bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intra-individual changes in the frequency of mosaic loss of chromosome Y over time estimated with a new method
Authors: Danielsson Marcus , Halvardson Jonatan , Davies Hanna , Moghadam Behrooz Torabi , Mattisson Jonas , Rychlicka-Buniowska Edyta , Jaszczyński Janusz , Heintz Julia , Lannfelt Lars , Giedraitis Vilmantas , Ingelsson Martin , Dumanski Jan P. , Forsberg Lars A. 
Published: May 2019

AbstractBackgroundMosaic loss of chromosome Y (LOY) is the most common somatic mutation and is associated with all-cause mortality, non-haematological cancers and Alzheimer’s disease among other outcomes. The predominant method used for estimating LOY is the intensity data generated by SNP-arrays, which is difficult to interpret due to its logarithmic scale. Here we describe a new way to convert the LOY mosaicism into a non-logarithmic scale, which instead represents the percentage of affected cells.MethodsWe compared three independent LOY readouts from matched samples, generated by SNP-array, whole genome sequencing and droplet digital PCR. The SNP-array standardization was derived from this comparison and was applied in analyses of serially collected samples from a large cohort of aging men. The sampling was performed up to five times, spanning up to 22 years.ResultsWe observed a higher correlation between the LOY measurements from SNP-array and the two other readouts when using the standardized, instead of the logarithmic, SNP-array data. We also observed a pronounced intra-individual variation of changes in the frequency of LOY within individual males over time.ConclusionsDescribing LOY measurements generated from SNP-arrays in percentage of cells without the Y chromosome makes comparisons to WGS and ddPCR measurements more precise and easier to interpret. This standardization could be applied to the vast amount of SNP-array data already generated in the scientific community, allowing further discoveries of LOY associated disease and outcomes. Additionally, the frequency of LOY in this study changed profoundly within men over time, likely as a result of aberrant clonal expansions.
High risk glioblastoma cells revealed by machine learning and single cell signaling profiles
Authors: Leelatian Nalin , Sinnaeve Justine , Mistry Akshitkumar M. , Barone Sierra M. , Diggins Kirsten E. , Greenplate Allison R. , Weaver Kyle D. , Thompson Reid C. , Chambless Lola B. , Mobley Bret C. , Ihrie Rebecca A. , Irish Jonathan M. 
Published: May 2019

AbstractRecent developments in machine learning implemented dimensionality reduction and clustering tools to classify the cellular composition of patient-derived tissue in multi-dimensional, single cell studies. Current approaches, however, require prior knowledge of either categorical clinical outcomes or cell type identities. These algorithms are not well suited for application in tumor biology, where clinical outcomes can be continuous and censored and cell identities may be novel and plastic. Risk Assessment Population IDentification (RAPID) is an unsupervised, machine learning algorithm that identifies single cell phenotypes and assesses clinical risk stratification as a continuous variable. Single cell mass cytometry evaluated 34 different phospho-proteins, transcription factors, and cell identity proteins in tumor tissue resected from patients bearingIDHwild-type glioblastomas. RAPID identified and characterized multiple biologically distinct tumor cell subsets that independently and continuously stratified patient outcome. RAPID is broadly applicable for single cell studies where atypical cancer and immune cells may drive disease biology and treatment responses.
Chloroplast nucleoids are highly dynamic in ploidy, number, and structure during angiosperm leaf development
Authors: Greiner Stephan , Golczyk Hieronim , Malinova Irina , Pellizzer Tommaso , Bock Ralph , Börner Thomas , Herrmann Reinhold G. 
Published: May 2019

