bluuebunny/crossref_metadata_2025 huggingface dataset:
Solubility of mimetite Pb5(AsO4)3Cl at 5 - 55°C
Authors: Bajda Tomasz
Published: June 2010

Environmetal context.The mobility of toxic arsenic compounds in the environment can be controlled by the solubility of certain minerals. To predict and model the fate and behaviour of these contaminants, the solubility and related thermodynamic properties of the lead and arsenic mineral mimetite were determined. The data obtained in this study will be used to optimise and increase the effectiveness of remediation procedures that are already applied to contaminated sites.
Abstract.The solubility of the synthesised mimetite was measured in a series of dissolution experiments at 5–55°C and at pH values between 2.00 and 2.75. The solubility product logKSP for the reaction Pb5(AsO4)3Cl ↔ 5Pb2+ + 3AsO43– + Cl– at 25°C is –76.35 ± 1.01. The free energy of formation ΔGf,2980 calculated from this measured solubility product equals –2634.3 ± 5.9 kJ mol–1. The temperature dependence of the logKSP is non-linear, indicating that the enthalpy of the reaction depends on the temperature. The enthalpy of the formation of mimetite ΔHf0, is –2965.9 ± 4.7 kJ mol–1, the entropy, ΔS0, is 39.5 J mol–1 K–1, and the heat capacity, ΔCp,f0 is –6172 ± 105 J mol–1 K–1. Hydrochemical modelling indicates that regardless of the composition of the background solution, Pb5(AsO4)3Cl is most stable at neutral to weakly alkaline pH.
Dynamic features of speciation analysis by adsorptive stripping techniques
Authors: Town Raewyn M. , van Leeuwen Herman P.
Published: June 2010

Environmental context.The environmental fate and bioavailability of metal ions in natural waters is determined by their thermodynamic stability and kinetic features, both of which are distributed. Competing ligand exchange – adsorptive stripping (CLE-AdS) is a technique that measures a certain portion of these complexes as determined by the stability of the selected competing ligand and the dynamic features of the sample complexes that remain following ligand exchange. Exploitation of CLE-AdS to determine a spectrum of sample complexes requires insight into its thermodynamic and kinetic windows.
Abstract.The kinetic features of the accumulation step of competing ligand exchange – adsorptive stripping (CLE-AdS) in metal speciation methodology are elaborated. During the adsorptive accumulation process, the flux of the surface active complex MLad towards the electrode may be modified by the coupled conversions of ML and M into MLad. An immediate consequence is that the accumulation flux of MLad can be greater than that corresponding to its mere bulk concentration: a labile ML contributes fully to the MLad accumulation, and a further flux enhancement can arise if ML is more mobile than MLad (DML > DMLad). Applying the conventional lability criterion, we present a framework for interpretation of CLE-AdS measurements in the presence of kinetic contributions from sample ML to the adsorptive accumulation of MLad. Measured accumulation fluxes for a kinetic case are well described by the presented theoretical framework. The dynamic analysis provides the basis for exploitation of CLE-AdS over a wider kinetic window than has been used to date. Consideration of the dynamics of sample species during the adsorptive accumulation step is fundamental for interpretation of metal speciation by CLE-AdS in complex natural systems that contain a distribution of complexes of different stability, lability, and mobility.
Assessing the climatic benefits of black carbon mitigation
Authors: Kopp Robert E. , Mauzerall Denise L.
Published: June 2010

To limit mean global warming to 2 °C, a goal supported by more than 100 countries, it will likely be necessary to reduce emissions not only of greenhouse gases but also of air pollutants with high radiative forcing (RF), particularly black carbon (BC). Although several recent research papers have attempted to quantify the effects of BC on climate, not all these analyses have incorporated all the mechanisms that contribute to its RF (including the effects of BC on cloud albedo, cloud coverage, and snow and ice albedo, and the optical consequences of aerosol mixing) and have reported their results in different units and with different ranges of uncertainty. Here we attempt to reconcile their results and present them in uniform units that include the same forcing factors. We use the best estimate of effective RF obtained from these results to analyze the benefits of mitigating BC emissions for achieving a specific equilibrium temperature target. For a 500 ppm CO2e (3.1 W m-2) effective RF target in 2100, which would offer about a 50% chance of limiting equilibrium warming to 2.5 °C above preindustrial temperatures, we estimate that failing to reduce carbonaceous aerosol emissions from contained combustion would require CO2emission cuts about 8 years (range of 1–15 years) earlier than would be necessary with full mitigation of these emissions.
Pyrimidine biosynthesis links mitochondrial respiration to the p53 pathway
Authors: Khutornenko Anastasia A. , Roudko Vladimir V. , Chernyak Boris V. , Vartapetian Andrey B. , Chumakov Peter M. , Evstafieva Alexandra G.
Published: June 2010

While many functions of the p53 tumor suppressor affect mitochondrial processes, the role of altered mitochondrial physiology in a modulation of p53 response remains unclear. As mitochondrial respiration is affected in many pathologic conditions such as hypoxia and intoxications, the impaired electron transport chain could emit additional p53-inducing signals and thereby contribute to tissue damage. Here we show that a shutdown of mitochondrial respiration per se does not trigger p53 response, because inhibitors acting in the proximal and distal segments of the respiratory chain do not activate p53. However, strong p53 response is induced specifically after an inhibition of the mitochondrial cytochrome bc1 (the electron transport chain complex III). The p53 response is triggered by the deficiency in pyrimidines that is developed due to a suppression of the functionally coupled mitochondrial pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH). In epithelial carcinoma cells the activation of p53 in response to mitochondrial electron transport chain complex III inhibitors does not require phosphorylation of p53 at Serine 15 or up-regulation of p14
ARF
. Instead, our data suggest a contribution of NQO1 and NQO2 in stabilization of p53 in the nuclei. The results establish the deficiency in pyrimidine biosynthesis as the cause of p53 response in the cells with impaired mitochondrial respiration.
Reorganization of columnar architecture in the growing visual cortex
Authors: Keil Wolfgang , Schmidt Karl-Friedrich , Löwel Siegrid , Kaschube Matthias
Published: June 2010

