bluuebunny/crossref_metadata_2025_split huggingface dataset:
Matching cell lines with cancer type and subtype of origin via mutational, epigenomic and transcriptomic patterns
Authors: Salvadores Marina , Fuster-Tormo Francisco , Supek Fran 
Published: October 2019

AbstractCell lines are commonly used as cancer models. Because the tissue and/or cell type of origin provide important context for understanding mechanisms of cancer, we systematically examined whether cell lines exhibit features matching the cancer type that supposedly originated them. To this end, we aligned the mRNA expression and DNA methylation data between ∼9,000 solid tumors and ∼600 cell lines to remove the global differences stemming from growth in cell culture. Next, we created classification models for cancer type and subtype using tumor data, and applied them to cell line data. Overall, the transcriptomic and epigenomic classifiers consistently identified 35 cell lines which better matched a different tissue or cell type than the one the cell line was originally annotated with; we recommend caution in using these cell lines in experimental work. Six cell lines were identified as originating from the skin, of which five were further corroborated by the presence of a UV-like mutational signature in their genome, strongly suggesting mislabelling. Overall, genomic evidence additionally supports that 22 (3.6% of all considered) cell lines may be mislabelled because we predict they originate from a different tissue/cell type. Finally, we cataloged 366 cell lines in which both transcriptomic and epigenomic profiles strongly resemble the tumor type of origin, designating them as ‘golden set’ cell lines. We suggest these cell lines are better suited for experimental work that depends on tissue identity and propose tentative assignments to cancer subtypes. Finally, we show that accounting for the uncertain tissue-of-origin labels can change the interpretation of drug sensitivity and CRISPR genetic screening data. In particular, in brain, lung and pancreatic cancer cell lines, many novel determinants of drug sensitivity or resistance emerged by focussing on the cell lines that are best matched to the cancer type of interest.
Competence to epithelialise coincides with competence to differentiate in pluripotent cells
Authors: Lin Chia-Yi , Tatar Tulin , Blin Guillaume , Malaguti Mattias , Migueles Rosa Portero , Shao Hongyu , Chen Naiming , Chambers Ian , Lowell Sally 
Published: October 2019

SummaryPluripotent cells reorganise themselves into an epithelium before they initiate differentiation, but it is not clear how these two events are mechanistically linked. Here we use quantitative imaging approaches to measure cellular rearrangements that accompany exit from naive pluripotency. We show that competence to epithelialise, like competence to differentiate, is a regulated process. The pro-differentiation transcription factor Tcf15 prospectively identifies cells that are competent to epithelialise. We identify early upregulation of the laminin receptor integrin alpha3 prior to differentiation and show that Tcf15 helps to regulate this change. Finally, we show that Tcf15 identifies and is required for efficient differentiation of a primed subpopulation of pluripotent cells. We conclude that competence to epithelialise is actively regulated and linked to differentiation-competence through the transcription factor Tcf15.
Accurate contact-based modelling of repeat proteins predicts the structure of Curlin and SPW repeats
Authors: Bassot Claudio , Elofsson Arne 
Published: October 2019

