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Association between sleep and behavioural problems among children with enuresis. This study was conducted to describe sleep problems in a sample of children with enuresis and to investigate the association between sleep and behavioural problems. In this cross-sectional study, 100 children with enuresis were recruited from paediatric enuresis clinic. The children's sleep problems and behaviours were assessed by the Children's Sleep Habits Questionnaire and Child Behaviour checklist. The most frequently reported sleep problems were in daytime sleepiness, bedtime resistance and sleep anxiety subscales. Children with T-scores ≥ 60 in internalising, externalising and total behavioural problems had higher scores on daytime sleepiness subscale and total score than children with T-scores < 60. Multivariate logistic regression analysis revealed that daytime sleepiness subscale was significantly related to behavioural disturbances. Sleep problems are common among this sample of children with enuresis, and the presence of sleep disturbance such as daytime sleepiness could explain the association between enuresis and disturbed daytime behaviour.

2023-12-16T01:27:04.234600

https://example.com/article/1736

Comparative bacterial genomics: defining the minimal core genome. A comparative genomics analysis revealed 702 genes present in the bacterial Gram-negative core gene set (92 species analyzed) and 959 genes in the Gram-positive core gene set (93 species analyzed). Mycoplasma genitalium, which has the smallest known genome (517 genes) of a non-symbiont, was used in a three-way reciprocal analysis with the Gram-negative core genes and the Gram-positive core genes, and 151 common bacterial core genes were found. Of these 151 core genes, 39 were putative genes encoding the 30S and 50S ribosomal subunits, whilst among recognized cell division genes, only one gene, the major ftsZ, was present. In addition, 86 reciprocal matches were identified between the 151 common bacterial genes and a previously determined 2,723 common eukaryotic core gene set. An analysis was also done to optimize the threshold bit score used to declare that genes were homologous, and a bit score cutoff of 40 was selected.

2024-03-12T01:27:04.234600

https://example.com/article/7051

The semiconductor device is in the form of a semiconductor chip formed as a recording head of an ink-jet printer or in the form of a semiconductor wafer having at least two semiconductor chips. The semiconductor chip has at least an ink ejection unit, an integrated circuit composed of a drive circuit...http://www.google.ca/patents/US6663227?utm_source=gb-gplus-sharePatent US6663227 - Semiconductor device and process for producing the same The semiconductor device is in the form of a semiconductor chip formed as a recording head of an ink-jet printer or in the form of a semiconductor wafer having at least two semiconductor chips. The semiconductor chip has at least an ink ejection unit, an integrated circuit composed of a drive circuit for driving the ink ejection unit, bonding pads and a metal film covering at least part of an upper layer of the integrated circuit. The metal film is formed to extend from the integrated circuit to an edge of the semiconductor chip. The semiconductor wafer further has at least one grounding pad being formed of the metal film in a region peripheral to the semiconductor wafer and which is outside the semiconductor chips. The metal film is formed not only to extend from each of the integrated circuits to the edge of each of the semiconductor chips but also in a region between the semiconductor chips and the metal films formed to extend to edges of all the semiconductor chips are interconnected via the region between the semiconductor chips and also connected to the grounding pad. Images(6) Claims(15) What is claimed is: 1. A semiconductor device as a semiconductor chip formed as a recording head of an ink-jet printer, said semiconductor chip comprising at least an ink ejection unit, an integrated circuit comprising a drive circuit for driving the ink ejection unit, bonding pads and a metal film covering at least part of an upper layer of said integrated circuit, said metal film being formed to extend from said integrated circuit to an edge of said semiconductor chip and to be electrically insulated from said integrated circuit. 2. The semiconductor device according to claim 1, wherein said metal film also covers further an upper layer of at least one of said bonding pads in such a way as to extend from said bonding pad to an edge of said semiconductor chip. 3. The semiconductor device according to claim 1, wherein said ink ejection unit includes heat-generating resistors, said metal film is formed of the same material as said heat-generating resistors, and said recording head of said ink-jet printer is a recording head of a thermal ink-jet printer. 4. A semiconductor device as a semiconductor wafer including: at least two semiconductor chips, each semiconductor chip being formed as a recording head of an ink-jet printer and having at least an ink ejection unit, an integrated circuit comprising a drive circuit for driving the ink ejection unit, bonding pads and a metal film covering at least one part of an upper layer of said integrated circuit; and at least one grounding pad being formed of said metal film in a peripheral region of said semiconductor wafer and which is outside said semiconductor chips; wherein said metal film is formed not only to extend from each of said integrated circuits to an edge of each of said semiconductor chips but also in a region between said semiconductor chips, and wherein the metal film is formed to extend to the edges of all semiconductor chips are interconnected via the region between said semiconductor chips and also connected to said grounding pad. 5. The semiconductor device according to claim 4, wherein said metal film also covers further an upper layer of at least one of said bonding pads in such a way as to extend from said bonding pad to an edge of each of said semiconductor chips. 6. The semiconductor device according to claim 4, wherein the region between said semiconductor chips is a scribing line. 7. The semiconductor device according to claim 4, wherein said ink ejection unit includes heat-generating resistors, said metal film is formed of the same material as said heat-generating resistors, and said recording head of said ink-jet printer is a recording head of a thermal ink-jet printer. 8. A process for producing a semiconductor device in a semiconductor wafer having at least two semiconductor chips formed thereon, each serving as a recording head of an ink-jet printer, comprising the steps of: forming at least an ink ejection unit and an integrated circuit composed of a drive circuit for driving the ink ejection unit on a semiconductor substrate for each of said semiconductor chips; covering at least part of an upper layer of the integrated circuit on each of said semiconductor chips to form metal films that each extend from said integrated circuit to an edge of each of said corresponding semiconductor chips and which are also interconnected via region between said semiconductor chips, and also forming at least one grounding pad from said metal film in a region peripheral to said semiconductor wafer and which is outside said semiconductor chips, said grounding pad being connected to said metal film via the region between said semiconductor chips; and applying a processing step with said metal films being grounded via said grounding pad. 9. The process for producing the semiconductor device according to claim 8, wherein said ink ejection unit includes said heat-generating resistors, said recording head of said ink-jet printer is a recording head of a thermal ink-jet printer, and said metal films are formed of the same material as said heat-generating resistors simultaneously with formation of said heat-generating resistors after forming said drive circuit. 10. The process for producing the semiconductor device according to claim 8, wherein not only said integrated circuit but also bonding pads are further formed on the semiconductor substrate for each of said semiconductor chips, and wherein said metal film also covers further an upper layer of at least one of said bonding pads in such a way as to extend from said bonding pad to an edge of each of said semiconductor chips. 11. The process for producing the semiconductor device according to claim 8, wherein said processing step is either a step of forming an ink channel for supplying ink to each of said ink ejection unit or a step of boring ink supply holes through said semiconductor substrate for supplying ink to the ink channel or both steps. 12. The process for producing the semiconductor device according to claim 8, wherein said region between said semiconductor chips is a scribing line. 13. The process for producing the semiconductor device according to claim 8, wherein said metal films are also formed on a reverse side of said semiconductor wafer which is opposite a side where said integrated circuits for said semiconductor chips are formed. 14. The process for producing the semiconductor device according to claim 13, wherein said metal films formed on the reverse side of said semiconductor wafer cover the entire surface of the reverse side of said semiconductor wafer. 15. The process for producing the semiconductor device according to claim 13, wherein said metal films formed on the reverse side of said semiconductor wafer are removed after finishing said processing step. Description BACKGROUND OF THE INVENTION This invention relates to a semiconductor device and a process for producing the same. More particularly, it relates to the technology of semiconductor device fabrication for ensuring that elements formed in an integrated circuit on a semiconductor chip will not break down electrically due to processing steps such as sand blasting and dry etching. The semiconductor device contemplated by the invention is formed as the recording head of ink-jet printer. A typical process for producing the recording head of a thermal ink-jet printer comprises the steps of preparing a semiconductor device by forming heaters (heat-generating resistors) and their drive circuit on a semiconductor chip (substrate), forming an ink channel and ink supply holes and forming a cavity on each heater that serves as an ink chamber, attaching an orifice plate to the entire surface of the semiconductor device, and opening ink ejection orifices (nozzles) in a position corresponding to each heater. Conventionally, ink channels and ink supply holes are formed by anisotropic etching of a semiconductor chip with a liquid etchant such as hydrazine or potassium hydroxide (KOH), with the regions other than the ink channels and ink supply holes being masked with a photoresist. However, hydrazine is a very strong carcinogen and has a potential hazard of explosion; KOH is such a strong etchant that it can potentially strip the resist and damage the areas other than the ink channels and ink supply holes. Alternative methods of forming ink channels and ink supply holes are laser ablation and sand blasting. In sand blasting, small-diameter particles of a blasting medium such as alumina are blown at high speed against a semiconductor device (substrate), with the regions other than ink channels and ink supply holes being masked, to form ink channels and ink supply holes simultaneously in a plurality of semiconductor chips formed on a semiconductor wafer. Sand blasting has the advantage of forming ink channels and ink supply holes in higher resolution with better efficiency than laser ablation. However, the sand blasting process involving the blowing of small-diameter particles with dry air is not without problems. On account of the friction between the particles and the air, static electricity is generated and the resulting static buildup on the surface of the semiconductor chip can potentially break down the semiconductor device. In the case of the recording head of a thermal ink-jet printer, the drive circuit formed as an element of an integrated circuit on the semiconductor chip may break down due to static buildup during production. Speaking further of the recording head of a thermal ink-jet printer, orifices are usually formed by dry etching an orifice plate while masking the regions other than those corresponding to the individual heaters. However, when orifices are opened by dry etching, molecules in the state of an ion plasma cause static buildup on the oxidized film formed on each heater and can potentially break down the drive circuit connected to each heater. SUMMARY OF THE INVENTION The present invention has been accomplished under these circumstances and has an object providing a semiconductor device furnished with a structure which ensures that elements that comprise a drive circuit for driving an ink ejection or delivery unit and which are formed in an integrated circuit on a semiconductor chip to comprise the recording head of an ink-jet printer will not break down electrically during fabrication due to processing steps such as sand blasting and dry etching. Another object of the invention is to provide a process for producing the semiconductor device. The first object of the invention can be attained by a semiconductor device according to its first aspect which is in the form of a semiconductor chip formed as a recording head of an ink-jet printer, the semiconductor chip comprising at least an ink ejection unit, an integrated circuit composed of a drive circuit for driving the ink ejection unit, bonding pads and a metal film covering at least part of an upper layer of the integrated circuit, the metal film being formed to extend from the integrated circuit to an edge of the semiconductor chip. Preferably, the metal film also covers further an upper layer of at least one of the bonding pads in such a way as to extend from the bonding pad to an edge of the semiconductor chip. According to its first aspect, the invention also provides a semiconductor device as a semiconductor wafer including at least two semiconductor chips of the structure described above and at least one grounding pad being formed of the metal film in a region peripheral to the semiconductor wafer and which is outside the semiconductor chips, wherein the metal film is also formed in a region between the semiconductor chips, and wherein the metal films formed to extend to edges of all the semiconductor chips are interconnected via the region between the semiconductor chips and also connected to the grounding pad. Preferably, the region between the semiconductor chips is a scribing line. In each of the embodiments described above, the ink ejection unit includes heat-generating resistors, the metal film is formed of the same material as the heat-generating resistors, and the recording head of the ink-jet printer is a recording head of a thermal ink-jet printer. The second object of the invention can be attained by a process according to its second aspect for producing a semiconductor device in a semiconductor wafer having at least two semiconductor chips formed thereon, each serving as a recording head of an ink-jet printer, which process comprises the steps of forming at least an ink ejection unit and an integrated circuit composed of a drive circuit for driving the ink ejection unit on a semiconductor substrate for each of the semiconductor chips, covering at least part of an upper layer of the integrated circuit on each of the semiconductor chips to form metal films that each extend from the integrated circuit to an edge of each of the corresponding semiconductor chips and which are also interconnected via a region between the semiconductor chips, and also forming at least one grounding pad from the metal film in a region peripheral to the semiconductor wafer and which is outside the semiconductor chips, the grounding pad being connected to the metal film via the region between the semiconductor chips, and applying a processing step with the metal films being grounded via the grounding pad. Preferably, the ink ejection unit includes the heat-generating resistors, the recording head of the ink-jet printer is a recording head of a thermal ink-jet printer, and the metal films are formed of the same material as the heat-generating resistors simultaneously with formation of the heat-generating resistors after forming the drive circuit. Preferably, not only the integrated circuit but also bonding pads are further formed on the semiconductor substrate for each of the semiconductor chips, and the metal film also covers further an upper layer of at least one of the bonding pads in such a way as to extend from the bonding pad to an edge of each of the semiconductor chips. Preferably, the processing step is either a step of forming an ink channel for supplying ink to each of the ink ejection unit or a step of boring ink supply holes through each of the semiconductor substrate for supplying ink to the ink channel or both steps. Preferably, the region between the semiconductor chips is a scribing line. Preferably, the metal films are also further formed on a reverse side of the semiconductor wafer which is opposite a side where the integrated circuits for the semiconductor chips are formed. Preferably, the metal films formed on the reverse side of the semiconductor wafer cover the entire surface of the reverse side of the semiconductor wafer. Preferably, the metal films formed on the reverse side of the semiconductor wafer are removed after finishing of the processing step. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows a structural outline for the recording head of a thermal ink-jet printer which is an embodiment of the semiconductor device according to the first aspect of the invention; FIG. 2 is a cross-sectional layout of an embodiment of the recording head shown in FIG. 1; FIG. 3 is a plan view showing in conceptual form an embodiment of the semiconductor device according to the first aspect of the invention; FIG. 4 is a flowchart for exemplary steps in the process for producing the semiconductor device according to the second aspect of the invention; FIG. 5A to FIG. 5D are sections A—A of the semiconductor device in the process of fabrication according to the invention; FIG. 6A and FIG. 6B are sections B—B of the semiconductor device in the process of fabrication according to the invention; and FIG. 7 is a section of the semiconductor device in the process of fabrication by another example of the invention process. PREFERRED EMBODIMENT OF THE INVENTION The semiconductor device of the invention and the process for producing it are described below in detail with reference to the preferred embodiments shown in the accompanying drawings. The recording head of a thermal ink-jet printer as an embodiment of the semiconductor device which is formed as the recording head of an ink-jet printer according to the first aspect of the invention is described below. FIG. 1 shows a structural outline for an embodiment of the recording head of a thermal ink-jet printer according to the first aspect of the invention. As shown, the recording head generally indicated by 10 comprises heat-generating resistors 11 (R1, R2, . . . , Rn) associated with individual orifices (nozzles) and their drive circuit 12. The orifices are recording elements that perform printing. The drive circuit 12 comprises driver transistors T1, T2, . . . Tn respectively associated with the heat-generating resistors R1, R2, . . . Rn and their control circuit 14. The heat-generating resistors R1, R2, . . . Rn are connected at one end to a common ground GND and are connected at the other end to the sources of the associated driver transistors T1, T2, . . . Tn. The drains of the driver transistors T1, T2, . . . Tn are connected to a common power supply VDD and their gates are each supplied with a control signal from the control circuit 14. The number of the heat-generating resistors R1, R2, . . . Rn is not limited to any particular value. In the recording head 10, the driver transistors T1, T2, . . . Tn are turned on and off under the control of the control circuit 14. If the driver transistors T1, T2, . . . Tn are turned on, an electric current flows to the associated heat-generating resistors R1, R2, . . . Rn which then generate heat. If the driver transistors T1, T2, . . . Tn are turned off, no current flows to the heat-generating resistors R1, R2, . . . Rn and they do not generate heat. We now describe a layout of the recording head of a thermal ink-jet printer. FIG. 2 is a cross-sectional layout for an embodiment of the recording head shown in FIG. 1. The recording head generally indicated by 10 in FIG. 2 is an embodiment of the semiconductor device according to the first aspect of the invention that has been produced by the semiconductor fabrication technology using the process according to the second aspect of the invention and which is used as the recording head of a thermal ink-jet printer. In the center of the region of a semiconductor chip 16 on a semiconductor substrate 15 such as a silicon substrate, an ink channel 18 through which ink is supplied to orifices is made by excavating the surface of the semiconductor substrate 15 and it extends perpendicular to the paper on which FIG. 2 is drawn. In order to supply ink to the ink channel 18, a plurality of ink supply holes (through-holes) 20 providing communication between the back side of the semiconductor substrate 15 for the semiconductor chip 16 and the ink channel 18 are opened (bored) at given spacings in the direction in which the ink channel 18 extends. A support frame 22 is provided as a support member for proper placement of the semiconductor chip 16. Ink channels (or ink supply holes) 24 are formed in the support frame 22 to ensure that ink supplied from an ink tank (not shown) are fed via the ink supply holes 20 into the ink channel 18 formed in the obverse side of the semiconductor substrate 15 for the semiconductor chip 16. On opposite sides of the ink channel 18, two orifice rows are formed in symmetrical positions, with each row consisting of a plurality of orifices 26 that are arranged at equal spacings along the ink channel 18. Each orifice 18 is in a hollow cylindrical form and made in an orifice plate 28 that is formed of polyimide or the like and placed on top of the semiconductor chip 16. For a resolution of 360 npi (nozzles per inch), orifices 26 are arranged perpendicular to the paper on a pitch of about 71 μm per row so that an overall resolution of 720 npi can be realized by two rows. On top of the semiconductor substrate 15 for the semiconductor chip 16 but below the orifice rows, heat-generating resistors 11 are formed to control ink ejection or delivery from the individual orifices 26. A drive circuit 12 for driving the individual heat-generating resistors 11 is formed on the surface of the semiconductor chip 16 (semiconductor substrate 15) in areas, with the ink channel 18 lying in between, which are outside the orifice rows. Between the surface of the semiconductor chip 16 and the orifice plate 28, there are formed partitions 30 that define an ink flow path through which ink is supplied from the ink channel 18 to each orifice 26. Ink from the ink tank flows through the ink channel 24 in the support frame 22 to be supplied into the ink channel 18 in the surface of the semiconductor chip 16 (semiconductor substrate 15) via the ink supply holes 20 opened in the semiconductor chip 16 (semiconductor substrate 15); from the ink channel 18, the ink flows through the ink flow path defined by the partitions 30 and is distributed to the orifice rows formed on opposite sides of the ink channel 18. The individual heat-generating resistors 11 (R1, R2, . . . , Rn) are controlled by the drive circuit 12 in accordance with image data and a predetermined amount of ink is ejected or delivered from the associated orifices 26. The semiconductor device of the invention which is to be used as the recording head of an ink-jet printer is described in greater detail with reference to FIG. 3. FIG. 3 is a plan view showing in conceptual form an embodiment of the semiconductor device according to the first aspect of the invention. Shown conceptually in FIG. 3 is a semiconductor wafer 34 on which a plurality of semiconductor chips are formed so that each of them serves as the recording head 10 (see FIG. 2) of a thermal ink-jet printer. In FIG. 2, the recording head 10 is shown to have two orifice rows but in FIG. 3, in order to provide ease in explanation, the provision of only one orifice row is assumed as in the case of the recording head 10 shown in FIG. 1. As shown in FIG. 3, the semiconductor device of the invention, if it is in the form of a discrete semiconductor chip, has a metal film 36 applied to an upper layer in the region of the drive circuit 12 in such a way that it extends to an edge of the semiconductor chip 16. In other words, the metal film 36 is composed of two regions 36a and 36b; the first region 36a covers an upper layer of the drive circuit 12 and the second region 36b is an extension of the region 36a. In the illustrated case, a metal film 36 is also applied to an upper layer of a bonding pad 38 and it similarly extends to an edge of the semiconductor chip 16. In other words, the metal film 36 also is composed of two regions 36c and 36d, the first region 36c covering an upper layer of the bonding pad 38 and the second region 36d being an extension of the region 36c. The metal film 36 composed of the region 36c which covers an upper layer of the bonding pad 38 and the region 36d which is extension to an edge of the semiconductor chip 16 is an optional element and more than one such metal film may be provided depending on the case. If a plurality of semiconductor devices are to be fabricated from a semiconductor wafer 34, a metal film 36 is also applied along the region (scribing line) 40 between individual semiconductor chips 16 to form a line region 36e and two regions 36b and 36d of a metal film 36 which extend to an edge of every semiconductor chip 16 are interconnected by the line region 36e of the metal film 36 formed on each scribing line 40. A grounding pad 42, made of the same metal film, is formed in a region that is peripheral to the semiconductor wafer 34 and which is outside the individual semiconductor chips 16 and this grounding pad 42 is connected to the metal film 36 applied along the scribing lines 40. After finishing of the fabrication process, the semiconductor chips 16 formed on the semiconductor wafer 34 are separated apart on the scribing lines 40, yielding discrete semiconductor chips 16. The metal film 36 in the line regions 36e formed on the scribing lines 40 in the semiconductor wafer 34 is removed when the latter is scribed into discrete semiconductor chips 16; as a result, the only metal film 36 that is left intact on each discrete semiconductor chip 16 is composed of four regions 36a-36d, the first region 36a covering an upper layer of the drive circuit 12, the second region 36b extending to an edge of the semiconductor chip 16, the third region 36c covering an upper layer of the bonding pad 38, and the fourth region 36d extending to an edge of the semiconductor chip 16. The metal film 36 may be applied to cover the entire surface of the drive circuit 12 as indicated by 36a in FIG. 3. If desired, the surface of the drive circuit 12 may partly be left uncoated with the metal film 36; in this case, the drive circuit 12 is covered with the metal film 36 except in regions that are electrically sensitive to external effects such as static capacity. In each of the semiconductor chips 16, the metal film 36 covering an upper layer of the drive circuit 12 (to define the region 36a) and the metal film 36 covering an upper layer of the bonding pad 38 (to define the region 36c) may each extend to the metal film 36 formed on the scribing lines 40 (to define the line region 36e). Alternatively, these metal films 36 may be connected on the semiconductor chip 16 and one or more of such connected metal films may extend to the metal film 36 on the scribing lines 40. In order to provide ease in the process to be described below for fabricating the semiconductor device, the metal film 36 may be formed of known metal compounds such as TaSiO for making the heat-generating resistors 11 with known metals such as Ni for making conductive wires with that connect the heat-generating resistors 11 to the drive circuit 12. In addition, metals such as Al, W, Ti, Mo, Ta, Pt and Au that are used in the conventional semiconductor fabrication processes and their alloys can all be employed. These metals may be used either individually or in combination; in the latter case, layers of different metals may be placed one on top of another. In the invention, the thickness of the metal film 36 is not limited to any particular value; however, the preferred range is from 10 nm (100 Å) to 10 μm and the more preferred range is from 0.1 μm (100 nm) to 1 μm. Needless to say, at least a certain insulation film is provided between the metal film 36 and each of the drive circuit 12 and the bonding pad 38. The insulation film may be formed of any electrical insulator and examples include those which are commonly used in semiconductor devices, such as SiO2, SiN, borosilicate glass and polyimides. The process for producing the above-described semiconductor device according to the second aspect of the invention is described below with reference to the flowchart in FIG. 4 which shows the process of producing the semiconductor device as the recording head of an inkjet printer, as well as FIGS. 5A to 5D and FIGS. 6A and 6B which show steps involved in the production process. FIGS. 5A, 5B, 5C and 5D are sections A—A of the semiconductor device in the process of fabrication in steps S1, S4, S6 and S8, respectively (see the flowchart in FIG. 4), and FIGS. 6A and 6B are sections B—B of the semiconductor device in the process of fabrication in steps S1 and S3, respectively (see the flowchart in FIG. 4). First, consider a plurality of semiconductor devices on a semiconductor wafer 34 and apply the semiconductor fabrication technology to form the drive circuit 12 in a region of each semiconductor chip 16 on the semiconductor substrate 15 as shown in FIG. 5A and FIG. 6A (step S1). Thereafter, a protective layer 44 such as a TEOS layer for the drive circuit 12 is formed over the drive circuit 12 and its peripheral area as shown in FIG. 5A. On both sides of the drive circuit 12, a conductor such as an Al conductor 46 is formed to provide electrical connection from the drive circuit 12. In the next step S2, heat-generating resistors 11 are formed. For instance, a two-layer metal film 36 is applied to the entire surface of the semiconductor wafer 34. This metal film is composed of a metal layer 37a, typically formed of TaSiO, which serves as the constituent material of the heat-generating resistors 11 and a metal layer 37b, typically formed of Ni, which serves as the constituent material of the conductive wire for connecting the heat-generating resistors 11 and the drive circuit 12. Then, using a heat-generating resistor forming mask, the two layers of the metal film 36 are photoetched to provide the region of heat-generating resistors 11 in which the two-layer metal film 36 has been stripped of the Ni layer 37b (see FIG. 5B). In the embodiment under consideration, the double-layered metal film 36 is etched with a different mask pattern than has been used to form the heat-generating resistors 11. As a result, an upper layer of the drive circuit 12 is also covered with a two-layer metal film 36 which is made of a TaSiO layer 37a and a Ni layer 37b as in the case of the heat-generating resistors 11 but in a region independent thereof (step S3). The protective layer 44 on the topmost part of the drive circuit 12 is not shown in FIG. 6B. The metal film 36 covering an upper layer of the drive circuit 12 extends to an edge of each semiconductor chip 16 and the resulting extensions 36b permit all semiconductor chips 16 on the semiconductor wafer 34 to be interconnected via the scribing lines 40. Simultaneously with the formation of the heat-generating resistors 11, an upper layer of the bonding pads 38 (Al conductors 46) formed on each semiconductor chip 16 is also covered with a double-layered metal film 36 (particularly the region 36c) by the same photoetching step (see FIG. 5B). In this case, at least the metal film 36 (particularly the region 36c) which is applied to an upper layer of the bonding pad 36 that corresponds to the ground terminal extends to an edge of the semiconductor chip 16 and the resulting extension 36d connects to the metal film 36 (particularly the line region 36e) which is applied to the scribing line 40. In the same photoetching step, a grounding pad 42 (see FIG. 3) is formed in a region that is peripheral to the semiconductor wafer 34 and which is outside the semiconductor chips 16. The grounding pad 42 is also connected to the two-layered metal film 36 covering the scribing lines 40. The number of grounding pads 42 is not limited to any particular value as long as at least one such grounding pad is used. Thus, by using the metal film 36 applied to form heat-generating resistors and conductors, an upper layer of the drive circuit 12, an upper layer of the bonding pads 38 and the like can be covered with the metal film 36 without increasing the number of fabrication steps involved. The constituent materials for the heat-generating resistors and conductors are not limited to those used in the embodiment described above and other materials may of course be used. If desired, the step of forming the heat-generating resistors 11 and conductors may be separate from the step of forming the metal film 36 on an upper layer of the drive circuit 12. An advantage in this case is that the heat-generating resistors and conductors can be formed of different materials from the metal film 36 on an upper layer of the drive circuit 12. If the heat-generating resistors and conductors are to be formed of different materials than the metal film 36 on an upper layer of the drive circuit 12, the metals used in ordinary semiconductor fabrication processes such as Al, W, Ti, Mo, Ta and Pt and their alloys can all be used to make the metal film 36 covering an upper layer of the drive circuit 12 and the like. The metal film 36 may be applied to cover the entire surface of an upper layer in the drive circuit 12 or, depending on the need, its coverage may be partial. The metal film 36 except the one applied to form the heat-generating resistors, namely, the metal film 36 which is applied to an upper layer of the drive circuit 12 and the bonding pads 38 (particularly, regions 36a and 36c), to top of the scribing lines 40 (line regions 36e) and to the areas spanning each of the drive circuit 12 and the bonding pads 38 and the scribing lines 40 to form extensions (regions 36b and 36d), is not limited to a double-layered film; it may be formed of a single layer or it may be formed of three or more layers. For example, the metal film 36 except the one applied to form the heat-generating resistors, namely, the metal film 36 which is applied to an upper layer of the drive circuit 12 and the bonding pads 38, to top of the scribing lines 40 and to the areas spanning each of the drive circuit 12 and the bonding pads 38 and the scribing lines 40 may be a single-layered film solely formed of TaSiO. Subsequently, as shown in FIG. 5B, the bonding pads 38 and the grounding pad 42 for each semiconductor chip 16 are plated with gold by either electroplating or electroless plating (S4). This ensures that the bonding pads 38 and the grounding pad 42 will not be oxidized in the next thermal oxidation step but retain their conductivity. Preferably, the bonding pads 38 and the grounding pad 42 for each semiconductor chip 16 are plated with gold after masking the other regions. If no such masking is done before gold plating, not only the metal film 36 on the bonding pads 38 and the grounding pad 42 but those on the drive circuit 12 and the scribing lines 40 also plated with gold, leading to a dramatic increase in the use of the gold plating solution. By performing the aforementioned masking, the use of the gold plating solution can be considerably reduced. If desired, the Ni conductive wire (37b) connecting each of the heat-generating resistors 11 and the drive circuit 12 may be plated with gold. This contributes to lowering the resistance of the conductive wire. Subsequently, the surface of each heat-generating resistor 11 is subjected to thermal oxidation treatment (S5). As a result, an electrical insulating coat 11a is formed on the surface of each heat-generating resistor 11. The formed insulating coat 11a has very high strength and is resistant to the corrosive action of ink. Hence, the protective film which is required by the recording head of the conventional thermal ink-jet printer in order to provide resistance against cavitation and corrosion can be dispensed with, reducing the energy input and the like and realizing a recording head that is compact and which still has high thermal efficiency. Subsequently, as shown in FIG. 5C, those regions of the semiconductor substrate 15 for the semiconductor chip 16 in which ink supply holes 20 are to be formed are excavated by sand blasting the obverse and/or reverse side of the semiconductor wafer 34 (particularly, the semiconductor substrate 15) not only to form an ink channel 18 but also to open (bore) ink supply holes 20 through each semiconductor chip 16 (particularly, its semiconductor substrate 15) (S6). After these processing steps, as shown in FIG. 5D, partitions 30 are formed on the surface of the semiconductor chip 16 to define cavities over the heat-generating resistors 11 that serve as ink chambers 31; then, the orifice plate 28 is attached to the surface of the semiconductor wafer 34 (or the semiconductor chip 16) (S7) and orifices 26 are opened (bored) by dry etching (S8). In the invention, when processing steps are performed as by sand blasting to form the ink channel 18 and open the ink supply holes 20 and by dry etching to open the orifices 26, the metal film 36 applied to cover an upper layer in each of the drive circuits 12, bonding pads 38 and the grounding pads 42 is grounded electrically via the grounding pad 42 on the semiconductor wafer 34 so as to guide electric charges into the ground. This is effective in preventing electrical breakdown of the drive circuits 12 in the invention. Described above are the basic construction of the semiconductor device of the invention and the process for producing the same. In the process of the invention for producing the semiconductor device, the metal film 36 is provided on the surface of the semiconductor wafer 34 where the drive circuit 12 is formed on each semiconductor chip 16 and its provision is effected prior to processing steps such as sand blasting to form the ink channel 18 and open the ink supply holes 20 and dry etching to open the orifices 26. This is not the sole case of the invention and, as shown in FIG. 7, a metal film 50 is preferably provided on the reverse side of the semiconductor wafer 34 (particularly, its semiconductor substrate 15) in addition to the metal film 36 on the obverse side. The metal film 50 to be provided on the reverse side of the semiconductor wafer 34 may be of the same or different composition than the metal film 36. If the metal film 50 is to be provided, it preferably covers the entire surface of the reverse side of the semiconductor wafer 34 (semiconductor substrate 15). After the metal films 36 and 50 are thusly formed on the obverse and reverse sides, respectively, of the semiconductor wafer 34 with drive circuits 12 on it, processing steps are conducted as by sand blasting to form the ink channels 18 and bore the ink supply holes 20 and by dry etching to open the orifices 26. Even if static electricity is generated during these processing steps, the resulting electric charges can be flowed into the ground more effectively than when only one surface of the semiconductor wafer 34 is covered with the metal film 36 and, hence, the drive circuit 12 can more positively be protected against breakdown due to static charge-up. After forming the ink channels 18, ink supply holes 20 and orifices 26 by the processing steps, the metal film 50 formed on the reverse side of the semiconductor wafer 34 is preferably removed by a suitable method such as dry or wet etching. Needless to say, the unwanted areas of the metal film 36 on the obverse side of the semiconductor wafer 34 may also be etched away or otherwise removed after the processing steps. To perform processing steps such as excavation and boring of the semiconductor substrate 15 for the semiconductor chip 16, holes may be opened through it from one side, i.e., either the obverse or reverse side. If desired, holes may be opened simultaneously from both sides of the semiconductor chip 16; alternatively, holes may first be opened from either one side of the semiconductor chip 16 to an intermediate depth and then holes are opened into the other side of the semiconductor chip 16 until it is tunneled through. The invention is applicable to the recording heads of both monochromatic and full-color thermal ink-jet printers which employ semiconductor devices. While various constructions are known for the recording heads including the top shooter type (face ink-jet) and the side shooter type (edge ink-jet), all of them can be used in the invention. Orifices can be arranged in any desired number of rows and there is no limitation on the number of recording elements that can be provided. In the embodiments described above, the semiconductor device of the invention is used with the recording head of a thermal ink-jet printer which ejects ink upon heating. However, this is not the sole case of the invention and the claimed semiconductor device is applicable to all other known types of ink-jet printer including the pressure type which ejects ink by vibrating the diaphragm with the aid of a piezoelectric device or under static electric force. In the invention, the heat-generating resistors used in the thermal type as well as the piezoelectric device and the like that are used in the pressure type are collectively referred to as the ink ejection or delivery unit. It should also be noted that the applicability of the invention is not limited to the recording head of a thermal ink-jet printer but that it is also applicable to semiconductor devices of such a type that the elements of an IC circuit formed on a semiconductor chip may potentially experience electrical breakdown due to processing steps performed in the fabrication process. While the semiconductor device of the invention and the process for its production have been described above in detail with reference to various embodiments, it goes without saying that the invention is by no means limited to the foregoing embodiments and various improvements and modifications can be made without departing from the spirit and scope of the invention. As described above in detail, the invention is characterized in that the metal film formed on an upper layer of each of the IC circuits and bonding pads is grounded via the grounding pad formed on the semiconductor wafer before the latter is processed to fabricate semiconductor devices. As a result, the elements of the IC circuit in each semiconductor device can be prevented from undergoing electric breakdown due to processing steps such as sand blasting and dry etching and this offers the advantage of improving the production yield for semiconductor devices.

2023-10-15T01:27:04.234600

https://example.com/article/2925

How we diagnose the antiphospholipid syndrome. The antiphospholipid syndrome (APS) is an acquired thrombophilia, characterized by the occurrence of venous and arterial events. This article examines the laboratory and key clinical aspects of APS. Particular focus is given to anti-beta 2-glycoprotein I (beta(2)GPI) antibodies in view of their recent inclusion in the APS classification criteria. The clinical utility of using the beta(2)GPI enzyme-linked immunosorbent assay, in conjunction with the established lupus anticoagulant assays and cardiolipin enzyme-linked immunosorbent assay, for diagnosing and risk stratifying patients suspected of having APS is discussed. The relative importance of the various assays in diagnosing obstetric APS (early and late gestation miscarriages) is explored. The implications of recent epidemiologic findings for possibly understanding the underlying pathophysiologic mechanisms of obstetric APS are highlighted. Insights into which patients with obstetric APS may be at most risk of thrombotic complications are presented.

