bluuebunny/crossref_metadata_2025 huggingface dataset:
Frailty Phenotype and Deficit Accumulation Frailty Index in Predicting Recovery After Transcatheter and Surgical Aortic Valve Replacement
Authors: Shi Sandra , Afilalo Jonathan , Lipsitz Lewis A , Popma Jeffrey J , Khabbaz Kamal R , Laham Roger J , Guibone Kim , Grodstein Francine , Lux Eliah , Kim Dae Hyun
Published: August 2018

Background

Frailty phenotype and deficit-accumulation frailty index (FI) are widely used measures of frailty. Their performance in predicting recovery after surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) has not been compared.

Methods

Patients undergoing SAVR (n = 91) or TAVR (n = 137) at an academic medical center were prospectively assessed for frailty phenotype and FI. Outcomes were death or poor recovery, defined as a decline in ability to perform 22 daily activities and New York Heart Association class 3 or 4 at 6 months after surgery. The predictive ability of frailty phenotype versus FI and their additive value to a traditional surgical risk model were evaluated using C-statistics, net reclassification improvement (NRI), and integrated discrimination improvement.

Results

TAVR patients had higher prevalence of phenotypic frailty (85% vs 38%, p < .001) and greater mean FI (0.37 vs 0.24, p < .001) than SAVR patients. In the overall cohort, FI had a higher C-statistic than frailty phenotype (0.74 vs 0.63, p = .01) for predicting death or poor recovery. Adding FI to the traditional model improved prediction (NRI, 26.4%, p = .02; integrated discrimination improvement, 7.7%, p < .001), while adding phenotypic frailty did not (NRI, 4.0%, p = .70; integrated discrimination improvement, 1.6%, p = .08). The additive value of FI was evident in TAVR patients (NRI, 42.8%, p < .01) but not in SAVR patients (NRI, 25.0%, p = .29). Phenotypic frailty did not add significantly in either TAVR (NRI, 6.8%, p = .26) or SAVR patients (NRI, 25.0%, p = .29).

Conclusions

Deficit-accumulation FI provides better prediction of death or poor recovery than frailty phenotype in older patients undergoing SAVR and TAVR.
Comorbidity Subgroups Among Medicare Beneficiaries Seeking Health Care for Musculoskeletal Pain
Authors: Lentz Trevor A , Marlow Nicole M , Beneciuk Jason M , Fillingim Roger B , George Steven Z
Published: August 2018

Background

Treatment of musculoskeletal pain in older adults may be more effective if it incorporates integrated management of comorbid health conditions. The purpose of this study was to define empirically derived comorbidity subgroups among Medicare beneficiaries with an index condition of osteoarthritis (OA) or low back pain (LBP) as a precursor to the development of comorbidity-specific pain treatment pathways.

Methods

This study included Medicare beneficiaries participating in the Medicare Current Beneficiary Survey (MCBS) and seeking care for OA (n = 723) or LBP (n = 617) with data available for 3 years after entry into the survey. We identified 30 comorbidity diagnoses using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes in claims data during beneficiaries’ first year in the survey. Latent class analysis defined comorbidity subgroups, and posterior probabilities were used to assign subgroup classification. Self-reported disability was compared over three consecutive years for each subgroup.

Results

We identified similar comorbidity subgroups for OA and LBP. The subgroups included (range of percent prevalence) low comorbidity (47.6%–54.4%), nonvascular (21.8%–28.6%), diabetes (12.2%–15.0%), renal disease with complicated hypertension (5.5%–5.8%), and complex cardiac disease/high comorbidity (3.3%–5.8%). OA and LBP subgroups with more complex comorbidity burden generally demonstrated higher disability over 3 years.

Conclusions

Five comorbidity subgroups were identified, with a large proportion of older adults classified into the subgroup defined by a low probability of most comorbidities. These findings provide direction for the development of pain treatment pathways that are tailored to address common comorbidity profiles among older adults.
Matrix decompositions using sub-Gaussian random matrices
Authors: Aizenbud Yariv , Averbuch Amir
Published: August 2018

In recent years, several algorithms which approximate matrix decomposition have been developed. These algorithms are based on metric conservation features for linear spaces of random projection types. We present a new algorithm, which achieves with high probability a rank-$r$ singular value decomposition (SVD) approximation of an $n \times n$ matrix and derive an error bound that does not depend on the first $r$ singular values. Although the algorithm has an asymptotic complexity similar to state-of-the-art algorithms and the proven error bound is not as tight as the state-of-the-art bound, experiments show that the proposed algorithm is faster in practice while providing the same error rates as those of the state-of-the-art algorithms. We also show that an i.i.d. sub-Gaussian matrix with large probability of having null entries is metric conserving. This result is used in the SVD approximation algorithm, as well as to improve the performance of a previously proposed approximated LU decomposition algorithm.
Efficacy of Pharmacotherapy for Smoking Cessation in Adolescent Smokers: A Meta-analysis of Randomized Controlled Trials
Authors: Myung Seung-Kwon , Park Joo-Young
Published: August 2018

Introduction

This study aimed to evaluate the efficacy of pharmacotherapy for smoking cessation among adolescent smokers by using a meta-analysis of randomized controlled trials (RCTs).