AbstractRepeat proteins are an abundant class in eukaryotic proteomes. They are involved in many eukaryotic specific functions, including signalling. For many of these families, the structure is not known. Recently, it has been shown that the structure of many protein families can be predicted by using contact predictions from direct coupling analysis and deep learning. However, their unique sequence features present in repeat proteins is a challenge for contact predictions DCA-methods. Here, we show that using the deep learning-based PconsC4 is more effective for predicting both intra and interunit contacts among a comprehensive set of repeat proteins. In a benchmark dataset of 819 repeat proteins about one third can be correctly modelled and among 51 PFAM families lacking a protein structure, we produce models of five families with estimated high accuracy.Author SummaryRepeat proteins are widespread among organisms and particularly abundant in eukaryotic proteomes. Their primary sequence present repetition in the amino acid sequences that origin structures with repeated folds/domains. Although the repeated units are easy to be recognized in primary sequence, often structure information are missing. Here we used contact prediction for predicting the structure of repeats protein directly from their primary sequences. We benchmark our method on a dataset comprehensive of all the known repeated structures. We evaluate the contact predictions and the obtained models set for different classes of proteins and different lengths of the target, and we benchmark the quality assessment of the models on repeats proteins. Finally, we applied the methods on the repeat PFAM families missing of resolved structures, five of them modelled with high accuracy.
Large DNA virus promoted the endosymbiotic evolution to make a photosynthetic eukaryote
Authors: Matsuo Mitsuhiro , Katahata Atsushi , Tachikawa Makoto , Minakuchi Yohei , Noguchi Hideki , Toyoda Atsushi , Fujiyama Asao , Suzuki Yutaka , Hata Takayuki , Satoh Soichirou , Nakayama Takuro , Kamikawa Ryoma , Nomura Mami , Inagaki Yuji , Ishida Ken-ichiro , Obokata Junichi 
Published: October 2019

AbstractChloroplasts in photosynthetic eukaryotes originated from a cyanobacterial endosymbiosis far more than 1 billion years ago1-3. Due to this ancientness, it remains unclear how this evolutionary process proceeded. To unveil this mystery, we analysed the whole genome sequence of a photosynthetic rhizarian amoeba4, Paulinella micropora5,6, which has a chloroplast-like organelle that originated from another cyanobacterial endosymbiosis7-10 about 0.1 billion years ago11. Here we show that the predacious amoeba that engulfed cyanobacteria evolved into a photosynthetic organism very quickly in the evolutionary time scale, probably aided by the drastic genome reorganization activated by large DNA virus. In the endosymbiotic evolution of eukaryotic cells, gene transfer from the endosymbiont genome to the host nucleus is essential for the evolving host cell to control the endosymbiont-derived organelle12. In P. micropora, we found that the gene transfer from the free-living and endosymbiotic bacteria to the amoeba nucleus was rapidly activated but both simultaneously ceased within the initiation period of the endosymbiotic evolution, suggesting that the genome reorganization drastically proceeded and completed. During this period, large DNA virus appeared to have infected the amoeba, followed by the rapid amplification and diversification of virus-related genes. These findings led us to re-examine the conventional endosymbiotic evolutionary scenario that exclusively deals with the host and the symbiont, and to extend it by incorporating a third critical player, large DNA virus, which activates the drastic gene transfer and genome reorganization between them. This Paulinella version of the evolutionary hypothesis deserves further testing of its generality in evolutionary systems and could shed light on the unknown roles of large DNA viruses13 in the evolution of terrestrial life.
Structural Brain Imaging Studies Offer Clues about the Effects of the Shared Genetic Etiology among Neuropsychiatric Disorders
Authors: Radonjić Nevena V. , Hess Jonathan L. , Rovira Paula , Andreassen Ole , Buitelaar Jan K. , Ching Christopher R. K. , Franke Barbara , Hoogman Martine , Jahanshad Neda , McDonald Carrie , Schmaal Lianne , Sisodiya Sanjay M. , Stein Dan J. , van den Heuvel Odile A. , van Erp Theo G.M. , van Rooij Daan , Veltman Dick J. , Thompson Paul , Faraone Stephen V. 
Published: October 2019

