bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic and transcriptomic signals of thermal tolerance in heat-tolerant corals (Platygyra daedalea) of the Arabian/Persian Gulf
Authors: Kirk Nathan L. , Howells Emily J. , Abrego David , Burt John A. , Meyer Eli
Published: September 2017

Scleractinian corals occur in tropical regions near their upper thermal limits, and are severely threatened by rising ocean temperatures. Ocean warming leads to loss of symbiotic algae (Symbiodinium), reduced fitness for the coral host, and degradation of the reef. However, several recent studies have shown that natural populations of corals harbor genetic variation in thermal tolerance that may support adaptive responses to warming. Here we’ve extended these approaches to study heat tolerance of corals in the Persian/Arabian Gulf, where heat-tolerant local populations have adapted to warm summer temperatures (>36°C). To evaluate whether selection has depleted genetic variation in thermal tolerance, estimate the potential for future adaptive responses, and understand the functional basis for these corals’ unusual heat tolerance, we measured thermal tolerance using controlled crosses in the Gulf coralPlatygyra daedalea. We found that heat tolerance is highly heritable in this population (0.487-0.748), suggesting substantial potential for adaptive responses to selection for thermal tolerance. To identify genetic markers associated with this variation, we conducted genomewide SNP genotyping in parental corals and tested for relationships between paternal genotype and thermal tolerance of the offspring. We found that multilocus SNP genotypes explained a large fraction of variation in thermal tolerance in these crosses (69%). To investigate the functional basis of these differences in thermal tolerance, we profiled transcriptional responses in tolerant and susceptible families, revealing substantial sire effects on transcriptional responses to thermal stress. We also studied sequence variation in these expressed sequences, identifying alleles and functional groups associated with thermal tolerance. Our findings demonstrate that corals in these populations harbor extensive genetic variation in thermal tolerance, and these heat-tolerant phenotypes differ in both gene sequences and transcriptional stress responses from their susceptible counterparts.
Inferring parameters for a lattice-free model of cell migration and proliferation using experimental data
Authors: Browning Alexander P. , McCue Scott W. , Binny Rachelle N. , Plank Michael J. , Shah Esha T. , Simpson Matthew J.
Published: September 2017

Collective cell spreading takes place in spatially continuous environments, yet it is often modelled using discrete lattice-based approaches. Here, we use data from a series of cell proliferation assays, with a prostate cancer cell line, to calibrate a spatially continuous individual based model (IBM) of collective cell migration and proliferation. The IBM explicitly accounts for crowding effects by modifying the rate of movement, direction of movement, and the rate of proliferation by accounting for pair-wise interactions. Taking a Bayesian approach we estimate the free parameters in the IBM using rejection sampling on three separate, independent experimental data sets. Since the posterior distributions for each experiment are similar, we perform simulations with parameters sampled from a new posterior distribution generated by combining the three data sets. To explore the predictive power of the calibrated IBM, we forecast the evolution of a fourth experimental data set. Overall, we show how to calibrate a lattice-free IBM to experimental data, and our work highlights the importance of interactions between individuals. Despite great care taken to distribute cells as uniformly as possible experimentally, we find evidence of significant spatial clustering over short distances, suggesting that standard mean-field models could be inappropriate.
Increased axonal bouton stability during learning in the mouse model of MECP2 duplication syndrome
Authors: Ash Ryan T. , Fahey Paul G. , Park Jiyoung , Zoghbi Huda Y. , Smirnakis Stelios M.
Published: September 2017

MECP2-duplication syndrome is an X-linked form of syndromic autism caused by genomic duplication of the region encoding Methyl-CpG-binding protein 2. Mice overexpressingMECP2demonstrate altered patterns of learning and memory, including enhanced motor learning. Previous work associated this enhanced motor learning to abnormally increased stability of dendritic spine clusters formed in the apical tuft of corticospinal, area M1, neurons during rotarod training. In the current study, we measure the structural plasticity of axonal boutons in Layer 5 (L5) pyramidal neuron projections to layer 1 of area M1 during motor learning. In wild-type mice we find that during rotarod training, bouton formation rate changes minimally, if at all, while bouton elimination rate doubles. Notably, the observed upregulation in bouton elimination with learning is absent inMECP2-duplication mice. This result provides further evidence of imbalance between structural stability and plasticity in this form of syndromic autism. Furthermore, the observation that axonal bouton elimination doubles with motor learning in wild-type animals contrasts with the increase of dendritic spine consolidation observed in corticospinal neurons at the same layer. This dissociation suggests that different area M1 microcircuits may manifest different patterns of structural synaptic plasticity during motor learning.

