bluuebunny/crossref_metadata_2025_split huggingface dataset:
Voluntary alcohol consumption disrupts coupling of prefrontal cortical activity to arousal
Authors: Sipe Grayson , Linares-Garcia Ivan , Nguyen My , Vazey Elena , Huda Rafiq 
Published: February 2021

AbstractAlcohol use disorder (AUD) exacts a major personal, societal, and economic toll. Top-down control from the prefrontal cortex (PFC), a critical hub for decision making, executive, and other cognitive functions, is key for the regulation of alcohol consumption. Arousal exerts profound effects on cortical processing, allowing it to potentially modulate PFC functions relevant for alcohol consumption and AUD. Despite this, it is unclear whether and how arousal-mediated modulation of PFC circuits relates to voluntary alcohol drinking behaviors. Two-photon microscopy is ideally suited for dissecting the neural circuit mechanisms underlying the effect of alcohol on intact circuits in behaving animals. We addressed a major limitation of this technology by developing a novel behavioral paradigm for voluntary drinking in head-fixed mice. We recorded responses of layer 2/3 excitatory neurons in the anterior cingulate cortex (ACC) subdivision of the PFC as mice voluntarily consumed ethanol, along with video recording of the pupil to track momentary fluctuations in arousal. Ethanol consumption bidirectionally modified the activity of subsets of ACC neurons, both at slow (minutes) and fast (sub-second) time scales. Remarkably, we found that the coupling of arousal to ACC activity before drinking was associated with subsequent ethanol engagement behavior. In turn, ethanol consumption modulated neuronal-arousal coupling. Together, our results suggest neuronal-arousal coupling as a key biomarker for alcohol drinking and lays the groundwork for future studies to dissect the therapeutic potential of this process for AUD and other substance use disorders.
Rampant prophage movement among transient competitors drives rapid adaptation during infection
Authors: Marshall Christopher W. , Gloag Erin S. , Lim Christina , Wozniak Daniel J. , Cooper Vaughn S. 
Published: February 2021

AbstractInteractions between bacteria, their close competitors, and viral parasites are common in infections but understanding of these eco-evolutionary dynamics is limited. Most examples of adaptations caused by phage lysogeny are through the acquisition of new genes. However, integrated prophages can also insert into functional genes and impart a fitness benefit by disrupting their expression, a process called active lysogeny. Here, we show that active lysogeny can fuel rapid, parallel adaptations in establishing a chronic infection. These recombination events repeatedly disrupted genes encoding global regulators, leading to increased cyclic-di-GMP levels and elevated biofilm production. The implications of prophage-mediated adaptation are broad, as even transient members of microbial communities can alter the course of evolution and generate persistent phenotypes associated with poor clinical outcomes.One Sentence SummaryBacteriophage act as genetic regulators that are key to establishing chronic infections and are rapidly shared among co-infecting strains.
Sequence-specific minimizers via polar sets
Authors: Zheng Hongyu , Kingsford Carl , Marçais Guillaume 
Published: February 2021

AbstractMinimizers are efficient methods to samplek-mers from genomic sequences that unconditionally preserve sufficiently long matches between sequences. Well-established methods to construct efficient minimizers focus on sampling fewerk-mers on a random sequence and use universal hitting sets (sets ofk-mers that appear frequently enough) to upper bound the sketch size. In contrast, the problem of sequence-specific minimizers, which is to construct efficient minimizers to sample fewerk-mers on a specific sequence such as the reference genome, is less studied. Currently, the theoretical understanding of this problem is lacking, and existing methods do not specialize well to sketch specific sequences. We propose the concept of polar sets, complementary to the existing idea of universal hitting sets. Polar sets arek-mer sets that are spread out enough on the reference, and provably specialize well to specific sequences. Link energy measures how well spread out a polar set is, and with it, the sketch size can be bounded from above and below in a theoretically sound way. This allows for direct optimization of sketch size. We propose efficient heuristics to construct polar sets, and via experiments on the human reference genome, show their practical superiority in designing efficient sequence-specific minimizers. A reference implementation and code for analyses under an open-source license are athttps://github.com/kingsford-group/polarset.
Combining chemogenomic and gene-dose assays to investigate drug synergy
Authors: Gaikani Hamid , Smith Andrew M. , Lee Anna Y. , Giaever Guri , Nislow Corey 
Published: February 2021

