bluuebunny/crossref_metadata_2025 huggingface dataset:
Apparatus for vectorial Kerr confocal microscopy
Authors: Savoini M. , Ciccacci F. , Duò L. , Finazzi M.
Published: March 2011

We present a confocal microscopy setup that is able to record magneto-optical hysteresis cycles separating the in-plane and out-of-plane magnetization components. This apparatus is based on a modified commercial microscope, where the light beam has been deviated from the cylindrical symmetry axis of the objective lenses by inserting a translating plate in the optical path. The instrument allows for the magneto-optical imaging with a lateral resolution of 600 nm at λ = 635 nm light wavelength.
Current rectification induced by asymmetrical electrode materials in a molecular device
Authors: Pan J. B. , Zhang Z. H. , Ding K. H. , Deng X. Q. , Guo C.
Published: March 2011

Molecular devices are constructed based on a molecule connected into both electrodes with different metal materials, and their transport properties are investigated by the first-principles method. The result shows that such devices can generate two asymmetrical Schottky barriers at contacts; the current rectification thus is created. This rectification is also fully rationalized by the calculated transmission spectra and the spatial distribution of the lowest unoccupied molecular orbital and highest occupied molecular orbital states. Our study suggests that it might be a very important way for both electrodes using different materials to realize a molecular rectification.
Terahertz optical-Hall effect characterization of two-dimensional electron gas properties in AlGaN/GaN high electron mobility transistor structures
Authors: Schöche S. , Shi Junxia , Boosalis A. , Kühne P. , Herzinger C. M. , Woollam J. A. , Schaff W. J. , Eastman L. F. , Schubert M. , Hofmann T.
Published: March 2011

The free-charge carrier mobility, sheet density, and effective mass of a two-dimensional electron gas are exemplarily determined in the spectral range from 640 GHz to 1 THz in a AlGaN/GaN heterostructure using the optical-Hall effect at room temperature. Complementary midinfrared spectroscopic ellipsometry measurements are performed for analysis of heterostructure constituents layer thickness, phonon mode, and free-charge carrier parameters. The electron effective mass is determined to be (0.22±0.04)m0. The high-frequency sheet density and carrier mobility parameters are in good agreement with results from dc electrical Hall effect measurements, indicative for frequency-independent carrier scattering mechanisms of the two-dimensional carrier distribution.
Projection of Si 1s photoexcited orbitals into resonant Auger electron spectra in KLL decays of Si(CH3)4 and SiF4
Authors: Suzuki I. H. , Kono Y. , Ikeda A. , Ouchi T. , Ueda K. , Takahashi O. , Higuchi I. , Tamenori Y. , Nagaoka S.
Published: March 2011

Spectator resonant KL23L23 Auger electron spectra have been measured in the Si 1s photoexcitation region of Si(CH3)4 using monochromatized undulator radiation combined with a hemispherical electron spectrometer. The broad peak with high intensity in a total ion yield spectrum, coming mainly from excitation of a 1s electron into the 6t2 vacant orbital, induces a spectator Auger decay in which the excited electron remains in its excited orbital. The component on the higher energy side of this peak through 1s excitation into a Rydberg orbital produces resonant Auger decays in which the excited Rydberg electron moves into a slightly higher Rydberg orbital, or is partly shaken up to a significantly higher Rydberg orbital. These findings of Si(CH3)4 indicate a clear contrast to those for SiF4, in which the 1s excitation into a Rydberg orbital induces a shake-down phenomenon as well as a shake-up one. The results of these molecules exhibit a clear splitting effect among excited orbitals which are smeared out by overlapping due to lifetime widths and due to densely populated levels in the 1s electron excitation spectrum. This is consistent with the calculation on photoexcitation within the framework of density functional theory.
Industrial effluent treatment: Theoretical and experimental analysis
Authors: Velmurugan V. , Srithar K.
Published: March 2011

Industries like textile and tannery are facing effluent disposal as well as water scarcity problems. To solve these two problems, an attempt has been made to convert the industrial effluent into potable water by using solar desalination methods. Effluent from textile industry is taken for analysis. In this work, single basin type solar still with fin at basin, stepped solar still with two different basin depths, and minisolar pond are the three types of solar devices used for effluent desalination. Sensible heat storage materials like pebble, black rubber, sponge, and sand are used in single basin and stepped solar stills to enhance the productivity. A minisolar pond is also connected with these stills to preheat the still water. For presettling the effluent, an effluent settling tank is fabricated. Maximum productivity occurs when the stepped solar still is modified with fin, pebble, and sponge and integrated with a minisolar pond. Theoretical analysis is made to validate the experimental results. Chemical analysis is also made for raw effluent, settled effluent, and desalinated water. For converting the desalinated water into potable water, some minerals are added. Cost analysis is also made.
The hidden ingenuity in titin structure
Authors: Benichou Itamar , Givli Sefi
Published: March 2011

Titin is a giant protein that functions as a shock absorber in sarcomeres—the basic contractile unit of muscles. When stretched, thermal disturbances are expected to make titin follow the Maxwell path (global minimizer) of its energy. This path involves neither energy dissipation nor hysteresis. Therefore, a basic question is how does titin releases energy so efficiently? By adopting a simple mechanical model of a chain comprised from bistable elements, we show that dissipation depends on both system size and the height of the energy barrier separating equilibrium configurations. In this sense, titin is an optimal product of evolution.
Charge carrier velocity distributions in field-effect transistors
Authors: Lee Chen-Guan , Cobb Brian , Ferlauto Laura , Dodabalapur Ananth
Published: March 2011

