bluuebunny/crossref_metadata_2025 huggingface dataset:
SparseIso: a novel Bayesian approach to identify alternatively spliced isoforms from RNA-seq data
Authors: Shi Xu , Wang Xiao , Wang Tian-Li , Hilakivi-Clarke Leena , Clarke Robert , Xuan Jianhua
Published: September 2017

Motivation

Recent advances in high-throughput RNA sequencing (RNA-seq) technologies have made it possible to reconstruct the full transcriptome of various types of cells. It is important to accurately assemble transcripts or identify isoforms for an improved understanding of molecular mechanisms in biological systems.

Results

We have developed a novel Bayesian method, SparseIso, to reliably identify spliced isoforms from RNA-seq data. A spike-and-slab prior is incorporated into the Bayesian model to enforce the sparsity for isoform identification, effectively alleviating the problem of overfitting. A Gibbs sampling procedure is further developed to simultaneously identify and quantify transcripts from RNA-seq data. With the sampling approach, SparseIso estimates the joint distribution of all candidate transcripts, resulting in a significantly improved performance in detecting lowly expressed transcripts and multiple expressed isoforms of genes. Both simulation study and real data analysis have demonstrated that the proposed SparseIso method significantly outperforms existing methods for improved transcript assembly and isoform identification.

Availability and implementation

The SparseIso package is available at http://github.com/henryxushi/SparseIso.

Supplementary information

Supplementary data are available at Bioinformatics online.
Augmented Th17 differentiation in Trim21 deficiency promotes a stable phenotype of atherosclerotic plaques with high collagen content
Authors: Brauner Susanna , Jiang Xintong , Thorlacius Gudny Ella , Lundberg Anna M , Östberg Therese , Yan Zhong-Qun , Kuchroo Vijay K , Hansson Göran K , Wahren-Herlenius Marie
Published: September 2017

Aims

Patients with hyperlipidemia are at risk of atherosclerosis, but not all develop cardiovascular disease, highlighting the importance of other risk factors such as inflammation. Both the innate and adaptive arms of the immune system have been suggested in the initiation and propagation of plaque formation. Tri-partite motif (TRIM) 21 is a regulator of tissue inflammation and pro-inflammatory cytokine production, and has been implicated in chronic inflammatory disease. Here, we investigate a potential role for TRIM21 in coronary artery disease.

Methods and results

Trim21-deficient or wild-type bone marrow was transplanted into Ldlr-/- mice fed a hypercholesterolemic diet. The Trim21-/-->Ldlr-/- mice developed larger atherosclerotic plaques, with significantly higher collagen content compared to mice transplanted with wild-type cells. High collagen content of the atheroma is stabilizing, and has recently been linked to IL-17. Interestingly, Trim21-/-->Ldlr-/- mice had elevated CD4 and IL-17 mRNA expression in plaques, and increased numbers of activated CD4+ T cells in the periphery. An increased differentiation of naïve T cells lacking Trim21 into Th17 cells was confirmed in vitro, with transcriptomic analysis revealing upregulation of genes of a non-pathogenic Th17 phenotype. Also, decreased expression of matrix metalloproteinases (MMPs) was noted in aortic plaques. Analysis of human carotid plaques confirmed that TRIM21 expression negatively correlates with the expression of key Th17 genes and collagen, but positively to MMPs also in patients, linking our findings to a clinical setting.

Conclusion

In this study, we demonstrate that TRIM21 influences atherosclerosis via regulation of Th17 responses, with TRIM21 deficiency promoting IL-17 expression and a more fibrous, stable, phenotype of the plaques.
11. Identities and US foreign policy
Authors: Rowley Christina , Weldes Jutta
Published: September 2017

This chapter examines the role of identity in constructing U.S. foreign policy. Using a critical social constructivist approach, it argues that particular conceptions of U.S. identity constitute U.S. interests, thus providing the foundations for foreign policy. After providing an overview of the influence of interests on foreign policy, the chapter considers the basic assumptions of critical social constructivism, taking into account the social construction of reality and the concepts of discourse and articulation. It then analyses discourses as sites of power, identity, and representation, along with the importance of identity in U.S. foreign policy. It also looks at U.S. presidents’ articulations of state identity and foreign policy over the last six decades.
Nontuberculous Mycobacterial Infections After Silicone Breast Implant Reconstruction Emphasize a Diversity of Infecting Mycobacteria
Authors: Romero Fabian A , Powell Eleanor A , Babady N Esther , Kaltsas Anna , Figueroa Cesar J , Pulitzer Melissa , Mehrara Babak J , Glickman Michael S , Morjaria Sejal
Published: September 2017

Postsurgical skin and soft tissue infections (SSTIs) caused by nontuberculous mycobacteria (NTM) are uncommon, indolent, difficult to treat, and often mimic pyogenic bacterial infections. Here we present 3 cases of NTM infections following placement of silicone implants for reconstructive breast surgery. These cases emphasize the importance of a high index of suspicion for NTM in patients with SSI after a prosthetic reconstruction refractory to conventional antibiotic therapy and the importance of early investigation with mycobacterial-specific diagnostics.
Stem Cell–based Therapies for Sepsis
Authors: Keane Colm , Jerkic Mirjana , Laffey John G.
Published: September 2017

Sepsis is a life-threatening syndrome resulting in shock and organ dysfunction stemming from a microbial infection. Sepsis has a mortality of 40% and is implicated in half of all in-hospital deaths. The host immune response to microbial infection is critical, with early-phase sepsis characterized by a hyperinflammatory immune response, whereas the later phase of sepsis is often complicated by suppression. Sepsis has no treatment, and management remains supportive.

