bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic correlation and causal relationships between cardio-metabolic traits and Lung function Impairment
Authors: Wielscher Matthias , Amaral Andre F.S. , van der Plaat Diana , Wain Louise V. , Sebert Sylvain , Mosen-Ansorena David , Auvinen Juha , Herzig Karl-Heinz , Dehghan Abbas , Jarvis Debbie L , Jarvelin Marjo-Riitta
Published: September 2020

Background

Associations of low lung function with features of poor cardio-metabolic health have been reported. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability or are confounded by environmental factors.

Methods

We performed three analyses: 1) cardio-metabolic health to lung function association tests in NFBC1966, 2) cross trait LD score regression to compare genetic backgrounds and 3) Mendelian Randomization (MR) analysis to assess the causal effect of cardio-metabolic traits and disease on lung function, and vice versa (bidirectional MR). Genetic associations were obtained from UK Biobank data or published large-scale genome-wide association studies (N > 82,000).

Results

We observed negative genetic correlation between lung function and cardio-metabolic traits and diseases. In Mendelian Randomisation analysis (MR) we found associations between Type 2 Diabetes instruments and FVC as well as FEV1/FVC. BMI instruments were associated to all lung function traits and CRP instruments to FVC. These genetic association provide evidence for a causal effect of cardio-metabolic traits on lung function. Multivariable MR suggested independence of these causal effects from other tested cardio-metabolic traits and diseases. Analysis of lung function specific SNPs revealed a potential causal effect of FEV1/FVC on blood pressure.

Conclusions

The present study overcomes many limitations of observational studies by using Mendelian Randomisation. We provide evidence for an independent causal effect of T2D, CRP and BMI on lung function with some of the T2D effect on lung function being mediated by CRP. Furthermore, this analysis suggests a potential causal effect of FEV1/FVC on blood pressure. Our detailed analysis of the interplay between cardio-metabolic traits and impaired lung function provides the opportunity to improve the quality of existing intervention strategies.
Comparison of COVID-19 outcomes among shielded and non-shielded populations: A general population cohort study of 1.3 million
Authors: Jani Bhautesh D , Ho Frederick K , Lowe David J , MacBride-Stewart Sean , Mair Frances S , Pell Jill P
Published: September 2020

Background

Shielding (extended self-isolation) of people judged, a priori, to be at high-risk from COVID-19 has been used by some countries to protect the individuals and reduce demand on health services. It is unclear how well this strategy works in either regard.

Methods

A general population study was conducted using linked primary care, prescribing, laboratory, hospital and death records up to end of May 2020. Poisson regression models and population attributable fractions were used to compare COVID-19 outcomes by overall risk category, and individual risk criteria: confirmed infection, hospitalisation, intensive care unit (ICU) admission, population mortality and case-fatality.

Results

Of the 1.3 million population, 32,533 (2.47%) had been advised to shield, a further 347,374 (26.41%) were classified as moderate risk. Testing for COVID-19 was more common in the shielded (6.75%) and moderate (1.99%) than low (0.72%) risk categories. Referent to low-risk, the shielded group had higher risk of confirmed infection (RR 7.91, 95% 7.01-8.92), case-fatality (RR 5.19, 95% CI 4.12-6.53) and population mortality (RR 48.64, 95% 37.23-63.56). The moderate risk had intermediate risk of confirmed infection (RR 4.11, 95% CI 3.82-4.42) and population mortality (RR 26.10, 95% CI 20.89-32.60), but had comparable case-fatality (RR 5.13, 95% CI 4.24-6.21) to the shielded, and accounted for a higher proportion of deaths (PAF 75.27% vs 13.38%). Age ≥70 years made the largest contribution to deaths (49.53%) and was associated with an 8-fold risk of infection, 7-fold case-fatality and 74-fold mortality.

Conclusions

Shielding has not been effective at preventing deaths in those with highest risk. To be effective as a population strategy, shielding criteria would need to be widely expanded to include other criteria, such as the elderly.
COMPARATIVE ANALYSIS OF COVID-19 MORTALITY IN BRAZIL, RIO DE JANEIRO, CAMPOS DOS GOYTACAZES, MACAÉ, CABO FRIO AND RIO DAS OSTRAS1
Authors: Guimarães Antonio C. C. , Coelho Karla Santa Cruz , da Cruz Kathleen Tereza , de Oliveira Souza Bárbara Soares , de Almeida Janimayri Forastieri , Coelho Gustavo Fialho , Ferreira Gabriella Ramos Lacerda
Published: September 2020

Objective

To analyze quantitatively and comparatively the deaths by COVID-19 of the four largest municipalities in the North of Rio de Janeiro and Baixada Litorânea of Rio de Janeiro, within the national context.

Methods

We used data from the Civil Registry and demographic information to elaborate a general picture of the pandemic up to the 31st epidemiological week in several aspects: evolution, scope, age, sex, race and impact on other causes of death.

Results

We characterized the evolution of the pandemic. We found an exponential dependence on the mortality rate by age and a higher lethality in the male population. We determined that COVID-19 represents an important fraction of the causes of death in 2020, being associated with a significant excess of deaths in relation to 2019 and also with the change in mortality patterns due to other causes.

