bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polygenic score for physical activity provides odds for multiple common diseases
Authors: Sillanpää Elina , Palviainen Teemu , gen Finn , Ripatti Samuli , Kujala Urho M. , Kaprio Jaakko 
Published: February 2021

ABSTRACTPurposeIt has been suggested that genetic pleiotropy, in which the same genes affect two or more traits, may partially explain the frequently observed associations between high physical activity (PA) and later reduced morbidity or mortality. However, the evidence about pleiotropy from human studies is limited. This study investigated associations between PA polygenic risk scores (PRSs) and cardiometabolic diseases among the Finnish population.MethodsPRSs for device-measured overall PA were adapted to a FinnGen study cohort of 218,792 individuals with genome-wide genotyping and extensive digital longitudinal health register data. Associations between PA PRS and body mass index (BMI), diseases, and mortality were analysed with linear and logistic regression models. The number of different disease endpoints varied between 894 and 111,108 in FinnGen cohort.ResultsA high PA PRS predicted a lower BMI (β −0.025 kg/m2per one standard deviation (SD) change in PA PRS, SE 0.013, p=1.87×10−80). The PA PRS also predicted a lower risk for diseases that typically develop later in life or not at all among highly active individuals. A lower disease risk was systematically observed for cardiovascular diseases [odds ratio, OR per 1 SD change in PA PRS 0.95, p=9.5*10−19) and, for example, hypertension [OR 0.93, p=2.7*10−44), type 2 diabetes (OR 0.91, p=4.1*10−42), and coronary heart disease (OR 0.95 p=1.2*10−9). Participants with high PA PRS had also lower mortality risk (OR 0.97, p=0.0003). We did not observe statistically significant associations with hypothetical control conditions, such as osteoarthritis and osteoporosis.ConclusionsGenetically less active persons are at a higher risk of developing cardiometabolic diseases, which may partly explain the previously observed associations between low PA and higher disease and mortality risk. The same inherited physical fitness and metabolism related mechanisms may be associated both with PA levels and with cardiometabolic disease risk.
General Health Checks in Adult Primary Care: A Review
Authors: Liss David T. , Uchida Toshiko , Wilkes Cheryl L. , Radakrishnan Ankitha , Linder Jeffrey A. 
Published: February 2021

ABSTRACTImportanceGeneral health checks—also known as general medical exams, periodic health evaluations, checkups, or wellness visits—to identify and prevent disease are extremely common in adult primary care. Although general health checks are often expected and advocated by patients, clinicians, payers, and health systems, others question their value. The current evidence was updated and recommendations provided for conducting general health checks in adults.ObservationsRandomized trials and observational studies with control groups from prior systematic reviews and an updated literature review through December 2020 were included. Out of 19 included randomized trials (906 to 59,616 participants; follow-up, 1 to 30 years), 5 evaluated a single general health check and 7 evaluated annual health checks. All of 12 included observational studies (240 to 471,415 participants; follow-up, cross-sectional to 5 years) evaluated a single general health check. General health checks were generally not associated with decreased mortality, cardiovascular events, or cardiovascular disease incidence. For example, in the South-East London Screening Study (n=7,229), adults age 40 to 64 who were invited to two health checks over two years experienced no 8-year mortality benefit (6% overall). However, general health checks were associated with increased detection of chronic diseases, such as depression and hypertension; moderate improvements in controlling risk factors such as blood pressure and cholesterol; increased clinical preventive service uptake, such as colorectal and cervical cancer screening; and improvements in patient-reported outcomes, such as quality of life and self-rated health. General health checks were sometimes associated with modest improvements in health behaviors such as physical activity and diet. For example, in the OXCHECK trial (n=4121), fewer intervention participants exercised less than once per month (68% versus 71%). Potential adverse effects in individual studies included an increased risk of stroke and increased mortality attributed to increased completion of advanced directives.Conclusions and RelevanceGeneral health checks were not associated with reduced mortality or cardiovascular events, but were associated with increased chronic disease recognition and treatment; risk factor control, preventive service uptake, and patient-reported outcomes. Primary care teams may reasonably offer general health checks, especially for groups at high risk of overdue preventive services, uncontrolled risk factors, low self-rated health, or poor connection to primary care.
Mutations in bdcA and valS correlate with quinolone resistance in wastewater Escherichia Coli
Authors: Malekian Negin , Al-Fatlawi Ali , Berendonk Thomas U. , Schroeder Michael 
Published: February 2021

