bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic variants related to antihypertensive targets inform drug efficacy and side effects
Authors: Gill Dipender , Georgakis Marios K. , Koskeridis Fotios , Jiang Lan , Feng Qiping , Wei Wei-Qi , Theodoratou Evropi , Elliott Paul , Denny Joshua C. , Malik Rainer , Evangelou Evangelos , Dehghan Abbas , Dichgans Martin , Tzoulaki Ioanna 
Published: November 2018

AbstractBackgroundDrug effects can be investigated through natural variation in the genes for their protein targets. We aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are amongst the most commonly used medications worldwide.MethodsWe identified genetic instruments for antihypertensive drug classes as variants in the gene for the corresponding target that associated with systolic blood pressure at genome-wide significance. To validate the instruments, we compared Mendelian randomisation (MR) estimates for drug effects on coronary heart disease (CHD) and stroke risk to randomised controlled trial (RCT) results. Phenome-wide association study (PheWAS) in the UK Biobank was performed to identify potential side effects and repurposing opportunities, with findings investigated in the Vanderbilt University Biobank (BioVU) and in observational analysis of the UK Biobank.FindingsWe identified suitable genetic instruments for beta-blockers (BBs) and calcium channel blockers (CCBs). MR estimates for their effect on CHD and stroke risk respectively were comparable to results from RCTs against placebo. PheWAS in the UK Biobank identified an association of the CCB genetic risk score (scaled to drug effect) with increased risk of diverticulosis (odds ratio [OR] 1.23, 95%CI 1.10-1.38), with a consistent estimate found in BioVU (OR 1.16, 95%CI 0.94-1.44). Association with diverticulosis was further supported in observational analysis of CCB use in the UK Biobank (OR 1.08, 95%CI 1.02-1.15).InterpretationWe identified valid genetic instruments for BBs and CCBs. Using genetic and observational approaches, we highlighted a previously unreported potential detrimental effect of CCBs on risk of diverticulosis. This work serves as a proof of concept that investigation of genetic variants can offer a complementary approach to exploring the efficacy and side effects of anti-hypertensive medications.FundingWellcome Trust.
Intense and sustained pain reduces cortical responses to auditory stimuli: implications for the interpretation of Heterotopic Noxious Conditioning Stimulation in humans
Authors: Torta DM , Jure FA , Andersen OK , Biurrun Manresa JA 
Published: November 2018

AbstractPhasic pain stimuli are inhibited when they are applied concomitantly with a conditioning tonic stimulus at another body location (Heterotopic Noxious Conditioning Stimulation, HNCS). While this effect is thought to rely on a spino-bulbo-spinal mechanism in animals (Diffuse Noxious Inhibitory Controls, DNIC), the underlying neurophysiology in humans may further involve other pathways. In this study, we investigated the role of supraspinal mechanisms in HNCS by presenting auditory stimuli during a conditioning tonic painful stimulus (the Cold Pressor Test, CPT). Considering that auditory stimuli are not conveyed through the spinal cord, any changes in brain responses to auditory stimuliduringHNCS can be ascribed entirely to supraspinal mechanisms. High-density electroencephalography (EEG) was recorded during HNCS and auditory stimuli were administered in three blocks,before,during, andafterHNCS. Nociceptive Withdrawal Reflexes (NWRs) were recorded at the same time points to investigate spinal processing. Our results showed that AEPs were significantly reducedduringHNCS. Moreover, the amplitude of the NWR was significantly diminishedduringHNCS in most participants. Given that spinal and supraspinal mechanisms operate concomitantly during HNCS, the possibility of isolating their individual contributions to DNIC-like effects in humans is questionable. We conclude that the net effects of HCNS cannot be measured independently from attentional/cognitive influences.
Integrated Stress Response Deregulation underlies Vanishing White Matter and is a target for therapy
Authors: Abbink Truus E.M. , Wisse Lisanne E. , Jaku Ermelinda , Thiecke Michiel J. , Voltolini-González Daniel , Fritsen Hein , Bobeldijk Sander , Braak Timo J. ter , Polder Emiel , Postma Nienke L. , Bugiani Marianna , Struijs Eduard A. , Verheijen Mark , Straat Nina , van der Sluis Sophie , Thomas Adri A.M. , Molenaar Douwe , van der Knaap Marjo S. 
Published: November 2018

