bluuebunny/crossref_metadata_2025 huggingface dataset:
Heat capacity changes in carbohydrates and protein–carbohydrate complexes
Authors: Chavelas Eneas A. , García-Hernández Enrique
Published: March 2009

Carbohydrates are crucial for living cells, playing myriads of functional roles that range from being structural or energy-storage devices to molecular labels that, through non-covalent interaction with proteins, impart exquisite selectivity in processes such as molecular trafficking and cellular recognition. The molecular bases that govern the recognition between carbohydrates and proteins have not been fully understood yet. In the present study, we have obtained a surface-area-based model for the formation heat capacity of protein–carbohydrate complexes, which includes separate terms for the contributions of the two molecular types. The carbohydrate model, which was calibrated using carbohydrate dissolution data, indicates that the heat capacity contribution of a given group surface depends on its position in the saccharide molecule, a picture that is consistent with previous experimental and theoretical studies showing that the high abundance of hydroxy groups in carbohydrates yields particular solvation properties. This model was used to estimate the carbohydrate's contribution in the formation of a protein–carbohydrate complex, which in turn was used to obtain the heat capacity change associated with the protein's binding site. The model is able to account for protein–carbohydrate complexes that cannot be explained using a previous model that only considered the overall contribution of polar and apolar groups, while allowing a more detailed dissection of the elementary contributions that give rise to the formation heat capacity effects of these adducts.
Proteolytic activation of human pancreatitis-associated protein is required for peptidoglycan binding and bacterial aggregation
Authors: Medveczky Péter , Szmola Richárd , Sahin-Tóth Miklós
Published: March 2009

PAP (pancreatitis-associated protein) is a 16 kDa lectin-like protein, which becomes robustly up-regulated in the pancreatic juice during acute pancreatitis. Trypsin cleaves the N-terminus of PAP, which in turn forms insoluble fibrils. PAP and its paralogue, the pancreatic stone protein, induce bacterial aggregation and, more recently, PAP was shown to bind to the peptidoglycan of Gram-positive bacteria and exert a direct bactericidal effect. However, the role of N-terminal processing in the antibacterial function of PAP has remained unclear. In the present study, we demonstrate that N-terminal cleavage of PAP by trypsin at the Arg37–Ile38 peptide bond or by elastase at the Ser35–Ala36 peptide bond is a prerequisite for binding to the peptidoglycan of the Gram-positive bacterium Bacillus subtilis. The tryptic site in PAP was also efficiently cleaved by nprE (extracellular neutral metalloprotease) secreted from B. subtilis. Trypsin-mediated processing of PAP resulted in the formation of the characteristic insoluble PAP species, whereas elastase-processed PAP remained soluble. N-terminally processed PAP induced rapid aggregation of B. subtilis without significant bacterial killing. The bacteria-aggregating activities of trypsin-processed and elastase-processed PAP were comparable. In contrast with previous reports, the Gram-negative Escherichia coli bacterium was not aggregated. We conclude that N-terminal processing is necessary for the peptidoglycan binding and bacteria-aggregating activity of PAP and that trypsin-processed and elastase-processed forms are functionally equivalent. The observations also extend the complement of proteases capable of PAP processing, which now includes trypsins, pancreatic elastases and bacterial zinc metalloproteases of the thermolysin type.
Competition between NarL-dependent activation and Fis-dependent repression controls expression from the Escherichia coli yeaR and ogt promoters
Authors: Squire Derrick J. P. , Xu Meng , Cole Jeffrey A. , Busby Stephen J. W. , Browning Douglas F.
Published: March 2009

The Escherichia coli NarL protein is a global gene regulatory factor that activates transcription at many target promoters in response to nitrate and nitrite ions. Although most NarL-dependent promoters are also co-dependent on a second transcription factor, FNR protein, two targets, the yeaR and ogt promoters, are activated by NarL alone with no involvement of FNR. Biochemical and genetic studies presented here show that activation of the yeaR promoter is dependent on the binding of NarL to a single target centred at position −43.5, whereas activation at the ogt promoter requires NarL binding to tandem DNA targets centred at position −45.5 and −78.5. NarL-dependent activation at both the yeaR and ogt promoters is decreased in rich medium and this depends on Fis, a nucleoid-associated protein. DNase I footprinting studies identified Fis-binding sites that overlap the yeaR promoter NarL site at position −43.5, and the ogt promoter NarL site at position −78.5, and suggest that Fis represses both promoters by displacing NarL. The ogt gene encodes an O6-alkylguanine DNA alkyltransferase and, hence, this is the first report of expression of a DNA repair function being controlled by nitrate ions.
Characterization of Citrus sinensis type 1 mitochondrial alternative oxidase and expression analysis in biotic stress
Authors: Daurelio Lucas Damián , Checa Susana Karina , Barrio Jorgelina Morán , Ottado Jorgelina , Orellano Elena Graciela
Published: March 2009