SummaryChloroplast nucleoids are large, compact nucleoprotein structures containing multiple copies of the plastid genome. Studies on structural and quantitative changes of plastid DNA (ptDNA) during leaf development are scarce and have produced controversial data. We have systematically investigated nucleoid dynamics and ptDNA quantities in mesophyll ofArabidopsis, tobacco, sugar beet, and maize from the early post-meristematic stage until necrosis. DNA of individual nucleoids was quantified by DAPI-based supersensitive epifluorescence microscopy. Nucleoids occurred in scattered, stacked or ring-shaped arrangements and in recurring patterns during leaf development remarkably similar between the species studied. Nucleoids per organelle varied from few in meristematic plastids to >30 in mature chloroplasts (corresponding to about 20-750 nucleoids per cell). Nucleoid ploidies ranged from haploid to >20-fold even within individual organelles, with average values between 2.6- and 6.7-fold and little changes during leaf development. DNA quantities per organelle increased gradually from about a dozen plastome copies in tiny plastids of apex cells to 70-130 copies in chloroplasts of about 7 μm diameter in mature mesophyll tissue, and from about 80 plastome copies in meristematic cells to 2,600-3,300 copies in mature diploid mesophyll cells without conspicuous decline during leaf development. Pulsed-field electrophoresis, restriction of high-molecular weight DNA from chloroplasts and gerontoplasts, and CsCl equilibrium centrifugation of single- and double-stranded ptDNA revealed no noticeable fragmentation of the organelle DNA during leaf development, implying that plastid genomes in mesophyll tissues are remarkably stable until senescence.Significance StatementPlastid DNA is organized in nucleoids that are highly dynamic in organization, structure and amount during leaf development. The present investigation fully resolves now this dynamic and is a precise cytogenetic characterization of nucleoids DNA spanning the entire life cycle of the leaf.
Nanoscale spatial dependence of avidity in an IgG1 antibody
Authors: Jendroszek Agnieszka , Kjaergaard Magnus 
Published: May 2019

AbstractAntibodies are secreted proteins that are crucial to recognition of pathogens by the immune system and are also efficient pharmaceuticals. The affinity and specificity of target recognition can increase remarkably through avidity effects, when the antibody can bind a multivalent antigen through more than one epitope simultaneously. A key goal of antibody engineering is thus to optimize avidity, but little is known about the nanoscale spatial dependence of avidity in antibodies. Here, we develop a set of anti-parallel coiled-coils spanning from 8-21 nm and validate their structure using biophysical techniques. We use the coiled-coils to control the spacing between two epitopes, and measure how antigen spacing affects the stability of the bivalent antibody:antigen complex. We find a maximal avidity enhancement at a spacing of 14 nm, but only see a ∼2-fold variation of avidity in the range from 8-21 nm. In contrast to recent studies, we find the avidity to be relatively insensitive to epitope spacing near the avidity maximum as long as it is within the spatial tolerance of the antibody. The coiled-coil systems developed here may prove a useful protein nanocaliper for profiling the spatial tolerance and avidity profile of bispecific antibodies.
The phosphatase inhibitor Sds23 regulates cell division symmetry in fission yeast
Authors: Schutt Katherine L. , Moseley James B. 
Published: May 2019

AbstractAnimal and fungal cells divide through the assembly, anchoring, and constriction of a contractile actomyosin ring (CAR) during cytokinesis. The timing and position of the CAR must be tightly controlled to prevent defects in cell division, but many of the underlying signaling events remain unknown. The conserved heterotrimeric protein phosphatase PP2A controls the timing of events in mitosis, and upstream pathways including Greatwall-Ensa regulate PP2A activity. A role for PP2A in CAR regulation has been less clear, although loss of PP2A in yeast causes defects in cytokinesis. Here, we report that Sds23, an inhibitor of PP2A family protein phosphatases, promotes the symmetric division of fission yeast cells through spatial control of cytokinesis. We found thatsds23Δ cells divide asymmetrically due to misplaced CAR assembly, followed by sliding of the CAR away from its assembly site. These mutant cells exhibit delayed recruitment of putative CAR anchoring proteins including the glucan synthase Bgs1. Our observations likely reflect a broader role for regulation of PP2A in cell polarity and cytokinesis becausesds23Δ phenotypes were exacerbated when combined with mutations in the fission yeast Ensa homolog, Igo1. These results identify the PP2A regulatory network as a critical component in the signaling pathways coordinating cytokinesis.
Anti-microbial immunity is impaired in COPD patients with frequent exacerbations
Authors: Singanayagam Aran , Loo Su-Ling , Calderazzo Maria , Finney Lydia J , Trujillo Torralbo Maria-Belen , Bakhsoliani Eteri , Girkin Jason , Veerati Punnam , Pathinayake Prabuddha S , Nichol Kristy S , Reid Andrew , Foottit Joseph , Johnston Sebastian L , Bartlett Nathan W , Mallia Patrick 
Published: May 2019