The measurement of the distribution of charge carrier velocities in a field-effect transistor can provide considerable insight into charge transport mechanisms and structure-property relationships. We have developed such a method and have applied it to study temperature-dependent velocity distributions in solution-processed zinc-tin oxide thin-film transistors. Two distinct transport pathways, each with a different activation energy, have been observed, in contrast to a single activation energy yielded by steady-state measurements. Our results show that more insight into charge transport behavior and phenomena can be obtained with such time-resolved transport measurements.
Probing dipole coupled nanomagnets using magnetoresistance read
Authors: Lyle Andrew , Klemm Angeline , Harms Jonathan , Zhang Yisong , Zhao Hui , Wang Jian-Ping
Published: March 2011

We experimentally demonstrated magnetoresistance (MR) read of dipole coupled nanomagnets using magnetic tunnel junctions. The MR allowed the magnetic state of individual nanomagnets to be electrically measured. The sensitivity of the read scheme enabled a systematic study regarding the nanomagnet spacing and revealed a transition in behavior. Below a spacing of 15 nm the dipole field overcomes the individual shape anisotropy and redefines the individual element easy axis along the direction transmission line. The demonstration of MR electrical read marks a significant step forward for applications such as magnetic quantum cellular automata logic devices.
Improving the on-current of In0.7Ga0.3As tunneling field-effect-transistors by p++/n+ tunneling junction
Authors: Zhao Han , Chen Yen-Ting , Wang Yanzhen , Zhou Fei , Xue Fei , Lee Jack C.
Published: March 2011

We have compared the device performance of In0.7Ga0.3As HfO2 gate dielectric tunneling field-effect-transistors (TFETs) using p++/i or p++/n+ tunneling junctions. Devices with p++/n+ tunneling junctions show 61% and 20% higher current at Vg-Vth=0.5 and 2 V compared to the ones with p++/i junctions. These p++/n+ TFETs exhibit an on-current of 60 μA/μm and a minimum subthreshold swing of 84 mV/dec. Device characteristics of TFETs using p++/n+ tunneling diodes with various n+ region doping concentrations have been simulated, results indicate the doping concentration of the n+ region plays an important role in determining the on-current and providing a well gate-controlled tunneling behavior.
Determination of the trap-assisted recombination strength in polymer light emitting diodes
Authors: Kuik Martijn , Nicolai Herman T. , Lenes Martijn , Wetzelaer Gert-Jan A. H. , Lu Mingtao , Blom Paul W. M.
Published: March 2011

The recombination processes in poly(p-phenylene vinylene) based polymer light-emitting diodes (PLEDs) are investigated. Photogenerated current measurements on PLED device structures reveal that next to the known Langevin recombination also trap-assisted recombination is an important recombination channel in PLEDs, which has not been considered until now. The dependence of the open-circuit voltage on light intensity enables us to determine the strength of this process. Numerical modeling of the current-voltage characteristics incorporating both Langevin and trap-assisted recombination yields a correct and consistent description of the PLED, without the traditional correction of the Langevin prefactor. At low bias voltage the trap-assisted recombination rate is found to be dominant over the free carrier recombination rate.
Shallow donor and DX states of Si in AlN
Authors: Son N. T. , Bickermann M. , Janzén E.
Published: March 2011

In unintentionally Si-doped AlN, the electron paramagnetic resonance (EPR) spectrum of the Si shallow donor (g=1.9905) was observed in darkness at room temperature. The temperature dependence of the EPR signal suggests that Si in AlN is a DX center with the DX− state lying at ∼78 meV below the neutral shallow donor state. With such relatively small thermal activation energy, Si is expected to behave as a shallow dopant in AlN at normal device operating temperatures.
Polarization-sensitive photoresponse of nanographite
Authors: Obraztsov Petr A. , Mikheev Gennady M. , Garnov Sergei V. , Obraztsov Alexander N. , Svirko Yuri P.
Published: March 2011

We report on polarization-sensitive direct current photoresponse of nanographite films in a 532–4000 nm spectral range. It is found that irradiation of the nanographite by the nanosecond laser pulses produces the electric current with intensity depending on the incidence angle and polarization of the laser beam. The obtained dependencies of the photoresponse on wavelength and polarization of excitation laser beam are discussed in terms of the surface photogalvanic and photon drag effects.
Light-induced long-ranged disorder effect in ultradilute two-dimensional holes in GaAs heterojunction-insulated-gate field-effect-transistors
Authors: Huang Jian , Pfeiffer L. N. , West K. W.
Published: March 2011

Comparing the results of transport measurements of strongly correlated two-dimensional holes in a GaAs heterojunction-insulated-gate field-effect-transistor obtained before and after a brief photoillumination, the light-induced disorder is found to cause qualitative changes suggesting altered carrier states. For charge concentrations ranging from 3×1010 down to 7×108 cm−2, the post-illumination hole mobility exhibits a severe suppression for charge densities below 2×1010 cm−2 while almost no change for densities above. The long-ranged nature of the disorder is identified. The temperature dependence of the conductivity is also drastically modified by the disorder reconfiguration from being nonactivated to activated.
Signal processing in cellular clocks
Authors: Forger Daniel B.
Published: March 2011

