bluuebunny/crossref_metadata_2025 huggingface dataset:
In Search of the Popular Subject: Identity Formation, Constitution-making and the Democratic Consolidation of the EU
Authors: Trenz Hans-Jörg
Published: December 2009

This article addresses the critical issue of how constitutional designing of the EU is related to the expression of collective identities. A European collective identity is perceived in terms of the discursive representation of the underlying demos of a European democracy. Against the common view that holds the self-identified political community as prior and independent of constitutional designing, it is claimed that democracy rather operates through the identification of popular subjectness. The demos is signified and recognised as distinct and internally coherent through democratic practice. In the empirical part, it is tested out to what extent public debates on EU-constitution-making were linked to the identification of the popular subject of democracy. By drawing on a comparative media survey of constitutional debates from 2002–2007, the article distinguishes different markers of collective identities (national, European or multiple) that were used for representing and signifying democratic subjects in the EU.
Global warming increases flood risk in mountainous areas
Authors: Allamano P. , Claps P. , Laio F.
Published: December 2009

The paper aims at assessing the impact of global warming on flood risk in mountainous regions, providing measurable evidence of possible hydrologic changes due to temperature increase. It shows that large floods in mountain basins are now more frequent than in the past and that they may become even more frequent under global warming. The morpho‐climatic model used for prediction is very simple and does not require calibration, which makes it suitable for application in scarcely gauged mountainous areas of the world.
Perennial pack ice in the southern Beaufort Sea was not as it appeared in the summer of 2009
Authors: Barber David G. , Galley Ryan , Asplin Matthew G. , De Abreu Roger , Warner Kerri‐Ann , Pućko Monika , Gupta Mukesh , Prinsenberg Simon , Julien Stéphane
Published: December 2009

In September 2009 we observed a much different sea icescape in the Southern Beaufort Sea than anticipated, based on remotely sensed products. Radarsat derived ice charts predicted 7 to 9 tenths multi‐year (MY) or thick first‐year (FY) sea ice throughout most of the Southern Beaufort Sea in the deep water of the Canada Basin. In situ observations found heavily decayed, very small remnant MY and FY floes interspersed with new ice between floes, in melt ponds, thaw holes and growing over negative freeboard older ice. This icescape contained approximately 25% open water, predominantly distributed in between floes or in thaw holes connected to the ocean below. Although this rotten ice regime was quite different that the expected MY regime in terms of ice volume and strength, their near‐surface physical properties were found to be sufficiently alike that their radiometric and scattering characteristics were almost identical.
Slow diffusive fault slip propagation following the 6 April 2009 L'Aquila earthquake, Italy
Authors: Amoruso A. , Crescentini L.
Published: December 2009

Two laser strainmeters that operate at 1400‐m depth, about 20 km NE of the epicenter of the 6 April 2009 magnitude‐6.3 L'Aquila, Italy, earthquake, have produced a clear record of postseismic strain. Here we show the results from the analysis of the data related to the first few days after the event. Strain after about 1.5 days is fully consistent with afterslip on a stationary region of the earthquake causative fault. The preceding few‐hour‐long transient (whose seismic moment history is quasi‐exponential) is fully consistent with unilateral diffusive slip propagation toward the shallower part of the same fault. The propagation path ends where later afterslip probably occurred. Slip propagation similar to heat diffusion has been suggested to explain the observed scaling law between amplitude and duration of slow earthquakes; here we give the first observational evidence of the role and details of slow rupture propagation.
Penetration of lightning MF signals to the upper ionosphere over VLF ground‐based transmitters
Authors: Parrot M. , Inan U. S. , Lehtinen N. G. , Pinçon J. L.
Published: December 2009

The MF data recorded by the low‐altitude satellite DEMETER have been used to survey the MF waves around the Earth. A global map of the MF emissions indicates that there exists a wave activity in the frequency range 2–2.5 MHz above the main powerful VLF ground‐based transmitters operating in the frequency range 18–50 kHz. It is shown that this is due to the high‐frequency part of whistlers induced by the thunderstorm activity. They can penetrate trough the ionosphere at the locations of the transmitters because these transmitters induce large ionospheric perturbations. This means that an integrated map over several months is able to show these MF emissions above all main VLF transmitters. The discrepancy between intensities of the emissions in winter and summer (in the Northern Hemisphere) is explained by considering the geographic variations of the plasma frequency below the satellite. It is shown that the MF waves spread in longitude in the hemisphere opposite to the VLF transmitters.
Autophagy: where next?
Authors: Rubinsztein David C.
Published: December 2009

How far are we in understanding autophagy and the processes it regulates? What challenges lie ahead? If we decipher how autophagy affects disease, we might obtain new leads to fight it.
Postdockin' in the free world
Authors: Jacobs Howy
Published: December 2009

Does postdoctoral research experience properly train biological scientists? Howy Jacobs explores the shortcomings of the current system and suggests how we might improve the lot of those currently on the long road to scientific fame and fortune.
Opening a new DOR to autophagy
Authors: Spowart Jaeline , Lum Julian J.
Published: December 2009

Our understanding of the autophagic pathway and the mechanisms that target specific components for degradation is still in its infancy. A new regulator, DOR, and a receptor that specifically targets mitochondria for degradation, Nix, provide new insights into this important process.
Challenges in modeling disturbances' effects on terrestrial carbon cycling
Authors: Bond-Lamberty Ben
Published: December 2009

