bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Pathogenic Structural Variants in Rare Disease Patients through Genome Sequencing
Authors: Holt James M. , Birch Camille L. , Brown Donna M. , Gajapathy Manavalan , Sosonkina Nadiya , Wilk Brandon , Wilk Melissa A. , Spillmann Rebecca C. , Stong Nicholas , Lee Hane , Huang Alden Y. , Bonner Devon , Kohler Jennefer N. , Macnamara Ellen F. ,   Undiagnosed Diseases Network, Nelson Stanley F. , Shashi Vandana , Worthey Elizabeth A. 
Published: May 2019

AbstractPurposeClinical whole genome sequencing is becoming more common for determining the molecular diagnosis of rare disease. However, standard clinical practice often focuses on small variants such as single nucleotide variants and small insertions/deletions. This leaves a wide range of larger “structural variants” that are not commonly analyzed in patients.MethodsWe developed a pipeline for processing structural variants for patients who received whole genome sequencing through the Undiagnosed Diseases Network (UDN). This pipeline called structural variants, stored them in an internal database, and filtered the variants based on internal frequencies and external annotations. The remaining variants were manually inspected and then interesting findings were reported as research variants to clinical sites in the UDN.ResultsOf 477 analyzed UDN cases, 286 cases (≈ 60%) received at least one structural variant as a research finding. The variants in 16 cases (≈ 4%) are considered “Certain” or “Highly likely” molecularly diagnosed and another 4 cases are currently in review. Of those 20 cases, at least 13 were identified originally through our pipeline with one finding leading to identification of a new disease. As part of this paper, we have also released the collection of variant calls identified in our cohort along with heterozygous and homozygous call counts. This data is available at https://github.com/HudsonAlpha/UDN_SV_export.ConclusionStructural variants are key genetic features that should be analyzed during routine clinical genomic analysis. For our UDN patients, structural variants helped solve ≈ 4% of the total number of cases (≈ 13% of all genome sequencing solves), a success rate we expect to improve with better tools and greater understanding of the human genome.
The effects of dyslipidaemia and cholesterol modulation on erythrocyte susceptibility to malaria parasite infection
Authors: Koch Marion , Cegla Jaimini , Jones Ben , Lu Yuning , Mallat Ziad , Blagborough Andrew , Angrisano Fiona , Baum Jake 
Published: May 2019

ABSTRACTMalaria disease commences when blood-stage parasites, called merozoites, invade human red blood cells (RBCs). Whilst the process of invasion is traditionally seen as being entirely merozoite-driven, emerging data suggests RBC biophysical properties markedly influence invasion. Cholesterol is a major determinant of cell membrane biophysical properties. We set out to assess whether cholesterol content in the RBC membrane affects susceptibility to merozoite invasion. Here we demonstrate that RBC bending modulus (a measure of deformability) is markedly affected by artificial modulation of cholesterol content and negatively correlated with merozoite invasion efficiency. Contextualising this observation, we tested a mouse model of hypercholesterolemia and human clinical samples from patients with a range of serum cholesterol concentrations for parasite susceptibility. Hypercholesterolaemia in both human and murine subjects had little effect merozoite invasion efficiency. Furthermore, on testing, RBC cholesterol content in both murine and human hypercholesterolaemia settings was found to be unchanged from normal controls. Serum cholesterol is, therefore, unlikely to impact on RBC susceptibility to merozoite entry. Our work, however, suggests that native polymorphisms that affect RBC membrane lipid composition would be expected to affect parasite entry. This supports investigation of RBC biophysical properties in endemic settings, which may yet identify naturally protective lipid-related polymorphisms.
Liver-Chip: Reproducing Human and Cross-Species Toxicities
Authors: Jang Kyung-Jin , Otieno Monicah A. , Ronxhi Janey , Lim Heng-Keang , Ewart Lorna , Kodella Konstantia , Petropolis Debora , Kulkarni Gauri , Rubins Jonathan E. , Conegliano David , Nawroth Janna , Simic Damir , Lam Wing , Singer Monica , Barale Erio , Singh Bhanu , Sonee Manisha , Streeter Anthony J. , Manthey Carl , Jones Barry , Srivastava Abhishek , Andersson Linda C. , Williams Dominic , Park Hyoungshin , Barrile Riccardo , Sliz Josiah , Herland Anna , Haney Suzzette , Karalis Katia , Ingber Donald E. , Hamilton Geraldine A. 
Published: May 2019