Methods

PubMed, EMBASE, and Cochrane Library were searched from the inception to January 20, 2018. We included RCTs of pharmacotherapy for smoking cessation among adolescent smokers aged less than 20 years. Data were pooled using a random-effects meta-analysis. The primary outcome measures were a smoking abstinence rate and its relative risk (RR) at the longest follow-up period in each study validated by biochemical markers.

Results

Among a total of 1035 articles searched, nine RCTs, which involved 1188 adolescent smokers aged 12–20 years with 627 in the intervention group and 561 in the control group, were included in the final analysis. In the random-effects meta-analysis of all the nine trials, pharmacotherapy showed a increased abstinence rate (RR = 1.62; 95% confidence interval [CI] = 1.08 to 2.44, I2 = 0.0%), compared with the control group. Subgroup meta-analyses by follow-up period showed an increased abstinence rate at 4 weeks (RR = 1.87; 95% CI = 1.22 to 2.87; n = 4) and a nonsignificantly increased abstinence rate during the longer term follow-up periods at 8, 12, 24, and 52 weeks.

Conclusions

The current meta-analysis suggests that pharmacotherapy can be considered as an aid for smoking cessation in the short-term period among adolescent smokers. However, further large RCTs are warranted to determine its long-term efficacy and safety.

Implications

In this meta-analysis of nine RCTs with 1188 adolescent smokers aged 12–20 years, pharmacotherapy showed an increased abstinence rate, compared with the control group. In the subgroup meta-analyses by follow-up period, it showed the increased abstinence rate at 4 weeks and no efficacy on abstinence during the longer term follow-up periods up to 52 weeks. Further large RCTs are warranted to determine the long-term efficacy and safety of pharmacotherapy in adolescent smokers.
The independent role of deprivation in abdominal obesity beyond income poverty. A population-based household survey in Chinese adults
Authors: Chung Gary Ka-Ki , Chung Roger Yat-Nork , Chan Dicken Cheong-Chun , Lai Francisco Tsz-Tsun , Wong Hung , Lau Maggie Ka-Wai , Wong Samuel Yeung-Shan , Yeoh Eng-Kiong
Published: August 2018

Background

Individual-level deprivation takes into account the non-monetary aspects of poverty that neither income poverty nor socio-economic factors could fully capture; however, it has rarely been considered in existing studies on social inequality in obesity. Therefore, we examined the associations of deprivation, beyond income poverty, with both general and abdominal obesity.

Methods

A territory-wide two-stage stratified random sample of 2282 community-dwelling Hong Kong adults was surveyed via face-to-face household interviews between 2014 and 2015. Deprivation was assessed by a Deprivation Index specific to the Hong Kong population. General obesity was defined as body mass index (BMI) ≥ 25 kg/m2, while abdominal obesity was defined as waist circumference (WC) ≥ 90 cm/80 cm for male/female. Multivariable binary logistic regressions were performed.

Results

Deprivation was independently associated with abdominal obesity (odds ratios (OR) = 1.68; 95% confidence intervals (CI): 1.27–2.22); however, no significant association was found with general obesity (OR=1.03; CI: 0.77–1.38). After additional adjustment for BMI, deprivation remained strongly associated with abdominal obesity (OR=2.00; CI: 1.41–2.83); and after further adjustment for WC, deprivation had a marginal inverse association with general obesity (OR=0.72; CI: 0.51–1.01).

Conclusions

Deprivation is an important risk factor of abdominal obesity and plays a critical role in capturing the preferential abdominal fat deposition beyond income poverty.
Is There a Safe Level for Recording Vestibular Evoked Myogenic Potential? Evidence From Cochlear and Hearing Function Tests
Authors: Singh Niraj Kumar , Keloth Nainitha Kizhake , Sinha Sachchidanand
Published: August 2018

Objective:

There is a growing concern among the scientific community about the possible detrimental effects of signal levels used for eliciting vestibular evoked myogenic potentials (VEMPs) on hearing. A few recent studies showed temporary reduction in amplitude of otoacoustic emissions (OAE) after VEMP administration. Nonetheless, these studies used higher stimulus levels (133 and 130 dB peak equivalent sound pressure level [pe SPL]) than the ones often used (120 to 125 dB pe SPL) for clinical recording of VEMP. Therefore, it is not known whether these lower levels also have similar detrimental impact on hearing function. Hence, the present study aimed at investigating the effect of 500 Hz tone burst presented at 125 dB pe SPL on hearing functions.

Design:

True experimental design, with an experimental and a control group, was used in this study. The study included 60 individuals with normal auditory and vestibular system. Of them, 30 underwent unilateral VEMP recording (group I) while the remaining 30 did not undergo VEMP testing (group II). Selection of participants to the groups was random. Pre- and post-VEMP assessments included pure-tone audiometry (250 to 16,000 Hz), distortion product OAE, and subjective symptoms. To simulate the time taken for VEMP testing in group I, participants in group II underwent these tests twice with a gap of 15 minutes.

