Structural vaccinology, molecular simulation and immune simulation approaches to design multi-epitopes vaccine against John Cunningham virus.

The JCV (John Cunningham Virus) is known to cause progressive multifocal leukoencephalopathy, a condition that results in the formation of tumors. Symptoms of this condition such as sensory defects, cognitive dysfunction, muscle weakness, homonosapobia, difficulties with coordination, and aphasia. To date, there is no specific and effective treatment to completely cure or prevent John Cunningham polyomavirus infections. Since the best way to control the disease is vaccination. In this study, the immunoinformatic tools were used to predict the high immunogenic and non-allergenic B cells, helper T cells (HTL), and cytotoxic T cells (CTL) epitopes from capsid, major capsid, and T antigen proteins of JC virus to design the highly efficient subunit vaccines. The specific immunogenic linkers were used to link together the predicted epitopes and subjected to 3D modeling by using the Robetta server. MD simulation was used to confirm that the newly constructed vaccines are stable and properly fold. Additionally, the molecular docking approach revealed that the vaccines have a strong binding affinity with human TLR-7. The codon adaptation index (CAI) and GC content values verified that the constructed vaccines would be highly expressed in E. coli pET28a (+) plasmid. The immune simulation analysis indicated that the human immune system would have a strong response to the vaccines, with a high titer of IgM and IgG antibodies being produced. In conclusion, this study will provide a pre-clinical concept to construct an effective, highly antigenic, non-allergenic, and thermostable vaccine to combat the infection of the John Cunningham virus.

Pathogen recognition pathway gene variants and inflammasome sensors gene expression in tuberculosis patients under treatment.

BACKGROUND: Several epidemiological studies have suggested that genetic variations in encoding pattern recognition receptors (PRRs) genes such as Toll Like Receptors (TLRs) and their signaling products, may influence the susceptibility, severity and outcome of tuberculosis (TB). After sensing a pathogen, the cell responds producing an inflammatory response, to restrain the pathogen's successful course of infection. Herein we assessed single nucleotide polymorphisms (SNP) and gene expression from pathogen recognition and inflammasome pathways in Brazilian TB patients. METHODS AND RESULTS: For genetic association analysis we included MYD88 and TLR4, PRRs sensing proteins. Allele distribution for MYD88 rs6853 (A > G) and TLR4 rs7873784 (C > G) presented conserved among the tested samples with statistically differential distribution in TB patients versus controls. However, when testing according to sample ethnicity (African or Caucasian-derived individuals) we identified that the rs6853 G/G genotype was associated with a lower susceptibility to TB in Caucasian population. Meanwhile, the rs7873784 G/G genotype was associated with a higher TB susceptibility in Afro-descendant ethnicity individuals. We also aimed to verify MYD88 and the inflammasome genes NLRP1 and NLRC4 expression in order to connect to active TB and/or clinical aspects. CONCLUSIONS: We identified that inflammasome gene expression in TB patients under treatment display a similar pattern as in healthy controls, indicating that TB treatment impairs NLRP1 inflammasome activation.

Farnesyl Diphosphate Synthase Gene Associated with Loss of Bone Mass Density and Alendronate Treatment Failure in Patients with Primary Osteoporosis.

