bluuebunny/crossref_metadata_2025 huggingface dataset:
Galectin-1-deficient mice are protected againstTrypanosoma cruziinfection through altered neutrophil migration and production of reactive oxygen species and nitric oxide
Authors: Riul Thalita Bachelli , de Campos Helioswilton Sales , de Souza Lima-Junior Djalma , Azzolini Ana Elisa Caleiro Seixas , de Barros Cardoso Cristina Ribeiro , Stowell Sean R. , Cummings Richard D. , Valim Yara Maria Lucisano , Dias-Baruffi Marcelo
Published: September 2020

Trypanosoma cruziis an intracellular parasite that causes Chagas disease that affects millions of people worldwide. Many cellular and molecular aspects of this neglected disease are not fully understood. Prior studies have shown that galectin-1 (Gal-1), a β-galactoside-binding protein that regulates leukocyte recruitment to the inflammatory site, and promotesT. cruziinfection, but the mechanism is unclear. Here, we report that C57BL/6 mice lacking Gal-1 (Lgals1−/−) exhibited lower parasitemia and higher survival rates than their wildtype (WT) counterparts when infected withT. cruziY strain. Two weeks after infection,Lgals1−/−mice displayed greater neutrophil accumulation in infection site and heart tissue than WT mice. InT. cruzi-infectedLgals1−/−mice, infiltrated neutrophils produced increased levels of reactive oxygen species (ROS), while macrophages and neutrophils produced increased levels of nitric oxide (NO), which reduced replication and viability of parasitesin vitroand downregulated IL-1β production. Pharmacological inhibition of NADPH oxidase and NO synthase during earlyin vivoinfection reversed the protective effect of Gal-1 deficiency inLgals1−/−mice. Together, our findings demonstrate that lacking Gal-1 favors neutrophil migration to the infection site and increases production of ROS and NO, thereby controlling the early steps ofT. cruziinfection by reducing parasitemia and prolonging survival of infected mice.
Type I Interferon Limits Viral Dissemination-Driven Clinical Heterogeneity in a Native Murine Betacoronavirus Model of COVID-19
Authors: Qing Hua , Sharma Lokesh , Hilliard Brandon K. , Peng Xiaohua , Swaminathan Anush , Tian Justin , Israni-Winger Kavita , Zhang Cuiling , Leão Delva , Ryu Seungjin , Habet Victoria , Wang Lin , Tian Xuefei , Ma Yina , Ishibe Shuta , Young Lawrence H. , Kotenko Sergei , Compton Susan , Booth Carmen J. , Ring Aaron M. , Dixit Vishwa Deep , Wilen Craig B. , Pereira João P. , Dela Cruz Charles S. , Wang Andrew
Published: September 2020

Emerging clinical data demonstrates that COVID-19, the disease caused by SARS-CoV2, is a syndrome that variably affects nearly every organ system. Indeed, the clinical heterogeneity of COVID-19 ranges from relatively asymptomatic to severe disease with death resultant from multiple constellations of organ failures. In addition to genetics and host characteristics, it is likely that viral dissemination is a key determinant of disease manifestation. Given the complexity of disease expression, one major limitation in current animal models is the ability to capture this clinical heterogeneity due to technical limitations related to murinizing SARS-CoV2 or humanizing mice to render susceptible to infection. Here we describe a murine model of COVID-19 using respiratory infection with the native mouse betacoronavirus MHV-A59. We find that whereas high viral inoculums uniformly led to hypoxemic respiratory failure and death, lethal dose 50% (LD50) inoculums led to a recapitulation of most hallmark clinical features of COVID-19, including lymphocytopenias, heart and liver damage, and autonomic dysfunction. We find that extrapulmonary manifestations are due to viral metastasis and identify a critical role for type-I but not type-III interferons in preventing systemic viral dissemination. Early, but not late treatment with intrapulmonary type-I interferon, as well as convalescent serum, provided significant protection from lethality by limiting viral dissemination. We thus establish a Biosafety Level II model that may be a useful addition to the current pre-clinical animal models of COVID-19 for understanding disease pathogenesis and facilitating therapeutic development for human translation.
A bacterial artificial chromosome (BAC)-vectored noninfectious replicon of SARS-CoV-2
Authors: Zhang Yang , Song Wuhui , Chen Shuiye , Yuan Zhenghong , Yi Zhigang
Published: September 2020

Vaccines and antiviral agents are in urgent need to stop the COVID-19 pandemic. To facilitate antiviral screening against SARS-CoV-2 without requirement for high biosafety level facility, we developed a bacterial artificial chromosome (BAC)-vectored replicon of SARS-CoV-2, nCoV-SH01 strain, in which secretedGaussialuciferase (sGluc) was encoded in viral subgenomic mRNA as a reporter gene. The replicon was devoid of structural genes spike (S), membrane (M), and envelope (E). Upon transfection, the replicon RNA replicated in various cell lines, and was sensitive to interferon alpha (IFN-α), remdesivir, but was resistant to hepatitis C virus inhibitors daclatasvir and sofosbuvir. Replication of the replicon was also sensitive overexpression of zinc-finger antiviral protein (ZAP). We also constructed a four-plasmidin-vitroligation system that is compatible with the BAC system, which makes it easy to introduce desired mutations into the assembly plasmids forin-vitroligation. This replicon system would be helpful for performing antiviral screening and dissecting virus-host interactions.
Ketogenesis restrains aging-induced exacerbation of COVID in a mouse model
Authors: Ryu Seungjin , Shchukina Irina , Youm Yun-Hee , Qing Hua , Hilliard Brandon K. , Dlugos Tamara , Zhang Xinbo , Yasumoto Yuki , Booth Carmen J. , Fernández-Hernando Carlos , Suárez Yajaira , Khanna Kamal M. , Horvath Tamas L. , Dietrich Marcelo O. , Artyomov Maxim N. , Wang Andrew , Dixit Vishwa Deep
Published: September 2020

