bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overestimated Polygenic Prediction due to Overlapping Subjects in Genetic Datasets
Authors: Park David Keetae , Chen Mingshen , Kim Seungsoo , Joo Yoonjung Yoonie , Loving Rebekah K. , Kim Hyoung Seop , Cha Jiook , Yoo Shinjae , Kim Jong Hun 
Published: January 2022

ABSTRACTRecently, polygenic risk score (PRS) has gained significant attention in studies involving complex genetic diseases and traits. PRS is often derived from summary statistics, from which the independence between discovery and replication sets cannot be monitored. Prior studies, in which the independence is strictly observed, report a relatively low gain from PRS in predictive models of binary traits. We hypothesize that the independence assumption may be compromised when using the summary statistics, and suspect an overestimation bias in the predictive accuracy. To demonstrate the overestimation bias in the replication dataset, prediction performances of PRS models are compared when overlapping subjects are either present or removed. We consider the task of Alzheimer’s disease (AD) prediction across genetics datasets, including the International Genomics of Alzheimer’s Project (IGAP), AD Sequencing Project (ADSP), and Accelerating Medicine Partnership - Alzheimer’s Disease (AMP-AD). PRS is computed from either sequencing studies for ADSP and AMP-AD (denoted as rPRS) or the summary statistics for IGAP (sPRS). Two variables with the high heritability in UK Biobank, hypertension, and height, are used to derive an exemplary scale effect of PRS. Based on the scale effect, the expected performance of sPRS is computed for AD prediction. Using ADSP as a discovery set for rPRS on AMP-AD, ΔAUC and ΔR2(performance gains in AUC and R2by PRS) record 0.069 and 0.11, respectively. Both drop to 0.0017 and 0.0041 once overlapping subjects are removed from AMP-AD. sPRS is derived from IGAP, which records ΔAUC and ΔR2of 0.051±0.013 and 0.063±0.015 for ADSP and 0.060 and 0.086 for AMP-AD, respectively. On UK Biobank, rPRS performances for hypertension assuming a similar size of discovery and replication sets are 0.0036±0.0027 (ΔAUC) and 0.0032±0.0028 (ΔR2). For height, ΔR2is 0.029±0.0037. Considering the high heritability of hypertension and height of UK Biobank, we conclude that sPRS results from AD databases are inflated. The higher performances relative to the size of the discovery set were observed in PRS studies of several diseases. PRS performances for binary traits, such as AD and hypertension, turned out unexpectedly low. This may, along with the difference in linkage disequilibrium, explain the high variability of PRS performances in cross-nation or cross-ethnicity applications, i.e., when there are no overlapping subjects. Hence, for sPRS, potential duplications should be carefully considered within the same ethnic group.
PRICE COVID19 Data Report December 2021 Pakistan Registry of Intensive Care
Authors: farooq Ahmed , Arsalan Rahatullah , Aisha Mufti Kulsoom , Muhammad Asim , Hayat Muhammad , Altaf Aneela , Taqi Arshad , Kumar Ashok , Rehman Attaur , Haidri Fakhir Raza , Hussain Iqbal , Chaudhry Mobin , Rehman Safdar , Malik Irfan , Saleem Jodat , Ali Liaquat , Zia Muhammad Ashraf , Khan Maria Ali , Sheikh Mohiuddin , Ashraf Muhammad Sheharyar , Rana Muhammad Asim , Khoso Muhammad Nasir , Rizvi Saadiya , Shaikh Naseem Ali , Salahuddin Nawal , Khan Qurat-ul-Ain , Sikander Rana Imran , Ali Syed Muneeb , Khan Rashid Nasim , Babar Sairah , Beane Abigail , Dondorp Arjen M , Kodippily Chamira , Priyadarshani Dilanthi , Udayanga Ishara , Ishani Pramodya , Darshana Sri , Rashan Thalha , Haniffa Rashan , Murthy Srinivas , Hashmi Madiha 
Published: January 2022

Abstract
Pakistan Registry of Intensive Care (PRICE) is a platform that has enabled standardized COVID-19 clinical data collection based on ISARIC/WHO Clinical Characterization Protocol. The near real-time data platform includes epidemiology, severity of illness, microbiology, treatment and outcomes of patients admitted with suspected or laboratory confirmed COVID19 infection to 67 intensive care and high dependency units across the country. Data has been extracted and analysed at regular intervals to inform stakeholders and improve care practices. This is our 28th report including all patients with suspected or confirmed COVID-19 from 26th March 2020 to 26th December 2021.

