The SARS-CoV-2 B.1.617.2 (Delta) variant was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha) 1 . In vitro, B.1.617.2 is 6-fold less sensitive to serum neutralising antibodies from recovered individuals, and 8-fold less sensitive to vaccine-elicited antibodies as compared to wild type (WT) Wuhan-1 bearing D614G. Serum neutralising titres against B.1.617.2 were lower in ChAdOx-1 versus BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies against the receptor binding domain (RBD) and N-terminal domain (NTD). B.1.617.2 demonstrated higher replication efficiency in both airway organoid and human airway epithelial systems compared to B.1.1.7, associated with B.1.617.2 spike in a predominantly cleaved state compared to B.1.1.7. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralising antibody as compared to WT spike. Additionally we observed that B.1.617.2 had higher replication and spike mediated entry as compared to B.1.617.1, potentially explaining B.1.617.2 dominance. In an analysis of over 130 SARS-CoV-2 infected healthcare workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx-1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era. India's first wave of SARS-CoV-2 infections in mid-2020 was relatively mild and was controlled by a nationwide lockdown. Since easing of restrictions, India has seen expansion in cases of COVID-19 since March

After escaping relatively unscathed during the first wave of the COVID-19 pandemic, India witnessed a ferocious second COVID-19 wave, starting in March 2021 and accounting for about half of global cases by the first week of May. SARS-CoV-2 had spread widely throughout India in the first wave, with the third national serosurvey in January 2021 finding that 21.4% of adults and 25.3% of 10-to 17-year-old adolescents were seropositive (1). Delhi, the national capital, was not included in the national serosurvey but had undergone multiple periods of high transmission in 2020 (Fig. 1A). In a district-wise stratified serosurvey conducted by the Delhi Government in January 2021, overall seropositivity was reported to be 56.1% (95% CI, 55.5-56.8%), ranging from 49.1% to 62.2% across 11 districts (2). This was expected to confer some protection from future outbreaks.Despite high seropositivity, Delhi was amongst the most affected cities during the second wave. The rise in new cases was exceptionally rapid in April, going from approximately 2000 to 20,000 between 31 March and 16 April. This was accompanied by a rapid rise in hospitalizations and ICU admissions (Fig. 1B). In this emergency situation with saturated bed occupancy by 12 April, major private hospitals were declared by the state as full COVID care-only and senior medical students, including from alternative medicine branches, were pressed into service (3). Deaths rose proportionately (Fig. 1C) and the case-fatality ratio (CFR), estimated as the scaling factor between time-advanced cases and deaths (Fig. 1D), was stable (mean, SD; 1.9, 0.3%). Population spread of SARS-CoV-2 is underestimated by test positive cases alone (1, 2). To better understand the degree of spread and the factors leading to the unexpectedly severe outbreak, we used all available data including testing, sequencing, serosurveys, and serially followed cohorts.In the absence of finely resolved or serial data from national and state surveys, we focused on data for Delhi participants of a national serosurvey of Council of Scientific and

Defining the molecular genetic alterations underlying pancreatic cancer may provide unique therapeutic insight for this deadly disease. Toward this goal, we report here an integrative DNA microarray and sequencing-based analysis of pancreatic cancer genomes. Notable among the alterations newly identified, genomic deletions, mutations, and rearrangements recurrently targeted genes encoding components of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex, including all three putative DNA binding subunits (ARID1A, ARID1B, and PBRM1) and both enzymatic subunits (SMARCA2 and SMARCA4). Whereas alterations of each individual SWI/SNF subunit occurred at modest-frequency, as mutational "hills" in the genomic landscape, together they affected at least one-third of all pancreatic cancers, defining SWI/SNF as a major mutational "mountain." Consistent with a tumor-suppressive role, re-expression of SMARCA4 in SMARCA4-deficient pancreatic cancer cell lines reduced cell growth and promoted senescence, whereas its overexpression in a SWI/SNFintact line had no such effect. In addition, expression profiling analyses revealed that SWI/SNF likely antagonizes Polycomb repressive complex 2, implicating this as one possible mechanism of tumor suppression. Our findings reveal SWI/SNF to be a central tumor suppressive complex in pancreatic cancer.comparative genomic hybridization array | cancer gene discovery | tumor suppressor P ancreatic ductal adenocarcinoma, more commonly known as pancreatic cancer, remains a leading cause of cancer deaths in the developed world (1, 2). Each year, the number of patients diagnosed with pancreatic cancer is nearly equal to the number that will die from the disease, underscoring the inadequacy of current therapies. Indeed, the overall 5-y survival rate is less than 5% (3). A more complete characterization of its molecular pathogenesis may suggest new avenues for targeted therapy.Much has been learned of the molecular genetic alterations underlying pancreatic cancer (reviewed in 4, 5). Early events, identified in early precursor lesions [pancreatic intraepithelial neoplasia (PanIN)], include activational mutation (and/or amplification) of the KRAS2 oncogene, occurring in 75-90% of pancreatic cancers, and inactivation of the CDKN2A (p16 INK4A ) cell-cycle regulator in 80-95% of cases. Later events (identified in more advanced PanIN) include inactivation of the TP53 tumor suppressor in 50-75% of pancreatic cancers, and loss of SMAD4 (DPC4) in 45-55% of cases.

