bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toxoplasmosis: An important risk factor for acquiring SARS-CoV-2 infection and a severe course of Covid-19 disease
Authors: Flegr Jaroslav 
Published: May 2021

SummaryBackgroundLatent toxoplasmosis, i.e. a lifelong infection with the protozoan parasiteToxoplasmagondii, affects about a third of human population worldwide. In the past ten years, numerous studies had shown that infected subjects have a significantly higher incidence of mental and physical health problems and are more prone to exhibiting the adverse effects of various diseases.MethodsA cross-sectional internet study was performed on a population of 4,499Toxoplasma-free and 786Toxoplasma-infected subjects and looked for factors which positively or negatively affect the risk of SARS-CoV-2 infection and likelihood of a severe course of Covid-19.FindingsLogistic regression and partial Kendall correlation controlled for sex, age, and size of the place of residence showed that latent toxoplasmosis had the strongest effect on the risk of infection (OR = 1·50) before sport (OR = 1·30), and borreliosis (1·27). It also had the strongest effect on the risk of severe course of infection (Tau = 0·146), before autoimmunity, immunodeficiency, male sex, keeping a cat, being overweight, borreliosis, higher age, or chronic obstructive pulmonary disease. Toxoplasmosis augmented the adverse effects of other risk factors but was not the proximal cause of the effect of cat keeping (in the form of higher likelihood of Covid infection and higher severity of the course of infection), which was observed especially in a subset ofToxoplasma-infected subjects (Tau = 0·153). Effects of keeping a cat were detected only in subjects from multi-member families, suggesting that a cat could a vector for the transmission of SARS-CoV-2 within a family.InterpretationsToxoplasmosis is currently not considered a risk factor for Covid-19 andToxoplasma- infected subjects are neither informed about their higher risks nor prioritised in vaccination programs. Because toxoplasmosis affects a large segment of the human population, its impact on Covid-19-associated effects on public health could be considerable.
Fc-independent neutralization of SARS-CoV-2 by recombinant human monoclonal antibodies
Authors: Noy-Porat Tal , Edri Avishay , Alcalay Ron , Makdasi Efi , Gur David , Aftalion Moshe , Evgy Yentl , Beth-Din Adi , Levy Yinon , Epstein Eyal , Radinsky Olga , Zauberman Ayelet , Lazar Shirley , Yitzhaki Shmuel , Marcus Hadar , Porgador Angel , Rosenfeld Ronit , Mazor Ohad 
Published: May 2021

AbstractThe use of passively-administered neutralizing antibodies is a promising approach for the prevention and treatment of SARS-CoV-2 infection. Antibody-mediated protection may involve immune system recruitment through Fc-dependent activation of effector cells and the complement system. However, the role of Fc-mediated functions in the efficaciousin vivoneutralization of SARS-CoV-2 is not yet clear. Delineating the role this process plays in antibody-mediated protection will have a great impact on the design of such therapeutics. Here, the Fc of two highly potent SARS-CoV-2 neutralizing human monoclonal antibodies, targeting distinct domains of the spike, was engineered to abrogate their Fc-dependent functions. The protective activity of these antibodies was tested against lethal SARS-CoV-2 infections in K18-hACE2 transgenic mice, both before or two days post-exposure in comparison to their original, Fc-active antibodies. Antibody treatment with both Fc-variants similarly rescued the mice from death, reduced viral load and prevented signs of morbidity. In addition, surviving animals developed a significant endogenous immune response towards the virus. Taken together, this work provides important insight regarding the contribution of Fc-effector functions in antibody-mediated protection, which should aid in future design of effective antibody-based therapies.
Anticancer pan-ErbB inhibitors reduce inflammation and tissue injury and exert broad-spectrum antiviral effects
Authors: Saul Sirle , Karim Marwah , Ghita Luca , Huang Pei-Tzu , Chiu Winston , Durán Verónica , Lo Chieh-Wen , Kumar Sathish , Bhalla Nishank , Leyssen Pieter , Alem Farhang , Boghdeh Niloufar A. , Tran Do HN , Cohen Courtney A. , Brown Jacquelyn A. , Huie Kathleen E. , Tindle Courtney , Sibai Mamdouh , Ye Chengjin , Khalil Ahmed Magdy , Martinez-Sobrido Luis , Dye John M. , Pinsky Benjamin A. , Ghosh Pradipta , Das Soumita , Solow-Cordero David E. , Jin Jing , Wikswo John P. , Jochmans Dirk , Neyts Johan , Jonghe Steven De , Narayanan Aarthi , Einav Shirit 
Published: May 2021