Many cortical areas increase in size considerably during postnatal development, progressively displacing neuronal cell bodies from each other. At present, little is known about how cortical growth affects the development of neuronal circuits. Here, in acute and chronic experiments, we study the layout of ocular dominance (OD) columns in cat primary visual cortex during a period of substantial postnatal growth. We find that despite a considerable size increase of primary visual cortext, the spacing between columns is largely preserved. In contrast, their spatial arrangement changes systematically over this period. Whereas in young animals columns are more band-like, layouts become more isotropic in mature animals. We propose a novel mechanism of growth-induced reorganization that is based on the “zigzag instability,” a dynamical instability observed in several inanimate pattern forming systems. We argue that this mechanism is inherent to a wide class of models for the activity-dependent formation of OD columns. Analyzing one representative of this class, the Elastic Network model, we show that this mechanism can account for the preservation of column spacing and the specific mode of reorganization of OD columns that we observe. We conclude that column width is preserved by systematic reorganization of neuronal selectivities during cortical expansion and that this reorganization is well described by the zigzag instability. Our work suggests that cortical circuits may remain plastic for an extended period in development to facilitate the modification of neuronal circuits to adjust for cortical growth.
Dual roles of PGE
2
-EP4 signaling in mouse experimental autoimmune encephalomyelitis
Authors: Esaki Yoshiyasu , Li Youxian , Sakata Daiji , Yao Chengcan , Segi-Nishida Eri , Matsuoka Toshiyuki , Fukuda Kazuhiko , Narumiya Shuh
Published: June 2010

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS). Although prostaglandin (PG) concentrations are increased in cerebrospinal fluid of MS patients, the role of PGs in MS is unknown. We examined this issue by subjecting mice deficient in each PG receptor type or subtype to EAE induction and using agonists or antagonists selective for each of the four PGE receptor (EP) subtypes. Among PG receptor-deficient mice, only EP4
−/−
mice manifested significant suppression of EAE, which was mimicked in wild-type mice and to a greater extent, in EP2
−/−
mice by administration of the EP4 antagonist ONO-AE3-208 during the immunization phase. EP4 antagonism during immunization also suppressed the generation of antigen-specific T helper (Th) 1 and Th17 cells in wild-type mice and to a greater extent, in EP2
−/−
mice. ONO-AE3-208 administration at EAE onset had little effect on disease severity, and its administration throughout the experimental period did not cause significant reduction of the peak of disease, suggesting that, in addition to its facilitative action during the immunization phase, EP4 exerts a preventive action in the elicitation phase. Administration of the EP4 agonist ONO-AE1-329 at EAE onset delayed and suppressed disease progression as well as inhibited the associated increase in permeability of the blood–brain barrier. Thus, PGE
2
exerts dual functions in EAE, facilitating Th1 and Th17 cell generation redundantly through EP4 and EP2 during immunization and attenuating invasion of these cells into the brain by protecting the blood–brain barrier through EP4.
Mechanism of chromosomal transfer of
Enterococcus faecalis
pathogenicity island, capsule, antimicrobial resistance, and other traits
Authors: Manson Janet M. , Hancock Lynn E. , Gilmore Michael S.
Published: June 2010

The
Enterococcus faecalis
pathogenicity island (PAI) encodes known virulence traits and >100 additional genes with unknown roles in enterococcal biology. Phage-related integration and excision genes, and direct repeats flanking the island, suggest it moves as an integrative conjugative element (ICE). However, transfer was observed not to require these genes. Transfer only occurred from donors possessing a pheromone responsive-type of conjugative plasmid, and was invariably accompanied by transfer of flanking donor chromosome sequences. Deletion of plasmid transfer functions, including the
cis
-acting origin of transfer (
oriT
), abolished movement. In addition to demonstrating PAI movement by a mechanism involving plasmid integration, we observed transfer of a selectable marker placed virtually anywhere on the chromosome. Transfer of this selectable marker was observed to be accompanied by chromosome-chromosome transfer of vancomycin resistance, MLST markers, and capsule genes as well. Plasmid mobilization therefore appears to be a major mechanism for horizontal gene transfer in the evolution of antibiotic resistant
E. faecalis
strains capable of causing human infection.
Identification of RL-TGR, a coreceptor involved in aversive chemical signaling
Authors: Cohen Staci P. , Haack Karla K. V. , Halstead-Nussloch Gwyneth E. , Bernard Karen F. , Hatt Hanns , Kubanek Julia , McCarty Nael A.
Published: June 2010