Increasing age is the strongest predictor of risk of COVID-19 severity. Unregulated cytokine storm together with impaired immunometabolic response leads to highest mortality in elderly infected with SARS-CoV-2. To investigate how aging compromises defense against COVID-19, we developed a model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain MHV-A59 (mCoV-A59) that recapitulated majority of clinical hallmarks of COVID-19. Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue and hypothalamus, including neutrophilia and loss of γδ T cells in lungs. Ketogenic diet increases beta-hydroxybutyrate, expands tissue protective γδ T cells, deactivates the inflammasome and decreases pathogenic monocytes in lungs of infected aged mice. These data underscore the value of mCoV-A59 model to test mechanism and establishes harnessing of the ketogenic immunometabolic checkpoint as a potential treatment against COVID-19 in the elderly.

Highlights

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Natural MHV-A59 mouse coronavirus infection mimics COVID-19 in elderly.

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Aged infected mice have systemic inflammation and inflammasome activation

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Murine beta coronavirus (mCoV) infection results in loss of pulmonary γδ T cells.

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Ketones protect aged mice from infection by reducing inflammation.

eTOC Blurb

Elderly have the greatest risk of death from COVID-19. Here, Ryu et al report an aging mouse model of coronavirus infection that recapitulates clinical hallmarks of COVID-19 seen in elderly. The increased severity of infection in aged animals involved increased inflammasome activation and loss of γδ T cells that was corrected by ketogenic diet.
Evolutionary Dynamics of Non-Coding Regions in Pancreatic Ductal Adenocarcinoma
Authors: Hayashi Akimasa , Ho Yu-jui , Makohon-Moore Alvin P. , Zucker Amanda , Hong Jungeui , Reiter Johannes G. , Huang Jinlong , Zhang Lance , Attiyeh Marc A. , Baez Priscilla , Kappagantula Rajya , Melchor Jerry P. , O’Reilly Eileen M. , Socci Nicholas D. , Oki Shinya , Lowe Scott W. , Iacobuzio-Donahue Christine A.
Published: September 2020

While the non-coding genome appears to play a role, the dynamic nature of noncoding alterations with respect to clonal progression of solid tumors remains unexplored. To address this gap in knowledge we performed multiregional whole genome sequencing and clonal analysis to elucidate the evolutionary dynamics of non-coding regions in pancreatic cancer relative to those of the coding genome. We find that the mutational burden of noncoding DNA is higher than coding DNA. However, when noncoding DNA was segregated into enhancer and non-enhancer regions, enhancers were more similar to coding DNA. Mutational signatures of noncoding and coding DNA further revealed the similar mutational spectra of enhancers to coding DNA whereas the mutational spectra of non-enhancer, noncoding DNA had an entirely different pattern. These findings shed light on the role of noncoding DNA in pancreatic cancer.
Antimicrobial emulsifier – glycerol monolaurate impacts gut micobiome inducing distinct effects on metabolic syndrome in low-fat diet fed mice
Authors: Jiang Zengliang , Xiao Congmei , Zhang Xi , Zhao Minjie , Liu Tao , Xu Yisong , Zhang Hui , Zheng Ju-Sheng , Feng Fengqin
Published: September 2020

Previous study demonstrated 150 mg·kg−1glycerol monolaurate (GML) consumption induced gut microbiota dysbiosis and metabolic syndrome (MetS) in low-fat diet fed mice. However, little is known about the dose-effect of dietary GML modulating the gut microbiome alterations and its impacts on the induction of MetS in low-fat diet. Dietary GML-induced effects on MetS and gut microbiota alterations were investigated, combined with antibiotics-treated germ-free experiment and specific gut microbiota transplantation. Our results demonstrated that high-dose (500 mg·kg−1) GML alleviated MetS by significantly decreasing the body weight, weight gain, food intake, fat droplet size and percentage of abdominal fat, serum triglycerides (TG), LDL, LPS, TNF-α and atherogenic index, compared to the medium-dose (150 mg·kg−1) GML. Importantly, high-dose GML significantly increasedLactobacillus reutericompared to the medium-dose GML. Co-occurrence network analysis revealedLactobacillus reuteriwas positively associated with the metabolic improvement of high-dose GML. Notably, antibiotics-treated germ-free experiment andLactobacillus reuteritransplantation demonstrated that altered gut microbiota was necessary and sufficient for GML-induced distinct effects on metabolic syndrome. Our results indicate that GML impacts gut microbiome inducing distinct effects on metabolic syndrome, thereby calling for reassessing the safe dosage of GML and other non-specific antibacterial food additives.