AbstractBackgroundGenomewide association studies have found significant genetic correlations among many neuropsychiatric disorders. In contrast, we know much less about the degree to which structural brain alterations are similar among disorders and, if so, the degree to which such similarities have a genetic etiology.MethodsFrom the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium, we acquired standardized mean differences (SMDs) in regional brain volume and cortical thickness between cases and controls. We had data on 41 brain regions for: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), epilepsy, major depressive disorder (MDD), obsessive compulsive disorder (OCD) and schizophrenia (SCZ). These data had been derived from 24,360 patients and 37,425 controls.ResultsThe SMDs were significantly correlated between SCZ and BD, OCD, MDD, and ASD. MDD was positively correlated with BD and OCD. BD was positively correlated with OCD and negatively correlated with ADHD. These pairwise correlations among disorders were correlated with the corresponding pairwise correlations among disorders derived from genomewide association studies (r = 0.49).ConclusionsOur results show substantial similarities in sMRI phenotypes among neuropsychiatric disorders and suggest that these similarities are accounted for, in part, by corresponding similarities in common genetic variant architectures.
The plasma membrane as a competitive inhibitor and positive allosteric modulator of KRas4B signaling
Authors: Neale C. , García A.E. 
Published: October 2019

AbstractMutant Ras proteins are important drivers of human cancers, yet no approved drugs act directly on this difficult target. Over the last decade, the idea has emerged that oncogenic signaling can be diminished by molecules that drive Ras into orientations in which effector binding interfaces are occluded by the cell membrane. To support this approach to drug discovery, we characterize the orientational preferences of membrane-bound K-Ras4B in 1.45 milliseconds aggregate time of atomistic molecular dynamics simulations. Individual simulations probe active or inactive states of Ras on membranes with or without anionic lipids. We find that the membrane orientation of Ras is relatively insensitive to its bound guanine nucleotide and activation state but depends strongly on interactions with anionic phosphatidylserine lipids. These lipids slow Ras’ translational and orientational diffusion and promote a discrete population in which small changes in orientation control Ras’ competence to bind multiple regulator and effector proteins. Our results suggest that compound-directed conversion of constitutively active mutant Ras into functionally inactive forms may be accessible via subtle perturbations of Ras’ orientational preferences at the membrane surface.Statement of SignificanceMutations that lock Ras proteins in active states can undermine cellular decision making and drive cancer. Because there are no drugs to deactivate Ras, we use simulations to relate Ras’ three-dimensional orientation at the membrane surface to its signaling competence. Data shows that Ras reorientation is generally rapid, but can be trapped in one of three states by membrane adhesion of the globular signaling domain. One of these states is stabilized by negatively charged lipids and brings an effector binding interface toward the membrane surface, potentially obstructing protein-protein interactions required for propagation of the growth signal. Rare events drive a second type of membrane-based signaling obstruction that correlate with configurational changes in Ras’ globular domain, yielding a potential drug target.
Conflict of Interest Policies at German medical schools - A long way to go
Authors: Grabitz Peter , Friedmann Zoe , Gepp Sophie , Hess Leonard U. , Specht Lisa , Struck Maja , Tragert Sophie , Walther Tobias , Klemperer David 
Published: October 2019

AbstractBackgroundMost medical students are in contact with the pharmaceutical or medical device industry during their studies. Medical schools play an important role in protecting students from undue commercial influence and educating them about pharmaceutical marketing practices. Such influence has been shown to affect later prescribing behaviour with potential adverse effects for patient care. While in North America, many medical schools formulated and implemented conflicts of interest (COI) policies, only few such institutional policies have been reported in Germany. We aimed to analyze the quantity and quality of policies and curricula on COI at medical schools across Germany.MethodsWe collected relevant COI policies and teaching activities by conducting a search of the websites of all 38 German medical schools using standardized keywords for COI policies and teaching. Further, we surveyed all medical schools’ dean’s offices and adapted a scoring system for obtained results with 13 categories based on prior similar studies.ResultsWe identified relevant policies for one medical school via the web-search. The response rate of the deans’ survey was 16 of 38 (42.1%). In total, we identified COI-related policies for 2 of 38 (5.3%) German medical schools, yet no policy was sufficient to address all COI-related categories that were assessed in this study. The maximum score achieved was 12 of 26. 36 (94.7%) schools scored 0. No medical school reported curricular teaching on COI.ConclusionOur results indicate a low level of action by medical schools to protect students from undue commercial influence. No participating dean was aware of any curriculum or instruction on COI at their respective school. The German Medical Students Association and international counterparts have called for a stronger focus on COI in the classroom. We conclude that for German medical schools there is still a long way to go.
Formation of ultralong DH regions through genomic rearrangement
Authors: Smider Brevin A. , Smider Vaughn V. 
Published: October 2019