Key findings from 8624 patients who met eligibility criteria, are as follows:
●	Median age of 60 years (IQR 50-70).
●	The most common symptoms were shortness of breath (n = 6428, 77.8%), fever (n = 6091, 73.8%), and Cough (n = 3354, 38.9%)
●	The most common comorbidity was hypertension followed by diabetes.
●	During the course of illness 2804 (32.6%) patients received non-invasive ventilation, whereas 2474 (28.8%) patients had mechanical ventilation as their highest organ support. In addition, 2246 (26.1%) patients needed haemodynamic support and 1249 (14.7%) patients required renal replacement therapy as their highest organ support.
●	Median APACHE II score was 18
●	Overall mortality at ICU discharge was 39.2%
●	Increasing age and requirement for invasive mechanical ventilation were independent risk factors for mortality increased the risk of death
Multiscale computer modeling of spreading depolarization in brain slices
Authors: Kelley Craig , Newton Adam JH , Hrabetova Sabina , McDougal Robert A. , Lytton William W 
Published: January 2022

AbstractSpreading depolarization (SD) is a slow-moving wave of neuronal depolarization accompanied by a breakdown of ion concentration homeostasis, followed by long periods of neuronal silence (spreading depression), and associated with several neurological conditions. We developed multiscale (ions to tissue slice) computer models of SD in brain slices using the NEURON simulator: 36,000 neurons (2 voltage-gated ion channels; 3 leak channels; 3 ion exchangers/pumps) in the extracellular space (ECS) of a slice (1 mm sides, varying thickness) with ion (K+, Cl−, Na+) and O2 diffusion and equilibration with a surrounding bath. Glia and neurons cleared K+ from the ECS via Na+/K+ pumps. SD propagated through the slices at realistic speeds of 2–4 mm/min, which increased by as much as 50% in models incorporating the effects of hypoxia or propionate. In both cases, the speedup was mediated principally by ECS shrinkage. Our model allows us to make testable predictions, including: 1. SD can be inhibited by enlarging ECS volume; 2. SD velocity will be greater in areas with greater neuronal density, total neuronal volume, or larger/more dendrites; 3. SD is all-or-none: initiating K+ bolus properties have little impact on SD speed; 4. Slice thickness influences SD due to relative hypoxia in the slice core, exacerbated by SD in a pathological cycle; 5. SD and high neuronal spike rates will be observed in the core of the slice. Cells in the periphery of the slice near an oxygenated bath will resist SD.SignificanceSpreading depolarization (SD) is a slow moving wave of electrical and ionic imbalances in brain tissue and is a hallmark of several neurological disorders. We developed a multiscale computer model of brain slices with realistic neuronal densities, ions, and oxygenation. Our model shows that SD is exacerbated by and causes hypoxia, resulting in strong SD dependence on slice thickness. Our model also predicts that the velocity of SD propagation is not dependent on its initiation, but instead on tissue properties, including the amount of extracellular space and the total area of neuronal membrane, suggesting faster SD following ischemic stroke or traumatic brain injury.
Predicting Response to McGurk Illusion Based on Periodic and Aperiodic Prestimulus EEG Activity
Authors: Singh Vinsea A V , Kumar Vinodh G , Banerjee Arpan , Roy Dipanjan 
Published: January 2022

AbstractStudies have reported that prestimulus brain oscillations guide perceptual experiences during AV speech perception. However, ’what’ features of these prestimulus activity drives perception remains unknown. In this electroencephalography (EEG) study, we investigated the relationship between prestimulus periodic oscillations and aperiodic components with subsequent perception of the McGurk illusion at single-trial levels. Using logistic mixed-effect models, we determined which spectral features from different sensor regions predicted response to the illusory perception. We found that lower alpha (8-12 Hz) and beta (15-30 Hz) band oscillations over parieto-occipital sensors predicted illusion perception. We also found lower aperiodic offset values over parieto-temporal sensors, and lower ‘global’ effect of exponent over the scalp, that predicted the response to McGurk illusion. We conclude that the predominant source of the prestimulus oscillatory state is aperiodic background activity, and that variations in these arrhythmic components account for inter-trial and inter-individual variability in perception of the McGurk illusion.
Outcomes of SARS-CoV-2 Omicron infection in residents of Long-Term Care
Authors: Krutikov Maria , Stirrup Oliver , Nacer-Laidi Hadjer , Azmi Borscha , Fuller Chris , Tut Gokhan , Palmer Tom , Shrotri Madhumita , Irwin-Singer Aidan , Baynton Verity ,   The COVID-19 Genomics UK (COG-UK) consortium, Hayward Andrew , Moss Paul , Copas Andrew , Shallcross Laura 
Published: January 2022

