Structural basis for the mechanism of interaction of SARS-CoV-2 B.1.640.2 variant RBD with the host receptors hACE2 and GRP78.

The inflicted chaos instigated by the SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) globally continues with the emergence of novel variants. The current global outbreak is aggravated by the manifestation of novel variants, which affect the effectiveness of the vaccine, attachment with hACE2 (human Angiotensin-converting enzyme 2) and immune evasion. Recently, a new variant named University Hospital Institute (IHU) (B.1.640.2) was reported in France in November 2021 and is spreading globally affecting public healthcare. The B.1.640.2 SARS-CoV-2 strain revealed 14 mutations and 9 deletions in spike protein. Thus, it is important to understand how these variations in the spike protein impact the communication with the host. A protein coupling approach along with molecular simulation protocols was used to interpret the variation in the binding of the wild type (WT) and B.1.640.2 variant with hACE2 and Glucose-regulating protein 78 (GRP78) receptors. The initial docking scores revealed a stronger binding of the B.1.640.2-RBD with both the hACE2 and GRP78. To further understand the crucial dynamic changes, we looked at the structural and dynamic characteristics and also explored the variations in the bonding networks between the WT and B.1.640.2-RBD (receptor-binding domain) in association with hACE2 and GRP78, respectively. Our findings revealed that the variant complex demonstrated distinct dynamic properties in contrast to the wild type due to the acquired mutations. Finally, to provide conclusive evidence on the higher binding by the B.1.640.2 variant the TBE was computed for each complex. For the WT with hACE2 the TBE was quantified to be-61.38 ± 0.96 kcal/mol and for B.1.640.2 variant the TBE was estimated to be -70.47 ± 1.00 kcal/mol. For the WT-RBD-GRP78 the TBE -was computed to be 32.32 ± 0.56 kcal/mol and for the B.1.640.2-RBD a TBE of -50.39 ± 0.88 kcal/mol was reported. This show that these mutations are the basis for higher binding and infectivity produced by B.1.640.2 variant and can be targeted for drug designing against it.Communicated by Ramaswamy H. Sarma.

1,4,9,9-tetramethyloctahydro-4,7-(epoxymethano)azulen-5(1H)-one, a natural product as a potential inhibitor of COVID-19: Extraction, crystal structure, and virtual screening approach

In the present work, we describe the extraction of a natural product namely 1,4,9,9-tetramethyloctahydro-4,7-(epoxymethano)azulen-5(1H)-one, and its structure was confirmed by single crystal X-ray diffraction analysis. The conformations of the 5-, 6-, and 7-membered rings in the title compound, C15H24O2, have been probed by a Cremer-Pople puckering analysis. C—H···O hydrogen bonds generate chains in the crystal that stretch along the c-axis direction. The Hirshfeld surface analysis method was used to stabilize the crystal packing of the natural compound. Accompanied by experimental studies, quantum chemical calculations were also performed to compare the structural elucidation and the results of these geometrical parameters exhibited excellent agreement. The compound was also docked with several drug targets of the SARS-CoV-2 virus and found to show the best binding with the main protease enzyme, having a binding energy of -12.31 kcal/mol and interacting with His41 and Cys145 residues. The dynamic stability deciphered the complex to be stable with an average RMSD of 3.8 Å. The compound dynamics with the enzyme showed the compound conformation to be highly stable. The intermolecular binding free energy determined the compound-main protease enzyme to show high interaction energy of < 40 kcal/mol. Together, these studies demonstrate the compound to be a lead structure against SARS-CoV-2.

1,4,9,9-tetramethyloctahydro-4,7-(epoxymethano)azulen-5(1H)-one, a natural product as a potential inhibitor of COVID-19: Extraction, crystal structure, and virtual screening approach.