AbstractCow antibodies are very unusual in having exceptionally long CDR H3 regions. The genetic basis for this length largely derives from long heavy chain diversity (DH) regions, with a single “ultralong” DH, IGHD8-2, encoding over fifty amino acids. Most bovine IGHD regions are homologous but have several nucleotide repeating units that diversify their lengths. Genomically, most DH regions exist in three clusters that appear to have formed from DNA duplication events. The cluster containing IGHD8-2 underwent a rearrangement and deletion event in relation to the other clusters in the region corresponding to IGHD8-2, with possible fusion of two DH regions and expansion of short repeats to form the ultralong IGHD8-2 gene. Length heterogeneity within DH regions is a unique evolutionary genomic mechanism to create immune diversity, including formation of ultralong CDR H3 regions.
Continuous force measurements reveal no inhibitory control deficits in Parkinson’s disease
Authors: Pickering Jade S. , McBride Jennifer , Leroi Iracema , Poliakoff Ellen 
Published: October 2019

AbstractSuppression of unwanted motor responses can be disrupted by Parkinson’s disease. People with Parkinson’s (PwP) can show maladaptive reward-driven behaviours in the form of impulse control behaviours, which are associated with use of the dopaminergic treatments used to alleviate the motor symptoms of the disease. However, the effects of Parkinson’s itself on impulsive behaviour and control are unclear – empirical studies have yielded mixed findings, and some imaging studies have shown a functional deficit in the absence of a measurable change in behaviour. Here, we investigated the effects of Parkinson’s on response activation and control by studying the dynamics of response in standard inhibitory control tasks – the Stop Signal and Simon tasks – using a continuous measure of response force. Our results are largely in favour of the conclusion that response inhibition appears to be intact in PwP, even when using a more sensitive measure of behavioural control relative to traditional button-press measures. Our findings provide some clarity as to the effects of Parkinson’s on response inhibition and show continuous response force measurement can provide a sensitive means of detecting erroneous response activity in PwP, which could also be generalised to studying related processes in other populations.Open dataData and analysis can be found on the Open Science Framework (osf.io/kx6h3/)Pre-print templateWiernik, B.M. (2019, October 11). Preprint templates. osf.io/hsv6a/
Weakly-Supervised Prediction of Cell Migration Modes in Confocal Microscopy Images Using Bayesian Deep Learning
Authors: Gupta Anindya , Larsson Veronica , Matuszewski Damian , Strömblad Staffan , Wählby Carolina 
Published: October 2019

ABSTRACTCell migration is pivotal for their development, physiology and disease treatment. A single cell on a 2D surface can utilize continuous or discontinuous migration modes. To comprehend the cell migration, an adequate quantification for single cell-based analysis is crucial. An automatized approach could alleviate tedious manual analysis, facilitating large-scale drug screening. Supervised deep learning has shown promising outcomes in computerized microscopy image analysis. However, their implication is limited due to the scarcity of carefully annotated data and uncertain deterministic outputs. We compare three deep learning models to study the problem of learning discriminative morphological representations using weakly annotated data for predicting the cell migration modes. We also estimate Bayesian uncertainty to describe the confidence of the probabilistic predictions. Amongst three compared models, DenseNet yielded the best results with a sensitivity of 87.91% ± 13.22 at a false negative rate of 1.26% ± 4.18.
Structure of herpes simplex virus pUL7:pUL51, a conserved complex required for efficient herpesvirus assembly
Authors: Butt Benjamin G. , Owen Danielle J. , Jeffries Cy M. , Ivanova Lyudmila , Houghton Jack W. , Ahmed Md. Firoz , Antrobus Robin , Svergun Dmitri I. , Welch John J. , Crump Colin M. , Graham Stephen C. 
Published: October 2019