Conclusion

Mortality is an effective and powerful indicator for understanding the infection and its pandemic, and it must be taken into account during the construction of public policies to deal with it.
Comprehensive characterization of protein-protein interaction network perturbations by human disease mutations
Authors: Cheng Feixiong , Zhao Junfei , Wang Yang , Lu Weiqiang , Liu Zehui , Zhou Yadi , Martin William , Wang Ruisheng , Huang Jin , Hao Tong , Yue Hong , Ma Jing , Hou Yuan , Castrillon Jessica , Fang Jiansong , Lathia Justin D. , Keri Ruth A. , Lightstone Felice C. , Antman Elliott Marshall , Rabadan Raul , Hill David E. , Eng Charis , Vidal Marc , Loscalzo Joseph
Published: September 2020

Technological and computational advances in genomics and interactomics have made it possible to identify rapidly how disease mutations perturb interaction networks within human cells. In this study, we investigate at large-scale the effects of network perturbations caused by disease mutations within the human three-dimensional (3D), structurally-resolved macromolecular interactome. We show that disease-associated germline mutations are significantly enriched in sequences encoding protein-protein interfaces compared to mutations identified in healthy subjects from the 1000 Genomes and ExAC projects; these interface mutations correspond to protein-protein interaction (PPI)-perturbing alleles including p.Ser127Arg in PCSK9 at the PCSK9-LDLR interface. In addition, somatic missense mutations are significantly enriched in PPI interfaces compared to non-interfaces in 10,861 human exomes across 33 cancer subtypes/types from The Cancer Genome Atlas. Using a binomial statistical model, we computationally identified 470 PPIs harboring a statistically significant excess number of missense mutations at protein-protein interfaces (termed putative oncoPPIs) in pan-cancer analysis. We demonstrate that the oncoPPIs, including histone H4 complex in individual cancer types, are highly correlated with patient survival and drug resistance/sensitivity in human cancer cell lines and patient-derived xenografts. We experimentally validate the network effects of 13 oncoPPIs using a systematic binary interaction assay. We further showed that ALOX5 p.Met146Lys at the ALOX5-MAD1L1 interface and RXRA p.Ser427Phe at the RXRA-PPARG interface promote significant tumor cell growth using cell line-based functional assays, providing a functional proof-of-concept. In summary, if broadly applied, this human 3D interactome network analysis offers a powerful tool for prioritizing alleles with mutations altering PPIs that may contribute to the pathobiology of human diseases, and may offer disease-specific targets for genotype-informed therapeutic discovery.
Belief states and categorical-choice biases determine reward-based learning under perceptual uncertainty
Authors: Bruckner Rasmus , Heekeren Hauke R. , Ostwald Dirk
Published: September 2020

In natural settings, learning and decision making often takes place under considerable perceptual uncertainty. Here we investigate the computational principles that govern reward-based learning and decision making under perceptual uncertainty about environmental states. Based on an integrated perceptual and economic decision-making task where unobservable states governed the reward contingencies, we analyzed behavioral data of 52 human participants. We formalized perceptual uncertainty with a belief state that expresses the probability of task states based on sensory information. Using several Bayesian and Q-learning agent models, we examined to which degree belief states and categorical-choice biases determine human learning and decision making under perceptual uncertainty. We found that both factors influenced participants’ behavior, which was similarly captured in Bayesian-inference and Q-learning models. Therefore, humans dynamically combine uncertain perceptual and reward information during learning and decision making, but categorical choices substantially modulate this integration. The results suggest that categorical commitments to the most likely state of the environment may generally give rise to categorical biases on learning under uncertainty.
Investigating the effect of biomass fuel use and Kitchen location on Maternal Report of Birth size: A Cross-Sectional Analysis of 2016 Ethiopian Demographic Health Survey data
Authors: Kanno Girum Gebremeskel , Anbesse Adane Tesfaye , Shaka Mohammed Feyisso , Legesse Miheret Tesfu , Andarge Sewitemariam Desalegn
Published: September 2020

Household air pollution from the use of biomass fuels has been associated with low birth weight in many developing countries. We investigated the effect of indoor air pollution from biomass fuel use and kitchen location on maternal reports of birth size in newborn children in Ethiopia using secondary cross-sectional data from Ethiopian Demographic Health Survey conducted in 2016. Birth weight from child health card and/or mothers’ recall was the dependent dichotomous variable. Fuel type was classified as high pollution fuels, and low pollution fuels. Hierarchical logistic regression was used to assess the effect of fuel type on birth weight. The prevalence of low birth weight was 25.9% and the use of biomass fuels was significantly associated with higher odds of having low birth weight baby in the bivariate analysis, after controlling for child and maternal factors. In the final model, the association turned insignificant with AOR, 1.3 (95% 0.9, 1.9). The kitchen location, Gender of the baby, Mother’s Anemia Status, Maternal Chat chewing, and wealth Index were significant factors in the final model. The use of biomass fuels and kitchen location were associated with reduced child size at birth. Further observational studies should investigate this association using more direct methods.