The higher plant mitochondrial electron transport chain contains an alternative pathway that ends with the AOX (alternative oxidase). The AOX proteins are encoded by a small gene family composed of two discrete gene subfamilies. Aox1 is present in both monocot and eudicot plants, whereas Aox2 is only present in eudicot plants. We isolated a genomic clone from Citrus sinensis containing the Aox1a gene. The orange Aox1a consists of four exons interrupted by three introns and its promoter harbours diverse putative stress-specific regulatory motifs including pathogen response elements. The role of the Aox1a gene was evaluated during the compatible interaction between C. sinensis and Xanthomonas axonopodis pv. citri and no induction of the Aox1a at the transcriptional level was observed. On the other hand, Aox1a was studied in orange plants during non-host interactions with Pseudomonas syringae pv. tomato and Xanthomonas campestris pv. vesicatoria, which result in hypersensitive response. Both phytopathogens produced a strong induction of Aox1a, reaching a maximum at 8 h post-infiltration. Exogenous application of salicylic acid produced a slight increase in the steady-state level of Aox1a, whereas the application of fungi elicitors showed the highest induction. These results suggest that AOX1a plays a role during biotic stress in non-host plant pathogen interaction.
Common genetic variation in DDAH2 is associated with intracerebral haemorrhage in a Chinese population: a multi-centre case-control study in China
Authors: Bai Yongyi , Chen Jingzhou , Sun Kai , Xin Ying , Liu Junhao , Hui Rutai
Published: March 2009

ADMA (asymmetric ω-NG,NG-dimethylarginine), an endogenous inhibitor of NOS (NO synthase), has been shown to be an independent predictor of cerebrovascular disorders. DDAH2 (dimethylarginine dimethylaminohydrolase 2) promotes the metabolism of ADMA and plays a key role in the regulation of the acute inflammatory response. We hypothesized that genetic variation in DDAH2 might alter the susceptibility to ICH (intracerebral haemorrhage). The hypothesis was tested in two independent case-control studies. We used a haplotype-tagging SNP (single nucleotide polymorphism) approach to identify tag SNPs in DDAH2. The SNPs were genotyped in 1603 stroke patients and 1525 control subjects. The study was replicated in another independent case-control study including 322 stroke patients and 891 control subjects. A promoter variant −449C/G (rs805305) in DDAH2 was identified and found to be in complete linkage disequilibrium with the only tag SNP (rs707916) in the region containing DDAH2. Genotype analyses were conducted for both dominant and additive models. The C allele of the −449 locus resulted in a significantly reduced risk of ICH {dominant model: OR (odds ratio), 0.51 [95% CI (confidence interval), 0.38–0.68], P=6.60×10−6; additive model: OR, 0.64 (95% CI, 0.52–0.80), P=5.21×10−5} than the wild-type genotype. No association was observed between the DDAH2 variant and atherothrombotic stroke. The findings were replicated in the second independent population. In conclusion, our results suggest that the DDAH2 common variant may play a protective role in the development of ICH, implicating that the DDAH2/ADMA pathway may act as a critical regulator of cerebral small-vessel disorders.
The Development of Swallowing Respiratory Coordination
Authors: Huckabee Maggie-Lee
Published: March 2009

Research exists that evaluates the mechanics of swallowing respiratory coordination in healthy children and adults as well and individuals with swallowing impairment. The research program summarized in this article represents a systematic examination of swallowing respiratory coordination across the lifespan as a means of behaviorally investigating mechanisms of cortical modulation. Using time-locked recordings of submental surface electromyography, nasal airflow, and thyroid acoustics, three conditions of swallowing were evaluated in 20 adults in a single session and 10 infants in 10 sessions across the first year of life. The three swallowing conditions were selected to represent a continuum of volitional through nonvolitional swallowing control on the basis of a decreasing level of cortical activation. Our primary finding is that, across the lifespan, brainstem control strongly dictates the duration of swallowing apnea and is heavily involved in organizing the integration of swallowing and respiration, even in very early infancy. However, there is evidence that cortical modulation increases across the first 12 months of life to approximate more adult-like patterns of behavior. This modulation influences primarily conditions of volitional swallowing; sleep and naïve swallows appear to not be easily adapted by cortical regulation. Thus, it is attention, not arousal that engages cortical mechanisms.
The Interaction of Pulmonary Physiology and Swallowing: A Juggling Act for the Physician and Speech-Language Pathologist
Authors: Dikeman Karen J. , Kazandjian Marta S. , Tun Elbert , Niyazova Panina , Tsai Tien-Tsai , Russo Daniel J.
Published: March 2009

Patients who are dependent upon tracheostomy and/or ventilator use present a particular challenge to health-care providers. The interaction of pulmonary physiology and deglutition is complex, as illustrated in the course of patients who are in the weaning process. Speech language pathologists (SLPs) should work closely with their physician colleagues to understand the influence of multiple medical co-morbidities on intervention. In traditional medicine, the clinician's objective is to connect a patient's many symptoms and complaints to a single disease entity. However, in caring for the ventilator dependent geriatric population, a symptom such as dysphagia typically results from the interplay of various, multi-organ symptoms, and conditions. This article strives to demonstrate the “juggling act” that the physician and SLP must balance between the patient's current medical condition, pulmonary dysfunction, and disordered swallowing. Clinical case studies illustrate the benefit of swallowing intervention on quality of life. While the care of patients with tracheostomy and ventilator dependence requires a team approach, with respiratory therapy and nursing vital members, this article emphasizes the roles of the SLP and physician.
Interlayer exchange coupling in Co2FeAl0.5Si0.5/Cr/Co2FeAl0.5Si0.5 trilayers
Authors: Furubayashi T. , Kodama K. , Goripati H. S. , Takahashi Y. K. , Inomata K. , Hono K.
Published: March 2009