AbstractSingle mutations can confer resistance to antibiotics. Identifying such mutations can help to develop and improve drugs. Here, we systematically screen for candidate quinolone resistance-conferring mutations. We sequenced highly diverse wastewaterE. coliand performed a genome-wide association study (GWAS) correlating over 200,000 mutations against quinolone resistance phenotypes. We uncovered 13 statistically significant mutations including one located at the active site of the biofilm dispersal genes bdcA and six silent mutations in the aminoacyl-tRNA synthetase valS. The study also recovered the known mutations in the topoisomerases gyrA and parC.In summary, we demonstrate that GWAS effectively and comprehensively identifies resistance mutations without a priori knowledge of targets and mode of action. The results suggest that bdcA and valS may be novel resistance genes with biofilm dispersal and translation as novel resistance mechanisms.
Triku: a feature selection method based on nearest neighbors for single-cell data
Authors: Ascensión Alex M. , Ibañez-Solé Olga , Inza Inaki , Izeta Ander , Araúzo-Bravo Marcos J. 
Published: February 2021

AbstractFeature selection is a relevant step in the analysis of single-cell RNA sequencing datasets. Triku is a feature selection method that favours genes defining the main cell populations. It does so by selecting genes expressed by groups of cells that are close in the nearest neighbor graph. Triku efficiently recovers cell populations present in artificial and biological benchmarking datasets, based on mutual information and silhouette coefficient measurements. Additionally, gene sets selected by triku are more likely to be related to relevant Gene Ontology terms, and contain fewer ribosomal and mitochondrial genes. Triku is available athttps://gitlab.com/alexmascension/triku.
Distinguishing excess mutations and increased cell death based on variant allele frequencies
Authors: Gergely Tibély , Schrempf Dominik , Derényi Imre , Szöllősi Gergely J. 
Published: February 2021

AbstractTumors often harbor orders of magnitude more mutations than healthy tissues. The increased number of mutations may be due to an elevated mutation rate or frequent cell death and correspondingly rapid cell turnover, or a combination of the two. It is difficult to disentangle these two mechanisms based on widely available bulk sequencing data, where sequences from individual cells are intermixed and, thus, the cell lineage tree of the tumor cannot be resolved. Here we present a method that can simultaneously estimate the cell turnover rate and the rate of mutations from bulk sequencing data. Our method works by simulating tumor growth and finding the parameters with which the observed data can be reproduced with maximum likelihood. Applying this method to a real tumor sample, we find that both the mutation rate and the frequency of death may be high.Author SummaryTumors frequently harbor an elevated number of mutations, compared to healthy tissue. These extra mutations may be generated either by an increased mutation rate or the presence of cell death resulting in increased cellular turnover and additional cell divisions for tumor growth. Separating the effects of these two factors is a nontrivial problem. Here we present a method which can simultaneously estimate cell turnover rate and genomic mutation rate from bulk sequencing data. Our method is based on the estimation of the parameters of a generative model of tumor growth and mutations. Applying our method to a human hepatocellular carcinoma sample reveals an elevated per cell division mutation rate and high cell turnover.
DARPP-32 promotes ERBB3-mediated resistance to molecular targeted therapy in EGFR-mutated lung adenocarcinoma
Authors: Alam Sk. Kayum , Zhang Yongchang , Wang Li , Zhu Zhu , Hernandez Christina E. , Zhou Yuling , Yang Nong , Lei Jian , Chen Xiaoyan , Zeng Liang , Klein Mark A. , Hoeppner Luke H. 
Published: February 2021