Chemical signaling plays an important role in predator–prey interactions and feeding dynamics. Like other organisms that are sessile or slow moving, some marine sponges contain aversive compounds that defend these organisms from predation. We sought to identify and characterize a fish chemoreceptor that detects one of these compounds. Using expression cloning inXenopusoocytes coexpressing the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, the beta-2 adrenergic receptor (β2AR), and fractions of a zebrafish cDNA library, we isolated a cDNA clone encoding receptor activity–modifying protein (RAMP)-like triterpene glycoside receptor (RL-TGR), a novel coreceptor involved in signaling in response to triterpene glycosides. This coreceptor appears to be structurally and functionally related to RAMPs, a family of coreceptors that physically associate with and modify the activity of G protein–coupled receptors (GPCRs). In membranes from formoside-responsive oocytes, RL-TGR was immunoprecipitated in an apparent complex with β2AR. In HEK293 cells, coexpression of β2AR induced the trafficking of RL-TGR from the cytoplasm to the plasma membrane. These results suggest that RL-TGR in the predatory fish physically associates with the β2AR or another, more physiologically relevant GPCR and modifies its pharmacology to respond to triterpene glycosides found in sponges that serve as a potential food source for the fish. RL-TGR forms a coreceptor that responds to a chemical defense compound in the marine environment, and its discovery might lead the way to the identification of other receptors that mediate chemical defense signaling.
Endocytosis-like protein uptake in the bacterium
Gemmata obscuriglobus
Authors: Lonhienne Thierry G. A. , Sagulenko Evgeny , Webb Richard I. , Lee Kuo-Chang , Franke Josef , Devos Damien P. , Nouwens Amanda , Carroll Bernard J. , Fuerst John A.
Published: June 2010

Endocytosis is a process by which extracellular material such as macromolecules can be incorporated into cells via a membrane-trafficking system. Although universal among eukaryotes, endocytosis has not been identified in Bacteria or Archaea. However, intracellular membranes are known to compartmentalize cells of bacteria in the phylum
Planctomycetes
, suggesting the potential for endocytosis and membrane trafficking in members of this phylum. Here we show that cells of the planctomycete
Gemmata obscuriglobus
have the ability to uptake proteins present in the external milieu in an energy-dependent process analogous to eukaryotic endocytosis, and that internalized proteins are associated with vesicle membranes. Occurrence of such ability in a bacterium is consistent with autogenous evolution of endocytosis and the endomembrane system in an ancestral noneukaryote cell.
Disruption of the olivo-cerebellar circuit by Purkinje neuron-specific ablation of BK channels
Authors: Chen Xiaowei , Kovalchuk Yury , Adelsberger Helmuth , Henning Horst A. , Sausbier Matthias , Wietzorrek Georg , Ruth Peter , Yarom Yosef , Konnerth Arthur
Published: June 2010

The large-conductance voltage- and calcium-activated potassium (BK) channels are ubiquitously expressed in the brain and play an important role in the regulation of neuronal excitation. Previous work has shown that the total deletion of these channels causes an impaired motor behavior, consistent with a cerebellar dysfunction. Cellular analyses showed that a decrease in spike firing rate occurred in at least two types of cerebellar neurons, namely in Purkinje neurons (PNs) and in Golgi cells. To determine the relative role of PNs, we developed a cell-selective mouse mutant, which lacked functional BK channels exclusively in PNs. The behavioral analysis of these mice revealed clear symptoms of ataxia, indicating that the BK channels of PNs are of major importance for normal motor coordination. By using combined two-photon imaging and patch-clamp recordings in these mutant mice, we observed a unique type of synaptic dysfunction in vivo, namely a severe silencing of the climbing fiber–evoked complex spike activity. By performing targeted pharmacological manipulations combined with simultaneous patch-clamp recordings in PNs, we obtained direct evidence that this silencing of climbing fiber activity is due to a malfunction of the tripartite olivo-cerebellar feedback loop, consisting of the inhibitory synaptic connection of PNs to the deep cerebellar nuclei (DCN), followed by a projection of inhibitory DCN afferents to the inferior olive, the origin of climbing fibers. Taken together, our results establish an essential role of BK channels of PNs for both cerebellar motor coordination and feedback regulation in the olivo-cerebellar loop.
Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns
Authors: Dominguez-Bello Maria G. , Costello Elizabeth K. , Contreras Monica , Magris Magda , Hidalgo Glida , Fierer Noah , Knight Rob
Published: June 2010

Upon delivery, the neonate is exposed for the first time to a wide array of microbes from a variety of sources, including maternal bacteria. Although prior studies have suggested that delivery mode shapes the microbiota's establishment and, subsequently, its role in child health, most researchers have focused on specific bacterial taxa or on a single body habitat, the gut. Thus, the initiation stage of human microbiome development remains obscure. The goal of the present study was to obtain a community-wide perspective on the influence of delivery mode and body habitat on the neonate's first microbiota. We used multiplexed 16S rRNA gene pyrosequencing to characterize bacterial communities from mothers and their newborn babies, four born vaginally and six born via Cesarean section. Mothers’ skin, oral mucosa, and vagina were sampled 1 h before delivery, and neonates’ skin, oral mucosa, and nasopharyngeal aspirate were sampled <5 min, and meconium <24 h, after delivery. We found that in direct contrast to the highly differentiated communities of their mothers, neonates harbored bacterial communities that were undifferentiated across multiple body habitats, regardless of delivery mode. Our results also show that vaginally delivered infants acquired bacterial communities resembling their own mother's vaginal microbiota, dominated by
Lactobacillus
,
Prevotella,
or
Sneathia
spp., and C-section infants harbored bacterial communities similar to those found on the skin surface, dominated by
Staphylococcus
,
Corynebacterium
, and
Propionibacterium
spp. These findings establish an important baseline for studies tracking the human microbiome's successional development in different body habitats following different delivery modes, and their associated effects on infant health.
Spatial and spectral detection of protein monolayers with deterministic aperiodic arrays of metal nanoparticles
Authors: Lee Sylvanus Y. , Amsden Jason J. , Boriskina Svetlana V. , Gopinath Ashwin , Mitropolous Alexander , Kaplan David L. , Omenetto Fiorenzo G. , Negro Luca Dal
Published: June 2010