Aminobisphosphonates (NBPs) are the first-choice medication for osteoporosis (OP); NBP treatment aims at increasing bone mineral density (BMD) by inhibiting the activity of farnesyl diphosphate synthase (FDPS) enzyme in osteoclasts. Despite its efficacy, inadequate response to the drug and side effects have been reported. The A allele of the rs2297480 (A > C) SNP, found in the regulatory region of the FDPS gene, is associated with reduced gene transcription. This study evaluates the FDPS variant rs2297480 (A > C) association with OP patients' response to alendronate sodium treatment. A total of 304 OP patients and 112 controls were enrolled; patients treated with alendronate sodium for two years were classified, according to BMD variations at specific regions (lumbar spine (L1-L4), femoral neck (FN) and total hip (TH), as responders (OP-R) (n = 20) and non-responders (OP-NR) (n = 40). We observed an association of CC genotype with treatment failure (p = 0.045), followed by a BMD decrease in the regions L1-L4 (CC = -2.21% ± 2.56; p = 0.026) and TH (CC = -2.06% ± 1.84; p = 0.015) after two years of alendronate sodium treatment. Relative expression of the FDPS gene was also evaluated in OP-R and OP-NR patients. Higher expression of the FDPS gene was also observed in OP-NR group (FC = 1.84 ± 0.77; p = 0.006) when compared to OP-R. In conclusion, the influence observed of FDPS expression and the rs2897480 variant on alendronate treatment highlights the importance of a genetic approach to improve the efficacy of treatment for primary osteoporosis.

miRNAs and NFKB1 and TRAF6 target genes: The initial functional study in CD14+ monocytes in rheumatoid arthritis patients.

We predicted miRNAs with regulatory impact on NFKB1 and TRAF6 gene expression and selected the miR-194-5p, miR-124-3p, miR-9-5p, and miR-340-5p and their target genes for expression analyses on CD14+ monocytes from rheumatoid arthritis (RA) patients and healthy controls. Additionally, we evaluated the influence of genes and miRNA expression on RA patients' cytokine levels. No difference was observed in genes or miRNAs expression when compared to healthy controls and RA patients or clinical parameters. However, we found a significant difference between miR-194-5p and miR-9-5p levels (FC=-2.31; p=0.031; FC=-3.05;p=0.031, respectively) and non-prednisone users as compared to prednisone using patients. We conducted correlation analyses to identify the strength of the relationship between expression data and cytokine plasma levels. We observed a moderate positive correlation between miR-124-3p expression and IL-6 plasma levels (r=0.46; p=0.033). In addition, overexpression of miRNAs was concomitant to TRAF6 and NFKB1 genes as indicated by correlation analyses: TRAF6 and miR-194-5p (r=0.60;p<0.001) and miR-9-5p (r=0.63;p<0.001) and NFKB1 and miR-194-5p (r=0.72;p<0.001), miR-9-5p (r=0.72;p<0.001) and miR-340-5p (r=0.61;p<0.001). NFKB1 and TRAF6 genes and miRNAs monocyte expression do not appear to be related to RA but showed a significant difference in different groups of RA therapy. In addition, increased levels of miRNAs can be linked to concomitant overexpression of TRAF6 and NFKB1 in monocytes and act as its regulators.

Can telomeric changes orchestrate the development of autoinflammatory skin diseases?

Telomeres, the safeguarding caps at the tips of chromosomes, are pivotal in the aging process of cells and have been linked to skin ailments and inflammatory conditions. Telomeres undergo a gradual reduction in length and factors such as oxidative stress hasten this diminishing process. Skin diseases including inflammatory conditions can be correlated with the shortening of telomeres and the persistent activation of DNA damage response in skin tissues. Telomere dysfunction could disrupt the balance of the skin, impairs wound healing, and may contribute to abnormal cytokine production. Skin aging and processes related to telomeres may function as one of the triggers for skin diseases. The presence of proinflammatory cytokines and dysfunctional telomeres in conditions such as Dyskeratosis Congenita implies a possible connection between the shortening of telomeres and the onset of chronic inflammatory skin disorders. In autoinflammatory skin diseases, chronic inflammation hinders wound healing thus aggravating the progression of the disease. The NF-ĸB pathway might contribute to the initiation or progression of chronic disorders by influencing mechanisms associated with telomere biology. The intricate connections between telomeres, telomerase, telomere-associated proteins, and skin diseases are still a complex puzzle to be solved. Here, we provide an overview of the impact of telomeres on both health and disease with a specific emphasis on their role in skin, inflammation and autoinflammatory skin disorders.

Biosensing circulating MicroRNAs in autoinflammatory skin diseases: Focus on Hidradenitis suppurativa.