SIGNIFICANCE STATEMENT

Abnormal balance between synaptic stability and plasticity is a feature of several autism spectrum disorders, often corroborated by in vivo studies of dendritic spine turnover. Here we provide the first evidence that abnormally increased stability of axonal boutons, the presynaptic component of excitatory synapses, occurs during motor learning in the MECP2 duplication syndrome mouse model of autism. In contrast, in normal controls, axonal bouton elimination in L5 pyramidal neuron projections to layer 1 of area M1 doubles with motor learning. The fact that axonal projection boutons get eliminated, while corticospinal dendritic spines get consolidated with motor learning in layer 1 of area M1, suggests that structural plasticity manifestations differ across different M1 microcircuits.
Statistical power of gene-set enrichment analysis is a function of gene set correlation structure
Authors: Swanson David M.
Published: September 2017

Motivation:

We describe why statistical power for both self-contained and competitive gene-set tests is a function of the correlation structure of co-expressed genes, and why this characteristic is undesirable for gene-set analyses. Variable statistical power as a function of gene correlation structure has not been observed or studied previously. The observation is important in part because gene-set testing methodology is well-developed, yet this fundamental feature of many of its tests is unknown and has the potential to reinterpret past gene-set test results and guide future implementations, including those using sequence data. Type 1 error inflation is also amenable for study in our statistical framework; while it has been well-studied and described previously for both self-contained and competitive tests, it has less often been done in an analytical framework. Our observations apply to four commonly-used gene-set testing approaches for microarrays, including CAMERA, ROAST, SAFE, and GAGE, and a recently proposed one for RNAseq, MAST.

Results:

We characterize situations in which power is especially small relative to effect sizes of genes in a set for both competitive and self-contained gene-set tests. We propose three alternative tests, one of which replicates the properties of permutation-based self-contained tests, but avoids the need for even recently proposed, rotation-based approximations to permutations. The two other proposed tests have the unique property that statistical power is not a function of co-expression correlation in the gene-set and therefore is the preferred methodology. We compare our proposed tests to leading gene-set tests and apply them to an already-published study of smoking exposure on pregnant women.

Contact:

dms866@mail.harvard.edu

Supplementary Material:

Online supplementary material includes additional simulation results supporting the relationship between the “mixed” and “directional” gene-set tests of ROAST and closed-form implementations of them.
A singleVibrionales16S rRNA oligotype dominates the intestinal microbiome in two geographically separated Atlantic cod populations
Authors: Riiser Even Sannes , Haverkamp Thomas H.A. , Borgan Ørnulf , Jakobsen Kjetill S. , Jentoft Sissel , Star Bastiaan
Published: September 2017

Background

Host-microbe interactions are particularly intriguing in Atlantic cod (Gadus morhua), as it lacks the MHC II complex involved in presentation of extracellular pathogens. Nonetheless, little is known about the diversity of its microbiome in natural populations. Here, we use 16S rRNA high-throughput sequencing to investigate the microbial community composition in gut content and mucosa of 22 adult individuals from two coastal populations in Norway, located 470 km apart.

Results

We identify a core microbiome of 23 OTUs (97% sequence similarity) in all individuals that comprises 93% of the total number of reads. The most abundant orders are classified asVibrionales, Fusobacteriales, ClostridialesandBacteroidales. While mucosal samples show significantly lower diversity than gut content samples, no differences in OTU community composition are observed between the two populations. The differential abundance of oligotypes within two common OTUs does reveal limited spatial segregation. Remarkably, the most abundant OTU consists of a single oligotype (orderVibrionales, genusPhotobacterium) that represents nearly 50% of the reads in both locations.

