bluuebunny/crossref_metadata_2025 huggingface dataset:
Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans
Authors: Cirrito John R. , Disabato Brianne M. , Restivo Jessica L. , Verges Deborah K. , Goebel Whitney D. , Sathyan Anshul , Hayreh Davinder , D'Angelo Gina , Benzinger Tammie , Yoon Hyejin , Kim Jungsu , Morris John C. , Mintun Mark A. , Sheline Yvette I.
Published: August 2011

Aggregation of amyloid-β (Aβ) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aβ levels. Serotonin-dependent reductions in Aβ were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aβ plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aβ accumulation in cognitively normal individuals.
Mammalian Pragmin regulates Src family kinases via the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif that is exploited by bacterial effectors
Authors: Safari Fatemeh , Murata-Kamiya Naoko , Saito Yasuhiro , Hatakeyama Masanori
Published: August 2011

Several pathogenic bacteria have adopted effector proteins that, upon delivery into mammalian cells, undergo tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) or EPIYA-like sequence motif by host kinases such as Src family kinases (SFKs). This EPIYA phosphorylation triggers complex formation of bacterial effectors with SH2 domain-containing proteins that results in perturbation of host cell signaling and subsequent pathogenesis. Although the presence of such an anomalous protein interaction suggests the existence of a mammalian EPIYA-containing protein whose function is mimicked or subverted by bacterial EPIYA effectors, no molecule that uses the EPIYA motif for biological function has so far been reported in mammals. Here we show that mammalian Pragmin/SgK223 undergoes tyrosine phosphorylation at the EPIYA motif by SFKs and thereby acquires the ability to interact with the SH2 domain of the C-terminal Src kinase (Csk), a negative regulator of SFKs. The Pragmin–Csk interaction prevents translocalization of Csk from the cytoplasm to the membrane and subsequent inactivation of membrane-associated SFKs. As a result, SFK activity is sustained in cells where Pragmin is phosphorylated at the EPIYA motif. Because EPIYA phosphorylation of Pragmin is mediated by SFKs, cytoplasmic sequestration of Csk by Pragmin establishes a positive feedback regulation of SFK activation. Remarkably, the
Helicobacter pylori
EPIYA effector CagA binds to the Csk SH2 domain in place of Pragmin and enforces membrane recruitment of Csk and subsequent inhibition of SFKs. This work identifies Pragmin as a mammalian EPIYA effector and suggests that bacterial EPIYA effectors target Pragmin to subvert SFKs for successful infection.
The central cavity in trimeric glutamate transporters restricts ligand diffusion
Authors: Leary Greg P. , Holley David C. , Stone Emily F. , Lyda Brent R. , Kalachev Leonid V. , Kavanaugh Michael P.
Published: August 2011

A prominent aqueous cavity is formed by the junction of three identical subunits in the excitatory amino acid transporter (EAAT) family. To investigate the effect of this structure on the interaction of ligands with the transporter, we recorded currents in voltage-clamped
Xenopus
oocytes expressing EAATs and used concentration jumps to measure binding and unbinding rates of a high-affinity aspartate analog that competitively blocks transport (β-2-fluorenyl-aspartylamide; 2-FAA). The binding rates of the blocker were approximately one order of magnitude slower than
l
-Glu and were not significantly different for EAAT1, EAAT2, or EAAT3, but 2-FAA exhibited higher affinity for the neuronal transporter EAAT3 as a result of a slower dissociation rate. Unexpectedly, the rate of recovery from block was increased by
l
-Glu in a saturable and concentration-dependent manner, ruling out a first-order mechanism and suggesting that following unbinding, there is a significant probability of ligand rebinding to the same or neighboring subunits within a trimer. Consistent with such a mechanism, coexpression of wild-type subunits with mutant (R447C) subunits that do not bind glutamate or 2-FAA also increased the unblocking rate. The data suggest that electrostatic and steric factors result in an effective dissociation rate that is approximately sevenfold slower than the microscopic subunit unbinding rate. The quaternary structure, which has been conserved through evolution, is expected to increase the transporters' capture efficiency by increasing the probability that following unbinding, a ligand will rebind as opposed to being lost to diffusion.
Bacterial community comparisons by taxonomy-supervised analysis independent of sequence alignment and clustering
Authors: Sul Woo Jun , Cole James R. , Jesus Ederson da C. , Wang Qiong , Farris Ryan J. , Fish Jordan A. , Tiedje James M.
Published: August 2011

High-throughput sequencing of 16S rRNA genes has increased our understanding of microbial community structure, but now even higher-throughput methods to the Illumina scale allow the creation of much larger datasets with more samples and orders-of-magnitude more sequences that swamp current analytic methods. We developed a method capable of handling these larger datasets on the basis of assignment of sequences into an existing taxonomy using a supervised learning approach (taxonomy-supervised analysis). We compared this method with a commonly used clustering approach based on sequence similarity (taxonomy-unsupervised analysis). We sampled 211 different bacterial communities from various habitats and obtained ∼1.3 million 16S rRNA sequences spanning the V4 hypervariable region by pyrosequencing. Both methodologies gave similar ecological conclusions in that β-diversity measures calculated by using these two types of matrices were significantly correlated to each other, as were the ordination configurations and hierarchical clustering dendrograms. In addition, our taxonomy-supervised analyses were also highly correlated with phylogenetic methods, such as UniFrac. The taxonomy-supervised analysis has the advantages that it is not limited by the exhaustive computation required for the alignment and clustering necessary for the taxonomy-unsupervised analysis, is more tolerant of sequencing errors, and allows comparisons when sequences are from different regions of the 16S rRNA gene. With the tremendous expansion in 16S rRNA data acquisition underway, the taxonomy-supervised approach offers the potential to provide more rapid and extensive community comparisons across habitats and samples.
Minimization of the
Legionella pneumophila
genome reveals chromosomal regions involved in host range expansion
Authors: O’Connor Tamara J. , Adepoju Yewande , Boyd Dana , Isberg Ralph R.
Published: August 2011

