bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program
Authors: Verma Anurag , Tsao Noah , Thomann Lauren , Ho Yuk-Lam , Iyengar Sudha , Luoh Shiuh-Wen , Carr Rotonya , Crawford Dana , Efird Jimmy T. , Huffman Jennifer , Hung Adriana , Ivey Kerry , Levin Michael , Lynch Julie , Natarajan Pradeep , Pyarajan Saiju , Bick Alexander , Costa Lauren , Genovese Giulio , Hauger Richard , Madduri Ravi , Pathak Gita , Polimanti Renato , Voight Benjamin , Vujkovic Marijana , Zekavat Maryam , Zhao Hongyu , Ritchie Marylyn D ,   VA Million Veteran Program COVID-19 Science Initiative, Chang Kyong-Mi , Cho Kelly , Casas Juan P. , Tsao Philip S. , Gaziano J. Michael , O’Donnell Christopher , Damrauer Scott , Liao Katherine 
Published: May 2021

AbstractThe study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n=35) or hospitalization (n=42) due to severe COVID-19 using genome-wide association summary from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828= 53 and nrs505922=59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p=1.32 × 10−199), and thrombosis ORrs505922 1.33, p=2.2 ×10−265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p=4.12 × 10−191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p=2.26× 10−12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p=6.48 ×10−23, lupus OR 0.84, p=3.97 × 10−06. PheWAS stratified by genetic ancestry demonstrated differences in genotype-phenotype associations across ancestry. LMNA (rs581342) associated with neutropenia OR 1.29 p=4.1 × 10−13 among Veterans of African ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.
Synergistic associations of cognitive and motor impairments with functional outcome in covert cerebral small vessel disease
Authors: Jokinen Hanna , Laakso Hanna M. , Ahlström Matti , Arola Anne , Lempiäinen Juha , Pitkänen Johanna , Paajanen Teemu , Sikkes Sietske A. M. , Koikkalainen Juha , Lötjönen Jyrki , Korvenoja Antti , Erkinjuntti Timo , Melkas Susanna 
Published: May 2021

ABSTRACTObjectiveCognitive and motor impairments are the key clinical manifestations of cerebral small vessel disease (SVD), but their interrelations and combined effects on functional outcome have not been elucidated. We investigated the associations between cognitive and motor functions and their interactions and mediating effects on instrumental activities of daily living (IADL) and quality of life in older individuals with various degrees of white matter hyperintensities (WMH).MethodsParticipants of the Helsinki Small Vessel Disease Study (n=152) were assessed according to an extensive clinical, neuropsychological and MRI protocol. Cognitive composite scores for global cognition, processing speed, executive functions and memory were constructed from multiple tests within each domain. Physical examination included measures of gait speed, balance (single-leg-stance) and functional mobility (timed-up-and-go test). IADL was evaluated with a proxy-based Amsterdam IADL questionnaire and quality of life with a self-report EUROHIS-Qol index. Volumes of WMH and gray matter (GM) were obtained with automated segmentation. Sets of linear regression analyses were used to model the associations between motor and cognitive performances, WMH and GM volumes, and IADL and quality of life.ResultsDomain-specific cognitive and motor functions had strong interrelations with each other, and they were significantly associated with IADL, quality of life as well as WMH and GM volumes. A consistent pattern on significant interactions between cognitive and motor functions was found on IADL, but not on quality of life. In particular, low cognitive scores together with decline in the timed-up-and-go test and gait speed were strongly related to impaired IADL. The association of WMH volume with IADL was mediated by global cognition, whereas the association of GM volume with IADL was mediated by global cognition and timed up-and-go performance.ConclusionThe results highlight the complex interplay and synergism between motor and cognitive abilities on functional outcome in SVD. The combined effect of motor and cognitive disturbances on IADL is likely to be greater than the individual effects of each of the two impairments. WMH and brain atrophy contribute to disability through cognitive and motor impairment.
Risk factors for early childhood growth faltering in rural Cambodia
Authors: Lai Amanda , Velez Irene , Ambikapathi Ramya , Seng Krisna , Cumming Oliver , Brown Joe 
Published: May 2021

