bluuebunny/crossref_metadata_2025 huggingface dataset:
Licensing to a More Efficient Rival
Authors: Anderson Fridtjof
Published: July 2013

This paper studies licensing of a cost‐reducing innovation in an environment with horizontal product differentiation where the licensee is the most efficient firm in absence of the innovation. We derive the optimal two‐part tariff and show that when we allow for negative royalty rates, the optimal contract may involve the patentee paying its rival a per‐unit subsidy.
Population structure of the Chagas disease vector, Triatoma infestans, at the urban–rural interface
Authors: Foley Erica A. , Khatchikian Camilo E. , Hwang Josephine , Ancca‐Juárez Jenny , Borrini‐Mayori Katty , Quıspe‐Machaca Victor R. , Levy Michael Z. , Brisson Dustin ,   the Chagas Disease Working Group in Arequipa
Published: July 2013

The increasing rate of biological invasions resulting from human transport or human‐mediated changes to the environment has had devastating ecological and public health consequences. The kissing bug, Triatoma infestans, has dispersed through the Peruvian city of Arequipa. The biological invasion of this insect has resulted in a public health crisis, putting thousands of residents of this city at risk of infection by Trypanosoma cruzi and subsequent development of Chagas disease. Here, we show that populations of Tria. infestans in geographically distinct districts within and around this urban centre share a common recent evolutionary history although current gene flow is restricted even between proximal sites. The population structure among the Tria. infestans in different districts is not correlated with the geographical distance between districts. These data suggest that migration among the districts is mediated by factors beyond the short‐range migratory capabilities of Tria. infestans and that human movement has played a significant role in the structuring of the Tria. infestans population in the region. Rapid urbanization across southern South America will continue to create suitable environments for Tria. infestans, and knowledge of its urban dispersal patterns may play a fundamental role in mitigating human disease risk.
Using biogeographical history to inform conservation: the case of Preble's meadow jumping mouse
Authors: Malaney Jason L. , Cook Joseph A.
Published: July 2013

The last Pleistocene deglaciation shaped temperate and boreal communities in North America. Rapid northward expansion into high latitudes created distinctive spatial genetic patterns within species that include closely related groups of populations that are now widely spread across latitudes, while longitudinally adjacent populations, especially those near the southern periphery, often are distinctive due to long‐term disjunction. Across a spatial expanse that includes both recently colonized and long‐occupied regions, we analysed molecular variation in zapodid rodents to explore how past climate shifts influenced diversification in this group. By combining molecular analyses with species distribution modelling and tests of ecological interchangeability, we show that the lineage including the Preble's meadow jumping mouse (Zapus hudsonius preblei), a US federally listed taxon of conservation concern, is not restricted to the southern Rocky Mountains. Rather, populations along the Front Range are part of a single lineage that is ecologically indistinct and extends to the far north. Of the 21 lineages identified, this Northern lineage has the largest geographical range and low measures of intralineage genetic differentiation, consistent with recent northward expansion. Comprehensive sampling combined with coalescent‐based analyses and niche modelling leads to a radically different view of geographical structure within jumping mice and indicates the need to re‐evaluate their taxonomy and management. This analysis highlights a premise in conservation biology that biogeographical history should play a central role in establishing conservation priorities.
Molecular characterization of trophic ecology within an island radiation of insect herbivores (Curculionidae: Entiminae: Cratopus)
Authors: Kitson James J. N. , Warren Ben H. , Vincent Florens F. B. , Baider Claudia , Strasberg Dominique , Emerson Brent C.
Published: July 2013

The phytophagous beetle family Curculionidae is the most species‐rich insect family known, with much of this diversity having been attributed to both co‐evolution with food plants and host shifts at key points within the early evolutionary history of the group. Less well understood is the extent to which patterns of host use vary within or among related species, largely because of the technical difficulties associated with quantifying this. Here we develop a recently characterized molecular approach to quantify diet within and between two closely related species of weevil occurring primarily within dry forests on the island of Mauritius. Our aim is to quantify dietary variation across populations and assess adaptive and nonadaptive explanations for this and to characterize the nature of a trophic shift within an ecologically distinct population within one of the species. We find that our study species are polyphagous, consuming a much wider range of plants than would be suggested by the literature. Our data suggest that local diet variation is largely explained by food availability, and locally specialist populations consume food plants that are not phylogenetically novel, but do appear to represent a novel preference. Our results demonstrate the power of molecular methods to unambiguously quantify dietary variation across populations of insect herbivores, providing a valuable approach to understanding trophic interactions within and among local plant and insect herbivore communities.
Multilocus phylogeographic assessment of the California Mountain Kingsnake (Lampropeltis zonata) suggests alternative patterns of diversification for the California Floristic Province
Authors: Myers E. A. , Rodríguez‐Robles J. A. , DeNardo D. F. , Staub R. E. , Stropoli A. , Ruane S. , Burbrink F. T.
Published: July 2013