Legionella pneumophila
is a bacterial pathogen of amoebae and humans. Intracellular growth requires a type IVB secretion system that translocates at least 200 different proteins into host cells. To distinguish between proteins necessary for growth in culture and those specifically required for intracellular replication, a screen was performed to identify genes necessary for optimal growth in nutrient-rich medium. Mapping of these genes revealed that the
L. pneumophila
chromosome has a modular architecture consisting of several large genomic islands that are dispensable for growth in bacteriological culture. Strains lacking six of these regions, and thus 18.5% of the genome, were viable but required secondary point mutations for optimal growth. The simultaneous deletion of five of these genomic loci had no adverse effect on growth of the bacterium in nutrient-rich media. Remarkably, this minimal genome strain, which lacked 31% of the known substrates of the type IVB system, caused only marginal defects in intracellular growth within mouse macrophages. In contrast, deletion of single regions reduced growth within amoebae. The importance of individual islands, however, differed among amoebal species. The host-specific requirements of these genomic islands support a model in which the acquisition of foreign DNA has broadened the
L. pneumophila
host range.
Structure of the Newcastle disease virus hemagglutinin-neuraminidase (HN) ectodomain reveals a four-helix bundle stalk
Authors: Yuan Ping , Swanson Kurt A. , Leser George P. , Paterson Reay G. , Lamb Robert A. , Jardetzky Theodore S.
Published: August 2011

The paramyxovirus hemagglutinin-neuraminidase (HN) protein plays multiple roles in viral entry and egress, including binding to sialic acid receptors, activating the fusion (F) protein to activate membrane fusion and viral entry, and cleaving sialic acid from carbohydrate chains. HN is an oligomeric integral membrane protein consisting of an N-terminal transmembrane domain, a stalk region, and an enzymatically active neuraminidase (NA) domain. Structures of the HN NA domains have been solved previously; however, the structure of the stalk region has remained elusive. The stalk region contains specificity determinants for F interactions and activation, underlying the requirement for homotypic F and HN interactions in viral entry. Mutations of the Newcastle disease virus HN stalk region have been shown to affect both F activation and NA activities, but a structural basis for understanding these dual affects on HN functions has been lacking. Here, we report the structure of the Newcastle disease virus HN ectodomain, revealing dimers of NA domain dimers flanking the N-terminal stalk domain. The stalk forms a parallel tetrameric coiled-coil bundle (4HB) that allows classification of extensive mutational data, providing insight into the functional roles of the stalk region. Mutations that affect both F activation and NA activities map predominantly to the 4HB hydrophobic core, whereas mutations that affect only F-protein activation map primarily to the 4HB surface. Two of four NA domains interact with the 4HB stalk, and residues at this interface in both the stalk and NA domain have been implicated in HN function.
Long-range pseudoknot interactions dictate the regulatory response in the tetrahydrofolate riboswitch
Authors: Huang Lili , Ishibe-Murakami Satoko , Patel Dinshaw J. , Serganov Alexander
Published: August 2011

Tetrahydrofolate (THF), a biologically active form of the vitamin folate (B
9
), is an essential cofactor in one-carbon transfer reactions. In bacteria, expression of folate-related genes is controlled by feedback modulation in response to specific binding of THF and related compounds to a riboswitch. Here, we present the X-ray structures of the THF-sensing domain from the
Eubacterium siraeum
riboswitch in the ligand-bound and unbound states. The structure reveals an “inverted” three-way junctional architecture, most unusual for riboswitches, with the junction located far from the regulatory helix P1 and not directly participating in helix P1 formation. Instead, the three-way junction, stabilized by binding to the ligand, aligns the riboswitch stems for long-range tertiary pseudoknot interactions that contribute to the organization of helix P1 and therefore stipulate the regulatory response of the riboswitch. The pterin moiety of the ligand docks in a semiopen pocket adjacent to the junction, where it forms specific hydrogen bonds with two moderately conserved pyrimidines. The aminobenzoate moiety stacks on a guanine base, whereas the glutamate moiety does not appear to make strong interactions with the RNA. In contrast to other riboswitches, these findings demonstrate that the THF riboswitch uses a limited number of available determinants for ligand recognition. Given that modern antibiotics target folate metabolism, the THF riboswitch structure provides insights on mechanistic aspects of riboswitch function and may help in manipulating THF levels in pathogenic bacteria.
Prosody in spontaneous humor
Authors: Flamson Thomas , Bryant Gregory A. , Barrett H. Clark
Published: August 2011