Many biochemical events within a cell need to be timed properly to occur at specific times of day, after other events have happened within the cell or in response to environmental signals. The cellular biochemical feedback loops that time these events have already received much recent attention in the experimental and modeling communities. Here, we show how ideas from signal processing can be applied to understand the function of these clocks. Consider two signals from the network
s
(
t
) and
r
(
t
), either two variables of a model or two experimentally measured time courses. We show how
s
(
t
) can be decomposed into two parts, the first being a function of
r
(
t
), and the second the derivative of a function of
r
(
t
). Geometric principles are then derived that can be used to understand when oscillations appear in biochemical feedback loops, the period of these oscillations, and their time course. Specific examples of this theory are provided that show how certain networks are prone or not prone to oscillate, how individual biochemical processes affect the period, and how oscillations in one chemical species can be deduced from oscillations in other parts of the network.
Subjective and objective learning effects dissociate in space and in time
Authors: Schwiedrzik Caspar M. , Singer Wolf , Melloni Lucia
Published: March 2011

Perceptual learning not only improves sensitivity, but it also changes our subjective experience. However, the question of how these two learning effects relate is largely unexplored. Here we investigate how subjects learn to see initially indiscriminable metacontrast-masked shapes. We find that sensitivity and subjective awareness increase with training. However, sensitivity and subjective awareness dissociate in space: Learning effects on performance are lost when the task is performed at an untrained location in another quadrant, whereas learning effects on subjective awareness are maintained. This finding indicates that improvements in shape sensitivity involve visual areas up to V4, whereas changes in subjective awareness involve other brain regions. Furthermore, subjective awareness dissociates from sensitivity in time: In an early phase of perceptual learning, subjects perform above chance on trials that they rate as subjectively invisible. Later, this phenomenon disappears. Subjective awareness is thus neither necessary nor sufficient for achieving above-chance objective performance.
The serine-threonine kinase LKB1 is essential for survival under energetic stress in zebrafish
Authors: van der Velden Yme U. , Wang Liqin , Zevenhoven John , van Rooijen Ellen , van Lohuizen Maarten , Giles Rachel H. , Clevers Hans , Haramis Anna-Pavlina G.
Published: March 2011

Mutations in the serine-threonine kinase (LKB1) lead to a gastrointestinal hamartomatous polyposis disorder with increased predisposition to cancer (Peutz–Jeghers syndrome). LKB1 has many targets, including the AMP-activated protein kinase (AMPK) that is phosphorylated under low-energy conditions. AMPK phosphorylation in turn, affects several processes, including inhibition of the target of rapamycin (TOR) pathway, and leads to proliferation inhibition. To gain insight into how LKB1 mediates its effects during development, we generated zebrafish mutants in the single LKB1 ortholog. We show that in zebrafish lkb1 is dispensable for embryonic survival but becomes essential under conditions of energetic stress. After yolk absorption, lkb1 mutants rapidly exhaust their energy resources and die prematurely from starvation. Notably, intestinal epithelial cells were polarized properly in the lkb1 mutants. We show that attenuation of metabolic rate in lkb1 mutants, either by application of the TOR inhibitor rapamycin or by crossing with von Hippel–Lindau (vhl) mutant fish (in which constitutive hypoxia signaling results in reduced metabolic rate), suppresses key aspects of the lkb1 phenotype. Thus, we demonstrate a critical role for LKB1 in regulating energy homeostasis at the whole-organism level in a vertebrate. Zebrafish models of Lkb1 inactivation could provide a platform for chemical genetic screens to identify compounds that target accelerated metabolism, a key feature of tumor cells.
Butyrophilin-like 1 encodes an enterocyte protein that selectively regulates functional interactions with T lymphocytes
Authors: Bas Anna , Swamy Mahima , Abeler-Dörner Lucie , Williams Gareth , Pang Dick J. , Barbee Susannah D. , Hayday Adrian C.
Published: March 2011

Although local regulation of T-cell responses by epithelial cells is increasingly viewed as important, few molecules mediating such regulation have been identified.Skint1, a recently identified member of the Ig-supergene family expressed by thymic epithelial cells and keratinocytes, specifies the murine epidermal intraepithelial lymphocyte (IEL) repertoire. Investigating whetherSkint1-related molecules might regulate IEL in other compartments, this study focuses on buytrophilin-like 1 (Btnl1), which is conspicuously similar toSkint1and primarily restricted to small intestinal epithelium. Btnl1 protein is mostly cytoplasmic, but surface expression can be induced, and in vivo Btnl1 can be detected adjacent to the IEL. In a newly developed culture system, enforced epithelial cell expression ofBtnl1attenuated the cells’ response to activated IEL, as evidenced by suppression of IL-6 and other inflammatory mediators. These findings offer a unique perspective on emerging genetic data thatBtnlgenes may comprise novel and important local regulators of gut inflammation.
Mean-field modeling of thalamocortical dynamics and a model-driven approach to EEG analysis
Authors: Victor Jonathan D. , Drover Jonathan D. , Conte Mary M. , Schiff Nicholas D.
Published: March 2011

