bluuebunny/crossref_metadata_2025_split huggingface dataset:
Scutellaria baicalensisextract and baicalein inhibit replication of SARS-CoV-2 and its 3C-like proteasein vitro
Authors: Liu Hongbo , Ye Fei , Sun Qi , Liang Hao , Li Chunmei , Lu Roujian , Huang Baoying , Tan Wenjie , Lai Luhua 
Published: April 2020

AbstractCOVID-19 has become a global pandemic that threatens millions of people worldwide. There is an urgent call for developing effective drugs against the virus (SARS-CoV-2) causing this disease. The main protease of SARS-CoV-2, 3C-like protease (3CLpro), is highly conserved across coronaviruses and is essential for the maturation process of viral polyprotein. Scutellariae radix (Huangqin in Chinese), the root ofScutellaria baicalensishas been widely used in traditional Chinese medicine to treat viral infection related symptoms. The extracts ofS. baicalensishave exhibited broad spectrum antiviral activities. We studied the anti-SARS-CoV-2 activity ofS. baicalensisand its ingredient compounds. We found that the ethanol extract ofS. baicalensisinhibits SARS-CoV-2 3CLproactivityin vitroand the replication of SARS-CoV-2 in Vero cells with an EC50of 0.74 μg/ml. Among the major components ofS. baicalensis, baicalein strongly inhibits SARS-CoV-2 3CLproactivity with an IC50of 0.39 μM. We further identified four baicalein analogue compounds from other herbs that inhibit SARS-CoV-2 3CLproactivity at microM concentration. Our study demonstrates that the extract ofS. baicalensishas effective anti-SARS-CoV-2 activity and baicalein and analogue compounds are strong SARS-CoV-2 3CLproinhibitors.
Positive selection of ORF3a and ORF8 genes drives the evolution of SARS-CoV-2 during the 2020 COVID-19 pandemic
Authors: Velazquez-Salinas Lauro , Zarate Selene , Eberl Samantha , Gladue Douglas P. , Novella Isabel , Borca Manuel V. 
Published: April 2020

AbstractIn this study, we analyzed full-length SARS-CoV-2 genomes from multiple countries to determine early trends in the evolutionary dynamics of the novel COVID-19 pandemic. Results indicated SARS-CoV-2 evolved early into at least three phylogenetic groups, characterized by positive selection at specific residues of the accessory proteins OFR3a and ORF8a. We also report evidence of epistatic interactions among sites in the genome that may be important in the generation of variants adapted to humans. These observations might impact not only public health, but also suggest more studies are needed to understand the genetic mechanisms that may affect the development of therapeutic and preventive tools, like antivirals and vaccines.
The SARS-CoV-2 receptor-binding domain elicits a potent neutralizing response without antibody-dependent enhancement
Authors: Quinlan Brian D. , Mou Huihui , Zhang Lizhou , Guo Yan , He Wenhui , Ojha Amrita , Parcells Mark S. , Luo Guangxiang , Li Wenhui , Zhong Guocai , Choe Hyeryun , Farzan Michael 
Published: April 2020

SUMMARYThe SARS-coronavirus 2 (SARS-CoV-2) spike (S) protein mediates entry of SARS-CoV-2 into cells expressing the angiotensin-converting enzyme 2 (ACE2). The S protein engages ACE2 through its receptor-binding domain (RBD), an independently folded 197-amino acid fragment of the 1273-amino acid S-protein protomer. Antibodies to the RBD domain of SARS-CoV (SARS-CoV-1), a closely related coronavirus which emerged in 2002-2003, have been shown to potently neutralize SARS-CoV-1 S-protein-mediated entry, and the presence of anti-RBD antibodies correlates with neutralization in SARS-CoV-2 convalescent sera. Here we show that immunization with the SARS-CoV-2 RBD elicits a robust neutralizing antibody response in rodents, comparable to 100 µg/ml of ACE2-Ig, a potent SARS-CoV-2 entry inhibitor. Importantly, anti-sera from immunized animals did not mediate antibody-dependent enhancement (ADE) of S-protein-mediated entry under conditions in which Zika virus ADE was readily observed. These data suggest that an RBD-based vaccine for SARS-CoV-2 could be safe and effective.
Magnetic Bead-Quantum Dot (MB-Qdot) CRISPR Assay for Instrument-Free Viral DNA Detection
Authors: Bao Mengdi , Jensen Erik , Chang Yu , Korensky Grant , Du Ke 
Published: April 2020

