bluuebunny/crossref_metadata_2025_split huggingface dataset:
Broad-spectrum antiviral inhibitors targeting pandemic potential RNA viruses
Authors: Garcia Gustavo , Irudayam Joseph Ignatius , Jeyachandran Arjit Vijay , Dubey Swati , Chang Christina , Cario Sebastian Castillo , Price Nate , Arumugam Sathya , Marquez Angelica L. , Shah Aayushi , Fanaei Amir , Chakravarty Nikhil , Joshi Shantanu , Sinha Sanjeev , French Samuel W. , Parcells Mark , Ramaiah Arunachalam , Arumugaswami Vaithilingaraja 
Published: January 2023

ABSTRACTRNA viruses continue to remain a clear and present threat for potential pandemics due to their rapid evolution. To mitigate their impact, we urgently require antiviral agents that can inhibit multiple families of disease-causing viruses, such as arthropod-borne and respiratory pathogens. Potentiating host antiviral pathways can prevent or limit viral infections before escalating into a major outbreak. Therefore, it is critical to identify broad-spectrum antiviral agents. We have tested a small library of innate immune agonists targeting pathogen recognition receptors, including TLRs, STING, NOD, Dectin and cytosolic DNA or RNA sensors. We observed that TLR3, STING, TLR8 and Dectin-1 ligands inhibited arboviruses, Chikungunya virus (CHIKV), West Nile virus (WNV) and Zika virus, to varying degrees. Cyclic dinucleotide (CDN) STING agonists, such as cAIMP, diABZI, and 2’,3’-cGAMP, and Dectin-1 agonist scleroglucan, demonstrated the most potent, broad-spectrum antiviral function. Comparative transcriptome analysis revealed that CHIKV-infected cells had larger number of differentially expressed genes than of WNV and ZIKV. Furthermore, gene expression analysis showed that cAIMP treatment rescued cells from CHIKV-induced dysregulation of cell repair, immune, and metabolic pathways. In addition, cAIMP provided protection against CHIKV in a CHIKV-arthritis mouse model. Cardioprotective effects of synthetic STING ligands against CHIKV, WNV, SARS-CoV-2 and enterovirus D68 (EV-D68) infections were demonstrated using human cardiomyocytes. Interestingly, the direct-acting antiviral drug remdesivir, a nucleoside analogue, was not effective against CHIKV and WNV, but exhibited potent antiviral effects against SARS-CoV-2, RSV (respiratory syncytial virus), and EV-D68. Our study identifies broad-spectrum antivirals effective against multiple families of pandemic potential RNA viruses, which can be rapidly deployed to prevent or mitigate future pandemics.
High tissue-specificity of lncRNAs maximises the prediction of tissue of origin of circulating DNA
Authors: Mouhou Elyas , Genty Fabien , M’selmi Walid El , Chouali Hanae , Zagury Jean-François , Clerc Sigrid Le , Proudhon Charlotte , Noirel Josselin 
Published: January 2023

