bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using a GTR+Γ substitution model for dating sequence divergence when stationarity and time-reversibility assumptions are violated
Authors: Barba-Montoya Jose , Tao Qiqing , Kumar Sudhir 
Published: July 2020

AbstractMotivationAs the number and diversity of species and genes grow in contemporary datasets, two common assumptions made in all molecular dating methods, namely the time-reversibility and stationarity of the substitution process, become untenable. No software tools for molecular dating allow researchers to relax these two assumptions in their data analyses. Frequently the same General Time Reversible (GTR) model across lineages along with a gamma (+Γ) distributed rates across sites is used in relaxed clock analyses, which assumes time-reversibility and stationarity of the substitution process. Many reports have quantified the impact of violations of these underlying assumptions on molecular phylogeny, but none have systematically analyzed their impact on divergence time estimates.ResultsWe quantified the bias on time estimates that resulted from using the GTR+Γ model for the analysis of computer-simulated nucleotide sequence alignments that were evolved with non-stationary (NS) and non-reversible (NR) substitution models. We tested Bayesian and RelTime approaches that do not require a molecular clock for estimating divergence times. Divergence times obtained using a GTR+Γ model differed only slightly (∼3% on average) from the expected times for NR datasets, but the difference was larger for NS datasets (∼10% on average). The use of only a few calibrations reduced these biases considerably (∼5%). Confidence and credibility intervals from GTR+Γ analysis usually contained correct times. Therefore, the bias introduced by the use of the GTR+Γ model to analyze datasets, in which the time-reversibility and stationarity assumptions are violated, is likely not large and can be reduced by applying multiple calibrations.AvailabilityAll datasets are deposited in Figshare:https://doi.org/10.6084/m9.figshare.12594638.Contacts.kumar@temple.edu
Corticohippocampal Neuroenergetics and histomorphology in aluminium-induced neurotoxicity: Putative therapeutic roles of ascorbic acid and nicotine
Authors: Temitayo Gbadamosi Ismail , Olaiya Omotoso Gabriel 
Published: July 2020

AbstractAlzheimer’s disease (AD) is the most common cause of dementia and is hallmarked by β-amyloid plaque and neurofibrillary tangles deposition in the central nervous system. The complex mechanism that underlies AD pathogenesis has made the development of a definitive cure futile. Exploring the possible therapeutic advantages of combining two neuromodulatory molecules with different mechanisms of neuroprotection is an interesting way of drug discovery. Ascorbic acid (AA), a potent antioxidant molecule, and nicotine (NIC), an allosteric modulator of nAChRs, have both been documented to independently proffer neuroprotection in experimental and clinical neurodegenerative cases. This study elucidated the putative therapeutic advantages of combining ascorbic acid and nicotine as a treatment regimen against the aluminium-induced Alzheimer-like corticohippocampal histopathology, anxiety, and perturbed neuroenergetics in rats induced withRats treated with 100 mg/kg aluminium chloride for 28 days presented with significantly increased stretch attend posture frequency and centre square entry. Aluminium significantly depleted the activities of glucose-6-phosphate dehydrogenase (G6PDH) while increasing lactate levels. Corticohippocampal histomorphology of these animals showed poor histoarchitecture, increased congophilic and argentophilic densities that were coupled with increased anti-NSE immunopositivity. Animals post-treated with NIC (10mg/kg) and AA (100mg/kg) for 28 days presented with reduced anxiety level and improved corticohippocampal histomorphology. AA normalized G6PDH and lactate levels while the congophilic density was reduced by NIC. Corticohippocampal argentophilic density anti-NSE immunopositivity were also normalized by AA+NIC.The findings from this study have shown that a combination of ascorbic acid and nicotine effectively mitigated aluminium-induced corticohippocampal histopathology and perturbed neuroenergetics.
A data-driven method to identify frequency boundaries in multichannel electrophysiology data
Authors: Cohen Michael X 
Published: July 2020