AbstractFrom the earliest days of using natural remedies to modern applications of clinically tested medications, combining therapies for disease treatment has been standard practice. Combination treatments can exhibit synergistic effects, broadly defined as a greater-than-additive effect of two or more therapeutic agents. Indeed, clinicians often use their experience and expertise to tailor such combinations in the hopes of maximizing the therapeutic effect. Alongside these efforts, computational studies into understanding and predicting the biophysical underpinnings of how synergy is achieved have benefitted from high-throughput screening and computational biology. One challenge is how to best design and analyze the results of synergy studies performed at scale, especially because the number of possible combinations to test quickly becomes unmanageable, and the tools to analyze the resulting data are quite new. Nevertheless, the benefits of such studies are clear — by combining multiple drugs in the treatment of infectious disease and cancer, for instance, one can lessen host toxicity and simultaneously reduce the likelihood of resistance to treatment. In this study, we extend the widely validated chemogenomic HIPHOP assay to drug combinations. We identify a class of “combination-specific sensitive strains” that suggest mechanisms for the synergies we observe and further suggest focused follow-up studies.
Efficient CRISPR/Cas9 mutagenesis for neurobehavioral screening in adult zebrafish
Authors: Shaw Dana Klatt , Mokalled Mayssa H. 
Published: February 2021

ABSTRACTAdult zebrafish are increasingly used to interrogate mechanisms of disease development and tissue regeneration. Yet, the prospect of large-scale genetics in adult zebrafish has traditionally faced a host of biological and technical challenges. Here, we describe an experimental pipeline that combines high-efficiency CRISPR/Cas9 mutagenesis with functional phenotypic screening to identify genes required for spinal cord repair in adult zebrafish. Using CRISPR/Cas9 dual-guide ribonucleic proteins, we show selective and combinatorial mutagenesis of 17 genes at 28 target sites with efficiencies exceeding 85% in adult F0‘crispants’. We find that capillary electrophoresis is a reliable method to measure indel frequencies, while avoiding the limitations of restriction enzyme-based genotyping. Using a quantifiable behavioral assay, we identify 7 single- or duplicate-gene crispants with reduced functional recovery after spinal cord injury. To rule out off-target effects, we generate germline mutations that recapitulate the crispant regeneration phenotypes. This study provides a platform that combines high-efficiency somatic mutagenesis with a functional phenotypic readout to perform medium- to large-scale genetic studies in adult zebrafish.
A Thermostable, Flexible RNA Vaccine Delivery Platform for Pandemic Response
Authors: Gerhardt Alana , Voigt Emily , Archer Michelle , Reed Sierra , Larson Elise , Van Hoeven Neal , Kramer Ryan , Fox Christopher , Casper Corey 
Published: February 2021

AbstractCurrent RNA vaccines against SARS-CoV-2 are limited by instability of both the RNA and the lipid nanoparticle delivery system, requiring storage at −20°C or −70°C and compromising universally accessible vaccine distribution. This study demonstrates the thermostability and adaptability of a nanostructured lipid carrier (NLC) RNA vaccine delivery system for use in pandemic preparedness and pandemic response. Liquid NLC is stable at refrigerated temperatures for ≥ 1 year, enabling stockpiling and rapid deployment by point-of-care mixing with any vaccine RNA. Alternatively, NLC complexed with RNA may be readily lyophilized and stored at room temperature for ≥ 8 months or refrigerated temperature for ≥ 21 months. This thermostable RNA vaccine platform could significantly improve distribution of current and future pandemic response vaccines, particularly in low-resource settings.One Sentence SummaryAn RNA vaccine delivery system stable at room temperature for 8+ months and refrigerated for 21+ months.
A novel biomechanical injury risk score demonstrates correlation with lower limb posterior chain injury in fifty elite level rugby union athletes
Authors: Hughes Rhys , Cross Matt , Stokes Keith 
Published: February 2021