IMPORTANCE

Growing evidence indicate that the broad use of food emulsifying agents may lead to increase the societal incidence of obesity/ MetS and other chronic inflammatory diseases. GML is widely and regularly consumed as a generally safe food emulsifier and as a potent antimicrobial agent in commonly foods such as meat products, cereals and soft beverage by the general public. Our results indicate that GML impacts gut microbiome inducing distinct effects on metabolic syndrome. Our study provides important and timely evidence supporting the emerging concept that non-specific antibacterial food additives have two-sided effect on gut microbiota contributing to the uncertainties for the incidence of obesity/metabolic syndrome and other chronic inflammatory diseases.
Gut metabolites influence susceptibility of neonatal mice to cryptosporidiosis
Authors: VanDussen Kelli L. , Funkhouser-Jones Lisa J. , Akey Marianna E. , Schaefer Deborah A. , Ackman Kevin , Riggs Michael W. , Stappenbeck Thaddeus S. , Sibley L. David
Published: September 2020

The protozoan parasiteCryptosporidiumis a leading cause of diarrheal disease in those with compromised or under-developed immune systems, particularly infants and toddlers in resource-poor localities. As an enteric pathogen,Cryptosporidiuminvades the apical surface of intestinal epithelial cells, where it resides in close proximity to metabolites in the intestinal lumen. However, the effect of gut metabolites on susceptibility toCryptosporidiuminfection remains largely unstudied. Here, we first identified which gut metabolites are prevalent in neonatal mice when they are most susceptible toCryptosporidium parvuminfection, and then tested the isolated effects of these metabolites onC. parvuminvasion and growth. Our findings demonstrate that medium or long-chain saturated fatty acids inhibitC. parvumgrowth, while long-chain unsaturated fatty acids enhanceC. parvuminvasion. The influence of these two classes of metabolites onC. parvuminfection likely reflects the streamlined metabolism inC. parvum, which is unable to synthesize fatty acids. Hence, gut metabolites, either from diet or produced by the microbiota, play an important role in the early susceptibility to cryptosporidiosis seen in young animals.

Importance

Cryptosporidiumoccupies a unique intracellular niche that exposes the parasite to both host cell contents and the intestinal lumen, including metabolites from the diet and produced by the microbiota. Both dietary and microbial products change over the course of early development, and could contribute to the changes seen in susceptibility to cryptosporidiosis in humans and mice. Consistent with this model, we show that the immature gut metabolome influenced growth ofC. parvum in vitroand may increase susceptibility to infection in young mice. Interestingly, metabolites that significantly altered parasite growth were fatty acids, a class of molecules thatCryptosporidiumis unable to synthesize de novo. The enhancing effects of polyunsaturated fatty acids and the inhibitory effects of saturated fatty acids provide further insight into reliance on fatty acid salvage and metabolism of this enteric parasite.
Non-optimal codon usage is critical for protein structure and function of the master general amino acid control regulator CPC-1
Authors: Lyu Xueliang , Liu Yi
Published: September 2020

Under amino acid starvation condition, eukaryotic organisms activate a general amino acid control response. In Neurospora crassa, Cross Pathway Control-1 (CPC-1), the ortholog of the Saccharomyces cerevisiae bZIP transcription factor GCN4, functions as the master regulator of the general amino acid control response. Codon usage biases are a universal feature of eukaryotic genomes and are critical for regulation of gene expression. Although codon usage has also been implicated in the regulation of protein structure and function, genetic evidence supporting this conclusion is very limited. Here we show that Neurospora cpc-1 has a non-optimal NNU-rich codon usage profile that contrasts with the strong NNC codon preference in the genome. Although substitution of the cpc-1 NNU codons with synonymous NNC codons elevated CPC-1 expression in Neurospora, it altered CPC-1 degradation rate and abolished its amino acid starvation-induced protein stabilization. The codon-manipulated CPC-1 protein also exhibited different sensitivity to limited protease digestion. Furthermore, CPC-1 functions in rescuing the cell growth of the cpc-1 deletion mutant and activating the expression of its target genes were impaired by the synonymous codon changes. Together, these results reveal the critical role of codon usage in regulating of CPC-1 expression and function, and establish a genetic example of the importance of codon usage in protein structure.

Abstract importance

General amino acid control response is critical for organisms to adapt to amino acid starvation condition. The preference to use certain synonymous codons are a universal feature of all genomes. Synonymous codon changes were previously thought to be silent mutations. In this study, we show that the Neurospora cpc-1 gene has an unusual codon usage profile compared to other genes in the genome. We found that codon optimization of the cpc-1 gene without changing its amino acid sequence resulted in elevated CPC-1 expression, altered protein degradation rate and impaired protein functions due to changes in protein structure. Together, these results reveal the critical role of synonymous codon usage in regulating of CPC-1 expression and function, and establish a genetic example of the importance of codon usage in protein structure.
Cerebral Venous Sinus Thrombosis Associated with SARS-CoV-2; a Multinational Case Series
Authors: Mowla Ashkan , Shakibajahromi Banafsheh , Shahjouei Shima , Borhani-Haghighi Afshin , Rahimian Nasrin , Baharvahdat Humain , Naderi Soheil , Khorvash Fariborz , Altafi Davar , Ebrahimzadeh Seyed Amir , Farahmand Ghasem , Far Alaleh Vaghefi , Sharma Vijay K. , Neshin Saeideh Aghayari Sheikh , Tsivgoulis Georgios , Zand Ramin
Published: September 2020

Background

SARS-CoV-2 induced coagulopathy can lead to thrombotic complications such as stroke. Cerebral venous sinus thrombosis (CVST) is a less common type of stroke which might be triggered by COVID-19. We present a series of CVST cases with SARS-CoV-2 infection.

Methods

In a multinational retrospective study, we collected all cases of CVST in SARS-CoV-2 infected patients admitted to nine tertiary stroke centers from the beginning of the pandemic to June 30th, 2020. We compared the demographics, clinical and radiological characteristics, risk factors, and outcome of these patients with a control group of non-SARS-CoV-2 infected CVST patients in the same seasonal period of the years 2012-2016 from the country where the majority of cases were recruited.

