bluuebunny/crossref_metadata_2025_split huggingface dataset:
Currency Unions, Export Margins, and Product Differentiation: An Empirical Assessment for European Monetary Union
Authors: Badinger Harald , Türkcan Kemal 
Published: January 2014

AbstractThis paper reconsiders the trade effects of the euro, providing a decomposition into its effects on the extensive margin and intensive margin. Furthermore, it relates the more disaggregated estimates for 93 two‐digit HS product groups to the elasticity of substitution, thereby testing a key hypothesis of heterogenous firm trade theory. The estimates for the period 1996–2011 suggest a trade effect of the euro of some 28%, which has mainly materialized through the intensive margin. A negative net effect of the euro on the extensive margin is found for several product groups, supporting anecdotal evidence that firms have consolidated their product varieties in response to the elimination of exchange rate variability. Finally, the disaggregated estimates are in line with heterogenous firm trade theory models, suggesting that a large elasticity of substitution dampens the effect of a trade cost reduction on the extensive margin and amplifies its effect on the intensive margin.
Large deletions involving the regulatory upstream regions of A4GALT give rise to principally novel P1PK‐null alleles
Authors: Westman Julia S. , Hellberg Åsa , Peyrard Thierry , Thuresson Britt , Olsson Martin L. 
Published: January 2014

BackgroundCells of the clinically important p histo‐blood group phenotype lack P1, Pk, and P glycosphingolipid antigens. All cases investigated so far are due to alterations in the 4‐α‐galactosyltransferase‐encoding Exon 3 of A4GALT. Repetitive elements in the genome can mediate DNA rearrangements, the most abundant being the Alu family of repeats.Study Design and MethodsThe aim of this study was to determine the genetic basis of three p samples with intact A4GALT open reading frames, using long‐range polymerase chain reaction (PCR) and sequencing. In addition, transcript measurements were performed with quantitative PCR.ResultsThis is the first report of the p phenotype as the result of large deletions in A4GALT, comprising the proposed promoter and noncoding Exons 1 and 2a. The breakpoints were different in all three samples and revealed the presence of Alu or MIRb sequences directly flanking, or in close proximity to, all junctions. Furthermore, no A4GALT transcripts could be detected.ConclusionIn summary, our data elucidate a new explanation underlying the p phenotype, implicating the deleted regions of A4GALT as crucial for P1 and Pk synthesis, possibly due to loss of binding sites for erythroid transcription factors. Furthermore, analysis of these regions will improve genetic blood group prediction.
Ectopic release of glutamate contributes to spillover at parallel fibre synapses in the cerebellum
Authors: Balakrishnan Saju , Dobson Katharine L. , Jackson Claire , Bellamy Tomas C. 
Published: January 2014

Key points
Release of neurotransmitter can sometimes occur outside of the synaptic cleft, a process known as ectopic release.
Spillover of the excitatory transmitter glutamate between synapses occurs when parallel fibres in the cerebellum are stimulated at high frequencies.
We investigated the effect of activity‐dependent and pharmacological reduction of ectopic release on the time course of postsynaptic currents and found that the decay time is reduced, suggesting that ectopic release contributes to spillover at the synapses.
This finding suggests that ectopic transmission can cause activation of extrasynaptic receptors even at low frequencies, and so may play a significant role in synaptic plasticity.
The results help us understand how signalling in and around the synapse can alter network activity in the cerebellum, a brain region essential for fine motor coordination.
AbstractIn the rat cerebellar molecular layer, spillover of glutamate between parallel fibre synapses can lead to activation of perisynaptic receptors that mediate short‐ and long‐term plasticity. This effect is greatest when clusters of fibres are stimulated at high frequencies, suggesting that glutamate clearance mechanisms must be overwhelmed before spillover can occur. However, parallel fibres can also release transmitter directly into the extracellular space, from ‘ectopic’ release sites. Ectopic transmission activates AMPA receptors on the Bergmann glial cell processes that envelop parallel fibre synapses, but the possible contribution of this extrasynaptic release to intersynaptic communication has not been explored. We exploited long‐term depression of ectopic transmission, and selective pharmacology, to investigate the impact of these release sites on the time course of Purkinje neuron excitatory postsynaptic currents (EPSCs). Depletion of ectopic release pools by activity‐dependent long‐term depression decreased EPSC decay time, revealing a ‘late’ current that is present when fibres are stimulated at low frequencies. This effect was enhanced when glutamate transporters were inhibited, and reduced when extracellular diffusion was impeded. Blockade of N‐type Ca2+ channels inhibited ectopic transmission to Bergmann glia and decreased EPSC decay time. Similarly, perfusion of the Ca2+ chelator EGTA‐AM into the slice progressively eliminated ectopic transmission to glia and decreased EPSC decay time with closely similar time courses. Collectively, this evidence suggests that ectopically released glutamate contributes to spillover transmission, and that ectopic release therefore degrades the spatial precision of synapses that fire infrequently, and may make them more prone to exhibit plasticity.
Acoustical Standards News
Authors: Blaeser Susan B. , Schomer Paul D. 
Published: January 2014

