bluuebunny/crossref_metadata_2025 huggingface dataset:
Distribution and paralogue specificity of mammalian deSUMOylating enzymes
Authors: Kolli Nagamalleswari , Mikolajczyk Jowita , Drag Marcin , Mukhopadhyay Debaditya , Moffatt Nela , Dasso Mary , Salvesen Guy , Wilkinson Keith D.
Published: July 2010

The covalent attachment of SUMO (small ubiquitin-like protein modifier) to target proteins results in modifications in their activity, binding interactions, localization or half-life. The reversal of this modification is catalysed by SENPs (SUMO-specific processing proteases). Mammals contain four SUMO paralogues and six SENP enzymes. In the present paper, we describe a systematic analysis of human SENPs, integrating estimates of relative selectivity for SUMO1 and SUMO2, and kinetic measurements of recombinant C-terminal cSENPs (SENP catalytic domains). We first characterized the reaction of each endogenous SENP and cSENPs with HA–SUMO-VS [HA (haemagglutinin)-tagged SUMO-vinyl sulfones], active-site-directed irreversible inhibitors of SENPs. We found that all cSENPs and endogenous SENP1 react with both SUMO paralogues, whereas all other endogeneous SENPs in mammalian cells and tissues display high selectivity for SUMO2-VS. To obtain more quantitative data, the kinetic properties of purified cSENPs were determined using SUMO1- or SUMO2-AMC (7-amino-4-methylcoumarin) as substrate. All enzymes bind their respective substrates with high affinity. cSENP1 and cSENP2 process either SUMO substrate with similar affinity and catalytic efficiency; cSENP5 and cSENP6 show marked catalytic specificity for SUMO2 as measured by Km and kcat, whereas cSENP7 works only on SUMO2. Compared with cSENPs, recombinant full-length SENP1 and SENP2 show differences in SUMO selectivity, indicating that paralogue specificity is influenced by the presence of the variable N-terminal domain of each SENP. Our data suggest that SUMO2 metabolism is more dynamic than that of SUMO1 since most SENPs display a marked preference for SUMO2.
Perceptual Assessment of Voice Quality: Past, Present, and Future
Authors: Kreiman Jody , Gerratt Bruce R.
Published: July 2010

Despite many years of research, we still do not know how to measure vocal quality. This paper reviews the history of quality assessment, describes some reasons why current approaches are unlikely to be fruitful, and proposes an alternative approach that addresses the primary difficulties with existing protocols.
Is low carbon society embedding or embedded in economy? Speed on the constraint or liberation from it
Authors: Machida Wataru , Miwa Kyoko , Nishioka Shuzo
Published: July 2010

The aim of this paper is to define low carbon society (LCS) based on the phase diagram with the variables from the IPAT [Human Impact (I) on the environment equals the product of population (P) affluence (A) and technology (T)], starting from the problem definitions: (1) Economy is not everything for LCS and (2) it is not clear if speed on the constraint is more important than liberation from it. To tackle these problems, two research questions are set: (1) What are the basic indicators, objects, and constraints to shape the argument of LCSs and (2) what are the historical paths of several countries and what can be said for their future paths toward carbon societies? Time series data from 1900 or before are used, while the phase diagram with the variables from the IPAT equation is used as the core methodology. In addition to the IPAT variables, the importance of land per capita shall be considered as another basic indicator for LCS related to the carrying capacity. The three different kinds of objects [i.e., total gross domestic product (GDP), GDP per capita, and social indicator] and the two constraints (i.e., total emission and emission per capita) are considered, and it is shown that the combination of these objects and constraints strongly affects the argument of the carrying capacity of climate and land, development of economic system and economic man, and other human developments. Among the four cases analyzed in the phase diagram, the case where GDP per capita is object and total emission is constraint is given the most attention and requires the further research in the future since it does not contradict with a definition of LCS. It is also suggested that if changing the direction of the path with low carbon technology development takes time and cost, institutional arrangement would be additionally necessary in addition to market mechanism where optimal solutions are found on constraint.
Renewable energy and low carbon economy transition in India
Authors: Shukla P. R. , Dhar Subash , Fujino Junichi
Published: July 2010

Cooperation of large developing countries such as India would be important in achieving a low carbon future, which can help in restricting the global temperature rise to 2 °C. Global modeling studies of such low carbon scenarios point to a prominent role for renewable energy. This paper reports scenarios for a low carbon future in India. An integrated modeling framework is used for assessing the alternate development pathways having equal cumulative CO2 emissions. The modeling period ranges from 2005 to 2050. The first pathway assumes a conventional development pattern together with a carbon price that aligns India’s emissions to an optimal 450 ppmv CO2-eq. stabilization global response. The second emissions pathway assumes an underlying sustainable development pattern. A low carbon future will be good for renewable energy under both the development pathways, though the share of renewable energy will be higher under a sustainable pathway. Renewable energy faces competition from low carbon technologies like nuclear and carbon capture and storage in the electricity sector. Solar, wind, biomass, and biofuels emerge as the four competitive renewable energy choices for India. Renewable development however depends critically on the reduction in the costs and in the ability to integrate the intermittent renewables within the existing systems for which technology transfer and capacity building hold the key.
Theory of infrared nanospectroscopy by photothermal induced resonance
Authors: Dazzi A. , Glotin F. , Carminati R.
Published: July 2010