Higher brain function depends on task-dependent information flow between cortical regions. Converging lines of evidence suggest that interactions between cortical regions and the central thalamus play a key role in establishing the dynamic patterns of functional connectivity that normally support these processes. In patients with chronic disturbances of cognitive function due to severe brain injury, dysfunction of this circuitry likely plays a crucial role in pathogenesis. However, assaying thalamocortical interactions is challenging even in healthy subjects and more so in severely impaired patients. To approach this problem, we apply a dynamical-systems approach to motivate an analysis of the electroencephalogram (EEG). We begin with a model for a single thalamocortical module [Robinson PA, Rennie CJ, Rowe DL (2002)
Phys Rev E Stat Nonlin Soft Matter Phys
65:041924; Robinson PA, Rennie CJ, Wright JJ, Bourke PD (1998)
Phys Rev E Stat Nonlin Soft Matter Phys
58:3557–3571]. When two such modules interact via shared thalamic inhibition, multistable behavior emerges; each mode is characterized by a different pattern of coherence between cortical regions. This observation suggests that changing patterns of cortical coherence are a hallmark of normal thalamocortical dynamics. In a preliminary study, we test this idea by analyzing the EEG of a patient with chronic brain injury, who has a marked improvement in behavior and frontal brain metabolism in response to zolpidem. The analysis shows that following zolpidem administration, changing patterns of coherence are identified between the frontal lobes and between frontal and distant brain regions. These observations support the role of the central thalamus in the organization of patterns of cortical interactions and suggest how indexes of thalamocortical dynamics can be extracted from the EEG.
Transfer of IgG in the female genital tract by MHC class I-related neonatal Fc receptor (FcRn) confers protective immunity to vaginal infection
Authors: Li Zili , Palaniyandi Senthilkumar , Zeng Rongyu , Tuo Wenbin , Roopenian Derry C. , Zhu Xiaoping
Published: March 2011

IgG is a major Ig subclass in mucosal secretions of the human female genital tract, where it predominates over the IgA isotype. Despite the abundance of IgG, surprisingly little is known about where and how IgG enters the lumen of the genital tract and the exact role local IgG plays in preventing sexually transmitted diseases. We demonstrate here that the neonatal Fc receptor, FcRn, is expressed in female genital tract epithelial cells of humans and mice and binds IgG in a pH-dependent manner. In vitro we show that FcRn mediates bidirectional IgG transport across polarized human endometrial HEC-1-A monolayers and primary human genital epithelial cells. Furthermore, endosomal acidification appears to be a prerequisite for FcRn-mediated IgG transcytosis; IgG transcytosis was demonstrated in vivo by translocation of systemically administered IgG into the genital lumen in WT but not FcRn-KO mice. The biological relevance of FcRn-transported IgG was demonstrated by passive immunization using herpes simplex virus-2 (HSV-2)–specific polyclonal serum, which conferred significantly higher protection against intravaginal challenge infection by the HSV-2 186 strain in WT mice than in FcRn-KO mice. These studies demonstrate that FcRn-mediated transport is a mechanism by which IgG can act locally in the female genital tract in immune surveillance and in host defense against sexually transmitted diseases.
Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer
Authors: Sproul Duncan , Nestor Colm , Culley Jayne , Dickson Jacqueline H. , Dixon J. Michael , Harrison David J. , Meehan Richard R. , Sims Andrew H. , Ramsahoye Bernard H.
Published: March 2011

Aberrant promoter hypermethylation is frequently observed in cancer. The potential for this mechanism to contribute to tumor development depends on whether the genes affected are repressed because of their methylation. Many aberrantly methylated genes play important roles in development and are bivalently marked in ES cells, suggesting that their aberrant methylation may reflect developmental processes. We investigated this possibility by analyzing promoter methylation in 19 breast cancer cell lines and 47 primary breast tumors. In cell lines, we defined 120 genes that were significantly repressed in association with methylation (SRAM). These genes allowed the unsupervised segregation of cell lines into epithelial (EPCAM+ve) and mesenchymal (EPCAM−ve) lineages. However, the methylated genes were already repressed in normal cells of the same lineage, and >90% could not be derepressed by treatment with 5-aza-2′-deoxycytidine. The tumor suppressor genes APC and CDH1 were among those methylated in a lineage-specific fashion. As predicted by the epithelial nature of most breast tumors, SRAM genes that were methylated in epithelial cell lines were frequently aberrantly methylated in primary tumors, as were genes specifically repressed in normal epithelial cells. An SRAM gene expression signature also correctly identified the rare claudin-low and metaplastic tumors as having mesenchymal characteristics. Our findings implicate aberrant DNA methylation as a marker of cell lineage rather than tumor progression and suggest that, in most cases, it does not cause the repression with which it is associated.
Shape of tropoelastin, the highly extensible protein that controls human tissue elasticity
Authors: Baldock Clair , Oberhauser Andres F. , Ma Liang , Lammie Donna , Siegler Veronique , Mithieux Suzanne M. , Tu Yidong , Chow John Yuen Ho , Suleman Farhana , Malfois Marc , Rogers Sarah , Guo Liang , Irving Thomas C. , Wess Tim J. , Weiss Anthony S.
Published: March 2011

