bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nkx2.5-dependent alterations of the embryonic heart DNA methylome identify novel cis-regulatory elements in cardiac development
Authors: Gorsi Bushra , Mosbruger Timothy L. , Smith Megan , Hill Jonathon T. , Yost H. Joseph 
Published: September 2017

AbstractTranscription factor Nkx2.5 is frequently mutated in congenital heart disease, but the mechanisms by which Nkx2.5 regulates heart development are poorly understood. By generating comprehensive DNA methylome maps from zebrafish embryonic hearts innxk2.5mutants and siblings, we discovered that Nkx2.5 regulates DNA methylation patterns during cardiac morphogenesis. We identified hundreds of Nkx-dependent heart-specific Differentially Methylated Regions (nhDMRs). A majority of the nhDMRs were hypomethylated innkx2.5−/-hearts, correlating with changes in the mutant transcriptome, suggesting Nkx2.5 functions largely as a repressor. Distinct Nkx DNA-binding motifs were significantly enriched in subclasses of nhDMRs. Furthermore, nhDMRs were significantly associated with histone H3K4me1 and H3K27ac post-translational modifications, suggesting Nkx2.5 regulates gene expression by differential methylation of cis-regulatory elements. Using transgenics, we validated several nhDMRs with enhancer activities in the heart. We propose a novel role of Nkx2.5 mediated DNA methylation is integral in activating and repressing Nkx2.5 target genes during heart development.
Down-regulation of LRIG1 by miR-20a modulates gastric cancer multidrug resistance
Authors: Zhou Lin , Li Xiaowei , Zhou Fan , Jin Zhi’an , Chen Di , Wang Pin , Zhang Shu , Zhuge Yuzheng , Shang Yulong , Zou Xiaoping 
Published: September 2017

AbstractMultidrug resistance (MDR) significantly restricts the clinical efficacy of gastric cancer (GC) chemotherapy, and it is critical to search novel targets to predict and overcome MDR. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) has been proved to be correlated with drug resistance in several cancers. The present study revealed that LRIG1 was overexpressed in chemo-sensitive GC tissues and decreased expression of LRIG1 predicted poor survival in GC patients. We observed that up-regulation of LRIG1 enhanced chemo-sensitivity in GC cells. Interestingly, miR-20a, which was overexpressed in GC MDR cell lines and tissues, was identified to regulate LRIG1 expression by directly targeting its 3′untranslated region. We also found that inhibition of miR-20a suppressed GC MDR, and up-regulation showed opposite effects. Moreover, we demonstrated that the miR-20a/LRIG1 axis regulated GC cell MDR through EGFR mediated PI3K/AKT and MAPK/ERK signaling pathways. Finally, LRIG1 expression in human GC tissues is inversely correlated with miR-20a and EGFR. Taken together, the newly identified miR-20a/LRIG1/EGFR link provides insight into the MDR process of GC, and targeting this axis represents a novel potential therapeutic strategy to block GC chemo-resistance.
DNA metabarcoding potentially reveals multi-assemblage eutrophication responses in an eastern North American river
Authors: Craine Joseph M. , Cannon Matthew V. , Elmore Andrew J. , Guinn Steven M. , Fierer Noah 
Published: September 2017

AbstractFreshwater aquatic ecosystems provide a wide range of ecosystem services, yet provision of these services is increasingly threatened by human activities. Directly quantifying freshwater biotic assemblages has long been a proxy for assessing changing environmental conditions, yet traditional aquatic biodiversity assessments are often time consuming, expensive, and limited to only certain habitats and certain taxa. Sequencing aquatic environmental DNA via metabarcoding has the potential to remedy these deficiencies. Such an approach could be used to quantify changes in the relative abundances of a broad suite of taxa along environmental gradients, providing data comparable to that obtained using more traditional bioassessment approaches. To determine the utility of metabarcoding for comprehensive aquatic biodiversity assessments, we sampled aquatic environmental DNA at 25 sites that spanned the full length of the Potomac River from its headwaters to the Potomac estuary. We measured dissolved nutrient concentrations and also sequenced amplified marker genes using primer pairs broadly targeting four taxonomic groups. The relative abundances of bacteria, phytoplankton, invertebrate, and vertebrate taxa were distinctly patterned along the river with significant differences in their abundances across headwaters, the main river, and the estuary. Within the main river, changes in the abundances of these broad taxonomic groups reflected either increasing river size or a higher degree of eutrophication. The larger and more eutrophic regions of the river were defined by high total dissolved phosphorus in the water, a unique suite of bacteria, phytoplankton such as species of thediatomNitzschia, invertebrates like the freshwater snailPhysella acuta, and high abundance of fish including the common carp (Cyprinus carpio). Taxonomic richness of phytoplankton and vertebrates increased downriver while it consistently decreased for bacteria. Given these results, multi-assemblage aquatic environmental DNA assessment of surface water quality is a viable tool for bioassessment. With minimal sampling effort, we were able to construct the equivalent of a freshwater water quality index, differentiate closely-related taxa, sample places where traditional monitoring would be difficult, quantify species that are difficult to detect with traditional techniques, and census taxa that are generally captured with more traditional bioassessment approaches. To realize the full potential of aquatic environmental DNA for bioassessment, research is still needed on primer development, a geographically broad set of reference sites need to be characterized, and reference libraries need to be further developed to improve taxonomic identification.
Genetic and metabolic regulation ofMycobacterium tuberculosisacid growth arrest
Authors: Baker Jacob J. , Abramovitch Robert B. 
Published: September 2017