AbstractNonclinical rodent and non-rodent toxicity models used to support clinical trials of candidate drugs may produce discordant results or fail to predict complications in humans contributing to drug failures in the clinic. Here we applied microengineered Organ-on-Chip (Organ-Chip) technology to design rat, dog, and human Liver-Chips containing species-specific primary hepatocytes interfaced with liver sinusoidal endothelial cells, with or without Kupffer cells and hepatic stellate cells, cultured under physiological fluid flow. The Liver-Chips detected diverse phenotypes of liver toxicity including hepatocellular injury, steatosis, cholestasis, and fibrosis as well as species-specific toxicities when treated with tool compounds. Multi-species Liver-Chips may provide a useful platform for prediction of liver toxicity and inform human relevance of liver toxicities detected in animal studies to better determine safety and human risk.One Sentence SummaryMicroengineered Organ-Chip technology has been used to design rat, dog and human Liver-Chips that recapitulate species-specific liver toxicities.
Pathways Analyzer: Design of a Tool for the Synthetic Assembly of Escherichia Coli K-12 MG1655 Bacteria for Biofuel Production
Authors: Vasquez Laura , Alvarado Ricardo , Orozco Allan 
Published: May 2019

ABSTRACTSummaryDue to the impact of environmental pollution, the importance of producing high quality biofuels and to leverage organic waste that normally would have no use has increased over time. Through synthetic biology, it is possible to improve existing organisms to process waste that is traditionally not used for biofuel production, such as whey.With the redesign of metabolic pathways, it is possible to create connections for the implementation of new organisms that carry out functions that are normally not present in nature.From a computational point of view, metabolic pathways, which can be found in data sources as KEGG, can be converted to a graph data structure. These transformations enable the use of well-known algorithms, which enables the optimization of the analyses required to achieve the assembly of new organisms.The present work aims to design a tool for the transformation of metabolic pathways and the development of path finding algorithms that establish relevant links between compounds that are essential to the biofuel production process.As a result, a catalog of biobricks is created from the analysis of a subset of paths which can be used in the design stage of the synthetic assembly of the E. coli bacteria. The assembly’s structure and functions are characterized according to the pieces used.Finally, new constructions are visualized with the goal of demonstrating and supporting the analysis processes, thus assisting people that work in the field of Synthetic Biology.AvailabilityPathways Analyzer is accessible at: https://gitlab.com/lvasquezcr/pathways-analyzer/
First report of marine sponge Chelonaplysilla delicata (Demospongiae: Darwinellidae) from the Andaman Sea/Indian Ocean with a baseline information of epifauna on a mesophotic shipwreck
Authors: Das Rocktim Ramen , Immanuel Titus , Lakra Raj Kiran , baath Karan , Thiruchitrambalam Ganesh 
Published: May 2019

AbstractDuring a biodiversity assessment on a wreck located in the Andaman Sea (Andaman Islands), a single specimen of sponge Chelonaplysilla delicata was recorded. Our finding confirms the species taxonomy and highlights the current observation as a first report from the Andaman Sea/ Indian Ocean. The baseline information of epifauna is further stated in this study.
Skeletal muscle MACF1 maintains myonuclei and mitochondria localization through microtubules to control muscle functionalities
Authors: Ghasemizadeh Alireza , Christin Emilie , Guiraud Alexandre , Couturier Nathalie , Risson Valérie , Girard Emmanuelle , Jagla Christophe , Soler Cedric , Laddada Lilia , Sanchez Colline , Jaque Francisco , Garcia Audrey , Lanfranchi Marine , Jacquemond Vincent , Gondin Julien , Courchet Julien , Schaeffer Laurent , Gache Vincent 
Published: May 2019

AbstractSkeletal muscle is made from multinuclear myofiber, where myonuclei are positioned at the periphery or clustered below neuromuscular junctions (NMJs). While mispositioned myonuclei are the hallmark of numerous muscular diseases, the molecular machinery maintaining myonuclei positioning in mature muscle is still unknown. Here, we identified microtubule-associated protein MACF1 as an evolutionary conserved regulator of myonuclei positioning, in vitro and in vivo, controlling the “microtubule code” and stabilizing the microtubule dynamics during myofibers maturation, preferentially at NMJs. Specifically, MACF1 governs myonuclei motion, mitochondria positioning and structure and acetylcholine receptors (AChRs) clustering. Macf1-KO in young and adult mice decreases muscle excitability and causes evolutionary myonuclei positioning alterations in adult mice, paralleled with high mitochondria content and improved resistance to fatigue. We present MACF1 as a primary actor of the maintenance of synaptic myonuclei and AChRs clustering, peripheral myonuclei positioning and mitochondria organization through the control of microtubule network dynamics in muscle fibers.
Mitotic ER exit site dissociation and reassembly is regulated by TANGO1 phosphorylation status
Authors: Maeda Miharu , Komatsu Yukie , Saito Kota 
Published: May 2019

