bluuebunny/crossref_metadata_2025_split huggingface dataset:
The lamellipodium is a myosin independent mechanosensor
Authors: Oakes Patrick W. , Bidone Tamara C. , Beckham Yvonne , Skeeters Austin V. , Ramirez-San Juan Guillermina R. , Winter Stephen P. , Voth Gregory A. , Gardel Margaret L. 
Published: September 2017

AbstractThe ability of adherent cells to sense changes in the mechanical properties of their extracellular environments is critical to numerous aspects of their physiology. It has been well documented that cell attachment and spreading are sensitive to substrate stiffness. Here we demonstrate that this behavior is actually biphasic, with a transition that occurs around a Young’s modulus of ∼7 kPa. Furthermore, we demonstrate that, contrary to established assumptions, this property is independent of myosin II activity. Rather, we find that cell spreading on soft substrates is inhibited due to reduced nascent adhesion formation within the lamellipodium. Cells on soft substrates display normal leading edge protrusion activity, but these protrusions are not stabilized due to impaired adhesion assembly. Enhancing integrin-ECM affinity through addition of Mn2+recovers nascent adhesion assembly and cell spreading on soft substrates. Using a computational model to simulate nascent adhesion assembly, we find that biophysical properties of the integrin-ECM bond are optimized to stabilize interactions above a threshold matrix stiffness that is consistent with the experimentally observations. Together these results suggest that myosin II-independent forces in the lamellipodium are responsible for mechanosensation by regulating new adhesion assembly, which in turn, directly controls cell spreading. This myosin II-independent mechanism of substrate stiffness sensing could potentially regulate a number of other stiffness sensitive processes.Significance StatementCell physiology can be regulated by the mechanics of the extracellular environment. Here, we demonstrate that cell spreading is a mechanosensitive process regulated by weak forces generated at the cell periphery and independent of motor activity. We show that stiffness sensing depends on the kinetics of the initial adhesion bonds that are subjected to forces driven by protein polymerization. This work demonstrates how the binding kinetics of adhesion molecules are sensitively tuned to a range of forces that enable mechanosensation.
An integrated analysis of the epigenetic, genetic, and transcriptional patterns associated with outcome across cancer types
Authors: Smith Joan C. , Sheltzer Jason M. 
Published: September 2017

AbstractSuccessful treatment decisions in cancer depend on the accurate assessment of patient risk. To improve our understanding of the molecular alterations that underlie deadly malignancies, we analyzed genomic profiles from 33,036 solid tumors with known patient outcomes. Contrary to expectations, we find that mutations in cancer driver genes are almost never associated with patient survival time. In contrast, copy number changes in these same genes are broadly prognostic. Analysis of methylation, microRNA, mRNA, and protein expression patterns in primary tumors define several additional prognostic patterns, including signatures of tumor mitotic activity and tissue de-differentiation. Co-expression analysis with a cell cycle meta-gene distinguished proliferation-dependent and ‐independent prognostic features, allowing us to construct multivariate survival models with improved stratification power. In total, our analysis provides a comprehensive resource for biomarker and therapeutic target identification, and suggests that copy number and methylation profiling should complement tumor sequencing efforts to improve patient risk assessment.
Necrosis triggered byMycobacterium tuberculosisalters macrophage triglyceride metabolism and inflammatory response in a DGAT1 – dependent manner
Authors: Jaisinghani Neetika , Dawa Stanzin , Singh Kaurab , Nandy Ananya , Menon Dilip , Bhandari Purva , Khare Garima , Tyagi Anil , Gandotra Sheetal 
Published: September 2017

