bluuebunny/crossref_metadata_2025 huggingface dataset:
DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein-dynactin-cargo adaptor complexes
Authors: Hoang Ha Thi , Schlager Max A. , Carter Andrew P. , Bullock Simon L
Published: December 2016

Mutations in the human DYNC1H1 gene are associated with neurological diseases. DYNC1H1 encodes the heavy chain of cytoplasmic dynein-1, a 1.4 MDa motor complex that traffics organelles, vesicles and macromolecules towards microtubule minus ends. The effects of the DYNC1H1 mutations on dynein motility, and consequently their links to neuropathology, are not understood. Here, we address this issue using a recombinant expression system for human dynein coupled to single-molecule resolution in vitro motility assays. We functionally characterise 14 DYNC1H1 mutations identified in humans diagnosed with malformations in cortical development (MCD) or spinal muscular atrophy with lower extremity predominance (SMALED), as well as three mutations that cause motor and sensory defects in mice. Two of the human mutations, R1962C and H3822P, strongly interfere with dynein’s core mechanochemical properties. The remaining mutations selectively compromise the processive mode of dynein movement that is activated by binding to the accessory complex dynactin and the cargo adaptor BICD2. Mutations with the strongest effects on dynein motility in vitro are associated with MCD. The vast majority of mutations do not affect binding of dynein to dynactin and BICD2, and are therefore expected to result in linkage of cargoes to dynein-dynactin complexes that have defective long-range motility. This observation offers an explanation for the dominant effects of DYNC1H1 mutations in vivo. Collectively, our results suggest that compromised processivity of cargo-motor assemblies contributes to human neurological disease and provide insight into the influence of different regions of the heavy chain on dynein motility.
On the origin of nonequivalent states: how we can talk about preprints
Authors: Neylon Cameron , Pattinson Damian , Bilder Geoffrey , Lin Jennifer
Published: December 2016

Increasingly, preprints are at the center of conversations across the research ecosystem. But disagreements remain about the role they play. Do they “count” for research assessment? Is it ok to post preprints in more than one place? In this paper, we argue that these discussions often conflate two separate issues, the history of the manuscript and the status granted it by different communities. In this paper, we propose a new model that distinguishes the characteristics of the object, its “state”, from the subjective “standing” granted to it by different communities. This provides a way to discuss the difference in practices between communities, which will deliver more productive conversations and facilitate negotiation on how to collectively improve the process of scholarly communications not only for preprints but other forms of scholarly contributions.
Familial heterogeneity in breast cancer predisposition: a study of 22 Utah families
Authors: O’Brien Elizabeth , Kerber Richard A. , White Raymond L.
Published: December 2016

The problem of “missing heritability” in genome-wide analyses of complex diseases is thought to be attributable to some combination of: rare variants of moderate to large effect, common variants of very small effect, and epigenetic, epistatic, or shared environmental effects. Rare variants do not affect large numbers of people by definition, but identified genes and pathways frequently lead to important insights into pathogenesis, and become targets of chemoprevention or therapy. Family studies remain an efficient way to identify rare variants with sizable effects on disease risk. We present a genome-wide study of breast cancer in 22 large high-risk families including 154 women diagnosed with breast cancer. Appropriate marker spacing was achieved by simulation studies of founder haplotypes to reduce the chance that linkage disequilibrium produced spurious linkage peaks. For each family, we generated 100 simulations of null linkage genome-wide to estimate the probability that individual results were due to chance. We identified a total of 12 putative susceptibility regions with per-family genome-wide probability < 0.05. These regions were located on 10 chromosomes; 10 of the 22 families showed linkage at these locations; two or more families showed linkage to 6 regions on 5 chromosomes (4q, 5q, 6p, 14q, 18p, and 18q). These results indicate that there is considerable heterogeneity among families in genomic regions and thus variants predisposing to breast cancer. Moreover, they suggest that uncommon high– or medium-risk genetic variants remain to be found, and that family designs can be an efficient way to identify them.
Paradoxes in Leaky Microbial Trade
Authors: Kallus Yoav , Miller John H. , Libby Eric
Published: December 2016

Microbes produce metabolic resources that are important for cell growth yet leak across membranes into the extracellular environment. Other microbes in the same environment can use these resources and adjust their own metabolic production accordingly—causing other resources to leak into the environment. The combined effect of these processes is an economy in which organismal growth and metabolic production are coupled to others in the community. We propose a model for the co-evolving dynamics of metabolite concentrations, production regulation, and population frequencies for the case of two cell types, each requiring and capable of producing two metabolites. In this model, beneficial trade relations emerge without any coordination, via individual-level production decisions that maximize each cell’s growth rate given its perceived environment. As we vary production parameters of the model, we encounter three paradoxical behaviors, where a change that should intuitively benefit some cell type, actually harms it. (1) If a cell type is more efficient than its counterpart at producing a metabolite and becomes even more efficient, its frequency in the population can decrease. (2) If a cell type is less efficient than its counterpart at producing a metabolite but becomes less inefficient, the growth rate of the population can decrease. (3) Finally, if a cell type controls its counterpart’s production decisions so as to maximize its own growth rate, the ultimate growth rate it achieves can be lower than if the two cell types each maximized their own growth. These three paradoxes highlight the complex and counter-intuitive dynamics that emerge in simple microbial economies.
Impact of implementation choices on quantitative predictions of cell-based computational models
Authors: Kursawe Jochen , Baker Ruth E. , Fletcher Alexander G.
Published: December 2016