Light scattering phenomena in periodic systems have been investigated for decades in optics and photonics. Their classical description relies on Bragg scattering, which gives rise to constructive interference at specific wavelengths along well defined propagation directions, depending on illumination conditions, structural periodicity, and the refractive index of the surrounding medium. In this paper, by engineering multifrequency colorimetric responses in deterministic aperiodic arrays of nanoparticles, we demonstrate significantly enhanced sensitivity to the presence of a single protein monolayer. These structures, which can be readily fabricated by conventional Electron Beam Lithography, sustain highly complex structural resonances that enable a unique optical sensing approach beyond the traditional Bragg scattering with periodic structures. By combining conventional dark-field scattering micro-spectroscopy and simple image correlation analysis, we experimentally demonstrate that deterministic aperiodic surfaces with engineered structural color are capable of detecting,
in the visible spectral range
, protein layers with thickness of a few tens of Angstroms.
Expert credibility in climate change
Authors: Anderegg William R. L. , Prall James W. , Harold Jacob , Schneider Stephen H.
Published: June 2010

Although preliminary estimates from published literature and expert surveys suggest striking agreement among climate scientists on the tenets of anthropogenic climate change (ACC), the American public expresses substantial doubt about both the anthropogenic cause and the level of scientific agreement underpinning ACC. A broad analysis of the climate scientist community itself, the distribution of credibility of dissenting researchers relative to agreeing researchers, and the level of agreement among top climate experts has not been conducted and would inform future ACC discussions. Here, we use an extensive dataset of 1,372 climate researchers and their publication and citation data to show that (i) 97–98% of the climate researchers most actively publishing in the field surveyed here support the tenets of ACC outlined by the Intergovernmental Panel on Climate Change, and (ii) the relative climate expertise and scientific prominence of the researchers unconvinced of ACC are substantially below that of the convinced researchers.
Mycobacterium tuberculosis
persistence mutants identified by screening in isoniazid-treated mice
Authors: Dhar Neeraj , McKinney John D.
Published: June 2010

Tuberculosis (TB) is notoriously difficult to cure, requiring administration of multiple antibiotics for 6 mo or longer. Conventional anti-TB drugs inhibit biosynthetic processes involved in cell growth and division, such as DNA replication, RNA transcription, protein translation, and cell wall biogenesis. Although highly effective against bacteria cultured in vitro under optimal growth conditions, these antibiotics are less effective against bacteria grown in vivo in the tissues of a mammalian host. The factors that contribute to the antibiotic tolerance of bacteria grown in vivo are unknown, although altered metabolism and sluggish growth are hypothesized to play a role. To address this question, we identified mutations in
Mycobacterium tuberculosis
that impaired or enhanced persistence in mice treated with isoniazid (INH), a front-line anti-TB drug. Disruption of
cydC
, encoding a putative ATP-binding cassette transporter subunit, accelerated bacterial clearance in INH-treated mice without affecting growth or survival in untreated mice. Conversely, transposon insertions within the
rv0096
–
rv0101
gene cluster attenuated bacterial growth and survival in untreated mice but paradoxically prevented INH-mediated killing of bacteria in treated mice. These contrasting phenotypes were dependent on the interaction of the bacteria with the tissue environment because both mutants responded normally to INH when grown in macrophages ex vivo or in axenic cultures in vitro. Our findings have important implications because persistence-impairing mutations would be missed by conventional genetic screens to identify candidate drug targets. Conversely, persistence-enhancing mutations would be missed by standard diagnostic methods, which are performed on bacteria grown in vitro, to detect drug resistance.
An earlyAustralopithecus afarensispostcranium from Woranso-Mille, Ethiopia
Authors: Haile-Selassie Yohannes , Latimer Bruce M. , Alene Mulugeta , Deino Alan L. , Gibert Luis , Melillo Stephanie M. , Saylor Beverly Z. , Scott Gary R. , Lovejoy C. Owen
Published: June 2010

Only one partial skeleton that includes both forelimb and hindlimb elements has been reported forAustralopithecus afarensis. The diminutive size of this specimen (A.L. 288-1 ["Lucy"]) has hampered our understanding of the paleobiology of this species absent the potential impact of allometry. Here we describe a large-bodied (i.e., well within the range of livingHomo) specimen that, at 3.58 Ma, also substantially antedates A.L. 288–1. It provides fundamental evidence of limb proportions, thoracic form, and locomotor heritage inAustralopithecus afarensis. Together, these characteristics further establish that bipedality inAustralopithecuswas highly evolved and that thoracic form differed substantially from that of either extant African ape.
Exploiting cross-priming to generate protective CD8 T-cell immunity rapidly
Authors: Pham Nhat-Long L. , Pewe Lecia L. , Fleenor Courtney J. , Langlois Ryan A. , Legge Kevin L. , Badovinac Vladimir P. , Harty John T.
Published: June 2010