ABSTRACTWe have developed a novel detection system which couples CRISPR-Cas recognition of target sequences, Cas mediated nucleic acid probe cleavage, and quantum dots as highly sensitive reporter molecules for instrument-free detection of viral nucleic acid targets. After target recognition and Cas mediated cleavage of biotinylated ssDNA probe molecules, the probe molecules are bound to magnetic particles. A complimentary ssDNA oligonucleotide quantum dot conjugate is then added, which only hybridizes to un-cleaved probes on the magnetic beads. After separation of hybridized from unhybridized quantum dot conjugates by magnetic sequestration, the signal is measured fluorometrically to provide a signal proportional to the cleaved probes and therefore the amount of target nucleic acid. To demonstrate the power of this assay, a 250 bp DNA target sequence matching a portion of the African swine fever virus (ASFV) genome is used and a detection limit of ~0.5 nM is achieved without target amplification using a simple portable ultraviolet flashlight. The positive samples are readily confirmed by visual inspection, completely avoiding the need for complicated devices and instruments. This work establishes the feasibility of a simple, instrument free assay for rapid nucleic acid screening in both hospitals and point-of-care settings.
Clinical features and management of severe COVID-19: A retrospective study in Wuxi, Jiangsu Province, China
Authors: Jiang Xiufeng , Tao Jianxin , Wu Hui , Wang Yixin , Zhao Wei , Zhou Min , Huang Jiehui , You Qian , Hua Meng , Zhu Feng , Zhang Xiaoqing , Qian Meifang , Qiu Yuanwang 
Published: April 2020

AbstractObjectiveWe aimed to investigate clinical features and management of 55 COVID-19 patients in Wuxi, especially severe COVID-19.MethodsEpidemiological, demographic, clinical, laboratory, imaging, treatment, and outcome data of patients were collected. Follow-up lasted until April 6, 2020.ResultsAll 55 patients included 47 (85.5%) non-severe patients and 8 (14.5%) severe patients. Common comorbidities were hypertension and diabetes. Common symptoms were fever, cough and sputum. Lymphopenia was a common laboratory finding, and ground-glass opacity was a common chest CT feature. All patients received antiviral therapy of α-interferon inhalation and lopinavir-ritonavir tablets. Common complications included acute liver injury and respiratory failure. All patients were discharged. No death was occurred and no medical staff got infected. Patients with severe COVID-19 showed significantly older age, decreased lymphocytes, increased C reactive protein, and higher frequency of bilateral lung infiltration compared to non-severe patients. Significantly more treatments including antibiotic therapy and mechanical ventilation, longer hospitalization stay and higher cost were shown on severe patients.ConclusionsOur study suggested that patients with severe COVID-19 may be more likely to have an older age, present with lymphopenia and bilateral lung infiltration, receive multiple treatments and stay longer in hospital.
COVID-19 lockdowns cause global air pollution declines with implications for public health risk
Authors: Venter Zander S. , Aunan Kristin , Chowdhury Sourangsu , Lelieveld Jos 
Published: April 2020

AbstractThe lockdown response to COVID-19 has caused an unprecedented reduction in global economic activity. We test the hypothesis that this has reduced tropospheric and ground-level air pollution concentrations using satellite data and a network of >10,000 air quality stations. After accounting for the effects of meteorological variability, we find remarkable declines in ground-level nitrogen dioxide (NO2: −29 % with 95% confidence interval −44% to −13%), ozone (O3: −11%; −20% to −2%) and fine particulate matter (PM2.5: −9%; −28% to 10%) during the first two weeks of lockdown (n = 27 countries). These results are largely mirrored by satellite measures of the troposphere although long-distance transport of PM2.5 resulted in more heterogeneous changes relative to NO2. Pollutant anomalies were related to short-term health outcomes using empirical exposure-response functions. We estimate that there was a net total of 7400 (340 to 14600) premature deaths and 6600 (4900 to 7900) pediatric asthma cases avoided during two weeks post-lockdown. In China and India alone, the PM2.5-related avoided premature mortality was 1400 (1100 to 1700) and 5300 (1000 to 11700), respectively. Assuming that the lockdown-induced deviations in pollutant concentrations are maintained for the duration of 2020, we estimate 0.78 (0.09 to 1.5) million premature deaths and 1.6 (0.8 to 2) million pediatric asthma cases could be avoided globally. While the state of global lockdown is not sustainable, these findings illustrate the potential health benefits gained from reducing “business as usual” air pollutant emissions from economic activities. Explore trends here: www.covid-19-pollution.zsv.co.zaSignificance statementThe global response to the COVID-19 pandemic has resulted in unprecedented reductions in economic activity. We find that lockdown events have reduced air pollution levels by approximately 20% across 27 countries. The reduced air pollution levels come with a substantial health co-benefit in terms of avoided premature deaths and pediatric asthma cases that accompanied the COVID-19 containment measures.
COVID-19: Recovering estimates of the infected fatality rate during an ongoing pandemic through partial data
Authors: Villa Matteo , Myers James F. , Turkheimer Federico 
Published: April 2020

