation and acne scars which combines carbon dioxide (CO₂) laser ablation with fractional photothermolysis. ",
"The objective is to evaluate the efficacy and side effects of a new fractional CO₂ ablative device (Fraxel Re:pair) for skin rejuvenation and acne scars in Asians. ",
"Nine patients underwent one full-face treatment. ",
"The energy levels ranged from 30-70 mJ with coverage between 30% and 45%. ",
"Improvement in skin texture, laxity, wrinkles, enlarged pores, overall pigmentation irregularity, and adverse effects were assessed up to 6 months post-treatment. ",
"Standardized photographs using the Canfield Visia CR system® were assessed by two independent observers. ",
"Subjective improvement was assessed by patient questionnaires. ",
"Nine Chinese patients (skin types III and IV, mean age 44.8) were included. ",
"Statistically significant improvements were seen for skin texture, skin laxity, wrinkles, enlarged pores, and acne scars. ",
"The post-inflammatory hyperpigmentation rate was 55.5% and 11.1% at 1 and 6 months post-treatment, respectively. ",
"Eighty-six percent of patients were overall satisfied to very satisfied with the treatment. ",
"Ablative fractional CO₂ laser resurfacing was overall safe and effective for skin rejuvenation and acne scars in Asians. ",
"However, in view of the high post-inflammatory rate and the statistically significant but only mild to moderate improvement after a single treatment as observed in this study, there is a need to review the current role of fractional ablative CO₂ laser treatment as compared to fractional non-ablative for skin rejuvenation and acne scar treatment in Asians."
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"(CNN) It's probably been a long time since you put pen to paper to compose a letter, take notes, make a list or sign a check.",
"\n\nFor old times' sake, why not give it a try in honor of the original John Hancock\n\nNational Handwriting Day falls each year on January 23, the birthday (according to the Gregorian calendar) of the American Revolutionary leader and first signer of the U.S. Declaration of Independence. (",
"While the U.S. government recognizes Hancock's birthday as January 12, others recognize his birthday as January 23 based on our modern-day calendar.)",
"\n\nThe Writing Instrument Manufacturers Association started this holiday in 1977 to acknowledge the history and influence of penmanship. ",
"Its reason for being grows more urgent each year as pens, pencils and paper lose ground to the QWERTY keyboard.",
"\n\nThe earliest forms of writing date approximately 5,000 years ago. ",
"Once upon a time, children learned how to write in cursive as part of handwriting lessons in school. ",
"Those lessons are falling by the wayside as states adopt Common Core standards , which only require manuscript handwriting instruction until the first grade and cursive instruction is not mandated at all.",
"\n\nRead More"
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"Yankees still struggling to hit with runners in scoring position but hoping that luck comes to their side\n\nAP Photo/Kathy WillensThe Yankees are last in the AL at hitting with runners in scoring position and Robinson Cano is their worst everyday player, hitting .148 in those situations.",
"\n\nNEW YORK — To a man, the Yankees shrugged when asked once more to explain the inexplicable.",
"\n\n“I hope it’s bad luck,” Mark Teixeira said after a loss in which his team managed just one hit with runners in scoring position. “",
"At this point, maybe it’s not.”",
"\n\nIn virtually every important offensive category, the Yankees rank in the top five in the American League. ",
"They reach base. ",
"They hit for power. ",
"They score runs.",
"\n\nWith men in scoring position, however, they could rightfully consider themselves the unluckiest hitters on the face of the Earth.",
"\n\nThat’s what the numbers say about the Yanks, who have hit the ball well with runners in scoring position, though they’ve had little to show for it. ",
"Entering play today, their .218 average with men in scoring position ranks last in the American League.",
"\n\nStatistically, they’ve deserved better.",
"\n\n“I don’t imagine that there’s been a team that’s (gone) through it as long as we have and was 14 games or 15 games over .500,” manager Joe Girardi said. “",
"Now, I imagine there are some teams that have (gone) through it and their records haven’t been as good.”",
"\n\nIndeed, they have gotten away with blowing more scoring chances than any other lineup in the league. ",
"At 41-27, the Yankees begin the Subway Series against the Mets tonight with the second-best record in the AL. ",