AbstractHerpesviruses are an ancient family of highly-prevalent human and animal pathogens that acquire their membrane envelopes in the cytoplasm of infected cells. While multiple conserved viral proteins are known to be required for efficient herpesvirus production, many of these proteins lack identifiable structural homologues and the molecular details of herpesvirus assembly remain unclear. We have characterized the complex of assembly proteins pUL7 and pUL51 from herpes simplex virus (HSV)-1, an α-herpesvirus, using multi-angle light scattering and small-angle X-ray scattering with chemical crosslinking. HSV-1 pUL7 and pUL51 form a stable 1:2 complex that is capable of higher-order oligomerization in solution. We solved the crystal structure of this complex, revealing a core heterodimer comprising pUL7 bound to residues 41–125 of pUL51. While pUL7 adopts a previously-unseen compact fold, the extended helix-turn-helix conformation of pUL51 resembles the cellular endosomal complex required for transport (ESCRT)-III component CHMP4B, suggesting a direct role for pUL51 in promoting membrane scission during virus assembly. We demonstrate that the interaction between pUL7 and pUL51 homologues is conserved across human α-, β- and γ-herpesviruses, as is their association withtrans-Golgi membranes in cultured cells. However, pUL7 and pUL51 homologues do not form complexes with their respective partners from different virus families, suggesting that the molecular details of the interaction interface have diverged. Our results demonstrate that the pUL7:pUL51 complex is conserved across the herpesviruses and provide a structural framework for understanding its role in herpesvirus assembly.Significance StatementHerpesviruses are extremely common human pathogens that cause diseases ranging from cold sores to cancer. Herpesvirus acquire their membrane envelope in the cytoplasm via a conserved pathway, the molecular details of which remain unclear. We have solved the structure of a complex between herpes simplex virus (HSV)-1 proteins pUL7 and pUL51, two proteins that are required for efficient HSV-1 assembly. We show that formation of this complex is conserved across distantly-related human herpesviruses, as is the association of these homologues with cellular membranes that are used for virion assembly. While pUL7 adopts a previously-unseen fold, pUL51 resembles key cellular membrane-remodeling complex components, suggesting that the pUL7:pUL51 complex may play a direct role in deforming membranes to promote virion assembly.
Factors associated with women achieving and maintaining abstinence from alcohol: a rapid evidence assessment
Authors: Marlow Sally , Stahl Daniel , Gilchrist Gail 
Published: October 2019

Purpose
The purpose of this paper is to review the literature on the factors related to women’s ability to achieve and maintain abstinence from alcohol.

Design/methodology/approach
A rapid evidence assessment was carried out in four stages: definitions and research questions were agreed, search and selection were completed, data were extracted, quality of studies was assessed, and findings were synthesised and presented.

Findings
Medline, PsycINFO, CINAHL and ASSIA were searched for cohort studies published in English during January 2000–February 2015. Expanded search terms for Women, Alcohol and Abstinence, and Cohort were used to identify relevant studies for inclusion, resulting in 1,040 records. Of these, 32 manuscripts from 31 studies were eligible for inclusion in the review. Alcohol-related factors such as increased quantity and frequency of alcohol consumption were related to lower likelihood of achieving and maintaining abstinence; treatment factors such as type of treatment and number of treatment episodes were related to higher and lower likelihood; demographic factors such as financial problems and poor housing status were related to lower likelihood; and psychological factors such as craving, other drug use and comorbid health problems were linked to lower likelihood.

Originality/value
To the authors’ knowledge, this is the first time the factors related to the specific outcome of abstinence in women have been synthesised. Many of the factors found are also known to contribute to vulnerability for developing alcohol problems. The review revealed the paucity of studies with female only samples, or where results for women were reported separately.