AbstractVanishing white matter (VWM) is a fatal, stress-sensitive leukodystrophy that mainly affects children and is currently without treatment. VWM is caused by recessive mutations in eukaryotic initiation factor 2B (eIF2B) that is crucial for initiation of mRNA translation and its regulation under stress conditions. Mice with bi-allelic missense mutations in eIF2B recapitulate human VWM. VWM pathomechanisms are unclear. Using polysomal profiling to screen for mRNAs with altered translation we observed most prominent changes in expression of integrated stress response (ISR) mRNAs in brains of mutant compared to wild-type mice; expression levels correlated with disease severity. We substantiated these findings in VWM patients’ brains. ISRIB, an ISR inhibitor, normalized expression of mRNA markers, ameliorated white matter pathology and improved motor skills in VWM mice, thus showing that the ISR is central in VWM pathomechanisms and a viable target for therapy.One Sentence SummaryISRIB ameliorates ISR deregulation and clinical signs in VWM mice
Effects of childhood maltreatment on social cognition and brain functional connectivity in borderline personality disorder patients
Authors: Duque Xochitl , Alcalá-Lozano Ruth , González-Olvera Jorge J. , Garza-Villarreal Eduardo A. , Pellicer Francisco 
Published: November 2018

AbstractBorderline personality disorder (BPD) is a chronic condition characterized by high levels of impulsivity, affective instability, and difficulty to establish and manage interpersonal relationships. This paper assessed differences in performance on social cognitive paradigms (MASC, RMTE) and how it related to child abuse. Specifically, it evaluated the relationship between performance on cognitive paradigms and baseline brain connectivity in patients with BPD, compared to healthy controls.BPD patients had higher levels of childhood maltreatment, increased impulsivity and aggression, and more dissociative symptoms than control subjects. For the sexual abuse subdimension, there were no differences between the BPD and the control groups, but there was a negative correlation between MASC scores and total childhood maltreatment levels, as well as between physical abuse, physical negligence, and MASC. Both groups showed that the higher the level of childhood maltreatment, the lower the performance on the MASC social cognitive test. Further, in the BPD group, there was hypoconnectivity between the structures responsible for emotion regulation and social cognitive responses that have been described as part of the frontolimbic circuitry. The more serious the child abuse, the lower the connectivity.
Spike: A GPU Optimised Spiking Neural Network Simulator
Authors: Ahmad Nasir , Isbister James B. , Smithe Toby St. Clere , Stringer Simon M. 
Published: November 2018

ABSTRACTSpiking Neural Network (SNN) simulations require internal variables – such as the membrane voltages of individual neurons and their synaptic inputs – to be updated on a sub-millisecond resolution. As a result, a single second of simulation time requires many thousands of update calculations per neuron. Furthermore, increases in the scale of SNN models have, accordingly, led to manyfold increases in the runtime of SNN simulations. Existing solutions to this problem of scale include high performance CPU based simulators capable of multithreaded execution (“CPU parallelism”). More recent GPU based simulators have emerged, which aim to utilise GPU parallelism for SNN execution. We have identified several key speedups, which give GPU based simulators up to an order of magnitude performance increase over CPU based simulators on several benchmarks. We present the Spike simulator with three key optimisations: timestep grouping, active synapse grouping, and delay insensitivity. Combined, these optimisations massively increase the speed of executing a SNN simulation and produce a simulator which is, on a single machine, faster than currently available simulators.
The CspC pseudoprotease regulates germination of Clostridioides difficile spores in response to multiple environmental signals
Authors: Rohlfing Amy E. , Eckenroth Brian E. , Forster Emily R. , Kevorkian Yuzo , Lauren Donnelly M. , de la Puebla Hector Benito , Doublié Sylvie , Shen Aimee 
Published: November 2018

