Two immunoglobulin (Ig) diversification mechanisms collaborate to provide protective humoral immunity. Combinatorial assembly of IgH and IgL V region exons from gene segments generates preimmune Ig repertoires, expressed as B cell receptors (BCRs). Secondary diversification occurs when Ig V regions undergo somatic hypermutation (SHM) and affinity-based selection toward antigen in activated germinal center (GC) B cells. Secondary diversification is thought to only ripen the antigen-binding affinity of Igs that already exist (i.e., cognate Igs) because of chance generation during preimmune Ig diversification. However, whether stochastic activation of noncognate B cells can generate new affinity to antigen in GCs is unclear. Using a mouse model whose knock-in BCR does not functionally engage with immunizing antigen, we found that chronic immunization induced antigen-specific serological responses with diverse SHM-mediated antibody affinity maturation pathways and divergent epitope targeting. Thus, intrinsic GC B cell flexibility allows for somatic, noncognate B cell evolution, permitting de novo antigen recognition and subsequent antibody affinity maturation without initial preimmune BCR engagement.

Substance abuse refers to the harmful or hazardous use of any psychoactive substance including licit and illicit drugs, other than when medically indicated. According to a UN report, 1 million heroin addicts are registered in India, and unofficially, there are as many as 5 million. Among all the states Punjab stood third in substance abuse and also injectable drug use. The present study was thus conducted to assess the sociodemographic profile and pattern of substance abuse among patients attending a Drug de-addiction centre.

The incidence of mother-to-newborn SARS-CoV-2 transmission appears low and may be associated with biological and social factors. However, data are limited on the factors associated with neonatal clinical or viral testing outcomes.

In the ongoing COVID-19 pandemic, an increased incidence of ROCM was noted in India among those infected with COVID. We determined risk factors for rhino-orbito-cerebral mucormycosis (ROCM) post Coronavirus disease 2019 (COVID-19) among those never and ever hospitalized for COVID-19 separately through a multicentric, hospital-based, unmatched case-control study across India.

The ability of immunoglobulin (Ig) to recognize pathogens is critical for optimal immune fitness. Early events that shape preimmune Ig repertoires, expressed on IgM+ IgD+ B cells as B cell receptors (BCRs), are poorly defined. Here, we studied germ-free mice and conventionalized littermates to explore the hypothesis that symbiotic microbes help shape the preimmune Ig repertoire. Ig-binding assays showed that exposure to conventional microbial symbionts enriched frequencies of antibacterial IgM+ IgD+ B cells in intestine and spleen. This enrichment affected follicular B cells, involving a diverse set of Ig-variable region gene segments, and was T cell-independent. Functionally, enrichment of microbe reactivity primed basal levels of small intestinal T cell-independent, symbiont-reactive IgA and enhanced systemic IgG responses to bacterial immunization. These results demonstrate that microbial symbionts influence host immunity by enriching frequencies of antibacterial specificities within preimmune B cell repertoires and that this may have consequences for mucosal and systemic immunity.

The 30-day readmission rate after hospitalization for a sickle cell crisis (SCC) is extremely high. Accurate information on readmission diagnoses, total readmission costs and factors associated with readmission is required to effectively plan resource allocation and to plan interventions to reduce readmission rates. The present study aimed to examine readmission diagnoses and factors associated with all-cause 30-day readmission after hospitalization for SCC. We analyzed 2016 nationwide readmission database (NRD) to identify patterns of 30-day readmission by patient demographic characteristics and time after hospitalization for SCC. We estimated the percentage and most common readmission diagnoses for 30-day and 7-day readmissions after discharge. We studied the relationship between risk factors and readmission and the impact of readmission on patient outcomes and resulting financial burden on health care in dollars. In 2016, of 67,887 discharges after index hospitalizations, 18099 (26.9%) were readmitted within 30-days. Of all readmissions, 5166 (7.6%) were readmitted within 7 days. The spectrum of readmission diagnoses was largely similar in both 30-day and 7-day readmission with more than 80% patients in both time periods readmitted with diagnoses related to SCC. The mean length of stay for readmitted patients was significantly longer than the index hospitalization (5.3 days (5.1-5.5) vs 4.9 days (CI 4.8-5.1, p < 0.01). Also, the mean cost of hospitalization in readmitted patients $8485 was significantly higher than the index hospitalization $8064 p < 0.01. In 2016, readmission among patients with SCC incurred an additional 95,445 hospitalization days resulting a total charge of $609 million and a total cost of $152 million in the US. On Multivariate analysis, age group 18-30 years, discharge against medical advice, higher Charlson comorbidity index, low socioeconomic status and admission at high volume centers were associated with a higher likelihood of 30-day readmission. Among patients hospitalized for SCC, 30-day readmissions were frequent throughout the month post hospitalization and resulted in an enormous financial burden on the United States healthcare system.