AbstractWhile molecular targeted therapies have improved prognoses of advanced stage lung adenocarcinoma expressing oncogenic driver mutations, acquired therapeutic resistance continues to be a major problem. Epidermal growth factor receptor (EGFR) activating mutations are among the most common targetable genetic alterations in lung adenocarcinoma, and EGFR tyrosine kinase inhibitors (TKIs) are recommended first-line therapy for EGFR mutation positive cancer patients. Unfortunately, most patients develop resistance to EGFR TKIs and rapid disease progression occurs. A better mechanistic understanding of therapy refractory cancer progression is necessary to develop new therapeutic approaches to predict and prevent acquired resistance to EGFR TKIs. Here, we identify a new mechanism of ERBB3-mediated resistance to EGFR TKIs in human lung adenocarcinoma. Specifically, we show that dopamine and cyclic AMP-regulated phosphoprotein, Mr 32000 (DARPP-32) physically recruits ERBB3 to EGFR to mediate a switch from EGFR homodimers to EGFR:ERBB3 heterodimers to bypass EGFR TKI-mediated inhibition to potentiate ERBB3-dependent activation of oncogenic AKT and ERK signaling that drives therapy refractory tumor cell survival. In a cohort of paired tumor specimens derived from 30 lung adenocarcinoma patients before and after the development of EGFR TKI refractory disease progression, we reveal that DARPP-32 as well as kinase-activated EGFR and ERBB3 proteins are overexpressed upon acquired EGFR TKI resistance. In vivo studies suggest that ablation of DARPP-32 protein activity sensitizes gefitinib-resistant lung tumor xenografts to EGFR TKI treatment, while DARPP-32 overexpression increases gefitinib-refractory lung cancer progression in gefitinib-sensitive lung tumors orthotopically xenografted into mice. Taken together, our findings introduce a DARPP-32-mediated, ERBB3-dependent mechanism used by lung tumor cells to evade EGFR TKI-induced cell death, potentially paving the way for the development of new therapies to prevent or overcome therapy-refractory lung adenocarcinoma progression.
MSA Transformer
Authors: Rao Roshan , Liu Jason , Verkuil Robert , Meier Joshua , Canny John F. , Abbeel Pieter , Sercu Tom , Rives Alexander 
Published: February 2021

AbstractUnsupervised protein language models trained across millions of diverse sequences learn structure and function of proteins. Protein language models studied to date have been trained to perform inference from individual sequences. The longstanding approach in computational biology has been to make inferences from a family of evo lutionarily related sequences by fitting a model to each family independently. In this work we combine the two paradigms. We introduce a protein language model which takes as input a set of sequences in the form of a multiple sequence alignment. The model interleaves row and column attention across the input sequences and is trained with a variant of the masked language modeling objective across many protein families. The performance of the model surpasses current state-of-the-art unsupervised structure learning methods by a wide margin, with far greater parameter efficiency than prior state-of-the-art protein language models.
SIPA1L1/SPAR1 is a non-PSD protein involved in GPCR signaling
Authors: Matsuura Ken , Kobayashi Shizuka , Konno Kohtarou , Yamasaki Miwako , Horiuchi Takahiro , Senda Takao , Hayashi Tomoatsu , Satoh Kiyotoshi , Arima-Yoshida Fumiko , Iwasaki Kei , Negishi Lumi , Yasui-Shimizu Naomi , Kohu Kazuyoshi , Kawahara Shigenori , Kirino Yutaka , Nakamura Tsutomu , Watanabe Masahiko , Yamamoto Tadashi , Manabe Toshiya , Akiyama Tetsu 
Published: February 2021

AbstractSIPA1L1 (also known as SPAR1) has been proposed to regulate synaptic functions that are important in maintaining normal neuronal activities, such as regulating spine growth and synaptic scaling, as a component of the postsynaptic density (PSD)-95/N-methyl-D-aspartate receptor (NMDA-R)-complex. However, contrary to this view, our super-resolution and immunoelectron microscopic analyses demonstrate that SIPA1L1 is mainly localized to general submembranous and cytoplasmic regions in neurons, but scarcely to PSD. Our screening for native interactors of SIPA1L1 identified spinophilin and neurabin-1, regulators of G protein-coupled receptor (GPCR) signaling, but rejected PSD-95/NMDA-R-complex components. Furthermore,Sipa1l1-/-mice showed normal spine size distribution and NMDA-R-dependent synaptic plasticity. Nevertheless,Sipa1l1-/-mice showed aberrant responses to α2-adrenergic receptor (a spinophilin target) or adenosine A1 receptor (a neurabin-1 target) agonist stimulation and striking behavioral anomalies, such as hyperactivity, enhanced anxiety, learning impairments, social interaction deficits, and enhanced epileptic seizure susceptibility. Our findings revealed unexpected properties of SIPA1L1, suggesting a possible association of SIPA1L1 deficiency with neuropsychiatric disorders related to dysregulated GPCR signaling, such as epilepsy, attention deficit hyperactivity disorder (ADHD), autism, or fragile X syndrome.
Modest changes inSpi1dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease
Authors: Jones Ruth E. , Andrews Robert , Holmans Peter , Hill Matthew , Taylor Philip R. 
Published: February 2021