Conclusions

Our results show that the intestinal bacterial community of two geographically separated coastal populations of Atlantic cod is dominated by a limited number of highly abundant 16S rRNA oligotypes shared by all specimens examined. The ubiquity of these oligotypes suggests that the northern coastal Atlantic cod gut microbiome is colonized by a limited number of species with excellent dispersal capabilities that are well suited to thrive in their host environment.
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

Transcription 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

Multidrug 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

Freshwater 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

Mycobacterium 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 Summary

The 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.
Quantitative Characterization of Biological Age and Frailty Based on Locomotor Activity Records
Authors: Pyrkov Timothy V. , Getmantsev Evgeny , Zhurov Boris , Avchaciov Konstantin , Pyatnitskiy Mikhail , Menshikov Leonid , Khodova Kristina , Gudkov Andrei V. , Fedichev Peter O.
Published: September 2017

We performed a systematic evaluation of the relationships between locomotor activity and signatures of frailty, morbidity, and mortality risks using physical activity records from the 2003 – 2006 National Health and Nutrition Examination Survey (NHANES) and UK BioBank (UKB). We proposed a statistical description of the locomotor activity tracks and transformed the provided time series into vectors representing physiological states for each participant. The Principal Components Analysis of the transformed data revealed a winding trajectory with distinct segments corresponding to subsequent human development stages. The extended linear phase starts from 35 40 years old and is associated with the exponential increase of mortality risks according to the Gompertz mortality law. We characterized the distance traveled along the aging trajectory as a natural measure of biological age and demonstrated its significant association with frailty and hazardous lifestyles, along with the remaining lifespan and healthspan of an individual. The biological age explained most of the variance of the log-hazard ratio that was obtained by fitting directly to mortality and the incidence of chronic diseases. Our findings highlight the intimate relationship between the supervised and unsupervised signatures of the biological age and frailty, a consequence of the low intrinsic dimensionality of the aging dynamics.
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

As 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.
Comparative Analysis of Cell Ultrastructure with Evidences of Programmed Death in Tissue Cultures of Cereals
Authors: N.K. Bishimbayeva , E.V. Rakhimova
Published: September 2017

Degrading cells of wheat and barley callus have all known ultrastructural features, which are characteristic for apoptotic cells: intense vacuolization, increasing the size of the nucleus, cupped invaginations of plastids, mitochondria saving until the last stages of cell degradation and the formation of vesicles, similar to apoptotic bodies. It is the first showed that degrading cells in embryogenic callus are characterized with the destruction of the nuclear membrane and the allocated substances of fibrillar nature in the periplasmic space and on the surface of cells.
Progressive polarity loss and luminal collapse disrupt tissue organization in carcinoma
Authors: Halaoui Ruba , Rejon Carlis , Chatterjee Sudipa June , Szymborski Joseph , Meterissian Sarkis , Muller William J. , Omeroglu Atilla , McCaffrey Luke
Published: September 2017

Epithelial cancers (carcinoma) account for 80%–90% of all cancers. The development of carcinoma is associated with disrupted epithelial organization and solid ductal structures. The mechanisms underlying the morphological development of carcinoma are poorly understood, but it is thought that loss of cell polarity is an early event. Here we report the characterization of the development of human breast lesions leading to carcinoma. We identified a unique mechanism that generates solid ducts in carcinoma through progressive loss of polarity and collapse of the luminal architecture. This program initiates with asymmetric divisions of polarized cells that generate a stratified epithelium containing both polarized and depolarized cells. Stratified regions form cords that penetrate into the lumen, subdividing it into polarized secondary lumina. The secondary lumina then collapse with a concomitant decrease in RhoA and myosin II activity at the apical membrane and ultimately lose apical–basal polarity. By restoring RhoA activity in mice, ducts maintained lumen and cell polarity. Notably, disrupted tissue architecture through luminal collapse was reversible, and ducts with a lumen were re-established after oncogene suppression in vivo. This reveals a novel and common mechanism that contributes to carcinoma development by progressively disrupting cell and tissue organization.
Enzymatic modules of the SAGA chromatin-modifying complex play distinct roles in Drosophila gene expression and development
Authors: Li Xuanying , Seidel Christopher W. , Szerszen Leanne T. , Lange Jeffrey J. , Workman Jerry L. , Abmayr Susan M.
Published: September 2017