MicroRNAs (miRNAs) play a crucial role in the early diagnosis of autoinflammatory diseases, with Hidradenitis Suppurativa (HS) being a notable example. HS, an autoinflammatory skin disease affecting the pilosebaceous unit, profoundly impacts patients' quality of life. Its hidden nature, with insidious initial symptoms and patient reluctance to seek medical consultation, often leads to a diagnostic delay of up to 7 years. Recognizing the urgency for early diagnostic tools, recent research identified significant differences in circulating miRNA expression, including miR-24-1-5p, miR-146a-5p, miR26a-5p, miR-206, miR338-3p, and miR-338-5p, between HS patients and healthy controls. These miRNAs serve as potential biomarkers for earlier disease detection. Traditional molecular biology techniques, like reverse transcription quantitative-polymerase chain reaction (RT-qPCR), are employed for their detection using specific primers and probes. Alternatively, short peptides offer a versatile and effective means for capturing miRNAs, providing specificity, ease of synthesis, stability, and multiplexing potential. In this context, we present a computational simulation pipeline designed for crafting peptide sequences that can capture circulating miRNAs in the blood of patients with autoinflammatory skin diseases, including HS. This innovative approach aims to expedite early diagnosis and enhance therapeutic follow-up, addressing the critical need for timely intervention in HS and similar conditions.

Analysis of E2F1 single-nucleotide polymorphisms reveals deleterious non-synonymous substitutions that disrupt E2F1-RB protein interaction in cancer.

Cancer is a medical condition that is caused by the abnormal growth and division of cells, leading to the formation of tumors. The E2F1 and RB pathways are critical in regulating cell cycle, and their dysregulation can contribute to the development of cancer. In this study, we analyzed experimentally reported SNPs in E2F1 and assessed their effects on the binding affinity with RB. Out of 46, nine mutations were predicted as deleterious, and further analysis revealed four highly destabilizing mutations (L206W, R232C, I254T, A267T) that significantly altered the protein structure. Molecular docking of wild-type and mutant E2F1 with RB revealed a docking score of -242 kcal/mol for wild-type, while the mutant complexes had scores ranging from -217 to -220 kcal/mol. Molecular simulation analysis revealed variations in the dynamics features of both mutant and wild-type complexes due to the acquired mutations. Furthermore, the total binding free energy for the wild-type E2F1-RB complex was -64.89 kcal/mol, while those of the L206W, R232C, I254T, and A267T E2F1-RB mutants were -45.90 kcal/mol, -53.52 kcal/mol, -55.67 kcal/mol, and -61.22 kcal/mol, respectively. Our study is the first to extensively analyze E2F1 gene mutations and identifies candidate mutations for further validation and potential targeting for cancer therapeutics.

Abrogation of ORF8-IRF3 binding interface with Carbon nanotube derivatives to rescue the host immune system against SARS-CoV-2 by using molecular screening and simulation approaches.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to over six million deaths worldwide. In human immune system, the type 1 interferon (IFN) pathway plays a crucial role in fighting viral infections. However, the ORF8 protein of the virus evade the immune system by interacting with IRF3, hindering its nuclear translocation and consequently downregulate the type I IFN signaling pathway. To block the binding of ORF8-IRF3 and inhibit viral pathogenesis a quick discovery of an inhibitor molecule is needed. Therefore, in the present study, the interface between the ORF8 and IRF3 was targeted on a high-affinity carbon nanotube by using computational tools. After analysis of 62 carbon nanotubes by multiple docking with the induced fit model, the top five compounds with high docking scores of - 7.94 kcal/mol, - 7.92 kcal/mol, - 7.28 kcal/mol, - 7.19 kcal/mol and - 7.09 kcal/mol (top hit1-5) were found to have inhibitory activity against the ORF8-IRF3 complex. Molecular dynamics analysis of the complexes revealed the high compactness of residues, stable binding, and strong hydrogen binding network among the ORF8-nanotubes complexes. Moreover, the total binding free energy for top hit1-5 was calculated to be - 43.21 ± 0.90 kcal/mol, - 41.17 ± 0.99 kcal/mol, - 48.85 ± 0.62 kcal/mol, - 43.49 ± 0.77 kcal/mol, and - 31.18 ± 0.78 kcal/mol respectively. These results strongly suggest that the identified top five nanotubes (hit1-5) possess significant potential for advancing and exploring innovative drug therapies. This underscores their suitability for subsequent in vivo and in vitro experiments, marking them as promising candidates worthy of further investigation.