ABSTRACTObjectivesLower limb posterior chain injury (PCI) is common amongst athletic populations, with multi-factorial risk factors including age, previous injury, strength measurements, range of motion and training load. Biomechanics are commonly considered in the prevention and rehabilitation of PCI by performance staff. However, there is no documented testing method to assess for associations between biomechanics and PCI. The aim of this study was to investigate whether there is an association between an easily applicable, novel biomechanical assessment tool and PCI.MethodsFifty male elite-level rugby union athletes (age 22.83±5.08) participating in the highest tier of England were tested at the start of the 2019 pre-season period and PCIs (N=48) were recorded over the 2019/20 playing season. Participants’ biomechanics were analysed using two-dimensional video analysis against an Injury Risk Score (IRS) system in the performance of the combined movement – prone hip extension and knee flexion. Participants’ biomechanics in carrying out this movement were scored against the 10-point IRS, where the more compensatory movement recorded sees an increase in an individual’s IRS. Participants’ IRS were then compared against the number of PCI sustained and Spearman’s correlation coefficient was utilised for analysis.ResultsThere is a good significant association between IRS and PCI (R=0.573, p<0.001). Linear Regression demonstrated that an increase of 1 in IRS was associated with a 35% increase in PCI incidence (R2=0.346).ConclusionA good significance between the IRS and PCI provides preliminary support for its use as an injury risk assessment tool.
Muscle strength is associated with COVID-19 hospitalization in adults 50 years of age or older
Authors: Cheval Boris , Sieber Stefan , Maltagliati Silvio , P. Millet Grégoire , Formánek Tomáš , Chalabaev Aïna , Cullati Stéphane , Boisgontier Matthieu P. 
Published: February 2021

AbstractBackgroundWeak muscle strength has been associated with a wide range of adverse health outcomes. Yet, whether individuals with weaker muscle strength are more at risk for hospitalization due to severe COVID-19 is still unclear. The objective of this study was to investigate the independent association between muscle strength and COVID-19 hospitalization.MethodsData from adults 50 years of age or older were analyzed using logistic models adjusted for several chronic conditions, body-mass index, age, and sex. Hand-grip strength was repeatedly measured between 2004 and 2017 using a handheld dynamometer. COVID-19 hospitalization during the lockdown was self reported in summer 2020 and was used as an indicator of COVID-19 severity.ResultsThe study was based on the Survey of Health, Ageing and Retirement in Europe (SHARE) and included 3600 older adults (68.8 ± 8.8 years, 2044 females), amongst whom 316 were tested positive for the severe acute respiratory syndrome coronavirus 2 (8.8%) and 83 (2.3 %) were hospitalized due to COVID-19. Results showed that higher grip strength was associated with a lower risk of COVID-19 hospitalization (adjusted odds ratio [OR] per increase of 1 standard deviation in grip strength = .64, 95% confidence interval [95% CI] = .45–.87,p= .015). Results also showed that age (OR for a 10-year period = 1.70, 95% CI = 1.32–2.20,p< .001) and obesity (OR = 2.01, 95% CI = 1.00–3.69,p= .025) were associated with higher risk of COVID-19 hospitalization. Sensitivity analyses using different measurements of grip strength as well as robustness analyses based on rare-events logistic regression and a different sample of participants (i.e., COVID-19 patients) were consistent with the main results.ConclusionMuscle strength is an independent risk factor for COVID-19 severity in adults 50 years of age or older.
Elevated mucosal antibody responses against SARS-CoV-2 are correlated with lower viral load and faster decrease in systemic COVID-19 symptoms
Authors: Fröberg Janeri , Gillard Joshua , Philipsen Ria , Lanke Kjerstin , Rust Joyce , van Tuijl Diana , Bousema Teun , Simonetti Elles , van der Gaast – de Jongh Christa E. , Bos Mariska , van Kuppeveld Frank J. , Bosch Berend-Jan , Nabuurs-Franssen Marrigje , van der Geest-Blankert Nannet , van Daal Charlotte , Huynen Martijn A. , de Jonge Marien I. , Diavatopoulos Dimitri A. 
Published: February 2021

ABSTRACTMucosal antibodies play a key role in protection against SARS-CoV-2 exposure, but their role during primary infection is not well understood. We assessed mucosal antibody responses during primary infection with SARS-CoV-2 and examined their relationship with viral load and clinical symptoms. Elevated mucosal IgM was associated with lower viral load. RBD and viral spike protein-specific mucosal antibodies were correlated with decreases in systemic symptoms, while older age was associated with an increase in respiratory symptoms. Up to 42% of household contacts developed SARS-CoV-2-specific mucosal antibodies, including children, indicating high transmission rates within households in which children might play an important role.
Colchicine use in patients with COVID-19: a systematic review and meta-analysis
Authors: Chiu Leonard , Lo Chun-Han , Shen Max , Chiu Nicholas , Aggarwal Rahul , Lee Jihui , Choi Young-Geun , Lam Henry , Prsic Elizabeth Horn , Chow Ronald , Shin Hyun Joon 
Published: February 2021