2024-05-21T01:27:04.234600

https://example.com/article/4693

INTRODUCTION {#SEC1} ============ Petabytes of raw and processed data generated with microarray, RNA-Seq (bulk and single-cell) and mass spectrometry for small molecules and proteins are available through public data repositories ([@B1]). These data represent multiple species, organs, genotypes and conditions; some are the results of groundbreaking research. Buried in these data are biological relationships among molecules that have not yet been explored. Integrative analysis of data from the multiple studies representing diverse biological conditions is the key to fully exploit these vast data resources for scientific discovery ([@B5],[@B6]). Such analysis allows efficient reuse and recycling of these available data and metadata ([@B1],[@B5],[@B7]). Higher statistical power can be attained with bigger datasets, and the wide variety of biological conditions can reveal the complex regulatory structure of genes. Yet, despite the availability of such vast data resources, most bioinformatic studies use only a limited amount of the available data. A common goal of analyzing omics data is to infer functional roles of particular features (genes, proteins, metabolites or other biomolecules) by investigating co-expression and differential expression patterns. A wide variety of R-based ([@B8]) tools can provide specific analyses ([@B9]). Such tools are based upon rigorous statistical frameworks and produce accurate results when the model assumptions hold. Several tools avoid the need to code by providing 'shiny' interfaces ([@B13]) to various subsets of R's functionalities ([@B14]). Such R tools based on the 'shiny' interface have the general limitations that they are not well suited for very large datasets and can have limited interactivity. Increasing the usability of the vast data resources by enabling efficient exploratory analysis would provide a tremendous opportunity to probe the expression of transcripts, genes, proteins, metabolites and other features across a variety of different conditions. Such exploration can generate novel hypotheses for experimentation, and hence improving the fundamental understanding of the function of genes, proteins and their roles in complex biological networks ([@B6],[@B21]). At present, there are very limited options for researchers to interact with expression datasets using the fundamental principles of exploratory data analysis ([@B26]). Exploratory data analysis is a technique to gain insight into a dataset, often using graphical methods which can reveal complex associations, patterns or anomalies within data at different resolutions. By adding interactivity for visualizations and statistical analyses, researchers with little or no programming experience are able to directly explore the underlying, often complex and multidimensional, data themselves. Researchers in diverse domains (e.g. experts in Parkinson's disease, malaria or nitrogen metabolism) can mine and re-mine the same data, extracting information and deriving testable hypotheses pertinent to their particular areas of expertise. These hypotheses can inform the design of new laboratory experiments. Being able to explore and interact with data becomes even more critical as datasets become larger. The information content inherent in the vast stores of public data is enormous. Due to the sheer size and complexity of such big data, there is a pressing requirement for effective interactive analysis and visualization tools ([@B27],[@B28]). In this paper, we present MetaOmGraph (MOG), a Java software, to interactively explore and visualize large expression datasets. MOG overcomes the challenges posed by the size and complexity of big datasets by efficient handling of the data files. Further, by incorporating metadata, MOG adds extra dimensions to the analyses and provides flexibility in data exploration. At any stage of the analysis, a researcher can save her/his progress. Saved MOG projects can be shared, reused and included in publications. MOG is user-centered software, designed for exploring diverse types of numerical data and their metadata, but specialized for expression data. MATERIALS AND METHODS {#SEC2} ===================== Overview {#SEC2-1} -------- MOG is an interactive software that can run on any operating system capable of running Java (Linux, Mac and Windows). MOG's Graphical User Interface (GUI) is the central component through which all the functionality is accessed (Figure [1](#F1){ref-type="fig"}). Access to MOG is easy. MOG is a standalone program and runs on the researcher's computer; thus, the researcher does not need to rely on internet accessibility for computations, and is not slowed down by the data transfer latency. Furthermore, the data in a researcher's project is secure, remaining on the researcher's computer, particularly important for confidential data such as human RNA-Seq. {#F1} ### Interactive data exploration {#SEC2-1-1} MOG displays all the data in interactive tables and trees, providing a flexible and structured view of the data. The user can interactively filter or select data for analysis. This ability is particularly important for aggregated datasets, as users may wish to split data into groups of studies, treatments or organs. A novel aspect of MOG is its capability of producing *interactive* visualizations. The researcher can visualize data via line charts, histograms, box plots, volcano plots, scatter plots and bar charts, each of which is programmed to allow real-time interaction with the data and the metadata. Users can group, sort, filter, change colors and shapes, zoom and pan interactively, via the GUI. At any point in the exploration, the researcher can look-up external databases: GeneCards ([@B29]), Ensembl ([@B30]), EnsemblPlants ([@B31]), RefSeq ([@B32]), TAIR ([@B33]) and ATGeneSearch (<http://metnetweb.gdcb.iastate.edu/MetNet_atGeneSearch.htm>) for additional information about the genomic features in the dataset. Researchers can also easily access SRA and GEO databases using the accessions present in the study metadata. ### Efficient, multithreaded and robust {#SEC2-1-2} A key advantage of MOG is its minimal memory usage, enabling datasets to be analyzed that are too large for other available tools. Researchers with a laptop/desktop computer can easily run MOG with data files containing thousands of samples and fifty thousands of transcripts. MOG achieves computational efficiency via two complementary approaches. First, MOG indexes the data file, rather than storing the whole data in main memory. This enables MOG to work with very large files using a minimal amount of memory. Second, MOG speeds up the computations using multithreading, optimizing the use of multi-core processors. MOG is robust and can cope with most of the errors and exceptions (such as missing values or forbidden characters) that can occur when handling diverse data types. Bug reports can be submitted with a single click, if encountered. ### Data-type agnostic {#SEC2-1-3} Although specifically created for the analysis of omics data, which is the focus of this paper, MOG is designed to be flexible enough to generally handle numerical data. A user can supplement a MOG project with any type of metadata about the features, and about the studies. Thus, a MOG user can interactively analyze and visualize voluminous data on any topic. For example, a user could create a project on: transmission of mosquito-borne infectious diseases world-wide; public tax return data for world leaders over the past 40 years; daily sales at Dimo's Pizza over 5 years; player statistics across all Women's National Basketball Association (WNBA) teams; climate history and projections since 1900. ### Leverage of third party Java libraries {#SEC2-1-4} In addition to the functionality we have programmed into MOG, MOG borrows some functionality from freely available and extensively tested third-party Java libraries (JFreeChart, Apache Commons Math, Nitrite and JDOM). We have combined these to create a highly modular system that is amendable to changes and extensions and developers can easily implement new statistical analyses and visualizations in the future. MOG is an open source project and we plan to expand and develop it further through community driven efforts. Information on how to contribute to MOG, and who to contact with further questions, is provided at <https://github.com/urmi-21/MetaOmGraph/blob/master/CONTRIBUTING.md>. ### Interface to R {#SEC2-1-5} Based on the utility and popularity of R for data analysis, we have implemented a GUI to facilitate execution of R scripts through MOG. MOG's GUI enables a user to interactively select or filter data using MOG; these data are then passed to R. This avoids the need to constantly write new R code to specify different genes and samples for analyses. For example, a user can write an R script for hierarchical clustering of genes based on the expression levels, interactively select or filter data using MOG, and execute the R script. More details on how to use MOG for executing R scripts are provided in the user manual available from (<https://github.com/urmi-21/MetaOmGraph/tree/master/manual>). Creating a new MOG project or using an existing one {#SEC2-2} --------------------------------------------------- A user can quickly create a new MOG project using two delimited files: (i) a file with unique identifiers (IDs) for each feature (e.g. gene), metadata about that feature and numerical data quantifying each feature across multiple conditions (e.g. multiple samples and studies), and (ii) a file containing unique identifiers for each sample and metadata about the samples and studies in the datafile. These are virtually combined by MOG, using the unique identifier in each file ([Supplementary Figure S1](#sup1){ref-type="supplementary-material"}). Selecting appropriate methods for data normalization, batch correction and vetting are important considerations for a user when creating a new project ([Supplementary File 1](#sup1){ref-type="supplementary-material"}). New MOG projects, as well as those from well-vetted datasets, including the human and *Arabidopsis thaliana* datasets described herein, can be re-opened, analyzed, modified or shared. Ongoing exploration results, such as correlations, lists and other interactive analyses, can be saved in any MOG project, regardless of whether it was obtained from our website or created from custom data. Detecting statistical association within data {#SEC2-3} --------------------------------------------- Measures of statistical association between a pair of features in a dataset quantify the similarity in their expression patterns across the samples that comprise that dataset ([@B34]). Genes with significant statistical association may participate in common biological processes and pathways ([@B23],[@B34],[@B38]). Genes with significant association only under specific conditions may reveal their functional significance under those conditions ([@B39],[@B40]). MOG provides the researcher with several statistical measures to estimate associations/co-expression among the features. It can also compute association between samples, which reflects similarity between the samples. Choosing appropriate statistical measures and interpretations for each dataset is left to the user. ### Correlation, mutual information and relatedness {#SEC2-3-1} We have incorporated four key methods that measure association among pairs of features. Each has its own advantages and disadvantages, depending on the types of relationships the researcher wishes to detect, and the characteristics of the dataset being explored. MOG can compute pairwise Pearson and Spearman correlation for pairs of selected features across all samples or conversely, between selected samples across all features. The Pearson correlation coefficient measures the extent of a linear relationship between two random variables, *X* and *Y*, whereas, the Spearman correlation coefficient measures monotonic relationships between the two variables. Both excel at detecting linear relationships, however, Spearman is less sensitive to outliers ([@B41]). Pearson and Spearman correlations are often used to find co-expressed genes and generate matrices used for inferring gene expression networks ([@B23],[@B35],[@B39]). MOG also computes pairwise mutual information (MI) between selected features across samples. MI quantifies the amount of information shared between two random variables. Let (*X*, *Y*) be a pair of discrete random variables over the space $\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$\mathcal {X} \times \mathcal {Y}$\end{document}$. Then, the MI for *X* and *Y* is defined as:$$\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$$\begin{equation*} I(X;Y)=\sum _{y\in \mathcal {Y}} \sum _{x\in \mathcal {X}} p(x,y) \log \left( \frac{p(x,y)}{p(x)p(y)} \right), \end{equation*}$$\end{document}$$where, *p*(*x*, *y*) is the joint probability mass function of *X* and *Y*, and *p*(*x*) and *p*(*y*) are the marginal probability mass functions for *X* and *Y*, respectively. Compared to correlation measures, MI is a more general approach that can detect complex, non-linear associations. The interpretation of the MI value is different than that of correlation values: an MI value of zero, *I*(*X*; *Y*) = 0, implies statistical independence of *X* and *Y*, whereas a correlation value of zero need not imply statistical independence ([@B41]). MI has been applied to detect non-linear associations in gene expression datasets ([@B25],[@B42]). MOG computes MI using B-splines density estimation, as described in Daub *et al.* ([@B42]). MOG can also determine the context likelihood of relatedness (CLR) ([@B37]). CLR determinations aim to identify biologically relevant associations by discounting features (e.g. genes) that have promiscuous associations. Specifically, the CLR compares the MI value between each pair of features to the background distribution of MI values that include either of these features ([@B37]). ### Meta-analysis of correlation coefficients {#SEC2-3-2} MOG can perform meta-analysis of Pearson correlations. Studies using microarray data showed that meta-analysis and analysis of pooled normalized samples each bring out meaningful, but different, relationships among genes ([@B24]). For meta-analysis of correlation coefficients, MOG calculates a weighted average of the individual Pearson correlation coefficients computed from each study. The weights are proportional to the sample size, i.e. correlations estimated from larger studies are more trusted ([@B45],[@B46]). Meta-analysis can be useful when multiple studies run a similar experiment (e.g. effect of heat-stress on *A. thaliana*), but may not control ancillary sources of variation (e.g. coverage variation in RNA-Seq data). MOG provides a choice between a fixed effects model (FEM) or a random effects model (REM) ([@B45],[@B46]) for the meta-analysis. The FEM combines the estimated effects by assuming that all studies probe the same correlation in the same population, i.e. studies are homogeneous. In contrast, the REM allows studies to be heterogeneous, with additional, uncontrolled sources of variation ([@B45],[@B46]). The FEM does not account for all heterogeneities, thus the researcher should choose a model and interpret the results with appropriate caution. Differential expression between groups {#SEC2-4} -------------------------------------- Determining differentially expressed features from aggregated datasets provides direction for further data exploration. In MOG, we have incorporated several popular statistical methods to evaluate differential expression between two groups of samples. For analysis of groups with independent samples, we have implemented: Mann--Whitney U test (a non-parametric test that makes no assumptions about data distribution); Student's *t*-test (assumes equal variance and normally distributed data); Welch's *t*-test (does not assume equal variance, assumes a normal distribution of data); and a permutation test (makes no assumptions about data distribution; computes null distribution empirically using the data). For analysis of groups with paired samples, we have implemented: a Paired *t*-test (assumes normal distribution of data); a Wilcoxon signed-rank test (a non-parametric test; no assumption of data distribution); and a permutation test for paired samples (makes no assumptions about data distribution but computes null distribution empirically using the data). MOG's methods to identify differentially expressed genes are general statistical methods which are designed for large sample sizes (30 or more samples for gene expression data). Computation of these methods via MOG permits interactivity, which promotes data exploration. A limitation of the interactive differential expression analysis methods implemented in MOG is that they are designed for large sample sizes and use normalized data as input. For smaller sample sizes, a user can apply specialized model-based methods, accessible through R, to infer differentially expressed genes in RNA-Seq or microarray datasets. For example, methods like edgeR ([@B12]), DESeq2 ([@B11]) and limma ([@B10]) require raw counts as input and can provide more reliable differential expression analysis ([@B47]) for smaller sample sizes. Tools like ideal ([@B20]) and DEBrowser ([@B19]) provide interactive interface for accessing these popular differential expression analysis methods ([@B10]). Differential correlation between groups {#SEC2-5} --------------------------------------- Features whose correlation with other features is significantly different only under particular environmental, genetic or developmental conditions are designated as differentially correlated. Such *shifting* biological interactions among these genes or their regulators ([@B40],[@B48]) reflect the context-dependency of gene expression. MOG can find the features whose Pearson correlation to a user-selected feature differs significantly between two groups of samples. To do this, MOG applies a Fisher transformation ([@B49]) and performs a hypothesis test for equality of Pearson correlation coefficients from the two groups. (The difference of the two Fisher transformed Pearson correlation coefficients follows a normal distribution ([@B40])). The researcher can choose to conduct a test for statistical significance on the Fisher transformed Pearson correlation coefficients or on the raw Pearson correlation coefficients. Statistical significance determinations {#SEC2-6} --------------------------------------- For each statistical test, MOG provides a non-parametric option (a permutation test) and parametric options (calculations under distributional assumptions) to estimate *P*-values. Empirical *P*-values are calculated by a permutation test that estimates the null distribution of a test statistic by randomly permuting the labels of the observed data points (assuming that the labels are exchangeable under the null hypothesis) ([@B50]). Because permutation tests do not rely on any data distribution, they are applicable even if parametric assumptions are not met. More permutations yield more precise estimates of the null distribution and *P*-values, but at the cost of longer computation times. MOG accelerates computation of permutation tests by multithreading, and processing the permuted datasets in parallel ([Supplementary File 1](#sup1){ref-type="supplementary-material"}). MOG provides three popular parametric methods to adjust the *P*-values for multiple comparisons: the Bonferroni method ([@B51]), the Holm method ([@B52]) and the Benjamini--Hochberg (BH) method ([@B53]). Bonferroni and Holm methods are applied to control the family-wise error rate (FWER), whereas the BH method controls the false discovery rate (FDR). Controlling the FWER limits the total number of false positives; the Holm method is less conservative as compared to the Bonferroni method. In contrast, controlling the FDR controls the proportion of false positives among the significant tests. Datasets {#SEC2-7} -------- To create case-studies with MOG, we assembled MOG projects based on three technical platforms. ### Human cancer RNA-Seq dataset (7142 samples) {#SEC2-7-1} We created a new MOG project based on the well-vetted dataset from Wang *et al.*, ([@B21]). This dataset combines RNA-Seq data from The Cancer Genome Atlas (TCGA, tumor and non-tumor samples) (<https://cancergenome.nih.gov/>) and Genotype Tissue Expression (GTEX, non-tumor samples) ([@B54]). To create the MOG project, we excluded from the dataset any organ types in which the number of tumor or non-tumor samples was \<30. To ensure statistical independence among the samples, we removed all non-tumor samples from TCGA and included only one TCGA tumor-sample per patient ([Supplementary File 2](#sup1){ref-type="supplementary-material"}). We also excluded an outlier sample with very low expression values, based on a preliminary exploration of sample replicates using MOG (See 'Results' section). We then compiled metadata for the studies/samples and for the genes and integrated this metadata into the dataset. We downloaded the study and sample metadata (TCGA metadata from TCGAbiolinks ([@B55]); GTEX metadata from GTEX's website (<https://gtexportal.org/home>)). We were unable to locate metadata for 17 of the TCGA samples and excluded these samples from the dataset ([Supplementary File 2](#sup1){ref-type="supplementary-material"}). We extracted metadata about the genes from the HGNC (<https://www.genenames.org/>), NCBI Gene (<https://www.ncbi.nlm.nih.gov/gene>), Ensembl ([@B30]), Cancer Gene Census ([@B56]) and OMIM ([@B57]) databases and added these information to the gene metadata in our dataset. We also eliminated the 1870 genes that were not reported for all studies resulting in a dataset, called herein, '*Hu-cancer-RNASeq-dataset*'. We generated the MOG project (*Hu-Cancer-18212-7412-RNASeq.mog*) from the *Hu-cancer-RNASeq-dataset* and its metadata. The MOG project contains expression values for 18 212 genes, 30 fields of metadata detailing each gene, across 7142 samples representing 14 different cancer types and associated non-tumor tissues (Table [1](#tbl1){ref-type="table"}); it also has 23 fields of metadata describing each study and sample in the dataset. We used MOG to *log*~2~ transform the data for subsequent analyses. ###### Tumor and non-tumor samples in the *Hu-cancer-RNASeq-dataset* and the number of *up*regulated and *down*regulated genes in each tumor type with respect to the corresponding normal samples, as calculated by MOG TCGA disease GTEX \#TCGA \#GTEX Total \#Up \#Down ---------------------------------------------- ----------- -------- -------- ------- ------ -------- Breast invasive carcinoma (BRCA) Breast 965 89 1054 1093 2827 Colon adenocarcinoma (COAD) Colon 277 339 616 1401 3036 Esophageal carcinoma (ESCA) Esophagus 182 659 841 1989 2229 Kidney Chromophobe (KICH) Kidney 60 32 92 986 4214 Kidney renal clear cell carcinoma (KIRC) Kidney 470 32 502 1877 2263 Kidney renal papillary cell carcinoma (KIRP) Kidney 236 32 268 1152 2737 Liver hepatocellular carcinoma (LIHC) Liver 295 115 410 1527 1485 Lung adenocarcinoma (LUAD) Lung 491 313 804 1361 2753 Lung squamous cell carcinoma (LUSC) Lung 486 313 799 2210 3734 Prostate adenocarcinoma (PRAD) Prostate 426 106 532 577 1633 Stomach adenocarcinoma (STAD) Stomach 380 192 572 1527 1631 Thyroid carcinoma (THCA) Thyroid 441 318 759 993 1525 Uterine Corpus Endometrial Carcinoma (UCEC) Uterus 141 82 223 2135 3250 Uterine Carcinosarcoma (UCS) Uterus 47 82 129 2419 2491 ### *A. thaliana* microarray dataset (424 samples) {#SEC2-7-2} We created a new MOG project, *AT-Affy-22746-424-microarray.mog*, based on the *A. thaliana* curated microarray dataset (*'AT-microarray-dataset'*) from Mentzen and Wurtele ([@B23]). This dataset had been compiled using 963 Affymetrix ATH1 chips with 22 746 probes from 70 diverse studies encompassing different conditions of development, stress, genotype and environment. All chips in the dataset were individually normalized and scaled to a common mean using MAS 5.0 algorithm. Only chips with good quality biological replicates were kept and all the biological replicates were averaged to yield 424 samples. At last, median absolute deviation (MAD)-based normalization ([@B58]) was applied to the data. We compiled new metadata for the genes from TAIR gene annotations ([@B33]) and added phylostratal inferences ([@B59]). The sample metadata were obtained from Mentzen and Wurtele ([@B23]). ### *A. thaliana* metabolomics GC-MS dataset (656 samples) {#SEC2-7-3} The small molecule composition (metabolomics) data that we used to create a MOG project were from 656 GC-MS samples describing the effect of 50 knock out (or knock down) mutations of genes of mostly unknown functions on the accumulation of metabolites in *A. thaliana* ([@B60]) (called herein, *'AT-metab-dataset'*). We downloaded these data from the Plant/Eukaryotic and Microbial Resource (PMR) ([@B61]). We created the MOG project *AT-Mutation-242-656-metab.mog* with this dataset. RESULTS {#SEC3} ======= We illustrate MOG's usability and flexibility by exploring three diverse datasets from different perspectives. The statistical analyses and visualizations shown were generated exclusively using MOG. Often, our exploration led us to conclusions consistent with prior experimental or *in silico* results. In other cases, the exploration led us to completely novel predictions that could be tested experimentally. Preliminary exploration of the *Hu-cancer-RNASeq-dataset* {#SEC3-1} --------------------------------------------------------- Determining that a dataset is valid, properly normalized and free of batch effects is a critical preliminary step in the analysis. To verify that samples from similar biological conditions exhibit similar expression patterns for all the genes, we used MOG to compute pairwise Pearson correlations among samples from the same biological condition (tumor/non-tumor and organ type). All the samples had high Pearson correlations (\>0.70) with others taken from the same organ and tumor status, except one sample from lung adenocarcinoma (LUAD), which we removed from the dataset (Additional File 1). We visualized the distribution of Pearson correlation values for non-tumor samples. For homogeneous samples, such distributions should appear unimodal. However, several organs show multimodal distributions ([Supplementary Figure S2](#sup1){ref-type="supplementary-material"}). This finding led us to conjecture that samples might have been taken from different anatomical sites within these organs. By exploring further with MOG, we were able to identify additional metadata on sub-locations in the colon and esophagus that support this conjecture ([Supplementary Figure S2](#sup1){ref-type="supplementary-material"}). However, the stomach sample metadata does not further specify location (or any other obvious factor, such as gender, race or age) that might distinguish subgroups of samples. Because the stomach samples are of several distinct types, a researcher might want to consider analyzing them as such. Using MOG to identify a catalog of differentially expressed genes in cancers {#SEC3-2} ---------------------------------------------------------------------------- We wanted to identify *key genes* that are regulated by, or implicated in, the molecular and cellular processes driving cancer, and to further explore the processes in which these genes are involved. For this task, we used MOG first to identify the differentially expressed genes in samples from each tumor type versus corresponding non-tumor samples, and then to examine the expression patterns of these genes. We define a gene as differentially expressed between two groups if it meets each of the following criteria:Estimated fold change in expression of 2-fold or more (log  fold change, \|*logFC*\| ≥ 1 where *logFC* is calculated as in limma ([@B10]).)Mann--Whitney U test, on the log~2~ transformed data, is significant between the two groups (BH corrected *P*-value \<10^−3^) In each type of cancer in the *Hu-cancer-RNASeq-dataset*, between 2000--5000 of the 18 212 genes are differentially expressed (Table [1](#tbl1){ref-type="table"} and [Supplementary File 3](#sup1){ref-type="supplementary-material"}). Thirty-five of these genes are consistently differentially expressed in all of the cancers (Table [2](#tbl2){ref-type="table"}). ###### MOG identifies 35 genes as differentially expressed in all of the 14 tumor types Upregulated in each cancer Downregulated in each cancer ---------------------------- ------------------------------ BIRC5, BUB1, CDC45 ADH1B, C7, CHRDL1 CDKN2A, CENPF, DLGAP5 CMTM5, DCN, DES FAM111B, KIF4A, KIF20A DPT, GPM6A, GSTM5 MELK, MKI67, PBK HPD, HSPB6, MRGPRF PKMYT1, TOP2A, TPX2 NKAPL, PEG3, PI16 UBE2C PTGDS, SCN7A, TCEAL2 TGFBR3 (Mann--Whitney U test, \|FC\| ≥ 2, BH corrected *P*-value \<10^−3^). Several genes that are deeply implicated in cancer are not differentially expressed in any of the tumor types we analyzed. One example is tumor suppressor protein 53 (TP53) (Figure [2](#F2){ref-type="fig"} A and B). (TP53 is differentially expressed in colorectal tumors ([@B62]); colorectal tumors are not included in the *Hu-cancer-RNAseq-dataset*). ![MOG visualizations of expression of selected genes across all tumor types and non-tumor samples. Tumor samples, black dots; non-tumor samples, red dots. Correlations and differential expression analyses were performed using MOG (Mann--Whitney U test, \|*FC*\| ≥ 2, BH corrected *P*-value \<10^-3^). Plots were generated in MOG by interactively splitting the gene expression data into the categories 'tumor' and 'non-tumor' using the sample metadata. (**A**) Histogram showing the distribution of Tumor Protein P53 (TP53) expression (number of bins set to 50). (**B**) Box plot summarizing the expression of TP53 over all tumor versus all non-tumor samples. The horizontal line inside the box represents the median log expression, which is 9.1 for non-tumor samples and 9.6 for tumor samples. (**C**) Scatter plot visualizing co-expression of mitotic checkpoint serine/threonine kinase (BUB1) and kinesin family member 4A (KIF4A) (both are upregulated across all tumor types). (Spearman correlation=0.92 in non-tumor samples; Spearman correlation=0.84 in tumor samples; Spearman correlation=0.94 over both tumor and non-tumor samples). (**D**) Scatter plot visualizing co-expression of genes cyclin dependent kinase inhibitor 2A (CDKN2A) and KIF4A. Both are upregulated across all tumor types, but they are are not co-expressed. (**E**) Scatter plots visualizing transforming growth factor beta receptor3 (TGFBR3), which has a complex role as regulator of angiogenesis ([@B117]), decorin (DCN), autophagy, mitophagy and embryonic cell development including endovascular differentiation ([@B118]). TGFBR3 and DCN are downregulated across all tumor types and are co-expressed in non-tumor samples (Spearman correlation=0.64) but not in tumor cells (Spearman correlation=0.14). The co-expression of TGFBR3 and DCN in only the non-tumor samples suggests that the processes in which each gene participates are associated under normal conditions; the loss of this association in tumors is consistent with a hypothesis that an imbalance, or factors that cause that imbalance, may further contribute to the etiology of cancer. (**F**) Scatter plot visualizing co-expression of genes dermatopontin (DPT) and DCN Spearman correlations are 0.82 (tumor samples), 0.69 (non-tumor samples) and 0.84 (combined samples) (Both gene are downregulated across all tumor types.)](gkz1209fig2){#F2} Fifteen of the 16 genes upregulated across all tumor types are co-expressed across the tumor samples, across the non-tumor samples and across the combined tumor plus non-tumor samples (Figure [2](#F2){ref-type="fig"} C and [Supplementary File 4](#sup1){ref-type="supplementary-material"}). Cyclin dependent kinase inhibitor (CDKN2A) is an outlier (Spearman correlation \< 0.50) (Figure [2](#F2){ref-type="fig"} D and [Supplementary File 4](#sup1){ref-type="supplementary-material"}). This co-expression might imply that these 15 genes function together as a module in both tumor and non-tumor cells. In contrast, there is no co-expression cluster among the 19 genes that are downregulated across all cancer types; 62 individual gene pairs are correlated across all the samples (Spearman correlation ≥ 0.60) ([Supplementary File 4](#sup1){ref-type="supplementary-material"}). Expression of seven of these gene pairs is strongly correlated only among tumor samples but is not correlated among non-tumor samples; conversely, 18 gene pairs are strongly correlated among non-tumor samples but not among the tumor samples (e.g. Figure [2E](#F2){ref-type="fig"})---this finding indicates a context-dependent coordination of these gene pairs. Four gene pairs are strongly correlated among both tumor and in non-tumor samples (e.g Figure [2F](#F2){ref-type="fig"}). ### Functional analysis of differentially expressed genes {#SEC3-2-1} To determine whether the genes that are differentially expressed in cancers are involved in known biological processes, we performed gene ontology (GO) enrichment analysis using GO::TermFinder ([@B63]) and Revigo ([@B64]) on the genes that are upregulated, downregulated or not significantly changed across all the cancer types. Consistent with the behavior of cancer cells, upregulated genes are significantly enriched in GO terms related to cell proliferation: cell cycle, cell division, organelle organization, regulation of cellular component organization and regulation of cell cycle ([Supplementary File 4 and Figure S3](#sup1){ref-type="supplementary-material"}). The 5784 genes that did not change expression were enriched in GO terms RNA processing, mRNA metabolic process, nucleic acid metabolic process and gene expression ([Supplementary Figure S4](#sup1){ref-type="supplementary-material"} and File 4). The downregulated genes show no significant GO term enrichment. Using MOG for gene-level exploration {#SEC3-3} ------------------------------------ With the aim to use MOG from the vantage point of an individual gene, we selected the glypican 3 (GPC3) gene as an interesting candidate for a case study. GPC3, encoding a glycosylphosphatidylinositol-linked heparan sulfate proteoglycan, is located on the X chromosome and has been implicated as a critical regulator of tissue growth and morphogenesis ([@B65]). GPC3 inhibits cell proliferation and hedgehog signaling during embryonic development ([@B66]). In tumors, GPC3's role is complex and not well understood. It can promote or inhibit cell growth depending on the cancer type ([@B67],[@B68]). Mutations in GPC3 have been linked to Wilms tumor as well as Simpson-Golabi-Behmel syndrome (SGBS) ([@B69],[@B70]). ### GPC3 Expression patterns {#SEC3-3-1} We explored expression patterns of GPC3 with regards to the 14 tumor types. Differential expression of GPC3 in non-tumor versus tumor samples varies by organ. GPC3 expression is 30-fold higher in the LIHC samples than in the non-tumor liver samples, and 8-fold higher in the UCS samples compared to the non-tumor uterus samples ([Supplementary File 5](#sup1){ref-type="supplementary-material"}). In contrast, GPC3 is downregulated in nine tumor types (BRCA, COAD, ESCA, KIRC, KIRP, LUAD, LUSC, THCA and UCEC) and unchanged in three tumor types (KICH, STAD and PRAD) (Figure [3A](#F3){ref-type="fig"} and [B](#F3){ref-type="fig"}; [Supplementary File 5](#sup1){ref-type="supplementary-material"}). {#F3} These results are consistent with targeted studies of liver, breast and lung tumors. GPC3 expression is upregulated in liver cancer ([@B67],[@B71]), and has been suggested as a diagnostic biomarker and as a potential target for cancer immunotherapy in hepatocellular carcinoma ([@B71]). GPC3 is downregulated in breast ([@B74]), lung ([@B75]) and ovarian cancers ([@B76]), and it may act as a tumor suppressor in lung and renal cancer ([@B76],[@B77]). ### GPC3 Co-expression patterns {#SEC3-3-2} We then investigated co-expression patterns of GPC3 in the tumor and non-tumor tissues from different organs (Additional File 3). GPC3 co-expression patterns differ between tumor and non-tumor samples according to the organ sampled (Figure [3C](#F3){ref-type="fig"}), moreover, the genes whose expression is correlated with GPC3 are distinct according to organ types, all reflecting the complex role of this gene ([Supplementary File 5](#sup1){ref-type="supplementary-material"}). For example, 4219 genes are co-expressed with GPC3 in non-tumor esophagus samples, whereas no gene is co-expressed with GPC3 in non-tumor samples from prostate and stomach ([Supplementary File 5](#sup1){ref-type="supplementary-material"}). Co-expressed genes also differed according to whether disease was present. For seven organs, fewer genes were co-expressed with GPC3 in tumor samples than in non-tumor samples ([Supplementary File 5](#sup1){ref-type="supplementary-material"}). For example, 192 genes were co-expressed with GPC3 in non-tumor liver samples, whereas no genes were significantly co-expressed with GPC3 in LIHC tumor samples (Figure [3D](#F3){ref-type="fig"} and [E](#F3){ref-type="fig"}). We analyzed GO term enrichment for those organs with more than 10 GPC3-co-expressed genes: colon, esophagus, kidney and liver. The term cell adhesion is enriched in GPC3-co-expressed genes from colon, esophagus, kidney and liver. The terms cell development, extracellular matrix organization and multicellular organism development are enriched among GPC3-co-expressed genes in colon, esophagus and kidney. Other GO terms are over-represented in a organ-specific manner ([Supplementary File 5](#sup1){ref-type="supplementary-material"}). ### GPC3-associated clusters in tumor versus non-tumor samples from liver {#SEC3-3-3} To further explore potential interactions of GPC3 with other genes, we used MOG to build two gene co-expression networks from the 3012 genes that are differentially expressed in LIHC---one network from non-tumor liver samples, and a second from LIHC samples (Additional File 3). Then, we imported each network into Cytoscape ([@B78]) and identified the tightly connected modules using MCODE ([@B79]). In the network built from non-tumor liver samples, MCODE ranked the GPC3-containing cluster second most significant (73 nodes (genes); MCODE score 30.7). GPC3 was directly connected with 21 genes in this cluster ([Supplementary Figure S5](#sup1){ref-type="supplementary-material"}), which is most enriched in GO terms: sulfur compound catabolic process, aminoglycan catabolic process and extracellular matrix organization ([Supplementary Figure S6](#sup1){ref-type="supplementary-material"} and File 5). In contrast, in the LIHC samples, GPC3 was not significantly co-expressed with any other genes, and thus was absent from the entire LIHC network. However, the LIHC network does contain a module with 114 genes (MCODE score 94.3), 33 of which are in the GPC3-containing cluster identified from the non-tumor network (17 of these genes are directly connected with GPC3 in the non-tumor network) ([Supplementary Figure S5](#sup1){ref-type="supplementary-material"}). This cluster is enriched in GO terms: extracellular matrix organization, blood vessel development and vasculature development ([Supplementary File 5 and Figure S7](#sup1){ref-type="supplementary-material"}). Stage-wise analysis of *Hu-cancer-RNASeq-dataset* {#SEC3-4} ------------------------------------------------- ### Identifying new candidate biomarkers for cancers {#SEC3-4-1} To identify potential biomarkers for tumors, we used MOG to distinguish genes whose expression is associated with the disease progression. We used MOG to separate samples by organ, and then by early stage (stage I or stage II) and late stage (stage III and later), based on the study metadata. At last, we performed a Mann--Whitney U test on those genes that are upregulated in tumor versus non-tumor samples ([Supplementary File 3](#sup1){ref-type="supplementary-material"}) to reveal the genes that are upregulated in late stage compared to early stage (expression increase 2-fold or more, and BH corrected *P*-value \< 0.05). These genes have increasing expression with cancer progression. We similarly identified the genes that have a decreasing pattern of expression with cancer progression. ESCA, KIRP, KIRC THCA all included metadata and had sufficient numbers per stage to detect differentally expressed genes. (Full results in Additional file 4.) MOG reveals 221 genes that increase expression during tumor progression (gene numbers for each tumor type are: ESCA:91, KIRP:89, THCA:25, KIRC:24), and 227 genes that decrease expression (gene numbers for each tumor type: ESCA:89, KIRP:68, LIHC:64, KIRC:13) ([Supplementary File 6](#sup1){ref-type="supplementary-material"} and Additional File 4). Of these 448 genes, 122 are flagged as prognostic markers by The Human Protein Atlas (THPA), which identifies prognostic markers by survival analysis ([@B80]). For example, Figure [4B](#F4){ref-type="fig"} and [C](#F4){ref-type="fig"} shows the expression pattern of two such genes, Phosphoenolpyruvate Carboxykinase 1 (PCK1, known to be downregulated in KIRC ([@B81]) and general marker of renal failure ([@B82])) and Chromosome 10 Open Reading Frame 99 (C10orf99, a known colon cancer inhibitor ([@B83]), and positive marker of KIRC ([@B84])), in KIRC and KIRP. ![MOG visualization of expression of selected genes during progression of three types of renal cancer. (**A**) Box plots summarizing CD70 expression in non-tumor kidney and in different stages of KICH, KIRC and KIRP cancer progression. CD70 is designated as prognostic unfavorable for renal cancer by THPA ([@B80]). However, although CD70 levels in tumor samples increase 93-fold in KIRC and 14-fold in KIRP, CD70 levels *decrease* in KICH by 3-fold (*logFC* = −1.56; B-H corrected *P*-value = 0.004). (**B** and **C**) Line charts showing average expression of PCK1 (blue) and C10orf99 (green) over different stages of KIRC (B) and KIRP (C). The vertical lines are error bars. THPA designates PCK1 as prognostic favorable and C10orf99 as prognostic unfavorable for renal cancer.](gkz1209fig4){#F4} Three hundred and twenty-seven genes that were identified in our study as differentially expressed in at least one tumor type were *not* labeled as prognostic in THPA ([Supplementary File 6](#sup1){ref-type="supplementary-material"}). For example, out of the 111 genes that increase during progression of KIRC or KIRP, only 56 were flagged as unfavorable prognostic for renal cancer by THPA. Of the 79 genes MOG identifies as decreasing with cancer progression in KIRC or KIRP, 39 were labeled as prognostic favorable for renal cancer by THPA. Twenty-seven genes out of the 64 that we identified by MOG as decreasing with cancer progression in LIHC were labeled by THPA as prognostic favorable for liver cancer. Out of 25 genes identified as having increasing pattern in THCA, none were labeled as prognostic by THPA. We propose that these genes may provide new candidates as biomarkers for prognosis of these tumor types ([Supplementary File 6](#sup1){ref-type="supplementary-material"}). A number of the 327 genes identified as differentially expressed in MOG but not listed in THPA have been experimentally evaluated for their potential as prognostic markers (Table [3](#tbl3){ref-type="table"}). For example, ARG1, CYP2C8, CYP3A4, CYP3A7 and CYP4A11, which we identified using MOG as decreasing expression with LIHC progression, have each been recently studied as prognostic markers for hepatocellular carcinoma ([@B85]). MOG analysis provides additional support for use of these genes as biomarkers. ###### Genes identified by MOG as showing changing expression with cancer progression (B-H corrected *P*-value \< 0.05) that had been identified in experimental studies as potential prognostic biomarkers but were not marked as prognostic for the given cancer type in The Human Protein Atlas (THPA) ([@B80]) Disease Gene Gene name Pattern Ref. --------- --------- ---------------------- ------------ ------------------- LIHC ARG1 arginase 1 Decreasing ([@B85]) LIHC CYP2C8 cytochrome P450 Decreasing ([@B86]) family 2 subfamily C member 8 LIHC CYP3A4 cytochrome P450 Decreasing ([@B87]) family 3 subfamily A member 4 LIHC CYP3A7 cytochrome P450 Decreasing ([@B87]) family 3 subfamily A member 7 LIHC CYP4A11 cytochrome P450 Decreasing ([@B88]) family 4 subfamily A member 11 THCA CHI3L1 chitinase 3 like 1 Increasing ([@B119]) THCA SFTPB surfactant protein B Increasing ([@B120]) THCA CD207 CD207 molecule Increasing ([@B121]) THCA MUC21 mucin 21, cell Increasing ([@B121]) surface associated THCA MMP7 matrix Increasing ([@B122],[@B123]) metallopeptidase 7 THCA IGFL2 IGF like family Increasing ([@B121]) member 2 THCA KLK7 kallikrein related Increasing ([@B124],[@B125]) peptidase 7 THCA FN1 fibronectin 1 Increasing ([@B126]) Using MOG to analyze and visualize the results by tumor type can reveal more nuanced information. For example, the Cluster of Differentiation 70 (CD70) gene is flagged by THPA and high CD70 expression is prognostic unfavorable for renal cancer. MOG analysis shows CD70 expression is higher in two types of renal tumors, KIRC and KIRP, and increases with disease progression (Figure [4A](#F4){ref-type="fig"}), but CD70 levels in another renal tumor type, KICH, have slightly *lower* expression than in non-tumor samples; thus, specifically in the case of KICH, *low* CD70 levels might be an unfavorable prognosis. For prognosis and personalized medicine ([@B89],[@B90]) *exceptions* can be extremely important, because specific tumor sub-types might respond differently to a particular treatment. By using MOG to explore RNA-Seq from large numbers of conditions and organs, a researcher can visualize data for individual samples or groups of that show changed expression of a prognostic marker or sets of markers, and compare these to those that do not. Such exploration could suggest statistical analyses to try out in other, independent datasets to determine whether subsets of non-canonical samples might have a biologically distinct signature, revealing a different modality for a particular cancer. This in turn could be followed up by targeted experimental approaches or clinical studies. Exploring genes of unknown functions in *AT-microarray-dataset* {#SEC3-5} --------------------------------------------------------------- Our aim in the case study of *AT-microarray-dataset* was to explore patterns of expression of genes with little or nothing known about them. The well-vetted dataset we used ([@B23]), encompasses expression values for 22 746 genes across 424 *A. thaliana* samples, representing 71 diverse studies and a wide variety of environmental, genetic and developmental conditions ([@B23]). We updated the gene metadata to the current TAIR annotations ([@B33]) and added phylostrata designations (obtained from phylostratr ([@B59])). We sought to identify genes of unknown or partially known function that might be involved in photosynthesis, the process that gave rise to the earth's oxygenated atmosphere and the associated evolution of extant complex eukaryotic species. We focused particularly on regulation of the assembly and disassembly of the photosystem I and II light harvesting complexes; these dynamic processes respond sensitively to shifts in light and other environmental factors ([@B91]). In particular, Met1 (AT1G55480) is a 36 Kda protein that regulates the assembly of the photosystem II (PSII) complex ([@B94]). To explore genes that might be involved in PSII assembly, we calculated Spearman correlation of Met1 expression with that of the 22 746 genes represented on the Affymetrix chip (Figure [5](#F5){ref-type="fig"}). This analysis finds 104 genes whose expression is highly correlated to Met1 (Spearman's coefficient \> 0.9) across all conditions ([Supplementary File 7](#sup1){ref-type="supplementary-material"}). ![Spearman correlation followed by line-plot visualization, using MOG, shows that Met1 (At1G55480) is highly expressed in photosynthetic organs and highly correlated with several genes of unknown function. The 'peaks' of expression are all leaf samples; the 'troughs' of expression are predominantly root and cell culture samples. *AT-microarray-dataset* representing 71 diverse studies and a wide variety of environmental, genetic and developmental conditions ([@B23]). Several genes of unknown function are closely co-expressed in this cluster.](gkz1209fig5){#F5} We examined whether genes of photosynthesis were over-represented in this Met1-co-expressed cohort. Among the Met1 co-expressed genes, the Gene Ontology (GO) Biological Functional terms most highly over-represented (*P*-value \< 10^−5^) are integral to the light reactions of photosynthesis: generation of precursor metabolites and energy; photosynthetic electron transport in photosystem I (PSI); reductive pentose-phosphate cycle; response to cytokinin; and PS2 assembly ([Supplementary File 7](#sup1){ref-type="supplementary-material"}). For example, the gene most highly correlated with Met1 is At2g04039, a gene encoding the NdhV protein, which is thought to stabilize the nicotinamide dehydrogenase (NDH) complex of PS1 ([@B95]); phylostratal analysis ([@B59]) indicates that NdhV has homologs across the photosynthetic organisms, streptophyta (land plants and most green algae). Eighteen of the Met1 co-expressed genes are designated as 'unknown function' or 'uncharacterized'; six are restricted to Viridiplantae. These genes would be good candidates to evaluate experimentally for a possible function in photosynthetic light reaction. Our next aim was to use MOG to directly explore an orphan gene (a gene encoding a protein unrecognizable by homology to those of other species) ([@B59],[@B96]), and to determine potential processes that it might be involved in. First, we filtered each gene's target description to retain 'unknown'. From these, we filtered to retain only the phylostratigraphic designation '*A. thaliana*'. From this gene list, we identified genes that had an expression value greater than 100 in at least five samples. We selected the orphan gene of unknown function, At2G04675, for exploratory analysis. At2G04675 encodes a predicted protein of 67 aa with no known sequence domains (domains searched using CDD ([@B98])). A Pearson correlation analysis of the expression pattern of At2G04675 with the other genes represented on the Affymetrix chip showed 48 genes had a Pearson correlation of higher than 0.95 ([Supplementary File 7](#sup1){ref-type="supplementary-material"}); these genes are expressed almost exclusively in pollen (the male gametophyes of flowering plants) (Figure [6](#F6){ref-type="fig"}). The exploration implicates At2G04675 as a candidate for involvement in some aspect of pollen biology. ![MOG line chart visualization shows the expression of orphan gene At2G04675 over the *AT-microarray-dataset* representing 71 diverse studies and a wide variety of environmental, genetic and developmental conditions ([@B23]). X-axis are samples, and Y-axis indicates their expression value. The orphan gene At2G04675 is of no known function, and genes highly correlated with At2G04675 are expressed almost exclusively in pollen/male gametophyte samples. Each line represents a gene. (Lines in this visualization are for clarity and the connections from sample to sample do not imply a relationship).](gkz1209fig6){#F6} Using MOG to further explore genes that are associated with pollen, we identified sets of leaf and pollen samples ([Supplementary Figure S8](#sup1){ref-type="supplementary-material"} and Additional File 5), and then calculated genes that are differentially expressed in the leaf samples versus the pollen samples using a Mann--Whitney U test (fold change of 2-fold or more; BH corrected *P*-value \< 10^−3^) (Additional File 5). The GO terms most highly enriched (*P*-value \< 10^−20^) among genes upregulated in pollen are processes of cell cycle, mitosis, organellar fission, chromosome organization and DNA repair (Additional File 5). This reflects and emphasizes the critical role of these processes in male gametophyte development, particularly sperm biogenesis. Each angiosperm pollen grain must produce two viable sperm each used in the double fertilization of the ovule. Above all else, proper mitogenesis is essential to the function of a pollen grain. We visualized the *leaf versus pollen* differential analysis by volcano plot (Figure [7](#F7){ref-type="fig"} and [Supplementary Figure S9](#sup1){ref-type="supplementary-material"}), this time to explore genes upregulated in leaf. Among these is At1G67860, an Arabidopsis specific gene encoding a protein of 'unknown function'. We used MOG to correlate expression of this gene versus all genes across all samples. One hundred sixteen genes, dispersed across all five chromosomes, are co-expressed with At1G67860 (Spearman correlation ≥ 0.65) ([Supplementary File 7](#sup1){ref-type="supplementary-material"}). The genes are expressed almost exclusively in mature leaf ([Supplementary Figure S10](#sup1){ref-type="supplementary-material"}). Most have no known function; a GO enrichment test indicates that GO biological processes overrepresented (*P*-value \< 10^−3^) among the genes are: defense response, response to stress, response to external biotic stimulus and response to other organism ([Supplementary File 7](#sup1){ref-type="supplementary-material"}). {#F7} Identifying co-expressed metabolites in *AT-metab-dataset* {#SEC3-6} ---------------------------------------------------------- Metabolomics is providing a growing resource for understanding metabolic pathways and identifying the structural and regulatory genes that shape these pathways and their interconnected lattice ([@B61],[@B99]). Here, we use the *AT-metab-dataset* metabolomics dataset that represents a comprehensive study of 50 mutants with a normal morphological phenotype but altered metabolite levels, and 19 wild-type control lines ([@B60]). There are 8--16 biological replicates for each genetic line; data is corrected for batch effects. Data and metadata were retrieved from PMR ([@B61]). The aim of this case study was to tease out co-expressed metabolites that are affected by genetic perturbations. We identified a group of four highly co-expressed metabolites (Pearson correlation \> 0.8): the amino acid arginine, its precursor L-ornithine, cyclic ornithine (3-amino-piperidine-2-one), and one unidentified metabolite. Plots across the means of the biological replicates of each sample ([Supplementary Figure S11](#sup1){ref-type="supplementary-material"}), shows accumulation of these metabolites is upregulated over 4-fold in four mutant lines: *mur9*, mutants have altered cell wall constituents; *vtc1*, encodes GDP-mannose pyrophosphorylase, required for synthesis of manose, major constituent of cell walls, upregulated upon bacterial infection; *cim13*, gene of unknown function associated with disease resistance, *eto1*, negative regulator of biosynthesis of the plant hormone ethylene. An arginine-derived metabolite, nitrous oxide, has been widely implicated in signaling pathways in plants ([@B101]). MOG analysis might suggest to a researcher a potential relationship between arginine and the cell wall defense response, providing a suggestion for future experimentation. Comparison to other software {#SEC3-7} ---------------------------- Few tools that do not require coding are available for on-the-fly exploration of expression data. Most are 'shiny' ([@B13]) apps ([@B15],[@B102]) providing a web interface to a limited number of R packages for data visualization, batch correction, differential expression analysis, PCA analysis (among samples) and gene enrichment analysis. Although shiny ([@B13]) is constantly improving, existing tools written in R ([@B15]) must rely on R's present capabilities for interactive applications ([@B103]). In contrast to R, Java, MOG's platform, has been used to develop numerous software with interfaces that are interactive and user-friendly (e.g. ([@B78],[@B104])), and MOG provides the researcher with specialized GUIs and methods for exploratory data analysis. MOG's GUI allows direct interactivity with the data through interactive tables, trees and visualizations, so that a researcher can easily explore data from different perspectives. Most available R-based tools read all data directly into the main memory. Thus, on a laptop/desktop computer, analysis of a big dataset is slow (or crashes) if the available memory is not sufficiently large. For example, a dataset of 100 000 human transcripts over 5000 samples (500 000 000 expression values) requires at least 4GB (8 byte for each value) of free memory to be loaded into memory at once. To circumvent this problem, R developers can use the new DelayedArray ([@B107]) framework together with DelayedMatrixStats ([@B108]) which can enable efficient handling of big datasets with R. For example, iSEE's ([@B18]) code is compatible with using DelayedArray ([@B107]) objects. In contrast, MOG uses an indexing strategy to read data only when it is needed, which drastically reduces the total memory consumption of the system. Table [4](#tbl4){ref-type="table"} compares five of the most recent tools for exploratory analysis of expression data to MOG. (More details are provided in [Supplementary File 8](#sup1){ref-type="supplementary-material"}.) ###### MOG compared to existing tools for exploratory analysis of expression data MOG PIVOT iSEE iGEAK IRIS-EDA DEvis -------------------------------------- ------------------------------- ------------------- -------------------------------- -------------------- ------------------- ----------- Reference This paper ([@B15]) ([@B18]) ([@B16]) ([@B17]) ([@B102]) Year 2019 2018 2018 2019 2019 2019 Platform/GUI Java/Swing R/Shiny R/Shiny R/Shiny R/Shiny R/None Interactive tables and trees Yes No No No No No Interactive drag and drop operations Yes No No No No No Interactive visualizations Yes Partial Partial Partial Partial No Interactively subset data Yes Partial Partial Partial No No Save progress Yes Yes Partial (if user saves R code) No No No Use any R package Yes No No No No No Supported data types Omics or other numerical data RNA-Seq/scRNA-Seq Omics RNA-Seq/microarray RNA-Seq/scRNA-Seq RNA-Seq MW U test (sec.) 7 1260 NA NA NA NA MOG's GUI, designed with Java swing, is fully interactive; in contrast, other available tools are based on R and provide limited or no interactivity. A MOG user can execute any R package/script with interactively selected subsets of data if s/he wishes to perform additional analysis, whereas only a limited number of R-packages are available in the other tools. The last row compares the Mann--Whitney U test's execution time for MOG and PIVOT using the liver tumor and non-tumor datasets (18 212 genes over 410 samples). A more detailed comparison of the tools is available in [Supplementary File 8](#sup1){ref-type="supplementary-material"}. ### Benchmarking {#SEC3-7-1} We benchmarked MOG's performance with the *Hu-cancer-RNASeq-dataset* (18 212 genes over 7142 samples) using a laptop with 64 bit Windows 10, 8 GB RAM and Intel(R) Core(TM) i5-7300HQ CPU; the system's resource utilization was monitored by Windows Performance Monitor tool (WPMT) ([@B109]). During benchmarking, only the software being tested was running. MOG's efficiency was compared to that of one of the R-based 'shiny' web-app ([@B13]) (choosing PIVOT, because it permits loading normalized data). PIVOT repeatedly crashed and failed to load the full *Hu-cancer-RNASeq-dataset* (Additional File 6), but was able to load a subset of data consisting only of 410 tumor and non-tumor liver samples. We measured the execution time (time taken to compute and display output) of the Mann--Whitney U test for differentially expressed genes in tumor versus non-tumor samples. The test completed in 21 min with PIVOT, but only seven seconds with MOG (Figure [8](#F8){ref-type="fig"}). We kept MOG running idle until total runtime reached 30 min and compared memory and processor usage ([Supplementary File 8](#sup1){ref-type="supplementary-material"}); average memory usage of PIVOT (1869 MB) was about twice that of MOG (995 MB) ([Supplementary File 8](#sup1){ref-type="supplementary-material"}). Peak % processor time (CPU) was greater for MOG; however, MOG completed its task much more quickly, and over the 30 min, the *average* % processor time was 64% for PIVOT but only 2% for MOG (Figure [8A](#F8){ref-type="fig"}). {#F8} We benchmarked MOG's performance on datasets of different sizes, created by splitting the *Hu-cancer-RNASeq-dataset* by organ type (tumor and non-tumor samples). For each dataset, we performed a Mann--Whitney U test on all the genes for tumor versus non-tumor groups. MOG took only 31 s to compute a Mann--Whitney U test on 18 212 genes over 1054 samples (Figure [8B](#F8){ref-type="fig"} and Additional File 6). We then measured the execution time for calculating Pearson correlations of one gene with all others. MOG took only a couple of seconds to compute a Pearson correlation over 1000 samples and 16 s to compute over 7142 samples (Figure [8C](#F8){ref-type="fig"}). DISCUSSION AND CONCLUSION {#SEC4} ========================= We demonstrated MOG's functionalities by exploring three different well-validated datasets: a human RNA-Seq dataset from non-tumor and tumor samples (*Hu-cancer-RNASeq-dataset*), an *A. thaliana* microarray dataset (*AT-microarray-dataset*) and an *A. thaliana* metabolomics dataset (*AT-metab-dataset*). In each case, known information was recapitulated in the MOG analysis, and new potential relationships became apparent. During exploration of the *Hu-cancer-RNASeq-dataset* by MOG, we created a catalog of genes that are differentially expressed in different types of tumors, identifying in this process 35 genes that are consistently upregulated or downregulated in every type of cancer in the dataset. GPC3 ([@B67],[@B71]) was identified by MOG as a biomarker gene for liver cancer. Gene-level resolution analysis by MOG revealed that the cadre of genes that are co-expressed with the GPC3 gene change drastically among the individual organs, and between tumor samples and corresponding non-tumor samples. By mining the sample and study metadata, we identified genes that showed regulation with cancer progression. Many of the genes we identified have been reported previously in the literature and in THPA to be prognostic biomarkers for different cancers. Many other genes that MOG identified as differentially expressed genes are *not marked as prognostic in THPA*. These genes present potential new biomarkers for disease progression. Because each tumor type has many variations, investigating multiple candidate prognostic markers in individual tumors can provide critical information for personalized medicine ([@B110]). Using the *AT-microarray-dataset*, we explored expression patterns of genes with unknown functions including orphan genes, identifying 18 mostly plant-restricted genes that are tightly co-expressed with genes central to photosystem assembly. We also identified an Arabidopsis-specific gene, At2G04675, to be highly expressed in pollen development, suggesting a potential involvement of this gene in gametogenesis. With the *AT-metab-dataset*, we identified a potential relationship between arginine and the cell wall defense response. Such exploratory analyses provide clues as to how to approach experimentally testing the function of these genes or metabolites. Processing multiple heterogeneous RNA-Seq data is a formidable and unsolved challenge. We have intentionally not added capabilities for data processing (e.g. alignment, normalization, and batch-correction to minimize unwanted technical and biological effects) into MOG for two reasons. First, the selection of appropriate statistical and computational methods depends on the data structure and the biological questions to be asked. Different types of data have different characteristics ([@B111]), and if statistical methods are misapplied during normalization and batch-correction, especially when the data are from multiple heterogeneous studies, the resultant dataset may be misleading. Much as if using R or MATLAB statistical software, a MOG user must consider these technicalities. Second, the data science field is far from unsettled ([@B112]) with new approaches and variations being developed each year. (GoogleScholar retrieved over 10 000 journal articles from the first half of 2019 for 'RNA-Seq normalization methods'). Potentially a researcher could use MOG as a tool to compare the results of different methods of processing the same raw data. Such interactive comparisons would enable biologists to gain insight as to which processing methods best reflect experimentally-established 'ground truths'. This approach would provide a complement to the more typical validation of a dataset by determining GO term enrichment in gene clusters. Analyses performed while exploring and statistically analyzing datasets on MOG can be saved; by clicking 'save', all the analyses that have been performed are added as objects to the MOG project file. Results obtained with MOG can be shared by sharing the saved MOG project file. If a user wishes to document the information to reproduce the analysis, she/he needs to manually specify the parameters and methods used. In the future, we plan to implement automated report generation for each analysis. MOG is a novel Java software for interactive exploratory analysis of big 'omics datasets or other datasets. By using an indexing strategy to read data only when it is needed, the total memory consumption of the system is minimized, enabling MOG to perform much more efficiently than the available R-based software. Visualizations produced by MOG are fully interactive, and enable researchers to detect and mine interesting data points and probe the relationships among them. The statistical methods implemented in MOG help to guide exploration of hidden patterns in a user-friendly manner. By integrating metadata, MOG affords an opportunity to extract new insights into the relationships between gene expression and gene structure, gene location, or any of the diverse information entered by scientists about the biology and experimental conditions. Taken together these features can aid a researcher in developing new, experimentally testable hypotheses. DATA AVAILABILITY {#SEC5} ================= We subscribe to FAIR data and software practices ([@B116]). MOG is free and open source software published under the MIT License. MOG software, user guide and all compiled datasets in this article are freely downloadable from <http://metnetweb.gdcb.iastate.edu/MetNet_MetaOmGraph.htm>. MOG's source code and user guide is available at <https://github.com/urmi-21/MetaOmGraph/>. MOG's source code (version 1.8.0) at the time of submission is archived and can be accessed using the DOI:10.5281/zenodo.3520986. Additional files are available at <https://github.com/urmi-21/MetaOmGraph/tree/master/MOG_SupportingData>. Supplementary Material ====================== ###### Click here for additional data file. We especially thank Nick Ransom for his formative role in MOG's early development. We are grateful to our collaborators, Kevin Bassler, Pramesh Singh and Ling Li, for their help and feedback. We much appreciate the efforts of Jing Li, Priyanka Bhandhary, Arun Seetharam and the early-adopters who beta-tested MOG and provided valuable feedback. SUPPLEMENTARY DATA {#SEC6} ================== [Supplementary Data](https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkz1209#supplementary-data) are available at NAR Online. FUNDING {#SEC7} ======= National Science Foundation Grant \[IOS 1546858, in part\]; Orphan Genes, An Untapped Genetic Reservoir of Novel Traits; Center for Metabolic Biology, Iowa State University. Funding for open access charge: National Science Foundation Grant \[IOS 1546858\]. *Conflict of interest statement*. None declared.

2023-08-19T01:27:04.234600

https://example.com/article/1561

Recently added to that list: playground equipment in auditoriums to cater to 3- to 12-year-olds. Cinépolis, which has more than 4,900 auditoriums worldwide, last month introduced Cinépolis Junior at theaters in Los Angeles and San Diego. They are equipped with a 55-foot-long and 25-foot-high play structure with two slides and two platforms with “wobble hoppers” (similar to stationary pogo sticks) and “stand n’ spins” (smaller versions of merry-go-rounds). A separate area enclosed with a colorful fence has green lawn turf and plastic animal sculptures for climbing and crawling. Cinépolis USA, a Dallas-based subsidiary with theaters in California, Connecticut, Florida, New Jersey and New York, plans to open more junior auditoriums in the United States. Adrian Mijares Elizondo, the chief executive of Cinépolis USA, said early accounts on social media left the mistaken impression that the playground was open during movie screenings. Children are allowed to play for 20 minutes before the movie begins and the lights are fully on. When it is time for the movie to start, a cartoon character appears on screen to tell parents and children to take their seats, and the lights are dimmed. There is a 15-minute intermission during which the children can play. An attendant monitors the play area so children do not enter while the movie is showing, a company statement said. The auditoriums have unconventional seating, with oversize bean bags and pillows and poolside-style lounge chairs, as well as more traditional seats. Introductory ticket prices are $1 more than standard tickets, though prices vary by location, time of day and seat type. Only movies rated G or PG are screened, so no “The Fate of the Furious” in between trips down the slides. Children must be accompanied by an adult, and adults must be with a child 12 and under, the company said. What is the allure for parents to bring children to a movie theater and incur the expense of tickets and snacks instead of staying home and watching a movie? Mr. Elizondo’s rationale: “You can watch only so many movies at your house. At some point, you just want to leave the house.” Watching a movie at home cannot compete with watching one in a theater, he said, adding, “Only a movie theater can completely take you out of everyday life.” The company opened its first Cinépolis Junior in Mexico in 2014 and has introduced the amenity to more than two dozen sites in Costa Rica, Guatemala, Mexico and Spain. While Cinépolis has introduced playground equipment to movie theaters, it is not the first to try to attract parents. Other theaters host “Crybaby Matinees” and “Diaper Date Nights,” times when parents with babies are welcome. The company acquired the two California theaters in February 2015 and spent $1 million to convert the auditoriums, which opened to packed houses largely on the strength of family-friendly movies, such as “Beauty and the Beast,” “The Boss Baby” and “Smurfs: The Lost Village,” Mr. Elizondo said. Image The Cinépolis Junior auditorium features oversize pillows that can seat two.CreditMike Blake/Reuters The openings also coincided with spring break for schools. “It was a crazy March,” he said. “It’s been a great few weeks.” “It’s one more way of expanding the audience,” he said. “The idea that there is only one moviegoing audience is kind of obsolete.” With the junior auditoriums, the company hopes to attract a segment of the market that has seesawed in the past few years: people with young children. The number of frequent moviegoers — those who go to the movies once a month or more — ages 2 to 11 decreased to 3.1 million in 2016 from 4.3 million in 2013, according to a report from the Motion Picture Association of America. It was up slightly from 2015. Jacqui Saldana of the blog Baby Boy Bakery visited one of the auditoriums and wrote that the play area allowed children to “get their wiggles out” before a screening and families to enjoy a visit to a movie theater “with ease.” Faith Popcorn, the chief executive of BrainReserve, a marketing consulting company, who has written on consumer trends, was skeptical that the concept would catch on. “What happens when kids get noisy, get into fights, get injured?” she wrote in an email. “It’s not going to be a happy cocooning experience for anyone in that theater.” With virtual reality and augmented reality expected to explode into a multibillion-dollar business by 2020, the future is not in movie theaters but instead is “in headsets and a new kind of immersive experience — way more intoxicating and addictive than climbing on a jungle gym while a kiddie movie plays,” she wrote. A version of this article appears in print on , on Page B3 of the New York edition with the headline: Play Date and a Movie? Theaters Have It Covered. Order Reprints | Today’s Paper | Subscribe

2023-09-11T01:27:04.234600

https://example.com/article/7151

A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3′ termini of the linear proviral DNA; covalent joining of the recessed 3′ OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes. Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)]. All three enzymes have been shown to be essential for the replication of HIV. It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, including reverse transcriptase inhibitors such as azidothymidine (AZT) and efavirenz and protease inhbitors such as indinavir and nelfinavir. The compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication. The inhibition of integrase in vitro and HIV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro in HIV infected cells. The particular advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication.

2023-12-13T01:27:04.234600

https://example.com/article/4110

Trump announces new crackdown on North Korea's trade 'The regime can no longer count on others to facilitate its trade and banking activities,' Trump said. President Donald Trump announced Thursday that he had signed a new executive order expanding the U.S. government’s authority to target individuals, companies and financial institutions with ties to North Korea, escalating the U.S. campaign of economic pressure against the repressive regime. “Foreign banks will face a clear choice: do business with the United States or facilitate trade with the lawless regime in North Korea,” Trump said at the start of a meeting in New York with the Japanese prime minister and South Korean president. “The regime can no longer count on others to facilitate its trade and banking activities.” The White House has been searching for new ways to crack down on the secretive state's missile program. Last month, Trump threatened "fire and fury" if North Korea did not back off. On Tuesday, he told the United Nations General Assembly that dictator Kim Jong Un was on a "suicide mission." The North Korean leader responded to Trump's speech on Friday morning in a statement from Pyongyang, calling Trump "deranged" and "unfit to hold the prerogative of supreme command of a country. He called Trump "a rogue and a gangster fond of playing with fire." "I will make the man holding the prerogative of the supreme command in the U.S. pay dearly for his speech calling for totally destroying the DPRK," read the statement carried by North's official Korean Central News Agency. POLITICO Playbook newsletter Sign up today to receive the #1-rated newsletter in politics Email Sign Up By signing up you agree to receive email newsletters or alerts from POLITICO. You can unsubscribe at any time. This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply. The order announced Thursday, however, does not impose any new sanctions but rather expands the Treasury Department's authority to target people who trade in goods, services or technology with North Korea. The president added that the U.S. will also seek to identify new industries that could be targeted, including textiles, fishing, information technology and manufacturing. The move appears aimed primarily at businesses and individuals in China, which is North Korea’s neighbor, and could agitate relations with Beijing, though the order likely did not come as a surprise. If only a few Chinese businesses — or just minor ones — are targeted, the government in Beijing may look away. But because so much of China's economy is state-controlled, including some major banks, the possibility remains for new fissures between the U.S. and China. China itself is deeply worried about North Korea’s nuclear ambitions, and it has backed recent U.N. Security Council resolutions imposing new sanctions on the regime there. But China also wants to avoid a military confrontation that could lead to the fall of the North Korean government. Such a collapse would leave China with a failed state on its doorstep, as well as a likely flood of North Korean refugees streaming across its border. Trump on Thursday praised a “bold move” by China’s central bank to direct that nation’s other banks to stop doing business with North Korea. China is North Korea’s largest trading partner and has historically been its chief patron on the world stage and protector inside the United Nations Security Council. “It was a somewhat unexpected move and we appreciate it,” the president said. Treasury Secretary Steven Mnuchin told reporters Thursday that Trump’s order “significantly expands” his agency’s authority to cut off funding to the North Korean regime and its weapons program anywhere in the world. “For too long, North Korea has evaded sanctions and used the international financial system to facilitate funding for its weapons and mass destruction and ballistic missile programs,” he said. “No bank in any country should be used to facilitate Kim Jong Un’s destructive behavior.” Mnuchin cast the sanctions as going beyond the Security Council’s latest resolutions. Designations will occur on a rolling basis, he said, beginning “with all activity today.” “These sanctions are very significant because not only does it allow us to sanction individuals or entities, but it allows us to freeze or block any transaction with any financial institution anywhere in the world that facilitates any transactions with the blocked person,” he said. “The objective is for them to stop their missile tests and give up their nuclear weapons.” United Nations Ambassador Nikki Haley told reporters at a separate briefing later Thursday that the goal of U.S. sanctions has been to slash North Korea’s revenue to reduce its “reckless behavior.” “If they don’t have the funding for the ballistic missiles, for the nuclear production, then they can do less of it. That’s the goal of the sanctions,” she said. “It doesn’t mean that it’s necessarily gonna change Kim’s attitude or his belief on what he wants to do, but it will slow down the production of the nuclear process going forward.” Trump, in his General Assembly address earlier this week, said, “No one has shown more contempt for other nations and for the well-being of their own people than the depraved regime in North Korea. He added that its “reckless pursuit of nuclear weapons and ballistic missiles threatens the entire world with unthinkable loss of human life.” “The United States has great strength and patience, but if it is forced to defend itself or its allies, we will have no choice but to totally destroy North Korea,” the president said. “Rocket Man is on a suicide mission for himself and for his regime.” Asked about the president’s pledge to destroy North Korea, if provoked, Haley said Thursday, “I think that’s just common sense.” “If you look at it, we have said multiple times … we don’t want war. That’s the last thing anyone wants,” Haley said. “We don’t want loss of life. That’s the last thing anyone wants. But at the same time, we’re not going to run scared. If, for any reason, North Korea attacks the United States or our allies, the U.S. will respond. Period. That’s what’s going to happen.” Victoria Guida contributed to this report.

2023-12-27T01:27:04.234600

https://example.com/article/4372

1. Field of the Invention This invention relates to a positive sensitive resin composition comprising a novel copolymer of 4-(1-methylethenyl)phenol, a (meth)acrylate and a (meth)acrylic acid (PIPE copolymer), an ether-bond-containing olefinic unsaturated compound and an acid-generating agent, as well as a process for forming a resist pattern therewith. In particular, it relates to a positive sensitive resin composition comprising a copolymer of 4-(1-methylethenyl)phenol, a (meth)acrylate and a (meth)acrylic acid useful as a base polymer, an ether-bond-containing olefinic unsaturated compound and an acid-generating agent, as well as a process for forming a resist pattern by applying or adhering the composition to a substrate and then irradiating it with an active energy beam such as ultraviolet rays, visible light and heat rays for developing it. 2. Description of the Related Art A resist material in combination with an exposure technique has been utilized in lithography such as patterned circuit formation in an electron device and printing. An application of such patterned circuit formation in an electron device may be, for example, a process for manufacturing a color filter for a variety of multicolored liquid-crystal color displays such as a liquid-crystal color television. Such a color filter has been conventionally manufactured by, for example, screen printing and electrodeposition. However, as a color display has been improved for its resolution, it has been more important to refine a pattern. Thus, a variety of patterning processes utilizing photolithography has been investigated. For example, JP-A 8-94827 has disclosed a process for manufacturing a color filter comprising the steps of [1] forming a transparent conductive layer on a transparent substrate; [2] forming a positive photosensitive coating layer; [3] exposing a part of the transparent conductive layer; [4] forming a colored area by electrodeposition; and [5] repeating the steps [3] and [4] as required. Of these steps, a pattern refinement level depends on the steps [2] and [3], in which photolithography is used. In particular, it significantly depends on a positive photosensitive composition applied on the transparent conductive layer. The above invention employs a positive photosensitive composition essentially comprising (a) a polymer containing both carboxyl and hydroxyphenyl groups in one molecule, (b) a compound containing two or more vinyl ether groups in one molecule, and (c) a compound generating an acid by irradiating an active energy beam. This photosensitive composition is developed as follows; by heating the film on which the positive photosensitive composition has been applied, an addition reaction of the carboxyl group and/or hydroxyphenyl group with the vinyl ether group forms a crosslink, which is insoluble to a solvent or an alkali developing solution, and then, after irradiating with an active energy beam and then, as necessary, heating the film, an acid generated in the irradiated area acts as a catalyst to cleave the crosslink structure and thus to again make the irradiated area soluble to a solvent or an alkali developing solution. For further improving a resolution, a preferable polymer (base polymer) in a positive photosensitive composition is one containing both carboxyl and hydroxyphenyl groups in one molecule which meets all the following five requirements as much as possible; (a) a higher solubility to a solution which solves a crosslinking agent, an acid-generating agent and others (solvent solubility); (b) a certain dissolution rate of the cloven crosslink moieties in an alkali developing solution after exposure (dissolution rate in an alkali developing solution); (c) good diffusivity of an acid generated by irradiation with an active energy beam (acid diffusivity); (d) transparency of a photosensitive coating at an exposure wavelength (transparency); and (e) thermal stability during the heating step after application of the film and exposure (thermal stability). As an example of a polymer meeting these requirements somewhat, a copolymer from p-hydroxystyrene, n-butyl acrylate and acrylic acid has been disclosed in, for example, JP-As 8-94827 and 8-94829. We have, however, investigated the copolymer for its performance and have concluded that it is insufficiently soluble in a solvent or thermally stable. JP-A 61-293249 has disclosed a binary copolymer of 4-(1-methylethenyl)phenol and n-butyl acrylate as an example of a copolymer for a resin composition exhibiting damping property. The copolymer has an extremely lower dissolution rate in an alkali developing solution and is poorly compatible with a vinyl ether compound. It cannot be, therefore, used as it is.