Practical Implications

The findings from this study have important implication at national level for policy makers. Ethiopia is a country with a huge proportion of the population depends on biomass fuels for cooking. Despite the progress made to reduce the burden of maternal and infant mortality and morbidity in the pre SDG era, LBW is still one of the challenges that need to be addressed. Identifying the link between biomass fuel use and kitchen location with low birth weight can help the efforts to revise, amend or implement programs that help achieve the SDG goal six, by engaging the energy and health sectors together.
Top End Pulmonary Hypertension Study: Understanding Epidemiology, Therapeutic Gaps and Prognosis in Remote Australian Setting
Authors: Naing Pyi , Playford David , Strange Geoff , Abeyaratne Asanga , Berhane Thomas , Jospeph Sanjay , Costelloe Ellie , Hall Maddison , Scalia Gregory M , Forrester Douglas L , Falhammar Henrik , Kangaharan Nadarajah
Published: September 2020

Introduction

The Top End of Australia has a high proportion of Indigenous people with a high burden of chronic cardiac and pulmonary diseases likely to contribute to pulmonary hypertension (PH). The epidemiology of PH has not been previously studied in this region.

Methods

Patients with PH were identified from the Northern Territory echocardiography database from January 2010 to December 2015 and followed to the end of 2019 or death. PH was defined as a tricuspid regurgitation velocity ≥2.75 m/s measured by Doppler echocardiography. The etiology of PH, as categorized by published guidelines, was determined by reviewing electronic health records.

Results

1764 patients were identified comprising 49% males and 45% Indigenous people. The prevalence of PH was 955 per 100,000 population (with corresponding prevalence of 1587 for Indigenous people). Hypertension, atrial fibrillation, diabetes and respiratory disease were present in 85%, 45%, 41% and 39%, respectively. Left heart disease was the leading cause for PH (58%), the majority suffering from valvular disease (predominantly rheumatic). Pulmonary arterial hypertension (PAH), respiratory disease related PH, chronic thromboembolic PH (CTEPH) and unclear multifactorial PH represented 4%, 16%, 2% and 3%, respectively. Underlying causes were not identifiable in 17% of the patients. Only 31% of potentially eligible patients were on PAH-specific therapy. At census, there was 40% mortality, with major predictors being age, ePASP and Indigenous ethnicity.

Conclusion

PH is prevalent in Northern Australia, with a high frequency of modifiable risk factors and other treatable conditions. Whether earlier diagnosis, interpretation and intervention improves outcomes merits further assessment.
Quantifying the Effects of Social Distancing on the Spread of COVID-19
Authors: Daghriri Talal , Ozmen Ozlem
Published: September 2020

This paper studies the interplay between the social distancing and the spread of COVID-19 disease—a widely spread pandemic that has affected nearly most of the world population. Starting in China, the virus has reached the United States of America with devastating consequences. Other countries severely affected by the pandemic are Brazil, Russia, United Kingdom, Spain, India, Italy, and France. Even though it is not possible to eliminate the spread of the virus from the world or any other country, it might be possible to reduce its effect by decreasing the number of infected people. Implementing such policies needs a good understanding of the system’s dynamics, generally not possible with mathematical linear equations or Monte Carlo methods because human society is a complex adaptive system with complex and continuous feedback loops. As a result, we use agent-based methods to conduct our study. Moreover, recent agent-based modeling studies for the COVID-19 pandemic show significant promise assisting decision-makers in managing the crisis through applying some policies such as social distancing, disease testing, contact tracing, home isolation, providing good emergency and hospitalization strategies, and preventing traveling would lead to reducing the infection rates. Based on imperial college modeling studies that prove increasing levels of interventions could slow down the spread of disease and infection cases as much as possible, and taking into account that social distancing policy is considered to be the most important factor that was recommended to follow. Our proposed model is designed to test if increasing the social distancing policies strictness can slow down the spread of disease significantly or not, and find out what is the required safe level of social distancing. So, the model was run six times, with six different percentages of social distancing with keeping the other parameters levels fixed for all experiments. The results of our study show that social distancing affects the spread of COVID-19 significantly, where the spread of disease and infection rates decrease once social distancing procedures are implemented at higher levels. Also, the behavior space tool was used to run ten experiments with different levels of social distancing, which supported the previous results. We concluded that applying and increasing social distancing policy levels led to significantly reduced infection rates, which result in decreasing deaths. Both types of experiments prove that infection rates are reduced dramatically when the level of social distancing intervention is implemented between 80% to 100%.
Extracorporeal Shockwave Therapy Versus Ultrasound Therapy for Plantar Fasciitis: Systematic Review and Meta-Analysis
Authors: Al-Siyabi Zeyana , Karam Mohammad , Al-Hajri Ethar , Alsaif Abdulmalik
Published: September 2020

Objective

To compare the outcomes of Extracorporeal Shockwave Therapy (ESWT) versus Ultrasound Therapy (UST) in plantar fasciitis.

Methods

A systematic review and meta-analysis were performed. An electronic search identifying studies comparing ESWT and UST for plantar fasciitis was conducted. Primary outcomes were morning and activity pain, functional impairment and the American Orthopaedic Foot and Ankle Society (AOFAS) scale score. Secondary outcomes included fascial thickness, primary efficacy success rate, activity limitations, pain intensity and satisfaction.