AbstractGenetic association studies have identified multiple variants at theSPI1locus that modify risk and age of onset for Alzheimer’s Disease (AD). Reports linking risk variants to gene expression suggest that variants denoting higherSPI1expression are likely to have an earlier AD onset, and several other AD risk genes contain PU.1 binding sites in the promoter region. Overall, this suggests altered levels ofSPi1may alter microglial phenotype potentially impacting AD. This study determined how the mouse microglial transcriptome was altered following modest changes toSpi1expression in primary microglia. RNA-sequencing was performed on microglia with reduced or increasedSpi1/PU.1 expression to provide an unbiased approach to determine transcriptomic changes affected bySpi1. In summary, a reduction in microglialSpi1resulted in the dysregulation of transcripts encoding proteins involved in DNA replication pathways while an increasedSpi1results in an upregulation of genes associated with immune response pathways. Additionally, a subset of 194Spi1dose-sensitive genes was identified and pathway analysis suggests that several innate immune and interferon response pathways are impacted by the concentration ofSpi1. Together these results suggestSpi1levels can alter the microglial transcriptome and suggests interferon pathways may be altered in individuals with AD relatedSpi1risk SNPs.
Endothelial alpha globin is a nitrite reductase
Authors: Keller T.C. Stevenson , Keller Alexander S. , Brás Broseghini-Filho Gilson , Butcher Joshua T. , Page Henry R. Askew , Islam Aditi , Tan Zhe Yin , DeLalio Leon J. , Lechauve Christophe , Brooks Steven , Sharma Poonam , Hong Kwangseok , Xu Wenhao , Simão Padilha Alessandra , Ruddiman Claire A. , Best Angela K. , Macal Edgar , Kim-Shapiro Daniel B. , Christ George , Yan Zhen , Cortese-Krott Miriam M. , Ricart Karina , Patel Rakesh , Bender Timothy P. , Sonkusare Swapnil K. , Weiss Mitchell J. , Ackerman Hans , Columbus Linda , Isakson Brant E. 
Published: February 2021

AbstractSmall artery vasodilation in response to hypoxia is essential for matching oxygen supply to tissue oxygen demand. One source of hypoxic dilation via nitric oxide (NO) signaling is nitrite reduction by erythrocytic hemoglobin (α2β2). However, the alpha subunit of hemoglobin is also expressed in resistance artery endothelium and localized to myoendothelial junctions, a subcellular domain that contacts underlying vascular smooth muscle cells. We hypothesized that nitrite reduction mediated by endothelial alpha globin may occur at myoendothelial junctions to regulate hypoxic vasodilation. To test this concept, we created two novel mouse strains: one lacking alpha globin specifically in endothelium (ECHba1Δ/Δ) and one where alpha globin is mutated such that its inhibitory association with endothelial NO synthase (eNOS) is prevented (Hba1WT/Δ36-39). In ECHba1Δ/ΔorHba1WT/Δ36-39mice hemoglobin levels, hematocrit and erythrocyte counts were unchanged from littermate controls. Loss of the full alpha globin protein from the endothelium in the EC Hba1Δ/Δmodel was associated with decreased exercise capacity and decreased intracellular nitrite utilization in hypoxic conditions. These effects were not seen inHba1WT/Δ36-39animals. Hypoxia induced vasodilation was decreased by 60% in isolated thoracodorsal arteries from ECHba1Δ/Δ, while infusion of erythrocytes only partially rescued the dilatory response. Lastly, unlike other models where blood pressure is decreased, ECHba1Δ/Δblood pressure was not altered in response to hypoxia. Overall, we conclude that alpha globin in the resistance artery endothelium can act as a nitrite reductase to provide a local vasodilatory response to hypoxia.
Tyrosine 121 moves revealing a druggable pocket that couples catalysis to ATP-binding in serine racemase
Authors: Koulouris Chloe R. , Gardiner Sian E. , Harris Tessa K. , Elvers Karen T. , Roe S. Mark , Gillespie Jason A. , Ward Simon E. , Grubisha Olivera , Nicholls Robert A. , Atack John R. , Bax Benjamin D. 
Published: February 2021