2024-05-26T01:27:04.234600

https://example.com/article/2929

1. Field of the Invention The present invention relates to an active-matrix type display device having an active element and more particularly to the active-matrix type display device having a self-emissive type device such as an organic EL (Electro-Luminescent) device. The present application claims priority of Japanese Patent Application No.2000-217907 filed on Jul. 18, 2000, which is hereby incorporated by reference. 2. Description of the Related Art In recent years, portable information terminals have become widespread rapidly as typified by i-mode portable cellular phones (i-mode is a trademark of NTT DOCOMO company) and, as a display device for such the portable information terminals, a liquid crystal display is widely used. When a back light is incorporated into the liquid crystal display, luminance on an entire screen is increased, thus presenting a problem in that the liquid crystal display consumes much power. To solve this problem, a display into which an organic EL device is incorporated as the display device suitably used for portable information terminals (hereinafter referred to as an organic EL display device) is disclosed in Nikkei Electronics (March 15 issue, No. 765, 2000, pages 55-62). Main contents described in the above literature will be described below. As the display device using an emissive-type display device which emits light when a current flows, a PDP (Plasma Display Panel) and/or the EL display device are known. The EL display device is classified into an inorganic EL display device and the organic EL display device and is further classified by its structure into a simple-matrix type EL device and an active-matrix type EL device. FIG. 3 is a schematic conceptual block diagram showing configurations of the conventional simple-matrix type organic EL display device. As shown in FIG. 3, the conventional simple-matrix type organic EL display device includes an EL device 31, a capacitor 32 connected between an anode and a cathode of the EL device 31, a data line 33 connected to the anode and a scanning line 34 connected to the cathode, which are mounted in a matrix form. The conventional simple-matrix type organic EL display device further has a data line driving circuit 35 and a scanning line driving circuit 36. The data line driving circuit 35 activates one of the data lines 33 and the scanning line driving circuit 36 activates one of the scanning lines 34, thus passing currents through the EL devices 31 each connecting to the data line 33 and scanning line 34 from the data line 33 to the scanning line 34 and causing the EL device 31 to emit light at a value of a luminance corresponding to a value of the current. Though structure of the simple-matrix type organic EL display device is comparatively simple and its manufacturing costs can be reduced, it is difficult to increase the number of pixels and difficult to achieve a high definition display device. In the simple-matrix type organic EL display device, since the scanning lines 34 are selected one by one to cause the pixels to emit light, emissive time of each of the pixels is 1/the number of scanning lines in one frame period. To maintain the luminance at a specified level within limited time, it is necessary to instantly pass a large electric current through each of the pixels, which presents basic problems in that the luminance becomes low as accumulated emissive time is lengthened and a life of emissive material is shortened due to flowing of such the large electric current as the driving current through the simple-matrix type organic EL display device. Next, operations and configurations of the conventional active-matrix type organic EL display device will be described by referring to FIG. 4. The conventional active-matrix type organic EL display device includes an EL device 41, a TFT (Thin Film Transistor) 42 connected between an anode of the EL device 41 and a bias line 47, a TFT 43 connected between a gate of the TFT 42 and a data line 45, and a capacitor connected between a gate of the TFT 42, and the bias line 47, which are arranged in a matrix form. The conventional active-matrix type organic EL display device further has a data line driving circuit 48 and a scanning line driving circuit 49, and bias voltage source 410. When a scanning line 46 is activated by the scanning line driving circuit 49, a TFT 43 connected to the activated scanning line 46 is brought into conduction and a current flows through a data line 45 and through the TFT 43 from the data line driving circuit 48 to a capacitor 44, causing the capacitor 44 to be charged. When a gate voltage of the TFT 42 becomes higher than a threshold voltage, the TFT 42 becomes conducting, causing currents to be fed through the bias line 47 from a bias voltage source 410 to the El device 41 and causing the EL device 41 to emit light at a value of the luminance corresponding to a value of the current. As is apparent from the above description, unlike in a case of the simple-matrix type organic EL display device, the active-matrix type organic EL display device has a characteristic that, even if the number of the scanning line is increased, same emissive time as frame period can be secured. In the comparison of the active-matrix type liquid crystal display device with the active-matrix type organic EL display device, though transmittance (that is, it is equivalent to luminance of the active-matrix type organic EL display device) of the active-matrix type liquid crystal display device is proportional to a voltage applied to the liquid crystal, the luminance of the active-matrix type organic EL display device is proportional to a current and the voltage output from the bias voltage source 410 to the bias line 47 is maintained at a specified level. Since the organic EL display device is a current-driven type display device, the TFT adapted to simply perform ON/OFF operations such as those used in the active-matrix type liquid crystal display device cannot be used and the TFT having on-resistance being small enough to pass sufficient currents is required. Such the TFT is difficult to produce using technology to manufacture a general amorphous silicon TFT. To manufacture such the TFT, it is necessary to use a process of manufacturing low-temperature polysilicon TFT being used in some kind of a high definition display device. If the low-temperature polysilicon TFT is used, it is possible to form the TFT and/or driving circuits on a glass substrate and, when multi-gray shades are generally displayed, almost all circuits on a scanning line side and partial circuits (selection switches) on a data line side are formed on the glass substrate and complicated circuits used to control gray shade displaying are implemented by semiconductor circuits formed on a single crystal substrate. To achieve full color displaying, in the active-matrix type liquid crystal display device, red, green, and blue color filters are used. In the active-matrix type organic EL display device, the full color displaying is implemented by mounting organic EL devices each emitting light in red, green, or blue. However, this method presents problems in that a life of the organic EL emitting light in red is shorter than that of other organic EL emitting light in other colors and in that the color of the emitted light is not purely red but is nearly orange. Moreover, there is available another method in which the red color, green color, and blue color are mixed to produce white color and pixels each corresponding to each of the red, green, and blue colors are formed by using color filter as in a case of the liquid crystal display device. However, in the above active-matrix organic EL display device, though the luminance can be controlled by the currents that are passed through the organic EL devices making up each of the pixels, since materials of the organic EL devices each emitting light in red, green, or blue are different, it is difficult to control production processes so that the luminance and life of each of the pixels are made equal. Furthermore, when such the organic EL device is employed as the display device of portable cellular phones, reduction in power consumption in particular is required. However, in the conventional active-matrix type organic EL display device, time during which displayed contents are not changed exceeds a specified period of time, it is impossible to decrease the luminance for each of pixels, lines or frames, or to lower the luminance for the pixels, the lines or the frames making up an image requiring no more luminous display, thus making it difficult to greatly lower the power consumption.

2024-03-24T01:27:04.234600

https://example.com/article/3478

Banca di Valle Camonica Banca di Valle Camonica S.p.A. was an Italian bank based in Breno, in the Province of Brescia, Lombardy. The bank is named after Val Camonica. History Found in 1872, Banca di Valle Camonica was a subsidiary of Banca San Paolo di Brescia since 1963. The parent company merged with Credito Agrario Bresciano to form Banca Lombarda Group. In 2007 the bank became part of UBI Banca. References Category:Defunct banks of Italy Category:Companies based in Lombardy Category:Buildings and structures in the Province of Brescia Category:Banks established in 1872 Category:1872 establishments in Italy Category:Former UBI Banca subsidiaries

2023-09-28T01:27:04.234600

https://example.com/article/1175

Denervation-induced changes in electrophysiologic parameters of the smooth muscle of the guinea-pig and rat was deferens. In order to further elucidate the mechanisms by which postganglionic denervation causes changes in the dose-response curves obtained in smooth muscle, microelectrodes have been used to investigate cellular changes in the denervated guinea-pig and rat vas deferens. In the guinea-pig vas deferens, chronic denervation produced a partial depolarization (mean change of 8.5 mV) without any change in threshold for the action potential. In the rat vas deferens there was no change in resting potential but the threshold membrane potential because more negative (6.5 mV). Thus, in both species, but apparently by different mechanisms, the resting and threshold membrane potentials are brought closer together by denervation. Such an effect would clearly contribute to the well documented increase in sensitivity to depolarizing agonists which is produced by chronic denervation. In both species, denervation increased the space constant of the smooth muscle, an indication of increased electrical coupling among the cells. This observation is consistent with morphologic evidence of improved coupling induced by denervation and presented previously from this laboratory. The improved coupling appears to be associated with the increased maximum response of the denervated vasa deferentia of both species. These results are discussed in references to known similarities and differences in electrophysiologic characteristics between normal guinea-pig and rat vasa deferentia.

2023-08-16T01:27:04.234600

https://example.com/article/6800

Naomi Klein tells Owen Jones that Donald Trump’s administration is using a ‘new formula’ for pushing through its agenda. Rather than the disaster capitalism she outlined in her book The Shock Doctrine, Klein says the Republican party is using Donald Trump’s ‘mental instability, out-of-control ego and general man-babyness’ to distract from their policies, which are ‘savaging’ environmental standards and already-inadequate financial regulations An extended version of this interview is available on Owen Jones’s YouTube channel

2023-09-25T01:27:04.234600

https://example.com/article/5520

The present invention relates to a system and method for the compensation of assay measurements of analytes from small quantities of biological fluids harvested from tissue of a subject utilizing conditions at the harvesting and assay or measurement site. Current analyte assay devices suffer from inaccuracies resulting from a variety of confounding conditions at the harvesting site. For example, blood glucose meters adjust an assay measurement for ambient temperature conditions associated with the glucose test strip when it is inserted in the meter. As attempts are made to reduce the volume of biological fluid collected or the time required for the assay, these conditions become more and more detrimental to an accurate assay measurement. The conditions include, but are not limited to, humidity, temperature, ambient light, pressure, etc. For example, this is particularly the case in a system that measures a glucose concentration from blood or interstitial fluid collected in a harvesting device that is placed in or about the surface of a tissue. Attribute compensation is even more important in a system that monitors an analyte on a continuous basis from a harvesting device that is kept in contact with the tissue for several hours, days or even weeks. Through the use of appropriate sensors, these conditions may be monitored and compensated for in the desired assay measurement.

2024-06-21T01:27:04.234600

https://example.com/article/6216

Rep. George Miller of California says a new GAO report points out important gaps in the nation's systems for reporting child abuse by school personnel. By Gil Aegerter and Joel Seidman, NBC News Sexual abuse of children by teachers or other public school employees is likely underestimated because of a patchwork reporting system and involvement of numerous local, state and federal agencies in investigating such claims, according to a new government report obtained exclusively by NBC News. The report by the Government Accountability Office, released Thursday, raises numerous questions about how closely public schools are following federal requirements for mandatory reporting of child sexual abuse allegations or suspicions involving the public school employees who oversee the 50 million children enrolled in the nation’s public K-12 schools. The report also raises doubts about the accuracy of the data on the scope of the problem. "While Education, HHS and Justice all have data systems that capture information from state and local entities about child abuse, none capture(s) the extent of sexual abuse and misconduct perpetrated by public K-12 school personnel," the report said. One key issue is who receives reports from educators. Under the Child Abuse Prevention and Treatment Act, each state is required to have a law for mandatory reporting requirements, along with procedures for screening and investigating reports. Most states require that allegations be reported to a state or local child protection service, the GAO report said, while about two-thirds designated law enforcement (there was overlap in the two categories). "I was quite stunned by the fact that there's still several states that don't have that requirement to report to law enforcement," said Rep. George Miller, D-Calif., who requested the report. "They report to each other but that doesn't necessarily solve the problem. It may in fact lead to problems." Even when state law requires reports to be made to outside agencies, sometimes the information never goes beyond a school district, the report said – whether because of uncertainty about whether a report is necessary, delays in reporting or outright failure to report allegations or suspicions of abuse. Miller said such confusion was unacceptable. "Many school districts believe they just have a need to report to their school principal, to the superintendent of the school," Miller told NBC News. "They don't recognize that under state law, where they have the laws, they have an obligation to report this to law enforcement officials." The GAO report cites a case in which an elementary school teacher who had been suspected of inappropriate behavior in one district was allowed to resign, then went to work at a school in another district. After he again was accused of inappropriate behavior, school officials in the new district investigated but then reported to the parents that the investigation had been closed. Only when a teacher reported rumors to her police officer husband did a criminal investigation begin: The teacher eventually pleaded guilty to eight counts of aggravated sexual abuse in the second district and two counts in the first district. Neither district reported the allegations to state authorities. The GAO report does not name the school where the abuse occurred or the teacher, but by comparing details from the GAO report with published accounts NBC News identified it as a case involving the Urbana, Ill., school district and Jon White, who was sentenced in 2008 to 60 years in prison. The Urbana school district superintendent and the elementary school principal were convicted of misdemeanors for not reporting the allegations, and the district’s human resources officer pleaded guilty to the same charge. All received sentences of court supervision and community service, and all retired after the police investigation began. The former principal and former HR director declined to comment to NBC News. The former superintendent did not respond to a request for comment. Rep. George Miller, D-Calif., said he was stunned that some states don't require teachers to report suspicions of child abuse to law enforcement agencies. "Why struggle so hard to say 'I was confused about my duty to report'? Just report it," he told NBC News. "There's no punishment for reporting a suspicion that turns out to be nothing." Bruno said the families are still grappling with the psychological effect on their daughters. "I'm not sure they know the damage yet," he said. "It might be analogous to being exposed to a toxic chemical. You sit back and hope that 20 years from now nothing bad is going to happen. But you just don't know." The GAO report found that the confusion involved not only state laws but also the reporting requirements under Title IX, part of the federal education law that prohibits sex discrimination -- including sexual harassment -- in federally funded education programs. Investigators visited school districts in several states and found that some were interpreting Title IX to include mandatory reporting of adult-to-adult or student-to-student incidents, but not adult-to-student incidents. GAO investigators said they also found that most states do not require training of educators on sexual abuse, even though experts say it's critical to preventing abuse. The report said such training might keep school officials from discounting their own suspicions or observations. Such was the case in Urbana, said Denny Mickunas, a plaintiffs personal injury attorney who assisted Bruno in the lawsuits. "They essentially blew off those complaints," he said. "As with many pedophiles, Jon White was very adept at manipulating not only children but the adults around them." There was a discrepancy in the report about how many states make reporting mandatory for educators. "According to GAO's survey, 46 states have laws that require school personnel to report child abuse and designate the agency that investigates reports (local law enforcement and/or child protection services (CPS), and 43 establish penalties for not reporting," the report said. But the five states identified by GAO staff as having responded "no" or not having responded to the survey questions do indeed have such laws. It was unclear if the responses were a result of the wording of the questions, a misunderstanding of the questions or some other issue. The GAO report said its survey found that background checks were the primary tool used by states to prevent sexual abuse, but the report added that there was wide variation in what those checks encompassed. Five states reported having no background checks for school employees, the report said. Six reported consulting only state law enforcement data, and three said they consulted only federal data. Forty-two states reported having professional standards or codes of conduct, and 22 of those reported that those codes helped to define boundaries between students and teachers or staff, including the use of cell phones and social media. Fifteen states said they specifically address "grooming" – "behavior intended to establish trust with a student to facilitate future sexual activity." The report says the federal government, led by the education secretary, should: Develop comprehensive materials for states, districts and schools that outline steps to prevent and respond to child sexual abuse by school personnel. Identify mechanisms to better track and analyze the prevalence of child sexual abuse by school personnel through existing federal data collection systems. Clarify responsibilities of personnel in public K-12 schools under Title IX. In a letter responding to the GAO, the Education Department said it: Was "taking action to revise its Adult Sexual Misconduct training module … to target a wider audience, including school volunteers." Would "explore methods to track and analyze the prevalence of child sexual abuse by school personnel." Would make clear that Title IX applies to sexual harassment at K-12 schools and prohibits sexual harassment of students by school employees. The department also said "it is vital that all states have a policy requiring background checks of all adults working with students."

2024-07-11T01:27:04.234600

https://example.com/article/5562

Q: Matlab plot won't return correct results I have written a function that is the beginning of a Poisson Process function n_t = PoisProc2(t,tao,SIZE) n_t=0; for n=1:SIZE if t>tao(1,n) n_t=n_t+1; end end end tao is simply an array of random doubles of length SIZE. For simplicity we'll say [1,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,20] So this functions purpose is to count how many elements of tao that t is greater than for any given t. This code works fine when I simply write PoisProc2(3,tao,20); the answer I get is 19 as expected, but if I write x=1:.01:20; y=PoisProc2(x,tao,20); plot(x,y,'-') y shows up as 0 in the workspace (I would expect an array of length 1901) and my plot also reads 0. I'm pretty new to Matlab, but this seems like a pretty simply thing I'm trying to do and I must be missing something obvious. Please help! A: Your code does not work as you are giving a vector. So your if condition is not working as you expect. First initialize n_t with a vector : n_t=zeros(1,length(t)) instead of if t>tao(1,n) n_t=n_t+1; end Vectorize your expression : n_t = n_t + (t>tao(1,n)) Cheers

2024-04-26T01:27:04.234600

https://example.com/article/5014

WINNIPEG, Manitoba -- The Canadian military was on standby Friday to respond to flooding in southern Manitoba as volunteers scrambled to fill sandbags against the rising Red River. A spring snowstorm dumped 10 inches of snow Thursday north of Winnipeg, where some 50 homes were flooded and 40 others were evacuated, the Winnipeg Sun reported Friday. Senior flood forecaster Alf Warkentin told the Sun it was an "almost unprecedented" situation where a major flood was preceded by a snowstorm and cold weather, which was helping ice form and slow the water's flow. Officials at all levels of government were also keeping their eyes to the south. Residents of Fargo, N.D., and Moorhead, Minn. prepared to flee in the face of a forecast crest of up to 43 feet on the Red River by Saturday. Canadian officials said the river's crest is anticipated to hit Winnipeg between April 12 and 17.

2023-08-15T01:27:04.234600

https://example.com/article/1626

Associated revisions Foreman::ThreadSession::Cleaner was included in Taxonomy concern,which postponed the session clearing (that should be the first thingto happen in filters) to phase after :authorize filter, effectivelydiscarding the login information leading to permission denied.

2023-08-27T01:27:04.234600

https://example.com/article/5926

At the age of four I was in my first wedding. Little did I know that moment would lead to a lifetime of participating in and overseeing one of the most important days in a couple’s life. In college, I became a hospitality major in large part because I had no idea what I wanted to do and my dad had been the General Manager of a hotel for many years before I came into the picture. When hearing the stories of his days in the hotel world, I thought that could be a good fit and had my first job in hospitality working the front desk of a hotel for a summer in Wisconsin. After many internships in Chicago during my college years, I found LOLA through the sorority community at DePaul and the rest somewhat fell into place! Working towards an end goal is definitely a motivator for me! Seeing everything come together in one beautiful, love filled day is the cherry on top. Clearly, my life wasn’t wedding filled enough, because I’ve also worked for a bridesmaids store in the Gold Coast. It definitely gave me another look at the wedding industry and what goes into the decision making process for many brides and grooms. When I have a free weekend you can find me at my families lake house, trying new restaurants in the city, watching the Blackhawks dominate or just curling up with a good book.

2023-10-21T01:27:04.234600

https://example.com/article/2772

Q: Show PopupWindow 3 seconds after Activity is created and last 3 seconds I have popup window in activity. What I want is that this popup starts after 3 seconds when activity is created and last for 3 seconds. Any help please? here is my code: try { LayoutInflater inflater1 = (LayoutInflater) MainActivity.this .getSystemService(Context.LAYOUT_INFLATER_SERVICE); // Inflate the view from a predefined XML layout View layout = inflater1.inflate(R.layout.activity_pop_up, (ViewGroup) findViewById(R.id.relativeLayoutZaFragment)); // create a 300px width and 470px height PopupWindow pw = new PopupWindow(layout, 300, 470, true); // display the popup in the center pw.showAtLocation(layout, Gravity.CENTER, 0, 0); } catch (Exception e) { e.printStackTrace(); } A: Try this boolean isShowing=false; In onCreate CountDownTimer timer=new CountDownTimer(3000,1000) { @Override public void onTick(long l) { } @Override public void onFinish() { if(isShowing){ //CLOSE } else{ isShowing=true; LayoutInflater inflater1 = (LayoutInflater) MainActivity.this .getSystemService(Context.LAYOUT_INFLATER_SERVICE); //Inflate the view from a predefined XML layout View layout = inflater1.inflate(R.layout.activity_pop_up, (ViewGroup) findViewById(R.id.relativeLayoutZaFragment)); // create a 300px width and 470px height PopupWindow pw = new PopupWindow(layout, 300, 470, true); // display the popup in the center pw.showAtLocation(layout, Gravity.CENTER, 0, 0) timer.start(); } } }; timer.start();

2023-11-26T01:27:04.234600

https://example.com/article/2928

2012 Trafford Metropolitan Borough Council election Elections to Trafford Council were held on 3 May 2012. One third of the council was up for election, with each successful candidate serving a four-year term of office, expiring in 2016. The Conservative Party held overall control of the council. The current composition of the Council is as follows: Election results Ward results The results for individual wards in the Election are as follows: Altrincham ward Ashton upon Mersey ward Bowdon ward Broadheath ward Brooklands ward Bucklow-St. Martins ward Cllr. Ian Platt left the Labour Party in late 2015 and served the remainder of his term in office as an Independent councillor. Clifford ward Davyhulme East ward Davyhulme West ward Flixton ward Gorse Hill ward Hale Barns ward Hale Central ward Longford ward Priory ward Sale Moor ward St. Mary's ward The Liberal Democrat candidate defected to the Labour Party two days before the election. Stretford ward Timperley ward Urmston ward Village ward References Official Trafford Council Election page Category:2012 English local elections 2012 Category:2010s in Greater Manchester

2023-11-29T01:27:04.234600

https://example.com/article/5206

Was in the mood to do this what-if scenario where Thanos won WITH the Black Order in Infinity War.Look Im sure that regardless of them winning or being dusted Thanos wouldve done the Farmer thing alone but this just jumped in my head since they were like his elites and I felt like doing it.Plus I was in a big mood to draw Thanos,Proxima and Corvus today XD

2023-11-01T01:27:04.234600

https://example.com/article/8605

MacDon FD1 - 45' FD1 FlexDraper® Headers FD1 - 45' Overview: Featuring MacDon Flex-Float Technology®, FD1 Series FlexDrapers continue to advance harvesting innovation. The flex advantage comes from a fixed reel-to-cutterbar relationship, which maintains a small gap between the reel fingers and cutterbar, while the Active Float System allows for instant lateral and vertical float response over rolling and uneven terrain. The result of our Flex-Float TechnologyTM is smooth, consistent, heads-first feeding that significantly boosts combine productivity. - Less Featuring MacDon Flex-Float Technology®, FD1 Series FlexDrapers continue to advance harvesting innovation. The flex advantage comes from a fixed reel-to-cutterbar relationship, which maintains a small gap between the reel fingers and cutterbar, while the Active Float System allows for instant lateral and vertical float... + Read More Send To A Friend Fields with asterisks* are required. Your friend will receive an email that contains a reference to this page. Please send this email only to people you know who would be interested in this information. Features Close Reel-to-cutterbar relationshipThe MacDon FD1 FlexDraper® features a fixed reel-to-cutterbar relationship. A small gap between the reel fingers and the cutterbar is maintained at all times, even at extreme flex, ensuring smooth, consistent, heads-first feeding of the crop over the entire width of the FlexDraper®. Active Float SystemMacDon's Active Float System reacts instantly to changing ground conditions. This immediate float response means you can cut extremely close to the ground without pushing soil. Two sets of coil springs on the FM100 Float Module support up to 97% of the header weight. The instant float response provides 4.8 degrees of lateral float and 178 mm (7”) of vertical float, independent of the combine feeder house. Best of all, this is a simple reliable mechanical system requiring only one sensor, so things won't break down when your harvest is on the line. MacDon’s Active Float System keeps our headers true-to-the-ground for a clean, even cut every time. Reel PerformanceUnlike other headers, the movement of our heavy-duty reel picks up and gently places crop onto the drapers. The FD1 reel features 4" finger spacing and a uniquely shaped cam, which allows the fingers to get underneath lodged and low-podding crop to pick it up before it's cut. Along with the header tilt control, which hydraulically angles the knife from the cab and fore-aft reel positioning, our headers can be adjusted for the toughest harvesting challenges. True Ground followingThe MacDon FD1 FlexDraper® is a floating, three-section flexible header with a split reel. This allows the entire header frame, cutterbar, and reel to follow ground contours as a unit, flexing up to 254 mm (10") on either end, while maintaining a close reel-to-cutterbar relationship. This unique three-section design lets the FD1 FlexDraper® deliver smooth, consistent, head-first feeding to the combine, even at extreme flex.

2024-01-22T01:27:04.234600

https://example.com/article/9994

Battle of Ramree Island The Battle of Ramree Island (also Operation Matador) was fought in January and February 1945, during the Second World War, as part of the XV Indian Corps offensive on the Southern Front in the Burma Campaign. Ramree Island (Yangbye Kywan) lies off the Burma coast, south of Akyab (now Sittwe). The island had been captured by the Imperial Japanese Army in early 1942, along with the rest of Southern Burma. In January 1945, the Allies launched an attack to retake Ramree and its neighbour Cheduba Island, to establish airbases on the islands for the supply of the mainland campaign. There have been reports of Japanese soldiers being eaten by saltwater crocodiles living in the inland mangrove swamps; the Guinness Book of World Records has listed it as "worst crocodile disaster in the world" and "most number of fatalities in a crocodile attack" but scientists and historians have dismissed this as implausible. Background The early capture of Akyab made the 26th Indian Infantry Division (Major-General Henry Chambers) available for an attack on Ramree Island, to the south, the island being long and wide, flat and an obvious site for airfields. A plan was ready by 2 January, when it was clear that the advance of the Fourteenth Army (Lieutenant-General William Slim) would soon pass beyond the range of its airbases at Imphal and Agartala; replacements at Chittagong, Akyab and Ramree would be needed. On 14 January, the 26th Indian Division was ordered to attack Ramree on 21 January, as a Royal Marine detachment from 3 Commando Brigade occupied Cheduba Island. The Japanese garrison of Ramree consisted of the II Battalion, 121st Infantry Regiment (Colonel Kanichi Nagazawa), part of the 54th Division, with artillery and engineer detachments to act as an independent force. Prelude The battle started with Operation Matador, an amphibious assault to capture the strategic port of Kyaukpyu at the north end of Ramree Island and the airfield near the port, south of Akyab across Hunter's Bay. The invasion force was led by three Joint Assault Commanders, Captain Bush RN, Major-General Cyril Lomax and Wing Commander H. Smith. Reconnaissance carried out on 14 January 1945, found that Japanese forces were placing artillery in caves overlooking the landing beaches on Ramree and the Royal Navy assigned the battleship , the escort carrier , light cruiser , the destroyers Rapid, Napier, Norman and Pathfinder, with the sloops Flamingo and RIN Kistna, to provide more firepower in support of the task force. On 21 January, an hour before the 71st Indian Infantry Brigade (Brigadier R. C. Cotterell-Hill) was to land, Queen Elizabeth opened fire with of -shell from the main battery, while aircraft from Ameer spotted the fall of shot. Phoebe also joined the bombardment, along with Consolidated B-24 Liberators, North American B-25 Mitchells and Republic P-47 Thunderbolts of 224 Group Royal Air Force (RAF), under the command of HQ RAF Bengal and Burma, that strafed and bombed the beaches. Battle The assault troops were slightly delayed when a motor launch and a landing craft struck mines but landed unopposed on the beaches west of Kyaukpyu at securing the beachhead by the afternoon. The following day, the 4th Indian Infantry Brigade (Brigadier J. F. R. Forman) landed, took over the beachhead and occupied Kyaukpyu and on 23 January, the 71st Infantry Brigade advanced southwards, down the west coast. Two days later Mayin was occupied and the troops reached the Yanbauk Chaung the next day. Resistance at the chaung from the troops of the II Battalion, 121st Regiment increased and on 31 January, the 71st Brigade was ordered to move inland, north-east towards Sane, then head south towards Ramree town. The 4th Brigade was to keep the defenders at Yanbauk Chaung under pressure and follow up vigorously should they retire. (On 26 January in Operation Sankey, a Royal Marine force landed on Cheduba island, about from the south-west coast of Ramree Island and found it unoccupied.) On Ramree, the Japanese garrison put up tenacious resistance but on 1 February, the 71st Indian Infantry Brigade reached Sane and parts of the 36th Indian Infantry Brigade, from reserve, took Sagu Kuyun Island and relieved the marines on Cheduba Island. When the British outflanked a Japanese stronghold, the abandoned the base and marched to join a larger battalion of Japanese soldiers across the island. The route took the Japanese through of mangrove swamp and as they struggled through it, the British encircled the area. Trapped in deep mud-filled land, tropical diseases soon started to afflict the soldiers, as did scorpions, tropical mosquitoes and saltwater crocodiles. On 7 February, the 71st Indian Infantry Brigade and supporting tanks reached the town of Ramree and found determined Japanese resistance. The 4th Indian Infantry Brigade had advanced to Ledaung Chaung and was sent east to reinforce the attack; the town fell on 9 February. The navy and the 26th Indian Infantry Division then concentrated on blockading the chaungs (small streams) on the east coast to prevent the Japanese from escaping to the mainland. A Japanese air raid on 11 February seriously damaged a destroyer with a near miss and forty small craft were sent by the Japanese from the mainland to rescue the survivors of the garrison. Japanese resistance on the island ended on 17 February and the Allied blockade was maintained until 22 February, sinking many of the rescue craft and inflicting many casualties on the Japanese troops hiding in the mangrove swamps; about managed to get away. Cheduba Island was not garrisoned and the 22nd East African Brigade was sent to hold Ramree Island. Aftermath Analysis In 1965, the British official historian Stanley Woodburn Kirby wrote that the Japanese defence of the island and the escape of about against "fearful odds", had been courageous and determined. It took until 16 April for the airfield to be used for transport sorties, Akyab having come into use on 1 April. It had been vital to complete the occupation of Ramree Island quickly, as Operation Dracula against Rangoon needed to commence in the first week of May at the latest, to have a chance of finishing before the monsoon. The experience in co-operation between the 26th Indian Division and the navy in the war of chaungs and small ports along the Arakan coast was intended to be exploited in the attack. An estimate put naval gunfire support from 4 January to 13 March for the land operations at Akyab, Ramree and Cheduba at The navy also carried of stores and Crocodile attack Some British soldiers, including the naturalist Bruce Stanley Wright, who participated in the battle, claimed that the large population of saltwater crocodiles native to the mangrove swamps on Ramree Island preyed on the trapped Japanese force at night and ate many soldiers. Wright gave a description in Wildlife Sketches Near and Far (1962), quoted by Frank McLynn, If Wright was correct, the Ramree Island crocodile attacks were the worst recorded in history. The British Burma Star Association seems to lend credence to the swamp attack stories but appears to draw a distinction between the survivors of one attack and the who were left to fend for themselves in the swamp. There is no corroboration of the event by contemporary British military reports or from Japanese soldiers and local Burmese civilians. Wright is the only source for a mass crocodile attack and his figures have been disputed by other historians, who call the event an urban myth. McLynn wrote The British official history (War against Japan volume IV, The Reconquest of Burma, 1965 [2004]) referred only to "crocodile-infested mangrove swamps". Footnotes References Further reading External links Bruce Stanley Wright, 17 September 1912 – 19 April 1975 Ramree Island Ramree Island Category:Deaths due to crocodile attacks Ramree Island Category:1945 in Burma Category:Naval battles of World War II involving the United Kingdom B Category:January 1945 events Category:February 1945 events

2023-08-13T01:27:04.234600

https://example.com/article/2557

venth biggest value? (a) 2/29 (b) 0 (c) -95 (d) 1 (e) 3 (f) -34/81 (g) -1 c Which is the biggest value? (a) 2.9 (b) 0.1 (c) -0.2 (d) 604 (e) 4 (f) 0.4 d Which is the biggest value? (a) 0.05 (b) 0.3 (c) 3/2 (d) 1 (e) -56 (f) -1 (g) 2/3 c Which is the biggest value? (a) 2 (b) 18 (c) -2541 (d) 0.024 b What is the fifth biggest value in -2/5, 318, -0.3, 0.0426, 2/5, 0? -0.3 Which is the smallest value? (a) -6/1535 (b) 3436 (c) 4 a Which is the fifth biggest value? (a) -4 (b) 4/7 (c) 2/11 (d) 3/8 (e) -0.79379 (f) 5/2 e What is the fifth biggest value in -0.08, 2049, 4/5, 5, 224/9? -0.08 What is the seventh biggest value in -19, -0.2, -2/3, -1/4, 0.2, -0.4, -602? -602 What is the fifth biggest value in -4, 65, -82, -5, 3? -82 Which is the biggest value? (a) -8430 (b) -2.1 (c) 5 (d) -2/11 c Which is the sixth smallest value? (a) 5 (b) -1/4 (c) 3 (d) 5.1 (e) -4 (f) 1 (g) 4.67 a Which is the second biggest value? (a) -0.012 (b) -3/7 (c) 16 (d) 2/3 (e) -1187 d Which is the second smallest value? (a) 0.3 (b) -111518558 (c) -3/5 c What is the fifth biggest value in 0.109, 1, 4, -13, 363, 2? 0.109 What is the fifth smallest value in 68/5, -1, -0.08, -3.6, -8/7? 68/5 Which is the smallest value? (a) -531/916 (b) 67/7 (c) -0.1 (d) -5 d Which is the sixth biggest value? (a) 895 (b) -3 (c) -0.3 (d) -3/5 (e) 161 (f) 0.2 b Which is the second biggest value? (a) -5 (b) 0.5 (c) 7557442 b What is the fourth biggest value in 7, -4, 30, 2.56, -0.3, -0.2, -2/25? -2/25 Which is the fifth smallest value? (a) -1.1 (b) 0.02 (c) -2 (d) -5 (e) -3382612 b Which is the fourth biggest value? (a) -1.14 (b) -1/7 (c) 4 (d) 6/1367 a What is the fourth smallest value in 0.3968, 5/7, -3, -2/9? 5/7 What is the fifth biggest value in -53, -1, 5, 562, 2, 0.5? -1 Which is the smallest value? (a) -3 (b) -1/72 (c) 5/6 (d) 4/9101 (e) -1/2 a Which is the third smallest value? (a) 4 (b) 2 (c) 2/9 (d) -0.52 (e) 2/3 (f) -0.06 (g) -0.29 f Which is the fifth biggest value? (a) -1/2 (b) -1.1 (c) 2/3 (d) 1 (e) -39.38 e Which is the smallest value? (a) -194846305 (b) -1 (c) 2/5 a Which is the second smallest value? (a) -4/3 (b) -381/44852 (c) -0.21 c Which is the third smallest value? (a) -2 (b) 0.08 (c) -0.5 (d) 1867984 (e) 4 b What is the biggest value in 2/515, -4, -2/611, 6, 1/3? 6 What is the third smallest value in -18896, -1.8, -7? -1.8 Which is the second smallest value? (a) -0.67 (b) 90 (c) 129 b Which is the second smallest value? (a) 2 (b) -4 (c) 8/3185 (d) 3/2 c Which is the fifth biggest value? (a) -3/2 (b) -5/4 (c) -1/5 (d) -2/19 (e) 4 (f) 546 (g) 28/9 c What is the second smallest value in -4, -292, 4/9, -0.5, -2/47, -1/3? -4 Which is the biggest value? (a) -2/9 (b) 154423 (c) 11 b What is the fourth biggest value in -0.01, 314, 1, -2/7, -2/25, -0.2, 11? -0.01 What is the second biggest value in -0.3, 1/119, -2, 0.3, 324/5? 0.3 What is the biggest value in -0.5, -0.2, 3, -3, 145/33? 145/33 Which is the second biggest value? (a) -0.2 (b) -765 (c) 0.0223 a What is the third smallest value in 1.5, -791114, 4? 4 What is the fourth biggest value in 0.5, -0.3, -35273001, -2, -1? -2 What is the second smallest value in 0.5, 0.01, -138/25? 0.01 What is the biggest value in 7.2, 10, -23, -1.4, 0.6? 10 What is the sixth biggest value in -2, 1/6, 0, 3, 2/9, 6.4, -40? -2 What is the biggest value in -1.5, 1/8, 1.03, 4, -255, 1/4, 0.2? 4 What is the third smallest value in -309, -1.27, 4/3, 2, -94, -1/2? -1.27 What is the fourth smallest value in -22, 0.267, -48, 2, 0.043? 0.267 What is the smallest value in 902, 0.07, 3, -3, -1.995? -3 What is the second smallest value in 2, 2/199155, -25? 2/199155 What is the seventh smallest value in -0.3, 1/3, 5, 48945/8, 0.5, -0.4, 1.4? 48945/8 Which is the smallest value? (a) -3 (b) 7 (c) 4.1 (d) 0.1 (e) 0.9 a Which is the third smallest value? (a) 3 (b) -98 (c) -0.2 (d) -5 (e) -104.3 (f) -9 f Which is the smallest value? (a) -3 (b) 73 (c) 5 (d) -1/1319 (e) 2 a What is the third biggest value in 8, 18, -213/8? -213/8 What is the fifth biggest value in 5, 0, 2/5, 10.06, 9, 2/7? 2/7 Which is the fourth biggest value? (a) -2/11 (b) 0.3 (c) 4 (d) -3 (e) 97141 a Which is the second biggest value? (a) -2 (b) 0.1387 (c) -10182 a What is the sixth biggest value in 2/7, -73, 6, -3/8, 1/3, -2, 1/2502? -2 Which is the biggest value? (a) 5 (b) 672269/12 (c) -0.2 (d) 0 (e) -0.3 b What is the biggest value in 3, 0.06, 6544, -245? 6544 What is the third smallest value in 2/19, -0.03, -5, -2/17, -3/182, -0.3, -2/7? -2/7 Which is the biggest value? (a) 0.4 (b) -13505/17 (c) 2/13 a What is the third smallest value in 20, -2/9, 4995, 0.4, 5, -2? 0.4 Which is the second smallest value? (a) -2/13 (b) -18 (c) -4037 (d) -2 (e) 0.3 b What is the second smallest value in -0.002, 341.6, -3, -11? -3 What is the fourth biggest value in -2/11, -14/587, 1760, -10, 4? -2/11 Which is the fourth smallest value? (a) -0.06 (b) 2/3 (c) -24/109 (d) 39 (e) 0.4 (f) 1 (g) 0 e What is the fourth biggest value in -1/7, -3, 113, -3/100, -3/7, 0.2, -0.1? -0.1 Which is the second biggest value? (a) -20788 (b) 0.0625 (c) -5 c Which is the third smallest value? (a) 4/301 (b) -0.5 (c) -18 (d) 9 (e) -2 (f) -0.1 b Which is the sixth biggest value? (a) 8/49 (b) 0.092 (c) -5 (d) 4 (e) 50 (f) 9 (g) 0.1 b Which is the third biggest value? (a) 3/22 (b) -6618 (c) 22 b What is the third smallest value in -2/11, -4/5, -1.7, -16/3, -1, 0.09? -1 Which is the fifth biggest value? (a) 3524 (b) -2/9 (c) -84/5 (d) -4 (e) -0.02 c Which is the biggest value? (a) 0.6947 (b) 3 (c) 2613 c What is the second biggest value in 0.4, -23, -14206506? -23 What is the seventh biggest value in -0.6, 3/235, 1, -0.3, -0.45, 1/6, -2/11? -0.6 Which is the fourth smallest value? (a) -9 (b) -2590/17 (c) -1 (d) -21 c Which is the second biggest value? (a) 0.03362 (b) 1.3002 (c) 2/5 c What is the second smallest value in -0.2, 0.5, 18335657? 0.5 What is the biggest value in -1.165, 525, 13? 525 Which is the biggest value? (a) 169541 (b) 1 (c) 0.3 (d) -1.42 a What is the second smallest value in -3/4, 1/57887, -6, -2/17, 1, 2/13? -3/4 Which is the third biggest value? (a) -22 (b) -0.5 (c) 451 (d) -9 (e) 1.4 b Which is the fifth smallest value? (a) -8 (b) 1/2 (c) 2 (d) 0.1 (e) -65/23 (f) 0.3 (g) -1 f Which is the seventh biggest value? (a) -0.1 (b) -0.4 (c) 3 (d) -4 (e) 2468 (f) -1/153 (g) -3 d Which is the second smallest value? (a) -2 (b) -25422/25 (c) 1 (d) -14 d Which is the third smallest value? (a) 58 (b) -3/2 (c) -48 (d) 10 (e) 1.3 (f) 0.3 f Which is the fourth smallest value? (a) 5 (b) 5/4 (c) 17 (d) -9.4 (e) -0.4 (f) 4/3 (g) -34 b Which is the fifth smallest value? (a) -0.02 (b) -2 (c) 0 (d) 15/11 (e) 67 e Which is the third biggest value? (a) -0.4 (b) -10 (c) 0.5 (d) 5 (e) 0.2 (f) 0.16 e Which is the sixth smallest value? (a) -0.5 (b) 3/4 (c) -65 (d) 0.09 (e) -4/9 (f) -1 b What is the second biggest value in -2/3, -50421, -15/11, -4? -15/11 Which is the sixth smallest value? (a) 0.1 (b) 65 (c) 26 (d) -6 (e) -2/247 (f) -1/12 (g) -0.3 c What is the third smallest value in -55, -3, -0.3, 17.38433? -0.3 Which is the fourth smallest value? (a) -4 (b) -0.1 (c) 0.5 (d) 4 (e) 1/9383 (f) 5 (g) 0 e What is the biggest value in 2, 152, 42219, -0.2? 42219 Which is the fourth biggest value? (a) 0.1 (b) -3 (c) -5 (d) -80230 (e) 11.1 (f) 1 b Which is the smallest value? (a) -2/17311 (b) -75/4 (c) -12/7 b Which is the fifth biggest value? (a) -0.4 (b) 1011 (c) -3/8 (d) -0.17 (e) -12/11 e Which is the biggest value? (a) -2/11 (b) -306 (c) -0.5 (d) 543 (e) 0.4 (f) -6 d What is the fifth biggest value in 2, -0.44, 53, -0.3, -9/4? -9/4 Which is the third biggest value? (a) 25/8 (b) -33149/2 (c) 26 b Which is the third smallest value? (a) 3/5 (b) 10 (c) 169 (d) -12/1103 b What is the third smallest value in 9216/67, 2/11, -14? 9216/67 What is the smallest value in 1606, -1/18, 325? -1/18 Which is the fourth biggest value? (a) 4 (b) 0.5 (c) -52431 (d) -0

2024-03-16T01:27:04.234600

https://example.com/article/9742

Cafe Club “Manushan” Type: CafeNeighborhood: CentroTelephone: 923-1592Address: Calle 55 x 58How to Get There from the Centro: Across the street from the popular hotel, Luz En Yucatan.Parking: Next door in the public lotAirConditioned: One room is sometimes air conditionedOutdoors: YesDrinks: Beer and Soft DrinksHours: Monday-Saturday from 7:00 am to 5:00 pmWebsite:Facebook:Notes: Cafe Club always has a few vegetarian dishes. The food is inexpensive, clean and healthy. A quick and easy place to eat in the centro. (Please rate this article) Loading ... Like this article? To be notified every time Yucatan Livingpublishes another article, just subscribe by clicking here.

2024-03-02T01:27:04.234600

https://example.com/article/6234

After two days of losses, the stock market today (Friday) reversed the slide and opened higher, thanks to better-than-expected earnings from Hewlett-Packard Co. (NYSE: HPQ) and American International Group Inc. (NYSE: AIG) Shortly before 1 p.m. on Wall Street, the Dow Jones Industrial Average was up 114 points to 13,994.62, the Standard & Poor's 500 Index added 10.6 to 1,513.02 and the Nasdaq advanced 25 to 3,156.34. While all three indexes are on track for their worst week of the year, the Dow is still up some 6% since the start of 2013, the S&P 500 has gained 5% and the Nasdaq has tacked on almost 4% despite giving back all of February's gains during the two-day selloff. What Happened to the Stock Market in February? Stocks began January with a bang, but failed to keep the momentum going in February. The Dow ended the first month of the year within reach of its all-time high of 14,164.53. Since the pause, the benchmark now rests about 2% from its record. The pullback comes as investors are growing cautious about banking on further gains. The S&P has logged seven consecutive weeks of gains, shrugging off negative news, including the looming automatic spending cuts set to kick in next Friday and mounting worries about economic conditions in Europe. The selloff was stoked Wednesday when minutes from the Fed's January FOMC meeting revealed some central bankers have become anxious about the impact the Fed's loose monetary policies will ultimately have on the economy. The Fed's stimulus measures have been a catalyst and cushion for equities since quantitative easing began in November 2008. "The economic backdrop is just not good enough to justify this market. We won't get to an all-time high until Washington gives us some clarity," Burt White, CIO at LPL Financial in Boston, told TheWall Street Journal. Earnings came in at 82 cents a share, better than the 71 cents forecast. The company also guided higher for the second quarter. Shares jumped 10.58% Friday at $18.92 and were on track for their biggest one-day gain. Investors applauded the cost-cutting efforts under CEO Meg Whitman, which appear to be working. "The turnaround is on track and we did better than we expected that we would. The patient showed some signs of improvement, and I think we should be encouraged," Whitman said on a conference call following the earnings release. Also helping markets were numbers from AIG. The company lost $4 billion during the last three months of 2012, dragged down by costs related to Hurricane Sandy. But the insurer, which became a household name after it received a $182 billion bailout package from the government at the height of the financial crisis in 2008, posted an operating profit that was better than expected. Shares gained 3.11% and were last trading at $38.42. Shares of Apple Inc. (Nasdaq: AAPL) added $2.72 to $488.75 after billionaire hedge fund manager and activist investor David Einhorn of Greenlight Capital unveiled a plan Thursday for the iPhone maker to issue preferred shares. He says such a move would give shareholders more value while allowing Apple to retain its $137 billion stash of cash. J.C. Penney Co. Inc. (NYSE: JCP) rose nearly 5% after the retailer squared off in court with rival Macy's Inc. (NYSE: M) over the right to sell items from the domestic diva Martha Stewart. Penney's appears to be the winner in this battle. Macy's shares shed almost 1%. Abercrombie & Fitch Co. (NYSE: ANF) shares slipped more than 7% despite reporting Q4 earnings that more than tripled and raising its dividend to 20 cents from 17.5 cents. The teen retailer reported a profit of $157.2 million, or $1.95 a share, up from $45.8 million, or 52 cents a share, a year earlier. Revenue rose 11% to $1.47 billion. But the New Albany, OH-based company plans to close 40-50 stores in the U.S. this year and projected earnings of $2.25 to $3.45 a share for 2013, below estimates of $3.63. By submitting your email address you will receive a free subscription to Money Morning and receive Money Morning Profit Alerts. You will also receive occasional special offers from Money Map Press and our affiliates. You can unsubscribe at anytime and we encourage you to read more about our privacy policy. You can view our VQScore top-rated stocks now by entering your email below: By submitting your email address you will receive a free subscription to VQScore and occasional special offers from Money Map Press and our affiliates. You can unsubscribe at anytime and we encourage you to read more about our privacy policy. Today's Markets DJIA37.07(0.14%)27,219.52 NASDAQ-17.75(0.22%)8,176.71 S&P-2.18(0.07%)3,007.39 ABOUT MONEY MORNING Money Morning gives you access to a team of ten market experts with more than 250 years of combined investing experience – for free. Our experts – who have appeared on FOXBusiness, CNBC, NPR, and BloombergTV – deliver daily investing tips and stock picks, provide analysis with actions to take, and answer your biggest market questions. Our goal is to help our millions of e-newsletter subscribers and Moneymorning.com visitors become smarter, more confident investors. By submitting your email address you will receive a free subscription to Money Morning and receive Money Morning Profit Alerts. You will also receive occasional special offers from Money Map Press and our affiliates. You can unsubscribe at anytime and we encourage you to read more about our privacy policy.

2024-06-13T01:27:04.234600

https://example.com/article/8218

I just finished watching the first few episodes of Evolution and felt like seeing if anyone thought the same as me on it. First off, am I the only one that thinks that so far the story sounds like a mashup of some people's fanfics? I actually think that I read a fanfic that had pretty much this scripting in it once. (Not complaining jut thinking) Second, what the heck happened to Aelieta's Lyoko abilities? Since when did she have to hit The Eye to destroy a monster with her energy fields? I can fully understand the others getting a bit out of shape and being owned on lyoko but their abilities shouldnt have been effected by that should they? I did have a third but i completely forgot about it There will be no mercy, only slain bodies and taken souls. Dont be afraid, be terrified. I'd recommend linking the picture, as swearing is not allowed on the open parts of the forum (everything except BKO). Of course, linking the picture would make it lose its impact. So.. YDV wrote:Well you see, the amount of time we didn't normally hang around BKO is kind of like potential energy, and then when we all finally came back at the same time it's like letting loose a catapult. 8D As you said a few posts above, a picture is worth a thousand words. Unfortunately for you, your picture reads with words that we don't allow in the open forum. At risk of this becoming a tirade on forum etiquette, I return to the original topic: To me, Evolution is alright. Certainly not the best series, certainly not the worst. I personally think that it has a lot of potential that as of yet is unrealized and shoved down a hole, and continues to be shoved down that hole with the various retcons and inconsistencies within the canon. As I told Carth several months back, Evolution is a tease. They keep teasing various plot points, but then hide behind filler or diverge into other plot points. All of the characters (save for Jim and Ulrich, to an extent) have lost the depth that made them believable characters in the original series; while we have seen Ulrich perform pencak silat within Evolution, what happened to Aelita aspiring to be a DJ? What happened to Odd being an artist? What about Yumi's tensions with her parents? Everyone has become a 2D cutout of the characters that they once were (ironic due to the 2D vs live action, I think), which as of yet has detracted from the show. Granted, as it stands the show is only 19 episodes aired right now, and I'd be surprised if there's not a second season (considering how Season 1 went with its episodic nature and its complete lack of plot progression until the last two episodes, and how it got 3 more seasons), so there's still time to fix it. Still, it feels like they are holding out on us, and not trying to live up to the legacy that the original Code Lyoko has. Why not? Many other forums allow you to speak freely without worry of censorship, if this is for the children's benefit I can assure you it is not necessary, as most of today's children are quite accustomed to such language. Besides, It's not like we're still catering to a bunch of ten-year-olds or any hyper-sensitive people who can't stand seeing the occasional profanity. If that were the case, we never would've waived the limits on the BKO forum. One breakthrough that helped set the stage for Darwin’s theory of evolution was the discovery that Earth was once home to animals that no longer exist. For hundreds of years, many people believed that all creatures were created at the same time, and that all of them were still around. Neither of these ideas turned out to be true. For example, a mammoth may look like a modern elephant, but it isn’t one. Scientist Georges Cuvier proved that in the 1790s, when he compared fossil mammoths with elephants alive today. Mammoths were not only different from elephants — they had “gone extinct.” They had died out and vanished from the Earth. The idea that some animals had become extinct was confirmed when people found strange fossils totally unlike any living animals. One fossil hunter was a young English girl named Mary Anning. Around 1810, she discovered the first complete specimen of an extinct ichthyosaur — a reptile with a sharklike body streamlined for life in the sea. Anning went on to find other important fossils. She was one of the great fossil hunters of all time. The fossils discovered by Anning and others were a real shock to people. During very ancient times, Earth was home to many kinds of animals that had since gone extinct. Fossils provided rock solid evidence that life was different in the past. But how far in the past? And what sorts of changes had occurred in living things during Earth’s long history? Keith Fordson Jr. wrote:One breakthrough that helped set the stage for Darwin’s theory of evolution was the discovery that Earth was once home to animals that no longer exist. For hundreds of years, many people believed that all creatures were created at the same time, and that all of them were still around. Neither of these ideas turned out to be true. For example, a mammoth may look like a modern elephant, but it isn’t one. Scientist Georges Cuvier proved that in the 1790s, when he compared fossil mammoths with elephants alive today. Mammoths were not only different from elephants — they had “gone extinct.” They had died out and vanished from the Earth. The idea that some animals had become extinct was confirmed when people found strange fossils totally unlike any living animals. One fossil hunter was a young English girl named Mary Anning. Around 1810, she discovered the first complete specimen of an extinct ichthyosaur — a reptile with a sharklike body streamlined for life in the sea. Anning went on to find other important fossils. She was one of the great fossil hunters of all time. The fossils discovered by Anning and others were a real shock to people. During very ancient times, Earth was home to many kinds of animals that had since gone extinct. Fossils provided rock solid evidence that life was different in the past. But how far in the past? And what sorts of changes had occurred in living things during Earth’s long history? So! Code Lyoko Evolution! The television series! How have you people been liking it as of late? Me, personally, I can't wait for the hiatus to be over. Though I'd be just as content with the Hungarian-English subs coming out too. I don't know French or Hungarian, so as long as the voices aren't too different I'll be fine. I did not have very high expectations for CLE ever since I heard of plans for continuation of the show, so I cannot say I am disappointed. Let's say that some aspects of it turned out way better than I anticipated and others failed as I expected them to fail. Visual side of the show makes me feel split. I appreciate the effort the authors put to convince us that live-action was the right option. I cannot complain about the casting, although I could nitpick about Sissi and Jean-Pierre. Young actors play their roles fairly well. Their lacks are visible, but not too distracting. I really like special effects in live action, I think they capture the atmosphere of the attacks on Earth in the animated series. At the same time I don't like the changes that were made to 3D part. Especially to the characters' avatars. This animation does not look 2012 to me, honestly. It looks kinda flat and lacks detail. The physics is ridiculously unnatural, as if the objects had no mass. Not to mention Tarantuals shooting lasers out of their heads. On plus side, we have Cortex and Digital Sea, which are simply beautiful. As for the story... it has the same disease as previous seasons. It fears being a continuous, complex story and favors episodic adventures. It is indeed a tease. It raises our hopes for solving some of the show's biggest mysteries, only to turn back to more lame Xana attacks. At the same time it extremely rushes things. Like Laura, or Yumi's staff. They had plenty of time through these 19 episodes for buildup, even minimal. As AppleFreak said, CLE is okay. It had potential to be something better, even with the budget Moonscoop had for it. It could use better writing and more effort from the creators. And more respect for the fans. It's its own thing. The creators weren't experts on the source material, and you could tell. Overall it's directed to a younger audience and doesn't really contain any plot points from the original series.

2023-09-19T01:27:04.234600

https://example.com/article/1268

Q: Login as different user in Gnome if you are have root privileges I want to login as a different user in Gnome and not to run a single program only, but I don't know the users password, I don't want to know it and I don't want to change it, but I'm sudoer. Is there any way to do so? The best thing I could think, was to change the user's password but to keep the old shadow file. But this seems to me very ugly and also uncomfortable. I'm also not sure if it's a good idea to change the shadow file on a running machine (but I suppose so, otherwise vipw -s would kind of useless). Is there an alternative? The reason I want to achieve this, is that I'd like to test things or to configure programs for users who aren't able to do on their own. Yeah of course I could do everything on the shell als root or as the specific user (and acutally this is what I'm doing until now), but there are things that you definitly don't want to do on the shell. Did any of you ever try to change the position of the gnome-panel on the shell instead of just selecting "bottom"? :) I don't think gksudo, sudo or su would help me. I want to have the whole gnome session. A: OLD-SCHOOL METHOD Create a ghost user, with the same UID: target: user1 (change to suit) cat /etc/passwd | grep user1 user1:x:1001:1001:User1 Q Lastname:/home/user1:/bin/bash add your ghost sudo useradd -d /home/user1 -f -1 -u 1001 -g 1001 -M -o ghost1 -s /bin/bash -p MySecret cat /etc/passwd | grep user1 user1:x:1001:1001:User1 Q Lastname:/home/user1:/bin/bash ghost1:x:1001:1001::/home/user1:/bin/bash su ghost1 NOTE: You can delete, with 'sudo userdel ghost1', but NOT when either account is logged in. Failsafe method: delete the new line in '/etc/passwd' file.