American National Standards (ANSI Standards) developed by Accredited Standards Committees S1, S2, S3, and S12 in the areas of acoustics, mechanical vibration and shock, bioacoustics, and noise, respectively, are published by the Acoustical Society of America (ASA). In addition to these standards, ASA publishes catalogs of Acoustical Standards, both National and International. To receive copies of the latest Standards catalogs, please contact Susan B. Blaeser.
Comments are welcomed on all material in Acoustical Standards News.
This Acoustical Standards News section in JASA, as well as the National and International Catalogs of Acoustical Standards, and other information on the Standards Program of the Acoustical Society of America, are available via the ASA home page: http://acousticalsociety.org.
Rapid Conversion of Pseudomonas aeruginosa to a Spherical Cell Morphotype Facilitates Tolerance to Carbapenems and Penicillins but Increases Susceptibility to Antimicrobial Peptides
Authors: Monahan Leigh G. , Turnbull Lynne , Osvath Sarah R. , Birch Debra , Charles Ian G. , Whitchurch Cynthia B. 
Published: January 2014

ABSTRACT

The Gram-negative human pathogen
Pseudomonas aeruginosa
tolerates high concentrations of β-lactam antibiotics. Despite inhibiting the growth of the organism, these cell wall-targeting drugs exhibit remarkably little bactericidal activity. However, the mechanisms underlying β-lactam tolerance are currently unclear. Here, we show that
P. aeruginosa
undergoes a rapid
en masse
transition from normal rod-shaped cells to viable cell wall-defective spherical cells when treated with β-lactams from the widely used carbapenem and penicillin classes. When the antibiotic is removed, the entire population of spherical cells quickly converts back to the normal bacillary form. Our results demonstrate that these rapid population-wide cell morphotype transitions function as a strategy to survive antibiotic exposure. Taking advantage of these findings, we have developed a novel approach to efficiently kill
P. aeruginosa
by using carbapenem treatment to induce
en masse
transition to the spherical cell morphotype and then exploiting the relative fragility and sensitivity of these cells to killing by antimicrobial peptides (AMPs) that are relatively inactive against
P. aeruginosa
bacillary cells. This approach could broaden the repertoire of antimicrobial compounds used to treat
P. aeruginosa
and serve as a basis for developing new therapeutic agents to combat bacterial infections.
Molecular Basis for the Differential Quinolone Susceptibility of Mycobacterial DNA Gyrase
Authors: Kumar Rupesh , Madhumathi Bhavani Shankar , Nagaraja Valakunja 
Published: January 2014

ABSTRACT

DNA gyrase is a type II topoisomerase that catalyzes the introduction of negative supercoils in the genomes of eubacteria. Fluoroquinolones (FQs), successful as drugs clinically, target the enzyme to trap the gyrase-DNA complex, leading to the accumulation of double-strand breaks in the genome. Mycobacteria are less susceptible to commonly used FQs. However, an 8-methoxy-substituted FQ, moxifloxacin (MFX), is a potent antimycobacterial, and a higher susceptibility of mycobacterial gyrase to MFX has been demonstrated. Although several models explain the mechanism of FQ action and gyrase-DNA-FQ interaction, the basis for the differential susceptibility of mycobacterial gyrase to various FQs is not understood. We have addressed the basis of the differential susceptibility of the gyrase and revisited the mode of action of FQs. We demonstrate that FQs bind both
Escherichia coli
and
Mycobacterium tuberculosis
gyrases in the absence of DNA and that the addition of DNA enhances the drug binding. The FQs bind primarily to the GyrA subunit of mycobacterial gyrase, while in
E. coli
holoenzyme is the target. The binding of MFX to GyrA of
M. tuberculosis
correlates with its effectiveness as a better inhibitor of the enzyme and its efficacy in cell killing.
Metabolism and Pharmacokinetics of the Anti-Hepatitis C Virus Nucleotide Prodrug GS-6620
Authors: Murakami Eisuke , Wang Ting , Babusis Darius , Lepist Eve-Irene , Sauer Dorothea , Park Yeojin , Vela Jennifer E. , Shih Robert , Birkus Gabriel , Stefanidis Dimitrios , Kim Choung U. , Cho Aesop , Ray Adrian S. 
Published: January 2014