AbstractBackgroundElectrophysiological recordings of the brain often exhibit neural oscillations, defined as narrowband bumps that deviate from the background power spectrum. These narrowband dynamics are grouped into frequency ranges, and the study of how activities in these ranges are related to cognition and disease is a major part of the neuroscience corpus. Frequency ranges are nearly always defined according to integer boundaries, such as 4-8 Hz for the theta band and 8-12 Hz for the alpha band.New methodA data-driven multivariate method is presented to identify empirical frequency boundaries based on clustering of spatiotemporal similarities across a range of frequencies. The method, termed gedBounds, identifies patterns in covariance matrices that maximally separate narrowband from broadband activity, and then identifies clusters in the correlation matrix of those spatial patterns over all frequencies, using the dbscan algorithm. Those clusters are empirically derived frequency bands, from which boundaries can be extracted.ResultsgedBounds recovers ground truth results in simulated data with high accuracy. The method was tested on EEG resting-state data from Parkinson’s patients and control, and several features of the frequency components differed between patients and controls.Comparison with existing methodsThe proposed method offers higher precision in defining subject-specific frequency boundaries compared to the current standard approach.ConclusionsgedBounds can increase the precision and feature extraction of spectral dynamics in electrophysiology data.
Alpha and theta oscillations contribute to attribute regulation in dietary decision making under self-control
Authors: HajiHosseini Azadeh , Hutcherson Cendri A. 
Published: July 2020

AbstractHow do different cognitive self-regulation strategies alter attribute value construction (AVC) and evidence accumulation (EA)? We recorded EEG during food choices while participants responded naturally or regulated their choices by focusing on healthy eating or decreasing their desire for all food. Using a drift diffusion model (DDM), we predicted the time course of neural signals associated with AVC and EA. Results suggested that suppression of frontal and occipital alpha power matched model-predicted EA signals: it tracked the goal-relevance of tastiness and healthiness attributes, predicted individual differences in successful down-regulation of tastiness, and conformed to the DDM-predicted time course of EA. We also found an earlier rise in frontal and occipital theta power that represented food tastiness more strongly during regulation, and predicted a weaker influence of food tastiness on behaviour. Our findings suggest that different regulatory strategies may commonly recruit theta-mediated control processes to modulate the attribute influence on EA.
SARS-CoV-2 infection in the lungs of human ACE2 transgenic mice causes severe inflammation, immune cell infiltration, and compromised respiratory function
Authors: Winkler Emma S. , Bailey Adam L. , Kafai Natasha M. , Nair Sharmila , McCune Broc T. , Yu Jinsheng , Fox Julie M. , Chen Rita E. , Earnest James T. , Keeler Shamus P. , Ritter Jon H. , Kang Liang-I , Dort Sarah , Robichaud Annette , Head Richard , Holtzman Michael J. , Diamond Michael S. 
Published: July 2020

ABSTRACTSevere Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) emerged in late 2019 and has spread worldwide resulting in the Coronavirus Disease 2019 (COVID-19) pandemic. Although animal models have been evaluated for SARS-CoV-2 infection, none have recapitulated the severe lung disease phenotypes seen in hospitalized human cases. Here, we evaluate heterozygous transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lung tissues with additional spread to other organs. Remarkably, a decline in pulmonary function, as measured by static and dynamic tests of respiratory capacity, occurs 4 days after peak viral titer and correlates with an inflammatory response marked by infiltration into the lung of monocytes, neutrophils, and activated T cells resulting in pneumonia. Cytokine profiling and RNA sequencing analysis of SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with prominent signatures of NF-kB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection recapitulates many features of severe COVID-19 infection in humans and can be used to define the mechanistic basis of lung disease and test immune and antiviral-based countermeasures.
Examining the boundary sharpness coefficient as an index of cortical microstructure and its relationship to age and sex in autism spectrum disorder
Authors: Olafson Emily , Bedford Saashi , Devenyi Gabriel A. , Patel Raihaan , Tullo Stephanie , Park Min Tae M. , Parent Olivier , Anagnostou Evdokia , Baron-Cohen Simon , Bullmore Edward T. , Chura Lindsay R. , Craig Michael C. , Ecker Christine , Floris Dorothea L. , Holt Rosemary J. , Lenroot Rhoshel , Lerch Jason P. , Lombardo Michael V. , Murphy Declan G. M. , Raznahan Armin , Ruigrok Amber N. V. , Spencer Michael D. , Suckling John , Taylor Margot J. ,   MRC AIMS Consortium, Lai Meng-Chuan , Chakravarty M. Mallar 
Published: July 2020