Stem cells constitute exciting potential therapeutic agents for sepsis. In this review, we examine the rationale for stem cells in sepsis, focusing on mesenchymal stem/stromal cells, which currently demonstrate the greatest therapeutic promise. We examine the preclinical evidence base and evaluate potential mechanisms of action of these cells that are important in the setting of sepsis. We discuss early-phase clinical trials and critically appraise translational barriers to the use of mesenchymal stem/stromal cells in patients with sepsis.
Climate change will lead to pronounced shifts in the diversity of soil microbial communities
Authors: Ladau Joshua , Shi Yu , Jing Xin , He Jin-Sheng , Chen Litong , Lin Xiangui , Fierer Noah , Gilbert Jack A , Pollard Katherine S , Chu Haiyan
Published: September 2017

Soil bacteria are key to ecosystem function and maintenance of soil fertility. Leveraging associations of current geographic distributions of bacteria with historic climate, we predict that soil bacterial diversity will increase across the majority (~75%) of the Tibetan Plateau and northern North America if bacterial communities equilibrate with existing climatic conditions. This prediction is possible because the current distributions of soil bacteria have stronger correlations with climate from ~50 years ago than with current climate. This lag is likely associated with the time it takes for soil properties to adjust to changes in climate. The predicted changes are location specific and differ across bacterial taxa, including some bacteria that are predicted to have reductions in their distributions. These findings demonstrate the widespread influence that climate change will have on belowground diversity and highlight the importance of considering bacterial communities when assessing climate impacts on terrestrial ecosystems.

IMPORTANCE

There have been many studies highlighting how plant and animal communities lag behind climate change, causing extinction and diversity debts that will slowly be paid as communities equilibrate. By virtue of their short generation times and dispersal abilities, soil bacteria might be expected to respond to climate change quickly and to be effectively in equilibrium with current climatic conditions. We found strong evidence to the contrary in Tibet and North America. These findings could significantly improve understanding of climate impacts on soil microbial communities.
Alternative splicing links histone modifications to stem cell fate decision
Authors: Xu Yungang , Zhao Weiling , Olson Scott D. , Prabhakara Karthik S. , Zhou Xiaobo
Published: September 2017

Background

Understanding the embryonic stem cell (ESC) fate decision between self-renewal and proper differentiation is important for developmental biology and regenerative medicine. Attention has focused on mechanisms involving histone modifications, alternative pre-mRNA splicing, and cell-cycle progression. However, their intricate interrelations and joint contributions to ESC fate decision remain unclear.

Results

We analyze the transcriptomes and epigenomes of human ESC and five types of differentiated cells. We identify thousands of alternatively spliced exons and reveal their development and lineage-dependent characterizations. Several histone modifications show dynamic changes in alternatively spliced exons and three are strongly associated with 52.8% of alternative splicing events upon hESC differentiation. The histone modification-associated alternatively spliced genes predominantly function in G2/M phases and ATM/ATR-mediated DNA damage response pathway for cell differentiation, whereas other alternatively spliced genes are enriched in the G1 phase and pathways for self-renewal. These results imply a potential epigenetic mechanism by which some histone modifications contribute to ESC fate decision through the regulation of alternative splicing in specific pathways and cell-cycle genes. Supported by experimental validations and extended dataset from Roadmap/ENCODE projects, we exemplify this mechanism by a cell cycle-related transcription factor, PBX1, which regulates the pluripotency regulatory network by binding to NANOG. We suggest that the isoform switch from PBX1a to PBX1b links H3K36me3 to hESC fate determination through the PSIP1/SRSF1 adaptor, which results in the exon skipping of PBX1.

Conclusion

We reveal the mechanism by which alternative splicing links histone modifications to stem cell fate decision.
Sample-Index Misassignment Impacts Tumor Exome Sequencing
Authors: Vodák Daniel , Lorenz Susanne , Nakken Sigve , Aasheim Lars Birger , Holte Harald , Bai Baoyan , Myklebost Ola , Meza-Zepeda Leonardo A. , Hovig Eivind
Published: September 2017

Sample pooling enabled by dedicated indexes is a common and cost-effective strategy used in high-throughput DNA sequencing. Index misassignment leading to cross-sample contamination has however been described as a general problem of sequencing instruments which utilize exclusion amplification. Using real-life data from multiple tumor sequencing projects, we demonstrate that co-multiplexed samples can induce artifactual calls closely resembling high-quality somatic variant calls, and argue that dual indexing is the most reliable countermeasure.
Estimating the scale of biomedical data generation using text mining
Authors: Rosenfeld Gabriel , Lin Dawei
Published: September 2017