AbstractIn an ongoing epidemic, the case fatality rate is not a reliable estimate of a disease’s severity. This is particularly so when a large share of asymptomatic or pauci-symptomatic patients escape testing, or when overwhelmed healthcare systems are forced to limit testing further to severe cases only. By leveraging data on COVID-19, we propose a novel way to estimate a disease’s infected fatality rate, the true lethality of the disease, in the presence of sparse and partial information. We show that this is feasible when the disease has turned into a pandemic and data comes from a large number of countries, or regions within countries, as long as testing strategies vary sufficiently. For Italy, our method estimates an IFR of 1.1% (95% CI: 0.2% – 2.1%), which is strongly in line with other methods. At the global level, our method estimates an IFR of 1.6% (95% CI: 1.1% – 2.1%). This method also allows us to show that the IFR varies according to each country’s age structure and healthcare capacity.
‘Keeping the kids at home’ can limit the persistence of contagious pathogens in social animals
Authors: Marescot L. , Franz M. , Benhaiem S. , Hofer H. , East M.L. , Kramer-Schadt S. 
Published: April 2020

ABSTRACTIn social species where offspring are reared together in communal burrows or similar structures, young animals typically do not engage in between-group contact during their development – a behavioural trait we call ‘offspring with restricted between-group contact’ (ORC). The impact of this trait on the persistence of contagious pathogens that generate lifelong immunity in their hosts is currently unclear. We hypothesize that in populations with ORC, the formation, in groups, of a ‘protective barrier’ of only recovered adults, prevents the transmission of this type of pathogens to the new susceptible hosts (i.e. young animals), thereby increasing the probability of epidemic fade-out. We implement a spatially implicit individual-based Susceptible-Infected-Recovered (SIR) model for a large range of host and pathogen traits and show that the epidemic fade-out probability is consistently higher in populations with ORC, especially when disease spread is fast (high basic reproduction number R0). We also show that ORC can counteract the cost of group-living in terms of disease risk to a greater extent than variation in other traits. We discuss our findings in relation to herd immunity and outline how they could be used to implement efficient management measures such as vaccinations.
Proteomic analysis of necroptotic extracellular vesicles
Authors: Shlomovitz Inbar , Yanovich-Arad Gali , Erlich Ziv , Edry-Botzer Liat , Zargarian Sefi , Cohen Hadar , Ofir-Birin Yifat , Regev-Rudzki Neta , Gerlic Motti 
Published: April 2020

AbstractNecroptosis is a regulated and inflammatory form of cell death. We, and others, have previously reported that necroptotic cells release extracellular vesicles (EVs). We have found that necroptotic EVs are loaded with proteins, including the phosphorylated form of the key necroptosis-executing factor, mixed lineage kinase domain-like kinase (MLKL). However, neither the exact protein composition, nor the impact, of necroptotic EVs have been delineated. To characterize their content, EVs from necroptotic and untreated U937 cells were isolated and analyzed by mass spectrometry-based proteomics. A total of 3337 proteins were identified, sharing a high degree of similarity with exosome proteome databases, and clearly distinguishing necroptotic and control EVs. A total of 352 proteins were significantly upregulated in the necroptotic EVs. Among these were MLKL and caspase-8, as validated by immunoblot. Components of the ESCRTIII machinery and inflammatory signaling were also upregulated in the necroptotic EVs, as well as currently unreported components of vesicle formation and transport, and necroptotic signaling pathways. Moreover, we found that necroptotic EVs can be phagocytosed by macrophages to modulate cytokine and chemokine secretion. Finally, we uncovered that necroptotic EVs contain tumor neoantigens, and are enriched with components of antigen processing and presentation. In summary, our study reveals a new layer of regulation during the early stage of necroptosis, mediated by the secretion of specific EVs that influences the microenvironment and may instigate innate and adaptive immune responses. This study sheds light on new potential players in necroptotic signaling and its related EVs, and uncovers the functional tasks accomplished by the cargo of these necroptotic EVs.
PALP: An imaging method for detecting and quantifying polyunsaturated phospholipids via peroxidation
Authors: Zou Yilong , Graham Emily T. , Huang Yuwei , Salmon Wendy , Yu Li , Schreiber Stuart L. 
Published: April 2020