The study of conversational humor has received relatively little empirical attention with almost no examinations of the role of vocal signals in spontaneous humor production. Here we report an analysis of spontaneous humorous speech in a rural Brazilian collective farm. The sample was collected over the course of ethnographic fieldwork in northeastern Brazil, and is drawn specifically from the monthly communal business meetings conducted in Portuguese. Our analyses focused on humorous utterances identified by the subsequent presence of laughter. Acoustic features of these utterances were compared to non-humorous utterances by the same speakers of similar length and immediately preceding them to look for prosodic contrasts. This corpus provided a unique opportunity for examining the way people mark their humorous productions in a non-humorous environment. Contrary to the notion that speakers must mark their production of humor in order to facilitate audience understanding, no significant marking of a joking “frame” was detected across a range of acoustic dimensions. The only consistent difference — that the set-up and punch line segments were louder than baseline speech before it — does not well support a marking hypothesis and more likely reflects speaker adjustments to the acoustic conditions of the meeting hall. We present these data from the perspective of the encryption theory of humor that predicts speakers will not generally mark spontaneous, conversational humor in most contexts.
Extracellular ATP acts on P2Y2 purinergic receptors to facilitate HIV-1 infection
Authors: Séror Claire , Melki Marie-Thérèse , Subra Frédéric , Raza Syed Qasim , Bras Marlène , Saïdi Héla , Nardacci Roberta , Voisin Laurent , Paoletti Audrey , Law Frédéric , Martins Isabelle , Amendola Alessandra , Abdul-Sater Ali A. , Ciccosanti Fabiola , Delelis Olivier , Niedergang Florence , Thierry Sylvain , Said-Sadier Najwane , Lamaze Christophe , Métivier Didier , Estaquier Jérome , Fimia Gian Maria , Falasca Laura , Casetti Rita , Modjtahedi Nazanine , Kanellopoulos Jean , Mouscadet Jean-François , Ojcius David M. , Piacentini Mauro , Gougeon Marie-Lise , Kroemer Guido , Perfettini Jean-Luc
Published: August 2011

Extracellular adenosine triphosphate (ATP) can activate purinergic receptors of the plasma membrane and modulate multiple cellular functions. We report that ATP is released from HIV-1 target cells through pannexin-1 channels upon interaction between the HIV-1 envelope protein and specific target cell receptors. Extracellular ATP then acts on purinergic receptors, including P2Y2, to activate proline-rich tyrosine kinase 2 (Pyk2) kinase and transient plasma membrane depolarization, which in turn stimulate fusion between Env-expressing membranes and membranes containing CD4 plus appropriate chemokine co-receptors. Inhibition of any of the constituents of this cascade (pannexin-1, ATP, P2Y2, and Pyk2) impairs the replication of HIV-1 mutant viruses that are resistant to conventional antiretroviral agents. Altogether, our results reveal a novel signaling pathway involved in the early steps of HIV-1 infection that may be targeted with new therapeutic approaches.
A retinoic acid–dependent checkpoint in the development of CD4+ T cell–mediated immunity
Authors: Pino-Lagos Karina , Guo Yanxia , Brown Chrysothemis , Alexander Matthew P. , Elgueta Raúl , Bennett Kathryn A. , De Vries Victor , Nowak Elizabeth , Blomhoff Rune , Sockanathan Shanthini , Chandraratna Roshantha A. , Dmitrovsky Ethan , Noelle Randolph J.
Published: August 2011

It is known that vitamin A and its metabolite, retinoic acid (RA), are essential for host defense. However, the mechanisms for how RA controls inflammation are incompletely understood. The findings presented in this study show that RA signaling occurs concurrent with the development of inflammation. In models of vaccination and allogeneic graft rejection, whole body imaging reveals that RA signaling is temporally and spatially restricted to the site of inflammation. Conditional ablation of RA signaling in T cells significantly interferes with CD4+ T cell effector function, migration, and polarity. These findings provide a new perspective of the role of RA as a mediator directly controlling CD4+ T cell differentiation and immunity.
CD103+ pulmonary dendritic cells preferentially acquire and present apoptotic cell–associated antigen
Authors: Desch A. Nicole , Randolph Gwendalyn J. , Murphy Kenneth , Gautier Emmanuel L. , Kedl Ross M. , Lahoud Mireille H. , Caminschi Irina , Shortman Ken , Henson Peter M. , Jakubzick Claudia V.
Published: August 2011

Cells undergoing programmed cell death (apoptosis) are removed in situ by macrophages and dendritic cells (DCs) through a specialized form of phagocytosis (efferocytosis). In the lung, there are two primary DC subsets with the potential to migrate to the local lymph nodes (LNs) and initiate adaptive immune responses. In this study, we show that only CD103+ DCs were able to acquire and transport apoptotic cells to the draining LNs and cross present apoptotic cell–associated antigen to CD8 T cells. In contrast, both the CD11bhi and the CD103+ DCs were able to ingest and traffic latex beads or soluble antigen. CD103+ DCs selectively exhibited high expression of TLR3, and ligation of this receptor led to enhanced in vivo cytotoxic T cell responses to apoptotic cell–associated antigen. The selective role for CD103+ DCs was confirmed in Batf3−/− mice, which lack this DC subtype. Our findings suggest that CD103+ DCs are the DC subset in the lung that captures and presents apoptotic cell–associated antigen under homeostatic and inflammatory conditions and raise the possibility for more focused immunological targeting to CD8 T cell responses.
The Proliferation of Brands: The Case of Food in Belgium, 1890-1940
Authors: Eeckhout Patricia Van Den , Scholliers Peter
Published: August 2011

