The pandemic caused by novel severe acute respiratory syndrome coronavirus (SARS‐CoV‐2) has resulted in over 452 822 deaths in the first 20 days of June 2020 due to the coronavirus virus disease 2019 ...(COVID‐19). The SARS‐CoV‐2 uses the host angiotensin‐converting enzyme 2 (ACE2) receptor to gain entry inside the human cells where it replicates by using the cell protein synthesis mechanisms. The knowledge of the tissue distribution of ACE2 in human organs is therefore important to predict the clinical course of the COVID‐19. Also important is the understanding of the viral receptor‐binding domain (RBD), a region within the spike (S) proteins, that enables the entry of the virus into the host cells to synthesize vaccine and monoclonal antibodies (mAbs). We performed an exhaustive search of human protein databases to establish the tissues that express ACE2 and performed an in‐depth analysis like sequence alignments and homology modeling of the spike protein (S) of the SARS‐CoV‐2 to identify antigenic regions in the RBD that can be exploited to synthesize vaccine and mAbs. Our results show that ACE2 is widely expressed in human organs that may explain the pulmonary, systemic, and neurological deficits seen in COVID‐19 patients. We show that though the S protein of the SARS‐CoV‐2 is a homolog of S protein of SARS‐CoV‐1, it has regions of dissimilarities in the RBD and transmembrane segments. We show peptide sequences in the RBD of SARS‐CoV‐2 that can bind to the major histocompatibility complex alleles and serve as effective epitopes for vaccine and mAbs synthesis.
Highlights
On the basis of our results in the present study, the distribution and density of ACE2 receptor can be computed to understand the multisystem and specific organ attacks as seen clinically in COVID‐19 caused by SARS‐CoV‐2. The expression of ACE2 in the brain provides and explanation to the neurological deficits seen in COVID‐19 as has been widely reported now. We show the emergence of mutation (99.97% sequence identities) between the SARS‐CoV‐2 (Wuhan‐Hu‐1 virus) compared with the recently deposited genomes of diverse clinical isolates (May 2020). By the homology modeling of receptor‐binding domain (RBD) of SARS‐CoV‐1 and SARS‐CoV‐2, we show the structural similarities between both the proteins. For vaccine and monoclonal antibody synthesis against SARS‐CoV‐2 we identified peptides sequences in the receptor‐binding domain (RBD) of SARS‐CoV‐2 with strong binding predictions to the MHC class I and class II allele with log‐transformed binding affinity, nM affinity, and ranks. As the amino acids in the RBD sequences predicted in this study are known to interact with human ACE2 receptors, synthesis of monoclonal antibodies against them can prove to be of translational value. Our results could be useful for designing effective prevention and treatment strategies in COVID‐19.
In recent decades, the identification of natural compounds that modulate the endocannabinoid system by fatty acid amide hydrolase (FAAH) inhibition has provided an interesting area of research. ...Daidzein, which is an isoflavone, has neurobiological activities that are effective against several neurological disorders which include depression. This study aimed to investigate the FAAH inhibitory activity of Daidzein through in-silico analysis via Molecular Operating Environment software together with the in-vitro FAAH inhibitory assay. Furthermore, the anti-depressive effect of Daidzein (20 mg/kg) was examined via open field test and forced swim test in both male and female mice groups. Finally, the level of depression and stress was measured by the plasma corticosterone level. Molecular docking has shown the probable binding of Daidzein with the FAAH enzyme via its ser-ser-lys catalytic triad. Daidzein binds to the active pocket of FAAH with excellent binding energy of -64.77 Kcal/mol and binding affinity of -11.77 Kcal/mol. The findings reported that Daidzein inhibited the FAAH enzyme with IC50 value at 1.3±0.13 µM concentration. The open field test showed that Daidzein had no significant effect on locomotory activity in both male and female groups compared to fluoxetine and Arch-5HT group. Daidzein has significantly decreased the immobility time in forced swim test, which is an indicator of an anti-depressive effect. The corticosterone level that regulates depression was significantly decreased in both male and female Daidzein-treated mice groups. This study highlighted the role of Daidzein as a therapeutic agent for depression via the inhibition of FAAH and modulation of corticosterone levels.