AbstractBackgroundRecently there has been a rapid, global increase in SARS-CoV-2 infections associated with the Omicron variant (B.1.1.529). Although severity of Omicron cases may be reduced, the scale of infection suggests hospital admissions and deaths may be substantial. Definitive conclusions about disease severity require evidence from populations with the greatest risk of severe outcomes, such as residents of Long-Term Care Facilities (LTCFs).MethodsWe used a cohort study to compare the risk of hospital admission or death in LTCF residents in England who had tested positive for SARS-CoV-2 in the period shortly before Omicron emerged (Delta dominant) and the Omicron-dominant period, adjusting for age, sex, vaccine type, and booster vaccination. Variants were confirmed by sequencing or spike-gene status in a subset.ResultsRisk of hospital admission was markedly lower in 1241 residents infected in the Omicron-period (4.01% hospitalised, 95% CI: 2.87-5.59) compared to 398 residents infected in the pre-Omicron period (10.8% hospitalised, 95% CI: 8.13-14.29, adjusted Hazard Ratio 0.50, 95% CI: 0.29-0.87, p=0.014); findings were similar in residents with confirmed variant. No residents with previous infection were hospitalised in either period. Mortality was lower in the Omicron versus the pre-Omicron period, (p<0.0001).ConclusionsRisk of severe outcomes in LTCF residents with the SARS-CoV-2 Omicron variant was substantially lower than that seen for previous variants. This suggests the current wave of Omicron infections is unlikely to lead to a major surge in severe disease in LTCF populations with high levels of vaccine coverage and/or natural immunity.Trial Registration NumberISRCTN 14447421
Modelling Quarantine Effects on SARS-CoV-2 Epidemiological Dynamics in Chilean Communes and their Relationship with the Social Priority Index
Authors: Salinas Dino G. , Bustamante María Leonor , Gallardo Mauricio O. 
Published: January 2022

ABSTRACTAn epidemiological model [Susceptible, Un-quarantined infected, Quarantined infected, Confirmed infected (SUQC)] has previously been developed and applied to incorporate quarantine measures and calculate COVID-19 contagion dynamics and pandemic control in some Chinese regions. Here, we generalized this model to incorporate the disease recovery rate and applied our model to records of the total number of confirmed cases of people infected with the SARS-CoV-2 virus in some Chilean communes. In each commune, two consecutive stages were considered: a stage without quarantine and an immediately subsequent quarantine stage imposed by the Ministry of Health. To adjust the model, typical epidemiological parameters were determined, such as the confirmation rate and the quarantine rate. The latter allowed us to calculate the reproduction number. The mathematical model adequately reproduced the data, indicating a higher quarantine rate when quarantine was imposed by the health authority, with a corresponding decrease in the reproduction number of the virus down to values that prevent or decrease its exponential spread. In general, during this second stage, the communes with the lowest social priority indices had the highest quarantine rates, and therefore, the lowest effective viral reproduction numbers. This study provides useful evidence to address the health inequity of pandemics. The mathematical model applied here can be used in other regions or easily modified for other cases of infectious disease control by quarantine.
Waning of Vaccine-Conferred Protection against SARS-CoV-2 Infection: Matched Case-Control Test-Negative Design Study in Two High-Risk Populations
Authors: Goldhaber-Fiebert Jeremy D. , Prince Lea , Chin Elizabeth T. , Leidner David , Studdert David M. , Salomon Joshua A. , Andrews Jason R. 
Published: January 2022

AbstractTo distinguish waning of vaccine responses from differential variant protection, we performed a test-negative case-control analysis during a Delta variant-dominant period in California’s prisons. We found that infection odds increased each 28-day period post-vaccination, reaching 3.4-fold (residents) to 4.7-fold (staff) increased odds of infection after 180 days.
Population dynamics of epithelial-mesenchymal heterogeneity in cancer cells
Authors: Jain Paras , Bhatia Sugandha , Thompson Erik W , Jolly Mohit Kumar 
Published: January 2022