AbstractSeveral studies have made it possible to envision a translational application of plasma DNA sequencing in cancer diagnosis and monitoring. However, the extremely low concentration of circulating tumour DNA (ctDNA) fragments among the total cell-free DNA (cfDNA) remains a formidable challenge to overcome and statistical models have yet to be improved enough to become of practical use. In this study, we set about appraising the predictive value of a variety of binary classification models based on cfDNA sequencing using fragmentation features extracted around transcription start sites (TSSs). We investigated (1) features summarising mapped fragment density around each TSS, (2) long non-coding RNA (lncRNA) genes versus coding genes and (3) selection criteria to generate gene classes to be assigned by the model. Given that, in healthy samples, most of the cfDNA comes from lymphomyeloid lineages, we could identify the model parametrisation with the best accuracy in those lineages using publicly available datasets of healthy patients’ cfDNA. Our results show that (1) the way tissue-specific gene classes are defined matters more than what fragmentation features are included, and (2) in particular, lncRNAs are more tissue specific than coding genes and stand out in terms of both sensitivity and specificity in our results.Author summaryDying cells, even in healthy individuals, release a fraction of the digested fragments of their genetic material into the bloodstream. Interestingly, these circulating cell-free DNA (cfDNA) fragments bear the footprint left by nucleosomes ; the position of which depends on the transcriptional state specific to each tissue. This footprint, given away by the sizes and genomic positions of cfDNA fragments, can be revealed by deep sequencing and statistical models can be trained to recognise the tissue from where those fragments originate. This information, if made sensitive enough, could be a useful medical technique to carry out so-called “liquid biopsies”, allowing clinicians to diagnose at an early stage or to precisely monitor a number of diseases, including cancer.In this work, we comprehensively evaluated the features of circulating DNA fragments in the vicinity of transcriptional start sites to increase the ability of statistical models to recognise the tissue of origin of cfDNA of healthy individuals. Broadly speaking, nucleosome patterns allow a statistical model distinguish active versus inactive genes or tissue-specific versus housekeeping genes. The purpose of this study was to find the classes of genes with the strongest ability to recognise the true tissue of origin. From this work, we conclude that long non-coding RNA genes allow for a more sensitive and specific detection of the tissue of origin.
Subtractive adaptation is a more effective and general mechanism in binocular rivalry than divisive adaptation
Authors: Inês Cravo Maria , Bernardes Rui , Castelo-Branco Miguel 
Published: January 2023

AbstractThe activity of neurons is influenced by random fluctuations and can be strongly modulated by firing rate adaptation, especially in sensory systems. Still, there is an ongoing debate about the characteristics of neuronal noise and the mechanisms of adaptation, and even less is known about how exactly they affect perception. Noise and adaptation play central roles in binocular rivalry, a visual phenomenon where two images compete for perceptual dominance. Here, we investigated the effects of different noise processes and adaptation mechanisms on visual perception by simulating a model of binocular rivalry with Gaussian white noise, Ornstein-Uhlenbeck noise, and pink noise, in variants with divisive adaptation, subtractive adaptation, and without adaptation. By simulating the nine versions of the model for a wide range of parameter values, we find that white noise only produces rivalry when paired with subtractive adaptation and that subtractive adaptation reduces the influence of noise intensity on rivalry strength and introduces convergence of the mean percept duration, an important metric of binocular rivalry, across all noise processes. In sum, our results show that white noise is an insufficient description of background activity in the brain and that subtractive adaptation is a stronger and more general switching mechanism in binocular rivalry than divisive adaptation, with important noise-filtering properties.Author SummaryVisual neurons adapt to the environment by reducing the number of spikes evoked by a constant stimulus. They are also susceptible to random spikes produced by nearby neurons. These two phenomena, adaptation and noise, are essential features of brain activity and affect how we perceive the world. Although we know a great deal about the visual system, our understanding of the properties and mechanisms of neuronal noise and adaptation is still piecemeal, and even less is known about how these microscopic processes affect macroscopic behaviors. We shed light on this question by studying a bistable visual phenomenon called binocular rivalry, where two images compete for perception and where noise and adaptation play important roles. We simulated the activity of neurons involved in binocular rivalry to test different hypotheses about the statistics of neuronal noise and the mechanisms of adaptation. Our results reveal important differences between subtractive and divisive adaptation, suggesting that subtractive adaptation is a stronger switching mechanism in binocular rivalry and an effective noise filter. Our simulations also show the fundamental distinction between noise with and without temporal correlation, supporting the correlated noise hypothesis.
Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial metabolic reprogramming
Authors: Wang Yongxing , Kulkarni Vikram V. , García Jezreel Pantaleón , Leiva-Juárez Miguel M. , Goldblatt David L. , Gulraiz Fahad , Chen Jichao , Donepudi Sri Ramya , Lorenzi Philip L. , Wang Hao , Wong Lee-Jun , Tuvim Michael J. , Evans Scott E. 
Published: January 2023

AbstractPneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infections an urgent need. We have previously shown that manipulating the lungs’ intrinsic host defenses by therapeutic delivery of a unique dyad of pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODNs) with mitochondrial voltage-dependent anion channel 1 (VDAC1) without dependence on Toll-like receptor 9 (TLR9). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), enhances mitochondrial membrane potential (ΔΨm), and differentially modulates ETC complex activities. These combined effects promote leak of electrons from ETC complex III, resulting in superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy that has the potential to broadly protect patients against pneumonia during periods of peak vulnerability without reliance on currently available antibiotics.Author SummaryPneumonia is a major cause of death worldwide. Increasing antibiotic resistance and expanding immunocompromised populations continue to enhance the clinical urgency to find new strategies to prevent and treat pneumonia. We have identified a novel inhaled therapeutic that stimulates lung epithelial defenses to protect mice against pneumonia in a manner that depends on production of reactive oxygen species (ROS). Here, we report that the induction of protective ROS from lung epithelial mitochondria occurs following the interaction of one component of the treatment, an oligodeoxynucleotide, with the mitochondrial voltage-dependent anion channel 1. This interaction alters energy transfer between the mitochondria and the cytosol, resulting in metabolic reprogramming that drives more electrons into the electron transport chain, then causes electrons to leak from the electron transport chain to form protective ROS. While antioxidant therapies are endorsed in many other disease states, we present here an example of therapeutic induction of ROS that is associated with broad protection against pneumonia without reliance on administration of antibiotics.
COVID-19 and Mental Health in China: Effects of Personality and Demographics
Authors: Zhang Xiao , Battisti Michele , Proto Eugenio 
Published: January 2023

AbstractChina was the first country affected by the COVID-19 virus and it reacted strongly in the first months of 2020. This paper presents new evidence on the deterioration in mental health in China between 2018 and 2020. Using two waves of the China Family Panel Studies (CFPS) we can follow the same individuals pre and during the pandemic periods. We find clear evidence of a moderate level of mental health deterioration between 2018 and 2020. The prevalence of severe cases of depression, measured using an eight-item version of the common CES-D scale, increased from 6.33% in 2018 to 7.54% in 2020; quantifiable as around a 19% increase. This deterioration is higher for individuals who are subject to strict lockdowns, about 0.3 symptoms more on average, and it is stronger among those who already reported symptoms of depression in the 2018 wave of data. The effects we find are larger for individuals with more open personalities: one standard deviation of the Openness trait corresponds to 0.08 more symptoms, while more Neurotic individuals do not seem to be more affected. Younger cohorts and individuals with lower levels of education are more affected. Males seem slightly more affected than females, although this difference is statistically non-significant.
Germline loss-of-functionPAMvariants are enriched in subjects with pituitary hypersecretion
Authors: Trivellin Giampaolo , Daly Adrian F. , Hernández-Ramírez Laura C. , Araldi Elisa , Tatsi Christina , Dale Ryan K. , Fridell Gus , Mittal Arjun , Faucz Fabio R. , Iben James R. , Li Tianwei , Vitali Eleonora , Stojilkovic Stanko S. , Kamenicky Peter , Villa Chiara , Baussart Bertrand , Chittiboina Prashant , Toro Camilo , Gahl William A. , Eugster Erica A. , Naves Luciana A. , Jaffrain-Rea Marie-Lise , de Herder Wouter W. , Neggers Sebastian JCMM , Petrossians Patrick , Beckers Albert , Lania Andrea G. , Mains Richard E. , Eipper Betty A. , Stratakis Constantine A. 
Published: January 2023

AbstractPituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. Following the identification of a loss-of-function variant (p.Arg703Gln) in thePAMgene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated pituitary adenomas kindreds forPAMvariants.PAMencodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides.Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. No germline CNVs or somatic single nucleotide variants (SNVs) were identified. We detected seven likely pathogenic heterozygous missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with GH excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or with different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally testedin vitrofor protein expression and trafficking by Western blotting, for splicing by minigene assays, and for amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of thePAMgene and rarePAMSNVs to diagnoses linked to pituitary gland hyperfunction.Identification ofPAMas a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.
Frequency and Clinical Characteristics of Breakthrough Cases Post COVID-19 Vaccine and Predictive Risk Factors in College Students
Authors: Abdulrazaq Manal Khudder , Al Redha Jebur Ahmed Abd , Ali Hamdan Baqer Jaafar , Ibrahim Ahmed khalid 
Published: January 2023

ABSTRACTBACKGROUNDCOVID-19 vaccines help protect against infection, severe illness, hospitalization and death. When someone who is vaccinated with either a primary series or a primary series plus a booster dose gets infected with the virus that causes COVID-19, it is referred to as a “vaccine breakthrough infection.”OBJECTIVESTo assess the frequency and clinical characteristics of breakthrough cases of COVID-19 infection and to study the predictive risk factors.SUBJECTS&METHODSA cross-sectional study was carried out including 604 undergraduate medical and non-medical students in Iraq from 10thof August to 29thof September 2022. Data was collected via an online specific questionnaire and analysed to estimate the frequency of COVID-19 breakthrough cases post vaccination, and number of doses of vaccine used. The association of different factors including age, gender, grade, body mass index, smoking, and comorbidities was also studied as predictive risk factors. We used the data to formulate tables, figures and perform statistical tests in IBM SPSS Statistics 25.RESULTSMean age of study sample was 21.78 year ± 3.26 and 339 (56%) were females. In terms of COVID-19 vaccination data, 97 (16%) have received one dose, 459 (76%) two doses and 48 (8%) three doses. Regarding PCR test, 74 (12%) were positive after the first dose compared to 49 (8%) after the second dose. About the symptoms developed, the most frequent were fever in 372 (61.1%), unusual fatigue in 96 (15.79%), chills in 29 (4.77%) and persistent cough in 26 (4.28%). For most predictive factors, results were statistically insignificant.CONCLUSIONSIn current study; demographic factors showed no statistically significant impact on prevalence of COVID-19 breakthrough cases. Despite this; number of participants who develop symptoms after the second dose of vaccine was high; and having 3 or more symptoms. About half of participants showed symptoms even after being fully vaccinated.
Toxicity-specific peripheral blood T and B cell dynamics in anti-PD-1 and combined immune checkpoint inhibition
Authors: van Eijs Mick J.M. , Verheijden Rik J. , van der Wees Stefanie A. , Nierkens Stefan , van Lindert Anne S.R. , Suijkerbuijk Karijn P.M. , van Wijk Femke 
Published: January 2023

AbstractImmune checkpoint inhibitors (ICI) have revolutionized the treatment landscape of advanced malignancies, but come with a diverse spectrum of immune-related adverse events (irAEs). Mechanistic studies can aid the transition from expert-opinion to evidence-based irAE treatment strategies. We aimed to longitudinally characterize peripheral blood T and B cell dynamics in ICI-treated patients by multicolor flow cytometry and serum multiplex immunoassay at baseline, ±3 weeks and ±6 weeks or upon clinically relevant irAEs. We analyzed samples from 44 ICI-treated patients (24 anti-PD-1 monotherapy, 20 combined anti-PD-1/anti-CTLA-4; cICI), of whom 21 developed irAEs, and 10 healthy donors. IrAEs after cICI were characterized by significantly enhanced proliferation of Th1-associated, mainly (CD4+) effector memory T cells, as well as Th17-associated immune responses and germinal center activation (reflected by CXCL13 and IL-21 increases). We observed no changes in CD21lo, memory, class-switched or newly activated B cell subsets. Especially double-positive PD-1+LAG-3+CD8+T cells showed enhanced cytotoxic capacity in patients with irAEs after cICI. Within anti-PD-1 monotherapy, irAEs were associated with modestly enhanced Th1-associated responses reflected by increased serum CXCL9 and CXCL10. In conclusion, ICI-induced toxicity is dominated by enhanced Th1-associated responses, but in cICI we also found evidence for Th17-associated responses and germinal center activation. Together, our data add to the growing body of evidence that irAEs may be driven by newly activated CD4+helper T cells, specifically after cICI. This study also supports tailored irAE treatment, based on ICI regimen, and to deploy specific strategies such as Th17 inhibition especially in cICI-associated irAEs.
Elective Surgery Before, During and After the COVID-19 Pandemic in England 2015 - 2022: A Database Study
Authors: Remsing Sandra , Reeves Katharine , Evison Felicity , Morton Dion , Chilton Peter , Bird Paul , Watson Samuel , Khunti Kamlesh , Lilford Richard 
Published: January 2023

