bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractWhile 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

ABSTRACTPrevious 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.IMPORTANCEGrowing 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

AbstractThe 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.ImportanceCryptosporidiumoccupies 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

ABSTRACTUnder 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 importanceGeneral 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

AbstractBackgroundSARS-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.MethodsIn 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.ResultsA 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).ConclusionCVST 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

SUMMARYSchizophrenia 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

AbstractCo-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

ABSTRACTObjectiveIn 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 MethodsWe 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.ResultsWe 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.ConclusionsThese 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

AbstractThis 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

AbstractThe 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 AbstractHighlightsCOVID-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

ABSTRACTThe 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

AbstractBreast 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.HighlightsVirtual 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.