bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human genotype-to-phenotype predictions: boosting accuracy with nonlinear models
Authors: Medvedev Aleksandr , Sharma Satyarth Mishra , Tsatsorin Evgenii , Nabieva Elena , Yarotsky Dmitry 
Published: July 2021

AbstractGenotype-to-phenotype prediction is a central problem of human genetics. In recent years, it has become possible to construct complex predictive models for phenotypes, thanks to the availability of large genome data sets as well as efficient and scalable machine learning tools. In this paper, we make a three-fold contribution to this problem. First, we ask if state-of-the-art nonlinear predictive models, such as boosted decision trees, can be more efficient for phenotype prediction than conventional linear models. We find that this is indeed the case if model features include a sufficiently rich set of covariates, but probably not otherwise. Second, we ask if the conventional selection of single nucleotide polymorphisms (SNPs) by genome wide association studies (GWAS) can be replaced by a more efficient procedure, taking into account information in previously selected SNPs. We propose such a procedure, based on a sequential feature importance estimation with decision trees, and show that this approach indeed produced informative SNP sets that are much more compact than when selected with GWAS. Finally, we show that the highest prediction accuracy can ultimately be achieved by ensembling individual linear and nonlinear models. To the best of our knowledge, for some of the phenotypes that we consider (asthma, hypothyroidism), our results are a new state-of-the-art.
Disinfection of SARS-CoV-2 using UVC reveals wavelength sensitivity contributes towards rapid virucidal activity
Authors: Mariita Richard M. , Wilson Miller Amy C. , Randive Rajul V. , McKay Lindsay G. A. , Storm Nadia , Griffiths Anthony 
Published: July 2021

AbstractSARS-CoV-2 can be disinfected using ultraviolet-C (UVC) light. For effective inactivation strategies, design and implementation, knowledge of UVC wavelength sensitivity, and disinfection rate of the relevant pathogen are required. This study aimed to determine the inactivation profile of SARS-CoV-2 using UVC irradiation with different wavelengths. Specifically, the study determined dosage, inactivation levels, and wavelength sensitivity of SARS-CoV-2. Assessment of SARS-CoV-2 (isolate USA/WA1-2020) inactivation at peak wavelengths of 259, 268, 270, 275 and 280 nm was performed using a plaque assay method. A UVC dose of 3.1 mJ/cm2 using 259 and 268 nm arrays yielded log reduction values (LRV) of 2.32 and 2.44, respectively. With a dose of 5 mJ/cm2, arrays of peak wavelengths at 259 and 268 nm obtained similar inactivation levels (LRV 2.97 and 2.80 respectively). The arrays of longer wavelength (270, 275 and 280 nm), demonstrated lower performances (≤LRV 2.0) when applying an irradiation dose of 5 mJ/cm2. Additional study with the 268 nm array revealed that a dose of 6.25 mJ/cm2 is enough to obtain a LRV of 3. These results suggest that 259 and 268 nm are the most efficient wavelengths for SARS-CoV-2 inactivation compared to longer UVC wavelengths, allowing the calculation of disinfection systems efficacy.
FiMAP: A Fast Identity-by-Descent Mapping Test for Biobank-scale Cohorts
Authors: Chen Han , Naseri Ardalan , Zhi Degui 
Published: July 2021

AbstractAlthough genome-wide association studies (GWAS) have identified tens of thousands of genetic loci, the genetic architecture is still not fully understood for many complex traits. Most GWAS and sequencing association studies have focused on single nucleotide polymorphisms or copy number variations, including common and rare genetic variants. However, phased haplotype information is often ignored in GWAS or variant set tests for rare variants. Here we leverage the identity-by-descent (IBD) segments inferred from a random projection-based IBD detection algorithm in the mapping of genetic associations with complex traits, to develop a computationally efficient statistical test for IBD mapping in biobank-scale cohorts. We used sparse linear algebra and random matrix algorithms to speed up the computation, and a genome-wide IBD mapping scan of more than 400,000 samples finished within a few hours. Simulation studies showed that our new method had well-controlled type I error rates under the null hypothesis of no genetic association in large biobank-scale cohorts, and outperformed traditional GWAS approaches and variant set tests when the causal variants were untyped and rare, or in the presence of haplotype effects. We also applied our method to IBD mapping of six anthropometric traits using the UK Biobank data and identified a total of 3,442 associations, 2,224 (65%) of which remained significant after conditioning on independent association variants in the ± 3 cM flanking regions from GWAS.
Low dose mRNA-1273 COVID-19 vaccine generates durable T cell memory and antibodies enhanced by pre-existing crossreactive T cell memory
Authors: Mateus Jose , Dan Jennifer M. , Zhang Zeli , Moderbacher Carolyn Rydyznski , Lammers Marshall , Goodwin Benjamin , Sette Alessandro , Crotty Shane , Weiskopf Daniela 
Published: July 2021

