bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variation in National COVID-19 Mortality Rates Across Asian Subgroups in the United States, 2020
Authors: Xu Jay J. 
Published: April 2022

AbstractProvisional U.S. national COVID-19 mortality data for the year 2020 analyzed by the CDC in March 2021 indicated that non-Hispanic Asians fared markedly better overall than other racial/ethnic minority groups–and marginally better than non-Hispanic Whites–in terms of age-adjusted mortality rates. However, Asians in the United States are composed of diverse array of origin subgroups with highly varying social, economic, and environmental experiences, which influence health outcomes. As such, lumping all Asians together into a single category can mask meaningful health disparities among more vulnerable Asian subgroups. To date, there has not been a national-level analysis of COVID-19 mortality outcomes between Asian subgroups. Utilizing final multiple cause of death data for 2020 and population projections from the U.S. Census Bureau’s Current Population Survey Annual Social and Economic Supplement for 2020, crude and age-adjusted national COVID-19 mortality rates, both overall and stratified by sex, were calculated for the six major single-race Asian origin subgroups (Asian Indian, Chinese, Filipino, Japanese, Korean, and Vietnamese) and a catch-all seventh category that comprises the remaining Asian subgroups (Other Asians), contrasting them to the corresponding mortality rates of other racial/ethnic groups. A substantially more nuanced picture emerges when disaggregating Asians into its diverse origin subgroups and stratifying by sex, with Filipino males and Asian males outside of the six major Asian subgroups in particular experiencing markedly higher age-adjusted mortality rates than their White male counterparts, whether comparisons were restricted to their non-Hispanic subsets or not. During the COVID-19 pandemic and in the post-pandemic recovery, it is imperative not to overlook the health needs of vulnerable Asian populations. Public health strategies to mitigate the effects of COVID-19 must avoid viewing Asians as a monolithic entity and recognize the heterogeneous risk profiles within the U.S. Asian population.
Chronotype and mortality - a 37-year follow-up study in Finnish adults
Authors: Hublin Christer , Kaprio Jaakko 
Published: April 2022

AbstractBackgroundThe only study on chronotype and mortality suggested small increases of all-cause and cardiovascular mortality in a 6.5-year follow-up. Our aim was to constructively replicate findings from it in a longer follow-up.MethodsA questionnaire was administered to the population-based Finnish Twin Cohort in 1981 (response rate 84%, age 24–101 years). The study population included 23,854 participants who replied to the question: “Try to assess to what extent you are a morning person or an evening person”, with four response alternatives (clearly a morning person, to some extent a morning person, to some extent an evening person, and clearly an evening person). Vital status and cause of death data were provided by nationwide registers up to the end of 2018. Hazard ratios and their 95% confidence intervals for mortality were computed; there were 8728 deaths over the follow-up period. Adjustments were made for education, alcohol, smoking, body mass index, and sleep length.ResultsThe model adjusted for all covariates showed a 9% increase in risk of all-cause mortality for the evening-type group (1.09, 1.01–1.18), with attenuation mainly due to smoking and alcohol, as they had larger consumption than those with morningness chronotypes. We observed no increase in cardiovascular mortality by chronotype. No increase in mortality was seen among the non-smokers who were at most light drinkers.ConclusionsOur results from this 37-year follow-up study suggest that there is little or no independent contribution of chronotype to all-cause and cardiovascular mortality.Key messagesThere is little or no independent contribution of chronotype to mortality.The increased risk of mortality associated with eveningness appears to be mainly mediated by a larger consumption of tobacco and alcohol than in those with a morningness chronotype.It is important to be aware of the increased health risks of evening-type persons.
Multi-task deep autoencoder to predict Alzheimer’s disease progression using temporal DNA methylation data in peripheral blood
Authors: Chen Li 
Published: April 2022