Results

Seven studies enrolling 369 patients were identified. No significant difference was found between ESWT and UST for functional impairment (Mean Difference [MD]= -2.90, P= 0.22), AOFAS scale score (MD= 35, P= 0.20) and pain in the first steps in the morning (MD= -4.72, P= 0.39). However, there was a significant improvement in pain during activity for the ESWT group (MD= -1.36, P= 0.005). For secondary outcomes, ESWT had improved results in terms of primary efficacy success rate, activity limitations and patient satisfaction. Reduction of planter fascia thickness showed no significant difference. Pain intensity after treatment had varied results amongst included studies.

Conclusion

ESWT is superior to UST for plantar fasciitis as it improves pain activity and intensity, primary efficacy success rate and activity limitations.
Early blood transcriptomic markers of necrotizing enterocolitis in preterm pigs
Authors: Pan Xiaoyu , Muk Tik , Ren Shuqiang , Gao Fei , Sangild Per
Published: September 2020

Preterm infants frequently develop necrotizing enterocolitis (NEC), a severe intestinal disorder associated with high mortality. Early detection of NEC is difficult due to poor specificity and sensitivity of clinical signs. We hypothesized that early development of NEC, before clear clinical symptoms appear, might affect expression of blood genes, potentially related to early systemic immune responses. Using preterm pigs as models for preterm infants, a retrospective analysis was performed on 129 infant formula fed pigs that had NEC diagnosis at necropsy on day 5. Clinical data including growth, activity, hematology, gastric residuals, incidence of diarrhea, bloody stool and abdominal distention were retrospectively reviewed. During this early postnatal period, except that bloody stool was observed in 19% of NEC pigs and absent in healthy pigs, no other clinical outcomes showed difference between NEC and healthy pigs. Whole blood transcriptome was compared between NEC pigs (NEC, n=20) and their litter-mate healthy controls (CON, n=19) on day 5, and revealed 344 differentially expressed genes (DEGs). PubMed literature search identified 123 genes that co-occurred with at least one of 9 NEC-related keywords (NEC, colitis, necrotic, hemorrhage, epithelial apoptosis, intestinal inflammation, inflammatory bowel disease, Crohn’s disease, ulcerative colitis). Co-expression network analysis suggested PAK2 as one of the hub genes. Using whole blood and dried blood spots (DBS) from another group of preterm pigs for validation, up-regulation of PAK2 and genes that co-occurred with NEC and other keywords in PubMed literatures (AOAH, ARG2, FKBP5 and STAT3) was confirmed in severe NEC cases. Specifically,ex vivostimulation of cord blood withS.epidermidisincreased ARG2. Our results show that whole blood gene expressions are affected in preterm pigs at an early stage when NEC is suspicious. Expression of target genes may be used to indicate NEC severity and associated bacterial infection. Routinely collected neonatal DBS may be used to develop early biomarkers for identifying infants with severe NEC lesions, thus providing better intervention strategy.
A new species of subgenusTyphlodromus(Anthoseius) De Leon (Acari: Phytoseiidae), and phytoseiid mites intercepted in samples imported from 12 different countries to Taiwan
Authors: Liao Jhih-Rong , Ho Chyi-Chen , Ko Chiun-Cheng
Published: September 2020

Global trade has increased the invasion risk of exotic organisms and damaged agricultural and natural ecosystems. The Bureau of Animal and Plant Health Inspection and Quarantine (BAPHIQ) handles quarantine services of animal- and plant-associated pests and diseases in Taiwan. The predatory mite family Phytoseiidae (Acari: Mesostigmata) is a well-known group due to the potential use of certain species as biocontrol agents for small phytophagous pests. Some species are available in commercial markets and frequently used in biological control in many agricultural systems especially in greenhouse crops. However, exotic biological control agents may interfere with native or naturalized populations of predatory mites and they may threaten indigenous populations via intraguild predation. The present study aims to provide the phytoseiid mite species found in plant quarantine from 2006–2013. Twenty-five species belonging two subfamilies and eight genera were found in samples imported to Tawan from twelve countries, including one new speciesTyphlodromus(Anthoseius)ueckermannisp. nov.from South Africa. The checklist provides distribution, remarks, and also an identification key for all species.
Experimental and computational studies on molecular mechanism by which Curcumin allosterically inhibits Dengue protease
Authors: Lim Liangzhong , Dang Mei , Roy Amrita , Kang Jian , Song Jianxing
Published: September 2020