The number of memory CD8 T cells generated by infection or vaccination correlates strongly with the degree of protection observed in infection and tumor models. Therefore, rapid induction of protective numbers of effector and memory CD8 T cells may be crucial in the case of malignancy, pandemic infection, or bioterrorism. Many studies have shown that amplifying T-cell numbers by prime-boost vaccination is most effective with a substantial time interval between immunizations. In contrast, immunization with peptide-coated mature dendritic cells (DCs) results in a CD8 T-cell response exhibiting accelerated acquisition of memory characteristics, including the ability to respond to booster immunization within days of initial priming. However, personalized DC immunization is too costly, labor intensive, and time-consuming for large-scale vaccination. Here, we demonstrate that in vivo cross-priming with cell-associated antigens or antigen-coated, biodegradable microspheres in the absence of adjuvant quickly generates CD8 T cells that display the phenotype and function of long-term memory populations. Importantly, cross-primed CD8 T cells can respond to booster immunization within days of the initial immunization to generate rapidly large numbers of effector and memory T cells that can protect against bacterial, viral, and parasitic infections, including lethal influenza and malaria-causingPlasmodiuminfection. Thus, accelerated CD8 T-cell memory after in vivo cross-priming in the absence of adjuvant is generalizable and can be exploited to generate protective immunity rapidly.
Structural analysis reveals the characteristic features of Mtr4, a DExH helicase involved in nuclear RNA processing and surveillance
Authors: Weir John R. , Bonneau Fabien , Hentschel Jendrik , Conti Elena
Published: June 2010

Mtr4 is a conserved RNA helicase that functions together with the nuclear exosome. It participates in the processing of structured RNAs, including the maturation of 5.8S ribosomal RNA (rRNA). It also interacts with the polyadenylating Trf4-Air2 heterodimer to form the so-called TRAMP (
Tr
f4-
A
ir2-
M
tr4
P
olyadenylation) complex. TRAMP is involved in exosome-mediated degradation of aberrant RNAs in nuclear surveillance pathways. We report the 2.9-Å resolution crystal structure of
Saccharomyces cerevisiae
Mtr4 in complex with ADP and RNA. The structure shows a central ATPase core similar to that of other DExH helicases. Inserted in the DExH core is a region characteristic of Mtr4 orthologues that folds into an elongated stalk connected to a β-barrel domain. This domain shows unexpected similarity to the KOW domain of L24, a ribosomal protein that binds 23S rRNA. We find that indeed the KOW domain of Mtr4 is able to bind in vitro transcribed tRNA
iMet
, suggesting it might assist in presenting RNA substrates to the helicase core. The interaction of Mtr4 with Trf4-Air2 is mediated not by the stalk/KOW insertion but by the DExH core. We find that in the context of the TRAMP complex, the DExH core functions independently in vitro as an RNA helicase and a protein-binding platform. Mtr4 has thus evolved specific structural and surface features to perform its multiple functions.
Control of transient, resurgent, and persistent current by open-channel block by Na channel β4 in cultured cerebellar granule neurons
Authors: Bant Jason S. , Raman Indira M.
Published: June 2010

Voltage-gated Na channels in several classes of neurons, including cells of the cerebellum, are subject to an open-channel block and unblock by an endogenous protein. The Na
V
β4 (
Scn4b
) subunit is a candidate blocking protein because a free peptide from its cytoplasmic tail, the β4 peptide, can block open Na channels and induce resurgent current as channels unblock upon repolarization. In heterologous expression systems, however, Na
V
β4 fails to produce resurgent current. We therefore tested the necessity of this subunit in generating resurgent current, as well as its influence on Na channel gating and action potential firing, by studying cultured cerebellar granule neurons treated with siRNA targeted against
Scn4b
. Knockdown of
Scn4b
, confirmed with quantitative RT-PCR, led to five electrophysiological phenotypes: a loss of resurgent current, a reduction of persistent current, a hyperpolarized half-inactivation voltage of transient current, a higher rheobase, and a decrease in repetitive firing. All disruptions of Na currents and firing were rescued by the β4 peptide. The simplest interpretation is that Na
V
β4 itself blocks Na channels of granule cells, making this subunit the first blocking protein that is responsible for resurgent current. The results also demonstrate that a known open-channel blocking peptide not only permits a rapid recovery from nonconducting states upon repolarization from positive voltages but also increases Na channel availability at negative potentials by antagonizing fast inactivation. Thus, Na
V
β4 expression determines multiple aspects of Na channel gating, thereby regulating excitability in cultured cerebellar granule cells.
Liver X receptor β and thyroid hormone receptor α in brain cortical layering
Authors: Tan Xin-jie , Fan Xiao-tang , Kim Hyun-jin , Butler Ryan , Webb Paul , Warner Margaret , Gustafsson Jan-Åke
Published: June 2010

In the past year, two members of the nuclear receptor family, liver X receptor β (LXRβ) and thyroid hormone receptor α (TRα), have been found to be essential for correct migration of neurons in the developing cortex in mouse embryos. TRα and LXRβ bind to identical response elements on DNA and sometimes regulate the same genes. The reason for the migration defect in the LXRβ
−/−
mouse and the possibility that TRα may be involved are the subjects of the present study. At E15.5, expression of reelin and VLDLR was similar but expression of apolipoprotein E receptor 2 (ApoER2) (the reelin receptor) was much lower in LXRβ
−/−
than in WT mice. Knockout of ApoER2 is known to lead to abnormal cortical lamination. Surprisingly, by postnatal day 14 (P14), no morphological abnormalities were detectable in the cortex of LXRβ
−/−
mice and ApoER2 expression was much stronger than in WT controls. Thus, a postnatal mechanism leads to increase in ApoER2 expression by P14. TRα also regulates ApoER2. In both WT and LXRβ
−/−
mice, expression of TRα was high at postnatal day 2. By P14 it was reduced to low levels in WT mice but was still abundantly expressed in the cortex of LXRβ
−/−
mice. Based on the present data we hypothesize that reduction in the level of ApoER2 is the reason for the retarded migration of later-born neurons in LXRβ
−/−
mice but that as thyroid hormone (TH) increases after birth the neurons do find their correct place in the cortex.
Adenosine-to-inosine RNA editing shapes transcriptome diversity in primates
Authors: Paz-Yaacov Nurit , Levanon Erez Y. , Nevo Eviatar , Kinar Yaron , Harmelin Alon , Jacob-Hirsch Jasmine , Amariglio Ninette , Eisenberg Eli , Rechavi Gideon
Published: June 2010