Elastin enables the reversible deformation of elastic tissues and can withstand decades of repetitive forces. Tropoelastin is the soluble precursor to elastin, the main elastic protein found in mammals. Little is known of the shape and mechanism of assembly of tropoelastin as its unique composition and propensity to self-associate has hampered structural studies. In this study, we solve the nanostructure of full-length and corresponding overlapping fragments of tropoelastin using small angle X-ray and neutron scattering, allowing us to identify discrete regions of the molecule. Tropoelastin is an asymmetric coil, with a protruding foot that encompasses the C-terminal cell interaction motif. We show that individual tropoelastin molecules are highly extensible yet elastic without hysteresis to perform as highly efficient molecular nanosprings. Our findings shed light on how biology uses this single protein to build durable elastic structures that allow for cell attachment to an appended foot. We present a unique model for head-to-tail assembly which allows for the propagation of the molecule’s asymmetric coil through a stacked spring design.
Language processing in the occipital cortex of congenitally blind adults
Authors: Bedny Marina , Pascual-Leone Alvaro , Dodell-Feder David , Fedorenko Evelina , Saxe Rebecca
Published: March 2011

Humans are thought to have evolved brain regions in the left frontal and temporal cortex that are uniquely capable of language processing. However, congenitally blind individuals also activate the visual cortex in some verbal tasks. We provide evidence that this visual cortex activity in fact reflects language processing. We find that in congenitally blind individuals, the left visual cortex behaves similarly to classic language regions: (i) BOLD signal is higher during sentence comprehension than during linguistically degraded control conditions that are more difficult; (ii) BOLD signal is modulated by phonological information, lexical semantic information, and sentence-level combinatorial structure; and (iii) functional connectivity with language regions in the left prefrontal cortex and thalamus are increased relative to sighted individuals. We conclude that brain regions that are thought to have evolved for vision can take on language processing as a result of early experience. Innate microcircuit properties are not necessary for a brain region to become involved in language processing.
Requirement for kinase-induced conformational change in eukaryotic initiation factor 2α (eIF2α) restricts phosphorylation of Ser51
Authors: Dey Madhusudan , Velyvis Algirdas , Li John J. , Chiu Elaine , Chiovitti David , Kay Lewis E. , Sicheri Frank , Dever Thomas E.
Published: March 2011

As phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) on Ser51 inhibits protein synthesis, cells restrict this phosphorylation to the antiviral protein kinase PKR and related eIF2α kinases. In the crystal structure of the PKR–eIF2α complex, the C-terminal lobe of the kinase contacts eIF2α on a face remote from Ser51, leaving Ser51 ∼20 
Å
from the kinase active site. PKR mutations that cripple the eIF2α-binding site impair phosphorylation; here, we identify mutations in eIF2α that restore Ser51 phosphorylation by PKR with a crippled substrate-binding site. These eIF2α mutations either disrupt a hydrophobic network that restricts the position of Ser51 or alter a linkage between the PKR-docking region and the Ser51 loop. We propose that the protected state of Ser51 in free eIF2α prevents promiscuous phosphorylation and the attendant translational regulation by heterologous kinases, whereas docking of eIF2α on PKR induces a conformational change that regulates the degree of Ser51 exposure and thus restricts phosphorylation to the proper kinases.
Abundant ammonia in primitive asteroids and the case for a possible exobiology
Authors: Pizzarello Sandra , Williams Lynda B. , Lehman Jennifer , Holland Gregory P. , Yarger Jeffery L.
Published: March 2011

Carbonaceous chondrites are asteroidal meteorites that contain abundant organic materials. Given that meteorites and comets have reached the Earth since it formed, it has been proposed that the exogenous influx from these bodies provided the organic inventories necessary for the emergence of life. The carbonaceous meteorites of the Renazzo-type family (CR) have recently revealed a composition that is particularly enriched in small soluble organic molecules, such as the amino acids glycine and alanine, which could support this possibility. We have now analyzed the insoluble and the largest organic component of the CR2 Grave Nunataks (GRA) 95229 meteorite and found it to be of more primitive composition than in other meteorites and to release abundant free ammonia upon hydrothermal treatment. The findings appear to trace CR2 meteorites’ origin to cosmochemical regimes where ammonia was pervasive, and we speculate that their delivery to the early Earth could have fostered prebiotic molecular evolution.
Evidence from Cameroon reveals differences in the genetic structure and histories of chimpanzee populations
Authors: Gonder Mary Katherine , Locatelli Sabrina , Ghobrial Lora , Mitchell Matthew W. , Kujawski Joseph T. , Lankester Felix J. , Stewart Caro-Beth , Tishkoff Sarah A.
Published: March 2011