Phylogeographic inference can determine the timing of population divergence, historical demographic processes, patterns of migration, and when extended to multiple species, the history of communities. Single‐locus analyses can mislead interpretations of the evolutionary history of taxa and comparative analyses. It is therefore important to revisit previous single‐locus phylogeographic studies, particularly those that have been used to propose general patterns for regional biotas and the processes responsible for generating inferred patterns. Here, we employ a multilocus statistical approach to re‐examine the phylogeography of Lampropeltis zonata. Using nonparametic and Bayesian species delimitation, we determined that there are two well‐supported species within L. zonata. Ecological niche modelling supports the delimitation of these taxa, suggesting that the two species inhabit distinct climatic environments. Gene flow between the two taxa is low and appears to occur unidirectionally. Further, our data suggest that gene flow was mediated by females, a rare pattern in snakes. In contrast to previous analyses, we determined that the divergence between the two lineages occurred in the late Pliocene (c. 2.07 Ma). Spatially and temporally, the divergence of these lineages is associated with the inundation of central California by the Monterey Bay. The effective population sizes of the two species appear to have been unaffected by Pleistocene glaciation. Our increased sampling of loci for L. zonata, combined with previously published multilocus analyses of other sympatric species, suggests that previous conclusions reached by comparative phylogeographic studies conducted within the California Floristic Province should be reassessed.
Visualization of the Modeled Degradation of Building Flooring Systems in Building Maintenance
Authors: Khosrowshahi Farzad , Ghodous Parisa , Sarshar Marjan
Published: July 2013

The development of a maintenance program for construction projects is a highly complex and data‐intensive undertaking. This exercise is characterized by the lack of relevant data on the one hand and the overwhelming amount of extraneous data on the other. The uncertainties and complexities have resulted in increased conservatism in the development of life‐cycle evaluation of building maintenance programming, subsequently, these programs tend to display the symptoms of either the maintenance actions being uneconomical or fall short of providing the appropriate service to the users of the building. The current research project is based on the premise that the visual approach will facilitate a just‐in‐time solution to maintenance scheduling, hence, the use of virtual simulation of the building is proposed. The broader aim of this research is to develop a complete building maintenance program through visualization of buildings as they degrade over time. Here, the focus is on the flooring system and the manner they degrade over time. This requires a better understanding of their pattern and rate of usage. To this end, anthroposophy and anthropocentric descriptions of human movement pattern have been used to describe the behavior of “subjects” and subsequently represent the pattern and density of the degradation of flooring systems. The mathematics representing this behavior has been developed which enables it to be embedded into the proposed overall visual building maintenance model.
An A‐tract at the AtzR binding site assists DNA binding, inducer‐dependent repositioning and transcriptional activation of the PatzDEF promoter
Authors: Porrúa Odil , López‐Sánchez Aroa , Platero Ana I. , Santero Eduardo , Shingler Victoria , Govantes Fernando
Published: July 2013

The LysR‐type regulator AtzR activates the Pseudomonas sp. ADP atzDEF operon in response to nitrogen limitation and cyanuric acid. Activation involves repositioning of the AtzR tetramer on the PatzDEF promoter and relaxation of an AtzR‐induced DNA bend. Here we examine the in vivo and in vitro contribution of an A5‐tract present at the PatzDEF promoter region to AtzR binding and transcriptional activation. Substitution of the A‐tract for the sequence ACTCA prevented PatzDEF activation and high‐affinity AtzR binding, impaired AtzR contacts with the activator binding site and shifted the position of the AtzR‐induced DNA bend. Analysis of a collection of mutants bearing different alterations in the A‐tract sequence showed that the extent of AtzR‐dependent activation does not correlate with the magnitude or orientation of the spontaneous DNA bend generated at this site. Our results support the notion that indirect readout of the A‐tract‐associated narrow minor groove is essential for the AtzR–DNA complex to achieve a conformation competent for activation of the PatzDEF promoter. Conservation of this motif in several binding sites of LysR‐type regulators suggests that this mechanism may be shared by other proteins in this family.
Patterns of diet‐related practices and prevalence of gastro‐esophageal reflux disease
Authors: Esmaillzadeh A. , Keshteli A. H. , Feizi A. , Zaribaf F. , Feinle‐Bisset C. , Adibi P.
Published: July 2013

Background

No studies have evaluated associations between patterns of diet‐related practices as determined by latent class analysis (LCA) and gastro‐esophageal reflux disease (GERD). We aimed to assess this relationship in a large sample of Iranian adults.

Methods

In a cross‐sectional study in 4763 adults, diet‐related practices were assessed in four domains, ‘meal pattern’, ‘eating rate’, ‘intra‐meal fluid intake’, and ‘meal‐to‐sleep interval’, using a pretested questionnaire. LCA was applied to identify classes of diet‐related practices. We defined GERD as the presence of heartburn sometimes, often or always.

Key Results

The prevalence of GERD in the study population was 23.5% (n = 1120). We identified two distinct classes of meal patterns: ‘regular’ and ‘irregular’, three classes of eating rates: ‘moderate’, ‘moderate‐to‐slow’, and ‘moderate‐to‐fast’, two major classes of fluid ingestion with meals: ‘moderate’ and ‘much intra‐meal drinking’, and two classes regarding the interval between meals and sleeping: ‘short’ and ‘long meal‐to‐sleep’ interval. After adjustment for potential confounders, subjects with ‘irregular meal pattern’ had higher odds of GERD compared with subjects with ‘regular meal pattern’ (OR: 1.21; 1.00–1.46). However, when taking into account BMI, the association disappeared. ‘Long meal‐to‐sleep interval’ was inversely associated with GERD compared with ‘short meal‐to‐sleep interval’ (OR: 0.73; 95% CI: 0.57–0.95). ‘Eating rate’ and ‘intra‐meal fluid intake’ were not significantly associated with GERD.