In the present work, we describe the extraction of a natural product namely 1,4,9,9-tetramethyloctahydro-4,7-(epoxymethano)azulen-5(1H)-one, and its structure was confirmed by single crystal X-ray diffraction analysis. The conformations of the 5-, 6-, and 7-membered rings in the title compound, C15H24O2, have been probed by a Cremer-Pople puckering analysis. C-H···O hydrogen bonds generate chains in the crystal that stretch along the c-axis direction. The Hirshfeld surface analysis method was used to stabilize the crystal packing of the natural compound. Accompanied by experimental studies, quantum chemical calculations were also performed to compare the structural elucidation and the results of these geometrical parameters exhibited excellent agreement. The compound was also docked with several drug targets of the SARS-CoV-2 virus and found to show the best binding with the main protease enzyme, having a binding energy of -12.31 kcal/mol and interacting with His41 and Cys145 residues. The dynamic stability deciphered the complex to be stable with an average RMSD of 3.8 Å. The compound dynamics with the enzyme showed the compound conformation to be highly stable. The intermolecular binding free energy determined the compound-main protease enzyme to show high interaction energy of < 40 kcal/mol. Together, these studies demonstrate the compound to be a lead structure against SARS-CoV-2.

Effectiveness Of Pcr Pool Testing For Screening Of Covid-19 Infection In Pakistan.

BACKGROUND: We tested the utility of mini-pool PCR testing for the rational use of PCR consumables in screening for CoViD-19. METHODS: After pilot experiments, 3-samples pool size was selected. One step RT-PCR was performed. The samples in the mini-pool having COVID gene amplification were tested individually. RESULTS: 1548 samples tested in 516 mini-pools resulted 396 mini-pools as negative and 120 as positive. Upon individual testing, 110 samples tested positive and 9 were inconclusive. 876 PCR reactions were performed to test 1548 samples, saving 43% PCR reagents. Centres with low prevalence resulted in most saving on reagents (50%), while centres with high prevalence resulted in more test reactions. Testing of individual samples resulted in delays in reporting. CONCLUSIONS: Pooling can increase lab capacity, however, pooling delays results and cause degradation of samples.

Incidence of SARS-CoV-2 re-infection in anti-nucleocapsid IgG-positive healthcare workers: a prospective cohort study.

BACKGROUND : Since the pandemic of SARS-CoV-2 began, our understanding of the pathogenesis and immune responses to this virus has continued to evolve. It has been shown that this infection produces natural detectable immune responses in many cases. However, the duration and durability of immunity and its effect on the severity of the illness are still under investigation. Moreover, the protective effects of antibodies against new SARS-CoV-2 variants still remain unclear. OBJECTIVES: To assess the incidence and associated demographic features of SARS-CoV-2 infection in anti-nucleocapsid IgG-positive and anti-nucleocapsid IgG-negative healthcare workers. MATERIAL AND METHODS: This prospective longitudinal cohort study was conducted in Peshawar Medical College group of hospitals of Prime Foundation. Anti-nucleocapsid IgG sero-positive and anti-nucleocapsid IgG sero-negative healthcare workers were followed for a period of 6 months (from 1 Aug 2020 to 31 Jan 2021), and the incidence of SARS-CoV-2 was confirmed by RT-PCR. RESULTS: A total number of 555 cohorts were followed for a period of 6 months; of them 365 (65.7%) were anti-nucleocapsid-negative (group A) and 190 (34.3%) were anti-nucleocapsid-positive (group B) healthcare workers. The mean age of the study cohort was 33.85 ± 9.80 (anti-N (-), 34.2 ± 10.58; anti-N ( +), 33.5 ± 9.50). The median antibody level in anti-nucleocapsid-positive HCWs was 15.95 (IQR: 5.24-53.4). Male gender was the majority in both groups (group A, 246 (67%), group B, 143 (48%)) with statistically significant difference (P < 0.05). Majority of the HCWs were blood group B in both groups (34% each). None of the 190 anti-nucleocapsid-positive HCWs developed subsequent SARS-CoV-2 re-infection, while 17% (n = 65) HCWs developed infection in anti-nucleocapsid-negative group during the 6-month follow-up period. CONCLUSION: In conclusion, none of the anti-nucleocapsid-positive HCWs developed SARS-CoV-2 re-infection in this study, and the presence of IgG anti-nucleocapsid antibodies substantially reduce the risk of re-infection for a period of 6 months.

Bacillus species; a potential source of anti-SARS-CoV-2 main protease inhibitors.

