bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spliceosomic dysregulation unveilsNOVA1as an actionable therapeutic target in pancreatic neuroendocrine tumors
Authors: Pedraza-Arevalo Sergio , Alors-Pérez Emilia , Blázquez-Encinas Ricardo , Herrera-Martínez Aura D. , Jiménez-Vacas Juan M. , Fuentes-Fayos Antonio C. , Reyes Óscar , Ventura Sebastián , Sánchez-Sánchez Rafael , Ortega-Salas Rosa , Serrano-Blanch Raquel , Gálvez-Moreno María A. , Gahete Manuel D. , Ibáñez-Costa Alejandro , Luque Raúl M. , Castaño Justo P. 
Published: February 2022

AbstractDysregulation of the splicing machinery is emerging as a hallmark in cancer due to its association with multiple dysfunctions in tumor cells. Inappropriate function of this machinery can generate tumor-driving splicing variants and trigger oncogenic actions. However, its role in pancreatic neuroendocrine tumors (PanNETs) is poorly defined. In this study we aimed to characterize the expression pattern of a set of splicing machinery components in PanNETs, and their relationship with aggressiveness features. A qPCR-based array was first deployed to determine the expression levels of components of the major (n=13) and minor spliceosome (n=4) and associated splicing factors (n=27), using a microfluidic technology in 20 PanNETs and non-tumoral adjacent samples. Subsequently,in vivoandin vitromodels were applied to explore the pathophysiological role ofNOVA1. Expression analysis revealed that a substantial proportion of splicing machinery components was altered in tumors. Notably, key splicing factors were overexpressed in PanNETs samples, wherein their levels correlated with clinical and malignancy features. Usingin vivoandin vitroassays, we demonstrate that one of those altered factors,NOVA1, is tightly related to cell proliferation, alters pivotal signaling pathways and interferes with responsiveness to drug treatment in PanNETs, suggesting a role for this factor in the aggressiveness of these tumors and its suitability as therapeutic target. Altogether, our results unveil a severe alteration of the splicing machinery in PanNETs and identify the putative relevance ofNOVA1in tumor development/progression, which could provide novel avenues to develop diagnostic biomarkers and therapeutic tools for this pathology.
Cell delivery peptides for small interfering RNAs targeting SARS-CoV-2 new variants through a bioinformatics and deep learning design
Authors: González Ricardo D. , Figueiredo Pedro R. , Carvalho Alexandra T. P. 
Published: February 2022

ABSTRACTNucleic acid technologies with designed delivery systems have surged as one the most promising therapies of the future, due to their contribution in combating SARS-CoV-2 severe disease. Nevertheless, the emergence of new variants of concern still represents a real threat in the years to come. It is here that the use of small interfering RNA sequences to inhibit gene expression and, thus, protein synthesis, may complement the already developed vaccines, with faster design and production. Here, we have designed new sequences targeting COVID-19 variants and other related viral diseases through bioinformatics, while also addressing the limited number of delivery peptides by a deep learning approach. Two sequences databases were produced, from which 62 were able to target the virus mRNA, and ten displayed properties present in delivery peptides, which we compared to the broad use TAT delivery peptide.
Predicting Epitope Candidates for SARS-CoV-2
Authors: Agarwal Akshay , Beck Kristen L. , Capponi Sara , Kunitomi Mark , Nayar Gowri , Seabolt Edward , Mahadeshwar Gandhar , Bianco Simone , Mukherjee Vandana , Kaufman James H. 
Published: February 2022

ABSTRACTEpitopes are short amino acid sequences that define the antigen signature to which an antibody binds. In light of the current pandemic, epitope analysis and prediction is paramount to improving serological testing and developing vaccines. In this paper, we leverage known epitope sequences from SARS-CoV, SARS-CoV-2 and other Coronaviridae and use those known epitopes to identify additional antigen regions in 62k SARS-CoV-2 genomes. Additionally, we present epitope distribution across SARS-CoV-2 genomes, locate the most commonly found epitopes, discuss where epitopes are located on proteins, and how epitopes can be grouped into classes. We also discuss the mutation density of different regions on proteins using a big data approach. We find that there are many conserved epitopes between SARS-CoV-2 and SARS-CoV, with more diverse sequences found in Nucleoprotein and Spike Glycoprotein.
A pair of isoleucyl-tRNA synthetases in Bacilli fulfill complementary roles to keep fast translation and provide antibiotic resistance
Authors: Zanki Vladimir , Bozic Bartol , Mocibob Marko , Ban Nenad , Gruic-Sovulj Ita 
Published: February 2022