Results:

No participant experienced any subjective symptom after VEMP testing. There was no significant interear and intergroup difference in pure-tone thresholds and distortion product OAE amplitude before and after VEMP recording (p > 0.05). Furthermore, the response rate of cervical VEMP was 100% at stimulus intensity of 125 dB pe SPL.

Conclusions:

Use of 500 Hz tone burst at 125 dB pe SPL does not cause any temporary or permanent changes in cochlear function and hearing, yet produces 100% response rate of cervical VEMP in normal-hearing young adults. Therefore, 125 dB pe SPL of 500 Hz tone burst is recommended as safe level for obtaining cervical VEMP without significantly losing out on its response rate, at least in normal-hearing young adults.
Muscle disease in scleroderma
Authors: Paik Julie J.
Published: August 2018

Purpose of review

This review discusses the most updated literature of muscle disease in scleroderma in the past year.

Recent findings

In the past year, two studies have highlighted that fibrosis is a prevalent histopathologic feature in muscle biopsies of patients with scleroderma muscle disease. In addition, microangiopathy was a common co-feature on muscle biopsies. A fibrosing myopathy, or fibrosis predominance on muscle histopathology, is associated with a unique clinical phenotype in patients with scleroderma. When compared with those with an inflammatory myopathy, patients with a fibrosing myopathy tend to have diffuse scleroderma, lower muscle enzymes, nonirritable myopathy, and elevated cardiac enzymes. These patients are also reported to have a higher risk of cardiopulmonary complications and cardiac death when compared with those with an inflammatory myopathy.

Although there are clear cases of overlap myositis, it is clear that muscle disease in scleroderma is being redefined, and it is crucial to start recognizing that the muscle is an organ that can directly be affected by scleroderma. Fibrosis can occur early in scleroderma muscle disease, and a unique histologic subtype of muscle disease, fibrosing myopathy, is associated with a higher risk of mortality.
Linking local adaptation with the evolution of sex differences
Authors: Connallon Tim , Débarre Florence , Li Xiang-Yi
Published: August 2018

Many conspicuous forms of evolutionary diversity occur within species. Two prominent examples include evolutionary divergence between populations differentially adapted to their local environments (local adaptation), and divergence between females and males in response to sex differences in selection (sexual dimorphismsensu lato). These two forms of diversity have inspired vibrant research programmes, yet these fields have largely developed in isolation from one another. Nevertheless, conceptual parallels between these research traditions are striking. Opportunities for local adaptation strike a balance between local selection, which promotes divergence, and gene flow—via dispersal and interbreeding between populations—which constrains it. Sex differences are similarly constrained by fundamental features of inheritance that mimic gene flow. Offspring of each sex inherit genes from same-sex and opposite-sex parents, leading to gene flow between each differentially selected half of the population, and raising the question of how sex differences arise and are maintained. This special issue synthesizes and extends emerging research at the interface between the research traditions of local adaptation and sex differences. Each field can promote understanding of the other, and interactions between local adaptation and sex differences can generate new empirical predictions about the evolutionary consequences of selection that varies across space, time, and between the sexes.

This article is part of the theme issue ‘Linking local adaptation with the evolution of sex differences’.
Sexual conflict in its ecological setting
Authors: Perry Jennifer C. , Rowe Locke
Published: August 2018

Sexual conflict can lead to rapid and continuous coevolution between females and males, without any inputs from varying ecology. Yet both the degree of conflict and selection on antagonistic traits are known to be sensitive to local ecological conditions. This leads to the longstanding question: to what extent does variation in ecological context drive sexually antagonistic coevolution? In water striders, there is much information about the impacts of ecological factors on conflict, and about patterns of antagonistic coevolution. However, the connection between the two is poorly understood. Here, we first review the multiple ways in which ecological context might affect the coevolutionary trajectory of the sexes. We then review ecological and coevolutionary patterns in water striders, and connections between them, in light of theory and new data. Our analysis suggests that ecological variation does impact observed patterns of antagonistic coevolution, but highlights significant uncertainty due to the multiple pathways by which ecological factors can influence conflict and its evolutionary outcome. To the extent that water striders are a reasonable reflection of other systems, this observation serves as both an opportunity and a warning: there is much to learn, but gaining insight may be a daunting process in many systems.

This article is part of the theme issue ‘Linking local adaptation with the evolution of sex differences'.
Hybridization, sex-specific genomic architecture and local adaptation
Authors: Runemark Anna , Eroukhmanoff Fabrice , Nava-Bolaños Angela , Hermansen Jo S. , Meier Joana I.
Published: August 2018