Nowadays, brands are inescapable. Economists and marketing experts trace this pervasive presence back to the 1980s when brands and branding seemed to promise new, crucial assets for both producers and consumers. Of course, brands existed much earlier, and although some authors claim that “brands are as old as known civilization,” most researchers accept that they burgeoned with the coming of large consumer-goods–oriented factories in the 1870s, generating the “first golden era for the modern brand mark” in the 1890s. The recent success of brands has stimulated historians' attention to product variety, advertisements, brand management, firms' and products' reputations, consumer loyalty, the significance of brands, and much more.
Religion, Human Relations, and Union Avoidance in the 1950s: The Electrical Industry's Southern Strategy and Its Limits
Authors: Fones-Wolf Elizabeth , Fones-Wolf Ken
Published: August 2011

Historians have become increasingly aware of how religion dovetailed with businessmen's goals of promoting free-enterprise ideologies and creating an anti-statist and anti-union political culture. But business expected more from religion; many employers believed that emphasizing spirituality could help them win community support and worker loyalty and avoid unions. When the electrical manufacturing industry began to move South after World War II, key employers had already witnessed the role that religion played in helping defeat the CIO's Southern Organizing Campaign. However, they balked at borrowing the overtly racist and reactionary evangelicalism that southern employers had effectively used. Instead, they looked for a more moderate religious model that would blend with their growing interest in human relations. They found it in Reverend George Heaton, an ordained Southern Baptist minister who had begun counseling employers during the 1930s. Heaton emphasized the sacred imperative driving good human relations and rejected the “fetish” of collective bargaining that he believed robbed individual freedom and the personal relationships that created harmonious workplace communities. As GE, Westinghouse, Magnavox, and Singer moved to the South, they all hired Heaton to be “minister” to their employees. This strategy had its limits, however, as this article will demonstrate using case studies of organizing drives in Rome, Georgia, and Greeneville, Tennessee. Nevertheless, Heaton was an important and understudied bridge between earlier paternalistic uses of religion and more modern Christian human relations.
Complete Duplication of Collecting System in a Horseshoe Kidney Presenting with Recurrent Urinary Tract Infections: Report of an Exceedingly Rare Congenital Anomaly and Review of Literature
Authors: Mirzazadeh Majid , Richards Kyle A.
Published: August 2011

We report the fifth case in the English literature of a horseshoe kidney with a complete ureteral duplication. Our case is unique in that the previous four cases occurred in the presence of a ureterocele, whereas our patient lacked this anomaly. Further, our patient was managed conservatively, whereas the previous four patients were managed with surgery.
The effects of hyperosmosis or high pH on a dual‐species biofilm of Enterococcus faecalis and Pseudomonas aeruginosa: an in vitro study
Authors: van der Waal S. V. , van der Sluis L. W. M. , Özok A. R. , Exterkate R. A. M. , van Marle J. , Wesselink P. R. , de Soet J. J.
Published: August 2011

van der Waal SV, van der Sluis LWM, Özok AR, Exterkate RAM, van Marle J, Wesselink PR, de Soet JJ. The effects of hyperosmosis or high pH on a dual‐species biofilm of Enterococcus faecalis and Pseudomonas aeruginosa: an in vitro study. International Endodontic Journal, 44, 1110–1117, 2011.

Aim  To investigate the effect of hyperosmotic hyperosmosis or alkaline stress on a dual‐species biofilm of Enterococcus faecalis and Pseudomonas aeruginosa.

Methodology  Biofilms were grown on glass cover slips suspended in bacterial inoculate for 96 h, after which the cover slips with attached biofilms were immersed in brain heart infusion broth (BHI‐broth) with 6 mol L−1 sodium chloride (NaCl) representing the hyperosmotic group or Ca(OH)2, pH 12.1, representing the alkaline group. Two per cent sodium hypochlorite and BHI‐ broth served as positive and negative controls, respectively. After treatment, the biofilms were washed, harvested and plated on blood‐agar plates after serial dilution. The bactericidal effect was assessed by determining the colony‐forming units (CFU). The effect on the biofilm mass was imaged with confocal laser scanning microscopy (CLSM).

Results  Hyperosmosis reduced the CFU of both species significantly after 72 h (P < 0.0001). After 168 h, P. aeruginosa was eradicated and the E. faecalis reduction was more than 99%. High pH could not induce a significant bacterial reduction. CLSM revealed dense flocculation of the biofilms incubated in alkaline broth.

Conclusion  Hyperosmosis effectively reduced a dual‐species biofilm of E. faecalis and P. aeruginosa, whilst high pH had limited bactericidal effect in this model.
Evaluation of trace elements, calcium, and magnesium levels in the plasma and erythrocytes of patients with essential hyperhidrosis
Authors: Güder Hüsna , Karaca Şemsettin , Cemek Mustafa , Kulaç Mustafa , Güder Semih
Published: August 2011

Background  Essential hyperhidrosis is a disease that expresses itself with excessive sweating in palmar, plantar, axillary, and craniofacial regions. The etiopathogenesis of the disease, which has particular importance because of leading to psychosocial morbidity, could have not been completely elucidated. In previous studies, it has been shown that oxidative stress might play a role in the pathogenesis.

