bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drug repurposing for ageing research using model organisms
Authors: Ziehm Matthias , Kaur Satwant , Ivanov Dobril K. , Ballester Pedro J. , Marcus David , Partridge Linda , Thornton Janet M. 
Published: December 2016

SummaryMany increasingly prevalent diseases share a common risk factor: age. However, little is known about pharmaceutical interventions against ageing, despite many genes and pathways shown to be important in the ageing process and numerous studies demonstrating that genetic interventions can lead to a healthier ageing phenotype. An important challenge is to assess the potential to repurpose existing drugs for initial testing on model organisms, where such experiments are possible. To this end, we present a new approach to rank drug-like compounds with known mammalian targets according to their likelihood to modulate ageing in the invertebratesC. elegansandDrosophila.Our approach combines information on genetic effects on ageing, orthology relationships and sequence conservation, 3D protein structures, drug binding and bioavailability. Overall, we rank 743 different drug-like compounds for their likelihood to modulate ageing. We provide various lines of evidence for the successful enrichment of our ranking for compounds modulating ageing, despite sparse public data suitable for validation. The top ranked compounds are thus prime candidates forin vivotesting of their effects on lifespan inC. elegansorDrosophila.As such, these compounds are promising as research tools and ultimately a step towards identifying drugs for a healthier human ageing.
The magnitude of trial-by-trial neural variability is reproducible over time and across tasks in humans
Authors: Arazi Ayelet , Gonen-Yaacovi Gil , Dinstein Ilan 
Published: December 2016

AbstractNumerous studies have shown that neural activity in sensory cortices is remarkably variable over time and across trials even when subjects are presented with an identical repeating stimulus or task. This trial-by-trial neural variability is relatively large in the pre-stimulus period and considerably smaller (quenched) following stimulus presentation. Previous studies have suggested that the magnitude of neural variability affects behavior such that perceptual performance is better on trials and in individuals where variability quenching is larger. To what degree are neural variability magnitudes of individual subjects flexible or static? Here, we used EEG recordings from adult humans to demonstrate that neural variability magnitudes in visual cortex are remarkably consistent across different tasks and recording sessions. While magnitudes of neural variability differed dramatically across individual subjects, they were surprisingly stable across four tasks with different stimuli, temporal structures, and attentional/cognitive demands as well as across experimental sessions separated by one year. These experiments reveal that, in adults, neural variability magnitudes are mostly solidified individual characteristics that change little with task or time, and are likely to predispose individual subjects to exhibit distinct behavioral capabilities.Significance statementBrain activity varies dramatically from one moment to the next. Recent research has revealed that humans exhibit different magnitudes of trial-by-trial neural variability, which explain differences in their perceptual performance. How stable are neural variability magnitudes over time and across tasks? Here, subjects performed four different experiments in two experimental sessions separated by one year. The results revealed that neural variability magnitudes were remarkably consistent over time and across tasks, suggesting that the magnitude of neural variability is a solidified neural characteristic that may predispose individual subjects to exhibit different behavioral capabilities.
Human pancreatic β cell lncRNAs control cell-specific regulatory networks
Authors: Akerman Ildem , Tu Zhidong , Beucher Anthony , Rolando Delphine M.Y. , Sauty-Colace Claire , Benazra Marion , Nakic Nikolina , Yang Jialiang , Wang Huan , Pasquali Lorenzo , Moran Ignasi , Garcia-Hurtado Javier , Castro Natalia , Gonzalez-Franco Roser , Stewart Andrew , Bonner Caroline , Piemonti Lorenzo , Berney Thierry , Groop Leif , Kerr-Conte Julie , Pattou Francois , Argmann Carmen , Schadt Eric , Ravassard Philippe , Ferrer Jorge 
Published: December 2016