AbstractThe gastrointestinal pathogen, Clostridioides difficile, initiates infection when its metabolically dormant spore form germinates in the mammalian gut. While most spore-forming bacteria use transmembrane germinant receptors to sense nutrient germinants, C. difficile uses the soluble pseudoprotease, CspC, to detect bile salt germinants. To gain insight into CspC’s unique mechanism of action, we solved its crystal structure. Guided by this structure, we identified CspC mutations that confer either hypo- or hyper-sensitivity to bile salt germinant. Surprisingly, hyper-sensitive CspC variants exhibited bile salt-independent germination as well as increased sensitivity to amino acid and/or calcium co-germinants. Since the mechanism by which C. difficile spores sense co-germinants is unknown, our study provides the first evidence that CspC senses distinct classes of co-germinants in addition to bile salts. Since we observed that specific residues control CspC’s responsiveness to these different signals, CspC is critical for regulating C. difficile germination in response to multiple environmental signals.
Differential gene expression supports a resource-intensive, defensive role for colony production in the bloom-forming haptophyte, Phaeocystis globosa
Authors: Brisbina Margaret Mars , Mitaraia Satoshi 
Published: November 2018

ABSTRACTPhaeocystis globosa forms dense, monospecific blooms in temperate, northern waters. Blooms are usually dominated by the colonial morphotype—non-flagellated cells embedded in a secreted mucilaginous mass. Colonial Phaeocystis blooms significantly affect food-web structure and function and negatively impact fisheries and aquaculture, but factors initiating colony production remain enigmatic. Destructive P. globosa blooms have been reported in tropical and subtropical regions more recently and warm-water blooms could become more common with continued climate change and coastal eutrophication. We therefore assessed genetic pathways associated with colony production by investigating differential gene expression between colonial and solitary cells in a warm-water Phaeocystis globosa strain. Our results illustrate a transcriptional shift in colonial cells with most of the differentially expressed genes downregulated, supporting a reallocation of resources associated with colony production. Dimethylsulfide and acrylate production and pathogen interaction pathways were upregulated in colonial cells, suggesting a defensive role for colony production. We identify several protein kinase signaling pathways that may influence the transition between morphotypes, providing targets for future research into factors triggering colony production. This study provides novel insights into genetic mechanisms involved in Phaeocystis colony formation and provides new evidence supporting a defensive role for Phaeocystis colonies.
Deformed Alignment of Super-Resolution Images for Semi-flexible Structures in 3D
Authors: Shi Xiaoyu , Garcia Galo , Wang Yina , Reiter Jeremy , Huang Bo 
Published: November 2018

AbstractDue to low labeling efficiency and structural heterogeneity in fluorescence-based single-molecule localization microscopy (SMLM), image alignment and quantitative analysis is often required to make accurate conclusions on the spatial relationships between proteins. Cryo-electron microscopy (EM) image alignment procedures have been applied to average structures taken with super-resolution microscopy. However, unlike cryo-EM, the much larger cellular structures analyzed by super-resolution microscopy are often heterogeneous, resulting in misalignment. And the light-microscopy image library is much smaller, which makes classification not realistic. To overcome these two challenges, we developed a method to deform semi-flexible ring-shaped structures and then align the 3D structures without classification. These algorithms can register semi-flexible structures with an accuracy of several nanometers in short computation time and with greatly reduced memory requirements. We demonstrated our methods by aligning experimental Stochastic Optical Reconstruction Microscopy (STORM) images of ciliary distal appendages and simulated structures. Symmetries, dimensions, and locations of protein complexes in 3D are revealed by the alignment and averaging for heterogeneous, tilted, and under-labeled structures.
Food web interaction strength distributions are conserved by greater variation between than within predator-prey pairs
Authors: Preston Daniel L. , Falke Landon P. , Henderson Jeremy S. , Novak Mark 
Published: November 2018