We present a theoretical investigation of the physics involved in a recently developed spectromicroscopy technique, called photothermal induced resonance (PTIR). With this technique, one measures the local infrared absorption spectrum of a sample shined with a tunable infrared laser pulse, and detects the induced photothermal expansion with the tip of an atomic force microscope (AFM). Simple physical assumptions allow us to describe analytically the heating and expansion of the sample, the excitation of the vibration modes of the AFM cantilever, and the detected signal. We show that the signal depends on the thermal expansion velocity rather than on the absolute displacement of the tip, and we investigate the influence of the laser pulse length. Eventually, we express the PTIR signal in terms of relevant parameters, and prove its proportionality to the sample absorbance. This analytical approach complement our experimental results and validates the PTIR method as a technique of choice for infrared spectroscopy of nanoscopic samples, getting around optical artifacts like reflectance perturbation.
AX-type defects in zinc-doped GaAs(1−x)P(x) on GaAs
Authors: Gfroerer T. H. , Hampton D. G. , Simov P. R. , Wanlass M. W.
Published: July 2010

GaAsP alloys are potential candidates for ∼1.5 to 1.8 eV photovoltaic converters in multijunction solar cells. We use thermally stimulated capacitance, deep level transient spectroscopy, and photocapacitance to characterize defects in p-type GaAs0.83P0.17 and GaAs0.72P0.28 grown lattice-mismatched on GaAs substrates. We observe several features typically associated with DX centers, including persistent photocapacitance, nonexponential thermally-activated capture and escape transients, and large Stokes shifts for optical thresholds. We use secondary ion mass spectroscopy and capacitance versus voltage measurements to ascertain the sulfur and zinc doping profiles in the n+/p diodes. The dramatic decrease in the effective doping concentration with temperature in the unilluminated GaAs0.72P0.28 diode and the magnitude of the capacitance change with illumination indicate that the defect concentration is comparable to the zinc doping, suggesting that zinc may facilitate the formation of AX complexes in this alloy.
Spectroscopic interpretation and velocimetry analysis of fluctuations in a cylindrical plasma recorded by a fast camera
Authors: Oldenbürger S. , Brandt C. , Brochard F. , Lemoine N. , Bonhomme G.
Published: July 2010

Fast visible imaging is used on a cylindrical magnetized argon plasma produced by thermionic discharge in the Mirabelle device. To link the information collected with the camera to a physical quantity, fast camera movies of plasma structures are compared to Langmuir probe measurements. High correlation is found between light fluctuations and plasma density fluctuations. Contributions from neutral argon and ionized argon to the overall light intensity are separated by using interference filters and a light intensifier. Light emitting transitions are shown to involve a metastable neutral argon state that can be excited by thermal plasma electrons, thus explaining the good correlation between light and density fluctuations. The propagation velocity of plasma structures is calculated by adapting velocimetry methods to the fast camera movies. The resulting estimates of instantaneous propagation velocity are in agreement with former experiments. The computation of mean velocities is discussed.
A rotatable electron spectrometer for multicoincidence experiments
Authors: Céolin D. , Forsell J.-O. , Wannberg B. , Legendre S. , Palaudoux J. , Öhrwall G. , Svensson S. , Piancastelli M. N.
Published: June 2010

We have developed a rotatable hemispherical spectrometer with good energy and angular resolution, which can be positioned with the lens axis arbitrarily within a solid angle of 1 π. The collection angle of the emitted electrons with respect to the polarization axis of the light is set by means of a three-axes goniometer, operating under vacuum. An important requirement for this setup was the possibility to perform coincidences between the electron analyzed by the spectrometer and one or several other particles, such as ions, electrons, or photons. The lens system and the hemispheres have been designed to accommodate such experimental demands, regarding parameters such as the resolving power, the acceptance angle, or the width of the kinetic energy window which can be recorded for a given pass energy. We have chosen to detect the impact position of the electron at the focal plane of the hemispherical analyzer with a delay line detector and a time-to-digital converter as acquisition card rather than using a conventional charge-coupled device camera.
Direct numerical simulations of turbulence subjected to a straining and destraining cycle
Authors: Gualtieri P. , Meneveau C.
Published: July 2010