AbstractPhenotypic heterogeneity is a hallmark of aggressive cancer behaviour and a clinical challenge. Despite much characterisation of this heterogeneity at a multi-omics level in many cancers, we have a limited understanding of how this heterogeneity emerges spontaneously in an isogenic cell population. Some longitudinal observations of dynamics in epithelial-mesenchymal heterogeneity, a canonical example of phenotypic heterogeneity, have offered us opportunities to quantify the rates of phenotypic switching that may drive such heterogeneity. Here, we offer a mathematical modeling framework that explains the salient features of population dynamics noted in PMC42-LA cells: a) predominance of EpCAMhigh subpopulation, b) re-establishment of parental distributions from the EpCAMhigh and EpCAMlow subpopulations, and c) enhanced heterogeneity in clonal populations established from individual cells. Our framework proposes that fluctuations or noise in content duplication and partitioning of SNAIL – an EMT-inducing transcription factor – during cell division can explain spontaneous phenotypic switching and consequent dynamic heterogeneity in PMC42-LA cells observed experimentally at both single-cell and bulk level analysis. Together, we propose that asymmetric cell division can be a potential mechanism for phenotypic heterogeneity.
CRISPR-based targeted haplotype-resolved assemblies of a megabase region
Authors: Li Taotao , Du Duo , Zhang Dandan , Ma Jiakang , Zhou Mengyu , Meng Weida , Jin Zelin , Lin Yicheng , Chen Ziqiang , Yuan Haozhe , Wang Jue , Dong Shulong , Sun Shaoyang , Ye Wenjing , Li Boshen , Zhang Zhao , Xie Zhi , Qiu Wenqing , Liu Yun 
Published: January 2022

AbstractConstructing high-quality haplotype-resolved genome assemblies has substantially improved the ability to detect and characterize genetic variants. A targeted approach providing readily access to the rich information from haplotype-resolved genome assemblies will be appealing to groups of basic researchers and medical scientists focused on specific genomic regions. Here, using the 4.5 megabase, notoriously difficult-to-assemble major histocompatibility complex (MHC) region as an example, we demonstrated an approach to construct haplotype-resolved de novo assemblies of targeted genomic regions with the CRISPR-based enrichment. Compared to the results from haplotype-resolved genome assemblies, our targeted approach achieved comparable completeness and accuracy with greatly reduced computing complexity, sequencing cost, as well as the amount of starting materials. Moreover, using the targeted assembled personal haplotypes as the reference both improves the quantification accuracy for sequencing data and enables allele-specific functional genomics analyses. Given its highly efficient use of resources, our approach can greatly facilitate population genetic studies of targeted regions, and may pave a new way to elucidate the molecular mechanisms in disease etiology.
Ethylene augments root hypoxia tolerance through amelioration of reactive oxygen species and growth cessation
Authors: Liu Zeguang , Hartman Sjon , van Veen Hans , Zhang Hongtao , Leeggangers Hendrika A.C.F. , Martopawiro Shanice , Bosman Femke , de Deugd Florian , Su Peng , Hummel Maureen , Rankenberg Tom , Hassall Kirsty L. , Bailey-Serres Julia , Theodoulou Frederica L. , Voesenek Laurentius A.C.J. , Sasidharan Rashmi 
Published: January 2022

AbstractFlooded plants experience impaired gas diffusion underwater, leading to oxygen deprivation (hypoxia). The volatile plant hormone ethylene is rapidly trapped in submerged plant cells and is instrumental for enhanced hypoxia acclimation. However, the precise mechanisms underpinning ethylene-enhanced hypoxia survival remain unclear. We studied the effect of ethylene pre-treatment on hypoxia survival of primaryArabidopsis thalianaroot tips. Both hypoxia itself and re-oxygenation following hypoxia are highly damaging to root tip cells and ethylene pre-treatments reduced this damage. Ethylene pre-treatment alone altered the abundance of transcripts and proteins involved in hypoxia responses, root growth, translation and reactive oxygen species (ROS) homeostasis. Through imaging and manipulating ROS abundancein planta, we demonstrate that ethylene limits excessive ROS formation during hypoxia and subsequent re-oxygenation and improves oxidative stress survival. In addition, we show that ethylene leads to rapid root growth cessation and this quiescence behaviour contributes to enhanced hypoxia tolerance. Collectively, our results show that the early flooding signal ethylene modulates a variety of processes that all contribute to hypoxia survival.
Functional gradients in the human lateral prefrontal cortex revealed by a comprehensive coordinate-based meta-analysis
Authors: Abdallah Majd , Zanitti Gaston , Iovene Valentin , Wassermann Demian 
Published: January 2022

