bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating vaccine efficacy against transmission via effect on viral load
Authors: Kennedy-Shaffer Lee , Kahn Rebecca , Lipsitch Marc 
Published: May 2021

AbstractDetermining policies to end the SARS-CoV-2 pandemic will require an understanding of the efficacy and effectiveness (hereafter, efficacy) of vaccines. Beyond the efficacy against severe disease and symptomatic and asymptomatic infection, understanding vaccine efficacy against transmission will help model epidemic trajectory and determine appropriate control measures. Recent studies have proposed using random virologic testing in individual randomized controlled trials to improve estimation of vaccine efficacy against infection. We propose to further use the viral load measures from these tests to estimate efficacy against transmission. This estimation requires a model of the relationship between viral load and transmissibility and assumptions about the vaccine effect on transmission and the progress of the epidemic. We describe these key assumptions, potential violations of them, and solutions that can be implemented to mitigate these violations. Assessing these assumptions and implementing this random sampling, with viral load measures, will enable better estimation of the crucial measure of vaccine efficacy against transmission.
Derivation and external validation of a simple risk score to predict in-hospital mortality in patients hospitalized for COVID-19
Authors: Mann Charlotte Z. , Abshire Chelsea , Yost Monica , Kaatz Scott , Swaminathan Lakshmi , Flanders Scott A. , Prescott Hallie C. , Gagnon-Bartsch Johann A. 
Published: May 2021

AbstractBackgroundAs SARS-CoV-2 continues to spread, and hospitals are treating a large number of patients with COVID-19, easy-to-use risk models that predict hospital mortality can assist in clinical decision making and triage.ObjectiveAs SARS-CoV-2 continues to spread, easy-to-use risk models that predict hospital mortality can assist in clinical decision making and triage. We aimed to develop a risk score model for in-hospital mortality in patients hospitalized with COVID-19 that was robust across hospitals and used clinical factors that are readily available and measured standardly across hospitals.MethodsIn this observational study we developed a risk score model using data collected by trained abstractors for patients in 20 diverse hospitals across the state of Michigan (Mi-COVID19) who were discharged between March 5, 2020 and August 14, 2020. Patients who tested positive for SARS-CoV-2 during hospitalization or were discharged with an ICD-10 code for COVID-19 (U07.1) were included. We employed an iterative forward selection approach to consider the inclusion of 145 potential risk factors available at hospital presentation. Model performance was externally validated with patients from 19 hospitals in the Mi-COVID19 registry not used in model development. We shared the model in an easy-to-use online application that allows the user to predict in-hospital mortality risk for a patient if they have any subset of the variables in the final model.ResultsOur final model includes the patient’s age, first recorded respiratory rate, first recorded pulse oximetry, highest creatinine level on day of presentation, and hospital’s COVID-19 mortality rate. No other factors showed sufficient incremental model improvement to warrant inclusion. The AUC for the derivation and validation sets were .796 and .829 respectively.ConclusionsRisk of in-hospital mortality in COVID-19 patients can be reliably estimated using a few factors, which are standardly measured and available to physicians very early in a hospital encounter.
Quantifying the impact of UVC in reducing airborne pathogen transmission and improving energy efficiency for healthy buildings: Kahn-Mariita equivalent ventilation model
Authors: Kahn Kevin , Mariita Richard M. 
Published: May 2021