While the impact of biomedical research has traditionally been measured using bibliographic metrics such as citation or journal impact factor, the data itself is an output which can be directly measured to provide additional context about a publication’s impact. Data are a resource that can be repurposed and reused providing dividends on the original investment used to support the primary work. Moreover, it is the cornerstone upon which a tested hypothesis is rejected or accepted and specific scientific conclusions are reached. Understanding how and where it is being produced enhances the transparency and reproducibility of the biomedical research enterprise. Most biomedical data are not directly deposited in data repositories and are instead found in the publication within figures or attachments making it hard to measure. We attempted to address this challenge by using recent advances in word embedding to identify the technical and methodological features of terms used in the free text of articles’ methods sections. We created term usage signatures for five types of biomedical research data, which were used in univariate clustering to correctly identify a large fraction of positive control articles and a set of manually annotated articles where generation of data types could be validated. The approach was then used to estimate the fraction of PLOS articles generating each biomedical data type over time. Out of all PLOS articles analyzed (n = 129,918), ~7%, 19%, 12%, 18%, and 6% generated flow cytometry, immunoassay, genomic microarray, microscopy, and high-throughput sequencing data. The estimate portends a vast amount of biomedical data being produced: in 2016, if other publishers generated a similar amount of data then roughly 40,000 NIH-funded research articles would produce ~56,000 datasets consisting of the five data types we analyzed.

One Sentence Summary

Application of a word-embedding model trained on the methods sections of research articles allows for estimation of the production of diverse biomedical data types using text mining.
Genomic sequencing identifies secondary findings in a cohort of parent study participants
Authors: Thompson Michelle L. , Finnila Candice R. , Bowling Kevin M. , Brothers Kyle B. , Neu Matthew B. , Amaral Michelle D. , Hiatt Susan M. , East Kelly M. , Gray David E. , Lawlor James M. J. , Kelley Whitley V. , Lose Edward J. , Rich Carla A. , Simmons Shirley , Levy Shawn E. , Myers Richard M. , Barsh Gregory S. , Bebin E. Martina , Cooper Gregory M.
Published: September 2017

PURPOSE

Clinically relevant secondary variants were identified in parents enrolled with a child with developmental delay and intellectual disability.

METHODS

Exome/genome sequencing and analysis of 789 ‘unaffected’ parents was performed.

RESULTS

Pathogenic/likely pathogenic variants were identified in 21 genes within 25 individuals (3.2%), with 11 (1.4%) participants harboring variation in a gene defined as clinically actionable by the ACMG. Of the 25 individuals, five carried a variant consistent with a previous clinical diagnosis, thirteen were not previously diagnosed but had symptoms or family history with probable association with the detected variant, and seven reported no symptoms or family history of disease. A limited carrier screen was performed yielding 15 variants in 48 (6.1%) parents. Parents were also analyzed as mate-pairs to identify cases in which both parents were carriers for the same recessive disease; this led to one finding inATP7B.Four participants had two findings (one carrier and one non-carrier variant). In total, 71 of the 789 enrolled parents (9.0%) received secondary findings.

CONCLUSION

We provide an overview of the rates and types of clinically relevant secondary findings, which may be useful in the design, and implementation of research and clinical sequencing efforts to identify such findings.
Functional redundancy of variant and canonical histone H3 lysine 9 modification inDrosophila
Authors: Penke Taylor J.R. , McKay Daniel J. , Strahl Brian D. , Matera A. Gregory , Duronio Robert J.
Published: September 2017

Histone post-translational modifications (PTMs) and differential incorporation of variant and canonical histones into chromatin are central modes of epigenetic regulation. Despite similar protein sequences, histone variants are enriched for different suites of PTMs compared to their canonical counterparts. For example, variant histone H3.3 occurs primarily in transcribed regions and is enriched for “active” histone PTMs like Lys9 acetylation (H3.3K9ac), whereas the canonical histone H3 is enriched for Lys9 methylation (H3K9me), which is found in transcriptionally silent heterochromatin. To determine the functions of K9 modification on variant versus canonical H3, we compared the phenotypes caused by engineeringH3.3K9RandH3K9Rmutant genotypes inDrosophila melanogaster. Whereas mostH3.3K9Rand a small number ofH3K9Rmutant animals are capable of completing development and do not have substantially altered protein coding transcriptomes, allH3.3K9RH3K9Rcombined mutants die soon after embryogenesis and display decreased expression of genes enriched for K9ac. These data suggest that the role of K9ac in gene activation during development can be provided by either H3 or H3.3. Conversely, we found that H3.3K9 is methylated at telomeric transposons, and this mark contributes to repressive chromatin architecture, supporting a role for H3.3 in heterochromatin that is distinct from that of H3. Thus, our genetic and molecular analyses demonstrate that K9 modification of variant and canonical H3 have overlapping roles in development and transcriptional regulation, though to differing extents in euchromatin and heterochromatin.
Evidence of sinks and sources in the PLC activated PIP2cycle
Authors: Suratekar Rohit , Raghu Padinjat , Krishna Sandeep
Published: September 2017