The COVID-19 being a preconized global pandemic by the World Health Organization needs persuasive immediate research for possible medications. The present study was carried out with a specific aim to computationally evaluate and identify compounds derived from Bacillus species as the plausible inhibitors against 3-chymotrypsin-like main protease (3CLpro) or main protease (MPro), which is a key enzyme in the life-cycle of coronavirus. The compounds were isolated from the crude extracts of Bacillus species. Among the isolated compounds, novel inhibitory leads were identified using in silico techniques. Molecular docking revealed that stigmasterol (-8.3 kcal/mol), chondrillasterol (-7.9 kcal/mol) and hexadecnoic acid (-6.9 kcal/mol)) among others bind in the substrate-binding pocket and also interacted with the catalytic dyad of the 3-CLpro. Further evaluation using 50 ns molecular dynamic simulation and MMPB-GBSA indicated that among the top three docking hits, hexadecanoic acid was found to be the most promising anti-COVID-19 lead against the main protease. Hexadecanoic acid might serve as a potent anti-SARS-CoV-2 compound to combat COVID-19, however, in vitro and in vivo validation and optimization is needed.Communicated by Ramaswamy H. Sarma.

Synthesis, X-ray crystal structure, Hirshfeld surface analysis and computational investigation into the potential inhibitory action of novel 6-(p-tolyl)-2-((p-tolyl)thio)methyl-7H-[1.2.4]triazolo[5,1-b][1,3,4]thiadiazine inhibits the main protease of COVID-19.

In recent times, the novel coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now become a worldwide pandemic. With over 71 million confirmed cases, even though the effectiveness and side effects of the specific drugs and vaccines approved for this disease are still limited. Scientists and researchers from all across the world are working to find a vaccine and a cure for COVID-19 by using large-scale drug discovery and analysis. Heterocyclic compounds are regarded to be valuable sources for the discovery of new antiviral medications against SARS-CoV-2 because virus occurrences are still on the rise, and infectivity and mortality may also rise shortly. In this regard, we have synthesized a new triazolothiadiazine derivative. The structure was characterized by NMR spectra and confirmed by X-ray diffraction analysis. The structural geometry coordinates of the title compound are well reproduced by DFT calculations. NBO and NPA analyses have been performed to determine the interaction energies between bonding and antibonding orbital, and natural atomic charges of heavy atoms. Molecular docking suggests that the compounds may have good affinity for SAR-CoV-2 main protease, RNA-dependent RNA polymerase and nucleocapsid enzymes, particularly the main protease enzyme (binding energy of -11.9 kcal mol-1). The predicted docked pose of the compound is dynamically stable and reports a major van der Waals contribution (-62.00 kcal mol-1) to overall net energy.Communicated by Ramaswamy H. Sarma.

Potential SARS-CoV-2 RdRp inhibitors of cytidine derivatives: Molecular docking, molecular dynamic simulations, ADMET, and POM analyses for the identification of pharmacophore sites.

The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is one of the optimum targets for antiviral drug design and development. The hydroxyl groups of cytidine structures were modified with different aliphatic and aromatic groups to obtain 5´-O-acyl and 2´,3´-di-O-acyl derivatives, and then, these derivatives were employed in molecular modeling, antiviral prediction, molecular docking, molecular dynamics, pharmacological and POM studies. Density functional theory (DFT) at the B3LYP/6-31G++ level analyzed biochemical behavior and molecular electrostatic potential (MESP) of the modified cytidine derivatives. The antiviral parameters of the mutated derivatives revealed promising drug properties compared with those of standard antiviral drugs. Molecular docking has determined binding affinities and interactions between the cytidine derivatives and SARS-CoV-2 RdRp. The modified derivatives strongly interacted with prime Pro620 and Lys621 residues. The binding conformation and interactions stability were investigated by 200 ns of molecular dynamics simulations and predicted the compounds to firmly dock inside the RdRp binding pocket. Interestingly, the binding residues of the derivatives were revealed in high equilibrium showing an enhanced binding affinity for the molecules. Intermolecular interactions are dominated by both Van der Waals and electrostatic energies. Finally, the pharmacokinetic characterization of the optimized inhibitors confirmed the safety of derivatives due to their improved kinetic properties. The selected cytidine derivatives can be suggested as potential inhibitors against SARS-CoV-2. The POM Theory supports the hypothesis above by confirming the existence of an antiviral (Oδ--O'δ-) pharmacophore site of Hits.