Conclusions & Inferences

Our data suggest certain associations between dietary patterns and GERD. These findings warrant evaluation in prospective studies to establish the potential value of modifications in dietary behaviors for the management of GERD.
Kant on the Ontological Argument
Authors: Proops Ian
Published: July 2013

The article examines Kant's various criticisms of the broadly Cartesian ontological argument as they are developed in the Critique of Pure Reason. It is argued that each of these criticisms is effective against its intended target, and that these targets include—in addition to Descartes himself—Leibniz, Wolff, and Baumgarten. It is argued that Kant's most famous criticism—the charge that being is not a real predicate—is directed exclusively against Leibniz. Kant's argument for this thesis—the argument proceeding from his example of a hundred thalers—although it may seem to beg the question, in fact succeeds against Leibniz. It does so because the charge of begging the question can be rebutted if one makes certain Leibnizian assumptions.
Relationship between photochemical reflectance index and leaf ecophysiological and biochemical parameters under two different water statuses: towards a rapid and efficient correction method using real‐time measurements
Authors: HMIMINA G. , DUFRÊNE E. , SOUDANI K.
Published: July 2013

The use of the photochemical reflectance index (PRI) as a promising proxy of light use efficiency (LUE) has been extensively studied, and some issues have been identified, notably the sensitivity of PRI to leaf pigment composition and the variability in PRI response to LUE because of stress. In this study, we introduce a method that enables us to track the short‐term PRI response to LUE changes because of photosynthetically active radiation (PAR) changes. The analysis of these short‐term relationships between PRI and LUE throughout the growing season in two species (Quercus robur L. and Fagus sylvatica L.) under two different soil water statuses showed a clear change in PRI response to LUE, which is related to leaf pigment content. The use of an estimated or approximated PRI0, defined as the PRI of perfectly dark‐adapted leaves, allowed us to separate the PRI variability due to leaf pigment content changes and the physiologically related PRI variability over both daily (PAR‐related) and seasonal (soil water content‐related) scales. The corrected PRI obtained by subtracting PRI0 from the PRI measurements showed a good correlation with the LUE over both of the species, soil water statuses and over the entire growing season.
A new role for glutathione in the regulation of root architecture linked to strigolactones
Authors: MARQUEZ‐GARCIA BELEN , NJO MARIA , BEECKMAN TOM , GOORMACHTIG SOFIE , FOYER CHRISTINE H.
Published: July 2013

Reduced glutathione (GSH) is required for root development but its functions are not characterised. The effects of GSH depletion on root development were therefore studied in relation to auxin and strigolactone (SL) signalling using a combination of molecular genetic approaches and pharmacological techniques. Lateral root density was significantly decreased in GSH synthesis mutants (cad2‐1, pad2‐1, rax1‐1) but not by the GSH synthesis inhibitor, buthionine sulfoximine (BSO). BSO‐induced GSH depletion did therefore not influence root architecture in the same way as genetic impairment. Root glutathione contents were similar in the wild type seedlings and max3‐9 and max4‐1 mutants that are deficient in SL synthesis and in the SL signalling mutant, max2‐1. BSO‐dependent inhibition of GSH synthesis depleted the tissue GSH pool to a similar extent in the wild type and SL synthesis mutants, with no effect on LR density. The application of the SL analogue GR24 increased root glutathione in the wild type, max3‐9 and max4‐1 seedlings but this increase was absent from max2‐1. Taken together, these data establish a link between SLs and the GSH pool that occurs in a MAX2‐dependent manner.
Some Implications of a Copy Theory of Labeling
Authors: Sheehan Michelle L.
Published: July 2013

A copy theory of labeling makes interesting empirical predictions when combined with a revised version of Kayne's (1994) Linear Correspondence Axiom and a category‐based version of c‐command. First, it forces the pronunciation of the highest copy in a chain, all else being equal, without the need for copy deletion. Second, it predicts certain differences between underlying and derived head‐initial specifiers and between head‐final and head‐initial specifiers. This serves to extend Uriagereka's (1999)PF‐based explanation of Huang's Condition on Extraction Domain (CED) to cover previously problematic or unexplained phenomena: (i) the apparent lack of subject‐island effects with head‐final specifiers; (ii) the nonislandhood of many derived specifiers (externally merged as complements); (iii) patterns of complement extraposition; and (iv) the Final‐over‐Final Constraint (see Holmberg 2000; Biberauer, Holmberg & Roberts 2008, to appear). All of the above phenomena arise under the copy theory of labeling as side effects of a revised version of Kayne's (1994) Linear Correspondence Axiom incorporating a head parameter, whereby asymmetric c‐command, defined between categories and unmediated by dominance, maps to precedence as a last resort.
Confidence intervals of reference limits in small reference sample groups
Authors: Braun J.P. , Concordet D. , Geffré A. , Bourges Abella N. , Trumel C.
Published: July 2013

Background

Reference intervals are the most common tool used to interpret results of laboratory tests. However, in veterinary clinical pathology, the number of available reference individuals is often small.

Objectives

The purpose of this study was to investigate the effects of small reference sample groups on the imprecision of the reference limits.

Methods

Gaussian and log‐Gaussian distributions of 10 ≤ n ≤ 750 values were analyzed. Reference limits and 90% confidence interval of limits (90% CI) were calculated. Imprecision of limits was estimated by the ratio of the width of the 90% CI: width of the reference interval (WCI/WRI).