Flaviviruses including DENV and ZIKV encode a unique two-component NS2B-NS3 protease essential for maturation/infectivity, thus representing a key target for designing anti-flavivirus drugs. Here for the first time, by NMR and molecular docking, we reveal that Curcumin allosterically inhibits the Dengue protease by binding to a cavity with no overlap with the active site. Further molecular dynamics (MD) simulations decode that the binding of Curcumin leads to unfolding/displacing the characteristic β-hairpin of the C-terminal NS2B and consequently disrupting the closed (active) conformation of the protease. Our study identified a cavity most likely conserved in all flaviviral NS2B-NS3 proteases, which could thus serve as a therapeutic target for discovery/design of small molecule allosteric inhibitors. Moreover, as Curcumin has been used as a food additive for thousands of years in many counties, it can be directly utilized to fight the flaviviral infections and as a promising starting for further design of potent allosteric inhibitors.
Robust differentiation of human enteroendocrine cells from intestinal stem cells
Authors: Zeve Daniel , Stas Eric , de Sousa Casal Joshua , Mannam Prabhath , Qi Wanshu , Yin Xiaolei , Dubois Sarah , Shah Manasvi S. , Syverson Erin P. , Hafner Sophie , Karp Jeffrey M. , Carlone Diana L. , Ordovas-Montanes Jose , Breault David T.
Published: September 2020

Enteroendocrine (EE) cells are the most abundant hormone-producing cells in humans and are critical regulators of energy homeostasis and gastrointestinal function. Challenges in converting human intestinal stem cells (ISCs) into functional EE cells,ex vivo, have limited progress in elucidating their role in disease pathogenesis and in harnessing their therapeutic potential. To address this, we employed small molecule targeting of the endocannabinoid receptor signaling pathway, JNK and FOXO1, known to mediate endodermal development and/or hormone production, together with directed differentiation of human ISCs from the duodenum and rectum. We observed marked induction of EE cell differentiation and gut-derived expression and secretion of SST, 5HT, GIP, CCK, GLP-1 and PYY upon treatment with various combinations of three small molecules: rimonabant, SP600125 and AS1842856. Robust differentiation strategies capable of driving human EE cell differentiation is a critical step towards understanding these essential cells and the development of cell-based therapeutics.
Functional and structural characterization of interactions between opposite subunits in HCN pacemaker channels
Authors: Kondapuram Mahesh , Frieg Benedikt , Yüksel Sezin , Schwabe Tina , Sattler Christian , Lelle Marco , Schweinitz Andrea , Schmauder Ralf , Benndorf Klaus , Gohlke Holger , Kusch Jana
Published: September 2020

Hyperpolarization-activated and cyclic nucleotide (HCN) modulated channels are tetrameric cation channels. In each of the four subunits, the intracellular cyclic nucleotide-binding domain (CNBD) is coupled to the transmembrane domain via a helical structure, the C-linker. High-resolution channel structures suggest that the C-linker enables functionally relevant interactions with the opposite subunit, which might be critical for coupling the conformational changes in the CNBD to the channel pore. We combined mutagenesis, patch-clamp technique, confocal patch-clamp fluorometry, and molecular dynamics simulations to show that residue K464 of the C-linker is essential for stabilizing the closed state of the mHCN2 channel by forming interactions with the opposite subunit. MD simulations revealed that both cAMP and K464E induce a rotation of the intracellular domain relative to the channel pore, weakening the autoinhibitory effect of the unoccupied CL-CNBD region. The adopted poses are in excellent agreement with structural results.
Nitrate and nitrite exposure increases anxiety-like behavior and alters brain metabolomic profile in zebrafish
Authors: García-Jaramillo Manuel , Beaver Laura M. , Truong Lisa , Axton Elizabeth R. , Keller Rosa M. , Prater Mary C. , Magnusson Kathy R. , Tanguay Robyn L. , Stevens Jan F. , Hord Norman G.
Published: September 2020

Introduction

Dietary nitrate lowers blood pressure and improves athletic performance in humans, yet data supporting observations that it may increase cerebral blood flow and improve cognitive performance are mixed. Here we tested the hypothesis that nitrate and nitrite treatment would improve indicators of learning and cognitive performance in a zebrafish (Danio rerio) model. We also explored the extent to which nitrate and nitrite treatment affected the brain metabolome in order to understand how nitrate and nitrite supplementation may affect indices of cognitive function.

Methods

Fish were exposed to sodium nitrate (606.9 mg/L), sodium nitrite (19.5 mg/L), or control water for 2-4 weeks and free swim, startle response, innate predator avoidance, social cohesion, and shuttle box assays were performed.

Results

Nitrate and nitrite treatment did not change fish weight, length, predator avoidance, or distance and velocity traveled in an unstressed environment. Nitrate- and nitrite-treated fish initially experienced more negative reinforcement and increased time to decision in the shuttle box assay, which is consistent with a decrease in associative learning or executive function however, over multiple trials, all treatment groups demonstrated behaviors associated with learning. Nitrate and nitrite treatment significantly increased anxiety-like behavior but did not alter epinephrine, norepinephrine or dopamine levels. Targeted LC-MS/MS analysis revealed no significant increase in brain nitrate or nitrite concentrations with treatment. An untargeted metabolomics analysis found 47 metabolites whose abundance was significantly altered in the brain with nitrate and nitrite treatment including an 18-19% reduction in the neurotransmitter γ-aminobutyric acid (GABA), and 17-22% reduction in its precursor, glutamine, which may contribute to the increased anxiety-like behavior.