Results

A total of 13 patients fulfilled the inclusion criteria (62% women, mean age 50.9± 11.2 years). Six patients were discharged with good outcomes (mRS≤2) and three patients died in hospital. Compared to the control group, the SARS-CoV-2 infected patients were significantly older (50.9 versus 36.7 years, p<0.001), had a lower rate of identified CVST risk factors (23.1% versus 84.2%, p<0.001), had more frequent cortical vein involvement (38.5% versus 10.5%, p: 0.025), and a non-significant higher rate of in-hospital mortality (23.1% versus 5.3%, p: 0.073).

Conclusion

CVST should be considered as potential comorbidity in SARS-CoV-2 infected patients presenting with neurological symptoms. Our data suggest that compared to non-SARS-CoV-2 infected patients, CVST occurs in older patients, with lower rates of known CVST risk factors and might lead to a poorer outcome in the SARS-CoV-2 infected group.
Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia
Authors:   The Schizophrenia Working Group of the Psychiatric Genomics Consortium, Ripke Stephan , Walters James TR , O’Donovan Michael C
Published: September 2020

Schizophrenia is a psychiatric disorder whose pathophysiology is largely unknown. It has a heritability of 60-80%, much of which is attributable to common risk alleles, suggesting genome-wide association studies can inform our understanding of aetiology1. Here, in 69,369 people with schizophrenia and 236,642 controls, we report common variant associations at 270 distinct loci. Using fine-mapping and functional genomic data, we prioritise 19 genes based on protein-coding or UTR variation, and 130 genes in total as likely to explain these associations. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in autism and developmental disorder. Associations were concentrated in genes expressed in CNS neurons, both excitatory and inhibitory, but not other tissues or cell types, and implicated fundamental processes related to neuronal function, particularly synaptic organisation, differentiation and transmission. We identify biological processes of pathophysiological relevance to schizophrenia, show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders, and provide a rich resource of priority genes and variants to advance mechanistic studies.
Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort
Authors: Qin Youwen , Havulinna Aki S. , Liu Yang , Jousilahti Pekka , Ritchie Scott C. , Tokolyi Alex , Sanders Jon G. , Valsta Liisa , Brożyńska Marta , Zhu Qiyun , Tripathi Anupriya , Vazquez-Baeza Yoshiki , Loomba Rohit , Cheng Susan , Jain Mohit , Niiranen Teemu , Lahti Leo , Knight Rob , Salomaa Veikko , Inouye Michael , Méric Guillaume
Published: September 2020

Co-evolution between humans and the microbial communities colonizing them has resulted in an intimate assembly of thousands of microbial species mutualistically living on and in their body and impacting multiple aspects of host physiology and health. Several studies examining whether human genetic variation can affect gut microbiota suggest a complex combination of environmental and host factors. Here, we leverage a single large-scale population-based cohort of 5,959 genotyped individuals with matched gut microbial shotgun metagenomes, dietary information and health records up to 16 years post-sampling, to characterize human genetic variations associated with microbial abundances, and predict possible causal links with various diseases using Mendelian randomization (MR). Genome-wide association study (GWAS) identified 583 independent SNP-taxon associations at genome-wide significance (p<5.0×10-8), which included notable strong associations withLCT(p=5.02×10-35),ABO(p=1.1×10-12), andMED13L(p=1.84×10-12). A combination of genetics and dietary habits was shown to strongly shape the abundances of certain key bacterial members of the gut microbiota, and explain their genetic association. Genetic effects from theLCTlocus onBifidobacteriumand three other associated taxa significantly differed according to dairy intake. Variation in mucin-degradingFaecalicatena lactarisabundances were associated withABO, highlighting a preferential utilization of secreted A/B/AB-antigens as energy source in the gut, irrespectively of fibre intake.Enterococcus faecalislevels showed a robust association with a variant inMED13L, with putative links to colorectal cancer. Finally, we identified putative causal relationships between gut microbes and complex diseases using MR, with a predicted effect ofMorganellaon major depressive disorder that was consistent with observational incident disease analysis. Overall, we present striking examples of the intricate relationship between humans and their gut microbial communities, and highlight important health implications.
Major depressive disorder but not bipolar disorder and schizophrenia is a causal factor for type 2 diabetes as determined by Mendelian randomization
Authors: Jin Heejin , Lee Jeewon , Oh Sohee , Lee Sanghun , Won Sungho
Published: September 2020

Objective

In many epidemiologic studies, type 2 diabetes has been reported to be associated with severe mental illness (SMI) such as schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD). However, the relationship between SMI and type 2 diabetes is bi-directional, and the causal relationship remains unclear due to various confounders. Therefore, a Mendelian randomization (MR) study is necessary to identify the causality between them.

Research Design and Methods

We conducted a two-sample MR study to identify the causal effect of SMI on type 2 diabetes using the inverse-variance weighted (IVW), MR-Egger, MR-Egger with a simulation extrapolation, weighted median approach, and MR-Pleiotropy RESidual Sum and Outlier methods. The most appropriate method was selected according to the instrument variables assumption.

Results

We found that MDD had a significant causal effect on type 2 diabetes from the results obtained using the IVW method (Odds ratio (OR): 1.191, 95% CI: 1.036–1.372, P = 0.014); however, this was not observed for BPD (IVW, OR: 1.006, 95% CI: 0.918–1.104, P = 0.892) or SCZ (IVW, OR: 1.016, 95% CI: 0.974–1.059, P = 0.463). The absence of reverse-causality between MDD and type 2 diabetes was also demonstrated from bi-directional MR studies.

