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

SUMMARY ISWI-family enzymes remodel chromatin by sliding nucleosomes along DNA, but the nucleosome translocation mechanism remains unclear. Here we use single-molecule FRET to probe nucleosome translocation by ISWI-family remodelers. Distinct ISWI-family members translocate nucleosomes with a similar stepping pattern maintained by the catalytic subunit of the enzyme. Nucleosome remodeling begins with a 7-bp step of DNA translocation followed by 3-bp subsequent steps towards the exit side of nucleosomes. These multi-bp, compound steps are comprised of 1-bp substeps. DNA movement on the entry side of the nucleosome occurs only after 7 bp of exit-side translocation and each entry-side step draws in a 3-bp equivalent of DNA that allows three additional base pairs to be moved to the exit side. Our results suggest a remodeling mechanism with precise coordination at different nucleosomal sites featuring DNA translocation towards the exit side in 1-bp steps preceding multi-bp steps of DNA movement on the entry side.

Nucleosome positioning governs access to eukaryotic genomes. Many genes show a stereotypic organisation at their 5 0 end: a nucleosome free region just upstream of the transcription start site (TSS) followed by a regular nucleosomal array over the coding region. The determinants for this pattern are unclear, but nucleosome remodelers are likely critical. Here we study the role of remodelers in global nucleosome positioning in S. pombe and the corresponding changes in expression. We find a striking evolutionary shift in remodeler usage between budding and fission yeast. The S. pombe RSC complex does not seem to be involved in nucleosome positioning, despite its prominent role in S. cerevisiae. While S. pombe lacks ISWI-type remodelers, it has two CHD1-type ATPases, Hrp1 and Hrp3. We demonstrate nucleosome spacing activity for Hrp1 and Hrp3 in vitro, and that together they are essential for linking regular genic arrays to most TSSs in vivo. Impaired arrays in the absence of either or both remodelers may lead to increased cryptic antisense transcription, but overall gene expression levels are only mildly affected.

The maintenance of open and repressed chromatin states is crucial for the regulation of gene expression. To study the genes involved in maintaining chromatin states, we generated a random mutant library in Schizosaccharomyces pombe and monitored the silencing of reporter genes inserted into the euchromatic region adjacent to the heterochromatic mating type locus. We show that Leo1–Paf1 [a subcomplex of the RNA polymerase II-associated factor 1 complex (Paf1C)] is required to prevent the spreading of heterochromatin into euchromatin by mapping the heterochromatin mark H3K9me2 using high-resolution genomewide ChIP (ChIP–exo). Loss of Leo1–Paf1 increases heterochromatin stability at several facultative heterochromatin loci in an RNAi-independent manner. Instead, deletion of Leo1 decreases nucleosome turnover, leading to heterochromatin stabilization. Our data reveal that Leo1–Paf1 promotes chromatin state fluctuations by enhancing histone turnover.