Dynamic antibody response in SARS-CoV-2 infected patients and COVID-19 vaccine recipients alongside vaccine effectiveness in comorbid and multimorbid groups.

Objectives: Underlying medical conditions are critical risk factors for COVID-19 susceptibility and its rapid clinical manifestation. Therefore, the preexisting burden of non-communicable diseases (NCDs) makes the preparedness for COVID-19 more challenging for low- and middle-income countries (LMICs). These countries have relied on vaccination campaigns as an effective measure to tackle COVID-19. In this study, we investigated the impact of comorbidities on humoral antibody responses against the specific receptor-binding domain (RBD) of SARS-CoV2. Methods: A total of 1005 patients were selected for the SARS-CoV-2 specific immunoglobulin G (IgG1, IgG2, IgG3, and IgG4 subclasses) and total antibody (TAb) tests (IgG and IgM), of which 912 serum samples were ultimately selected based on the specimen cutoff analyte value. Patients with multimorbidity (N = 60) were recruited for follow-up studies from the initial cohort, and their immune response (IgG and TAb) was measured at multiple time points after the second dose of vaccination. Siemens Dimension Vista SARS-CoV-2 IgG (CV2G) and SARS-CoV-2 TAb assay (CV2T) were used to carry out the serology test. Results: Out of a total of 912 participants, vaccinated individuals (N = 711) had detectable antibody responses up to 7-8 months. The synergistic effect of natural infection and vaccine response was also studied. Participants with breakthrough infections (N = 49) mounted a greater antibody response compared to individuals with normal vaccination response (N = 397) and those who were naturally infected before receiving the second dose of vaccine (N = 132). Investigation of the impact of comorbidities revealed that diabetes mellitus (DM) (N = 117) and kidney disease (N = 50) had a significant negative impact on the decline of the humoral antibody response against SARS-CoV-2. IgG and TAb declined more rapidly in diabetic and kidney disease patients compared to the other four comorbid groups. Follow-up studies demonstrated that antibody response rapidly declined within 4 months after receiving the second dose. Conclusion: The generalized immunization schedule for COVID-19 needs to be adjusted for high-risk comorbid groups, and a booster dose must be administered early within 4 months after receiving the second dose.

Comprehensive analysis predicting effects of deleterious SNPs of human progesterone receptor gene on its structure and functions: a computational approach.

Progesterone receptor plays a crucial role in the development of the mammary gland and breast cancer. Single nucleotide polymorphisms (SNPs) within its gene, PGR, are associated with the risk of miscarriages and preterm birth as well as many cancers across different populations. The main aim of this work is to investigate the most deleterious SNPs in the PGR gene to identify potential biomarkers for various disease susceptibility and treatments. Both sequence and structure-based computational approaches were adopted and in total 11 nsSNPs have been filtered out of 674 nsSNPs along with seven non-coding SNPs. R740Q, I744T and D746E belonged to a mutation cluster. R740Q, D746E along with S865L altered H-bond interactions within the receptor. The same mutations have been found to be associated with several cancers including uterine and breast cancer among others. It is, therefore, possible that the high-risk SNPs associated with cancers may exert their effect by causing changes in the protein structure, particularly in its bonding patterns, and thus affecting its function. In addition, seven non-coding SNPs that were located in the UTR region created a new miRNA site while three SNPs disrupted a conserved miRNA site. These high-risk SNPs can play an instrumental role in generating a dataset of the PGR gene's SNPs. Thus, the present study may pave the way to design and develop novel therapeutics for overcoming the challenges associated with certain cancers and pregnancy that result from a change in the protein structure and function due to the SNP mutations in the PGR gene.Communicated by Ramaswamy H. Sarma.

In Silico Design of siRNAs for Silencing CLEC5A Receptor as a Potential Therapeutic Approach Against Dengue and Japanese Encephalitis Virus Infection in Human.

Dengue and Japanese encephalitis virus (JEV) are mosquito-borne RNA viruses that can cause severe illness leading to death in the tropics and subtropics. Both of these viruses interact directly with the C-type lectin domain family 5, member A receptor (CLEC5A) on human macrophages which stimulates the release of proinflammatory cytokines. Since blockade of this interaction has been shown to suppress the secretion of cytokines, CLEC5A is considered a potential target for the development of new treatments to reduce virus-induced brain damage. Developing a vaccine against dengue is challenging because this virus can cause disease through 4 different serotypes. Therefore, the vaccine must immunize against all 4 serotypes to be effective, while unvaccinated people still contract JEV and suffer from its complications. Small interfering RNAs (siRNAs) play an important role in regulating gene expression by causing the degradation of target mRNAs. In this study, we attempted to rationally design potential siRNA molecules using various software, targeting the CLEC5A gene. In total, 3 siRNAs were found to be potential candidates for CLEC5A silencing. They showed good target accessibility, optimum guanine-cytosine (GC) content, the least chance of off-target effects, positive energy of folding, and strong interaction with Argonaute2 protein as denoted by a negative docking energy score. In addition, molecular dynamics simulation of the siRNA-Ago2-docked complexes showed the stability of the complexes over 1.5 nanoseconds. These predicted siRNAs might effectively downregulate the expression of the CLEC5A receptor and thus prove vital in the treatment of dengue and JEV infections.

Prediction of putative potential siRNAs for inhibiting SARS-CoV-2 strains, including variants of concern and interest.