AbstractMycobacterium tuberculosis(Mtb) senses and adapts to acidic environments during the course of infection. Acidic pH-dependent adaptations include the induction of metabolic genes associated with anaplerosis and growth arrest on specific carbon sources. In this study, reverse and forward genetic studies were undertaken to define new mechanisms underlying pH-dependent adaptations. Here we report that deletion of isocitrate lyase (icl1/2) or phosphoenolpyruvate carboxykinase (pckA) results in reduced growth at acidic pH and altered metabolite profiles, supporting that remodeling of anaplerotic metabolism is required for pH-dependent adaptation. Mtb cultured at pH 5.7 in minimal medium containing glycerol as a single carbon source exhibits an acid growth arrest phenotype, where the bacterium is non-replicating but viable and metabolically active. The bacterium uptakes and metabolizes glycerol and maintains ATP pools during acid growth arrest and becomes tolerant to detergent stress and the antibiotics isoniazid and rifampin. A forward genetic screen identified mutants that do not arrest their growth at acidic pH, including four enhanced acid growth (eag) mutants with three distinct mutations in the PPE gene MT3221. Overexpression of the MT3221(S211R) variant protein in wild type Mtb results in enhanced acid growth and reduced drug tolerance. Together, these findings provide new evidence for a genetic and physiological basis for acid growth arrest and support that growth arrest is an adaptive process and not simply a physiological limitation associated with acidic pH.Author SummaryThe bacteriumMycobacterium tuberculosis(Mtb) causes the disease tuberculosis in humans. During infection Mtb colonizes a variety of environments that have acidic environments and Mtb must adapt to these environments to cause disease. One of these adaptations is that Mtb slows and arrests its growth at acidic pH, and the goal of this study was to examine the genetics and physiology of these pH-dependent adaptations. We found that Mtb modifies its metabolism at acidic pH and that these adaptations are required for optimal growth. We also found that acidic pH and specific nutrient sources can promote the bacterium to enter a state of dormancy, called acid growth arrest, where the bacterium becomes tolerant to antibiotics. Mutants were identified that do not arrest their growth at acidic, revealing that acid growth arrest is a genetically controlled process. Overall, understanding how Mtb adapts to acidic pH has revealed pathway that are required for virulence and drug tolerance and thus may identify new targets for drug development that may function to shorten the course of TB therapy.
Electrical synapses between inhibitory neurons shape the responses of principal neurons to transient inputs in the thalamus
Authors: Pham Tuan , Haas Julie S. 
Published: September 2017

AbstractAs multimodal sensory information proceeds to the cortex, it is intercepted and processed by the nuclei of the thalamus. The main source of inhibition within thalamus is the reticular nucleus (TRN), which collects signals both from thalamocortical relay neurons and from thalamocortical feedback. Within the reticular nucleus, neurons are densely interconnected by connexin36-based gap junctions, known as electrical synapses. Electrical synapses have been shown to coordinate neuronal rhythms, including thalamocortical spindle rhythms, but their role in shaping or modulating transient activity is less understood. We constructed a four-cell model of thalamic relay and TRN neurons, and used it to investigate the impact of electrical synapses on closely timed inputs delivered to thalamic relay cells. We show that the electrical synapses of the TRN assist cortical discrimination of these inputs through effects of truncation, delay or inhibition of thalamic spike trains. We expect that these are principles whereby electrical synapses play similar roles in processing of transient activity in excitatory neurons across the brain.
An open‐source sensor‐logger for recording vertical movement in free‐living organisms
Authors: Shipley J. Ryan , Kapoor Julian , Dreelin Richard A. , Winkler David W. 
Published: September 2017

Abstract

Measuring individual‐based movements in free‐ranging animals is relevant to our understanding of many basic ecological principles (migration, competition, optimal foraging) but has been difficult to realize in a small size.

