Neutralizing antibody responses to SARS-CoV-2 Omicron variants: Post six months following two-dose & three-dose vaccination of ChAdOx1 nCoV-19 or BBV152.

BACKGROUND OBJECTIVES: The Omicron sub-lineages are known to have higher infectivity, immune escape and lower virulence. During December 2022 - January 2023 and March - April 2023, India witnessed increased SARS-CoV-2 infections, mostly due to newer Omicron sub-lineages. With this unprecedented rise in cases, we assessed the neutralization potential of individuals vaccinated with ChAdOx1 nCoV (Covishield) and BBV152 (Covaxin) against emerging Omicron sub-lineages. METHODS: Neutralizing antibody responses were measured in the sera collected from individuals six months post-two doses (n=88) of Covishield (n=44) or Covaxin (n=44) and post-three doses (n=102) of Covishield (n=46) or Covaxin (n=56) booster dose against prototype B.1 strain, lineages of Omicron; XBB.1, BQ.1, BA.5.2 and BF.7. RESULTS: The sera of individuals collected six months after the two-dose and the three-dose demonstrated neutralizing activity against all variants. The neutralizing antibody (NAbs) level was highest against the prototype B.1 strain, followed by BA5.2 (5-6 fold lower), BF.7 (11-12 fold lower), BQ.1 (12 fold lower) and XBB.1 (18-22 fold lower). INTERPRETATION CONCLUSIONS: Persistence of NAb responses was comparable in individuals with two- and three-dose groups post six months of vaccination. Among the Omicron sub-variants, XBB.1 showed marked neutralization escape, thus pointing towards an eventual immune escape, which may cause more infections. Further, the correlation of study data with complete clinical profile of the participants along with observations for cell-mediated immunity may provide a clear picture for the sustained protection due to three-dose vaccination as well as hybrid immunity against the newer variants.

Pathogenomic in silico approach identifies NSP-A and Fe-IIISBP as possible drug targets in Neisseria Meningitidis MC58 and development of pharmacophores as novel therapeutic candidates.

Meningitis creates a life-threatening clinical crisis. Moreover, the administered antibiotics result into multi-drug resistance, thereby necessitating development of alternative therapeutic strategies. This study aimed at identifying novel-drug targets in Neisseria meningitidis and therapeutic molecules which can be exploited for the treatment of meningitis. Novel targets were identified by applying a pathogenomic approach involving protein data-set mining, subtractive channel analysis and subsequent qualitative analysis comprising of in silico pharmacokinetics, molecular docking and pharmacophore generation. Pathogenomic studies revealed Neisserial Surface Protein A (NSP-A) and Iron-III-Substrate Binding Protein (Fe-IIISBP) as potential targets. Two pharmacophore models comprising of 2-(biaryl) carbapenems, efavirenz, praziquantel and pyrimethamine for NSP-A and 2-(biaryl) carbapenems, trimipramine and pyrimethamine for Fe-IIISBP, showed successful docking, followed drug-likeness criteria and generated pharmacophore model with a score of 8.08 and 8.818, respectively, which had further been docked to the target stably. Thus, our study identifies NSP-A and Fe-IIISBP as novel targets in Neisseria meningitidis for which 2-(biaryl) carbapenems, efavirenz, praziquantel, trimipramine and pyrimethamine may be employed for effective treatment of meningitis.

Metagenomic analysis of bacterial communities during estrous cycle in Bos indicus.

The present study, using 16 s rRNA sequencing of the V3-V4 hypervariable region, was aimed to check diversity of vaginal microbiota throughout different stages of the estrous cycle in Bos indicus, with attention to changes in progesterone hormone and microorganism diversity. Metagenomic research was conducted on vaginal swabs obtained from nine healthy Indian Gir cows at estrus (day 0), metestrus (day 04), diestrus (day 12), and proestrus (day 16) phases of the estrous cycle. The findings revealed that the diestrus phase has a different bacterial diversity than the other three estrous cycle phases, implying that progesterone affects bacterial diversity. Proteobacteria and Firmicutes were the most abundant phyla at the phylum level, accounting for 94% of bacterial diversity. Actinobacteriota, Patescibacteria, Cyanobacteria, and Bacteroidota were among the less prevalent phyla observed in all samples. After statistical analysis, Bacillaceae, Alcaligenes, Enterobacteriaceae, and Morganellaceae families were more significant. The Enterobacteriaceae family was found to be lower in the diestrus phase than in the other three phases; in contrast, all statistically significant genera were high at the diestrus phase. The luteal stage had higher levels of Micrococcus, Stenotrophomonas, UGC-010, Massilia, and Methylobacillus than the follicular stage, and statistical analysis revealed substantial difference between the luteal and follicular stages. Lactobacillus genus was present in both the estrus and diestrus phases. This study represents an important step toward the understanding of microbial diversity within different stages of the estrous cycle of Indian cows.

