bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-dose rifamycins enable shorter oral treatment in a murine model of Mycobacterium ulcerans disease
Authors: Omansen Till F. , Almeida Deepak , Converse Paul J. , Li Si-Yang , Lee Jin , Stienstra Ymkje , van der Werf Tjip , Grosset Jacques H. , Nuermberger Eric L. 
Published: August 2018

AbstractBuruli ulcer (BU), caused by Mycobacterium ulcerans, is a neglected tropical skin and soft tissue infection that is associated with disability and social stigma. The mainstay of BU treatment is an eight-week course of 10 mg/kg rifampin (RIF) and 150 mg/kg streptomycin (STR). Recently, the injectable STR has been shown to be replaceable with oral clarithromycin (CLR) for smaller lesions for the last four weeks of treatment. A shorter, all-oral, highly efficient regimen for BU is needed, as the long treatment duration and indirect costs currently burden patients and health systems. Increasing the dose of RIF or replacing it with the more potent rifamycin drug rifapentine (RPT) could provide such a regimen. Here, we performed a dose-ranging experiment of RIF and RPT in combination with CLR over four weeks of treatment in a mouse model of M. ulcerans disease. A clear dose-dependent effect of RIF on both clinical and microbiological outcomes was found, with no ceiling effect observed with tested doses up to 40 mg/kg. RPT-containing regimens were more effective on M. ulcerans. All RPT-containing regimens achieved culture negativity after only four weeks while only the regimen with the highest RIF dose (40 mg/kg) did so. We conclude that there is dose-dependent efficacy of both RIF and RPT and that a ceiling effect is not reached with the current standard regimen used in the clinic. A regimen based on higher rifamycin doses that are currently being evaluated against tuberculosis in clinical trials could shorten and improve therapy of Buruli ulcer.
Global identification of functional microRNA::mRNA interactions in Drosophila
Authors: Wessels Hans-Hermann , Lebedeva Svetlana , Hirsekorn Antje , Mukherjee Neelanjan , Ohler Uwe 
Published: August 2018

AbstractMicroRNAs (miRNAs) are key mediators of post-transcriptional gene expression silencing. Although Drosophila has been of critical importance for miRNA discovery, biogenesis and function, there has been no comprehensive experimental annotation of functional miRNA target sites. To close this gap, we generated the first in vivo map of miRNA::mRNA interactions in Drosophila melanogaster, making use of crosslinked nucleotides in Argonaute (AGO) crosslinking and immunoprecipitation (CLIP) experiments that enable an unambiguous assignment of miRNAs to AGO binding sites at much higher signal-to-noise ratio than computational predictions alone.Absolute quantification of cellular miRNA levels showed the miRNA pool in Drosophila cell lines to be more diverse than previously reported. Benchmarking two different CLIP approaches, we identified a similar predictive potential to unambiguously assign thousands of miRNA::mRNA pairs from AGO1 interaction data at unprecedented depth. Quantitative RNA-Seq and subcodon-resolution ribosomal footprinting data upon AGO1 depletion enabled the determination of miRNA-mediated effects on target expression and translation. We thus provide the first comprehensive resource of miRNA target sites as well as their quantitative functional impact in Drosophila.
Streptococcal superantigen-induced expansion of human tonsil T cells leads to altered T follicular helper cell phenotype, B cell death, and reduced immunoglobulin release
Authors: Davies Frances J. , Olme Carl , Lynskey Nicola N. , Turner Claire E. , Sriskandan Shiranee 
Published: August 2018