AbstractSpecies interactions in food webs are usually recognized as dynamic, varying across species, space and time due to biotic and abiotic drivers. Yet food webs also show emergent properties that appear consistent, such as a skewed frequency distribution of interaction strengths (many weak, few strong). Reconciling these two properties requires an understanding of the variation in pairwise interaction strengths and its underlying mechanisms. We estimated stream sculpin feeding rates in three seasons at nine sites in Oregon to examine variation in trophic interaction strengths both across and within predator-prey pairs. We considered predator and prey densities, prey body mass, and abiotic factors as putative drivers of within-pair variation over space and time. We hypothesized that consistently skewed interaction strength distributions could result if individual interaction strengths show relatively little variation, or alternatively, if interaction strengths vary but shift in ways that conserve their overall frequency distribution. We show that feeding rate distributions remained consistently and positively skewed across all sites and seasons. The mean coefficient of variation in feeding rates within each of 25 focal species pairs across surveys was less than half the mean coefficient of variation seen across species pairs within a given survey. The rank order of feeding rates also remained relatively conserved across streams, seasons and individual surveys. On average, feeding rates on each prey taxon nonetheless varied by a hundredfold across surveys, with some feeding rates showing more variation in space and others in time. For most species pairs, feeding rates increased with prey density and decreased with high stream flows and low water temperatures. For nearly half of all species pairs, factors other than prey density explained the most variation, indicating that the strength of density dependence in feeding rates can vary greatly among a generalist predator’s prey species. Our findings show that although individual interaction strengths exhibit considerable variation in space and time, they can nonetheless remain relatively consistent, and thus predictable, compared to the even larger variation that occurs across species pairs. These insights help reconcile how the skewed nature of interaction strength distributions can persist in highly dynamic food webs.
species2vec: A novel method for species representation
Authors: Angelov Boyan 
Published: November 2018

AbstractWord embeddings are omnipresent in Natural Language Processing (NLP) tasks. The same technology which defines words by their context can also define biological species. This study showcases this new method - species embedding (species2vec). By proximity sorting of 6761594 mammal observations from the whole world (2862 different species), we are able to create a training corpus for the skip-gram model. The resulting species embeddings are tested in an environmental classification task. The classifier performance confirms the utility of those embeddings in preserving the relationships between species, and also being representative of species consortia in an environment.
A new family of neural wiring receptors across bilaterians defined by phylogenetic, biochemical and structural evidence
Authors: Cheng Shouqiang , Park Yeonwoo , Kurleto Justyna D. , Jeon Mili , Zinn Kai , Thornton Joseph W. , Özkan Engin 
Published: November 2018

ABSTRACTThe evolution of complex nervous systems was accompanied by the expansion of groups of protein families, most notably cell adhesion molecules, surface receptors and their ligands. These proteins mediate axonal guidance, synapse targeting, and other neuronal wiring-related functions. Recently, members of a set of thirty interacting cell surface proteins belonging to two newly defined families of the immunoglobulin superfamily (IgSF) in fruit flies were discovered to label different subsets of neurons in the brain and ventral nerve cord. They have been shown to be involved in synaptic targeting and morphogenesis, retrograde signaling, and neuronal survival. Here we show that these proteins, denoted as Dprs and DIPs, belong to a family of two and three-Ig domain molecules in bilaterians generally known for neuronal wiring functions. In protostomes, the ancestral Dpr/DIP gene has duplicated to form heterophilic partners, such as Dprs and DIPs, while in deuterostomes, they have evolved to create the IgLON family of neuronal receptors. In support of this phylogeny, we show that IgLONs interact with each other, and that their complexes can be broken by mutations designed using homology models based on Dpr and DIP structures. Similarly, the nematode orthologs ZIG-8 and RIG-5 can form heterophilic and homophilic complexes structurally matching Dpr-DIP and DIP-DIP complexes. The evolutionary, biochemical and structural relationships we demonstrate here provides insights into neural development and the rise of complexity in metazoans.Significance StatementCell surface receptors assign and display unique identities to neurons, and direct proper and robust wiring of neurons to create functional neural circuits. Recent work has identified two new classes of receptors in fruit flies, called the Dpr and DIP families with 30 members, which interact in 38 pairwise combinations. These proteins are implicated in neural identity, wiring and survival in many parts of the fly nervous system. Here, using evolutionary, biochemical and structural evidence, we show that Dprs and DIPs are members of an ancient bilaterian family of receptors. Members of this family share functional roles relevant to wiring across species, and are likely crucial in the emergence of the bilaterian nervous systems common to vertebrate and invertebrate animals.
Developing and Evaluating Mappings of ICD-10 and ICD-10-CM Codes to PheCodes
Authors: Wu Patrick , Gifford Aliya , Meng Xiangrui , Li Xue , Campbell Harry , Varley Tim , Zhao Juan , Carroll Robert , Bastarache Lisa , Denny Joshua C , Theodoratou Evropi , Wei Wei-Qi 
Published: November 2018