Recurrent hypoglycemia dampens functional regulation mediated via Neurexin-1, Neuroligin-2 and Mint-1 docking proteins: Intensified complications during diabetes.

Glycemic regulation is important for maintaining critical physiological functions. Extreme variation in levels of circulating glucose are known to affect insulin secretion. Elevated insulin levels result in lowering of circulating glycemic levels culminating into hypoglycemia. Recurrence of hypoglycemia are often noted owing to fasting conditions, untimely meals, irregular dietary consumption, or as a side-effect of disease pathophysiology. Such events of hypoglycemia threaten to hamper the patterns of insulin secretion in diabetic condition. Insulin vesicle docking is a prerequisite phase which ensures anchoring of the vesicles to the ß-cell membrane in order to expel the insulin cargo. Neurexin and Neuroligin are the marker docking proteins which assists in the tethering of the insulin granules to the secretory membrane. However, these cell adhesion molecules indirectly affect the glycemic levels by regulating insulin secretion. The effect of extreme levels of glycemic fluctuations on these molecules, and how it affects the docking machinery remains obscure. Our current study demonstrates down-regulated expression of Neurexin-1, Neuroligin-2 and Mint-1 molecules during hyperglycemia, hypoglycemia and diabetic hypoglycemia in rodents as well as for an in-vitro system using MIN6 cell-line. Studies with fluorescently labelled insulin revealed presence of lessened functional insulin secretory granules, concomitant with the alterations in morphology and as a result of hypoglycemia in control and diabetic condition which was found to be further deteriorating. Our studies indicate towards a feeble vesicular anchorage, which may partly be responsible for dwindled insulin secretion during diabetes. However, hypoglycemia poses as a potent diabetic complication in further deteriorating the docking machinery. To the best of our knowledge this is the first report which demonstrates the effect of hypoglycemic events in affecting insulin secretion by weakening insulin vesicular anchorage in normal and diabetic individuals.

Extreme Glycemic Fluctuations Debilitate NRG1, ErbB Receptors and Olig1 Function: Association with Regeneration, Cognition and Mood Alterations During Diabetes.

Neuronal regeneration is crucial for maintaining intact neural interactions for perpetuation of cognitive and emotional functioning. The NRG1-ErbB receptor signaling is a key pathway for regeneration in adult brain and also associated with learning and mood stabilization by modulating synaptic transmission. Extreme glycemic stress is known to affect NRG1-ErbB-mediated regeneration in brain; yet, it remains unclear how the ErbB receptor subtypes are differentially affected due to such metabolic variations. Here, we assessed the alterations in NRG1, ErbB receptor subtypes to study the regenerative potential, both in rodents as well as in neuronal and glial cell models of hyperglycemia and hypoglycemic insults during hyperglycemia. The pro-oxidant and anti-oxidant status leading to degenerative changes in brain regions were determined. The spatial memory and anxiogenic behaviour of experimental rodents were tested using 'T' maze and Elevated Plus Maze. Our data revealed that the extreme glycemic discrepancies during diabetes and recurrent hypoglycemia lead to altered expression of NRG1, ErbB receptor subtypes, Syntaxin1 and Olig1 that shows association with impaired regeneration, synaptic dysfunction, demyelination, cognitive deficits and anxiety.

Hypoglycemia causes dysregulation of Neuregulin 1, ErbB receptors, Ki67 in cerebellum and brainstem during diabetes: Implications in motor function.

Hypoglycemia induced brain injury poses a major setback to optimal blood glucose regulation during diabetes. It causes irreversible injury in several brain regions culminating in improper function. Neuregulin 1 and ErbB receptors are involved in regeneration during adulthood as well as in glucose homeostasis. We intended to understand the influence of extreme discrepancies in glycemic levels on Neuregulin 1, ErbB receptor subtypes and Ki67 expression in relation to motor deficits as a consequence of cellular dysfunction/degeneration in the cerebellum and brainstem during diabetes. Elevated oxidative stress and compromised antioxidant system havocs cerebellum and brainstem related function. Cellular alteration of Purkinje neurons in the cerebellum and presence of axonal spheroids in the brainstem are suggestive of impairment to neural circuits involved in motor function. Down regulation of Neuregulin 1, ErbB 2, ErbB 3, ErbB 4 and Ki67 expression observed during diabetes and hypoglycemia may critically cause regenerative deficiency in cerebellum. The coincident up regulation of Neuregulin 1, ErbB 2, ErbB 3 and ErbB 4 in brainstem during diabetes is an attempt to maintain regenerative homeostasis to ensure its function. However, hypoglycemic insults results in down regulation of Neuregulin 1, ErbB 4 expression that severely compromises their role in brainstem. Grid walking test confirmed motor impairment during diabetes that showed further deterioration due to hypoglycemic stress. Thus altered expression of Neuregulin 1, ErbB receptor subtypes and Ki67 during diabetes and hypoglycemia contributes to reduced cellular proliferation and deficits in motor function.