The history of the genusPanis a topic of enduring interest. Chimpanzees (Pan troglodytes) are often divided into subspecies, but the population structure and genetic history of chimpanzees across Africa remain unclear. Some population genetics studies have led to speculation that, until recently, this species constituted a single population with ongoing gene flow across its range, which resulted in a continuous gradient of allele frequencies. Chimpanzees, designated here asP. t. ellioti, occupy the Gulf of Guinea region that spans southern Nigeria and western Cameroon at the center of the distribution of this species. Remarkably, few studies have included individuals from this region, hindering the examination of chimpanzee population structure across Africa. Here, we analyzed microsatellite genotypes of 94 chimpanzees, including 32 designated asP. t. ellioti. We find that chimpanzees fall into three major populations: (i) Upper Guinea in western Africa (P. t. verus); (ii) the Gulf of Guinea region (P. t. ellioti); and (iii) equatorial Africa (P. t. troglodytesandP. t. schweinfurthii). Importantly, the Gulf of Guinea population is significantly different genetically from the others, sharing a last common ancestor with the populations in Upper Guinea ~0.46 million years ago (mya) and equatorial Africa ~0.32 mya. Equatorial chimpanzees are subdivided into up to three populations occupying southern Cameroon, central Africa, and eastern Africa, which may have constituted a single population until ~0.10–0.11 mya. Finally, occasional hybridization may be occurring between the Gulf of Guinea and southern Cameroon populations.
Active liquid-like behavior of nucleoli determines their size and shape in
Xenopus laevis
oocytes
Authors: Brangwynne Clifford P. , Mitchison Timothy J. , Hyman Anthony A.
Published: March 2011

For most intracellular structures with larger than molecular dimensions, little is known about the connection between underlying molecular activities and higher order organization such as size and shape. Here, we show that both the size and shape of the amphibian oocyte nucleolus ultimately arise because nucleoli behave as liquid-like droplets of RNA and protein, exhibiting characteristic viscous fluid dynamics even on timescales of < 1 min. We use these dynamics to determine an apparent nucleolar viscosity, and we show that this viscosity is ATP-dependent, suggesting a role for active processes in fluidizing internal contents. Nucleolar surface tension and fluidity cause their restructuring into spherical droplets upon imposed mechanical deformations. Nucleoli exhibit a broad distribution of sizes with a characteristic power law, which we show is a consequence of spontaneous coalescence events. These results have implications for the function of nucleoli in ribosome subunit processing and provide a physical link between activity within a macromolecular assembly and its physical properties on larger length scales.
Attractive emulsion droplets probe the phase diagram of jammed granular matter
Authors: Jorjadze Ivane , Pontani Lea-Laetitia , Newhall Katherine A. , Brujić Jasna
Published: March 2011

It remains an open question whether statistical mechanics approaches apply to random packings of athermal particles. Although a jamming phase diagram has recently been proposed for hard spheres with varying friction, here we use a frictionless emulsion system in the presence of depletion forces to sample the available phase space of packing configurations. Using confocal microscopy, we access their packing microstructure and test the theoretical assumptions. As a function of attraction, our packing protocol under gravity leads to well-defined jammed structures in which global density initially increases above random close packing and subsequently decreases monotonically. Microscopically, the fluctuations in parameters describing each particle, such as the coordination number, number of neighbors, and local packing fraction, are for all attractions in excellent agreement with a local stochastic model, indicating that long-range correlations are not important. Furthermore, the distributions of local cell volumes can be collapsed onto a universal curve using the predicted
k
-gamma distribution, in which the shape parameter
k
is fixed by the polydispersity while the effect of attraction is captured by rescaling the average cell volume. Within the Edwards statistical mechanics framework, this result measures the decrease in compactivity with global density, which represents a direct experimental test of a jamming phase diagram in athermal systems. The success of these theoretical tools in describing yet another class of materials gives support to the much-debated statistical physics of jammed granular matter.
Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors
Authors: Chakrabarty Anindita , Sánchez Violeta , Kuba María G. , Rinehart Cammie , Arteaga Carlos L.
Published: March 2011

We examined the effects of an inhibitor of PI3K, XL147, against human breast cancer cell lines with constitutive PI3K activation. Treatment with XL147 resulted in dose-dependent inhibition of cell growth and levels of pAKT and pS6, signal transducers in the PI3K/AKT/TOR pathway. In HER2-overexpressing cells, inhibition of PI3K was followed by up-regulation of expression and phosphorylation of multiple receptor tyrosine kinases, including HER3. Knockdown of FoxO1 and FoxO3a transcription factors suppressed the induction of HER3, InsR, IGF1R, and FGFR2 mRNAs upon inhibition of PI3K. In HER2
+
cells, knockdown of HER3 with siRNA or cotreatment with the HER2 inhibitors trastuzumab or lapatinib enhanced XL147-induced cell death and inhibition of pAKT and pS6. Trastuzumab and lapatinib each synergized with XL147 for inhibition of pAKT and growth of established BT474 xenografts. These data suggest that PI3K antagonists will inhibit AKT and relieve suppression of receptor tyrosine kinase expression and their activity. Relief of this feedback limits the sustained inhibition of the PI3K/AKT pathway and attenuates the response to these agents. As a result, PI3K pathway inhibitors may have limited clinical activity overall if used as single agents. In patients with HER2-overexpressing breast cancer, PI3K inhibitors should be used in combination with HER2/HER3 antagonists.
E1- and ubiquitin-like proteins provide a direct link between protein conjugation and sulfur transfer in archaea
Authors: Miranda Hugo V. , Nembhard Nikita , Su Dan , Hepowit Nathaniel , Krause David J. , Pritz Jonathan R. , Phillips Cortlin , Söll Dieter , Maupin-Furlow Julie A.
Published: March 2011