While gene flow can reduce the potential for local adaptation, hybridization may conversely provide genetic variation that increases the potential for local adaptation. Hybridization may also affect adaptation through altering sexual dimorphism and sexual conflict, but this remains largely unstudied. Here, we discuss how hybridization may affect sexual dimorphism and conflict due to differential effects of hybridization on males and females, and then how this, in turn, may affect local adaptation. First, in species with heterochromatic sexes, the lower viability of the heterogametic sex in hybrids could shift the balance in sexual conflict. Second, sex-specific inheritance of the mitochondrial genome in hybrids may lead to cytonuclear mismatches, for example, in the form of ‘mother's curse’, with potential consequences for sex ratio and sex-specific expression. Third, sex-biased introgression and recombination may lead to sex-specific consequences of hybridization. Fourth, transgressive segregation of sexually antagonistic alleles could increase sexual dimorphism in hybrid populations. Sexual dimorphism can reduce sexual conflict and enhance intersexual niche partitioning, increasing the fitness of hybrids. Adaptive introgression of alleles reducing sexual conflict or enhancing intersexual niche partitioning may facilitate local adaptation, and could favour the colonization of novel habitats. We review these consequences of hybridization on sex differences and local adaptation, and discuss how their prevalence and importance could be tested empirically.

This article is part of the theme issue ‘Linking local adaptation with the evolution of sex differences'.
Genetic constraints on microevolutionary divergence of sex-biased gene expression
Authors: Allen Scott L. , Bonduriansky Russell , Chenoweth Stephen F.
Published: August 2018

The evolution of sex-specific phenotypes is an important dimension of diversification and local adaptation. The sex-dependent regulation of gene expression is considered a key genomic mechanism facilitating sex-dependent adaptation. In many species, genes with male-biased expression evolve faster in DNA sequence and expression level than genes with female-biased or sexually monomorphic expression. While positive selection may be responsible for rapid DNA sequence evolution, why expression of male-biased genes also evolves rapidly remains unclear. Beyond sex differences in selection, some aspects of the genetic architecture of gene expression could contribute to the rapid evolution of male-biased gene expression. First, male-biased genes might simply have greater standing genetic variance than female-biased genes. Second, male-biased genes could be less constrained by pleiotropy, either within or between sexes. Here, we evaluate these alternative explanations on an intraspecific scale using a series of quantitative genetic experiments conducted on natural variation in male and female gene expression in the flyDrosophila serrata. Male-biased genes had significantly higher genetic variance than female-biased genes and were generally more narrowly expressed across tissues, suggesting lower within-individual pleiotropy. However, consistent with stronger constraints due to between-sex pleiotropy, their between-sex genetic correlations,rMF, were higher than for female-biased genes and more strongly negatively associated with sex bias. Using an extensive clinal dataset, we tested whether sex differences in gene expression divergence among populations have been shaped by pleiotropy.Here too, male-biased gene divergence was more strongly associated with between-sex pleiotropy than was female-biased gene divergence. Systematic differences in genetic variance and pleiotropy may be important factors influencing sex-specific adaptation arising through changes in gene expression.

This article is part of the theme issue ‘Linking local adaptation with the evolution of sex differences’.
Linking sex differences to the evolution of infectious disease life-histories
Authors: Hall Matthew D. , Mideo Nicole
Published: August 2018

Sex differences in the prevalence, course and severity of infection are widespread, yet the evolutionary consequences of these differences remain unclear. Understanding how male–female differences affect the trajectory of infectious disease requires connecting the contrasting dynamics that pathogens might experience within each sex to the number of susceptible and infected individuals that are circulating in a population. In this study, we build on theory using genetic covariance functions to link the growth of a pathogen within a host to the evolution and spread of disease between individuals. Using theDaphnia–Pasteuriasystem as a test case, we show that on the basis of within-host dynamics alone, females seem to be more evolutionarily liable for the pathogen, with higher spore loads and greater divergence among pathogen genotypes as infection progresses. Between-host transmission, however, appears to offset the lower performance of a pathogen within a male host, making even subtle differences between the sexes evolutionarily relevant, as long as the selection generated by the between-host dynamics is sufficiently strong. Our model suggests that relatively simple differences in within-host processes occurring in males and females can lead to complex patterns of genetic constraint on pathogen evolution, particularly during an expanding epidemic.

This article is part of the theme issue ‘Linking local adaptation with the evolution of sex differences’.
Three-Dimensional Histology of Whole Zebrafish by Sub-Micron Synchrotron X-ray Micro-Tomography
Authors: Ding Yifu , Vanselow Daniel J. , Yakovlev Maksim A. , Katz Spencer R. , Lin Alex Y. , Clark Darin P. , Vargas Phillip , Xin Xuying , Copper Jean E. , Canfield Victor A. , Ang Khai C. , Wang Yuxin , Xiao Xianghui , Carlo Francesco De , Rossum Damian B. van , Rivière Patrick La , Cheng Keith C.
Published: August 2018

Histological studies providing cellular insights into tissue architecture have been central to biological discovery and remain clinically invaluable today. Extending histology to three dimensions would be transformational for research and diagnostics. However, three-dimensional histology is impractical using current techniques. We have customized sample preparation, synchrotron X-ray tomographic parameters, and three-dimensional image analysis to allow for complete histological phenotyping using whole larval and juvenile zebrafish. The resulting digital zebrafish can be virtually sectioned and visualized in any plane. Whole-animal reconstructions at subcellular resolution also enable computational characterization of the zebrafish nervous system by region-specific detection of cell nuclei and quantitative assessment of individual phenotypic variation. Three-dimensional histological phenotyping has potential use in genetic and chemical screens, and in clinical and toxicological tissue diagnostics.