AbstractTargeting host factors exploited by multiple viruses could offer broad-spectrum solutions for pandemic preparedness. Seventeen candidates targeting diverse functions emerged in a screen of 4,413 compounds for SARS-CoV-2 inhibitors. We demonstrated that lapatinib and other approved inhibitors of the ErbB family receptor tyrosine kinases suppress replication of SARS-CoV-2, Venezuelan equine encephalitis virus (VEEV), and other emerging viruses with a high barrier to resistance. Lapatinib suppressed SARS-CoV-2 entry and later stages of the viral life cycle and showed synergistic effect with the direct-acting antiviral nirmatrelvir. We discovered that ErbB1, 2 and 4 bind SARS-CoV-2 S1 protein and regulate viral and ACE2 internalization, and they are required for VEEV infection. In human lung organoids, lapatinib protected from SARS-CoV-2-induced activation of ErbB-regulated pathways implicated in non-infectious lung injury, pro-inflammatory cytokine production, and epithelial barrier injury. Lapatinib suppressed VEEV replication, cytokine production and disruption of the blood-brain barrier integrity in microfluidic-based human neurovascular units, and reduced mortality in a lethal infection murine model. We validated lapatinib-mediated inhibition of ErbB activity as an important mechanism of antiviral action. These findings reveal regulation of viral replication, inflammation, and tissue injury via ErbBs and establish a proof-of-principle for a repurposed, ErbB-targeted approach to combat emerging viruses.
SETDB1 regulates microtubule dynamics
Authors: Hernandez-Vicens Rosari , Pernicone Nomi , Listovsky Tamar , Gerlitz Gabi 
Published: May 2021

SummarySETDB1 is a methyltransferase responsible for the methylation of histone H3-lysine-9, which is mainly related to heterochromatin formation. SETDB1 is overexpressed in various cancer types and is associated with an aggressive phenotype. In agreement with its activity, it mainly exhibits a nuclear localization; however, in several cell types a cytoplasmic localization was reported. Here we show that a substantial cytoplasmic pool of SETDB1 is colocalized with microtubules. Significantly, silencing of SETDB1 led to faster polymerization and reduced rate of catastrophe events of microtubules in parallel to reduced proliferation rate and slower mitotic kinetics. Interestingly, over-expression of either wild-type or catalytic dead SETDB1 altered microtubule polymerization rate to the same extent, suggesting that SETDB1 affects MT dynamics by a methylation-independent mechanism. Finding interaction between SETDB1 and the tubulin deacetylase HDAC6 and increased tubulin acetylation levels upon silencing of SETDB1 suggest a model in which SETDB1 affects microtubule dynamics by interacting with both microtubules and HDAC6 to enhance tubulin deacetylation. Overall, our results suggest a novel cytoplasmic role for SETDB1 in the regulation of microtubule dynamics.
Stabilization of the SARS-CoV-2 Spike receptor-binding domain using deep mutational scanning and structure-based design
Authors: Ellis Daniel , Brunette Natalie , Crawford Katharine H. D. , Walls Alexandra C. , Pham Minh N. , Chen Chengbo , Herpoldt Karla-Luise , Fiala Brooke , Murphy Michael , Pettie Deleah , Kraft John C. , Malone Keara D. , Navarro Mary Jane , Ogohara Cassie , Kepl Elizabeth , Ravichandran Rashmi , Sydeman Claire , Ahlrichs Maggie , Johnson Max , Blackstone Alyssa , Carter Lauren , Starr Tyler N. , Greaney Allison J. , Lee Kelly K. , Veesler David , Bloom Jesse D. , King Neil P. 
Published: May 2021