Results

For Gaussian distributions, the WCI/WRI ratio cannot be expected to be lower than 0.2 when n < 55. In log‐Gaussian distributions, the ratio greatly increases for the upper limit with skewness toward high values, whereas it moderately decreases for the lower limit.

Conclusion

Independent of the size of the reference sample group, it is very important to report the CIs of the reference limits, which can be very large for small reference sample groups. When the sample size is very small (n < 20), calculations maybe misleading and it is better to instead report all values.
Breed‐specific biochemical reference intervals for the adult Dogue de Bordeaux
Authors: Lavoué R. , Geffré A. , Braun J.P. , Peeters D. , Trumel C.
Published: July 2013

Background

Breed‐specific reference intervals are of increasing interest in veterinary medicine. The health monitoring of the Dogue de Bordeaux, a breed predisposed to familial juvenile glomerulonephropathy and hypothyroidism, would benefit from specific reference intervals.

Objective

The purpose of this study was to establish breed‐specific biochemical reference intervals for the Dogue de Bordeaux in accordance with the International Federation of Clinical Chemistry and Clinical and Laboratory Standards Institute guidelines.

Methods

One hundred and twenty Dogues de Bordeaux from France and Belgium were recruited. Complete urinalysis and chemistry panels, venous blood gas variables, total thyroxin and thyroid stimulating hormone, and fibrinogen and antithrombin were measured for each dog. Reference intervals were determined using the non‐parametric method. Confounding variables such as sex, age and color of facial mask were analyzed.

Results

Due to pre‐defined criteria for exclusion, 62 healthy dogs were finally selected for the reference intervals determination. Using the instrument manufacturer's generic canineRIfor most analytes did not have a significant impact on potential clinical decisions, except for total proteins,ALT,AST, total cholesterol, lipase and total thyroxin, for which possible clinically relevant differences were noted.

Conclusion

Specific reference intervals for biochemical analytes in the Dogue de Bordeaux were determined under controlled pre‐analytical and analytical conditions, and according to international recommendations. The use of these breed‐specific reference intervals is recommended when using the specified analytic instruments, especially for the 6 analytes for which the reference intervals differed considerably from those provided by manufacturers.
Spike timing‐dependent plasticity at GABAergic synapses in the ventral tegmental area
Authors: Kodangattil Jayaraj N. , Dacher Matthieu , Authement Michael E. , Nugent Fereshteh S.
Published: July 2013

Key points

GABAergic synapses onto ventral tegmental area (VTA) dopamine neurons express a bidirectional spike timing‐dependent plasticity (STDP; both long‐term potentiation and long‐term depression).

GABAergic synapses in the VTA obey the classical Hebbian learning rules of STDP.

GABAergic STDP in VTA dopamine neurons is expressed postsynaptically.

GABAergic STDP is heterosynaptic and NMDA receptor dependent.

Pairing of pre‐ and postsynaptic spiking is necessary for induction of GABAergic STDP.

Abstract  Persistent changes in excitatory and inhibitory synaptic strengths to the ventral tegmental area (VTA) dopamine (DA) neurons in response to addictive drugs may underlie the transition from casual to compulsive drug use. While an enormous amount of work has been done in the area of glutamatergic plasticity of the VTA, little is known regarding the learning rules governing GABAergic plasticity in the VTA. Spike timing‐dependent plasticity, STDP, has attracted considerable attention primarily due to its potential roles in processing and storage of information in the brain and there is emerging evidence for the existence of STDP at inhibitory synapses. We therefore used whole‐cell recordings in rat midbrain slices to investigate whether near‐coincident pre‐ and postsynaptic firing induces a lasting change in synaptic efficacy of VTA GABAergic synapses. We found that a Hebbian form of STDP including long‐term potentiation (LTP) and long‐term depression (LTD) can be induced at GABAergic synapses onto VTA DA neurons and relies on the precise temporal order of pre‐ and postsynaptic spiking. Importantly, GABAergic STDP is heterosynaptic (NMDA receptor dependent): triggered by correlated activities of the presynaptic glutamatergic input and postsynaptic DA cells. GABAergic STDP is postsynaptic and has an associative component since pre‐ or postsynaptic spiking per se did not induce STDP. STDP of GABAergic synapses in the VTA provides physiologically relevant forms of inhibitory plasticity that may underlie natural reinforcement of reward‐related behaviours. Moreover, this form of inhibitory plasticity may mediate some of the reinforcing, aversive and addictive properties of drugs of abuse.
Permeability and contractile responses of collecting lymphatic vessels elicited by atrial and brain natriuretic peptides
Authors: Scallan Joshua P. , Davis Michael J. , Huxley Virginia H.
Published: July 2013

Key points

Atrial and brain natriuretic peptides (ANP and BNP, respectively) are hormones released into the bloodstream when heart muscle is stretched (e.g. zero‐gravity, hypertension, congestive heart failure) and serve to reduce the blood volume.

One way that these peptides relieve blood volume is to increase the permeability of the smallest blood vessels, facilitating fluid and protein distribution into the tissue spaces.

Whether these peptides target lymphatic vessel function to participate in fluid distribution is currently unknown.

ANP and BNP (100 nm) both elicited significant increases in lymphatic vessel permeability, but altered contractile function differentially in vivo.

A likely consequence is that more fluid leaks from the lymphatics into the tissues, which represents a novel compensation for volume overload. This work demonstrates for the first time that lymphatic vessel permeability can be regulated in vivo.