AbstractUnderstanding human immune responses to SARS-CoV-2 RNA vaccines is of interest for a panoply of reasons. Here we examined vaccine-specific CD4+ T cell, CD8+ T cell, binding antibody, and neutralizing antibody responses to the 25 μg Moderna mRNA-1273 vaccine over 7 months post-immunization, including multiple age groups, with a particular interest in assessing whether pre-existing crossreactive T cell memory impacts vaccine-generated immunity. Low dose (25 μg) mRNA-1273 elicited durable Spike binding antibodies comparable to that of convalescent COVID-19 cases. Vaccine-generated Spike memory CD4+ T cells 6 months post-boost were comparable in quantity and quality to COVID-19 cases, including the presence of TFH cells and IFNγ-expressing cells. Spike CD8+ T cells were generated in 88% of subjects, with equivalent percentages of CD8+ T cell memory responders at 6 months post-boost compared to COVID-19 cases. Lastly, subjects with pre-existing crossreactive CD4+ T cell memory had increased CD4+ T cell and antibody responses to the vaccine, demonstrating a biological relevance of SARS-CoV-2 crossreactive CD4+ T cells.One-Sentence SummaryThe mRNA-1273 vaccine induces a durable and functional T cell and antibody response comparable to natural infection.
Structural connectivity of subthalamic nucleus stimulation for improving freezing of gait
Authors: Strelow Joshua N. , Baldermann Juan C. , Dembek Till A. , Jergas Hannah , Petry-Schmelzer Jan N. , Schott Frederik , Dafsari Haidar , Moll Christian K.E. , Hamel Wolfgang , Gulberti Alessandro , Visser-Vandewalle Veerle , Fink Gereon R. , Pötter-Nerger Monika , Barbe Michael T. 
Published: July 2021

AbstractGait impairments such as freezing of gait (FOG) are among the most common and disabling symptoms of Parkinson’s disease (PD). While the efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with early or advanced PD has been proven in large randomised controlled trials, its effect on gait impairments is still insufficiently understood. Moreover, there is uncertainty about pathways that need to be modulated to improve gait impairments. In this bi-centric study, we investigated how STN-DBS alters FOG in 47 subjects with PD. We assessed freezing prevalence and severity using the Freezing of Gait Questionnaire and Item 14 of the Unified Parkinson’s Disease Rating Scale-II. Using a model of publicly available basal-ganglia pathways we determined a connectivity profile for postoperative changes in FOG. Compared to preoperative baseline, freezing of gait significantly improved six months postoperatively, marked by reduced frequency and duration of freezing episodes. We found that optimal stimulation sites for improving freezing of gait structurally connected to primary and supplementary motor areas, the dorsolateral prefrontal cortex and to the globus pallidus. Stimulation of the lenticular fasciculus was associated with worsening of freezing of gait. Our findings highlight the need for optimal identification and characterisation for network structures that can be implemented in stereotactic planning and can additionally pose a target for postoperative stimulation strategies.
Genome-Wide Association Study of Estradiol Levels, and the Causal Effect of Estradiol on Bone Mineral Density
Authors: Schmitz Daniel , Ek Weronica E. , Berggren Elin , Höglund Julia , Karlsson Torgny , Johansson Åsa 
Published: July 2021

AbstractContextEstradiol is the primary female sex hormone and plays an important role for skeletal health in both sexes. Several enzymes are involved in estradiol metabolism but few genome-wide association studies (GWAS) have been performed to characterize the genetic contribution to variation in estrogen levels.ObjectiveIdentify genetic loci affecting estradiol levels and estimate causal effect of estradiol on bone mineral density (BMD).DesignWe performed GWAS for estradiol in males (N = 147,690) and females (N = 163,985) from UK Biobank (UKB). Estradiol was analyzed as a binary phenotype; above/below detection limit (175 pmol/L). We further estimated the causal effect of estradiol on BMD using Mendelian randomization.ResultsWe identified 14 independent loci associated (P<5×10−8) with estradiol levels in males, of which one (CYP3A7) was genome-wide and seven nominally (P<0.05) significant in females. In addition, one female specific locus was identified. Most loci contain functionally relevant genes that have not been discussed in relation to estradiol levels in previous GWAS. For example, SRD5A2, which encodes a steroid 5-alpha reductase that is involved in processing androgens, and UGT3A1 and UGT2B7 which encode enzymes likely to be involved in estradiol elimination. The allele that tags the O blood group, at the ABO locus, was associated with higher estradiol levels. We identified a causal effect of high estradiol levels on increased BMD in both males (P=1.58×10−11) and females (P=7.48×10−6).ConclusionOur findings further support the importance of the body’s own estrogen to maintain skeletal health in males and in females.
Adulthood asthma as a consequence of childhood adversity: a systematic review of epigenetically affected genes
Authors: Saygideğer Yasemin , Özkan Hakan , Baydar Oya , Yılmaz Özge 
Published: July 2021