In many eukaryotic signalling cascades, receptor mediated phospholipase C (PLC) activity triggers phosphatidylinositol 4,5 bisphosphate (PIP2) hydrolysis leading to information transfer in cells. Coupled with PLC activation is a sequence of reactions spread across multiple compartments by which PIP2is resynthesized, a process essential to maintain PIP2levels and support sustained PLC signalling. The biochemical strategies to co-ordinate these reactions and support PIP2levels have remained poorly understood. In particular, the question of whether the PIP2cycle is a closed cycle with no net addition or loss of metabolites has not been addressed. Using mathematical modelling approaches, we find that a closed PIP2cycle cannot explain experimentally observed changes in the metabolic intermediates when changing enzyme activities in the PIP2cycle. Thus, we propose that the PIP2cycle likely includes at least one metabolic source and one sink whose net activity results in the experimentally observed regulation of this key signalling pathway.
An automated confocal micro-extensometer enables in vivo quantification of mechanical properties with cellular resolution
Authors: Robinson Sarah , Huflejt Michal , Barbier de Reuille Pierre , Braybrook Siobhan A. , Schorderet Martine , Reinhardt Didier , Kuhlemeier Cris
Published: September 2017

How complex developmental-genetic networks are translated into organs with specific 3D shapes remains an open question. This question is particularly challenging because the elaboration of specific shapes is in essence a question of mechanics. In plants, this means how the genetic circuitry affects the cell wall. The mechanical properties of the wall and their spatial variation are the key factors controlling morphogenesis in plants. However, these properties are difficult to measure and investigating their relation to genetic regulation is particularly challenging. To measure spatial variation of mechanical properties, one must determine the deformation of a tissue in response to a known force with cellular resolution. Here we present an automated confocal micro-extensometer (ACME), which greatly expands the scope of existing methods for measuring mechanical properties. Unlike classical extensometers, ACME is mounted on a confocal microscope and utilizes confocal images to compute the deformation of the tissue directly from biological markers, thus providing cellular scale information and improved accuracy. ACME is suitable for measuring the mechanical responses in live tissue. As a proof of concept we demonstrate that the plant hormone gibberellic acid induces a spatial gradient in mechanical properties along the length of the Arabidopsis hypocotyl.

Terms

Stress

is the force acting on the material per unit area.

Strain

the relative increase in length of the material, and can be expressed as a percentage change in length.

Mechanical properties

describe the stress-strain relationship for a material. If we apply the same force to a material that is twice as thick/stiff? it will deform half as much, if the material is otherwise the same.

Elastic

elastic materials deform instantly and reversibly.

Creep

a time-dependent irreversible strain that occurs when a constant force is applied and maintained. Creep is measured using creep tests. A force is applied and maintained for a period of time. The force is removed to reveal the reversible and irreversible deformation.
A histone acetylome-wide association study of Alzheimer’s disease: neuropathology-associated regulatory variation in the human entorhinal cortex
Authors: Marzi Sarah J. , Ribarska Teodora , Smith Adam R. , Hannon Eilis , Poschmann Jeremie , Moore Karen , Troakes Claire , Al-Sarraj Safa , Beck Stephan , Newman Stuart , Lunnon Katie , Schalkwyk Leonard C. , Mill Jonathan
Published: September 2017

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by the progressive accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles in the neocortex. Recent studies have implicated a role for regulatory genomic variation in AD progression, finding widespread evidence for altered DNA methylation associated with neuropathology. To date, however, no study has systematically examined other types of regulatory genomic modifications in AD. In this study, we quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) - a robust mark of active enhancers and promoters that is strongly correlated with gene expression and transcription factor binding - in entorhinal cortex samples from AD cases and matched controls (n = 47) using chromatin immunoprecipitation followed by highly parallel sequencing (ChIP-seq). Across ~182,000 robustly detected H3K27ac peak regions, we found widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (FDR < 0.05) between AD cases and controls. These differentially acetylated peaks are enriched in disease-specific biological pathways and include regions annotated to multiple genes directly involved in the progression of Aβ and tau pathology (e.g.APP,PSEN1,PSEN2,MAPT), as well as genomic regions containing variants associated with sporadic late-onset AD. This is the first study of variable H3K27ac yet undertaken in AD and the largest study investigating this modification in the entorhinal cortex. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease, integrating our data with results obtained from genome-wide association studies as well as other epigenetic marks profiled on the same samples.
Cell size control driven by the circadian clock and environment in cyanobacteria
Authors: Martins Bruno M. C. , Tooke Amy K. , Thomas Philipp , Locke James C. W.
Published: September 2017