Abstract  Atrial and brain natriuretic peptides (ANP and BNP, respectively) are cardiac hormones released into the bloodstream in response to hypervolaemia or fluid shifts to the central circulation. The actions of both peptides include natriuresis and diuresis, a decrease in systemic blood pressure, and inhibition of the renin–angiotensin–aldosterone system. Further, ANP and BNP elicit increases in blood microvessel permeability sufficient to cause protein and fluid extravasation into the interstitium to reduce the vascular volume. Given the importance of the lymphatic vasculature in maintaining fluid balance, we tested the hypothesis that ANP or BNP (100 nm) would likewise elevate lymphatic permeability (Ps) to serum albumin. Using a microfluorometric technique adapted to in vivo lymphatic vessels, we determined that rat mesenteric collecting lymphatic Ps to rat serum albumin increased by 2.0 ± 0.4‐fold (P= 0.01, n= 7) and 2.7 ± 0.8‐fold (P= 0.07, n= 7) with ANP and BNP, respectively. In addition to measuring Ps responses, we observed changes in spontaneous contraction amplitude and frequency from the albumin flux tracings in vivo. Notably, ANP abolished spontaneous contraction amplitude (P= 0.005) and frequency (P= 0.006), while BNP augmented both parameters by ∼2‐fold (P < 0.01 each). These effects of ANP and BNP on contractile function were examined further by using an in vitro assay. In aggregate, these data support the theory that an increase in collecting lymphatic permeability opposes the absorptive function of the lymphatic capillaries, and aids in the retention of protein and fluid in the interstitial space to counteract volume expansion.
IgG Receptors in Alzheimer’s Disease
Authors: Ferrarelli Leslie K.
Published: July 2013

An interaction between the IgG receptor FcγRIIb and β-amyloid contributes to the neuropathology of Alzheimer’s disease.
A Gene for Early Acceptance
Authors: Mueller Kristen L.
Published: July 2013

A single gene predicts transplantation compatibility reactions in the star ascidian,
Botryllus schlosseri
.
Chromosome 5 Monosomy of Candida albicans Controls Susceptibility to Various Toxic Agents, Including Major Antifungals
Authors: Yang Feng , Kravets Anatoliy , Bethlendy Gabor , Welle Stephen , Rustchenko Elena
Published: July 2013

Candida albicansis a prevailing fungal pathogen with a diploid genome that can adapt to environmental stresses by losing or gaining an entire chromosome or a large portion of a chromosome. We have previously found that the loss of one copy of chromosome 5 (Ch5) allows for adaptation to the toxic sugarl-sorbose.l-Sorbose is similar to caspofungin and other antifungals from the echinocandins class, in that it represses synthesis of cell wall glucan in fungi. Here, we extended the study of the phenotypes controlled by Ch5 copy number. We examined 57 strains, either disomic or monosomic for Ch5 and representing five different genetic backgrounds, and found that the monosomy of Ch5 causes elevated levels of chitin and repressed levels of 1,3-β-glucan components of the cell wall, as well as diminished cellular ergosterol. Increased deposition of chitin in the cell wall could be explained, at least partially, by a 2-fold downregulation ofCHT2on the monosomic Ch5 that encodes chitinase and a 1.5-fold upregulation ofCHS7on Ch1 that encodes the protein required for wild-type chitin synthase III activity. Other important outcomes of Ch5 monosomy consist of susceptibility changes to agents representing four major classes of antifungals. Susceptibility to caspofungin increased or decreased and susceptibility to 5-fluorocytosine decreased, whereas susceptibility to fluconazole and amphotericin B increased. Our results suggest that Ch5 monosomy represents an unrecognizedC. albicansregulatory strategy that impinges on multiple stress response pathways.
β-Lactam Antibiotics Targeting PBP1 Selectively Enhance Daptomycin Activity against Methicillin-Resistant Staphylococcus aureus
Authors: Berti Andrew D. , Sakoulas George , Nizet Victor , Tewhey Ryan , Rose Warren E.
Published: July 2013

The activity of daptomycin (DAP) against methicillin-resistant
Staphylococcus aureus
(MRSA) is enhanced in the presence of subinhibitory concentrations of antistaphylococcal β-lactam antibiotics by an undefined mechanism. Given the variability in the penicillin-binding protein (PBP)-binding profiles of different β-lactam antibiotics, the purpose of this study was to examine the relative enhancement of DAP activity against MRSA by different β-lactam antibiotics to determine if a specific PBP-binding profile is associated with the ability to enhance the anti-MRSA activity of DAP. We determined that both broad- and narrow-spectrum β-lactam antibiotics known to exhibit PBP1 binding demonstrated potent enhancement of DAP anti-MRSA activity, whereas β-lactam antibiotics with minimal PBP1 binding (cefoxitin, ceftriaxone, cefaclor, and cefotaxime) were less effective. We suspect that PBP1 disruption by β-lactam antibiotics affects pathways of cell division in
S. aureus
that may be a compensatory response to DAP membrane insertion, resulting in DAP hypersusceptibility.
DNA Duplexes with Hydrophobic Modifications Inhibit Fusion between HIV-1 and Cell Membranes
Authors: Xu Liang , Cai Lifeng , Chen Xueliang , Jiang Xifeng , Chong Huihui , Zheng Baohua , Wang Kun , He Junlin , Chen Wei , Zhang Tao , Cheng Maosheng , He Yuxian , Liu Keliang
Published: July 2013