Conclusion

Nitrate and nitrite treatment did not adversely affect multiple parameters of zebrafish health but was associated with mild anxiety-like behavior, changes in the brain metabolome, and caused a short-term decrease in executive function or associative learning.
The genetic status of IDH1/2 and EGFR dictates the vascular landscape and the progression of gliomas
Authors: Segura-Collar Berta , Garranzo-Asensio María , Herranz Beatriz , Hernández-SanMiguel Esther , Casas Bárbara. S. , Matheu Ander , Pérez-Núñez Ángel , Sepúlveda-Sánchez Juan M. , Hernández-Laín Aurelio , Palma Verónica , Gargini Ricardo , Sánchez-Gómez Pilar
Published: September 2020

Rationale

Glioma progression is driven by the induction of vascular alterations but how the tumor genotype influence these changes is still a pending issue. We propose to study the underlying mechanisms by which the genetic changes in isocitrate dehydrogenase 1/2 (IDH1/2) and epidermal growth factor receptor (EGFR) genes establish the different vascular profiles of gliomas.

Methods

We stratified gliomas based on the genetic status of IDH1/2 and EGFR genes. For that we used in silico data and a cohort of 93 glioma patients, where we analyzed the expression of several transcripts and proteins. For the in vitro and in vivo studies, we used a battery of primary glioblastoma cells derived from patients, as well as novel murine glioma cell lines expressing wild-type or mutant EGFR. In these models, the effect of the small molecule ibrutinib or the downregulation of CD248 and SOX9 was evaluated to establish a molecular mechanism.

Results

We show that IDH1/2 mutations associate with a normalized vasculature. By contrast, EGFR mutations stimulate the plasticity of glioma cells and their capacity to function as pericytes in a bone-marrow and X-linked (BMX)/SOX9 dependent manner. The presence of tumor-derived pericytes stabilize the profuse vasculature and confers a growth advantage to these tumors, although they render them sensitive to pericyte-targeted molecules. Wild-type/amplified EGFR gliomas are enriched in blood vessels too, but they show a highly disrupted blood-brain-barrier due to a decreased BMX/SOX9 activation and pericyte coverage. This leads to poor nutrient supply, necrosis and hypoxia.

Conclusions

The function of tumor-derived pericytes delimitates two distinct and aggressive vascular phenotypes in IDH1/2 wild-type gliomas. Our results lay the foundations for a vascular dependent stratification of gliomas and suggest different therapeutic vulnerabilities depending on the genetic status of EGFR.

Graphical Abstract. Schematic view of IDH and EGFR function in the regulation of glioma microenvironment.

Mutant IDH gliomas express low levels of angiogenic molecules and have a vasculature reminiscent of normal tissue. EGFR mutations drive glioma growth by promoting tumor-to-pericyte transdifferentiation and vascular stabilization in a BMX-SOX9 dependent way. Leaky vessels with hypoxia and necrosis characterize tumors overexpressing the wild-type isoform of the receptor. These phenotypes determine the response to therapy of the different IDH wild-type gliomas.
Investigation of COVID-19 comorbidities reveals genes and pathways coincident with the SARS-CoV-2 viral disease
Authors: Dolan Mary E. , Hill David P. , Mukherjee Gaurab , McAndrews Monica S. , Chesler Elissa J. , Blake Judith A.
Published: September 2020

The emergence of the SARS-CoV-2 virus and subsequent COVID-19 pandemic initiated intense research into the mechanisms of action for this virus. It was quickly noted that COVID-19 presents more seriously in conjunction with other human disease conditions such as hypertension, diabetes, and lung diseases. We conducted a bioinformatics analysis of COVID-19 comorbidity-associated gene sets, identifying genes and pathways shared among the comorbidities, and evaluated current knowledge about these genes and pathways as related to current information about SARS-CoV-2 infection. We performed our analysis using GeneWeaver (GW), Reactome, and several biomedical ontologies to represent and compare common COVID-19 comorbidities. Phenotypic analysis of shared genes revealed significant enrichment for immune system phenotypes and for cardiovascular-related phenotypes, which might point to alleles and phenotypes in mouse models that could be evaluated for clues to COVID-19 severity. Through pathway analysis, we identified enriched pathways shared by comorbidity datasets and datasets associated with SARS-CoV-2 infection.
Baseline T cell immune phenotypes predict virologic and disease control upon SARS-CoV infection
Authors: Graham Jessica B. , Swarts Jessica L. , Leist Sarah R. , Schäfer Alexandra , Menachery Vineet D. , Gralinski Lisa E. , Jeng Sophia , Miller Darla R. , Mooney Michael A. , McWeeney Shannon K. , Ferris Martin T. , de Villena Fernando Pardo-Manuel , Heise Mark T. , Baric Ralph S. , Lund Jennifer M.
Published: September 2020