Virtual Screening of Artemisia annua Phytochemicals as Potential Inhibitors of SARS-CoV-2 Main Protease Enzyme.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a human coronaviruses that emerged in China at Wuhan city, Hubei province during December 2019. Subsequently, SARS-CoV-2 has spread worldwide and caused millions of deaths around the globe. Several compounds and vaccines have been proposed to tackle this crisis. Novel recommended in silico approaches have been commonly used to screen for specific SARS-CoV-2 inhibitors of different types. Herein, the phytochemicals of Pakistani medicinal plants (especially Artemisia annua) were virtually screened to identify potential inhibitors of the SARS-CoV-2 main protease enzyme. The X-ray crystal structure of the main protease of SARS-CoV-2 with an N3 inhibitor was obtained from the protein data bank while A. annua phytochemicals were retrieved from different drug databases. The docking technique was carried out to assess the binding efficacy of the retrieved phytochemicals; the docking results revealed that several phytochemicals have potential to inhibit the SARS-CoV-2 main protease enzyme. Among the total docked compounds, the top-10 docked complexes were considered for further study and evaluated for their physiochemical and pharmacokinetic properties. The top-3 docked complexes with the best binding energies were as follows: the top-1 docked complex with a -7 kcal/mol binding energy score, the top-2 docked complex with a -6.9 kcal/mol binding energy score, and the top-3 docked complex with a -6.8 kcal/mol binding energy score. These complexes were subjected to a molecular dynamic simulation analysis for further validation to check the dynamic behavior of the selected top-complexes. During the whole simulation time, no major changes were observed in the docked complexes, which indicated complex stability. Additionally, the free binding energies for the selected docked complexes were also estimated via the MM-GB/PBSA approach, and the results revealed that the total delta energies of MMGBSA were -24.23 kcal/mol, -26.38 kcal/mol, and -25 kcal/mol for top-1, top-2, and top-3, respectively. MMPBSA calculated the delta total energy as -17.23 kcal/mol (top-1 complex), -24.75 kcal/mol (top-2 complex), and -24.86 kcal/mol (top-3 complex). This study explored in silico screened phytochemicals against the main protease of the SARS-CoV-2 virus; however, the findings require an experimentally based study to further validate the obtained results.

Genome-Based Multi-Antigenic Epitopes Vaccine Construct Designing against Staphylococcus hominis Using Reverse Vaccinology and Biophysical Approaches.

Staphylococcus hominis is a Gram-positive bacterium from the staphylococcus genus; it is also a member of coagulase-negative staphylococci because of its opportunistic nature and ability to cause life-threatening bloodstream infections in immunocompromised patients. Gram-positive and opportunistic bacteria have become a major concern for the medical community. It has also drawn the attention of scientists due to the evaluation of immune evasion tactics and the development of multidrug-resistant strains. This prompted the need to explore novel therapeutic approaches as an alternative to antibiotics. The current study aimed to develop a broad-spectrum, multi-epitope vaccine to control bacterial infections and reduce the burden on healthcare systems. A computational framework was designed to filter the immunogenic potent vaccine candidate. This framework consists of pan-genomics, subtractive proteomics, and immunoinformatics approaches to prioritize vaccine candidates. A total of 12,285 core proteins were obtained using a pan-genome analysis of all strains. The screening of the core proteins resulted in the selection of only two proteins for the next epitope prediction phase. Eleven B-cell derived T-cell epitopes were selected that met the criteria of different immunoinformatics approaches such as allergenicity, antigenicity, immunogenicity, and toxicity. A vaccine construct was formulated using EAAAK and GPGPG linkers and a cholera toxin B subunit. This formulated vaccine construct was further used for downward analysis. The vaccine was loop refined and improved for structure stability through disulfide engineering. For an efficient expression, the codons were optimized as per the usage pattern of the E coli (K12) expression system. The top three refined docked complexes of the vaccine that docked with the MHC-I, MHC-II, and TLR-4 receptors were selected, which proved the best binding potential of the vaccine with immune receptors; this was followed by molecular dynamic simulations. The results indicate the best intermolecular bonding between immune receptors and vaccine epitopes and that they are exposed to the host's immune system. Finally, the binding energies were calculated to confirm the binding stability of the docked complexes. This work aimed to provide a manageable list of immunogenic and antigenic epitopes that could be used as potent vaccine candidates for experimental in vivo and in vitro studies.

One-pot synthesis, X-ray crystal structure, and identification of potential molecules against COVID-19 main protease through structure-guided modeling and simulation approach.