Aims  Assessing the levels of trace elements such as Se, Zn, Cu, Fe, and Mg that have an important role in oxidative stress, as well as Ca and Mg that have an important role in membrane physiology, in patients with essential hyperhidrosis.

Materials and methods  Blood samples taken from the patient group with essential hyperhidrosis (42) and the control group (37) were separated into plasma and erythrocytes, and the levels of the bioelements were measured by use of ICP‐OES device.

Results  Erythrocyte levels of Se, Fe, Cu, Zn, Ca, and Mg were detected significantly higher in patients with essential hyperhidrosis. Furthermore, plasma levels of Cu, Ca, and Mg were significantly lower in patients with essential hyperhidrosis. Plasma levels of Se, Fe, and Zn showed no statistical difference between two groups.

Dicussion  It was thought that the high levels of Cu and Fe in erythrocytes may play a role in increased intracellular oxidative stress, whereas the increase in Se and Zn levels may be secondary to increased oxidative stress. Low extracellular concentrations of Ca and Mg raise the thought that they play a role either enhancing the membrane excitability of eccrine sweat glands or influencing the autonomic nerve system.

Conclusion  The levels of trace elements, which were determined to be different from the control group, may play a role in the pathogenesis of essential hyperhidrosis either in direct relation with or without oxidative mechanisms.
Cutaneous simulants of infectious disease
Authors: Ricketts Janelle R. , Rothe Marti J. , Grant‐Kels Jane M.
Published: August 2011

Many cutaneous conditions can mimic infection. If these lesions are not accurately recognized, they may be treated with antimicrobial agents, which adds cost, potential risk, and inconvenience to the patient and the healthcare system. The presenting signs and symptoms of many ulcerating, pustular, morbilliform, bullous, neoplastic, granulomatous, autoimmune, and neutrophilic conditions, as well as clinical vasculitis, cellulitis, folliculitis, and panniculitis, have been mistaken for infection. This review emphasizes the clinical presentation, physical exam, and diagnostic workup of many of these conditions to assist the clinician in ascertaining the correct diagnosis. In addition, general treatment options are provided for each disease category.
Developmental underpinnings of differences in rodent novelty‐seeking and emotional reactivity
Authors: Clinton Sarah M. , Stead John D. H. , Miller Sue , Watson Stanley J. , Akil Huda
Published: August 2011

Innate differences in human temperament strongly influence how individuals cope with stress and also predispose towards specific types of psychopathology. The present study examines the developing brain in an animal model of temperamental differences to examine how altered neurodevelopment may engender differences in emotional reactivity that are stable throughout the animal’s life. We utilize selectively‐bred High Responder (bHR) and Low Responder (bLR) rats that exhibit dramatic emotional behavior differences, with bHRs exhibiting exaggerated novelty‐exploration, aggression, impulsivity and drug self‐administration, and bLRs showing marked behavioral inhibition and exaggerated anxiety‐like and depressive‐like behavior. Using Affymetrix microarrays, we assessed bLR and bHR gene expression in the developing brain on postnatal days (P)7, 14 and 21, focusing on the hippocampus and nucleus accumbens, two regions related to emotionality and known to differ in adult bLR and bHR rats. We found dramatic gene expression differences between bLR and bHR in the P7 and P14 hippocampus, with minimal differences in the nucleus accumbens. Some of the most profound differences involved genes critical for neurodevelopment and synaptogenesis. Stereological studies evaluated hippocampal structure in developing bHR and bLR pups, revealing enhanced hippocampal volume and cell proliferation in bLR animals. Finally, behavioral studies showed that the characteristic bHR and bLR behavioral phenotypes emerge very early in life, with exploratory differences apparent at P16 and anxiety differences present by P25. Together these data point to specific brain regions and critical periods when the bHR and bLR phenotypes begin to diverge, which may eventually allow us to test possible therapeutic interventions to normalize extreme phenotypes (e.g. the anxiety‐prone nature of bLRs or drug addiction proclivity of bHRs).
A Method of Accelerating Transport Simulation When Groundwater Pumping Is Simulated
Authors: Zhang Jim , Randall Glenn , Wei Xinyu
Published: August 2011

In solving groundwater transport problems with numerical models, the computation time (CPU processing time) of transport simulation is approximately inversely proportional to the transport time‐step size. Therefore, large time‐step sizes are favorable for achieving short computation time. However, transport time‐step size must be sufficiently small to avoid numerical instability if an explicit scheme is used (and to guarantee enough model accuracy if an implicit scheme is used). For a transport model involving groundwater pumping, a small transport time‐step size is often required due to the high groundwater velocities near the pumping well. Small grid spacing often specified near the pumping well also limits the time‐step size. This paper presents a method to increase transport time‐step size in a transport model when groundwater pumping is simulated. The key to this approach is to numerically decrease the groundwater seepage velocities in grid cells near the pumping well by increasing the effective porosity so that the transport time‐step size can be increased without violating stability constraints. Numerical tests reveal that by using the proposed method, the computation time of transport simulation can be reduced significantly, while the transport simulation results change very little.
Potentially pathogenic free‐living amoebae (FLA) isolated in Spanish wastewater treatment plants
Authors: García A. , Goñi P. , Clavel A. , Lobez S. , Fernandez M. T. , Ormad M. P.
Published: August 2011

