Comparative sequence analyses reveal sites of ancestral chromosomal fusions in the Indian muntjac genome

Comparative mapping and sequencing was used to characterize the sites of ancestral chromosomal fusions in the Indian muntjac genome

Histone Modifications within the Human X Centromere Region

Human centromeres are multi-megabase regions of highly ordered arrays of alpha satellite DNA that are separated from chromosome arms by unordered alpha satellite monomers and other repetitive elements. Complexities in assembling such large repetitive regions have limited detailed studies of centromeric chromatin organization. However, a genomic map of the human X centromere has provided new opportunities to explore genomic architecture of a complex locus. We used ChIP to examine the distribution of modified histones within centromere regions of multiple X chromosomes. Methylation of H3 at lysine 4 coincided with DXZ1 higher order alpha satellite, the site of CENP-A localization. Heterochromatic histone modifications were distributed across the 400–500 kb pericentromeric regions. The large arrays of alpha satellite and gamma satellite DNA were enriched for both euchromatic and heterochromatic modifications, implying that some pericentromeric repeats have multiple chromatin characteristics. Partial truncation of the X centromere resulted in reduction in the size of the CENP-A/Cenp-A domain and increased heterochromatic modifications in the flanking pericentromere. Although the deletion removed ∼1/3 of centromeric DNA, the ratio of CENP-A to alpha satellite array size was maintained in the same proportion, suggesting that a limited, but defined linear region of the centromeric DNA is necessary for kinetochore assembly. Our results indicate that the human X centromere contains multiple types of chromatin, is organized similarly to smaller eukaryotic centromeres, and responds to structural changes by expanding or contracting domains

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Establishment and persistence of the copse snail, Arianta arbustorum (Linnaeus, 1758) (Gastropoda: Helicidae) in Canada

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H4K20 trimethylation (H4K20me3) at the X centromere in two human cell lines and one of the mouse-human somatic cell hybrids.

<p>Each number across the schematic representation of the centromere is a genomic site that was interrogated by ChIP-PCR. Control regions, including GAPDH, AFM and X-linked ZXDA are also included. The bar graph shows relative enrichment for H3K27 methylation (n = 3 with SD) calculated as percentage of input.</p

Cell lines included in the study.

<p>Cell lines included in the study.</p

H3K27 trimethylation (H3K27me3) at the X centromere in human cells and mouse-human somatic cell hybrids.

<p>Each number across the schematic representation of the centromere is a genomic site that was interrogated by ChIP-PCR. The bar graph shows relative enrichment for H3K27 methylation (n = 3 with SD). Control regions, including GAPDH, AFM and X-linked ZXDA are also included. The bar graph shows relative enrichment for H3K27 methylation (n = 3 with SD) calculated as percentage of input.</p

H3K27 mono-methylation (H3K27me1) at the X centromere in human cells and mouse-human somatic cell hybrids.

<p>Each number across the schematic representation of the centromere is a genomic site that was interrogated by ChIP-PCR. Control regions, including GAPDH, AFM and X-linked ZXDA are also included. The bar graph shows relative enrichment for H3K27 methylation (n = 3 with SD) calculated as percentage of input.</p

H3K9me2 enrichment at X centromeres in human cell lines and mouse-human hybrids.

<p>The schematic shows the structure of the X centromere. Each number along the centromere represents a genomic site or control region that was interrogated by ChIP-PCR with a specific histone antibody. Each bar graph shows relative enrichment for each histone modification (n≥3 with SD). Control regions, including GAPDH, AFM and X-linked ZXDA are also included. The bar graph shows enrichment calculated as percentage of input.</p