Ecosystem disturbance presents modelers with a number of problems, of which the disturbance event itself may be the least problematic. First, most ecosystem models depend on reaching a steady state before the main computation begins; this already-tricky initial value problem is complicated by disturbances during spinup, which may prevent steady state from being reached. Second, vegetation dynamics becomes more important in disturbed ecosystems, with nutrient cycling, albedo, and evapotranspiration all changing markedly. Succession is handled crudely (or not at all) by many large-scale models, however. Third, disturbances tend to export the carbon--and its climate forcing potential--from the system under study, complicating and expanding the scope of the problem at hand, whether the modeler likes it or not. And finally, humans tend to be intimately involved in disturbances in many ecosystems in some surprising ways. This talk looks at each of these factors in turn, with reference to specific modeling examples or problems, and considers their consequences for the modeling of the North American carbon cycle and the increasing disturbances that affect it.
Comment to "Endogenous Viral Etiology of Prion Diseases"
Authors: Bandea Claudiu
Published: December 2009

This note is intended as a comment to a paper in Nature Precedings entitled "Endogenous viral etiology of prion diseases":http://precedings.nature.com/documents/3887/version/1 . Because it contains illustrations that could not be displayed in the comments section of that paper, I’m posting this comment here as a PDF document.
Regulation of mRNA cap methylation
Authors: Cowling Victoria H.
Published: December 2009

The 7-methylguanosine cap added to the 5′ end of mRNA is essential for efficient gene expression and cell viability. Methylation of the guanosine cap is necessary for the translation of most cellular mRNAs in all eukaryotic organisms in which it has been investigated. In some experimental systems, cap methylation has also been demonstrated to promote transcription, splicing, polyadenylation and nuclear export of mRNA. The present review discusses how the 7-methylguanosine cap is synthesized by cellular enzymes, the impact that the 7-methylguanosine cap has on biological processes, and how the mRNA cap methylation reaction is regulated.
Low voltage active pressure sensor based on polymer space-charge-limited transistor
Authors: Chao Yu-Chiang , Lai Wei-Jen , Chen Chun-Yu , Meng Hsin-Fei , Zan Hsiao-Wen , Horng Sheng-Fu
Published: December 2009

Low voltage active pressure sensor is realized by vertically stacking a pressure sensitive rubber on a polymer space-charge-limited transistor. The sensor can be turned on and off by modulating the metal-grid base voltage within the range of 3 V. The output current is irrelevant to the pressure as the sensor is off. As the sensor is turned on, the output current values can be used to monitor the pressure. Reversible pressure sensing characteristics is observed below the pressure of 7.11 psi. The response time of the sensor to the pressure is as short as 22 ms.
Double wavelength ultraviolet light sensitive organic photodetector
Authors: Yan Fei , Liu Huihui , Li Wenlian , Chu Bei , Su Zisheng , Zhang Guang , Chen Yiren , Zhu Jianzhuo , Yang Dongfang , Wang Junbo
Published: December 2009

The authors demonstrate an organic ultraviolet (UV) photodetector (PD) device in which 1,3,5-tris(3-methylphenyl-phenylamino)-triphenyamine and 1,3,5-tris(N-phenylbenzimidazol-2-yl)-benzene were used as the electron donor and acceptor, respectively. The PD diode offers responses of 75.2 and 22.5 mA/W as the 365 and 330 nm UV light with 1.0 mW/cm2 intensities illuminate the PD diode through anode and cathode sides, respectively. It is interesting that only the planar heterojunction structure diode can provide the special response feature while bulk-heterojunction device could not do it. The working mechanism of the PD diode was also discussed in detail.
Evidences for the depletion region induced by the polarization of ferroelectric semiconductors
Authors: Yuan Guo-Liang , Wang Junling
Published: December 2009

Ferroelectric materials possess spontaneous polarization pointing from negative to positive bound surface charges. When a ferroelectric semiconductor is polarized, the induced electric field can drive free carriers, e.g., electrons in an n-type material, to neutralize surface charges until such field becomes zero. Such diffusion of free carriers induces a depletion region. Polarization switch can move the depletion region to the opposite surface, thus it can be used to manipulate any properties that are affected by such depletion region, such as unidirectional current and photovoltaic current.
Spall damage of copper under supported and decaying shock loading
Authors: Luo Sheng-Nian , Germann Timothy C. , Tonks Davis L.
Published: December 2009

We investigate spall damage of single crystal Cu under supported (square) and decaying (Taylor wave) shock wave loading with molecular dynamics simulations. Varying the target-to-flyer plate thickness ratio R (with target thickness fixed) as well as the impact velocity induces square and Taylor waves with different pulse shapes, durations and strengths, which are well correlated with prespall damage, spall strength, and spall damage. Taylor wave loading results in higher spall strength than the supported shock loading at the same impact velocities, and the spall strength can be similar for both loadings with the same peak free surface velocities, while Taylor wave loading induces less spall damage than square wave loading. Void nucleation is preceded by plasticity and solid-state disordering. Multiple spall events appear to be independent of each other at the early stage of spallation. In applying the acoustic method for deducing the spall strength from the free surface velocity histories, one should consider the proper sound speed and R. The method works better for large R (Taylor waves) than for small R (square waves). However, this method may significantly underestimate strain rate for both types of loading.
Magnetohydrodynamic energy conversion by using convexly divergent channel
Authors: Murakami Tomoyuki , Okuno Yoshihiro
Published: December 2009