In many turbulent flows, significant interactions between fluctuations and mean velocity gradients occur in nonequilibrium conditions, i.e., the turbulence does not have sufficient time to adjust to changes in the velocity gradients applied by the large scales. The simplest flow that retains such physics is the time dependent homogeneous strain flow. A detailed experimental study of initially isotropic turbulence subjected to a straining and destraining cycle was reported by Chen et al. [“Scale interactions of turbulence subjected to a straining-relaxation-destraining cycle,” J. Fluid Mech. 562, 123 (2006)]. Direct numerical simulation (DNS) of the experiment of Chen et al. [“Scale interactions of turbulence subjected to a straining-relaxation-destraining cycle,” J. Fluid Mech. 562, 123 (2006)] is undertaken, applying the measured straining and destraining cycle in the DNS. By necessity, the Reynolds number in the DNS is lower. The DNS study provides a complement to the experimental one including time evolution of small-scale gradients and pressure terms that could not be measured in the experiments. The turbulence response is characterized in terms of velocity variances, and similarities and differences between the experimental data and the DNS results are discussed. Most of the differences can be attributed to the response of the largest eddies, which, even if are subjected to the same straining cycle, evolve under different conditions in the simulations and experiment. To explore this issue, the time evolution of different initial conditions parametrized in terms of the integral scale is analyzed in computational domains with different aspect ratios. This systematic analysis is necessary to minimize artifacts due to unphysical confinement effects of the flow. The evolution of turbulent kinetic energy production predicted by DNS, in agreement with experimental data, provides a significant backscatter of kinetic energy during the destraining phase. This behavior is explained in terms of Reynolds stress anisotropy and nonequilibrium conditions. From the DNS, a substantial persistency of anisotropy is observed up to small scales, i.e., at the level of velocity gradients. Due to the time dependent deformation, we find that the major contribution in the Reynolds stresses budget is provided by the production term and by the pressure/strain correlation, resulting in large time variation of velocity intensities. The DNS data are compared with predictions from the classical Launder–Reece–Rodi isoptropic production [B. E. Launder et al., “Progress in the development of a Reynolds stress turbulence closure,” J. Fluid Mech. 68, 537 (1975)] Reynolds stress model, showing good agreement with some differences for the redistribution term.
Interaction between cells in dielectrophoresis and electrorotation experiments
Authors: Sancho Miguel , Martínez Genoveva , Muñoz Sagrario , Sebastián José L. , Pethig Ronald
Published: June 2010

Progress in microelectrode-based technologies has facilitated the development of sophisticated methods for manipulating and separating cells, bacteria, and other bioparticles. For many of these various applications, the theoretical modeling of the electrical response of compartmentalized particles to an external field is important. In this paper we address the analysis of the interaction between cells immersed in rf fields. We use an integral formulation of the problem derived from a consideration of the charge densities induced at the interfaces of the particle compartments. The numerical solution by a boundary element technique allows characterization of their dielectric properties. Experimental validation of this theoretical model is obtained by investigating two effects: (1) The influence that dipolar “pearl chaining” has on the dielectrophoretic behavior of human T lymphocytes and (2) the frequency variation of the spin and orbital torques of approaching insulinoma β-cells in a rotating field.
Dynamic double layer effects on ac-induced dipoles of dielectric nanocolloids
Authors: Basuray Sagnik , Wei Hsien-Hung , Chang Hsueh-Chia
Published: June 2010

Normal and tangential surface ionic currents around low-permittivity nanocolloids with surface charges are shown to produce three different conductive mechanisms for ac-induced dipoles, all involving dynamic space charge accumulation at the double layer/bulk interface with a conductivity jump. However, the distinct capacitor dimensions and diffusive contributions produce three disparate crossover frequencies at which the induced dipole reverses direction relative to the bulk field. A highly conducting collapsed diffuse layer, with bulk ion mobility, renders the particle conductive and produces an ionic strength independent crossover frequency for weak electrolytes. A precipitous drop in crossover frequency occurs at high ionic strengths when charging occurs only at the poles through field focusing around the insulated colloid. A peculiar maximum in crossover frequency exists between these two asymptotes for colloids smaller than a critical size when normal charging of the diffuse layer occurs over the entire surface. The crossover frequency data for latex nanocolloids of various sizes in different electrolytes of wide ranging ionic strengths are collapsed by explicit theoretical predictions without empirical parameters.
Composition measurement of the Ni-silicide transient phase by atom probe tomography
Authors: Hoummada K. , Blum I. , Mangelinck D. , Portavoce A.
Published: June 2010

The transient phase observed during the reaction of a Ni(Pt) alloy with a (001)Si substrate is studied using in situ x-ray diffraction and atom probe tomography microscopy. This transient phase exhibits a diffraction peak at 47°, and is found to have a uniform composition corresponding to Ni0.6Si0.4. During the reaction, it is located between a δ-Ni2Si layer and a thin (nanocrystalline or amorphous) NiSi layer in contact with Si. The Pt atoms are found in the δ-Ni2Si grain boundaries, while they have not been detected in the NiSi layer.
Technology roadmap for low carbon society in China
Authors: Kejun Jiang , Qiang Liu , Xing Zhuang , Xiulian Hu
Published: July 2010

Mid- and long-term energy requirements and greenhouse gas emission scenarios for China were presented by using the Integrated Policy Assessment Model of China. Technologies are the key component to reach a low carbon future. Technologies are identified with the scenario analysis. In order to realize the low carbon future, a technology roadmap was presented to reach the emission reduction up to 2050 in China. Twenty-eight key technologies are given in the paper for the technology roadmap, presenting learning curves. With full adoption of these key technologies, we do see ample opportunities for China to make the emission stable after 2020, without a large increase, and even start to have a deep reduction after 2030.
A complex fluid exhibits unexpected heterogeneous flow
Authors: Miller Johanna
Published: July 2010

Depending on the conditions, the localized flow can persist for minutes, hours, or more than a day.
World lays groundwork for future linear collider
Authors: Feder Toni
Published: July 2010

New physics from the Large Hadron Collider can best be explored with a large lepton collider; realizing one will require mobilizing accelerator and particle physicists, funding agencies, and politicians.
Rutherford’s geophysicists
Authors: Good Gregory A.
Published: July 2010

Although both trained in nuclear physics, Edward Bullard and Patrick Blackett enjoyed careers that, taken together,spanned the broad range of Earth sciences, including seismology, geomagnetism, marine geology, and plate tectonics.
Power and spin in the beautiful game
Authors: Goff John Eric
Published: July 2010