AbstractThere is growing evidence that viruses responsible for pandemics, such as MERS and SARS, are mainly spread through aerosols. Recommendations have been introduced to reduce the transmission risk of virulent airborne viral particles by increasing ventilation rates, expressed in air-changes-per-hour (ACH), effectively improving the dilution of airborne pathogens via mechanical ventilation. However, the infrastructural and operational costs associated with upgrades of Heating, Ventilation, and Air Conditioning (HVAC) systems make these solutions expensive. It is well documented that UVC disinfection can help lower exposure risks by inactivating viruses in shared enclosed spaces, and the performances of such solutions be translated into equivalent ventilation (equivalent ACH or eACH). Here, we present the first framework to extract the optimum UVC output requirements for a target eACH, and improve facilities ability to comply with ventilation guidelines at lower energy costs. The Kahn-Mariita (KM) model considers the air quality of a shared enclosed space over time by supplementing existing mechanical ventilation with localized UVC air treatment, whether in recirculating units or upper-air systems, and extracts the systems requirements based on end-user needs by incorporating variables such as room size, occupancy, existing ventilation, and target eACH. An example of a conference room shows that a UVC chamber with an air recirculation rate of 160m3/h increases the ventilation from ACH=3 to eACH=7.9 and reduce down-time from 46 minutes to <10 minutes with as little 1W of UVC output. A recirculation rate of 30m3/h however offers no noticeable benefits above 200mW, with a maximum reachable eACH=3.9 and down-time of approximately 31 minutes. The KM model is unique in that it allows for the first time to find the optimum UVC output needs to ensure air quality is maintained and transmission risk minimized, while increasing energy savings. Recent studies suggest mechanically increasing fresh air supply will more than double the energy costs of HVAC systems, while the use of UVC reduces energy demand as much as by 50%. The KM model approaches air quality and energy efficiency in a unified way by incorporating UVC as a supplement to existing ventilation to increase eACH, reduce down-time, and increase the closed space occupancy.
Unbiased and UMI-informed sequencing of cell-free miRNAs at single-nucleotide resolution
Authors: van Eijndhoven M.A.J. , Aparicio-Puerta E. , Gómez-Martín C. , Medina J.M. , Drees E.E.E. , Bradley E.J. , Bosch L. , Scheepbouwer C. , Hackenberg M. , Pegtel D.M. 
Published: May 2021

AbstractTerminal nucleotidyl transferases are enzymes that add non-templated nucleotides to RNA molecules. In the case of microRNAs, this process was shown to be functionally relevant for their maturation process and generation of isomiRs with non-canonical mRNA targets. Deconvolution of these posttranscriptional modifications is challenging in particular for extracellular miRNAs that are considered as a target for minimally-invasive diagnostics. Massively parallel RNA sequencing is the only method that can truthfully reveal isomiR diversity in biological samples and determine relative quantities. Improvements aside, current small RNA sequencing strategies remain imprecise. We developed IsoSeek that diverges from these methods by making use of randomized 5’- and 3’-adapters combined with a 10N unique molecular identifier (UMI). Using synthetic miRNA and isomiR spike-in sets and testing depletion and RNA competition strategies in 7 sequencing rounds of >100 samples, we rigorously optimized and validated the technical accuracy of the IsoSeek method. In genetically-altered HEK293, we characterized the terminal uridylase (TUT4/TUT7) dependent miRNA uridylome and discovered extensive uridylation of disease-associated miRNAs. Notably, 3’-uridylated isomiR profiles of plasma extracellular vesicles (EVs) rely on UMI-correction. Thus, IsoSeek advances our knowledge of cell-free miRNAs and supports development into non-invasive biomarkers.
Phonological and temporal regularities lead to differential ERP effects in self- and externally generated speech
Authors: Emmendorfer Alexandra K. , Bonte Milene , Jansma Bernadette M. , Kotz Sonja A. 
Published: May 2021

ABSTRACTSome theories of predictive processing propose reduced sensory and neural responses to anticipated events. Support comes from M/EEG studies, showing reduced auditory N1 and P2 responses to self-compared to externally generated events, or when stimulus properties are more predictable (e.g. prototypical). The current study examined the sensitivity of N1 and P2 responses to statistical regularities of speech. We employed a motor-to-auditory paradigm comparing ERP responses to externally and self-generated pseudowords, varying in phonotactic probability and syllable stress. We expected to see N1 and P2 suppression for self-generated stimuli, with greater suppression effect for more predictable features such as high phonotactic probability and first syllable stress in pseudowords. We observe an interaction between phonotactic probability and condition on the N1 amplitude, with an enhanced effect of phonotactic probability in processing self-generated stimuli. However, the directionality of this effect was reversed compared to what was expected, namely a larger N1 amplitude for high probability items, possibly indicating a perceptual bias toward the more predictable item. We further observed an effect of syllable stress on the P2 amplitude, with greater amplitudes in response to first syllable stress items. The current results suggest that phonotactic probability plays an important role in processing self-generated speech, supporting feedforward models involved in speech production.
Controlled bio-inspired self-organised criticality
Authors: olde Scheper Tjeerd V. 
Published: May 2021