ABSTRACT

The anti-hepatitis C virus nucleotide prodrug GS-6620 employs a double-prodrug approach, with
l
-alanine-isopropyl ester and phenol moieties attached to the 5′-phosphate that release the nucleoside monophosphate in hepatocytes and a 3′-isobutyryl ester added to improve permeability and oral bioavailability. Consistent with the stability found in intestinal homogenates, following oral administration, intact prodrug levels in blood plasma were the highest in dogs, followed by monkeys, and then were the lowest in hamsters. In contrast, liver levels of the triphosphate metabolite at the equivalent surface area-adjusted doses were highest in hamsters, followed by in dogs and monkeys. Studies in isolated primary hepatocytes suggest that relatively poor oral absorption in hamsters and monkeys was compensated for by relatively efficient hepatocyte activation. As intestinal absorption was found to be critical to the effectiveness of GS-6620 in nonclinical species, stomach pH, formulation, and food effect studies were completed in dogs. Consistent with
in vitro
absorption studies in Caco-2 cells, the absorption of GS-6620 was found to be complex and highly dependent on concentration. Higher rates of metabolism were observed at lower concentrations that were unable to saturate intestinal efflux transporters. In first-in-human clinical trials, the oral administration of GS-6620 resulted in poor plasma exposure relative to that observed in dogs and in large pharmacokinetic and pharmacodynamic variabilities. While a double-prodrug approach, including a 3′-isobutyryl ester, provided higher intrinsic intestinal permeability, this substitution appeared to be a metabolic liability, resulting in extensive intestinal metabolism and relatively poor oral absorption in humans.
Inhibition of Hepatitis C Virus Replication by GS-6620, a Potent
C
-Nucleoside Monophosphate Prodrug
Authors: Feng Joy Y. , Cheng Guofeng , Perry Jason , Barauskas Ona , Xu Yili , Fenaux Martijn , Eng Stacey , Tirunagari Neeraj , Peng Betty , Yu Mei , Tian Yang , Lee Yu-Jen , Stepan George , Lagpacan Leanna L. , Jin Debi , Hung Magdeleine , Ku Karin S. , Han Bin , Kitrinos Kathryn , Perron Michel , Birkus Gabriel , Wong Kelly A. , Zhong Weidong , Kim Choung U. , Carey Anne , Cho Aesop , Ray Adrian S. 
Published: January 2014

ABSTRACT

As a class, nucleotide inhibitors (NIs) of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase offer advantages over other direct-acting antivirals, including properties, such as pangenotype activity, a high barrier to resistance, and reduced potential for drug-drug interactions. We studied the
in vitro
pharmacology of a novel
C
-nucleoside adenosine analog monophosphate prodrug, GS-6620. It was found to be a potent and selective HCV inhibitor against HCV replicons of genotypes 1 to 6 and against an infectious genotype 2a virus (50% effective concentration [EC
50
], 0.048 to 0.68 μM). GS-6620 showed limited activities against other viruses, maintaining only some of its activity against the closely related bovine viral diarrhea virus (EC
50
, 1.5 μM). The active 5′-triphosphate metabolite of GS-6620 is a chain terminator of viral RNA synthesis and a competitive inhibitor of NS5B-catalyzed ATP incorporation, with