AbstractGolgi fragmentation and ER exit site dissociation are considered as the leading causes of mitotic block of secretion from the ER. Although the mechanisms of Golgi fragmentation have been extensively characterized, ER exit block early in mitosis is not well-understood. We previously found that TANGO1 organizes ER exit sites by directly interacting with Sec16. Here, we showed that TANGO1 is phosphorylated by casein kinase 1 (CK1) during mitosis. Interestingly, the interaction with Sec16 was abrogated by phosphorylation of TANGO1, leading to dissociation of the ER exit sites. Moreover, a TANGO1 mutant deficient in phosphorylation inhibited the mitotic dissociation of ER exit sites. In contrast, a TANGO1 mutant mimicking CK1-mediated phosphorylation dissociated ER exit sites in interphase cells. Although CK1 activity remains constant throughout the cell cycle, PP1, a phosphatase for which activity decreases during mitosis, participates in the regulation of TANGO1 phosphorylation. This is the first report demonstrating the mechanisms of ER exit site dissociation during mitosis.
Efficient RNA-mediated reprogramming of human somatic cells to naïve pluripotency facilitated by tankyrase inhibition
Authors: Bredenkamp Nicholas , Yang Jian , Clarke James , Stirparo Giuliano Giuseppe , von Meyenn Ferdinand , Baker Duncan , Drummond Rosalind , li Dongwei , Wu Chuman , Rostovskaya Maria , Smith Austin , Guo Ge 
Published: May 2019

ABSTRACTIn contrast to conventional human pluripotent stem cells (hPSC) that are related to post-implantation embryo stages, naïve hPSC exhibit features of pre-implantation epiblast. Naïve hPSC are established by resetting conventional hPSC, or are derived from dissociated embryo inner cell masses. Here we investigate conditions for transgene-free reprogramming of human somatic cells to naïve pluripotency. We find that tankyrase inhibition promotes RNA-mediated induction of naïve pluripotency. We demonstrate application to independent human fibroblast cultures and endothelial progenitor cells. We show that induced naïve hPSC can be clonally expanded with a diploid karyotype and undergo somatic lineage differentiation following formative transition. Induced naïve hPSC lines exhibit distinctive surface marker, transcriptome, and methylome properties of naïve epiblast identity. This system for efficient, facile, and reliable induction of transgene free naïve hPSC offers a robust platform, both for delineation of human reprogramming trajectories and for evaluating the attributes of isogenic naïve versus conventional hPSC.
Polygenic Susceptibility of Aortic Aneurysms Associates to the Diameter of the Aneurysm Sac: the Aneurysm-Express Biobank Cohort
Authors: van Laarhoven Constance J.H.C.M. , van Setten Jessica , van Herwaarden Joost A. , de Kleijn Dominique P.V. , Pasterkamp Gerard , de Borst Gert J. , van der Laan Sander W. 
Published: May 2019

AbstractPurposeAbdominal aortic aneurysms (AAA) have a multifactorial pathology with both genetic and environmental risk factors. Recent genome-wide association studies (GWAS) have discovered ten genetic risk loci for AAA. To what extent these genetic loci contribute to the aneurysm pathology is yet unknown. This study aims to investigate whether genetic risk variants are associated with three clinical features: diameter of aneurysm sac, type of artery and symptoms.MethodsWe used aneurysm tissue from 415 patients included within the Aneurysm-Express biobank. A best fit polygenic risk score (PRS) based on previous GWAS effect size estimates was modeled for each clinical parameter by comparing model predictions across different p-value thresholds. Next, the established 10 risk variants for AAA were tested individually for association with selected clinical phenotypes. Models were corrected for age, sex, ancestral background, smoking status and diameter of the aneurysm sac or artery type if applicable, and data was normalized.ResultsThe best fit PRS (including 272 SNPs with PT=0.01015) showed a significant correlation with diameter of the aneurysm sac (R2 = 0.019, p = 0.001). No association was found with clinical symptoms or type of artery. Individual variant analysis showed no clear associations with any of the clinical features.ConclusionsWithin the Aneurysm-Express Biobank Study, a weighted polygenic score of AAA susceptibility explained 1.9% of the phenotypic variation (p = 0.001) in aneurysm diameter. Individual risk variant analysis showed no clear associations. Given our limited sample size, future biobank collaborations need to confirm a potential causal role of individual SNPs on the pathology of aneurysms.
A microwell cell capture device reveals variable response to dobutamine in isolated cardiomyocytes
Authors: Clark J. A. , Weiss J. D. , Campbell S. G. 
Published: May 2019