How cells maintain their size has been extensively studied under constant conditions. In the wild, however, cells rarely experience constant environments. Here, we examine how the 24-hour circadian clock and environmental cycles modulate cell size control and division timings in the cyanobacteriumSynechococcus elongatususing single-cell time-lapse microscopy. Under constant light, wild type cells follow an apparent sizer-like principle. Closer inspection reveals that the clock generates two subpopulations, with cells born in the subjective day following different division rules from cells born in subjective night. A stochastic model explains how this behaviour emerges from the interaction of cell size control with the clock. We demonstrate that the clock continuously modulates the probability of cell division throughout day and night, rather than solely applying an on-off gate to division as previously proposed. Iterating between modelling and experiments, we go on to show that the combined effects of the environment and the clock on cell division are explained by an effective coupling function. Under naturally graded light-dark cycles, this coupling shifts cell division away from dusk and dawn, when light levels are low and cell growth is reduced. Our analysis allows us to disentangle, and predict the effects of, the complex interactions between the environment, clock, and cell size control.
Neurochondrin interacts with the SMN protein suggesting a novel mechanism for Spinal Muscular Atrophy pathology
Authors: Thompson Luke , Morrison Kim , Shirran Sally , Botting Catherine , Sleeman Judith
Published: September 2017

Spinal Muscular Atrophy (SMA) is an inherited neurodegenerative condition caused by reduction in functional Survival Motor Neurones Protein (SMN). SMN has been implicated in transport of mRNA in neural cells for local translation. We previously identified microtubule-dependant mobile vesicles rich in SMN and the splicing factor SmB, a member of the Sm protein family, in neural cells. By comparing the proteome of SmB to that of SmN, a neural-specific Sm protein, we now show that the essential neural protein neurochondrin (NCDN) interacts with Sm proteins and SMN in the context of mobile vesicles in neurites. NCDN has roles in protein localisation in neural cells, and in maintenance of cell polarity. NCDN is required for the correct localisation of SMN, suggesting they may both be required for formation and transport of trafficking vesicles. NCDN provides a potential therapeutic target for SMA together with, or in place of, those targeting SMN expression.
Dynamic threat processing
Authors: Meyer Christian , Padmala Srikanth , Pessoa Luiz
Published: September 2017

During real-life situations, multiple factors interact dynamically to determine threat level. In the current functional MRI study involving healthy adult human volunteers, we investigated interactions between proximity, direction (approach vs. retreat), and speed during a dynamic threat-of-shock paradigm. As a measure of threat-evoked physiological arousal, skin conductance responses were recorded during fMRI scanning. Whereas some brain regions tracked individual threat-related factors, others were also sensitive to combinations of these variables. In particular, signals in the anterior insula tracked the interaction between proximity and direction where approach vs. retreat responses were stronger when threat was closer compared to farther. A parallel proximity-by-direction interaction was also observed in physiological skin conductance responses. In the right amygdala, we observed a proximity by direction interaction, but intriguingly in the opposite direction as the anterior insula; retreat vs. approach responses were stronger when threat was closer compared to farther. In the right bed nucleus of the stria terminalis, we observed an effect of threat proximity, whereas in the right periaqueductal gray/midbrain we observed an effect of threat direction and a proximity by direction by speed interaction (the latter was detected in exploratory analyses but not in a voxelwise fashion). Together, our study refines our understanding of the brain mechanisms involved during aversive anticipation in the human brain. Importantly, it emphasizes that threat processing should be understood in a manner that is both context sensitive and dynamic.
Raspberry Pi Powered Imaging for Plant Phenotyping
Authors: Tovar Jose C. , Hoyer J. Steen , Lin Andy , Tielking Allison , Tessman Monica , Miller Michael , Callen Steven T. , Castillo S. Elizabeth , Fahlgren Noah , Carrington James C. , Nusinow Dmitri A. , Gehan Malia A.
Published: September 2017

Premise of the study: Image-based phenomics is a powerful approach to capture and quantify plant diversity. However, commercial platforms that make consistent image acquisition easy are often cost-prohibitive. To make high-throughput phenotyping methods more accessible, low-cost microcomputers and cameras can be used to acquire plant image data.

Methods and Results: We used low-cost Raspberry Pi computers and cameras to manage and capture plant image data. Detailed here are three different applications of Raspberry Pi controlled imaging platforms for seed and shoot imaging. Images obtained from each platform were suitable for extracting quantifiable plant traits (shape, area, height, color)en masseusing open-source image processing software such as PlantCV.