One Sentence Summary

Synchrotron X-ray micro-tomography can be used to rapidly create 3-dimensional images of fixed and stained specimens without sectioning, enabling computational histological phenotyping at cellular resolution.
HTSlib-js: Developer toolkit for a client-side JavaScript interface for HTSlib
Authors: Park Jeongbin , Childs Liam H. , Schlesner Matthias , Eils Roland
Published: August 2018

Background

An increasing number of bioinformatics tools are developed in JavaScript to provide an interactive visual interface to users. However, there are no tools yet that enable fast client-side analysis of large, high-throughput sequencing file formats, such as BAM and VCF files.

Results

We present HTSlib-js, an asm.js-based JavaScript wrapper for HTSlib, the de facto standard for processing BAM and VCF files. HTSlib-js exploits recent technological advances in web browser engines that dramatically increase the performance of browser-based tools to enable swift processing of files in the aforementioned formats. HTSlib-js enables quick development of JavaScript-based applications that include processing of aligned sequence reads and variant calling data.

Conclusions

HTSlib-js constitutes a toolkit for developers to easily write fast, accessible, browser-based applications that place an emphasis on data visualization, interactivity and privacy. Real-world examples demonstrate the capabilities of HTSlib-js and serve as guide for own developments.
SWI/SNF chromatin remodeling controls Notch-responsive enhancer accessibility
Authors: Pillidge Zoe , Bray Sarah J
Published: August 2018

Notch signaling plays a key role in many cell fate decisions during development by directing different gene expression programs via the transcription factor CSL, known as Su(H) inDrosophila.Which target genes are responsive to Notch signaling is influenced by the chromatin state of enhancers, yet how this is regulated is not fully known. Detecting an increase in the histone variant H3.3 in response to Notch signaling, we tested which chromatin remodelers or histone chaperones were required for the changes in enhancer accessibility to Su(H) binding. This revealed a crucial role for the Brahma SWI/SNF chromatin remodeling complex in conferring enhancer accessibility and enabling the transcriptional response. The Notch-responsive regions had high levels of nucleosome turnover which were dependent on the Brahma complex, increased with Notch signaling and primarily involved histone H3.3. Together these results highlight the importance of SWI/SNF-mediated nucleosome turnover in rendering enhancers responsive to Notch.
Whole genome sequencing reveals high complexity of copy number variation at insecticide resistance loci in malaria mosquitoes
Authors: Lucas Eric R. , Miles Alistair , Harding Nicholas J. , Clarkson Chris S. , N. Lawniczak Mara K. , Kwiatkowski Dominic P. , Weetman David , Donnelly Martin J. ,   The Anopheles gambiae 1000 Genomes Consortium
Published: August 2018

Background

Polymorphisms in the copy number of a genetic region can influence gene expression, coding sequence and zygosity, making them powerful actors in the evolutionary process. Copy number variants (CNVs) are however understudied, being more difficult to detect than single nucleotide polymorphisms. We take advantage of the intense selective pressures on the major malaria vector Anopheles gambiae, caused by the widespread use of insecticides for malaria control, to investigate the role of CNVs in the evolution of insecticide resistance.

Results

Using the whole-genome sequencing data from 1142 samples in the An. gambiae 1000 genomes project, we identified 1557 independent increases in copy number, encompassing a total of 267 genes, which were enriched for gene families linked to metabolic insecticide resistance. The five major candidate genes for metabolic resistance were all found in at least one CNV, and were often the target of multiple independent CNVs, reaching as many as 16 CNVs in Cyp9k1. These CNVs have furthermore been spreading due to positive selection, indicated by high local CNV frequencies and extended haplotype homozygosity.

Conclusions

Our results demonstrate the importance of CNVs in the response to selection, with CNVs being closely associated with genes involved in the evolution of resistance to insecticides, highlighting the urgent need to identify their relative contributions to resistance and to track their spread as the application of insecticide in malaria endemic countries intensifies. Our detailed descriptions of CNVs found across the species range provides the tools to do so.
Stress alters social behavior and sensitivity to pharmacological activation of kappa opioid receptors in an age-specific manner in Sprague Dawley rats
Authors: Varlinskaya Elena I. , Spear Linda Patia , Diaz Marvin R.
Published: August 2018