Latent tuberculosis infection is attributed in part to the existence of Mycobacterium tuberculosis in a persistent non-replicating dormant state that is associated with tolerance to host defence mechanisms and antibiotics. We have recently reported that vitamin C treatment of M. tuberculosis triggers the rapid development of bacterial dormancy. Temporal genome-wide transcriptome analysis has revealed that vitamin C-induced dormancy is associated with a large-scale modulation of gene expression in M. tuberculosis.

To evaluate practice patterns in the treatment of corneal ulcer by ophthalmologists during COVID-19 pandemic in the Indian subcontinent.

Introduction Limited access/exorbitant cost of fibroscan and the associated risks with biopsy to assess fibrosis in non-alcoholic fatty liver disease (NAFLD) patients has made exigent demand of serum-based fibrosis scores to be validated for their accuracy and efficacy. The objective of the study was to compare the accuracy of FIB-4 (fibrosis-4) and FIB-5 (fibrofast) scores to rule out advanced fibrosis in NAFLD patients. Methods A total of 145 patients were categorized as group I with mild/moderate fibrosis (MF) comprising of F0 to F2 and group II with advanced fibrosis (AF) comprising of F3 and F4 based on fibroscan kPa (kilopascal) score. Results Group II had significantly higher alanine transaminase (ALT), aspartate transaminase (AST), haemoglobin % (Hb %), bilirubin and alkaline phosphatase (ALP) values and significantly lower platelet count and albumin as compared to group I. The FIB-4 score was significantly higher in group II [1.8 (1.1 - 4.7)], as compared with group I [0.98 (0.63 - 1.67)], p-value = 0.0001. FIB-5 score of group II [-6.4 (-8.8 - 3.4)] was significantly lower as compared with group I [-4.8 (-6.8 - 2.0)], p-value = 0.003. FIB-4 and FIB-5 had area under receiver operator characteristic (AUROC) curve of 0.712 and 0.655, respectively. FIB-4 at cut-off of <2.02 had a negative predictive value (NPV) of 90.7%. FIB-5 at a cut-off of <-7.11 has an NPV of 94.1% and at a cut-off of <-3.24 had an NPV of 88.9%. Conclusion We concluded that both FIB-4 and FIB-5 can be used to rule out advanced fibrosis in NAFLD patients in a resource-limited and indigent setting as both the scores have NPV greater than 90%.

The present study was undertaken to study the breastfeeding practices and the influence of literacy and prevailing cultural factors on different aspects of breastfeeding.

Bacillus anthracis (BA) is a major bioterrorism concern which has evolved complex regulatory mechanisms for its virulence factors. Secreted proteases play an imperative role in the pathogenesis of BA, however their regulation remains elusive. Two component systems (TCS) are often employed by bacteria to sense and adapt to the environmental perturbations. In several pathogens, TCS are commonly associated with the regulation of virulence factors including proteases. The genome of BA encodes 41 TCS pairs, however, the role of any TCS in regulation of its proteases is not known.