AbstractTuberculosis granulomas represent a site of controlling bacterial dissemination at the cost of host tissue damage. Within the heterogenous array of TB granulomas, some contain triglyceride (TG) rich foamy macrophages, the etiology and function of which remains largely unexplained. Here we show that necrosis of tuberculosis lesions andM. tuberculosis(Mtb) infected macrophages elicits a bystander response of triglyceride storage. We elucidate a role for the RD1 region of mycobacterial genome to be a key player in this phenomenon. TG storage in necrosis associated foamy macrophages promoted the pro-inflammatory state of macrophages while silencing expression of diacylglycerol O-acyltransferase (DGAT1) suppressed expression of pro-inflammatory genes. Surprisingly, acute infection with Mtb led to lipolysis of host TG, rather than synthesis, suggesting mobilization of triglyceride stored within macrophage lipid droplets to be involved in the inflammatory response to infection. Our data is likely to open new avenues for management of the inflammatory response during infection.
Tiny niches and translocations: The challenge of identifying suitable recipient sites for small and immobile species
Authors: Brooker Rob W. , Brewer Mark J. , Britton Andrea J. , Eastwood Antonia , Ellis Christopher , Gimona Alessandro , Poggio Laura , Genney David R. 
Published: September 2017

Abstract

Assisted colonisation, one form of species translocation, has been proposed as a tool for helping species to track suitable conditions in a changing climate. There are considerable practical challenges associated with it, including predicting where to place translocated individuals. This problem may be particularly big for small and immobile species, where small‐scale microenvironmental conditions de‐couple them from environmental conditions as projected in large‐scale climate models.

To investigate this problem, we developed a survey‐based model to predict the occurrence of our target species, the fruticose terricolous arctic‐alpine lichen, Flavocetraria nivalis, within the Cairngorm Mountains.

We then undertook an experimental translocation of this species. A second model, using variables that were significant in the survey‐based model, was only fair at predicting the initial pattern of survival at the recipient site.

However, model fit of the translocation survival model improved over time as the distribution of surviving individuals more accurately reflected the distribution of suitable environmental conditions. In addition, model predictive power increased with the addition of data on microclimatic conditions at recipient plots.

Synthesis and applications. Our results demonstrate that, for species which respond strongly to local environmental conditions, are immobile and, to some extent, decoupled from larger scale climates, it may be difficult to build a priori accurate predictive models of habitat suitability. In these cases, a combination of modelling and expert judgement, along with the movement of substantial numbers of transplants, may be the appropriate options for maximising the success of assisted colonisation.
Capillary Electrophoresis Based on Nucleic Acid Detection as Used in Food Analysis
Authors: Lian Dong‐Sheng , Zeng Hua‐Song 
Published: September 2017

AbstractFood safety and food production are closely related to the health of consumers. Food‐related accidents often cause tremendous losses of personnel and property. Thus, rapid detection and analysis of ingredients in food, tracing food sources, studying the optimal conditions for food production, and more are vital for preventing incidents related to safety. Conventional analysis based on proteomics, microbial cultures, and morphology, as well as biochemical tests based on metabonomics, are considered gold standards and used frequently, but they are labor‐intensive, time‐consuming, tedious, error‐prone, and incapable of meeting the demand for rapid and precise detection at a large scale. Alternative detection methods that utilize capillary electrophoresis have the advantages of high efficiency, high throughput, high speed, and automation; these methods are coupled with various nucleic acid detection strategies to overcome the drawbacks of traditional identification methods, and to prevent false results. Therefore, this review focuses on the application of capillary electrophoresis based on nucleic acid detection in food analysis and provides an introduction to the limitations, advantages, and future developments of this approach.
Supplementation with the Methyl Donor Betaine Prevents Congenital Defects Induced by Prenatal Alcohol Exposure
Authors: Karunamuni Ganga , Sheehan Megan M. , Doughman Yong Qiu , Gu Shi , Sun Jiayang , Li Youjun , Strainic James P. , Rollins Andrew M. , Jenkins Michael W. , Watanabe Michiko 
Published: September 2017