ABSTRACTIntroductionColchicine may inhibit inflammasome signaling and reduce proinflammatory cytokines, a purported mechanism of COVID-19 pneumonia. The aim of this systematic review and meta-analysis is to report on the state of the current literature on the use of colchicine in COVID-19 and to investigate the reported clinical outcomes in COVID-19 patients by colchicine usage.MethodsThe literature was searched from January 2019 through January 28, 2021. References were screened to identify studies that reported the effect of colchicine usage on COVID-19 outcomes including mortality, intensive care unit (ICU) admissions, or mechanical ventilation. Studies were meta-analyzed for mortality by the subgroup of trial design (RCT vs observational) and ICU status. Studies reporting an risk ratio (RR), odds ratio (OR) and hazard ratio (HR) were analyzed separately.ResultsEight studies, reporting on 16,248 patients, were included in this review. The Recovery trial reported equivalent mortality between colchicine and non-colchicine users. Across the other studies, patients who received colchicine had a lower risk of mortality - HR of 0.25 (95% CI: 0.09, 0.66) and OR of 0.22 (95% CI: 0.09, 0.57). There was no statistical difference in risk of ICU admissions between patients with COVID-19 who received colchicine and those who did not – OR of 0.26 (95% CI: 0.06, 1.09).ConclusionColchicine may reduce the risk of mortality in individuals with COVID-19. Further prospective investigation may further determine the efficacy of colchicine as treatment in COVID-19 patients in various care settings of the disease, including post-hospitalization and long-term care.
Associations between total MRI-visible small vessel disease burden and domain-specific cognitive abilities in a community-dwelling older-age cohort
Authors: Hamilton OKL , Cox SR , Ballerini L , Bastin ME , Corley J , Gow AJ , Muñoz Maniega S , Redmond P , M del C Valdés-Hernández , Wardlaw JM , Deary IJ 
Published: February 2021

AbstractCerebral small vessel disease (SVD) is a leading cause of vascular cognitive impairment, however the precise nature of SVD-related cognitive deficits, and their associations with structural brain changes, remain unclear. We combined computational volumes and visually-rated MRI markers of SVD to quantify total SVD burden, using data from the Lothian Birth Cohort 1936 (n=540; age:72.6±0.7 years). We found negative associations between total SVD burden and general cognitive ability (standardised β: −0.363; 95%CI: [−0.49, −0.23]; p(FDR)<0.001), processing speed (−0.371 [−0.50, −0.24]; p(FDR)<0.001), verbal memory (−0.265; [−0.42, −0.11]; p(FDR)=0.002), and visuospatial ability (−0.170; [−0.32, −0.02]; p(FDR)=0.029). Only the association between SVD burden and processing speed remained after accounting for covariance with general cognitive ability (−0.325; [−0.61, −0.04]; p(FDR)=0.029). This suggests that SVD’s association with poorer processing speed is not driven by, but isindependentof its association with poorer general cognitive ability. Tests of processing speed may be particularly sensitive to the cognitive impact of SVD, but all major cognitive domains should be tested to determine the full range of SVD-related cognitive characteristics.
SEVERE COVID-19 IS MARKED BY DYSREGULATED SERUM LEVELS OF CARBOXYPEPTIDASE A3 AND SEROTONIN
Authors: Soria-Castro Rodolfo , Meneses-Preza Yatsiri G. , Rodríguez López Gloria M. , Romero-Ramírez Sandra , Sosa-Hernandez Víctor A. , Cervantes-Díaz Rodrigo , Pérez-Fragoso Alfredo , Torres-Ruíz José J. , Gómez-Martín Diana , Campillo-Navarro Marcia , Álvarez-Jiménez Violeta D. , Pérez-Tapia Sonia M. , Chávez-Blanco Alma D. , Estrada-Parra Sergio , Maravillas-Montero José L. , Chacón Salinas Rommel 
Published: February 2021