Interlayer exchange couplings were examined for Co2FeAl0.5Si0.5(CFAS)/Cr/CFAS trilayered films grown on MgO (001) single crystal and thermally oxidized Si substrates. The films were (001) epitaxial on MgO and (110) textured polycrystalline on SiO2. Strong exchange couplings were observed for the films with the 1.5 nm thick Cr spacer layer. A 90° coupling is dominant in the (001) epitaxial film. In contrast, an antiparallel coupling exists in the polycrystalline one. The relationship of interlayer couplings with the structure is discussed.
Thermoelectric performance of NiyMo3Sb7−xTex (y≤0.1, 1.5≤x≤1.7)
Authors: Xu H. , Kleinke K. M. , Holgate T. , Zhang H. , Su Z. , Tritt T. M. , Kleinke H.
Published: March 2009

Mo 3 Sb 7 − x Te x is a high temperature thermoelectric material, reported to reach figure of merit (ZT)=0.8 at 1023 K. Various p-type samples of NiyMo3Sb7−xTex were prepared with y≤0.1 and 1.5≤x≤1.7 via high temperature reactions at 993 K. Adding transition metal atoms into the empty cube formed by Sb atoms significantly alters the band structure and thus the thermoelectric properties. Electronic band structure calculations indicate that adding Ni slightly increases the charge carrier concentration, while higher Te content causes a decrease. Thermoelectric properties were determined on pellets densified via hot pressing at 993 K. Seebeck as well as electrical and thermal conductivity measurements were performed up to 1023 K. The highest ZT value thus far was obtained from a sample of nominal composition Ni0.06Mo3Sb5.4Te1.6, which amounts to 0.93 at 1023 K.
Oscillating chemistry explains complex, self-assembled crystal aggregates
Authors: Wilson Mark
Published: March 2009

Leaflike sheets, wormy ropes, and helical filaments are just some of the shapes that can emerge, under the right conditions, from inorganic compounds.
Accelerators shrink to meet growing demand for proton therapy
Authors: Matthews Jermey N. A.
Published: March 2009

Smaller, cheaper accelerators promise to make proton radiation therapy available to more cancer patients.
Physics in the oil sands of Alberta
Authors: Gray Murray , Xu Zhenghe , Masliyah Jacob
Published: March 2009

Alberta’s petroleum reserves are comparable to Saudi Arabia’s, but accessing that oil poses challenges in the physics of fluids and particulates.
The extraordinary sound of the hang
Authors: Morrison Andrew , Rossing Thomas D.
Published: March 2009

An increasingly popular percussion instrument created less than 10 years ago has inspired musicians and physicists alike to explore its sonic properties.
Laser-driven plasma-wave electron accelerators
Authors: Leemans Wim , Esarey Eric
Published: March 2009

Surfing a plasma wave, a bunch of electrons or positrons can experience much higher accelerating gradients than a conventional RF linac could provide.
The Triangle-Bisection Illusion
Authors: Anstis Stuart , Gregory Richard , Heard Priscilla
Published: March 2009

In the triangle-bisection illusion, a dot is inscribed exactly halfway up the height of an equilateral triangle, but it looks apparently far more than halfway up. The illusion is found for second-order triangles defined by stereo depth and by equiluminous texture. It is strongest for equilateral triangles, and even stronger for concave triangles with curved sides. We propose that the observers are probably responding to the centre of area or centre of gravity of the triangle rather than to its half-height.
Brunswikian Resources for Event-Perception Research
Authors: Kirlik Alex
Published: March 2009

Recent psychological research aimed at determining whether dynamic event perception is direct or mediated by cue-based inference convincingly demonstrates evidence of both modes of perception or apprehension. This work also shows that noise is involved in attaining any perceptual variable, whether it perfectly (invariantly) specifies or imperfectly (fallibly) indicates the value of a target or criterion variable. As such, event-perception researchers encounter both internal (sensory or inferential) and external ecological sources of noise or uncertainty, owing to the organism's possible use of imperfect or ‘nonspecifying’ variables (or cues) and cue-based inference. Because both sources play central roles in Egon Brunswik's theory of probabilistic functionalism and methodology of representative design, event-perception research will benefit by explicitly leveraging original Brunswikian and, more recent, neo-Brunswikian scientific resources. Doing so will result in a more coherent and powerful approach to perceptual and cognitive psychology than is currently displayed in the scientific literature.
Distance Perception in Autism and Typical Development
Authors: Giovannini Lorena , Jacomuzzi Alessandra C , Bruno Nicola , Semenza Carlo , Surian Luca
Published: March 2009

Children with autism and typically developing children walked blindfolded to a previously seen target (blindwalking task) and matched the frontal to the sagittal extent of a pattern formed by ropes on the ground (L-matching task). All participants were accurate in the blindwalking task. Children with autism were also very accurate in the matching task. By contrast, in the matching task typically developing children made substantial underestimations that were inversely correlated with age. These findings support models that posit independent representations for the egocentric distance to a target location and for the spatial extent to a target object relative to the other spatial extents. These latter representations involve a form of large-scale pattern perception that may mature more slowly than representations of egocentric distance and develop atypically in autism.
Normal prostate morphology in relaxin-mutant mice
Authors: Ganesan Avinash , Klonisch Thomas , McGuane Jonathan T. , Feng Shu , Agoulnik Alexander I. , Parry Laura J.
Published: March 2009