Aim: To predict siRNAs as a therapeutic intervention for highly infectious new variants of SARS-CoV-2. Methods: Conserved coding sequence regions of 11 SARS-CoV-2 proteins were used to construct siRNAs through sampling of metadata comprising 214,256 sequences. Results: Predicted siRNAs S1: 5'-UCAUUGAGAAAUGUUUACGCA-3' and S2: 5'-AAAGACAUCAGCAUACUCCUG-3' against RdRp of SARS-CoV-2 satisfied all the stringent filtering processes and showed good binding characteristics. The designed siRNAs are expected to inhibit viral replication and transcription of various coronavirus strains encompassing variants of concern and interest. Conclusion: The predicted siRNAs are expected to be potent against SARS-CoV-2, and following in vitro and in vivo validations may be considered as potential therapeutic measures.

MPDB 1.0: a medicinal plant database of Bangladesh.

UNLABELLED: The term of medicinal plants include a various types of plants used in herbalism with medicinal activities. These plants are considered as rich resources of ingredients which can be used as complementary and alternative medicines and, also in drug developments and synthesis. In addition, some plants regarded as valuable origin of nutrition. Thus, all these plants are recommended as therapeutic agents. Information related to medicinal plants and herbal drugs accumulated over the ages are scattered and unstructured which make it prudent to develop a curated database for medicinal plants. MPDB 1.0 database is dedicated to provide the first window to find the plants around Bangladesh claimed to have medicinal and/or nutritive values by accumulating data from the published literatures. This database contains 406 medicinal plants with their corresponding scientific, family and local names as well as utilized parts for treatment from different districts of Bangladesh. Information regarding ailments is available for 353 plants. In addition, we have found active compounds for 78 plants with their corresponding PubMed ID. AVAILABILITY: www.medicinalplantbd.net.

Renin gene polymorphisms in bangladeshi hypertensive population.

OBJECTIVE: Linkages of renin gene polymorphisms with hypertension have been implicated in several populations with contrasting results. Present study aims to assess the pattern of renin gene polymorphisms in Bangladeshi hypertensive individuals. METHODOLOGY: Introns 1, 9 of renin gene and 4063 bases upstream of promoter sequence of renin gene were amplified from the genomic DNA of the total 124 (hypertensive and normotensive) subjects using respective primers. Polymerase chain reaction-based restriction fragment length polymorphisms were performed using BglI, MboI and TaqI restriction enzymes. RESULTS: Homozygosity was common in renin gene regarding BglI (bb=48.4%, Bb=37.9%, BB=13.7%, χ (2) =1.91, P>0.05), TaqI (TT=81.5%, Tt=14.5%, tt=4.0%, χ (2) =7.50, P<0.01) and MboI (mm=63.7%, Mm=32.3%, MM=4.0%, χ (2) =0.00, P>0.05) polymorphisms among total study population. For BglI and TaqI genotype distribution, hypertensive subjects (BglI: χ (2) =6.66, P<0.05; TaqI: χ (2) = 10.28, P<0.005) significantly deviate from Hardy-Weinberg Equilibrium law compared to normotensive subjects (BglI: χ (2) =0.51, P>0.05; TaqI: χ (2) =0.20, P>0.05). On the other hand, with respect to MboI polymorphisms of renin gene, only normotensive subjects deviate from the law (patients: χ (2) =1.28, P>0.05; vs controls: χ (2) =6.81, P<0.01). In the context of allelic frequency, common T allele was clearly prevalent (T frequency=0.86, t frequency = 0.14) for TaqI, but rare alleles b and m were more frequent for both BglI (b frequency=0.69, B frequency=0.31) and MboI (m frequency=0.80 M frequency=0.20) polymorphisms, respectively. CONCLUSION: Thus, we report that Bangladeshi hypertensive subjects did not show any distinct pattern of renin gene polymorphisms compared to their healthy control subjects with regard to their genotypic and allelic frequencies.

Qualitative and quantitative analyses of (pro)renin receptor in the medium of cultured human umbilical vein endothelial cells.

A 30-kDa protein in the medium of cultured human umbilical vein endothelial cells (HUVECs) was identified as (pro)renin receptor, (P)RR, by western blot analysis using anti-human (P)RR antibodies. The protein bound recombinant human prorenin with a K(D) of 4.0 nmol l(-1) and activated prorenin. These observations suggest the presence of soluble (P)RR, s(P)RR, in the medium of cultured HUVECs. For quantification of the s(P)RR in the medium, an enzyme-linked immunosorbent assay (ELISA) was established. The quantitative range of the ELISA was validated over a nominal range of 7.5-300 pmol l(-1) in the wells of a microtiter plate. The assay system showed good linearity (r(2)=0.99) with interassay (5.8-9.7%) and intraassay (2.1-7.0%) precision. Using this method, the concentration of s(P)RR in the culture medium of HUVECs was measured to be 32 pmol l(-1). Therefore, these results show qualitative and quantitative evidence that prorenin can be activated after binding to s(P)RR secreted from cultured HUVECs.

Functional characterization of the decoy peptide, [R10P]IFLKRMPSI[19P].

Decoy peptide (R10PIFLKRMPSI19P) showed its beneficial role in ameliorating the end-stage organ damage related disorders. Subsequently, in vivo and in vitro studies have been carried out to verify its effectiveness in several models using different experimental approaches. These studies with decoy peptide including the "handle" sequence have focused on the association of the (pro)renin receptor and prorenin in the pathogenesis of diabetes and hypertension. However, the function of (pro)renin receptor might be more complex than it was anticipated as it is not only distributed intracellularly and appeared on the cell membrane but also found in plasma. The decoy resembling the N-terminal sequence of prorenin has been useful in determining the structure-function relationship of prorenin and (P)RR. Therefore, this review tries to shed light on the use of decoy peptide in elucidating the functional properties of both prorenin and (pro)renin receptor by pointing out recent studies.