Pancreatic cancer, the fourth leading cause of cancer death in the United States, is frequently associated with the amplification and deletion of specific oncogenes and tumor-suppressor genes (TSGs), respectively. To identify such novel alterations and to discover the underlying genes, we performed comparative genomic hybridization on a set of 22 human pancreatic cancer cell lines, using cDNA microarrays measuring approximately 26,000 human genes (thereby providing an average mapping resolution of <60 kb). To define the subset of amplified and deleted genes with correspondingly altered expression, we also profiled mRNA levels in parallel using the same cDNA microarray platform. In total, we identified 14 high-level amplifications (38-4934 kb in size) and 15 homozygous deletions (46-725 kb). We discovered novel localized amplicons, suggesting previously unrecognized candidate oncogenes at 6p21, 7q21 (SMURF1, TRRAP), 11q22 (BIRC2, BIRC3), 12p12, 14q24 (TGFB3), 17q12, and 19q13. Likewise, we identified novel polymerase chain reaction-validated homozygous deletions indicating new candidate TSGs at 6q25, 8p23, 8p22 (TUSC3), 9q33 (TNC, TNFSF15), 10q22, 10q24 (CHUK), 11p15 (DKK3), 16q23, 18q23, 21q22 (PRDM15, ANKRD3), and Xp11. Our findings suggest candidate genes and pathways, which may contribute to the development or progression of pancreatic cancer.

Our earlier studies on transcriptional signals of mycobacteria had revealed that (i) strong promoters occur less frequently in the slowly growing pathogen Mycobacterium tuberculosis H37Rv than in the fast-growing saprophyte M. smegmatis and (ii) mycobacterial promoters function poorly in Escherichia coli. We now present evidence that RNA polymerases of M. smegmatis, M. tuberculosis, and M. bovis BCG recognize promoter elements with comparable efficiencies. Analysis of these randomly isolated mycobacterial promoters by DNA sequencing, primer extension, and deletion experiments revealed that their ؊10 regions are highly similar to those of E. coli promoters, in contrast to their ؊35 regions, which can tolerate a greater variety of sequences, owing presumably to the presence of multiple sigma factors with different or overlapping specificities for ؊35 regions, as reported earlier for the Streptomyces promoters. A comparison of the ؊10 and ؊35 binding domains of MysA, HrdB, and RpoD (the principal sigma factors of M. smegmatis, Streptomyces aureofaciens, and E. coli, respectively) showed that all three sigma factors have nearly identical ؊10 binding domains. However, the ؊35 binding domains of the principal mycobacterial and streptomycete sigma factors, although nearly identical to each other, are vastly different from the corresponding region of the sigma factor of E. coli. Thus, the transcriptional signals of mycobacteria have features in common with Streptomyces promoters but differ from those of E. coli because of major differences in the ؊35 regions of the promoters and the corresponding binding domain in the sigma factor.The genus Mycobacterium includes pathogens that cause the highest number of bacterial infections and human deaths every year (2). Because of the emergence of multidrug-resistant strains of Mycobacterium tuberculosis (7) and the increasing incidence of mycobacterial infections in human immunodeficiency virus-positive cases (4), tuberculosis has emerged as a major global threat to health. Despite their highly pathogenic nature, progress towards an understanding of gene structure and gene expression in mycobacteria has been slow. The lack of information on mycobacterial transcriptional signals has particularly impeded our understanding of the regulation of gene expression in these organisms.Only a few mycobacterial promoters have been studied. These include promoters for the 16S rRNA genes of M. smegmatis ( (21); and the three promoters responsible for transcribing the repressor-like gp71 protein of mycobacteriophage L5 (22). It is, however, difficult to assess the nature of transcriptional signals in mycobacteria by comparison of these promoter sequences, as many of these belong to specifically regulated genes and thus may not contribute towards the elucidation of constitutive gene expression in mycobacteria. The purpose of an unbiased study of mycobacterial transcriptional signals will be best achieved by analysis of randomly isolated promoters by using a promoter probe vector. We had earlier r...