The COVID-19 pandemic has revealed that infection with SARS-CoV-2 can result in a wide range of clinical outcomes in humans, from asymptomatic or mild disease to severe disease that can require mechanical ventilation. An incomplete understanding of immune correlates of protection represents a major barrier to the design of vaccines and therapeutic approaches to prevent infection or limit disease. This deficit is largely due to the lack of prospectively collected, pre-infection samples from indiviuals that go on to become infected with SARS-CoV-2. Here, we utilized data from a screen of genetically diverse mice from the Collaborative Cross (CC) infected with SARS-CoV to determine whether circulating baseline T cell signatures are associated with a lack of viral control and severe disease upon infection. SARS-CoV infection of CC mice results in a variety of viral load trajectories and disease outcomes. Further, early control of virus in the lung correlates with an increased abundance of activated CD4 and CD8 T cells and regulatory T cells prior to infections across strains. A basal propensity of T cells to express IFNg and IL17 over TNFa also correlated with early viral control. Overall, a dysregulated, pro-inflammatory signature of circulating T cells at baseline was associated with severe disease upon infection. While future studies of human samples prior to infection with SARS-CoV-2 are required, our studies in mice with SARS-CoV serve as proof of concept that circulating T cell signatures at baseline can predict clinical and virologic outcomes upon SARS-CoV infection. Identification of basal immune predictors in humans could allow for identification of individuals at highest risk of severe clinical and virologic outcomes upon infection, who may thus most benefit from available clinical interventions to restrict infection and disease.

We used a screen of genetically diverse mice from the Collaborative Cross infected with mouse-adapted SARS-CoV in combination with comprehensive pre-infection immunophenotyping to identify baseline circulating immune correlates of severe virologic and clinical outcomes upon SARS-CoV infection.
Engines of change: Transposable element mutation rates are high and vary widely among genotypes and populations ofDaphnia magna
Authors: Ho Eddie K. H. , Bellis E.S. , Calkins Jaclyn , Adrion Jeffrey R. , Latta Leigh C. , Schaack S.
Published: September 2020

Transposable elements (TEs) represent a large and dynamic portion of most eukaryotic genomes, yet little is known about their mutation rates or the correspondence between rates and long-term patterns of accrual. We compare TE activity over long and short time periods by quantifying TE profiles and mutation rates (with and without minimizing selection) among 9 genotypes from three populations ofDaphnia magnasampled along a latitudinal gradient. The patterns of genome-wide variation observed in nature mirror direct estimates of rates and spectra observed in a multi-year laboratory mutation accumulation experiment, where net rates range from -11.98 to 12.79 x 10-5per copy per generation across genotypes. Overall, gains outnumber losses and both types of events are highly deleterious based on comparing lines with and without selection minimized. The rate and spectrum of TE mutations vary widely among genotypes and across TE families/types, even within the same population. We compare TE mutation rates to previously published rates of base substitution, microsatellite mutation, and gene conversion for the same genotypes, and show a correlation only with the latter. Our study provides strong evidence for the notion that TEs represent a highly mutagenic force in the genome. Furthermore, the variation we observe underscores the need to expand the repertoire of mutations studied to include a wider array of mutation types with different underlying mechanisms in order to better understand the evolution of the mutation rate and the ways in which genetic variation is generated genome wide.
The effect of ABO blood group and antibody class on the risk of COVID-19 infection and severity of clinical outcomes
Authors: Almadhi Marwa Ali , Abdulrahman Abdulkarim , Alawadhi Abdulla , A.Rabaan Ali , AlQahtani Manaf
Published: September 2020

The current COVID-19 pandemic has affected more than 22 million cases and caused immense burdens on governments and healthcare systems worldwide. Since its emergence in December 2019, research has been focused on ways to not only treat the infected but also identify those at risk and prevent spread. There is currently no known biological biomarker that can predict the risk of being infected. A growing set of studies have emerged that show an association between ABO blood group and the risk of COVID-19 infection. In this study, we used retrospective observational data in Bahrain to investigate the association between ABO blood group and risk of infection as well as susceptibility to a more severe ICU-requiring infection. We found that individuals with blood group B were at a higher risk of infection, while those with blood group AB were at a lower risk. No association was observed between blood group and the risk of a severe ICU-requiring COVID-19 infection. We extended the analysis to study the association by antibodies present; anti-a (blood groups B and O) and anti-b (blood groups A and O). Antibodies were not found to be associated with either risk of infection or susceptibility to severe infection. The current study, along with the variation in blood group association results, indicates that blood group may not be the most ideal biomarker to predict risk of COVID-19 infection.
Endocytosis of BRASSINOSTEROID INSENSITIVE1 Is Partly Driven by a Canonical Tyr-Based Motif
Authors: Liu Derui , Kumar Rahul , Claus Lucas A.N. , Johnson Alexander J. , Siao Wei , Vanhoutte Isabelle , Wang Peng , Bender Kyle W. , Yperman Klaas , Martins Sara , Zhao Xiuyang , Vert Grégory , Van Damme Daniël , Friml Jiří , Russinova Eugenia
Published: September 2020