AbstractIntroductionInadequate nutrition in early life and exposure to sanitation-related enteric pathogens have been linked to poor growth outcomes in children. Despite rapid development in Cambodia, high prevalence of growth faltering and stunting continue to persist. This study aimed to assess nutrition and WASH variables and their association with nutritional status of children under 24 months in rural Cambodia.MethodsWe conducted surveys in 491 villages across 55 rural communes in Cambodia in September 2016 to measure associations between child, household, and community-level risk factors for stunting and length-for-age z-score (LAZ). A primary survey measured child-level variables, including anthropometric measures and risk factors for growth faltering and stunting, for 4,036 children under 24 months of age from 3,877 households (approximately 8 households per village). For LAZ, we calculated bivariate and adjusted associations (as mean differences) with 95% confidence intervals using generalised estimating equations (GEEs) to fit linear regression models with robust standard errors. For stunting, we calculated unadjusted and adjusted prevalence ratios (PRs) with 95% confidence intervals using GEEs to fit Poisson regression models with robust standard errors. For all models assessing effects of household-level variables, we used GEEs to account for clustering at the village level.ResultsAfter adjustment for potential confounding, presence of water and soap at a household’s handwashing station was found to be significantly associated (p<0.05) with increased LAZ (adjusted mean difference in LAZ +0.10, 95% CI: 0.03, 0.16), and household use of an improved drinking water source was associated with less stunting in children compared to households that did not use an improved source of drinking water (aPR 0.81, 95% CI: 0.66, 0.98); breastfeeding was associated with a lower LAZ score (−0.16, 95% CI: −0.27, −0.05). No other feeding practices (i.e., dietary diversity, meal frequency, minimum acceptable diet) or sanitation variables (i.e., household’s safe disposal of child stools, household-level sanitation, community-level sanitation) were associated with LAZ scores or stunting in children under 24 months of age. In an age-stratified analysis, children under 12 months of age were longer (LAZ +0.12, 95% CI: 0.02, 0.21) if there was presence of water and soap at the household handwashing station; at the community level, higher prevalence of shared sanitation (percentage of households in a village who report to use shared sanitation facilities) was negatively associated with child length (LAZ - 0.36, 95% CI: −0.66, −0.07).
Combined Metabolic Activators Reduces Liver Fat in Nonalcoholic Fatty Liver Disease Patients
Authors: Zeybel Mujdat , Altay Ozlem , Arif Muhammad , Li Xiangyu , Yang Hong , Fredolini Claudia , Akyildiz Murat , Saglam Burcin , Gonenli Mehmet Gokhan , Ural Dilek , Kim Woonghee , Schwenk Jochen M. , Zhang Cheng , Shoaie Saeed , Nielsen Jens , Uhlén Mathias , Borén Jan , Mardinoglu Adil 
Published: May 2021

ABSTRACTNonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMA) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo-controlled 10-week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomics data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host-microbiome interactions. In conclusion, we observed that CMA can be used develop a pharmacological treatment strategy in NAFLD patients.
Electronic early notification of sepsis in hospitalized ward patients: a study protocol for a stepped-wedge cluster randomized controlled trial
Authors: Arabi Yaseen M , Saawi Abdulmohsen Al , Zahrani Mohammed Al , Khathaami Ali Al , AlHazme Raed H , Mutrafy Abdullah Al , Qarni Ali Al , Shouabi Ahmed Al , Qasim Eman Al , Abdukahil Sheryl Ann , Al-Rabeeah Fawaz Q , Ghamdi Huda Al , Ghamdi Ebtisam Al , Alansari Mariam , Abuelgasim Khadega A , Alattasi Abdulaleem , Alchin John , Al-Dorzi Hasan M , Ghamdi Abdulaziz A , Al-Hameed Fahad , Alharbi Ahmad , Hussein Mohamed , Jastaniah Wasil , AlKatheri Mufareh Edah , AlMarhabi Hassan , Mustafa Hani T , Jones Joan , Al-Qahtani Saad , Qahtani Shaher , Qureshi Ahmad S , Salih Salih Bin , Alselaim Nahar , Tashkandi Nabeeha , Vishwakarma Ramesh Kumar , AlWafi Emad , Alyami Ali H , Yousef Zeyad Al ,   for the SCREEN Trial Group
Published: May 2021

AbstractBackgroundTo examine the effect of screening for sepsis using an electronic sepsis alert versus no alert in hospitalized patients admitted to wards on hospital mortality.MethodsThis study is conducted in 45 medical-surgical-oncology wards in five hospitals. Based on the quick Sequential Organ Failure Assessment (qSOFA), an electronic alert has been developed in the hospital Electronic Medical Record system. The alert system sends notifications of “Possible Sepsis Alert” to the bedside nurse, charge nurse, and primary medical team and requires an acknowledgment in the health information system from the bedside nurse and physician. In addition, data on the alert are displayed on management dashboards for each ward. Initially, all wards had a masked alert for 2 months. Hospital wards are then allocated in a randomized fashion to either active or masked alert, such that the alert is activated in five new randomly selected wards every two months until all wards have the active alert. The primary endpoint is in-hospital mortality by 90 days.DiscussionThe trial has started in October 2019 and is expected to continue for 22 months enrolling more than 62550 hospitalized patients.Trial registrationClinicalTrials.govNCT04078594. Registered on September 6, 2019,https://clinicaltrials.gov/ct2/show/NCT04078594
Modeling third waves of Covid-19 spread with piecewise differential and integral operators: Turkey, Spain and Czechia
Authors: Atangana Abdon , İğret Araz Seda 
Published: May 2021