ABSTRACTIsolated ventricular cardiomyocytes exhibit substantial cell-to-cell variability, even when obtained from the same small volume of myocardium. In this study, we investigated the possibility that cardiomyocyte responses to β-adrenergic stimulus are also highly heterogeneous. In order to achieve the throughput and measurement duration desired for these experiments, we designed and validated a novel microwell system that immobilizes and uniformly orients isolated adult cardiomyocytes. In this configuration, detailed drug responses of dozens of cells can be followed in parallel for intervals exceeding one hour. At the conclusion of an experiment, specific cells can also be harvested via a precision aspirator for single-cell gene expression profiling. Using this system, we followed changes in Ca2+ signaling and contractility of individual cells under sustained application of either dobutamine or omecamtiv mecarbil. Both compounds increased average cardiomyocyte contractility over the course of an hour, but responses of individual cells to dobutamine were significantly more variable. Surprisingly, some dobutamine-treated cardiomyocytes augmented Ca2+ release without increasing contractility. Other cells responded with increased contractility in spite of unchanged Ca2+ release. Single-cell gene expression analysis revealed a significant correlation between expression of PRKACA and cellular sensitivity to dobutamine, demonstrating that variable drug responses among cells are not merely experimental artifacts. By enabling direct comparison of the functional behavior of an individual cell and the genes it expresses, this new system constitutes a unique tool for interrogating cardiomyocyte drug responses and discovering the genes that modulate them.SIGNIFICANCEWe have created a microwell capture device that allows drug responses of dozens of isolated adult cardiomyocytes to be monitored for extended intervals. Using the device, we observed striking diversity in the Ca2+ handling and contractility responses of each cell to a β-adrenergic agonist. This included cells that responded to dobutamine by doubling the amplitude of Ca2+ release while decreasing contractility and vice-versa. We further show that these diverse responses can be linked to gene expression differences between cells. This work demonstrates the feasibility of linking the drug responses of individual cells with their gene expression. It opens the possibility of exploiting cell-to-cell variation to discover new genes that participate in and modulate regulatory cascades.
Deconvolution of Nucleic-acid Length Distributions: A Gel Electrophoresis Analysis Tool and Applications
Authors: Ziraldo Riccardo , Shoura Massa J. , Fire Andrew Z. , Levene Stephen D. 
Published: May 2019

ABSTRACTNext-generation DNA-sequencing (NGS) technologies, which are designed to streamline the acquisition of massive amounts of sequencing data, are nonetheless dependent on various preparative steps to generate DNA fragments of required concentration, purity, and average size (molecular weight). Current automated electrophoresis systems for DNA- and RNA-sample quality control, such as Agilent’s Bioanalyzer ®and TapeStation ® products, are costly to acquire and use; they also provide limited information for samples having broad size distributions. Here we describe a software tool that helps determine the size distribution of DNA fragments in an NGS library, or other DNA sample, based on gel-electrophoretic line profiles. The software, developed as an ImageJ plug-in, allows for straightforward processing of gel images, including lane selection and fitting of univariate functions to intensity distributions. The user selects the option of fitting either discrete profiles in cases where discrete gel bands are visible, or continuous profiles, having multiple bands buried under a single broad peak. The method requires only modest imaging capabilities and is a cost-effective, rigorous alternative characterization method to augment existing techniques for library quality control.
Choosing and learning: outcome valence differentially affects learning from free versus forced choices
Authors: Chambon Valérian , Théro Héloïse , Vidal Marie , Vandendriessche Henri , Haggard Patrick , Palminteri Stefano 
Published: May 2019