After a ball leaves a soccer player’s foot, surface roughness and asymmetric air forces contribute to some jaw-dropping trajectories.
Phylogeny of Utetheisa s. str. (Lepidoptera:Noctuidae:Arctinae) with comments on the evolution of colour, hind wing scales and origin of New World species
Authors: DaCosta M. A.
Published: June 2010

Species of Utetheisa Hübner incorporate pyrrolizidine alkaloids into their defence strategy where they are protective against both invertebrate and vertebrate predators, and courtship behaviours by males incorporate the alkaloids into their pheromones. Although Utetheisa’s chemical ecology is well understood, the systematics is less clear. A phylogeny of Utetheisa was constructed based on adult morphology. The final data matrix consisted of 29 species and 105 characters (268 states) from adults scored from both nongenitalic and genitalic characters as follows: 3 head (8 states), 4 leg (8 states), 21 wing (49 states), 44 male abdominal and genitalic characters (124 states), and 33 female abdominal and genitalic characters (79 states). The resulting parsimony and Bayesian analyses demonstrated that Utetheisa s. str. is monophyletic and sister to U. Pitasila (Moore). UtetheisaAtasca (Swinhoe) is more closely related to outgroup taxa than it is to other Utetheisa species. Monophyly of Utetheisa s. str. is strongly supported by a posterior probability of 0.98. Colour was lost once and male wing androconia evolved independently in several species, all of which feed on hosts in Boraginaceae. Forbes’ hypothesis of an Old World origin for the genus is corroborated and two origins for New World species are supported.
Pilumnus Leach (Decapoda:Pilumnidae Samouelle) from Mediterranean and adjacent Atlantic waters: a COI analysis
Authors: Oliveira-Biener Ulla , Melzer Roland R. , Miller Michael A.
Published: June 2010

A molecular taxonomy is presented based on 544 base pair sequences of the mitochondrial COI gene (Palumbi segment) from 141 bristle crabs of the genus Pilumnus from the Mediterranean Sea and adjacent Atlantic Ocean, plus outgroups. The sample includes all currently valid autochthonous Mediterranean species. Six well-supported COI lineages were detected, three of which exclusively comprise representatives of Pilumnus inermis, P. spinifer and P. villosissimus, respectively. On the other hand, crabs that would be attributed to P. hirtellus according to current morphology-based taxonomy were distributed over three COI clades, two of which are interpreted as representing cryptic lineages. We compare our findings to previous analyses using sets of external morphological characters, and discuss the partial mismatch between the morphology- and gene-based classifications.
A-type lamin dynamics in bovine somatic cell nuclear transfer embryos
Authors: Kelly Richard D. W. , Alberio Ramiro , Campbell Keith H. S.
Published: July 2010

The persistence of A-type nuclear lamin in somatic cell nuclear transfer (SCNT) embryos has been proposed as a marker for incomplete nuclear reprogramming. Using monoclonal antibodies to A/C- (A/C-346 and A/C-131C3) and B-type lamin, we compared distribution during early development of bovine IVF, parthenogenetic and SCNT embryos. A/C-346 staining was observed in the pronuclei of IVF embryos and in nuclei at the two-cell stage, but was not detected in subsequent cleavage stages up to and including hatched blastocysts. In contrast, A/C-131C3 and anti-lamin B2 stained all preimplantation stage embryos. Parthenogenetic and SCNT embryos had similar staining patterns to IVF embryos for all three antibodies, demonstrating correct nuclear architecture reprogramming. Inhibiting protein synthesis with cycloheximide (CHX) in parthenogenetic and SCNT embryos did not affect lamin A/C localisation, suggesting that lamin A/C is maternal in origin. However, activation with CHX delayed lamin A/C incorporation compared with 6-dimethylaminopurine activation. In SCNT embryos, staining for both A/C- and B-type lamin was delayed compared with parthenotes, although lamin B2 incorporation preceded lamin A/C in both. In conclusion, the lamin A/C distribution in SCNT bovine embryos paralleled that of IVF and parthenogenetic controls and therefore is not a marker of incomplete reprogramming.
Oocyte glutathione and fertilisation outcome of Macaca nemestrina and Macaca fascicularis in in vivo- and in vitro-matured oocytes
Authors: Curnow E. C. , Ryan J. P. , Saunders D. M. , Hayes E. S.
Published: July 2010

Fertilisation and development of IVM non-human primate oocytes is limited compared with that of in vivo-matured (IVO) oocytes. The present study describes the IVM of macaque oocytes with reference to oocyte glutathione (GSH). Timing of maturation, comparison of IVM media and cysteamine (CYS) supplementation as a modulator of GSH were investigated. A significantly greater proportion of oocytes reached MII after 30 h compared with 24 h of IVM. Following insemination, IVM oocytes had a significantly lower incidence of normal fertilisation (i.e. 2PN = two pronuclei and at least one polar body) and a higher rate of abnormal fertilisation (1PN = one pronucleus and at least one polar body) compared with IVO oocytes. Immunofluorescence of 1PN zygotes identified incomplete sperm head decondensation and failure of male pronucleus formation as the principal cause of abnormal fertilisation in IVM oocytes. The IVO oocytes had significantly higher GSH content than IVM oocytes. Cumulus-denuded oocytes had significantly lower GSH following IVM compared with immature oocytes at collection. Cysteamine supplementation of the IVM medium significantly increased the GSH level of cumulus-intact oocytes and reduced the incidence of 1PN formation, but did not improve GSH levels of the denuded oocyte. Suboptimal GSH levels in macaque IVM oocytes may be related to reduced fertilisation outcomes.
Prolonged interval between fusion and activation impairs embryonic development by inducing chromosome scattering and nuclear aneuploidy in pig somatic cell nuclear transfer
Authors: You Jinyoung , Song Kilyoung , Lee Eunsong
Published: July 2010