We have developed a freely available, open‐source, non‐invasive datalogger that can measure an animal's altitude or elevation (A) at sampling intervals greater than once per second, storing up to 10,000 total samples, depending on programme size.

The realized design weighs 370 mg, opening a wealth of opportunities to study animals as small as 10 g without exceeding the 4% rule‐of‐thumb for the relative mass of telemetry devices.

In addition, power management is provided via a modern ultra‐low‐power microcontroller, making it possible to record altitude data over extended periods (>100 days) by extending battery lifetimes.

First results from testing and field applications of this design underline its suitability for reliable and extended monitoring of how animals interact with the environment. Our empirical results show this design can provide high‐resolution data with altitude measurements accurate to the nearest several metres at 1‐s intervals, provided a local known elevation pressure reference, elucidating fine‐scale differences between species/individuals in their use of the air column over 10‐day intervals.
Using Virtual Reality Simulation Environments to Assess Competence for Emergency Medicine Learners
Authors: McGrath Jillian L. , Taekman Jeffrey M. , Dev Parvati , Danforth Douglas R. , Mohan Deepika , Kman Nicholas , Crichlow Amanda , Bond William F. 
Published: September 2017

AbstractImmersive learning environments that use virtual simulation (VS) technology are increasingly relevant as medical learners train in an environment of restricted clinical training hours and a heightened focus on patient safety. We conducted a consensus process with a breakout group of the 2017 Academic Emergency Medicine Consensus Conference “Catalyzing System Change Through Health Care Simulation: Systems, Competency, and Outcomes.” This group examined the current uses of VS in training and assessment, including limitations and challenges in implementing VS into medical education curricula. We discuss the role of virtual environments in formative and summative assessment. Finally, we offer recommended areas of focus for future research examining VS technology for assessment, including high‐stakes assessment in medical education. Specifically, we discuss needs for determination of areas of focus for VS training and assessment, development and exploration of virtual platforms, automated feedback within such platforms, and evaluation of effectiveness and validity of VS education.
MiR‐21‐Mediated Suppression of Smad7 Induces TGFβ1 and Can Be Inhibited by Activation of Nrf2 in Alcohol‐Treated Lung Fibroblasts
Authors: Marts Lucian T. , Green David E. , Mills Stephen T. , Murphy Tamara , Sueblinvong Viranuj 
Published: September 2017

BackgroundWe previously demonstrated that chronic alcohol ingestion augments TGFβ1 expression in the lung fibroblast and increases the risk of fibroproliferative disrepair in a mouse model of acute lung injury. The effect of alcohol on TGFβ1 is mitigated by treatment with sulforaphane (SFP), which can activate nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2). However, the mechanisms by which alcohol amplifies, or SFP attenuates, TGFβ1 expression in the fibroblast are not known. MicroRNA (miR)‐21 has been shown to inhibit Smad7, a TGFβ1 signaling inhibitor. In this study, we hypothesized that alcohol augments TGFβ1 expression through up‐regulation of miR‐21, which subsequently inhibits Smad7.MethodsPrimary mouse lung fibroblasts were cultured ± alcohol ± SFP and assessed for gene expression of miR‐21, and gene and/or protein expression of Nrf2, Nrf2‐regulated antioxidant enzymes, Smad7, STAT3, and TGFβ1. NIH 3T3 fibroblasts were transfected with a miR‐21 inhibitor and cultured ± alcohol. α‐SMA, Smad7, and TGFβ1 protein expression were then assessed. In parallel, NIH 3T3 lung fibroblasts were transfected with Nrf2 silencing RNA (siRNA) and cultured ± alcohol ± SFP. Gene expression of miR‐21, Nrf2, Smad7, and TGFβ1 was assessed.ResultsMiR‐21 gene expression was increased by 12‐fold at 48 hours, and Smad7 gene expression and protein expression were reduced by ~30% in alcohol‐treated fibroblasts. In parallel, inhibition of miR‐21 attenuated alcohol‐mediated decrease in Smad7 and increase in TGFβ1 and α‐SMA protein expression. Treatment with SFP mitigated the effect of alcohol on miR‐21, Smad7 and total and phosphorylated STAT3, and restored Nrf2‐regulated antioxidant gene expression. Silencing of Nrf2 prevented the effect of SFP on miR‐21, Smad7, and TGFβ1 gene expression in alcohol‐treated NIH 3T3 fibroblasts.ConclusionsAlcohol treatment increases TGFβ1 in fibroblasts, at least in part, through augmentation of miR‐21, which then inhibits Smad7 expression. These effects can be attenuated by activation of Nrf2 with SFP.
Why do surgeons receive more complaints than their physician peers?
Authors: Tibble Holly M. , Broughton Nigel S. , Studdert David M. , Spittal Matthew J. , Hill Nicola , Morris Jennifer M. , Bismark Marie M. 
Published: September 2017

