bluuebunny/crossref_metadata_2025_split huggingface dataset:
High dose dietary vitamin D allocates surplus calories to muscle and growth instead of fat via modulation of myostatin and leptin signaling
Authors: Long Caela , Tara Zahra , Casella Alex , Mark Julian , Roizen Jeffrey D. 
Published: May 2022

ABSTRACTObesity is the leading proportional cause for diabetes, heart disease and cancer. Obesity occurs because the body stores surplus calories as fat. Fat cells secrete a hormone, leptin, that modulates energy balance at the brain. Changes in fat mass are mirrored by changes in serum leptin. Increases in leptin cause the brain to decrease appetite and increase energy expenditure. However in obesity, leptin sensitivity is decreased which mutes leptin mediated changes in appetite and energy expenditure. We have limited understanding of what controls leptin production by fat or how sensitive the brain is to leptin. Muscle produces a hormone, myostatin, that plays an analogous role to the role that leptin plays in fat. Absent myostatin leads to increased muscle mass and strength. We also do not know what controls myostatin production or sensitivity. Although fat mass and muscle mass are closely linked, the interplay between leptin and myostatin remains unexplored. Vitamin D improves lean mass via what are thought to be primarily trophic effects at the muscle. Here we show that high dose dietary vitamin D preferentially allocates excess calories to muscle and growth instead of storage as fat by decreasing myostatin production and increasing leptin production and sensitivity. That is, high dose vitamin D improves organismal energy sensing. Obesity, aging and other chronic inflammatory diseases are associated with decreased muscle function and mass. Our work provides a physiologic framework for how high-dose vitamin D would be effective in these pathologies to increase allocation of calories to muscle instead of fat and reveals novel interplay between the myostatin and leptin signaling whereby myostatin conveys energy needs to modulate leptin effects on calorie allocation. Furthermore, our work reveals how physiologic seasonal variation in vitamin D may be important in controlling season-specific metabolism and calorie allocation to fat in winter and muscle in summer.
Spatially selective stimulation of the pig vagus nerve to modulate target effect versus side effect
Authors: Blanz Stephan L. , Musselman Eric D. , Settell Megan L. , Knudsen Bruce E. , Nicolai Evan N. , Trevathan James K. , Verner Ryan S. , Begnaud Jason , Suminski Aaron J. , Williams Justin C. , Shoffstall Andrew J. , Grill Warren M. , Pelot Nicole A. , Ludwig Kip A. 
Published: May 2022

AbstractElectrical stimulation of the cervical vagus nerve using implanted electrodes (VNS) is FDA-approved for the treatment of drug-resistant epilepsy, treatment-resistant depression, and most recently, chronic ischemic stroke rehabilitation. However, VNS is critically limited by the unwanted stimulation of nearby neck muscles – a result of non-specific stimulation activating motor nerve fibers within the vagus. Prior studies suggested that precise placement of small epineural electrodes can modify VNS therapeutic effects, such as cardiac responses. However, it remains unclear if placement can alter the balance between intended effect and limiting side effect.We used an FDA investigational device exemption approved six-contact epineural cuff to deliver VNS in pigs and quantified how epineural electrode location impacts on- and off-target VNS activation. Detailed post-mortem histology was conducted to understand how the underlying neuroanatomy impacts observed functional responses. Here we report the discovery and characterization of clear neuroanatomy-dependent differences in threshold and saturation for responses related to both effect (change in heart rate) and side effect (neck muscle contractions). The histological and electrophysiological data were used to develop and validate subject-specific computation models of VNS, creating a well-grounded quantitative framework to optimize electrode location-specific activation of nerve fibers governing intended effect versus unwanted side effect.
Sex-Related Differences in Eicosanoid Levels in Chronic Thromboembolic Pulmonary Hypertension
Authors: Alotaibi Mona , Fernandes Timothy , Tang Amber B. , Magalang Gino Alberto , Watrous Jeramie D. , Long Tao , Pretorius Victor , Madani Michael , Kim Nick H. , Jain Mohit , Cheng Susan 
Published: May 2022