AbstractBackgroundStreptococcal pyrogenic exotoxin (SPE)A expression is epidemiologically linked to streptococcal tonsillo-pharyngitis and outbreaks of scarlet fever, although the mechanisms by which superantigens confer advantageStreptococcus pyogenesare unclear.S. pyogenesis an exclusively human pathogen. As the leukocyte profile of tonsil differs from peripheral blood, the impact of SPEA production on human tonsil cell function was investigated.MethodsHuman tonsil cells from routine tonsillectomy, were co-incubated with purified streptococcal superantigens or isogenic streptococcal culture supernatants, differing only in superantigen content. Tonsil cell proliferation was quantified by tritium-incorporation, and cell surface characteristics assessed by flow-cytometry. Soluble mediators were measured using ELISA and quantitative (q)RT-PCR was performed for immunoglobulin gene expression.ResultsTonsil T cells proliferated in response to SPEA and demonstrated typical release of pro-inflammatory cytokines. When cultured in the absence of superantigen, tonsil preparations released large quantities of immunoglobulin over 7d. In contrast, marked B cell apoptosis and abrogation of total IgA, IgM, and IgG production occurred in the presence of SPEA and other superantigens. In SPEA-stimulated cultures, T follicular helper (TfH) cells showed a reduction in CXCR5 expression, but up-regulation of CD134 (OX40), CD278 (ICOS) and CD150 (SLAM) expression, indicative of a phenotypic change in the TfH population and associated with impaired chemotactic response to CXCL13.ConclusionsSPEA and other superantigens cause dysregulated tonsil immune function, driving T cells from TFH to a proliferating phenotype, with resultant loss of B cells and immunoglobulin production, providing superantigen-producing bacteria with a likely survival advantage.
Empirical Analysis and Modeling of Argos Doppler Location Errors in Romania
Authors: Rozylowicz Laurentiu , Bodescu Florian P. , Ciocanea Cristiana M. , Gavrilidis Athanasios A. , Manolache Steluta , Matache Marius L. , Miu Iulia V. , Moale Ionut C. , Nita Andreea , Popescu Viorel D. 
Published: August 2018

ABSTRACTBackgroundAdvances in wildlife tracking technology have allowed researchers to understand the spatial ecology of many terrestrial and aquatic animal species. Argos Doppler is a technology that is widely used for wildlife tracking owing to the small size and low weight of the Argos transmitters. This allows them to be fitted to small-bodied species. The longer lifespan of the Argos units in comparison to units outfitted with miniaturized global positioning system (GPS) technology has also recommended their use. In practice, large Argos location errors often occur due to communication conditions such as transmitter settings, local environment, and the behavior of the tracked individual.MethodsConsidering the geographic specificity of errors and the lack of benchmark studies in Eastern Europe, the research objectives were: (1) to evaluate the accuracy of Argos Doppler technology under various environmental conditions in Romania, (2) to investigate the effectiveness of straightforward destructive filters for improving Argos Doppler data quality, and (3) to provide guidelines for processing Argos Doppler wildlife monitoring data. The errors associated with Argos locations in four geographic locations in Romania were assessed during static, low-speed and high-speed tests. The effectiveness of the Douglas Argos distance angle filter algorithm was then evaluated to ascertain its effect on the minimization of localization errors.ResultsArgos locations received in the tests had larger associated horizontal errors than those indicated by the operator of the Argos system, including under ideal reception conditions. Positional errors were similar to those obtained in other studies outside of Europe. The errors were anisotropic, with larger longitudinal errors for the vast majority of the data. Errors were mostly related to speed of the Argos transmitter at the time of reception, but other factors such as topographical conditions and orientation of antenna at the time of the transmission also contributed to receiving low-quality data. The Douglas-Argos filter successfully excluded the largest errors while retaining a large amount of data when the threshold was set to the local scale (2 km).DiscussionFilter selection requires knowledge about the movement patterns and behavior of the species of interest, and the parametrization of the selected filter typically requires a trial and error approach. Selecting the proper filter reduces the errors while retaining a large amount of data. However, the post-processed data typically includes large positional errors; thus, we recommend incorporating Argos error metrics such as error ellipse or use complex modeling approaches when working with filtered data.
A human cell model of cardiac pathophysiological valvulogenesis
Authors: Neri Tui , Hiriart Emilye , Vliet Patrick van , Faure Emilie , Norris Russell A , Farhat Batoul , Lefrancois Julie , Moore-Morris Thomas , Zaffran Stéphane , Faustino Randolph S. , Zambon Alexander C , Sugi Yukiko , Desvignes Jean-Pierre , Salgado David , Levine Robert A. , de la Pompa Jose Luis , Terzic André , Evans Sylvia M. , Markwald Roger , Pucéat Michel 
Published: August 2018