ABSTRACTThe unprecedented global demand for SARS-CoV-2 vaccines has demonstrated the need for highly effective vaccine candidates that are thermostable and amenable to large-scale manufacturing. Nanoparticle immunogens presenting the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein (S) in repetitive arrays are being advanced as second-generation vaccine candidates, as they feature robust manufacturing characteristics and have shown promising immunogenicity in preclinical models. Here, we used previously reported deep mutational scanning (DMS) data to guide the design of stabilized variants of the RBD. The selected mutations fill a cavity in the RBD that has been identified as a linoleic acid binding pocket. Screening of several designs led to the selection of two lead candidates that expressed at higher yields than the wild-type RBD. These stabilized RBDs possess enhanced thermal stability and resistance to aggregation, particularly when incorporated into an icosahedral nanoparticle immunogen that maintained its integrity and antigenicity for 28 days at 35-40°C, while corresponding immunogens displaying the wild-type RBD experienced aggregation and loss of antigenicity. The stabilized immunogens preserved the potent immunogenicity of the original nanoparticle immunogen, which is currently being evaluated in a Phase I/II clinical trial. Our findings may improve the scalability and stability of RBD-based coronavirus vaccines in any format and more generally highlight the utility of comprehensive DMS data in guiding vaccine design.
Safety, immunogenicity and protection provided by unadjuvanted and adjuvanted formulations of recombinant plant-derived virus-like particle vaccine candidate for COVID-19 in non-human primates
Authors: Pillet Stéphane , Arunachalam Prabhu S. , Andreani Guadalupe , Golden Nadia , Fontenot Jane , Aye Pyone , Röltgen Katharina , Lehmick Gabrielle , Dubé Charlotte , Gobeil Philipe , Trépanier Sonia , Charland Nathalie , D’Aoust Marc-André , Russell-Lodrigue Kasi , Blair Robert V. , Boyd Scott , Bohm Rudolph B. , Rappaport Jay , Villinger François , Ward Brian J. , Pulendran Bali , Landry Nathalie 
Published: May 2021

AbstractAlthough antivirals are important tools to control the SARS-CoV-2 infection, effective vaccines are essential to control the current pandemic. Plant-derived virus-like particle (VLP) vaccine candidates have previously demonstrated immunogenicity and efficacy against influenza. Here we report the immunogenicity and protection induced in macaques by intramuscular injections of VLP bearing SARS-CoV-2 spike protein (CoVLP) vaccine candidate formulated with or without Adjuvant System 03 (AS03) or cytosine phosphoguanine (CpG) 1018. Although a single dose of unadjuvanted CoVLP vaccine candidate stimulated humoral and cell-mediated immune responses, booster immunization (at 28 days after prime) and adjuvants significantly improved both responses with a higher immunogenicity and protection provided by AS03 adjuvanted CoVLP. Fifteen microgram CoVLP adjuvanted with AS03 induced a balanced IL-2 driven response along with IL-4 expression in CD4 T cells and mobilization of CD4 follicular helper cells (Tfh). Animals were challenged by multiple routes (i.e. intratracheal, intranasal and ocular) with a total viral dose of 106 plaque forming units of SARS-CoV-2. Lower viral replication in nasal swabs and broncho-alveolar lavage (BAL) as well as fewer SARS-CoV-2 infected cells and immune cell infiltrates in the lungs concomitant with reduced levels of pro-inflammatory cytokines and chemotactic factors in BAL were observed in the animals immunized with CoVLP adjuvanted with AS03. No clinical, pathologic or virologic evidences of vaccine associated enhanced disease (VAED) were observed in vaccinated animals. CoVLP adjuvanted with AS03 was therefore selected for vaccine development and clinical trials.
Allicin inhibits SARS-CoV-2 replication and abrogates the antiviral host response in the Calu-3 proteome
Authors: Mösbauer Kirstin , Fritsch Verena Nadin , Adrian Lorenz , Bernhardt Jörg , Gruhlke Martin Clemens Horst , Slusarenko Alan John , Niemeyer Daniela , Antelmann Haike 
Published: May 2021

ABSTRACTThe Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic is a major health burden. Volatile garlic organosulfur compounds, such as the thiol-reactive allicin (diallyl thiosulfinate) exert strong antimicrobial activity against various respiratory pathogens. Here, we investigated the antiviral activity of allicin against SARS-CoV-2 in infected Vero E6 and Calu-3 lung cells. Calu-3 cells showed greater allicin tolerance due >4-fold increased GSH levels compared to Vero E6. However, biocompatible allicin doses efficiently inhibited viral replication in both cell lines. Proteome analyses of SARS-CoV-2 infected Calu-3 cells revealed a strong induction of the antiviral interferon-stimulated gene (ISG) signature (e.g. cGAS, Mx1, IFIT, IFIH, IFI16, IFI44, 2’5’OAS and ISG15), pathways of vesicular transport, tight junctions (KIF5A/B/C, OSBPL2, CLTC1, ARHGAP17) and ubiquitin modification (UBE2L3/5), as well as reprogramming of host metabolism, transcription and translation. Allicin abrogated the ISG host response and reverted the host cellular pathways to levels of uninfected Calu-3 cells, confirming the antiviral and immunomodulatory activity of allicin in the host proteome. Thus, biocompatible doses of allicin could be promising for protection of lung cells against SARS-CoV-2.
An innovative approach for determining composite wheat quality index to identify quality enriched genotypes - insights and implications
Authors: Mohan D , Sendhil R , Gupta Om Prakash , Pandey Vanita , Gopalareddy K , Singh Gyanendra Pratap 
Published: May 2021