ABSTRACTBackgroundPatients with frequent exacerbations represent a chronic obstructive pulmonary disease (COPD) sub-group requiring better treatment options. The aim of this study was to determine the innate immune mechanisms that underlie susceptibility to frequent exacerbations in COPD.MethodsWe measured sputum expression of immune mediators and bacterial loads in samples from patients with COPD at stable state and during virus-associated exacerbations.Ex vivoimmune responses to rhinovirus infection in differentiated bronchial epithelial cells (BECs) sampled from patients with COPD were additionally evaluated. Patients were stratified as frequent exacerbators (≥2 exacerbations in the preceding year) or infrequent exacerbators (<2 exacerbations in the preceding year) with comparisons made between these groups.ResultsFrequent exacerbators had reduced sputum cell mRNA expression of the anti-viral immune mediators type I and III interferons and reduced interferon-stimulated gene (ISG) expression when clinically stable and during virus-associated exacerbation. RV-induction of interferon and ISGsex vivowas also impaired in differentiated BECs from frequent exacerbators. Frequent exacerbators also had reduced sputum levels of the anti-microbial peptide mannose-binding lectin (MBL)-2 with an associated increase in sputum bacterial loads at 2 weeks following virus-associated exacerbation onset. MBL-2 levels correlated negatively with bacterial loads during exacerbation.ConclusionThese data implicate deficient airway innate immunity in the increased propensity to exacerbations observed in some patients with COPD. Therapeutic approaches to boost innate antimicrobial immunity in the lung could be a viable strategy for prevention/treatment of frequent exacerbations.
Maximum likelihood method quantifies the overall contribution of gene-environment interaction to continuous traits: an application to complex traits in the UK Biobank
Authors: Sulc Jonathan , Mounier Ninon , Günther Felix , Winkler Thomas , Wood Andrew R. , Frayling Timothy M. , Heid Iris M. , Robinson Matthew R. , Kutalik Zoltán 
Published: May 2019

AbstractAs genome-wide association studies (GWAS) increased in size, numerous gene-environment interactions (GxE) have been discovered, many of which however explore only one environment at a time and may suffer from statistical artefacts leading to biased interaction estimates. Here we propose a maximum likelihood method to estimate the contribution of GxE to complex traits taking into account all interacting environmental variables at the same time, without the need to measure any. This is possible because GxE induces fluctuations in the conditional trait variance, the extent of which depends on the strength of GxE. The approach can be applied to continuous outcomes and for single SNPs or genetic risk scores (GRS). Extensive simulations demonstrated that our method yields unbiased interaction estimates and excellent confidence interval coverage. We also offer a strategy to distinguish specific GxE from general heteroscedasticity (scale effects). Applying our method to 32 complex traits in the UK Biobank reveals that for body mass index (BMI) the GRSxE explains an additional 1.9% variance on top of the 5.2% GRS contribution. However, this interaction is not specific to the GRS and holds for any variable similarly correlated with BMI. On the contrary, the GRSxE interaction effect for leg impedance is significantly (P < 10−56) larger than it would be expected for a similarly correlated variable . We showed that our method could robustly detect the global contribution of GxE to complex traits, which turned out to be substantial for certain obesity measures.
Acylcarnitine Metabolomic Profiles Inform Clinically-Defined Major Depressive Phenotypes
Authors: Ahmed Ahmed T. , MahmoudianDehkordi Siamak , Bhattacharyya Sudeepa , Arnold Matthias , Liu Duan , Neavin Drew , Moseley M. Arthur , Thompson J. Will , John Williams Lisa St , Louie Gregory , Skime Michelle K. , Wang Liewei , Riva-Posse Patricio , McDonald William , Bobo William V. , Craighead W. Edward , Krishnan Ranga , Weinshilboum Richard M. , Dunlop Boadie W. , Millington David S. , Rush A. John , Frye Mark A. ,   The Mood Disorders Precision Medicine Consortium (MDPMC), Kaddurah-Daouk Rima 
Published: May 2019