We describe a magnetohydrodynamic (MHD) electrical power generator equipped with a convexly divergent channel, as determined through shock-tunnel-based experiments. The quality of MHD power-generating plasma and the energy conversion efficiency in the convexly divergent channel are compared with those from previous linearly divergent channel. The divergence enhancement in the channel upstream is effective for suppressing an excessive increase in static pressure, whereby notably high isentropic efficiency is achieved.
Si segregation in polycrystalline Co2MnSi films with grain-size control
Authors: Hirohata A. , Ladak S. , Aley N. P. , Hix G. B.
Published: December 2009

In order to characterize the interface/surface properties of polycrystalline Co2MnSi Heusler alloy films, grain-size evolution with increasing annealing time has been investigated. Here, samples with nanometer-scale grains have been prepared by our specially-designed sputtering system in order to maximize the interface/surface area. Our well-controlled grains clearly show Si phase segregation. This Si phase becomes conductive near room temperature and may be responsible for the significant decrease in tunneling magnetoresistance previously reported by [Wang et al., Appl. Phys. Lett. 93, 122506 (2008)].
Atomic structure evolution in bulk metallic glass under compressive stress
Authors: Wang G. , Mattern N. , Pauly S. , Bednarčik J. , Eckert J.
Published: December 2009

The structural behavior of Cu64.5Zr35.5 bulk metallic glass under compressive stress was investigated by means of in situ high energy x-ray synchrotron diffraction. The topological and chemical short-range order of the glass changes reversible upon loading within the elastic range. The number density of Cu–(Zr,Cu) and Zr–Zr nearest neighbor atomic pairs becomes oriented along the loading direction. The macroscopic stress state is reflected by the medium-range order. The determination of the components of the strain tensor from the shift of the positions of the nearest neighbor distances is not possible due to the structure changes.
Reducing extrinsic hysteresis in first-order La(Fe,Co,Si)13 magnetocaloric systems
Authors: Moore J. D. , Morrison K. , Sandeman K. G. , Katter M. , Cohen L. F.
Published: December 2009

Simultaneous magnetization and sample temperature measurements were performed as a function of magnetic field and magnetic field sweep-rates to study the influence of these conditions on the hysteresis of the magnetocaloric transition in La(Fe1−x−yCoxSiy)13 samples. The large magnetocaloric effect in the compounds that show a first-order transition cause a significant departure from isothermal conditions leading to dynamic sweep-rate dependent magnetic hysteresis. Here we show how this deleterious effect can be greatly reduced by changing the sample geometry or by use of materials which show a second-order transition only. The key signatures of nonisothermal conditions in the magnetization data are highlighted.
Millisecond flash lamp annealing of shallow implanted layers in Ge
Authors: Wündisch C. , Posselt M. , Schmidt B. , Heera V. , Schumann T. , Mücklich A. , Grötzschel R. , Skorupa W. , Clarysse T. , Simoen E. , Hortenbach H.
Published: December 2009

Shallow n+ layers in Ge are formed by phosphorus implantation and subsequent millisecond flash lamp annealing. Present investigations are focused on the dependence of P redistribution, diffusion and electrical activation on heat input into the sample and flash duration. In contrast to conventional annealing procedures an activation up to 6.5×1019 cm−3 is achieved without any dopant redistribution and noticeable diffusion. Present results suggest that independently of pretreatment the maximum activation should be obtained at a flash energy that corresponds to the onset of P diffusion. The deactivation of P is explained qualitatively by mass action analysis which takes into account the formation of phosphorus-vacancy clusters.
Electronic transport in monolayer graphene nanoribbons produced by chemical unzipping of carbon nanotubes
Authors: Sinitskii Alexander , Fursina Alexandra A. , Kosynkin Dmitry V. , Higginbotham Amanda L. , Natelson Douglas , Tour James M.
Published: December 2009

We report on the structural and electrical properties of graphene nanoribbons (GNRs) produced by the oxidative unzipping of carbon nanotubes. GNRs were reduced by hydrazine at 95 °C and further annealed in Ar/H2 at 900 °C; monolayer ribbons were selected for the fabrication of electronic devices. GNR devices on Si/SiO2 substrates exhibit an ambipolar electric field effect typical for graphene. The conductivity of monolayer GNRs (∼35 S/cm) and mobility of charge carriers (0.5–3 cm2/V s) are less than the conductivity and mobility of pristine graphene, which could be explained by oxidative damage caused by the harsh H2SO4/KMnO4 used to make GNRs. The resistance of GNR devices increases by about three orders of magnitude upon cooling from 300 to 20 K. The resistance/temperature data is consistent with the variable range hopping mechanism, which, along with the microscopy data, suggests that the GNRs have a nonuniform structure.
Ultrahigh contrast light valve driven by electrocapillarity of liquid gallium
Authors: Tsai Jeff T. H. , Ho Chih-Ming , Wang Fu-Cheng , Liang Chi-Te
Published: December 2009