AbstractRanking test entries or test sites on a quality basis is very difficult in wheat as value addition is perceived by several grain properties and end-products. Here, a novel approach has been developed and tested by deriving wheat quality index based on principal component analysis of 13 physico-chemical grain parameters and 3 end products of 45 wheat varieties. Depending upon the observed index range (0.15 to 0.71), the cultivars were assorted into 3 distinct classesi.e. elite, moderate and poor. The top group ascertained high quality standards of grain suited for bread andchapatiwhereas bottom group assured better cookies quality. This technique was also tested to differentiate quality enriched test sites within a zone or demarcate the most suited production environments to harness good quality wheat. The index will have an implication on farmers (premium price for varietal segregation), industry (product specific quality cultivars), and consumers (superior quality products).
Clinical Strains of Pseudomonas aeruginosa secret LasB protease to induce hemorrhagic diffused alveolar damage and acute lung injury in mice
Authors: Zhu Yajie , Ge Xiaoli , Xie Di , Wang Shangyuan , Chen Feng , Pan Shuming 
Published: May 2021

AbstractBackgroundAcute lung injury and acute respiratory distress syndrome are most often caused by bacterial pneumonia, characterized by severe dyspnea and high mortality. Knowledge about the lung injury effects of current clinical bacteria strains is lacking. The aim of this study was to investigate the ability of representative pathogenic bacteria isolated from patients to cause ALI/ARDS in mice and identify the virulent factors.Method7 major bacteria species were isolated from clinical sputum and instilled in to mice airway unilaterally. Histology study was used to judge the lung injury effect. Virulence genes were examined by PCR. Sequence type of P. aeruginosa strains were identified by MLST. LC-MS/MS was used to identify the suspicious protein bands. LasB was purified through DEAE-cellulose column and its toxicity was tested both in vitro and in vivo.ResultsStaphylococcus aureus, Streptococcus pneumoniae, Streptococcus agalactiae, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli were randomly separated and tested 3 times. Among them, gram-negative bacteria are more potential than gram-positive bacteria to cause acute lung injury. However, P. aeruginosa is the only pathogen which induced diffused alveolar damage, hemorrhage and hyaline membrane in the lung of mice. The lung injury effect is associated to the excreted matrix metalloproteinase LasB of P. aeruginosa. Purified LasB recapitulated hemorrhagic acute lung injury identical to P. aeruginosa infection in vivo. We found this was due to the powerful degradation effect of LasB on both lung extracellular matrix and key proteins in coagulation cascade without inducing cellular apoptosis.ConclusionP. aeruginosa strains are most capable to induce ALI/ARDS among major clinical pathogenic bacteria, this ability is specifically attributed to their LasB production.
Night warming alters mean warming effects on predator–prey interactions by modifying predator demographics and interaction strengths
Authors: Ma Gang , Bai Chun‐Ming , Rudolf Volker H. W. , Ma Chun‐Sen 
Published: May 2021

Abstract

Temperatures are increasing globally, but this increase is not symmetrical; instead, night‐time minimum air temperatures increase faster than daytime maximum temperatures. However, we still know little about when and how this differential increase in maximum versus minimum air temperatures affects ecological interactions between species. Understanding the connection between different types (night vs. day) of warming and interspecific interactions is essential to predict the ecological consequences of climate change for natural ecosystems.

Here we used experiments in a common predator (lady beetle)–prey (aphid) system to examine how night warming, thermal regime (constant vs. fluctuating) and prey density influence demographic rates and per capita feeding rate and thus predation pressure. We mainly focused on the demographic variables and prey consumption as well as energy‐related variables of the predators to understand how changes in night‐time temperature, temperature regime and prey density affect predator performances and to differentiate these effects between constant and fluctuating thermal conditions.