AbstractSeveral collected data representing the spread of some infectious disease have demonstrated that the spread does not really exhibit homogeneous spread. Clear examples can include the spread of Spanish flu and Covid-19. Collected data depicting numbers of daily new infections in the case of Covid-19 from countries like Turkey, Spain show three waves with different spread patterns. A clear indication of crossover behaviors. While modelers have suggested many mathematical models to depicting these behaviors, it becomes clear that their mathematical models cannot really capture the crossover behaviors, especially passage from deterministic resetting to stochastics. Very recently Atangana and Seda have suggested a concept of piecewise modeling consisting in defining a differential operator piece-wisely, the idea was first in chaos and outstanding patterns were captured. In this paper, we extend this concept to the field of epidemiology with the aim to depict waves with different patterns. Due to the novelty of this concept, a different approach to insure the existence and uniqueness of system solutions are presented. A piecewise numerical approach is presented to derive numerical solutions of such models. An illustrative example is presented and compared with collected data from 3 different countries including Turkey, Spain and Czechia. The obtained results let no doubt for us to conclude that this concept is a new window that will help mankind to better understand nature.
Partial reprogramming restores youthful gene expression through transient suppression of cell identity
Authors: Roux Antoine , Zhang Chunlian , Paw Jonathan , Solorio José-Zavalara , Vijay Twaritha , Kolumam Ganesh , Kenyon Cynthia , Kimmel Jacob C. 
Published: May 2021

AbstractTransient induction of pluripotent reprogramming factors has been reported to reverse some features of aging in mammalian cells and tissues. However, the impact of transient reprogramming on somatic cell identity programs and the necessity of individual pluripotency factors remain unknown. Here, we mapped trajectories of transient reprogramming in young and aged cells from multiple murine cell types using single cell transcriptomics to address these questions. We found that transient reprogramming restored youthful gene expression in adipocytes and mesenchymal stem cells but also temporarily suppressed somatic cell identity programs. We further screened Yamanaka Factor subsets and found that many combinations had an impact on aging gene expression and suppressed somatic identity, but that these effects were not tightly entangled. We also found that a transient reprogramming approach inspired by amphibian regeneration restored youthful gene expression in aged myogenic cells. Our results suggest that transient pluripotent reprogramming poses a neoplastic risk, but that restoration of youthful gene expression can be achieved with alternative strategies.
In vivo direct imaging of neuronal activity at high temporo-spatial resolution
Authors: Toi Phan Tan , Jang Hyun Jae , Min Kyeongseon , Kim Sung-Phil , Lee Seung-Kyun , Lee Jongho , Kwag Jeehyun , Park Jang-Yeon 
Published: May 2021

AbstractThere has been a longstanding demand for noninvasive neuroimaging methods capable of detecting neuronal activity at both high temporal and spatial resolution. Here, we propose a novel method that enables Direct Imaging of Neuronal Activity for functional MRI (termed DIANA-fMRI) that can dynamically image spiking activity in milliseconds precision, while retaining the original benefit of high spatial resolution of MRI. DIANA-fMRI was demonstrated through in vivo mice brain imaging at 9.4 T applying electrical whisker-pad stimulation, directly imaging the spiking activity as well as capturing its sequential propagation along the thalamocortical pathway, as further confirmed through in vivo spike recording and optogenetics. DIANA-fMRI will open up new avenues in brain science by providing a deeper understanding of the brain’s functional organization including neural networks.
Molecular architecture determines brain delivery of a transferrin-receptor targeted lysosomal enzyme
Authors: Arguello Annie , Mahon Cathal S. , Calvert Meredith E. K. , Chan Darren , Dugas Jason C. , Pizzo Michelle E. , Thomsen Elliot R. , Chau Roni , Damo Lorna A. , Duque Joseph , Earr Timothy , Fang Meng , Giese Tina , Kim Do Jin , Liang Nicholas , Lopez Isabel A. , Nguyen Hoang N. , Solanoy Hilda , Tsogtbaatar Buyankhishig , Ullman Julie C. , Wang Junhua , Dennis Mark S. , Diaz Dolores , Gunasekaran Kannan , Henne Kirk R. , Lewcock Joseph W. , Sanchez Pascal E. , Troyer Matthew D. , Harris Jeffrey M. , Scearce-Levie Kimberly , Shan Lu , Watts Ryan J. , Thorne Robert G. , Henry Anastasia G. , Kariolis Mihalis S. 
Published: May 2021

AbstractDelivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse biotherapeutics to platforms that bind the transferrin receptor (TfR), a brain endothelial cell target, to facilitate receptor-mediated transcytosis across the BBB. Here, we characterized the pharmacological behavior of two distinct TfR-targeted platforms fused to iduronate 2-sulfatase (IDS), a lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared the relative brain exposures and functional activities of both approaches in mouse models. IDS fused to a moderate-affinity, monovalent TfR binding enzyme transport vehicle (ETV:IDS) resulted in widespread brain exposure, internalization by parenchymal cells, and significant substrate reduction in the CNS of an MPS II mouse model. In contrast, IDS fused to a standard high-affinity bivalent antibody (IgG:IDS) resulted in lower brain uptake, limited biodistribution beyond brain endothelial cells, and reduced brain substrate reduction. These results highlight important features likely to impact the clinical development of TfR-targeting platforms in MPS II and potentially other CNS diseases.SummaryBrain delivery, biodistribution and pharmacodynamics of a lysosomal enzyme fused to a moderate-affinity transferrin receptor-directed blood-brain barrier enzyme transport vehicle are superior to a traditional high-affinity anti-TfR monoclonal antibody fusion.
PARROT: a flexible recurrent neural network framework for analysis of large protein datasets
Authors: Griffith Daniel , Holehouse Alex S. 
Published: May 2021

ABSTRACTThe rise of high-throughput experiments has transformed how scientists approach biological questions. The ubiquity of large-scale assays that can test thousands of samples in a day has necessitated the development of new computational approaches to interpret this data. Among these tools, machine learning approaches are increasingly being utilized due to their ability to infer complex non-linear patterns from high-dimensional data. Despite their effectiveness, machine learning (and in particular deep learning) approaches are not always accessible or easy to implement for those with limited computational expertise. Here we present PARROT, a general framework for training and applying deep learning-based predictors on large protein datasets. Using an internal recurrent neural network architecture, PARROT is capable of tackling both classification and regression tasks while only requiring raw protein sequences as input. We showcase the potential uses of PARROT on three diverse machine learning tasks: predicting phosphorylation sites, predicting transcriptional activation function of peptides generated by high-throughput reporter assays, and predicting the fibrillization propensity of amyloid beta with data generated by deep mutational scanning. Through these examples, we demonstrate that PARROT is easy to use, performs comparably to state-of-the-art computational tools, and is applicable for a wide array of biological problems.
Novel feature selection method via kernel tensor decomposition for improved multi-omics data analysis
Authors: Taguchi Y-h. , Turki Turki 
Published: May 2021

AbstractBackgroundFeature selection of multi-omics data analysis remains challenging owing to the size of omics datasets, comprising approximately 102–105features. In particular, appropriate methods to weight individual omics datasets are unclear, and the approach adopted has substantial consequences for feature selection. In this study, we extended a recently proposed kernel tensor decomposition (KTD)-based unsupervised feature extraction (FE) method to integrate multi-omics datasets obtained from common samples in a weight-free manner.MethodKTD-based unsupervised FE was reformatted as the collection of kernelized tensors sharing common samples, which was applied to synthetic and real datasets.ResultsThe proposed advanced KTD-based unsupervised FE method showed comparative performance to that of the previously proposed KTD method, as well as tensor decomposition-based unsupervised FE, but required reduced memory and central processing unit time. Moreover, this advanced KTD method, specifically designed for multi-omics analysis, attributesP-values to features, which is rare for existing multi-omics–oriented methods.ConclusionsThe sample R code is available athttps://github.com/tagtag/MultiR/
Depression-like state induced by low-frequency repetitive transcranial magnetic stimulation to ventral medial frontal cortex in monkeys
Authors: Nakamura Shinya , Kishimoto Yodai , Sekino Masaki , Nakamura Motoaki , Tsutsui Ken-Ichiro 
Published: May 2021

AbstractThe medial frontal cortex (MFC), especially its ventral part, has long been of great interest with respect to the pathology of mood disorders. A number of human brain imaging studies have demonstrated the abnormalities of this brain region in patients with mood disorders, however, whether it is critically involved in the pathogenesis of such disorders remains to be fully elucidated. In this study, we conducted a causal study to investigate how the suppression of neural activity in the ventral region of the MFC (vMFC) affects the behavioral and physiological states of monkeys by using repetitive transcranial magnetic stimulation (rTMS). By using low-frequency rTMS (LF-rTMS) as an inhibitory intervention, we found that LF-rTMS targeting the vMFC induced a depression-like state in monkeys, which was characterized by a reduced spontaneous behavioral activity, increased plasma cortisol level, impaired sociability, and decreased motivation level. On the other hand, no such significant changes in behavioral and physiological states were observed when targeting the other MFC regions, dorsal or posterior. We further found that the administration of an antidepressant agent, ketamine, ameliorated the abnormal behavioral and physiological states induced by the LF-rTMS intervention. These findings indicate the causal involvement of the vMFC in the regulation of mood and affect and the validity of the LF-rTMS-induced dysfunction of the vMFC as a nonhuman primate model of the depression-like state.