This letter describes an ultrahigh contrast valve driven by the electrocapillarity of liquid gallium. We demonstrate that a micrometer-sized gallium droplet can be used to fabricate a prototype backlight transmissive pixel cell by transforming the droplet into a flat thin film. This light valve exhibits significantly high backlight utility (96%), an exceptional contrast ratio (106:1), and fast response time (0.49 ms). The high contrast ratio originated from the exceptional reflectivity of gallium, which can block backlight to prevent any transmission in the off state of our device. Without using any polarizer, the backlight utility can be improved dramatically compared to a conventional liquid crystal display. The backlight utility and switching time obtained from this prototype light valve is higher than that of commercial liquid crystal displays. This concept is also applicable to a wide variety of electro-optical devices.
Mid-IR plasmonic antennas on silicon-rich oxinitride absorbing substrates: Nonlinear scaling of resonance wavelengths with antenna length
Authors: Šikola T. , Kekatpure R. D. , Barnard E. S. , White J. S. , Van Dorpe P. , Břínek L. , Tomanec O. , Zlámal J. , Lei D. Y. , Sonnefraud Y. , Maier S. A. , Humlíček J. , Brongersma M. L.
Published: December 2009

We report on the resonant properties of platinum dipole antennas fabricated on a silicon-rich-oxinitride thin film that exhibits significant absorption in the mid-infrared of the electromagnetic spectrum (λ−1≈1100 cm−1). A nonlinear scaling between the resonant wavelength and the antenna length has been found and quantitatively confirmed by full-field electromagnetic simulations. The resonant wavelength increases linearly with antenna length for small lengths and tends to saturate for large ones (length >4 μm). This saturation effect is attributed to the coupling of a geometrical antenna resonance and an absorption resonance of the substrate material.
Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease
Authors: Feinberg Andrew P. , Irizarry Rafael A.
Published: December 2009

Neo-Darwinian evolutionary theory is based on exquisite selection of phenotypes caused by small genetic variations, which is the basis of quantitative trait contribution to phenotype and disease. Epigenetics is the study of nonsequence-based changes, such as DNA methylation, heritable during cell division. Previous attempts to incorporate epigenetics into evolutionary thinking have focused on Lamarckian inheritance, that is, environmentally directed epigenetic changes. Here, we propose a new non-Lamarckian theory for a role of epigenetics in evolution. We suggest that genetic variants that do not change the mean phenotype could change the variability of phenotype; and this could be mediated epigenetically. This inherited stochastic variation model would provide a mechanism to explain an epigenetic role of developmental biology in selectable phenotypic variation, as well as the largely unexplained heritable genetic variation underlying common complex disease. We provide two experimental results as proof of principle. The first result is direct evidence for stochastic epigenetic variation, identifying highly variably DNA-methylated regions in mouse and human liver and mouse brain, associated with development and morphogenesis. The second is a heritable genetic mechanism for variable methylation, namely the loss or gain of CpG dinucleotides over evolutionary time. Finally, we model genetically inherited stochastic variation in evolution, showing that it provides a powerful mechanism for evolutionary adaptation in changing environments that can be mediated epigenetically. These data suggest that genetically inherited propensity to phenotypic variability, even with no change in the mean phenotype, substantially increases fitness while increasing the disease susceptibility of a population with a changing environment.
Sociocultural epistasis and cultural exaptation in footbinding, marriage form, and religious practices in early 20th-century Taiwan
Authors: Brown Melissa J. , Feldman Marcus W.
Published: December 2009

Social theorists have long recognized that changes in social order have cultural consequences but have not been able to provide an individual-level mechanism of such effects. Explanations of human behavior have only just begun to explore the different evolutionary dynamics of social and cultural inheritance. Here we provide ethnographic evidence of how cultural evolution, at the level of individuals, can be influenced by social evolution. Sociocultural epistasis—association of cultural ideas with the hierarchical structure of social roles—influences cultural change in unexpected ways. We document the existence of cultural exaptation, where a custom's origin was not due to acceptance of the later associated ideas. A cultural exaptation can develop in the absence of a cultural idea favoring it, or even in the presence of a cultural idea against it. Such associations indicate a potentially larger role for social evolutionary dynamics in explaining individual human behavior than previously anticipated.
FRMD4A regulates epithelial polarity by connecting Arf6 activation with the PAR complex
Authors: Ikenouchi Junichi , Umeda Masato
Published: December 2009

The Par-3/Par-6/aPKC/Cdc42 complex regulates the conversion of primordial adherens junctions (AJs) into belt-like AJs and the formation of linear actin cables during epithelial polarization. However, the mechanisms by which this complex functions are not well elucidated. In the present study, we found that activation of Arf6 is spatiotemporally regulated as a downstream signaling pathway of the Par protein complex. When primordial AJs are formed, Par-3 recruits a scaffolding protein, termed the FERM domain containing 4A (FRMD4A). FRMD4A connects Par-3 and the Arf6 guanine-nucleotide exchange factor (GEF), cytohesin-1. We propose that the Par-3/FRMD4A/cytohesin-1 complex ensures accurate activation of Arf6, a central player in actin cytoskeleton dynamics and membrane trafficking, during junctional remodeling and epithelial polarization.
Modulations in oscillatory activity with amplitude asymmetry can produce cognitively relevant event-related responses
Authors: van Dijk Hanneke , van der Werf Jurrian , Mazaheri Ali , Medendorp W. Pieter , Jensen Ole
Published: December 2009