Molecular screening of phytocompounds targeting the interface between influenza A NS1 and TRIM25 to enhance host immune responses.

BACKGROUND: Influenza A virus causes severe respiratory illnesses, especially in developing nations where most child deaths under 5 occur due to lower respiratory tract infections. The RIG-I protein acts as a sensor for viral dsRNA, triggering interferon production through K63-linked poly-ubiquitin chains synthesized by TRIM25. However, the influenza A virus's NS1 protein hinders this process by binding to TRIM25, disrupting its association with RIG-I and preventing downstream interferon signalling, contributing to the virus's evasion of the immune response. METHODS: In our study we used structural-based drug designing, molecular simulation, and binding free energy approaches to identify the potent phytocompounds from various natural product databases (>100,000 compounds) able to inhibit the binding of NS1 with the TRIM25. RESULTS: The molecular screening identified EA-8411902 and EA-19951545 from East African Natural Products Database, NA-390261 and NA-71 from North African Natural Products Database, SA-65230 and SA- 4477104 from South African Natural Compounds Database, NEA- 361 and NEA- 4524784 from North-East African Natural Products Database, TCM-4444713 and TCM-6056 from Traditional Chinese Medicines Database as top hits. The molecular docking and binding free energies results revealed that these compounds have high affinity with the specific active site residues (Leu95, Ser99, and Tyr89) involved in the interaction with TRIM25. Additionally, analysis of structural dynamics, binding free energy, and dissociation constants demonstrates a notably stronger binding affinity of these compounds with the NS1 protein. Moreover, all selected compounds exhibit exceptional ADMET properties, including high water solubility, gastrointestinal absorption, and an absence of hepatotoxicity, while adhering to Lipinski's rule. CONCLUSION: Our molecular simulation findings highlight that the identified compounds demonstrate high affinity for specific active site residues involved in the NS1-TRIM25 interaction, exhibit exceptional ADMET properties, and adhere to drug-likeness criteria, thus presenting promising candidates for further development as antiviral agents against influenza A virus infections.

Harnessing artificial intelligence for advancing early diagnosis in hidradenitis suppurativa.

This perspective delves into the integration of artificial intelligence (AI) to enhance early diagnosis in hidradenitis suppurativa (HS). Despite significantly impacting Quality of Life, HS presents diagnostic challenges leading to treatment delays. We present a viewpoint on AI-powered clinical decision support system designed for HS, emphasizing the transformative potential of AI in dermatology. HS diagnosis, primarily reliant on clinical evaluation and visual inspection, often results in late-stage identification with substantial tissue damage. The incorporation of AI, utilizing machine learning and deep learning algorithms, addresses this challenge by excelling in image analysis. AI adeptly recognizes subtle patterns in skin lesions, providing objective and standardized analyses to mitigate subjectivity in traditional diagnostic approaches. The AI integration encompasses diverse datasets, including clinical records, images, biochemical and immunological data and OMICs data. AI algorithms enable nuanced comprehension, allowing for precise and customized diagnoses. We underscore AI's potential for continuous learning and adaptation, refining recommendations based on evolving data. Challenges in AI integration, such as data privacy, algorithm bias, and interpretability, are addressed, emphasizing the ethical considerations of responsible AI deployment, including transparency, human oversight, and striking a balance between automation and human intervention. From the dermatologists' standpoint, we illustrate how AI enhances diagnostic accuracy, treatment planning, and long-term follow-up in HS management. Dermatologists leverage AI to analyze clinical records, dermatological images, and various data types, facilitating a proactive and personalized approach. AI's dynamic nature supports continuous learning, refining diagnostic and treatment strategies, ultimately reshaping standards of care in dermatology.