Human and chimpanzee genomes are almost identical, yet humans express higher brain capabilities. Deciphering the basis for this superiority is a long sought-after challenge. Adenosine-to-inosine (A-to-I) RNA editing is a widespread modification of the transcriptome. The editing level in humans is significantly higher compared with nonprimates, due to exceptional editing within the primate-specific
Alu
sequences, but the global editing level of nonhuman primates has not been studied so far. Here we report the sequencing of transcribed
Alu
sequences in humans, chimpanzees, and rhesus monkeys. We found that, on average, the editing level in the transcripts analyzed is higher in human brain compared with nonhuman primates, even where the genomic
Alu
structure is unmodified. Correlated editing is observed for pairs and triplets of specific adenosines along the
Alu
sequences. Moreover, new editable species-specific
Alu
insertions, subsequent to the human–chimpanzee split, are significantly enriched in genes related to neuronal functions and neurological diseases. The enhanced editing level in the human brain and the association with neuronal functions both hint at the possible contribution of A-to-I editing to the development of higher brain function. We show here that combinatorial editing is the most significant contributor to the transcriptome repertoire and suggest that
Alu
editing adapted by natural selection may therefore serve as an alternate information mechanism based on the binary A/I code.
Dissecting the involvement of tropomyosin-related kinase A and p75 neurotrophin receptor signaling in NGF deficit-induced neurodegeneration
Authors: Capsoni Simona , Tiveron Cecilia , Vignone Domenico , Amato Gianluca , Cattaneo Antonino
Published: June 2010

NGF, the principal neurotrophic factor for basal forebrain cholinergic neurons (BFCNs), has been correlated to Alzheimer's disease (AD) because of the selective vulnerability of BFCNs in AD. These correlative links do not substantiate a comprehensive cause–effect mechanism connecting NGF deficit to overall AD neurodegeneration. A demonstration that neutralizing NGF activity could have consequences beyond a direct interference with the cholinergic system came from studies in the AD11 mouse model, in which the expression of a highly specific anti-NGF antibody determines a neurodegeneration that encompasses several features of human AD. Because the transgenic antibody binds to mature NGF much more strongly than to proNGF and prevents binding of mature NGF to the tropomyosin-related kinase A (TrkA) receptor and to p75 neurotrophin receptor (p75NTR), we postulated that neurodegeneration in AD11 mice is provoked by an imbalance of proNGF/NGF signaling and, consequently, of TrkA/p75NTR signaling. To test this hypothesis, in this study we characterize the phenotype of two lines of transgenic mice, one in which TrkA signaling is inhibited by neutralizing anti-TrkA antibodies and a second one in which anti-NGF mice were crossed to p75NTR
exonIII(−/−)
mice to abrogate p75NTR signaling. TrkA neutralization determines a strong cholinergic deficit and the appearance of β-amyloid peptide (Aβ) but no tau-related pathology. In contrast, abrogating p75NTR signaling determines a full rescue of the cholinergic and Aβ phenotype of anti-NGF mice, but tau hyperphosphorylation is exacerbated. Thus, we demonstrate that inhibiting TrkA signaling activates Aβ accumulation and that different streams of AD neurodegeneration are related in complex ways to TrkA versus p75NTR signaling.
Evidence for a first-order liquid-liquid transition in high-pressure hydrogen from ab initio simulations
Authors: Morales Miguel A. , Pierleoni Carlo , Schwegler Eric , Ceperley D. M.
Published: June 2010

Using quantum simulation techniques based on either density functional theory or quantum Monte Carlo, we find clear evidence of a first-order transition in liquid hydrogen, between a low conductivity molecular state and a high conductivity atomic state. Using the temperature dependence of the discontinuity in the electronic conductivity, we estimate the critical point of the transition at temperatures near 2,000 K and pressures near 120 GPa. Furthermore, we have determined the melting curve of molecular hydrogen up to pressures of 200 GPa, finding a reentrant melting line. The melting line crosses the metalization line at 700 K and 220 GPa using density functional energetics and at 550 K and 290 GPa using quantum Monte Carlo energetics.
A cation counterflux supports lysosomal acidification
Authors: Steinberg Benjamin E. , Huynh Kassidy K. , Brodovitch Alexandre , Jabs Sabrina , Stauber Tobias , Jentsch Thomas J. , Grinstein Sergio
Published: June 2010

The profound luminal acidification essential for the degradative function of lysosomes requires a counter-ion flux to dissipate an opposing voltage that would prohibit proton accumulation. It has generally been assumed that a parallel anion influx is the main or only counter-ion transport that enables acidification. Indeed, defective anion conductance has been suggested as the mechanism underlying attenuated lysosome acidification in cells deficient in CFTR or ClC-7. To assess the individual contribution of counter-ions to acidification, we devised means of reversibly and separately permeabilizing the plasma and lysosomal membranes to dialyze the cytosol and lysosome lumen in intact cells, while ratiometrically monitoring lysosomal pH. Replacement of cytosolic Cl− with impermeant anions did not significantly alter proton pumping, while the presence of permeant cations in the lysosomal lumen supported acidification. Accordingly, the lysosomes were found to acidify to the same pH in both CFTR- and ClC-7–deficient cells. We conclude that cations, in addition to chloride, can support lysosomal acidification and defects in lysosomal anion conductance cannot explain the impaired microbicidal capacity of CF phagocytes.
Clathrin heavy chain mediates TACC3 targeting to mitotic spindles to ensure spindle stability
Authors: Lin Chiou-Hong , Hu Chi-Kuo , Shih Hsiu-Ming
Published: June 2010