Event-related responses and oscillatory activity are typically regarded as manifestations of different neural processes. Recent work has nevertheless revealed a mechanism by which slow event-related responses are created as a direct consequence of modulations in brain oscillations with nonsinusoidal properties. It remains unknown if this mechanism applies to cognitively relevant event-related responses. Here, we investigated whether sustained event-related fields (ERFs) measured during working memory maintenance can be explained by modulations in oscillatory power. In particular, we focused on contralateral delayed activity (CDA) typically observed in working memory tasks in which hemifield specific attention is manipulated. Using magnetoencephalography, we observed sustained posterior ERFs following the presentation of the memory target. These ERFs were systematically lateralized with respect to the hemisphere in which the target was presented. A strikingly similar pattern emerged for modulations in alpha (9–13 Hz) power. The alpha power and ERF lateralization were strongly correlated over subjects. Based on a mechanistic argument pertaining to the nonsinusoidal properties of the alpha activity, we conclude that the ERFs modulated by working memory are likely to be directly produced by the modulations in oscillatory alpha activity. Given that posterior alpha activity typically reflects disengagement, we conclude that the CDA is not attributable to an additive process reflecting memory maintenance per se but, rather, is a consequence of how attentional resources are allocated.
Pulmonary surfactant phosphatidylglycerol inhibits respiratory syncytial virus–induced inflammation and infection
Authors: Numata Mari , Chu Hong Wei , Dakhama Azzeddine , Voelker Dennis R.
Published: December 2009

Respiratory syncytial virus (RSV) is the most common cause of hospitalization for respiratory tract infection in young children. It is also a significant cause of morbidity and mortality in elderly individuals and in persons with asthma and chronic obstructive pulmonary disease. Currently, no reliable vaccine or simple RSV antiviral therapy is available. Recently, we determined that the minor pulmonary surfactant phospholipid, palmitoyl-oleoyl-phosphatidylglycerol (POPG), could markedly attenuate inflammatory responses induced by lipopolysaccharide through direct interactions with the Toll-like receptor 4 (TLR4) interacting proteins CD14 and MD-2. CD14 and TLR4 have been implicated in the host response to RSV. Treatment of bronchial epithelial cells with POPG significantly inhibited interleukin-6 and -8 production, as well as the cytopathic effects induced by RSV. The phospholipid bound RSV with high affinity and inhibited viral attachment to HEp2 cells. POPG blocked viral plaque formation in vitro by 4 log units, and markedly suppressed the expansion of plaques from cells preinfected with the virus. Administration of POPG to mice, concomitant with viral infection, almost completely eliminated the recovery of virus from the lungs at 3 and 5 days after infection, and abrogated IFN-γ (IFN-γ) production and the enhanced expression of surfactant protein D (SP-D). These findings demonstrate an important approach to prevention and treatment of RSV infections using exogenous administration of a specific surfactant phospholipid.
A mouse model of osteochondromagenesis from clonal inactivation of
Ext1
in chondrocytes
Authors: Jones Kevin B. , Piombo Virginia , Searby Charles , Kurriger Gail , Yang Baoli , Grabellus Florian , Roughley Peter J. , Morcuende Jose A. , Buckwalter Joseph A. , Capecchi Mario R. , Vortkamp Andrea , Sheffield Val C.
Published: December 2009

We report a mouse model of multiple osteochondromas (MO), an autosomal dominant disease in humans, also known as multiple hereditary exostoses (MHE or HME) and characterized by the formation of cartilage-capped osseous growths projecting from the metaphyses of endochondral bones. The pathogenesis of these osteochondromas has remained unclear. Mice heterozygous for
Ext1
or
Ext2
, modeling the human genotypes that cause MO, occasionally develop solitary osteochondroma-like structures on ribs [Lin et al. (2000)
Dev Biol
224(2):299–311; Stickens et al. (2005)
Development
132(22):5055–5068]. Rather than model the germ-line genotype, we modeled the chimeric tissue genotype of somatic loss of heterozygosity (LOH), by conditionally inactivating
Ext1
via head-to-head
loxP
sites and temporally controlled
Cre
-recombinase in chondrocytes. These mice faithfully recapitulate the human phenotype of multiple metaphyseal osteochondromas. We also confirm homozygous disruption of
Ext1
in osteochondroma chondrocytes and their origin in proliferating physeal chondrocytes. These results explain prior modeling failures with the necessity for somatic LOH in a developmentally regulated cell type.
Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to
HHEX
,
SOX4
, and
IRX3
Authors: Ragvin Anja , Moro Enrico , Fredman David , Navratilova Pavla , Drivenes Øyvind , Engström Pär G. , Alonso M. Eva , Mustienes Elisa de la Calle , Skarmeta José Luis Gómez , Tavares Maria J. , Casares Fernando , Manzanares Miguel , van Heyningen Veronica , Molven Anders , Njølstad Pål R. , Argenton Francesco , Lenhard Boris , Becker Thomas S.
Published: December 2009

Genome-wide association studies identified noncoding SNPs associated with type 2 diabetes and obesity in linkage disequilibrium (LD) blocks encompassing
HHEX-IDE
and introns of
CDKAL1
and
FTO
[Sladek R, et al. (2007)
Nature
445:881–885; Steinthorsdottir V, et al. (2007)
Nat. Genet
39:770–775; Frayling TM, et al. (2007)
Science
316:889–894]. We show that these LD blocks contain highly conserved noncoding elements and overlap with the genomic regulatory blocks of the transcription factor genes
HHEX
,
SOX4
, and
IRX3
. We report that human highly conserved noncoding elements in LD with the risk SNPs drive expression in endoderm or pancreas in transgenic mice and zebrafish. Both
HHEX
and
SOX4
have recently been implicated in pancreas development and the regulation of insulin secretion, but
IRX3
had no prior association with pancreatic function or development. Knockdown of its orthologue in zebrafish,
irx3a,
increased the number of pancreatic ghrelin-producing epsilon cells and decreased the number of insulin-producing β-cells and glucagon-producing α-cells, thereby suggesting a direct link of pancreatic
IRX3
function to both obesity and type 2 diabetes.
Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition
Authors: Rasola Andrea , Sciacovelli Marco , Chiara Federica , Pantic Boris , Brusilow William S. , Bernardi Paolo
Published: December 2009