AbstractIsoleucyl-tRNA synthetase (IleRS) is an essential enzyme that covalently couples isoleucine to the corresponding tRNA. Bacterial IleRSs group in two clades, ileS1 and ileS2, the latter bringing resistance to the natural antibiotic mupirocin. Generally, bacteria rely on either ileS1 or ileS2 as a standalone housekeeping gene. However, we have found an exception by noticing that Bacillus species with genomic ileS2 consistently also keep ileS1, which appears mandatory in the family Bacillaceae. Taking Priestia (Bacillus) megaterium as a model organism, we showed that PmIleRS1 is constitutively expressed, while PmIleRS2 is stress-induced. Both enzymes share the same level of the aminoacylation accuracy. Yet, PmIleRS1 exhibited a twofold faster aminoacylation turnover (kcat) than PmIleRS2 and permitted a notably faster cell-free translation. At the same time, PmIleRS2 displayed a 104-fold increase in its Ki for mupirocin, arguing that the aminoacylation turnover in IleRS2 could have been traded-off for antibiotic resistance. As expected, a P. megaterium strain deleted for ileS2 was mupirocin-sensitive. Interestingly, an attempt to construct a mupirocin-resistant strain lacking ileS1, a solution not found among species of the family Bacillaceae in nature, led to a viable but compromised strain. Our data suggests that PmIleRS1 is kept to promote fast translation, whereas PmIleRS2 is maintained to provide antibiotic resistance when needed. This is consistent with an emerging picture in which fast-growing organisms predominantly use IleRS1 for competitive survival.
Dual Inhibition of Cathepsin L and 3CL-Pro by GC-376 Constrains SARS Cov2 Infection Including Omicron Variant
Authors: Kumar Prabhakaran , Ratia Kiira M , Richner Justin M , Thatcher Gregory R J , Kadam Rashmi , Smieszek Sandra P , Przychodzen Bartlomiej P , Koprivica Vuk , Birznieks Gunther , Polymeropoulos Mihael H , Prabhakar Bellur S 
Published: February 2022

AbstractRecurrent waves of SARS CoV2 infections remain a major global health concern. Emergence of highly infectious variants with reduced sensitivity to neutralization by vaccines and monoclonal antibodies (mAb) necessitates a deeper understanding of factors involved in SARS CoV2 infections and identification of drug candidates to halt infection. Here, we determined the primacy of endosomal protease cathepsin-L in mediating SARS CoV2 entry and screened a library of well-annotated bioactive compounds for potent cathepsin-L inhibitory activity. Whilst the potent cathepsin-L inhibitors were capable of inhibiting SARS CoV2 entry and cytopathic effect (CPE) in less susceptible cell lines such as human ACE2 expressing 293T cells, these drugs failed to inhibit SARS CoV2 in highly susceptible cell lines such as human TMPRSS2 or human-ACE2-TMPRSS2 overexpressing Vero E6 cells. Only drugs with dual inhibitory effect on both host cathepsin-L and virus 3CL-Protease enzymes such as Z-FA-FMK and GC-376 were capable of inhibiting prototypic (USA-WA1/2020, Lineage A) SARS CoV2 induced CPE in highly susceptible cell lines. Moreover, these drugs inhibited delta (Lineage-B.1.617.2) and omicron (Lineage-B.1.1.529) infection with equal potency showing that the newer mutations harbored in these variants did not affect the mechanism of action of these drugs such as cathepsin-L or 3CL-Pro inhibition. Moreover, our early evidence that 3CL-Pro inhibition can effectively inhibit omicron-induced CPE in highly susceptible cell lines suggests that the recently FDA-approved oral drug, a 3CL-Pro inhibitor which is a combination of nirmatrelvir/ritonavir (Paxlovid) could be effective against omicron variant which shows reduced sensitivity to vaccines and mAb.ImportanceWe report that cathepsin-L and 3CL-Pro as major targets for designing antivirals against SARS CoV2. Dual inhibition of cathepsin-L and 3CL-Pro by GC-376 renders it effective in inhibiting SARS CoV2-induced cytopathic effect in highly susceptible cell lines. Moreover, this candidate drug is equally effective against prototypic SARS CoV2 lineage A and emerging variants such as delta and omicron which show reduced sensitivity to vaccines and monoclonal antibodies. Given the recent wave of SARS CoV2 omicron variant infection around the world, and 3CL-Pro inhibitor nirmatrelvir is one of the components of the FDA-approved Paxlovid, our findings are timely, important and should be of broad interest.
The rise and fall of SARS-CoV-2 variants and the emergence of competing Omicron lineages
Authors: Wiegand Tanner , McVey Aidan , Nemudraia Anna , Nemudryi Artem , Wiedenheft Blake 
Published: February 2022