AbstractPositivity bias refers to learning more from positive than negative events. This learning asymmetry could either reflect a preference for positive events in general, or be the upshot of a more general, and perhaps, ubiquitous, “choice-confirmation” bias, whereby agents preferentially integrate information that confirms their previous decision. We systematically compared these two theories with 3 experiments mixing free- and forced-choice conditions, featuring factual and counterfactual learning and varying action requirements across “go” and “no-go” trials. Computational analyses of learning rates showed clear and robust evidence in favour of the “choice-confirmation” theory: participants amplified positive prediction errors in free-choice conditions while being valence-neutral on forced-choice conditions. We suggest that a choice-confirmation bias is adaptive to the extent that it reinforces actions that are most likely to meet an individual’s needs, i.e. freely chosen actions. In contrast, outcomes from unchosen actions are more likely to be treated impartially, i.e. to be assigned no special value in self-determined decisions.
High-throughput propagation of human prostate tissue from induced-pluripotent stem cells
Authors: Hepburn AC , Curry EL , Moad M , Steele RE , Franco OE , Wilson L , Singh P , Crawford SE , Gaughan Luke , Mills IG , Hayward SW , Robson CN , Heer R 
Published: May 2019

AbstractPrimary culture of human prostate organoids is slow, inefficient and laborious. To overcome this, we demonstrate a new high-throughput model where rapidly proliferating and easily handled induced pluripotent stem cells, for the first time, enable generation of human prostate tissue in vivo and in vitro. Using a co-culture technique with urogenital sinus mesenchyme, we recapitulated the in situ prostate histology, including the stromal compartment and the full spectrum of epithelial differentiation. This approach overcomes major limitations in primary cultures of human prostate stem, luminal and neuroendocrine cells, as well as the stromal microenvironment. These models provide new opportunities to study prostate development, homeostasis and disease.
Modeling methylation dynamics with simultaneous changes in CpG islands
Authors: Grosser Konrad , Metzler Dirk 
Published: May 2019

AbstractMotivationProbabilistic models for methylation dynamics of CpG sites are usually based on sequence evolution models that assume indepedence between sites. In vertebrate genomes, CpG sites can be clustered in CpG islands, and the amount of methylation in a CpG island can change due to gene regulation processes. We propose a probabilistic model of methylation dynamics that accounts for simultaneous methylation changes in multiple CpG sites belonging to the same CpG island. We further propose a Markov-chain Monte-Carlo method to fit this model to methylation data from cell type phylogenies and apply this method to available data from murine haematopoietic cells.ResultsBranch lengths in cell phylogenies show the amount of changes in methylation in the development of one cell type from another. We show that accounting for CpG island wide methylation changes has a strong effect on the inferred branch lengths and leads to a significantly better model fit for the methylation data from murine haematopoietic cells.AvailabilityAn implementation of the methods presented in this article is freely available as C++ source code onhttps://github.com//statgenlmu//IWEPoissonPaperunder the terms of the GNU general public license (GPLv3).
Kinetics of cytokine receptor trafficking determine signaling and functional selectivity
Authors: Martinez-Fabregas J. , Wilmes S. , Wang L. , Hafer M. , Pohler E. , Lokau J. , Garbers C. , Cozzani A. , Piehler J. , Kazemian M. , Mitra S. , Moraga I. 
Published: May 2019

ABSTRACTCytokines activate downstream signaling networks via assembly of cell surface receptors, but it is unclear whether modulation of cytokine-receptor binding parameters can modify biological outcomes. We have engineered variants of IL-6 with different affinities to the gp130 receptor chain to investigate how cytokine receptor binding kinetics influence functional selectivity. Engineered IL-6 variants showed a range of signaling amplitudes, from minimal to full agonist, and induced biased signaling, with changes in receptor binding kinetics affecting more profoundly STAT1 than STAT3 phosphorylation. We show that this differential signaling arises from defective translocation of ligand-gp130 complexes to the endosomal compartment and competitive STAT1/STAT3 binding to phospho-tyrosines in gp130, and results in unique patterns of STAT3 binding to chromatin. This, in turn, leads to a graded gene expression response and substantial differences in ex vivo differentiation of Th17, Th1 and Treg cells. These results provide a molecular understanding of signaling biased by cytokine receptors, and demonstrate that manipulation of signaling thresholds is a useful strategy to decouple cytokine functional pleiotropy.