Conclusions

These results clearly reveal important knowledge on the causal role of MDD in the risk of type 2 diabetes without a residual confounding, whereas the causality of BPD and SCZ was not shown. Therefore, careful attention should be paid to MDD patients in type 2 diabetes prevention and treatment.
Effect of Lockdown Implementation, Environmental & Behavioural factors, Diet and Virus Mutations on COVID-19 Outcomes: A Study on Critical Containment Zones of Indian state of Maharashtra
Authors: Mohite Onkar T. , Avhad Arvind S. , Sutar Prasad P. , Pawar Vaibhav S.
Published: September 2020

This work details the study of critical containment zones in Maharashtra within a time (April 9 2020 - July 31 2020) in the context of COVID-19. The effects of lockdown implementation, community isolation, environmental factors, demographic aspects, behavioural factors, diet etc. have been investigated. The effect of the aforementioned factors on the infected cases, cumulative infected cases, recoveries, cumulative recoveries, active cases, deaths and cumulative deaths are analyzed. The integrated effects of the aforementioned factors on COVID-19 outcomes are further amplified due to adequate and inadequate health facilities. The study will be helpful to scientists, researchers, pharmacists and biotechnologists in new vaccine design & to accommodate above factors for the betterment of susceptible & infected people of Maharashtra and similar demographies across the globe. Further, it pinpoints the need for more awareness and control strategies among the people to reduce the havoc, stress, fear, anxiety, pathogenicity and thereby reducing mortality.
Impact and Correlation of Air Quality and Climate Variables with COVID-19 Morbidity and Mortality in Dhaka, Bangladesh
Authors: Pavel Md Riad Sarkar , Salam Abdus , Yesmin Mahbuba , Ahsan Nazmul , Zaman Shahid Uz , Jeba Farah
Published: September 2020

The COVID-19 pandemic unexpectedly stopped the steady life and enhanced environmental quality. To apprehend the transmission of COVID-19 and the improvement of air quality, we have studied air quality indicators (PM2.5, PM10, AQI, and NO2), CO2 emission, and climate variables (temperature, relative humidity, rainfall, and wind velocity) in the extremely polluted and densely populated Southeast Asian megacity Dhaka, Bangladesh from March to June 2020. The Kendall and Spearman correlations were chosen to test the connotation of air quality and climate variables with COVID-19 morbidity and mortality. The average concentrations of PM2.5, PM10, and CO2 were 65.0 ± 37.9 and 87.1 ± 52.8 µm m-3, and 427 ± 11.8 ppm, respectively. The average PM2.5 and PM10 drastically reduced up to 62% during COVID-19 lockdown in Dhaka comparing with March 2020 (before lockdown). Comparing with the same period in 2019, PM2.5 reduced up to 33.5%. The average NO2 concentration was 35.0 µmol m-2 during the lockdown period in April, whereas 175.0 µmol m-2 during March (before lockdown). A significant correlation was observed between COVID-19 cases and air quality indicators. A strong correlation was obtained between climate variables and the total number of COVID-19 morbidity and mortality representing a favorable condition for spreading the virus. Our study will be very expedient for policymakers to establish a mechanism for air pollution mitigation based on scientific substantiation, and also will be an essential reference for the advance research to improve urban air quality and the transmission of the SARS-CoV-2 virus in the tropical nations.

Graphical Abstract

Highlights

COVID-19 lockdown drastically reduced PM2.5 and PM10 concentrations up to 62%.

During lockdown, NO2 emission abridged up to 80%, CO2 emission dropped by 2-4%.

Climate variables revealed strong correlation with COVID-19 morbidity and mortality.

COVID-19 cases and mortality had significant correlation with air quality indicators.

Knowledge from enormous improved air quality will be transmitted to the policy execution.
TIN2 facilitates TRF1-mediatedtrans- andcis-interactions on physiologically relevant long telomeric DNA
Authors: Pan Hai , Kaur Parminder , Liu Ming , Xu Pengning , Mahn Chelsea , Barnes Ryan , Tang Qingyu , Hao Pengyu , Bhattaram Dhruv , You Changjiang , Piehler Jacob , Weninger Keith , Riehn Robert , Smith Susan , Opresko Patricia L. , Wang Hong
Published: September 2020

The shelterin complex consisting of TRF1, TRF2, RAP1, TIN2, TPP1, and POT1, functions to prevent false recognition of telomeres as double-strand DNA breaks, and to regulate telomerase and DNA repair protein access. TIN2 is a core component linking double-stranded telomeric DNA binding proteins (TRF1 and TRF2) and proteins at the 3’ overhang (TPP1-POT1). Since knockdown of TIN2 also removes TRF1 and TRF2 from telomeres, determining TIN2’s unique mechanistic function has been elusive. Here, we investigated DNA molecular structures promoted by TRF1-TIN2 using complementary single-molecule imaging platforms, including atomic force microscopy (AFM), total internal reflection fluorescence microscopy (TIRFM), and the DNA tightrope assay. We demonstrate that TIN2S and TIN2L isoforms facilitate TRF1-mediated DNA compaction (cis-interactions) and DNA-DNA bridging (trans-interactions) in a telomeric sequence- and length-dependent manner. On the short telomeric DNA substrate (6 TTAGGG repeats), the majority of TRF1 mediated telomeric DNA-DNA bridging events are transient with a lifetime of ~1.95 s. On longer DNA substrates (270 TTAGGG), TIN2 forms multi-protein complexes with TRF1 and stabilizes TRF1-mediated DNA-DNA bridging events that last for at least minutes. Preincubation of TRF1 with its regulator protein Tankyrase 1 significantly reduces TRF1-TIN2 mediated DNA-DNA bridging, whereas TIN2 protects the disassembly of TRF1-TIN2 mediated DNA-DNA bridging upon Tankyrase 1 addition. Our study provides evidence that TIN2 functions to promote TRF1 mediatedtrans-interactions of telomeric DNA, leading to new mechanistic insight into sister telomere cohesion.
Evaluation Of The Quercetin Semisynthetic Derivatives Interaction With Breast Cancer Resistance Protein
Authors: Manukyan A.E. , Hovhannisyan A.A.
Published: September 2020