Although antimicrobial resistance before the Covid-19 pandemic is a top priority for global public health, research is already ongoing on novel organic compounds with antimicrobial and antiviral properties in changing medical environments in connection with Covid 19. Thanks to the Biginelli reaction, which allows the synthesis of pyrimidine compounds, blockers of calcium channels, antibodies, antiviral, antimicrobial, anti-inflammatory, or antioxidant therapeutic compounds were investigated. In this paper, we aim to present Biginelli's synthesis, its therapeutic properties, and the structural-functional relationship in the test compounds that allows the synthesis of antimicrobial compounds. Both the DFT and TD-DFT computations of spectral data, molecular orbitals (HOMO, LUMO) analysis, and electrostatic potential (MEP) surfaces are carried out as an add-on to synthetic research. Hirshfeld surface analysis was also used to segregate the different intermolecular hydrogen bonds involved in the molecular packing strength. Natural Bond Orbital (NBO) investigation endorses the existence of intermolecular interactions mediated by lone pair, bonding, and anti-bonding orbitals. The dipole moment, linear polarizability, and first hyperpolarizabilities have been explored as molecular parameters. All findings based on DFT exhibit the best consistency with experimental findings, implying that synthesized molecules are highly stable. To better understand the binding mechanism of the SARS-CoV-2 Mpro, we performed molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations.

A Qualitative-Quantitative Analysis Of The Psychological Impact Of Coronavirus (Covid-19) Pandemic On The Healthcare Professionals

COVID-19 pandemic has emerged as a global health emergency. It poses a serious challenge to healthcare professionals since they provide healthcare facilities to affected population in extremely stressful circumstances, which may affect their psychological wellbeing. Keeping this in mind, this study was conducted to understand the psychological impact of COVID-19 pandemic on healthcare professionals. Following PRISMA protocol, all research papers published between January 2020 and May 2020 were searched in databases like, e.g., Pub-Med, Science Direct and Google-Scholar databases. After screening through proper inclusion criteria, only 26 studies were finally selected for detailed analysis. Results revealed that healthcare professionals suffered from a variety of psychological disorders, particularly from depression, anxiety, and sleep problems. There were also different predisposing factors that have increased the risk of such adverse psychological symptoms among healthcare professionals. And to deal with such symptoms, the healthcare professionals had adopted different coping strategies. The review concludes that COVID-19 pandemic has a severe impact on the psychological well-being of healthcare professionals, therefore, a broad range of interventions are required for mitigating adverse psychological impact of COVID-19 pandemic among healthcare professionals.

Synthesis, crystal structure, and a molecular modeling approach to identify effective antiviral hydrazide derivative against the main protease of SARS-CoV-2.

In the fall of 2019, a new type of coronavirus took place in Wuhan city, China, and rapidly spread across the world and urges the scientific community to develop antiviral therapeutic agents. In our effort we have synthesized a new hydrazide derivative, (E)-N'-(1-(4-bromophenyl)ethylidene)-2-(6-methoxynaphthalen-2-yl)propanehydrazide for this purpose because of its potential inhibitory proprieties. The asymmetric unit of the title molecule consists of two independent molecules differing noticeably in conformation. In the crystal, the independent molecules are linked by N-H···O and C-H···O hydrogen bonds and C-H···π(ring) interactions into helical chains extending along the b-axis direction. The chains are further joined by additional C-H···π(ring) interactions into the full 3-D structure. To obtain a structure-activity relationship, the DFT-NBO analysis is performed to study the intrinsic electronic properties of the title compound. Molecular modeling studies were also conducted to examine the binding affinity of the compound for the SARS-CoV-2 main protease enzyme and to determine intermolecular binding interactions. The compound revealed a stable binding mode at the enzyme active pocket with a binding energy value of -8.1 kcal/mol. Further, stable dynamics were revealed for the enzyme-compound complex and reported highly favorable binding energies. The net MMGBSA binding energy of the complex is -37.41 kcal/mol while the net MMPBSA binding energy is -40.5 kcal/mol. Overall, the compound disclosed the strongest bond of ing the main protease enzyme and might be a good lead for further structural optimization.

Identifying higher risk subgroups of health care workers for priority vaccination against COVID-19.