Conclusion: This protocol describes three low-cost platforms for image acquisition that are useful for quantifying plant diversity. When coupled with open-source image processing tools, these imaging platforms provide viable low-cost solutions for incorporating high-throughput phenomics into a wide range of research programs.
RNA editing in bacteria recodes multiple proteins and regulates an evolutionarily conserved toxin-antitoxin system
Authors: Bar-Yaacov Dan , Mordret Ernest , Towers Ruth , Biniashvili Tammy , Soyris Clara , Schwartz Schraga , Dahan Orna , Pilpel Yitzhak
Published: September 2017

Adenosine (A) to inosine (I) RNA editing is widespread in eukaryotes. In prokaryotes, however, A-to-I RNA editing was only reported to occur in tRNAs but not in protein-coding genes. By comparing DNA and RNA sequences of Escherichia coli, we show for the first time that A-to-I editing occurs also in prokaryotic mRNAs and has the potential to affect the translated proteins and cell physiology. We found 15 novel A-to-I editing events, of which 12 occurred within known protein-coding genes where they always recode a tyrosine (TAC) into a cysteine (TGC) codon. Furthermore, we identified the tRNA-specific adenosine deaminase (tadA) as the editing enzyme of all these editing sites, thus making it the first identified RNA editing enzyme that modifies both tRNAs and mRNAs. Interestingly, several of the editing targets are self-killing toxins that belong to evolutionarily conserved toxin-antitoxin pairs. We focused on hokB, a toxin that confers antibiotic tolerance by growth inhibition, as it demonstrated the highest level of such mRNA editing. We identified a correlated mutation pattern between the edited and a DNA hard-coded Cys residue positions in the toxin and demonstrated that RNA editing occurs in hokB in two additional bacterial species. Thus, not only the toxin is evolutionarily conserved but also the editing itself within the toxin is. Finally, we found that RNA editing in hokB increases as a function of cell density and enhances its toxicity. Our work thus demonstrates the occurrence, regulation, and functional consequences of RNA editing in bacteria.
Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation
Authors: Traynelis Joshua , Silk Michael , Wang Quanli , Berkovic Samuel F. , Liu Liping , Ascher David B. , Balding David J. , Petrovski Slavé
Published: September 2017

Gene panel and exome sequencing have revealed a high rate of molecular diagnoses among diseases where the genetic architecture has proven suitable for sequencing approaches, with a large number of distinct and highly penetrant causal variants identified among a growing list of disease genes. The challenge is, given the DNA sequence of a new patient, to distinguish disease-causing from benign variants. Large samples of human standing variation data highlight regional variation in the tolerance to missense variation within the protein-coding sequence of genes. This information is not well captured by existing bioinformatic tools, but is effective in improving variant interpretation. To address this limitation in existing tools, we introduce the missense tolerance ratio (MTR), which summarizes available human standing variation data within genes to encapsulate population level genetic variation. We find that patient-ascertained pathogenic variants preferentially cluster in low MTR regions (P < 0.005) of well-informed genes. By evaluating 20 publicly available predictive tools across genes linked to epilepsy, we also highlight the importance of understanding the empirical null distribution of existing prediction tools, as these vary across genes. Subsequently integrating the MTR with the empirically selected bioinformatic tools in a gene-specific approach demonstrates a clear improvement in the ability to predict pathogenic missense variants from background missense variation in disease genes. Among an independent test sample of case and control missense variants, case variants (0.83 median score) consistently achieve higher pathogenicity prediction probabilities than control variants (0.02 median score; Mann-Whitney U test, P < 1 × 10−16). We focus on the application to epilepsy genes; however, the framework is applicable to disease genes beyond epilepsy.
A survey of school-family-community partnerships in Kenya
Authors: Nyatuka Benard Omenge
Published: September 2017

Purpose

The creation of sound school-family-community partnerships is being widely acknowledged as it strengthens school programs, family practices, student learning and behavior, as well as development. Active participation of parents and communities in the school tends to reduce the traditional unidirectional accountability of teachers as a sole party responsible for learners’ success. Furthermore, such collaboration is said to cultivate new hope about schools and education, especially among rural communities. However, key stakeholders in education claimed that school-family-community partnerships were weak in primary schools in Kakamega County, Kenya (Ministry of Education (MOE), 2010). The paper aims to discuss these issues.

Design/methodology/approach

This study was designed to generate relevant empirical evidence. The study was guided by the Social Capital Theory (Field, 2003; Horvat et al., 2003; Coleman, 1994; Bourdieu and Wacquant, 1992) whose central thesis is that social networks are a valuable asset, as interaction enables people to build communities, commit themselves to each other, and knit the social fabric. Using stratified random sampling, a sample of 361 primary school teachers in 34 schools drawn from a population of 8,964 teachers in 848 primary schools, cutting across the 12 districts in the county, was involved in the study. A questionnaire was developed and used to collect the teachers’ views of school-family-community partnership practices in the schools. The data generated were analyzed and presented by means of such descriptive statistics as frequencies, percentages, and the mean.

Findings

The findings revealed gaps with respect to collaboration among schools, families, and the community as the key focus in this study. Results indicated that the school-family-community partnerships in the county remained at a transactional rather than a transformational level. In light of the findings, relevant policy recommendations were proposed to improve practice, with particular attention to providing meaningful professional learning as well as desirable student outcomes.