The dynorphin/kappa (DYN/KOR) system has been identified as a primary target of stress due to behavioral effects, such as dysphoria, aversion, and anxiety-like alterations that result from activation of this system. Numerous adaptations in the DYN/KOR system have also been identified in response to stress. However, whereas most studies examining the function of the DYN/KOR system have been conducted in adults, there is growing evidence suggesting that this system is ontogenetically regulated. Likewise, the outcome of exposure to stress also differs across ontogeny. Based on these developmental similarities, the objective of this study was to systematically test effects of a selective KOR agonist, U62066, on various aspects of social behavior across ontogeny in non-stressed male and female rats as well as in males and females with a prior history of repeated exposure to restraint (90 min/day, 5 exposures). We found that the social consequences of repeated restraint differed as a function of age: juvenile stress produced substantial increases in play fighting, whereas adolescent and adult stress resulted in decreases in social investigation and social preference. The KOR agonist U62066 dose-dependently reduced social behaviors in non-stressed adults, producing social avoidance at the highest dose tested, while younger animals displayed reduced sensitivity to this socially suppressing effect of U62066. Interestingly, in stressed animals, the socially suppressing effects of the KOR agonist were blunted at all ages, with juveniles and adolescents exhibiting increased social preference in response to certain doses of U62066. Taken together, these findings support the hypothesis that the DYN/KOR system changes with age and differentially responds and adapts to stress across development.
Gene-Specific Predictability of Protein Levels from mRNA Data in Humans
Authors: Moulana Alief , Scanteianu Adriana , Jones DeAnalisa , Stern Alan D. , Bouhaddou Mehdi , Birtwistle Marc R.
Published: August 2018

Transcriptomic data are widely available, and the extent to which they are predictive of protein abundances remains debated. Using multiple public databases, we calculate mRNA and mRNA-to-protein ratio variability across human tissues to quantify and classify genes for protein abundance predictability confidence. We propose that such predictability is best understood as a spectrum. A gene-specific, tissue-independent mRNA-to-protein ratio plus mRNA levels explains ∼80% of protein abundance variance for more predictable genes, as compared to ∼55% for less predictable genes. Protein abundance predictability is consistent with independent mRNA and protein data from two disparate cell lines, and mRNA-to-protein ratios estimated from publicly-available databases have predictive power in these independent datasets. Genes with higher predictability are enriched for metabolic function, tissue development/cell differentiation roles, and transmembrane transporter activity. Genes with lower predictability are associated with cell adhesion, motility and organization, the immune system, and the cytoskeleton. Surprisingly, many genes that regulate mRNA-to-protein ratios are constitutively expressed but also exhibit ratio variability, suggesting a general autoregulation mechanism whereby protein expression profile changes can be implemented quickly, or homeostatic sensing stabilizes protein abundances under fluctuating conditions. Gene classifications and their mRNA-to-protein ratios are provided as a resource to facilitate protein abundance predictions by others.
A heterogeneous spatial model in which savanna and forest coexist in a stable equilibrium
Authors: Durrett Rick , Ma Ruibo
Published: August 2018

In work with a variety of co-authors, Staver and Levin have argued that savanna and forest coexist as alternative stable states with discontinuous changes in density of trees at the boundary. Here we formulate a nonhomogeneous spatial model of the competition between forest and savanna. We prove that coexistence occurs for a time that is exponential in the size of the system, and that after an initial transient, boundaries between the alternative equilibria remain stable.
The Mycobacterium tuberculosis Phosphate-Sensing Pst/SenX3-RegX3 System Regulates ESX-5 Secretion to Evade Host Immunity
Authors: Elliott Sarah R. , White Dylan W. , Tischler Anna D.
Published: August 2018

The Mycobacterium tuberculosis Type VII secretion system ESX-5, which has been implicated in virulence, is activated at the transcriptional level by the phosphate starvation responsive Pst/SenX3-RegX3 signal transduction system. Deletion of pstA1, which encodes a Pst phosphate transporter component, causes constitutive activation of the response regulator RegX3, hyper-secretion of ESX-5 substrates and attenuation in the mouse infection model. We hypothesized that constitutive activation of ESX-5 secretion causes attenuation of the ΔpstA1 mutant. To test this, we uncoupled ESX-5 from regulation by RegX3. Using electrophoretic mobility shift assays, we defined a RegX3 binding site in the esx-5 locus. Deletion or mutation of the RegX3 binding site reversed hyper-secretion of the ESX-5 substrate EsxN by the ΔpstA1 mutant and abrogated induction of EsxN secretion in response to phosphate limitation by wild-type M. tuberculosis. Deletion of the esx-5 RegX3 binding site (ΔBS) suppressed attenuation of the ΔpstA1 mutant in Irgm1-/- mice, suggesting that constitutive ESX-5 secretion limits M. tuberculosis evasion of host immune responses that are independent of Irgm1. However, the ΔpstA1ΔBS mutant remained attenuated in both NOS2-/- and C57BL/6 mice, suggesting that factors other than ESX-5 secretion also contribute to attenuation of the ΔpstA1 mutant. In addition, a ΔpstA1ΔesxN mutant lacking the hyper-secreted ESX-5 substrate EsxN remained attenuated in Irgm1-/- mice, suggesting that ESX-5 substrates other than EsxN cause increased susceptibility to host immunity. Our data indicate that while M. tuberculosis requires ESX-5 for virulence, it tightly controls secretion of ESX-5 substrates to avoid elimination by host immune responses.
Education, intelligence and Alzheimer’s disease: Evidence from a multivariable two-sample Mendelian randomization study
Authors: Anderson Emma L , Howe Laura D , Wade Kaitlin H , Ben-Shlomo Yoav , Hill W. David , Deary Ian J , Sanderson Eleanor C , Zheng Jie , Korologou-Linden Roxanna , Stergiakouli Evie , Smith George Davey , Davies Neil M , Hemani Gibran
Published: August 2018

Objectives

To examine whether educational attainment and intelligence have causal effects on risk of Alzheimer’s disease (AD), independently of each other.