The aim of the present study was to examine the effect of various intervals between electrofusion and activation (FA interval) on the nuclear remodelling and development of somatic cell nuclear transfer (SCNT) embryos in pigs. Reconstructed oocytes were activated at 0 (simultaneous fusion and activation; SFA), 1, 2 and 3 h (delayed activation) after electrofusion; these groups were designated as DA1, DA2 and DA3, respectively. When oocyte nuclear status was examined at 0.5, 1, 2 and 3 h after electrofusion, the incidence of chromosome scattering was increased (P < 0.01) as the FA interval was extended (0.0%, 12.0%, 77.3% and 78.0%, respectively). Extending the FA interval led to an increase (P < 0.01) in the percentage of oocytes containing multiple (≥3) pseudopronuclei (PPN) (0.0% of SFA; 5.3% of DA1; 21.7% of DA2; and 33.5% of DA3). The development of SCNT embryos to the blastocyst stage was decreased (P < 0.05) in DA2 (5.7%) and DA3 (5.0%) compared with SFA (18.1%) and DA1 (19.5%). Our results demonstrate that extending the FA interval impairs the development of SCNT pig embryos by inducing chromosome scattering and the formation of multiple PPN, which may result in increased nuclear aneuploidy.
Tolerance adaptation and precipitation changes complicate latitudinal patterns of climate change impacts
Authors: Bonebrake Timothy C. , Mastrandrea Michael D.
Published: June 2010

Global patterns of biodiversity and comparisons between tropical and temperate ecosystems have pervaded ecology from its inception. However, the urgency in understanding these global patterns has been accentuated by the threat of rapid climate change. We apply an adaptive model of environmental tolerance evolution to global climate data and climate change model projections to examine the relative impacts of climate change on different regions of the globe. Our results project more adverse impacts of warming on tropical populations due to environmental tolerance adaptation to conditions of low interannual variability in temperature. When applied to present variability and future forecasts of precipitation data, the tolerance adaptation model found large reductions in fitness predicted for populations in high-latitude northern hemisphere regions, although some tropical regions had comparable reductions in fitness. We formulated an evolutionary regional climate change index (ERCCI) to additionally incorporate the predicted changes in the interannual variability of temperature and precipitation. Based on this index, we suggest that the magnitude of climate change impacts could be much more heterogeneous across latitude than previously thought. Specifically, tropical regions are likely to be just as affected as temperate regions and, in some regions under some circumstances, possibly more so.
Probing potassium channel function in vivo by intracellular delivery of antibodies in a rat model of retinal neurodegeneration
Authors: Raz-Prag Dorit , Grimes William N. , Fariss Robert N. , Vijayasarathy Camasamudram , Campos Maria M. , Bush Ronald A. , Diamond Jeffrey S. , Sieving Paul A.
Published: June 2010

Inward rectifying potassium (Kir) channels participate in regulating potassium concentration (K
+
) in the central nervous system (CNS), including in the retina. We explored the contribution of Kir channels to retinal function by delivering Kir antibodies (Kir-Abs) into the rat eye in vivo to interrupt channel activity. Kir-Abs were coupled to a peptide carrier to reach intracellular epitopes. Functional effects were evaluated by recording the scotopic threshold response (STR) and photopic negative response (PhNR) of the electroretinogram (ERG) noninvasively with an electrode on the cornea to determine activity of the rod and cone pathways, respectively. Intravitreal delivery of Kir2.1-Ab coupled to the peptide carrier diminished these ERG responses equivalent to dimming the stimulus 10- to 100-fold. Immunohistochemistry (IHC) showed Kir2.1 immunostaining of retinal bipolar cells (BCs) matching the labeling pattern obtained with conventional IHC of applying Kir2.1-Ab to fixed retinal sections postmortem. Whole-cell voltage-clamp BC recordings in rat acute retinal slices showed suppression of barium-sensitive Kir2.1 currents upon inclusion of Kir2.1-Ab in the patch pipette. The in vivo functional and structural results implicate a contribution of Kir2.1 channel activity in these electronegative ERG potentials. Studies with Kir4.1-Ab administered in vivo also suppressed the ERG components and showed immunostaining of Müller cells. The strategy of administering Kir antibodies in vivo, coupled to a peptide carrier to facilitate intracellular delivery, identifies roles for Kir2.1 and Kir4.1 in ERG components arising in the proximal retina and suggests this approach could be of further value in research.
Bcl-XL represents a druggable molecular vulnerability during aurora B inhibitor-mediated polyploidization
Authors: Shah O. Jameel , Lin Xiaoyu , Li Leiming , Huang Xiaoli , Li Junling , Anderson Mark G. , Tang Hua , Rodriguez Luis E. , Warder Scott E. , McLoughlin Shaun , Chen Jun , Palma Joann , Glaser Keith B. , Donawho Cherrie K. , Fesik Stephen W. , Shen Yu
Published: June 2010