‘Cell-based’ models provide a powerful computational tool for studying the mechanisms underlying the growth and dynamics of biological tissues in health and disease. An increasing amount of quantitative data with cellular resolution has paved the way for the quantitative parameterisation and validation of such models. However, the numerical implementation of cell-based models remains challenging, and little work has been done to understand to what extent implementation choices may influence model predictions. Here, we consider the numerical implementation of a popular class of cell-based models called vertex models, which are often used to study epithelial tissues. In two-dimensional vertex models, a tissue is approximated as a tessellation of polygons and the vertices of these polygons move due to mechanical forces originating from the cells. Such models have been used extensively to study the mechanical regulation of tissue topology in the literature. Here, we analyse how the model predictions may be affected by numerical parameters, such as the size of the time step, and non-physical model parameters, such as length thresholds for cell rearrangement. We find that vertex positions and summary statistics are sensitive to several of these implementation parameters. For example, the predicted tissue size decreases with decreasing cell cycle durations, and cell rearrangement may be suppressed by large time steps. These findings are counter-intuitive and illustrate that model predictions need to be thoroughly analysed and implementation details carefully considered when applying cell-based computational models in a quantitative setting.
Antisocial rewarding in structured populations
Authors: Santos Miguel dos , Peña Jorge
Published: December 2016

Cooperation in collective action dilemmas usually breaks down in the absence of additional incentive mechanisms. This tragedy can be escaped if cooperators have the possibility to invest in reward funds that are shared exclusively among cooperators(prosocial rewarding). Yet, the presence of defectors who do not contribute to the public good but do reward themselves(antisocial rewarding) deters cooperation in the absence of additional countermeasures. A recent simulation study suggests that spatial structure is sufficient to prevent antisocial rewarding from deterring cooperation. Here we reinvestigate this issue assuming mixed strategies and weak selection on a game-theoretic model of social interactions, which we also validate using individual-based simulations. We show that increasing reward funds facilitates the maintenance of prosocial rewarding but prevents its evolution from rare, and that spatial structure can sometimes select against the evolution of prosocial rewarding. Our results suggest that, even in spatially structured populations, additional mechanisms are required to prevent antisocial rewarding from deterring cooperation in public goods dilemmas.
SNVPhyl: A Single Nucleotide Variant Phylogenomics pipeline for microbial genomic epidemiology
Authors: Petkau Aaron , Mabon Philip , Sieffert Cameron , Knox Natalie , Cabral Jennifer , Iskander Mariam , Iskander Mark , Weedmark Kelly , Zaheer Rahat , Katz Lee S. , Nadon Celine , Reimer Aleisha , Taboada Eduardo , Beiko Robert G. , Hsiao William , Brinkman Fiona , Graham Morag ,   the IRIDA Consortium, Van Domselaar Gary
Published: December 2016

Motivation

The recent widespread application of whole-genome sequencing (WGS) for microbial disease investigations has spurred the development of new bioinformatics tools, including a notable proliferation of phylogenomics pipelines designed for infectious disease surveillance and outbreak investigation. Transitioning the use of WGS data out of the research lab and into the front lines of surveillance and outbreak response requires user-friendly, reproducible, and scalable pipelines that have been well validated.

Results

SNVPhyl (Single Nucleotide Variant Phylogenomics) is a bioinformatics pipeline for identifying high-quality SNVs and constructing a whole genome phylogeny from a collection of WGS reads and a reference genome. Individual pipeline components are integrated into the Galaxy bioinformatics framework, enabling data analysis in a user-friendly, reproducible, and scalable environment. We show that SNVPhyl can detect SNVs with high sensitivity and specificity and identify and remove regions of high SNV density (indicative of recombination). SNVPhyl is able to correctly distinguish outbreak from non-outbreak isolates across a range of variant-calling settings, sequencing-coverage thresholds, or in the presence of contamination.

Availability

SNVPhyl is available as a Galaxy workflow, Docker and virtual machine images, and a Unix-based command-line application. SNVPhyl is released under the Apache 2.0 license and available athttp://snvphyl.readthedocs.io/or athttps://github.com/phac-nml/snvphyl-galaxy.
Early survival and delayed death of developmentally-born dentate gyrus neurons
Authors: Cahill Shaina P. , Yu Ru Qi , Green Dylan , Todorova Evgenia V. , Snyder Jason S.
Published: December 2016