Design

Two-sample univariable and multivariable Mendelian Randomization (MR) to estimate the causal effects of education on intelligence and vice versa, and the total and independent causal effects of both education and intelligence on risk of AD.

Participants

17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer’s Project (IGAP) consortium

Main outcome measure

Odds ratio of AD per standardised deviation increase in years of schooling and intelligence

Results

There was strong evidence of a causal, bidirectional relationship between intelligence and educational attainment, with the magnitude of effect being similar in both directions. Similar overall effects were observed for both educational attainment and intelligence on AD risk in the univariable MR analysis; with each SD increase in years of schooling and intelligence, odds of AD were, on average, 37% (95% CI: 23% to 49%) and 35% (95% CI: 25% to 43%) lower, respectively. There was little evidence from the multivariable MR analysis that educational attainment affected AD risk once intelligence was taken into account, but intelligence affected AD risk independently of educational attainment to a similar magnitude observed in the univariate analysis.

Conclusions

There is robust evidence for an independent, causal effect of intelligence in lowering AD risk, potentially supporting a role for cognitive training interventions to improve aspects of intelligence. However, given the observed causal effect of educational attainment on intelligence, there may also be support for policies aimed at increasing length of schooling to lower incidence of AD.
Evaluation of RNA-seq normalization methods using challenging datasets
Authors: Uebbing Severin
Published: August 2018

RNA-seq is a powerful tool for both discovery and experimentation. Most RNA-seq studies rely on library normalization to compare samples or to reliably estimate quantitative gene expression levels. Over the years a number of RNA-seq normalization methods have been proposed. Review studies testing these methods have provided evidence that commonly used methods perform well in simple normalization tasks, but their performance in challenging normalization tasks has yet to be evaluated. Here I test RNA-seq normalization methods using two challenging normalization scenarios. My assessment reveals surprising shortcomings of some commonly used methods and identifies an underappreciated method as the most promising normalization strategy for common, yet challenging RNA-seq experiments.
Linking Darwin’s naturalisation hypothesis and Elton’s diversity–invasibility hypothesis in experimental grassland communities
Authors: Feng Yanhao , Fouqueray Timothée Donatien , van Kleunen Mark
Published: August 2018

Darwin’s naturalisation hypothesis posing that phylogenetic distance of alien species to native residents predicts invasion success, and Elton’s diversity–invasibility hypothesis posing that diversity of native communities confers resistance to invasion, are both rooted in ideas of species coexistence. Because the two hypotheses are inherently linked, the mechanisms underlying them may interact in driving the invasion success. Even so, these links and interactions have not been explicitly disentangled in one experimental study before.

To disentangle the links between the two hypotheses, we used 36 native grassland herbs to create greenhouse mesocosms with 90 grassland communities of different diversities, and introduced each of five herbaceous alien species as seeds and seedlings. We used phylogeny and four functional traits (plant height, specific leaf area, leaf size, and seed mass) to calculate different measures of phylogenetic and functional distance and diversity. Specifically, we tested how the alien–native distance (phylogenetic or functional) and the native diversity (phylogenetic or functional) affected each other in their effects on germination, seedling survival, growth, and reproduction of the aliens.

Overall, our results supported both hypotheses. Multivariate functional distance based on four traits jointly had stronger positive effects than phylogenetic distance and the univariate ones based on each trait separately. Moreover, the aliens were more successful if they were more competitive by being taller and having larger leaves with a lower SLA than the native residents. Univariate functional diversity based on each trait separately had stronger negative effects than phylogenetic and multivariate functional diversity. Most importantly, we found that the effects of alien–native phylogenetic and multivariate functional distance became stronger as diversity increased. Our analyses with single traits also showed that the strength of the effects of both alien–native hierarchical functional distances (indicative of competitive inequalities) and absolute functional distances (indicative of niche differences) increased at higher diversities, where competition is more severe.

Synthesis. Our study explicitly demonstrates for the first time how the mechanisms underlying the two classical invasion hypotheses interact in driving invasion success in grassland communities. This may help to explain some of the puzzling results of studies testing either of the two hypotheses.
Below‐ground plant traits influence tundra plant acquisition of newly thawed permafrost nitrogen
Authors: Hewitt Rebecca E. , Taylor D. Lee , Genet Hélène , McGuire A. David , Mack Michelle C.
Published: August 2018

The release of permafrost‐derived nitrogen (N) has the potential to fertilize tundra vegetation, which in turn may stimulate productivity and thus offset carbon (C) losses from thawing permafrost. Below‐ground plant traits may mediate ecosystem response to permafrost thaw and associated feedbacks to the atmosphere by differentially conferring access to deep, newly thawed permafrost N. Yet, identifying roots and quantifying root N uptake from deep, cold soils in complex plant communities has proved challenging to date.