AbstractAutism spectrum disorder (ASD) is associated with atypical brain development. However, the phenotype of regionally specific increased cortical thickness observed in ASD may be driven by several independent biological processes that influence the gray/white matter boundary, such as synaptic pruning, myelination, or atypical migration. Here, we propose to use the boundary sharpness coefficient (BSC), a proxy for alterations in microstructure at the cortical gray/white matter boundary, to investigate brain differences in individuals with ASD, including factors that may influence ASD-related heterogeneity (age, sex, and intelligence quotient). Using a vertex-based meta-analysis and a large multi-center magnetic resonance structural imaging (MRI) dataset, with a total of 1136 individuals, 415 with ASD (112 female; 303 male) and 721 controls (283 female; 438 male), we observed that individuals with ASD had significantly greater BSC in the bilateral superior temporal gyrus and left inferior frontal gyrus indicating an abrupt transition (high contrast) between white matter and cortical intensities. Increases were observed in different brain regions in males and females, with larger effect sizes in females. Individuals with ASD under 18 had significantly greater BSC in the bilateral superior temporal gyrus and right postcentral gyrus; individuals with ASD over 18 had significantly increased BSC in the bilateral precuneus and superior temporal gyrus. BSC correlated with ADOS-2 CSS in individuals with ASD in the right medial temporal pole. Importantly, there was a significant spatial overlap between maps of the effect of diagnosis on BSC when compared to cortical thickness. These results invite studies to use BSC as a possible new measure of cortical development in ASD and to further examine the microstructural underpinnings of BSC-related differences and their impact on measures of cortical morphology.
Dosage-sensitive functions in embryonic development drove the survival of genes on sex-specific chromosomes in snakes, birds, and mammals
Authors: Bellott Daniel W. , Page David C. 
Published: July 2020

AbstractDifferent ancestral autosomes independently evolved into sex chromosomes in snakes, birds, and mammals. In snakes and birds, females are ZW, while males are ZZ; in mammals, females are XX and males are XY. While X and Z chromosomes retain nearly all ancestral genes, sex-specific W and Y chromosomes suffered extensive genetic decay. In both birds and mammals, the genes that survived on sex-specific chromosomes are enriched for broadly expressed, dosage sensitive regulators of gene expression, subject to strong purifying selection. To gain deeper insight into the processes that govern survival on sex-specific chromosomes, we carried out a meta-analysis of survival across 41 species — three snakes, 24 birds and 14 mammals — doubling the number of ancestral genes under investigation and increasing our power to detect enrichments among survivors relative to non-survivors. Out of 2573 ancestral genes, representing an eighth of the ancestral amniote genome, only 322 survive on present-day sex-specific chromosomes. Survivors are enriched for dosage sensitive developmental processes, particularly development of the face. However, there was no enrichment for expression in sex-specific tissues, involvement in sex-determination or gonadogenesis pathways, or conserved sex-biased expression. Broad expression and dosage sensitivity contributed independently to gene survival, suggesting that pleiotropy imposes additional constraints on the evolution of dosage compensation. We propose that maintaining the viability of the heterogametic sex drove gene survival on amniote sex-specific chromosomes, and that subtle modulation of the expression of survivor genes and their autosomal orthologs has disproportionately large effects on development and disease.
Discovery of clinically approved drugs capable of inhibiting SARS-CoV-2in vitroinfection using a phenotypic screening strategy and network-analysis to predict their potential to treat covid-19
Authors: Sales-Medina Douglas Ferreira , Ferreira Ludmila Rodrigues Pinto , Romera Lavínia M. D. , Gonçalves Karolina Ribeiro , Guido Rafael V. C. , Courtemanche Gilles , Buckeridge Marcos S. , Durigon Édison L. , Moraes Carolina B. , Freitas-Junior Lucio H. 
Published: July 2020