The storage and persistence of memories depends on plasticity in the hippocampus. Adult neurogenesis produces new neurons that mature through critical periods for plasticity and cellular survival, which determine their contributions to learning and memory. However, most granule neurons are generated prior to adulthood; the maturational timecourse of these neurons is poorly understood compared to adult-born neurons, but is essential to identify how the dentate gyrus, as a whole, contributes to behavior. To characterize neurons born in the early postnatal period, we labeled dentate gyrus neurons born on postnatal day 6 (P6) with BrdU and quantified maturation and survival across early (1 hour to 8 weeks old) and late (2-6 months old) cell ages. We find that the dynamics of developmentally-born neuron survival is essentially the opposite of neurons born in adulthood: P6-born neurons did not go through a period of cell death during their immature stages (from 1-8 weeks). In contrast, 17% of P6-born neurons died after reaching maturity, between 2-6 months of age. Delayed death was evident from the loss of BrdU+cells as well as pyknotic BrdU+caspase3+neurons within the superficial granule cell layer. Patterns of DCX, NeuN and activity-dependent Fos expression indicate that developmentally-born neurons mature over several weeks and a sharp peak in zif268 expression at 2 weeks suggests that developmentally-born neurons mature faster than adult-born neurons (which peak at 3 weeks). Collectively, our findings are relevant for understanding how developmentally-born dentate gyrus neurons contribute to memory and disorders throughout the lifespan. High levels of early survival and zif268 expression may promote learning, while also rendering neurons sensitive to insults at defined stages. Late neuronal death in young adulthood may result in the loss of hundreds of thousands of dentate gyrus neurons, which could impact memory persistence and contribute to hippocampal/dentate gyrus atrophy in disorders such as depression.
Variability and stability of large-scale cortical oscillation patterns
Authors: Cox Roy , Schapiro Anna C , Stickgold Robert
Published: December 2016

Individual differences in brain organization exist at many spatial and temporal scales, contributing to the substantial heterogeneity underlying human thought and behavior. Oscillatory neural activity is crucial for these behaviors, but how such rhythms are expressed across the cortex within and across individuals has not been thoroughly characterized. Combining electroencephalography (EEG) with representational similarity and multivariate classification techniques, we provide a systematic characterization of brain-wide activity across frequency bands and oscillatory features during rest and task performance. Results indicate that oscillatory profiles exhibit sizable group-level correspondences, indicating the presence of common templates of oscillatory organization. At the same time, we observed well-defined subject-specific network profiles that were discernible above and beyond the structure shared across individuals. These individualized patterns were sufficiently stable over time to allow successful classification of individuals several months later. Finally, our findings indicate that the network structure of rhythmic activity varies considerably across distinct oscillatory frequencies and features, suggesting the existence of multiple, parallel information processing streams embedded in distributed electrophysiological activity. Together, these findings affirm the richness of spatiotemporal EEG signals and emphasize the utility of multivariate network analyses for understanding the role of brain oscillations in physiology and behavior.
APOBEC3A/B-induced mutagenesis is responsible for 20% of heritable mutations in the TpCpW context
Authors: Seplyarskiy Vladimir B. , Andrianova Maria A. , Bazykin Georgii A.
Published: December 2016

APOBEC3A/B cytidine deaminase is responsible for the majority of cancerous mutations in a large fraction of cancer samples. However, its role in heritable mutagenesis remains very poorly understood. Recent studies have demonstrated that both in yeast and in human cancerous cells, most APOBEC3A/B-induced mutations occur on the lagging strand during replication and on the nontemplate strand of transcribed regions. Here, we use data on rare human polymorphisms, interspecies divergence, and de novo mutations to study germline mutagenesis and to analyze mutations at nucleotide contexts prone to attack by APOBEC3A/B. We show that such mutations occur preferentially on the lagging strand and on nontemplate strands of transcribed regions. Moreover, we demonstrate that APOBEC3A/B-like mutations tend to produce strand-coordinated clusters, which are also biased toward the lagging strand. Finally, we show that the mutation rate is increased 3′ of C→G mutations to a greater extent than 3′ of C→T mutations, suggesting pervasive trans-lesion bypass of the APOBEC3A/B-induced damage. Our study demonstrates that 20% of C→T and C→G mutations in the TpCpW context—where W denotes A or T, segregating as polymorphisms in human population—or 1.4% of all heritable mutations are attributable to APOBEC3A/B activity.
HapCUT2: robust and accurate haplotype assembly for diverse sequencing technologies
Authors: Edge Peter , Bafna Vineet , Bansal Vikas
Published: December 2016

Many tools have been developed for haplotype assembly—the reconstruction of individual haplotypes using reads mapped to a reference genome sequence. Due to increasing interest in obtaining haplotype-resolved human genomes, a range of new sequencing protocols and technologies have been developed to enable the reconstruction of whole-genome haplotypes. However, existing computational methods designed to handle specific technologies do not scale well on data from different protocols. We describe a new algorithm, HapCUT2, that extends our previous method (HapCUT) to handle multiple sequencing technologies. Using simulations and whole-genome sequencing (WGS) data from multiple different data types—dilution pool sequencing, linked-read sequencing, single molecule real-time (SMRT) sequencing, and proximity ligation (Hi-C) sequencing—we show that HapCUT2 rapidly assembles haplotypes with best-in-class accuracy for all data types. In particular, HapCUT2 scales well for high sequencing coverage and rapidly assembled haplotypes for two long-read WGS data sets on which other methods struggled. Further, HapCUT2 directly models Hi-C specific error modalities, resulting in significant improvements in error rates compared to HapCUT, the only other method that could assemble haplotypes from Hi-C data. Using HapCUT2, haplotype assembly from a 90× coverage whole-genome Hi-C data set yielded high-resolution haplotypes (78.6% of variants phased in a single block) with high pairwise phasing accuracy (∼98% across chromosomes). Our results demonstrate that HapCUT2 is a robust tool for haplotype assembly applicable to data from diverse sequencing technologies.
Efficacy, safety and drug survival of conventional agents in pediatric psoriasis: A multicenter, cohort study
Authors: Ergun Tulin , Seckin Gencosmanoglu Dilek , Alpsoy Erkan , Bulbul‐Baskan Emel , Saricam Merve Hatun , Salman Andac , Onsun Nahide , Sarioz Abdullah
Published: December 2016