ABSTRACTThere is an accumulating data that shows relation between childhood adversity and vulnerability to chronic diseases as well as epigenetic influences that in turn give rise to these diseases. Asthma is one of the chronic diseases that is influenced from genetic regulation of the inflammatory biomolecules and therefore the hypothesis in this research was childhood adversity might have caused epigenetic differentiation in the asthma related genes in the population who had childhood trauma. To test this hypothesis, the literature was systematically reviewed to extract epigenetically modified gene data of the adults who had childhood adversity, and affected genes were further evaluated for their association with asthma. PRISMA guidelines were adopted and PubMed and Google Scholar were included in the searched databases, to evaluate epigenetic modifications in asthma related genes of physically, emotionally or sexually abused children. After retrieving a total of 12,085 articles, 36 of them were included in the study. Several genes and pathways that may contribute to pathogenesis of asthma development, increased inflammation or response to asthma treatment were found epigenetically affected by childhood traumas. Childhood adversity, causing epigenetic changes in DNA, may lead to asthma development or influence the course of the disease and therefore should be taken into account for the prolonged health consequences.
Simulated Diagnostic Performance of Ultra-Low-Field MRI: Harnessing Open-Access Datasets to Evaluate Novel Devices
Authors: Arnold T. Campbell , Baldassano Steven N. , Litt Brian , Stein Joel M. 
Published: July 2021

AbstractThe purpose of this study is to demonstrate a method for virtually evaluating novel imaging devices using machine learning and open-access datasets, here applied to a new, ultra-low-field strength (ULF), 64mT, portable MRI device. Paired 3T and 64mT brain images were used to develop and validate a transformation converting standard clinical images to ULF-quality images. Separately, 3T images were aggregated from open-source databases spanning four neuropathologies: low-grade glioma (LGG, N=76), high-grade glioma (HGG, N=259), stroke (N=28), and multiple sclerosis (MS, N=20). The transformation method was then applied to the open-source data to generate simulated ULF images for each pathology. Convolutional neural networks (DenseNet-121) were trained to detect pathology in axial slices from either 3T or simulated 64 mT images, and their relative performance was compared to characterize the potential diagnostic capabilities of ULF imaging. Algorithm performance was measured using area under the receiver operating characteristic curve. Across all cohorts, pathology detection was similar between 3T and simulated 64mT images (LGG: 0.97 vs. 0.98; HGG: 0.96 vs. 0.95; stroke: 0.94 vs. 0.94; MS: 0.90 vs 0.87). Pathology detection was further characterized as a function of lesion size, intensity, and contrast. Simulated images showed decreasing sensitivity for lesions smaller than 4 cm2(∼2.25 cm in diameter). While simulations cannot replace prospective trials during the evaluation of medical devices, they can provide guidance and justification for prospective studies. Simulated data derived from open-source imaging databases may facilitate testing and validation of new imaging devices.HighlightsUltra-low-field, point-of-care MRI has potential to detect a range of pathologies including brain tumors, strokes, and multiple sclerosis. However, determining the diagnostic capabilities and appropriate use case for such devices requires further prospective studies.Open-source image datasets provide a powerful tool for accelerating imaging research and enable simulated trials that can guide prospective clinical trials or device development.
Heart Rate Variability as a Prospective Predictor of Early COVID-19 Symptoms
Authors: Ponomarev Alexey , Tyapochkin Konstantin , Surkova Ekaterina , Smorodnikova Evgeniya , Pravdin Pavel 
Published: July 2021