Background: Health care workers (HCWs) are exposed to high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to close contact with infected patients in hospital. The objective of this study was to estimate the seroprevalence and to identify the exposure risk of various subgroups among HCWs to prioritize them for early vaccination. Methods: This was a multicentre cross-sectional study conducted between 15 and 29 June 2020. A total of 987 HCWs were recruited randomly from two major tertiary-care hospitals of Peshawar city, Pakistan. The HCWs included doctors, nurses, paramedics and hospital support staff. The US Food and Drug Administration (FDA)-approved kit was used for the detection of SARS-CoV-2 antibodies. Results: Overall, 310 (31.4%) HCWs were seropositive for SARS-CoV-2 antibodies (95% confidence interval, CI: 28.5-34.4). Seroprevalence was higher in males (33.5%) and in age group 51-60 years (40.9%). Seropositivity increased with increasing age from 8.3% in age group ⩽20 to 40.9% in 51-60 years of age group (p < 0.05). The highest seroprevalence was identified in paramedical staff (42·5%, 95% CI: 36.6-48.6) followed by nursing staff (38·8%, 95% CI: 32.1-45.7). In logistic regression, being a male HCW led to higher risk of seropositivity (odds ratio, OR: 1.50, 95% CI: 1·06-2.13. p < 0.05) compared with female staff members. The odds of seropositivity was higher in nurses (OR: 3·47, 95% CI: 1.99-6.05. p < 0.01), paramedical staff (OR: 3·19, 95% CI: 1.93-5.28. p < 0.01) and hospital support staff (OR: 2·47, 95% CI: 1.29-4.7. p < 0.01) compared with consultants. Conclusion: Overall, our results concluded that nursing and paramedical staff are at higher risk and should be vaccinated on priority.

Identifying higher risk subgroups of health care workers for priority vaccination against COVID-19

Background: Health care workers (HCWs) are exposed to high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to close contact with infected patients in hospital. The objective of this study was to estimate the seroprevalence and to identify the exposure risk of various subgroups among HCWs to prioritize them for early vaccination. Methods: This was a multicentre cross-sectional study conducted between 15 and 29 June 2020. A total of 987 HCWs were recruited randomly from two major tertiary-care hospitals of Peshawar city, Pakistan. The HCWs included doctors, nurses, paramedics and hospital support staff. The US Food and Drug Administration (FDA)–approved kit was used for the detection of SARS-CoV-2 antibodies. Results: Overall, 310 (31.4%) HCWs were seropositive for SARS-CoV-2 antibodies (95% confidence interval, CI: 28.5–34.4). Seroprevalence was higher in males (33.5%) and in age group 51–60 years (40.9%). Seropositivity increased with increasing age from 8.3% in age group ⩽20 to 40.9% in 51–60 years of age group (p < 0.05). The highest seroprevalence was identified in paramedical staff (42·5%, 95% CI: 36.6–48.6) followed by nursing staff (38·8%, 95% CI: 32.1–45.7). In logistic regression, being a male HCW led to higher risk of seropositivity (odds ratio, OR: 1.50, 95% CI: 1·06–2.13. p < 0.05) compared with female staff members. The odds of seropositivity was higher in nurses (OR: 3·47, 95% CI: 1.99–6.05. p < 0.01), paramedical staff (OR: 3·19, 95% CI: 1.93–5.28. p < 0.01) and hospital support staff (OR: 2·47, 95% CI: 1.29–4.7. p < 0.01) compared with consultants. Conclusion: Overall, our results concluded that nursing and paramedical staff are at higher risk and should be vaccinated on priority.

Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019.

IMPORTANCE: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden. OBJECTIVE: To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019. EVIDENCE REVIEW: The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs). FINDINGS: In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles. CONCLUSIONS AND RELEVANCE: The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.

Discovery of Potential Antiviral Compounds against Hendra Virus by Targeting Its Receptor-Binding Protein (G) Using Computational Approaches.