Aurora kinase B inhibitors induce apoptosis secondary to polyploidization and have entered clinical trials as an emerging class of neocytotoxic chemotherapeutics. We demonstrate here that polyploidization neutralizes Mcl-1 function, rendering cancer cells exquisitely dependent on Bcl-XL/-2. This “addiction” can be exploited therapeutically by combining aurora kinase inhibitors and the orally bioavailable BH3 mimetic, ABT-263, which inhibits Bcl-XL, Bcl-2, and Bcl-w. The combination of ABT-263 with aurora B inhibitors produces a synergistic loss of viability in a range of cell lines of divergent tumor origin and exhibits more sustained tumor growth inhibition in vivo compared with aurora B inhibitor monotherapy. These data demonstrate that Bcl-XL/-2 is necessary to support viability during polyploidization in a variety of tumor models and represents a druggable molecular vulnerability with potential therapeutic utility.
LIM-domain proteins, LIMD1, Ajuba, and WTIP are required for microRNA-mediated gene silencing
Authors: James Victoria , Zhang Yining , Foxler Daniel E. , de Moor Cornelia H. , Kong Yi Wen , Webb Thomas M. , Self Tim J. , Feng Yungfeng , Lagos Dimitrios , Chu Chia-Ying , Rana Tariq M. , Morley Simon J. , Longmore Gregory D. , Bushell Martin , Sharp Tyson V.
Published: June 2010

In recent years there have been major advances with respect to the identification of the protein components and mechanisms of microRNA (miRNA) mediated silencing. However, the complete and precise repertoire of components and mechanism(s) of action remain to be fully elucidated. Herein we reveal the identification of a family of three LIM domain-containing proteins, LIMD1, Ajuba and WTIP (Ajuba LIM proteins) as novel mammalian processing body (P-body) components, which highlight a novel mechanism of miRNA-mediated gene silencing. Furthermore, we reveal that LIMD1, Ajuba, and WTIP bind to Ago1/2, RCK, Dcp2, and eIF4E in vivo, that they are required for miRNA-mediated, but not siRNA-mediated gene silencing and that all three proteins bind to the mRNA 5′ m
7
GTP cap–protein complex. Mechanistically, we propose the Ajuba LIM proteins interact with the m
7
GTP cap structure via a specific interaction with eIF4E that prevents 4EBP1 and eIF4G interaction. In addition, these LIM-domain proteins facilitate miRNA-mediated gene silencing by acting as an essential molecular link between the translationally inhibited eIF4E-m
7
GTP-5
′
cap and Ago1/2 within the miRISC complex attached to the 3′-UTR of mRNA, creating an inhibitory closed-loop complex.
Mutant superoxide dismutase 1-induced IL-1β accelerates ALS pathogenesis
Authors: Meissner Felix , Molawi Kaaweh , Zychlinsky Arturo
Published: June 2010

ALS is a fatal motor neuron disease of adult onset. Neuroinflammation contributes to ALS disease progression; however, the inflammatory trigger remains unclear. We report that ALS–linked mutant superoxide dismutase 1 (SOD1) activates caspase-1 and IL-1β in microglia. Cytoplasmic accumulation of mutant SOD1 was sensed by an ASC containing inflammasome and antagonized by autophagy, limiting caspase-1–mediated inflammation. Notably, mutant SOD1 induced IL-1β correlated with amyloid-like misfolding and was independent of dismutase activity. Deficiency in caspase-1 or IL-1β or treatment with recombinant IL-1 receptor antagonist (IL-1RA) extended the lifespan of G93A-
SOD1
transgenic mice and attenuated inflammatory pathology. These findings identify microglial IL-1β as a causative event of neuroinflammation and suggest IL-1 as a potential therapeutic target in ALS.
Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing
Authors: Walsh Tom , Lee Ming K. , Casadei Silvia , Thornton Anne M. , Stray Sunday M. , Pennil Christopher , Nord Alex S. , Mandell Jessica B. , Swisher Elizabeth M. , King Mary-Claire
Published: June 2010

Inherited loss-of-function mutations in the tumor suppressor genes
BRCA1
,
BRCA2
, and multiple other genes predispose to high risks of breast and/or ovarian cancer. Cancer-associated inherited mutations in these genes are collectively quite common, but individually rare or even private. Genetic testing for
BRCA1
and
BRCA2
mutations has become an integral part of clinical practice, but testing is generally limited to these two genes and to women with severe family histories of breast or ovarian cancer. To determine whether massively parallel, “next-generation” sequencing would enable accurate, thorough, and cost-effective identification of inherited mutations for breast and ovarian cancer, we developed a genomic assay to capture, sequence, and detect all mutations in 21 genes, including
BRCA1
and
BRCA2
, with inherited mutations that predispose to breast or ovarian cancer. Constitutional genomic DNA from subjects with known inherited mutations, ranging in size from 1 to >100,000 bp, was hybridized to custom oligonucleotides and then sequenced using a genome analyzer. Analysis was carried out blind to the mutation in each sample. Average coverage was >1200 reads per base pair. After filtering sequences for quality and number of reads, all single-nucleotide substitutions, small insertion and deletion mutations, and large genomic duplications and deletions were detected. There were zero false-positive calls of nonsense mutations, frameshift mutations, or genomic rearrangements for any gene in any of the test samples. This approach enables widespread genetic testing and personalized risk assessment for breast and ovarian cancer.
Finite Element Analysis of Normal Pressure Hydrocephalus: Influence of CSF Content and Anisotropy in Permeability
Authors: Shahim K. , Drezet J.-M. , Molinari J.-F. , Sinkus R. , Momjian S.
Published: June 2010