ABSTRACTA sex paradox is seen in pulmonary arterial hypertension (PAH) whereby female sex is a risk factor for development of the disease but male sex is often associated with poorer outcomes. Although data are limited regarding the potential molecular mechanisms underlying sex-specific variations in PAH including its various subtypes, there is emerging evidence regarding the potential role of sex differences in pathways governing the balance between underlying inflammatory and vasoactive mechanisms. Chronic thromboembolic pulmonary hypertension (CTEPH) is a subtype of pulmonary hypertension that is classically characterized as a procoagulant state and yet also involving some degree of proinflammatory activity. Therefore, we sought to determine whether eicosanoid mediators, endogenous lipid signaling molecules that have been implicated in a range of inflammatory and vasoactive responses, vary by sex in patients with CTEPH. We studied 287 patients (43.5% female) with confirmed CTEPH from a single center and assayed plasma samples using liquid chromatography – mass spectrometry to profile 500 eicosanoid analytes. We found significant sex-specific variations in eicosanoid profiles after adjusting for age and BMI, with males demonstrating a predominance of inflammatory-pathway related eicosanoids. Sex-specific variation in eicosanoid pathway related mechanisms may underlie sexual dimorphism in CTEPH outcomes.
Device-measured physical activity, sedentary time, and sleep in patients with arrhythmogenic cardiomyopathy: descriptive values and stability over 30 measurement days
Authors: Ruiz-González David , Ramos-Maqueda Javier , Migueles Jairo H. , Antonio Vargas-Hitos José , Ruiz-Salas Amalio , Jiménez-Jáimez Juan , Soriano-Maldonado Alberto 
Published: May 2022

AbstractIntroductionRegular exercise and sports are contraindicated in arrhythmogenic cardiomyopathy (AC) patients, which might lead them to an unhealthy sedentary lifestyle. This study aimed to objectively describe the patterns of physical activity (PA), sedentary time (SED), and sleep in patients with AC, and to examine the reproducibility of accelerometer-derived measures over four consecutive weeks.MethodsA total of 71 (49.6 [SD=17.5] years) patients with AC wore a wrist-worn Axivity AX3 accelerometer for 30 consecutive days to monitor their physical activity, sedentary time, and sleep habits. The reproducibility of each metric across the 4 assessment weeks was assessed with the intraclass correlation coefficients (ICCs) derived from linear-mixed models adjusted for age, body mass index (BMI), and season.ResultsThe participants spent a median of 12.2 [IQR 2.1] h/d in SED, 6.4 [IQR 1.0] h/d sleeping, and 17.9 [IQR 24.5] min/d in moderate-to-vigorous physical activity (MVPA), and 59% of the participants did not reach the 150 min/d of MVPA recommended by the WHO for people living with chronic disease. No significant differences in PA were found by sex and age groups. Otherwise, patients aged ≥50 years (n= 33) spent 38.9 min/d (95% CI 5.8 to 72.2, p≤0.05) more in periods of ≥30 minutes of SED than those <50 years. Participants with obesity (n=10) accumulated 66.6 min/d (95% CI 5.2 to 128.1, p = <0.05) more SED in periods of ≥30 minutes and 22.8 min/d (95% CI 0.7 to 44.9, p≤0.05) less MVPA than those without obesity. The ICCs ranged from 0.67 for time in bed to 0.92 for light-intensity physical activity using a 7-day assessment period. However, the ICCs increased from 0.03 for LPA to 0.18 for time in bed when an assessment period of 14 days was chosen.ConclusionPatients with AC engage in large periods of SED, insufficient PA and sleep. Importantly, nearly 60% of the participants did not meet the minimum amount of PA recommended by the WHO for people living with chronic diseases and only 20% met the sleep recommendations. Device-measured PA and SED are stable across weeks, indicating that a 7-day assessment period might provide a reproducible measure of PA and SED and, to a lower extent, sleep.
SARS-CoV-2 diagnostic testing rates determine the sensitivity of genomic surveillance programs
Authors: Han Alvin X. , Toporowski Amy , Sacks Jilian A. , Perkins Mark D. , Briand Sylvie , van Kerkhove Maria , Hannay Emma , Carmona Sergio , Rodriguez Bill , Parker Edyth , Nichols Brooke E. , Russell Colin A. 
Published: May 2022