AbstractThe control of extensive complex biological systems is considered to depend on feedback mechanisms. Reduced systems modelling has been effective to describe these mechanisms, but this approach does not sufficiently encompass the required complexity that is needed to understand how localised control in a biological system can provide global stable states. Self-Organised Criticality (SOC) is a characteristic property of locally interacting physical systems which readily emerges from changes to its dynamic state due to small nonlinear perturbations. Small changes in the local states, or in local interactions, can greatly affect the total system state of critical systems. It has long been conjectured that SOC is cardinal to biological systems that show similar critical dynamics and also may exhibit near power-law relations. Rate Control of Chaos (RCC) provides a suitable robust mechanism to generate SOC systems which operates at the edge of chaos. The bio-inspired RCC method requires only local instantaneous knowledge of some of the variables of the system, and is capable of adapting to local perturbations. Importantly, connected RCC controlled oscillators can maintain global multi-stable states, and domains with power-law relations may emerge. The network of oscillators deterministically stabilises into different orbits for different perturbations and the relation between the perturbation and amplitude can show exponential and power-law correlations. This is representative of a basic mechanism of protein production and control, that underlies complex processes such as homeostasis. Providing feedback from the global state, the total system dynamic behaviour can be boosted or reduced. Controlled SOC can provide much greater understanding of biological control mechanisms, that are based on distributed local producers, remote consumers of biological resources, with globally defined control.Author summaryUsing a nonlinear control method inspired by enzymatic control, which is capable of stabilising chaotic systems into periodic orbits or steady-states, it is shown that a controlled system can be created that is scale-free and in a critical state. This means that the system can easily move from one stable orbit to another using only a small local perturbation. Such a system is known as self-organised criticality, and is shown in this system to be deterministic. Using a known perturbation, it will result in a scale-free response of the system that can be in a power law relation. It has been conjectured that biosystems are in a self-organised critical state, and these models show that this is a suitable approach to allow local systems to control a global state, such as homeostatic control. The underlying principle is based on rate control of chaos, and can be used to understand how biosystems can use localised control to ensure stability at different dynamic scales without supervising mechanisms.
Dog10K_Boxer_Tasha_1.0: A long-read assembly of the dog reference genome
Authors: Jagannathan Vidhya , Hitte Christophe , Kidd Jeffrey M. , Masterson Patrick , Murphy Terence D. , Emery Sarah , Davis Brian , Buckley Reuben M. , Liu Yanhu , Zhang Xiangquan , Leeb Tosso , Zhang Ya-ping , Ostrander Elaine A. , Wang Guo-dong 
Published: May 2021

AbstractThe domestic dog has evolved to be an important biomedical model for studies regarding the genetic basis of disease, morphology and behavior. Genetic studies in the dog have relied on a draft reference genome of a purebred female boxer dog named “Tasha” initially published in 2005. Derived from a Sanger whole genome shotgun sequencing approach coupled with limited clone-based sequencing, the initial assembly and subsequent updates have served as the predominant resource for canine genetics for 15 years. While the initial assembly produced a good quality draft, as with all assemblies produced at the time it contained gaps, assembly errors and missing sequences, particularly in GC-rich regions, which are found at many promoters and in the first exons of protein coding genes. Here we present Dog10K_Boxer_Tasha_1.0, an improved chromosome-level highly contiguous genome assembly of Tasha created with long-read technologies, that increases sequence contiguity >100-fold, closes >23,000 gaps of the Canfam3.1 reference assembly and improves gene annotation by identifying >1200 new protein-coding transcripts. The assembly and annotation are available at NCBI under the accession GCF_000002285.5.
Fine-scale quantification of GC-biased gene conversion intensity in mammals
Authors: Galtier Nicolas 
Published: May 2021

