scholarly journals ACE2 Netlas: In-silico functional characterization and drug-gene interactions of ACE2 gene network to understand its potential involvement in COVID-19 susceptibility

2020 ◽  
Author(s):  
Gita A Pathak ◽  
Frank R Wendt ◽  
Aranyak Goswami ◽  
Flavio De Angelis ◽  
Renato Polimanti ◽  
...  
Keyword(s):  
Gene Network ◽  
Functional Characterization ◽  
Gene Interaction ◽  
Biological Properties ◽  
Angiotensin Converting Enzyme 2 ◽  
Interaction Database ◽  
Functional Consequences ◽  
Multi Level ◽  
Ace2 Gene

AbstractAngiotensin-converting enzyme-2 (ACE2) receptor has been identified as the key adhesion molecule for the transmission of the SARS-CoV-2. However, there is no evidence that human genetic variation in ACE2 is singularly responsible for COVID-19 susceptibility. Therefore, we performed a multi-level characterization of genes that interact with ACE2 (ACE2-gene network) for their over-represented biological properties in the context of COVID-19.The phenome-wide association of 51 genes including ACE2 with 4,756 traits categorized into 26 phenotype categories, showed enrichment of immunological, respiratory, environmental, skeletal, dermatological, and metabolic domains (p<4e-4). Transcriptomic regulation of ACE2-gene network was enriched for tissue-specificity in kidney, small intestine, and colon (p<4.7e-4). Leveraging the drug-gene interaction database we identified 47 drugs, including dexamethasone and spironolactone, among others.Considering genetic variants within ± 10 kb of ACE2-network genes we characterized functional consequences (among others) using miRNA binding-site targets. MiRNAs affected by ACE2-network variants revealed statistical over-representation of inflammation, aging, diabetes, and heart conditions. With respect to variants mapped to the ACE2-network, we observed COVID-19 related associations in RORA, SLC12A6 and SLC6A19 genes.Overall, functional characterization of ACE2-gene network highlights several potential mechanisms in COVID-19 susceptibility. The data can also be accessed at https://gpwhiz.github.io/ACE2Netlas/

scholarly journals ACE2 Netlas: In silico Functional Characterization and Drug-Gene Interactions of ACE2 Gene Network to Understand Its Potential Involvement in COVID-19 Susceptibility

2021 ◽  
Vol 12 ◽  
Author(s):  
Gita A. Pathak ◽  
Frank R. Wendt ◽  
Aranyak Goswami ◽  
Dora Koller ◽  
Flavio De Angelis ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Gene Network ◽  
Genome Wide Association Study ◽  
Functional Characterization ◽  
Gene Interaction ◽  
Biological Properties ◽  
Interaction Database ◽  
Genome Wide ◽  
Ace2 Gene

Angiotensin-converting enzyme-2 (ACE2) receptor has been identified as the key adhesion molecule for the transmission of the SARS-CoV-2. However, there is no evidence that human genetic variation in ACE2 is singularly responsible for COVID-19 susceptibility. Therefore, we performed an integrative multi-level characterization of genes that interact with ACE2 (ACE2-gene network) for their statistically enriched biological properties in the context of COVID-19. The phenome-wide association of 51 genes including ACE2 with 4,756 traits categorized into 26 phenotype categories, showed enrichment of immunological, respiratory, environmental, skeletal, dermatological, and metabolic domains (p &lt; 4e-4). Transcriptomic regulation of ACE2-gene network was enriched for tissue-specificity in kidney, small intestine, and colon (p &lt; 4.7e-4). Leveraging the drug-gene interaction database we identified 47 drugs, including dexamethasone and spironolactone, among others. Considering genetic variants within ± 10 kb of ACE2-network genes we identified miRNAs whose binding sites may be altered as a consequence of genetic variation. The identified miRNAs revealed statistical over-representation of inflammation, aging, diabetes, and heart conditions. The genetic variant associations in RORA, SLC12A6, and SLC6A19 genes were observed in genome-wide association study (GWAS) of COVID-19 susceptibility. We also report the GWAS-identified variant in 3p21.31 locus, serves as trans-QTL for RORA and RORC genes. Overall, functional characterization of ACE2-gene network highlights several potential mechanisms in COVID-19 susceptibility. The data can also be accessed at https://gpwhiz.github.io/ACE2Netlas/.