AbstractThe first step in SARS-CoV-2 genomic surveillance is testing to identify infected people. However, global testing rates are falling as we emerge from the acute health emergency and remain low in many low- and middle-income countries (LMICs) (mean = 27 tests/100,000 people/day). We simulated COVID-19 epidemics in a prototypical LMIC to investigate how testing rates, sampling strategies, and sequencing proportions jointly impact surveillance outcomes and showed that low testing rates and spatiotemporal biases delay time-to-detection of new variants by weeks-to-months and can lead to unreliable estimates of variant prevalence even when the proportion of samples sequenced is increased. Accordingly, investments in wider access to diagnostics to support testing rates of ∼100 tests/100,000 people/day could enable more timely detection of new variants and reliable estimates of variant prevalence. The performance of global SARS-CoV-2 genomic surveillance programs is fundamentally limited by access to diagnostic testing.
Parents’ intention to vaccinate their child for COVID-19: a cross-sectional survey (CoVAccS – wave 3)
Authors: Smith Louise E. , Sherman Susan M. , Sim Julius , Amlôt Richard , Cutts Megan , Dasch Hannah , Sevdalis Nick , Rubin G James 
Published: May 2022

AbstractObjectivesTo investigate UK parents’ vaccination intention at a time when COVID-19 vaccination was available to some children.Study designData reported are from the second wave of a prospective cohort study.MethodsOnline survey of 270 UK parents (conducted 4-15 October 2021). At this time, vaccination was available to 16- and 17-year-olds and had become available to 12- to 15- year-olds two weeks prior. We asked participants whose child had not yet been vaccinated how likely they were to vaccinate their child for COVID-19. Linear regression analyses were used to investigate factors associated with intention. Parents were also asked for their main reasons behind vaccination intention. Open-ended responses were analysed using content analysis.ResultsParental vaccination intention was mixed (likely: 39.3%, 95% CI 32.8%, 45.7%; uncertain: 33.9%, 27.7%, 40.2%; unlikely: 26.8%, 20.9%, 32.6%). Intention was associated with: parental COVID-19 vaccination status; greater perceived necessity and social norms regarding COVID-19 vaccination; greater COVID-19 threat appraisal; and lower vaccine safety and novelty concerns. In those who intended to vaccinate their child, the main reasons for doing so were to protect the child and others. In those who did not intend to vaccinate their child, the main reason was safety concerns.ConclusionsParent COVID-19 vaccination and psychological factors explained a large percentage of the variance in vaccination intention for one’s child. How fluctuating infection rates, more children being vaccinated, and the UK’s reliance on vaccination as a strategy to live with COVID-19 may impact parents’ intention to vaccinate their child requires further study.
Leveraging social network topology could improve the efficiency of SARS-CoV-2 epidemic control strategies in resource-limited contexts
Authors: Evans MV , Ramiadantsoa T , Kauffman K , Moody J , Nunn C , Rabezara JY , Raharimalala P , Randriamoria TM , Soarimalala V , Titcomb G , Garchitorena A , Roche B 
Published: May 2022

ABSTRACTTargeted surveillance allows public health authorities to implement testing and isolation strategies when diagnostic resources are limited. When transmission patterns are determined by social contact rates, the consideration of social network topologies in testing schemes is one avenue for targeted surveillance, specifically by prioritizing those individuals likely to contribute disproportionately to onward transmission. Yet, it remains unclear how to implement such surveillance and control when network data is unavailable, as is often the case in resource-limited settings. We evaluated the efficiency of a testing strategy that targeted individuals based on their degree centrality on a social network compared to a random testing strategy in the context of low testing capacity. We simulated SARS-CoV-2 dynamics on two contact networks from rural Madagascar and measured the epidemic duration, infection burden, and tests needed to end the epidemics. In addition, we examined the robustness of this approach when individuals’ true degree centralities were unknown and were instead estimated via readily-available socio-demographic variables (age, gender, marital status, educational attainment, and household size). Targeted testing reduced the infection burden by between 5 - 50% at low testing capacities, while requiring up to 28% fewer tests than random testing. Further, targeted tested remained more efficient when the true network topology was unknown and prioritization was based on socio-demographic characteristics, demonstrating the feasibility of this approach under realistic conditions. Incorporating social network topology into epidemic control strategies is an effective public health strategy for health systems suffering from low testing capacity and can be implemented via socio-demographic proxies when social networks are unknown.*French abstract available in Supplemental Materials
Comorbidities and sociodemographic factors on COVID-19 fatalities
Authors: Gerken Jacob , Zapata Demi , Kuivinen Daniel , Zapata Isain 
Published: May 2022