ABSTRACTPolyunsaturated phospholipids are essential for multiple cellular functions; however, their uncontrolled peroxidation leads to ferroptosis. Here we describephotochemicalactivation of membranelipidperoxidation (PALP), which uses localized laser pulses to induce lipid peroxidation photochemically. While PALP bypasses enzymatic requirements for lipid peroxidation, the resulting BODIPY-C11-based signal is largely correlated with local polyunsaturated phospholipid concentration on membranes. This technique enables non-invasive reporting of lipid unsaturation levels and sensitivity to ferroptosis in live cells.
miR-34c-3p regulates PKA activity independent of cAMP via ablation of PRKAR2B inTheileria annulata-infected leukocytes
Authors: Haidar Malak , Tajeri Shahin , Momeux Laurence , Mourier Tobias , Ben-Rached Fathia , Mfarrej Sara , Rchiad Zineb , Pain Arnab , Langsley Gordon 
Published: April 2020

AbstractMicroRNAs (miRNAs) are small non-coding RNAs that can play critical roles in regulating various cellular processes including during many parasitic infections. Here, we report a regulatory role for miR-34c-3p in cAMP-independent regulation of PKA activity inTheileria annulatainfection of bovine leukocytes. We identifiedprkar2b(cAMP-dependent protein kinase A type II-beta regulatory subunit), as a novel miR-34c-3p target gene and demonstrated how infection-induced up-regulation of miR-34c-3p in leukocytes repressed PRKAR2B expression to increase PKA activity and promote the virulent disseminating tumour phenotype ofT. annulata-transformed macrophages. Finally, we demonstrate that miR-34c-3p regulation ofprkar2bexpression is generalizable, by confirming thatPlasmodium falciparuminfection of red blood cells also raises intracellular levels of miR-34c-3p and show that this negatively regulates hostprkar2bexpression so increasing PKA activity. Infection-induced increase in miR-34c-3p levels, therefore, represents a novel cAMP-independent way of regulating host cell PKA activity in infections byTheileriaandPlasmodiumparasites.Abstract ImportanceTheileriaandPlasmodiuminfections of leukocytes and erythrocytes; respectively, lead to an increase in host cell miR-34c-3p levels and we identifiedprkar2b(cAMP-dependent protein kinase A type II-beta regulatory subunit), as a specific miR-34c-3p target gene. We demonstrate how infection-induced up-regulation of miR-34c-3p repressed PRKAR2B expression to increase PKA activity independent of fluxes in cAMP. Thus, in two different host-parasite combinations infection-induced increase in miR-34c-3p represents a novel epigenetic way of increasing in host PKA activity that contributes to the pathology of disease.
Optimization of multiplexed CRISPR/Cas9 system for highly efficient genome editing inSetaria viridis
Authors: Weiss Trevor , Wang Chunfang , Kang Xiaojun , Zhao Hui , Gamo Maria Elena , Starker Colby G. , Crisp Peter A. , Zhou Peng , Springer Nathan M. , Voytas Daniel F. , Zhang Feng 
Published: April 2020

AbstractIn recent years,Setaria viridishas been developed as a model plant to better understand the C4 photosynthetic pathway in major crops. With the increasing availability of genomic resources forS. viridisresearch, highly efficient genome editing technologies are needed to create genetic variation resources for functional genomics. Here, we developed a protoplast assay to rapidly optimize the multiplexed CRISPR/Cas9 system inS. viridis.Targeted mutagenesis efficiency was further improved by an average of 1.4-fold with the exonuclease,Trex2.Distinctive mutation profiles were found in the Cas9_Trex2 samples with 94% of deletions larger than 10bp, and less than 1% of mutations being insertions. Further analyses indicated that 52.2% of deletions induced by Cas9_Trex2, as opposed to 3.5% by Cas9 alone, were repaired through microhomology-mediated end joining (MMEJ) rather than the canonical NHEJ DNA repair pathway. Combined with the robust agrobacterium-mediated transformation method with more than 90% efficiency, the multiplex CRISPR/Cas9_Trex2 system was demonstrated to induce targeted mutations in two tightly linked genes,svDrm1aandsvDrm1b,at the frequency ranging from 73% to 100% in T0 plants. These mutations were transmitted to at least 60% of the transgene-free T1 plants with 33% of them containing bi-allelic or homozygous mutations in both genes. This highly efficient multiplex CRISPR/Cas9_Trex2 system makes it possible to create a large mutant resource forS. viridisin a rapid and high throughput manner, and has the potential to be widely applicable in achieving more predictable MMEJ-mediated mutations in many plant species.
Blueprint for a Pop-up SARS-CoV-2 Testing Lab
Authors:   Innovative Genomics Institute SARS-CoV-2 Testing Consortium, Hockemeyer Dirk , Urnov Fyodor , Green Ralph , Doudna Jennifer A. 
Published: April 2020