Discovery of new drugs for the treatment of AIDS typically possessing unique structures associated with novel mechanisms of action has been of great importance due to the quick drug-resistant mutations of HIV-1 strains. The work presented in this report describes a novel class of DNA duplex-based HIV-1 fusion inhibitors. Hydrophobic groups were introduced into a DNA duplex skeleton either at one end, at both ends, or in the middle. These modified DNA duplexes inhibited fusion between HIV-1 and human cell membranes at micro- or submicromolar concentrations. Respective inhibitors adopted an aptamer pattern instead of a base-pairing interaction pattern. Structure-activity relationship studies of the respective DNA duplexes showed that the rigid and negatively charged DNA skeletons, in addition to the presence of hydrophobic groups, were crucial to the anti-HIV-1 activity of these compounds. A fluorescent resonance energy transfer (FRET)-based inhibitory assay showed that these duplex inhibitors interacted with the primary pocket in the gp41 N-terminal heptad repeat (NHR) instead of interacting with the lipid bilayers.
Clotrimazole Dampens Vaginal Inflammation and Neutrophil Infiltration in Response to Candida albicans Infection
Authors: Wilson Duncan , Hebecker Betty , Moyes David L. , Miramón Pedro , Jablonowski Nadja , Wisgott Stephanie , Allert Stefanie , Naglik Julian R. , Hube Bernhard
Published: July 2013

The pathology of vulvovaginal candidiasis (VVC) caused by
Candida albicans
is associated with a nonprotective inflammatory response and is frequently treated with clotrimazole. We investigated the mechanisms by which clotrimazole resolves VVC. Low levels of clotrimazole, which do not block fungal growth, inhibit expression of a “danger response” transcription factor, c-Fos, block production of proinflammatory cytokines, and inhibit neutrophil infiltration to the site of infection.
Reconstitution of an Active Arginine Deiminase Pathway in Mycoplasma pneumoniae M129
Authors: Rechnitzer Hagai , Rottem Shlomo , Herrmann Richard
Published: July 2013

Some species of the genusMycoplasmacode for the arginine deiminase pathway (ADI), which enables these bacteria to produce ATP from arginine by the successive reaction of three enzymes: arginine deiminase (ArcA), ornithine carbamoyltransferase (ArcB), and carbamate kinase (ArcC). It so far appears that independently isolated strains ofMycoplasma pneumoniaeencode an almost identical truncated version of the ADI pathway in which the proteins ArcA and ArcB have lost their original enzymatic activities due to the deletion of significant regions of these proteins. To study the consequences of a functional ADI pathway,M. pneumoniaeM129 was successfully transformed with the cloned functionalarcA,arcB, andarcCgenes fromMycoplasma fermentans. Enzymatic tests showed that while theM. pneumoniaeArcAB and ArcABC transformants possess functional arginine deiminase, ornithine carbamoyltransferase, and carbamate kinase, they were unable to grow on arginine as the sole energy source. Nevertheless, infection of a lung epithelial cell line, A549, with theM. pneumoniaetransformants showed that almost 100% of the infected host cells were nonviable, while most of the lung cells infected with nontransformedM. pneumoniaewere viable under the same experimental conditions.
Combined Stimulation of Toll-Like Receptor 5 and NOD1 Strongly Potentiates Activity of NF-κB, Resulting in Enhanced Innate Immune Reactions and Resistance to Salmonella enterica Serovar Typhimurium Infection
Authors: Tukhvatulin Amir I. , Gitlin Ilya I. , Shcheblyakov Dmitry V. , Artemicheva Natalia M. , Burdelya Lyudmila G. , Shmarov Maxim M. , Naroditsky Boris S. , Gudkov Andrei V. , Gintsburg Alexander L. , Logunov Denis Y.
Published: July 2013

Pathogen recognition receptors (PRRs) are essential components of host innate immune systems that detect specific conserved pathogen-associated molecular patterns (PAMPs) presented by microorganisms. Members of two families of PRRs, transmembrane Toll-like receptors (TLRs 1, 2, 4, 5, and 6) and cytosolic NOD receptors (NOD1 and NOD2), are stimulated upon recognition of various bacterial PAMPs. Such stimulation leads to induction of a number of immune defense reactions, mainly triggered via activation of the transcription factor NF-κB. While coordination of responses initiated via different PRRs sensing multiple PAMPS present during an infection makes clear biological sense for the host, such interactions have not been fully characterized. Here, we demonstrate that combined stimulation of NOD1 and TLR5 (as well as other NOD and TLR family members) strongly potentiates activity of NF-κB and induces enhanced levels of innate immune reactions (e.g., cytokine production) both
in vitro
and
in vivo
. Moreover, we show that an increased level of NF-κB activity plays a critical role in formation of downstream responses. In live mice, synergy between these receptors resulting in potentiation of NF-κB activity was organ specific, being most prominent in the gastrointestinal tract. Coordinated activity of NOD1 and TLR5 significantly increased protection of mice against enteroinvasive
Salmonella
infection. Obtained results suggest that cooperation of NOD and TLR receptors is important for effective responses to microbial infection
in vivo
.
Identification of Salmonella enterica Serovar Typhimurium Genes Regulated during Biofilm Formation on Cholesterol Gallstone Surfaces
Authors: Gonzalez-Escobedo Geoffrey , Gunn John S.
Published: July 2013