The peptide hormone relaxin is expressed in the prostate gland and secreted into the seminal plasma; however, its function within the prostate has not been established. Relaxin-mutant mice (Rln–/–) were reported to have abnormal prostate morphology, but there was no prostate phenotype in relaxin receptor-mutant (Rxfp1–/–) mice. The present study aimed to verify the phenotypes in the anterior, dorsal and lateral lobes of the prostate gland of Rln–/– and Rxfp1–/– mice at different adult ages. Rln–/– mice were also treated with relaxin to evaluate the effects of exogenously administered hormone on prostate morphology. Comparisons between these three lobes of the prostate demonstrated no obvious differences in duct morphology, epithelial height or collagen density between Rln+/+ and Rln–/– mice at 2, 4, 6, 8 and 12 months of age. This was similar in Rxfp1–/– mice. Relaxin treatment did not affect morphology or epithelial cell height in the different lobes. Furthermore, prostate lobe morphology in transgenic mice overexpressing relaxin Tg(Rln) was not different from the wild-type controls. Rxfp1 was detected in the prostate throughout adult life, but there was no consistent expression of relaxin. In summary, the present study found no evidence to support a prostate phenotype in adult Rln- or Rxfp1-mutant mice.
Fine-scale habitat selection by adult female swamp wallabies (Wallabia bicolor)
Authors: Swan Matthew , Di Stefano Julian , Greenfield Andrew , Coulson Graeme
Published: March 2009

Animals typically use habitat in a non-random way, but the factors influencing habitat selection may change throughout the 24-h cycle. In this study, we quantified resources at used and available locations to test two predictions about the fine-scale habitat selection of seven adult female swamp wallabies (Wallabia bicolor). We predicted that selection would be (i) non-random and (ii) differ between diurnal and nocturnal periods with respect to both food and shelter. Variables quantifying food abundance and lateral cover were recorded at 56 diurnal, 17 nocturnal and 143 randomly selected available locations. Logistic regression indicated that diurnal habitat selection was positively correlated with lateral cover, and the cover of trees, shrubs and forbs, whereas nocturnal selection was positively correlated with forb cover only. Diurnal locations had more lateral cover than nocturnal locations. The data were consistent with our first prediction, but only partially supported our second. At a fine scale, diurnal habitat selection was influenced by the co-availability of shelter and food resources, whereas nocturnal selection was influenced by food availability only, indicating that factors influencing habitat selection changed throughout the 24-h cycle.
LOK is a major ERM kinase in resting lymphocytes and regulates cytoskeletal rearrangement through ERM phosphorylation
Authors: Belkina Natalya V. , Liu Yin , Hao Jian-Jiang , Karasuyama Hajime , Shaw Stephen
Published: March 2009

ERM (ezrin-radixin-moesin) proteins mediate linkage of actin cytoskeleton to plasma membrane in many cells. ERM activity is regulated in part by phosphorylation at a C-terminal threonine, but the identity of ERM kinases is unknown in lymphocytes and incompletely defined in other mammalian cells. Our studies show that lymphocyte-oriented kinase (LOK) is an ERM kinase in vitro and in vivo. Mass spectrometric analysis indicates LOK is abundant at the lymphocyte plasma membrane and immunofluorescence studies show LOK enrichment at the plasma membrane near ERM. In vitro peptide specificity analyses characterize LOK as a basophilic kinase whose optimal substrate sequence resembles the ERM site, including unusual preference for tyrosine at P–2. LOK's activity on moesin peptide and protein was comparable to reported ERM kinases ROCK and PKC but unlike them LOK displayed preferential specificity for moesin compared to traditional basophilic kinase substrates. Two genetic approaches demonstrate a role for LOK in ERM phosphorylation: cell transfection with LOK kinase domain augments ERM phosphorylation and lymphocytes from LOK knockout mice have >50% reduction in ERM phosphorylation. The findings on localization and specificity argue that LOK is a direct ERM kinase. The knockout mice have normal hematopoietic cell development but notably lymphocyte migration and polarization in response to chemokine are enhanced. These functional alterations fit the current understanding of the role of ERM phosphorylation in regulating cortical reorganization. Thus, these studies identify a new ERM kinase of importance in lymphocytes and confirm the role of ERM phosphorylation in regulating cell shape and motility.
Distinct developmental mechanisms underlie the evolutionary diversification of
Drosophila
sex combs
Authors: Tanaka Kohtaro , Barmina Olga , Kopp Artyom
Published: March 2009

Similar selective pressures can lead to independent origin of similar morphological structures in multiple evolutionary lineages. Developmental mechanisms underlying convergent evolution remain poorly understood. In this report, we show that similar sex comb morphology in closely related
Drosophila species
is produced by different cellular mechanisms. The sex comb is a recently evolved, male-specific array of modified bristles derived from transverse bristle rows found on the first thoracic legs in both sexes. “Longitudinal” sex combs oriented along the proximo-distal leg axis evolved independently in several
Drosophila
lineages. We show that in some of these lineages, sex combs originate as one or several transverse bristle rows that subsequently rotate 90° and align to form a single longitudinal row. In other species, bristle cells that make up the sex combs arise in their final longitudinal orientation. Thus, sex combs can develop through either sex-specific patterning of bristle precursor cells or male-specific morphogenesis of sexually monomorphic precursors. Surprisingly, the two mechanisms produce nearly identical morphology in some species. Phylogenetic analysis shows that each of these mechanisms has probably evolved repeatedly in different
Drosophila
lineages, suggesting that selection can recruit different cellular processes to produce similar functional solutions.
Hydrogen sulfide as a mediator of human corpus cavernosum smooth-muscle relaxation
Authors: d'Emmanuele di Villa Bianca Roberta , Sorrentino Raffaella , Maffia Pasquale , Mirone Vincenzo , Imbimbo Ciro , Fusco Ferdinando , De Palma Raffaele , Ignarro Louis J. , Cirino Giuseppe
Published: March 2009