Hydrocephalus is a cerebral disease where brain ventricles enlarge and compress the brain parenchyma towards the skull leading to symptoms like dementia, walking disorder and incontinence. The origin of normal pressure hydrocephalus is still obscure. In order to study this disease, a finite element model is built using the geometries of the ventricles and the skull measured by magnetic resonance imaging. The brain parenchyma is modelled as a porous medium fully saturated with cerebrospinal fluid (CSF) using Biot′s theory of consolidation (1941). Owing to the existence of bundles of axons, the brain parenchyma shows locally anisotropic behaviour. Indeed, permeability is higher along the fibre tracts in the white matter region. In contrast, grey matter is isotropic. Diffusion tensor imaging is used to establish the local CSF content and the fibre tracts direction together with the associated local frame where the permeability coefficients are given by dedicated formulas. The present study shows that both inhomogeneous CSF content and anisotropy in permeability have a great influence on the CSF flow pattern through the parenchyma under an imposed pressure gradient between the ventricles and the subarachnoid spaces.
How individuals with self‐reported anxiety and depression experienced a combination of individual counselling with an adventurous outdoor experience: A qualitative evaluation
Authors: Kyriakopoulos Alex
Published: July 2010

Background: Adventure therapy is a short‐term experiential psychotherapeutic approach that utilises adventurous activities and being in natural environments in order to facilitate therapeutic change in clients. The present paper examines how students with self‐reported anxiety and depression experienced participating in an innovative intervention that combined individual therapy with an adventurous outdoor experience. Clients participating in the Adventure Therapy Project received between 10–15 one‐to‐one counselling sessions prior to the outdoor experience, as well as ongoing counselling following it. Method: Interpretative Phenomenological Analysis was used in order to record and analyse the experiences of three male and three female students who presented at a major UK university student counselling service with self‐reported depression and anxiety. Findings: Twelve themes emerged which were categorised into four major domains: enhancing intrapersonal relationships; improving interpersonal relationships; providing an experiential outdoor venue for achieving therapeutic change; offering a secure, personal place for achieving inner healing. The intervention was perceived to improve the ways in which interviewees related towards themselves and other people. Interviewees perceived the counselling sessions as offering a safe therapeutic space within which they could unveil their anxieties and achieve inner healing. Conclusions: Outdoor experiences offer an experiential venue for achieving personal change and, it appears enhance the therapeutic process. Prior and subsequent individual therapy increases the benefits of such experiences.
Reconsidering the dimensions of expertise: from linear stages towards dual processing
Authors: Kinchin Ian M. , Cabot B.
Published: June 2010

This paper explores the developing concept of expertise, taking the Dreyfus and Dreyfus staged model as its starting point. It analyses criticism of the Dreyfus model and considers more recent attempts to resolve the tensions implicit within it. The authors go on to suggest ways some
of the later modifications can be improved. The traditional notion of intuition is revisited and thereafter a new and novel way of visualising expertise is presented as a dual-processing relationship between chains of practice and the underlying networks of understanding. These chain and net
knowledge structures have been revealed through the analysis of concept maps produced by numerous cohorts of students and teachers. It is argued that a visualisation of the dynamic relationship between the dimensions of expertise provides an emerging theoretical framework for a more general
reappraisal of teaching in higher education. This reconsideration of expertise may be the catalyst for dialogue about educational practice within disciplines (between lecturers and between lecturers and students), and between lecturers and educational developers. This dialogue will strengthen
disciplinary communities of practice and place the agenda for pedagogic change within the context of the academic disciplines.
Cell-surface residence of sphingosine 1-phosphate receptor 1 on lymphocytes determines lymphocyte egress kinetics
Authors: Thangada Shobha , Khanna Kamal M. , Blaho Victoria A. , Oo Myat Lin , Im Dong-Soon , Guo Caiying , Lefrancois Leo , Hla Timothy
Published: June 2010

The sphingosine 1-phosphate receptor 1 (S1P1) promotes lymphocyte egress from lymphoid organs. Previous work showed that agonist-induced internalization of this G protein–coupled receptor correlates with inhibition of lymphocyte egress and results in lymphopenia. However, it is unclear if S1P1 internalization is necessary for this effect. We characterize a knockin mouse (S1p1rS5A/S5A) in which the C-terminal serine-rich S1P1 motif, which is important for S1P1 internalization but dispensable for S1P1 signaling, is mutated. T cells expressing the mutant S1P1 showed delayed S1P1 internalization and defective desensitization after agonist stimulation. Mutant mice exhibited significantly delayed lymphopenia after S1P1 agonist administration or disruption of the vascular S1P gradient. Adoptive transfer experiments demonstrated that mutant S1P1 expression in lymphocytes, rather than endothelial cells, facilitated this delay in lymphopenia. Thus, cell-surface residency of S1P1 on T cells is a primary determinant of lymphocyte egress kinetics in vivo.
Increase in Use of Vancomycin for Clostridium difficile Infection in US Hospitals
Authors: Pakyz Amy L. , Carroll Norman V. , Harpe Spencer E. , Oinonen Michael , Polk Ronald E.
Published: June 2010