Network-base approaches to identify therapeutic biomarkers in hepatocellular carcinoma and search for drug hunting utilizing molecular dynamics simulations.

The presence of conditions like Alpha-1 antitrypsin deficiency, hemochromatosis, non-alcoholic fatty liver diseases and metabolic syndrome can elevate the susceptibility to hepatic cellular carcinoma (HCC). Utilizing network-based gene expression profiling via network analyst tools, presents a novel approach for drug target discovery. The significance level (p-score) obtained through Cytoscape in the intended center gene survival assessment confirms the identification of all target center genes, which play a fundamental role in disease formation and progression in HCC. A total of 1064 deferential expression genes were found. These include MCM2 with the highest degree, followed by 4917 MCM6 and MCM4 with a 3944-degree score. We investigated the regulatory kinases involved in establishing the protein-protein interactions network using X2K web tool. The docking approach yields a favorable binding affinity of -8.7 kcal/mol against the target MCM2 using Auto-Dock Vina. Interestingly after simulating the complex system via AMBER16 package, results showed that the root mean square deviation values remained within 4.74 Å for a protein and remains stable throughout the time intervals. Additionally, the ligand's fit to the protein exhibited fluctuations at some intervals but remains stable. Finally, Gibbs free energy was found to be at its lowest at 1 kcal/mol which presents the real time interactive binding of the atomic residues among inhibitor and protein. The displacement of the ligand was measured showing stable movement and displacement along the active site. These findings increased our understanding for potential biomarkers in hepatocellular carcinoma and an experimental approach will further enhance our outcomes in future.Communicated by Ramaswamy H. Sarma.

Cardiovascular challenges in the era of antiretroviral therapy for AIDS/ HIV: A comprehensive review of research advancements, pathophysiological insights, and future directions.

Cardiovascular disease, particularly coronary heart disease, is becoming more common among those living with HIV. Individuals with HIV face an increased susceptibility to myocardial infarction, also known as a heart attack, as compared to the general population in developed countries. This heightened risk can be attributed mainly to the presence of effective antiretroviral drugs and the resulting longer lifespan. Some cardiac issues linked to non-antiretroviral medications, including myocarditis, endocarditis, cardiomyopathy with dilation, pulmonary hypertension, and oedema of the heart, may affect those not undergoing highly active antiretroviral therapy (ART). Impaired immune function and systemic inflammation are significant contributors to this phenomenon after initiating highly aggressive antiretroviral treatment ART. It is becoming more challenging to determine the best course of treatment for HIV-associated cardiomyopathy due to new research suggesting that protease inhibitors might have a negative impact on the development of HF. Currently, the primary focus of research on ART medications is centered on the cardiovascular adverse effects of nucleoside reverse transcriptase inhibitors and protease inhibitors. This review paper thoroughly evaluates the advancements achieved in cardiovascular disease research and explores the potential implications for prospects. Additionally, it considers the field's future prospects while examining how ART might be altered and its clinical applications.

In silico-designed antimicrobial peptide targeting MRSA and E. coli with antibacterial and antibiofilm actions.