Breast cancer resistance protein (BCRP, ABCG2) is one of the ATP binding cassette (ABC) transporter proteins which involved in multi-drug resistance of cancer therapy. BCRP is expressed in various types of human cancer and inhibiting can be a solution to overcome multidrug resistance. Significant effort has been devoted to develop treatment strategies to overcome BCRP-mediated resistance. In addition, BCRP is expressed also in many normal tissues and plays an important role in drug absorption, distribution, and elimination. In order to design an effective cancer treatment strategy, a lot of flavones and their derivatives are used as anticancer drug compounds. One of the most promising flavonols is quercetin and quercetin semisynthetic derivatives which can inhibit the expression of BCRP.

Highlights

Virtual screening using multiple docking program for consensus predictions.

Virtual screening of the quercetin derivatives as potential inhibitors of BCRP.

Selected derivatives bind to the main amino acids of proteins.

Selected derivatives meet the criteria necessary for their consideration as drugs.
Interspecies Chimeric Conditions Affect the Developmental Rate of Human Pluripotent Stem Cells
Authors: Brown Jared , Barry Christopher , Schmitz Matthew T. , Argus Cara , Bolin Jennifer M. , Schwartz Michael P. , Van Aartsen Amy , Steill John , Swanson Scott , Stewart Ron , Thomson James A. , Kendziorski Christina
Published: September 2020

Human pluripotent stem cells hold significant promise for regenerative medicine. However, long differentiation protocols and immature characteristics of stem cell-derived cell types remain challenges to the development of many therapeutic applications. In contrast to the slow differentiation of human stem cellsin vitrothat mirrors a nine-month gestation period, mouse stem cells develop according to a much faster three-week gestation timeline. Here, we tested if co-differentiation with mouse pluripotent stem cells could accelerate the differentiation speed of human embryonic stem cells. Following a six-week RNA-sequencing time course of neural differentiation, we identified 929 human genes that were upregulated earlier and 535 genes that exhibited earlier peaked expression profiles in chimeric cell cultures than in human cell cultures alone. Genes with accelerated upregulation were significantly enriched in Gene Ontology terms associated with neurogenesis, neuron differentiation and maturation, and synapse signaling. Moreover, chimeric mixed samples correlated within uterohuman embryonic samples earlier than human cells alone, and acceleration was dose-dependent on human-mouse co-culture ratios. Differences in the timing and expression levels of genes corresponding to neuron cell types and brain region identity under chimeric conditions were also observed. The altered developmental rates and lineage outcomes described in this report have implications for accelerating human stem cell differentiation and the use of interspecies chimeric embryos in developing human organs for transplantation.

Author Summary

Human pluripotent stem cells often require longin vitroprotocols to form mature cell types of clinical relevance for potential regenerative therapies, a ramification of a nine-month developmental clockin uterothat also runsex utero. What controls species-specific developmental time and whether the timer is amenable to acceleration is unknown. Further, interspecies chimeric embryos are increasingly being created to study early human development or explore the potential growth of human organs for transplantation. How the conflicting developmental speeds of cells from different species co-differentiating together affect each other is not understood. Here, using genome-wide transcriptional analysis of RNA-sequencing time courses, we show that 1) co-differentiating human embryonic stem cells intermixed with mouse stem cells accelerated elements of human developmental programs, 2) the acceleration was dose-dependent on the proportion of mouse cells, and 3) human cells in chimeric samples correlated toin uterosamples earlier than human only samples. Our results provide evidence that some components of species-specific developmental clocks may be susceptible to acceleration.
Advanced Retinal Imaging and Ocular Parameters of the Rhesus Macaque Eye
Authors: Lin Kira H. , Tran Tu , Kim Soohyun , Park Sangwan , Stout J. Timothy , Chen Rui , Rogers Jeffrey , Yiu Glenn , Thomasy Sara , Moshiri Ala
Published: September 2020

Purpose

To determine the normal ocular biometric and perform advanced retinal imaging and functional assessment of a non-human primate used commonly in scientific research, the rhesus macaque.

Methods

We performed ocular phenotyping on rhesus macaques at the California National Primate Research Center. This consisted of anterior and posterior segment eye examination by ophthalmologists, advanced retinal imaging, and functional retinal electrophysiology.