SARS-CoV-2 causes multiorgan damage to vital organs and tissue that are known to be due to a combination of tissue tropisms and cytokine-mediated damage that it can incite in COVID-19. The effects of ...SARS-Co-2 on the lymphocytes and therefore on the immune response have attracted attention recently in COVID-19 to understand its effects in causing a chronic state of ongoing infection with Long-COVID. The associated lymphopaenia and autoimmune disease state, which is an apparent paradox, needs to be researched to dissect possible mechanisms underlying this state. This paper attempts to unravel the aforesaid immune paradox effects of SARS-CoV-2 on the lymphocytes and discusses appropriate treatment modalities with antiviral drugs and nutraceuticals which could prove virucidal in SARS-CoV-2 seeding monocytes and lymphocytes in patients with COVID-19 and Long-COVID. Importantly it proposes a new in vitro treatment modality of immune regulating cells that can help patients fight the lymphopaenia associated with COVID-19 and Long-COVID.
Advances in modern semiconductor integrated circuits have always demanded faster and more sensitive analytical methods on a large-scale wafer. The surface of wafers is fundamentally essential to ...start building circuits, and quantitative measures of the surface potential, defects, contamination, passivation quality, and uniformity are subject to inspection. The present study provides a new approach to access those by means of terahertz (THz) emission spectroscopy. Upon femtosecond laser illumination, THz radiation, which is sensitive to the surface electric fields of the wafer, is generated. Here, we systematically research the THz emission properties of silicon surfaces under different surface conditions, such as the initial surface with a native oxide layer, a fluorine-terminated surface, and a hydrogen-terminated surface. Meanwhile, a strong doping concentration dependence of the THz emission amplitude from the silicon surface has been revealed in different surface conditions, which implies a semiquantitative connection between the THz emission and the surface band bending with the surface dipoles. Laser-induced THz emission spectroscopy is a promising method for evaluating local surface properties on a wafer scale.
The Antarctic ozone hole arises from ozone destruction driven by elevated levels of ozone destroying (active) chlorine in Antarctic spring. These elevated levels of active chlorine have to be formed ...first and then maintained throughout the period of ozone destruction. It is a matter of debate how this maintenance of active chlorine is brought about in Antarctic spring, when the rate of formation of HCl (considered to be the main chlorine deactivation mechanism in Antarctica) is extremely high. Here we show that in the heart of the ozone hole (16–18 km or 85–55 hPa, in the core of the vortex), high levels of active chlorine are maintained by effective chemical cycles (referred to as HCl null cycles hereafter). In these cycles, the formation of HCl is balanced by immediate reactivation, i.e. by immediate reformation of active chlorine. Under these conditions, polar stratospheric clouds sequester HNO3 and thereby cause NO2 concentrations to be low. These HCl null cycles allow active chlorine levels to be maintained in the Antarctic lower stratosphere and thus rapid ozone destruction to occur. For the observed almost complete activation of stratospheric chlorine in the lower stratosphere, the heterogeneous reaction HCl + HOCl is essential; the production of HOCl occurs via HO2 + ClO, with the HO2 resulting from CH2O photolysis. These results are important for assessing the impact of changes of the future stratospheric composition on the recovery of the ozone hole. Our simulations indicate that, in the lower stratosphere, future increased methane concentrations will not lead to enhanced chlorine deactivation (through the reaction CH4 + Cl ⟶ HCl + CH3) and that extreme ozone destruction to levels below ≈ 0.1 ppm will occur until mid-century.
Despite advances in drug discovery and modifications in the chemotherapeutic regimens, human infections caused by free-living amoebae (FLA) have high mortality rates (~95%). The FLA that cause fatal ...human cerebral infections include Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba spp. Novel drug-target discovery remains the only viable option to tackle these central nervous system (CNS) infection in order to lower the mortality rates caused by the FLA. Of these FLA, N. fowleri causes primary amoebic meningoencephalitis (PAM), while the A. castellanii and B. Mandrillaris are known to cause granulomatous amoebic encephalitis (GAE). The infections caused by the FLA have been treated with drugs like Rifampin, Fluconazole, Amphotericin-B and Miltefosine. Miltefosine is an anti-leishmanial agent and an experimental anti-cancer drug. With only rare incidences of success, these drugs have remained unsuccessful to lower the mortality rates of the cerebral infection caused by FLA. Recently, with the help of bioinformatic computational tools and the discovered genomic data of the FLA, discovery of newer drug targets has become possible. These cellular targets are proteins that are either unique to the FLA or shared between the humans and these unicellular eukaryotes. The latter group of proteins has shown to be targets of some FDA approved drugs prescribed in non-infectious diseases. This review out-lines the bioinformatics methodologies that can be used in the discovery of such novel drug-targets, their chronicle by in-vitro assays done in the past and the translational value of such target discoveries in human diseases caused by FLA.