K
i

/

K
m

values of 0.23 and 0.18 for HCV NS5B genotypes 1b and 2a, respectively. With its unique dual substitutions of 1′-CN and 2′-
C
-Me on the ribose ring, the active triphosphate metabolite was found to have enhanced selectivity for the HCV NS5B polymerase over host RNA polymerases. GS-6620 demonstrated a high barrier to resistance
in vitro
. Prolonged passaging resulted in the selection of the S282T mutation in NS5B that was found to be resistant in both cellular and enzymatic assays (>30-fold). Consistent with its
in vitro
profile, GS-6620 exhibited the potential for potent anti-HCV activity in a proof-of-concept clinical trial, but its utility was limited by the requirement of high dose levels and pharmacokinetic and pharmacodynamic variability.
Multilaboratory Study of Epidemiological Cutoff Values for Detection of Resistance in Eight Candida Species to Fluconazole, Posaconazole, and Voriconazole
Authors: Espinel-Ingroff A. , Pfaller M. A. , Bustamante B. , Canton E. , Fothergill A. , Fuller J. , Gonzalez G. M. , Lass-Flörl C. , Lockhart S. R. , Martin-Mazuelos E. , Meis J. F. , Melhem M. S. C. , Ostrosky-Zeichner L. , Pelaez T. , Szeszs M. W. , St-Germain G. , Bonfietti L. X. , Guarro J. , Turnidge J. 
Published: January 2014

ABSTRACTAlthough epidemiological cutoff values (ECVs) have been established forCandidaspp. and the triazoles, they are based on MIC data from a single laboratory. We have established ECVs for eightCandidaspecies and fluconazole, posaconazole, and voriconazole based on wild-type (WT) MIC distributions for isolates ofC. albicans(n= 11,241 isolates),C. glabrata(7,538),C. parapsilosis(6,023),C. tropicalis(3,748),C. krusei(1,073),C. lusitaniae(574),C. guilliermondii(373), andC. dubliniensis(162). The 24-h CLSI broth microdilution MICs were collated from multiple laboratories (in Canada, Brazil, Europe, Mexico, Peru, and the United States). The ECVs for distributions originating from ≥6 laboratories, which included ≥95% of the modeled WT population, for fluconazole, posaconazole, and voriconazole were, respectively, 0.5, 0.06 and 0.03 μg/ml forC. albicans, 0.5, 0.25, and 0.03 μg/ml forC. dubliniensis, 8, 1, and 0.25 μg/ml forC. glabrata, 8, 0.5, and 0.12 μg/ml forC. guilliermondii, 32, 0.5, and 0.25 μg/ml forC. krusei, 1, 0.06, and 0.06 μg/ml forC. lusitaniae, 1, 0.25, and 0.03 μg/ml forC. parapsilosis, and 1, 0.12, and 0.06 μg/ml forC. tropicalis. The low number of MICs (<100) for other less prevalent species (C. famata,C. kefyr,C. orthopsilosis,C. rugosa) precluded ECV definition, but their MIC distributions are documented. Evaluation of our ECVs for some species/agent combinations using published individual MICs for 136 isolates (harboring mutations in or upregulation ofERG11,MDR1,CDR1, orCDR2) and 64 WT isolates indicated that our ECVs may be useful in distinguishing WT from non-WT isolates.
Serum-Mediated Activation of Macrophages Reflects TcVac2 Vaccine Efficacy against Chagas Disease
Authors: Gupta Shivali , Silva Trevor S. , Osizugbo Jessica E. , Tucker Laura , Spratt Heidi M. , Garg Nisha J. 
Published: January 2014

ABSTRACTChagas disease is endemic in Latin America and an emerging infectious disease in the United States. No effective treatments are available. The TcG1, TcG2, and TcG4 antigens are highly conserved in clinically relevantTrypanosoma cruziisolates and are recognized by B and T cells in infected hosts. Delivery of these antigens as a DNA prime/protein boost vaccine (TcVac2) elicited lytic antibodies and type 1 CD8+T cells that expanded upon challenge infection and provided >90% control of parasite burden and myocarditis in chagasic mice. Here we determined if peripheral blood can be utilized to capture the TcVac2-induced protection from Chagas disease. We evaluated the serum levels ofT. cruzikinetoplast DNA (TckDNA),T. cruzi18S ribosomal DNA (Tc18SrDNA), and murine mitochondrial DNA (mtDNA) as indicators of parasite persistence and tissue damage and monitored the effect of sera on macrophage phenotype. CirculatingTckDNA/Tc18SrDNA and mtDNA were decreased by >3- to 5-fold and 2-fold, respectively, in vaccinated infected mice compared to nonvaccinated infected mice. Macrophages incubated with sera from vaccinated infected mice exhibited M2 surface markers (CD16, CD32, CD200, and CD206), moderate proliferation, a low oxidative/nitrosative burst, and a regulatory/anti-inflammatory cytokine response (interleukin-4 [IL-4] plus IL-10 > tumor necrosis factor alpha [TNF-α]). In comparison, macrophages incubated with sera from nonvaccinated infected mice exhibited M1 surface markers, vigorous proliferation, a substantial oxidative/nitrosative burst, and a proinflammatory cytokine response (TNF-α ≫ IL-4 plus IL-10). Cardiac infiltration of macrophages and TNF-α and oxidant levels were significantly reduced in TcVac2-immunized chagasic mice. We conclude that circulatingTcDNA and mtDNA levels and macrophage phenotype mediated by serum constituents reflectin vivolevels of parasite persistence, tissue damage, and inflammatory/anti-inflammatory state and have potential utility in evaluating disease severity and efficacy of vaccines and drug therapies.
Neutrophils Are a Source of Gamma Interferon during Acute Salmonella enterica Serovar Typhimurium Colitis
Authors: Spees Alanna M. , Kingsbury Dawn D. , Wangdi Tamding , Xavier Mariana N. , Tsolis Renée M. , Bäumler Andreas J. 
Published: January 2014