"But even Girardi acknowledges that something has to change if the Yankees hope to win a World Series.",
"\n\n“It is something that has to get better,” he said.",
"\n\nWhat that entails exactly remains a murky question. ",
"A debate rages on about the ability to hit with runners in scoring position, which by extension is another form of performing in the clutch. ",
"For some, hitting with runners on is a repeatable skill. ",
"For others, it is mainly a function of luck. ",
"And for many, it is an imprecise combination of both.",
"\n\n“I think it comes down to getting a good pitch to hit,” slugger Alex Rodriguez said. “",
"Sometimes, you’re going to hit into some bad luck, you’re going to hit some balls at people. ",
"Like (longtime umpire) Durwood Merrill would say, sometimes you make a Hall of Fame pitch, and you have to tip your cap.”",
"\n\nConclusive answers remain elusive, though this much is clear: With runners in scoring position, the Yankees have hit into more than their share of bad luck.",
"\n\nThis season, they have a line-drive rate of 17.5 percent with men in scoring position. ",
"According to estimates on FanGraphs, at that rate, the Yankees’ average for balls in play should be around .303. ",
"That should translate into a much higher batting average with men in scoring position.",
"\n\nInstead, the .229 average for balls in play is the lowest mark in the league by nearly 50 points — and a strong indicator of bad luck. ",
"And whether that luck turns before the end of the season ultimately remains a matter of chance.",
"\n\n“I’m not a betting man,” Girardi said. “",
"But if I was, I would bet that it’s going to change.”",
"\n\nIn the past, the Yankees have been rewarded for understanding the factors that can make batting averages deceiving. ",
"When they traded for Nick Swisher before the 2009 season, they believed his batting average would bounce back, even though it had fallen to a paltry .219 with the White Sox.",
"\n\nWhat did the Yankees see that others didn’t? ",
"They recognized that Swisher had run into abnormally bad luck. ",
"Despite a healthy line-drive rate, his batting average for balls in play plummeted, which artificially deflated his average.",
"\n\nIt’s the same phenomenon that has afflicted the batting average with runners in scoring position this season.",
"\n\nUltimately, Swisher bounced back to become an All-Star-caliber player. ",
"But that turnaround didn’t begin until the 2009 season. ",
"The Yankees clearly hope for a quicker reversal of fortune when it comes to hitting with men in scoring position.",
"\n\nLogic dictates if they continue to do what they’re doing, if they keep putting the ball in play, if they keep making solid contact, the results will likely turn. ",
"But until that happens, they must lean on little more than hope.",
"\n\nGirardi and hitting coach Kevin Long have preached all season the importance of staying the course. ",
"They insist the bats in the lineup are too good to struggle over the long term.",
"\n\nHowever, the wait hasn’t been easy, and the answers are just as elusive now as they have been all season.",
"\n\n“It’s just not happening for us,” Girardi said. “",
"I don’t really have a reason for it. ",
"We’ve hit some balls hard and they’ve been outs. ",
"I believe it is something that’s going to change.”"
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"Ahh, your reply did clarify your position, which I agree with for the most part.",
"One thing:\n\nQuote:One Satanist proclaiming one thing to be unsatanic will not be for another\n\nI would say the very 'proclaiming' of someones aesthetics to be unSatanic, unSatanic. ",
"Someone that understands the philosophy knows there is no right or wrong aesthetic, and would recognise the solopsism in trying to dictate otherwise. ",
"With that I agree.",
"However, there are things that are inherantly unSatanic, no matter how many proclaimed Satanists state otherwise.",
"\n\n_________________________ \"One thing I have learned in a long life: that all our science, measured against reality, is primitive and childlike and yet it is the most precious thing we have.\" - ",
"Albert Einstein\n--------------------\n\nI find a bit of truth in the post. ",
"But, I think you're taking it to a bit of an extreme degree. ",
"Just because someone dresses in black and wears baphomets and blah blah blah, doesn't necessarily mean that they are just attention-whoring. ",
"I think the problem is more the intent of the apparel than the actual style of dress itself.",