Originality/value

This is one of the largest county-level studies in Kenya directly addressing teacher-family partnerships and illuminating the ways in which schools can build internal capacity for effective family engagement.
The role of stress‐regulation genes in moderating the association of stress and daily‐life psychotic experiences
Authors: Cristóbal‐Narváez P. , Sheinbaum T. , Myin‐Germeys I. , Kwapil T. R. , de Castro‐Catala M. , Domínguez‐Martínez T. , Racioppi A. , Monsonet M. , Hinojosa‐Marqués L. , van Winkel R. , Rosa A. , Barrantes‐Vidal N.
Published: September 2017

Objective

The interaction of single nucleotide polymorphisms with both distal and proximal environmental factors across the extended psychosis phenotype is understudied. This study examined (i) the interaction of relevant SNPs with both early‐life adversity and proximal (momentary) stress on psychotic experiences (PEs) in an extended psychosis sample; and (ii) differences between early‐psychosis and non‐clinical groups for these interactions.

Methods

Two hundred and forty‐two non‐clinical and 96 early‐psychosis participants were prompted randomly eight times daily for 1 week to complete assessments of current experiences, including PEs and stress. Participants also reported on childhood trauma and were genotyped for 10 SNPs on COMT, RGS4, BDNF, FKBP5, and OXTR genes.

Results

Unlike genetic variants, distal and proximal stressors were associated with PEs in both samples and were more strongly associated with PEs in the early‐psychosis than in the non‐clinical group. The RGS4 TA and FKBP5 CATT haplotypes interacted with distal stress, whereas the A allele of OXTR (rs2254298) interacted with proximal stress, increasing momentary levels of PEs in the early‐psychosis group. No interactions emerged with COMT or BDNF variants.

Conclusion

Individual differences in relevant stress‐regulation systems interact with both distal and proximal psychosocial stressors in shaping the daily‐life manifestation of PEs across the psychosis continuum.
Resting state perfusion in the language network is linked to formal thought disorder and poor functional outcome in schizophrenia
Authors: Stegmayer K. , Stettler M. , Strik W. , Federspiel A. , Wiest R. , Bohlhalter S. , Walther S.
Published: September 2017

Objective

Formal thought disorder (FTD) is a core symptom in schizophrenia. Here, we focus on resting state cerebral blood flow (rCBF) linked to dimensions of FTD.

Methods

We included 47 schizophrenia spectrum patients and 30 age‐ and gender‐matched healthy controls. We assessed FTD with the assessment of thought, language, and communication (TLC) and imaging on a 3T MRI scanner. Within patients, we tested the association of FTD dimensions and in a subgroup (n = 27) the association of functional outcome after 6 months with whole brain rCBF.

Results

Negative FTD was most prominently associated with perfusion within the superior temporal gyrus, while positive FTD was associated with perfusion within the supplementary motor area, and inferior frontal gyrus. Perfusion within the left supramarginal gyrus was associated with social functioning after 6 months.

Conclusions

Distinguishable associations of rCBF with FTD dimensions point to distinct underlying pathophysiology. The location of aberrant perfusion patterns suggests that negative FTD might reflect defective access to semantic memory while positive FTD likely reflects defective suppression of irrelevant information during increased speech production. Finally, the neural correlates of thought block were also predictive of poor functional outcome. Thus, functional outcome and distinct FTD dimensions may share some pathophysiology.
Intraoperative cervical treatment does not affect the prevalence of vaginal bleeding 1 year postoperatively after subtotal hysterectomy. A register study from the Swedish National Register for Gynecological Surgery
Authors: Borendal Wodlin Ninnie
Published: September 2017

Introduction

The objectives were to establish the prevalence of persistent vaginal bleeding following subtotal hysterectomy, to analyze the effect of intraoperative cervical treatment on the occurrence of persistent vaginal bleeding, and to evaluate the impact of persistent vaginal bleeding on the patient‐reported opinion concerning result of surgery and medical condition.

Material and methods

Retrospective study with data from the Swedish National Register for Gynecological Surgery including 5240 women undergoing subtotal hysterectomy for benign conditions between January 2004 and June 2016. Demographic and clinical data were obtained from the pre‐ and perioperative forms. Data concerning occurrence of persistent vaginal bleeding, rating of medical condition and contentment with result of surgery were collected from the 1‐year inquiry form. Statistical analyses were performed with multivariable logistic regression models. The results are presented as adjusted odd ratios and 95% confidence intervals.

Results

Persistent vaginal bleeding occurred in 18.6%. Intraoperative cervical treatment did not affect the frequency of persistent vaginal bleeding (adjusted odds ratio 1.48; 95% confidence interval 0.93–2.37). More than 90% were satisfied with the result of the hysterectomy, but women with persistent vaginal bleeding were less content compared with those without persistent vaginal bleeding (adjusted odds ratio 0.42; 95% confidence interval 0.26–0.67). The self‐perception of the medical condition did not differ between the women with and without persistent vaginal bleeding (adjusted odds ratio 1.16; 95% confidence interval 0.33–4.12).