Clathrin-mediated endocytosis (CME) and its core endocytic machinery are evolutionarily conserved across all eukaryotes. In mammals, the heterotetrameric adaptor protein complex-2 (AP-2) sorts plasma membrane (PM) cargoes into vesicles via the recognition of motifs based on Tyr or di-Leu in their cytoplasmic tails. However, in plants, very little is known about how PM proteins are sorted for CME and whether similar motifs are required. In Arabidopsis (Arabidopsis thaliana), the brassinosteroid (BR) receptor BR INSENSITIVE1 (BRI1) undergoes endocytosis, which depends on clathrin and AP-2. Here, we demonstrate that BRI1 binds directly to the medium AP-2 subunit (AP2M). The cytoplasmic domain of BRI1 contains five putative canonical surface-exposed Tyr-based endocytic motifs. The Tyr-to-Phe substitution in Y898KAI reduced BRI1 internalization without affecting its kinase activity. Consistently, plants carrying the BRI1Y898F mutation were hypersensitive to BRs. Our study demonstrates that AP-2–dependent internalization of PM proteins via the recognition of functional Tyr motifs also operates in plants.
Local culture as a corporate social responsibility multiplier: Confucian values' mediation between firm policies and employees' attitude
Authors: Chen Jian-Yu , Lim Suk-Jun , Nam Hyun-Jung , Phillips Joe
Published: September 2020

Purpose

The Western-centric nature of research into corporate social responsibility (CSR) has left gaps in one’s understanding of local culture's role in augmenting or undermining the impact of firms' CSR policies. This paper constructs and tests variables measuring “Confucian values” mediation between Chinese employees' perceived CSR and their job satisfaction, organizational commitment and organizational citizenship behavior.

Design/methodology/approach

The hypotheses were tested through structural equation modeling, using data from 311 responses completed by employees at Chinese private companies, located in China's Cheng-Yu economic area (Chongqing and Chengdu).

Findings

Chinese employees' perceived CSR had a positive significant effect on job attitudes (job satisfaction and organizational commitment). However, perceived CSR had no significant positive impact on organizational citizenship behavior. The authors also found that Confucian values are a partial mediator between perceived CSR and job attitudes and a full mediator between perceived CSR and organizational citizenship behavior.

Originality/value

The results enrich one’s understanding of cultural values in these relationships and suggest further research into how firms and governments in Confucian-based societies can better operationalize Confucian values to argument the firm's and country's CSR identity, thus improving job attitudes and public relations among customers who share this cultural heritage. For non-Confucian societies and foreign firms operating in China, the results encourage searches for Confucian value substitutes, such as trust and education, to incorporate into CSR mechanisms that promote these values among employees. The authors suggest approaches for furthering these agendas.
A new tapped sources stack succored modified HX bridge MLI
Authors: Chandrasekaran Kannan , Mohanty Nalin Kant , Ranganathan Selvarasu
Published: September 2020

Purpose

Multilevel inverter (MLI) is a prevailing sensible alternative to two-level inverters that offer a high-quality output voltage waveform, wherein the multiple input direct current (DC) levels are established by using isolated DC sources, batteries and renewable energy sources. The purpose of this paper is to develop MLI to offer lower total harmonic distortion (THD), higher output voltage levels and reduced switching components for high power applications.

Design/methodology/approach

In this paper, a new tapped sources stack succored modified HX bridge MLI (TSSSMHXBMLI) topology is proposed which includes two modules, such as tapped sources stack (TSS) and modified HX bridge inverter, which perform their function in a single stage. Also, this paper outlines the formulaic implementation of the multicarrier/sub-harmonic pulse width modulation (MCPWM/SHPWM) in a Xilinx Spartan3E-500 field programmable gate array (FPGA) is suitable for the developed MLI.

Findings

The feasibility of the suggested topology is well proved by both simulation and experiment results.

Practical implications

This paper examines a new topology of TSSSMHXBMLI with a view to minimize total count of switching components against basic MLI topologies. The operating sequence of the suggested TSSSMHXBMLI topology is verified with the simulation study followed by an experimental investigation.

Originality/value

The simulation and experimental results of suggested MLI topology reveals to obtain lower THD, higher output voltage levels and reduced switching components for high power applications.
Steel strip surface inspection through the combination of feature selection and multiclass classifiers
Authors: Zhang Z.F. , Liu Wei , Ostrosi Egon , Tian Yongjie , Yi Jianping
Published: September 2020

Purpose

During the production process of steel strip, some defects may appear on the surface, that is, traditional manual inspection could not meet the requirements of low-cost and high-efficiency production. The purpose of this paper is to propose a method of feature selection based on filter methods combined with hidden Bayesian classifier for improving the efficiency of defect recognition and reduce the complexity of calculation. The method can select the optimal hybrid model for realizing the accurate classification of steel strip surface defects.

Design/methodology/approach

A large image feature set was initially obtained based on the discrete wavelet transform feature extraction method. Three feature selection methods (including correlation-based feature selection, consistency subset evaluator [CSE] and information gain) were then used to optimize the feature space. Parameters for the feature selection methods were based on the classification accuracy results of hidden Naive Bayes (HNB) algorithm. The selected feature subset was then applied to the traditional NB classifier and leading extended NB classifiers.

Findings

The experimental results demonstrated that the HNB model combined with feature selection approaches has better classification performance than other models of defect recognition. Among the results of this study, the proposed hybrid model of CSE + HNB is the most robust and effective and of highest classification accuracy in identifying the optimal subset of the surface defect database.

Originality/value

The main contribution of this paper is the development of a hybrid model combining feature selection and multi-class classification algorithms for steel strip surface inspection. The proposed hybrid model is primarily robust and effective for steel strip surface inspection.