AbstractMotivationTraditional approaches for diagnosing Alzheimer’s disease (AD) such as brain imaging and cerebrospinal fluid are invasive and expensive. It is desirable to develop a useful diagnostic tool by exploiting biomarkers obtained from peripheral tissues due to their noninvasive and easily accessible characteristics. However, the capacity of using DNA methylation data in peripheral blood for predicting AD progression is rarely known. It is also challenging to develop an efficient prediction model considering the complex and high-dimensional DNA methylation data in a longitudinal study.ResultsWe develop two multi-task deep autoencoders, which are based on convolutional autoencoder and long short-term memory autoencoder to learn the compressed feature representations by jointly minimizing the reconstruction error and maximizing the prediction accuracy. By benchmarking on longitudinal methylation data collected from peripheral blood in Alzheimer’s Disease Neuroimaging Initiative, we demonstrate that the multi-task deep autoencoders outperform state-of-the-art machine learning approaches for both predicting AD progression and reconstructing the temporal methylation profiles. In addition, the proposed multi-task deep autoencoders can predict AD progression accurately using only historical data and the performance is further improved by including all temporal data.Availabilityhttps://github.com/lichen-lab/MTAE
Active emulsions in living cell membranes driven by contractile stresses and transbilayer coupling
Authors: Saha Suvrajit , Das Amit , Patra Chandrima , Anilkumar Anupama Ambika , Sil Parijat , Mayor Satyajit , Rao Madan 
Published: April 2022

AbstractThe spatiotemporal organisation of proteins and lipids on the cell surface has direct functional consequences for signaling, sorting and endocytosis. Earlier studies have shown that multiple types of membrane proteins including transmembrane proteins that have cytoplasmic actin binding capacity and lipid-tethered GPI-anchored proteins (GPI-APs) form nanoscale clusters driven by active contractile flows generated by the actin cortex. To gain insight into the role of lipids in organizing membrane domains in living cells, we study the molecular interactions that promote the actively generated nanoclusters of GPI-APs and transmembrane proteins. This motivates a theoretical description, wherein a combination of active contractile stresses and transbilayer coupling drive the creation of active emulsions, mesoscale liquid ordered (lo) domains of the GPI-APs and lipids, at temperatures greater than equilibrium lipid-phase segregation. To test these ideas we use spatial imaging of homo-FRET combined with local membrane order and demonstrate that mesoscopic domains enriched in nanoclusters of GPI-APs are maintained by cortical actin activity and transbilayer interactions, and exhibit significant lipid order, consistent with predictions of the active composite model.
Vimentin Intermediate Filaments Can Enhance or Abate Active Cellular Forces in a Microenvironmental Stiffness-Dependent Manner
Authors: Alisafaei Farid , Mandal Kalpana , Swoger Maxx , Yang Haiqian , Guo Ming , Janmey Paul A , Patteson Alison E , Shenoy Vivek B. 
Published: April 2022

AbstractThe mechanical properties of cells are largely determined by the cytoskeleton, which is a complex network of interconnected biopolymers consisting of actin filaments, microtubules, and intermediate filaments. While disruption of the actin filament and microtubule networks is known to decrease and increase cell-generated forces, respectively, the effect of intermediate filaments on cellular forces is not well understood. Using a combination of theoretical modeling and experiments, we show that disruption of vimentin intermediate filaments can either increase or decrease cell-generated forces, depending on microenvironment stiffness, reconciling seemingly opposite results in the literature. On the one hand, vimentin is involved in the transmission of actomyosin-based tensile forces to the matrix and therefore enhances traction forces. On the other hand, vimentin reinforces microtubules and their stability under compression, thus promoting the role of microtubules in suppressing cellular traction forces. We show that the competition between these two opposing effects of vimentin is regulated by the microenvironment stiffness. For low matrix stiffness, the force-transmitting role of vimentin dominates over their microtubule-reinforcing role and therefore vimentin increases traction forces. At high matrix stiffness, vimentin decreases traction forces as the microtubule-reinforcing role of vimentin becomes more important with increasing matrix stiffness. Our theory reconciles seemingly disparate experimental observations on the role of vimentin in active cellular forces and provides a unified description of stiffness-dependent chemo-mechanical regulation of cell contractility by vimentin.SignificanceVimentin is a marker of the epithelial to mesenchymal transition which takes place during important biological processes including embryogenesis, metastasis, tumorigenesis, fibrosis, and wound healing. While the roles of the actin and microtubule networks in the transmission of cellular forces to the extracellular matrix are known, it is not clear how vimentin intermediate filaments impact cellular forces. Here, we show that vimentin impacts cellular forces in a matrix stiffness-dependent manner. Disruption of vimentin in cells on soft matrices reduces cellular forces, while it increases cellular forces in cells on stiff matrices. Given that cellular forces are central to both physiological and pathological processes, our study has broad implications for understanding the effect of vimentin on cellular forces in different microenvironments.
Thermal Effects on Neurons During Stimulation of the Brain
Authors: Kim Taeken , Kadji Herve , Whalen Andrew J. , Ashourvan Arian , Freeman Eugene , Fried Shelley I. , Tadigadapa Srinivas , Schiff Steven J. 
Published: April 2022