AbstractBackgroundAcylcarnitines have important functions in mitochondrial energetics and β-oxidation, and have been implicated to play a significant role in metabolic functions of the brain. This retrospective study examined whether plasma acylcarnitine profiles can help biochemically distinguish the three phenotypic subtypes of major depressive disorder (MDD)—(core depression (CD+), anxious depression (ANX+), and neurovegetative symptoms of melancholia (NVSM+))—following treatment with a selective serotonin reuptake inhibitor (SSRI).MethodsDepressed outpatients (n=240) from the Mayo Clinic Pharmacogenomics Research Network were treated with citalopram or escitalopram for eight weeks. Plasma samples collected at baseline and eight weeks post-treatment were profiled for multiple-, short-, medium- and long-chain acylcarnitine levels using AbsoluteIDQ®p180-Kit and LC-MS. Linear mixed effects models were used to examine whether acylcarnitine levels discriminate the clinical phenotypes at baseline or eight weeks post-treatment, and whether temporal changes in acylcarnitine profiles differ between groups.ResultsAt baseline, significantly lower concentrations of short- and long-chain acylcarnitines were found in CD+ and NVSM+ compared to ANX+, and the short-chain acylcarnitines remained lower after eight weeks. At eight weeks, the medium- and long-chain acylcarnitines were significantly lower in NVSM+ compared to ANX+. Regarding changes baseline to week eight, short-chain acylcarnitine levels significantly increased in CD+ and ANX+, and medium- and long-chain acylcarnitines significantly decreased in NVSM+ and CD+.ConclusionsIn depressed patients treated with SSRIs, β-oxidation and mitochondrial energetics as evaluated by levels and changes in acylcarnitines may provide the biochemical basis of the clinical heterogeneity of MDD, especially when combined with clinical characteristics.
Leaf—An open-source, model-agnostic, data-driven web application for cohort discovery and translational biomedical research
Authors: Dobbins Nicholas J , Spital Clifford , Black Robert , Morrison Jason , de Veer Bas , Zampino Liz , Harrington Robert , Britt Bethene , Stephens Kari , Wilcox Adam , Tarczy-Hornoch Peter , Mooney Sean D. 
Published: May 2019

AbstractObjectiveAcademic medical centers and health systems are increasingly challenged with supporting appropriate secondary use of data that originate from multiple sources. Enterprise Data Warehouses (EDWs) have emerged as central resources for these data, but they often require an informatician to extract meaningful information, thereby limiting direct access by end users. To overcome this challenge, we have developed Leaf, a lightweight self-service web application for querying and extracting clinical data from heterogeneous data sources.Materials and MethodsLeaf utilizes a flexible biomedical concept system to define hierarchical items and ontologies. Each Leaf concept contains both textual representations and associated SQL query building blocks, exposed by a simple drag-and-drop user interface. Leaf generates abstract syntax trees which are compiled into dynamic SQL queries.ResultsLeaf is a successful production-supported tool at the University of Washington, which hosts a central Leaf instance querying an EDW with over 300 active users. Through the support of UW Medicine (https://uwmedicine.org), the Institute of Translational Health Sciences (https://www.iths.org) and the National Center for Data to Health (https://ctsa.ncats.nih.gov/cd2h/), Leaf source code has been released into the public domain athttps://github.com/uwrit/leaf.DiscussionLeaf allows the querying of single or multiple clinical databases simultaneously, even those of different data models. This enables fast installation without costly extraction or duplication from existing databases.ConclusionLeaf differs from existing cohort discovery tools because it does not specify a required data model and is designed to seamlessly integrate with existing enterprise user authentication systems and clinical databases in situ. We demonstrate its unique technical strengths and success alongside its friendly user interface. We believe Leaf to be useful for health system analytics, clinical research data warehouses, precision medicine biobanks and clinical studies involving large patient cohorts.
Quantifying the Benefit Offered by Transcript Assembly on Single-Molecule Long Reads
Authors: Tung Laura H. , Shao Mingfu , Kingsford Carl 
Published: May 2019