Bangladesh summer monsoon rainfall (BSMR), typically from June through September (JJAS), represents the main source of water for multiple sectors. However, its high spatial and interannual ...variability makes the seasonal prediction of BSMR crucial for building resilience to natural disasters and for food security in a climate‐risk‐prone country. This study describes the development and implementation of an objective system for the seasonal forecasting of BSMR, recently adopted by the Bangladesh Meteorological Department (BMD). The approach is based on the use of a calibrated multi‐model ensemble (CMME) of seven state‐of‐the‐art general circulation models (GCMs) from the North American Multi‐Model Ensemble project. The lead‐1 (initial conditions of May for forecasting JJAS total rainfall) hindcasts (spanning 1982–2010) and forecasts (spanning 2011–2018) of seasonal total rainfall for the JJAS season from these seven GCMs were used. A canonical correlation analysis (CCA) regression is used to calibrate the raw GCMs outputs against observations, which are then combined with equal weight to generate final CMME predictions. Results show, compared to individual calibrated GCMs and uncalibrated MME, that the CCA‐based calibration generates significant improvements over individual raw GCM in terms of the magnitude of systematic errors, Spearman's correlation coefficients, and generalised discrimination scores over most of Bangladesh areas, especially in the northern part of the country. Since October 2019, the BMD has been issuing real‐time seasonal rainfall forecasts using this new forecast system.
This study aimed to develop an improved seasonal forecast system for the prediction of Bangladesh's summer monsoon rainfall. The system is based on a calibrated multi‐model ensemble (CMME) approach, using state‐of‐the‐art general circulation models (GCM). A canonical correlation analysis‐based regression is used to calibrate the raw outputs from the GCMs, which are then combined with equal weight to generate a final CMME prediction. Results suggest that this forecast system is feasible and might be used in the implementation of climate services.
Statins are a cornerstone guideline-directed medical therapy for secondary prevention of ischemic heart disease (IHD). However, recent temporal trends and disparities in statin utilization for ...ischemic heart disease have not been well characterized.
This retrospective analysis included data from outpatient adult visits with IHD from the National Ambulatory Medical Care Survey (NAMCS) between January 2006 and December 2018. We examined the trends and predictors of statin utilization in outpatient adult visits with IHD.
Between 2006 and 2018, we identified a total of 542,704,112 weighted adult ambulatory visits with IHD and of those 46.6% were using or prescribed statin. Middle age (50-74 years) (adjusted odds ratio aOR 1.65, 95% confidence interval CI 1.28-2.13 p<0.001) and old age (≥75 years) (aOR= 1.66, CI 1.26-2.19, p <0.001) compared to young age (18-49 years), and male sex (aOR= 1.35, CI 1.23-1.48, p <0.001) were associated with greater likelihood of statin utilization, whereas visits with non-Hispanic (NH) Black patients (aOR= 0.75, CI 0.61-0.91, p =0.005) and Hispanic patients (aOR= 0.74, CI 0.60-0.92, p =0.006) were associated with decreased likelihood of statin utilization compared to NH White patient visits. Compared with private insurance, statin utilization was nominally lower in Medicare (aOR= 0.91, CI 0.80-1.02, p =0.112), Medicaid (aOR= 0.78, CI 0.59-1.02, p =0.072) and self-pay/no charge (aOR= 0.72, CI 0.48-1.09, p =0.122) visits, however did not reach statistical significance. There was no significant uptake in statin utilization from 2006 (44.1%) to 2018 (46.2%) (p =0.549).
Substantial gaps remain in statin utilization for patients with IHD, with no significant improvement in use between 2006 and 2018. Persistent disparities in statin prescription remain, with the largest treatment gaps among younger patients, women, and racial/ethnic minorities (NH Blacks and Hispanics).
PDF