The Spt–Ada–Gcn5–acetyltransferase (SAGA) chromatin-modifying complex is a transcriptional coactivator that contains four different modules of subunits. The intact SAGA complex has been well characterized for its function in transcription regulation and development. However, little is known about the roles of individual modules within SAGA and whether they have any SAGA-independent functions. Here we demonstrate that the two enzymatic modules of Drosophila SAGA are differently required in oogenesis. Loss of the histone acetyltransferase (HAT) activity blocks oogenesis, while loss of the H2B deubiquitinase (DUB) activity does not. However, the DUB module regulates a subset of genes in early embryogenesis, and loss of the DUB subunits causes defects in embryogenesis. ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) analysis revealed that both the DUB and HAT modules bind most SAGA target genes even though many of these targets do not require the DUB module for expression. Furthermore, we found that the DUB module can bind to chromatin and regulate transcription independently of the HAT module. Our results suggest that the DUB module has functions within SAGA and independent functions.
Dynamic assembly and activation of estrogen receptor α enhancers through coregulator switching
Authors: Murakami Shino , Nagari Anusha , Kraus W. Lee
Published: September 2017

Although many features of active transcriptional enhancers have been defined by genomic assays, we lack a clear understanding of the order of events leading to enhancer formation and activation as well as the dynamics of coregulator interactions within the enhancer complex. Here, we used selective loss- or gain-of-function mutants of estrogen receptor α (ERα) to define two distinct phases of ligand-dependent enhancer formation. In the first phase (0–20 min), p300 is recruited to ERα by Mediator as well as p300's acetylhistone-binding bromodomain to promote initial enhancer formation, which is not competent for sustained activation. In the second phase (20–45 min), p300 is recruited to ERα by steroid receptor coregulators (SRCs) for enhancer maturation and maintenance. Successful transition between these two phases (“coregulator switching”) is required for proper enhancer function. Failure to recruit p300 during either phase leads to abortive enhancer formation and a lack of target gene expression. Our results reveal an ordered and cooperative assembly of ERα enhancers requiring functional interplay among p300, Mediator, and SRCs, which has implications for hormone-dependent gene regulation in breast cancers. More broadly, our results demonstrate the unexpectedly dynamic nature of coregulator interactions within enhancer complexes, which are likely to be a defining feature of all enhancers.
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

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

Immersive 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

Background

We 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.

Methods

Primary 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.

Results

MiR‐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.

Conclusions

Alcohol 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

Background

Compared 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.

Methods

We 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.

Results

The 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.

Discussion

Surgeons 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

Aim

Endothelial 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.

Methods

We 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.

Results

In 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.

Conclusion

miR‐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

Aims

Dual‐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.

Methods

The 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.

Results

Simulation 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.

Conclusions

Suboptimal 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

Aim

We 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.

Methods

Healthy 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.

Results

A 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.

Conclusion

After 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.
Salidroside, a Chemopreventive Glycoside, Diminishes Cytotoxic Effect of Cisplatin in Vitro
Authors: Zduriencikova Martina , Cholujova Dana , Duraj Jozef , Mastihubova Maria , Mastihuba Vladimir , Karnisova Potocka Elena , Galova Eliska , Sevcovicova Andrea , Klapakova Martina , Horvathova Eva
Published: September 2017

Natural products represent the source or the inspiration for the majority of the active ingredients of medicines because of their structural diversity and a wide range of biological effects. Our aims in this study were (i) to synthesize enzymatically salidroside (SAL), the most effective phenylethanoid glycoside in Rhodiola species; (ii) to examine its antioxidant capacity using cell‐free assays (reducing power, DPPH radicals scavenging and Fe2+‐chelating assays); (iii) to assess its DNA‐protective potential on plasmid DNA (DNA topology assay) and in HepG2 cells (comet assay) damaged by Fe2+ ions and hydrogen peroxide, respectively; and (iv) to investigate the effects of SAL, cisplatin (CDDP) and combined treatments of SAL + CDDP on cell viability (MTT test), level of DNA damage (comet assay), proliferation, cell cycle (flow cytometry) and the expression of signalling molecules associated with cell growth and apoptotic pathways (Western immunoblotting). We found out that SAL manifested low antioxidant and DNA‐protective capacity in all assays used. In both parental A2780 and CDDP‐resistant A2780/CP human ovarian carcinoma cells, SAL itself exerted in fact no impact on the viability, while in combination with CDDP it showed antagonistic effect supporting the chemopreventive activity on the CDDP‐induced cell damage. These results were confirmed by the partial reversal of the cell cycle alterations and the DNA damage level, as well as with partial restoration of cell survival/signalling pathways, when the expression of these molecules partially returned to their proper levels.
A comprehensive approach to evaluating and classifying sun-protective clothing
Authors: Downs N.J. , Harrison S.L.
Published: September 2017