We studied human cancer cell models in which we detected constitutive activation of ERK. A fraction of active ERK was found to be located in mitochondria in RWPE-2 cells, obtained by v-Ki-Ras transformation of the epithelial prostate RWPE-1 cell line; in metastatic prostate cancer DU145 cells; and in osteosarcoma SAOS-2 cells. All these tumor cells displayed marked resistance to death caused by apoptotic stimuli like arachidonic acid and the BH3 mimetic EM20-25, which cause cell death through the mitochondrial permeability transition pore (PTP). PTP desensitization and the ensuing resistance to cell death induced by arachidonic acid or EM20-25 could be ablated by inhibiting ERK with the drug PD98059 or with a selective ERK activation inhibitor peptide. ERK inhibition enhanced glycogen synthase kinase-3 (GSK-3)-dependent phosphorylation of the pore regulator cyclophilin D, whereas GSK-3 inhibition protected from PTP opening. Neither active ERK in mitochondria nor pore desensitization was observed in non-transformed RWPE-1 cells. Thus, in tumor cells mitochondrial ERK activation desensitizes the PTP through a signaling axis that involves GSK-3 and cyclophilin D, a finding that provides a mechanistic basis for increased resistance to apoptosis of neoplastic cells.
Myelin-associated glycoprotein mediates membrane fusion and entry of neurotropic herpesviruses
Authors: Suenaga Tadahiro , Satoh Takeshi , Somboonthum Pranee , Kawaguchi Yasushi , Mori Yasuko , Arase Hisashi
Published: December 2009

Varicella-zoster virus (VZV) and herpes simplex virus (HSV) are prevalent neurotropic herpesviruses that cause various nervous system diseases. Similar to other enveloped viruses, membrane fusion is an essential process for viral entry. Therefore, identification of host molecules that mediate membrane fusion is important to understand the mechanism of viral infection. Here, we demonstrate that myelin-associated glycoprotein (MAG), mainly distributed in neural tissues, associates with VZV glycoprotein B (gB) and promotes cell-cell fusion when coexpressed with VZV gB and gH/gL. VZV preferentially infected MAG-transfected oligodendroglial cells. MAG also associated with HSV-1 gB and enhanced HSV-1 infection of promyelocytes. These findings suggested that MAG is involved in VZV and HSV infection of neural tissues.
Total Flavonoids Extracted from Xiaobuxin‐Tang on the Hyperactivity of Hypothalamic‐Pituitary‐Adrenal Axis in Chronically Stressed Rats
Authors: An Lei , Zhang You-Zhi , Liu Xin-Min , Yu Neng-Jiang , Chen Hong-Xia , Zhao Nan , Yuan Li , Li Yun-Feng
Published: December 2009

Our previous studies have demonstrated that the total flavonoids (XBXT‐2) isolated from the extract of Xiaobuxin‐Tang (XBXT), a traditional Chinese herbal decoction, ameliorated behavioral alterations and hippocampal dysfunctions in chronically stressed rats. Studies over the last decades have suggested that the hyperactivity of hypothalamic‐pituitary‐adrenal (HPA) axis is one of the most consistent findings in stress‐related depression. Herein, we used the same chronic mild stress model of rats as before to further investigate the effect of XBXT‐2 on the hyperactivity of HPA axis, including the stress hormones levels and glucocorticoid receptors (GRs) expression. Our ELISA results showed that chronic administration of XBXT‐2 (25, 50 mg kg−1, p.o., 28 days, the effective doses for behavioral responses) significantly decreased serum corticosterone level and its upstream stress hormone adrenocorticotropic hormone (ACTH) level in chronically stressed rats. Furthermore, western blotting result demonstrated XBXT‐2 treatment ameliorated stress‐induced decrease of GRs expression in hippocampus, an important target involved in the hyperactivity of HPA axis. These results were similar to that of classic antidepressant imipramine treatment (10 mg kg−1, p.o.). In conclusion, the modulation of HPA axis produced by XBXT‐2, including the inhibition of stress hormones levels and up‐regulation of hippocampal GRs expression, may be an important mechanism underlying its antidepressant‐like effect in chronically stressed rats.
Phosphorylation of Photosystem II Controls Functional Macroscopic Folding of Photosynthetic Membranes inArabidopsis
Authors: Fristedt Rikard , Willig Adrian , Granath Pontus , Crèvecoeur Michèle , Rochaix Jean-David , Vener Alexander V.
Published: December 2009