We have constructed a promoter selection vector for mycobacteria to analyze the sequences involved in mycobacterial transcriptional regulation. The vector pSD7 contains extrachromosomal origins of replication from Escherichia coli as well as from Mycobacterium fortuitum and a kanamycin resistance gene for positive selection in mycobacteria. The promoterless chloramphenicol acetyltransferase (CAT) reporter gene has been used to detect mycobacterial promoter elements in a homologous environment and to quantify their relative strengths. Using pSD7, we have isolated 125 promoter clones from the slowly growing pathogen Mycobacterium tuberculosis H37Rv and 350 clones from the fast-growing saprophyte Mycobacterium smegmatis. The promoters exhibited a wide range of strengths, as indicated by their corresponding CAT reporter activities (5 to 2,500 nmol/min/mg of protein). However, while most of the M. smegmatis promoters supported relatively higher CAT activities ranging from 100 to 2,500 nmol/min/mg of protein, a majority of those from M. tuberculosis supported CAT activities ranging from 5 to only about 100 nmol/min/mg of protein. Our results indicate that stronger promoters occur less frequently in the case of M. tuberculosis compared with M. smegmatis. To assess the extent of divergence of mycobacterial promoters vis-a-vis those of E. coli, the CAT activities supported by the promoters in E. coli were measured and compared with their corresponding activities in mycobacteria. Most of the mycobacterial promoter elements functioned poorly in E. coli. The homologous selection system that we have developed has thus enabled the identification of mycobacterial promoters that apparently function

Pancreatobiliary cancers have among the highest mortality rates of any cancer type. Discovering the full spectrum of molecular genetic alterations may suggest new avenues for therapy. To catalogue genomic alterations, we carried out array-based genomic profiling of 31 exocrine pancreatic cancers and 6 distal bile duct cancers, expanded as xenografts to enrich the tumor cell fraction. We identified numerous focal DNA amplifications and deletions, including in 19% of pancreatobiliary cases gain at cytoband 18q11.2, a locus uncommonly amplified in other tumor types. The smallest shared amplification at 18q11.2 included GATA6, a transcriptional regulator previously linked to normal pancreas development. When amplified, GATA6 was overexpressed at both the mRNA and protein levels, and strong immunostaining was observed in 25 of 54 (46%) primary pancreatic cancers compared to 0 of 33 normal pancreas specimens surveyed. GATA6 expression in xenografts was associated with specific microarray gene-expression patterns, enriched for GATA binding sites and mitochondrial oxidative phosphorylation activity. siRNA mediated knockdown of GATA6 in pancreatic cancer cell lines with amplification led to reduced cell proliferation, cell cycle progression, and colony formation. Our findings indicate that GATA6 amplification and overexpression contribute to the oncogenic phenotypes of pancreatic cancer cells, and identify GATA6 as a candidate lineage-specific oncogene in pancreatobiliary cancer, with implications for novel treatment strategies.

Glucose homeostasis in mammals is achieved by the actions of counterregulatory hormones, namely insulin, glucagon and glucocorticoids. Glucose levels in the circulation are regulated by the liver, the metabolic centre which produces glucose when it is scarce in the blood. This process is catalysed by two rate-limiting enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) whose gene expression is regulated by hormones. Hormone response units (HRUs) present in the two genes integrate signals from various signalling pathways triggered by hormones. How such domains are arranged in the regulatory region of these two genes, how this complex regulation is accomplished and the latest advancements in the field are discussed in this review.