2024-06-05T01:27:04.234600

https://example.com/article/9647

Q: Regular Expression Delete Everything Before Line I am trying to use a regex to delete everything before a certain line in a multi-line string. Is there a regex expression that captures everything before (and including) an expression? import re sample = ''' This is content I need to delete I do not need any of this. === Text I need Is here''' content = re.sub(r'\n===', "", sample) print(content) A: If you want to be left with just Text I need Is here (so without any more newlines after the ===) you can use content = re.sub(r'(.|\n)*===\n*', "", sample) The (.|\n)* will get rid of all the text and newlines up to the === and the \n* will delete the following newlines. You can also leave this last part out if you want to keep the newlines after ===. So content = re.sub(r'(.|\n)*===', "", sample) will result in // newline // newline Text I need Is here There will be two newlines left (one directly after the === and the second one for the empty line). If you just want one newline before Text I need... then use: r'(.|\n)*===\n'

2024-06-11T01:27:04.234600

https://example.com/article/1685

Introduction {#s1} ============ Bacterial infections have threatened mankind ever since its first existence. Infection control gained a major success with the discovery of antibiotics in 1923. However, this success lasted less than a century, and toward the turn of the century, the first reports of antibiotic-resistant bacterial pathogens appeared (Davies and Davies, [@B12]). The latest new antibiotic class was discovered in 1986, after which shortening of the effective lifetime of new antibiotics, and financial and regulatory hurdles cooled down the passion of pharmaceutical companies to develop new antibiotics. It is estimated that the number of deaths attributable to antimicrobial-resistant bacterial infections will rise to 10 million per year by 2050, at a cost of more than US\$100 trillion (O\'Neill, [@B46]). An additional problem in infection control, next to antibiotic resistance, is the presentation of infectious bacteria in a biofilm mode of growth. In a biofilm mode of growth, adhering bacteria produce a matrix of extracellular polymeric substances (EPS), in which they protect themselves against the host immune system and environmental attacks, such as posed by UV exposure, pH changes, and antibiotics (Hall-Stoodley et al., [@B21]). The EPS matrix impedes penetration of antibiotics, yielding survival of bacteria residing in the depth of a biofilm, which necessitates long-term and high-dose antimicrobial treatment to eradicate infectious biofilms, not seldom followed by recurrence of the infection after treatment (Fux et al., [@B18]). To counter the increasing threat of bacterial infections, numerous nanotechnology-based antimicrobials and smart, antimicrobial-delivery nanocarriers are being designed (Liu et al., [@B36]), such as carbon quantum dots, graphene, gold, silver, iron oxide, or polymeric nanoparticles, including micelles or antimicrobial dendrimers. However, the antimicrobial efficacy of many new nanoparticles are insignificant for clinical usage and only achieve about 90% reductions in bacterial viability (1 log unit), while a minimum of 99.9--99.99% (3--4 log units) is required to achieve any clinical efficacy (Liu X. et al., [@B32]). ROS are sometimes called "the sword of nanotechnology," and taking lessons from cancer therapy, several methods have become available to generate ROS (Sun et al., [@B52]; Liu X. et al., [@B32]). ROS produced by different types of nanoparticles in combination with the addition of external H~2~O~2~ (Gao et al., [@B19]; Liu et al., [@B35]; Naha et al., [@B41]) has been shown to be effective in biofilm eradication. However, the use of cascade reactions to counter bacterial infections through ROS production using endogenously present substrate, i.e., without addition of external H~2~O~2~, has not yet been extensively considered. A cascade reaction, also called tandem or domino reaction, is a chemical process that integrates at least two reactions, of which each subsequent reaction can only start when the previous reaction step is completed (Ricca et al., [@B48]). Enzymatic cascade reactions combine a series of enzymatic substrate transformations to produce a final product. In liner cascade reactions, the product of the first enzymatic reaction becomes the substrate of a second reaction (Ricca et al., [@B48]). Enzymatic cascade reactions widely occur in living organisms (Ricca et al., [@B48]). Photosynthesis and aerobic respiration, for instance, are enzymatic cascade reactions producing carbohydrates and carbon dioxide, respectively. Industrially, enzymatic cascade reactions are used in the one-pot synthesis of chemicals. Liner cascade reactions are the most widely used type of cascade reaction in cancer and infection therapy. Using naturally occurring substrates in the human body such as endogenous glucose and oxygen, cascade reactions can be used to produce highly toxic ROS ([Figure 1A](#F1){ref-type="fig"}) (Yan et al., [@B61]), as an anti-cancer drug (Li et al., [@B29]) or antimicrobial (André et al., [@B2]; Liu et al., [@B38]; Liu X. et al., [@B32]) ([Figure 1B](#F1){ref-type="fig"}). ![Schematics of cascade reactions for combating infectious biofilms. **(A)** Different substrates and enzymes involved in substrate transformations to generate different types of ROS. **(B)** ROS can combat infectious biofilms by degrading the EPS matrix of an infectious biofilm (Yan et al., [@B61]), disrupting bacterial cell membranes (Wang et al., [@B58]), and damaging intra-cellular DNA of biofilm inhabitants (Rowe et al., [@B49]; Cadet and Wagner, [@B5]).](fchem-07-00861-g0001){#F1} In this review, we will focus on recent progress in the design of cascade reactions as a new strategy in infection control, taking lessons from current developments aimed toward using cascade reactions in cancer therapy. Use of cascade reactions for infection control is slowly emerging, yet offering equal or more perspective than new antibiotics or non-ROS-based infection-control strategies, because hitherto bacterial resistance to ROS has not been reported and is generally considered highly unlikely to develop. Chemistry of Cascade Reactions {#s2} ============================== In this section, different kinds of cascade reactions are classified by substrate. The conditions and mechanisms to achieve these cascade reactions are summarized. Glucose and Oxygen ------------------ Glucose is the most important carbohydrate in the human body and can yield gluconic acid and H~2~O~2~ upon reaction with oxygen (Itskov and Carlos, [@B25]; Fan et al., [@B16]), according to Glucose \+ O 2 → Gluconicacid \+ H 2 O 2 The production of H~2~O~2~ according to reaction (1) can be catalyzed by glucose oxidase (GOx), as the first reaction in a liner cascade reaction ([Figure 1A](#F1){ref-type="fig"}). This catalytic process can be divided into a reductive and oxidative half-reaction, as shown in [Figure 2A](#F2){ref-type="fig"}. In the reductive half-reaction, β-D-glucose loses two electrons to form δ-gluconolactone, which is subsequently hydrolyzed to gluconic acid. After receiving two electrons from the reductive half-reaction, the flavin ring of GOx becomes reduced to FADH~2~ after which, in the oxidative half-reaction, the same two electrons transferred from GOx-FADH~2~ to oxygen yield H~2~O~2~ and GOx in an oxidized state (Witt et al., [@B59]). Reaction (1) can also be catalyzed by gold nanoparticles and modified graphitic carbon nitride, as shown schematically in [Figures 2B,C](#F2){ref-type="fig"}, respectively. ![Substrate transformations in cascade reactions generating ROS, based on glucose and oxygen as substrates. **(A)** Generation of H~2~O~2~ from glucose using GOx (Witt et al., [@B59]) (with permission of Portland Press). **(B)** Catalysis of glucose transformation to H~2~O~2~ using catalytic, gold nanoparticles (Comotti et al., [@B10]) (with permission of John Wiley and Sons). **(C)** Modified carbon nitride as a bifunctional glucose-peroxidase enzyme-mimic (Zhang et al., [@B63]) (with permission of Nature Publishing Group). **(D)** Activation of H~2~O~2~ on Fe~3~O~4~ nanoparticles to achieve transformation of H~2~O~2~ to ROS (Wang et al., [@B57]) (with permission of Elsevier). **(E)** V~2~O~5~ nanowires catalyze transformation of H~2~O~2~ to ${\cdot \text{O}}_{2}^{-}$ in the presence of ABTS \[2,2′-azinobis(3-ethylbenzthiazoline-6-sulfonate)\] (André et al., [@B2]) (with permission of John Wiley and Sons).](fchem-07-00861-g0002){#F2} In the second reaction of the cascade, different artificial, catalytic nanoparticles can be employed to transform H~2~O~2~ into ·OH, ^1^O~2~ (singlet oxygen), and ${\cdot \text{O}}_{2}^{-}$ (Cho et al., [@B9]). These catalytic nanoparticles include AuNPs (Zhang et al., [@B63]), iron oxide (Fan et al., [@B15]; Duan et al., [@B14]; Gao et al., [@B19]; Liu et al., [@B35]; Naha et al., [@B41]), silver halides (Wang et al., [@B56]), platinum (Liu X. et al., [@B33]; Wu et al., [@B60]), cerium oxide (Niu et al., [@B45]; Celardo et al., [@B7]), vanadium oxide (André et al., [@B2]), 2D metallo-porphyrinic metal-organic framework (MOF) nanosheets (Huang et al., [@B23]), and molybdenum disulfide (MoS~2~) nanoflowers (Yin et al., [@B62]). Metal-free artificial catalysts include modified carbon nitride (Yin et al., [@B62]), graphene oxide (Song et al., [@B50]), and graphene quantum dots (Sun et al., [@B52]; Duan et al., [@B14]). Importantly, these catalytic nanoparticles can be functionally modified to enhance their catalytic activity. However, mechanisms to transform H~2~O~2~ into ·OH, ^1^O~2~, and ${\cdot \text{O}}_{2}^{-}$ are different for different artificial catalytic nanoparticles. Proposed catalytic mechanisms for iron oxide nanoparticles and V~2~O~5~ nanowires are summarized in [Figures 2D,E](#F2){ref-type="fig"} (Natalio et al., [@B42]). Light irradiation can also be used as a catalytic mediator to split H~2~O~2~ into two ·OH (Chang et al., [@B8]). Glucose and L-arginine ---------------------- In another cascade reaction involving glucose ([Figure 1A](#F1){ref-type="fig"}), L-arginine can be employed to produce highly toxic nitric oxide (NO) by oxidation of the guanidine function of L-arginine (see also [Figure 3](#F3){ref-type="fig"}). Interestingly, gluconic acid, as a by-product in reaction (1), leads to a pH decrease, accelerating L-arginine catalytic transformation of H~2~O~2~ into NO (Fan et al., [@B16]). ![The mechanism of NO generation through reaction between L-arginine and H~2~O~2~ (Fan et al., [@B16]).](fchem-07-00861-g0003){#F3} H~2~O~2~ -------- H~2~O~2~ can also act as a substrate for generating ^1^O~2~ in cascade reactions, as catalyzed in the first cascade reaction by catalase, a tetrameric heme protein ([Figure 4A](#F4){ref-type="fig"}) (Alfonso-Prieto et al., [@B1]) or artificial, catalytic nanoparticles, such as cerium oxide nanoparticles ([Figure 4B](#F4){ref-type="fig"}) (Herget et al., [@B22]). In the second reaction, also light can be used to transform O~2~ into singlet oxygen, which requires the presence of a suitable photosensitizer (Li et al., [@B29]), such as tetrapyrroles (absorption band around 400 nm), porphyrins (absorption band around 630 nm), chlorins (absorption band around 650--690 nm), or "bacteriochlorins" with an absorption band shifted further into the red (Castano et al., [@B6]). ![Proposed mechanisms of enzymatic transformations using H~2~O~2~ as a substrate. **(A)** Transformation of H~2~O~2~ by catalase into O~2~ (Alfonso-Prieto et al., [@B1]). **(B)** Transformation of H~2~O~2~ using catalytic cerium oxide nanoparticles ("nanoceria") into O~2~ (Celardo et al., [@B7]) (with permission of the Royal Society of Chemistry).](fchem-07-00861-g0004){#F4} H~2~O~2~ and halides -------------------- In the presence of H~2~O~2~ and halides X^−^ \[such as chloride (Cl^−^) or bromide (Br^−^) ions\], vanadium peroxidase (see [Figure 5A](#F5){ref-type="fig"}), V~2~O~5~ nanowires (Natalio et al., [@B42]) ([Figure 5B](#F5){ref-type="fig"}), and CeO~2−x~ nanorods (Herget et al., [@B22]) ([Figure 5C](#F5){ref-type="fig"}) can also be used in the first cascade reaction \[see reaction (2)\], followed by the second reaction \[reaction (3)\] H 2 O 2 \+ X \- \+ H \+ → H 2 O \+ HOX HOX \+ H 2 O 2 → 1 O 2 \+ X \- \+ H 2 O \+ H \+ ![Proposed mechanisms of enzymatic transformations using H~2~O~2~ and halides as substrates. **(A)** Transformation of H~2~O~2~ and halides by vanadium peroxidase (Ligtenbarg et al., [@B31]) (with permission of Elsevier). **(B)** Transformation of H~2~O~2~ and halides by V~2~O~5~ nanowires (Natalio et al., [@B42]) (with permission of Nature Publishing Group). **(C)** CeO~2−x~ nanorod as catalase (Herget et al., [@B22]) (with permission of John Wiley and Sons).](fchem-07-00861-g0005){#F5} H~2~O and CaO~2~ ---------------- An H~2~O~2~-free cascade reaction is based on water (H~2~O) and calcium peroxide (CaO~2~), as substrates ([Figure 1A](#F1){ref-type="fig"}) according to Yan et al. ([@B61]) Ca O 2 \+ 2 H 2 O → H 2 O 2 \+ Ca ( OH ) 2 CaO~2~ reacts with H~2~O through a redox reaction, in which CaO~2~ as a reducing agent loses four electrons. After obtaining the corresponding electrons, H~2~O is oxidized to H~2~O~2~ after which, in the second reaction of the cascade, H~2~O~2~ can be transformed into ·OH, ^1^O~2~ and ${\cdot \text{O}}_{2}^{-}$ by any of the reactions described in sections Glucose and Oxygen and Glucose and L-Arginine. Application of Cascade Reactions in Cancer Therapy {#s3} ================================================== The main substrates and enzymes in cascade reactions producing ROS that are currently considered for anti-tumor therapy involve glucose and oxygen, glucose and L-arginine, or H~2~O~2~/Cl^−^ as substrates ([Figure 6](#F6){ref-type="fig"}). GOx and Fe~3~O~4~ nanoparticles have been contained into dendritic silica nanocarriers to initiate a cascade reaction, using endogenous glucose present in tumor cells to generate H~2~O~2~ (Huo et al., [@B24]). As a second step, the Fe~3~O~4~ nanoparticles catalyze H~2~O~2~ into highly toxic ·OH. *In vivo*, this cascade reaction demonstrated suppression of mammary tumor growth. Instead of using GOx and Fe~3~O~4~ nanoparticles in dendritic silica to produce ROS (hydroxyl radicals), GOx and catalase have also been integrated in MOF nanocarriers (Li et al., [@B29]). Here, as the second step in the cascade reaction, H~2~O~2~ produced endogenously or from oxidation of glucose by GOx, is converted to oxygen by catalase. After that, singlet oxygen (^1^O~2~) is generated under 660-nm light irradiation (Li et al., [@B29]). Alternatively, another cascade reaction involving photodynamics based on one enzyme was described (Chang et al., [@B8]), in which GOx was conjugated to polymer dots to convert glucose into H~2~O~2~. Under light irradiation, the H~2~O~2~ generated was photolyzed to hydroxyl radicals. {#F6} Glucose and L-arginine have also been used as substrates in cascade reactions to produce NO (see also [Figure 6](#F6){ref-type="fig"}) in order to kill tumor cells (Fan et al., [@B16]). To this end, GOx and L-arginine have been contained in hollow, mesoporous organosilica nanocarriers, and after generation of H~2~O~2~ from glucose present in tumor sites using GOx, reaction of H~2~O~2~ with L-arginine generated NO, which was shown to prolong the life of tumor-bearing mice. Finally, endogenous ^**·**^$\text{O}_{2}^{-}$ and Cl^−^ have been used as substrates in cascade reactions (Wang et al., [@B56]). Using superoxide dismutase (SOD) and chloroperoxidase (CPO), endogenous ^**·**^$\text{O}_{2}^{-}$ can be catalyzed by SOD to H~2~O~2~, which is subsequently further oxidized with the aid of Cl^−^ and CPO to ^1^O~2~. This cascade reaction showed negligible toxicity to healthy cells, but was highly toxic to tumor cells. Application of Cascade Reactions for Bacterial Infection Control: Lessons From Tumor Treatment {#s4} ============================================================================================== Based on the similarity between tumor sites and bacterial biofilms ([Table 1](#T1){ref-type="table"}), we can take lessons from the cascade reactions considered for tumor therapy, as shown in [Figure 6](#F6){ref-type="fig"}. All endogenous substrates used for cancer therapy are available in bacterial infection sites, and ROS shows highly toxic toward all bacterial pathogens, regardless of their Gram character (Vatansever et al., [@B54]). Therefore, cascade reactions are nowadays started to be considered as an alternative strategy for the control of infectious biofilms. The number of studies applying cascade reaction for bacterial infection control is limited however (see overview in [Table 2](#T2){ref-type="table"}), but their results warrant analysis and offer future perspective that are new for infection control. ###### Similarities between tumor sites and infectious biofilms, stimulating the application of cascade reactions in infectious bacterial biofilms, taking lessons from their application in tumor treatment. **Similarity** **Tumor site** **Infectious biofilm** ----------------------------------- ----------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------------------------- Hampered transport Tumors larger than 2 mm^3^, limit oxygen diffusion (Trédan et al., [@B53]; Danhier et al., [@B11]). The EPS matrix limits transport of nutrients to the depth of a biofilm (Flemming et al., [@B17]; Billings et al., [@B4]). Acidic pH Acidic pH between 6.0 and 7.0 (Justus et al., [@B26]). Acidic pH \< 6.0 (Koo et al., [@B28]; Liu et al., [@B36]). Endogenous substrate availability High killing efficacy of ROS toward tumor cells (Postiglione et al., [@B47]). ROS can destruct the EPS matrix and kill biofilm bacteria (Walch et al., [@B55]). Clinical treatment Occurrence of resistance against chemotherapeutics, recurrence of tumor growth (Mansoori et al., [@B39]). Occurrence of resistance against antimicrobials, recurrence of infection (Aslam et al., [@B3]). ###### Summary of cascade reactions considered for infection control, including substrates required, nanocarriers of cascade reaction components, types of ROS generated, and antimicrobial activities observed. --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- **Substrate** **Nanocarrier** **ROS** **Antimicrobial activity** **References** ------------------------------- ------------------------------- ------------------------------------- -------------------------------------------------------------- ------------------------ Glucose/Oxygen  ·OH \- Against planktonic *S. aureus* and *E. coli*\ Liu X. et al., [@B32] - Improved infected wound healing in mice  ·OH \- Against planktonic MRSA\ Li et al., [@B30] - Inhibiting MRSA biofilm formation CaO~2~/H~2~O  ·OH \- Against planktonic *S. aureus* and *E. coli*\ Yan et al., [@B61] - Inhibiting *S. aureus* biofilm formation\ - Dispersing *S. aureus* biofilm\ - *In vivo* implant-related periprosthetic infection of mice H~2~O~2~/Br^−^  ^1^O~2~ \- Against planktonic *S. aureus* and *E. coli*\ Natalio et al., [@B42] - Inhibiting *S. aureus*, and *E. coli* biofilm formation --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Cascade Reactions Considered for Bacterial Infection Control ------------------------------------------------------------ Application of cascade reactions as a new infection-control strategy is currently in its infancy, and to our knowledge, only four studies so far have considered the use of cascade reactions for infection control (see [Table 2](#T2){ref-type="table"}) that employ different nanocarriers for the cascade reaction components. Two cascade reactions based on glucose and O~2~ as substrate have been evaluated for their antimicrobial activity. GOx absorbed in ultrathin two-dimensional (2D) MOF nanosheet carriers (Liu X. et al., [@B32]), *in vitro* generated ROS that killed planktonic *Escherichia coli* and *Staphylococcus aureus* after 5 h incubation with 15 mM glucose in the growth medium. Bacterial killing was far lower (88 and 90% for *E. coli* and *S. aureus*, respectively) than the 99.9--99.99% efficacy limit considered to be required for clinical efficacy (Liu et al., [@B36]). However, when locally applied as a 2D MOF/GOx band-aid on infected (3 × 10^7^ CFU/site *S. aureus*) wounds in mice, mice treated with 2D MOF/GOx band-aids containing 50 μl of a 10 mM glucose solution showed faster wound healing after 3 days of treatment, retrieving less (91% reduction) CFUs than when treated with blank band-aids. Glucose and O~2~ were also used as substrates in combination with another peroxidase, hemoglobin (Hb) to catalyze H~2~O~2~ into ^·^OH. Cascade reaction components were contained in MnCO~3~ nanocarriers (Li et al., [@B30]). In growth medium supplemented with glucose to a concentration of 12.5 mM, i.e., substantially higher than endogenously occurring (before eating \<6.1 mM; Stumvoll et al., [@B51]), GOx-Hb nanocarriers yielded 7 log unit inhibition in planktonic MRSA growth ([Figure 7](#F7){ref-type="fig"}). In addition, biomass analysis based on Crystal Violet staining indicated the ability of GOx-Hb nanocarriers to inhibit MRSA biofilm formation during 48 h exposure to GOx-Hb and incubation in glucose supplemented growth medium. Nanocarriers containing denatured GOx did not inhibit biofilm formation. ![CFUs (MRSA) in growth medium supplemented with glucose (12.5 mM) after 24 h of growth, as a function of GOx-Hb nanocarrier concentration. For control, nanocarriers with denatured GOx (dGOx-Hb) were included (Li et al., [@B30]) (with permission of ACS).](fchem-07-00861-g0007){#F7} A cascade reaction using CaO~2~ and H~2~O as substrates to generate hydroxyl radicals was fabricated by containing CaO~2~ and hemin-carrying graphene into alginate (Yan et al., [@B61]). Importantly, these alginate nanocarriers did not contain any H~2~O~2~ as a substrate and CaO~2~ and H~2~O were locally converted into ROS. Planktonically, these nanocarriers yielded relatively low killing of *S. aureus* and *E. coli* (90 and 95%, respectively, after 6 h exposure). Also, 72-h *S. aureus* biofilm growth in the presence of the cascade reaction components containing nanocarriers was low, yielding \<5-μm-thick biofilms vs. 25 μm in their absence. In addition, exposure of an existing *S. aureus* biofilm to the cascade reaction components containing nanocarriers eradicated 81% of its inhabitants. Interestingly, these cascade reaction components containing nanocarriers caused biofilm dispersal, degrading DNA and proteins, as major components of the EPS-matrix holding a biofilm together. Finally, *S. aureus*-infected wounds (1 × 10^5^ CFU/site) in rats gradually healed after 7 days (\>90% bacterial killing) when treated with these alginate nanocarriers, with obvious swelling and pus formation in control groups. H~2~O~2~ has also been used in combination with Br^−^ as substrates in the presence of V~2~O~5~ nanowires, with an intended, initial use in the marine environment (Natalio et al., [@B42]). V~2~O~5~ nanowires can work as natural haloperoxidases to transform bromide ions to hypobromous acid (HOBr) in the presence of H~2~O~2~ (Natalio et al., [@B42]). The antimicrobial activity against human pathogens was low, however, decreasing planktonic growth of *E. coli* by only 78% and of *S. aureus* by only 96% in the presence of V~2~O~5~ nanowires (0.075 mg/ml), Br~2~ (1 mM), and H~2~O~2~ (10 μM), and as compared to bacteria grown in the absence of additives. Advantages and Disadvantages of Cascade Reactions for Biofilm Control --------------------------------------------------------------------- The main advantages for infection-control cascade reactions include the fact that they are non-antibiotic based. Bacteria possess little or no resistance against ROS, although some bacterial species can develop resistance against specific ROS species, such as ^**·**^$\text{O}_{2}^{-}$ and H~2~O~2~, but not against ^**·**^OH and ^1^O~2~ (Vatansever et al., [@B54]). Often, however, different species of ROS are generated at the same time in catalytic reactions. ROS as generated in cascade reactions kills both Gram-positive and Gram-negative bacterial strains in a non-specific way. On the one hand, this may be considered an advantage, but on the other hand, the commensal microflora can also be affected, unless the cascade reaction can be localized in or near the infection site. Although nanocarriers and artificial enzymes used in cascade reactions are relatively easy to synthesize and modify, confining ROS generation to an infection site may be more troublesome. As a drawback of the current status of cascade reactions, the amount of ROS generated is generally low and antimicrobial efficacies reported are below the limit of 3--4 log units considered necessary for clinical efficacy (Yan et al., [@B61]; Liu et al., [@B36]). Although the amount of ROS generated can be enhanced by adding more substrate (Fan et al., [@B16]), this needs to be done carefully in order to prevent collateral damage to tissue surrounding an infection site. This, too, requires confining of ROS generation to an infection site. Perspectives of the Use of Cascade Reactions for Infection Control {#s5} ================================================================== The antimicrobial activity of ROS (Rowe et al., [@B49]; Cadet and Wagner, [@B5]; Vatansever et al., [@B54]; Gao et al., [@B19]; Wang et al., [@B58]; Liu et al., [@B35]; Yan et al., [@B61]) and the potential advantages of the use of cascade reaction as a new infection-control strategy warrant their further development for infection control, but several challenges have to be overcome before their clinical use becomes into sight. The biggest challenge in the further development of infection-control cascade reactions is to increase their bacterial killing efficacy to levels that can be expected to be clinically effective (i.e., minimally 3--log unit reductions in CFUs, equal to minimal percentage reductions of 99.9--99.99%). This should preferentially be done using endogenously available substrates, but this option should be carefully balanced against the potential damage that high concentrations of ROS can do to tissue cells surrounding an infection site (Li et al., [@B30]). Alternatively, additional substrate can be locally administered to increase local ROS generation, which may reduce collateral tissue damage. Collateral tissue cell damage might be fully prevented by using self-targeting, pH-responsive nanocarriers that penetrate and accumulate in infectious biofilms (Liu Y. et al., [@B34]), to confine the occurrence of the cascade reaction and generation of ROS to inside the biofilm itself. A further advantage of such confinement would be that it will create long-term presence of ROS in a biofilm to enhance bacterial killing, despite the short lifetime (nanoseconds) of individual ROS molecules, arguably too short to yield effective bacterial killing. Nevertheless, cascade reactions generating relatively low levels of ROS might still be clinically useful in combination with clinically applied antibiotics to enhance their fading efficacies (Nguyen et al., [@B44]). Synergistic action between different antimicrobials is a common phenomenon, and it is known to even yield killing of bacterial pathogens that are resistant to either of the antimicrobials when applied in monotherapy (Klahn and Brönstrup, [@B27]). This approach bears advantages for downward clinical translation of infection-control cascade reactions, because it builds on existing clinically applied antibiotics, from which further development of infection-control cascade reactions can be facilitated more easily. Moreover, it might increase the effective lifetime of current and new antibiotics to be developed (Liu et al., [@B37]), with the potential to reduce the induction of antibiotic resistance (Mao et al., [@B40]). As a final perspective of infection-control cascade reactions, specific patient groups with elevated endogenous substrate levels may benefit from cascade reactions. Diabetic patients, for instance, can suffer from difficult-to-heal infected wounds and have elevated glucose levels (ranging from ≥7.0 mM before to ≥11.1 mM after eating) compared with healthy glucose levels (ranging from \<5.6 mM before to 7.8 mM after eating) (Stumvoll et al., [@B51]). Local generation of ROS through suitable cascade reactions may be extremely suitable for treating diabetic foot ulcers that have been demonstrated to be caused by hard-to-treat infectious biofilms (Neut et al., [@B43]). Cancer patients are another specific patient group for which infection-control cascade reactions could be useful. There is growing evidence that bacteria can metabolize chemotherapeutic drugs (Geller et al., [@B20]). Accordingly, intra-tumor bacteria may contribute to resistance against chemotherapeutic drugs among certain tumors. Since tumor sites possess elevated levels of H~2~O~2~ (50--100 μM around a tumor site vs. 20 nM elsewhere in the body) (De Garcia Lux et al., [@B13]), infection-control cascade reactions based on endogenous H~2~O~2~ substrate availability may play a role for this specific patient groups in treating tumor-associated infections. In short, cascade reactions have potential as a new infection control strategy, but much work remains to be done to solve the challenges listed above in order to make cascade reactions into a real clinical addendum to the antimicrobial armamentarium of modern medicine. Author Contributions {#s6} ==================== All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. Conflict of Interest -------------------- HB is also director of a consulting company, SASA BV. The remaining authors declare no conflicts of interest with respect to authorship and/or publication of this article. Opinions and assertions contained herein are those of the authors and are not construed as necessarily representing views of their respective employers. **Funding.** This work was financially supported by the National Natural Science Foundation of China (21620102005, 51933006, and 51773099). [^1]: Edited by: Sergio F. Sousa, University of Porto, Portugal [^2]: Reviewed by: Geelsu Hwang, University of Pennsylvania, United States; Hyun Lee, University of Illinois at Chicago, United States [^3]: This article was submitted to Medicinal and Pharmaceutical Chemistry, a section of the journal Frontiers in Chemistry [^4]: †These authors have contributed equally to this work

2023-08-07T01:27:04.234600

https://example.com/article/6076

Every year, many children unfortunately died from being stranded in their car seats under hot or cold weather when their parents or drivers of the cars forgot to take them out of the cars after parking. As the pace of people's life becoming even faster and more things distracting car drivers after parking their cars (e.g. urgent office matter causing a driver to rush to the office without noticing the child remained in the car after parking), more children may be injured or die under such circumstances in the future.

2024-07-16T01:27:04.234600

https://example.com/article/5472

Bullying and victimization remain significant problems among school-age children (Cook et al., 2010). Greater understanding of this behavioral process is necessary to create more effective interventions and treatments toward the goal of improving the quality of life for children. One theory of bullying is the compensation model of aggression (Nail, Bihm, & Simon, in press; Staub, 1989). It proposes that bullying is driven primarily by the personality of the bully, as bullies attempt to compensate, or make up for, their own feelings of weakness and vulnerability by dominating others. Essentially, the bully's feelings of insecurity are thought to be turned outward and converted into aggression against others-typically those who are physically weaker and readily available, such as smaller classmates (Kaukiainen et al., 2002) or a bully's spouse (Gondolf, 1985). The compensation model has been supported by a number of studies that have found a positive correlation between a defensive personality structure and bullying or aggression in schools (e.g., Nail et al., in press; Sandstrom & Jordan, 2008). Defensive personality can be operationally defined in various ways, but one is defensive egotism-i.e., students who think too highly of themselves and always want to be the center of attention. A major problem with the support for compensation model, however, is that almost all of the findings to date have been correlational in nature, whereas the model proposes that a defensive personality causes bullying. The proposed research will address this problem. It is well established in the literature that manipulated laboratory threats can cause increases in aggression, especially for those with a defensive personality structure (e.g., Bushman et al., 2009). It is also well established that threat-induced defensiveness can be reduced or eliminated by interventions that allow people to affirm core aspects of their self image (e.g., McGregor, Nail et al., 2005). What is not known is whether self-affirmation interventions can cause decreases in bullying. The defensive egotism of seventh graders will be assessed by the reports of their classmates and teachers. Later on a Monday morning, randomly chosen students will write an essay explaining (a) why their most important values are important to them (viz., self-affirmation participants) or (b) why their least important values migt be important to others (non-self-affirmation/control participants). On Friday afternoon of that week, students and teachers will report the dependent variables-the bullying and aggression of their classmates and students, respectively, over the past week. If the compensation model is correct, only non-self- affirmation/control participants will show the usual positive link between defensive egotism and bullying/aggression. Self-affirmation participants should have little need to feed their ego by bullying others that week because their self-concept will have been bolstered by the writing task. Such findings will point to the need for a more holistic model of bullying reduction-one that combine's current whole-school, administrative efforts with targeted, therapeutic interventions for bullies.

2024-02-14T01:27:04.234600

https://example.com/article/9202

The possible utilization of nuclear pockets of lymphocytes in the diagnosis of enzootic bovine leucosis. A comparative study of the presence of lymphocytosis and nuclear pockets in lymphocytes was carried out using blood samples from animals belonging to herds with bovine enzootic leucosis and from herds free from leucosis. It was found that there was a correlation between the presence of such nuclear projections in a certain percentage of the lymphocytes and a state of lymphocytosis. As this correlation seemed to be independent of the aetiology of the lymphocytosis, it was not considered possible to employ the demonstration of nuclear pockets as a more specific tool in the diagnosis of bovine enzootic leucosis than the lymphocyte counts in themselves.

2023-10-12T01:27:04.234600

https://example.com/article/8050

Friday, February 9, 2007 Anna Nicole Smith and Rosie O'Donnell The irony is that just a few hours before Anna Nicole died Rosie was being Rosie and whining on The View about how sick of seeing her she was, even doing an impression of her trying to speak. She said: "If I have to see Anna Nicole Smith one more time on television, one more time, that woman and her paternity tests and she can hardly even speak now. She can't even speak. (insert insulting impression here) It's a tragedy all around. Her son died. She has this little baby. There's obviously some kind of medication or substance involved." I do not wish anybody to die, but I do wish Anna Nicole Smith and Rosie O'Donnell could switch places. At least Anna Nicole Smith was entertaining to watch. What does Rosie O'Donnell contribute to society and the entertainment world except for making everybody else look that much better. And Rosie O'Donnell making fun of the way somebody speaks is like Richard Simmons making fun of someone for being gay.

2024-07-14T01:27:04.234600

https://example.com/article/7394

/* Copyright 2015 The Kubernetes Authors. Licensed under the Apache License, Version 2.0 (the "License"); you may not use this file except in compliance with the License. You may obtain a copy of the License at http://www.apache.org/licenses/LICENSE-2.0 Unless required by applicable law or agreed to in writing, software distributed under the License is distributed on an "AS IS" BASIS, WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied. See the License for the specific language governing permissions and limitations under the License. */ package server import ( "net/http" "strings" "github.com/golang/glog" "k8s.io/apimachinery/pkg/types" "k8s.io/apiserver/pkg/authentication/authenticator" "k8s.io/apiserver/pkg/authentication/user" "k8s.io/apiserver/pkg/authorization/authorizer" ) // KubeletAuth implements AuthInterface type KubeletAuth struct { // authenticator identifies the user for requests to the Kubelet API authenticator.Request // authorizerAttributeGetter builds authorization.Attributes for a request to the Kubelet API authorizer.RequestAttributesGetter // authorizer determines whether a given authorization.Attributes is allowed authorizer.Authorizer } // NewKubeletAuth returns a kubelet.AuthInterface composed of the given authenticator, attribute getter, and authorizer func NewKubeletAuth(authenticator authenticator.Request, authorizerAttributeGetter authorizer.RequestAttributesGetter, authorizer authorizer.Authorizer) AuthInterface { return &KubeletAuth{authenticator, authorizerAttributeGetter, authorizer} } func NewNodeAuthorizerAttributesGetter(nodeName types.NodeName) authorizer.RequestAttributesGetter { return nodeAuthorizerAttributesGetter{nodeName: nodeName} } type nodeAuthorizerAttributesGetter struct { nodeName types.NodeName } func isSubpath(subpath, path string) bool { path = strings.TrimSuffix(path, "/") return subpath == path || (strings.HasPrefix(subpath, path) && subpath[len(path)] == '/') } // GetRequestAttributes populates authorizer attributes for the requests to the kubelet API. // Default attributes are: {apiVersion=v1,verb=<http verb from request>,resource=nodes,name=<node name>,subresource=proxy} // More specific verb/resource is set for the following request patterns: // /stats/* => verb=<api verb from request>, resource=nodes, name=<node name>, subresource=stats // /metrics/* => verb=<api verb from request>, resource=nodes, name=<node name>, subresource=metrics // /logs/* => verb=<api verb from request>, resource=nodes, name=<node name>, subresource=log // /spec/* => verb=<api verb from request>, resource=nodes, name=<node name>, subresource=spec func (n nodeAuthorizerAttributesGetter) GetRequestAttributes(u user.Info, r *http.Request) authorizer.Attributes { apiVerb := "" switch r.Method { case "POST": apiVerb = "create" case "GET": apiVerb = "get" case "PUT": apiVerb = "update" case "PATCH": apiVerb = "patch" case "DELETE": apiVerb = "delete" } requestPath := r.URL.Path // Default attributes mirror the API attributes that would allow this access to the kubelet API attrs := authorizer.AttributesRecord{ User: u, Verb: apiVerb, Namespace: "", APIGroup: "", APIVersion: "v1", Resource: "nodes", Subresource: "proxy", Name: string(n.nodeName), ResourceRequest: true, Path: requestPath, } // Override subresource for specific paths // This allows subdividing access to the kubelet API switch { case isSubpath(requestPath, statsPath): attrs.Subresource = "stats" case isSubpath(requestPath, metricsPath): attrs.Subresource = "metrics" case isSubpath(requestPath, logsPath): // "log" to match other log subresources (pods/log, etc) attrs.Subresource = "log" case isSubpath(requestPath, specPath): attrs.Subresource = "spec" } glog.V(5).Infof("Node request attributes: attrs=%#v", attrs) return attrs }

2023-08-05T01:27:04.234600

https://example.com/article/3972

1. Technical Field Various embodiments of the present invention relate to a three-dimensional (3D) semiconductor integrated circuit and a method of manufacturing the same, and more particularly, to a 3D semiconductor integrated circuit capable of improving gate pick-up failures, and a method of manufacturing the same. 2. Related Art With the rapid development of mobile and digital information communication and the consumer-electronic industry, studies on existing electronic charge controlled-devices may encounter limitations. To overcome the limitations, new functional memory devices having novel designs need to be developed. Particularly, next-generation memory devices with large capacities, ultra-high speed and ultra-low power need to be developed to satisfy demands of large capacity memories used in main information devices. Resistive memory devices using a resistance material as a memory medium have been suggested as the next-generation memory devices, and typical examples of resistive memory devices are phase-change random access memories (PCRAMs), resistance RAMS (ReRAMs), or magnetic RAMS (MRAMs). A resistive memory device may be typically formed of a switching device and a resistance device and may store data “0” or “1,” according to a state of the resistance device. A final target of the resistive memory devices is to improve integration density and to integrate as many memory cells as possible in a limited small area. In recent years, methods of forming the resistive memory devices into 3D structures have been also suggested, and there is a growing need for a method of stably stacking a plurality of memory cells having narrower line width. A typical method of manufacturing a resistive memory device having a 3D structure includes a method of forming a switching device using a vertical pillar as a vertical channel layer. The 3D channel structure having a vertical pillar, has a vertical surround gate. The vertical surround gate structure may be formed to surround a lower region of the pillar. The vertical surround gates may form a gate pick-up in a predetermined region. The gate pick-up line may be electrically contacted to the gate using a general contact process. Since the gate is formed to surround a circumference of a lower portion of the pillar, an over-etching process is used to form a contact hole (hereinafter, referred to as a gate pick-up hole) for forming the gate pick-up line. However, when using the over-etching process, the contact hole may penetrate a substrate region (for example, source region) located below the pillar, and thus a short circuit between the gate pick-up line and the substrate portion (for example, source region) of the pillar, may be caused. As described above, as the gate is formed to surround the circumference of the lower portion of the pillar, the contact hole for forming the gate pick-up line also has a depth approaching a height of the pillar. Therefore, an aspect ratio of the contact hole in which the gate pick-up line is formed is increased, and thus a void may occur in the gate pick-up line.

2023-11-30T01:27:04.234600

https://example.com/article/9882

Q: Difference between poststop and terminate in Akka? In akka the poststop method is called when an actor is stopped. Also a watch can be configured on the supervisor so that when an actor is terminated a Terminated message is received within the supervisor. Is there any advantage of using the postStop instead of Terminated? The only difference I can see is that postStop is called(within actor) when an actor is stopped and Terminated is called(within supervisor) when actor is Terminated. When an actor is stopped is'nt it also terminated ? A: First of all, postStop() is called from preRestart() default implementation of the same actor (see here), while Terminated message is sent to the parent only when the actor is really stopped, not when it is just restarted. Hence in default setup postStop() may be called more times than Terminated message is sent. But the main idea is that post* and pre* hooks are needed to cleanup the actor's own state, and Terminated message (the whole watch system, in fact) is intended to coordinate multiple actors behavior and state. Their purpose is different, and while you can send custom Terminated-like messages from postStop() hook, you really shouldn't. A: postStop is a callback inside the actor itself. You would use that to clean up state that is internal to the actor, or fire further messages based on the state. Watching for Terminated allows an external actor to be notified when another actor has died. It does not rely on the terminated actor itself to do anything.

2024-01-19T01:27:04.234600

https://example.com/article/5955

Pages Wednesday, April 16, 2014 Searching For Love Online: 6 Things You Need To Know Do guys still harass ladies by tailing them in a car or walking closely behind them to get their numbers or contacts? I remember that was the deal sometime ago and few people probably still practise that. You all will agree it is a lot easier chatting another up on the social media these days. One can comfortably hide behind the keypads swelling with false confidence while typing things one would have lacked the courage to say if there were no barriers. Technology generally has made sure our physical contacts with other human beings are becoming less and less, but the thing is, one barely notices this trend. I stay connected with my friends that I haven’t seen in years and I feel like when we see, it will feel like we saw ourselves the day before because of the closeness I feel through voice messages and picture updates. Some researchers even arrived at a conclusion that one feels the emotions that the emojis used in some of the apps on these social media represent. Meaning I am probably happy when I use the dancing smiley and depressed when I use the sad face smiley. I know someone that got married to a guy she met on bbm, he proposed to her the first day they saw themselves physically. While that might seem like a risk, I must confess they have had a great marriage so far. Not everyone is as lucky. I have heard countless tales of online relationship woes. The line between physical and virtual has become blurred and many people are becoming more and more involved in online relationships. Do you still wonder if the social media is the right place to meet the one you would want to spend forever with? Well, these are some things for you to consider; ·What exactly are you looking for? Many people have been treated to shocks of their lives when they finally meet the person that has been making their adrenaline rise really high. The person sometimes doesn’t measure up in any way to the pictures. If you are big on physical looks, then, you might want to reconsider before getting in an online relationship because what you see is not always what you get. ·Getting to know the other person outside of the social media is absolutely necessary. We all come from different backgrounds that we don’t feel the need to reveal in our online profiles. Behind a humorous profile might be a dark and depressed individual. If one doesn’t spend time with the other person, this dark side might be a terrible surprise at a much later time. Understand that no matter how much you think you know an individual on line, the person is largely a stranger. Be careful who you allow into your life. It is advisable to court yourselves outside the media to get better acquainted. ·Have reasonable expectations. Consider geographical barriers. It is almost ridiculous to think something could come out of a relationship with someone that one has slim chances of ever meeting. You can’t be in Nigeria while your online lover is in Australia or Finland. There will be a cultural shock and you might never be able to adapt.It is ridiculous to think there is a future in an online relationship of up to four years where the other party has been avoiding a physical meet up. I won’t act like some of these relationships don’t finally work out but a good number don’t. ·Always take your time. You need not rush into something solid suddenly. You need to consider the other person’s values. Do they correspond with yours? Do you stand for the same things? In answering these questions, you need to look in the right places. There are different sites that tend to different relationship needs, find your category. Join a Christian dating site if you have to. I am not saying this erases the other things you should be looking out for but it limits the negatives you might be opening yourself to. ·When you want to meet up, pick a neutral place in the outdoors. Visiting the other person’s house might not be a good decision. Take your time to build your trust in the other person. ·Above all, don’t forget the role of prayer, ask God to know His thoughts on what you are involving yourself in. If you get a good feeling in your spirit, keep at it. I know the older generation frown at online relationships but it has become a big part of our lives in the present times. Least we can do is arm ourselves with the right tools when getting into it.

2023-12-24T01:27:04.234600

https://example.com/article/1856

G&H CUSTOM SPORTER RIFLES The Griffin & Howe Custom Rifle, the benchmark for custom rifles since 1923 The style has changed very little since Seymour Griffin and James V. Howe joined forces to meet the needs of discriminating sportsmen and sportswomen. You can share the prestige of owning a Griffin & Howe Custom Rifle, made to your specifications in the caliber of your choice, from .22 Hornet up to the .416 Rigby, or even the crushing .505 Gibbs. The Classic Griffin & Howe French Walnut Stock with hand rubbed London Oil finish will give you years of pleasure and pride of ownership. A Griffin & Howe quick detachable top mount or side mount and quarter rib with folding leaf sights complete the typical custom made rifle by Griffin & Howe. Special engraving and gold inlays are also available. If you wish to move into the exclusive realm of a Griffin & Howe Custom Rifle, please allow approximately 12-18 months for us to handcraft the firearms of your dreams. The price for one of our aristocratic, handmade rifles starts at $13,500.00. Special features and larger calibers can bring the price up to $18,000.00, for the sportsman or sportswoman who will settle for nothing but the ultimate. Griffin & Howe Barrel Band Our Barrel bands are individually handmade and fitted for those who prefer their sling attached to the barrel rather than the stock. In this way, the muzzle weight height over the head is lowered while the rifle is slung over the shoulder, making passage through heavier timber easier. Positioning the swivel on the barrel helps prevent pinching and bruising of the hand while firing heavy calibers.The Griffin & Howe Barrel Band (includes the band, installation and rebluing of the barrel), available on an installed basis only: $370.00

2023-09-01T01:27:04.234600

https://example.com/article/2557

/* * {EasyGank} Copyright (C) {2015} {CaMnter} * * This program comes with ABSOLUTELY NO WARRANTY; for details type `show w'. * This is free software, and you are welcome to redistribute it * under certain conditions; type `show c' for details. * * The hypothetical commands `show w' and `show c' should show the appropriate * parts of the General Public License. Of course, your program's commands * might be different; for a GUI interface, you would use an "about box". * * You should also get your employer (if you work as a programmer) or school, * if any, to sign a "copyright disclaimer" for the program, if necessary. * For more information on this, and how to apply and follow the GNU GPL, see * <http://www.gnu.org/licenses/>. * * The GNU General Public License does not permit incorporating your program * into proprietary programs. If your program is a subroutine library, you * may consider it more useful to permit linking proprietary applications with * the library. If this is what you want to do, use the GNU Lesser General * Public License instead of this License. But first, please read * <http://www.gnu.org/philosophy/why-not-lgpl.html>. */ package com.camnter.easygank.bean; import com.google.gson.annotations.SerializedName; import java.io.Serializable; import java.util.Date; /** * Description：BaseGankData ( Gank数据的类型，无论是Android，还是福利，都是这样的数据 ) * Created by：CaMnter * Time：2016-01-03 17:28 */ public class BaseGankData implements Serializable { // 发布人 @SerializedName("who") public String who; // 发布时间 @SerializedName("publishedAt") public Date publishedAt; // 标题 @SerializedName("desc") public String desc; // 类型， 一般都是"福利" @SerializedName("type") public String type; // 图片url @SerializedName("url") public String url; // 是否可用 @SerializedName("used") public Boolean used; // 对象id @SerializedName("objectId") public String objectId; // 创建时间 @SerializedName("createdAt") public Date createdAt; // 更新时间 @SerializedName("updatedAt") public Date updatedAt; }

2024-04-29T01:27:04.234600

https://example.com/article/6360

Q: chrome js and jquery: add a link? I'm trying to add a text link into youtube page with "user javascript and css" extension. But the following js code does nothing, and I'm not sure but Chrome Console seems have said nothing about my js. $(window).load(function() { var ytu = document.getElementsById('eow-title'); var newlink = document.createElement('a'); newlink.setAttribute('href', window.location.href); newlink.setAttribute('innerHTML', document.title); newlink.setAttribute('target', '_blank'); $(newlink).insertAfter(ytu); }); I've checked jquery2.1.0 min option. A: You are mixing up javascript and jQuery Objects which is bad practice: $(window).on("load", document, function() { var ytu = $('.yt-user-info'); var newlink = $("<a></a>"); newlink.attr('href', window.location.href); newlink.html("Title: " + document.title); newlink.attr('target', '_blank'); newlink.insertAfter(ytu.eq(0)); }); <script src="https://cdnjs.cloudflare.com/ajax/libs/jquery/3.3.1/jquery.min.js"></script> <a class="yt-user-info">A</a>

2024-01-13T01:27:04.234600

https://example.com/article/9261

interface InterfaceWithDefault { default boolean qix() { return true; } default boolean gul() { return false; } boolean bar(); } abstract class AbstractMethodFromInterface implements InterfaceWithDefault { abstract boolean bar(); // Compliant } interface InterfaceExtendsDefault extends InterfaceWithDefault { boolean qix(); // Noncompliant [[sc=11;ec=14]] {{Add the "@Override" annotation above this method signature}} @Override boolean gul(); // Compliant - hide default behavior } class ImplemInterfaceWithDefault implements InterfaceWithDefault { public boolean gul() { return false; } // Noncompliant [[sc=18;ec=21]] {{Add the "@Override" annotation above this method signature}} }

2023-08-07T01:27:04.234600

https://example.com/article/1608

package org.bouncycastle.math.ec.custom.djb; import java.math.BigInteger; import org.bouncycastle.math.ec.ECFieldElement; import org.bouncycastle.math.raw.Nat256; import org.bouncycastle.util.Arrays; public class Curve25519FieldElement extends ECFieldElement.AbstractFp { public static final BigInteger Q = Nat256.toBigInteger(Curve25519Field.P); // Calculated as ECConstants.TWO.modPow(Q.shiftRight(2), Q) private static final int[] PRECOMP_POW2 = new int[]{ 0x4a0ea0b0, 0xc4ee1b27, 0xad2fe478, 0x2f431806, 0x3dfbd7a7, 0x2b4d0099, 0x4fc1df0b, 0x2b832480 }; protected int[] x; public Curve25519FieldElement(BigInteger x) { if (x == null || x.signum() < 0 || x.compareTo(Q) >= 0) { throw new IllegalArgumentException("x value invalid for Curve25519FieldElement"); } this.x = Curve25519Field.fromBigInteger(x); } public Curve25519FieldElement() { this.x = Nat256.create(); } protected Curve25519FieldElement(int[] x) { this.x = x; } public boolean isZero() { return Nat256.isZero(x); } public boolean isOne() { return Nat256.isOne(x); } public boolean testBitZero() { return Nat256.getBit(x, 0) == 1; } public BigInteger toBigInteger() { return Nat256.toBigInteger(x); } public String getFieldName() { return "Curve25519Field"; } public int getFieldSize() { return Q.bitLength(); } public ECFieldElement add(ECFieldElement b) { int[] z = Nat256.create(); Curve25519Field.add(x, ((Curve25519FieldElement)b).x, z); return new Curve25519FieldElement(z); } public ECFieldElement addOne() { int[] z = Nat256.create(); Curve25519Field.addOne(x, z); return new Curve25519FieldElement(z); } public ECFieldElement subtract(ECFieldElement b) { int[] z = Nat256.create(); Curve25519Field.subtract(x, ((Curve25519FieldElement)b).x, z); return new Curve25519FieldElement(z); } public ECFieldElement multiply(ECFieldElement b) { int[] z = Nat256.create(); Curve25519Field.multiply(x, ((Curve25519FieldElement)b).x, z); return new Curve25519FieldElement(z); } public ECFieldElement divide(ECFieldElement b) { // return multiply(b.invert()); int[] z = Nat256.create(); Curve25519Field.inv(((Curve25519FieldElement)b).x, z); Curve25519Field.multiply(z, x, z); return new Curve25519FieldElement(z); } public ECFieldElement negate() { int[] z = Nat256.create(); Curve25519Field.negate(x, z); return new Curve25519FieldElement(z); } public ECFieldElement square() { int[] z = Nat256.create(); Curve25519Field.square(x, z); return new Curve25519FieldElement(z); } public ECFieldElement invert() { // return new Curve25519FieldElement(toBigInteger().modInverse(Q)); int[] z = Nat256.create(); Curve25519Field.inv(x, z); return new Curve25519FieldElement(z); } /** * return a sqrt root - the routine verifies that the calculation returns the right value - if * none exists it returns null. */ public ECFieldElement sqrt() { /* * Q == 8m + 5, so we use Pocklington's method for this case. * * First, raise this element to the exponent 2^252 - 2^1 (i.e. m + 1) * * Breaking up the exponent's binary representation into "repunits", we get: * { 251 1s } { 1 0s } * * Therefore we need an addition chain containing 251 (the lengths of the repunits) * We use: 1, 2, 3, 4, 7, 11, 15, 30, 60, 120, 131, [251] */ int[] x1 = this.x; if (Nat256.isZero(x1) || Nat256.isOne(x1)) { return this; } int[] x2 = Nat256.create(); Curve25519Field.square(x1, x2); Curve25519Field.multiply(x2, x1, x2); int[] x3 = x2; Curve25519Field.square(x2, x3); Curve25519Field.multiply(x3, x1, x3); int[] x4 = Nat256.create(); Curve25519Field.square(x3, x4); Curve25519Field.multiply(x4, x1, x4); int[] x7 = Nat256.create(); Curve25519Field.squareN(x4, 3, x7); Curve25519Field.multiply(x7, x3, x7); int[] x11 = x3; Curve25519Field.squareN(x7, 4, x11); Curve25519Field.multiply(x11, x4, x11); int[] x15 = x7; Curve25519Field.squareN(x11, 4, x15); Curve25519Field.multiply(x15, x4, x15); int[] x30 = x4; Curve25519Field.squareN(x15, 15, x30); Curve25519Field.multiply(x30, x15, x30); int[] x60 = x15; Curve25519Field.squareN(x30, 30, x60); Curve25519Field.multiply(x60, x30, x60); int[] x120 = x30; Curve25519Field.squareN(x60, 60, x120); Curve25519Field.multiply(x120, x60, x120); int[] x131 = x60; Curve25519Field.squareN(x120, 11, x131); Curve25519Field.multiply(x131, x11, x131); int[] x251 = x11; Curve25519Field.squareN(x131, 120, x251); Curve25519Field.multiply(x251, x120, x251); int[] t1 = x251; Curve25519Field.square(t1, t1); int[] t2 = x120; Curve25519Field.square(t1, t2); if (Nat256.eq(x1, t2)) { return new Curve25519FieldElement(t1); } /* * If the first guess is incorrect, we multiply by a precomputed power of 2 to get the second guess, * which is ((4x)^(m + 1))/2 mod Q */ Curve25519Field.multiply(t1, PRECOMP_POW2, t1); Curve25519Field.square(t1, t2); if (Nat256.eq(x1, t2)) { return new Curve25519FieldElement(t1); } return null; } public boolean equals(Object other) { if (other == this) { return true; } if (!(other instanceof Curve25519FieldElement)) { return false; } Curve25519FieldElement o = (Curve25519FieldElement)other; return Nat256.eq(x, o.x); } public int hashCode() { return Q.hashCode() ^ Arrays.hashCode(x, 0, 8); } }

2024-07-06T01:27:04.234600

https://example.com/article/9635

# Captive Portal for the Bash Bunny Author: Sebkinne Version: 1.1 ## Description Redirects and spoofs all DNS requests to the Bash Bunny, and serves a configurable captive portal. All captured credentials will be logged in the payload's folder in a file named *capture.log*. ## Configuration Configured for Windows by default. Swap RNDIS_ETHERNET for ECM_ETHERNET on Mac/*nix. The *portal.html* file can be modified as seen fit, but changes must remain in the file (no external images, css, or javascript). To capture more information from the user, simply add more form inputs to *portal.html*, and update the *INPUTS* line in payload.txt. Example: `INPUTS=(email username password)` ## STATUS | LED | Status | | ---------------- | ----------------------------------- | | Green (blinking) | The captive portal is starting up | | Blue (solid) | The captive portal is ready for use |

2024-06-03T01:27:04.234600

https://example.com/article/8411

package gov.nysenate.openleg.service.sobi; import gov.nysenate.openleg.BaseTests; import gov.nysenate.openleg.processor.legdata.LegDataProcessService; import org.junit.Test; import org.slf4j.Logger; import org.slf4j.LoggerFactory; import org.springframework.beans.factory.annotation.Autowired; public class LegDataProcessServiceTest extends BaseTests { private static final Logger logger = LoggerFactory.getLogger(LegDataProcessServiceTest.class); @Autowired private LegDataProcessService legDataProcessService; @Test public void ingestTest() { legDataProcessService.ingest(); } @Test public void fullTest() { legDataProcessService.collate(); legDataProcessService.ingest(); } }

2024-07-15T01:27:04.234600

https://example.com/article/5815

<?xml version="1.0" encoding="UTF-8"?> <archive type="com.apple.InterfaceBuilder3.CocoaTouch.XIB" version="7.03"> <data> <int key="IBDocument.SystemTarget">768</int> <string key="IBDocument.SystemVersion">9J61</string> <string key="IBDocument.InterfaceBuilderVersion">677</string> <string key="IBDocument.AppKitVersion">949.46</string> <string key="IBDocument.HIToolboxVersion">353.00</string> <object class="NSMutableArray" key="IBDocument.EditedObjectIDs"> <bool key="EncodedWithXMLCoder">YES</bool> </object> <object class="NSArray" key="IBDocument.PluginDependencies"> <bool key="EncodedWithXMLCoder">YES</bool> <string>com.apple.InterfaceBuilder.IBCocoaTouchPlugin</string> </object> <object class="NSMutableDictionary" key="IBDocument.Metadata"> <bool key="EncodedWithXMLCoder">YES</bool> <object class="NSArray" key="dict.sortedKeys"> <bool key="EncodedWithXMLCoder">YES</bool> </object> <object class="NSMutableArray" key="dict.values"> <bool key="EncodedWithXMLCoder">YES</bool> </object> 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2023-12-11T01:27:04.234600

https://example.com/article/9094

Washington Capitals forward Tom Wilson was injured Tuesday night when he was sent to the ice on a late, crushing hit by the Vegas Golden Knights' Ryan Reeves. Briefly Thursday, a photo of that incident, signed by Reaves, appeared on the website of the Las Vegas-based memorabilia dealer Inscriptagraphs. The item later was taken down on the website and on eBay. A screen grab of the 16x20 photo sent to the Capitals blog Russian Machine Never Breaks showed Reaves' signature and the inscription: "He ran into a lion in the jungle." "The photos were not distributed and they have been destroyed," Golden Knights spokesman Eric Tosi told USA TODAY Sports by email. According to the blog, a caption touting the photo read: "This photo is a must have photo for all VGK fans as it is from when Ryan laid out Washington Capitals forward Tom Wilson on December 4, 2018! In addition, Ryan hand inscribed this photo “he ran into a lion in the jungle”: which is the quote he said after the game about the incident in which Ryan was ejected out of the game for!" The Athletic reported that Reaves did sign the photos and later called Inscriptagraphs to have them destroyed when he realized it was in bad taste. Ryan Reaves says he did sign the pictures of his hit on Tom Wilson. He later realized it was in bad taste, so he called the memorabilia store back and told them to destroy them. None of the photos were sold. #VegasBorn⁠ ⁠ Wilson's helmet popped off and he fell face first on the ice after the hit. Reaves received an interference major and a game misconduct on the play, but didn't get any further discipline from the league. Wilson, in his 11th game back from a 14-game suspension (his fourth suspension in the past two seasons) for a preseason head hit, was wobbly as he left the game, didn't return and missed Thursday's game with a concussion.