AbstractThe human lateral prefrontal cortex (LPFC) enables flexible goal-directed behavior. Yet, its organizing principles remain actively debated despite decades of research. Meta-analysis efforts to map the LPFC have either been restricted in scope or suffered from limited expressivity in meta-analysis tools. The latter short-coming hinders the complexity of questions that can be expressed in a meta-analysis and hence limits the specificity of structure-function associations. Here, we adopt NeuroLang, a novel approach to meta-analysis based on first-order probabilistic logic programming, to infer the organizing principles of the LPFC with greater specificity from 14,371 neuroimaging publications. Our results reveal a rostrocaudal and a dorsoventral gradient, respectively explaining the most and second-most variance in whole-brain meta-analytic connectivity in the LPFC. Moreover, we find a cross-study agreement on a spectrum of increasing abstraction from caudal to rostral LPFC both in specific network connectivity and structure-function associations that supports a domain-general role for the mid-LPFC. Furthermore, meta-analyzing inter-hemispheric asymmetries along the rostrocaudal gradient reveals specific associations with topics of language, memory, response inhibition, and error processing. Overall, we provide a comprehensive mapping of the organizing principles of task-dependent activity in the LPFC, grounding future hypothesis generation on a quantitative overview of past findings.
SHARPIN serine 146 phosphorylation mediates ARP2/3 interaction, cancer cell invasion and metastasis
Authors: Butt Umar , Khan Meraj H , Pouwels Jeroen , Westermarck Jukka 
Published: January 2022

AbstractThe adaptor protein SHARPIN is involved in a number of cellular processes and promotes cancer progression and metastasis. However, how the choice between different functions of SHARPIN is post-translationally regulated is unclear. Here we have characterized SHARPIN phosphorylation by mass spectrometry and in vitro kinase assay. Focusing on two uncharacterized phosphorylation sites, serine 131 and 146, in the unstructured linker region of SHARPIN, we demonstrate their role in SHARPIN-ARP2/3 complex interaction, whereas they play no role in integrin inhibition or LUBAC activation. Consistent with its novel role in ARP2/3 regulation, serine 146 (S146) phosphorylation of SHARPIN promoted lamellopodia formation. Notably, CRISPR-Cas9 mediated knockout of SHARPIN abrogated three-dimensional (3D) invasion of several cancer cell lines. The 3D invasion of cancer cells was rescued by overexpression of the wild-type SHARPIN, but not by SHARPIN S146A mutant, identifying S146 as an invasion promoting phosphorylation switch. Finally, we demonstrate that inhibition of phosphorylation at S146 significantly reduces the in vivo metastasis in the zebrafish model. Collectively, these results demonstrate that SHARPIN S146 phosphorylation constitutes a single functional determinant of cancer cell invasion both in vitro and in vivo.
Amphibian mucus triggers a developmental transition in the frog-killing chytrid fungus
Authors: Robinson Kristyn A , Prostak Sarah M , Campbell Grant Evan H , Fritz-Laylin Lillian K 
Published: January 2022

AbstractThe frog-killing fungusBatrachochytrium dendrobatidis(Bd) grows within the mucus-coated skin of amphibians. Each lifecycle,Bdtransitions from its motile, dispersal form to its sessile growth form in a complex process called encystation. Although encystation is critical toBdgrowth, whether and how this developmental transition is triggered by external signals was previously unknown. We discovered that exposure to amphibian mucus triggers rapid and reproducible encystation within minutes. This response can be recapitulated with purified mucin, the bulk component of mucus, but not by similarly-viscous methylcellulose or simple sugars. Mucin-induced encystation does not require gene expression, but does require surface adhesion, calcium signaling, and modulation of the actin cytoskeleton. Mucus-induced encystation may represent a key mechanism for synchronizingBddevelopment with arrival at the host.
Probabilistic Edge Weights fine-tune Boolean network dynamics
Authors: Deritei Dávid , Kunšič Nina , Csermely Péter 
Published: January 2022

AbstractBiological systems are noisy by nature. This aspect is reflected in our experimental measurements and should be reflected in the models we build to better understand these systems. Noise can be especially consequential when trying to interpret specific regulatory interactions, i.e. regulatory network edges. In this paper, we propose a method to explicitly encode edge-noise in Boolean dynamical systems by probabilistic edge-weight (PEW) operators. PEW operators have two important features: first, they introduce a form of edge-weight into Boolean models through the noise, second, the noise is dependent on the dynamical state of the system, which enables more biologically meaningful modeling choices. Moreover, we offer a simple-to-use implementation in the already well-established BooleanNet framework. In two application cases, we show how the introduction of just a few PEW operators in Boolean models can fine-tune the emergent dynamics and increase the accuracy of qualitative predictions. This includes fine-tuning interactions which cause non-biological behaviors when switching between asynchronous and synchronous update schemes in dynamical simulations. Moreover, PEW operators also open the way to encode more exotic cellular dynamics, such as cellular learning, and to implementing edge-weights for regulatory networks inferred from omics data.