AbstractThird-generation sequencing technologies benefit transcriptome analysis by generating longer sequencing reads. However, not all single-molecule long reads represent full transcripts due to incomplete cDNA synthesis and the sequencing length limit of the platform. This drives a need for long read transcript assembly. We quantify the benefit that can be achieved by using a transcript assembler on long reads. Adding long-read-specific algorithms, we evolved Scallop to make Scallop-LR, a long-read transcript assembler, to handle the computational challenges arising from long read lengths and high error rates. Analyzing 26 SRA PacBio datasets using Scallop-LR, Iso-Seq Analysis, and StringTie, we quantified the amount by which assembly improved Iso-Seq results. Through combined evaluation methods, we found that Scallop-LR identifies 2100–4000 more (for 18 human datasets) or 1100–2200 more (for eight mouse datasets) known transcripts than Iso-Seq Analysis, which does not do assembly. Further, Scallop-LR finds 2.4–4.4 times more potentially novel isoforms than Iso-Seq Analysis for the human and mouse datasets. StringTie also identifies more transcripts than Iso-Seq Analysis. Adding long-read-specific optimizations in Scallop-LR increases the numbers of predicted known transcripts and potentially novel isoforms for the human transcriptome compared to several recent short-read assemblers (e.g. StringTie). Our findings indicate that transcript assembly by Scallop-LR can reveal a more complete human transcriptome.
Caveolae set levels of epithelial monolayer tension to eliminate tumor cells
Authors: Teo Jessica L. , Gomez Guillermo A. , Noordstra Ivar , Verma Suzie , Tomatis Vanesa , Acharya Bipul R. , Balasubramaniam Lakshmi , Katsuno-Kambe Hiroko , Templin Rachel , McMahon Kerrie-Ann , Ju Robert J. , Stebhens Samantha J. , Ladoux Benoit , Parton Robert G. , Yap Alpha S. 
Published: May 2019

AbstractMechanical tension governs epithelial morphogenesis and homeostasis, but its regulation remains poorly understood. Tension is commonly contractile, arising when the actomyosin cortices of cells are mechanically coupled together by cadherin adhesion. Here we report that caveolae control levels of epithelial tension and show that this is necessary for oncogene-transfected cells to be eliminated by apical extrusion. Depletion of caveolin-1 (CAV1) in the surrounding epithelium, but not in the oncogene-expressing cells, blocked extrusion leading to the retention and proliferation of transformed cells within the monolayer. Tensile stress was aberrantly elevated in CAV1-depleted monolayers due to elevated levels of phosphoinositide-4,5-bisphosphate (PtdIns(4,5)P2) causing increased recruitment of the formin, FMNL2. Oncogenic extrusion was restored to CAV1-deficient monolayers when tension was corrected by depleting FMNL2, blocking PtdIns(4,5)P2, or disabling the interaction between FMNL2 and PtdIns(4,5)P2. Thus, by controlling lipid signalling to the actin cytoskeleton, caveolae regulate mechanical tension for epithelial homeostasis.
Monitoring quinolone resistance due to Haemophilus influenzae mutations (2012–17)
Authors: Nagatomo Yasuhiro , Shirakura Tetsuro , Fukuchi Kunihiko , Takuma Takahiro , Tokimatsu Issei , Niki Yoshihito 
Published: May 2019

AbstractAmong drug-resistant bacteria of recent concern, we determined minimum inhibitory concentrations (MICs) of six different quinolone antibacterial agents in Haemophilus influenzae and performed molecular genetic analysis in addition to the exploration for β-lactamase-producing and β-lactamase negative ampicillin-resistant H. influenzae (BLNAR). A total of 144 clinical H. influenzae strains isolated at the Showa University Hospital between 2012 and 2017 were subjected to MIC determination for penicillin/quinolone antibacterial agents using the nitrocefin method and the Clinical and Laboratory Standards Institute broth microdilution method. Moreover, amino acid mutations in the quinolone resistance-determining regions (QRDRs) were analyzed in the isolates showing MIC value of ≥ 0.25 µg/ml of quinolone antibacterial agents. Increasing proportions of BLNAR were noted, with 15% in 2015 to 43.5% in 2016 and 63.6% in 2017. Among quinolone antibacterial agents, all isolates remained susceptible to sitafloxacin (STFX), and STFX showed strong inhibitory potencies against both DNA gyrase and topoisomerase IV. For moxifloxacin (MXF), however, strains with MIC value of 0.5 µg/ml were detected every year since 2013 except 2015. Amino acid mutations were investigated in 17 isolates (11.8%) with MXF MIC value of ≥0.25 µg/ml, and confirmed in 11 isolates (7.6%), of which mutations of GyrA were found in 9 isolates. Future antibacterial drug regimens may need to address the emergence of quinolone-resistant H. influenzae.