Clostridium difficile infection (CDI) is a potentially serious disease for which the epidemiology has recently changed, because of an emerging drug-resistant strain of the pathogen. Metronidazole and oral vancomycin are the primary treatment agents.2 Metronidazole has been historically favored as the first-line agent, partly to reduce the selection pressure for vancomycin-resistant enterococci (VRE), although metronidazole can also select for VRE. Vancomycin was traditionally reserved for metronidazole treatment failure or life-threatening disease. In a study conducted before emergence of the epidemic strain, vancomycin was reported to be superior for the initial treatment of severe CDI and for treatment of CDI that does not respond to metronidazole. Expert opinion calling for the use of vancomycin as first-line therapy, especially for severe CDI emergence of the epidemic strain, and reports of decreased metronidazole efficacy may have impacted CDI treatment practices. The purpose of this study was to characterize trends in CDI treatment in US hospitals.
Hydrothermally grown nanostructured WO3 films and their electrochromic characteristics
Authors: Jiao Zhihui , Sun Xiao Wei , Wang Jinmin , Ke Lin , Demir Hilmi Volkan
Published: June 2010

We report the synthesis of nanostructured tungsten trioxide (WO3) films and their electrochromic characteristics. Plate-like monoclinic WO3 nanostructures were grown directly on fluorine-doped tin oxide glass substrates by a simple and low-cost crystal-seed-assisted hydrothermal method. The growth mechanism of the film is investigated. HRTEM analysis reveals the single crystalline quality of the WO3 nanostructure. The film exhibits tunable transmittance modulation under different voltages and repetitive cycling between the clear and blue states has no deleterious effect on its electrochromic performance after 3000 cycles. The electrochromic device composed of the WO3 film has high electrochromic stability, colour contrast and reasonable switching response with a colouration efficiency of 38.2 cm2 C−1 at 632.8 nm.
Integration of pathway knowledge into a reweighted recursive feature elimination approach for risk stratification of cancer patients
Authors: Johannes Marc , Brase Jan C. , Fröhlich Holger , Gade Stephan , Gehrmann Mathias , Fälth Maria , Sültmann Holger , Beißbarth Tim
Published: July 2010

Motivation: One of the main goals of high-throughput gene-expression studies in cancer research is to identify prognostic gene signatures, which have the potential to predict the clinical outcome. It is common practice to investigate these questions using classification methods. However, standard methods merely rely on gene-expression data and assume the genes to be independent. Including pathway knowledge a priori into the classification process has recently been indicated as a promising way to increase classification accuracy as well as the interpretability and reproducibility of prognostic gene signatures.

Results: We propose a new method called Reweighted Recursive Feature Elimination. It is based on the hypothesis that a gene with a low fold-change should have an increased influence on the classifier if it is connected to differentially expressed genes. We used a modified version of Google's PageRank algorithm to alter the ranking criterion of the SVM-RFE algorithm. Evaluations of our method on an integrated breast cancer dataset comprising 788 samples showed an improvement of the area under the receiver operator characteristic curve as well as in the reproducibility and interpretability of selected genes.

Availability: The R code of the proposed algorithm is given in Supplementary Material.

Contact:  m.johannes@DKFZ-heidelberg.de; tim.beissbarth@ams.med.uni-goettingen.de

Supplementary information:  Supplementary data are available at Bioinformatics online.
Do we have enough information to apply the ecosystem approach to management of deep-sea fisheries? An example from the West of Scotland
Authors: Heymans Johanna J. , Howell Kerry L. , Ayers Morag , Burrows Michael T. , Gordon John D. M. , Jones Emma G. , Neat Francis
Published: July 2010

Heymans, J. J., Howell, K. L., Ayers, M., Burrows, M. T., Gordon, J. D. M., Jones, E. G., and Neat, F. 2011. Do we have enough information to apply the ecosystem approach to management of deep-sea fisheries? An example from the West of Scotland. – ICES Journal of Marine Science, 68: 265–280. There is currently a global call for more use of an ecosystem approach to fisheries management (EAFM), and ecosystem models such as Ecopath with Ecosim (EwE) are being used to provide a holistic view of ecosystem–fisheries interactions. Although these can be useful for an EAFM, the relative paucity of data available for deep-sea ecosystems raises concerns whether we can effectively apply an EAFM to the deep sea. The deep-sea ecosystem off the west coast of Scotland has been studied for longer and in more detail than most. This study assimilates the significant published and unpublished information available on this ecosystem into an EwE model. The results suggest that there are sufficient data available to construct an ecosystem model, but the quality of the data varies and serious potential sources of error are present in biomass and discard estimates. The assumptions needed to produce a model are varied and must be considered when interpreting the outputs of the model. Ecosystem modelling provides a unique view of the deep-water ecosystem and facilitates hypothesis development concerning predator–prey and inter-fishery interactions. Sharks are used to illustrate the benefits of using an ecosystem model to describe changes in their biomass and their prey species. The results show that both fishing for sharks and fishing for their prey affect the biomass of sharks.