2024-03-07T01:27:04.234600

https://example.com/article/7608

Tubulin genes and malformations of cortical development. A large number of genes encoding for tubulin proteins are expressed in the developing brain. Each is subject to specific spatial and temporal expression patterns. However, most are highly expressed in post-mitotic neurons during stages of neuronal migration and differentiation. The major tubulin subclasses (alpha- and beta-tubulin) share high sequence and structural homology. These globular proteins form heterodimers and subsequently co-assemble into microtubules. Microtubules are dynamic, cytoskeletal polymers which play key roles in cellular processes crucial for cortical development, including neuronal proliferation, migration and cortical laminar organisation. Mutations in seven genes encoding alpha-tubulin (TUBA1A), beta-tubulin (TUBB2A, TUBB2B, TUBB3, TUBB4A, TUBB) and gamma-tubulin (TUBG1) isoforms have been associated with a wide and overlapping range of brain malformations or "Tubulinopathies". The majority of cortical phenotypes include lissencephaly, polymicrogyria, microlissencephaly and simplified gyration. Well-known hallmarks of the tubulinopathies include dysmorphism of the basal ganglia (fusion of the caudate nucleus and putamen with absence of the anterior limb of the internal capsule), midline commissural structures hypoplasia and/or agenesis (anterior commissure, corpus callosum and fornix), hypoplasia of the oculomotor and optic nerves, cerebellar hypoplasia or dysplasia and dysmorphism of the hind-brain structures. The cortical and extra-cortical brain phenotypes observed are largely dependent on the specific tubulin gene affected. In the present review, all the published data on tubulin family gene mutations and the associated cortical phenotypes are summarized. In addition, the most typical neuroimaging patterns of malformations of cortical development associated with tubulin gene mutations detected on the basis of our own experience are described.

2023-10-26T01:27:04.234600

https://example.com/article/8918

What’s the difference between a wine cougar and an anna nicole smith? Ch. Beaumont 1995 One of my favourite winebloggers are the BrixChix out in my sunny California. I was reading a post of their’s the other day about a discussion regarding whether wines should be drunk young or not. Liza, one of the BrixChix likes her wines young and refers to herself as a “wine cougar”. I’m sure you’ve all heard of the term “cougar” used to describe older women who prefer younger men. Well, Liza likes her wines young, the younger the better as far as she’s concerned. Although, she’s no cradle robber! I, on the other hand, would probably call myself, what Liza refers to as, an ‘Anna Nicole Smith’. The older the better as far as I’m concerned. Luckily, Borough Wines , where I work, agrees with me and they have managed to get their hands on some lovely clarets from the mid 1990’s. Now, many of you may like your wines young but good claret always needs time to mature, much like one half of the human race. The majority are from the Haut Medoc but they also had a few St. Emilions in the mix. My favourite was the 1995 Ch. Beaumont. A cru bourgeois from the Haut Medoc, the chateau has been around since 1824 and they produce the quintessential claret. The ’95 is a blend of cabernet sauvignon, merlot and cabernet franc and spends between 12 – 18 months in oak. When I opened this one, red licorice and lovely lifted blackberry fruit notes on the nose, followed by tobacco and leather jabs. I had this wine with a dinner of steak and chips and it was delicious. After decanting, fabulous blackcurrant flavours came to the fore with plenty of soft silky tannins. The wine finished off with a long black plum finish. Delicious. I could have savoured this one all night long but this oldie would only last so long and before I knew it, the bottle had given up the ghost. Oh well, on to the next, as Anna Nicole might have said…. The Chateau Beaumont 1995 is a steal at £30 in the market stall at Borough Wines in Borough Market. Share this: Like this: 2 Comments Denise, this is very funny. And Liza is great, one of my fav WBC peeps. I never thought I’d say it, but I, too am in the Anna Nicole Smith camp. That did feel really, really wrong to say. Enjoy the old ones, Diane Thanks, Diane but I do have to give all props to the BrixChix. When I saw “wine cougar” I just knew I had to use it somewhere and Twitter just didn’t seem worthy of it (at least not on it’s own!) Maybe Anna Nicole was really onto something, just took us a while to sort it out! And long live the wine cougars!

2023-08-16T01:27:04.234600

https://example.com/article/6954

Distribution, molecular characterization of pituitary adenylate cyclase-activating polypeptide and its precursor encoding messenger RNA in human and rat tissues. The distribution of a novel neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), was studied in the brain of the rat and man and a variety of other rat tissues using Northern blot hybridization and two radioimmunoassays for PACAP 1-38 and PACAP 1-27. The assay, using PACAP 1-38 as standard and an antibody to PACAP 21-38 and radiolabelled tracer, revealed immunoreactive PACAP in all brain regions examined, with the highest concentrations in the rat being in the hypothalamus, nucleus accumbens and substantia nigra (380 +/- 34, 310 +/- 37 and 346 +/- 30 pmol/g wet tissue, means +/- S.E.M., n = 5 respectively), whilst in man the highest concentrations were found in the pituitary gland (15.8 +/- 4.7 pmol/g). Immunoreactive PACAP 1-38 was also detected in the rat gastrointestinal tract, adrenal gland and testis. The assay using PACAP 1-27 as standard and label and an antibody to PACAP 1-27 detected immunoreactive PACAP only in the rat hypothalamus (12.6 +/- 1.8 pmol/g wet tissue, n = 5). PACAP mRNA of approximately 2.7 kb in size was detectable in all brain regions of both rat and man, and its distribution paralleled that of the immunoreactive peptide. Gel permeation chromatography of different regions of human and rat hypothalamus, and also rat spinal cord and small intestine, showed a broad immunoreactive peak corresponding to PACAP 1-38. Fast protein liquid chromatography (FPLC) resolved this peak into two immunoreactive peaks, the majority eluting in the position of synthetic PACAP 1-38.(ABSTRACT TRUNCATED AT 250 WORDS)

2024-01-29T01:27:04.234600

https://example.com/article/1644

<html> <head> <title>DarkBASIC Professional Help File</title> </head> <body background="..\..\gfx\dbpro_bg.jpg"> <!-- Page Header --> <center><table width="340" border="0" cellpadding="0" cellspacing="0"> <tr> <td><img src="..\..\gfx\dbph_head_1.jpg" width="102" height="51"></td> <td><a href="..\..\main.htm"><img src="..\..\gfx\dbph_head_2.jpg" width="47" height="51" border="0"></a></td> <td><a href="..\..\commands.htm"><img src="..\..\gfx\dbph_head_3.jpg" width="50" height="51" border="0"></a></td> <td><a href="..\..\examples.htm"><img src="..\..\gfx\dbph_head_4.jpg" width="47" height="51" border="0"></a></td> <td><a href="..\..\documents.htm"><img src="..\..\gfx\dbph_head_5.jpg" width="46" height="51" border="0"></a></td> <td><a href="..\..\index.htm"><img src="..\..\gfx\dbph_head_6.jpg" width="56" height="51" border="0"></a></td> </tr> </table></center> <font face="Verdana"> <table width="100%" border="0" cellpadding="0" cellspacing="0"> <tr><td> <!-- Function Head --> <font face="Verdana" size="5"> <b> SPRITE COLLISION </b> <font face="Verdana" size="2"> <p> This command will return a one if the specified sprite is overlapping the target sprite specified. </p> </font> <!-- Synopsis --> <table width="590" cellpadding="3"> <tr><td bgcolor="#0d4283"><font color="#ffffff" size="3"><b>&nbsp; Syntax </b></font></td></tr> </table> <font face="Verdana" size="2"> <pre> Return Integer=SPRITE COLLISION(Sprite Number, Target Sprite Number) </pre> </font> <!-- Parameters --> <table width="590" cellpadding="3"> <tr><td bgcolor="#0d4283"><font color="#ffffff" size="3"><b>&nbsp; Parameters </b></font></td></tr> </table> <font face="Verdana" size="2"> <pre> Sprite Number </pre> <blockquote> Integer <br> The sprite number </blockquote> <pre> Target Sprite Number </pre> <blockquote> Integer <br> The target sprite number, and if a target sprite has not been specified and a value of zero has been used, this command will return the sprite number of any sprite overlapping it </blockquote> </font> <BR> <!-- Returns --> <table width="590" cellpadding="3"> <tr><td bgcolor="#0d4283"><font color="#ffffff" size="3"><b>&nbsp; Returns </b></font></td></tr> </table> <font face="Verdana" size="2"> <p> This value is an integer number such as 1. </p> </font> <!-- Description --> <table width="590" cellpadding="3"> <tr><td bgcolor="#0d4283"><font color="#ffffff" size="3"><b>&nbsp; Description </b></font></td></tr> </table> <font face="Verdana" size="2"> <p> If a target sprite has not been specified and a value of zero has been used, this command will return the sprite number of any sprite overlapping it. The parameters should be specified using integer values. </p> </font> <!-- Examples --> <table width="590" cellpadding="3"> <tr><td bgcolor="#0d4283"><font color="#ffffff" size="3"><b>&nbsp; Example Code </b></font></td></tr> </table> <font face="Verdana" size="2"> <pre> cls<BR> load image "man.bmp",1<BR> sprite 1,100,100,1<BR> sprite 2,100,110,1<BR> wait 1000*8<BR> do<BR> paste sprite 1,mousex(),mousey()<BR> num=sprite collision(1,0)<BR> if num>0<BR> cls<BR> cls<BR> print "we have it sprite number "+str$(num)cls<BR> endif<BR> cls<BR> loop<BR> end<BR> </pre> </font> <!-- See Also --> <table width="590" cellpadding="3"> <tr><td bgcolor="#0d4283"><font color="#ffffff" size="3"><b>&nbsp; See also </b></font></td></tr> </table> <font face="Verdana" size="2"> <p> <a href="..\sprite.htm">SPRITE Commands Menu<BR> </a> <a href="..\..\index.htm">Index</a><BR> </p> </font> <BR> <!-- Function Footer --> </font> </td></tr></table> <br> <!-- Page Footer --> <table width="100%" border="0" cellpadding="0" cellspacing="0"> <tr> <td align="center"><img src="..\..\gfx\dbph_foot_1.jpg" width="340" height="38"></td> </tr> </table> </body> </html>

2023-10-31T01:27:04.234600

https://example.com/article/2798

Aistear – we need your unwanted toys Junior and Senior Infants have been developing their social and language skills through aistear for the last 4 years. Aistear shows how important play is for your child’s learning and development and we have seen the benefits of it since its introduction in the infant classes. Through aistear we cover topics such as those listed on the boxes in the picture included in this news feed. We would be extremely grateful if you would kindly send in any unwanted toys, books, jigsaws, small world figurine and cars that may accompany these themes, all donations are welcome anytime of the year. We thank all parents who have in the past donated, these resources have been an invaluable source to the children’s learning.

2024-04-12T01:27:04.234600

https://example.com/article/9615

Broncos cinderella NBC bid ends with third place finish Wednesday Aug 15, 2012 at 1:00 PMAug 15, 2012 at 1:49 PM Midnight finally struck for the Cinderella team in the NBC World Series on Friday night.El Dorado dropped a 2-1 decision to defending champion Santa Barbara in the semifinals.The Broncos, who finished fifth in the Jayhawk League and weren’t given much of a chance in the NBC, wound up tied for third place with the Hays Larks. Midnight finally struck for the Cinderella team in the NBC World Series on Friday night.El Dorado dropped a 2-1 decision to defending champion Santa Barbara in the semifinals.The Broncos, who finished fifth in the Jayhawk League and weren’t given much of a chance in the NBC, wound up tied for third place with the Hays Larks. Hays lost in the semifinals to the Seattle Studs 6-2. Earlier in the tournament, El Dorado defeated Seattle 1-0.Tied 1-1, the Broncos loaded the bases with no outs in the sixth. Chuck Duarte opened with a double. Daniel Baptista and Tyler Coughenour drew walks. Chris Godinez grounded to third and Duarte was forced at home, leaving the bases loaded.David Harris struck out, and Tyler Buchanan grounded out to end the inning.Trailing 1-0, El Dorado tied it in the fifth. Buchanan walked, was sacrificed to second by Anthony Perez. Buchanan moved to third on a wild pitch and scored on Arturo Corona’s sacrifice fly to left.Brandon Faulkner took the loss for El Dorado, going eight innings and striking out seven.Perez was chosen the Most Inspritional Player. While at Tabor College, he broke a thumb but still returned to play. Then, he broke his collarbone, and doctors said he would be out for six months. He returned to play for the Broncos in July and played the remainder of the season.The Broncos finished with a 29-24 record.NBC World Series Awards#14 Josh Stone, Best Pitcher#41 Daniel Baptista, Best 1st Baseman#27 Pat Hon, Coach of the Tournament

2024-03-25T01:27:04.234600

https://example.com/article/4642

Q: Dynamic Programming Tiles http://www.spoj.pl/problems/GNY07H/ In this question we have to find number of ways to arrange 2X1 tiles in 4Xw (w >=1) rectangle ? I have tried this question and has given much time to it but was not able to come up with any solution . how to approach for these kinds of problem. meaning how to make dp recurrence for them. ? A: You can build the 4xW rectangle row-by-row. When you build the next row the previous row can be in 6 different states: XXXX (1 - filled) XX-- (2) -XX- (3) --XX (4) X--X (5) ---- (6 - empty) For example if the previous row is (5), you have to put two vertical dominos, and then the next row is going to be (3): XXXX XABX -AB- Let X(W,q) denote the possible combinations of a 4xW rectangle where the last row is in state q and the rest is completely filled. If you know X(W-1,q) for all the 6 q states you can easily calculate X(W,q). You know the initial states X(1,q) (q=1..6 -> 1, 1, 1, 1, 1, invalid). So you can increase W and get these numbers for each W. The final result is X(W,1) (last row filled). A: I too am a beginner at this variation of Dynamic programming, but this link mentions http://apps.topcoder.com/forums/;jsessionid=A5053396424C9F9BBB9337ECAC9C6C17?module=Thread&threadID=770579&start=0&mc=2#1643035 that you need to apply "Dynamic programming with profiles", and that link also points to a tutorial http://apps.topcoder.com/forums/?module=Thread&threadID=697369&start=0&mc=19 specifically, "layer count+ layer profile". From the above link: "This is the toughest type of DP state domain. It is usually used in tiling or covering problems on special graphs. The classic examples are: calculate number of ways to tile the rectangular board with dominoes (certain cells cannot be used); or put as many chess figures on the chessboard as you can so that they do not hit each other (again, some cells may be restricted)." Other more approachable tutorials on this technique are available at: http://sk765.blogspot.in/2012/02/dynamic-programming-with-profile.html http://sk765.blogspot.in/2012/02/dynamic-programming-with-profile_13.html http://sk765.blogspot.in/2012/02/dynamic-programming-with-profile_7469.html http://sk765.blogspot.in/2012/02/dynamic-programming-with-profile_6894.html I'm working my way through them as well. This isn't an answer to the particular question you asked, but more of a general technique that people follow when solving this class of problems.

2024-02-04T01:27:04.234600

https://example.com/article/1261

Fully qualified electrician with experience in domestic properties and commercial environments. Specialising in all aspects of electrical installation and maintenance including fuseboards installations, new sockets, downlights and problem solving. Latest homeowner review Reviewed by R on 19/1/2019 David was very friendly and helpful. A proper tradesman: honest, efficient, professional and affordable. I absolutely recommend his services. Great job. Thanks David Here at Grovebell Electrical we specialize in the reactive maintenance of domestic and commercial electrical installations. With qualified Electricians of 10+ years we guarantee that there is no job to complex for our engineers. Although we focus on the maintenance of existing installations, we are also able to provide new installations across both sectors with the piece of mind of a 12-month guarantee on all work undertaken. We have vast experience of high value domestic installation. From multi-million pound apartments in Kensington and Chelsea to the bespoke high spec town houses of West Ealing. Where we had the enormous task of installing a Chandelier worth 15k. (see cover photo) I am new to this platform hence no review etc. I am trained to industry standards; +City & Guilds Electrical Installation +18th Edition wiring regulations + Joint industry Board (JIB) Graded +Electrical contractors association (ECA) +Scotland Electrical Trade association (Select) + Public liability insured up to 1million GBP All works carried out by myself are finished off to a high standard to ensure customer satisfaction! Latest homeowner review Reviewed by Christian on 1/12/2018 Jason did a great job installing outdoor up-lights in our garden. He was reliable, punctual and delivered the project in time and in scope on budget. I would hire Jason again and can highly recommend him. About Folarinmaintains: We are a family run company that specialise in electrical interior, exterior, handyman and general maintenance. We offer Same Day Service and guarantee our work for 12 Months. Most jobs fixed within a few hours. Experience/Quality/Peace of mind: We install/remove and cover all aspects of electrical work from as small as changing a light bulb, emergency callouts to completing an entire rewire and this is for both Landlords as well as private home owners, domestic and commercial properties. We take pride in our work and always complete to the highest standard and that is why we offer a 12 months Guarantee! Qualifications: City and guilds electrical installation levels 1-3 17th edition in electrical installation BS7671 Extensive years of experience. WHAT THE CUSTOMER WANTS IS WHAT WE WANT TO DELIVER. If you are looking for a reliable and professional electrician in London, I can help. From single plug socket to installing new consumer unit in your property, I offer comprehensive range of electrical services, I also specialise in LED lighting. see pic. Latest homeowner review Reviewed by Haikal on 11/1/2019 Great communication. Unable to proceed with the job due to personal circumstances. I am new to rated people but I have over 17 years experience in the electrical repair and installation service . Latest homeowner review Reviewed by Michael on 15/12/2018 Would recommend Sunkanmi anytime. He agreed and arrived at appointment within short notice, fitted my alarm and checked fault with my outdoor security light. He also gave some recommendations for outdoor lights. His charges not too expensive too ...well done! We are NICEIC Approved Electricians with 17 years of experience; and are Certified for Domestic, Commercial & Industrial work. We are also an Approved contractor for the Able Group; and Certify & Maintain many Schools and Churches. References available! Qualified Electrician with 20+ years' experience in electrical installation (part and complete), kitchen rewiring, fire alarm, fuse board replacement. All work meet BS7671 standard and fully insured. I can guarantee high quality work to suit all budgets. Latest homeowner review Reviewed by Shah on 8/1/2019 Approached the job in a professional manner and completed it with quiet efficiency.

2023-08-26T01:27:04.234600

https://example.com/article/7644

*4 and give o. -34 Rearrange (161*b + 751 - 751)*(-1 - 1 - 3) to v*b + i and give v. -805 Rearrange 1 - 2*o**2 - 4*o**2 + 3*o - 30*o**3 + 7*o**2 + o**2 - o**2 to c*o + s + b*o**2 + a*o**3 and give a. -30 Express -280 + 2281*h - 1142*h - 65 - 1142*h in the form a*h + c and give c. -345 Rearrange (-1492*j**2 + 605*j - 20*j + 1489*j**2)*(-1 + 4 - 5) to k + o*j**2 + q*j and give q. -1170 Express -582828*i**2 + 582821*i**2 + 12*i + 2*i in the form l*i**2 + g + x*i and give l. -7 Rearrange (-7*y - 2*y + 28*y)*(-5 + 0 + 4) - 3 - 17 - 15 + 33 + y to w*y + c and give c. -2 Rearrange -7634*a - 3387*a - 2668*a - 7199*a - 7419*a to the form s + v*a and give v. -28307 Express -152*p - 1223*p + 1906*p + 7772*p as v*p + o and give v. 8303 Rearrange (1 - 1 + 21)*(-784 + 784 - 347*z) to the form s*z + d and give s. -7287 Express -991*b + 55*b - 744*b - 452*b as m + u*b and give u. -2132 Express (61*g + 90*g + 3*g)*(-62 + 62 + 44*g) + g**2 + 2*g**2 - 2*g**2 in the form l*g + r + b*g**2 and give b. 6777 Express (-45 - 14 + 13)*(-3 - 1 + 1)*(1 - 1 - 18*y)*(-2*y + 0*y + 0*y) as w + b*y**2 + x*y and give b. 4968 Rearrange 322*i - 137*i + 485*i**2 - 480*i**2 to the form q*i**2 + n*i + f and give q. 5 Express (-g + 5*g + 1 - 2*g)*(10*g + 12009 - 5960 - 5559) in the form b + u*g + v*g**2 and give u. 990 Express -21796 + 21794 + h - 46*h**2 - 5*h**4 + 6*h**3 + 47*h**2 in the form p*h**4 + b*h**3 + a*h + d + j*h**2 and give d. -2 Rearrange -24*n**2 + 111*n**2 + 168 - 99*n**2 to d*n**2 + g + h*n and give d. -12 Rearrange (8 + 172 + 14 - o + (-3 + 2 - 1)*(-1 + 1 + 2*o))*(0*o + 6*o - 2*o)*(0 + 0 + 3) to p*o**2 + h*o + v and give p. -60 Rearrange 54976 - 27487 - 27489 - 9548*b**2 to the form f*b**2 + k*b + l and give f. -9548 Express -2938*m - 6407*m + 1359*m - 716*m in the form v + c*m and give c. -8702 Rearrange -i - i**4 + 36 - i**4 + 92 + 76*i**3 + 3*i**2 + 32 - 74*i**3 to v*i**2 + f*i**3 + j + t*i + r*i**4 and give t. -1 Express -1165*m + 3744*m + 3360*m as p*m + r and give p. 5939 Rearrange (5 - 4 - 2 + 5*f)*(f**3 - f**3 + f**3)*(-25 - 12 + 5)*(-3 + 3 + 2)*(-2 + 5 - 1) to z*f**4 + g*f + b*f**3 + p + t*f**2 and give t. 0 Express 440*x**2 - 11210*x + 11210*x in the form q*x + h + d*x**2 and give d. 440 Express -2*p - 4*p - 2*p - 3*p - 3*p + 4*p + (2 - 6 + 2)*(20*p + 69 - 69) + (0 - 1 - 1)*(0 + 0 + 8*p) + p + 1 - 1 as t + v*p and give v. -65 Rearrange (-28*m + 4*m + 0*m)*(m - 6*m + 3*m) + 29*m**2 - 66*m - 2 + 66*m to a + p*m + z*m**2 and give z. 77 Express (-18 + 18 + 12*d)*(1 - 1 - 1 - d) + (4*d - 2*d + 0*d)*(2*d - 6*d + 2*d) + 17*d**2 - 118 + 118 as g + m*d + v*d**2 and give m. -12 Express 645*t - 1907*t + 635*t - 8 + 197*t**3 + 627*t + 2*t**2 in the form s + g*t**3 + i*t**2 + z*t and give i. 2 Express (-4 - 4 + 3)*(s + 0 + 0) + (-95 - 11 + 14)*(-4*s + 5*s + 10*s) in the form x + t*s and give t. -1017 Express (11*o**2 - 3*o**2 - 28*o**2 + (4*o + 0*o - 3*o)*(4 - 4 - 2*o))*(-4449 + 4449 - 112*o) as k*o**3 + c + s*o**2 + r*o and give r. 0 Rearrange (3*l - 3*l + 2*l)*(-518068 - 1435*l + 259032 + 259038) to the form v*l**2 + z*l + f and give v. -2870 Rearrange -2*q**4 - 75154 + 75145 - 8*q + q**3 - 7*q**2 - 6*q + q**3 to the form p*q + z + x*q**2 + o*q**4 + u*q**3 and give z. -9 Rearrange -3*y + 3*y + y + (-1 - 1 + 0)*(0 + 0 - 2*y) - y + 1 - 1 - 9*y - 35*y - 19*y + (-y + 4*y - y)*(2 - 2 + 3) to q + g*y and give g. -53 Rearrange 23000*i**2 + 617*i**3 - 45996*i**2 - 2*i**4 - 1 + 22996*i**2 + 3*i to the form v*i + m + s*i**3 + c*i**2 + r*i**4 and give s. 617 Rearrange (2*b + 0 + 0)*(334*b - 610*b - 96*b) + (4*b - 5*b + 3*b)*(8*b + 0*b + 6*b) to u*b + o*b**2 + w and give o. -716 Rearrange -10*j**3 - 4 - 2*j**2 + 922*j**4 + 4 - 460*j**4 - 4 - 439*j**4 to k*j**3 + b*j + f*j**2 + i*j**4 + n and give n. -4 Express -2*b**4 + 4*b**4 - 5*b**4 + (47*b**2 - 47*b**2 + 14*b**3)*(3*b - 6*b - 9*b) as z*b**2 + x + i*b + s*b**3 + h*b**4 and give h. -171 Rearrange (-40825 - 40805 + o**3 + 10*o + 81609)*(0 + 2*o + 0) to x*o**4 + g*o**2 + l + s*o**3 + w*o and give l. 0 Rearrange -1259*c + 3709*c + 2431*c - 2060*c + 3441*c to b + n*c and give n. 6262 Express 78*a - 2 - 112*a**3 - 75*a - 2*a**4 + 0*a**2 + 0*a**2 + 109*a**3 as t*a**2 + m*a**3 + v*a**4 + g + c*a and give m. -3 Express 10419*x + 74080 - 74080 as w + c*x and give w. 0 Express (-4894 + 1381 + 1882 - 1389 - 2377 - 7178)*(v - 2*v - 2*v) in the form m*v + z and give m. 37725 Express -232*c - 217*c - 213*c - 498 - 172 + 658*c as l*c + v and give l. -4 Express -4*f**2 + 24*f**3 - 59 - 29 - 6*f**3 + 5*f**3 + 89 - 4*f as s*f + t*f**3 + h + o*f**2 and give h. 1 Express (-2*t + t + 0*t + (9*t - 2*t - t)*(1 - 2 - 1))*(-113*t + 4*t + 14*t) as j + c*t + w*t**2 and give w. 1235 Rearrange (148 - 445 - 9911*j + 148 + 150)*(-3 + 3 - 1)*(1 + 1 - 3) to the form o + g*j and give o. 1 Rearrange 501 + 588*r**2 - 588*r**2 + 11*r**3 to the form u + x*r + t*r**3 + a*r**2 and give t. 11 Rearrange 118016*t - 118016*t - 1235*t**2 to q*t + x*t**2 + c and give x. -1235 Express -112 - 2610 - 2*c - 292 + 174 - 867 as m*c + a and give m. -2 Rearrange (-2*a + 6*a - 2*a)*(-7 + 7 - 13*a**2)*(-171*a - 499*a + 268*a) to the form p*a**2 + b*a**3 + u + o*a**4 + d*a and give o. 10452 Express 167 + 164 - 494 + 163 + 30700*g as k + x*g and give x. 30700 Express -29*a - 37*a**2 - 17*a - 2 + 43*a + 5 as g*a + w + q*a**2 and give q. -37 Rearrange 77 + 24*r + 21*r - 74*r + 29*r + 24*r to the form f + o*r and give o. 24 Express 68902 - 68902 - 30525*g + (1 - 4 + 1)*(-3*g - 2*g + 3*g) + 0*g + g + g in the form t*g + z and give t. -30519 Rearrange (-37783 + 37853 - 2*v + 3*v)*(0*v**3 + v**3 - 3*v**3) to the form y*v**3 + f*v**4 + x*v**2 + g*v + c and give y. -140 Express -182 - 181 - 178 + 502 + 116*f as a + w*f and give a. -39 Rearrange 4*t**4 + 154*t + 16*t**2 - 42*t - 39*t - 37*t - 37*t - 1 + t**3 to k*t**2 + q*t**3 + w*t**4 + o + l*t and give o. -1 Rearrange (-20*n**2 + 11*n**2 + 0*n**2)*(4 - 3*n**2 - 4) + (3 - 3 - n**3)*(n + n + n)*(-21 + 4 + 5) to g*n + j*n**2 + d*n**4 + m + i*n**3 and give g. 0 Rearrange 31*w - 33 - 27 - 49 + 25*w + 152 to the form u*w + s and give s. 43 Express 61*a - 258*a + 66*a - 75 + 61*a + 59*a in the form m + s*a and give s. -11 Rearrange 19*g + 6*g - 66 + 225 - 26*g to the form h + f*g and give h. 159 Express 3*h - 2*h**3 - 13 + 5*h**2 + 2*h + 69 - 3*h - 3*h in the form x + w*h**3 + o*h + r*h**2 and give x. 56 Express -604 + 11*x - 1423 - 8*x + 2240 - 1240 as k*x + c and give k. 3 Express 38*i - 42*i**3 - 38*i + (-135*i**2 - 1182 + 1182)*(-2 + 2 - 3*i) in the form y*i + z + b*i**2 + f*i**3 and give f. 363 Express 5*d**4 - 30 + 3*d**4 - 2*d**4 + 187*d**3 + 2*d**2 - 2*d**4 - 188*d**3 as v*d**3 + h + b*d + x*d**2 + j*d**4 and give j. 4 Express 435 + 500 - 165*r - 941 in the form q*r + x and give q. -165 Rearrange -6681*k**2 - 2188*k**2 - 765*k**2 to s + r*k**2 + t*k and give r. -9634 Express (-1134*z - 650*z + 344*z)*(2*z**2 + z - z) + 54 + 6*z**3 - 54 as p*z + o*z**3 + n*z**2 + y and give o. -2874 Express -5518 - 29146*o + 5518 - 5202*o in the form f + b*o and give b. -34348 Rearrange -3 + 163847*t - 81765*t - 81368*t to the form c + x*t and give x. 714 Express -407*q + 68*q**4 - 10*q**4 + q**3 + 409*q in the form x*q**4 + d*q**3 + i*q + j + t*q**2 and give x. 58 Express -2664*v - 2337*v + 4*v**3 + 8*v**3 + 5*v**3 - 19*v**3 in the form a + w*v + r*v**3 + m*v**2 and give w. -5001 Rearrange 1249*n**3 - 2477*n**3 + 655*n**2 - 2*n + 1230*n**3 to the form j*n**2 + r*n + p*n**3 + y and give j. 655 Express 18733 - 18733 - 27396*w + (2 + 3 - 4)*(w + 2*w - 5*w) as i*w + t and give i. -27398 Express (32*o**2 + 108 - 108)*((-o + 2*o - 2*o)*(-3*o + 5*o - o) + (0*o - 5*o - 2*o)*(2 - 2 - o)) in the form v*o**2 + k + i*o + p*o**3 + m*o**4 and give p. 0 Rearrange -31*m**4 - 35*m**4 - 22*m**4 - 38*m**4 + m + 145*m**4 + 24*m**2 to the form u*m**2 + v*m + p + t*m**4 + h*m**3 and give t. 19 Rearrange -33*c - 126 + 64*c - 731 - 30*c - 857 to b + t*c and give b. -1714 Rearrange 2 + 4320*v - 8632*v + 1 + 4317*v + 47*v**2 to c*v + g + q*v**2 and give g. 3 Rearrange (-18 - 7*n + 18)*(0 - n + 0) + 78 + 8*n**2 - 150 + 84 to p*n + z*n**2 + f and give f. 12 Rearrange (2*g + 2*g + 3*g)*(-54 - 33 - 26 + 15)*((2*g + 2*g - 2*g)*(-5*g + 0*g + 3*g) - 2*g**2 - g**2 + g**2) to h*g + w*

2023-09-10T01:27:04.234600

https://example.com/article/7990

Q: How do I check an MPMediaItem for MPMediaType of just audio? I expect I need to do a bitwise comparison but I am unclear on how that is done in Objective-C syntax. The enum definition of MPMediaType is below. What I need to do is ensure the MPMediaItem is not video at all because AVAssetReader is choking on video files despite filtering to MPMediaTypeAnyAudio with my media query. How can I ensure the MPMediaItem is one of the only audio types? enum { // audio MPMediaTypeMusic = 1 << 0, MPMediaTypePodcast = 1 << 1, MPMediaTypeAudioBook = 1 << 2, MPMediaTypeAudioITunesU = 1 << 3, // available in iOS 5.0 MPMediaTypeAnyAudio = 0x00ff, // video (available in iOS 5.0) MPMediaTypeMovie = 1 << 8, MPMediaTypeTVShow = 1 << 9, MPMediaTypeVideoPodcast = 1 << 10, MPMediaTypeMusicVideo = 1 << 11, MPMediaTypeVideoITunesU = 1 << 12, MPMediaTypeAnyVideo = 0xff00, MPMediaTypeAny = ~0 }; typedef NSInteger MPMediaType; A: To retrieve all the music tracks from the music library, try: MPMediaPropertyPredicate *predicate = [MPMediaPropertyPredicate predicateWithValue:[NSNumber numberWithInteger:MPMediaTypeMusic] forProperty:MPMediaItemPropertyMediaType]; MPMediaQuery *query = [[MPMediaQuery alloc] init]; [query addFilterPredicate:predicate]; NSArray *items = [query items]; To retrieve music, audio books and podcasts: MPMediaPropertyPredicate *predicate = [MPMediaPropertyPredicate predicateWithValue [NSNumber numberWithInteger:MPMediaTypeMusic | MPMediaTypePodcast | MPMediaTypeAudioBook] forProperty:MPMediaItemPropertyMediaType comparisonType:MPMediaPredicateComparisonContains]; A: I found that an MPMediaQuery predicate on MPMediaTypeAnyAudio was not enough. So I instead ran the following check on the media type and it is the best way to prevent video content from coming through. NSInteger mediaType = [[aMediaItem valueForProperty:MPMediaItemPropertyMediaType] intValue]; if (mediaType <= MPMediaTypeAnyAudio) { return TRUE; } I found the actual values from the enum of media types had these values which let me use this simple integer comparison. MPMediaTypeMusic: 1 MPMediaTypePodcast: 2 MPMediaTypeAudioBook: 4 MPMediaTypeAudioITunesU: 8 (iOS 5) MPMediaTypeAnyAudio: 255 MPMediaTypeMovie: 256 MPMediaTypeTVShow: 512 MPMediaTypeVideoPodcast: 1024 MPMediaTypeMusicVideo: 2048 MPMediaTypeVideoITunesU: 4096 MPMediaTypeAnyVideo: 65280

2023-10-08T01:27:04.234600

https://example.com/article/3710

Mayor voices support for LGBT athletes in ‘You Can Play’ video Mayor Hancock voiced his support for LGBT athletes in a "You Can Play" video, released on Feb. 11, 2014. Mayor voices support for LGBT athletes in ‘You Can Play’ video Mayor Hancock voiced his support for LGBT athletes in a "You Can Play" video, released on Feb. 11, 2014. DENVER — Denver mayor Michael B. Hancock announced the release of his “You Can Play” video Tuesday, which is intended as a message of support and encouragement for LGBT athletes across Colorado. Hancock is the first mayor in the U.S. to openly show his support for LGBT athletes, said a release from the city of Denver on Tuesday. “I know the importance of team work both in and away from the game,” Hancock said in the video. “Including our friends and accepting our differences is the right thing to do. Together, we are a better team. We can all play.” “Mayor Hancock is a great sports fan, and he sends an important message that teamwork extends beyond the field, court or rink, into classrooms and offices,” said Brian Kitts, You Can Play co-founder. “Acknowledging the contribution of everyone on a team, regardless of their background or orientation, is a key to building any successful team.” Other Colorado pro athletes participating in You Can Play initiatives are Denver Nuggets’ Kenneth Faried, Randy Foye and Quincy Miller, as well as players from the Colorado Rapids, Denver Cutthroats, Colorado Mammoth and Denver Outlaws, said Tuesday’s release.

2023-09-21T01:27:04.234600

https://example.com/article/7934

Tip: When pouring the 2nd flavor, don’t pour in the same spot, move it around when pouring. If 1st layer is still soft after an hour, refrigerate a bit longer until Jello has firmed. If 1st layer is too soft and you pour the 2nd layer, it’ll blend in with the 1st layer. If 1st layer is too firm, layer may separate when eating.

2024-05-12T01:27:04.234600

https://example.com/article/9162

Q: ng-click event gets bind to child li in angular js Hey I am binding menuIconClick($event) function on li using ng-click directive.But gets bind to child li also. Code like as follow %div.sideNavBar %ul.navBar %li.icons-briefcase-static{'ng-click'=>"menuIconClick($event)"} // binding here only %ul.subMenu %li All sites // but gets call here also %li{'ng-repeat'=>"site in sites"} {{site.name}} %li.icons-users-disabled %div.lock.icons-lock-disabled The template is in HAML. I didn't got why? Any help appreciated A: Try putting the icon & icon click event as a separate element, not on the parent element. DOM events bubble up the hierarchy, so if the parent element has an ng-click handler, then clicking any child element will also trigger that parent click handler unless you stop the event propagation. You could either stop the event propagation, similar to: AngularJS ng-click stopPropagation or change your DOM structure so that the briefcase icon is not a parent of the submenu: %div.sideNavBar %ul.navBar %li %a.icons-briefcase-static{'ng-click'=>"menuIconClick($event)"} // no longer a parent %ul.subMenu %li All sites // click here won't bubble up to ng-click %li{'ng-repeat'=>"site in sites"} {{site.name}} %li.icons-users-disabled %div.lock.icons-lock-disabled

2023-09-09T01:27:04.234600

https://example.com/article/7986

Staff Nurse Recruitment In Gujarat Health And Family Department Information: Gujarat Health and Family department has announced notification of latest recruitment as Gujarat Health and Family department recruitment 2014 and inviting online application on official site at ojas1.guj.nic.in and also on ojas2.guj.nic.in as well for total 2568 staff nurse vacancies. This department generally looks after the all government medical hospitals and institutes and when required it recruits candidates. More Detailed Information Will Be Given Below And Also Check In Official Notification.

2023-08-26T01:27:04.234600

https://example.com/article/9997

package parser import ( "fmt" "regexp" "sort" "strconv" "strings" "github.com/smartystreets/goconvey/web/server/contract" ) var ( testNamePattern = regexp.MustCompile("^=== RUN:? +(.+)$") ) func ParsePackageResults(result *contract.PackageResult, rawOutput string) { newOutputParser(result, rawOutput).parse() } type outputParser struct { raw string lines []string result *contract.PackageResult tests []*contract.TestResult // place holders for loops line string test *contract.TestResult testMap map[string]*contract.TestResult } func newOutputParser(result *contract.PackageResult, rawOutput string) *outputParser { self := new(outputParser) self.raw = strings.TrimSpace(rawOutput) self.lines = strings.Split(self.raw, "\n") self.result = result self.tests = []*contract.TestResult{} self.testMap = make(map[string]*contract.TestResult) return self } func (self *outputParser) parse() { self.separateTestFunctionsAndMetadata() self.parseEachTestFunction() } func (self *outputParser) separateTestFunctionsAndMetadata() { for _, self.line = range self.lines { if self.processNonTestOutput() { break } self.processTestOutput() } } func (self *outputParser) processNonTestOutput() bool { if noGoFiles(self.line) { self.recordFinalOutcome(contract.NoGoFiles) } else if buildFailed(self.line) { self.recordFinalOutcome(contract.BuildFailure) } else if noTestFiles(self.line) { self.recordFinalOutcome(contract.NoTestFiles) } else if noTestFunctions(self.line) { self.recordFinalOutcome(contract.NoTestFunctions) } else { return false } return true } func (self *outputParser) recordFinalOutcome(outcome string) { self.result.Outcome = outcome self.result.BuildOutput = strings.Join(self.lines, "\n") } func (self *outputParser) processTestOutput() { if isNewTest(self.line) { self.registerTestFunction() } else if isTestResult(self.line) { self.recordTestMetadata() } else if isPackageReport(self.line) { self.recordPackageMetadata() } else { self.saveLineForParsingLater() } } func (self *outputParser) registerTestFunction() { testName := testNamePattern.FindStringSubmatch(self.line)[1] self.test = contract.NewTestResult(testName) self.tests = append(self.tests, self.test) self.testMap[self.test.TestName] = self.test } func (self *outputParser) recordTestMetadata() { testName := strings.Split(self.line, " ")[2] if test, ok := self.testMap[testName]; ok { self.test = test self.test.Passed = !strings.HasPrefix(self.line, "--- FAIL: ") self.test.Skipped = strings.HasPrefix(self.line, "--- SKIP: ") self.test.Elapsed = parseTestFunctionDuration(self.line) } } func (self *outputParser) recordPackageMetadata() { if packageFailed(self.line) { self.recordTestingOutcome(contract.Failed) } else if packagePassed(self.line) { self.recordTestingOutcome(contract.Passed) } else if isCoverageSummary(self.line) { self.recordCoverageSummary(self.line) } } func (self *outputParser) recordTestingOutcome(outcome string) { self.result.Outcome = outcome fields := strings.Split(self.line, "\t") self.result.PackageName = strings.TrimSpace(fields[1]) self.result.Elapsed = parseDurationInSeconds(fields[2], 3) } func (self *outputParser) recordCoverageSummary(summary string) { start := len("coverage: ") end := strings.Index(summary, "%") value := summary[start:end] parsed, err := strconv.ParseFloat(value, 64) if err != nil { self.result.Coverage = -1 } else { self.result.Coverage = parsed } } func (self *outputParser) saveLineForParsingLater() { self.line = strings.TrimLeft(self.line, "\t") if self.test == nil { fmt.Println("Potential error parsing output of", self.result.PackageName, "; couldn't handle this stray line:", self.line) return } self.test.RawLines = append(self.test.RawLines, self.line) } // TestResults is a collection of TestResults that implements sort.Interface. type TestResults []contract.TestResult func (r TestResults) Len() int { return len(r) } // Less compares TestResults on TestName func (r TestResults) Less(i, j int) bool { return r[i].TestName < r[j].TestName } func (r TestResults) Swap(i, j int) { r[i], r[j] = r[j], r[i] } func (self *outputParser) parseEachTestFunction() { for _, self.test = range self.tests { self.test = parseTestOutput(self.test) if self.test.Error != "" { self.result.Outcome = contract.Panicked } self.test.RawLines = []string{} self.result.TestResults = append(self.result.TestResults, *self.test) } sort.Sort(TestResults(self.result.TestResults)) }

2024-01-22T01:27:04.234600

https://example.com/article/4510

package com.linkedin.databus.bootstrap.common; /* * * Copyright 2013 LinkedIn Corp. All rights reserved * * Licensed under the Apache License, Version 2.0 (the "License"); * you may not use this file except in compliance with the License. * You may obtain a copy of the License at * * http://www.apache.org/licenses/LICENSE-2.0 * * Unless required by applicable law or agreed to in writing, * software distributed under the License is distributed on an * "AS IS" BASIS, WITHOUT WARRANTIES OR CONDITIONS OF ANY * KIND, either express or implied. See the License for the * specific language governing permissions and limitations * under the License. * */ import java.io.IOException; import com.linkedin.databus.core.util.ConfigBuilder; import com.linkedin.databus.core.util.InvalidConfigException; public class BootstrapConfig extends BootstrapConfigBase implements ConfigBuilder<BootstrapReadOnlyConfig> { public BootstrapConfig() throws IOException { super(); } @Override public BootstrapReadOnlyConfig build() throws InvalidConfigException { LOG.info("Bootstrap service using http port:" + _container.getHttpPort()); LOG.info("Bootstrap service DB hostname:" + _bootstrapDBHostname); LOG.info("Bootstrap service batch size:" + _bootstrapBatchSize); LOG.info("Bootstrap service snapshot batch size:" + getBootstrapSnapshotBatchSize()); LOG.info("Bootstrap service catchup batch size:" + getBootstrapCatchupBatchSize()); LOG.info("Bootstrap producer log size:" + _bootstrapLogSize); LOG.info("Backoff Timer Config :" + _retryTimer); return new BootstrapReadOnlyConfig(_bootstrapDBUsername, _bootstrapDBPassword, _bootstrapDBHostname, _bootstrapDBName, _bootstrapBatchSize, getBootstrapSnapshotBatchSize(), getBootstrapCatchupBatchSize(), _bootstrapLogSize, _bootstrapDBStateCheck, _client.build(), _container.build(), _retryTimer.build()); } }

2024-03-26T01:27:04.234600

https://example.com/article/5332

Klippel-Trénaunay syndrome (KTS) is a congenital malformation with an incidence of 1 out of 27,500 live births described in 1900 including a triad of port-wine stain/capillary vascular malformation, venous malformation/varicose veins, soft tissue, and bony hypertrophy in affected limbs \[[@b1-kja-d-18-00050]\]. Although a combined spinal-epidural technique for an elective cesarean section and an epidural analgesia for vaginal delivery have been already presented \[[@b2-kja-d-18-00050],[@b3-kja-d-18-00050]\], this is the first report that describes spinal anesthesia for an urgent cesarean section in a patient with KTS. A 23-year-old woman (gravidity: 1, parity: 0) was referred to our Anesthesia Preadmission Clinic at 37 weeks of gestation because of KTS complicating her pregnancy. She weighed 115 kg and was 170 cm in height (body mass index 39.8 kg/m^2^). She had been diagnosed with KTS at the age of 16 and received several surgical treatments for her right foot varicosities and opioid therapy till the beginning of gestation because of pain in the right leg. She did not have a history of thrombosis or hemorrhage. On hospital admission at 37 weeks of gestation for planned delivery, physical examination showed prominent hypertrophy and multiple varicosities of the right leg ([Fig. 1](#f1-kja-d-18-00050){ref-type="fig"}). The circumferences of the thigh, calf, ankle, and knee were 12, 15, 11, and 10 cm, respectively, larger than the left side. Laboratory studies revealed a normal coagulation profile and hemoglobin (Hb) count of 8.5 g/dl. She was scheduled for a magnetic resonance imaging (MRI) scan to determine the existence of arterio-venous malformations (AVM) or hemangiomas in the pelvis, birth canal, spinal cord, bronchial tube, and brain before delivery, but she had not yet undergone MRI. She was admitted to our delivery unit at 38 weeks of gestation for an urgent cesarean section due to abnormal cardiotocography (type 2 urgency according to Lucas' classification). On admission, she was anxious and had breakfast two hours before. On physical examination, her airway revealed a Mallampati Class III and her back had normal anatomy with clearly palpable landmarks with no evidence of port-wine stains. Ultrasound revealed no signs of detectable vascular abnormalities. She refused any attempt of awake intubation. MRI of lumbar spine performed six years ago showed no AVM or hemangioma. After discussing rapidly the risks and benefits of general and spinal anesthesia, we decided that spinal anesthesia was safer in this case. However, we informed her the possibility of intraoperative conversion to general anesthesia in case significant hemorrhage occurred during the operation. Two 16-gauge intravenous catheters were placed in the left antecubital fossa bilaterally. Aspiration and antibiotic prophylaxis were performed routinely. In the meantime, an intravenous bolus of 0.9% saline 500 ml was administered before neuraxial anesthesia. Monitors included an electrocardiogram, finger pulse oximetry, and noninvasive blood pressure. In sitting position, spinal anesthesia at L~3-4~ intervertebral space was performed with 5 μg of sufentanil and 10 mg of hyperbaric bupivacaine. Then, the patient was positioned in the supine position with uterus displacement and her legs were lifted 30 degrees. A T4 anesthetic block was obtained without developing hypotension after neuraxial block. Her systolic blood pressure remained greater than 100 mmHg. A female baby weighing 2,964 g was delivered; her Apgar scores were 8 and 9 at 1 and 5 min, respectively. Abnormal bleeding vessels were noted around the uterine incision during the operation. The estimated blood loss was about 2,000 ml and two units of packed red blood cells were required. Two hours after surgery the Hb count was 8.4 g/dl and coagulation profile was normal. The rest of patient's postoperative course was unremarkable. To prevent thromboembolic disease, low-dose heparin (6,000 U/day) injection was administered for three postoperative days. The patient was discharged with her baby in good health. A planned anesthesia for a KTS patient is challenging and with due emphasis on airway, hemodynamics, and neuraxial vascular malformation bleeding can result in a favorable outcome. Airway management in such patients may be difficult owing to the soft tissue hypertrophy characteristic of pregnancy and possible underestimated hemangiomas typical of KTS. Hemorrhagic complications may arise as a result of pelvic varicosities being injured by surgery \[[@b4-kja-d-18-00050]\]. A whole body MRI is recommended before performing a cesarean section to prevent hemorrhage complications and the anesthesiologist should pay attention to detect abnormal vessels of bronchial tube and lumbar spine \[[@b5-kja-d-18-00050]\]. In this case, an MRI was scheduled, but not executed yet. An MRI of the lumbar spine of six years before was negative for abnormal vessels around the spinal cord. Moreover, considering that an accurate examination of the spine and ultrasound scan excluded detectable central nervous system hemangiomas, we decided for a spinal anesthesia. Two more issues have influenced the choice of neuraxial technique: preoperative fasting recommendations were not respected because of urgency and the Mallampati class 3 airway revealed a probable difficult airway management. Given these concerns and a normal coagulation profile, a spinal anesthesia was executed assuming that a potential risk of difficult airway management and pulmonary aspiration were greater than possible complications correlated to the less probable presence of abnormal vessels near the spine. Another crucial point was the vasodilatation of the right leg varicosities after spinal anesthesia and its potential impact on hemodynamics, which could result in decreased venous return. The lifting of the leg by approximately thirty degrees increased venous return releasing the amount of blood eventually seized in the varicosities. A significant intraoperative blood loss should be expected and at least one unit of packed red blood cells should be readily available to be transfused as has been done in this case. The optimal management of a non-urgent scenario is to perform a neuraxial blockade only after having ascertained a negative spine MRI finding. In case of urgent cesarean section, the risks and benefits of each anesthesia technique must be compared. {#f1-kja-d-18-00050}

2023-12-15T01:27:04.234600

https://example.com/article/2141

Plered Plered (also Pleret) was the location of the palace of Amangkurat I of Mataram (). Amangkurat moved the capital there from the nearby Karta in 1647. During the Trunajaya rebellion, the capital was occupied and sacked by the rebels, and Amangkurat died during the retreat from the capital. His son and successor Amangkurat II later moved the capital to Kartasura. It was twice occupied by Diponegoro, during the Java War (1825–1830) between his forces and the Dutch. The Dutch assaulted the walled complex in June 1826, which was Diponegoro's first major defeat in the war. Following the Java War, the town's decline accelerated and today it is in ruins. The remains are now located in the Bantul Regency, Special Region of Yogyakarta, Indonesia, close to the banks of the Opak River, and south of Kota Gede. It has been researched for archaeological remains It is located to the east of the site of Sultan Agung's Karta Palace at Karta. It is also the location of extensive irrigation and other water works which occurred at the time of the palace being used. History Construction Sultan Agung () built the previous court complex at Karta and moved the capital there in the first decade of his reign. The decision to move to a new capital might have been made during his reign in 1634, when a fire in Karta killed "many people of the court". In 1644, Sultan Agung started building an artificial lake in an area which became known as Plered. He died two years later and was succeeded by his son Amangkurat I. In 1647, shortly after taking the throne, Amagkurat built his royal residence near the lake and moved the court there. In contrast to Karta, which was made of wood, the royal compound at Plered was built of brick. Amangkurat continued to expand this complex up to 1666. Fall of Plered during Trunajaya rebellion In 1677, during the Trunajaya rebellion, Plered was taken by the rebel forces, consisting of Madurese troops, as well as Javanese forces from East Java and central northern coast, led by Raden Kajoran. The defenders, led by Amangkurat's four eldest son, offered an ineffective defense and were defeated. Consequently, Amangkurat and the royal family fled the court, and soon after the rebels entered the complex and plundered it. The rebels also took the royal treasury of at least 300,000 Spanish reals. According to a man claiming to witness the fall of Plered, Sp. Rl. 300,000 was taken to Trunajaya's capital in Kediri, while Amangkurat II (son and successor of Amangkurat I) later said that Sp. Rl. 150,000 was taken to Kediri while Sp. Rl. 200,000 remained in Plered with Trunajaya's local commander. During the retreat, Amangkurat I died near Tegal and was succeeded by his son, Amangkurat II. Another son, Pangeran Puger occupied Plered after the rebels left, and made a rival claim to the kingdom. Unable to take Plered from his brother, Amangkurat moved his capital to the newly-built Kartasura in 1680. During Diponegoro War Although abandoned as a capital, Plered played another role during the Java War or the Diponegoro War (1825–1830) between the Dutch and the Javanese forces under Prince Diponegoro. Diponegoro occupied Plered in 1825 and kept his weapons and livestock there. He used it as a base to attack convoys supplying the nearby Imogiri held by the Dutch. In April 1826, the Dutch under General Van Geen attacked Plered. Diponegoro did not engage in combat and withdrew to the west. Van Geen entered Plered and took the weapons and livestock kept there as booty. Lacking forces to keep the town, he subsequently withdrew to Yogyakarta. Subsequently, Diponegoro reocuppied the town and fortified it. In June 1826, Dutch forces with a strong contingent of Madurese auxiliaries besieged the town. On 9 June, the besiegers detonated a mine under the ramparts, causing a breach through which they attacked. After a day "bloody fighting", the attackers completely occupied Plered. This battle was Diponegoro's first major defeat in the war. The Dutch left a garrison of 700 men, and there was no further attempt from Diponegoro to retake it. Decline Following the Diponegoro War, the town's decline accelerated and when G. P. Rouffaer drew a map in 1889, it was already in ruins. Layout Because of the destruction of the buildings, the layout of Plered could only be approximated from historical reports, such as Van Goens' description of his 1648 visit to the palace, a map by Rouffaers based on his visit to the ruins in 1889, another map by Louw in 1897, and Javanese texts such as the babads as well as modern archaeological analysis of the site. The kraton of Plered was a walled structure in a shape that is roughly square but not perfectly symmetrical. Van Goens wrote its circumference was 600 roede (2256 meter), while Indonesian archaeologist Widya Nayati estimated it to be 3040 meter. Rouffers' report said that the walls (which was then already destroyed) had been 5-6 meters high and 150-centimeters thick, Van Goens wrote that it was 18-20 feet-high and 12-feet thick, and Indonesian archaeologists Alifah and Hery Priswanto estimated the thickness to be between 220 and 280 centimetres. The walls were made of bricks, tuff, and andesite. Rouffers' map named some buildings inside the complex, including a mosque, a tiger cage, and names such as Sitiinggil, Keben, and Srimanganti. The tiger cage was the first known permanent tiger cage in Javanese courts. Around the walled complex there were settlements named after their inhabitants, e.g. Kauman for the Ulama, Gerjen for the tailors (gerji in Javanese), and these names are still used today. Today Today ricefields occupied most of the former enclosure. Remains of the town became a cultural heritage site ("Cagar Budaya"), located in Bantul Regency, Special Region of Yogyakarta. See also Yogyakarta Kota Gede Notes Bibliography Category:History of Java Category:1645 establishments in Indonesia Category:Bantul Regency Category:Palaces in Java

2024-06-04T01:27:04.234600

https://example.com/article/4919

2002 Skate America The 2002 Skate America was the first event of six in the 2002–03 ISU Grand Prix of Figure Skating, a senior-level international invitational competition series. It was held at the Spokane Arena in Spokane, Washington on October 23–27. Medals were awarded in the disciplines of men's singles, ladies' singles, pair skating, and ice dancing. Skaters earned points toward qualifying for the 2002–03 Grand Prix Final. The compulsory dance was the Austrian Waltz. Results Men Reigning Olympic champion Alexei Yagudin withdrew with injury after the short program in what became the final competition of his amateur career. Brian Joubert went on to win the event for his first international title. Ladies Yukari Nakano and Ludmila Nelidina both landed a triple axel in their free skating, together becoming the first female skaters to perform the jump in international competition since Midori Ito landed it at the 1992 Winter Olympics. Nakano landed it first and Nelidina, who skated after her, also performed it successfully. Pairs Ice dancing References External links 2002 Smart Ones Skate America Skate America, 2002 Category:Skate America

2023-10-18T01:27:04.234600

https://example.com/article/6078

india Updated: Aug 25, 2019 11:21 IST The Indian Air Force (IAF) is hoping that its fresh attempt to procure 114 fighter jets will be a speedier hunt than the process that led to the procurement of French Rafale which took more than 10 years. After the Rafale contract was curtailed from 126 to 36, the IAF had once again hit the global market for procuring 114 jets. All the leading fighter manufacturers like Boeing, Lockheed Martin, Eurofighter, Russian United Aircraft Corporation and Saab are in the fray for the estimated $15 billion contract. These companies had taken part in the Medium Multi Role Combat Aircraft (MMRCA) bidding process earlier also. As the companies contest to get the Indian order, they have made several offers to sweeten the deals. The US aircraft makers have offered to set up production lines of F-16 and F-16 jets in India. New Delhi and Paris are discussing the possibilities of supplying 36 more Rafale. Several other options are also on the table. The delay in induction of new line of fighter jets has already impacted IAF’s war preparation plans. The MiG-21s are being phased out but the replacements have not come in time due to various reasons. The IAF will get its first Rafale next month but the entire fleet of 36 will be operational in another four years. The IAF is also looking to get mothballed MiG-29s from Russia along with placing new order for additional Su-30 MKIs. There is an urgent need to tap all the sources as the plan to upgrade Jaguar fighters, pending for several years, has made no headway. (The story has been published from a wire feed without any modifications to the text).