SummaryRecent studies have uncovered thousands of long non-coding RNAs (IncRNAs) in human pancreatic β cells. β cell lncRNAs are often cell type-specific, and exhibit dynamic regulation during differentiation or upon changing glucose concentrations. Although these features hint at a role of lncRNAs in β cell gene regulation and diabetes, the function of β cell lncRNAs remains largely unknown. In this study, we investigated the function of β cell-specific lncRNAs and transcription factors using transcript knockdowns and co-expression network analysis. This revealed lncRNAs that function in concert with transcription factors to regulate β cell-specific transcriptional networks. We further demonstrate that lncRNAPLUTOaffects local three-dimensional chromatin structure and transcription ofPDX1,encoding a key β cell transcription factor, and that bothPLUTOandPDX1are downregulated in islets from donors with type 2 diabetes or impaired glucose tolerance. These results implicate lncRNAs in the regulation of β cell-specific transcription factor networks.
Brain connectivity dynamics during social interaction reflect social network structure
Authors: Schmälzle Ralf , O’Donnell Matthew Brook , Garcia Javier O. , Cascio Christopher N. , Bayer Joseph , Bassett Danielle S. , Vettel Jean , Falk Emily B. 
Published: December 2016

AbstractSocial ties are crucial for humans. Disruption of ties through social exclusion has a marked effect on our thoughts and feelings; however, such effects can be tempered by broader social network resources. Here, we use functional magnetic resonance imaging data acquired from 80 male adolescents to investigate how social exclusion modulates functional connectivity within and across brain networks involved in social pain and understanding the mental states of others (i.e., mentalizing). Furthermore, using objectively logged friendship network data, we examine how individual variability in brain reactivity to social exclusion relates to the density of participants’ friendship networks, an important aspect of social network structure. We find increased connectivity within a set of regions previously identified as a mentalizing system during exclusion relative to inclusion. These results are consistent across the regions of interest as well as a whole-brain analysis. Next, examining how social network characteristics are associated with task-based connectivity dynamics, participants who showed greater changes in connectivity within the mentalizing system when socially excluded by peers had less dense friendship networks. This work provides novel insight to understand how distributed brain systems respond to social and emotional challenges, and how such brain dynamics might vary based on broader social network characteristics.
Chromatin domains are encoded and molded by isochores: Isochores encode chromatin domains and chromosome compartments
Authors: Bernardi Giorgio 
Published: December 2016

AbstractThe formation of mammalian chromatin domains was investigated by analyzing the domain/isochore connection. This showed that LADs correspond to GC-poor isochores and are compositionally flat, flexible chromatin structures because of the local nucleosome depletions associated with the presence of oligo-A’s. In contrast, TADs correspond to GC-rich isochores that consist of single or (much more frequently) multiple, GC peaks that shape the single or multiple, loops of TADs. Indeed, the increasing nucleosome depletions linked to the GC gradients of isochore peaks lead to an increasing chromatin flexibility (accompanied by an increasing accessibility and decreasing supercoiling). In conclusion, isochores not only encode but also mold chromatin architecture; while architectural proteins play a role in closing and insulating TAD loops. An extension of this model concerns the encoding of open and closed chromosome compartments by alternating GC-rich and GC-poor isochores, the interactions among compartments defining the 3-D chromosome folding.
When GWAS meets the Connectivity Map: drug repositioning for seven psychiatric disorders
Authors: So Hon-Cheong , Chau Carlos K.L. , Chiu Wan-To , Ho Kin-Sang , Lo Cho-Pong , Yim Stephanie Ho-Yue , Sham Pak C. 
Published: December 2016

AbstractOur knowledge of disease genetics has advanced rapidly during the past decade, with the advent of high-throughput genotyping technologies such as genome-wide association studies (GWAS). However, few methodologies were developed and systemic studies performed to identify novel drug candidates utilizing GWAS data. In this study we focus on drug repositioning, which is a cost-effective approach to shorten the developmental process of new therapies. We proposed a novel framework of drug repositioning by comparing GWAS-imputed transcriptome with drug expression profiles from the Connectivity Map. The approach was applied to 7 psychiatric disorders. We discovered a number of novel repositioning candidates, many of which are supported by preclinical or clinical evidence. We found that the predicted drugs are significantly enriched for known psychiatric medications, or therapies considered in clinical trials. For example, drugs repurposed for schizophrenia are strongly enriched for antipsychotics (p= 4.69E-06), while those repurposed for bipolar disorder are enriched for antipsychotics (p= 2.26E-07) and antidepressants (p= 1.17E-05). These findings provide support to the usefulness of GWAS signals in guiding drug discoveries and the validity of our approach in drug repositioning. We also present manually curated lists of top repositioning candidates for each disorder, which we believe will serve as a useful resource for researchers.
GeneSeqToFamily: the Ensembl Compara GeneTrees pipeline as a Galaxy workflow
Authors: Thanki Anil S. , Soranzo Nicola , Haerty Wilfried , Davey Robert P. 
Published: December 2016