Mitotic spindles play essential roles in chromosome congression and segregation during mitosis. Aurora A regulates spindle assembly in part via phosphorylating human TACC3 on S558, which triggers TACC3 relocalization to mitotic spindles and stabilizes microtubules (MTs). In this study, we identified clathrin heavy chain (CHC) as an adaptor protein to recruit S558-phosphorylated TACC3 onto the spindle during mitosis for MT stabilization. CHC binds phospho-S558 TACC3 via its linker domain and first CHC repeat. CHC depletion or mutation on phospho-TACC3 binding abrogates TACC3 spindle relocalization. Depletion of either or both CHC and TACC3 yields similar defective phenotypes: loss of ch-TOG on spindles, disorganized spindles, and chromosome misalignment with comparable mitotic delay. Our findings elucidate the association between aurora A phosphorylation and spindle apparatus and demonstrate that regulation from aurora A is mediated by CHC in recruiting phospho-TACC3 and subsequently ch-TOG to mitotic spindles.
The nucleoporin Nup188 controls passage of membrane proteins across the nuclear pore complex
Authors: Theerthagiri Gandhi , Eisenhardt Nathalie , Schwarz Heinz , Antonin Wolfram
Published: June 2010

All transport across the nuclear envelope (NE) is mediated by nuclear pore complexes (NPCs). Despite their enormous size, ∼60 MD in vertebrates, they are comprised of only ∼30 distinct proteins (nucleoporins or Nups), many of which form subcomplexes that act as building blocks for NPC assembly. One of these evolutionarily conserved subcomplexes, the Nup93 complex, is a major structural component linking the NPC to the membranes of the NE. Using in vitro nuclear assembly assays, we show that two components of the Nup93 complex, Nup188 and Nup205, are dispensable for NPC formation. However, nuclei lacking Nup188 increase in size by several fold compared with wild type. We demonstrate that this phenotype is caused by an accelerated translocation of integral membrane proteins through NPCs, suggesting that Nup188 confines the passage of membrane proteins and is thus crucial for the homeostasis of the different nuclear membranes.
Dual recognition of CENP-A nucleosomes is required for centromere assembly
Authors: Carroll Christopher W. , Milks Kirstin J. , Straight Aaron F.
Published: June 2010

Centromeres contain specialized nucleosomes in which histone H3 is replaced by the histone variant centromere protein A (CENP-A). CENP-A nucleosomes are thought to act as an epigenetic mark that specifies centromere identity. We previously identified CENP-N as a CENP-A nucleosome-specific binding protein. Here, we show that CENP-C also binds directly and specifically to CENP-A nucleosomes. Nucleosome binding by CENP-C required the extreme C terminus of CENP-A and did not compete with CENP-N binding, which suggests that CENP-C and CENP-N recognize distinct structural elements of CENP-A nucleosomes. A mutation that disrupted CENP-C binding to CENP-A nucleosomes in vitro caused defects in CENP-C targeting to centromeres. Moreover, depletion of CENP-C with siRNA resulted in the mislocalization of all other nonhistone CENPs examined, including CENP-K, CENP-H, CENP-I, and CENP-T, and led to a partial reduction in centromeric CENP-A. We propose that CENP-C binds directly to CENP-A chromatin and, together with CENP-N, provides the foundation upon which other centromere and kinetochore proteins are assembled.
TIM1 is an endogenous ligand for LMIR5/CD300b: LMIR5 deficiency ameliorates mouse kidney ischemia/reperfusion injury
Authors: Yamanishi Yoshinori , Kitaura Jiro , Izawa Kumi , Kaitani Ayako , Komeno Yukiko , Nakamura Masaki , Yamazaki Satoshi , Enomoto Yutaka , Oki Toshihiko , Akiba Hisaya , Abe Takaya , Komori Tadasuke , Morikawa Yoshihiro , Kiyonari Hiroshi , Takai Toshiyuki , Okumura Ko , Kitamura Toshio
Published: June 2010

Leukocyte mono-immunoglobulin (Ig)–like receptor 5 (LMIR5)/CD300b is a DAP12-coupled activating receptor predominantly expressed in myeloid cells. The ligands for LMIR have not been reported. We have identified T cell Ig mucin 1 (TIM1) as a possible ligand for LMIR5 by retrovirus-mediated expression cloning. TIM1 interacted only with LMIR5 among the LMIR family, whereas LMIR5 interacted with TIM4 as well as TIM1. The Ig-like domain of LMIR5 bound to TIM1 in the vicinity of the phosphatidylserine (PS)-binding site within the Ig-like domain of TIM1. Unlike its binding to TIM1 or TIM4, LMIR5 failed to bind to PS. LMIR5 binding did not affect TIM1- or TIM4-mediated phagocytosis of apoptotic cells, and stimulation with TIM1 or TIM4 induced LMIR5-mediated activation of mast cells. Notably, LMIR5 deficiency suppressed TIM1-Fc–induced recruitment of neutrophils in the dorsal air pouch, and LMIR5 deficiency attenuated neutrophil accumulation in a model of ischemia/reperfusion injury in the kidneys in which TIM1 expression is up-regulated. In that model, LMIR5 deficiency resulted in ameliorated tubular necrosis and cast formation in the acute phase. Collectively, our results indicate that TIM1 is an endogenous ligand for LMIR5 and that the TIM1–LMIR5 interaction plays a physiological role in immune regulation by myeloid cells.
Assessing Hand Hygiene Resources and Practices at a Large African Teaching Hospital
Authors: Owusu-Ofori Alex , Jennings Rebecca , Burgess Jennifer , Prasad Priya A. , Acheampong Faustina , Coffin Susan E.
Published: June 2010

Objective.