AbstractGenetically modified mice have advanced our understanding of valve development and related pathologies. Yet, little is known regarding human valvulogenesis in health and diseases. Genuine humanin vitromodels that reproduce valvular (patho)biology are thus needed. We here developed a human pluripotent stem cell-derived model fit to decode the early steps of human valvulogenesis and to recapitulate valve disease traits in a dish.Using cellular based, single cell omics-informed andin vivo-validated approaches, we derived a population of pre-valvular endocardial cells from a pluripotent stem cell source. These human prevalvular cells (HPVCs) expressed gene patterns conforming to the atrio-ventricular canal (AVC) endocardium signature originally established in E9.0 mouse embryos. In fact, HPVC treated with BMP2, cultured onto mouse AVC cushions, or transplanted into the AVC of embryonic mouse hearts, underwent endothelial-to-mesenchymal transition and expressed markers of valve interstitial cells of different valvular layers demonstrating tissue functionality. HPVCs also differentiated into tendinous/chondrogenic cells in line with the valvular repertoire. Extending this valvulogenic model to patient specific iPS cells, we recapitulated features of mitral valve prolapse and uncovered that dysregulation of the SHH pathway is likely to be at the origin of the disease thus providing a putative therapeutic target.Human pluripotent stem cells recapitulate early valvulogenesis and provide a powerful model to systematically decipher the origin and lineage contribution of different valvular cell types in humans as well as to study valve diseases in a dish.
Rapid environmental change in games: complications and curiosities
Authors: Trimmer Pete C , Barrett Brendan J , McElreath Richard , Sih Andrew 
Published: August 2018

AbstractHuman-induced rapid environmental change (HIREC) has recently led to alterations in the fitness and behavior of many organisms. Game theory is an important tool of behavioral ecology for analyzing evolutionary situations involving multiple individuals. However, game theory bypasses the details by which behavioral phenotypes are determined, taking the functional perspective straight from expected payoffs to predicted frequencies of behaviors. In contrast with optimization approaches, we identify that to use existing game theoretic models to predict HIREC effects, additional mechanistic details (or assumptions) will often be required. We illustrate this in relation to the hawk-dove game by showing that three different mechanisms, each of which support the same ESS prior to HIREC (fixed polymorphism, probabilistic choice, or cue dependency), can have a substantial effect on behavior (and success) following HIREC. Surprisingly, an increase in the value of resources can lead to a reduction in payoffs (and vice versa), both in the immediate- and long-term following HIREC. An increase in expected costs also increases expected payoffs. Along with these counter-intuitive findings, this work shows that simply understanding the behavioral payoffs of existing games is insufficient to make predictions about the effects of HIREC.It’s the little details that are vital. Little things make big things happen.John Wooden
TCF7L2 Regulation of GATA6-dependent and -Independent Vascular Smooth Muscle Cell Plasticity and Intimal Hyperplasia
Authors: Srivastava Roshni , Rolyan Harshavardhan , Xie Yi , Li Na , Bhat Neha , Hong Lingjuan , Esteghamat Fatemehsadat , Adeniran Adebowale , Geirsson Arnar , Zhang Jiasheng , Ge Guanghao , Nobrega Marcelo , Martin Kathleen A. , Mani Arya 
Published: August 2018