ABSTRACTIntroductionPrevious studies have evaluated comorbidities and sociodemographic factors individually or by type but not comprehensively. This study aims to analyze the influence of a wide variety of factors in a single study to better understand the big picture of their effects on case-fatalities.MethodsCounty-level comorbidities, social determinants of health such as income and race, measures of preventive healthcare, age, education level, average household size, population density, and political voting patterns were all evaluated on a national and regional basis. Analysis was performed through Generalized Additive Models and adjusted by CCVI.ResultsFactors associated with reducing COVID-19 case fatality rates were mostly sociodemographic factors such as age, education and income, and preventive health measures. Obesity, minimal leisurely activity, binge drinking, and higher rates of individuals taking high blood pressure medication were associated with increased case fatality rate in a county. Political leaning influences case case-fatality rates. Regional trends showed contrasting effects where larger household size was protective in the Midwest, yet harmful in Northeast. Notably, higher rates of respiratory comorbidities such as asthma and COPD diagnosis were associated with reduced case-fatality rates in the Northeast. Increased rates of CKD within counties were often the strongest predictor of increased case-fatality rates for several regions.ConclusionOur findings highlight the importance of considering the full context when evaluating contributing factors to case-fatality rates. The spectrum of factors identified in this study must be analyzed in the context of one another and not in isolation.
An apical protein, Pcr2, is required for persistent movement by the human parasiteToxoplasma gondii
Authors: Lopez Jonathan Munera , Tengganu Isadonna F. , Liu Jun , Murray John , Arias Padilla Luisa F. , Zhang Ying , Brown Peter T. , Florens Laurence , Hu Ke 
Published: May 2022

ABSTRACTThe phylum Apicomplexa includes thousands of species of unicellular parasites that cause a wide range of human and animal diseases such as malaria and toxoplasmosis. To infect, the parasite must first initiate active movement to disseminate through tissue and invade into a host cell, and then cease moving once inside. The parasite moves by gliding on a surface, propelled by an internal cortical actomyosin-based motility apparatus. One of the most effective invaders in Apicomplexa isToxoplasma gondii, which can infect any nucleated cell and any warm-blooded animal. During invasion, the parasite first makes contact with the host cell “head-on” with the apical complex, which features an elaborate cytoskeletal apparatus and associated structures. Here we report the identification and characterization of a new component of the apical complex,Preconoidalregion protein2(Pcr2). Pcr2 knockout parasites replicate normally, but they are severely diminished in their capacity for host tissue destruction due to significantly impaired invasion and egress, two vital steps in the lytic cycle. When stimulated for calcium-induced egress, Pcr2 knockout parasites become active, and secrete effectors to lyse the host cell. Calcium-induced secretion of the major adhesin, MIC2, also appears to be normal. However, the movement of the Pcr2 knockout parasite is spasmodic, which drastically compromises egress. In addition to faulty motility, the ability of the Pcr2 knockout parasite to assemble the moving junction is impaired. Both defects likely contribute to the poor efficiency of invasion. Interestingly, actomyosin activity, as indicated by the motion of mEmerald tagged actin chromobody, appears to be largely unperturbed by the loss of Pcr2, raising the possibility that Pcr2 may act downstream of or in parallel with the actomyosin machinery.
Measuring single-virus fusion kinetics using an assay for nucleic acid exposure
Authors: Villamil Giraldo Ana M. , Mannsverk Steinar , Kasson Peter M. 
Published: May 2022