Salmonellaspp. are able to form biofilms on abiotic and biotic surfaces.In vivostudies in our laboratory have shown thatSalmonellacan form biofilms on the surfaces of cholesterol gallstones in the gallbladders of mice and human carriers. Biofilm formation on gallstones has been demonstrated to be a mechanism of persistence. The purpose of this work was to identify and evaluateSalmonellasp. cholesterol-dependent biofilm factors. Differential gene expression analysis between biofilms on glass or cholesterol-coated surfaces and subsequent quantitative real-time PCR (qRT-PCR) revealed that type 1 fimbria structural genes and a gene encoding a putative outer membrane protein (ycfR) were specifically upregulated inSalmonella entericaserovar Typhimurium biofilms grown on cholesterol-coated surfaces. Spatiotemporal expression ofycfRand FimA verified their regulation during biofilm development on cholesterol-coated surfaces. Surprisingly, confocal and scanning electron microscopy demonstrated that a mutant of type 1 fimbria structural genes (ΔfimAICDHF) and aycfRmutant showed increased biofilm formation on cholesterol-coated surfaces.In vivoexperiments usingNramp1+/+mice harboring gallstones showed that only the ΔycfRmutant formed extensive biofilms on mouse gallstones at 7 and 21 days postinfection; ΔfimAICDHFwas not observed on gallstone surfaces after the 7-day-postinfection time point. These data suggest that inSalmonellaspp., wild-type type 1 fimbriae are important for attachment to and/or persistence on gallstones at later points of chronic infection, whereas YcfR may represent a specific potential natural inhibitor of initial biofilm formation on gallstones.
In VivoPhysiological and Transcriptional Profiling Reveals Host Responses to Clostridium difficile Toxin A and Toxin B
Authors: D'Auria Kevin M. , Kolling Glynis L. , Donato Gina M. , Warren Cirle A. , Gray Mary C. , Hewlett Erik L. , Papin Jason A.
Published: July 2013

Toxin A (TcdA) and toxin B (TcdB) ofClostridium difficilecause gross pathological changes (e.g., inflammation, secretion, and diarrhea) in the infected host, yet the molecular and cellular pathways leading to observed host responses are poorly understood. To address this gap, we evaluated the effects of single doses of TcdA and/or TcdB injected into the ceca of mice, and several endpoints were analyzed, including tissue pathology, neutrophil infiltration, epithelial-layer gene expression, chemokine levels, and blood cell counts, 2, 6, and 16 h after injection. In addition to confirming TcdA's gross pathological effects, we found that both TcdA and TcdB resulted in neutrophil infiltration. Bioinformatics analyses identified altered expression of genes associated with the metabolism of lipids, fatty acids, and detoxification; small GTPase activity; and immune function and inflammation. Further analysis revealed transient expression of several chemokines (e.g.,Cxcl1andCxcl2). Antibody neutralization of CXCL1 and CXCL2 did not affect TcdA-induced local pathology or neutrophil infiltration, but it did decrease the peripheral blood neutrophil count. Additionally, low serum levels of CXCL1 and CXCL2 corresponded with greater survival. Although TcdA induced more pronounced transcriptional changes than TcdB and the upregulated chemokine expression was unique to TcdA, the overall transcriptional responses to TcdA and TcdB were strongly correlated, supporting differences primarily in timing and potency rather than differences in the type of intracellular host response. In addition, the transcriptional data revealed novel toxin effects (e.g., altered expression of GTPase-associated and metabolic genes) underlying observed physiological responses toC. difficiletoxins.
‘Care left undone’ during nursing shifts: associations with workload and perceived quality of care
Authors: Ball Jane E , Murrells Trevor , Rafferty Anne Marie , Morrow Elizabeth , Griffiths Peter
Published: July 2013

Background

There is strong evidence to show that lower nurse staffing levels in hospitals are associated with worse patient outcomes. One hypothesised mechanism is the omission of necessary nursing care caused by time pressure—‘missed care’.

Aim

To examine the nature and prevalence of care left undone by nurses in English National Health Service hospitals and to assess whether the number of missed care episodes is associated with nurse staffing levels and nurse ratings of the quality of nursing care and patient safety environment.

Methods

Cross-sectional survey of 2917 registered nurses working in 401 general medical/surgical wards in 46 general acute National Health Service hospitals in England.

Results

Most nurses (86%) reported that one or more care activity had been left undone due to lack of time on their last shift. Most frequently left undone were: comforting or talking with patients (66%), educating patients (52%) and developing/updating nursing care plans (47%). The number of patients per registered nurse was significantly associated with the incidence of ‘missed care’ (p<0.001). A mean of 7.8 activities per shift were left undone on wards that are rated as ‘failing’ on patient safety, compared with 2.4 where patient safety was rated as ‘excellent’ (p <0. 001).

