Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

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

Regulation of Osteoclast Differentiation and Skeletal Maintenance by Histone Deacetylases

Bone is a dynamic tissue that must respond to developmental, repair, and remodeling cues in a rapid manner with changes in gene expression. Carefully-coordinated cycles of bone resorption and formation are essential for healthy skeletal growth and maintenance. Osteoclasts are large, multinucleated cells that are responsible for breaking down bone by secreting acids to dissolve the bone mineral and proteolytic enzymes that degrade the bone extracellular matrix. Increased osteoclast activity has a severe impact on skeletal health, and therefore, osteoclasts represent an important therapeutic target in skeletal diseases, such as osteoporosis. Progression from multipotent progenitors into specialized, terminally-differentiated cells involves carefully-regulated patterns of gene expression to control lineage specification and emergence of the cellular phenotype. This process requires coordinated action of transcription factors with co-activators and co-repressors to bring about proper activation and inhibition of gene expression. Histone deacetylases (HDACs) are an important group of transcriptional co-repressors best known for reducing gene expression via removal of acetyl modifications from histones at HDAC target genes. This review will cover the progress that has been made recently to understand the role of HDACs and their targets in regulating osteoclast differentiation and activity and, thus, serve as potential therapeutic target

Validity of smartphone pedometer applications

Abstract Background Given the widespread use of smartphone pedometer applications and the relatively limited number of published validity tests, this study examined the validity of three popular commercial smartphone pedometer applications (i.e., Accupedo, Moves, and Runtastic Pedometer). Participants Convenience samples of males and females were recruited for laboratory tests [n = 11; mean: aged 24.18 years (±3.06)] and a free-living test [n = 18; mean: aged 28.78 years (±9.52)]. Methods Five conditions were assessed: (a) 20-step test, (b) 40-step stair climbing, (c) treadmill walking and running at different speeds, (d) driving, and (e) 3-day free-living. The Yamax SW-200 pedometer and observed step counts were used as criterion measures. Results Analyses identified an unacceptable error percentage in all of the applications compared to the pedometer. Conclusions Given the inaccuracy of these applications, caution is required in their promotion to the public for self-monitoring physical activity and in their use as tools for assessing physical activity in research trials

Validity of smartphone pedometer applications

Background: Given the widespread use of smartphone pedometer applications and the relatively limited number of published validity tests, this study examined the validity of three popular commercial smartphone pedometer applications (i.e., Accupedo, Moves, and Runtastic Pedometer). Participants Convenience samples of males and females were recruited for laboratory tests [n = 11; mean: aged 24.18 years (±3.06)] and a free-living test [n = 18; mean: aged 28.78 years (±9.52)]. Methods Five conditions were assessed: (a) 20-step test, (b) 40-step stair climbing, (c) treadmill walking and running at different speeds, (d) driving, and (e) 3-day free-living. The Yamax SW-200 pedometer and observed step counts were used as criterion measures. Results Analyses identified an unacceptable error percentage in all of the applications compared to the pedometer. Conclusions Given the inaccuracy of these applications, caution is required in their promotion to the public for self-monitoring physical activity and in their use as tools for assessing physical activity in research trials.Education, Faculty ofNon UBCKinesiology, School ofReviewedFacult

MOESM1 of Validity of smartphone pedometer applications

Additional file 1. Instructions and tracking sheet provided to participants in the free-living test

Class II and IV HDACs function as inhibitors of osteoclast differentiation

<div><p>Histone deacetylases (HDACs) are negative regulators of transcription and have been shown to regulate specific changes in gene expression. In vertebrates, eighteen HDACs have thus far been identified and subdivided into four classes (I-IV). Key roles for several HDACs in bone development and biology have been elucidated through <i>in vitro</i> and <i>in vivo</i> models. By comparison, there is a paucity of data on the roles of individual HDACs in osteoclast formation and function. In this study, we investigated the gene expression patterns and the effects of suppressing individual class II (<i>Hdac4</i>, <i>5</i>, <i>6</i>, <i>9</i>, and <i>10</i>) and class IV (<i>Hdac11</i>) HDACs during osteoclast differentiation. We demonstrated that HDAC class II and IV members are differentially expressed during osteoclast differentiation. Additionally, individual shRNA-mediated suppression of <i>Hdac4</i>, <i>5</i>, <i>9</i>, <i>10</i> and <i>11</i> expression resulted in increased multinucleated osteoclast size and demineralization activity, with little to no change in the overall number of multinucleated osteoclasts formed compared with control shRNA-treated cells. We also detected increased expression of genes highly expressed in osteoclasts, including <i>c-Fos</i>, <i>Nfatc1</i>, <i>Dc-stamp</i> and <i>Cathepsin K</i>. These observations indicate that HDACs cooperatively regulate shared targets in a non-redundant manner.</p></div

Suppression of <i>Hdac5</i> enhances osteoclast differentiation.

<p>Representative images of TRAP staining (A) of osteoclast cultures. <i>Hdac5</i>#1 represents <i>Hdac5</i> shRNA #1and <i>Hdac5</i>#2 represents <i>Hdac5</i> shRNA #2. Quantification of the number (B) and average size of TRAP-stained multinucleated osteoclasts (C). Representative photographs (D) and quantification (E) of demineralization activity of control and <i>Hdac5</i> shRNA-expressing osteoclast cultures grown on calcium phosphate-coated plates. Scale bar represents 200 μm. Western blot (F) of control and <i>Hdac5</i> shRNA-expressing cells with relative expression of shRNA expressing cells relative to control expressing cells indicated under the blots. Expression profile (G-J) of osteoclast genes <i>c-Fos</i>, <i>Nfatc1</i>, <i>Dc-stamp and Ctsk</i>. Data presented are the mean of three independent experiments. * p <0.05; ** p <0.01; *** p < 0.001; ns = not significant compared to control infected cells.</p