BackgroundCompared with other doctors, surgeons are at an increased risk of medicolegal events, including patient complaints and negligence claims. This retrospective study aimed to describe the frequency and nature of complaints involving surgeons compared with physicians.MethodsWe assembled a national data set of complaints about surgeons and physicians lodged with medical regulators in Australia from 2011 to 2016. We classified the complaints into 19 issues across four domains: treatment and procedures, other performance, professional conduct and health. We assessed differences in complaint risk using incidence rate ratios (IRRs). Finally, we used a multivariate model to identify predictors of complaints among surgeons.ResultsThe rate of complaints was 2.3 times higher for surgeons than physicians (112 compared with 48 complaints per 1000 practice years, P < 0.001). Two‐fifths (41%) of the higher rate of complaints among surgeons was attributable to issues other than treatments and procedures, including fees (IRR = 2.68), substance use (IRR = 2.10), communication (IRR = 1.98) and interpersonal behaviour (IRR = 1.92). Male surgeons were at a higher risk of complaints, as were specialists in orthopaedics, plastic surgery and neurosurgery.DiscussionSurgeons are more than twice as likely to attract complaints as their physician peers. This elevated risk arises partly from involvement in surgical procedures and treatments, but also reflects wider concerns about interpersonal skills, professional ethics and substance use. Improved understanding of these patterns may assist efforts to reduce harm and support safe practise.
MicroRNA‐214‐3p: A link between autophagy and endothelial cell dysfunction in atherosclerosis
Authors: Wang J. , Wang W.‐N. , Xu S.‐B. , Wu H. , Dai B. , Jian D.‐D. , Yang M. , Wu Y.‐T. , Feng Q. , Zhu J.‐H. , Zhang L. , Zhang L. 
Published: September 2017

AbstractAimEndothelial cell injury assumes a fundamental part in the pathogenesis of atherosclerosis, and endothelial cell autophagy has protective effects on the development of atherosclerosis, although the underlying molecular regulation mechanism is indistinct. This study aimed to investigate whether microRNA‐214‐3p (miR‐214‐3p) is involved in the endothelial cell autophagy regulation of atherosclerosis.MethodsWe utilized ApoE−/− mice provided with a high‐fat diet (HFD) as atherosclerosis model. We analysed the level of miR‐214‐3p and the levels of autophagy‐related protein 5 (ATG5) and autophagy‐related protein 12 (ATG12) in the purified CD31+ endothelial cells from mouse aorta. Bioinformatics analysis and a dual‐luciferase reporter assay were performed to confirm the binding target of miR‐214‐3p. In vitro study, human umbilical vein endothelial cells (HUVECs) were transfected with miR‐214‐3p mimics/inhibitor and stimulated with 100 μg/mL oxidized low‐density lipoprotein (ox‐LDL) for 12 hours to initiate a stress‐repairing autophagic process.ResultsIn mouse models, we identified an inverse correlation between miR‐214‐3p, ATG5 and ATG12. We observed that in young HUVECs, ox‐LDL‐initiated autophagy was repressed by miR‐214‐3p overexpression, as evaluated by autophagic protein analysis, microtubule‐associated protein 1 light chain 3B‐II (LC3B‐II) immunofluorescence assay and transmission electron microscopy (TEM). Also, miR‐214‐3p promoted ox‐LDL accumulation in HUVECs and THP‐1 monocyte adhesion. Conversely, in old HUVECs, suppression of miR‐214‐3p preserved the ability to initiate a protective autophagy reaction to the ox‐LDL stimulation.ConclusionmiR‐214‐3p regulates ox‐LDL‐initiated autophagy in HUVECs by directly targeting the 3′UTR of ATG5 and may have a suitable role in the pathogenesis of atherosclerosis.
Impact of non‐adherence on the safety and efficacy of uric acid‐lowering therapies in the treatment of gout
Authors: Hill‐McManus Daniel , Soto Elena , Marshall Scott , Lane Steven , Hughes Dyfrig 
Published: September 2017