AbstractAll artificial stimulation of the brain deposits thermal energy in the brain. This occurs through either Joule heating of the conductors carrying current through electrodes and magnetic coils, or through dissipation of energy in the conductive brain. Similarly, temperature affects all biological processes and chemical reactions. Although electrical interaction with brain tissue is inseparable from thermal effects when electrodes are used, magnetic induction enables us to separate Joule heating from induction effects by contrasting AC and DC driving of magnetic coils using the same energy deposition within the conductors. Since mammalian cortical neurons have no known sensitivity to static magnetic fields, and if there is no evidence of effect on spike timing to oscillating magnetic fields, we can presume that the induced electrical currents within the brain are below the molecular shot noise where any interaction with tissue is purely thermal. In this study, we examined a range of frequencies produced from micromagnetic coils operating below the molecular shot noise threshold for electrical interaction with single neurons. We found that small temperature increases and decreases of 1°C caused consistent transient suppression and excitation of neurons during temperature change. Numerical modeling of the biophysics demonstrated that the Na-K pump, and to a lesser extent the Nernst potential, could account for these transient effects. Such effects are dependent upon compartmental ion fluxes, and the rate of temperature change. A new bifurcation is described in the model dynamics that accounts for the transient suppression and excitation; in addition, we note the remarkable similarity of this bifurcation’s rate dependency with other thermal rate-dependent tipping points in planetary warming dynamics. Furthermore, bifurcations in the steady state dynamics leading to stable firing suppression are described for slightly higher temperatures. These experimental and theoretical findings demonstrate that stimulation of the brain must take into account small thermal effects that are ubiquitously present in electrical and magnetic stimulation. More sophisticated models of electrical current interaction with neurons combined with thermal effects will be required in order to more accurately enable model-based control of neuronal circuitry.
A Low-Dose Triple Antibody Cocktail Against the Ectodomain of the Matrix Protein 2 of Influenza A Is A Universally Effective and Viral Escape Mutant Resistant Therapeutic Agent
Authors: Kim Teha , Bimler Lynn , Ronzulli Sydney L. , Song Amber Y. , Johnson Scott K. , Jones Cheryl A. , Tompkins S. Mark , Paust Silke 
Published: April 2022

ABSTRACTInfluenza, a negative sense single-strand RNA virus of the genus Orthomyxoviridae, causes respiratory illness in humans and animals and significant morbidity and mortality worldwide. While exposure to a specific influenza A strain causes homologous protection, two immune-dominant influenza A virus (IAV)-encoded epitopes - Hemagglutinin (HA) and Neuraminidase (NA) - undergo antigenic shift and drift, resulting in IAVs to which humans lack pre-existing immunity. Without a universal vaccine or therapeutic agent, influenza virus infections will significantly threaten human health. The extracellular domain of the Matrix protein 2-ion channel (M2e) is an ideal antigenic target for a universal influenza therapy: it is highly conserved across influenza A serotypes, has a low mutation rate, and is essential for viral entry and replication. However, less than 20% of humans generate M2e-specific antibodies in response to IAV exposure, thus lacking the benefits of M2e-MAb-mediated immunity. To therapeutically address this deficit, we generated several non-neutralizing M2e-specific monoclonal antibodies (M2e-MAbs) with strong universal IAV treatment potential. Using three MAbs that bind to M2e differentially and competitively, we developed a low-dose M2e-MAb triple cocktail as an effective universal prophylactic and therapeutic agent. We identified the low-dose M2e-MAb triple cocktail’s optimal antibody-clone combination, isotype, minimum effective dosage, and administration time points in mouse models challenged with human and zoonotic BSL-2 and BSL-3 IAV strains, demonstrating its universal potential. Using the IgG2a isotype, which had proven most effective, we established FcγRI, FcγRIII, and FcγRIV as required for M2e-MAb-mediated protection of IAV-challenged mice. Importantly, we established individual M2e-MAbs and the resulting triple cocktail as effective and viral escape mutant-resistant treatments in immunocompetent and immunodeficient mice. These unique qualities provide precedence for prioritizing our M2e-MAbs for therapeutic development.CONFLICT OF INTEREST STATEMENTSP serves on the scientific advisory board for Shoreline Biosciences, Qihan Biotechnology and is a Scientific Consultant for Qihan Biotechnology and the Genomics Institute of the Novartis Research Foundation. The remaining authors declare no competing interests.
Dietary αKG inhibits SARS CoV-2 infection and rescues inflamed lungs to restore normal O2saturation in animals
Authors: Agarwal Sakshi , Kaur Simrandeep , Asuru Tejeswara Rao , Joshi Garima , Shrimali Nishith M , Singh Anamika , Singh Oinam Ningthemmani , Srivastva Puneet , Shrivastava Tripti , Vrati Sudhanshu , Surjit Milan , Guchhait Prasenjit 
Published: April 2022