Hydrogen sulfide (H
2
S) is synthesized by 2 enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE).
l
-Cysteine (
l
-Cys) acts as a natural substrate for the synthesis of H
2
S. Human penile tissue possesses both CBS and CSE, and tissue homogenates efficiently convert
l
-Cys to H
2
S. CBS and CSE are localized in the muscular trabeculae and the smooth-muscle component of the penile artery, whereas CSE but not CBS is also expressed in peripheral nerves. Exogenous H
2
S [sodium hydrogen sulfide (NaHS)] or
l
-Cys causes a concentration-dependent relaxation of strips of human corpus cavernosum.
l
-Cys relaxation is inhibited by the CBS inhibitor, aminoxyacetic acid (AOAA). Electrical field stimulation of human penile tissue, under resting conditions, causes an increase in tension that is significantly potentiated by either propargylglycine (PAG; CSE inhibitor) or AOAA. In rats, NaHS and
l
-Cys promote penile erection, and the response to
l
-Cys is blocked by PAG. Our data demonstrate that the
l
-Cys/H
2
S pathway mediates human corpus cavernosum smooth-muscle relaxation.
Immunostimulatory activity of haptenated proteins
Authors: Palm Noah W. , Medzhitov Ruslan
Published: March 2009

Antigen recognition alone is insufficient for the activation of adaptive immune responses mediated by conventional lymphocytes. Additional signals that indicate the origin of the antigen are also required. These signals are generally provided by the innate immune system upon recognition of conserved microbial structures by a variety of pattern recognition receptors (PRRs). The Toll-like receptors (TLRs) are the best-characterized family of PRRs and control the activation of adaptive immune responses to a variety of immunizations and infections. However, recent studies have questioned the role of TLRs in the induction of antibody responses and, thus, this issue has become controversial. In contrast to earlier studies supporting a role for TLRs in antibody responses, these studies used haptenated antigens rather than native antigens for immunization, but did not consider the potential effect of antigen haptenation on immunogenicity. Here, we show that commonly used haptenated proteins, unlike native proteins, are inherently immunogenic. This immunogenicity is TLR-independent, but the T and B cell responses induced are primarily hapten-specific, rather than protein-specific. Thus, although haptens have immunostimulatory activity, it is distinct from classical adjuvants, which induce immune responses directed at the admixed antigens. Our results thus highlight an unappreciated and unique immunogenicity of haptenated proteins, and provide an experimental explanation for a seeming discrepancy between published results.
Globalization and human cooperation
Authors: Buchan Nancy R. , Grimalda Gianluca , Wilson Rick , Brewer Marilynn , Fatas Enrique , Foddy Margaret
Published: March 2009

Globalization magnifies the problems that affect all people and that require large-scale human cooperation, for example, the overharvesting of natural resources and human-induced global warming. However, what does globalization imply for the cooperation needed to address such global social dilemmas? Two competing hypotheses are offered. One hypothesis is that globalization prompts reactionary movements that reinforce parochial distinctions among people. Large-scale cooperation then focuses on favoring one's own ethnic, racial, or language group. The alternative hypothesis suggests that globalization strengthens cosmopolitan attitudes by weakening the relevance of ethnicity, locality, or nationhood as sources of identification. In essence, globalization, the increasing interconnectedness of people worldwide, broadens the group boundaries within which individuals perceive they belong. We test these hypotheses by measuring globalization at both the country and individual levels and analyzing the relationship between globalization and individual cooperation with distal others in multilevel sequential cooperation experiments in which players can contribute to individual, local, and/or global accounts. Our samples were drawn from the general populations of the United States, Italy, Russia, Argentina, South Africa, and Iran. We find that as country and individual levels of globalization increase, so too does individual cooperation at the global level vis-à-vis the local level. In essence, “globalized” individuals draw broader group boundaries than others, eschewing parochial motivations in favor of cosmopolitan ones. Globalization may thus be fundamental in shaping contemporary large-scale cooperation and may be a positive force toward the provision of global public goods.
Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis
Authors: Xia Xiaobo , Lemieux Madeleine E. , Li Wei , Carroll Jason S. , Brown Myles , Liu X. Shirley , Kung Andrew L.
Published: March 2009