AbstractBackgroundGene duplication is a major factor contributing to evolutionary novelty, and the contraction or expansion of gene families has often been associated with morphological, physiological and environmental adaptations. The study of homologous genes helps us to understand the evolution of gene families. It plays a vital role in finding ancestral gene duplication events as well as identifying genes that have diverged from a common ancestor under positive selection. There are various tools available, such as MSOAR, OrthoMCL and HomoloGene, to identify gene families and visualise syntenic information between species, providing an overview of syntenic regions evolution at the family level. Unfortunately, none of them provide information about structural changes within genes, such as the conservation of ancestral exon boundaries amongst multiple genomes. The Ensembl GeneTrees computational pipeline generates gene trees based on coding sequences and provides details about exon conservation, and is used in the Ensembl Compara project to discover gene families.FindingsA certain amount of expertise is required to configure and run the Ensembl Compara GeneTrees pipeline via command line. Therefore, we have converted the command line Ensembl Compara GeneTrees pipeline into a Galaxy workflow, called GeneSeqToFamily, and provided additional functionality. This workflow uses existing tools from the Galaxy ToolShed, as well as providing additional wrappers and tools that are required to run the workflow.ConclusionsGeneSeqToFamily represents the Ensembl Compara pipeline as a set of interconnected Galaxy tools, so they can be run interactively within the Galaxy’s user-friendly workflow environment while still providing the flexibility to tailor the analysis by changing configurations and tools if necessary. Additional tools allow users to subsequently visualise the gene families produced by the workflow, using the Aequatus.js interactive tool, which has been developed as part of the Aequatus software project.
OptiClust: Improved method for assigning amplicon-based sequence data to operational taxonomic units
Authors: Westcott Sarah L. , Schloss Patrick D. 
Published: December 2016

AbstractAssignment of 16S rRNA gene sequences to operational taxonomic units (OTUs) is a computational bottleneck in the process of analyzing microbial communities. Although this has been an active area of research, it has been difficult to overcome the time and memory demands while improving the quality of the OTU assignments. Here we developed a new OTU assignment algorithm that iteratively reassigns sequences to new OTUs to optimize the Matthews correlation coefficient (MCC), a measure of the quality of OTU assignments. To assess the new algorithm, OptiClust, we compared it to ten other algorithms using 16S rRNA gene sequences from two simulated and four natural communities. Using the OptiClust algorithm, the MCC values averaged 15.2 and 16.5% higher than the OTUs generated when we used the average neighbor and distance-based greedy clustering with VSEARCH, respectively. Furthermore, on average, OptiClust was 94.6-times faster than the average neighbor algorithm and just as fast as distance-based greedy clustering with VSEARCH. An empirical analysis of the efficiency of the algorithms showed that the time and memory required to perform the algorithm scaled quadratically with the number of unique sequences in the dataset. The significant improvement in the quality of the OTU assignments over previously existing methods will significantly enhance downstream analysis by limiting the splitting of similar sequences into separate OTUs and merging of dissimilar sequences into the same OTU. The development of the OptiClust algorithm represents a significant advance that is likely to have numerous other applications.
Generation of heritable germline mutations in the jewel waspNasonia vitripennisusing CRISPR/Cas9
Authors: Li Ming , Cook Au Lauren Yun , Douglah Deema , Chong Abigail , White Bradley J. , Ferree Patrick M. , Akbari Omar S. 
Published: December 2016