AbstractThe appearance and spread of the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) led to the official declaration of a global pandemic, with states in the US implementing shelter-in-place orders at an unprecedented scale. SARS-CoV-2 has a robust person-to-person transmission rate and an asymptomatic period of two weeks or more, leading to widespread infection that has overwhelmed healthcare infrastructures around the globe. Effective public health measures require extensive, accurate, and rapid testing to determine infection rates. Here we describe the strategy we used to establish a CLIA-licensed clinical laboratory to perform a validated Laboratory-Developed Test (LDT) for SARS-CoV-2 in Berkeley, California and the surrounding Bay Area community. Our procedures for implementing the technical, regulatory, and data management workstreams necessary for clinical sample processing provide a roadmap to aid others in setting up similar testing centers.Note on Nomenclaturein accordance with established virology and infectious disease nomenclature, throughout this document we use “SARS-CoV-2” to refer to the viral agent causing infection and “COVID-19” to refer to the human infectious disease caused by that viral agent.
A phenotype-specific framework for identifying the eye abnormalities causative nonsynonymous-variants
Authors: Liu Han-Kui , Dang Xiao , Guan Li-Ping , Tian Chang-Geng , Zhang Sheng-Hai , Ye Chen , Tellier Laurent Christian Asker M. , Chen Fang , Yang Huan-Ming , Sun Hao-Xiang , Wu Ji-Hong , Zhang Jian-Guo 
Published: April 2020

AbstractThe most important role of variant pathogenicity predictors is to identify the disease-phenotype causative variant in studying monogenic diseases. In the last decade, machine-learning based predictors exhibited a relatively accurate performance for distinguishing the pathogenic variants and contributed a significant role for all disease-spectrums. Yet, few predictors can investigate the phenotypic significance of variants. Here we presented a phenotype-specific framework aimed to directly point out the phenotypic significance of predicted candidates, and showed its advancing performance in eye abnormalities. By training on eye-abnormalities causative variants, our method presented 96.2% accuracy, 96.1% precision, 93.4% recall for pathogenicity identification. Inconsistent with the modeling performance, identifying the single phenotype-causative variant from various sequencing variants is challenging for all predictors. Underlying the phenotype-oriented, our method significantly promoted the precision and reduced the cost for identifying the single causative variant from thousands of candidates. These advances highlight the significance of the phenotype-specific training method for studying disease.
Generalized gametic relationships for flexible analyses of parent-of-origin effects
Authors: Reinsch N. , Mayer M. , Blunk I. 
Published: April 2020

AbstractGenomic imprinting causes alleles to influence the phenotype in a parent-of-origin-specific manner. In attempts to determine the effects of imprinted loci, gametic relationship matrices have widely been used in pedigree-based parent-of-origin analyses of population data. One drawback of this is the size of these matrices because they represent each individual by two gametic effects. Significantly fewer equations are needed if a previously published reduced imprinting model is used that relates observations from progeny without its own offspring to the transmitting abilities of their parents. This can be accomplished using a numerator relationship matrix, with only a single row and column per parent and ancestors. However, the reduced model is not applicable when the parents have records. To better handle the curse of dimensionality, we propose a combination of average gametic effects (transmitting abilities) for individuals without their own records and single gametic effects for others. The generalized gametic relationship matrix is the covariance of this mixture of genetic effects that allows for a significant reduction in the number of equations in gametic models depending on the trait, depth of pedigree, and population structure. It can also render the reduced model much more flexible by including observations from parents. Rules for setting-up its inverse from a pedigree are derived and implemented on an open-source program. The application of the same principles to phased marker data leads to a genomic version of the generalized gametic relationships. The implementation of generalized gametic models to the ASReml package is illustrated through worked examples.