BackgroundDespite decades of public education about dire consequences of prenatal alcohol exposure (PAE), drinking alcohol during pregnancy remains prevalent. As high as 40% of live‐born infants exposed to alcohol during gestation and diagnosed with fetal alcohol syndrome have congenital heart defects that can be life‐threatening. In animal models, the methyl donor betaine, found in foods such as wheat bran, quinoa, beets, and spinach, ameliorated neurobehavioral deficits associated with PAE, but effects on heart development are unknown.MethodsPreviously, we modeled a binge drinking episode during the first trimester in avian embryos. Here, we investigated whether betaine could prevent adverse effects of alcohol on heart development. Embryos exposed to ethanol (EtOH) with and without an optimal dose of betaine (5 μM) were analyzed at late developmental stages. Cardiac morphology parameters were rapidly analyzed and quantified using optical coherence tomography. DNA methylation at early stages was detected by immunofluorescent staining for 5‐methylcytosine in sections of embryos treated with EtOH or cotreated with betaine.ResultsCompared to EtOH‐exposed embryos, betaine‐supplemented embryos had higher late‐stage survival rates and fewer gross head and body defects than seen after alcohol exposure alone. Betaine also reduced the incidence of late‐stage cardiac defects such as absent vessels, abnormal atrioventricular (AV) valves, and hypertrophic ventricles. Furthermore, betaine cotreatment brought measurements of great vessel diameters, interventricular septum thickness, and AV leaflet volumes in betaine‐supplemented embryos close to control values. Early‐stage 5‐methycytosine staining revealed that DNA methylation levels were reduced by EtOH exposure and normalized by co‐administration with betaine.ConclusionsThis is the first study demonstrating efficacy of the methyl donor betaine in alleviating cardiac defects associated with PAE. These findings highlight the therapeutic potential of low‐concentration betaine doses in mitigating PAE‐induced birth defects and have implications for prenatal nutrition policies, especially for women who may not be responsive to folate supplementation.
Association between mode of delivery and astigmatism in preschool children
Authors: Liu Fengyang , Yang Xubo , Tang Angcang , Liu Longqian 
Published: September 2017

AbstractPurposeTo determine whether mode of delivery has any impact on astigmatism.MethodsThis case–control study was performed in the Department of Ophthalmology in 2015. Exposure was mode of delivery [vaginal delivery (VD) or caesarean section (CS), which here included both elective and emergency CS]. Outcome was astigmatism (≥2.5 D), which was determined by cycloplegic refraction. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed to assess the associations between mode of delivery and astigmatism from logistic regression models.ResultsOf the 659 children studied here (341 boys; mean age, 4.37 years), 440 were born by CS and 219 by VD. The incidence of severe astigmatism (≥2.5 D) in the CS and VD groups was 22.06% and 13.24%, respectively. Children delivered by CS had a 77.9% higher risk of severe astigmatism compared with vaginally delivered children (OR = 1.779; 95% CI, 1.121 to 2.824). After dividing CS into elective CS and emergency CS, children delivered by elective CS had an 87.3% increased risk of severe astigmatism (OR = 1.873; 95% CI, 1.157 to 3.032), but children delivered by emergency CS did not differ from vaginally delivered children. In addition, the children whose mothers had histories of breastfeeding had a 44.6% lower risk of severe astigmatism than children whose mother did not breastfeed them (OR = 0.554, 95% CI, 0.335–0.914).ConclusionBirth by CS, especially elective CS, increases the risk of severe astigmatism (≥2.50 D) in childhood.
SUMO co‐expression modifies KV11.1 channel activity
Authors: Steffensen A. B. , Andersen M. N. , Mutsaers N. , Mujezinovic A. , Schmitt N. 
Published: September 2017

AbstractAimThe voltage‐gated potassium channel KV11.1 is the molecular basis for the IKr current, which plays an important role in cardiac physiology. Its malfunction is associated with both inherited and acquired cardiac arrhythmias. Native currents differ from those in experimental models, suggesting additional regulatory mechanisms. We hypothesized that the post‐translational modification sumoylation fine‐tunes channel activity.MethodsThe functional effects of sumoylation on KV11.1 were addressed by employing two‐electrode voltage‐clamp (TEVC) experiments in Xenopus laevis oocytes. Site‐directed mutagenesis enabled a further analysis of the SUMO‐target amino acids. We assessed protein expression levels and used confocal imaging for localization studies.ResultsCo‐expression with Ubc9 and SUMO alters the electrophysiological properties of KV11.1 leading to a decrease in steady‐state current amplitude largely due to faster inactivation and alteration of deactivation kinetics. We identified three lysines (K21, K93 and K116) in the PAS domain as the putative SUMO‐targets.ConclusionThis study indicates KV11.1 as a sumoylation target and offers three main targets: K21, K93, and K116. Furthermore, it proposes an underlying mechanism for the observed kinetic impact of the PAS domain.
Factor Xa inhibition by rivaroxaban in the trough steady state can significantly reduce thrombin generation
Authors: Horinaka Shigeo , Sugawara Rie , Yonezawa Yutaka , Ishimitsu Toshihiko 
Published: September 2017