AbstractIn late December of 2019, high throughput sequencing technologies enabled rapid identification of SARS-CoV-2 as the etiological agent of COVID-19, and global sequencing efforts are now a critical tool for monitoring the ongoing spread and evolution of this virus. Here, we analyze a subset (n=83,204) of all publicly available SARS-CoV-2 genomes (n=~5.6 million) that were randomly selected, but equally distributed over the course of the pandemic. We plot the emergence and extinction of new variants of concern (VOCs) over time and show how this corresponds to the ongoing accumulation of mutations in SARS-CoV-2 genomes and individual proteins. While the accumulation of mutations generally follows a linear regression, non-synonymous mutations are significantly greater in Omicron viruses than in previous variants–especially in the spike and nucleoproteins–and these differences are more pronounced in a recently identified sub-lineage (BA.2) of Omicron.ImportanceOmicron is the fifth SARS-CoV-2 variant to be designated a Variant of Concern (VOC) by the World Health Organization (WHO). Here we provide a retrospective analysis of SARS-CoV-2 variants and explain how the Omicron variant is distinct. Our work shows that the spike and nucleoproteins have accumulated the most mutations in Omicron variants, but that the accessory proteins of SARS-CoV-2 sequences are changing most rapidly relative to their size. Collectively, this “Observation” provides a concise overview of SARS-CoV-2 evolution, reveals mutational differences between two Omicron lineages, and highlights changes in the SARS-CoV-2 proteome that have been under reported.
The REinfection in COVID-19 Estimation of Risk (RECOVER) study: Reinfection and serology dynamics in a cohort of Canadian healthcare workers
Authors: Racine Étienne , Boivin Guy , Longtin Yves , McCormack Deirde , Decaluwe Hélène , Savard Patrice , Cheng Matthew P. , Hamelin Marie-Ève , Tadount Fazia , Adams Kelsey , Bourdin Benoîte , Nantel Sabryna , Gilca Vladimir , Corbeil Jacques , De Serres Gaston , Quach Caroline 
Published: February 2022

ABSTRACTBackgroundUnderstanding the immune response to natural infection by SARS-CoV-2 is key to pandemic management, especially in the current context of emerging variants. Uncertainty remains regarding the efficacy and duration of natural immunity against reinfection.MethodWe conducted an observational prospective cohort study in Canadian healthcare workers (HCWs) with a history of PCR-confirmed SARS-CoV-2 infection to : (i) measure the average incidence rate of reinfection and (ii), describe the serological immune response to the primary infection.ResultsWe detected 5 cases of reinfection over 14 months of follow-up, for a reinfection incidence rate of 3.3 per 100 person-years. Median duration of seropositivity was 420 days in symptomatics at primary infection compared to 213 days in asymptomatics (p<0.0001). Other variables associated with prolonged seropositivity for IgG against the spike protein included age 55 and above, obesity, and non-Caucasian ethnicity.SummaryAmong healthcare workers, the incidence of reinfection with SARS-CoV-2 following a primary infection remained rare, although our analysis predates the circulation of the Omicron variant.
A scoping review protocol onin vivohuman plastic exposure and health impacts
Authors: Goodes Louise M. , Wong Enoch V.S. , Alex Jennifer , Mofflin Louise , Toshniwal Priyanka , Brunner Manuel , Solomons Terena , White Emily , Choudhury Omrik , Seewoo Bhedita J. , Mulders Yannick R. , Dale Tristan , Newman Hamish J. , Naveed Alina , Lowe Andrew B. , Hendrie Delia V. , Symeonides Christos , Dunlop Sarah A. 
Published: February 2022