AbstractGC-biased gene conversion (gBGC) is a molecular evolutionary force that favours GC over AT alleles irrespective of their fitness effect. Quantifying the variation in time and across genomes of its intensity is key to properly interpret patterns of molecular evolution. In particular, the existing literature is unclear regarding the relationship between gBGC strength and species effective population size,Ne. Here we analysed the nucleotide substitution pattern in coding sequences of closely related species of mammals, thus accessing a high resolution map of the intensity of gBGC. Our maximum likelihood approach shows that gBGC is pervasive, highly variable among species and genes, and of strength positively correlated withNein mammals. We estimate that gBGC explains up to 60% of the total amount of synonymous AT→GC substitutions. We show that the fine-scale analysis of gBGC-induced nucleotide substitutions has the potential to inform on various aspects of molecular evolution, such as the distribution of fitness effects of mutations and the dynamics of recombination hotspots.
Screening bioactive food compounds in honey bees suggests curcumin blocks alcohol-induced damage to longevity and DNA methylation
Authors: Rasmussen Erik M. K. , Seier Kristine L. , Pedersen Ingrid K. , Kreibich Claus , Amdam Gro V. , Münch Daniel , Dahl John Arne 
Published: May 2021

AbstractVarious bioactive food compounds may confer health and longevity benefits, possibly through altering or preserving the human epigenome. While bioactive food compounds are widely being marketed as ‘improving health and longevity’ by counteracting harmful effects of poor nutrition and lifestyle, claimed effects are often not adequately documented. Using the honey bee (Apis mellifera) as a model species, we here employed a multi-step screening approach to investigate seven compounds for effects on lifespan and DNA methylation using ELISA and whole genome bisulfite sequencing (WGBS). A positive longevity effect was detected for valproic acid, isovaleric acid, and cyanocobalamin. For curcumin, we found that lifespan shortening caused by ethanol intake, was restored when curcumin and ethanol were co-administered. Furthermore, we identified region specific DNA methylation changes as a result of ethanol intake. Ethanol specific changes in DNA methylation were fully or partially blocked in honey bees receiving ethanol and curcumin together. Ethanol-affected and curcumin-blocked differentially methylated regions covered genes involved in fertility, temperature regulation and tubulin transport. Our results demonstrate fundamental negative effects of low dose ethanol consumption on lifespan and associated DNA methylation changes and present a proof-of-principle on how longevity and DNA methylation changes can be negated by the bioactive food component curcumin. Our findings provide a fundament for further studies of curcumin in mice and humans and offer an avenue to explore regarding possible prevention of health issues related to alcohol consumption.
The ICP22 protein of Herpes Simplex Virus 1 promotes RNA Polymerase II activity on Viral Immediate Early Genes
Authors: Birkenheuer Claire H. , Baines Joel D. 
Published: May 2021