AbstractGenetic variations in Wnt-coreceptor LRP6 and Wnt-regulated transcription factor TCF7L2 have been among the strongest genetic signals for type2 diabetes (T2DM) and coronary artery disease (CAD). Mice with a CAD-linked LRP6 mutation exhibit obstructive coronary artery disease characterized by reduced TCF7L2 expression and dedifferentiation of vascular smooth muscle cell (VSMC). While TCF7L2 maintains stemness and promotes proliferation in embryonic tissues and adult stem cells, its role and mechanisms of action in VSMC differentiation is not understood. Using multiple mouse models, we demonstrate here that TCF7L2 promotes differentiation and inhibits proliferation of VSMCs. TCF7L2 accomplishes these effects by stabilization of GATA6 and upregulation of SM-MHC and cell cycle inhibitors. Accordingly, TCF7L2 haploinsufficient mice exhibited increased susceptibility to, while mice overexpressing TCF7L2 were protected against injury-induced intimal hyperplasia compared to wildtype littermates. Consequently, the overexpression of TCF7L2 in LRP6 mutant mice rescued the injury induced intimal hyperplasia. These novel findings imply cell type-specific functional role of TCF7L2 and provide critical insight into poorly understood mechanisms underlying pathogenesis of intimal hyperplasia.
Neuraminidase Inhibition Contributes to Influenza A Virus Neutralization by Anti-Hemagglutinin Stem Antibodies
Authors: Kosik Ivan , Angeletti Davide , Gibbs James S. , Angel Matthew , Takeda Kazuyo , Kosikova Martina , Nair Vinod , Hickman Heather D. , Xie Hang , Brooke Christopher C. , Yewdell Jonathan W. 
Published: August 2018

SummaryBroadly neutralizing antibodies (Abs) that bind the influenza virus hemagglutinin (HA) stem may enable universal influenza vaccination. Here, we show that anti-stem Abs sterically inhibit viral neuraminidase activity against large substrates, with activity inversely proportional to the length of the fibrous NA stalk that supports the enzymatic domain. By modulating NA stalk length in recombinant IAVs, we show that anti-stem Abs inhibit virus release from infected cells by blocking NA, accounting for theirin vitroneutralization activity. NA inhibition contributes to anti-stem Ab protection in influenza infected mice, likely due at least in part to NA-mediated inhibition of FcγR dependent activation of innate immune cells by antibody bound to virions. FDA approved NA inhibitors enhance anti-stem based Fcγdependent immune cell activation, raising the possibility of therapeutic synergy between NA inhibitors and anti-stem mAb treatment in humans.
Phase Transitioned Nuclear Oskar Promotes Cell Division of Drosophila Primordial Germ Cells
Authors: Kistler Kathryn E. , Trcek Tatjana , Hurd Thomas R. , Chen Ruoyu , Liang Feng-Xia , Sall Joseph , Kato Masato , Lehmann Ruth 
Published: August 2018

ABSTRACTGerm granules are non-membranous ribonucleoprotein granules deemed the hubs for post-transcriptional gene regulation and functionally linked to germ cell fate across species. Little is known about the physical properties of germ granules and how these relate to germ cell function. Here we study two types of germ granules in theDrosophilaembryo: cytoplasmic germ granules that instruct primordial germ cells (PGCs) formation and nuclear germ granules within early PGCs with unknown function. We show that cytoplasmic and nuclear germ granules are phase transitioned condensates nucleated by Oskar protein that display liquid as well as hydrogel-like properties. Focusing on nuclear granules, we find that Oskar drives their formation in heterologous cell systems. Multiple, independent Oskar protein domains synergize to promote granule phase separation. Deletion of Oskar’s nuclear localization sequence specifically ablates nuclear granules in cell systems. In the embryo, nuclear germ granules promote germ cell divisions thereby increasing PGC number for the next generation.
Dimethylarsenic acid (DMA) accumulation positively correlates with realgar-induced subchronic toxicity in rats
Authors: Yi Yan , Gao Shuangrong , Xia Jing , Zhao Yong , Li Chunying , Zhang Yushi , Wang Lianmei , Pan Chen , Liu Suyan , Han Jiayin , Liang Aihua , Shen Ji 
Published: August 2018