AbstractBackgroundGlobal plastic production has increased exponentially since the 1960s, with more than 6300 million metric tons of plastic waste generated to date. Studies have found a range of human health impacts associated with exposure to plastic chemicals. However, only a fraction of plastic chemicals used have been studiedin vivo, and then often in animals, for acute toxicological effects. With many questions still unanswered about how long-term exposure to plastic impacts human health, there is an urgent need to map humanin vivoresearch conducted to date, casting a broad net by searching terms for a comprehensive suite of plastic chemical exposures and the widest range of health domains.MethodsThis protocol describes a scoping review that will follow the recommended framework outlined in2017 Guidance for the Conduct of Joanna Briggs Institute (JBI) Scoping Reviews, to be reported in accordance withPreferred Reporting Items for Systematic ReviewsandMeta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. A literature search of primary clinical studies in English from 1960 onwards will be conducted in MEDLINE (Ovid) and EMBASE (Ovid) databases. References eligible for inclusion will be identified through a quality-controlled, multi-level screening process. Extracted data will be presented in diagrammatic and tabular form, with a narrative summary addressing the review questions.DiscussionThis scoping review will comprehensively map the primary research undertaken to date on plastic exposure and human health. Secondary outputs will include extensive databases on plastic chemicals and human health outcomes/impacts.RegistrationOpen Science Framework (OSF)-Standard Pre-Data Collection Registration,https://osf.io/gbxpsDOI: 10.17605/OSF.IO/GBXPS
The effect of competition between health opinions on epidemic dynamics
Authors: Teslya Alexandra , Nunner Hendrik , Buskens Vincent , Kretzschmar Mirjam E 
Published: February 2022

Past major epidemic events showed that when an infectious disease is perceived to cause severe health outcomes, individuals modify health behavior affecting epidemic dynamics. To investigate the effect of this feedback relationship on epidemic dynamics, we developed a compartmental model that couples a disease spread framework with competition of two mutually exclusive health opinions (health-positive and health-neutral) associated with different health behaviors. The model is based on the assumption that individuals switch health opinions as a result of exposure to opinions of others through interpersonal communications. To model opinion switch rates, we considered a family of functions and identified the ones that allow health opinions to co-exist. In the disease-free population, either the opinions cannot co-exist and one of them is always dominating (monobelief equilibrium) or there is at least one stable co-existence of opinions equilibrium. In the latter case, there is multistability between the co-existence equilibrium and the two monobelief equilibria. When two opinions co-exist, it depends on their distribution whether the infection can invade. If presence of the infection leads to increased switching to a health-positive opinion, the epidemic burden becomes smaller than indicated by the basic reproduction number. Additionally, a feedback between epidemic dynamics and health opinion dynamics may result in (sustained) oscillatory dynamics and a switch to a different stable opinion distribution. Our model captures feedback between spread of awareness through social networks and infection dynamics and can serve as a basis for more elaborate individual-based models.Significance StatementDisease epidemics often co-evolve with opinions on health-related behavior. Most existing models have difficulties understanding co-existence of different opinions in a population when the disease is not present, while we do observe this. We modeled opinion switching process by using an innovative way to capture the dependence of opinion switching rate on the population state. We combined this with network interaction patterns and were able to derive conditions under which a stable co-existence of opinions can occur. We used this insight to explain appearance of epidemic cycles and the population switching between different distributions of opinions. Our work demonstrates that for information interventions accurate understanding of opinion propagation processes is crucial.
Elevated brain-derived cell-free DNA among patients with first psychotic episode - a proof-of-concept study
Authors: Lubotzky Asael , pelov Ilana , Teplitz Ronen , Neiman Daniel , Smadja Adama , Zemmour Hai , Piyanzin Sheina , Ochana Bracha-Lea , Spalding Kirsty L. , Glaser Benjamin , Shemer Ruth , Dor Yuval , Kohn Yoav 
Published: February 2022

AbstractBackgroundSchizophrenia is a common, severe and debilitating psychiatric disorder. Despite extensive research there is as yet no biological marker that can aid in its diagnosis and course prediction. This precludes early detection and intervention. Imaging studies suggest brain volume loss around the onset and over the first few years of schizophrenia, and apoptosis has been proposed as the underlying mechanism. Cell free DNA fragments (cfDNA) are released into the bloodstream following cell death. Tissue-specific methylation patterns allow the identification of the tissue origins of cfDNA.MethodsWe developed a cocktail of brain specific DNA methylation markers, and used it to assess the presence of brain-derived cfDNA in the plasma of patients with a first psychotic episode.ResultsWe detected significantly elevated neuron- (p=0.0013), astrocyte- (p=0.0016), oligodendrocyte- (p=0.0129) and whole brain-derived (p=0.0012) cfDNA in the plasma of patients during their first psychotic episode (n=29), compared with healthy controls (n=31). Increased cfDNA levels were not correlated with psychotropic medications use. Area Under the Curve (AUC) was 0.77, with 65% sensitivity at 90% specificity in patients with a psychotic episode.ConclusionsPotential interpretations of these findings include increased brain cell death, disruption of the blood brain barrier or a defect in clearance of material from dying brain cells. Brain-specific cfDNA methylation markers can potentially assist early detection and monitoring of schizophrenia and thus allow early intervention and adequate therapy.
Impact of COVID-19 pandemic and anti-pandemic measures on tuberculosis, viral hepatitis, HIV/AIDS and malaria – a systematic review
Authors: Kessel Barbora , Heinsohn Torben , Ott Jördis J , Wolff Jutta , Hassenstein Max J , Lange Berit 
Published: February 2022