ABSTRACTHuman serine racemase (hSR) catalyses racemisation of L-serine to D-serine, the latter of which is a co-agonist of the NMDA subtype of glutamate receptors that are important in synaptic plasticity, learning and memory. In a ‘closed’ hSR structure containing the allosteric activator ATP, the inhibitor malonate is enclosed between the large and small domains while ATP is distal to the active site, residing at the dimer interface with the Tyr121 hydroxyl group contacting the ATP a-phosphate. In contrast, in ‘open’ hSR structures, Tyr121 sits in the core of the small domain with its hydroxyl contacting the key catalytic residue Ser84. The ability to regulate SR activity by flipping Tyr121 from the core of the small domain to the dimer interface appears to have evolved in animals with a CNS. Multiple X-ray crystallographic enzymefragment structures show that Tyr121 is flipped out of its pocket, suggesting that this pocket is druggable.
Invivogeneration of BK and JC polyomavirus defective viral genomes in human urine samples associated with higher viral loads
Authors: Addetia Amin , Phung Quynh , Bradley Benjamin T. , Lin Michelle , Zhu Haiying , Xie Hong , Huang Meei-Li , Greninger Alexander L. 
Published: February 2021

ABSTRACTDefective viral genomes (DVGs) are parasitic viral sequences containing point mutations, deletions, or duplications that might interfere with replication. DVGs are often associated with viral passage at high multiplicities of infection in culture systems but have been increasingly reported in clinical specimens. To date however, only RNA viruses have been shown to contain DVGs in clinical specimens. Here, using direct deep sequencing with multiple library preparation strategies and confirmatory ddPCR of urine samples taken from immunosuppressed individuals, we show clinical BKPyV and JCPyV strains contain widespread genomic rearrangements across multiple loci that likely interfere with viral replication. BKPyV DVGs were universally derived from type I subtype BKPyV. The presence of DVGs was associated with specimens containing higher viral loads but never reached clonality, consistent with a model of parasitized replication. These DVGs persisted during clinical infection as evidenced in two separate pairs of samples containing BK virus collected from the same individual up to 302 days apart. In a separate individual, we observed the generation of DVGs after a 57.5-fold increase in viral load. In summary, by extending the presence of DVGs in clinical specimens to DNA viruses, we demonstrate the ubiquity of DVGs in clinical virology.IMPORTANCEDefective viral genomes (DVGs) can have a significant impact on the production of infectious virus particles. DVGs have only been identified in cultured viruses passaged at high multiplicities of infection and RNA viruses collected from clinical specimens -- no DNA virus in the wild has been shown to contain DVGs. Here, we identified BK and JC polyomavirus DVGs in clinical urine specimens and demonstrated that these DVGs are more frequently identified in samples with higher viral loads. The strains containing DVGs had rearrangements throughout their genomes with the majority affecting genes required for viral replication. Longitudinal analysis showed these DVGs can persist during an infection, but do not reach clonality within the chronically infected host. Our identification of polyomavirus DVGs suggests these parasitic sequences exist across the many classes of viruses capable of causing human disease.
Burst Control
Authors: Leleo Eilam Goldenberg , Segev Idan 
Published: February 2021

AbstractThe output of neocortical layer 5 pyramidal cells (L5PCs) is expressed by a train of single spikes with intermittent bursts of multiple spikes at high frequencies. The bursts are the result of nonlinear dendritic properties, including Na+, Ca2+, and NMDA spikes, that interact with the ∼10,000 synapses impinging on the neuron’s dendrites. Output spike bursts are thought to implement key dendritic computations, such as coincidence detection of bottom-up inputs (arriving mostly at the basal tree) and top-down inputs (arriving mostly at the apical tree). In this study we used a detailed nonlinear model of L5PC receiving excitatory and inhibitory synaptic inputs to explore the conditions for generating bursts and for modulating their properties. We established the excitatory input conditions on the basal versus the apical tree that favor burst and show that there are two distinct types of bursts. Bursts consisting of 3 or more spikes firing at < 200 Hz, which are generated by stronger excitatory input to the basal versus the apical tree, and bursts of ∼2-spikes at ∼250 Hz, generated by prominent apical tuft excitation. Localized and well-timed dendritic inhibition on the apical tree differentially modulates Na+, Ca2+, and NMDA spikes and, consequently, finely controls the burst output. Finally, we explored the implications of different burst classes and respective dendritic inhibition for regulating synaptic plasticity.