"\n\nFor instance, mindless teens (we were all one at one time, I think) dressing in black wearing Marilyn Manson shirts and saying their Satanists are, of course, quite counter-productive and about as satanic as a televangelist.",
"\n\nBut, if a Satanist wants to wear the clothes and the baphomet *shrug* let them. ",
"They're grown people, usually. ",
"Most of them, I would hope, have been dressing themselves for years. ",
"While attention-whoring does seem to be one of my peeves I won't criticize anyone for their style. ",
"Myself I'm a bit of a mixture of everything. ",
"I'm in the US Army. ",
"It's a difficult place to be a Satanist. ",
"You kind of have to do a certain amount of conforming here. ",
"But, I do it more because I like to draw as little attention to myself as possible. ",
"Just makes life easier to be the guy that slips through the cracks.",
"\n\nHmm, I seem to have wandered slightly off-topic here.",
"\n\nAt any rate, it's the intent of the clothing rather than the clothing itself, I think. ",
"Annoying, but not really a problem, I think. ",
"At least not one worthy of much of my attention, in my opinion.",
"\n\nIn closing, you're right about one thing. ",
"Sleep is good before posting\n\nA whole lot of it goes back to the theories of lesser magic. ",
"I've said it before and I will say it again, I pump out as much of a Satanic look as I can simply for the fear. ",
"In a town where Xian's rule through fear, they eventually trick themselves into fearing their own shadows. ",
"When I entered the midst, Fear slided into place. ",
"Those that do not fear me tend to get to know me, as through my looks I aspire wonder. ",
"Then, after a few Tarot readings or something of that nature, they begin to come to me for me to make their every dicision for them. ",
"Just yesterday, one of my loyal subjects brought in his girlfriend to get a reading, and she believed it just as much as he did. ",
"When the sheep stray from the herd, they are much easier to pick off.",
"\n\n_________________________\n\"There is a beast in man that should be exercised, not exorcised.\" ",
"~ Anton Szandor LaVey\n\nQuote: Satanism does not need warriors or leaders. ",
"Satanism needs to be lived and not taught. ",
"A Satanist should not be trying to \"lead\" other Satanists. ",
"Satanists are individuals with individual needs and wants.",
"\n\nSatanists don't need leaders, as such, but in a group of Satanists, you will have types that have \"leadership qualities\" that allow them to take charge, move to the front of the line, come up with ideas, and give directions. ",
"Some of us aren't that assertive, patient, or organized, so we might be independent workers or people who set things up in \"the background.\"",
"\n\n_________________________\n\"Gentlemen, the verdict is guilty, on all ten counts of first-degree stupidity. ",
"The penalty phase will now begin.",
"\"--Divine, \"Pink Flamingos.\"",
"\n\nI find televangelists to be most Satanic indeed.",
"They use charisma and manipulation to further their own financial ends, all the while convincing their marks no such thing is happening.",
"What could be more Satanic than that?",
"\n\n_________________________ \"One thing I have learned in a long life: that all our science, measured against reality, is primitive and childlike and yet it is the most precious thing we have.\" - ",
"Albert Einstein\n--------------------\n\nWell excuse me for liking Black clothing. ",
"I have loved and worn black most of my life, long before my Satanic realization, as far as wearing black to make a statement of any sort their is no problem with this as long as the statement made is not anti-Satanic.",
"What the hell is a Lemming? ",
"Other than the small animal of course.",
"Then we have the \"Shock factor\", It's sometimes enjoyable to see the Xtians squirm and as a Satanist I tend to do those things I enjoy.",
"When it comes to herd conformity I don't guess I quite make it as anything but \"A fashion victim\" or so I've been told by the herdlings.",
"Dark eveDrkMasterPrince\n\n_________________________\n\"That which does not kill us makes us stronger\"\"The dreams of youth are the regrets of maturity\"\n\nWe must understand that behind the \"herd conformity\" stand hundreds of thousands of years of social evolution. \"",
"Mirroring\" as a way of saying \"I like you\" is wired deep in the core of our mind as well as many other things, such as agreement with the \"opinion of the majority\" (in fact there is no such thing at all!). ",
"It takes time to get rid of those instincts and choose to go your own way. ",
"The stronger you become, the more \"social resistance\" you meet. ",
"You can change yourself, but you cannot change the crowd. ",
"Everything in fact, is bollocks..."