Conclusions

Nurses working in English hospitals report that care is frequently left undone. Care not being delivered may be the reason low nurse staffing levels adversely affects quality and safety. Hospitals could use a nurse-rated assessment of ‘missed care’ as an early warning measure to identify wards with inadequate nurse staffing.
Procedural sedation with propofol for emergency DC cardioversion
Authors: Kaye Philip , Govier Matthew
Published: July 2013

Many emergency patients present with cardiac arrhythmias requiring emergency direct current countershock cardioversion (DCCV) as a part of their management. Almost all require sedation to facilitate the procedure. Propofol has been used for procedural sedation in Emergency Medicine since 1995. In 1996, in a review article inAnaesthesia, it was recommended as the drug which most closely approaches the ideal agent for DCCV. However, the existing evidence for the dosage requirements and safety of propofol in emergency DCCV is limited. We report a prospective case series of patients who underwent sedation-facilitated DCCV using propofol in the emergency department with both sedation and DCCV delivered by emergency physicians. The results indicate propofol is a safe drug for procedural sedation to facilitate emergency DCCV in patients with an atrial tachyarrhythmia without any evidence of haemodynamic compromise. A dose of 1 mg/kg appears to be safe in the majority of these patients. Using the adverse event reporting tool produced by the World SIVA International Sedation Task Force there were no moderate or sentinel adverse events in these patients. A reduced dose should be considered in older patients to prevent transient complications. Propofol at a dose of 0.5 mg/kg appears to be a safe drug for procedural sedation to facilitate emergent or urgent DCCV in patients with an atrial tachyarrhythmia with evidence of haemodynamic compromise. There were no sentinel adverse events associated with its use. Evidence to support the use of propofol to facilitate emergency DCCV for ventricular tachycardia is limited.
Geothermobarometry of spinel peridotites from southern British Columbia: implications for the thermal conditions in the upper mantle
Authors: Greenfield A.M.R. , Ghent E.D. , Russell J.K.
Published: July 2013

Spinel lherzolite xenoliths within alkali basalts exposed at Rayfield River and Big Timothy Mountain, south-central British Columbia, represent samples of the underlying lithospheric mantle. Electron microprobe analysis shows that most xenoliths comprise compositionally homogeneous grains of olivine, orthopyroxene, clinopyroxene, and spinel. We applied the following mineral-pair geothermometers to these rocks: orthopyroxene–clinopyroxene, spinel–orthopyroxene, and spinel–olivine. Temperatures calculated using the Brey and Köhler calibration of two-pyroxene thermometry were constrained in pressure by being required to lie on a model geotherm we develop for this region of B.C. The model geotherm is constrained to produce a temperature at the Moho (33 km) of 825 ± 25 °C to match the lowest temperature peridotite xenoliths recovered in this study. Although the overall effect of pressure on the temperature calculations is negligible (∼2 °C for 0.1 GPa), the simultaneous solution of the model geotherm and the pressure-dependent Brey–Köhler two-pyroxene thermometry removes the need for adopting an arbitrary pressure. We take these temperatures to represent peak mantle lithosphere temperatures. Fourteen Rayfield River xenoliths return two-pyroxene temperatures between 841 and 962 °C corresponding to depths of 34–42 km. Orthopyroxene–spinel and olivine–spinel results are 889 ± 60 and 825 ± 88 °C, respectively. Five Big Timothy xenoliths have two-pyroxene temperatures spanning 840–1058 °C and corresponding to depths of 34–48 km. Mean orthopyroxene–spinel and olivine–spinel temperatures are 844 ± 63 and 896 ± 232 °C, respectively. We argue that the differences in ranges of temperature do not represent closure temperatures imposed during cooling either in the mantle or during transport by the magma. Rather, these differences reflect differences in the original calibrations of the geothermometers or different degrees of equilibration in exchange reactions in dry rocks. Isochemical phase diagrams (pseudosections) constrain the pressure–temperature (P–T) field in which spinel is stable. These diagrams suggest that the spinel-bearing peridotites equilibrated at pressures ranging from ∼9.6 to 14 kbar (10 kbar = 1 GPa).
Resveratrol attenuates left ventricular remodeling in old rats with COPD induced by cigarette smoke exposure and LPS instillation
Authors: Hu Yi Xin , Cui Hua , Fan Li , Pan Xiu Jie , Wu Ji Hua , Shi Suo Zhu , Cui Shao Yuan , Wei Zhi Min , Liu Lin
Published: July 2013

The objective of this study was to investigate left cardiac damage and the cardioprotective effects of resveratrol in old rats with COPD. Rats 22 months old were divided into three groups: control (CTL), smoking and lipopolysaccharides (SM/LPS), and SM/LPS plus resveratrol (SM/LPS-Res). Cardiac function, pathology, oxidative stress, and apoptosis index were measured. Expression of myocardial SIRT1 was studied by real-time quantitative polymerase chain reaction (PCR) and Western blot detection. The heart weight – body weight ratio (LVW/BW) increased in the SM/LPS group compared with the CTL group. Both the LVW/BW and the area of fibrosis in the SM/LPS-Res group decreased compared with those in the SM/LPS group. 8-OHdG expression increased in cardiac tissue of rats in the SM/LPS group, which could be inhibited by resveratrol. Resveratrol significantly increased the activity of superoxide dismutase (SOD) and reduced the cardiac malonyldialdehyde (MDA) level in the SM/LPS-Res group. There was a significant decrease in the extent of cardiomyocyte apoptosis in the SM/LPS-Res group compared with the SM/LPS group. SIRT1 mRNA increased in the SM/LPS-Res group compared with the SM/LPS group. In conclusion, resveratrol attenuated cardiac oxidative damage and left ventricular remodeling and enhanced the decreased expression of SIRT1 in hearts of old rats with emphysema and thus might be a therapeutic modality for cardiac injury complicated in chronic obstructive pulmonary disease (COPD).