Photosynthetic thylakoid membranes in plants contain highly folded membrane layers enriched in photosystem II, which uses light energy to oxidize water and produce oxygen. The sunlight also causes quantitative phosphorylation of major photosystem II proteins. Analysis of the Arabidopsis thaliana stn7xstn8 double mutant deficient in thylakoid protein kinases STN7 and STN8 revealed light-independent phosphorylation of PsbH protein and greatly reduced N-terminal phosphorylation of D2 protein. The stn7xstn8 and stn8 mutants deficient in light-induced phosphorylation of photosystem II had increased thylakoid membrane folding compared with wild-type and stn7 plants. Significant enhancement in the size of stacked thylakoid membranes in stn7xstn8 and stn8 accelerated gravity-driven sedimentation of isolated thylakoids and was observed directly in plant leaves by transmission electron microscopy. Increased membrane folding, caused by the loss of light-induced protein phosphorylation, obstructed lateral migration of the photosystem II reaction center protein D1 and of processing protease FtsH between the stacked and unstacked membrane domains, suppressing turnover of damaged D1 in the leaves exposed to high light. These findings show that the high level of photosystem II phosphorylation in plants is required for adjustment of macroscopic folding of large photosynthetic membranes modulating lateral mobility of membrane proteins and sustained photosynthetic activity.
Fatty acid analyses reveal high degrees of omnivory and dietary plasticity in pond‐dwelling tadpoles
Authors: WHILES MATT R. , GLADYSHEV MICHAIL I. , SUSHCHIK NADEZDA N. , MAKHUTOVA OLESIA N. , KALACHOVA GALINA S. , PETERSON SCOT D. , REGESTER KURT J.
Published: December 2009

1. Understanding the trophic relationships of consumers is central to ecology, but constructing meaningful food webs is often difficult because of a lack of detailed information on consumption versus assimilation and high degrees of omnivory.

2. We used fatty acid analyses to examine the trophic relationships of three common larval anurans (Pseudacris crucifer, Lithobates catesbeianus and Lithobates clamitans) that are often classified as grazers or detritivores. Tadpoles and potential food sources were sampled in four ponds in southern Illinois and analysed for fatty acid composition. Single linkage cluster analysis was then used to compare fatty acid profiles among tadpole gut contents, tadpole muscle tissues and available food resources.

3. Diets varied among species and within species among ponds, but organic sediments consistently contributed most to the fatty acid composition of the gut contents of all species. Fatty acid profiles also indicated that larval insects and phytoplankton were consumed by both L. catesbeianus and L. clamitans in one pond, while L. clamitans and P. crucifer consumed mainly periphyton along with sediments in another pond, and these diet differences appeared linked to physical differences among ponds, with periphyton and/or phytoplankton contributing more to tadpole diets in less shaded ponds.

4. The fatty acid composition of muscle tissues of L. clamitans, the dominant tadpole in these systems, indicated that plant detritus and bacteria, which were the dominant components of organic sediments in the ponds, were common components of the assimilatory diet.

5. Results demonstrate the utility of fatty acid analyses for assessing both consumption and assimilation. The tadpole assemblages we examined derive much of their energy from heterotrophic and allochthonous sources and exhibit high dietary plasticity. This information will allow for more accurate and comprehensive assessments of trophic interactions in freshwater habitats, as well as aid in amphibian conservation, management and captive propagation efforts.
DNA mismatch repair deficiency in sporadic colorectal cancer and Lynch syndrome
Authors: Poulogiannis George , Frayling Ian M , Arends Mark J
Published: December 2009

Poulogiannis G, Frayling I M & Arends M J (2010) Histopathology56, 167–179

DNA mismatch repair deficiency in sporadic colorectal cancer and Lynch syndrome

DNA mismatch repair (MMR) deficiency is one of the best understood forms of genetic instability in colorectal cancer (CRC), and is characterized by the loss of function of the MMR pathway. Failure to repair replication‐associated errors due to a defective MMR system allows persistence of mismatch mutations all over the genome, but especially in regions of repetitive DNA known as microsatellites, giving rise to the phenomenon of microsatellite instability (MSI). A high frequency of instability at microsatellites (MSI‐H) is the hallmark of the most common form of hereditary susceptibility to CRC, known as Lynch syndrome (LS) (previously known as hereditary non‐polyposis colorectal cancer syndrome), but is also observed in ∼15–20% of sporadic colonic cancers (and rarely in rectal cancers). Tumour analysis by both MMR protein immunohistochemistry and DNA testing for MSI is necessary to provide a comprehensive picture of molecular abnormality, for use in conjunction with family history data and other clinicopathological features, in order to distinguish LS from sporadic MMR‐deficient CRC. Identification of the gene targets that become mutated in MMR‐deficient tumours may explain, at least in part, some of the clinical, pathological and biological features of MSI‐H CRCs and holds promise for developing novel therapeutics.
Microchimerism in renal allografts: clinicopathological associations according to the type of chimeric cells
Authors: Ferlicot Sophie , Vernochet Amélia , Romana Serge , Ortin‐Serrano Monique , Letierce Alexia , Brégerie Olivier , Durrbach Antoine , Guettier Catherine
Published: December 2009

Ferlicot S, Vernochet A, Romana S, Ortin‐Serrano M, Letierce A, Brégerie O, Durrbach A & Guettier C (2010) Histopathology56, 188–197

Microchimerism in renal allografts: clinicopathological associations according to the type of chimeric cells

Aims:  Recent studies have highlighted the presence of microchimerism in various solid allografts. The biological significance of these chimeric cells is controversial. They may be beneficial, leading to better tolerance of grafts or participating in tissue repair or, in contrast, deleterious if involved in chronic lesions. The aim was to assess the frequency and cellular nature of microchimerism in female renal grafts of male recipients by combined fluorescence in situ hybridization (FISH) for Y chromosome and immunohistochemistry and to investigate associations between intragraft microchimerism and histological lesions or allograft outcome.