This work studies the characterization of pathogenic free‐living amoebae (FLA) from sewage effluents. Some of them, such as Acanthamoeba, Naegleria, Hartmannella, Sappinia, Balamuthia and Paravahlkampfia have been reported as a cause of diseases in humans. Therefore, the study of their habitats and their pathogenicity has become necessary. The population of potentially pathogenic FLA was analysed in five Spanish wastewater treatment plants. Five of the seven FLA isolated were identified as genus Acanthamoeba genotypes T3, T4, T7 and T9. Hartmannella and Naegleria were also isolated. Acanthamoeba demonstrated great thermotolerance and osmotolerance. It was also observed that treatment with sodium hypochlorite showed no significative reduction in the number of amoeba at concentrations of 0–100 ppm. The high resistance of FLA cysts to disinfection methods is a trojan horse for public health insofar as they colonize water systems and allow the survival of intracellular microorganisms resistant to FLA. The results of this work advance current knowledge of the FLA population.
Sex and ageing differences in resting arterial pressure regulation: the role of the β‐adrenergic receptors
Authors: Hart Emma C. , Charkoudian Nisha , Wallin B. Gunnar , Curry Timothy B. , Eisenach John , Joyner Michael J.
Published: August 2011

Non‐Technical Summary  In young men, sympathetic nerve activity is directly related to the level of vasoconstrictor tone in the peripheral vasculature. However, in young women this relationship does not exist, suggesting that certain factors (potentially related to the female sex hormones) offset the transfer of sympathetic nerve activity into vasoconstrictor tone in this population. In the present study we show that, in young women, the β‐adrenergic receptors (which cause vasodilatation in response to noradrenaline) blunt the vasoconstrictor effect of resting sympathetic nerve activity in young women. This mechanism does not occur in young men or postmenopausal women. It is possible that the β‐adrenergic receptors may partially protect young women against the sometimes harmful effects of high sympathetic nerve activity. This may explain why the risk of developing hypertension is greater in young men and postmenopausal women (who have very high sympathetic nerve activity) compared to young women.
SLW-1 Modeling of Radiative Heat Transfer in Nonisothermal Nonhomogeneous Gas Mixtures With Soot
Authors: Solovjov Vladimir P. , Lemonnier Denis , Webb Brent W.
Published: August 2011

The spectral line weighted-sum-of-gray-gases (SLW) model consisting only of a single gray gas and of one clear gas is developed as an efficient spectral method for modeling radiation transfer in gaseous medium. The model is applied here in prediction of radiative transfer in nonisothermal and nonhomogeneous gas mixtures with nongray soot. The absorption spectrum of the gas mixture and soot particles is treated as a spectrum of a single effective gas, reducing the problem to the simplest case of the SLW model with a single gray gas and a clear gas. Good accuracy can be achieved by the optimal choice of the model’s gray gas absorption coefficient and its weight by application of the absorption-line blackbody distribution functions of individual species in the mixture calculated with a high-resolution spectral database. The SLW-1 model is validated by comparison with benchmark solutions using the line-by-line method, the SLW method with a large number of gray gases, and the SNB model.
Nucleate Pool Boiling Heat Transfer Measurement and Flow Visualization for Ammonia-Water Mixture
Authors: Sathyabhama A. , Ashok Babu T. P.
Published: August 2011

Visualization of bubble nucleation during nucleate pool boiling outside a vertical cylindrical heated surface was done for ammonia-water binary mixture in order to obtain a descriptive behavior of the boiling, which was directly compared with the measured heat transfer coefficient data at low pressure of 4–8 bar and at low mass fraction of 0 < x < 0.3 and at different heat flux. Still images taken with high speed camera are used to demonstrate the decrease in boiling heat transfer coefficient with increase in ammonia mass fraction. Jensen and Memmel model has better agreement with experimental bubble diameter. Further work is required to obtain quantitative information about bubble nucleation parameters. It is found that both Calus and Rice and Stephan–Koorner correlation can predict the experimental heat transfer coefficient values with a maximum deviation of ± 20%.
Gait Phase-Based Control for a Rotary Series Elastic Actuator Assisting the Knee Joint
Authors: Bae Joonbum , Kong Kyoungchul , Tomizuka Masayoshi
Published: August 2011

Actuators for physical human-robot interaction (pHRI) such as rehabilitation or assistive systems should generate the desired torque precisely. However, the resistive and inertia loads inherent in the actuators (e.g., friction, damping, and inertia) set challenges in the control of actuators in a force/torque mode. The resistive factors include nonlinear effects and should be considered in the controller design to generate the desired force accurately. Moreover, the uncertainties in the plant dynamics make the precise torque control difficult. In this paper, nonlinear control algorithms are exploited for a rotary series elastic actuator to generate the desired torque precisely in the presence of nonlinear resistive factors and modeling uncertainty. The sliding mode control smoothed by a boundary layer is applied to enhance the robustness for the modeling uncertainty without chattering phenomenon. In this paper, the rotary series elastic actuator (RSEA) is installed on the knee joint of an orthosis, and the thickness of the boundary layer is changed by gait phases in order to minimize the torque error without the chattering phenomenon. The performance of the proposed controller is verified by experiments with actual walking motions.
Measuring radon concentration in air using a diffusion cloud chamber
Authors: Cases R. , Ros E. , Zúñiga J.
Published: August 2011