AbstractHeart rate variability (HRV) is the fluctuation in the time interval between consecutive heartbeats, the measurement of which is a non-invasive method for assessing the autonomic status. The autonomic nervous system plays an important role in physiological situations, and in various pathological processes such as in cardiovascular diseases and viral infections. This study examined the cardiac autonomic responses, as measured by HRV before, after, and during coronavirus disease. In this study, we used beat interval data extracted from the Welltory app from 14 eligible subjects (9 men and 5 women) with a mean age (SD) of 44 (8.7) years. HRV analysis was performed through an assessment of time-domain indices (SDNN and RMSSD). Group analysis did not reveal any statistical difference between HRV metrics before, during, and after COVID-19. However, HRV at the individual level showed a statistically significant individual change during COVID-19 in some users. These data further support the usefulness of using individual-level HRV tracking for the detection of early diseases inclusive of COVID-19.
Anti-spike antibody response to natural SARS-CoV-2 infection in the general population
Authors: Wei Jia , Matthews Philippa C. , Stoesser Nicole , Maddox Thomas , Lorenzi Luke , Studley Ruth , Bell John I , Newton John N , Farrar Jeremy , Diamond Ian , Rourke Emma , Howarth Alison , Marsden Brian D. , Hoosdally Sarah , Jones E Yvonne , Stuart David I , Crook Derrick W. , Peto Tim E. A. , Pouwels Koen B. , Walker A. Sarah , Eyre David W. ,   the COVID-19 Infection Survey team
Published: July 2021

AbstractWe estimated the duration and determinants of antibody response after SARS-CoV-2 infection in the general population using representative data from 7,256 United Kingdom COVID-19 infection survey participants who had positive swab SARS-CoV-2 PCR tests from 26-April-2020 to 14-June-2021. A latent class model classified 24% of participants as ‘non-responders’ not developing anti-spike antibodies. These seronegative non-responders were older, had higher SARS-CoV-2 cycle threshold values during infection (i.e. lower viral burden), and less frequently reported any symptoms. Among those who seroconverted, using Bayesian linear mixed models, the estimated anti-spike IgG peak level was 7.3-fold higher than the level previously associated with 50% protection against reinfection, with higher peak levels in older participants and those of non-white ethnicity. The estimated anti-spike IgG half-life was 184 days, being longer in females and those of white ethnicity. We estimated antibody levels associated with protection against reinfection likely last 1.5-2 years on average, with levels associated with protection from severe infection present for several years. These estimates could inform planning for vaccination booster strategies.
ERAP1, ERAP2, and two copies of HLA-Aw19 alleles increase the risk for Birdshot Chorioretinopathy in HLA-A29 carriers
Authors: Gelfman Sahar , Monnet Dominique , Ligocki Ann J. , Tabary Thierry , Moscati Arden , Bai Xiaodong , Freudenberg Jan , Cooper Blerta , Kosmicki Jack A. , Wolf Sarah ,   Regeneron Genetics Center, Ferreira Manuel A. R. , Overton John , Weyne Jonathan , Stahl Eli A. , Baras Aris , Romano Carmelo , Cohen Jacques H. M. , Coppola Giovanni , Brézin Antoine 
Published: July 2021

AbstractPurposeBirdshot Chorioretinopathy (BSCR) is strongly associated with HLA-A29. This study was designed to elucidate the genetic modifiers of BSCR in HLA-A29 carriers.MethodsWe sequenced the largest BSCR cohort to date, including 286 cases and 108 HLA-A29 positive controls to perform genome wide common and rare variant associations. We further typed the HLA alleles of cases and 45,386 HLA-A29 controls of European ancestry to identify HLA alleles that associate with BSCR risk.ResultsCarrying a second allele that belongs to the HLA-Aw19 broad antigen family (including HLA-A29, A30, A31, and A33) increases the risk for BSCR (OR=4.44, p=2.2e-03). This result was validated by comparing allele frequencies to large HLA-A29-controlled cohorts (n=45,386, OR>2.5, p<1.3e-06). We also confirm that ERAP1 and ERAP2 haplotypes modulate the risk for disease within our HLA-A29 controlled cohort. A meta-analysis with an independent dataset confirmed that ERAP1 and ERAP2 haplotypes modulate the risk for disease at a genome-wide significant level: ERAP1-rs27432 (OR 2.46; 95% CI 1.85-3.26; p=4.07e-10), an eQTL decreasing ERAP1 expression, and ERAP2-rs10044354 (OR 1.95; 95% CI 1.55-2.44; p=6.2e-09), an eQTL increasing ERAP2 expression. Furthermore, ERAP2-rs2248374 that disrupts ERAP2 expression is protective (OR 0.56; 95% CI [0.45-0.70]; p=2.39e-07). BSCR risk is additively increased when combining ERAP1/ERAP2 risk genotypes with two copies of HLA-Aw19 alleles (OR 13.53; 95% CI 3.79-54.77, p=1.17e-05).ConclusionsThe genetic factors increasing BSCR risk demonstrate a pattern of increased processing, as well as increased presentation of ERAP2 specific peptides. This suggests a mechanism in which exceeding a peptide presentation threshold activates the immune response in choroids of A29 carriers.
An executive center for the intake of liquids
Authors: Dempsey Bowen , Sungeelee Selvee , Bokiniec Philip , Chettouh Zoubida , Diem Séverine , Autran Sandra , Harrell Evan R. , Poulet James F.A. , Birchmeier Carmen , Carrey Harry , Genovesio Auguste , McMullan Simon , Goridis Christo , Fortin Gilles , Brunet Jean-François 
Published: July 2021