The data on long‐term efficacy, safety and drug survival rates of conventional systemic therapeutics in pediatric psoriasis is lacking. The primary aim of this study is to investigate acitretin, methotrexate, cyclosporin efficacy, safety and drug survival rates in pediatric patients as well as predictors of drug survival. This is a multicenter study including 289 pediatric cases being treated with acitretin, methotrexate and cyclosporin in four academic referral centers. Efficacy, adverse events, reasons for discontinuation, 1, 2‐ and 3‐year drug survival rates, and determinants of drug survival were analyzed. A 75% reduction of Psoriasis Area and Severity Index score or better response rate was obtained in 47.5%, 34.1% and 40% of the patients who were treated with acitretin, methotrexate and cyclosporin, respectively. One‐year drug survival rates for acitretin, methotrexate and cyclosporin were 36.3%, 21.1% and 15.1%, respectively. The most significant determinant of drug survival, which diminished over time, was treatment response whereas arthritis, body mass index and sex had no influence. Although all three medications are effective and relatively safe in children, drug survival rates are low due to safety concerns at this age group. Effective disease control through their rational use can be expected to improve survival rates.
Density‐dependent vulnerability of forest ecosystems to drought
Authors: Bottero Alessandra , D'Amato Anthony W. , Palik Brian J. , Bradford John B. , Fraver Shawn , Battaglia Mike A. , Asherin Lance A.
Published: December 2016

Climate models predict increasing drought intensity and frequency for many regions, which may have negative consequences for tree recruitment, growth and mortality, as well as forest ecosystem services. Furthermore, practical strategies for minimizing vulnerability to drought are limited. Tree population density, a metric of tree abundance in a given area, is a primary driver of competitive intensity among trees, which influences tree growth and mortality. Manipulating tree population density may be a mechanism for moderating drought‐induced stress and growth reductions, although the relationship between tree population density and tree drought vulnerability remains poorly quantified, especially across climatic gradients.

In this study, we examined three long‐term forest ecosystem experiments in two widely distributed North American pine species, ponderosa pine Pinus ponderosa (Lawson & C. Lawson) and red pine Pinus resinosa (Aiton), to better elucidate the relationship between tree population density, growth and drought. These experiments span a broad latitude and aridity range and include tree population density treatments that have been purposefully maintained for several decades. We investigated how tree population density influenced resistance (growth during drought) and resilience (growth after drought compared to pre‐drought growth) of stand‐level growth during and after documented drought events.

Our results show that relative tree population density was negatively related to drought resistance and resilience, indicating that trees growing at lower densities were less vulnerable to drought. This result was apparent in all three forest ecosystems, and was consistent across species, stand age and drought intensity.

Synthesis and applications. Our results highlighted that managing pine forest ecosystems at low tree population density represents a promising adaptive strategy for reducing the adverse impacts of drought on forest growth in coming decades. Nonetheless, the broader applicability of our findings to other types of forest ecosystems merits additional investigation.
Impact of hunting along the migration corridor of pink‐footed geeseAnser brachyrhynchus– implications for sustainable harvest management
Authors: Clausen Kevin Kuhlmann , Christensen Thomas Kjær , Gundersen Ove Martin , Madsen Jesper
Published: December 2016

Hunting can potentially affect population size, age composition, sex‐ratio, behaviour and distribution of natural populations, and understanding its impacts is a prerequisite to manage quarry species sustainably. Harvest management relies strongly on the existence of both strictly regulated hunting efforts and efficient monitoring of populations, their demography and harvest. These conditions are rarely met in practice.

For the Svalbard‐breeding population of the pink‐footed gooseAnser brachyrhynchus, an internationally coordinated adaptive harvest management framework enables a flyway‐based assessment of harvest impact. Based on 25 years of population assessment and harvest data, we evaluate the differential impact of harvest along the migration corridor of the population.

The analysis reveals that (i) total harvest and harvest rate (proportion of the population killed by hunting) have increased substantially in recent years, (ii) compared to adult geese, juveniles were overrepresented in the hunting bag by a factor of 3·7, (iii) the proportion of juveniles in the hunting bag differed between the two countries (Norway and Denmark) with an open season, and was more than twice as high in the former compared to the latter, and (iv) the increase in harvest rate seemed to be driven by increased hunting mortality of juvenile birds, with no clear impact on the growth rate of the population. However, this may partly relate to the transient dynamics and population inertia commonly seen in long‐lived species such as geese, and a 3‐year consecutive decline towards the end of our study period might be the first signs of an impending decline.