2024-06-27T01:27:04.234600

https://example.com/article/3987

#!/bin/sh major="0" minor="9.7b" slib=libssl sh_slib=$slib.so.$major.$minor clib=libcrypto sh_clib=$clib.so.$major.$minor FLAGS="-O3 -fomit-frame-pointer" SHFLAGS="-DPIC -fPIC" touch $sh_clib touch $sh_slib echo collecting all object files for $clib.so OBJS= find . -name \*.o -print > allobjs for obj in `ar t libcrypto.a` do OBJS="$OBJS `grep $obj allobjs`" done echo linking $clib.so gcc -G -o $sh_clib -h $sh_clib $OBJS -lnsl -lsocket rm -f $clib.so ln -s $sh_clib $clib.so echo collecting all object files for $slib.so OBJS= for obj in `ar t libssl.a` do OBJS="$OBJS `grep $obj allobjs`" done echo linking $slib.so gcc -G -o $sh_slib -h $sh_slib $OBJS -L. -lcrypto rm -f $slib.so ln -s $sh_slib $slib.so mv libRSAglue.a libRSAglue.a.orig mv libcrypto.a libcrypto.a.orig mv libssl.a libssl.a.orig

2023-09-27T01:27:04.234600

https://example.com/article/4306

Q: How to avoid stacking of jquery post() I have a script that searches my site for duplicate content as a user is typing in the title of a new post (just like on Quora). Right now it fires off a post request on keyup, leading to stacking of post requests. Any ideas on the best way to avoid this? $("#topic_title").keyup(function(){ var search_val=$(this).val(); $.post('/?post_type=topic&duplicate=1',{s:search_val},function(data){ if(data.length>0){ var results = $(data).find( '#results' ); $("#duplicates").html(results); } }); }); ** Thanks for all of the quality answers! I went with the abort() method for simplicity. Works like a charm. A: There are 2 things I will generally do in a situation like this: Only send off the request after no key is pressed for a certain time period, say .5 a second. This way if a person is typing quickly, you don't send off 10 requests, you just send one when they stop typing. This can be done by using setTimeout and clearTimeout. When a new request is sent, cancel the previous. This way there is only ever one active request. You really only care about the latest anyway. This can be done by using abort(). A rough outline: var timeout; var xhr; $("#topic_title").keyup(function(){ if(timeout) clearTimeout(timeout); if(xhr) xhr.abort(); timeout = setTimeout(function(){ doThePost(<parameters>); }, 500); }); function doThePost(){ xhr = $.post(...); }

2023-08-08T01:27:04.234600

https://example.com/article/4848

The invention relates to a device to be included in a positive crankcase ventilation system for an internal combustion engine, particularly a high performance gasoline engine and/or a turbo-charged or otherwise boosted gasoline engine. In the operation of an internal combustion engine, inevitably some of the intake air and gasoline vapor passes between the piston and cylinder wall into the crankcase, called blowby gas. That vapor needs to be disposed of, and it is then normally with a positive crankcase ventilation system that feeds that vapor back to the fresh air engine intake. However, the crankcase also has oil in it, and bits of the oil can get mixed with the blowby vapors and carried up into the intake. That oil is deleterious when it is burned, causing early failure of other parts of the engine. Accordingly, it is important to remove oil from the blowby vapor that is being recirculated. Oil in the combustion chamber will negatively affect performance and durability of an engine. It can, and most likely will, cause pre-ignition of the air fuel mixture. The venting promotes the capturing of oil and water vapor, thereby reducing the probability of oil in the combustion chamber. Furthermore, not enough oil in the crankcase will affect the durability of the engine. Once the oil vapor or liquid has been captured into the venting system/tank, at the proper time, it is desirable for the oil to be returned to the crankcase within the engine. If this is not accomplished, a low oil condition will result in the engine. This will result in higher operating temperatures; lack of sufficient lubrication and, eventually, engine failure.

2023-12-24T01:27:04.234600

https://example.com/article/2226

Another round for Mayor Osborn By Ben Urich Mayor Norman Osborn has announced a third run for Mayor. After City Council passed a bill — ushered through by Mayor Osborn — removing term limits on the Mayor’s Office, Osborn’s been cleared for a shot at an unprecedented third straight term. “The city has flourished under my administration. I believe we can achieve greater things if elected once more,” Osborn declared to the press. Osborn’s new platform focuses on improving citywide security, with promises to “end the city’s dependence on masked vigilantes like the Spider-Menace” by providing better “support” to the overwhelmed police force, alongside other initiatives. He hasn’t let us down. Could a third term be the charm for his administration?

2024-01-24T01:27:04.234600

https://example.com/article/1570

It is now well established that a person's risk for developing alcoholism[1](#fn1-arhw-19-3-249){ref-type="fn"} tends to reoccur in families ([@b25-arhw-19-3-249]; [@b9-arhw-19-3-249]; [@b26-arhw-19-3-249]; [@b19-arhw-19-3-249]). Although alcoholism is clearly familial, the role of genetics in a person's vulnerability to develop alcoholism continues to be debated. Most researchers would support the notion that some genetic influence occurs. The question to be asked is: How much of the variation between people in susceptibility to alcoholism is explained by genetic factors? It is also important to ask: How is genetic vulnerability moderated by personal factors (e.g., gender, age, and co-occurring psychiatric disorders) and environmental ones (e.g., cultural milieu and shared familial environment)? This review will discuss the role of genetic factors in the development of alcoholism in women. The data were obtained from the author's large, high-density-for-alcoholism pedigree study[2](#fn2-arhw-19-3-249){ref-type="fn"} of women. The article will discuss (1) the most recent studies of event-related potential[3](#fn3-arhw-19-3-249){ref-type="fn"} differences in women and their offspring and (2) the clinical characteristics of their offspring. Evidence for Genetic Mediation in Women ======================================= Several types of studies traditionally have been used in attempts to clarify the contribution of genetic influences to alcoholism, including family, adoption, and twin studies. Some of these studies support a genetic role in women's alcoholism. Family Data ----------- The first study to investigate the familial transmission of alcoholism separately for men and women alcoholics was completed by [@b7-arhw-19-3-249]. Applying a model (of transmission) that included both genetic and environmental factors, [@b7-arhw-19-3-249] concluded that the difference in alcoholism prevalence observed between men and women resulted entirely from cultural or nonfamilial environmental factors. Based on the most recent epidemiological data, the ratio of male to female alcoholism is 2:1 in the general population ([@b34-arhw-19-3-249]). Cloninger and colleagues found that equal numbers of alcoholic relatives were counted among both male and female alcoholics in their early study, suggesting that both genders have an equal likelihood that their disorder is inherited or is genetically mediated. Adoption Studies ---------------- In further support of alcoholism's familial nature, one line of research has indicated that the disease is more likely to be transmitted within families than are most psychiatric disorders ([@b38-arhw-19-3-249]). This high transmissibility could, however, result from the family environment (e.g., exposure to an alcoholic parent) rather than from genetic factors. In seeking to separate these two possible influences, a now-classic study of adopted children that concerned the etiology of alcoholism in men ([@b12-arhw-19-3-249]) suggested that transmission can occur even in the absence of exposure to an alcoholic parent. Few adoption studies have been conducted that address genetic factors in women's alcoholism. Thus, the conclusions that can be reached about genetic transmission based on adoption studies in women are tentative ([@b22-arhw-19-3-249]; [@b23-arhw-19-3-249]). Three adoption studies have been conducted that report results for female adoptees, one each in Sweden ([@b4-arhw-19-3-249]), Denmark ([@b13-arhw-19-3-249]), and the United States ([@b5-arhw-19-3-249]). The Swedish and Danish studies found too few alcoholic women to warrant any conclusions. However, [@b5-arhw-19-3-249] had a sufficiently large sample to conclude that genetic factors operated in the etiology of female alcoholism (for further discussion of adoption research, see the article by Cadoret, pp. 195--200). Twin Studies ------------ Further evidence for the genetic mediation of alcoholism in women can be gained from studies that have examined whether members of adult twin pairs match their twins in alcohol-related behaviors. This research compares the agreement in behavior between members of identical twin pairs (i.e., monozygotic \[MZ\] twins, whose genes are identical), with that of fraternal twin pairs (i.e., dizygotic \[DZ\] twins, who share an average of 50 percent of their genes). If a study finds twice the rate of agreement in the MZ twins as in the DZ twins, genetic influences are suggested to be at work (for further discussion, see the article by Prescott and Kendler, pp. 200--205). Agreement between members of twin pairs for both drinking behaviors ([@b15-arhw-19-3-249]) and alcohol dependence ([@b14-arhw-19-3-249]; [@b42-arhw-19-3-249]; [@b43-arhw-19-3-249]; [@b32-arhw-19-3-249]; [@b37-arhw-19-3-249]) have been studied. Although three studies utilizing clinical samples ([@b14-arhw-19-3-249]; [@b42-arhw-19-3-249]; [@b37-arhw-19-3-249]) did not find that MZ twins differed from DZ twins in a pattern suggestive of a genetic role, recent reports by [@b43-arhw-19-3-249] and [@b32-arhw-19-3-249] are more convincing. For example, Kendler and colleagues, studying a sample of more than 1,000 female MZ and DZ twin pairs from the general population, found substantially higher correlations of alcohol dependence between female MZ twins than between DZ twins; they ascribed more than 50 percent of the variation in the degree of alcoholism risk (i.e., variance) seen in their sample to genetic factors ([@b33-arhw-19-3-249]). Evidence for Two Types of Alcoholism in Women ============================================= Twin and adoption studies support a genetic component in women's alcoholism. It is likely, however, that genetic factors make a greater contribution to some women's development of the disorder than to other women's. Genetic risk for developing alcoholism appears to exist on a continuum ranging from virtually no risk to exceptionally high risk; the latter designation results from having a concentration of alcoholics in one's family (i.e., familial density). For simplicity of argument, however, the liability to develop alcoholism can be thought of as having two basic forms, distinguished by the extent to which each is influenced by genetic factors. [@b8-arhw-19-3-249] described two forms of alcoholism among men. Male type I alcoholics are those whose likelihood of drinking depends much more heavily on the environmental conditions under which they reside than on genetic influence. The type II male alcoholic, however, has been described as having familial alcoholism and as developing alcoholism at a much earlier age (i.e., early onset, often during adolescence) and to a more severe degree than the type I male. Accordingly, it is possible that two types of alcoholism exist in women. For example, studies by [@b11-arhw-19-3-249] and [@b35-arhw-19-3-249] provide evidence for more severe symptoms in women with early onset alcoholism (i.e., beginning before age 25). Women with the severe form of alcoholism also come from families with a greater density of alcoholism among their members. Likewise, preliminary results from Hill and colleagues suggest a very early onset of alcoholism for female alcoholics whose families display multigenerational alcoholism (discussed below). This profile suggests that a form similar to type II male alcoholism may exist in women. Some researchers, however, believe that all alcoholism in women is less severe than it is in men. For example, [@b10-arhw-19-3-249] have used the term "female-like" to describe a less severe and less genetically mediated form of alcoholism in men (i.e., type I alcoholism). This result was based on an analysis of data from the relatives of female and male alcoholics (i.e., the alcoholics were the primary subjects, or probands) in their study of families of alcoholics. Gilligan and colleagues concluded that greater genetic involvement was present within the families of male alcoholics than within the families of female alcoholics. Moreover, they concluded that two types of alcoholism existed in males, but only one type occurred in females. The researchers did not, however, test for more than one type of inheritance to explain the transmission of alcoholism among the female proband families. Thus, assumptions about the existence of only a single form of alcoholism in women may have been premature ([@b1-arhw-19-3-249]). The alcoholism field appears to have accepted the view of two types of male alcoholism while assuming, with a few notable exceptions ([@b11-arhw-19-3-249]; [@b22-arhw-19-3-249]; [@b35-arhw-19-3-249]), that only one type of alcoholism---one without a genetic etiology---exists in females. In fact, as suggested above, the familial form of alcoholism that appears to exist in women resembles the familial form (i.e., type II) seen in men. Evidence of familial transmission is readily apparent for cases in which alcoholism severity is greater. For example, in families having members with early onset-type alcoholism, in which multiple afflicted relatives are present (sometimes in multiple generations), the tendency for alcoholism to run in families is clear. Nevertheless, familial transmission still could be a result of common familial environmental factors rather than genetic ones. Although the data needed to draw firm conclusions about female alcoholism are missing, the literature reviewed above suggests that alcoholism can be genetically mediated in women. Late-onset alcoholism in women may well be influenced more by environmental factors (e.g., divorce or loss of maternal role in middle age \[empty-nest syndrome\]) than by genetic factors. To lend support to the existing evidence for more than one (i.e., heterogeneous) form of female alcoholism, detailed studies of the genetic aspects of alcoholism in women and in their families have been conducted and are discussed below. It may be concluded that the etiology of female alcoholism has as much likelihood of being mediated through genetic factors as does men's ([@b18-arhw-19-3-249]). The evidence for genetic mediation includes two twin studies of female alcoholism in which heritability was found to be significant ([@b43-arhw-19-3-249]; [@b32-arhw-19-3-249]) and an adoption study ([@b5-arhw-19-3-249]). Moreover, alcoholism appears to be heterogeneous in women, with one form (the early onset type) much more likely to be influenced by genetic factors than the other (late-onset) form ([@b11-arhw-19-3-249]; [@b35-arhw-19-3-249]; [@b22-arhw-19-3-249]). Genetic Mediation of Alcoholism in Women: Potential Risk Markers ================================================================ The process of becoming alcoholic still may be different for women than for men ([@b18-arhw-19-3-249]). This possibility suggests a need to search for markers of vulnerability for women as well as for men. Finding biological markers of alcoholism risk that are minimally affected by environmental factors (e.g., exposure to an alcoholic parent, sibling, or other family member) could prove useful in understanding the relative contribution of genetic factors to vulnerability for alcoholism. Additionally, these markers could be utilized in prevention efforts by providing a screen for alcoholism susceptibility. The search for useful markers of "risk" would be facilitated by the identification of a physiological trait in alcoholics that differs from nonalcoholics. Also, finding a marker that discriminates high- from low-risk persons who are not themselves alcoholic is an important step in this process. Ideally, one also would like to find a marker that is under genetic control. Locating neurobiological markers of vulnerability in women and girls is especially useful if susceptibility varies by gender. History of Event-Related Potential Research ------------------------------------------- One biological tool that has proved useful for investigating markers of alcoholism is measurement of the event-related potential (ERP) of the brain. The ERP is measured with the electroencephalogram (EEG), which amplifies the naturally occurring brain electrical activity at the scalp. The ERP is graphically displayed on a scan as a wave with several peaks and valleys (see [figure 1](#f1-arhw-19-3-249){ref-type="fig"}). ERP's occur in response to sensory, motor, or cognitive events. One component, the P300, is one of the positive peaks on the ERP wave and occurs approximately 300 milliseconds (ms) after an informative event. In laboratory tests, the P300 is elicited by asking a subject to respond to an unusual stimulus (e.g., "oddball" paradigms: a high tone in a series of low tones or a red circle in a series of green circles) by performing a simple task (e.g., pressing a button or counting the high tones). Researchers have examined the P300 both in alcoholics and in nonalcoholic persons at high risk for developing alcoholism. These studies have observed whether the relationship between being an alcoholic or being a high-risk nonalcoholic person is associated with reduced height (i.e., amplitude) of the P300 wave or with the time it takes for the stimulus to be presented and the P300 peak to occur (i.e., the P300 latency). P300 latency changes generally accompany exposure to neuro-toxic substances such as alcohol. Thus, latency changes can be associated with recent exposure to alcohol. ERP studies in male chronic alcoholics have shown evidence for a reduction in P300 amplitude in some investigations ([@b45-arhw-19-3-249]), but not in all studies ([@b41-arhw-19-3-249]; [@b17-arhw-19-3-249]; [@b36-arhw-19-3-249]; [@b27-arhw-19-3-249], [@b30-arhw-19-3-249]). Because alcoholics consume alcohol for extensive periods of time and at varying intervals before testing, uncovering P300 differences that may have existed before the onset of abusive drinking is not always possible. Numerous studies, however, have demonstrated deficits in the P300 component in nonalcoholic high-risk children and adolescents. Prior to a report from [@b29-arhw-19-3-249]), researchers had found the P300 deficit only in the offspring of male alcoholics ([@b3-arhw-19-3-249]; [@b48-arhw-19-3-249]; [@b28-arhw-19-3-249]; [@b23-arhw-19-3-249] [@b46-arhw-19-3-249]). The ERP, and the P300 component in particular, has value as a marker of alcoholism for two reasons. First, ERP's are associated with particular sensory and cognitive aspects of information processing. These processes may be affected in people at risk for alcoholism. Second, the ERP wave form has been found to be more similar between family members than between unrelated people. Thus, it appears to be under genetic control ([@b47-arhw-19-3-249]; [@b44-arhw-19-3-249]; [@b2-arhw-19-3-249]) and is unlikely to be influenced by environmental factors. Someone whose P300 amplitude is reduced and who is from a family with a high density of alcoholism could have an inherited risk of developing the disease. Thus, reduced P300 in women at high risk for developing alcoholism could lend support to the idea that the disease can be genetically mediated in women. Two studies have examined the P300 component in alcoholic women ([@b40-arhw-19-3-249]; [@b24-arhw-19-3-249]). One of these ([@b24-arhw-19-3-249]) looked at high-risk relatives of alcoholic women for possible P300 alterations, finding P300 amplitude deficits among the alcoholic women. [@b40-arhw-19-3-249] compared ERP characteristics of female alcoholics with those of female nonalcoholic control subjects using auditory and visual paradigms but found no differences in P300 amplitude or latency. The Biological Factors Family Study of Female Alcoholism ======================================================== Considering the evidence both questioning and/or supporting the existence of a severe form of genetically influenced alcoholism in women, and given the usefulness of the P300 as a potential marker for genetic vulnerability, Hill and colleagues designed a study to examine the nature of female familial alcoholism. They investigated the presence of a severe form of alcoholism and its relationship to any effects on P300 waves among women and children from families in which a high concentration of female alcoholics was present. Criteria for Families --------------------- In the study, multiple extended families with multigenerational alcoholism were located over a 6-year period as part of the Biological Risk Factors Family Study ([figure 2](#f2-arhw-19-3-249){ref-type="fig"}). One goal of this research has been to identify neurobiological indicators of risk, such as the P300, in alcoholic women and their relatives who are at high risk of developing the disease, particularly minor children from these families. In contrast to the methodology used by [@b40-arhw-19-3-249] (mentioned earlier; wherein the FHP designation could refer to just one alcoholic relative being present in a woman's family) Hill and colleagues' study ascertained FHP histories with the intention of finding families (i.e., pedigrees) with a high density of alcoholic members ([@b1-arhw-19-3-249]; [@b49-arhw-19-3-249]). The high-risk families in the study were found initially through a pair of female alcoholic siblings. This strategy results in the greatest chances of alcoholism occurring across generations within the same family. At least one member of each pair was in treatment for alcoholism when identified; if an alcoholic sibling did not exist, the presence of other alcoholic female relatives sometimes enabled the family to be included. All probands and first-degree relatives (i.e., parents, siblings, and children) included in the study were required to be largely free of psychiatric disorders (i.e., recurrent depression and schizophrenia were conditions for exclusion).[4](#fn4-arhw-19-3-249){ref-type="fn"} This requirement ensured that the neurobiological markers found would be specific to alcoholism and not to general "psychiatric morbidity." In addition, possible sources of variation were evaluated in all study participants, including socioeconomic status, familial environment, and menstrual cycle phase, along with overall neuropsychological test performance, to ensure that any differences between the groups did not result from these variables. All first-degree, adult relatives (both alcoholic and nonalcoholic) of the treated alcoholic women were studied. The children studied were the offspring of the alcoholic subjects and their siblings. To arrive at a diagnosis with respect to alcoholism and other psychopathology, two interviews were conducted, or two family history reports were gathered for each relative. The age of onset of alcoholism for women in this study was quite early, with a median of 16 years ([@b18-arhw-19-3-249]).[5](#fn5-arhw-19-3-249){ref-type="fn"} Because the study families were chosen for their high frequency of alcoholism (a minimum of two alcoholic members per family), the researchers hypothesized that the families' alcoholism would be genetically mediated (as was intended by research design). The study of high-density families would maximize the likelihood of finding biological markers, should they exist. The control families (i.e., the low-risk families) were selected for minimal psychopathology (including alcoholism) among the sister pairs and their first-degree relatives. These families were selected so that general psychiatric disorders in the high- and low-risk groups were equivalent (for further review of the methods involved in this study, see [@b18-arhw-19-3-249]; [@b23-arhw-19-3-249] [@b46-arhw-19-3-249]). Event-Related Potentials ======================== To verify their hypothesis that the alcoholic women did have a genetically influenced form of the disease, the researchers observed ERP's in the women and in their children. Adult women and minor children from the high- and low-risk pedigrees were evaluated using identical tests and recording conditions (one visual task and two listening tasks), enabling the assessment of important developmental and gender differences in P300 waves. ERP Differences in Alcoholic Women, Nonalcoholic Sisters, and Controls ---------------------------------------------------------------------- One phase of the study investigated possible differences in P300 that might be associated with alcoholism risk ([@b24-arhw-19-3-249]). The subjects studied included 25 alcoholic women, 31 of their high-risk nonalcoholic sisters, and 30 control women from low-risk families. ### Amplitude Is Reduced The P300 amplitude elicited from one auditory task was reduced significantly for the alcoholic women compared with the control women and their non-alcoholic sisters. For the other auditory and the visual task, alcoholic women also were found to have reduced P300 amplitude compared with their nonalcoholic sisters. P300 latency did not differ by group. This suggests that group differences in P300 did not result from differences in recent exposure to alcohol. The findings from this portion of the study suggest that reduction in P300 amplitude occurs only in alcoholic women. ### Significance of Findings The difference between the P300 amplitude of alcoholic women and that of their nonalcoholic sisters is of considerable significance. Although the reduction could result from the longstanding use of alcohol leading to neuropathological changes, this possibility appears unlikely because the women showed equal ability on tests of neuropsychological functioning. Any genetic influence on women in these families may be inherited by one sister and not by the other. In addition, a recent analysis of a large data set from alcoholic men, their high-risk brothers, and nonalcoholic controls showed no P300 amplitude reduction in adult males ([@b30-arhw-19-3-249]), a result also found by others ([@b41-arhw-19-3-249]; [@b17-arhw-19-3-249]; [@b36-arhw-19-3-249]). These results have led to speculation that P300 differences in high-risk populations may represent delays in development of cognitive functioning that typically are seen only in childhood. In contrast to findings in men, women who became alcoholic in adolescence persist in having reduced P300 amplitude in adulthood. Further research is needed to examine the possible gender differences (e.g., differences in the hormonal system) that might account for this phenomenon. At any rate, women alcoholics display clearly different neurophysiological characteristics from their nonalcoholic sisters, a condition that may have its antecedents in childhood. Demonstration of differences in childhood, prior to the initiation of drinking, would provide further evidence that the marker has etiological significance and is not merely a consequence of drinking. P300 in High-Risk Children From Female Alcoholism Families ---------------------------------------------------------- Because alcoholic women exhibit P300 amplitude reduction, their children also might have reduced P300, possibly indicating a genetic risk for developing alcoholism. ### Subjects Seventy-six children ages 8 to 18 were studied. Two groups of children (whose mean age was 11.3) were drawn from the high-risk families and the control families. Both groups contained 38 children: 17 males and 21 females. All children were free of alcohol and other drug (AOD) use at the time of testing, and only one child was a regular AOD user.[6](#fn6-arhw-19-3-249){ref-type="fn"} Because the mothers of both groups of children could have consumed alcohol during pregnancy, the study design included interviewing all mothers (even those who were social drinkers) about current and life-time AOD use to determine AOD use during pregnancy. Mothers of 12 high-risk children reported drinking during pregnancy (2 of the mothers also had used marijuana), and mothers of 26 children denied AOD use during pregnancy. ### Results for an Auditory ERP Task The P300 peak was studied in 35 high-risk children and 35 control children (matched in age). A significant effect was found in one task, in which the amplitude for the high-risk group was lower than that for the low-risk group ([@b29-arhw-19-3-249]). To control for prenatal alcohol exposure, data were reanalyzed to exclude the high-risk children whose mothers drank during pregnancy and their corresponding controls. Group differences remained even in this smaller sample of 24 children of mothers who reported abstinence when compared with control subjects. Thus, the P300 amplitude reduction in high-risk children appears to result from a familial vulnerability and not from prenatal alcohol exposure. ### Reduced P300 Amplitude in Girls From Female Alcoholism Families Because the study also was intended to discern whether female children would exhibit ERP characteristics similar to those found previously among high-risk male children, it focused on reanalyzing data with respect to P300 differences in daughters of alcoholic mothers ([figure 3](#f3-arhw-19-3-249){ref-type="fig"}). Because a reduction in P300 amplitude might result from the joint influence of having a biological mother and father who both were alcoholic, for this analysis, girls who had an alcoholic father were excluded. Female children with alcoholic mothers did display reduced P300 amplitude ([@b29-arhw-19-3-249]). The P300 results from the girls with alcoholic mothers suggest that the same neurobiological indicators of risk found in children from high-density-for-male-alcoholism families ([@b23-arhw-19-3-249]; [@b46-arhw-19-3-249]) are risk indicators in the high-density-for-female-alcoholism families. Interestingly, compared with low-risk boys, a greater proportion of high-risk boys exhibit P300 amplitude below the median of the control subjects (approximately one in three). A similar comparison for girls showed that approximately one in six high-risk girls exhibited P300 below the median of the controls. Thus, because alcoholism among females is less prevalent in the general population than it is among males, one would expect the ratio of girls to boys showing P300 reduction to be comparable to the ratio of female to male alcoholics in the general population. Although this study of offspring of alcoholic women has not yet followed the children prospectively, P300 appears to predict clinical outcome for alcohol dependence. This hypothesis is based on results from a companion study of children from male alcoholic families ([@b31-arhw-19-3-249]). In this 8-year followup study of children from high-risk-for-male alcoholism families, a relationship between P300 amplitude at age 10 and alcohol dependence existed at followup. Although it remains to be determined whether the childhood P300 reduction in the high-risk-for-female alcoholism families is specific to alcoholism or is a general marker of adult psychopathology, the repeated observations of differences between high- and low-risk children warrant long-term followup of these children. Psychopathology in Children From Female Alcoholism Families =========================================================== The importance of studying psychopathology in offspring from maternal alcoholism families is twofold. Psychopathology in children increases their risk for adult disorders, including alcohol dependence. Also, developing appropriate interventions for these children requires identifying both the type and extent of these problems. Hill and colleagues evaluated all available children in their sample who were between ages 8 and 18 for risk of psychopathology.[7](#fn7-arhw-19-3-249){ref-type="fn"} The high-risk children did not have significantly higher rates of particular childhood disorders (e.g., affective disorders, anxiety disorders, oppositional/ conduct disorders, or attention deficit disorders). When the total number of diagnoses were compared, however, the high-risk children showed significantly higher total rates of psychopathology. Next, the researchers asked whether parental alcoholism had any specific link to higher rates of psychopathology among these children. They examined the children's particular psychopathology and its relationship to three major variables: the mother's and custodial father's[8](#fn8-arhw-19-3-249){ref-type="fn"} alcoholism diagnosis and the age group of the child (under age 12 versus age 13 and over)([@b21-arhw-19-3-249]). Children who had only an alcoholic mother were almost five times as likely to develop psychopathology compared with low-risk children, regardless of their ages. Having, in addition, a custodial father who was alcoholic increased a child's relative odds of developing psychopathology. Moreover, these results suggest the particular importance of alcoholic role models as risk factors during adolescence; children over age 13 who did not have a custodial father who was alcoholic had a risk of 4.94 compared with a 30-fold increase in risk when both parents were alcoholic. Because the children evaluated were still, on average, quite young, it remains to be determined how many will succumb to an AOD-use disorder,[9](#fn9-arhw-19-3-249){ref-type="fn"} particularly alcohol dependence. However, the recurrence of alcoholism observed in more than one generation of the families studied in this research (approximately 50 percent of the relatives of these alcoholic women are alcoholic) suggests that these children have a greatly increased risk for alcoholism by adulthood. Long-term followup of children whose mothers have early onset familial alcoholism will establish the rates of alcohol dependence among offspring of these families and verify the preliminary observations that the neurobiological marker observed in children is a predictor of risk; that is, those with lower P300 will succumb more often to AOD-use disorders. Summary and Conclusions ======================= Review of the literature suggests that the existence of a genetically influenced form of alcoholism is as likely for women as it is for men. Similarly, two types of alcoholism appear to occur in women: (1) an early onset type that often develops before age 21 and occurs in women whose families have a particularly high frequency of alcoholism among their members and (2) a late-onset (i.e., midlife) type that appears to be associated with a peak in heavy drinking that occurs at this time ([@b18-arhw-19-3-249]) and that is more likely determined by environmental variables (e.g., loss of spouse). Early onset alcoholism in women represents a severe form of the disorder, with recurrence from generation to generation. Prevention efforts may be especially important for children from these families. Correlated with the presence of this severe form of alcoholism in families is a reduced P300 wave among some family members. Previously, when data were compared for children from families with a high density of male alcoholism, a number of striking differences in ERP characteristics emerged, including reduced P300 in high-risk children compared with control subjects ([@b28-arhw-19-3-249]; [@b23-arhw-19-3-249]; [@b46-arhw-19-3-249]). Recent research has shown that children of female alcoholics display similar P300 amplitude reduction ([@b29-arhw-19-3-249]). This finding suggests that P300 is a neurobiological marker for genetic alcoholism risk in children from both male and female alcoholism families. Comparison of the clinical and psychopathological characteristics of children from high-risk pedigrees, in which approximately 50 percent of both male and female relatives are alcoholic, reveals that these children are at greatly increased risk for childhood psychiatric disorders relative to controls. This conclusion stands in contrast with the more modest differences in psychopathology reported for children from high-risk families located through male alcoholics ([@b20-arhw-19-3-249]). Thus, it appears that the consequences of being a child of an alcoholic woman are represented by significant neurobiological markers of risk (e.g., reduction in P300 amplitude) and psychopathological conditions that may promote alcoholism. The author wishes to thank J. Locke, S. Gronlund, and E. Blauser for their excellent technical assistance and T. Smith, D. Muka, and L. Lowers for recruiting subjects and assisting in clinical evaluations. She also wishes to thank H. Yuan, Ph.D., C. Aston, Ph.D., and S. Steinhauer, Ph.D., for their continued support and collaboration. Also, the research group is indebted to the families who participated and to the treatment centers who allowed them to recruit families from their patient populations. As it is used in this article, the terms "alcoholism" and "alcohol dependence" refer to a disease characterized by abnormal alcohol-seeking behavior that leads to impaired control over drinking. The term "high density for alcoholism" refers to families in which the chance of a relative of the alcoholic's being alcoholic is far greater than it is in the general popultion (in Hill and colleagues' families, their risk is five times higher than in the general population). The event-related potential is a specific measure of the brain's electrophysiological response to a perceived stimulus. Psychiatric disorders were defined by the American Psychiatric Association's *Diagnostic and Statistical Manual of Mental Disorders, Third Edition*. In the general population, one-half of all alcoholic women experience onset after the age of 45, whereas for men, one-half are alcoholic by age 30 ([@b16-arhw-19-3-249]). For clarity, the term "alcohol and other drug (AOD) use" was used to standardize terminology throughout this article. However, the author used criteria listed in the American Psychatric Association's *Diagnostic and Statistical Manual of Mental Disorders, Third Edition*, which refers to "alcohol and/or drug use disorders." Lifetime rates of childhood psychopathology, as determined from the Schedule for Affective Disorders and Schizophrenia for School-Aged Children (K-SADS) ([@b39-arhw-19-3-249]; [@b6-arhw-19-3-249]), were compared for the two groups of children (i.e., the 38 at high risk for alcoholism and 38 control subjects at low risk). The custodial father is defined as a biological, step-, or adoptive father with whom the child resided at the time of evaluation. A total of 20 of the 38 custodial fathers were reported to be the biological father. The followup study will investigate AOD-use disorders as they are defined in the American Psychiatric Association's *Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition*. This research was supported by the National Institute on Alcohol Abuse and Alcoholism grants AA05909 and AA08082. {#f1-arhw-19-3-249} {#f2-arhw-19-3-249} {#f3-arhw-19-3-249}

2024-03-14T01:27:04.234600

https://example.com/article/1016

We’re very excited to welcome Automaton Games onto our SpatialOS platform, alongside the news that their team of developers will be turning their talents to developing a revolutionary massively multiplayer survival game with our tech and CryEngine. A massively multiplayer survival-combat game built with SpatialOS At the moment of writing, the as-yet-unnamed project is scheduled for release in 2018, with the first playable content slated for the Spring of that year. The game is set to use SpatialOS to help empower a game world that will support: 1,000 concurrent players occupying a detailed shared world A huge 12km x 12km explorable, graphically realistic and highly dynamic environment, enabling advanced tactical gameplay Strong character progression, social hubs and global-scale player-driven narrative that will shape a unique MMO experience An additional last-man standing Player vs Player arena combat mode, with up to 400 players in direct combat. Unprecedented world simulation and effects, including environmental destruction, roaming wildlife, dynamic weather, foliage displacement, tracks, blood trails, fire and water effects, fully immersing players into the experience of being the hunter – or the hunted. To accompany today’s announcement, Automaton has shared some early concept art and screenshots: MMO pedigree and CryEngine expertise Based in Cambridge UK, Automaton Games was founded in 2015 and boasts a wealth of MMO development veterans who have worked on titles like RuneScape and EVE Online. You may have heard of the studio as the maker of the popular psychological stealth FPS, Deceit. This multiplayer online game was released in 2017 and was the first game to use the CryEngine V platform and showcase its latest features. This CryEngine expertise will enhance the studio’s new project, which is built upon a successful integration of CryEngine and Improbable’s SpatialOS platform. Automaton also recently raised an impressive $10 million in funding from Cambridge Venture Partners with which to expand their operations. “We’ve spent the last two years building the technology for a next-generation massively multiplayer online game that requires an entirely new approach to game design and development,” James Thompson, CEO of Automaton, commented. “This project delivers an unprecedented fidelity and scale of world simulation, and complex interactions between authored and player-driven content. “I’m hugely excited that our next step is deploying this $10m investment to bring the game to launch in 2018. SpatialOS was an extremely natural fit for the platform on which to build our world simulation, since its paradigm fits squarely with the approaches we have taken to design a huge, dynamic virtual world, and we’re extremely excited to showcase what we’ve been able to achieve together in the coming year.” SpatialOS tech and groundbreaking games SpatialOS is Improbable’s distributed, cloud-based platform for game development and operation in the cloud, which allows developers to exceed the power of a single game engine or server. By building games with standard tools and deploying on SpatialOS, developers like Automaton Games can build virtual worlds that offer permanent, persistent and engaging experiences. “Our goal at Improbable is to give developers the power to make previously impossible games,” added Herman Narula, Improbable’s co-founder and CEO. “With Deceit, Automaton Studios proved that they could make a tense, engaging multiplayer game. We’re excited by their vision for this new game: the survival genre is seeing a huge amount of attention and excitement, and we’re excited to see what this talented team can do with the massive scale, persistent world and rich systems made possible by SpatialOS.” Automaton is the latest studio to announce a project on SpatialOS. Additional gaming and entertainment studios currently building products on SpatialOS include Bossa Studios (Worlds Adrift), Spilt Milk Studios (Lazarus), Klang (Seed), and Entrada Interactive (Rebel Horizons). Discuss this article on the SpatialOS forums.

2024-05-30T01:27:04.234600

https://example.com/article/1047

Hepatitis C is one of the most widespread infectious diseases in the world. About 180 million people are infected with hepatitis C virus (HCV) worldwide with a yearly incidence of 3-4 million. While the acute phase of infection is mostly asymptomatic, the majority of acutely infected individuals develops chronic hepatitis and is at increased risk of developing liver cirrhosis and hepatocellular carcinoma. Thus, HCV infection is a major contributor to end-stage liver disease and in developed countries to liver transplantation. HCV is a small, enveloped virus classified as a member of the Flaviviridae family. Its genome consists of a 9.6 kb single stranded RNA of positive polarity composed of 5′ and 3′ untranslated regions (UTR) and one long open reading frame (ORF) encoding a polyprotein, which is co- and post-translationally cleaved and thus yields the structural (Core, E1, E2), p7 and nonstructural (NS2, NS3, NS4A, NS4B, NS5A, NS5B) proteins. HCV isolates from around the world exhibit significant genetic heterogeneity. At least 7 major HCV genotypes (genotypes 1-7) have been identified, which differ by 31-33% at the nucleotide level and deduced amino acid level. In addition, there are numerous subtypes (a, b, c, etc.), which differ by 20-25% on the nucleotide and deduced amino acid level. Since its discovery in 1989, research on HCV has been hampered by the lack of appropriate cell culture systems allowing for research on the complete viral life cycle as well as new therapeutics and vaccines. In 2001, a genotype 2a isolate (JFH1) was described, which subsequently was found to yield high RNA titers in the replicon system without adaptive mutations. A major breakthrough occurred in 2005, when formation of infectious viral particles was reported after transfection of RNA transcripts from the JFH1 full-length consensus cDNA clone into Huh7 cells. At the same time, it was demonstrated that the intragenotypic 2a/2a recombinant genome (J6/JFH1), in which the structural genes (Core, E1, E2), p7 and NS2 of JFH1 were replaced by the respective genes of clone J6CF, produced infectious viral particles in Huh7.5 cells (a cell line derived from bulk Huh7 cells) with an accelerated kinetic. Cell culture derived J6/JFH viruses were apparently fully viable in vivo. Despite the importance of the described cell culture systems they represent only a single isolate (genotype 2a) of HCV. It is important to develop cell culture systems for representative strains of other HCV isolates, subtypes and genotypes, since neutralizing antibodies are not expected to cross-neutralize all genotypes and new specific antiviral compounds have differential efficiencies against different isolates, subtypes and genotypes. To date, only the JFH1 (genotype 2a) clone could autonomously replicate and release infectious virus in cultured human hepatoma cells, Huh7 and Huh7.5; its efficient growth depended on mutations. A JFH1 chimera with the 5′UTR-NS2 region from another genotype 2a strain cDNA clone, J6CF, had enhanced infectivity. Besides, an H77 (genotype 1a) clone containing replicon-derived mutations was shown to produce infectious virus particles. To facilitate HCV research and obtain basic knowledge for better and individualized treatment, the present inventors have aimed at developing culture systems for other HCV patient isolates. Hence, improved and alternative HCV genomes of all genotypes, which are capable of expressing said virus when transfected into cells and are capable of infectivity in vivo, would be advantageous.

2024-02-24T01:27:04.234600

https://example.com/article/1312

Anti-Bullying Code Last updated Wednesday 24 January 2018 Our school is special Kewaigue school is special. It is a happy and fun school where respect is very important. It is a school where we celebrate that we are all different. We want everyone to behave in a friendly, truthful, polite and respectful manner with no bullying. Everyone in school is equal and has the right to express an opinion in a secure and safe environment. BULLYING Bullying behaviour is directly contrary to the safe, caring and supportive environment, high standards of behaviour and shared values that we facilitate and expect at Kewaigue School. We have a legal duty to have an anti-bullying policy. We also have a responsibility to respond promptly and effectively to issues of bullying. Our aim, therefore, is to ensure bullying is prevented and where it does happen, it is dealt with swiftly and effectively. What is bullying? There are many definitions, but most have four things in common: · It is deliberately hurtful or harmful behaviour · It is repeated often over a period of time · It is difficult for those being bullied to prevent or put a stop to it · It causes feelings of distress, fear, loneliness and lack of confidence in those who are at the receiving end. Bullying can take many forms but the five main types are: · Physical (hitting, kicking, pushing, taking belongings) · Verbal (name calling, insults (including those of a racist, sexual or homophobic nature) taunting, mocking, making offensive personal comments; threatening, intimidating; creating situations in which someone is humiliated, or made to look ridiculous, or gets into trouble; · Non-verbal, involving body language, gesture and facial expression. Non-verbal behaviours can be just as hurtful and intimidating as those which involve abusive language. · Indirect (emotional, spreading nasty stories about someone, excluding someone from a social group, playing tricks and pranks) · Cyberbullying (when one person or a group of people aim to threaten, tease or embarrass someone else by using a mobile phone, the internet or other technologies) We are agreed that bullying behaviour in any form will not be tolerated if, when or where it affects children who come to our school. We expect all children to report bullying behaviour and not take on the role of a follower and/or bystander to this behaviour. We expect all parents to work in partnership with the Headteacher and other staff members (where appropriate) when this type of behaviour is reported and concerns their child in any way. If parents feel their child may be a victim of bullying behaviour, inform school immediately. A complaint will be taken seriously and appropriate action will follow. We have an anti-bullying code and clear procedures are in place if a “bullying” incident is reported. AWARENESS RAISING The whole school community will be made aware of our policy of behaviour and anti-bullying through school council meetings, assemblies, circle time, PSHCE sessions and access to it given through the school website and prospectus. CURRICULUM IMPLEMENTATION To ensure our policy is fully integrated into the life of the school, formal and informal opportunities will be planned and implemented to ensure everyone continues to abide by the procedures set out in this document. These may include the following; Assemblies PSHCE lessons Circle time Displays and posters Playground games led by children and staff Home-school diaries School website and prospectus SUPPORT Staff All staff will be kept abreast of current thinking with regard to anti­bullying and if required, support will be given to implement this policy. Opportunities for staff to receive training on matters relating to managing behaviour and positive handing will be given through courses available through the CPD programme and school based INSET. Victims Support for the victim is essential both immediately following the incident and during an agreed period of review. Peer support, staff support, parental support and outside agency support may all be essential to ensure that the victim does not suffer any long term damage. After a period of time staff will meet with the victim to reassess the situation and the relationship between those involved. Perpetrators It is recognized that support must be given to the perpetrator. Disciplinary procedures against the perpetrator(s) are intended to change or modify behaviour rather than label anyone as a bully. Such procedures may include: · Positive behaviour strategies · Withdrawal of activities · The establishment of mentoring or buddying system · Discussion about the effects of bullying · Peer mediation · Involvement of other agencies and services such as an Educational Psychologist, or the Behaviour Support Team. PARENTAL/CARER INVOLVEMENT Parents and carers will be expected to take responsibility for the behaviour of their child both inside and outside school. They will be encouraged to work in partnership with the school to assist in maintaining high standards of behaviour. The school will ensure that parents/carers are informed promptly of concerns regarding their child and are given opportunity to be involved in supporting school actions and responding to the needs of their child. Anti-Bullying Code · No-one has the right to make you feel upset. · In the playground make sure that you can always be seen by an adult. · If you think someone is coming to hurt you, walk away or run away. · If someone hits you do not hit back. This is what the person wants you to do so that they have an excuse to hit you again. Tell a teacher, or any adult in the school. You must also tell your parent. · If someone threatens you over and over again, that is bullying. Tell a teacher, or any adult in the school. You must also tell your parent. · If someone tries to force you to give them money, food or something that belongs to you, that is bullying. Never give anyone anything that you don’t want them to have. Tell your teacher, or any adult in the school. You must also tell your parent. REMEMBER TELL SOMEONE AND KEEP ON TELLING THEM UNTIL THEY LISTEN Sometimes adults think you are just “fussing” but the only way a bully will stop is if you tell an adult. So keep on telling them until they listen and do something about it. IF YOU THINK SOMEONE ELSE IS BEING BULLIED TELL SOMEONE The person being bullied may be too frightened to do anything about it. YOU CAN HELP by telling a teacher, or any adult in the school. What Do You Do If You Know Someone Is Being Bullied? a) Take action! Watching and doing nothing looks as if you are on the side of the bully. It makes the victim feel more unhappy and on their own. b) If you feel you cannot get involved, tell an adult immediately. Teachers will deal with the bully without getting you into trouble.