Methods and results:  We screened 33 renal biopsy specimens, including 11 with acute T‐cell‐mediated rejection and nine with transplant glomerulopathy, from 22 male recipients transplanted with female kidneys by FISH and immunohistochemistry with antibodies against smooth muscle actin (mesangial cells), CD31 (endothelial cells), KL1 (epithelial cells), CD45 (leucocyte common antigen) and glomerular epithelial protein 1 (podocytes). Tubular microchimerism was detected in 71% of the patients with a mean percentage of chimeric epithelial cells of 1.4%. Glomerular microchimerism involving podocytes, mesangial and endothelial cells was present with a mean number of chimeric cells per glomerular section of, respectively, 0.6, 2.66 and 3.53. There was an association between endothelial microchimerism and a previous episode of acute T‐cell‐mediated rejection.

Conclusions:  In conclusion, microchimerism in renal grafts occurs frequently, but at a low level and affects tubular cells and all glomerular cell compartments in human renal allografts.
Adherence to hypertension treatment guidelines in state facilities in KwaZulu‐Natal, South Africa
Authors: Cassimjee Mariam , Suleman Fatima
Published: December 2009

Rationale, aims and objectives  The province of KwaZulu‐Natal, South Africa, embarked on the Essential Drugs Programme (EDP) consisting of standard treatment guidelines (STGs) and essential drugs lists in May 1999. The use of these tools was aimed at promoting rational drug use. This study sought to determine the percentage of compliance to the STGs of the EDP in the treatment of hypertension in patients in the district of eThekwini.

Methods  A retrospective cross‐sectional randomized sampling of 100 prescriptions for hypertension per 21 health facility was conducted for the period of 3 months in 2007. Each prescription was assessed against modified World Health Organization indicators to determine compliance to STGs.

Results  The mean age of the sample was 55.235 years (±0.62). Hypertension featured as the most common diagnosis in the sample (57.5%). The mean result of compliance to the STGs for the eThekwini District was 22.05% (±20.03). The results of the multiple linear regression equation suggest that the variables selected in this study explain 86.79% of the variables impacting on treatment guideline adherence.

Conclusion  The low mean results for compliance to the STGs was due mainly to the absence of a diagnosis recorded on the prescription, and the addition of a new drug for each symptom without due consideration of polypharmacy, drug–disease and drug–drug interactions.
The intended and unintended consequences of clinical guidelines
Authors: Shackelton Rebecca J. , Marceau Lisa D , Link Carol L. , McKinlay John B.
Published: December 2009

Objectives  First, we examine whether clinical guidelines, designed to improve health care and reduce disparities in clinical practice, are achieving their intended consequences. Second, we contemplate potential unintended consequences of clinical guidelines.

Method  As part of a factorial experiment we presented primary care doctors (n = 192) with clinically authentic vignettes of a ‘patient’ with already diagnosed diabetes with an emerging foot neuropathy. Their proposed clinical actions were compared with established practice guidelines for this clinical situation.

Results  After establishing the existence of consistent socioeconomic disparities in the proposed management of the case presented, we found that reported use of practice guidelines had no measurable effect towards their reduction (one intended consequence). However, the reported use of practice guidelines appeared to precipitate more clinical actions, without eliminating documented disparities.

Conclusions  Consistent with other research we find that clinical practice guidelines are not producing a principal intended result, and may even produce unintended consequences.
Quantitative evaluation of a clinical intervention aimed at changing prescriber behaviour in response to new guidelines
Authors: Doyon Sophie , Perreault Mélissa , Marquis Christopher , Gauthier Josianne , Lebel Denis , Bailey Benoit , Collin Johanne , Bussières Jean‐François
Published: December 2009

Abstracts

Rational, aims and objectives  The objective of the study was to assess prescribers' compliance with guidelines for acute community‐acquired pneumonia management in a paediatric university hospital centre before and after its dissemination.

Method  This quasi‐experimental study without a control group was conducted before and after new community‐acquired pneumonia management guidelines were disseminated in a tertiary care paediatric hospital. The pre‐intervention (baseline) period was from October 2004 to March 2005. The intervention period was divided into two phases: (1) October 2005 to January 14, 2006 (consultation by peer leaders and networking) and (2) January 15, 2006, to March 2006 (dissemination of official guidelines and of a pre‐printed prescription sheet, an educational session led by a peer leader for residents and further networking). We used a compliance score to assess prescriptions written by prescribers who practised in the units where the guidelines had to be followed.

Results  The study included a total of 1151 prescriptions. The prescription compliance with the guidelines increased from 131/652 (20.1%) in the pre‐intervention period to 264/499 (52.9%) in the post‐intervention intervention period: a difference of 32.8% (CI 95% 27.4–38.0). Similar results were found if analysed according to affiliation (emergency department or wards). An inappropriate choice of antibiotic agent represented 347/521 (66.6%) of the causes of non‐compliance in the pre‐intervention period and 99/235 (42.1) in the intervention period: a difference of −24.5% (95% CI −31.8, −16.8).

Conclusion  Guideline dissemination for the management of acute community‐acquired pneumonia significantly increased prescriber compliance in the emergency department and on wards.