AbstractThe toxicity of realgar depends largely on different arsenic species accumulation and distribution in the body. Here, after continuous oral administration of different doses of realgar for 90 days and subsequent 60-day withdrawal period, clinical observations, food consumption, body weights, blood biochemistry, hematology, and histomorphological examination of rats were performed. Realgar 40mg·kg−1·d−1 and 170 mg·kg−1·d−1 of realgar (which is equivalent to 40-fold and 100-fold the maximum clinical dose, respectively) can cause toxicity in rats, including degreased body weight, peripheral blood neutrality abnormal ratio of granulocytes and lymphocytes, hypercoagulability of the blood, liver and kidney tissue damage, liver and kidney may be the main toxic target organs of realgar. The no observed adverse effect level (NOAEL) dose is 10 mg·kg−1. At the same time, the content and distribution of arsenic species in tissues were determined. The content of total arsenic (tAs) and Dimethylarsenic acid (DMA) in the tissues of the realgar group was significantly higher than those of the control group. After 60 days of discontinuation, the DMA content in the realgar group decreased, but it was still higher than that in the control group, and liver and kidney damage occurred during the administration period basically returned to normal. Therefore, the authors speculated that when the DMA content in the tissue exceeds a certain range, liver and kidney toxicity will be induced. However, when the DMA content is lower than the above threshold after drug withdrawal, the liver and kidney lesions can return to normal.
Service productivity vs service quality: a zero-sum game?
Authors: Rew Dongjun , Jung Joo , Cha Wonsuk 
Published: August 2018

PurposeThe purpose of this paper is to verify the relationship between productivity and quality in the services sector. More specifically, this study investigates the relationship between productivity and customer satisfaction and its effect on a firm’s performance. In addition, this study investigates the roles of productivity and customer satisfaction in the structural relationships among variables.Design/methodology/approachA theoretical model was proposed among innovation, productivity, customer satisfaction and firm performance. A sample of 127 firms from data sets of the American Customer Satisfaction Index and COMPUSTAT was collected. To test the hypotheses, this study used ordinal least squares analysis and path analysis.FindingsThe findings of this study verified that a positive relationship exists between productivity and customer satisfaction and that service productivity and customer satisfaction are positively associated with a firm’s performance. In addition, customer satisfaction was found to fully mediate the relationship between productivity and a firm’s performance.Research limitations/implicationsThis study only focused on a short period for each variable due to the difficulty of matching all the data sets used for measuring each variable, which limited the observation of the different effects of service productivity among industries.Practical implicationsThe findings of this study suggest that managers can improve productivity without sacrificing customer satisfaction. In addition, services firms should consider innovation, productivity and customer satisfaction in a holistic way because all of these affect a firm’s performance. Furthermore, services firms need to pay more attention to customer satisfaction, which plays an important role as a mediator in increasing a firm’s performance.Originality/valueThis study highlights the importance of the relationship between productivity and customer satisfaction in the services sector. In particular, this study extended the theory of service productivity by Rust and Huang (2012) to explore the role of service productivity and customer satisfaction in measuring a firm’s performance.
A multi-year SEM model predicting the impact of behavior attributes on overall patient satisfaction
Authors: Nottingham Quinton , Johnson Dana M. , Russell Roberta 
Published: August 2018

Purpose
Pressure from competition; inflexible third-party reimbursements; greater demand from government, regulatory and certifying agencies; discerning patients; and the quest of healthcare entities for greater profitably place demands and high expectations for service quality impacting overall patient experience. Extending a prior multivariate, single-period model of varied medical practices predicting patient experience to a three-year time period to understand whether there was a change in overall assessment using data analytics. The paper aims to discuss these issues.

Design/methodology/approach
SEM was employed on a per year and aggregated, three-year basis to gain insights into qualitative psychometric constructs predicting overall patient experience and strength of the relationships.

Findings
Statistically significant differences were uncovered between years indicating the strength of the relationships of latent variables on overall performance.

Research limitations/implications
Study focused on data gathered from a questionnaire mailed to patients who visited various outpatient medical clinics in a rural community with over 4,000 responses during the three-year study period. A higher percentage of female respondents over the age of 45 may limit the generalizability of the findings.

Practical implications
Practitioners can gain a broader understanding of different factors influencing overall patient experience. Administrative processes associated with the primary care provider are inconsequential. Patients are not as concerned with patient flow as they are with patient safety and health.

Originality/value
This research informs healthcare quality management of psychometrics and analytics to improve the overall patient experience in outpatient medical clinics.