AimsDual‐urate‐lowering therapy (ULT) with xanthine oxidase inhibitor and uricosuric medications is a treatment option for severe gout. Uricosuric agents can cause hyperuricosuria, a risk factor for nephrolithiasis and acute uric acid nephropathy. The aims of the present study were to simulate the relationship between suboptimal drug adherence and efficacy, and to quantify the risk of hyperuricosuria in gout patients receiving mono‐ and dual‐ULTs.MethodsThe impact of poor medication adherence was studied using two‐compartment pharmacokinetic (PK) models based on published evidence, and a semi‐mechanistic four‐compartment pharmacodynamic (PD) model. The PKPD model was used to simulate mono and dual‐ULT in gout patients with either under‐excretion (lowered clearance) or overproduction of uric acid, with suboptimal adherence modelled as either a single drug holiday of increasing duration or doses taken at random.ResultsSimulation results showed a surge in urinary uric acid occurring when dosing is restarted following missed doses. For under‐excreters taking a 20‐day drug holiday, the addition of 200 mg (or 400 mg) lesinurad to 80 mg febuxostat increased the percentage of patients experiencing hyperuricosuria from 0% to 1.4% (or 3.1%). In overproducers, restarting ULTs following drug holidays of more than 5 days leads to over 60% of patients experiencing hyperuricosuria.ConclusionsSuboptimal medication adherence may compromise the safety and efficacy of mono‐ and dual‐ULTs, especially in patients with gout resulting from an overproduction of uric acid. Clinicians and pharmacists should consider counselling patients with respect to the risks associated with partial adherence, and offer interventions to improve adherence or tailor treatments, where appropriate.
Pharmacokinetics of multiple doses of co‐crystal of tramadol–celecoxib: findings from a four‐way randomized open‐label phase I clinical trial
Authors: Videla Sebastián , Lahjou Mounia , Vaqué Anna , Sust Mariano , Escriche Marisol , Soler Lluis , Sans Artur , Sicard Eric , Gascón Neus , Encina Gregorio , Plata‐Salamán Carlos 
Published: September 2017

AimWe compared the pharmacokinetic (PK) profiles of co‐crystal of tramadol–celecoxib (CTC) vs. each reference product (alone and in open combination) after single (first dose) and multiple dosing.MethodsHealthy adults aged 18–50 years received, under fasted conditions, 15 twice‐daily doses of the following treatments (separated by ≥14‐day washout): 200 mg immediate‐release (IR) CTC (equivalent to 88 mg tramadol and 112 mg celecoxib; treatment 1); 100 mg IR tramadol (treatment 2), 100 mg celecoxib (treatment 3); and 100 mg IR tramadol and 100 mg celecoxib (treatment 4). The treatment sequence was assigned by computer‐generated randomization. PK parameters were calculated using non‐compartmental analysis. Parameters for CTC were adjusted according to reference product dose.ResultsA total of 30 subjects (20 males, mean age 35 years) were included. Multiple‐dose tramadol PK parameters for treatments 1, 2 and 4, respectively, were 551, 632 and 661 ng ml−1 [mean maximum plasma concentration (Cmax)]; 4796, 4990 and 5284 ng h ml−1 (area under the plasma concentration–time curve over the dosing interval at steady state); and 3.0, 2.0 and 2.0 h (median time to Cmax at steady state). For treatments 1, 3 and 4, multiple‐dose celecoxib PK parameters were 445, 536 and 396 ng ml−1; 2803, 3366 and 2897 ng h ml−1; and 2.0, 2.0 and 3.0 h. Single‐dose findings were consistent with multiple‐dose data. Types of adverse events were consistent with known reference product safety profiles.ConclusionAfter single (first dose) and multiple dosing, PK parameters for each active pharmaceutical ingredient in CTC were modified by co‐crystallization compared with reference products alone or in open combination.