Radon concentration in air is a major concern in lung cancer studies. A traditional technique used to measure radon abundance is the charcoal canister method. We propose a novel technique using a diffusion cloud chamber. This technique is simpler and can easily be used for physics demonstrations for high school and university students.
Using plasma experiments to illustrate a complex index of refraction
Authors: Gekelman W. , Pribyl P. , Wise J. , Lee A. , Hwang R. , Eghtebas C. , Shin J. , Baker B.
Published: August 2011

The index of refraction for the propagation of a wave in a plasma depends on the plasma density, background magnetic field, and frequency of the wave. The study of plasma wave propagation is an excellent tool for teaching students the subtleties involved in a complex media rather than in glass or water where the index of refraction is close to a constant. Whistler waves were launched and detected in a plasma physics laboratory at UCLA devoted to involving high school students and teachers. The magnetic field of the wave was measured in space and time and the wavenumbers at a variety of frequencies were determined. The index of refraction predicted by Appleton’s equation was used to reconstruct the two-dimensional phase fronts and compared to the laboratory data with excellent agreement. The experimental techniques are discussed in conjunction with their use as an educational tool.
The puzzling reliability of the Force Concept Inventory
Authors: Lasry Nathaniel , Rosenfield Steven , Dedic Helena , Dahan Ariel , Reshef Orad
Published: August 2011

The Force Concept Inventory (FCI) has influenced the development of many research-based pedagogies. However, no data exists on the FCI’s internal consistency or test-retest reliability. The FCI was administered twice to one hundred students during the first week of classes in an electricity and magnetism course with no review of mechanics between test administrations. High Kuder–Richardson reliability coefficient values, which estimate the average correlation of scores obtained on all possible halves of the test, suggest strong internal consistency. However, 31% of the responses changed from test to retest, suggesting weak reliability for individual questions. A chi-square analysis shows that change in responses was neither consistent nor completely random. The puzzling conclusion is that although individual FCI responses are not reliable, the FCI total score is highly reliable.
Classical Yang-Mills theory
Authors: Boozer A. D.
Published: August 2011

We consider classical Yang-Mills theory with point sources and derive equations of motion for the coupled particle-field system. As an example, we discuss the special case of Yang-Mills theory coupled to point particles in (1 + 1) dimensions. We formulate the initial value problem for the system and describe several example solutions.
Science Signaling
Podcast: 23 August 2011
Authors: Mansvelder Huibert D. , VanHook Annalisa M.
Published: August 2011

β2 subunit–containing nicotinic acetylcholine receptors in the prefrontal cortex are sufficient for acetylcholine-mediated enhancement of attentional focus.
Targeting Notch to Prevent Insulin Resistance
Authors: Foley John F.
Published: August 2011

Notch proteins drive hepatic glucose production in a FoxO1-dependent manner.
Death by Acetylation
Authors: Gough Nancy R.
Published: August 2011

Reduction in acetyl-CoA and protein N-acetylation is one mechanism by which Bcl-xL exerts its antiapoptotic effect.
Making Better Antibodies Through Inhibition
Authors: Mueller Kristen L.
Published: August 2011

Engagement of an inhibitory receptor improves the antitumor efficacy of a monoclonal antibody.
CD36 Goes Line Dancing
Authors: Gough Nancy R.
Published: August 2011

Single-particle tracking suggests that some of the surface receptor CD36 is confined in elongated linear domains that promote receptor clustering and signaling.
Carbapenems: Past, Present, and Future
Authors: Papp-Wallace Krisztina M. , Endimiani Andrea , Taracila Magdalena A. , Bonomo Robert A.
Published: August 2011

In this review, we summarize the current “state of the art” of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the β-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most β-lactamases, in some cases act as “slow substrates” or inhibitors of β-lactamases, and still target penicillin binding proteins. This “value-added feature” of inhibiting β-lactamases serves as a major rationale for expansion of this class of β-lactams. We describe the initial discovery and development of the carbapenem family of β-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.
Efficacy of NZ2114, a Novel Plectasin-Derived Cationic Antimicrobial Peptide Antibiotic, in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus
Authors: Xiong Yan Q. , Hady Wessam Abdel , Deslandes Antoine , Rey Astrid , Fraisse Laurent , Kristensen Hans-Henrik , Yeaman Michael R. , Bayer Arnold S.
Published: August 2011