The enormous magnitude of scientific research carried out in the field of NSAIDs and cyclooxygenases (COXs) is known. They are crucial in pain management. COX-2 inhibitors have evolved over the years; from traditional NSAIDs to isoform-specific. The present study is aimed to identify a cluster of amino acids in the catalytic site whose energy contribution can better explain COX-2 inhibitory activity accurately than the binding energy of the whole protein. Initially, MD simulations (25 ns) and MM-PBSA calculations were performed for 8 diarylheterocyclic inhibitors. Per-residue energy decomposition studies were carried out to elucidate the energy contribution of each amino acid, and their correlation with COX-2 inhibitory activity was enumerated. A cluster of catalytic amino acids whose free energy sum has a high correlation with biological data was identified. The cluster of Gln178, Ser339, Tyr341, Arg499, Phe504, Val509 and Ala513 showed the correlation of -0.60. Further, the study was extended to a total of 26 COX-2 inhibitors belonging to different classes to validate the applicability of the cluster of amino acids identified. Results clearly suggest that the cluster of amino acids identified provide accurate screening method, and can be applied to predict COX-2 inhibitory activity of small molecules.

Pulmonary mucoepidermoid carcinoma (PMEC) and pulmonary adenoid cystic carcinoma (PACC) are the two major types of primary salivary gland-type (PSGT) lung cancers. The demographic profile, clinicopathological features, and predictors of survival as an overall group have not been described for PSGT cancers of lung.

In this study we introduce a rescoring method to improve the accuracy of docking programs against mPGES-1. The rescoring method developed is a result of extensive computational study in which different scoring functions and molecular descriptors were combined to develop consensus and rescoring methods. 127 mPGES-1 inhibitors were collected from literature and were segregated into training and external test sets. Docking of the 27 training set compounds was carried out using default settings in AutoDock Vina, AutoDock, DOCK6 and GOLD programs. The programs showed low to moderate correlation with the experimental activities. In order to introduce the contributions of desolvation penalty and conformation energy of the inhibitors various molecular descriptors were calculated. Later, rescoring method was developed as empirical sum of normalised values of docking scores, LogP and Nrotb. The results clearly indicated that LogP and Nrotb recuperate the predictions of these docking programs. Further the efficiency of the rescoring method was validated using 100 test set compounds. The accurate prediction of binding affinities for analogues of the same compounds is a major challenge for many of the existing docking programs; in the present study the high correlation obtained for experimental and predicted pIC50 values for the test set compounds validates the efficiency of the scoring method.

Ras family proteins are membrane-bound GTPases that control proliferation, survival, and motility. Many forms of cancers are driven by the acquisition of somatic mutations in a RAS gene. In pancreatic cancer (PC), more than 90% of tumors carry an activating mutation in KRAS. Mutations in components of the Ras signaling pathway can also be the cause of RASopathies, a group of developmental disorders. In a subset of RASopathies, the causal mutations are in the LZTR1 protein, a substrate adaptor for E3 ubiquitin ligases that promote the degradation of Ras proteins. Here, we show that the function of LZTR1 is regulated by the glycogen synthase kinase 3 (GSK3). In PC cells, inhibiting or silencing GSK3 led to a decline in the level of Ras proteins, including both wild type Ras proteins and the oncogenic Kras protein. This decline was accompanied by a 3-fold decrease in the half-life of Ras proteins and was blocked by the inhibition of the proteasome or the knockdown of LZTR1. Irrespective of the mutational status of KRAS, the decline in Ras proteins was observed and accompanied by a loss of cell proliferation. This loss of proliferation was blocked by the knockdown of LZTR1 and could be recapitulated by the silencing of either KRAS or GSK3. These results reveal a novel GSK3-regulated LZTR1-dependent mechanism that controls the stability of Ras proteins and proliferation of PC cells. The significance of this novel pathway to Ras signaling and its contribution to the therapeutic properties of GSK3 inhibitors are both discussed.

The treatment with tyrosine kinase inhibitors (TKIs) has drastically improved the outcome of chronic myeloid leukemia (CML) patients. This study was conducted to examine the risk of secondary cancers (SCs) in the CML patients who were diagnosed and treated in the TKI era in the United States.

: In the United States (US), Kaposi's sarcoma (KS) is usually seen in the patients affected by human immunodeficiency virus (HIV). The racial differences in the incidence rates and survival of patients with KS have been reported in the US. We undertook this study to analyse the disparities in the race-specific incidence rate and survival of KS patients of two different races in the US based on SEER (Surveillance, Epidemiology and End Results) database.