AbstractCOVID-19 pandemic puts an enormous strain on health care systems worldwide and may have a detrimental effect on prevention, treatment and outcomes of tuberculosis (TB), viral hepatitis, HIV/AIDS and malaria, whose ending is part of the United Nations 2030 Agenda for Sustainable Development. We conducted a systematic review of scientific and grey literature in order to collect wide-ranging evidence with emphasis on quantification of the projected and actual indirect impacts of COVID-19 on the four infectious diseases with a global focus. We followed PRISMA guidelines and the protocol registered for malaria (CRD42021234974). We searched PubMed, Scopus, preView (last search: January 13, 2021) and websites of main (medical) societies and leading NGOs related to each of the four considered infectious diseases. The identified modelling studies warned about under-diagnosis (TB), anti-retroviral therapy interruption/decrease in viral load suppression (HIV), disruptions of insecticide-treated nets (ITN) distribution and access to effective treatment (malaria), and treatment delays and vaccination interruptions (viral hepatitis). The reported disruptions were very heterogeneous both between and within countries. If observed at several points in time, the initial drops (partly dramatic, e.g. TB notifications/cases, or HIV testing volumes decreased up to -80%) were followed by a gradual recovery. However, the often-missing assessment of the changes against the usual pre-pandemic fluctuations hampered the interpretation of less severe ones. Given the recurring waves of the pandemic and the unknown mid- to long-term effects of adaptation and normalisation, the real consequences for the fight against leading infectious diseases will only manifest over the coming years.
Implementation and economic effects of local non-pharmaceutical interventions
Authors: Godøy Anna , Grøtting Maja Weemes 
Published: February 2022

AbstractIn this paper, we analyze economic costs and consequences of local non-pharmaceutical interventions (NPIs) aimed at containing the COVID-19 pandemic. Using comprehensive data on municipal and regional policies in Norway, we implement a difference-in-differences framework identifying impacts of local NPIs from discontinuous differential shifts in outcomes following the implementation of new policies. In treated municipalities, local NPIs lead to persistent reductions in mobility, persistent increases in unemployment, and transient reductions in consumer spending. Analyses of spatial spillovers show that the implementation of local NPIs increases retail mobility in non-treated neighboring municipalities. Overall, our findings suggest that local NPIs have economic consequences for local economies and induce residents to shift their consumption of goods and services to neighboring municipalities.
Lem2 is essential for cardiac development by maintaining nuclear integrity
Authors: Ross Jacob A. , Arcos-Villacis Nathaly , Battey Edmund , Boogerd Cornelis , Marhuenda Emilie , Hodzic Didier , Prin Fabrice , Mohun Tim , Catibog Norman , Tapia Olga , Gerace Larry , Iskratsch Thomas , Shah Ajay M. , Stroud Matthew J. 
Published: February 2022

AbstractNuclear envelope integrity is essential for compartmentalisation of nucleus and cytoplasm. Importantly, mutations in nuclear envelope-encoding genes are the second-highest cause of familial dilated cardiomyopathy. One such nuclear envelope protein that causes cardiomyopathy in humans and affects mouse heart development is Lem2. However, its role in mechanically active tissue such as heart remains poorly understood.We generated mice in which Lem2 was specifically ablated in cardiomyocytes and carried out detailed physiological, tissue and cellular analyses. Importantly, our data showed that Lem2 was essential for cardiac development, and hearts from Lem2 cKO mice were morphologically and transcriptionally underdeveloped. Lem2 cKO hearts displayed high levels of DNA damage, nuclear rupture, and apoptosis. Crucially, we found that these defects were driven by muscle contraction as they were ameliorated by inhibiting myosin contraction and conversely were exacerbated upon myosin activation.Our data suggest that Lem2 is critical for integrity at the nascent nuclear envelope in fetal hearts, and protects the nucleus from the mechanical forces of muscle contraction. Taken together, these data provide novel insight into mechanisms underlying striated muscle diseases caused by altered nuclear envelope integrity.