AbstractThe immune response plays a critical role in the pathophysiology of SARS-CoV-2 infection ranging from protection to tissue damage. This is observed in the development of acute respiratory distress syndrome when elevated levels of inflammatory cytokines are detected. Several cells of the immune response are implied in this dysregulated immune response including innate immune cells and T and B cell lymphocytes. Mast cells are abundant resident cells of the respiratory tract, able to rapidly release different inflammatory mediators following stimulation. Recently, mast cells have been associated with tissue damage during viral infections, but little is known about their role in SARS-CoV-2 infection. In this study we examined the profile of mast cell activation markers in the serum of COVID-19 patients. We noticed that SARS-CoV-2 infected patients showed increased carboxypeptidase A3 (CPA3), and decreased serotonin levels in their serum. CPA3 levels correlated with C-reactive protein, the number of circulating neutrophils and quick SOFA. CPA3 in serum was a good biomarker for identifying severe COVID-19 patients, while serotonin was a good predictor of SARS-CoV-2 infection. In summary, our results show that serum CPA3 and serotonin levels are relevant biomarkers during SARS-CoV-2 infection, suggesting that mast cells are relevant players in the inflammatory response in COVID-19, might represent targets for therapeutic intervention.
Quantifying meaningful usage of a SARS-CoV-2 exposure notification app on the campus of the University of Arizona
Authors: Masel Joanna , Shilen Alexandra , Helming Bruce , Rutschman Jenna , Windham Gary , Pogreba-Brown Kristen , Ernst Kacey 
Published: February 2021

AbstractObjectiveTo measure meaningful, local exposure notification usage without in-app analytics.MethodsWe surveyed app usage via case investigation interviews at the University of Arizona, with a focus on the period from September 9 to November 28, 2020, after automating the issuance of secure codes to verify positive test results. As independent validation, we compared the number of verification codes issued to the number of local cases.ResultsForty six percent (286/628) of infected persons interviewed by university case investigators reported having the app, and 55% (157/286) of these app users shared their positive SARS-CoV-2 test result in the app prior to the case investigation interview, comprising 25% (157/628) of those interviewed. This is corroborated by a 33% (565/1,713) ratio of code issuance (inflated by some unclaimed codes) to cases. Combining the 25% probability that those who test positive rapidly share their test result with a 46% probability that a person they infected can receive exposure notifications, an estimated 11.4% of transmission pairs exhibit meaningful app usage. High usage was achieved without the use of “push” notifications, in the context of a marketing campaign that leveraged social influencers.ConclusionsUsage can be assessed, without in-app analytics, within a defined local community such as a college campus rather than an entire jurisdiction. With marketing, high uptake in dense social networks like universities makes exposure notification an impactful complement to traditional contact tracing. Integrating verification code delivery into patient results portals was successful in making the exposure notification process rapid.3 question summary box1)What is the current understanding of this subject?The extent to which exposure notification technology reduces SARS-CoV-2 transmission depends on usage among infected persons.2)What does this report add to the literature?A novel metric estimates meaningful usage, and demonstrates potential transmission reduction on a college campus. Clear benefit was seen from simplifying verification of positive test results with automation.3)What are the implications for public health practice?Defined communities can benefit from local deployment and marketing even in the absence of statewide deployment. Lifting current restrictions on deployment would allow more entities such as campuses to copy the model shown here to be successful.
Spatial-proteomics revealin-vivophospho-signaling dynamics at subcellular resolution
Authors: Martinez-Val Ana , Bekker-Jensen Dorte B. , Steigerwald Sophia , Mehta Adi , Tran Trung , Sikorski Krzysztof , Torres-Vega Estefanía , Kwasniewicz Ewa , Brynjólfsdóttir Sólveig Hlín , Frankel Lisa B. , Kjøbsted Rasmus , Krogh Nicolai , Lundby Alicia , Bekker-Jensen Simon , Lund-Johansen Fridtjof , Olsen Jesper V. 
Published: February 2021

AbstractDynamic change in subcellular localization of signaling proteins is a general concept that eukaryotic cells evolved for eliciting a coordinated response to stimuli. Mass spectrometry (MS)-based proteomics in combination with subcellular fractionation can provide comprehensive maps of spatio-temporal regulation of cells, but involves laborious workflows that does not cover the phospho-proteome level. Here we present a high-throughput workflow based on sequential cell fractionation to profile the global proteome and phospho-proteome dynamics across six distinct subcellular fractions. We benchmarked the workflow by studying spatio-temporal EGFR phospho-signaling dynamics in-vitro in HeLa cells and in-vivo in mouse tissues. Finally, we investigated the spatio-temporal stress signaling, revealing cellular relocation of ribosomal proteins in response to hypertonicity and muscle contraction. Proteomics data generated in this study can be explored throughhttps://SpatialProteoDynamics.github.io.