Conclusions

Nearly two in ten women may expect persistent vaginal bleeding following subtotal hysterectomy, and cervical treatment intraoperatively did not affect this. More than 90% were satisfied with the result but women with persistent vaginal bleeding were less content. Preoperative information on this risk of persistent vaginal bleeding may be important when choosing hysterectomy technique.
Dose‐dependent acute liver injury with hypersensitivity features in humans due to a novel microsomal prostaglandin E synthase 1 inhibitor
Authors: Jin Yan , Regev Arie , Kam Jeanelle , Phipps Krista , Smith Claire , Henck Judith , Campanale Kristina , Hu Leijun , Hall D. Greg , Yang Xiao Yan , Nakano Masako , McNearney Terry Ann , Uetrecht Jack , Landschulz William
Published: September 2017

Aims

LY3031207, a novel microsomal prostaglandin E synthase 1 inhibitor, was evaluated in a multiple ascending dose study after nonclinical toxicology studies and a single ascending dose study demonstrated an acceptable toxicity, safety and tolerability profile.

Methods

Healthy subjects were randomized to receive LY3031207 (25, 75 and 275 mg), placebo or celecoxib (400 mg) once daily for 28 days. The safety, tolerability and pharmacokinetic and pharmacodynamic profiles of LY3031207 were evaluated.

Results

The study was terminated when two subjects experienced drug‐induced liver injury (DILI) after they had received 225 mg LY3031207 for 19 days. Liver biopsy from these subjects revealed acute liver injury with eosinophilic infiltration. Four additional DILI cases were identified after LY3031207 dosing had been stopped. All six DILI cases shared unique presentations of hepatocellular injury with hypersensitivity features and demonstrated a steep dose‐dependent trend. Prompt discontinuation of the study drug and supportive medical care resulted in full recovery. Metabolites from metabolic activation of the imidazole ring were observed in plasma and urine samples from all subjects randomized to LY3031207 dosing.

Conclusions

This study emphasized the importance of careful safety monitoring and serious adverse events management in phase I trials. Metabolic activation of the imidazole ring may be involved in the development of hepatotoxicity of LY3031207.
Principles of pharmacology in the eye
Authors: Awwad Sahar , Mohamed Ahmed Abeer H A , Sharma Garima , Heng Jacob S , Khaw Peng T , Brocchini Steve , Lockwood Alastair
Published: September 2017

The eye is a highly specialized organ that is subject to a huge range of pathology. Both local and systemic disease may affect different anatomical regions of the eye. The least invasive routes for ocular drug administration are topical (e.g. eye drops) and systemic (e.g. tablets) formulations. Barriers that subserve as protection against pathogen entry also restrict drug permeation. Topically administered drugs often display limited bioavailability due to many physical and biochemical barriers including the pre‐corneal tear film, the structure and biophysiological properties of the cornea, the limited volume that can be accommodated by the cul‐de‐sac, the lacrimal drainage system and reflex tearing. The tissue layers of the cornea and conjunctiva are further key factors that act to restrict drug delivery. Using carriers that enhance viscosity or bind to the ocular surface increases bioavailability. Matching the pH and polarity of drug molecules to the tissue layers allows greater penetration. Drug delivery to the posterior segment is a greater challenge and, currently, the standard route is via intravitreal injection, notwithstanding the risks of endophthalmitis and retinal detachment with frequent injections. Intraocular implants that allow sustained drug release are at different stages of development. Novel exciting therapeutic approaches include methods for promoting transscleral delivery, sustained release devices, nanotechnology and gene therapy.
Colorectal surveillance after segmental resection for young‐onset colorectal cancer: is there evidence for extended resection?
Authors: Kozak V. N. , Kalady M. F. , Gamaleldin M. M. , Liang J. , Church J. M.
Published: September 2017

Aim

Although sporadic colorectal cancer (CRC) usually occurs in patients aged over 50, recent evidence suggests that the incidence is increasing in younger patients. Such patients are theoretically at high risk of metachronous neoplasia and may be candidates for extended prophylactic colectomy. This study aimed to define the risk of metachronous cancer/adenomas during follow‐up of younger patients who underwent segmental colectomy for CRC.

Method

A CRC database was used to identify patients aged under 50 who underwent surgery for CRC between 1994 and 2010. Patients diagnosed with hereditary cancer or inflammatory bowel disease were excluded. The primary end‐points were frequency of extended resection and the rates of metachronous cancer and high‐risk adenomas during follow‐up.

Results

There were 284 young patients with a resectable primary tumour, of whom 280 (98.6%) underwent segmental resection, 3 (1%) extended resection and 1 (0.4%) local resection. Endoscopic follow‐up was available for 150 of the patients who had segmental colectomy, with a mean age of 42.6 (±5.8) years at diagnosis and median follow‐up time of 68 months (interquartile range 45–105). Out of these 150 patients, 4 (2.7%) developed metachronous colonic adenocarcinoma at 24, 71, 151 and 228 months after index surgery. Thirty additional patients had at least one adenoma identified during surveillance, and three had sessile serrated polyps. Out of the three patients undergoing extended resection, none had metachronous cancer or advanced adenomas at an average follow‐up of 17 years.

Conclusion

A segmental colectomy or proctectomy is adequate treatment for patients presenting with CRC under the age of 50.