AbstractIt has long been known that orofacial movements for feeding can be triggered, coordinated, and often rhythmically organized at the level of the brainstem, without input from higher centers. We uncover two nuclei that can organize the movements for ingesting fluids in mammals. These neuronal groups, defined by unique transcriptional codes and developmental origins, IRtPhox2b and Peri5Atoh1, are located, respectively, in the intermediate reticular formation of the medulla and around the motor nucleus of the trigeminal nerve. They are premotor to all jaw-opening and tongue muscles. Stimulation of either, in awake animals, opens the jaw, while IRtPhox2b alone also protracts the tongue. Moreover, stationary stimulation of IRtPhox2b entrains a rhythmic alternation of tongue protraction and retraction, synchronized with jaw opening and closing, that mimics lapping. Finally, fiber photometric recordings show that IRtPhox2b is active during volitional lapping. Our study identifies one of the long hypothesized subcortical nuclei underpinning a stereotyped feeding behavior.
3D printed lung on a chip device with a stretchable nanofibrous membrane for modeling ventilator induced lung injury
Authors: Tas Sinem , Rehnberg Emil , Bölükbas Deniz A. , Beech Jason P. , Kazado Liora Nasi , Svenningsson Isak , Arvidsson Martin , Sandberg Axel , Dahlgren Kajsa A. , Edthofer Alexander , Gustafsson Anna , Isaksson Hanna , Wood Jeffery A. , Tegenfeldt Jonas O. , Wagner Darcy E. 
Published: July 2021

AbstractMechanical ventilation is often required in patients with pulmonary disease to maintain adequate gas exchange. Despite improved knowledge regarding the risks of over ventilating the lung, ventilator induced lung injury (VILI) remains a major clinical problem due to inhomogeneities within the diseased lung itself as well as the need to increase pressure or volume of oxygen to the lung as a life-saving measure. VILI is characterized by increased physical forces exerted within the lung, which results in cell death, inflammation and long-term fibrotic remodeling. Animal models can be used to study VILI, but it is challenging to distinguish the contributions of individual cell types in such a setup.In vitromodels, which allow for controlled stretching of specific lung cell types have emerged as a potential option, but these models and the membranes used in them are unable to recapitulate some key features of the lung such as the 3D nanofibrous structure of the alveolar basement membrane while also allowing for cells to be cultured at an air liquid interface (ALI) and undergo increased mechanical stretch that mimics VILI. Here we develop a lung on a chip device with a nanofibrous synthetic membrane to provide ALI conditions and controllable stretching, including injurious stretching mimicking VILI. The lung on a chip device consists of a thin (i.e. ∼20 µm) stretchable poly(caprolactone) (PCL) nanofibrous membrane placed between two channels fabricated in polydimethylsiloxane (PDMS) using 3D printed molds. We demonstrate that this lung on a chip device can be used to induce mechanotrauma in lung epithelial cells due to cyclic pathophysiologic stretch (∼25%) that mimics clinical VILI. Pathophysiologic stretch induces cell injury and subsequently cell death, which results in loss of the epithelial monolayer, a feature mimicking the early stages of VILI. We also validate the potential of our lung on a chip device to be used to explore cellular pathways known to be altered with mechanical stretch and show that pathophysiologic stretch of lung epithelial cells causes nuclear translocation of the mechanotransducers YAP/TAZ. In conclusion, we show that a breathable lung on a chip device with a nanofibrous membrane can be easily fabricated using 3D printing of the lung on a chip molds and that this model can be used to explore pathomechanisms in mechanically induced lung injury.