To gather baseline data on hand hygiene (HH) practices in an African hospital with a newly established infection prevention and control team.

Design.

Cross-sectional, observational study.

Setting.

Komfo Anokye Teaching Hospital, a large teaching hospital in Ghana with approximately 1,000 beds.

Participants.

All hospital staff with patient contact were eligible for assessment of HH practices.

Interventions.

HH observations were conducted using a standardized data collection tool and method based on the World Health Organization's “5 Moments of Hand Hygiene.” Small-group interviews were conducted to gather additional information on perceptions of HH and barriers to its use. HH resource needs were also assessed using a standardized tool.

Results.

HH was attempted in 12% of the opportunities and was performed appropriately in 4% of the opportunities. Most main wards (89%) had at least 1 functional HH station. The most commonly identified barriers to HH were limited resources and lack of knowledge on appropriate times to perform HH.

Conclusion.

We developed and applied tools to evaluate HH resources and practices in a large African hospital. These assessments were undertaken to guide future efforts to improve HH at this hospital but can also serve as a model of the way to perform a systematic assessment at acute care hospitals in developing countries.
Characteristics of Healthcare-Associated Infections Contributing to Unexpected In-Hospital Deaths
Authors: Morgan Daniel J. , Lomotan Lucia L. , Agnes Kathleen , McGrail Linda , Roghmann Mary-Claire
Published: June 2010

We reviewed the medical records of all the patients who died in our hospital during the period from 2004 through 2008 to determine the contribution of healthcare-associated infections to mortality. Of the 179 unexpected in-hospital deaths during that period, 55 (31%) were related to 69 healthcare-associated infections. The most common healthcare-associated infection was central line-associated bloodstream infection, and the most common organisms identified were members of the Enterobacteriaceae family. Overall, 45% of bacterial isolates were multidrug resistant.
On the Castelnuovo-Mumford regularity of the cohomology ring of a group
Authors: Symonds Peter
Published: June 2010

We prove Benson’s Regularity Conjecture that the regularity of the cohomology of a finite group is zero. We also prove some of his generalisations to other classes of groups.
Integral transforms and Drinfeld centers in derived algebraic geometry
Authors: Ben-Zvi David , Francis John , Nadler David
Published: June 2010

We study the interaction between geometric operations on stacks and algebraic operations on their categories of sheaves. We work in the general setting of derived algebraic geometry: our basic objects are derived stacks

X
X

and their

∞
\infty

-categories

Q
C

(
X
)

\mathrm {QC}(X)

of quasi-coherent sheaves. (When

X
X

is a familiar scheme or stack,

Q
C

(
X
)

\mathrm {QC}(X)

is an enriched version of the usual quasi-coherent derived category

D

q
c

(
X
)

D_{qc}(X)

.) We show that for a broad class of derived stacks, called perfect stacks, algebraic and geometric operations on their categories of sheaves are compatible. We identify the category of sheaves on a fiber product with the tensor product of the categories of sheaves on the factors. We also identify the category of sheaves on a fiber product with functors between the categories of sheaves on the factors (thus realizing functors as integral transforms, generalizing a theorem of Toën for ordinary schemes). As a first application, for a perfect stack

X
X

, consider

Q
C

(
X
)

\mathrm {QC}(X)

with its usual monoidal tensor product. Then our main results imply the equivalence of the Drinfeld center (or Hochschild cohomology category) of

Q
C

(
X
)

\mathrm {QC}(X)

, the trace (or Hochschild homology category) of

Q
C

(
X
)

\mathrm {QC}(X)

and the category of sheaves on the loop space of

X
X

. More generally, we show that the

E

n

\mathcal {E}_n

-center and the

E

n

\mathcal {E}_n

-trace (or

E

n

\mathcal {E}_n

-Hochschild cohomology and homology categories, respectively) of

Q
C

(
X
)

\mathrm {QC}(X)

are equivalent to the category of sheaves on the space of maps from the

n
n

-sphere into

X
X

. This directly verifies geometric instances of the categorified Deligne and Kontsevich conjectures on the structure of Hochschild cohomology. As a second application, we use our main results to calculate the Drinfeld center of categories of linear endofunctors of categories of sheaves. This provides concrete applications to the structure of Hecke algebras in geometric representation theory. Finally, we explain how the above results can be interpreted in the context of topological field theory.
Curve counting theories via stable objects I. DT/PT correspondence
Authors: Toda Yukinobu
Published: June 2010

The Donaldson-Thomas invariant is a curve counting invariant on Calabi-Yau 3-folds via ideal sheaves. Another counting invariant via stable pairs is introduced by Pandharipande and Thomas, which counts pairs of curves and divisors on them. These two theories are conjecturally equivalent via generating functions, called DT/PT correspondence. In this paper, we show the Euler characteristic version of DT/PT correspondence, using the notion of weak stability conditions and the wall-crossing formula.