AbstractThe disease caused by SARS-CoV2, covid-19, rapidly spreads worldwide, causing the greatest threat to global public health in the last 100 years. This scenario has become catastrophic as there are no approved vaccines to prevent the disease, and the main measures to contain the virus transmission are confinement and social distancing. One priority strategy is based on drug repurposing by pursuing antiviral chemotherapy that can control transmission and prevent complications associated with covid-19. With this aim, we performed a high content screening assay for the discovery of anti-SARS-CoV-2 compounds. From the 65 screened compounds, we have found four drugs capable to selectively inhibit SARS-CoV-2in vitroinfection: brequinar, abiraterone acetate, neomycin, and the extract ofHedera helix. Brequinar and abiraterone acetate had higher inhibition potency against SARS-CoV-2 than neomycin andHedera helixextract, respectively. Drugs with reported antiviral activity and in clinical trials for covid-19, chloroquine, ivermectin, and nitazoxanide, were also included in the screening, and the last two were found to be non-selective. We used a data mining approach to build drug-host molecules-biological function-disease networks to show in a holistic way how each compound is interconnected with host node molecules and virus infection, replication, inflammatory response, and cell apoptosis. In summary, the present manuscript identified four drugs with active inhibition effect on SARS-CoV-2in vitroinfection, and by network analysis, we provided new insights and starting points for the clinical evaluation and repurposing process to treat SARS-CoV-2 infection.Summary sentenceDiscovery of drug repurposing candidates, inhibitors of SARS-CoV-2 infectionin vitro, using a phenotypic screening strategy and network analysis.
Molecular analysis of binding region of an ACE2 as a receptor for SARS-CoV-2 between humans and mammals
Authors: Hayashi Takuma , Aboko Kaoru , Mandan Masaki , Yaegashi Nobuo , Konishi Ikuo 
Published: July 2020

AbstractIn June 2020, a second wave of coronavirus disease-2019 (COVID-19) infections raised concern in Beijing, where salmon sold a fresh fish wholesale market was suspected of being the source of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. It has raised questions in the press and elsewhere about the scientific basis of salmon as a source of infection. With the number of cases growing, the surface of a salmon chopping board in the market was examined for the presence of SARS-CoV-2 and a positive reaction was observed. Following these test results, there has been debate over whether salmon can be infected with SARS-CoV-2. To find assess this, we investigated the structural homology of angiotensin-converting enzyme 2 (ACE2), a host-side receptor for SARS-CoV-2, between humans and other species including salmon and mink. As a result, a high structural homology between ACE2 and mink, which has reportedly transmitted SARS-CoV-2 to humans, was confirmed. However, a non-high structural homology of ACE2 between salmon and humans was observed. Further experiments are needed to find the source of SARS-CoV-2 transmission to the salmon.
Ethanolamine improves colonic barrier functions and inflammatory immunoreactions via shifting microbiome dysbiosis
Authors: Zhou Jian , Xiong Xia , Wan Dan , Liu Hongnan , Shao Yirui , Wu Yuliang , Huang Xiali , Peng Chanfeng , Huang Pan , Zou Lijun , Yin Yulong 
Published: July 2020

AbstractEthanolamine(EA) often occurs at a relatively high concentration within the inflamed gut of IBD patients. To investigate the role of EA in colonic inflammation and host-microbiome dysbiosis, thirty-six ICR mice were treated with 3% DSS for a week to generate acute intestinal inflammation and then supplied with 0μM, 500μM (LowEA), and 3000 μM (HighEA) in drinking water for two weeks, after that,16s RNA sequencing was applied in characterizing the changes in colonic microbiota driven by different EA levels. An inflamed colonic organoid model via 3% DSS treatment was also established for further verification of these in vivo findings.EA significantly reduced proximal colonic crypt depth but increased distal colonic villus height in HighEA group. The protein and mRNA expression of occludin and Reg3β, BD1, BD2, and MUC2were significantly up-regulated in EA treated groups. EA decreased mucosal inflammation-related cytokines levels (IL1, IL6, IL17, TNFα, and INFγ) and increased the significantly increased concentration of sIgA. Serum aspartate aminotransferase and alanine aminotransferase were significantly down-regulated in the highEA group. EA increased the relative abundance ofBlautia, Roseburia, Lactobacillus, Faecalibaculum, Candidatus_Saccharimonas, Alloprevotella, andLachnoclostridum.and thus microbial metabolic pathways includingOxidative phosphorylation, Lipopolysaccharide biosynthesis, Arginine and proline metabolism, Folate biosynthesis, andBiotin metabolismwere more abundant in LowEA group than those in control. EA up-regulated the protein or mRNA expression of TLR4/MyD88 in colonic tissues and the DSS-treated colonic organoid model. This study firstly demonstrated that ethanolamine in altering host-microbiome dysbiosis, which may provide new insights into the role of dietary lipids in IBD.ImportanceInflammatory bowel disease (IBD) affects ~3.1 million people in the USA and is increasing in incidence worldwide. IBD pathogenesis has been associated with gut microbiome dysbiosis characterized as a decrease in gut microbial diversity. Extensive works have demonstrated the roles of dietary fiber, short-chain fatty acids, and aromatic amino acids in altering the composition of gut microbiota to restore immune homeostasis and alleviate inflammation via diverse mechanisms in IBD. However, little is known about essential sphingolipids like ethanolamine (EA), an essential compound in the CDP-ethanolamine pathway for phosphatidylethanolamine (PE) in both intestinal cells and bacteria. PE synthesis deficiency can ultimately result in a loss of membrane integrity and metabolic disorders in IBD. Our results demonstrate that ethanolamine could improve colonic barrier functions and inflammatory immunoreactions via shifting microbiome dysbiosis, which provides new insights into the role of dietary lipids in IBD.
Caspofungin resistance inCandia aurisdue to mutations inFks1 with adjunctive role of chitin and key cell wall stress response pathway genes
Authors: Sharma Dipti , Paul Raees A. , Chakrabarti Arunaloke , Bhattacharya Sanjay , Soman Rajeev , Shankarnarayan Shamanth A , Chavan Dipali , Singh Shreya , Das Parijit , Kaur Harsimran , Ghosh Anup K , Rudramurthy Shivaprakash M 
Published: July 2020