AimsThe aim of the present study was to demonstrate evidence of reduced thrombin generation at the trough plasma rivaroxaban concentration.MethodsA single‐centre, prospective, nonrandomized, drug‐intervention, self‐controlled study was conducted in 51 anticoagulation therapy‐naïve patients with nonvalvular atrial fibrillation. Plasma rivaroxaban concentration was measured by liquid chromatography tandem mass spectrometry (LC–MS/MS) and the anti‐factor Xa chromogenic assay. Partial thrombin time (PT), protein C activity, and protein S antigen, prothrombin fragment 1 + 2 (F1 + 2), D‐dimer, thrombomodulin (TM), thrombin–antithrombin complex (TAT), plasminogen activator inhibitor‐1 (PAI‐1) and tissue factor pathway inhibitor (TFPI) levels were also measured at the trough steady state after 4 weeks of rivaroxaban treatment and compared with baseline.ResultsPlasma concentrations obtained by the LC–MS/MS and anti‐Xa assays were correlated (r = 0.841, P < 0.001). The mean concentration of rivaroxaban at the trough steady state was 23.6 ng ml–1, at which F1 + 2, TAT and D‐dimer had decreased from the baseline values (P < 0.0001, P = 0.029 and P < 0.005, respectively). PT was prolonged (+0.59 s, P < 0.0001). TFPI increased from baseline to the trough steady state in the first to third quartile groups (+0.79 pg ml–1, P = 0.048). By contrast, PAI‐1, protein C activity, protein S antigen and TM remained within the normal range at the trough steady state.ConclusionsResidual plasma rivaroxaban at the trough steady state may explain the antithrombin effect of rivaroxaban in patients with nonvalvular atrial fibrillation.
Opportunities for Students to Prescribe: An Evaluation of 185 Consultations in the Student‐run Cardiovascular Risk Management Programme
Authors: Schutte Tim , Prince Katinka , Richir Milan , Donker Erik , van Gastel Leonie , Bastiaans Ferdynand , de Vries Henk , Tichelaar Jelle , van Agtmael Michiel 
Published: September 2017

AbstractInvolving students in cardiovascular risk management (CVRM) could offer patients a structured CVRM programme and students a valuable learning opportunity. We describe and evaluate a student‐run CVRM programme that was set up to offer primary prevention to patients with known risk factors in a general practitioner's practice. During a consultation, two undergraduate medical students assessed the patients' actual risk and formulated a CVRM plan, which they discussed with the patient after approval by a GP. After the consultations, patients were asked to complete evaluation/feedback questionnaires. From December 2014 to December 2015, 185 consultations were carried out by 46 students. Feedback questionnaires of 153 consultations were returned, in which patient satisfaction was 8.43 (1–10, min‐max). The cardiovascular risk of 95 patients was determined, and in >50% patients, it was ‘high’. Participating students and GPs were enthusiastic about the (pharmacotherapy) learning opportunities and improved CVRM care while contributing to real patient care in this CVRM programme.
Prenatal attitudes toward vaginal delivery and actual delivery mode: Variation by race/ethnicity and socioeconomic status
Authors: Attanasio Laura B. , Hardeman Rachel R. , Kozhimannil Katy B. , Kjerulff Kristen H. 
Published: September 2017