Synthesis and applications. Our findings highlight that the impact of harvest varies along the migration corridor and between age classes of a single species and suggest that allocation of hunting effort in time and space is important to optimise harvest. Our example demonstrates the need for internationally coordinated, detailed population and harvest data which are essential for sustainable harvest management.
Cats, connectivity and conservation: incorporating data sets and integrating scales for wildlife management
Authors: Pitman Ross T. , Fattebert Julien , Williams Samual T. , Williams Kathryn S. , Hill Russell A. , Hunter Luke T. B. , Robinson Hugh , Power John , Swanepoel Lourens , Slotow Rob , Balme Guy A.
Published: December 2016

Understanding resource selection and quantifying habitat connectivity are fundamental to conservation planning for both land‐use and species management plans. However, data sets available to management authorities for resource selection and connectivity analyses are often highly limited and fragmentary. As a result, measuring connectivity is challenging, and often poorly integrated within conservation planning and wildlife management. To exacerbate the challenge, scale‐dependent resource use makes inference across scales problematic, resource use is often modelled in areas where the species is not present, and connectivity is typically measured using a source‐to‐sink approach, erroneously assuming animals possess predefined destinations.

Here, we used a large carnivore, the leopard Panthera pardus, to characterise resource use and landscape connectivity across a vast, biodiverse region of southern Africa. Using a range of data sets to counter data deficiencies inherent in carnivore management, we overcame methodological limitations by employing occupancy modelling and resource selection functions across three orders of selection, and estimated landscape‐scale habitat connectivity – independent of a priori source and sink locations – using circuit theory. We evaluated whether occupancy modelling on its own was capable of accurately informing habitat connectivity, and identified conservation priorities necessary for applied management.

We detected markedly different scale‐dependent relationships across all selection orders. Our multi‐data, multi‐scale approach accurately predicted resource use across multiple scales and demonstrates how management authorities can more suitably utilise fragmentary data sets. We further developed an unbiased landscape‐scale depiction of habitat connectivity, and identified key linkages in need of targeted management. We did not find support for the use of occupancy modelling as a proxy for landscape‐scale habitat connectivity and further caution its use within a management context.

Synthesis and applications. Maintaining habitat connectivity remains a fundamental component of wildlife management and conservation, yet data to inform these biological and ecological processes are often scarce. We present a robust approach that incorporates multi‐scale fragmentary data sets (e.g. mortality data, permit data, sightings data), routinely collected by management authorities, to inform wildlife management and land‐use planning. We recommend that management authorities employ a multi‐data, multi‐scale connectivity approach – as we present here – to identify management units at risk of low connectivity.
Agricultural soil denitrifiers possess extensive nitrite reductase gene diversity
Authors: Coyotzi Sara , Doxey Andrew C. , Clark Ian D. , Lapen David R. , Van Cappellen Philippe , Neufeld Josh D.
Published: December 2016

Denitrification transforms nitrogen applied as fertilizer and emits N2O, which is a potent greenhouse gas. Very little is known about the identities of abundant and active denitrifiers in agricultural soils. We coupled DNA stable‐isotope probing (DNA‐SIP) with flow‐through reactors (FTRs) to detect active agricultural soil denitrifiers. The FTRs were incubated with nitrate and 13C6‐glucose under anoxic conditions and sampled at multiple time points. Labelled DNA from active microorganisms was analyzed by 16S rRNA gene fingerprinting, amplicon and shotgun metagenomic sequencing. Taxonomic representation of heavy fractions was consistent across sites and time points, including Betaproteobacteria (71%; Janthinobacterium, Acidovorax, Azoarcus and Dechloromonas), Alphaproteobacteria (8%; Rhizobium), Gammaproteobacteria (4%; Pseudomonas) and Actinobacteria (4%; Streptomycetaceae). Most nitrite‐reductase reads from heavy DNA annotated to the copper‐containing form (nirK). Assigned taxonomies of active denitrifiers based on reads matching the nirK gene were comparable to those obtained through nitric oxide (norB) and RNA polymerase (rpoB) annotations but not the nitrous oxide reductase gene (nosZ). Analysis of recovered metagenomes from heavy DNA demonstrated extensive nirK sequence family diversity, including novel taxonomic groups that are not captured by existing primers.
The expression of Longus type 4 pilus of enterotoxigenic Escherichia coli is regulated by LngR and LngS and by H‐NS, CpxR and CRP global regulators
Authors: De la Cruz Miguel A. , Ruiz‐Tagle Alejandro , Ares Miguel A. , Pacheco Sabino , Yáñez Jorge A. , Cedillo Lilia , Torres Javier , Girón Jorge A.
Published: December 2016