2023-11-28T01:27:04.234600

https://example.com/article/5993

Introduction {#s1} ============ In ruminal fermentation, H~2~ is produced from reducing equivalents released in glycolysis and pyruvate oxidative decarboxylation to acetyl-CoA (Figure [1](#F1){ref-type="fig"}). Methane is the main sink for H~2~ electrons in the rumen (Wolin et al., [@B98]). Interspecies H~2~ transfer from the fermentative community of bacteria, protozoa and fungi to methanogens is of great significance. Methanogenesis allows maintaining a low H~2~ pressure, shifting fermentation away from ethanol and lactate and toward acetate, which allows extra ATP generation by substrate level phosphorylation in acetate formation, and by electron transport-linked-phosphorylation in methanogenesis itself (Russell and Wallace, [@B75]; Wolin et al., [@B98]). However, despite its profound implication to ruminal fermentation, CH~4~ formation constitutes a loss of between 2 and 12% of the gross energy consumed by ruminants (Attwood and McSweeney, [@B10]). Also, CH~4~ emission by livestock is an important source of anthropogenic greenhouse gases emissions (Morgavi et al., [@B56]). {#F1} Because of these environmental and animal production efficiency issues, considerable research on the inhibition of ruminal methanogenesis has been conducted. Inhibition of methanogenesis poses the problem of the incorporation of the electrons not used in CH~4~ formation into alternative pathways. As methanogenesis is inhibited, H~2~ pressure increases, and this thermodynamically favors electron incorporation into propionate (Figure [1](#F1){ref-type="fig"}; Janssen, [@B38]). Nevertheless, incorporation of reducing equivalents spared from methanogenesis into propionate is not complete (Czerkawski, [@B20]), and H~2~ accumulates, especially if CH~4~ production is strongly inhibited, whether *in vitro* (e.g., Trei et al., [@B83]; Stanier and Davies, [@B78]; Sauer and Teather, [@B76]) or *in vivo* (e.g., Trei et al., [@B83]; Nollet et al., [@B62]; Kung et al., [@B44]; Mitsumori et al., [@B54]). It is therefore necessary to conduct research on the incorporation of accumulated H~2~ into electron sinks nutritionally useful to the animal. In order to better guide current research efforts in this area, it would be important to anticipate the outcomes of incorporating H~2~ into different electron sinks. The present theoretical analysis compares the hypothetical energetic and nutritional consequences of incorporating accumulated H~2~ into reductive acetogenesis or additional propionate formation beyond the typical acetate to propionate shift that occurs when methanogenesis is inhibited. Dihydrogen incorporation into a useful electron sink is a necessary part of an integral methanogenesis-inhibition strategy, because it minimizes gaseous digestible energy (DE) losses and avoids fermentation inhibition. Thus, it is important to predict, compare and anticipate how, not only fermentation, but whole animal digestion and metabolism, and hence production, could change if H~2~ was incorporated into different alternative electron sinks. Electron-incorporating processes alternative to methanogenesis other than reductive acetogenesis and propionate production will not be considered in the present analysis. Nitrate and sulphate reduction (Van Zijderveld et al., [@B95]), and reduction of oxygen entering the rumen through the rumen wall and in feed and water (Czerkawski, [@B20]) do not incorporate electrons into energy sources available to ruminants (although nitrate could replace urea as a source of N on an equal moles of N basis). Long chain fatty acids biohydrogenation only uses a small proportion of metabolic hydrogen produced in fermentation (Czerkawski, [@B20]). Microbial biomass synthesis also requires reducing power (Hungate et al., [@B36]), and both theoretical considerations (Czerkawski, [@B20]) and *in vitro* results (Ungerfeld et al., [@B89]; Guo et al., [@B30]) suggests that it can be an important alternative electron sink to CH~4~; however, consequences of methanogenesis inhibition on microbial growth are still incompletely quantified and understood as they involve multiple anabolic pathways in a complex microbial community, and this electron sink is therefore not compared to reductive acetogenesis and propionate production in this analysis. Procedures {#s2} ========== Stoichiometric calculations --------------------------- ### Typical ruminal fermentation Both starch and cellulose are hydrolyzed to glucose; however, the fermentation pattern of starch is lower in acetate to propionate ratio compared to cellulose (Bannink et al., [@B13]). Because acetate production results in the release of reducing equivalents, whereas propionate production incorporates them (Figure [1](#F1){ref-type="fig"}), fermentation of concentrates typically associates with less CH~4~ produced per mol of hexose fermented, as propionate production competes with methanogenesis for reducing equivalents (Czerkawski, [@B20]; Wolin et al., [@B98]). Two typical example fermentation stoichiometries for roughage- (Equation 1) and concentrate-based (Equation 2) diets are provided below. In Equation 1 (roughage), 1 mol of glucose is fermented to VFA and gases with 4 to 1 acetate to propionate ratio; in Equation 2 (concentrate), 1 mol of glucose is fermented to VFA and gases with 1.5 to 1 acetate to propionate ratio: $$\begin{array}{l} \left. \text{C}_{6}\text{H}_{12}\text{O}_{6}\rightarrow 4/3\text{CH}_{3}\text{COO}^{-} + 1/3\text{CH}_{3}\text{CH}_{2}\text{COO}^{-} \right. \\ {\text{\quad~~~~~~~~~~~~~~~} + 1/6\text{CH}_{3}\text{CH}_{2}\text{CH}_{2}\text{COO}^{-} + 11/6\text{H}^{+}} \\ {\text{\quad~~~~~~~~~~~~~~~} + \text{CO}_{2} + 2/3\text{CH}_{4} + 1/3\text{H}_{2}\text{O}} \\ \end{array}$$ $$\begin{array}{l} \left. \text{C}_{6}\text{H}_{12}\text{O}_{6}\rightarrow 12/13\text{CH}_{3}\text{COO}^{-} + 8/13\text{CH}_{3}\text{CH}_{2}\text{COO}^{-} \right. \\ {\text{\quad~~~~~~~~~~~~~~} + 3/13\text{CH}_{3}\text{CH}_{2}\text{CH}_{2}\text{COO}^{-} + 23/13\text{H}^{+}} \\ {\text{~~~~~~~~~~~~~~~~~~} + 25/26\text{CO}_{2} + 11/26\text{CH}_{4} + 7/13\text{H}_{2}\text{O}} \\ \end{array}$$ Acetate to propionate ratios for high-roughage and high-concentrate diets were obtained from a compilation of 300 treatment means from 79 *in vivo* studies in which ruminal VFA concentrations were reported (Figure [2](#F2){ref-type="fig"}; Ungerfeld, unpublished). Production of valerate, caproate and branched-chain VFA are not considered for the sake of simplification. It is also important to note that VFA proportions are also affected by factors other than the chemical fraction fermented (Bannink et al., [@B12]). {#F2} ### Methanogenesis-inhibited ruminal fermentation When methanogenesis is inhibited, reducing equivalents are diverted into alternative electron sinks. Some of these alternative electron sinks are typical to ruminal fermentation, like propionate (Czerkawski, [@B20]; Wolin et al., [@B98]; Janssen, [@B38]) and microbial growth (Czerkawski, [@B20]; Ungerfeld et al., [@B89]; Guo et al., [@B30]); in contrast, intermediate metabolites that are usually present at very low concentration or pressure, like H~2~ (Janssen, [@B38]) or format (Czerkawski, [@B20]), accumulate. A hypothetical situation in which methanogenesis in the roughage diet of Equation 1 is inhibited by 92% (similar extent of inhibition: Nollet et al., [@B60]; Goel et al., [@B29]; Tomkins et al., [@B82]; Mitsumori et al., [@B54]), with resulting H~2~ accumulation, is represented in Equation 3: $$\begin{array}{l} \left. \text{C}_{6}\text{H}_{12}\text{O}_{6} + 3/5\,\text{H}_{2}\text{O} + 66\text{X}/59\,\rightarrow 70/59\,\text{CH}_{3}\text{COO}^{-} \right. \\ {\quad + 28/59\,\text{CH}_{3}\text{CH}_{2}\text{COO}^{-} + 10/59\,\text{CH}_{3}\text{CH}_{2}\text{CH}_{2}\text{COO}^{-}} \\ {\quad + 108/59\,\text{H}^{+} + 867/590\text{CO}_{2} + 264/295\,\text{H}_{2} + 33/590\,\text{CH}_{4}} \\ {\quad + 66\text{X}\lbrack 2\text{H}\rbrack/59} \\ \end{array}$$ The sum of electron sinks other than CH~4~, propionate and H~2~ (i.e., mainly microbial biomass and formate) are represented in Equation 3 by the term X\[2H\], accounting in this example for 32% of total electron-pairs incorporated. The shift in the acetate to propionate ratio from 4 to 1 to 2.5 to 1 in Equation 3 with respect to Equation 1 resulted in propionate formation increasing its participation as an electron sink from 18% in Equation 1 to 27% in Equation 3; similar shifts in the acetate to propionate ratio as a consequence of methanogenesis inhibition were reported by Ungerfeld et al. ([@B87], [@B88]) *in vitro* and Mitsumori et al. ([@B54]) *in vivo*. Participation of CH~4~ as electron sink decreased from 73 to 6%, and the remaining 33% electron-pairs accumulated as H~2~ (calculations not shown). If the amount of hexose fermented does not change, C in the extra microbial biomass would come partly from less C in fermentation products (Dijkstra et al., [@B22]). The C shift from fermentation products to microbial biomass was not considered in Equation 3 in order to maintain the C balance explicit between fermented hexose and VFA and gases. It is important to consider that, although the stoichiometric changes chosen are arbitrary, they do not affect the energetic and nutritional comparison that will be conducted between reductive acetogenesis and additional propionate as potential electron sinks for the accumulated H~2~. This is because, for any fermentation stoichiometry alternative to Equation 3 that could be chosen, the simulation that will be conducted would still compare the outcome of incorporating the same amount of accumulated H~2~ into either reductive acetogenesis or additional propionate formation. ### Reductive acetogenesis Reductive acetogenesis involves the reduction of CO~2~ by H~2~ to acetate: $$\left. 2\,\text{CO}_{2} + 4\,\text{H}_{2}\rightarrow\text{CH}_{3}\text{COO}^{-} + \text{H}^{+} + 2\,\text{H}_{2}\text{O} \right.$$ Multiples of Equation 3 and 4 can be added up to result in different proportions of the accumulated H~2~ of Equation 3 being converted to acetate through reductive acetogenesis. Because H~2~ in Equation 3 is limiting in its ratio to CO~2~ in relation to the H~2~ to CO~2~ stoichiometry in Equation 4, reductive acetogenesis could, in theory, incorporate 100% of the accumulated H~2~ in Equation 3: $$\begin{array}{l} \left. \text{C}_{6}\text{H}_{12}\text{O}_{6} + 9/59\,\text{H}_{2}\text{O} + 66\text{X}/59\rightarrow 416/295\,\text{CH}_{3}\text{COO}^{-} \right. \\ {\quad + 28/59\,\text{CH}_{3}\text{CH}_{2}\text{COO}^{-} + 10/59\,\text{CH}_{3}\text{CH}_{2}\text{CH}_{2}\text{COO}^{-}} \\ {\quad + 606/295\,\text{H}^{+} + 603/590\,\text{CO}_{2} + 33/590\,\text{CH}_{4}} \\ {\quad + 66\text{X}\lbrack 2\text{H}\rbrack/59} \\ \end{array}$$ Total incorporation of H~2~ is a theoretical limit; even in the typical ruminal fermentation with functional methanogenesis, H~2~ concentration varies between 0.1 and 50 μM (Janssen, [@B38]). Generalizing Equation 5, incorporation of a positive fraction of accumulated H~2~ smaller or equal than unity into reductive acetogenesis is equal to: $$\begin{array}{l} \left. \text{C}_{6}\text{H}_{12}\text{O}_{6} + (177 - 132y)/295\,\text{H}_{2}\text{O} + 66\text{X}/59\rightarrow \right. \\ {\quad(350 + 66y)/295\,\text{CH}_{3}\text{COO}^{-} + 28/59\,\text{CH}_{3}\text{CH}_{2}\text{COO}^{-}} \\ {\quad + 10/59\,\text{CH}_{3}\text{CH}_{2}\text{CH}_{2}\text{COO}^{-} + (540 + 66y)/295\,\text{H}^{+}} \\ {\quad + (867 - 264y)/590\,\text{CO}_{2} + 264(1 - y)/295\,\text{H}_{2}} \\ {\quad + 33/590\,\text{CH}_{4} + 66\text{X}\lbrack 2\text{H}\rbrack/59} \\ \end{array}$$ where *y* is the proportion of accumulated H~2~ incorporated into reductive acetogenesis, 0 ≤ *y* ≤ 1. ### Propionate formation Some propionate producers utilize H~2~ for reducing fumarate to succinate (Figure [1](#F1){ref-type="fig"}; Henderson, [@B32]). In agreement, an increase in H~2~ concentration thermodynamically stimulates propionate production (Janssen, [@B38]). Thus, accumulated H~2~ could, theoretically, be also utilized toward the formation of more propionate beyond the acetate to propionate shift typically associated to the inhibition of ruminal methanogenesis (i.e., further than the acetate to propionate shift of Equation 3 with respect to Equation 1). If the amount of fermented hexoses remains constant, C utilized to produce additional propionate would represent C in fermented hexoses not metabolized to other VFA or not used in anabolism. In the present analysis, it will be assumed that each extra mol of propionate is formed at the expense of 1 mol of acetate that is not produced, i.e., an acetate to propionate fermentation shift beyond that one typically observed associated with methanogenesis inhibition. For each mol of acetate that is not produced, 2 mol of reducing equivalents-pairs are not released: $$\begin{array}{l} \left. \text{C}_{6}\text{H}_{12}\text{O}_{6} + 2\,\text{H}_{2}O\rightarrow 2\,\text{CH}_{3}\text{COO}^{-} + 2\text{H}^{+} \right. \\ {\quad + 2\,\text{CO}_{2} + 4 \times \lbrack 2\text{H}\rbrack} \\ \end{array}$$ Then, propionate formation competes for C with its major source of reducing equivalents, acetate formation. The acetate to propionate fermentation shift that redirects C and H~2~ toward propionate production is depicted in Equation 8: $$\left. \text{CH}_{3}\text{COO}^{-} + \text{CO}_{2} + 3\,\text{H}_{2}\rightarrow\text{CH}_{3}\text{CH}_{2}\text{COO}^{-} + 2\,\text{H}_{2}\text{O} \right.$$ Incorporation of 100% of accumulated H~2~ in Equation 3 into propionate formation would result in: $$\begin{array}{l} \left. \text{C}_{6}\text{H}_{12}\text{O}_{6} + 1/295\,\text{H}_{2}\text{O} + 66\text{X}/59\rightarrow 262/295\,\text{CH}_{3}\text{COO}^{-} \right. \\ {\quad + 228/295\,\text{CH}_{3}\text{CH}_{2}\text{COO}^{-} + 10/59\,\text{CH}_{3}\text{CH}_{2}\text{CH}_{2}\text{COO}^{-}} \\ {\quad + 108/59\,\text{H}^{+} + 691/590\,\text{CO}_{2} + 33/590\,\text{CH}_{4}} \\ {\quad + 66\text{X}\lbrack 2\text{H}\rbrack/59} \\ \end{array}$$ Equation 9 generalizes for any positive fraction of accumulated H~2~ smaller or equal than unity incorporated into extra propionate (*z*) as: $$\begin{array}{l} \left. \text{C}_{6}\text{H}_{12}\text{O}_{6} + (177 - 176z)/295\,\text{H}_{2}\text{O} + 66X/59\rightarrow \right. \\ {\quad(350 - 88z)/295\,\text{CH}_{3}\text{COO}^{-} + (140 + 88z)/295\,\text{CH}_{3}\text{CH}_{2}\text{COO}^{-}} \\ {\quad + 10/59\,\text{CH}_{3}\text{CH}_{2}\text{CH}_{2}\text{COO}^{-} + 108/59\,\text{H}^{+} + (867 - 176z)/590\,\text{CO}_{2}} \\ {\quad + 264(1 - z)/295\,\text{H}_{2} + 33/590\,\text{CH}_{4} + 66\text{X}\lbrack 2\text{H}\rbrack/59} \\ \end{array}$$ where 0 ≤ *z* ≤ 1. Simulated fermentation ---------------------- Stoichiometric responses in production of VFA and gases per mole of hexose fermented to H~2~ incorporation into reductive acetogenesis or additional propionate, were calculated as *y* or *z* in Equation 6 and 10, respectively, varied between 0 and 1. The kinetics of reductive acetogenesis or additional propionate production, if they were thermodynamically feasible, could vary under different conditions. This analysis does not specify an incubation timeframe (if a batch culture system) or a fermentation rate (if a continuous culture system). Also, it was assumed that incorporation of electrons into other processes remained constant as accumulated H~2~ was incorporated into reductive acetogenesis or propionate formation. Results with total incorporation of accumulated H~2~ into reductive acetogenesis or additional propionate production (i.e., Equation 5 and 9, respectively) were also compared to the corresponding roughage fermentation with CH~4~ as main electron sink and no H~2~ accumulation (Equation 1). Results {#s3} ======= As expected, the acetate to propionate ratio varied in opposite directions as accumulated H~2~ was incorporated into either reductive acetogenesis or additional propionate production, reaching 2.97 and 1.15 for total accumulated H~2~ incorporation into reductive acetogenesis and additional propionate production, respectively, (Figure [3](#F3){ref-type="fig"}). Hydrogen incorporation into reductive acetogenesis increased total VFA production, whereas H~2~ incorporation into additional propionate production did not change total VFA production because each additional mol of propionate was formed at the expense of one mol of acetate not produced (Figure [4](#F4){ref-type="fig"}). {#F3} {#F4} Heat (or enthalpy) of combustion is equal to the total energy released as heat by complete oxidation of a compound to CO~2~ and H~2~O at constant pressure. Whereas heat of combustion in gaseous fermentation products like CH~4~ and H~2~ is lost to the atmosphere, VFA are absorbed through the rumen wall and are the main energy source for ruminants. Heat of combustion in VFA is then accounted as metabolizable energy (ME), as gaseous DE (DE in this analysis corresponds to energy in hexoses available for fermentation) losses have been discounted. Volatile fatty acids heats of combustion obtained from Kohn and Boston ([@B41]) were used to calculate how heat of combustion output in VFA per mol of hexose fermented could vary whether accumulated H~2~ was incorporated into reductive acetogenesis or additional propionate (Figure [5](#F5){ref-type="fig"}). The responses in heat of combustion in VFA were virtually identical for H~2~ incorporation into reductive acetogenesis or additional propionate formation. Total H~2~ incorporation into either process resulted in a 12% gain in heat of combustion output in VFA compared to the corresponding fermentation with CH~4~ as main electron sink. {#F5} Even though incorporation of accumulated H~2~ into both reductive acetogenesis and additional propionate formation resulted in less CO~2~ released per mole of fermented hexose (not shown) due to CO~2~ incorporation into acetate or propionate, respectively, CO~2~ molar fraction in total gas produced actually increased (not shown). This is because the number of moles of H~2~ incorporated into either pathway was proportionally greater than the incorporation of CO~2~ \[the ratio between H~2~ and CO~2~ incorporated was of 2 to 1 for reductive acetogenesis (Equation 4) and of 3 to 1 for additional propionate formation (Equation 8)\], and the small amount of CH~4~ remained constant. The implication is that, if total gas pressure remained constant (i.e., \~10^5^ Pa), CO~2~ pressure would actually increase as H~2~ was incorporated into reductive acetogenesis or additional propionate formation, because greater number of H~2~ moles relative to CO~2~ would be incorporated into either pathway (not shown). Gibbs energy change (or Gibbs free energy change; ΔG) of a chemical reaction is the theoretical limit to the amount of work that can be extracted from that reaction at constant pressure and temperature; because this limit would theoretically only be reached in a completely reversible reaction, it is never reached in a real non-equilibrium system. Reactions with negative ΔG (exergonic) occur spontaneously provided their activation energy is overcome (catalysts decrease the activation energy of the reaction, allowing it to proceed faster). Reactions with positive ΔG (endergonic) are non-spontaneous i.e., they are thermodynamically unfeasible unless coupled to a reaction with negative ΔG larger in absolute value. Reactions with ΔG equal to zero are at equilibrium and their forward rate is equal to their reverse rate. Gibbs energy change was calculated both for incorporation of accumulated H~2~ into reductive acetogenesis or propionate production (Figure [6](#F6){ref-type="fig"}), and for the complete fermentation of glucose to VFA and gases for both electron-incorporating processes (Figure [7](#F7){ref-type="fig"}), as H~2~ incorporation varied between 0 and 100%, assuming a total gas pressure of 10^5^ Pa. Standard ΔG of formation of metabolites in Equation 1, 6 and 10 were obtained from Kohn and Boston ([@B41]) and Karadagli and Rittman ([@B40]). Gibbs energy changes were adjusted to a ruminal temperature of 39°C through the Van\'t Hoff equation (Kohn and Boston, [@B41]). Partial pressure for each gas was calculated from the Ideal Gas Law, and dissolved gases concentrations were calculated from Henry\'s Law (Kohn and Boston, [@B41]; Janssen, [@B38]). Glucose concentration was assumed to be 6 × 10^−4^ M (Janssen, [@B38]). Water concentration was assumed to be 50 M (Kohn and Boston, [@B41]). It is acknowledged that the upper limit of H~2~ pressure in Figure [6](#F6){ref-type="fig"} is high for most methanogenesis-inhibition experiments, but similar values have been reported in some *in vitro* batch culture (Van Nevel et al., [@B94]; O\'Brien et al., [@B63]) and *in vivo* (Rufener and Wolin, [@B74]; Trei et al., [@B83], [@B84]; Kung et al., [@B44]) experiments where methanogenesis was inhibited. {#F6} {#F7} Figure [6](#F6){ref-type="fig"} depicts the thermodynamic feasibility of further incorporation of accumulated H~2~ into reductive acetogenesis (Equation 4) or propionate formation from acetate, CO~2~ and H~2~ (Equation 8) with varying H~2~ pressure resulting from different percentages of accumulated H~2~ incorporation into either pathway. Gibbs energy change of methanogenesis corresponding to a low and a high H~2~ concentration of 0.2 and 2.3 μM, respectively, is shown as reference (low and high H~2~ concentration values for high forage diets were obtained from Janssen, [@B38], and converted to pressure using Henry\'s Law). As H~2~ pressure approached typical ruminal levels, both reductive acetogenesis and conversion of acetate to propionate rapidly approached equilibrium, as described by Ungerfeld and Kohn ([@B86]), whereas, expectedly, methanogenesis was still thermodynamically favorable (Kohn and Boston, [@B41]). Figure [7](#F7){ref-type="fig"} shows how the entire fermentation ΔG responded to varying H~2~ pressure resulting from accumulated H~2~ incorporation into reductive acetogenesis (Equation 6) or additional propionate formation (Equation 10), along with the corresponding roughage fermentation with CH~4~ as main electron sink (Equation 1). Estimated ΔG was comparable for both fermentation processes and varied little as accumulated H~2~ was incorporated into either reductive acetogenesis or additional propionate formation. Fermentation with CH~4~ as main electron sink was more favorable than theoretical 100% incorporation of accumulated H~2~ into either reductive acetogenesis or additional propionate formation. Discussion {#s4} ========== Consequences of incorporation of accumulated H~2~ resulting from methanogenesis inhibition into reductive acetogenesis or additional propionate will be discussed with respect to four aspects of ruminant nutrition interest: fermentation energetics, microbial protein production, ruminal pH, and VFA post-absorptive metabolism. Fermentation energetics ----------------------- The energetic equivalence of incorporating accumulated H~2~ into reductive acetogenesis or additional propionate is a result of the stoichiometries of both processes and of acetate and propionate heats of combustion. Reduction of 2 mol of CO~2~ with 4 mol of H~2~ to produce 1 mol of acetate results in a gain in heat of combustion in acetate per electron-pair incorporated equal to 876 kJ/4 mol H~2~ = 219 kJ/mol H~2~. Incorporation of 3 mol of H~2~ to produce 1 mol of propionate at the expense of 1 mol of acetate not being produced (Equation 9) results in a gain in heat of combustion in propionate per electron-pair incorporated equal to: (1529--876 kJ)/3 mol H~2~ = 218 kJ/mol H~2~. Ultimately, this result is predicted by the balance of the different types of chemical bonds broken and made (calculations not shown); even though incorporating accumulated H~2~ into reductive acetogenesis would result in greater total C retention in VFA compared to propionate production (not shown), a mole of propionate contains twice as many C atoms moles susceptible to be oxidized (i.e., methyl and methylene groups) than a mole of acetate, and total methyl plus methylene groups formed would be actually slightly greater if accumulated H~2~ was incorporated into propionate (Figure [8](#F8){ref-type="fig"}). {#F8} Incorporation of H~2~ into either reductive acetogenesis or propionate production resulted in an increase in heat of combustion in VFA of about 12% with respect to the corresponding fermentation with CH~4~ as main electron sink. As discussed, this energy gain corresponds to ME. Given that a range of 2 to 12% gross energy is lost as CH~4~ (Attwood and McSweeney, [@B10]), the corresponding range for a roughage diet of, for example, 60% energy metabolisability, would be 3 to 20%. Therefore, the proportion of ME lost as CH~4~ agrees with previous sources (Attwood and McSweeney, [@B10]). Apart from what could be the energetic consequence of incorporating accumulated H~2~ into reductive acetogenesis or propionogenesis, a very important question is, of course, why neither process is the main electron sink in ruminal fermentation, and methanogenesis is instead the dominant electron sink.. It has been shown that reductive acetogenesis is negligible in ruminal incubations (Nollet et al., [@B60]; Le Van et al., [@B46]), and attempts to induce it by adding reductive acetogens have been unsuccessful (López et al., [@B51]). Reductive acetogens have been isolated from the rumen (Leedle and Greening, [@B48]) and identified using molecular techniques (Henderson et al., [@B33]), but they seem to rely on mixotrophic growth i.e., substrates other than CO~2~ and H~2~, and to use diverse electron acceptors (Joblin, [@B39]; Drake et al., [@B23]). As a redox process, methanogenesis has a lower H~2~ threshold than reductive acetogenesis (Cord-Ruwisch et al., [@B18]), which allows methanogens to lower H~2~ partial pressure at a level at which reductive acetogenesis is thermodynamically unfeasible; reductive acetogenesis has been estimated to be close to equilibrium at ruminal conditions even without considering ATP generation (Kohn and Boston, [@B41]). Thus, adding reductive acetogens to rumen fermentation only enhances reductive acetogenesis enzyme kinetics, whereas the process is thermodynamically limited and therefore methanogenesis remains dominating. Two different low H~2~-threshold acetogens decreased methanogenesis between 64 and 97% when co-cultured with *Methanobrevibacter* sp. (Joblin, [@B39]); however, these co-cultures were grown under elevated H~2~ pressure, which would remove methanogenesis thermodynamic advantage, as opposed to ruminal conditions, where H~2~ originates only from fermentation. This experiment though would demonstrate a kinetic advantage in terms of *V*~max~ for utilizing H~2~ of these acetogens over their *Methanobrevibacter* competitor when reductive acetogenesis thermodynamic disadvantage was overcome. It is suggested to repeat this kind of experiments both in the presence of external H~2~ and as tri-cultures with H~2~-producing organisms. Similarly, the presence of a live yeast enhanced the competitive capacity of a reductive acetogen against a methanogen (Chaucheyras et al., [@B16]), but this again happened when the thermodynamic constraint to reductive acetogenesis was removed by growing the tri-culture under artificially elevated H~2~ pressure. Whereas it does not occur in the rumen, reductive acetogenesis co-exists with or even dominates over methanogenesis in other gut environments: wood-digesting termites, rodents, pigs, humans (Joblin, [@B39]), young rabbits (Piattoni et al., [@B72]), marsupials (Ouwerkerk et al., [@B68]), ostriches (Fievez et al., [@B26]), newborn lambs (Morvan et al., [@B57]) and ruminant hindguts (Immig, [@B37]), contributing to the host animal energetic requirements. Addition of the reductive acetogen *Peptostreptococcus productus* ATCC35244 to an *in vitro* reactor simulating the human gut inoculated with human faces resulted in a decrease in methanogenesis to a level below detection limit (Nollet et al., [@B61]), but did not affect methanogenesis in ruminal incubations (Nollet et al., [@B60]). It is therefore important to understand the reasons for why reductive acetogenesis occurs in those environments and does not occur in the rumen. Despite methanogenesis being thermodynamically more favorable than reductive acetogenesis, conditions like low pH or low temperature can diminish methanogenesis and make reductive acetogenesis more competitive in certain freshwater lake sediments, flooded rice paddies or tundra wetland soils (Drake et al., [@B23]). Transiently elevated H~2~ concentration in marine sediments resulting from a low sulphate concentration period allowed reductive acetogenesis to become thermodynamically feasible (Hoehler et al., [@B35]). In the wood-feeding termite *Reticulitermes flavipes* hindgut, reductive acetogens occupy the more reduced lumen with high H~2~ pressure, and methanogens are displaced to the micro-oxic periphery (Ebert and Brune, [@B24]). Association of reductive acetogens to H~2~-producing protozoa in the termite gut also seems to contribute to favoring reductive acetogenesis over methanogenesis in that environment (Leadbetter et al., [@B47]). In agreement, reductive acetogenesis seems to be an important hydrogen sink in the ruminant hindgut, where protozoa are absent (Immig, [@B37]). However, an explanation is yet missing for why spatial differences that may allow reductive acetogenesis becoming thermodynamically feasible in wood-feeding termite hindguts do not occur in the rumen i.e., why ruminal reductive acetogens do not displace methanogens from the more reducing microniches and why they do not associate with protozoa. Perhaps, rates of H~2~ production in environments like the wood-feeding termites hindgut lumen are greater than in the rumen and remove thermodynamic constraints to reductive acetogenesis. Under those conditions reductive acetogenesis could become dominant if reductive acetogens had a greater capacity to utilize H~2~ at high concentration (i.e., higher *V*~max~) than methanogens; then, as H~2~ availability decreases toward the termite hindgut periphery, reductive acetogenesis would become thermodynamically unfeasible and methanogenesis would become the H~2~ sink close to the hindgut epithelium. It is also possible that at low H~2~ pressure methanogens rely on a lower *K*~m~ for H~2~ to establish in the termite gut periphery. Although I am not aware of measured kinetic parameters of methanogens and reductive acetogens competing for H~2~ in the same environment, it has been proposed that microbial specialists (methanogens in this case) have greater affinities for the substrates they compete for than their generalist competitors (Lever, [@B49]). As opposed to reductive acetogenesis, propionate production is already an electron sink in ruminal fermentation, but second to methanogenesis with regard to its quantitative importance. As it has been shown, CH~4~ production and the VFA profile are intimately related. From a purely stoichiometric point of view, propionate could, theoretically, replace CH~4~ as an electron sink. For example: $$\begin{array}{l} \left. \text{C}_{6}\text{H}_{12}\text{O}_{6}\rightarrow 2/3\,\text{CH}_{3}\text{COO}^{-} + 4/3\,\text{CH}_{3}\text{CH}_{2}\text{COO}^{-} + 2\,\text{H}^{+} \right. \\ {\text{~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~} + 2/3\,\text{CO}_{2} + 2/3\,\text{H}_{2}\text{O}} \\ \end{array}$$ It is clear, however, that the stoichiometry proposed in Equation 11 is well outside what is observed for ruminal fermentation. The question that then arises is: is the competition between methanogenesis and propionate production for metabolic hydrogen in the rumen controlled by thermodynamics or by affinity for H~2~? Co-culturing of succinate and propionate producers with methanogens resulted in a decrease in succinate or propionate production (Chen and Wolin, [@B17]; Latham and Wolin, [@B45]; Marvin-Sikkema et al., [@B52]). In my opinion, those shifts in fermentation in co-cultures cannot not be explained by affinity for H~2~, because H~2~ transferred to methanogens needs to be first produced by hydrogenases in the fermentative organism; any competition for H~2~ must have been preceded by an intracellular shift in the flux of metabolic hydrogen driven either by thermodynamics or by kinetic competition between hydrogenases and fumarate or acrylyl-CoA reductases for NADH. Of course, the above results with co-cultures apply to organisms possessing the metabolic capacity to produce propionate or succinate, but not necessarily to the competition for H~2~ produced by the mixed microbiota that does not have this capacity. At least some propionate producers are able to use H~2~ to reduce fumarate to succinate (Henderson, [@B32]), which is manifested by the shift from acetate to propionate production occurring with an increase in H~2~ pressure (Janssen, [@B38]). How is then the competition between methanogens and propionate producers for the extracellular H~2~ pool controlled? It has been shown that methanogens have a lower *K*~m~ for H~2~ than fumarate reducers (Russell and Wallace, [@B75]; Asanuma et al., [@B7]). On the other hand, an analysis derived from published values concluded that opposite interconversion flows between VFA (i.e., Equation 8) are generally similar, which was interpreted as an indication that VFA are close to equilibrium much of the time, and that the range of VFA ratios commonly observed for ruminal fermentation, and hence CH~4~ production, could be the result of thermodynamic control (Ungerfeld and Kohn, [@B86]). Another important problem is that, as discussed, even in the methanogenesis-inhibited ruminal fermentation, neither reductive acetogenesis nor propionate production, incorporate the totality of reducing equivalents from inhibited CH~4~, as manifested by the fact that H~2~ accumulates. The question, therefore, is why H~2~ accumulates instead of being incorporated into reductive acetogenesis or propionate production or both. Organisms conducting the pathways depicted en Equation 4 and 8 would need to utilize some of the negative ΔG associated to those reactions to generate ATP to make their own endergonic anabolic reactions thermodynamically feasible to grow fast enough so as to not get washed out of the rumen. Gibbs energy change of ATP hydrolysis to ADP and phosphate is about −50 kJ/mol (Voet and Voet, [@B96]). Then, the ΔG needed for the reverse reaction, the generation of 1 mol of ATP, appears to be similar to the ΔG of reductive acetogenesis (Equation 4) and propionate production from acetate, CO~2~ and H~2~ (Equation 8) at 37 kPa H~2~ (0% incorporation of accumulated H~2~; Figure [6](#F6){ref-type="fig"}). This may therefore be taken as an indication that H~2~ accumulation in the methanogenesis-inhibited rumen results from the system reaching thermodynamic equilibrium regarding further incorporation of H~2~ reducing equivalents into reductive acetogenesis or propionate production. However, this interpretation would conflict with the decrease in H~2~ pressure observed upon addition of reductive acetogens to methanogenesis-inhibited batch cultures (Nollet et al., [@B60]; Le Van et al., [@B46]; López et al., [@B51]). Yet, organisms growing in batch cultures do not get washed out, and perhaps they could survive generating less than 1 ATP mol through ion gradient-driven phosphorylation per mol of acetate (Equation 4) or propionate (Equation 8) produced. Also, the discrepancy between the thermodynamic calculation for reductive acetogenesis in Figure [6](#F6){ref-type="fig"} and the experimental *in vitro* results (Nollet et al., [@B60]; Le Van et al., [@B46]; López et al., [@B51]) could be explained by H~2~ oversaturation in the liquid phase, where it is generated, with respect to the gas phase, which would result in H~2~-utilizing reactions being more favorable for microbes than what calculations assuming H~2~ saturation would suggest (Hackmann, [@B31]). Furthermore, H~2~ gradients exist in anaerobic environments (Boone et al., [@B14]), and are likely to exist between liquid and particle ruminal compartments (Czerkawski, [@B20]), making some reactions more favorable at particular locations. An example of a ruminal H~2~ gradient is the physical association of some methanogens with protozoa to be closer to a H~2~ source (Morgavi et al., [@B56]). Through adding propionate formation intermediates, Tatsuoka et al. ([@B79]) and Ebrahimi et al. ([@B25]) had some success at decreasing H~2~ accumulation in methanogenesis-inhibited ruminal batch incubations, which would indicate, that at least under their conditions, propionate formation was limited by thermodynamics or substrate kinetics (through the availability of a C skeleton). Fonty et al. ([@B27]) found that addition of fumarate to a methanogen-free ruminal incubation accelerated H~2~ utilization without affecting its final point at 24 h, which would suggest a limitation of a substrate kinetic nature. Microbial protein production ---------------------------- With most ruminant diets, microbial protein is the principal source of amino acids for the host animal (Bach et al., [@B11]). It is also the cheapest one, as ruminants can use N sources with no nutritional value to non-ruminants (Wallace et al., [@B97]). Microbial protein synthesis can be understood as the product between the number of moles of ATP generated in fermentation and the amount of protein synthesized per mole of ATP hydrolyzed. Generation of ATP is made possible by negative ΔG of fermentation reactions. Fermentation ΔG for incorporation of accumulated H~2~ into reductive acetogenesis or additional propionate formation was estimated to be similar (Figure [7](#F7){ref-type="fig"}). However, only part of fermentation ΔG in Figure [7](#F7){ref-type="fig"} is available to generate ATP; if all of ΔG associated to fermentation was coupled to an endergonic process like ATP generation, fermentation would be at equilibrium and come to a halt. It is difficult to compare Equation 6 and 10 with regard to ATP generation. Generation of ATP associated to ion-gradient-driven phosphorylation occurs both in reductive acetogenesis (Müller, [@B58]), the propionate randomizing pathway (Russell and Wallace, [@B75]), and methanogenesis (Thauer et al., [@B80]), and the stoichiometry of ATP generation per pair of electrons may not be constant (Reddy and Peck, [@B73]; Kröger and Winkler, [@B43]; Thauer et al., [@B80]). In addition, ATP generation in propionate production would vary depending on the mechanism of oxaloacetate formation and the ratio of C flow through the randomizing (via oxaloacetate and succinate) vs. non-randomizing (via lactate) pathway (Russell and Wallace, [@B75]). Thus, the proportion of fermentation ΔG in Figure [7](#F7){ref-type="fig"} actually utilized by cells to generate ATP is unknown and could vary depending on the organism and conditions. The typical roughage fermentation with CH~4~ as main electron sink depicted in Equation 1 appeared to be more exergonic than either Equation 6 or Equation 10 at any point of H~2~ accumulation (Figure [7](#F7){ref-type="fig"}), and, perhaps could conserve greater ΔG per mol of glucose fermented. On the other hand, methanogenesis inhibition *in vitro* has resulted in an increase in microbial N production (Ungerfeld et al., [@B89]; Guo et al., [@B30]), possibly due to greater availability of reducing equivalents for anabolic reactions (Czerkawski, [@B20]). Thus, even if methanogenesis inhibition resulted in a less exergonic fermentation, production of microbial N protein might still be favored because synthetic reactions could become energetically less costly (Czerkawski, [@B20]). More experimentation is needed to understand the effects of methanogenesis inhibition on microbial growth, and alternative explanations to stimulation of anabolic reactions have been proposed. Ungerfeld et al. ([@B89]) also speculated that the methanogenesis inhibitor propynoic acid might have improved microbial growth and efficiency through protozoal inhibition, although protozoa were not quantified in that study. Lila et al. ([@B50]) and Mohammed et al. ([@B55]) did not find changes in protozoal numbers as a consequence of inhibiting CH~4~ production in ruminal batch incubations. Microbial biomass production was not measured in those studies. The second factor determining the microbial protein production is the amount of protein synthesized per mole of ATP hydrolyzed. Anabolic efficiency is influenced by factors such as the presence of glucose phosphotransferase transport systems, disaccharides phosphorylases, energy conservation through transmembrane electrochemical gradients, variation in cell composition, variation in maintenance energy, and energy-spilling reactions (Russell and Wallace, [@B75]). It is unknown how mixed microbial populations conducting the pathways depicted in Equation 6 and 10 could compare with regards to those factors. Because they use the reductive acetyl-CoA pathway for both C fixation and catabolism, it has been speculated that reductive acetogens might be able to survive and replicate maintaining smaller genomes and fewer enzymes, which could decrease their energy requirements (Lever, [@B49]). Experimentation would be needed to understand how incorporation of accumulated H~2~ into reductive acetogenesis or propionate production can affect microbial protein production. Ruminal pH ---------- Incorporation of accumulated H~2~ into reductive acetogenesis would result in increased total VFA production, whereas additional propionate formation would not affect it (Figure [4](#F4){ref-type="fig"}). The relationship between VFA concentration and pH was weak across studies with different diets (Allen, [@B1]), but for this analysis a common basal diet is assumed, and possible changes in ruminal pH are discussed as the sole consequence of H~2~ incorporation into reductive acetogenesis or propionate production. Changes in VFA concentration need not reflect changes in VFA production proportionally, as VFA absorption also increases (Penner et al., [@B70], [@B71]); therefore, the calculation that follows represents an upper limit to pH decrease as a consequence of greater VFA production. Assuming a hypothetical but realistic total VFA concentration of 100 mM for maximum H~2~ accumulation (Equation 3), total incorporation of accumulated H~2~ into reductive acetogenesis (Equation 5) could result in a total VFA concentration of 112 mM due to maximal additional 12 mM acetate (calculation from Figure [4](#F4){ref-type="fig"}), if greater VFA production was not compensated to any extent by greater absorption. Buffering capacity (BC) of a solution is the molar H^+^ concentration required to cause a change in pH, at a certain pH: BC = *d*H^+^/*d*pH (Counotte et al., [@B19]). Ruminal fluid BC reported in various studies is summarized in Table [1](#T1){ref-type="table"}. Then, the expected decrease in pH for the maximum extra 12 mM H^+^ due to an additional 12 mM acetate concentration would be equal to −0.012 M/-BC. ###### **Ruminal fluid buffering capacity determinations and estimated maximal pH decrease for H~2~ incorporation into reductive acetogenesis**. **Reference** **BC (average and range, M H^+^/pH unit)** **pH of BC determination** **Calculated pH decrease** -------------------------------------------------------------- -------------------------------------------- -------------------------------------------- ---------------------------- Turner and Hodgetts ([@B85])[^a^](#TN1){ref-type="table-fn"} 0.028 (0.013--0.042) 5.80--6.90 0.63 Hodgson and Thomas ([@B34]) 0.071 (0.062--0.076) 5.54--6.84 0.37 Counotte et al. ([@B19])[^b^](#TN2){ref-type="table-fn"} 0.038 (0.021--0.063) 6.2[^c^](#TN3){ref-type="table-fn"} 0.52 Murphy et al. ([@B59])[^d^](#TN4){ref-type="table-fn"} 0.013 (0.009--0.02) 7[^e^](#TN5){ref-type="table-fn"} 1.12 Tissera et al. ([@B81]) 0.037 (0.037--0.038) 5.5 to 5.0[^f^](#TN6){ref-type="table-fn"} 0.52 Froetschel and Amos ([@B28])[^b^](#TN2){ref-type="table-fn"} 0.046 (0.044--0.048) 6.2[^g^](#TN7){ref-type="table-fn"} 0.46 Determined under a CO~2~ and N~2~ mixture (proportions not reported). Determined under CO~2~. Ruminal fluid pH was 6.09--7.20. Determined under a 50:50 CO~2~:N~2~ mixture and a 5 mm layer of mineral oil. Ruminal fluid pH was 5.80--6.14. Ruminal fluid pH was 5.77--5.81. Ruminal fluid pH was 6.49--6.8. In addition, if total gas pressure remained at 1 atm after total incorporation of accumulated H~2~ into reductive acetogenesis or additional propionate, CO~2~ pressure would increase from approximately 0.60 to 0.95 atm (calculations not shown). Based on Kohn and Dunlap ([@B42]), it can be derived (not shown) that if bicarbonate concentration remained constant, pH would change by: $$\Delta\text{pH} = \text{log}(0.60\text{atm}/0.95\text{atm}) = - 0.20$$ The expected decrease in pH for H~2~ incorporation into reductive acetogenesis calculated from BC, adjusted for Equation 12, is shown in Table [1](#T1){ref-type="table"}. In most cases, there was a moderate pH decrease. It should be considered that changes in VFA production could affect other physiological mechanisms such as buffer secretion due to bicarbonate secreted by rumen epithelium in exchange for absorbed VFA anions, most importantly acetate (Penner et al., [@B69]; Aschenbach et al., [@B9]). Therefore, effects of H~2~ incorporation into reductive acetogenesis or additional propionate on ruminal pH are difficult to predict accurately, and *in vivo* experimentation would be needed to completely understand how ruminal pH could be affected. Volatile fatty acids post-absorptive metabolism ----------------------------------------------- ### Efficiency of VFA utilization Utilization by the animal of heat of combustion in VFA is incomplete, as heat is lost in the conversion of ME to net energy (NE) for maintenance or production (heat increment, HI). Initial experiments with intra-ruminally-infused VFA in fasting (Armstrong and Blaxter, [@B3]; Armstrong et al., [@B5]) and fattening sheep (Armstrong and Blaxter, [@B4]) resulted in greater HI for pure acetate compared to pure propionate. Mixtures of VFA were similar to pure propionate in fasting animals (Armstrong and Blaxter, [@B3]; Armstrong et al., [@B5]), but a VFA mixture high in acetate was associated to a greater HI compared to one high in propionate when administered to sheep fed above maintenance (Armstrong et al., [@B6]). Later work found similar HI for VFA mixtures varying in acetate and propionate proportions in lactating cows (Ørskov et al., [@B64]), fasting and fattening lambs (Ørskov et al., [@B65]), and steers at different feeding levels, except for a decreased HI at the highest acetate molar proportion due to acetate excretion in urine (Ørskov et al., [@B67]; Ørskov and MacLeod, [@B66]). Therefore, it seems that the differences in VFA profiles resulting from the incorporation of accumulated H~2~ into reductive acetogenesis or additional propionate formation may not affect the efficiency of absorbed VFA utilization in animals at maintenance, thus likely resulting in similar NE outputs, given that heat of combustion output in VFA was similar (Figure [5](#F5){ref-type="fig"}); this issue would be unresolved for producing animals. ### Post-absorptive metabolic effects of VFA Apart from being energy sources, absorbed acetate and propionate have different metabolic consequences for ruminant post-absorptive metabolism (DiConstanzo et al., [@B21]). As a general frame of analysis, one could conceive the extra acetate or propionate formed through incorporation of accumulated H~2~ as an intervention analogous to adding a ketogenic or glycogenic supplement, respectively, to a basal diet. Although dietary effects on energy partition and milk production and composition are primarily explained by duodenal flow of conjugated linoleic acid isomers, they also partly respond to changes in production of acetate and propionate in the rumen (Maxin et al., [@B53]). It should be cautioned though that changes in pH and individual VFA ruminal concentrations could affect individual VFA absorption fluxes differently: absorption flux of propionate, but not of acetate, increased as a result of greater inclusion of dietary concentrates and corresponding greater propionate molar proportion and lower pH; the effect of diet on each VFA absorption flux seemed to follow changes in their concentrations, as rumen volume and fractional absorption rates of individual VFA were unaffected (Penner et al., [@B70]). Propionate is the main glucose precursor in ruminants, so it may be advantageous to produce more propionate in animals with high glucose requirements e.g., high-producing dairy cows (Aschenbach et al., [@B8]). However, dairy cows fed a ketogenic diet partitioned more energy to milk compared to those fed a glycogenic diet equal in NE (Van Knegsel et al., [@B90],[@B91],[@B92]), which agrees with changes in energy excretion in milk observed as a response to intra-ruminal infusion of acetate or propionate (Ørskov et al., [@B64]) and intramesenteric infusion of propionate (Casse et al., [@B15]). Ketogenic diets generally resulted in greater milk fat content and production, whereas both were lesser with glycogenic diets (Van Knegsel et al., [@B93], [@B90],[@B91]). In agreement, intra-ruminal infusion of acetate resulted in greater milk fat content and production compared to propionate infusion (Ørskov et al., [@B64]; Sheperd and Combs, [@B77]; Maxin et al., [@B53]). On the contrary, glycogenic diets often increased, and ketogenic diets decreased, milk protein content (Van Knegsel et al., [@B93], [@B90],[@B91]). Propionate infusion resulted in greater milk protein content (Sheperd and Combs, [@B77]). However, ketogenic diets are associated to greater negative energy balance and risk of ketosis (Van Knegsel et al., [@B93], [@B90],[@B92]). Importantly, there can be an interaction between the basal diet and the supplement regarding the risk of ketosis. Supplementing a ketogenic basal diet with fat resulted in an increase in circulating concentration of ß-hydroxybutyrate, in contrast to a glycogenic basal diet (Van Knegsel et al., [@B93]). Thus, consequences of incorporating accumulated H~2~ into reductive acetogenesis or additional propionate on the risk of ketosis may be more important with forage-based and fat-supplemented diets than with mixed diets. Van Knegsel et al. ([@B93]) did a thorough analysis of studies on the effects of ketogenic or glycogenic supplementation on reproduction and found it difficult to conclude on consistent effects. However, direct comparisons between ketogenic and glycogenic diets suggested that the latter may be advantageous for reproduction (Van Knegsel et al., [@B90],[@B92]). In animals with a production potential not limited by glucose supply, or with no risk of ketosis, there may be no a clear advantage of reductive acetogenesis or propionate formation as electron-incorporating pathway. Moreover, propionate is a major satiety signal in ruminants (Allen et al., [@B2]); thus, it may be preferable to incorporate accumulated H~2~ into reductive acetogenesis in animals whose basal diet already satisfies their glucose requirements, if their dry matter intake (DMI) is metabolically constrained, e.g., steers on high-concentrate diets. However, in feedlot steers with subclinical acidosis, incorporating H~2~ into reductive acetogenesis could result in further pH decrease, which could in turn diminish DMI. There may not be advantages to reductive acetogenesis vs. additional propionate formation as an electron-incorporating pathway in animals with low glucose requirements if feed intake is not to be maximized e.g., beef cows. Future directions ================= Evidently the conclusions reached through the present analysis would have to be tested through experimentation. Experimentally comparing effects of redirecting methanogenesis electrons toward reductive acetogenesis or propionate production on animal physiology and production is at present difficult, because attempts to inhibit methanogenesis have had little success in incorporating electrons into one or the other pathway. In my opinion, a question that precedes the question on how to incorporate methanogenesis electrons into reductive acetogenesis or propionate production, is, what limits those processes in the rumen i.e., how is H~2~ incorporation into reductive acetogenesis and propionate production physico-chemically controlled. Physico-chemical control of H~2~ incorporation into reductive acetogenesis or propionate production could be based primarily on enzyme or substrate kinetics, or thermodynamics. It is important to understand this in order to efficiently design strategies that can achieve successful incorporation of methanogenesis electrons into these pathways. For example, an enzyme kinetics limitation could be solved through microbial intervention e.g., microbial additives, overexpression of particular genes etc. On the other hand, a limitation of a substrate kinetics or thermodynamics nature would require an intervention at the level of substrate availability and/or product removal, and might be less feasible or profitable in practice. It would be best to test these hypotheses in very simplified systems, like chemostats running on soluble substrates where steady state constant kinetics and thermodynamic conditions can be attained. Defined cultures experiments on interspecies H~2~ transfer similar to the ones conducted some decades ago but including measurements of changes in the expression of genes encoding key enzymes such as hydrogenases and fumarate and acrylyl-CoA reductases, as well as the activities of those enzymes, are also suggested. Once this basic understanding was achieved, experimentation could move toward more realistic *in vitro* systems using solid substrates, and finally *in vivo* conditions. The underlying principle beyond this proposal is that a system can be better manipulated if we can understand how the flow of metabolites is controlled. Mechanistic understanding of ruminal fermentation will provide a long term solid basis to develop efficient strategies of manipulation of rumen fermentation and better predict and understand the outcomes of new strategies. In summary, incorporating accumulated H~2~ into reductive acetogenesis or additional propionate formation was found to be equivalent in terms of ME, and of NE for animals at maintenance; whether the efficiency of conversion of ME to NE in producing animals could be different if H~2~ was incorporated into reductive acetogenesis or additional propionate formation would remain unresolved. Incorporation of accumulated H~2~ into reductive acetogenesis could result in moderate ruminal pH decrease, although *in vivo* experimentation would be needed to characterize complex whole animal responses, as whole-animal responses other than ruminal fermentation could be affected. Research would be needed on the consequences of H~2~ incorporation into either pathway on microbial protein production. Post-absorptive consequences of either pathway on energy partition into milk and body tissues, risk of ketosis in dairy cows, and DMI could differ. Utilization of reductive acetogenesis as the preferred electron-incorporating pathway could stimulate energy partition into milk over body fat, although in high-producing dairy cows eating ketogenic diets could result in greater risk of ketosis. Incorporating accumulated H~2~ into propionate could increase milk protein and could decrease the risk of ketosis in animals eating ketogenic diets. However, in animals with metabolically constrained DMI and sufficient propionate or glucose supply, like steers on high-concentrate diets, incorporation of accumulated H~2~ into propionate could result in decreased DMI; in steers with subclinical acidosis though, reductive acetogenesis may cause further pH decline. Results of this comparison can be used to guide future research efforts in this area. This analysis shows that the production outcome of a successful ruminal methanogenesis intervention could depend on the alternative electron-incorporating pathway. Because of the different nutritional implications of either pathway, and because practical solutions to incorporate accumulated H~2~ into either pathway are not yet available, it is recommended to continue exploring both reductive acetogenesis and additional propionate production as electron sinks alternative to methanogenesis. Conflict of interest statement ------------------------------ The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. I wish to thank the reviewers for their constructive comments that helped improving this publication. Summary of equations with decimal coefficients Equation 1: Example of typical fermentation of glucose with a high-roughage diet $$\begin{array}{l} \left. \text{C}_{6}\text{H}_{12}\text{O}_{6}\rightarrow 1.333\,\text{CH}_{3}\text{COO}^{-} + 0.333\,\text{CH}_{3}\text{CH}_{2}\text{COO}^{-} \right. \\ {\quad + 0.167\,\text{CH}_{3}\text{CH}_{2}\text{CH}_{2}\text{COO}^{-} + 1.833\,\text{H}^{+} + \text{CO}_{2}} \\ {\quad + 0.667\,\text{CH}_{4} + 0.333\,\text{H}_{2}\text{O}} \\ \end{array}$$ Equation 2: Example of typical fermentation of glucose with a high-concentrate diet $$\begin{array}{l} \left. \text{C}_{6}\text{H}_{12}\text{O}_{6}\rightarrow 0.923\,\text{CH}_{3}\text{COO}^{-} + 0.615\,\text{CH}_{3}\text{CH}_{2}\text{COO}^{-} \right. \\ {\quad + 0.231\,\text{CH}_{3}\text{CH}_{2}\text{CH}_{2}\text{COO}^{-} + 1.769\,\text{H}^{+} + 0.962\,\text{CO}_{2}} \\ {\quad + 0.423\,\text{CH}_{4} + 0.538\,\text{H}_{2}\text{O}} \\ \end{array}$$ Equation 3: Example of methanogenesis inhibition in high-roughage diet of Equation 1 $$\begin{array}{l} \left. \text{C}_{6}\text{H}_{12}\text{O}_{6} + 0.6\,\text{H}_{2}\text{O} + 1.119\text{ X}\rightarrow 1.186\text{CH}_{3}\text{COO}^{-} \right. \\ {\quad + 0.475\,\text{CH}_{3}\text{CH}_{2}\text{COO}^{-} + 0.169\,\text{CH}_{3}\text{CH}_{2}\text{CH}_{2}\text{COO}^{-}} \\ {\quad + 1.831\,\text{H}^{+} + 1.469\,\text{CO}_{2} + 0.895\,\text{H}_{2} + 0.0559\,\text{CH}_{4}} \\ {\quad + 1.119\text{X}\lbrack 2\text{H}\rbrack} \\ \end{array}$$ Equation 4: Reductive acetogenesis $$\left. 2\,\text{CO}_{2} + 4\text{H}_{2}\rightarrow\text{CH}_{3}\text{COO}^{-} + \text{H}^{+} + 2\text{H}_{2}\text{O} \right.$$ Equation 5: Incorporation of 100% H~2~ in Equation 3 into reductive acetogenesis $$\begin{array}{l} \left. \text{C}_{6}\text{H}_{12}\text{O}_{6} + 0.153\text{H}_{2}\text{O} + 1.119\text{X}\rightarrow 1.410\text{CH}_{3}\text{COO}^{-} \right. \\ {\quad + 0.475\text{CH}_{3}\text{CH}_{2}\text{COO}^{-} + 0.169\text{CH}_{3}\text{CH}_{2}\text{CH}_{2}\text{COO}^{-}} \\ {\quad + 2.054\text{H}^{+} + 1.022\text{CO}_{2} + 0.0559\text{CH}_{4} + 1.119\text{X}\lbrack\text{2H}\rbrack} \\ \end{array}$$ Equation 6: Generalization of Equation 5 for proportions of H~2~ incorporation into reductive acetogenesis between 0 and 1 (0 ≤ *y* ≤ 1) $$\begin{array}{l} \left. \text{C}_{6}\text{H}_{12}\text{O}_{6} + (0.6 - 0.447y)\text{H}_{2}\text{O} + 1.119X\rightarrow \right. \\ {\quad(1.186 + 0.224y)\text{CH}_{3}\text{COO}^{-} + 0.475\text{CH}_{3}\text{CH}_{2}\text{COO}^{-}} \\ {\quad + 0.169\text{CH}_{3}\text{CH}_{2}\text{CH}_{2}\text{COO}^{-} + (1.831 + 0.224y)\text{H}^{+}} \\ {\quad + (1.469 - 0.447y)\,\text{CO}_{2} + 0.895(1 - y)\text{H}_{2} + 0.0559\text{CH}_{4}} \\ {\quad + 1.119\text{X}\lbrack 2\text{H}\rbrack} \\ \end{array}$$ Equation 7: Fermentation of glucose to acetate $$\left. \text{C}_{6}\text{H}_{12}\text{O}_{6} + 2\text{H}_{2}\text{O}\rightarrow 2\text{CH}_{3}\text{COO}^{-} + 2\text{H}^{+} + 2\text{CO}_{2} + 4 \times \lbrack 2\text{H}\rbrack \right.$$ Equation 8: Acetate to propionate shift in ruminal fermentation $$\left. \text{CH}_{3}\text{COO}^{-} + \text{CO}_{2} + 3\text{H}_{2}\rightarrow\text{CH}_{3}\text{CH}_{2}\text{COO}^{-} + 2\text{H}_{2}\text{O} \right.$$ Equation 9: Incorporation of 100% H~2~ in Equation 3 into propionate production $$\begin{array}{l} \left. \text{C}_{6}\text{H}_{12}\text{O}_{6} + 0.00339\text{H}_{2}\text{O} + 1.119\text{X}\rightarrow 0.888\text{CH}_{3}\text{COO}^{-} \right. \\ {\quad + 0.773\text{CH}_{3}\text{CH}_{2}\text{COO}^{-} + 0.169\text{CH}_{3}\text{CH}_{2}\text{CH}_{2}\text{COO}^{-}} \\ {\quad + 1.831\text{H}^{+} + 1.171\text{CO}_{2} + 0.0559\text{CH}_{4} + 1.119\text{X}\lbrack 2\text{H}\rbrack} \\ \end{array}$$ Equation 10: Generalization of Equation 9 for proportions of H~2~ incorporation into propionate production between 0 and 1 (0 ≤ *z* ≤ 1) $$\begin{array}{l} \left. \text{C}_{6}\text{H}_{12}\text{O}_{6} + (0.6 - 0.597z)\text{H}_{2}\text{O\!} + 1.119\text{X}\rightarrow(1.186 - 0.298z) \right. \\ {\quad\text{CH}_{3}\text{COO}^{-} + (0.475 + 0.298z)\text{CH}_{3}\text{CH}_{2}\text{COO}^{-}} \\ {\quad + 0.169\text{CH}_{3}\,\text{CH}_{2}\text{CH}_{2}\text{COO}^{-} + 1.831\text{H}^{+}} \\ {\quad + (1.469 - 0.298z)\text{CO}_{2} + 0.895(1 - z)\text{H}_{2} + 0.0559\text{CH}_{4}} \\ {\text{~~} + 1.119\text{X}\lbrack 2\text{H}\rbrack} \\ \end{array}$$ Equation 11: Theoretical fermentation of glucose to acetate and propionate $$\begin{array}{l} \left. \text{C}_{6}\text{H}_{12}\text{O}_{6}\rightarrow 0.667\text{CH}_{3}\text{COO}^{-} + 1.333\text{CH}_{3}\text{CH}_{2}\text{COO}^{-} \right. \\ {+ 2\text{H}^{+} + 0.667\text{CO}_{2} + 0.667\text{H}_{2}\text{O}} \\ \end{array}$$ [^1]: Edited by: Garret Suen, University of Wisconsin-Madison, USA [^2]: Reviewed by: Michael Poulsen, University of Copenhagen, Denmark; Hilario C. Mantovani, Universidade Federal de Viçosa, Brazil; Paul J. Weimer, United States Department of Agriculture, USA [^3]: This article was submitted to Systems Microbiology, a section of the journal Frontiers in Microbiology.