Antibiotic resistance is a paramount global health issue, with numerous bacterial strains continually fortifying their resistance against diverse antibiotics. This surge in resistance levels primarily stems from the overuse and misuse of antibiotics in human, animal, and environmental contexts. In this study, we advocate for exploring alternative molecules exhibiting antibacterial properties to counteract the escalating antibiotic resistance. We identified a synthetic antimicrobial peptide (AMP) by using computational search in AMP public databases and further engineering through molecular docking and dynamics. Microbiological evaluation, cytotoxicity, genotoycity, and hemolysis experiments were then performed. The designed AMP underwent rigorous testing for antibacterial and antibiofilm activities against Methicillin-Resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli), representing gram-positive and gram-negative bacteria, respectively. Subsequently, the safety profile of the AMP was assessed in vitro using human fibroblast cells and a human blood sample. The selected AMP demonstrated robust antibacterial and antibiofilm efficacy against MRSA and E. coli, with an added assurance of non-cytotoxicity and non-genotoxicity towards human fibroblasts. Also, the AMP did not demonstrate any hemolytic activity. Our findings emphasize the considerable promise of the AMP as a viable alternative antibacterial agent, showcasing its potential to combat antibiotic resistance effectively.

Mutational analysis of SARS-CoV-2 ORF6-KPNA2 binding interface and identification of potent small molecule inhibitors to recuse the host immune system.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surfaced on 31 December, 2019, and was identified as the causative agent of the global COVID-19 pandemic, leading to a pneumonia-like disease. One of its accessory proteins, ORF6, has been found to play a critical role in immune evasion by interacting with KPNA2 to antagonize IFN signaling and production pathways, resulting in the inhibition of IRF3 and STAT1 nuclear translocation. Since various mutations have been observed in ORF6, therefore, a comparative binding, biophysical, and structural analysis was used to reveal how these mutations affect the virus's ability to evade the human immune system. Among the identified mutations, the V9F, V24A, W27L, and I33T, were found to have a highly destabilizing effect on the protein structure of ORF6. Additionally, the molecular docking analysis of wildtype and mutant ORF6 and KPNA2 revealed the docking score of - 53.72 kcal/mol for wildtype while, -267.90 kcal/mol, -258.41kcal/mol, -254.51 kcal/mol and -268.79 kcal/mol for V9F, V24A, W27L, and I33T respectively. As compared to the wildtype the V9F showed a stronger binding affinity with KPNA2 which is further verified by the binding free energy (-42.28 kcal/mol) calculation. Furthermore, to halt the binding interface of the ORF6-KPNA2 complex, we used a computational molecular search of potential natural products. A multi-step virtual screening of the African natural database identified the top 5 compounds with best docking scores of -6.40 kcal/mol, -6.10 kcal/mol, -6.09 kcal/mol, -6.06 kcal/mol, and -6.03 kcal/mol for tophit1-5 respectively. Subsequent all-atoms simulations of these top hits revealed consistent dynamics, indicating their stability and their potential to interact effectively with the interface residues. In conclusion, our study represents the first attempt to establish a foundation for understanding the heightened infectivity of new SARS-CoV-2 variants and provides a strong impetus for the development of novel drugs against them.

Unraveling the Epigenetic Tapestry: Decoding the Impact of Epigenetic Modifications in Hidradenitis Suppurativa Pathogenesis.

Hidradenitis suppurativa (HS) is a chronic autoinflammatory skin disorder, which typically occurs during puberty or early adulthood. The pathogenesis of HS is complex and multifactorial; a close interaction between hormonal, genetic, epigenetics factors, host-specific aspects, and environmental influences contributes to the susceptibility, onset, severity, and clinical course of this disease, although the exact molecular mechanisms are still being explored. Epigenetics is currently emerging as an interesting field of investigation that could potentially shed light on the molecular intricacies underlying HS, but there is much still to uncover on the subject. The aim of this work is to provide an overview of the epigenetic landscape involved in HS. Specifically, in this in-depth review we provide a comprehensive overview of DNA methylation/hydroxymethylation, histone modifications, and non-coding RNAs (such as microRNA-miRNA-132, miRNA-200c, miRNA-30a-3p, miRNA-100-5b, miRNA-155-5p, miRNA-338-5p) dysregulation in HS patients. An interesting element of epigenetic regulation in HS is that the persistent inflammatory milieu observed in HS lesional skin could be exacerbated by an altered methylation profile and histone acetylation pattern associated with key inflammatory genes. Deepening our knowledge on the subject could enable the development of targeted epigenetic therapies to potentially restore normal gene expression patterns, and subsequentially ameliorate, or even reverse, the progression of the disease. By deciphering the epigenetic code governing HS, we strive to usher in a new era of personalized and effective interventions for this enigmatic dermatological condition.