Adaptation to hypoxia is mediated through a coordinated transcriptional response driven largely by hypoxia-inducible factor 1 (HIF-1). We used ChIP-chip and gene expression profiling to identify direct targets of HIF-1 transactivation on a genome-wide scale. Several hundred direct HIF-1 targets were identified and, as expected, were highly enriched for proteins that facilitate metabolic adaptation to hypoxia. Surprisingly, there was also striking enrichment for the family of 2-oxoglutarate dioxygenases, including the jumonji-domain histone demethylases. We demonstrate that these histone demethylases are direct HIF targets, and their up-regulation helps maintain epigenetic homeostasis under hypoxic conditions. These results suggest that the coordinated increase in expression of several oxygen-dependent enzymes by HIF may help compensate for decreased levels of oxygen under conditions of cellular hypoxia.
Mechanism of replication machinery assembly as revealed by the DNA ligase–PCNA–DNA complex architecture
Authors: Mayanagi Kouta , Kiyonari Shinichi , Saito Mihoko , Shirai Tsuyoshi , Ishino Yoshizumi , Morikawa Kosuke
Published: March 2009

The 3D structure of the ternary complex, consisting of DNA ligase, the proliferating cell nuclear antigen (PCNA) clamp, and DNA, was investigated by single-particle analysis. This report presents the structural view, where the crescent-shaped DNA ligase with 3 distinct domains surrounds the central DNA duplex, encircled by the closed PCNA ring, thus forming a double-layer structure with dual contacts between the 2 proteins. The relative orientations of the DNA ligase domains, which remarkably differ from those of the known crystal structures, suggest that a large domain rearrangement occurs upon ternary complex formation. A second contact was found between the PCNA ring and the middle adenylation domain of the DNA ligase. Notably, the map revealed a substantial DNA tilt from the PCNA ring axis. This structure allows us to propose a switching mechanism for the replication factors operating on the PCNA ring.
A transcriptionally silent RXRα supports early embryonic morphogenesis and heart development
Authors: Mascrez Bénédicte , Ghyselinck Norbert B. , Chambon Pierre , Mark Manuel
Published: March 2009

Retinoic acid (RA) receptors (RARs) α, β, and γ heterodimerized with rexinoid receptors (RXRs) α, β, and γ mediate the RA signal. To analyze the contribution of the transcriptional activity of RXRα, the main RXR during embryogenesis, we have engineered a mouse line harboring a transcriptionally silent RXRα mutant that lacks the activation functions AF1 and AF2. All homozygous mutants (

Rxra
afo

) display the ocular defects previously observed in compound
Rar
-null and
Rxra
/
Rar
-null mutants, thus demonstrating that a transcriptionally active RXRα is required during eye development. In contrast, the vast majority of

Rxra
afo

fetuses do not display the
Rxra
-null mutant hypoplasia of the myocardium, thus demonstrating that RXRα can act as a transcriptionally silent heterodimerization partner. Similarly, a transcriptionally silent RXRα mutant can support early embryogenesis, as

Rxra
afo
/Rxrb

-null embryos display a normal morphology, contrasting with the severe malformations exhibited by compound
Rxra
/
Rxrb
-null embryos. Along the same line, we show that a silent RXRα mutant is sufficient to allow the initial formation of the placental labyrinth, whereas later steps of trophoblast cell differentiation critically requires the AF2, but not the AF1, function of RXRα.
Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory
Authors: Campolongo Patrizia , Roozendaal Benno , Trezza Viviana , Hauer Daniela , Schelling Gustav , McGaugh James L. , Cuomo Vincenzo
Published: March 2009

Extensive evidence indicates that the basolateral complex of the amygdala (BLA) modulates the consolidation of memories for emotionally arousing experiences, an effect that involves the activation of the glucocorticoid system. Because the BLA expresses high densities of cannabinoid CB1 receptors, the present experiments investigated whether the endocannabinoid system in the BLA influences memory consolidation and whether glucocorticoids interact with this system. The CB1 receptor agonist WIN55,212-2 (5–50 ng per 0.2 μL per side), infused bilaterally into the BLA of male Sprague–Dawley rats immediately after inhibitory avoidance training, induced dose-dependent enhancement of 48-h retention. Conversely, the CB1 receptor antagonist AM251 (0.07–0.28 ng per 0.2 μL per side) administered after training into the BLA induced inhibitory avoidance retention impairment. Furthermore, intra-BLA infusions of a low and nonimpairing dose of AM251 (0.14 ng per 0.2 μL per side) blocked the memory enhancement induced by concurrent administration of WIN55,212-2. Delayed infusions of WIN55,212-2 or AM251 administered into the BLA 3 h after training or immediate posttraining infusions of these drugs into the adjacent central amygdala did not significantly alter retention performance. Last, intra-BLA infusions of a low and otherwise nonimpairing dose of AM251 (0.14 ng per 0.2 μL per side) blocked the memory-enhancing effect induced by systemic administration of corticosterone (3 mg/kg, s.c.). These findings indicate that endocannabinoids in the BLA enhance memory consolidation and suggest that CB1 activity within this brain region is required for enabling glucocorticoid effects on memory consolidation enhancement.
Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX
Authors: Pazgier Marzena , Liu Min , Zou Guozhang , Yuan Weirong , Li Changqing , Li Chong , Li Jing , Monbo Juahdi , Zella Davide , Tarasov Sergey G. , Lu Wuyuan
Published: March 2009