Results

Full eye exams were performed on 142 animals consisting of pupillary light reflex, tonometry, external exam and photography, anterior slit lamp examination, and posterior segment examination by indirect ophthalmoscopy. Ages of the rhesus macaques ranged from 0.7 to 29 years (mean=16.4 years, stdev=7.5 years). Anterior segment measurements such as intraocular pressure (n=142), corneal thickness (n=84), lens thickness (n=114), and axial length (n=114) were acquired. Advanced retinal imaging in the form of fundus photography (n=78), optical coherence tomography (n=60), and quantitative autofluorescence (n=44) were obtained. Electroretinography (n=75) was used to assay retinal function. Quantitative analyses of macular structure, retinal layer segmentation, and rod and cone photoreceptor electrical responses are reported. Quantitative assessments were made and variations between genders and age groups were analyzed to compare with established sex and age-related changes in human eyes.

Conclusions

The rhesus macaque has ocular structure and function very similar to that of the human eye. Age-related ocular changes between rhesus and humans are similar. In particular, macular structure and function are very similar to humans making this species particularly useful for the study of macular biology and development of therapies for inherited and age-related macular degenerations as well as cone photoreceptor disorders.
A hybrid high-resolution anatomical MRI atlas with sub-parcellation of cortical gyri using resting fMRI
Authors: Joshi Anand A. , Choi Soyoung , Liu Yijun , Chong Minqi , Sonkar Gaurav , Gonzalez-Martinez Jorge , Nair Dileep , Wisnowski Jessica L. , Haldar Justin P. , Shattuck David W. , Damasio Hanna , Leahy Richard M.
Published: September 2020

We present a new high-quality, single-subject atlas with sub-millimeter voxel resolution, high SNR, and excellent grey-white tissue contrast to resolve fine anatomical details. The atlas is labeled into two parcellation schemes: 1) the anatomical BCI-DNI atlas, which is manually labeled based on known morphological and anatomical features, and 2) the hybrid USCBrain atlas, which incorporates functional information to guide the sub-parcellation of cerebral cortex. In both cases, we provide consistent volumetric and cortical surface-based parcellation and labeling. The intended use of the atlas is as a reference template for structural coregistration and labeling of individual brains. A single-subject T1-weighted image was acquired at a resolution of 0.547mm×0.547mm×0.800mm five times and averaged. Images were processed by an expert neuroanatomist using semi-automated methods in BrainSuite to extract the brain, classify tissue-types, and render anatomical surfaces. Sixty-six cortical and 29 noncortical regions were manually labeled to generate the BCI-DNI atlas. The cortical regions were further sub-parcellated into 130 cortical regions based on multi-subject connectivity analysis using resting fMRI (rfMRI) data from the Human Connectome Project (HCP) database to produce the USCBrain atlas. In addition, we provide a delineation between sulcal valleys and gyral crowns, which offer an additional set of 26 sulcal subregions per hemisphere. Lastly, a probabilistic map is provided to give users a quantitative measure of reliability for each gyral subdivision. Utility of the atlas was assessed by computing adjusted Rand indices between individual sub-parcellations obtained through structural-only coregistration to the USCBrain atlas and sub-parcellations obtained directly from each subject’s resting fMRI data. Both atlas parcellations can be used with the BrainSuite, FreeSurfer, and FSL software packages.
RANKL from Bone Marrow Adipose Lineage Cells Promotes Osteoclast Formation and Bone Loss
Authors: Hu Yan , Li Xiaoqun , Zhi Xin , Cong Wei , Huang Biaotong , Chen Huiwen , Wang Yajun , Li Yinghua , Wang Lipeng , Fang Chao , Guo Jiawei , Liu Ying , Cui Jin , Cao Liehu , Weng Weizong , Zhou Qirong , Wang Sicheng , Chen Xiao , Su Jiacan
Published: September 2020

Receptor activator of NF-κB ligand (RANKL) is essential for osteoclast formation and bone remodeling. Nevertheless, the cellular source of RANKL for osteoclastogenesis has not been fully uncovered. Different from peripheral adipose tissue, bone marrow (BM) adipose lineage cells originate from bone marrow mesenchymal stromal cells(BMSCs). Here we demonstrate that adiponectin promoter-driven Cre expression (AdipoqCre) can target bone marrow adipose lineage cells. We cross theAdipoqCremice withranklfl/flmice to conditionally delete RANKL from BM adipose lineage cells. Conditional deletion of RANKL increases cancellous bone mass of long bones in mice by reducing the formation of trabecular osteoclasts and inhibiting bone resorption but does not affect cortical bone thickness or resorption of calcified cartilage.AdipoqCre; ranklfl/flmice exhibit resistance to estrogen deficiency and rosiglitazone (ROS) induced trabecular bone loss but show bone loss induced by unloading. BM adipose lineage cells therefore represent an essential source of RANKL for the formation of trabecula osteoclasts and resorption of cancellous bone during remodeling under physiological and pathological conditions. Targeting bone marrow adiposity is a promising way of preventing pathological bone loss.
Idiosyncratic variation in the fitness costs of tetracycline-resistance mutations inEscherichia coli
Authors: Card Kyle J. , Jordan Jalin A. , Lenski Richard E.
Published: September 2020

A bacterium’s fitness relative to its competitors, both in the presence and absence of antibiotics, plays a key role in its ecological success and clinical impact. In this study, we examine whether tetracycline-resistant mutants are less fit in the absence of the drug than their sensitive parents, and whether the fitness cost of resistance is constant or variable across independently derived lines. Tetracycline-resistant lines suffered, on average, a reduction in fitness of almost 8%. There was substantial among-line variation in the fitness cost. This variation was not associated with the level of phenotypic resistance conferred by the mutations, nor did it vary significantly across several different genetic backgrounds. The two resistant lines with the most extreme fitness costs involved functionally unrelated mutations on different genetic backgrounds. However, there was also significant variation in the fitness costs for mutations affecting the same pathway and even different alleles of the same gene. Our findings demonstrate that the fitness costs of antibiotic resistance do not always correlate with the phenotypic level of resistance or the underlying genetic changes. Instead, these costs reflect the idiosyncratic effects of particular resistance mutations and the genetic backgrounds in which they occur.
Inferring MHC interacting SARS-CoV-2 epitopes recognized by TCRs towards designing T cell-based vaccines
Authors: Mohseni Amir Hossein , Taghinezhad-S Sedigheh , Su Bing , Wang Feng
Published: September 2020