Enterotoxigenic Escherichia coli produces a long type 4 pilus called Longus. The regulatory elements and the environmental signals controlling the expression of Longus‐encoding genes are unknown. We identified two genes lngR and lngS in the Longus operon, whose predicted products share homology with transcriptional regulators. Isogenic lngR and lngS mutants were considerably affected in transcription of lngA pilin gene. The expression of lngA, lngR and lngS genes was optimally expressed at 37°C at pH 7.5. The presence of glucose and sodium chloride had a positive effect on Longus expression. The presence of divalent ions, particularly calcium, appears to be an important stimulus for Longus production. In addition, we studied H‐NS, CpxR and CRP global regulators, on Longus expression. The response regulator CpxR appears to function as a positive regulator of lng genes as the cpxR mutant showed reduced levels of lngRSA expression. In contrast, H‐NS and CRP function as negative regulators since expression of lngA was up‐regulated in isogenic hns and crp mutants. H‐NS and CRP were required for salt‐ and glucose‐mediated regulation of Longus. Our data suggest the existence of a complex regulatory network controlling Longus expression, involving both local and global regulators in response to different environmental signals.
The Political Limitations of Evidence: A Critique of the Electoral Reform Society's It's Good To Talk
Authors: Cunningham Michael
Published: December 2016

The Electoral Reform Society has called for more and better quality information to improve democratic debate in relation to referendums. This article argues that, particularly in relation to the European Union referendum, this would have had a marginal impact, because much of the debate was not reducible to facts and emotional and dispositional factors were of particular significance in the campaign.
Gallic acid improves endothelium‐dependent vasodilatory response to histamine in the mesenteric vascular bed of diabetic rats
Authors: Badavi Mohammad , Bazaz Amir , Dianat Mahin , Sarkaki Alireza
Published: December 2016

Background

Endothelial dysfunction is one of the many complications caused by diabetes mellitus. The aim of the present study was to evaluate the effects of gallic acid (GA) on the mesenteric vascular bed (MVB) response to histamine in diabetic rats.

Methods

Forty male Wistar rats were randomly assigned to a control group, an untreated alloxan‐induced diabetic group and three diabetic groups treated with different doses of GA. Six weeks after induction of diabetes and GA treatment, total antioxidant capacity (TAC), malondialdehyde (MDA) concentrations, and the vasodilatory response to histamine of the MVB (measured as changes in perfusion pressure) were determined.

Results

The vasodilatory response to histamine and TAC decreased, whereas MDA increased in the plasma from diabetic rats (P < 0.01). However, in the presence of 3 × 10−5 mol/L N

G
‐nitro‐l‐arginine methyl ester (a nitric oxide synthase inhibitor) and 1 × 10−5 mol/L indomethacin (an inhibitor of prostaglandin production), the vasodilatory response of the MVB to histamine was reduced in all groups (P < 0.001). Treatment of diabetic rats with 20 and 40 mg/kg per day GA, but not 10 mg/kg per day GA, increased TAC and decreased MDA concentrations (P < 0.01 and P < 0.001 vs untreated diabetic rats, respectively) and significantly improved the vasodilatory response to histamine (P < 0.05 and P < 0.001, respectively).

Conclusion

The results show that, in diabetic rats, the endothelium‐dependent vasodilatory response of the MVB to histamine is significantly decreased and depends on both nitric oxide‐ and prostaglandin‐producing pathways and may be mediated by oxidative stress. Treatment with the antioxidant GA restored the vasodilatory response of the MVB to histamine.
Cardiac tamponade and severe pericardial effusion in systemic sclerosis: report of nine patients and review of the literature
Authors: Fernández Morales Alejandro , Iniesta Nerea , Fernández‐Codina Andreu , Vaz de Cunha Joana , Pérez Romero Teresa , Hurtado García Robert , Simeón‐Aznar Carmen Pilar , Fonollosa Vicent , Cervera Ricard , Espinosa Gerard
Published: December 2016

Aim

To describe the clinical characteristics, treatment and outcome of patients with systemic sclerosis (SSc) developing severe pericardial effusion or cardiac tamponade.

Methods

SSc patients with severe pericardial effusion or cardiac tamponade from three Spanish hospitals were collected. In addition, a computer‐assisted (PubMed, MEDLINE) search of the literature to identify all cases of cardiac tamponade or severe pericardial effusion associated with SSc reported in English, French and Spanish from 1987 through September 2015 was performed.

Results

We included 40 patients (nine cases from the Spanish hospitals and 31 cases from the literature review). Most patients (87%) were female with a mean age at pericardial involvement of 49.3 ± 15.2 years (range: 18–80 years), and 22 (55%) patients had the diffuse cutaneous subtype. Twenty‐five (63%) patients presented with cardiac tamponade and the remaining 15 (37%) as severe or massive pericardial effusion. Pericardial involvement was previous or simultaneous to SSc diagnosis in 13 (32.5%) cases. In most cases (88.9%) pericardial fluid analysis disclosed an exudate. Half the patients received steroids and 35% needed surgical treatment. Five (12.5%) patients died due to cardiac tamponade, three of them during the acute phase and the remaining two, 2 and 9 months later, respectively.

Conclusions

Although cardiac tamponade or severe pericardial effusion is an infrequent complication in SSc patients, it can be the first manifestation of disease associated with the diffuse cutaneous subset. No specific treatment for this complication is known.
Factors associated with functional limitations in the daily living activities of Japanese hip osteoarthritis patients
Authors: Kondo Kyoko , Jingushi Seiya , Ohfuji Satoko , Sofue Muroto , Itoman Moritoshi , Matsumoto Tadami , Hamada Yoshiki , Shindo Hiroyuki , Takatori Yoshio , Yamada Harumoto , Yasunaga Yuji , Ito Hiroshi , Mori Satoshi , Owan Ichiro , Fujii Genji , Ohashi Hirotsugu , Fukushima Wakaba , Maeda Akiko , Inui Miki , Takahashi Shinji , Hirota Yoshio
Published: December 2016

Aim

As society ages, there is a vast number of elderly people with locomotive syndrome. In this study, the factors associated with functional limitations in daily living activities evaluated by female hip osteoarthritis (OA) patients were investigated.