ABSTRACTOur recent works described the rescue effect of α-ketoglutarate (αKG, a metabolite of Krebs cycle) on thrombosis and inflammation in animals. αKG augments activity of prolyl hydroxylase 2 (PHD2), which in turn degrades proline residues of substrates like phosphorylated Akt (pAkt) and hypoxia inducible factor (HIF)α. Here we describe the inhibitory effect of octyl αKG on pAkt as well as on HIF1α/HIF2α, and in turn decreasing SARS CoV-2 replication in Vero E6 cells. αKG failed to inhibit the viral replication and Akt phosphorylation in PHD2-knockdown U937 cells transiently expressing ACE2. Contrastingly, triciribine (TCN, an Akt-inhibitor) inhibited viral replication alongside a downmodulation of pAkt in PHD2-KD cells. Dietary αKG significantly inhibited viral infection and rescued hamsters from thrombus formation and inflammation in lungs, the known causes of acute respiratory distress syndrome (ARDS) in COVID-19. αKG supplementation also reduced the apoptotic death of lung tissues in infected animals, alongside a downmodulation of pAkt and HIF2α. αKG supplementation neither affected IgG levels against SARS CoV-2 RBD protein nor altered the neutralization antibody response against SARS CoV-2. It did not interfere with the percentage of interferon-γ positive (IFNγ+) CD4+ and IFNγ+CD8+ T cells in infected animals. The extended work in balb/c mice transiently expressing ACE2 showed a similar effect of αKG in reducing accumulation of inflammatory immune cells and cytokines, including IL6, IL1β and TNFα, in lungs as well as in circulation of infected animals. Pro-thrombotic markers like platelet microparticles and platelet-leukocyte aggregates were reduced significantly in infected mice after αKG supplementation. Importantly, αKG supplementation restored the O2saturation (SpO2) in circulation of SARS CoV-2 infected hamsters and mice, suggesting a potential therapeutic role of this metabolite in COVID-19 treatment.
Perturbed actin cap and nuclear morphology in primary fibroblasts of Huntington’s disease patients as a new phenotypic marker for personalized drug evaluation
Authors: Gharaba Saja , Paz Omri , Feld Lea , Abashidze Anastasia , Weinrab Maydan , Wolfenson Haguy , Weil Miguel 
Published: April 2022

AbstractHuman primary skin fibroblast cells from patient’s skin biopsies were used previously as a model to study different neurodegenerative diseases, including Huntington’s Disease (HD). These cells are directly isolated from the patient’s tissue without any alteration in the genome, retaining in culture conditions their endogenous cellular characteristics and biochemical properties, as well as their cellular proliferation capacity for several passages. The aim of this study was to identify a distinctive cellular phenotype in primary skin fibroblasts from various HD patients, using image-based high content analysis, which could be used in the future for personalized drug screening treatment evaluation. We show that HD fibroblasts have a distinctive nuclear morphology associated with a nuclear actin cap deficiency, which in turn affects cell motility in a similar manner to primary skin fibroblasts from Hutchinson-Gilford progeria syndrome (HGPS) patients used as known actin cap deficient cells. Moreover, treatment of the HD cells with either Latrunculin B, used to disrupt actin cap formation, or the antioxidant agent Mitoquinone, used to improve mitochondrial activity, show opposite effects on actin cap associated morphological features and cell motility. The former exacerbates the HD phenotype while the latter improves it. Deep data analysis of the HD nuclear and actin cap features using custom developed image analysis algorithms allow strong cluster classification distinct from HGPS and healthy matching controls, supporting the finding of a novel HD cellular phenotypic marker that could be modulated by pharmacological agents in this patient-based disease model.
Harnessing cellular perception apparatus for smart metabolic reprogramming
Authors: Tan Chunlin , Tao Fei , Xu Ping 
Published: April 2022