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"Jacki MacDonald\n\nJacki MacDonald [born Jenine MacDonald, in Brisbane, Queensland] is a former Australian television personality, who now works in radio broadcasting.",
"\n\nCareer\nPopular in her home state of Queensland, MacDonald appeared on a number of local programs in the 1970s including her own show, Jacki and all that Jazz, on QTQ-9 and a daily breakfast program, The Jacki Mac Show, on TVQ-0.",
"\n\nIn 1978 she was GTV-9's replacement for Daryl Somers and puppet sidekick Ossie Ostrich when the pair moved to 0-10. ",
"After she presented The Super Saturday Show for several months, Somers returned to Nine and she was asked to join them as co-presenter of a revival of Hey Hey It's Saturday, a role which she would continue for nine years. ",
"MacDonald was frequently made the butt of jokes in the show and when she came on the tune \"Folks Are Dumb Where I Come From\" would often be played (a reference to MacDonald coming from Queensland). ",
"In 1984, the same year as HHIS'''s move from a local morning timeslot to a national primetime slot, MacDonald also hosted The Ossie Ostrich Video Show, a national weekday children's program on Nine.",
"\n\nFor a short time MacDonald was also an anchor of TVQ-0's Eyewitness News bulletins in 1983, which made her one of the few presenters to appear for two different networks at the same time (in her case, the Nine and Ten networks).",
"\n\nDuring the 1970s and 1980s she won several TV Week Logie Awards for Most Popular Female Personality in Queensland.",
"\n\nMacDonald kept out of the spotlight following her departure from Hey Hey in 1988 (returning for two episodes in Brisbane in 1990). ",
" She returned to television in 1991 to host a season of Australia's Funniest Home Video Show after Graham Kennedy left. ",
"In 1992, former Hey Hey It's Saturday producer Gavan Disney approached her to co-host his new TV program Healthy Wealthy And Wise which was being produced for Network Ten. ",
"She continued with the new program for a couple of years before leaving television altogether. ",
"MacDonald appeared on the 2005 Network Ten special Seriously 40 which commemorated 40 years of Network Ten. ",
"On 7 October 2009 she made a guest appearance on the second Hey Hey reunion special. ",
" When Hey Hey returned as a series in 2010 she did two appearances. ",
"The first one was at a museum but the second she was very ill with the flu and used Skype to communicate. ",
"This was her last appearance.",
"\n\nMacDonald is now a regular show business commentator on Drive with Michael Smith for the Brisbane commercial talk radio station 4BC.",
"\n\nAwards and honours\n1983 - Advance Australia Ambassador\n\nPersonal life\nMacDonald's sister, Fiona MacDonald, is also a former television presenter who was on local television in Queensland before going on national programs such as Wombat and the Australian version of It's a Knockout''.",
"\n\nShe is married to Dr Michael Pitney, and they have three children.",
"\n\nReferences\n\nExternal links\n \n\nCategory:1953 births\nCategory:Australian game show hosts\nCategory:Living people\nCategory:People from Brisbane"
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"Origins of female genital diversity: Predation risk and lock-and-key explain rapid divergence during an adaptive radiation.",
"\nThe study of male genital diversity has long overshadowed evolutionary inquiry of female genitalia, despite its nontrivial diversity. ",
"Here, we identify four nonmutually exclusive mechanisms that could lead to genital divergence in females, and potentially generate patterns of correlated male-female genital evolution: (1) ecological variation alters the context of sexual selection (\"ecology hypothesis\"), (2) sexually antagonistic selection (\"sexual-conflict hypothesis\"), (3) female preferences for male genitalia mediated by female genital traits (\"female-choice hypothesis\"), and (4) selection against inter-population mating (\"lock-and-key hypothesis\"). ",
"We performed an empirical investigation of all four hypotheses using the model system of Bahamas mosquitofish inhabiting blue holes that vary in predation risk. ",
"We found unequivocal support for the ecology hypothesis, with females exhibiting a smaller genital opening in blue holes containing piscivorous fish. ",
"This is consistent with stronger postmating female choice/conflict when predators are present, but greater premating female choice in their absence. ",
"Our results additionally supported the lock-and-key hypothesis, uncovering a pattern of reproductive character displacement for genital shape. ",
"We found no support for the sexual conflict or female choice hypotheses. ",
"Our results demonstrate a strong role for ecology in generating female genital diversity, and suggest that lock-and-key may provide a viable cause of female genital diversification."
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