2024-02-14T01:27:04.234600

https://example.com/article/1874

1. Field of the Invention The invention concerns a method and a device for an evanescence-based multiplex sequencing of nucleic acid molecules immobilized on a support. 2. Description of the Prior Art The sequencing of the human genome consisting of about 3×109 bases or of the genome of other organisms as well as the determination and comparison of individual sequence variants requires the provision of sequencing methods that are rapid and can also be used routinely and inexpensively. Although major attempts have been made to accelerate conventional sequencing methods such as the enzymatic chain termination method of Sanger et al. (Proc. Natl. Acad. Sci. USA 74 (1977) 5463) especially by automation (Adams et al. Automated DNA Sequencing and Analysis (1994), New York, Academic Press), at present no more than 2000 bases per day can be determined with a sequencer. New approaches for overcoming the limitations of conventional sequencing methods have been developed in the last few years which include sequencing by scanning-tunnel microscopy (Lindsay and Phillip, Gen. Anal. Tech. Appl. 8 (1991), 8-13), by highly parallelized capillary electrophoresis (Huang et al., Anal. Chem. 64 (1992), 2149-2154; Kambara and Takahashi, Nature 361 (1993), 565-566), by oligonucleotide hybridization (Drmanac et al., Genomics 4 (1989), 114-128; Khrapko et al., FEBS Let. 256 (1989), 118-122; Maskos and Southern, Nucleic Acids Res. 20 (1992), 1675-1678 and 1679-1684) and by matrix-assisted laser desorption/ionization mass spectroscopy (Hillenkamp et al., Anal. Chem. 63 (1991), 1193A-1203A). Another method is single molecule sequencing (Dörre et al., Bioimaging 5 (1997), 139-152) in which nucleic acids are sequenced by progressive enzymatic degradation of fluorescent-labelled single-stranded DNA molecules and detection of the sequentially released monomer molecules in a microstructure channel. The advantage of this method is that only a single molecule of the target nucleic acid is sufficient to carry out a sequence determination. Although considerable advances have been made by using the above-mentioned methods, there is a major need for further improvements. Hence the object of the present invention was to provide a method for sequencing nucleic acids which represents a further improvement over the prior art and which allows a parallel determination of individual nucleic acid molecules in a multiplex format. A multiplex sequencing method is proposed in PCT/EP01/07462 in which nucleic acid molecules that carry several fluorescent marker groups are provided in an immobilized form on a support and the base sequence of several nucleic acid molecules is determined simultaneously on the basis of the time-dependent change in the fluorescence of the nucleic acid molecules or/and of the cleaved nucleotide building blocks caused by the cleavage of nucleotide building blocks.

2023-09-24T01:27:04.234600

https://example.com/article/3463

Issue No. 6, Autumn 2013 For years we did not see the sun without adventures. Over us, the canopy of trees grew blindingly close together and light was a filtered thing. To go to an open spot in the forest – to look up and see the sun – was an adventure, a mission of manhood, and a danger. What could have caused a barren cicatrix in the great forest, and what might that maker of openness do to a man exposed? But our people would go, see the sun some few brief moments, and come back to tell the wives, children, and those without courage, what the phantom burning ball looked like. We were content, though shadowed. Our lives knew the order of the trees, what gifts and perils came from what nameable altitudes, how to navigate the squatting trunks. Some of our clan might climb, and some became comfortable with the arboreal. But, for the most of our people, the ground was home. I know nothing of this. It was not yet my time. Rumor is, that, on an adventure to the edge of one of the mysterious holes in the forest where the sun could be seen, the one who was to be our greatest warrior stumbled, and upon reaching out to steady himself, absently took down a small tree. Imagine: had he not gone to see the sun, he would not have encountered the tree at all. In our past, there had been branches breaking, and the falling of rot: but this was a full tree, sapling though it might be, already in the warehouse of its ascendancy. It is said he placed but a hand on it and fell forward, taking the tree with him. His companions were astounded. They could not help him up for their wonder. Most, it is said, bent double to look at where the tree transitioned to horizontal, unable to touch it, their eyes drawn into slits and the silence withheld like the sex of noble children. A world is changed in moments that have no geometry. With the inrush of new possibilities, the sight of the sun was forgotten. Beginning with similar saplings, the adventurers – now becoming warriors – began to test the pushing over of trees. Some trees would come up by the roots, and some would snap; though most would sway and remain defiant. Soon, the ground was crawling with small trees that had by our warriors been sent violently into the horizontal plane. It was later, in small steps, warriors learned to work two, sometimes three, to a tree to bring down almost substantial trees: those with leaves high enough to make the under level of the canopy, to drag down when toppled the neighboring intertwined branches, to make smart holes in the dense green above. With that first return of our new warriors came the knowledge of breaking trees. We practiced, and came together to push over trees nearly as thick as a man. Our work became the understanding of trees repositioned, trees impoverished. In months, the people had pushed over thousands of trees. The bodies of wood lay about in subjugated piles and we sat upon them and rolled them about for fun and a child or two was crushed by stray wood encapsulated in momentum. Yet, soon, the novelty wore off. Trees of modest size had gone from vertical to horizontal, but they were still in the way, though differently. Above the people the high canopy still persisted and kept us separate from the sun, though more light leaked through and our ancestors became accustomed to it. But then, one unremembered but special day, a man licensed himself to be a carpenter. He took an apprentice and set to turning the stray wood into lumber. Lumber was not simply a tree pushed over. Lumber could be stacked. Lumber could be turned into order and cross order and depth. And, with the peg, the carpenter could turn lumber into houses, into fences, into ladders. We could live beneath the trees without needing their canopy; we could with horrible ladders climb into the depths of the higher greenness; we could fence the open land we were giving birth to. And, bare generations later, our elite developed an understanding of the carpenter’s potential other tools. Families of new and enigmatically powerful tools: tools that might make a man worth the work of many men; or make the work of many men the author of one outcome. At some point, the saw was born. It sang its coming ascendancy into our growing and grappling society. We listened enraptured by the song, lusting after the saw for its form and intent, if not for its simple curing existence. With this, our relation to the trees could yet again spring forward. To understand the saw was to be a different race. Shortly after the enlightenment, our people made saws of all sorts and breeds. Saws a man could use to nip down a small tree, and saws that a crew of men would use in wicked coordination to gnaw at the heart of the giants of the forest: trees without natural predators, with no need of anger or fear; trees that against the blade merely hummed a lullaby rhythm and then went murderously down. The saw could bring light everywhere. Our ancestors pushed back the edge of the forest. Ever further away it went in all directions. Soon, our war parties had to walk for days to reach a worthy tree. They began to organize into expeditions, carrying their wives and children, pack animals and provisions; disappearing into the brush to flank a stand of trees, to strategically work often from the backside towards home, cutting a small forest from the larger one. Rails of wood carried lumber back and forth, the excess rotting in the rains. There is no date in specific when it was first noticed that some of our best warriors had unselfconsciously grown leaves on their backs. And when the first thatch child was born, everyone for miles came to see the oddity. But the child suckled and moved, if stiffly, like a full flesh child, and he was let be. The hair of our women more and more waxed fern-like and in the suddenly full sun their heads would at times lean into the light. But still the warriors brought back lumber. The sun was now open for all, and to see it was no adventure. The forest was beaten back and the thatch children, the bramble children, the stick children did not even remember it. The forest was a rumor they might one day adventure to see, dragging themselves slowly across the good earth plain, each slow step sucking its moisture from the soil and pausing before, by pure will, being pulled into the next committed act of locomotion. Locomotion is a memory that is dear to me. I have heard of running and walking and I can imagine these things, but I do remember fondly dragging and I once myself did drag. I do not remember when I stopped, but others had rooted before me and at last when I rooted I could see no others still busying about in their houses, no others preparing to make war on the trees, no others making children by any other means than the casting out of their pollen. We tell our story branch to branch, rattle it in our leaves, ensure it moves across the dendrites of all our people. The story of how a shadowed people learned to battle the trees and beat back the forest, rising then themselves up into the sun: the story of a people who would not remain subjects under the canopy, but who could invent a way to make the legendary sunlight their own. I have passed it through my limbs, shivered it in my mature leaves, and sent it out in the buds that consume me. The gift is now yours. Across the next fingering limb of our canopy, tell it. Ken Poyner lives in the lower right hand corner of Virginia, with his power-lifter wife and a number of house animals. His 2013 e-book, Constant Animals, 42 brief but unruly fictions, is available at all the various e-book sites, and you should go buy it so he does not have to haunt you. Recent work is out in Corium, Analog Science Fiction, Spittoon, Poet Lore, Mobius, and many other places. He webs at kpoyner.com. Sandra Giles teaches at Abraham Baldwin Agricultural College in Tifton, in the department of Literature and Language and in an innovative bachelor’s degree program in Rural Studies. She holds a Ph.D. from Florida State University. Her work has been published in such journals as The Southeast Review, Wilderness House Literary Review, and Writer Advice and in anthologies such as On Writing and Shout Them From the Mountaintops II: Georgia Poems and Stories. Her work has received awards from New Millennium Writings and the Southeastern Writers Association. She has also published articles on teaching writing, including co-authoring a chapter in Creative Writing: A Guide to Its Pedagogies, forthcoming from Southern Illinois University Press.

2023-08-11T01:27:04.234600

https://example.com/article/8769

LONDON — British police insisted Monday that last week's drone sightings merit an ongoing investigation after questions were raised about whether the devices, which prompted a shutdown of the country's second-largest airport at the height of the Christmas travel season, ever existed at all. Drones were spotted at Gatwick Airport on Wednesday, leading to a 36-hour closure that affected more than 120,000 passengers. Another sighting on Friday led to a second brief shutdown. The airport was operating normally Monday, but military equipment remains in place to deter and track any fresh incursions. Two people from a town near the airport were arrested Friday night in connection with the drone sightings but were released Sunday without charges. No other suspects have been identified, and the hunt for the culprits is ongoing. But Sussex police chief Jason Tingley said Sunday it was possible that those who reported seeing drones after the first sightings raised alarms were mistaken. "Of course, that's a possibility. We are working with human beings saying they have seen something," Tingley told the BBC, prompting widespread consternation. Police issued further statements on Monday in an apparent attempt to clarify the situation. Officials received 67 reports from the public — including airport staff and passengers — of drone sightings between Wednesday and Friday last week, the statement said, and a forensic examination of a damaged drone found near the airport was underway. “We are interviewing those who have reported these sightings, [and] are carrying out extensive house to house enquiries," Tingley said in the statement. #GatwickDrones | We can unequivocally state between 19-21 Dec there have been numerous #drone sightings at @Gatwick_Airport. We want to bring those responsible for the disruption to justice and through @CrimestoppersUK there is a £50,000 reward https://t.co/U3cQKvgaMO pic.twitter.com/bx5dqW67wT — Sussex Police (@sussex_police) December 24, 2018 The airport is now offering a reward of over $60,000 for information leading to the arrest and conviction of those responsible. The closure of the airport was a safety measure, with authorities concerned the drones could disrupt airplane flight paths, disable jet engines or worse. The drone crisis at Gatwick, which is located 30 miles south of London and serves 46 million passengers a year, has had ripple effects throughout the international air travel system.

2024-07-07T01:27:04.234600

https://example.com/article/4748

Q: Angular 2 Form validation for dynamic fields I am working on an Angular 4.X project and I am creating some HTML input fields (mostly of type text) on button click. The creation of Input Boxes dynamically is working fine but I am not able to implement validation to those fields. I am getting the following error. Cannot read property 'invalid' of null(…) I have created a plunk for the same. Following is the link for the plunk that I have created -- https://plnkr.co/edit/PCFD43GK91zo2ivQ9lf7?p=preview For easy reference please find the code below -- //Root app component import {Component, NgModule} from '@angular/core' import {BrowserModule} from '@angular/platform-browser' import { FormBuilder, FormGroup, Validators, FormArray, FormControl } from '@angular/forms'; import { FormsModule, ReactiveFormsModule } from '@angular/forms'; @Component({ selector: 'my-app', template: `<hr> <div> <form [formGroup]="orderForm" (ngSubmit)="OnSubmit(orderForm.value)"> <div> <input type="text" formControlName="customerName"/> <input type="text" formControlName="email"/> </div> <div formArrayName="items" *ngFor="let item of items.controls; let i = index;"> <div [formGroupName]="i"> <input type="text" formControlName="name" placeholder="Item name"/> <small *ngIf="IsValidField('name')" class="text-danger"> Name is required </small> <input type="text" formControlName="description" placeholder="Item description"/> <small *ngIf="IsValidField('description')" class="text-danger"> Description is required </small> <input type="text" formControlName="price" placeholder="Item price"/> <small *ngIf="IsValidField('price')" class="text-danger"> Price is required </small> </div> Chosen name: {{ orderForm.controls.items.controls[i].controls.name.value }} </div> <button type="submit">Save</button> <button type="button" (click)="addItem()">Add More</button> </form> <div>`, }) export class App { constructor(private formBuilder: FormBuilder) { } public orderForm: FormGroup; ngOnInit() { this.orderForm = this.formBuilder.group({ customerName: '', email: '', items: this.formBuilder.array([ this.createItem()]) }); } createItem(): FormGroup { return this.formBuilder.group({ name: ['',[Validators.required,Validators.maxLength(10)]], description: '', price: ['',[Validators.required,Validators.pattern("[(0-9)*]")]] }); } get items(): FormArray { return this.orderForm.get('items') as FormArray; }; addItem(): void { this.items.push(this.createItem()); } public OnSubmit(formValue: any) { console.log(JSON.stringify(formValue)); } public IsValidField(field: string) { return (this.orderForm.get(field).invalid && this.orderForm.get(field).touched) || (this.orderForm.get(field).invalid && this.orderForm); } } @NgModule({ imports: [ BrowserModule, FormsModule, ReactiveFormsModule ], declarations: [ App ], bootstrap: [ App ] }) export class AppModule {} Any help would be appreciated. A: You're searching for dynamically added form fields inside orderForm, which isn't available there. You should query form correctly before accessing its value. I draw below figure which will help you to understand how the dynamically created form architecture. orderForm (FormGroup) | - Items (FormArray) | - 0 (FormGroup) - name - description - price | - 1 (FormGroup) - name - description - price | |......... So IsValidField function should get the index of formArray element, and field name. By which you can easily query form element. public IsValidField(i: number, field: any) { var f = this.orderForm .get('items') //retrieve items FormArray .get(i.toString()) //retrieve items FormGroup .get(field); //retrieve items form field return (f.invalid && f.touched) || (f.invalid && this.orderForm); } Then change IsValidField function call on *ngIf accordingly. *ngIf="IsValidField(i, 'name')" *ngIf="IsValidField(i, 'description')" *ngIf="IsValidField(i, 'price')" Demo Plunker

2023-11-15T01:27:04.234600

https://example.com/article/6866

uses GraphWPF; begin Window.Title := 'Использование FontOptions'; TextOut(10,10,'Обычный'); TextOut(10,40,'Жирный',Font.WithStyle(FontStyle.Bold)); TextOut(10,70,'20 пунктов',Font.WithSize(20)); TextOut(10,110,'Наклонный синий',Font.WithColor(Colors.Blue).WithStyle((FontStyle.Italic))); end.

2024-07-14T01:27:04.234600

https://example.com/article/3035

With instruments of this kind it is known to generate the light necessary for illuminating the treatment area by means of an electric lamp arranged in the instrument. The lamp may be arranged in the front region of the instrument so that its light is aimed directly on to the treatment area. In particular in the case of such instruments which are in two parts, so that it is possible to exchange different treatment tools and for the purpose of disinfection, wherein the front instrument part can be connected by a quick-fitting coupling to the rear instrument part and, in particular with regard to the latter, is held rotatably thereon, it is known to arrange the lamp in the region of the rear instrument part, preferably directly behind the separating point. The light generated by the lamp is guided by means of a light conductor extending longitudinally in the front instrument part to a light emission opening which is located in the front region of the front instrument part and is aimed towards the treatment area. The lamp may be arranged in the axis of rotation or the longitudinal centre axis of the instrument, as described in DE 31 04 239 C2, or the lamp may be arranged eccentrically, as described in DE 33 32 628 C2. Owing to the motor drive for the treatment tool, which may be either a mechanical drive (DE 33 32 628 C2) or a turbine drive (DE 31 04 239 C2), vibrations are generated in the instrument which also act on the lamp. In the known constructions, in which the lamp is held immovably in the region of its plug-in foot and/or its lamp bulb, vibrations lead to premature failure of the lamp. With lamps having a spiral-wound filament the most common cause of failure is a break in the spiral-wound filament. An instrument of the kind described in the introduction is in public use. In this known construction the lamp holder has a plug-in socket in the form of a hollow cylindrical bush, into which the lamp foot can be inserted, there being in the bush two contact elements which are spaced apart and formed by thoroughly bendable spring arms between which the lamp foot can be inserted. Owing to the fixed seating in the bush, the lamp is mounted rigidly. The contact elements serve only for electrical contacting. Furthermore the contact elements are supported laterally on a holding ring, with the intermediate arrangement of an insulating layer. In the contact position the contact elements are therefore practically immovable.

2023-08-13T01:27:04.234600

https://example.com/article/3556

Combined CO2-laser and alfa recombinant interferon treatment in five children with juvenile laryngeal papillomatosis. Juvenile laryngeal papillomatosis is a rare and benign tumoral disease of childhood characterized by numerous relapses despite complete resection. The ENT treatment of choice is to vaporize the papillomas with a CO2 laser. Since the discovery of a viral etiology (Human Papilloma Virus), resection has been followed by medical attempts to control the disease by using various antiviral treatments. Among the latter, alfa interferon has proved effective during the first six months of treatment. In this article, we report on five cases of refractory juvenile laryngeal papillomatosis treated by excision (CO2 laser in four children, surgical resections in one child) and alpha-r IFN 1.5 x 10(5) U/kg daily. With this strategy, three of the five children are currently disease-free for periods ranging from 22 to 68 months. This series includes one remarkable observation of one child who responded only to double doses of alpha-r IFN, after initial failure at conventional doses. This therapeutic scheme reduced the frequency of relapses in a fourth child. In only one child the treatment did fail to modify the natural course of the disease. Side effects were tolerable and included anorexia (one case), palmar erythema (one case), a flu-like syndrome (two cases) and mild transient transaminase rise (three cases) not precluding further treatment. CO2-laser caused one laryngeal oedema and synechia of the anterior commisure of the vocal laryngeal cords in one other case.

2024-02-28T01:27:04.234600

https://example.com/article/3169

Q: Jekyll include variables from external file With Jekyll, I know you can include a variable in the include line, like so: --- layout: default testVar: test1 --- {% include test_block.html testDivContent=page.testVar %} Is it possible to include another file that passes in the variable content (in this case testVar: test1) from an external file? So something like --- layout: default --- {% include testVar_file.html %} {% include test_block.html testDivContent=page.testVar %} Where testVar_file.html contains the variable testVar: test1 A: You can use a data file. _data/testVar_file.yml testVar: test1 index.md --- layout: default --- {% include test_block.html testDivContent=site.data.testVar_file.testVar %}

2024-02-29T01:27:04.234600

https://example.com/article/8966

You don’t have to be religious to appreciate the Tree Church in Ohaupo, New Zealand. A heavenly 100-seat chapel set among a 3-acre landscaped garden, the church boasts walls made of living trees planted around an iron frame. In 2011, Barry Cox, who runs a tree relocating business, decided that his backyard was missing an old stone church like the ones he had studied and admired on travels to Europe. — Slate Get a glimpse inside the Tree Church in the video below.And here's more tree love and cool churches on Archinect:Tree-hugging in the modern ageIt's official: trees are good for your healthNew photos of E. Fay Jones' Thorncrown Chapel unveiled to mark 35th anniversaryGreat Synagogue of Edirne in... View full entry » Todd Conversano never thought he'd be able to enlarge the 1950s ranch-style home he and his wife bought a decade ago. Two previous geological reports on the property north of Beverly Hills suggested that it would cause drainage problems or, worse, destabilize the steep slope above the lot. Instead, he came up with a smarter, cheaper and less intrusive solution. [...] "I figured out how to do it without touching the building," — latimes.com Using a "moment frame" as the platform, Conversano was able to lift the new addition to sit just above the existing house without adding any additional load to it. The new master suite was then connected to the rest of the house by a staircase, bridging the two structure's interiors. Conversano's... View full entry » The construction firm VolkerWessels unveiled plans on Friday for a surface made entirely from recycled plastic, which it said required less maintenance than asphalt and could withstand greater extremes of temperature– between -40C and 80C. Roads could be laid in a matter of weeks rather than months and last about three times as long, it claimed. The company said the environmental argument was also strong as asphalt is responsible for 1.6m tons of CO2 emissions a year globally — theguardian.com Related: Taiwan tests recycling's limits with bus stops out of bottlesAfrica's First Plastic Bottle House Rises in Nigeria View full entry » “Is there a line between architecture and art?” Sylvia Lavin, the influential architecture critic and scholar, asked Jimenez Lai, the architect-cum-artist, during a “Pillowtalk” reopening of his ongoing exhibit at Jai & Jai Gallery in Los Angeles. It’s a question that hovers over the... View full entry » Libraries tend to house their stacks indoors, which makes FLUX's art project Lacuna something of a first: a series of nook-friendly triangular wooden shelves, lightly canopied by pages suspended on wires, Lacuna was designed specifically for this year's Bay Area Book Festival. Better yet: the... View full entry » In the first, “Ideation” phase of the initiative, those working in the building efficiency area are invited to submit problem statements describing challenges that need to be overcome in order to promote better engagement with building occupants and to improve the ability to balance energy and occupant comfort objectives in a building. In addition to submitting problem statements, participants are invited to vote and comment on ideas that have already been submitted. — U.S. Department of Energy Following Bjarke Ingels Group's wildly successful BIG Maze last summer, one could only wonder how Washington D.C.'s National Building Museum would one-up itself this time around. Enter Alex Mustonen and Daniel Arsham of Snarkitecture, who envisioned the 10,000 square-foot indoor BEACH that opened... View full entry » Nicholas Korody interviewed Andrés Jacque (of the Office for Political Innovation) about COSMO, the winning entry of this year’s MoMA PS1 Young Architect’s Program competition. Therein he argued "I believe that the architect’s role nowadays can also be providing alternatives, and... View full entry » Most planners and architects can speak volumes about accessibility requirements [...].Tamara Petrovic and Garner Oh, partners of the architecture and design firm 0 to 1, are intimately aware of such needs. To address their son’s difficulty with balance and motor skills, the pair developed a range of products for the home that transform his living environment into a safe and appealing space for all members of the family and resist the institutional aesthetic often seen in special needs products. — urbanomnibus.net The Tom Bradley International Terminal at LAX debuted this week three new public art commissions designed to greet departing and arriving passengers and provide a measure of calm and reflection amid the chaos of air travel. The artists involved all have strong ties to Los Angeles -- Mark Bradford, Pae White and the Ball-Nogues studio each resides or works in the L.A. area. — latimes.com Adjaye is overseeing the newest installment of Cooper Hewitt, Smithsonian Design Museum’s “Selects” series, which spotlights the little-known West African textiles in the museum’s permanent collection. [...] It also offers the celebrated architect a chance to explore the surprising connections between textile making and building design. “What’s interesting to me is this idea of fabric and weaving as a kind of abstraction of making places that people come together in,” he says. — Smithsonian.com Related: First Look at the Museum of African American History and Culture View full entry » Today sees the launch of CNN Style, a new online destination for intelligent, stylish content spanning the worlds of fashion, design, architecture, art, autos and luxury. Throughout July, CNN Style welcomes renowned Polish-American architect Daniel Libeskind [...]. As guest editor, Libeskind has commissioned a series of pieces about architecture to be published through July, given an exclusive video interview to CNN Style and written about the interplay of architecture and emotion. — CNN The invitation was cryptic. A small piece of wood with a laser-burned message that read, "June 30, 2015. Please join us for tea and wishes overlooking the city. Sunrise, Griffith Park." — Los Angeles Times It's a rather charming story: an anonymous collective of artists have fashioned a Japanese-inspired teahouse out of charred wood reclaimed from the 2007 Griffith Park fire and offered it as a gift to the city. Surreptitiously assembled in parts, the teahouse was inaugurated yesterday morning for a... View full entry »

2023-09-10T01:27:04.234600

https://example.com/article/6297

We present results of spectroscopic observations of selected stars in the southern open cluster NGC 6134. We have determined the rotational velocities of the six known δ Scuti stars in NGC 6134 as well as several other non-variable stars with similar colour temperature in order to investigate if and variability is somehow connected: we find no such correlation. We also compare the distribution of of δ Scuti stars and non-variable stars with four other well-studied open clusters to look for any systematic behaviour, but we find no conclusive evidence for and variability to be connected. We have also used the spectra to carry out an abundance analysis of the δ Scuti stars in NGC 6134 to confirm the high metal content of the cluster. We find which is in agreement with the result obtained from Strömgren photometry. We also present photometry of the cluster, but we find no chemical peculiar stars based on this index. Current usage metrics show cumulative count of Article Views (full-text article views including HTML views, PDF and ePub downloads, according to the available data) and Abstracts Views on Vision4Press platform. Data correspond to usage on the plateform after 2015. The current usage metrics is available 48-96 hours after online publication and is updated daily on week days.

2024-06-12T01:27:04.234600

https://example.com/article/5158

Thwarted Linux backdoor hints at smarter hacks Kevin Poulsen SecurityFocus Software developers on Wednesday detected and thwarted a hacker's scheme to submerge a slick backdoor in the next version of the Linux kernel, but security experts say the abortive caper proves that extremely subtle source code tampering is more than just the stuff of paranoid speculation.

2024-06-02T01:27:04.234600

https://example.com/article/2038

Using the transporters DVD as a learning tool for children with Autism Spectrum Disorders (ASD). Data from two groups of children who were randomly allocated to those groups showed that the ability of children with ASD to identify and label basic and complex facial expressions following a 3-week home based DVD intervention significantly improved when viewing The Transporters DVD. Improvements in emotion recognition appear related to the content of the DVD as participants in a control group who observed an alternate DVD showed no such improvement. Although social behaviour improved significantly as a result of watching The Transporters, a significant improvement in social behaviour was however, also observed in the Thomas the Tank Engine condition suggesting the unique content of The Transporters DVD was not pivotal to the improvement of social behaviour in general.

2024-05-12T01:27:04.234600

https://example.com/article/6402

The field of the invention is instrument trays and containers. Various surgical tools and medical instruments are used in surgical procedures. These tools or instruments, many of which have sharp cutting or piercing surfaces, having traditionally been handed back and forth between surgeons and nurses in a operating room. Transferring such instruments hand to hand creates the potential for accidental cutting or stabbing. If the accidental cutting or stabbing occurs with a non-sterile instrument, the potential for infection arises. In addition, if the accidental cutting or stabbing is not immediately noticed, the skin and/or surgical glove barriers can be breached thereby risking infection to the nurse, surgeon, or patient.

2024-03-10T01:27:04.234600

https://example.com/article/7912

Spanish Printables and Lesson Plans for Niños Menu Tag Archives: clothing During the winter months, I introduce vocabulary related to clothing. It is a meaningful and practical way to teach not only clothing vocabulary but to also to talk about the weather and the seasons. Froggy Se Viste To introduce new vocabulary, I always use a children’s book or song to connect grammar and context to the theme. One of my favorite books is Froggy Se Viste by Jonathan London. The story is engaging and repetitive making the perfect combination to learn Spanish in context. That said, I modify the story emphasizing the sentence structures I want my students to learn. Here is a compilation of clothing materials in Spanish I created as well as other fun materials and lessons I found online.

2023-11-24T01:27:04.234600

https://example.com/article/5641

Free Telecom Daily Newsletter Get the latest news on Telcos, Next Generation Networks, Broadband, and other critical service provider topics sent straight to your Inbox. Join over 48,000 telecom professionals who subscribe to FierceTelecom for FREE! However, the company's operating margin declined 0.5 percent due to $122 million in restructuring and other charges. Taking out the one-time items, the operating margin rose to 17.2 percent from 15.7 percent. Meanwhile, net profit jumped to $110.6 million, or 22 cents per diluted share, from $91 million, or 18 cents a share a year earlier. "Juniper delivered solid first quarter results with strong year-over-year revenue growth," said Shaygan Kheradpir, chief executive officer of Juniper Networks, in the earnings release. "We are seeing continued demand from our customers reflecting a significant opportunity to capture share in meaningful, high-growth Cloud-Builder and High IQ networking across both service provider and enterprise market." The first quarter was a time of transition for Juniper. In response to shareholder pressure to trim costs, the vendor in February unveiled a new integrated operating plan (IOP) that includes cutting $160 million in operating costs by the first quarter of 2015 and returning capital to shareholders over the next three years. Earlier this month, it announced that it would lay off 6 percent of its employee base. Stuart Jeffrey, an equity analyst for Nomura, wrote in a research note that while Juniper's IOP is sound, "it still has risks." "Firstly, this strategy was articulated very early after the appointment of the new CEO," wrote Jeffrey. "Secondly, management is refusing to give any real details on the actual enablers of this strategy, other than to point out Juniper's existing array of assets, citing the need to protect competitively sensitive information." Regardless of its issues, Juniper saw continual gains in its product and service sets. Driven by strong performance of the MX platform, including its new MX2020/2010 and MX104 lines, routing revenue rose 7 percent year-over-year to $550 million. Switching rose 46 percent year-over-year to $192 million, while security declined 2 percent to $134 million. From a regional perspective, the Americas led the way with $681 million in revenue, while EMEA and Asia Pacific rose year-over-year to $296 million and $193 million, respectively. THE LIBRARY: EBOOK Viewing patterns of consumers are dramatically shifting toward watching content on IP-based mobile devices. This eBook delves into how ad insertion is evolving and improving, what can be done to make a more elegant user experience for OTT content and more! Download today.

2023-10-25T01:27:04.234600

https://example.com/article/7974

Q: Can I get a router to call a url on a timer? I am responsible for a small network spread over several buildings. We have accommodation areas that have a router providing access to the internet to guests. I would love to be able to get the routers to call a URL on the internet which I could use to monitor that the router is up. Ideally it would do this once an hour or every 10 mins etc. Is this possible? Does it have a specific name as I have never seen this ability on the home/office routers or switches we purchase. A: SLA monitors on Cisco devices can do HTTP calls. And certainly, if you were to use something with a *nix OS, you could script and schedule it yourself. That may be the best solution if you're on consumer devices - can your devices run DD-WRT? A: I know pfSense boxes support monitoring an address to check a WAN connection is up and to let it know when to failover if another WAN link if available. I can't remember of the top of my head but I think that specified address to monitor is also used to generate historical latency and packet loss graphs. In addition, I remember finding a basic script on the net that would reset the box if a specified address was unreachable. The bigger question is how you are going to know the remote routers are down if they are down adn unable to send you any info? I used to look after a few remote offices on building sites so all sorts of problems could arise - I set up a central nagios box at the head office and used it to ping monitor the remote routers so it would be aware of any lines going down at any remote sites. If static IP's isn't an option, you could even use dyndns if supported to let you ping the remote routers. Edit: Also let us know which brand/model router you are using in case someone on here knows of a method to do what you wish.

2024-04-10T01:27:04.234600

https://example.com/article/5832

/* * Copyright (C) Scott Cranton and Jakub Korab * https://github.com/CamelCookbook * * Licensed under the Apache License, Version 2.0 (the "License"); * you may not use this file except in compliance with the License. * You may obtain a copy of the License at * * http://www.apache.org/licenses/LICENSE-2.0 * * Unless required by applicable law or agreed to in writing, software * distributed under the License is distributed on an "AS IS" BASIS, * WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied. * See the License for the specific language governing permissions and * limitations under the License. */ package org.camelcookbook.monitoring.naming; import javax.management.MBeanServer; import javax.management.ObjectName; import org.apache.camel.CamelContext; import org.apache.camel.ProducerTemplate; import org.apache.camel.management.DefaultManagementNamingStrategy; import org.apache.camel.management.JmxSystemPropertyKeys; import org.apache.camel.spi.ManagementAgent; import org.junit.After; import org.junit.Before; import org.junit.Test; import org.slf4j.Logger; import org.slf4j.LoggerFactory; import static org.junit.Assert.*; public class JmxNamingContextTest { private static Logger LOG = LoggerFactory.getLogger(JmxNamingContextTest.class); private JmxNamingContextCamelApplication camelApp; private CamelContext context; private ProducerTemplate template; @Before public void setup() throws Exception { // Ensure JVM platform MBean Server will run System.setProperty(JmxSystemPropertyKeys.DISABLED, "false"); camelApp = new JmxNamingContextCamelApplication(); camelApp.setup(); context = camelApp.getContext(); template = context.createProducerTemplate(); // Force hostname to be "localhost" for testing purposes final DefaultManagementNamingStrategy naming = (DefaultManagementNamingStrategy) context.getManagementStrategy().getManagementNamingStrategy(); naming.setHostName("localhost"); naming.setDomainName("org.apache.camel"); // setup the ManagementAgent to include the hostname context.getManagementStrategy().getManagementAgent().setIncludeHostName(true); camelApp.start(); } @After public void tearDown() throws Exception { template = null; context = null; camelApp.tearDown(); camelApp = null; } @Test public void testNamingContext() throws Exception { final ManagementAgent managementAgent = context.getManagementStrategy().getManagementAgent(); assertNotNull(managementAgent); final MBeanServer mBeanServer = managementAgent.getMBeanServer(); assertNotNull(mBeanServer); final String mBeanServerDefaultDomain = managementAgent.getMBeanServerDefaultDomain(); assertEquals("org.apache.camel", mBeanServerDefaultDomain); final String managementName = context.getManagementName(); assertNotNull("CamelContext should have a management name if JMX is enabled", managementName); LOG.info("managementName = {}", managementName); // Get the Camel Context MBean ObjectName onContext = ObjectName.getInstance(mBeanServerDefaultDomain + ":context=localhost/" + managementName + ",type=context,name=\"" + context.getName() + "\""); assertTrue("Should be registered", mBeanServer.isRegistered(onContext)); // Get the first Route MBean by id ObjectName onRoute1 = ObjectName.getInstance(mBeanServerDefaultDomain + ":context=localhost/" + managementName + ",type=routes,name=\"first-route\""); LOG.info("Canonical Name = {}", onRoute1.getCanonicalName()); assertTrue("Should be registered", mBeanServer.isRegistered(onRoute1)); // Send a couple of messages to get some route statistics template.sendBody("direct:start", "Hello Camel"); template.sendBody("direct:start", "Camel Rocks!"); // Get an MBean attribute for the number of messages processed assertEquals(2L, mBeanServer.getAttribute(onRoute1, "ExchangesCompleted")); // Get the other Route MBean by id ObjectName onRoute2 = ObjectName.getInstance(mBeanServerDefaultDomain + ":context=localhost/" + managementName + ",type=routes,name=\"other-route\""); assertTrue("Should be registered", mBeanServer.isRegistered(onRoute2)); // Get an MBean attribute for the number of messages processed assertEquals(0L, mBeanServer.getAttribute(onRoute2, "ExchangesCompleted")); // Send some messages to the other route template.sendBody("direct:startOther", "Hello Other Camel"); template.sendBody("direct:startOther", "Other Camel Rocks!"); // Verify that the MBean statistics updated correctly assertEquals(2L, mBeanServer.getAttribute(onRoute2, "ExchangesCompleted")); // Check this routes running state assertEquals("Started", mBeanServer.getAttribute(onRoute2, "State")); // Stop the route via JMX mBeanServer.invoke(onRoute2, "stop", null, null); // verify the route now shows its state as stopped assertEquals("Stopped", mBeanServer.getAttribute(onRoute2, "State")); } }

2024-07-09T01:27:04.234600

https://example.com/article/9949

1. Field of the Invention The present invention relates generally to medical devices and methods. In particular, the present invention relates to an oral device that may be held in the mouth of a patient to reduce the incidence of obstructive sleep apnea or snoring. Obstructive sleep apnea (OSA) is a serious medical condition resulting from a temporary airway blockage which occurs as a patient sleeps. The airway blockage usually occurs between the soft palate and/or the back of the tongue and the pharynx. As the patient breathes, the reduced area in the upper airway can cause snoring, and more seriously, OSA. Sleep disruption caused by OSA can result in severe daytime sleepiness, chronic fatigue, headaches, depression, accidents, injuries, and of particular concern, OSA can reduce the amount of oxygen entering the lungs causing hypoxia. Hypoxia, in turn, can lead to pulmonary hypertension, heart disease, and stroke. Numerous invasive and less invasive treatments have been proposed for OSA. Of particular interest to the present invention, “continuous positive airway pressure” (CPAP) delivers a continuous stream of pressurized air directly to the person's upper airway. The positive pressure maintains patency of the airway and inhibits the collapse associated with OSA. Although generally effective, CPAP suffers from a number of drawbacks that have led to a high level of non-compliance. The patient must wear a bulky facial mask which can be uncomfortable, and the system generates noise that can make falling asleep difficult. CPAP is also difficult to use because the mask requires careful fitting to avoid air leaks and facial discomfort and because the mask can easily be dislodged during sleep. Moreover, a number of unpleasant side effects, such as sore throats, dry throat and eyes, headaches, and skin rashes from the mask frequently occur. These problems have resulted in a high level of non-compliance with CPAP therapy. As an improvement over CPAP, it has been proposed to apply a negative pressure to the forward end of the patient's mouth, typically at or just behind the lips, to pull the tongue forward in order to lift the rear portion of the tongue away from the back of the airway. See, for example, U.S. Patent Publication Nos. 2007/0277818, 2005/0166928 and 2005/0166929. While promising in theory, in practice it is very difficult to apply a vacuum in the region of the tip of the tongue to raise the base of the tongue and clear the patient's airway, particularly when the patient is lying on his or her back and gravity is pulling the tongue posteriorly. The tongue is a relatively large and compliant organ with significant mass, and applying a vacuum over a relatively small surface area at the tip will often not be effective in raising the back of the tongue against gravity. The moist and compliant tissues in the mouth are somewhat self-sealing, and this effect tends to inhibit the propagation of negative pressure, thereby confining the negative pressures to a relatively small area near the point of application. Thus, simply applying a vacuum at a location near the anterior tip of the tongue tends to draw the tongue up against the hard palate posterior to this location, creating a seal that restricts the propagation of vacuum through this region of contact toward the back of the oral cavity, where direct vacuum is usually required for maximum effectiveness. As another improvement over CPAP, it has been proposed to place various devices in direct contact with the posterior tissues of the mouth such as the soft palate and posterior portions of the tongue. A major disadvantage of these approaches is that contact with certain tissues near the posterior area of the tongue may elicit the gag reflex and in any case the presence of such devices so far back in the mouth can be uncomfortable. For these reasons, it would be desirable to provide alternative and improved methods and apparatus for treating obstructive sleep apnea and snoring. The methods and devices should be non-invasive and require no surgery or permanently implanted components. In addition, the methods and devices should be minimally intrusive with components that are comfortable and quiet so that disruption of the patient's sleep is minimized. Moreover, the methods and devices should avoid contacting the portions of the oral cavity that trigger the gag reflex. The methods and systems should also be simple to implement and be effective to significantly improve patency of a patient's airway during sleep. At least some of these objectives will be met by the inventions described hereinafter. 2. Description of the Background Art Oral and external devices for treating sleep apnea and snoring are described in U.S. Patent Publication Nos. US2005/166929; US2005/166928; US2008/0188947; US2007/0277818; US2008/0216843; and US2008/0210244; and in U.S. Pat. Nos. 7,182,082; 7,073,506; 7,073,505; 6,955,172; 6,877,513; 6,494,209; 5,957,133; 5,465,734; 4,676,240; 4,304,227; 4,169,473; and 3,132,647; and in Cartwright and Samelson “The effects of a non-surgical treatment for obstructive sleep apnea: the tongue retaining device;” Journal of the American Medical Association 248 (1982).

2023-12-25T01:27:04.234600

https://example.com/article/3329

Q: Efficiency of top vs. sample in Teradata In Teradata, which is more efficient - Sample or Top? Since sample is random, does that cause Teradata to do less work and result in faster returns? Routinely, I just want to see a few rows. Thread related: differences between top and sample in teradata sql A: I just ran three queries on a large Teradata dataset: SELECT * FROM table Sample 10; SELECT * Top 10 FROM table; (with no order by) SELECT * Top 10 FROM table ORDER BY column; The DBQL metrics show that by far, the Top 10 with no order is the least resource-intensive. I had about a 99% drop in I/O & CPU just changing from SAMPLE to TOP. So if your goal is purely efficiency, then TOP without the Order by is the clear winner going by TD's DBQL metrics.

2024-06-12T01:27:04.234600

https://example.com/article/4084

Q: Check in Check out For Sharepoint List Items is it possible to implement Check in Check out on Sharepoint List Items? A: Check-in/ Check-out is only available for document libraries. The physical check in/out process is done on the SPFile (document) and not the list item. List items can be tracked using versioning. sharepoint does not allow entry of values concurrently, meaning if you are modyfying list item 1 and user 2 also trys to do it, only after user 1 changes are submited user 2 can add his new value and in this case user 2 will get error, once user 1 done with his changes, user 2 will be allowed to change the list item. so when user 1 changes list item 1, its locked for user 2 or any other user trying to change the value of list item 1 and gives an error.

2024-04-15T01:27:04.234600

https://example.com/article/9399

Q: What's causing these 403 errors for the DocumentRoot on my Apache setup? I'm configuring Apache myself, and trying to force myself to (re-)learn the configuration process. It's been a long time! Version is Apache/2.2.21 running on Amazon Linux I'm planning on running a few sites from this server. I've created: /home/ec2-user/sites /home/ec2-user/sites/www.domain.ca /home/ec2-user/logs The first two contain index.html files. In the process of my experimentation, I've set my tree to 777 without any success, and have changed ownership and groups for directories and files to apache (which is what is sent in httpd.conf). I've chopped out some relevant parts of my httpd.conf file: DirectoryIndex index.html index.html.var DocumentRoot "/home/ec2-user/sites" <Directory "/"> Options None AllowOverride None </Directory> <Directory "/home/ec2-user/sites"> Options Indexes Order Allow,Deny Allow from All # Any other directory-specific stuff </Directory> <Directory "/home/ec2-user/www.domain.ca"> Order Allow,Deny Allow from All # Any other directory-specific stuff </Directory> # Default for when no domain name is given (i.e. access by IP address) <VirtualHost *:80> ServerAdmin me@gmail.com DocumentRoot /home/ec2-user/sites ErrorLog /home/ec2-user/logs/error_log TransferLog /home/ec2-user/logs/access_log </VirtualHost> # Add a VirtualHost definition for your domain which was once the system default. <VirtualHost www.domain.ca> ServerName www.domain.ca ServerAlias domain.ca ServerAdmin me@gmail.com DocumentRoot /home/ec2-user/sites/www.domain.ca ErrorLog /home/ec2-user/logs/domain.ca.error_log TransferLog /home/ec2-user/logs/domain.ca.access_log </VirtualHost> In the error logs, I'm just getting: Sun Dec 11 02:50:11 2011] [error] [client 174.95.145.253] (13)Permission denied: access to / denied [Sun Dec 11 02:50:14 2011] [error] [client 174.95.145.253] (13)Permission denied: access to / denied [Sun Dec 11 02:54:27 2011] [error] [client 174.95.145.253] (13)Permission denied: access to / denied [Sun Dec 11 02:54:32 2011] [error] [client 174.95.145.253] (13)Permission denied: access to / denied Admittedly this isn't a very interesting question, but I'm stumped, and am now just flipping settings trying to determine what's causing the problem. A: Is your whole tree of dirs set to 777? chmod 755 the parent directorys

2023-08-18T01:27:04.234600

https://example.com/article/2636

Mae Surin Karenni refugee which burnt by mystery fire on the 22nd May at 14:20PM till 17:30PM killed 37 people Included 15 students, 3 teachers, 2 education staff and injured more than 200 people. 1 middle school, 2 primary schools, 2 nursery schools and more than 400 houses were destroyed by fire. Saw Thaung Shwe, a camp resident said, “At first, we heard explosion and saw the smoke, then we rush to accident. We tried to stop fire burning but it was continually happened another house to another. Finally we had to give up.” Right now, the camp needs emergency relief. Naw Par Lweh, a Karenni Women Organisation(KnWO) said, “We are packing a gift from outsiders such as clothes, Pots, Mats and Blankets. Once the packs are enough for every house hold, then we will distribute to them. Why we have to do this way is to make clear that everyone get the same amount of gift without any concerning.” Karenni Refugee camp #2 was established since 1992 in Kun Yuam district, Mae Hong Son Province and home to more than 3000 refugees.

2024-04-26T01:27:04.234600

https://example.com/article/3992

394 F.Supp. 72 (1975) Charles TAYLOR, Plaintiff, v. PACIFIC INTERMOUNTAIN EXPRESS CO., a corporation, and Automobile Mechanics Union, Local 701, I. A. M., Defendants. No. 74 C 3346. United States District Court, N. D. Illinois, E. D. May 12, 1975. Harry Bell, Chicago, Ill., for plaintiff. Richard A. Kerwin, Burke, Kerwin & Towle, Chicago, Ill., for defendants. Equal Employment Opportunity Commission, Washington, D. C., amicus curiae. MEMORANDUM OPINION WILL, District Judge. The instant controversy revolves around the interpretation of a portion of § 706(f)(1) of the Equal Employment Opportunity Act, 42 U.S.C. § 2000e-5(f)(1). In relevant part the section provides: If a charge filed with the Commission pursuant to subsection (b) of this section is dismissed by the Commission, or if within one hundred and eighty days from the filing of such charge . . . the Commission has not entered into a conciliation agreement to which the person aggrieved is a party, the Commission . . . shall so notify the person aggrieved and within ninety days after the giving of such notice a civil action may be brought . . .. The plaintiff, Charles Taylor, has brought suit against Pacific Intermountain Express Company (Pacific), a corporation, and the Automobile Mechanics Union, Local 701 I.A.M. (Mechanics) *73 alleging violations of the Equal Employment Opportunity Act. Pursuant to the requirements of the Act, the plaintiff filed a charge with the Equal Employment Opportunity Commission (Commission) on February 16, 1971, charging that Pacific had violated the Act by engaging in unlawful employment practices, including discriminatory discharge, on the basis of race. Plaintiff also alleged that Local 701 of the Mechanics had refused to fairly represent him. Following proceedings before the Illinois Fair Employment Practices Commission, the federal commission undertook to investigate the charges made by plaintiff and, on June 3, 1973, issued a determination letter finding reasonable cause to believe that defendants had engaged in discriminatory employment practices based on race. After attempting to reach an acceptable conciliation agreement between defendants and plaintiff, the Commission on July 25, 1974 issued a letter to plaintiff stating in relevant part: As of this date, the Commission has been unable to reach a satisfactory agreement with the Respondent to properly settle the matters raised in the above-mentioned case. Therefore, you may at this time request in writing a Notice of Right to Sue which enables you to institute civil action in the appropriate U. S. District Court. If you are unable to locate an attorney, please contact our District Counsel, Ms. Dolores Knapp, 353-4359, in this office and efforts will be made to assist you in that regard. If you are unable to afford an attorney, the United States District Court is empowered, in its discretion, to appoint an attorney to represent you and to authorize commencement of suit without the payment of fees, cost or security. If you intend to pursue this matter in the U. S. District Court, it is requested that you sign the enclosed form in the appropriate place and return it in the self-addressed envelope to this office within 15 days from the receipt of this letter. On August 16, 1974, 22 days later, plaintiff requested a "right to sue" letter. The Commission issued such a letter on October 4, 1974. That letter advised plaintiff: Pursuant to Section 706(f-1) of Title VII of the Civil Rights Act of 1964, as amended, you are hereby notified that you may within ninety (90) days of receipt of this communication, institute a civil action in the appropriate Federal District Court. If you are unable to retain an attorney, the Federal District Court is authorized in its discretion to appoint an attorney to represent you and to authorize commencement of the suit without payment of fees, costs or security. If you decide to institute suit and find you need assistance, you may take this letter, along with any correspondence you have received from the Commission, to the Clerk of the Federal District Court nearest to the place where the alleged discrimination occurred, and request that a Federal District Judge appoint counsel to represent you. In the event you secure the services of an attorney, please pass the enclosed self-addressed card along to him. Relying thereon, the plaintiff brought the instant suit on November 19, 1974, 46 days after the issuance of the "right to sue" letter, but 117 days after the "failure to conciliate" letter was issued. The defendants have moved to dismiss on the ground that the suit was not commenced within the 90-day time period provided by § 2000e-5(f). They argue that the period began to run no later than when the plaintiff received the Commission's failure to conciliate letter; consequently, the complaint is beyond the statutory period. Plaintiff opposes the motion, contending that the statutory period began to run on the date the "right to sue" letter was issued; hence, the filing of plaintiff's complaint 46 days later is plainly within the statutory *74 period. The Commission has filed an amicus curiae brief in opposition to the motion to dismiss, to which the defendants have responded. Under the statute, the "failure to conciliate" notice to a complainant apparently commences the running of the statute. The language of § 2000e-5(f)(1), quoted earlier, explicitly provides that a complainant has 90 days in which to bring suit after being notified by the Commission that conciliation efforts have failed. See also Stebbins v. Continental Ins. Co., 143 U.S.App.D.C. 121, 442 F.2d 843 (1971) and Cunningham v. Litton Industries, 413 F.2d 887 (9th Cir. 1969); which hold that the letter indicating that the Commission has failed to effect conciliation with the respondent commences the running of the statutory period. In Harris v. Sherwood Medical Industries, Inc., 386 F.Supp. 1149 (E.D.Mo. 1974), the Court was confronted with the question of whether the "failure to conciliate" letter or the "right to sue" letter commences the running of the 90-day period. The Court held that the "failure to conciliate" letter controls. The Court explained that the sole purpose of the requirement of notification was "to provide formal notification to the claimant that his administrative remedies with the Commission have been exhausted." Such a purpose, the Court continued, did not include advice to complainants of their legal rights, and the courts have accepted the "notice of right to sue" language only because it was used by the Commission and not because they sought to establish additional elements of notice beyond those set forth in the statute. The Court concluded that, by adopting the practice of withholding a formal "right to sue" letter until requested, the Commission permits the charging party to exercise "complete control over commencement of the filing period," thereby effectively abolishing "any limitation period whatever, in frustration of the legislative intent." We agree with the Court in Sherwood Medical Industries, Inc., supra, that the notice of failure to conciliate commences the running of the statutory period. The Commission attempts to justify its two-letter system ("failure to conciliate" and "right to sue") on the ground that additional time is needed, after conciliation efforts have failed, to allow the Commission to determine whether it will bring suit against the respondent. The hiatus afforded by the two-letter system is particularly important, the Commission argues, in view of decisions which have held that the Commission is precluded from bringing suit, once the complainant has initiated suit on his or her own behalf. EEOC v. Mo. Pac. R. R., 493 F.2d 71 (8th Cir. 1974). These arguments are unpersuasive. Since a complainant is not required to wait a certain period of time before securing the right to sue letter, and, even under the Commission's format, may file suit immediately upon its receipt, there is no assured time lag between the two letters. Such a letter may as easily be requested the day following the complainant's receipt of the failure to conciliate notice as after a more extended period of time following such receipt. In any event, the Commission's internal administrative logistics and convenience do not warrant its ignoring or amending the clear statutory language. As noted in the foregoing factual discussion, here the right to sue letter was requested August 16 and issued on October 4, 1974. Presumably, in the interim, the Commission determined whether or not to sue in its own behalf. While we recognize the Commission's need to reconcile its administrative processes with the requirements of 42 U.S.C. 2000e-5(f)(1), such an adaptation may not include practices and procedures which extend the limitations period established by Congress. It should be noted that withholding notice to the complainant of failure to conciliate until after the Commission has determined whether or not it will sue would both accommodate the Commission's *75 internal administrative needs and not alter the statutory requirement that the period begin to run when notice of failure to conciliate has been given. In the absence of the particular equitable considerations present in the instant case, the plaintiff would be barred from maintaining this action. It is clear, however, that the plaintiff's failure to bring suit within 90 days of the July 25, 1974 notice of failure to conciliate was caused by the Commission's written declaration to him that the 90-day period would begin upon issuance of a "right to sue" letter. Having been informed in the failure to conciliate letter that he might do so, the plaintiff requested a right to sue letter 22 days after July 25, 1974, the date of that letter. The Commission delayed between August 16 and October 4 before issuing the latter letter. He then brought suit 46 days after the issuance of the "right to sue" letter. In neither case, nor in the aggregate, did plaintiff allow a period of 90 days to elapse. Had the Commission not delayed 49 days in issuing the right to sue letter, this suit would have been brought well within the 90 day period. The Seventh Circuit in Choate v. Caterpillar Tractor Co., 402 F.2d 357 (7th Cir. 1968) refused to permit the Commission's failure to enter conciliation efforts with the respondent to prejudice the rights of the complainant. The Court pointed out that the inefficient conduct of the Commission, over which the plaintiff had no control, should not defeat his rights. See also Gates v. Georgia-Pacific Corporation, 492 F.2d 292 (9th Cir. 1974) where the Ninth Circuit held that, because the letter sent by the Commission to the plaintiff did not advise her as to the time period within which she was required to file suit and because she promptly commenced her action upon learning of the limitation, she had timely filed suit in the District Court, even though filing occurred beyond the statutory limitations period. In the instant case, the Commission proceeded one step beyond a mere failure to advise and led the plaintiff to believe that his right to sue pivoted upon his receipt of a "right to sue" letter. The plaintiff was, accordingly, misinformed by the Commission as to his rights under the Act. Based on the equitable considerations expressed in Choate, supra, we hold that plaintiff's failure to file suit within 90 days after he received the "failure to conciliate" notice, does not bar his case. We trust that, in the future, the Commission will conform its procedures and communications to the statutory requirements. The suggestion in failure to conciliate letters that a complainant requires a right to sue letter before suit may be brought is clearly contrary to the statute. The statement in the right to sue letter that the complainant has 90 days after receipt thereof to file his action is likewise clearly inconsistent with the specific statutory language. The Commission must cease creating situations such as in the instant case in which the complainant, through no fault of his own and in reliance on Commission statements, fails to file suit within the statutory period. If the present statutory timetable is unsatisfactory and presents administrative difficulties to the Commission, its proper course of conduct is to seek amendment of the statute by Congress, not ignore or amend the clear statutory language by administrative fiat. An order denying defendants' motions to dismiss will enter.

2023-08-19T01:27:04.234600

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