Exploring the natural products chemical space to abrogate the F3L-dsRNA interface of monkeypox virus to enhance the immune responses using molecular screening and free energy calculations.

Amid the ongoing monkeypox outbreak, there is an urgent need for the rapid development of effective therapeutic interventions capable of countering the immune evasion mechanisms employed by the monkeypox virus (MPXV). The evasion strategy involves the binding of the F3L protein to dsRNA, resulting in diminished interferon (IFN) production. Consequently, our current research focuses on utilizing virtual drug screening techniques to target the RNA binding domain of the F3L protein. Out of the 954 compounds within the South African natural compound database, only four demonstrated notable docking scores: -6.55, -6.47, -6.37, and -6.35 kcal/mol. The dissociation constant (KD) analysis revealed a stronger binding affinity of the top hits 1-4 (-5.34, -5.32, -5.29, and -5.36 kcal/mol) with the F3L in the MPXV. All-atom simulations of the top-ranked hits 1 to 4 consistently exhibited stable dynamics, suggesting their potential to interact effectively with interface residues. This was further substantiated through analyses of parameters such as radius of gyration (Rg), Root Mean Square Fluctuation, and hydrogen bonding. Cumulative assessments of binding free energy confirmed the top-performing candidates among all the compounds, with values of -35.90, -52.74, -28.17, and -32.11 kcal/mol for top hits 1-4, respectively. These results indicate that compounds top hit 1-4 could hold significant promise for advancing innovative drug therapies, suggesting their suitability for both in vivo and in vitro experiments.

Elucidating the binding mechanism of SARS-CoV-2 NSP6-TBK1 and structure-based designing of phytocompounds inhibitors for instigating the host immune response.

SARS-CoV-2, also referred to as severe acute respiratory syndrome coronavirus 2, is the virus responsible for causing COVID-19, an infectious disease that emerged in Wuhan, China, in December 2019. Among its crucial functions, NSP6 plays a vital role in evading the human immune system by directly interacting with a receptor called TANK-binding kinase (TBK1), leading to the suppression of IFNß production. Consequently, in the present study we used the structural and biophysical approaches to analyze the effect of newly emerged mutations on the binding of NSP6 and TBK1. Among the identified mutations, four (F35G, L37F, L125F, and I162T) were found to significantly destabilize the structure of NSP6. Furthermore, the molecular docking analysis highlighted that the mutant NSP6 displayed its highest binding affinity with TBK1, exhibiting docking scores of -1436.2 for the wildtype and -1723.2, -1788.6, -1510.2, and -1551.7 for the F35G, L37F, L125F, and I162T mutants, respectively. This suggests the potential for an enhanced immune system evasion capability of NSP6. Particularly, the F35G mutation exhibited the strongest binding affinity, supported by a calculated binding free energy of -172.19 kcal/mol. To disrupt the binding between NSP6 and TBK1, we conducted virtual drug screening to develop a novel inhibitor derived from natural products. From this screening, we identified the top 5 hit compounds as the most promising candidates with a docking score of -6.59 kcal/mol, -6.52 kcal/mol, -6.32 kcal/mol, -6.22 kcal/mol, and -6.21 kcal/mol. The molecular dynamic simulation of top 3 hits further verified the dynamic stability of drugs-NSP6 complexes. In conclusion, this study provides valuable insight into the higher infectivity of the SARS-CoV-2 new variants and a strong rationale for the development of novel drugs against NSP6.