[P216]: A functional characterization of the Dlx1/2 and Arx gene network in regulating the differentiation of the basal ganglia

2006 ◽  
Vol 24 (8) ◽  
pp. 588-588
Author(s):  
V. Broccoli ◽  
G. Colasante ◽  
M. Bianchi ◽  
S. Giannelli ◽  
M. Maira ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Gene Network ◽  
Functional Characterization

scholarly journals Functionally distinct POMC-expressing neuron subpopulations in hypothalamus revealed by intersectional targeting

2021 ◽  
Author(s):  
Nasim Biglari ◽  
Isabella Gaziano ◽  
Jonas Schumacher ◽  
Jan Radermacher ◽  
Lars Paeger ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Energy State ◽  
Functional Characterization ◽  
Anatomical Distribution ◽  
Electrophysiological Properties ◽  
Functional Consequences ◽  
Glucagon Like Peptide 1 ◽  
Differential Ability

AbstractPro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus represent key regulators of metabolic homeostasis. Electrophysiological and single-cell sequencing experiments have revealed a remarkable degree of heterogeneity of these neurons. However, the exact molecular basis and functional consequences of this heterogeneity have not yet been addressed. Here, we have developed new mouse models in which intersectional Cre/Dre-dependent recombination allowed for successful labeling, translational profiling and functional characterization of distinct POMC neurons expressing the leptin receptor (Lepr) and glucagon like peptide 1 receptor (Glp1r). Our experiments reveal that POMCLepr+ and POMCGlp1r+ neurons represent largely nonoverlapping subpopulations with distinct basic electrophysiological properties. They exhibit a specific anatomical distribution within the arcuate nucleus and differentially express receptors for energy-state communicating hormones and neurotransmitters. Finally, we identify a differential ability of these subpopulations to suppress feeding. Collectively, we reveal a notably distinct functional microarchitecture of critical metabolism-regulatory neurons.

scholarly journals Functional Architecture of Deleterious Genetic Variants in the Genome of a Wrangel Island Mammoth

2020 ◽  
Vol 12 (3) ◽  
pp. 48-58 ◽  
Author(s):  
Erin Fry ◽  
Sun K Kim ◽  
Sravanthi Chigurapti ◽  
Katelyn M Mika ◽  
Aakrosh Ratan ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Small Population ◽  
Deleterious Mutations ◽  
Developmental Defects ◽  
Wrangel Island ◽  
Relict Populations ◽  
Deleterious Alleles ◽  
Large Populations ◽  
Functional Consequences

Abstract Woolly mammoths were among the most abundant cold-adapted species during the Pleistocene. Their once-large populations went extinct in two waves, an end-Pleistocene extinction of continental populations followed by the mid-Holocene extinction of relict populations on St. Paul Island ∼5,600 years ago and Wrangel Island ∼4,000 years ago. Wrangel Island mammoths experienced an episode of rapid demographic decline coincident with their isolation, leading to a small population, reduced genetic diversity, and the fixation of putatively deleterious alleles, but the functional consequences of these processes are unclear. Here, we show that a Wrangel Island mammoth genome had many putative deleterious mutations that are predicted to cause diverse behavioral and developmental defects. Resurrection and functional characterization of several genes from the Wrangel Island mammoth carrying putatively deleterious substitutions identified both loss and gain of function mutations in genes associated with developmental defects (HYLS1), oligozoospermia and reduced male fertility (NKD1), diabetes (NEUROG3), and the ability to detect floral scents (OR5A1). These data suggest that at least one Wrangel Island mammoth may have suffered adverse consequences from reduced population size and isolation.

scholarly journals Extracellular Vesicles from Plants: Current Knowledge and Open Questions

2021 ◽  
Vol 22 (10) ◽  
pp. 5366
Author(s):  
Ornella Urzì ◽  
Stefania Raimondo ◽  
Riccardo Alessandro
Keyword(s):  
Extracellular Vesicles ◽  
Current Knowledge ◽  
Functional Characterization ◽  
Biological Properties ◽  
Controversial Issues ◽  
Animal Cells ◽  
Natural Substances ◽  
Open Questions ◽  
Potential Use

The scientific interest in the beneficial properties of natural substances has been recognized for decades, as well as the growing attention in extracellular vesicles (EVs) released by different organisms, in particular from animal cells. However, there is increasing interest in the isolation and biological and functional characterization of these lipoproteic structures in the plant kingdom. Similar to animal vesicles, these plant-derived extracellular vesicles (PDEVs) exhibit a complex content of small RNAs, proteins, lipids, and other metabolites. This sophisticated composition enables PDEVs to be therapeutically attractive. In this review, we report and discuss current knowledge on PDEVs in terms of isolation, characterization of their content, biological properties, and potential use as drug delivery systems. In conclusion, we outline controversial issues on which the scientific community shall focus the attention shortly.

scholarly journals Functional architecture of deleterious genetic variants in the Wrangel Island mammoth genome

2017 ◽  
Author(s):  
Erin Fry ◽  
Sun K. Kim ◽  
Sravanthi Chigurapti ◽  
Katelyn M. Mika ◽  
Aakrosh Ratan ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Small Population ◽  
Developmental Defects ◽  
Wrangel Island ◽  
Relict Populations ◽  
Deleterious Alleles ◽  
Large Populations ◽  
Population Sizes ◽  
Functional Consequences