Background

National standards for clothing designed to protect the wearer from the harmful effects of solar ultraviolet radiation (UVR) have been implemented in Australia/New Zealand, Europe and the U.S.A. Industry standards reflect the need to protect the skin by covering a considerable proportion of the potentially exposed body surface area (BSA) and by reducing UVR-transmission through fabric (the Ultraviolet Protection Factor; UPF).

Objectives

This research aimed to develop a new index for rating sun-protective clothing that incorporates the BSA coverage of the garment in addition to the UPF of the fabric.

Methods

A mannequin model was fixed to an optical bench and marked with horizontal lines at 1-cm intervals. An algorithm (the Garment Protector Factor; GPF) was developed based on the number of lines visible on the clothed vs. unclothed mannequin and the UPF of the garment textile. This data was collected in 2015/16 and analysed in 2016.

Results

The GPF weights fabric UPF by BSA coverage above the minimum required by international sun-protective clothing standards for upper-body, lower-body and full-body garments. The GPF increases with BSA coverage of the garment and fabric UPF. Three nominal categories are proposed for the GPF: 0 ≤ GPF < 3 for garments that ‘meet’ minimum standards; 3 ≤ GPF < 6 for garments providing ‘good’ sun protection; and GPF ≥ 6 indicating ‘excellent’ protection.

Conclusions

Adoption of the proposed rating scheme should encourage manufacturers to design sun-protective garments that exceed the minimum standard for BSA coverage, with positive implications for skin cancer prevention, consumer education and sun-protection awareness.
Togetherness, teamwork and challenges: “Reflections on building an inclusive research network”
Authors: Riches Tanya N. , O'Brien Patricia M. ,   The CDS Inclusive Research Network
Published: September 2017

Accessible Summary

This article is about the Inclusive Research Network run by the Centre for Disability Studies.

It outlines our progress made towards an inclusive research network since 2010.

It highlights “inclusive research” from the view of people in our network.

It answers the questions “what is inclusive research?” and “what makes research inclusive?”

It compares the process of research undertaken by our network against Johnson and Walmsley ().

Three themes were an important part of inclusive research: togetherness, teamwork and challenges

It notes that “togetherness” is missing from Johnson and Walmsley principles of “inclusive research.”

Background

This article presents a case study of the Centre for Disability Studies’ Inclusive Research Network. The network is a dynamic group of around fifteen people who have intellectual and other disabilities, support workers and university researchers.

Methods

The study was based upon an evaluation of the group's research practice, as demonstrated by their work together over the last 7 years. Network members created focus groups to outline the process of their research. These reflections formed the basis of a presentation video recorded for the 50th anniversary of the International Association for the Scientific Study of Intellectual and Developmental Disabilities conference. The video outlined the groups’ understanding of “inclusive research.” A transcript of the script was used to analyse and reflect upon the group's processes. Thus, this article outlines inclusive research from the perspective of network members, evaluated against the founding principles of inclusive research presented in Johnson and Walmsley ()'s well‐known volume.

Results

The network member's answers show consistency with these principles developed by Johnson and Walmsley. Themes identified were the need for “teamwork” and “challenges” in following these principles.

Conclusion

In defining what inclusive research is and what makes research “inclusive,” the answers highlight the relational dynamics between the team members, and need to continually work on “togetherness.” The affective connection between researchers is to them a highly significant part of what is considered successful inclusive research, particularly for coresearchers with intellectual disabilities. This article suggests the affective dimension may be undervalued in the current literature.