Methods

This study was a cross‐sectional study. The subjects were 353 female patients who were newly diagnosed with hip OA at an orthopedic clinic with no history of hip joint surgery. Outcome indices were functional limitations in two daily living activities obtained from a questionnaire completed by the patients: (i) standing up (standing from a crouched position) and (ii) stair‐climbing (climbing and/or descending stairs). The odds ratios (ORs) and 95% confidence intervals (CIs) were computed for explanatory variables using the proportional odds model in logistic regression to evaluate their associations with functional limitations.

Results

Functional limitations in standing up were associated with heavy weight (third tertile vs. first tertile: 1.91, 1.11–3.27), participation in sports at school (0.62, 0.40–0.98), parity (vs. nullipara: 1.96, 1.08–3.56), old age and OA stage. Associations with functional limitations in stair‐climbing were seen with short height (< 151.0 cm vs. ≥ 156.0 cm: 2.05, 1.02–4.12), bilateral involvement (vs. unilateral: 1.71, 1.01–2.88), old age and OA stage.

Conclusion

Old age, OA stage, heavy weight, parity, shorter height and bilateral OA were associated with functional limitations in standing up and/or stair‐climbing, whereas participation in sports such as club activities in school maintained standing up.
Coastal bacterioplankton community response to diatom‐derived polysaccharide microgels
Authors: Taylor Joe D , Cunliffe Michael
Published: December 2016

Phytoplankton‐derived polysaccharide microgels, including transparent exopolymer particles (TEP), are a major component of the marine organic carbon pool. Previous studies have made correlative links between phytoplankton material and bacterioplankton, and performed experiments that assess general responses to phytoplankton, yet there is a lack of direct empirical evidence of specific bacterioplankton responses to natural phytoplankton polysaccharide microgels. In this study, we used diatom produced TEP in controlled incubation experiments to determine the impact of polysaccharide microgels on a coastal bacterioplankton community. Quantification of bacterial 16S rRNA gene transcripts showed that the addition of TEP caused an increase in bacterioplankton activity. Similarly, high‐throughput sequencing of RT‐PCR amplified bacterial 16S rRNA gene transcripts showed that active bacterioplankton community structure and diversity also changed in response to microgels. Alteromonadales and Rhodobacterales increased in abundance in response to TEP, suggesting that both bacterioplankton taxa utilize diatom‐derived microgels. However, through assessing 13C‐labelled TEP uptake via RNA Stable Isotope Probing, we show that only the Alteromonadales (genus Alteromonas) assimilated the TEP carbon. This study adds utilization of diatom‐derived TEP to the metabolic repertoire of the archetypal copiotrophic bacterioplankton Alteromonas, and indicates that the Rhodobacterales may utilize TEP for other purposes (e.g. attachment sites).
Interindividual and interethnic variability in drug disposition: polymorphisms in organic anion transporting polypeptide 1B1 (OATP1B1; SLCO1B1)
Authors: Lee Hannah H. , Ho Richard H.
Published: December 2016

OATP1B1 (SLCO1B1) is predominantly expressed at the basolateral membrane of hepatocytes and is critically important for the hepatic uptake and clearance of numerous drug substrates and endogenous compounds. In general, the organic anion transporting polypeptides (OATP; SLCO) represent a superfamily of uptake transporters that mediate the sodium‐independent transport of a diverse range of amphipathic organic compounds including bile salts, steroid conjugates, thyroid hormones, anionic peptides, numerous drugs and other xenobiotic substances. OATP1B1 is highly polymorphic and a number of relevant and ethnically dependent polymorphisms have been identified and functionally characterized. In particular, the SLCO1B1 521T>C and 388A>G polymorphisms are commonly occurring variants in ethnically diverse populations and numerous in vitro and clinical studies have evaluated the consequences of these variants to interindividual differences in drug disposition and response. OATP1B1 is particularly important for the disposition of HMG‐CoA reductase inhibitors, or statins, as it is known to efficiently transport most statins to their site of action within hepatocytes. Many studies have focused on the consequences of OATP1B1 variants to statin disposition in vitro and in vivo and would suggest that genetic variability in SLCO1B1 has important implications for statin pharmacokinetics, risk for statin‐induced myopathy, and modulation of statin treatment response. This review describes what is currently known regarding SLCO1B1 genotype, OATP1B1 protein expression and interindividual and interethnic consequences to drug disposition, with particular focus on statin pharmacokinetics and implications for drug response and toxicity.
Long‐term effects of peer victimization on social outcomes through the fourth decade of life in individuals born at normal or extremely low birthweight
Authors: Day Kimberly L. , Van Lieshout Ryan J. , Vaillancourt Tracy , Saigal Saroj , Boyle Michael H. , Schmidt Louis A.
Published: December 2016