The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53—a cellular process initiated by MDM2 and/or MDMX binding to the N-terminal transactivation domain of p53. MDM2 and MDMX in many tumors confer p53 inactivation and tumor survival, and are important molecular targets for anticancer therapy. We screened a duodecimal peptide phage library against site-specifically biotinylated p53-binding domains of human MDM2 and MDMX chemically synthesized via native chemical ligation, and identified several peptide inhibitors of the p53-MDM2/MDMX interactions. The most potent inhibitor (TSFAEYWNLLSP), termed PMI, bound to MDM2 and MDMX at low nanomolar affinities—approximately 2 orders of magnitude stronger than the wild-type p53 peptide of the same length (ETFSDLWKLLPE). We solved the crystal structures of synthetic MDM2 and MDMX, both in complex with PMI, at 1.6 Å resolution. Comparative structural analysis identified an extensive, tightened intramolecular H-bonding network in bound PMI that contributed to its conformational stability, thus enhanced binding to the 2 oncogenic proteins. Importantly, the C-terminal residue Pro of PMI induced formation of a hydrophobic cleft in MDMX previously unseen in the structures of p53-bound MDM2 or MDMX. Our findings deciphered the structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX, shedding new light on structure-based rational design of different classes of p53 activators for potential therapeutic use.
Mammalian end binding proteins control persistent microtubule growth
Authors: Komarova Yulia , De Groot Christian O. , Grigoriev Ilya , Gouveia Susana Montenegro , Munteanu E. Laura , Schober Joseph M. , Honnappa Srinivas , Buey Rubén M. , Hoogenraad Casper C. , Dogterom Marileen , Borisy Gary G. , Steinmetz Michel O. , Akhmanova Anna
Published: March 2009

End binding proteins (EBs) are highly conserved core components of microtubule plus-end tracking protein networks. Here we investigated the roles of the three mammalian EBs in controlling microtubule dynamics and analyzed the domains involved. Protein depletion and rescue experiments showed that EB1 and EB3, but not EB2, promote persistent microtubule growth by suppressing catastrophes. Furthermore, we demonstrated in vitro and in cells that the EB plus-end tracking behavior depends on the calponin homology domain but does not require dimer formation. In contrast, dimerization is necessary for the EB anti-catastrophe activity in cells; this explains why the EB1 dimerization domain, which disrupts native EB dimers, exhibits a dominant-negative effect. When microtubule dynamics is reconstituted with purified tubulin, EBs promote rather than inhibit catastrophes, suggesting that in cells EBs prevent catastrophes by counteracting other microtubule regulators. This probably occurs through their action on microtubule ends, because catastrophe suppression does not require the EB domains needed for binding to known EB partners.
Bcl-xL increases mitochondrial fission, fusion, and biomass in neurons
Authors: Berman Sarah B. , Chen Ying-bei , Qi Bing , McCaffery J. Michael , Rucker Edmund B. , Goebbels Sandra , Nave Klaus-Armin , Arnold Beth A. , Jonas Elizabeth A. , Pineda Fernando J. , Hardwick J. Marie
Published: March 2009

Mitochondrial fission and fusion are linked to synaptic activity in healthy neurons and are implicated in the regulation of apoptotic cell death in many cell types. We developed fluorescence microscopy and computational strategies to directly measure mitochondrial fission and fusion frequencies and their effects on mitochondrial morphology in cultured neurons. We found that the rate of fission exceeds the rate of fusion in healthy neuronal processes, and, therefore, the fission/fusion ratio alone is insufficient to explain mitochondrial morphology at steady state. This imbalance between fission and fusion is compensated by growth of mitochondrial organelles. Bcl-xL increases the rates of both fusion and fission, but more important for explaining the longer organelle morphology induced by Bcl-xL is its ability to increase mitochondrial biomass. Deficits in these Bcl-xL–dependent mechanisms may be critical in neuronal dysfunction during the earliest phases of neurodegeneration, long before commitment to cell death.
Ly49P recognition of cytomegalovirus-infected cells expressing H2-Dk and CMV-encoded m04 correlates with the NK cell antiviral response
Authors: Kielczewska Agnieszka , Pyzik Michal , Sun Tianhe , Krmpotic Astrid , Lodoen Melissa B. , Munks Michael W. , Babic Marina , Hill Ann B. , Koszinowski Ulrich H. , Jonjic Stipan , Lanier Lewis L. , Vidal Silvia M.
Published: March 2009

Natural killer (NK) cells are crucial in resistance to certain viral infections, but the mechanisms used to recognize infected cells remain largely unknown. Here, we show that the activating Ly49P receptor recognizes cells infected with mouse cytomegalovirus (MCMV) by a process that requires the presence of H2-Dk and the MCMV m04 protein. Using H2 chimeras between H2-Db and -Dk, we demonstrate that the H2-Dk peptide-binding platform is required for Ly49P recognition. We identified m04 as a viral component necessary for recognition using a panel of MCMV-deletion mutant viruses and complementation of m04-deletion mutant (Δm04) virus infection. MA/My mice, which express Ly49P and H2-Dk, are resistant to MCMV; however, infection with Δm04 MCMV abrogates resistance. Depletion of NK cells in MA/My mice abrogates their resistance to wild-type MCMV infection, but does not significantly affect viral titers in mice infected with Δm04 virus, implicating NK cells in host protection through m04-dependent recognition. These findings reveal a novel mechanism of major histocompatability complex class I–restricted recognition of virally infected cells by an activating NK cell receptor.
DIYA: a bacterial annotation pipeline for any genomics lab
Authors: Stewart Andrew C. , Osborne Brian , Read Timothy D.
Published: March 2009

Summary:DIYA (Do-It-Yourself Annotator) is a modular and configurable open source pipeline software, written in Perl, used for the rapid annotation of bacterial genome sequences. The software is currently used to take DNA contigs as input, either in the form of complete genomes or the result of shotgun sequencing, and produce an annotated sequence in Genbank file format as output.