The coronavirus disease 2019 (COVID-19) is triggered by severe acute respiratory syndrome mediated by coronavirus 2 (SARS-CoV-2) infection and was declared by WHO as a major international public health concern. While worldwide efforts are being advanced towards vaccine development, the structural modeling of TCR-pMHC (T Cell Receptor-peptide-bound Major Histocompatibility Complex) regarding SARS-CoV-2 epitopes and the design of effective T cell vaccine based on these antigens are still unresolved. Here, we present both pMHC and TCR-pMHC interfaces to infer peptide epitopes of the SARS-CoV-2 proteins. Accordingly, significant TCR-pMHC templates (Z-value cutoff > 4) along with interatomic interactions within the SARS-CoV-2-derived hit peptides were clarified. Also, we applied the structural analysis of the hit peptides from different coronaviruses to highlight a feature of evolution in SARS-CoV-2, SARS-CoV, bat-CoV, and MERS-CoV. Peptide-protein flexible docking between each of the hit peptides and their corresponding MHC molecules were performed, and a multi-hit peptides vaccine against the S and N glycoprotein of SARS-CoV-2 was designed. Filtering pipelines including antigenicity, and also physiochemical properties of designed vaccine were then evaluated by different immunoinformatics tools. Finally, vaccine-structure modeling and immune simulation of the desired vaccine were performed aiming to create robust T cell immune responses. We anticipate that our design based on the T cell antigen epitopes and the frame of the immunoinformatics analysis could serve as valuable supports for the development of COVID-19 vaccine.
S494 O-glycosylation site on the SARS-COV-2 RBD Affects the Virus Affinity to ACE2 and its Infectivity; A Molecular Dynamics Study
Authors: Rahnama Shadi , Irani Maryam Azimzadeh , Amininasab Mehriar , Ejtehadi Mohammad Reza
Published: September 2020

SARS-COV-2 is a strain of Coronavirus family which caused the extensive pandemic of COVID-19, which is still going on. Several studies showed that the glycosylation of virus spike (S) protein and the Angiotensin-Converting Enzyme 2 (ACE2) receptor on the host cell is critical for the virus infectivity. Molecular Dynamics (MD) simulations were used to explore the role of a novel mutated O-glycosylation site (D494S) on the Receptor Binding Domain (RBD) of S protein. This site was suggested as a key mediator of virus-host interaction. We showed that the decoration of S494 with elongated O-glycans results in stabilized interactions on the direct RBD-ACE2 interface with more favorable binding free energies for longer oligosaccharides. Hence, this crucial factor must be taken into account for any further inhibitory approaches towards RBD-ACE2 interaction.
Some theoretical aspects of reprogramming the standard genetic code
Authors: Nowak Kuba , Błażej Paweł , Wnetrzak Małgorzata , Mackiewicz Dorota , Mackiewicz Paweł
Published: September 2020

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Reprogramming of the standard genetic code in order to include non-canonical amino acids (ncAAs) opens a new perspective in medicine, industry and biotechnology. There are several methods of engineering the code, which allow us for storing new genetic information in DNA sequences and transmitting it into the protein world. Here, we investigate the problem of optimal genetic code extension from theoretical perspective. We assume that the new coding system should encode both canonical and new ncAAs using 64 classical codons. What is more, the extended genetic code should be robust to point nucleotide mutation and minimize the possibility of reversion from new to old information. In order to do so, we follow graph theory to study the properties of optimal codon sets, which can encode 20 canonical amino acids and stop coding signal. Finally, we describe the set of vacant codons that could be assigned to new amino acids. Moreover, we discuss the optimal number of the newly incorporated ncAAs and also the optimal size of codon blocks that are assigned to ncAAs.
Time and Space in Segmentation
Authors: Clark Erik
Published: September 2020

Arthropod segmentation and vertebrate somitogenesis are leading fields in the experimental and theoretical interrogation of developmental patterning. However, despite the sophistication of current research, basic conceptual issues remain unresolved. These include (1) the mechanistic origins of spatial organisation within the segment addition zone (SAZ); (2) the mechanistic origins of segment polarisation; (3) the mechanistic origins of axial variation; and (4) the evolutionary origins of simultaneous patterning. Here, I explore these problems using coarse-grained models of cross-regulating dynamical processes. In the morphogenetic framework of a row of cells undergoing axial elongation, I simulate interactions between an “oscillator”, a “switch”, and up to three “timers”, successfully reproducing essential patterning behaviours of segmenting systems. By comparing the output of these largely cell-autonomous models to variants that incorporate positional information, I find that scaling relationships, wave patterns, and patterning dynamics all depend on whether the SAZ is regulated by temporal or spatial information. I also identify three mechanisms for polarising oscillator output, all of which functionally implicate the oscillator frequency profile. Finally, I demonstrate significant dynamical and regulatory continuity between sequential and simultaneous modes of segmentation. I discuss these results in the context of the experimental literature.