AbstractThe revolutionary RNA-guided endonuclease CRISPR/Cas9 system has proven to be a powerful tool for gene editing in a plethora of organisms. Here, utilizing this system we developed an efficient protocol for the generation of heritable germline mutations in the parasitoid jewel wasp,Nasonia vitripennis, a rising insect model organism for the study of evolution, development of axis pattern formation, venom production, haplo-diploid sex determination, and host–symbiont interactions. To establish CRISPR-directed gene editing inN. vitripennis,we targeted a conserved eye pigmentation genecinnabar, generating several independent heritable germline mutations in this gene. Briefly, to generate these mutants, we developed a protocol to efficiently collectN. vitripenniseggs from a parasitized flesh fly pupa,Sarcophaga bullata, inject these eggs with Cas9/guide RNA mixtures, and transfer injected eggs back into the host to continue development. We also describe a flow for screening mutants and establishing stable mutant strains through genetic crosses. Overall, our results demonstrate that the CRISPR/Cas9 system is a powerful tool for genome manipulation inN. vitripennis, with strong potential for expansion to target critical genes, thus allowing for the investigation of a number of important biological phenomena in this organism.
Unfitness for Detention Among Arrestees with Suspected Mental Disorders in Paris, France
Authors: Lepresle Aude , Vidal Camille , Mairesse Eric , Chariot Patrick 
Published: December 2016

AbstractIn this retrospective study (11/2013–04/2014), we aimed to identify the factors associated with psychiatric hospitalization among detainees in police custody. We included 137 patients (M/F, 74%/26%; median age, 37 years), and 125 (91%) had a mental disorder. Seventy‐seven patients (56%) had involuntary hospitalization. Sixty patients (44%) were declared fit for detention, and 48 (80%) of these patients had a mental disorder. All patients who required urgent psychiatric care and could not provide valid consent for care were declared as requiring involuntary hospitalization. Forty‐nine of the 62 patients (79%) who required urgent psychiatric care and were suspected to have committed serious crimes were involuntarily admitted. In conclusion, we commonly found that some individuals with mental disorders were considered fit for detention in police cells.
Policy Dilemmas in Financing Long‐term Care in Europe
Authors: Costa‐Font Joan , Courbage Christophe , Zweifel Peter 
Published: December 2016

AbstractLong‐term care (LTC) is the largest insurable risk facing the elderly in most high‐income countries. Paradoxically, institutional responses to the need to insure ex ante (i.e. before the contingency occurs) the financial risks of needing LTC, either through social, private, or self insurance, exhibit limited development. In contrast, mechanisms to finance LTC ex post continue to develop, primarily those supported by the public sector (i.e. subsidies or tax deductions) and the family (i.e. intergenerational transfers). Both ex ante and ex post types of financing mechanisms are found to be subject to shortcomings which give rise to dilemmas for public policy. Governments confront these dilemmas in different ways, causing a great deal of heterogeneity in the financing and provision of LTC services across Europe.
‘I miss my family, it's been a while…’ A qualitative study of clinicians who live and work in rural/remote Australian Aboriginal communities
Authors: Irving Michelle , Short Stephanie , Gwynne Kylie , Tennant Marc , Blinkhorn Anthony 
Published: December 2016

AbstractObjectivesDental issues are more prevalent for Aboriginal Australians, especially those living in rural/remote locations, but distribution of clinicians is favoured towards metropolitan areas and are not always culturally competent. This study aimed to document the experiences of dental clinicians who relocated to rural/remote communities to provide dental services to Aboriginal communities in an effort to redress these gaps.SettingClinicians working in a new rural/remote dental service strategy to Aboriginal communities in Northern NSW.DesignQualitative semi‐structured face‐to‐face interviews and reflective diaries were analysed qualitatively.ParticipantsRelocating dental clinicians and their support team.ResultsThree major themes emerged: Theme one: Mastering the clinical environment through professional experiences: Increasing professional capabilities, clinical environment, valuing team work and gaining community respect. Theme two: Development and growth of the individual through personal and social experiences: culture shock, developing cultural competence, social impact, economic cost and personal adjustments and growth. Theme three: An overarching sense of achievement and advice to new clinicians.ConclusionRelocation to rural and remote communities to provide health services is a complex but rewarding process. Providing personal and professional support, to relocating clinicians resulted in an overall positive experience for the participants, where they increased their professional skills and developed personally. Living and working in the community increased their cultural competence. Barriers were overcome through effective communication, flexibility and teamwork. Funding for rural placements, such as these, is critical for rural and remote health services and should include long‐term appropriate funding for mentoring and support.
Evaluating distribution of the left branch of the middle colic artery and the left colic artery by CT angiography and colonography to classify blood supply to the splenic flexure
Authors: Fukuoka Asako , Sasaki Takahiro , Tsukikawa Satoshi , Miyajima Nobuyoshi , Ostubo Takehito 
Published: December 2016