AbstractTo determine the role of herpes simplex virus (HSV-1) ICP22 in viral transcription we performed precise nuclear run-on followed by deep sequencing (PRO-Seq) to map active RNA polymerase II (Pol II) on viral and cellular genomes in cells infected with a viral mutant lacking the entire ICP22-encoding α22 (US1/US1.5) gene, or a virus derived from the deletion mutant but bearing a restored α22 gene. At 3 hours post infection (hpi), the lack of ICP22 reduced Pol II activity at promoter proximal pause (PPP) sites on the α4 and α0 genes, and on the bodies of the α4, α0, and α27 genes. The decreased activity at α0 and α4 PPP sites at 3 hpi was distinguishable from effects caused by treatment with a viral DNA polymerase inhibitor. The ICP22 mutant had multiple defects at 6 hpi, including lower viral DNA replication and reduced Pol II activity on viral genes of all temporal classes. Between 3 and 6 hpi the repair virus, like wild type HSV-1, redirected Pol II activity from cellular genes to viral genes. In the absence of ICP22, the opposite occurred inasmuch as Pol II activity returned from the viral genome to cellular genes. These data indicate that ICP22 acts to increase Pol II activity at the PPP sites and bodies of viral immediate early genes at early times post infection, and directly or indirectly helps retain Pol II activity on the viral genome later in infection.ImportanceUsing a mutant lacking the full US1/US1.5 gene, this study establishes a role for ICP22 in increasing Pol II activity on viral immediate early genes by enhancing transcription initiation and/or elongation onto immediate early gene bodies. Unlike truncation mutants studied previously, the full null virus is unable to sustain DNA replication and Pol II activity on late genes, precluding later stages of the viral life cycle.
CREB regulates the expression of Type 1 Inositol 1,4,5-trisphosphate receptors
Authors: Arige Vikas , Terry Lara E. , Knebel Taylor R. , Wagner Larry E. , Yule David I. 
Published: May 2021

ABSTRACTInositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) play a central role in regulating intracellular calcium signals in response to a variety of internal/external cues. Dysregulation of IP3R signaling is the underlying cause for numerous pathological conditions. It is also well established that the activity of IP3Rs is governed by several post-translational modifications including phosphorylation by protein kinase A (PKA). However, the long-term effects of PKA activation on expression of IP3R sub-types, remains largely unexplored. In this report, we investigate the effect of chronic activation of PKA on expression of IP3R sub-types. We demonstrate that expression of IP3R1 is augmented upon prolonged activation of PKA or upon ectopic over-expression of CREB but does not alter IP3R2 and IP3R3 sub-type abundance. Conversely, inhibition of PKA or blocking endogenous CREB diminished IP3R1 expression. We also demonstrate that agonist-induced Ca2+-release mediated by IP3R1 is significantly attenuated upon blocking endogenous CREB. Moreover, CREB by regulating the expression of KRAS-induced actin-interacting protein (KRAP) ensures proper localization and licensing of IP3R1. Overall, we report a crucial role for CREB in governing both the expression and proper localization of IP3R1.Summary statementWe report a critical role of CREB in regulating the expression and proper localization of IP3R1. Agonist-induced Ca2+release and Ca2+puffs generated by IP3R1 are diminished upon blocking the function of endogenous CREB.
Thiolutin has complex effects in vivo but is a direct inhibitor of RNA Polymerase II in vitro
Authors: Qiu Chenxi , Arora Payal , Malik Indranil , Laperuta Amber J. , Pavlovic Emily M. , Ugochukwu Scott , Naik Mandar , Kaplan Craig 
Published: May 2021

AbstractThiolutin is a natural product transcription inhibitor with an unresolved mode of action. Thiolutin and the related dithiolopyrrolone holomycin chelate Zn2+and previous studies have concluded that RNA Polymerase II (Pol II) inhibitionin vivois indirect. Here, we present chemicogenetic and biochemical approaches to investigate thiolutin’s mode of action inSaccharomyces cerevisiae. We identify mutants that alter sensitivity to thiolutin. We provide genetic evidence that thiolutin causes oxidation of thioredoxinsin vivoand that thiolutin both induces oxidative stress and interacts functionally with multiple metals including Mn2+and Cu2+, and not just Zn2+. Finally, we show direct inhibition of RNA polymerase II (Pol II) transcription initiation by thiolutinin vitroin support of classical studies that thiolutin can directly inhibit transcriptionin vitro. Inhibition requires both Mn2+and appropriate reduction of thiolutin as excess DTT abrogates its effects. Pause prone, defective elongation can be observedin vitroif inhibition is bypassed. Thiolutin effects on Pol II occupancyin vivoare widespread but major effects are consistent with prior observations for Tor pathway inhibition and stress induction, suggesting that thiolutin usein vivoshould be restricted to studies on its modes of action and not as an experimental tool.