Based on our recent work with
Haloferax volcanii
, ubiquitin-like (Ubl) proteins (SAMP1 and SAMP2) are known to be covalently attached to proteins in archaea. Here, we investigated the enzymes required for the formation of these Ubl-protein conjugates (SAMPylation) and whether this system is linked to sulfur transfer. Markerless in-frame deletions were generated in
H. volcanii
target genes. The mutants were examined for: (
i
) the formation of Ubl protein conjugates, (
ii
) growth under various conditions, including those requiring the synthesis of the sulfur-containing molybdenum cofactor (MoCo), and (
iii
) the thiolation of tRNA. With this approach we found that UbaA of the E1/MoeB/ThiF superfamily was required for the formation of both SAMP1- and SAMP2-protein conjugates. In addition, UbaA, SAMP1, and MoaE (a homolog of the large subunit of molybdopterin synthase) were essential for MoCo-dependent dimethyl sulfoxide reductase activity, suggesting that these proteins function in MoCo-biosynthesis. UbaA and SAMP2 were also crucial for optimal growth at high temperature and the thiolation of tRNA. Based on these results, we propose a working model for archaea in which the E1-like UbaA can activate multiple Ubl SAMPs for protein conjugation as well as for sulfur transfer. In sulfur transfer, SAMP1 and SAMP2 appear specific for MoCo biosynthesis and the thiolation of tRNA, respectively. Overall, this study provides a fundamental insight into the diverse cellular functions of the Ubl system.
Deficiency of
Dgcr8
, a gene disrupted by the 22q11.2 microdeletion, results in altered short-term plasticity in the prefrontal cortex
Authors: Fénelon Karine , Mukai Jun , Xu Bin , Hsu Pei-Ken , Drew Liam J. , Karayiorgou Maria , Fischbach Gerald D. , MacDermott Amy B. , Gogos Joseph A.
Published: March 2011

Individuals with 22q11.2 microdeletions have cognitive and behavioral impairments and the highest known genetic risk for developing schizophrenia. One gene disrupted by the 22q11.2 microdeletion is
DGCR8
, a component of the “microprocessor” complex that is essential for microRNA production, resulting in abnormal processing of specific brain miRNAs and working memory deficits. Here, we determine the effect of
Dgcr8
deficiency on the structure and function of cortical circuits by assessing their laminar organization, as well as the neuronal morphology, and intrinsic and synaptic properties of layer 5 pyramidal neurons in the prefrontal cortex of
Dgcr8
+/−
mutant mice. We found that heterozygous
Dgcr8
mutant mice have slightly fewer cortical layer 2/4 neurons and that the basal dendrites of layer 5 pyramidal neurons have slightly smaller spines. In addition to the modest structural changes, field potential and whole-cell electrophysiological recordings performed in layer 5 of the prefrontal cortex revealed greater short-term synaptic depression during brief stimulation trains applied at 50 Hz to superficial cortical layers. This finding was accompanied by a decrease in the initial phase of synaptic potentiation. Our results identify altered short-term plasticity as a neural substrate underlying the cognitive dysfunction and the increased risk for schizophrenia associated with the 22q11.2 microdeletions.
Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma
Authors: Monje Michelle , Mitra Siddhartha S. , Freret Morgan E. , Raveh Tal B. , Kim James , Masek Marilyn , Attema Joanne L. , Li Gordon , Haddix Terri , Edwards Michael S. B. , Fisher Paul G. , Weissman Irving L. , Rowitch David H. , Vogel Hannes , Wong Albert J. , Beachy Philip A.
Published: March 2011

Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors of childhood that are almost universally fatal. Our understanding of this devastating cancer is limited by a dearth of available tissue for study and by the lack of a faithful animal model. Intriguingly, DIPGs are restricted to the ventral pons and occur during a narrow window of middle childhood, suggesting dysregulation of a postnatal neurodevelopmental process. Here, we report the identification of a previously undescribed population of immunophenotypic neural precursor cells in the human and murine brainstem whose temporal and spatial distributions correlate closely with the incidence of DIPG and highlight a candidate cell of origin. Using early postmortem DIPG tumor tissue, we have established in vitro and xenograft models and find that the Hedgehog (Hh) signaling pathway implicated in many developmental and oncogenic processes is active in DIPG tumor cells. Modulation of Hh pathway activity has functional consequences for DIPG self-renewal capacity in neurosphere culture. The Hh pathway also appears to be active in normal ventral pontine precursor-like cells of the mouse, and unregulated pathway activity results in hypertrophy of the ventral pons. Together, these findings provide a foundation for understanding the cellular and molecular origins of DIPG, and suggest that the Hh pathway represents a potential therapeutic target in this devastating pediatric tumor.
Kindlin-3–mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption
Authors: Schmidt Sarah , Nakchbandi Inaam , Ruppert Raphael , Kawelke Nina , Hess Michael W. , Pfaller Kristian , Jurdic Pierre , Fässler Reinhard , Moser Markus
Published: March 2011