AbstractIntroductionCT angiography has gained widespread acceptance for preoperative evaluation of blood supply in patients with colorectal cancer. However, there have been few reports that pertain to the splenic flexure, for which surgery is technically difficult. We used preoperative CT angiography and CT colonography to evaluate blood supply to the splenic flexure.MethodsWe defined the splenic flexure as the junction of the distal third of the transverse colon and the proximal third of the descending colon. We reviewed 191 cases and considered the descending colon as divided into the proximal third and the distal two‐thirds; we then determined which part of the descending colon the left colic artery (LCA) entered. We also considered the transverse colon as divided into the proximal two‐thirds and the distal third, and evaluated which part of the transverse colon the left branch of the middle colic artery entered.ResultWe classified blood supply to the splenic flexure into six types, described by the feeder vessels: type 1, the LCA (39.7%); type 2, the left branch of the middle colic artery (17.8%); type 3, the LCA and the left branch of the middle colic artery (9.9%); type 4, the accessory left colic artery (4.1%); type 5, the LCA and the accessory left colic artery (2.6%); and type 6, the marginal artery (25.6%).ConclusionWe classified blood supply to the splenic flexure into more complex types than previous reports had. Because we dissect the lymph nodes according to the type of blood supply, knowing the type before splenic flexure surgery is crucial.
Phase 2 study of tabalumab, a human anti‐B‐cell activating factor antibody, with bortezomib and dexamethasone in patients with previously treated multiple myeloma
Authors: Raje Noopur S. , Moreau Philippe , Terpos Evangelos , Benboubker Lotfi , Grząśko Norbert , Holstein Sarah A. , Oriol Albert , Huang Shang‐Yi , Beksac Meral , Kuliczkowski Kazimierz , Tai Datchen F. , Wooldridge James E. , Conti Ilaria , Kaiser Christopher J. , Nguyen Tuan S. , Cronier Damien M. , Palumbo Antonio 
Published: December 2016

SummaryIn this double‐blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N = 72), tabalumab 100 mg (N = 74), or tabalumab 300 mg (N = 74), each in combination with dexamethasone 20 mg and subcutaneous bortezomib 1·3 mg/m2on a 21‐day cycle. No significant intergroup differences were observed among primary (median progression‐free survival [mPFS]) or secondary efficacy outcomes. ThemPFSwas 6·6, 7·5 and 7·6 months for the tabalumab 100, 300 mg and placebo groups, respectively (tabalumab 100 mg vs. placebo Hazard ratio (HR) [95% confidence interval (CI)] = 1·13 [0·80–1·59],P = 0·480; tabalumab 300 mg vs. placeboHR[95%CI] = 1·03 [0·72–1·45],P = 0·884). The most commonly‐reported treatment‐emergent adverse events were thrombocytopenia (37%), fatigue (37%), diarrhoea (35%) and constipation (32%). Across treatments, patients with low baselineBAFF(also termedTNFSF13B) expression (n = 162) had significantly longermPFSthan those with highBAFFexpression (n = 55), using the 75th percentile cut‐off point (mPFS[95%CI] = 8·3 [7·0–9·3] months vs. 5·8 [3·7–6·6] months;HR[95%CI] = 1·59 [1·11–2·29],P = 0·015). Although generally well tolerated,PFSwas not improved during treatment with tabalumab compared to placebo. A higher dose of 300 mg tabalumab did not improve efficacy compared to the 100 mg dose. Nonetheless,BAFFappears to have some prognostic value in patients with multiple myeloma.