An overview of Zika virus genotypes and their infectivity

ABSTRACT Zika virus (ZIKV) is an enveloped, single-stranded RNA arbovirus belonging to the genus Flavivirus. It was first isolated from a sentinel monkey in Uganda in 1947. More recently, ZIKV has undergone rapid geographic expansion and has been responsible for outbreaks in Southeast Asia, the Pacific Islands, and America. In this review, we have highlighted the influence of viral genetic variants on ZIKV pathogenesis. Two major ZIKV genotypes (African and Asian) have been identified. The Asian genotype is subdivided into Southwest Asia, Pacific Island, and American strains, and is responsible for most outbreaks. Non-synonymous mutations in ZIKV proteins C, prM, E, NS1, NS2A, NS2B, NS3, and NS4B were found to have a higher prevalence and association with virulent strains of the Asian genotype. Consequently, the Asian genotype appears to have acquired higher cellular permissiveness, tissue persistence, and viral tropism in human neural cells. Therefore, mutations in specific coding regions of the Asian genotype may enhance ZIKV infectivity. Considering that mutations in the genomes of emerging viruses may lead to new virulent variants in humans, there is a potential for the re-emergence of new ZIKV cases in the future.

HIV-1 mother-to-child transmission in Brazil (1994-2016): a time series modeling

Abstract HIV-1 mother-to-child transmission (HIV-1 MTCT), is an important cause of children mortality worldwide. Brazil has been traditionally praised by its HIV/Aids program, which provides free-of-charge care for people living with HIV-1. Using public epidemiology and demographic databases, we aimed at modeling HIV-1 MTCT prevalence in Brazil through the years (1994-2016) and elaborate a statistical model for forecasting, contributing to HIV-1 epidemiologic surveillance and healthcare decision-making. We downloaded sets of live births and mothers' data alongside HIV-1 cases notification in children one year old or less. Through time series modeling, we estimated prevalence along the years in Brazil, and observed a remarkable decrease of HIV-1 MTCT between 1994 (10 cases per 100,000 live births) and 2016 (five cases per 100,000 live births), a reduction of 50%. Using our model, we elaborated a prognosis for each Brazilian state to help HIV-1 surveillance decision making, indicating which states are in theory in risk of experiencing a rise in HIV-1 MTCT prevalence. Ten states had good (37%), nine had mild (33%), and eight had poor prognostics (30%). Stratifying the prognostics by Brazilian region, we observed that the Northeast region had more states with poor prognosis, followed by North and Midwest, Southeast and South with one state of poor prognosis each. Brazil undoubtedly advanced in the fight against HIV-1 MTCT in the past two decades. We hope our model will help indicating where HIV-1 MTCT prevalence may rise in the future and support government decision makers regarding HIV-1 surveillance and prevention.

Prevalence of Guillain-Barré syndrome among Zika virus infected cases: a systematic review and meta-analysis

ABSTRACT Zika virus (ZIKV) is an emergent flavivirus transmitted mainly through Aedes spp. mosquitoes that is posing challenge to healthcare services in countries experiencing an outbreak. Usually ZIKV infection is mild, but in some cases it has been reported to progress into neurological diseases such as microcephaly in infants and Guillain-Barré syndrome (GBS) in adults. GBS is a debilitating autoimmune disorder that affects peripheral nerves. Since ZIKV caused massive outbreaks in South America in the past few years, we aimed to systematically review the literature and perform a meta-analysis to estimate the prevalence of GBS among ZIKV-infected individuals. We searched PubMed and Cochrane databases and selected three studies for a meta-analysis. We estimated the prevalence of ZIKV-associated GBS to be 1.23% (95% CI = 1.17-1.29%). Limitations include paucity of data regarding previous flavivirus infections and ZIKV-infection confirmation issues. Our estimate seems to be low, but cannot be ignored, since ZIKV outbreaks affects an overwhelming number of individuals and GBS is a life-threatening debilitating condition, especially in pregnant women. ZIKV infection cases must be closely followed to assure prompt care to reduce the impact of GBS associated-sequelae on the quality of life of those affected.