We found that warming effects on most of the individual demographic rates and per capita consumption rates of the predator differed between constant and fluctuating regimes. These differences scaled up to alter population stage structure and population growth rate of the predator and ultimately the predation pressure in our system. Furthermore, warming had stronger and negative consequences on predator population growth and thus predation pressure in constant regime, but little or even positive effects under fluctuating conditions. Importantly, these results are consistent across prey densities.

Our results suggest that compared to night warming, predictions based on mean warming can under‐ or overestimate species demographic rates and per capita predation effects, causing inaccurate or even misleading expectations on population structure, long‐term population growth and interspecific interactions. These results emphasize the importance of accounting for both ecologically relevant diurnal temperature cycle and lifelong demographics and per capita consumption when assessing how warming affects interspecific interactions. Our findings thus provide better understanding of how night warming will affect predator–prey interactions and energy flux within trophic cascades and also have implications for predicting the consequences of top‐down control in natural and agricultural ecosystems under climate change.

A free Plain Language Summary can be found within the Supporting Information of this article.
Why Firms Announce Good News Late: Earnings Management and Financial Reporting Timeliness*
Authors: Kim Mark P. , Pierce Spencer R. , Yeung Ira 
Published: May 2021

ABSTRACTPrior studies find that delayed earnings announcements tend to communicate unfavorable news, and investors react negatively when firms delay earnings announcements. However, these findings do not explain why investors discount delayed earnings, even after controlling for the earnings news, and why firms sometimes announce good news late. Motivated by theory from Trueman (1990) that attempts to explain these phenomena, we examine whether announcement delays indicate earnings management. We predict and find that good news firms with higher discretionary accruals are more likely to announce earnings late. Consistent with post fiscal year‐end activities driving announcement delays, we fail to find a relation between measures of real earnings management and late announcements. Using a last‐chance earnings management measure based on tax expense manipulation, we also predict and find strong evidence that good news firms engaging in last‐chance earnings management are more likely to delay earnings announcements. Consistent with Trueman's (1990) theory that earnings management explains why investors discount delayed earnings announcements, we find that, on average, earnings announcement returns are 1.4% lower for late announcers relying on last‐chance earnings management to report good news. Overall, our findings suggest that announcement delays provide information about not only the sign of the earnings news but also the potential for earnings management.
A cascade of care for alcohol use disorder: Using 2015–2019 National Survey on Drug Use and Health data to identify gaps in past 12‐month care
Authors: Mintz Carrie M. , Hartz Sarah M. , Fisher Sherri L. , Ramsey Alex T. , Geng Elvin H. , Grucza Richard A. , Bierut Laura J. 
Published: May 2021

AbstractBackgroundAlthough effective treatments exist, alcohol use disorder (AUD) is undertreated. We used a cascade of care framework to understand gaps in care for persons with AUD.MethodsUsing 2015–2019 National Survey on Drug Use and Health data, we evaluated the following steps in the cascade of care: (1) adult prevalence of AUD; (2) proportion of adults with AUD who utilized health care in the past 12 months; (3) proportion with AUD screened about their alcohol use; (4) proportion with AUD who received a brief intervention about their alcohol misuse; (5) proportion with AUD who received information about treatment for alcohol misuse; and (6) proportion with AUD who received treatment. Analyses were stratified by AUD severity.ResultsOf the 214,505 persons included in the sample, the weighted prevalence of AUD was 7.8% (95% CI 7.6–8.0%). Cascades of care showed the majority of individuals with AUD utilized health care in the past 12 months [81.4% (95% CI 80.7–82.1%)] and were screened about alcohol use [69.9% (95% CI 68.9–70.8%)]. However, only a minority of individuals received subsequent steps of care, including 11.6% (95% CI 11.0–12.2%) who reported receiving a brief intervention, 5.1% (95% CI 4.6–5.6%) who were referred to treatment, and 5.8% (95% CI 5.4–6.3%) who received treatment. Similar patterns were observed when cascades of care were stratified by AUD severity.ConclusionsPersons with AUD commonly utilize health care and are often screened about alcohol use, but few receive treatment. Healthcare settings—particularly primary care settings—represent a prime opportunity to implement AUD treatment to improve outcomes in this high‐risk population.