AbstractThe kinetics by which individual enveloped viruses fuse with membranes provide an important window into viral entry mechanisms. We have developed a real-time assay using fluorescent probes for single-virus genome exposure than can report on stages of viral entry including or subsequent to fusion pore formation and prior to viral genome trafficking. Encapsulating such fluorescence probes in the lumen of target membranes permits specific detection of fusion events and exclusion of leakage without fusion. Using this assay, we show that influenza virus fuses with liposomes of different sizes with indistinguishable kinetics, suggesting that the starting curvature of such liposomes does not control the rate-limiting steps in influenza entry.
Metabolic, Fibrotic, and Splicing Pathways Are All Altered in Emery-Dreifuss Muscular Dystrophy Spectrum Patients to Differing Degrees
Authors: de las Heras Jose I. , Todorow Vanessa , Krečinić-Balić Lejla , Hintze Stefan , Czapiewski Rafal , Webb Shaun , Schoser Benedikt , Meinke Peter , Schirmer Eric C. 
Published: May 2022

AbstractEmery-Dreifuss muscular dystrophy (EDMD) is a genetically and clinically variable disorder. Previous attempts to use gene expression changes find its pathomechanism were unavailing, so we here engaged a functional pathway analysis. RNA-Seq was performed on cells from 10 patients diagnosed with an EDMD spectrum disease with different mutations in 7 genes. Upon comparing to controls, the pathway analysis revealed that multiple genes involved in fibrosis, metabolism, myogenic signaling, and splicing were affected in all patients. Splice variant analysis revealed alterations of muscle-specific variants for several important muscle genes. Deeper analysis of metabolic pathways revealed a reduction in glycolytic and oxidative metabolism and reduced numbers of mitochondria across a larger set of 14 EDMD patients and 7 controls. Intriguingly, the gene expression signatures segregated the patients into three subgroups whose distinctions could potentially relate to differences in clinical presentation. Finally, differential expression analysis of miRNAs changing in the patients similarly highlighted fibrosis, metabolism, and myogenic signaling pathways. This pathway approach revealed a clear EDMD signature that can both be used as the basis for establishing a biomarker panel specific to EDMD and direct further investigation into its pathomechanism. Furthermore, the segregation of specific gene changes into three distinct categories that appear to correlate with clinical presentation may be developed into prognostic biomarkers, though this will first require their testing in a wider set of patients with more clinical information.
Revealing druggable cryptic pockets in the Nsp-1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography
Authors: Borsatto Alberto , Akkad Obaeda , Galdadas Ioannis , Ma Shumeng , Damfo Shymaa , Haider Shozeb , Kozielski Frank , Estarellas Carolina , Gervasio Francesco Luigi 
Published: May 2022

AbstractNon-structural protein 1 (Nsp1) is a main pathogenicity factor of α- and β-coronaviruses. Nsp1 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suppresses the host gene expression by sterically blocking 40S host ribosomal subunits and promoting host mRNA degradation. This mechanism leads to the downregulation of the translation-mediated innate immune response in host cells, ultimately mediating the observed immune evasion capabilities of SARS-CoV-2. Here, by combining extensive Molecular Dynamics simulations, fragment screening and crystallography, we reveal druggable pockets in Nsp1. Structural and computational solvent mapping analyses indicate the partial crypticity of these newly discovered and druggable binding sites. The results of fragment-based screening via X-ray crystallography confirm the druggability of the major pocket of Nsp1. Finally, we show how the targeting of this pocket could disrupt the Nsp1-mRNA complex and open a novel avenue to design new inhibitors for other Nsp1s present in homologous β-coronaviruses.
The rise of sparser single-cell RNAseq datasets; consequences and opportunities
Authors: Bouland Gerard A. , Mahfouz Ahmed , Reinders Marcel J.T. 
Published: May 2022

AbstractThere is an exponential increase in the number of cells measured in single-cell RNA sequencing (scRNAseq) datasets. Concurrently, scRNA-seq datasets become increasingly sparser as more zero counts are measured for many genes. We discuss that with increasing sparsity the binarized representation of gene expression becomes as informative as count-based expression. We show that downstream analyses based on binarized gene expressions give similar results to analyses based on count-based expressions. Moreover, a binarized representation scales to 17-fold more cells that can be analyzed using the same amount of computational resources. Based on these observations, we recommend the development of specialized tools for bit-aware implementations for downstream analyses tasks, creating opportunities to get a more fine-grained resolution of biological heterogeneity.