Hendra virus (HeV) belongs to the paramyxoviridae family of viruses which is associated with the respiratory distress, neurological illness, and potential fatality of the affected individuals. So far, no competitive approved therapeutic substance is available for HeV. For that reason, the current research work was conducted to propose some novel compounds, by adopting a Computer Aided Drug Discovery approach, which could be used to combat HeV. The G attachment Glycoprotein (Ggp) of HeV was selected to achieve the primary objective of this study, as this protein makes the entry of HeV possible in the host cells. Briefly, a library of 6000 antiviral compounds was screened for potential drug-like properties, followed by the molecular docking of short-listed compounds with the Protein Data Bank (PDB) structure of Ggp. Docked complexes of top two hits, having maximum binding affinities with the active sites of Ggp, were further considered for molecular dynamic simulations of 200 ns to elucidate the results of molecular docking analysis. MD simulations and Molecular Mechanics Energies combined with the Generalized Born and Surface Area (MMGBSA) or Poisson-Boltzmann and Surface Area (MMPBSA) revealed that both docked complexes are stable in nature. Furthermore, the same methodology was used between lead compounds and HeV Ggp in complex with its functional receptor in human, Ephrin-B2. Surprisingly, no major differences were found in the results, which demonstrates that our identified compounds can also perform their action even when the Ggp is attached to the Ephrin-B2 ligand. Therefore, in light of all of these results, we strongly suggest that compounds (S)-5-(benzylcarbamoyl)-1-(2-(4-methyl-2-phenylpiperazin-1-yl)-2-oxoethyl)-6-oxo-3,6-dihydropyridin-1-ium-3-ide and 5-(cyclohexylcarbamoyl)-1-(2-((2-(3-fluorophenyl)-2-methylpropyl)amino)-2-oxoethyl)-6-oxo-3,6-dihydropyridin-1-ium-3-ide could be considered as potential therapeutic agents against HeV; however, further in vitro and in vivo experiments are required to validate this study.

Computational modelling of potentially emerging SARS-CoV-2 spike protein RBDs mutations with higher binding affinity towards ACE2: A structural modelling study.

The spike protein of SARS-CoV-2 and the host ACE2 receptor plays a vital role in the entry to the cell. Among which the hotspot residue 501 is continuously subjected to positive selection pressure and induces unusual virulence. Keeping in view the importance of the hot spot residue 501, we predicted the potentially emerging structural variants of 501 residue. We analyzed the binding pattern of wild type and mutants (Spike RBD) to the ACE2 receptor by deciphering variations in the amino acids' interaction networks by graph kernels along with evolutionary, network metrics, and energetic information. Our analysis revealed that N501I, N501T, and N501V increase the binding affinity and alter the intra and inter-residue bonding networks. The N501T has shown strong positive selection and fitness in other animals. Docking results and repeated simulations (three times) confirmed the structural stability and tighter binding of these three variants, correlated with the previous results following the global stability trend. Consequently, we reported three variants N501I, N501T, and N501V could worsen the situation further if they emerged. The relations between the viral fitness and binding affinity is a complicated game thus the emergence of high affinity mutations in the SARS-CoV-2 RBD brings up the question of whether or not positive selection favours these mutations or not?

Annotation of Potential Vaccine Targets and Design of a Multi-Epitope Subunit Vaccine against Yersinia pestis through Reverse Vaccinology and Validation through an Agent-Based Modeling Approach.

Yersinia pestis is responsible for plague and major pandemics in Asia and Europe. This bacterium has shown resistance to an array of drugs commonly used for the treatment of plague. Therefore, effective therapeutics measurements, such as designing a vaccine that can effectively and safely prevent Y. pestis infection, are of high interest. To fast-track vaccine development against Yersinia pestis, herein, proteome-wide vaccine target annotation was performed, and structural vaccinology-assisted epitopes were predicted. Among the total 3909 proteins, only 5 (rstB, YPO2385, hmuR, flaA1a, and psaB) were shortlisted as essential vaccine targets. These targets were then subjected to multi-epitope vaccine design using different linkers. EAAK, AAY, and GPGPG as linkers were used to link CTL, HTL, and B-cell epitopes, and an adjuvant (beta defensin) was also added at the N-terminal of the MEVC. Physiochemical characterization, such as determination of the instability index, theoretical pI, half-life, aliphatic index, stability profiling, antigenicity, allergenicity, and hydropathy of the ensemble, showed that the vaccine is highly stable, antigenic, and non-allergenic and produces multiple interactions with immune receptors upon docking. In addition, molecular dynamics simulation confirmed the stable binding and good dynamic properties of the vaccine-TLR complex. Furthermore, in silico and immune simulation of the developed MEVC for Y. pestis showed that the vaccine triggered strong immune response after several doses at different intervals. Neutralization of the antigen was observed at the third day of injection. Conclusively, the vaccine designed here for Y. pestis produces an immune response; however, further immunological testing is needed to unveil its real efficacy.