Woolly mammoths were among the most abundant cold adapted species during the Pleistocene. Their once large populations went extinct in two waves, an end-Pleistocene extinction of continental populations followed by the mid-Holocene extinction of relict populations on St. Paul Island ~5,600 years ago and Wrangel Island ~4,000 years ago. Wrangel Island mammoths experienced an episode of rapid demographic decline coincident with their isolation, leading to a small population, reduced genetic diversity, and the fixation of putatively deleterious alleles, but the functional consequences of these processes are unclear. Here we show that the Wrangel Island mammoth accumulated many putative deleterious mutations that are predicted to cause diverse behavioral and developmental defects. Resurrection and functional characterization of Wrangel Island mammoth genes carrying these substitutions identified both loss and gain of function mutations in genes associated with developmental defects (HYLS1), oligozoospermia and reduced male fertility (NKD1), diabetes (NEUROG3), and the ability to detect floral scents (OR5A1). These results suggest that Wrangel Island mammoths may have suffered adverse consequences from their reduced population sizes and isolation.

scholarly journals The neutralizing antibody, LY-CoV555, protects against SARS-CoV-2 infection in non-human primates

2021 ◽  
pp. eabf1906
Author(s):  
Bryan E. Jones ◽  
Patricia L. Brown-Augsburger ◽  
Kizzmekia S. Corbett ◽  
Kathryn Westendorf ◽  
Julian Davies ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Functional Characterization ◽  
Neutralizing Antibody ◽  
Therapeutic Agents ◽  
Receptor Binding Domain ◽  
Angiotensin Converting Enzyme 2 ◽  
Cynomolgus Monkeys ◽  
Binding Inhibition ◽  
Vaccination Campaigns

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a public health threat for which preventive and therapeutic agents are urgently needed. Neutralizing antibodies are a key class of therapeutics which may bridge widespread vaccination campaigns and offer a treatment solution in populations less responsive to vaccination. Herein, we report that high-throughput microfluidic screening of antigen-specific B-cells led to the identification of LY-CoV555 (also known as bamlanivimab), a potent anti-spike neutralizing antibody from a hospitalized, convalescent patient with coronavirus disease 2019 (COVID-19). Biochemical, structural, and functional characterization of LY-CoV555 revealed high-affinity binding to the receptor-binding domain, angiotensin converting enzyme 2 binding inhibition, and potent neutralizing activity. A pharmacokinetic study of LY-CoV555 conducted in cynomolgus monkeys demonstrated a mean half-life of 13 days, and clearance of 0.22 mL/hr/kg, consistent with a typical human therapeutic antibody. In a rhesus macaque challenge model, prophylactic doses as low as 2.5 mg/kg reduced viral replication in the upper and lower respiratory tract in samples collected through study Day 6 following viral inoculation. This antibody has entered clinical testing and is being evaluated across a spectrum of COVID-19 indications, including prevention and treatment.

scholarly journals BRIEF DESCRIPTION OF THE BIOLOGICAL PROPERTIES OF CORONAVIRUS (COVID-19)

2021 ◽  
Author(s):  
David Aphkhazava ◽  
Marina Pirtskhalava ◽  
Malkhaz Vakhania ◽  
Mariam Kobiashvili ◽  
Tornike Mindiashvili ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Scientific Research ◽  
Biological Properties ◽  
Research Data ◽  
Infectious Process ◽  
Treatment And Prevention

The article provides morphological and functional characterization of the new coronavirus (COVID-19) based on the latest scientific research data, study of biological properties, epidemiology and the course of the infectious process in humans, some issues of treatment and prevention.

Functional characterization of human brown adipose tissue metabolism

2020 ◽  
Vol 477 (7) ◽  
pp. 1261-1286 ◽  
Author(s):  
Marie Anne Richard ◽  
Hannah Pallubinsky ◽  
Denis P. Blondin
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Functional Characterization ◽  
Human Infants ◽  
Positron Emission ◽  
Brown Adipose ◽  
Treatment Of Obesity ◽  
And Function

Brown adipose tissue (BAT) has long been described according to its histological features as a multilocular, lipid-containing tissue, light brown in color, that is also responsive to the cold and found especially in hibernating mammals and human infants. Its presence in both hibernators and human infants, combined with its function as a heat-generating organ, raised many questions about its role in humans. Early characterizations of the tissue in humans focused on its progressive atrophy with age and its apparent importance for cold-exposed workers. However, the use of positron emission tomography (PET) with the glucose tracer [18F]fluorodeoxyglucose ([18F]FDG) made it possible to begin characterizing the possible function of BAT in adult humans, and whether it could play a role in the prevention or treatment of obesity and type 2 diabetes (T2D). This review focuses on the in vivo functional characterization of human BAT, the methodological approaches applied to examine these features and addresses critical gaps that remain in moving the field forward. Specifically, we describe the anatomical and biomolecular features of human BAT, the modalities and applications of non-invasive tools such as PET and magnetic resonance imaging coupled with spectroscopy (MRI/MRS) to study BAT morphology and function in vivo, and finally describe the functional characteristics of human BAT that have only been possible through the development and application of such tools.

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