We investigated plant acquisition of experimentally added 15N isotope tracer applied at the permafrost boundary in graminoid‐ and shrub‐dominated tundra at Eight Mile Lake, Alaska, when the thaw front was close to its maximum depth, simulating the release of newly thawed permafrost N. We used molecular tools to verify species and estimate biomass, nitrogen, and isotope pools.

Root biomass depth distributions follow an asymptotic relationship with depth, typical of other ecosystems. Few species had roots occurring close to the thaw front. Rubus chamaemorus, a short‐statured non‐mycorrhizal forb, and Carex bigelowii, a sedge, consistently had the deepest roots. Twenty‐four hours after isotope addition, we observed that deep‐rooted, non‐mycorrhizal species had the highest 15N enrichment values in their fine root tissue indicating that they access deep N late in the growing season when the thaw front is deepest. Deep‐rooted plants are therefore able to immediately take up newly thawed permafrost‐derived N. During the following growing season, herbaceous, non‐mycorrhizal plants allocated tracer above‐ground before woody, mycorrhizal plants. Ectomycorrhizal deciduous and ericoid mycorrhizal evergreen shrubs, by contrast, did not have immediate access to the deep N tracer and assimilated it into new foliar tissue gradually over the following growing season.

Synthesis. Graminoids and forbs that have immediate access to deep N represent a modest C sink compared to C emissions from thawing permafrost. However, the effects of deep N fertilization on shrubs over longer time‐scales may stimulate productivity and account for a more considerable N and C sink, thus constraining the permafrost C‐climate feedback.
Challenges of heterotopic ossification—Molecular background and current treatment strategies
Authors: Łęgosz Paweł , Drela Katarzyna , Pulik Łukasz , Sarzyńska Sylwia , Małdyk Paweł
Published: August 2018

Heterotopic ossification (HO) is an abnormal formation of mature lamellar bone within extraskeletal soft tissues, such as muscles, tendons, and ligaments. This process is thought to be induced by inflammation associated with tissue injuries. HO is classified using two subtypes: resulting from injury or genetically inherited. HO formation is associated with polytrauma patients with traumatic brain injuries and spinal cord injuries. Moreover, HO is also considered to be a post‐operative risk factor in some orthopaedic procedures. In this review, we summarize our current understanding of the pathology of different types of HO and discuss its current and future therapies. Thus far, research has revealed cellular and molecular pathways leading to HO formation and proposed several possible mechanisms leading to HO and conserved signalling pathways common in the different HO subtypes. Non‐steroidal anti‐inflammatory drug treatment and localized low‐dose irradiation are currently the only available prophylactic treatments for HO. However, they are not always effective and do not target the osteogenic processes directly. New therapeutic strategies targeting the pathological processes of HO, such as bone morphogenetic protein (BMP) inhibitors like noggin, BMP type 1 receptor inhibitor, and nuclear retinoid acid receptor‐gamma (RARγ) agonists, are currently being investigated. In‐depth understanding of the HO pathological process could help to develop effective therapeutic strategies.
Pectic polysaccharides extracted from Rauvolfia verticillata (Lour.) Baill. var. hainanensis Tsiang ameliorate ulcerative colitis via regulating the MAPKs and NF‐κB pathways in dendritic cells
Authors: Miao Xin‐Pu , Sun Xiao‐Ning , Li Qiong‐Si , Cui Lu‐Jia , Wang Xuan‐Yu , Zhuang Gui‐Feng , Deng Tao‐Zhi
Published: August 2018

This study was to investigate the effects and mechanisms of pectic polysaccharides (PP) extracted from Rauvolfia verticillata (Lour.) Baill. var. hainanensis Tsiang on dextran sulphate sodium (DSS)‐induced ulcerative colitis (UC). Eighty female BALB/c mice were randomly divided into four groups: Control, DSS, DSS + salicylazosulfapyridine (SASP), and DSS+ PP. The disease activity index (DAI), overall physical activity, and blood stool were monitored daily to evaluate severity of UC. Histological scores of the colon were observed. The expression of nuclear factor κB (NF‐κB) and mitogen‐activated protein kinase (MAPKs) pathways in colon tissues and bone marrow‐derived dendritic cells (DCs) was assessed by western blot, immunohistochemistry, electrophoretic mobility shift assay (EMSA) and real time polymerase chain reaction (RT‐PCR). Cytokines were measured by enzyme‐linked immunosorbent assay (ELISA). The overall physical activity, DAI and histological scores decreased in DSS+SASP and DSS+PP groups, compared with the DSS‐alone group. Also, tumour necrosis factor α (TNF‐α) and interleukin 6 (IL‐6) reduced significantly while the expression of IκBα was up‐regulated, extracellular signal‐regulated kinase (ERK), Jun N‐terminal kinase (JNK) and p38 were activated, in DSS+SASP and DSS+PP groups. PP inhibited activation of MAPKs and NF‐κB pathways in the bone‐marrow‐derived DCs. In conclusion, PP significantly ameliorated murine DSS‐induced UC model, via regulation of MAPKs and NF‐κB pathways in DCs.