Exposure to early adversity is known to have deleterious effects on brain‐behaviour relations across the lifespan and across a range of domains. Here, we tested a cumulative risk hypothesis of adult social functioning and health outcomes in the fourth decade of life, using the oldest known longitudinally followed cohort of survivors of extremely low birthweight (ELBW; <1,000 g). We investigated the additional impact of peer victimization in youth on social outcomes at age 29–36 years in ELBW survivors and matched normal birthweight (NBW; >2,500 g) participants. In the combined sample, peer victimization was associated with lower likelihood of having children and household income, poorer family functioning and self‐esteem, more loneliness and chronic health conditions, less social support, and increased likelihood for contact with police. Moderation analyses indicated that among ELBW survivors, compared to their NBW counterparts, victimization was more strongly associated with being convicted of a crime and with having chronic health conditions. These findings highlight the negative long‐term impact of peer victimization on all children and that some outcomes may be differentially affected by prenatal and early post‐natal environments.

Statement of contribution

What is already known on this subject

Exposure to early adversity has deleterious effects on brain‐behaviour relations across the lifespan.

Extremely premature children have higher rates of exposure to adversities, including peer victimization.

Peer victimization is associated with adverse outcomes in adulthood in those born at term.

What does this study add?

Victimization negatively impacts the social outcomes of those born extremely premature and at term into adulthood.

Associations appear to be affected by individual differences in prenatal and early post‐natal environments.

Intervention is crucial when peer victimization occurs in children at risk, as well as those typically developing.
Comparing acquired angioedema with hereditary angioedema (types I/II): findings from the Icatibant Outcome Survey
Authors: Longhurst H J , Zanichelli A , Caballero T , Bouillet L , Aberer W , Maurer M , Fain O , Fabien V , Andresen I
Published: December 2016

Icatibant is used to treat acute hereditary angioedema with C1 inhibitor deficiency types I/II (C1-INH-HAE types I/II) and has shown promise in angioedema due to acquired C1 inhibitor deficiency (C1-INH-AAE). Data from the Icatibant Outcome Survey (IOS) were analysed to evaluate the effectiveness of icatibant in the treatment of patients with C1-INH-AAE and compare disease characteristics with those with C1-INH-HAE types I/II. Key medical history (including prior occurrence of attacks) was recorded upon IOS enrolment. Thereafter, data were recorded retrospectively at approximately 6-month intervals during patient follow-up visits. In the icatibant-treated population, 16 patients with C1-INH-AAE had 287 attacks and 415 patients with C1-INH-HAE types I/II had 2245 attacks. Patients with C1-INH-AAE versus C1-INH-HAE types I/II were more often male (69 versus 42%; P = 0·035) and had a significantly later mean (95% confidence interval) age of symptom onset [57·9 (51·33–64·53) versus 14·0 (12·70–15·26) years]. Time from symptom onset to diagnosis was significantly shorter in patients with C1-INH-AAE versus C1-INH-HAE types I/II (mean 12·3 months versus 118·1 months; P = 0·006). Patients with C1-INH-AAE showed a trend for higher occurrence of attacks involving the face (35 versus 21% of attacks; P = 0·064). Overall, angioedema attacks were more severe in patients with C1-INH-HAE types I/II versus C1-INH-AAE (61 versus 40% of attacks were classified as severe to very severe; P < 0·001). Median total attack duration was 5·0 h and 9·0 h for patients with C1-INH-AAE versus C1-INH-HAE types I/II, respectively.
Novel biomarkers for the assessment of paediatric systemic lupus erythematosus nephritis
Authors: Koutsonikoli A , Trachana M , Farmaki E , Tzimouli V , Pratsidou-Gertsi P , Printza N , Garyphallos A , Galanopoulou V , Kanakoudi-Tsakalidou F , Papachristou F
Published: December 2016

The discovery of serum biomarkers specific for paediatric lupus nephritis (pLN) will facilitate the non-invasive diagnosis, follow-up and more appropriate use of treatment. The aim of this study was to explore the role of serum high-mobility group box 1 (HMGB1) protein, antibodies against nucleosomes (anti-NCS), complement factor C1q (anti-C1q) and glomerular basement membrane (anti-GBM) in pLN. Serum samples of 42 patients with paediatric systemic lupus erythematosus (pSLE) (22 with pLN and 20 without renal involvement), 15 patients with other autoimmune nephritis (AN) and 26 healthy controls (HCs) were examined using enzyme-linked immunosorbent assay (ELISA). The activity of both pSLE and pLN was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) tool. The levels of all four biomarkers were significantly higher in pLN compared to AN and to HCs. The anti-NCS, anti-GBM and HMGB1 serum levels were significantly higher in pLN than in pSLE without renal involvement. The anti-C1q and the HMGB1 serum levels were correlated positively with pSLE activity. The HMGB1 serum levels were also correlated positively with pLN activity. These findings suggest that serum anti-NCS, anti-GBM and HMGB1 may serve as biomarkers specific for the presence of nephritis in pSLE. HMGB1 emerged as a useful biomarker for the assessment of pLN and pSLE activity, whereas anti-C1q only of pSLE activity.