AbstractBackgroundThe PheCode system was built upon the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) for phenome-wide association studies (PheWAS) in the electronic health record (EHR).ObjectiveHere, we present our work on the development and evaluation of maps from ICD-10 and ICD-10-CM codes to PheCodes.MethodsWe mapped ICD-10 and ICD-10-CM codes to PheCodes using a number of methods and resources, such as concept relationships and explicit mappings from the Unified Medical Language System (UMLS), Observational Health Data Sciences and Informatics (OHDSI), Systematized Nomenclature of Medicine - Clinical Terms (SNOMED CT), and National Library of Medicine (NLM). We assessed the coverage of the maps in two databases: Vanderbilt University Medical Center (VUMC) using ICD-10-CM and the UK Biobank (UKBB) using ICD-10. We assessed the fidelity of the ICD-10-CM map in comparison to the gold-standard ICD-9-CM→PheCode map by investigating phenotype reproducibility and conducting a PheWAS.ResultsWe mapped >75% of ICD-10-CM and ICD-10 codes to PheCodes. Of the unique codes observed in the VUMC (ICD-10-CM) and UKBB (ICD-10) cohorts, >90% were mapped to PheCodes. We observed 70-75% reproducibility for chronic diseases and <10% for an acute disease. A PheWAS with a lipoprotein(a) (LPA) genetic variant, rs10455872, using the ICD-9-CM and ICD-10-CM maps replicated two genotype-phenotype associations with similar effect sizes: coronary atherosclerosis (ICD-9-CM: P < .001, OR = 1.60 vs. ICD-10-CM: P < .001, OR = 1.60) and with chronic ischemic heart disease (ICD-9-CM: P < .001, OR = 1.5 vs. ICD-10-CM: P < .001, OR = 1.47).ConclusionsThis study introduces the initial “beta” versions of ICD-10 and ICD-10-CM to PheCode maps that will enable researchers to leverage accumulated ICD-10 and ICD-10-CM data for high-throughput PheWAS in the EHR.
53BP1 nuclear body-marked replication stress in a human mammary cell model of BRCA2 deficiency
Authors: Feng Weiran , Jasin Maria 
Published: November 2018

AbstractBRCA2 deficiency causes genome instability and breast and ovarian cancer predisposition, but also paradoxically promotes cell lethality. The nature of the acute, detrimental consequences of BRCA2 loss is not fully understood. We recently generated BRCA2 conditional models from a non-transformed human mammary cell line, through allele-specific gene targeting using CRISPR-Cas9, which we now describe. With these models, we discovered that BRCA2 deficiency triggers a DNA under replication-53BP1 nuclear body formation-G1 arrest axis due to homologous recombination defects. In this Extra-view, we extend these findings to show that 53BP1 nuclear bodies are spatially linked with downstream p53 activation. Replication stress that leads to common fragile site expression to induce 53BP1 nuclear body formation is aggravated by the loss of BRCA2. Additionally, replication stress that does not selectively lead to common fragile site expression is also able to induce 53BP1 nuclear body formation in BRCA2-deficient cells, indicating lesions form more globally throughout the genome. Furthermore, compromising replication fork reversal by SMARCAL1 depletion restores replication fork protection but does not diminish the high replication stress in the BRCA2-deficient cells, further emphasizing that fork protection plays a minor role in these cells. These results further elucidate the causes and consequences of replication stresses in the face of BRCA2 inactivation, providing insight into the barriers that need to be overcome for cells to become tumorigenic.