AbstractThe emergence of echinocandin resistance inC. aurishas become a major concern. Point mutations in Fks1 subunit of β-D-glucan synthase is the primary mechanism in echinocandin resistance. However, resistant isolates with wild typeFks1 are not infrequent. We screened 199 clinicalC. aurisisolates from 30 centres across India for echinocandin resistance. The cohort also contained six sequential isolates from a liver transplant recipient. Eleven isolates (5.7%) from 11 patients, and those six serial isolates had elevated echinocandin minimum inhibitory concentrations (MIC). Three of these 17 isolates carried S639F mutation in hot spot 1 region ofFks1. A novelFks1 mutation, F635Y was identified in two resistant isolates, and a related F635L mutation was detected in four of the six sequential isolates. Resistant isolates (MIC≥2 mg/L) and those with intermediate caspofungin susceptibility (MIC, 1.0 mg/L) demonstrated higher induction of chitin synthase gene,Chs1 [resistant, 2.2(1.3-5.8); intermediate, 6(2.5-11.2)] compared to susceptible isolates [1.2(0.8-2), P<0.05]. However, the expression of theFks1subunit of β-1, 3-glucan synthase was higher only in intermediate group [3.4(2-8.5), P<0.01].HOG1 MAP kinase showed higher inducible expression in intermediate isolates, while those ofHSP90-like protein andCnaB were comparable in resistant and intermediate groups. In one isolate pan-echinocandin resistance mediated by S639F mutation coupled with high basal chitin content was noted. This study reports novel mutation F635Y/L inFks1inC. auris, contributing to echinocandin resistance and suggests the possible adjunctive roles of chitin synthase,Fks1, and cell wall-remodeling pathway gene upregulation in caspofungin resistance.
A Strategy to Treat COVID-19 Disease with Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Non-clinical Pharmacokinetic Study
Authors: Tai Tien-Tzu , Wu Tzung-Ju , Wu Huey-Dong , Tsai Yi-Chen , Wang Hui-Ting , Wang An-Min , Shih Sheue-Fang , Chen Yee-Chun 
Published: July 2020

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly identified pathogen causing coronavirus disease 2019 (COVID-19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti-inflammatory drug, has been shown to inhibit SARS-CoV-2 infectionin vitroand tested in clinical studies. However, lung concentration (6.7 µg/mL) to predict thein vivoantiviral efficacy might not be achievable with the currently proposed oral dosing regimen. Further, a high cumulative doses of HCQ may raise concerns of systemic toxicity, including cardiotoxicity. Here, we described a non-clinical study to investigate the pharmacokinetics of a novel formulation of liposomal HCQ administrated by intratracheal (IT) instillation in Sprague-Dawley (SD) rats which achieved 129.4 µg/g (Cmax) in the lung. Compared to unformulated HCQ administered intravenous (IV), liposomal HCQ with normalized dose showed higher (∼30-fold) lung exposure, longer (∼2.5-fold) half-life in lung, but lower blood exposure with ∼20% of Cmaxand 74% of AUC and lower heart exposure with 24% of Cmaxand 58% of AUC. In conclusion, the pharmacokinetics results in an animal model demonstrate the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID-19.