ABSTRACTGamma interferon (IFN-γ) is an important driver of intestinal inflammation during colitis caused bySalmonella entericaserovar Typhimurium. Here we used the mouse colitis model to investigate the cellular sources of IFN-γ in the cecal mucosa during the acute phase of anS. Typhimurium infection. While IFN-γ staining was detected in T cells, NK cells, and inflammatory monocytes at 2 days after infection, the majority of IFN-γ-positive cells in the cecal mucosa were neutrophils. Furthermore, neutrophil depletion blunted mucosalIfngexpression and reduced the severity of intestinal lesions duringS. Typhimurium infection. We conclude that neutrophils are a prominent cellular source of IFN-γ during the innate phase ofS. Typhimurium-induced colitis.
Specialized Science
Authors: Casadevall Arturo , Fang Ferric C. 
Published: January 2014

ABSTRACT
As the body of scientific knowledge in a discipline increases, there is pressure for specialization. Fields spawn subfields that then become entities in themselves that promote further specialization. The process by which scientists join specialized groups has remarkable similarities to the guild system of the middle ages. The advantages of specialization of science include efficiency, the establishment of normative standards, and the potential for greater rigor in experimental research. However, specialization also carries risks of monopoly, monotony, and isolation. The current tendency to judge scientific work by the impact factor of the journal in which it is published may have roots in overspecialization, as scientists are less able to critically evaluate work outside their field than before. Scientists in particular define themselves through group identity and adopt practices that conform to the expectations and dynamics of such groups. As part of our continuing analysis of issues confronting contemporary science, we analyze the emergence and consequences of specialization in science, with a particular emphasis on microbiology, a field highly vulnerable to balkanization along microbial phylogenetic boundaries, and suggest that specialization carries significant costs. We propose measures to mitigate the detrimental effects of scientific specialism.
The association between hospitalisation for childhood head injury and academic performance: evidence from a population e-cohort study
Authors: Gabbe Belinda J , Brooks Caroline , Demmler Joanne C , Macey Steven , Hyatt Melanie A , Lyons Ronan A 
Published: January 2014

BackgroundChildhood head injury has the potential for lifelong disability and burden. This study aimed to establish the association between admission to hospital for childhood head injury and early academic performance.MethodsThe Wales Electronic Cohort for Children (WECC) study is comprised of record-linked routinely collected data, on all children born or residing in Wales. Anonymous linking fields are used to link child and maternal health, environment and education records. Data from WECC were extracted for children born between September 1998 and August 2001. A Generalised Estimating Equation model, adjusted for clustering based on the maternal identifier as well as other key confounders, was used to establish the association between childhood head injury and performance on the Key Stage 1 (KS1) National Curriculum assessment administered to children aged 5–7 years. Head injury was defined as an emergency admission for >24 h for concussion, skull fracture or intracranial injury prior to KS1 assessment.ResultsOf the 101 892 eligible children, KS1 results were available for 90 661 (89%), and 290 had sustained a head injury. Children who sustained an intracranial injury demonstrated significantly lower adjusted odds of achieving a satisfactory KS1 result than children who had not been admitted to hospital for head injury (adjusted OR 0.46, 95% CI 0.30 to 0.72).ConclusionsThe findings of this population e-cohort study quantify the impact of head injury on academic performance, highlighting the need for enhanced head injury prevention strategies. The results have implications for the care and rehabilitation of children admitted to hospital with head injury.