Availability: Distribution and source code are available at (https://sourceforge.net/projects/diyg/).

Contact:  tread@emory.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
The use of gene ontology evidence codes in preventing classifier assessment bias
Authors: Rogers Mark F. , Ben-Hur Asa
Published: March 2009

Motivation: The biological community's reliance on computational annotations of protein function makes correct assessment of function prediction methods an issue of great importance. The fact that a large fraction of the annotations in current biological databases are based on computational methods can lead to bias in estimating the accuracy of function prediction methods. This can happen since predicting an annotation that was derived computationally in the first place is likely easier than predicting annotations that were derived experimentally, leading to over-optimistic classifier performance estimates.

Results: We illustrate this phenomenon in a set of controlled experiments using a nearest neighbor classifier that uses PSI-BLAST similarity scores. Our results demonstrate that the source of Gene Ontology (GO) annotations used to assess a protein function predictor can have a highly significant influence on classifier accuracy: the average accuracy over four species and over GO terms in the biological process namespace increased from 0.72 to 0.87 when the classifier was given access to annotations that are assigned evidence codes that indicate a possible computational source, instead of experimentally determined annotations. Slightly smaller increases were observed in the other namespaces. In these comparisons the total number of annotations and their distribution across GO terms were kept the same.

Conclusion: In conclusion, taking into account GO evidence codes is required for reporting accuracy statistics that do not overestimate a model's performance, and is of particular importance for a fair comparison of classifiers that rely on different information sources.

Contact:  rogersma@cs.colostate.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Performance of Residents and Anesthesiologists in a Simulation-based Skill Assessment
Authors: Murray David J. , Boulet John R. , Avidan Michael , Kras Joseph F. , Henrichs Bernadette , Woodhouse Julie , Evers Alex S.
Published: March 2009

Background

Anesthesiologists and anesthesia residents are expected to acquire and maintain skills to manage a wide range of acute intraoperative anesthetic events. The purpose of this study was to determine whether an inventory of simulated intraoperative scenarios provided a reliable and valid measure of anesthesia residents' and anesthesiologists' skill.

Methods

Twelve simulated acute intraoperative scenarios were designed to assess the performance of 64 residents and 35 anesthesiologists. The participants were divided into four groups based on their training and experience. There were 31 new CA-1, 12 advanced CA-1, and 22 CA-2/CA-3 residents as well as a group of 35 experienced anesthesiologists who participated in the assessment. Each participant managed a set of simulated events. The advanced CA-1 residents, CA-2/CA-3 residents, and 35 anesthesiologists managed 8 of 12 intraoperative simulation exercises. The 31 CA-1 residents each managed 3 intraoperative scenarios.

Results

The new CA-1 residents received lower scores on the simulated intraoperative events than the other groups of participants. The advanced CA-1 residents, CA-2/CA-3 residents, and anesthesiologists performed similarly on the overall assessment. There was a wide range of scores obtained by individuals in each group. A number of the exercises were difficult for the majority of participants to recognize and treat, but most events effectively discriminated among participants who achieved higher and lower overall scores.

Conclusion

This simulation-based assessment provided a valid method to distinguish the skills of more experienced anesthesia residents and anesthesiologists from residents in early training. The overall score provided a reliable measure of a participant's ability to recognize and manage simulated acute intraoperative events. Additional studies are needed to determine whether these simulation-based assessments are valid measures of clinical performance.
Persistent Low-frequency Spontaneous Discharge in A-fiber and C-fiber Primary Afferent Neurons during an Inflammatory Pain Condition
Authors: Xiao Wen-Hua , Bennett Gary J.
Published: March 2009

Background

Primary afferent nociceptor sensitization and its accompanying spontaneous discharge are believed to be the proximate cause of the spontaneous pain and hypersensitivity that follow an acute tissue injury. Evidence for this comes almost entirely from studies limited to the first few minutes to an hour or two after injury, when the inflammatory reaction to injury has just begun. However, there is evidence that inflammatory pain mechanisms differ from acute pain mechanisms and that the mechanisms that drive and modulate inflammatory pain may evolve over time.

Methods

The authors surveyed spontaneous afferent discharge in rats with hind paw inflammation evoked by complete Freund adjuvant over the entire 14 days of the inflammatory pain condition, as determined in parallel experiments assessing allodynia and hyperalgesia.

Results

Inflammation-evoked heat hyperalgesia, mechanoallodynia, and mechanohyperalgesia began within hours, persisted until at least day 7, and resolved by day 14. A large percentage (23%) of A fibers had spontaneous discharge 2 days after inflammation, but the incidence was much reduced (to 7-9%) by 7 and 14 days. At all times, the A-fiber discharge frequency was low (<3.0 Hz) or very low (<0.3 Hz). A large percentage (24%) of C fibers had spontaneous discharge 2 and 7 days after inflammation, but this also declined to near control levels by day 14; C-fiber discharge frequency was also always low (most at 0.3-1.0 Hz).

Conclusions

The pain, allodynia, and hyperalgesia associated with an established inflammatory condition are associated with a persistent low-frequency spontaneous discharge in both A-fiber and C-fiber sensory afferents.