ABSTRACTObjectiveTo track elective surgery activity before, during and after the COVID-19 pandemic in England. To examine for hypothesised differences in use of independent vs NHS hospitals, and more urgent vs less urgent operations over the pre- and post-COVID time windows.DesignWe extracted data from the Hospital Episodes Statistics database from 1stApril 2015 to 30thApril 2022. This database contains all emergency and elective patient admissions, outpatient appointments and A&E attendances funded by the NHS in England.SettingNHS and Independent hospitals in England.ParticipantsAdult patients (over 18 years) admitted for elective surgery between April 2015 and April 2022, who were classified as being in priority groups 3 or 4.Main OutcomesTotal operations, operations by hospital type, and NHS England priority ranking.ResultsThe data show that there was a large reduction in the number of elective operations during lockdown with incomplete recovery thereafter. Also the proportion of more urgent surgeries and surgeries in independent hospitals increased in the post-COVID vs pre-COVID time windows.ConclusionUnder conditions of high-demand, higher value elective surgery procedures are awarded increasing priority and the Independent sector bears a larger share of the load.
Structure and its transformation of elliptical nege-like virus Tanay virus
Authors: Okamoto Kenta , Song Chihong , Sakaguchi Miako , Chalkiadaki Christina , Miyazaki Naoyuki , Nabeshima Takeshi , Morita Kouichi , Inoue Shingo , Murata Kazuyoshi 
Published: January 2023

AbstractNegeviruses that infect insects are recently identified virus species that are phylogenetically related to several plant viruses. They exhibit a unique virion structure, an elliptical core with a short projection. Negeviruses encode two structural proteins, a glycoprotein that forms a short projection, and an envelope protein that forms an elliptical core. The glycoprotein has been reported only in the negeviruses’ genes, and not in phylogenetically related plant viruses’ genes. In this report, we first describe the three-dimensional electron cryo-microscopy (cryo-EM) structure of Tanay virus (TANAV), one of the nege-like viruses. TANAV particle demonstrates a periodical envelope structure consisting of three layers surrounding the centered viral RNA. The elliptical core dynamically changes its shape under acidic and even low detergent conditions to form bullet-like or tubular shapes. The further cryo-EM studies on these transformed TANAV particles reveal their overall structural rearrangement. These findings suggest putative geometries of TANAV and its transformation in the life cycle, and the potential importance of the short projection for enabling cell entry to the insect hosts.Impact statementNegeviridae has recently been declared as a virus family that includes virus species exhibiting a unique particle structure that differs from other known viruses. They are known to be common mosquito viruses isolated around the world, but also phylogenetically related to several plant viruses that impair crop production. Therefore, the negeviruses may also play a role in plant ecosystems that threaten agriculture. However, the mechanism of infection and assembly of the negeviruses as well as their structure were unknown. In this study, intact and dissociated structures of the TANAV were first examined using cryo-EM single particle analysis (SPA) and electron cryo-tomography (cryo-ET). These results reveal new structural geometries of the TANAV particle and its dynamic transformation under acidic and even low-detergent conditions, providing new insights into the infection and assembly mechanism in negeviruses.