AbstractObjectivesResearchers documenting persistent racial/ethnic and socioeconomic status disparities in chances of cesarean delivery have speculated that women's birth attitudes and preferences may partially explain these differences, but no studies have directly tested this hypothesis. We examined whether women's prenatal attitudes toward vaginal delivery differed by race/ethnicity or socioeconomic status, and whether attitudes were differently related to delivery mode depending on race/ethnicity or socioeconomic status.MethodsData were from the First Baby Study, a cohort of 3006 women who gave birth to a first baby in Pennsylvania between 2009 and 2011. We used regression models to examine (1) predictors of prenatal attitudes toward vaginal delivery, and (2) the association between prenatal attitudes and actual delivery mode. To assess moderation, we estimated models adding interaction terms.ResultsPrenatal attitudes toward vaginal delivery were not associated with race/ethnicity or socioeconomic status. Positive attitudes toward vaginal delivery were associated with lower odds of cesarean delivery (AOR=0.60, P < .001). However, vaginal delivery attitudes were only related to delivery mode among women who were white, highly educated, and privately insured.ConclusionsThere are racial/ethnic differences in chances of cesarean delivery, and these differences are not explained by birth attitudes. Furthermore, our findings suggest that white and high‐socioeconomic status women may be more able to realize their preferences in childbirth.
Progression of care among women who use a midwife for prenatal care: Who remains in midwife care?
Authors: Weisband Yiska Loewenberg , Gallo Maria F. , Klebanoff Mark A. , Shoben Abigail B. , Norris Alison H. 
Published: September 2017

AbstractBackgroundPrenatal care provided by midwives provides a safe and cost‐effective alternative to care provided by physicians. However, no studies have evaluated the frequency of women who leave midwifery care, in a hospital setting. Our study objectives were to measure the frequency of transfers of care to physicians, to describe the sociodemographic and pregnancy‐related characteristics of women who transferred to the care of a physician during prenatal care and at delivery, and to assess correlates of these transfers.MethodsWe used electronic medical records to perform a retrospective cohort study of women who delivered at The Ohio State University Wexner Medical Center (OSUWMC) and had at least one prenatal care visit within OSUWMC's network. We report descriptive findings, using proportions and means with standard deviations. We used logistic regression, with Firth's bias correction as necessary, to assess correlates of transferring to a physician during prenatal care and at delivery.ResultsMost women who initiated prenatal care with a midwife remained in midwifery care throughout delivery, with 4.7% transferring to a physician during prenatal care, and an additional 21.4% transferring to a physician during delivery. After adjusting for pregnancy‐related factors, the black race was statistically significantly associated with leaving midwifery care during prenatal care (adjusted odds ratio AOR 3.0 [95% CI 1.4–6.6]) and delivery (AOR 2.5 [95% CI 1.5–4.3]).ConclusionFindings indicate that most women remain in midwifery care throughout pregnancy, but raise important questions with respect to the possible role that race has in pregnancy care.
Magnesium therapy improves outcome in Streptococcus pneumoniae meningitis by altering pneumolysin pore formation
Authors: Hupp Sabrina , Ribes Sandra , Seele Jana , Bischoff Carolin , Förtsch Christina , Maier Elke , Benz Roland , Mitchell Timothy J , Nau Roland , Iliev Asparouh I 
Published: September 2017

Background and PurposeStreptococcus pneumoniae is the most common cause of bacterial meningitis in adults and is characterized by high lethality and substantial cognitive disabilities in survivors. Here, we have studied the capacity of an established therapeutic agent, magnesium, to improve survival in pneumococcal meningitis by modulating the neurological effects of the major pneumococcal pathogenic factor, pneumolysin.Experimental ApproachWe used mixed primary glial and acute brain slice cultures, pneumolysin injection in infant rats, a mouse meningitis model and complementary approaches such as Western blot, a black lipid bilayer conductance assay and live imaging of primary glial cells.Key ResultsTreatment with therapeutic concentrations of magnesium chloride (500 mg·kg−1 in animals and 2 mM in cultures) prevented pneumolysin‐induced brain swelling and tissue remodelling both in brain slices and in animal models. In contrast to other divalent ions, which diminish the membrane binding of pneumolysin in non‐therapeutic concentrations, magnesium delayed toxin‐driven pore formation without affecting its membrane binding or the conductance profile of its pores. Finally, magnesium prolonged the survival and improved clinical condition of mice with pneumococcal meningitis, in the absence of antibiotic treatment.Conclusions and ImplicationsMagnesium is a well‐established and safe therapeutic agent that has demonstrated capacity for attenuating pneumolysin‐triggered pathogenic effects on the brain. The improved animal survival and clinical condition in the meningitis model identifies magnesium as a promising candidate for adjunctive treatment of pneumococcal meningitis, together with antibiotic therapy.