The blood cell–specific kindlin-3 protein is required to activate leukocyte and platelet integrins. In line with this function, mutations in the KINDLIN-3 gene in man cause immunodeficiency and severe bleeding. Some patients also suffer from osteopetrosis, but the underlying mechanism leading to abnormal bone turnover is unknown. Here we show that kindlin-3–deficient mice develop severe osteopetrosis because of profound adhesion and spreading defects in bone-resorbing osteoclasts. Mechanistically, loss of kindlin-3 impairs the activation of β1, β2, and β3 integrin classes expressed on osteoclasts, which in turn abrogates the formation of podosomes and sealing zones required for bone resorption. In agreement with these findings, genetic ablation of all integrin classes abolishes the development of podosomes, mimicking kindlin-3 deficiency. Although loss of single integrin classes gives rise to podosomes, their resorptive activity is impaired. These findings show that osteoclasts require their entire integrin repertoire to be regulated by kindlin-3 to orchestrate bone homeostasis.
Processing and turnover of the Hedgehog protein in the endoplasmic reticulum
Authors: Chen Xin , Tukachinsky Hanna , Huang Chih-Hsiang , Jao Cindy , Chu Yue-Ru , Tang Hsiang-Yun , Mueller Britta , Schulman Sol , Rapoport Tom A. , Salic Adrian
Published: March 2011

The Hedgehog (Hh) signaling pathway has important functions during metazoan development. The Hh ligand is generated from a precursor by self-cleavage, which requires a free cysteine in the C-terminal part of the protein and results in the production of the cholesterol-modified ligand and a C-terminal fragment. In this paper, we demonstrate that these reactions occur in the endoplasmic reticulum (ER). The catalytic cysteine needs to form a disulfide bridge with a conserved cysteine, which is subsequently reduced by protein disulfide isomerase. Generation of the C-terminal fragment is followed by its ER-associated degradation (ERAD), providing the first example of an endogenous luminal ERAD substrate that is constitutively degraded. This process requires the ubiquitin ligase Hrd1, its partner Sel1, the cytosolic adenosine triphosphatase p97, and degradation by the proteasome. Processing-defective mutants of Hh are degraded by the same ERAD components. Thus, processing of the Hh precursor competes with its rapid degradation, explaining the impaired Hh signaling of processing-defective mutants, such as those causing human holoprosencephaly.
The human Tp53 Arg72Pro polymorphism explains different functional prognosis in stroke
Authors: Gomez-Sanchez Jose C. , Delgado-Esteban Maria , Rodriguez-Hernandez Irene , Sobrino Tomas , Perez de la Ossa Natalia , Reverte Silvia , Bolaños Juan P. , Gonzalez-Sarmiento Rogelio , Castillo Jose , Almeida Angeles
Published: March 2011

The functional outcome after stroke is unpredictable; it is not accurately predicted by clinical pictures upon hospital admission. The presence of apoptotic neurons in the ischemic penumbra and perihematoma area may account for poor prognosis, but whether the highly variable stroke outcome reflects differences in genetic susceptibility to apoptosis is elusive. The p53 tumor suppressor protein, an important transcriptional regulator of apoptosis, naturally occurs in humans in two variants with single nucleotide polymorphisms resulting in Arg or Pro at residue 72. We show that poor functional outcome after either ischemic or hemorrhagic stroke was linked to the Arg/Arg genotype. This genotype was also associated with early neurological deterioration in ischemic stroke and with increased residual cavity volume in intracerebral hemorrhage. In primary cultured neurons, Arg72-p53, but not Pro72-p53, interacted directly with mitochondrial Bcl-xL and activated the intrinsic apoptotic pathway, increasing vulnerability to ischemia-induced apoptotic cell death. These results suggest that the Tp53 Arg/Arg genotype governs neuronal vulnerability to apoptosis and can be considered as a genetic marker predicting poor functional outcome after stroke.
Liver-expressed Igκ superantigen induces tolerance of polyclonal B cells by clonal deletion not κ to λ receptor editing
Authors: Ota Takayuki , Ota Miyo , Duong Bao Hoa , Gavin Amanda L. , Nemazee David
Published: March 2011

Little is know about the nature of peripheral B cell tolerance or how it may vary in distinct lineages. Although autoantibody transgenic studies indicate that anergy and apoptosis are involved, some studies claim that receptor editing occurs. To model peripheral B cell tolerance in a normal, polyclonal immune system, we generated transgenic mice expressing an Igκ–light chain–reactive superantigen targeted to the plasma membrane of hepatocytes (pAlb mice). In contrast to mice expressing κ superantigen ubiquitously, in which κ cells edit efficiently to λ, in pAlb mice, κ B cells underwent clonal deletion. Their κ cells failed to populate lymph nodes, and the remaining splenic κ cells were anergic, arrested at a semi-mature stage without undergoing receptor editing. In the liver, κ cells recognized superantigen, down-regulated surface Ig, and expressed active caspase 3, suggesting ongoing apoptosis at the site of B cell receptor ligand expression. Some, apparently mature, κ B1 and follicular B cells persisted in the peritoneum. BAFF (B cell–activating factor belonging to the tumor necrosis factor family) overexpression rescued splenic κ B cell maturation and allowed κ cells to populate lymph nodes. Our model facilitates analysis of tissue-specific autoimmunity, tolerance, and apoptosis in a polyclonal B cell population. The results suggest that deletion, not editing, is the major irreversible pathway of tolerance induction among peripheral B cells.