Cationic antimicrobial peptides (CAPs) play important roles in host immune defenses. Plectasin is a defensin-like CAP isolated from the saprophytic fungusPseudoplectania nigrella. NZ2114 is a novel variant of plectasin with potent activity against Gram-positive bacteria. In this study, we investigated (i) thein vivopharmacokinetic and pharmacodynamic (PK/PD) characteristics of NZ2114 and (ii) thein vivoefficacy of NZ2114 in comparison with those of two conventional antibiotics, vancomycin or daptomycin, in an experimental rabbit infective endocarditis (IE) model due to a methicillin-resistantStaphylococcus aureus(MRSA) strain (ATCC 33591). All NZ2114 regimens (5, 10, and 20 mg/kg of body weight, intravenously [i.v.], twice daily for 3 days) significantly decreased MRSA densities in cardiac vegetations, kidneys, and spleen versus those in untreated controls, except in one scenario (5 mg/kg, splenic MRSA counts). The efficacy of NZ2114 was clearly dose dependent in all target tissues. At 20 mg/kg, NZ2114 showed a significantly greater efficacy than vancomycin (P< 0.001) and an efficacy similar to that of daptomycin. Of importance, only NZ2114 (in 10- and 20-mg/kg regimens) prevented posttherapy relapse in cardiac vegetations, kidneys, and spleen, while bacterial counts in these target tissues continued to increase in vancomycin- and daptomycin-treated animals. Thesein vivoefficacies were equivalent and significantly correlated with three PK indices investigated:fCmax/MIC (the maximum concentration of the free, unbound fraction of a drug in serum divided by the MIC),fAUC/MIC (where AUC is the area under the concentration-time curve), andf%T>MIC(%T>MICis the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions), as analyzed by a sigmoid maximum-effect (Emax) model (R2> 0.69). The superior efficacy of NZ2114 in this MRSA IE model suggests the potential for further development of this compound for treating serious MRSA infections.
Genetic Features of
bla
NDM-1
-Positive Enterobacteriaceae
Authors: Poirel Laurent , Dortet Laurent , Bernabeu Sandrine , Nordmann Patrice
Published: August 2011

Genetic features associated with the
bla
NDM-1
gene were investigated in 6
Escherichia coli
, 7
Klebsiella pneumoniae
, 1
Citrobacter freundii
, 1
Proteus mirabilis
, and 1
Providencia stuartii
isolate of worldwide origin. Clonal diversity was observed for both
E. coli
and
K. pneumoniae
. The
bla
NDM-1
gene was carried by different plasmid types (IncA/C, IncF, IncL/M, or untypeable) and was likely chromosome borne in two isolates. The
bla
NDM-1
plasmids coharbored a variety of resistance determinants, including β-lactamase genes, quinolone resistance genes, and 16S RNA methylase genes.
Dynamics of Mutator and Antibiotic-Resistant Populations in a Pharmacokinetic/Pharmacodynamic Model of Pseudomonas aeruginosa Biofilm Treatment
Authors: Macià María D. , Pérez José L. , Molin Soeren , Oliver Antonio
Published: August 2011

Biofilm growth, antibiotic resistance, and mutator phenotypes are key components of chronic respiratory infections by
Pseudomonas aeruginosa
in cystic fibrosis patients. We examined the dynamics of mutator and antibiotic-resistant populations in
P. aeruginosa
flow-cell biofilms, using fluorescently tagged PAO1 and PAOMS (mutator [
mutS
] derivative) strains. Two-day-old biofilms were treated with ciprofloxacin (CIP) for 4 days (t4) at 2 μg/ml, which correlated with the mutant prevention concentration (MPC) and provided an AUC/MIC ratio of 384 that should predict therapeutic success. Biofilms were monitored by confocal laser scanning microscopy (CLSM), and the numbers of viable cells and resistant mutants (4- and 16-fold MICs) were determined. Despite optimized pharmacokinetic/pharmacodynamic (PK/PD) parameters, CIP treatment did not suppress resistance development in
P. aeruginosa
biofilms. One-step resistant mutants (MexCD-OprJ or MexEF-OprN overexpression) were selected for both strains, while two-step resistant mutants (additional GyrA or GyrB mutation) were readily selected only from the mutator strain. CLSM analysis of competition experiments revealed that PAOMS, even when inoculated at a 0.01 proportion, took over the whole biofilm after only 2 days of CIP treatment outnumbering PAO1 by 3 log at t4. Our results show that mutational mechanisms play a major role in biofilm antibiotic resistance and that theoretically optimized PK/PD parameters fail to suppress resistance development, suggesting that the increased antibiotic tolerance driven by the special biofilm physiology and architecture may raise the effective MPC, favoring gradual mutational resistance development, especially in mutator strains. Moreover, the amplification of mutator populations under antibiotic treatment by coselection with resistance mutations is for the first time demonstrated
in situ
for
P. aeruginosa
biofilms.
Prior Caspofungin Exposure in Patients with Hematological Malignancies Is a Risk Factor for Subsequent Fungemia Due to Decreased Susceptibility in Candida spp.: a Case-Control Study in Paris, France
Authors: Blanchard Elodie , Lortholary Olivier , Boukris-Sitbon Karine , Desnos-Ollivier Marie , Dromer Françoise , Guillemot Didier ,   the French Mycosis Study Group
Published: August 2011

Infections due to caspofungin-resistant
Candida
isolates in patients exposed to caspofungin therapy are increasing. We report here a nested case-control study which aimed at identifying factors associated with bloodstream infections caused by
Candida
spp. having reduced susceptibility to caspofungin (CRSC) in adults suffering from hematological malignancies. In univariate and multivariate analyses, infections with CRSC were associated with caspofungin exposure in the previous 30 days (odds ratio [OR] = 5.25; 95% confidence interval [95% CI], 1.68–16.35) and with an age of ≤65 years (OR = 3.27; 95% CI, 1.26–8.50).