AbstractMetabolic reprogramming (MRP) is a fundamental approach in synthetic biology that involves redirecting metabolic flux and remodeling metabolic networks. However, only few approaches have been made in effective metabolic operations, especially at global level of metabolic networks. Naturally existing cellular perception apparatuses (CPAs), such as histidine kinases (HKs), are considered to sit on sensitive nodes of the metabolic network, which can trigger natural MRP upon perceiving environmental fluctuations. We develop a plateform for global MRP by natural environmental stimulation based on the combinational interference of CPAs. The plateform consists of a CRISPRi-mediated dual-gene combinational knockdown (CDCK) strategy and survivorship-based metabolic interaction analysis (SMIA). A total of 35 histidine kinase (HK) genes and 24 glycine metabolism genes were selected as targets to determine effectiveness of our approach for fast-growing chassisVibrioFA2. Combined knockdown of several genes of HKs and glycine metabolism increased the glycine production. Other other hand, effects of CDCK on bacterial antibiotic resistance were assessed by targeting HKs. Many HKs were identified to be associated with antibiotic resistance inVibrioFA2, of which combinational knockdown of two HK genessasA_8and04288reduced the ampicillin resistance. This MRP strategy is powerful and cost-effective, and can be considered as a smart strategy capable of operating a broad range of metabolic networks in microorganisms.
Conformational Flexibility in Neutralization of SARS-CoV-2 by Naturally Elicited Anti-SARS-CoV-2 Antibodies
Authors: Li Ruofan , Mor Michael , Ma Bingting , Clark Alex E. , Alter Joel , Werbner Michal , Lee Jamie Casey , Leibel Sandra L. , Carlin Aaron F. , Dessau Moshe , Gal-Tanamy Meital , Croker Ben A. , Xiang Ye , Freund Natalia T. 
Published: April 2022

ABSTRACTAs new variants of SARS-CoV-2 continue to emerge, it is important to assess the neutralizing capabilities of naturally elicited antibodies against SARS-CoV-2. In the present study, we evaluated the activity of nine anti-SARS-CoV-2 monoclonal antibodies (mAbs), previously isolated from convalescent donors infected with the Wuhan-Hu-1 strain, against the SARS-CoV-2 variants of concern (VOC) Alpha, Beta, Gamma, Delta and Omicron. By testing an array of mutated spike receptor binding domain (RBD) proteins, cell-expressed spike proteins from VOCs, and neutralization of SARS-CoV-2 VOCs as pseudoviuses, or as the authentic viruses in culture, we show that mAbs directed against the ACE2 binding site (ACE2bs) are far more sensitive to viral evolution compared to anti-RBD non-ACE2bs mAbs, two of which kept their potency against all VOCs tested. At the second part of our study, we reveal the neutralization mechanisms at high molecular resolution of two anti-SARS-CoV-2 neutralizing mAbs by structural characterization. We solved the structures of the Delta-neutralizing ACE2bs mAb TAU-2303 with the SARS-CoV-2 spike trimer and RBD at 4.5 Å and 2.42 Å, respectively, revealing a similar mode of binding to that between the RBD and the ACE2 receptor. Furthermore, we provide five additional structures (at resolutions of 5.54 Å, 7.76 Å, 6.47 Å, 3.45 Å, and 7.32 Å) of a second antibody, non-ACE2bs mAb TAU-2212, complexed with the SARS-CoV-2 spike trimer. TAU-2212 binds an exclusively quaternary epitope, and exhibits a unique, flexible mode of neutralization that involves transitioning between five different conformations, with both arms of the antibody recruited for cross linking intra- and inter-spike RBD subunits. Our study provides new mechanistic insights about how antibodies neutralize SARS-CoV-2 and its emerging variants and provides insight about the likelihood of reinfections.