Blood pressure vs altitude in hypertensive and non-hypertensive himalayan trekkers

Introduction: Determine blood pressure (BP) response to changes in altitude in Himalayan trekkers with and without hypertension (HTN). Methods: BP was measured in Lukla (2800m), Namche (3400m), and either Pheriche or Dingboche (4400m) on ascent and descent. Hypertensive subjects were defined by self-reported diagnosis of HTN. Results: Trekkers had HTN (H, n=60) or no HTN (NH, n=604). Of those with HTN, 50 (83%) took one or more BP medications including ACEIs/ARBs (n=35, 48%), Ca++ channel blockers (n=15, 22%), beta-blockers (n=9, 13%), thiazide diuretics (n=7, 10%), and others (n=5, 7%). At 2800m, systolic BP (SBP) and diastolic BP (DBP) were greater in the H group than in the NH group [mean SBP= 151mmHg (95% CI 145.4-155.7) vs 127mmHg (95% CI 125.5 128.0); mean DBP=88mmHg (95% CI 85.1-91.7) vs 80mmHg (95% CI 79.3-80.8)] and remained higher at both 3400m [mean SBP=150mmHg (95% CI 143.7-156.9) vs 127mmHg (95% CI 125.8-128.5); mean DBP=88mmHg (95% CI 84.3-90.8) vs 82mmHg (95% CI 80.7-82.5)] and 4400m [mean SBP=144mmHg (95% CI 136.7-151.7) vs 128mmHg (95% CI 126.4-129.5); mean DBP=87mmHg (95% CI 83.2-91.7) vs 82mmHg (95% CI 81.3-83.2)]. Between 2800m and 3400m, BP increased in 37% of trekkers, decreased in 25%, and did not change in 38%; from 3400m to 4400m, BP increased in 35% of trekkers, decreased in 26%, and did not change in 40%. Prevalence of severe hypertension (BP\u3e180/120mmHg) was similar across altitudes but higher in the H group (9%; 10%; 8% vs 0.7%; 0.6%, 0.3%) at 2800m, 3400m, and 4400m, respectively. No subjects reported symptoms of hypertensive emergency (chest pain, stroke, etc.). Conclusion: Blood pressure response to altitude is variable. High prevalence of severe hypertension in hypertensive trekkers warrants further study regarding BP control at high altitude

Evolutionary conservation of regulated longevity assurance mechanisms

Short abstract: A multi-level cross-species comparative analysis of gene-expression changes accompanying increased longevity in mutant nematodes, fruit flies and mice with reduced insulin/IGF-1 signaling revealed candidate conserved mechanisms

A Decline in p38 MAPK Signaling Underlies Immunosenescence in Caenorhabditis elegans

The decline in immune function with aging, known as immunosenescence, has been implicated in evolutionarily diverse species, but the underlying molecular mechanisms are not understood. During aging in Caenorhabditis elegans, intestinal tissue deterioration and the increased intestinal proliferation of bacteria are observed, but how innate immunity changes during C. elegans aging has not been defined. Here we show that C. elegans exhibits increased susceptibility to bacterial infection with age, and we establish that aging is associated with a decline in the activity of the conserved PMK-1 p38 mitogen-activated protein kinase pathway, which regulates innate immunity in C. elegans. Our data define the phenomenon of innate immunosenescence in C. elegans in terms of the age-dependent dynamics of the PMK-1 innate immune signaling pathway, and they suggest that a cycle of intestinal tissue aging, immunosenescence, and bacterial proliferation leads to death in aging C. elegans

DAF-16/FoxO directly regulates an atypical AMP-activated protein kinase gamma isoform to mediate the effects of insulin/IGF-1 signaling on aging in Caenorhabditis elegans

The DAF-16/FoxO transcription factor controls growth, metabolism and aging in Caenorhabditis elegans. The large number of genes that it regulates has been an obstacle to understanding its function. However, recent analysis of transcript and chromatin profiling implies that DAF-16 regulates relatively few genes directly, and that many of these encode other regulatory proteins. We have investigated the regulation by DAF-16 of genes encoding the AMP-activated protein kinase (AMPK), which has ?, ? and ? subunits. C. elegans has 5 genes encoding putative AMP-binding regulatory ? subunits, aakg-1-5. aakg-4 and aakg-5 are closely related, atypical isoforms, with orthologs throughout the Chromadorea class of nematodes. We report that ?75% of total ? subunit mRNA encodes these 2 divergent isoforms, which lack consensus AMP-binding residues, suggesting AMP-independent kinase activity. DAF-16 directly activates expression of aakg-4, reduction of which suppresses longevity in daf-2 insulin/IGF-1 receptor mutants. This implies that an increase in the activity of AMPK containing the AAKG-4 ? subunit caused by direct activation by DAF-16 slows aging in daf-2 mutants. Knock down of aakg-4 expression caused a transient decrease in activation of expression in multiple DAF-16 target genes. This, taken together with previous evidence that AMPK promotes DAF-16 activity, implies the action of these two metabolic regulators in a positive feedback loop that accelerates the induction of DAF-16 target gene expression. The AMPK ? subunit, aakb-1, also proved to be up-regulated by DAF-16, but had no effect on lifespan. These findings reveal key features of the architecture of the gene-regulatory network centered on DAF-16, and raise the possibility that activation of AMP-independent AMPK in nutritionally replete daf-2 mutant adults slows aging in C. elegans. Evidence of activation of AMPK subunits in mammals suggests that such FoxO-AMPK interactions may be evolutionarily conserved

A plasmid DNA-launched SARS-CoV-2 reverse genetics system and coronavirus toolkit for COVID-19 research

The recent emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the underlying cause of Coronavirus Disease 2019 (COVID-19), has led to a worldwide pandemic causing substantial morbidity, mortality, and economic devastation. In response, many laboratories have redirected attention to SARS-CoV-2, meaning there is an urgent need for tools that can be used in laboratories unaccustomed to working with coronaviruses. Here we report a range of tools for SARS-CoV-2 research. First, we describe a facile single plasmid SARS-CoV-2 reverse genetics system that is simple to genetically manipulate and can be used to rescue infectious virus through transient transfection (without in vitro transcription or additional expression plasmids). The rescue system is accompanied by our panel of SARS-CoV-2 antibodies (against nearly every viral protein), SARS-CoV-2 clinical isolates, and SARS-CoV-2 permissive cell lines, which are all openly available to the scientific community. Using these tools, we demonstrate here that the controversial ORF10 protein is expressed in infected cells. Furthermore, we show that the promising repurposed antiviral activity of apilimod is dependent on TMPRSS2 expression. Altogether, our SARS-CoV-2 toolkit, which can be directly accessed via our website at https://mrcppu-covid.bio/, constitutes a resource with considerable potential to advance COVID-19 vaccine design, drug testing, and discovery science

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Identification of ATF-7 and the insulin signaling pathway in the regulation of metallothionein in C. elegans suggests roles in aging and reactive oxygen species.

It has been proposed that aging results from the lifelong accumulation of intracellular damage via reactions with reactive oxygen species (ROS). Metallothioneins are conserved cysteine-rich proteins that function as efficient ROS scavengers and may affect longevity. To better understand mechanisms controlling metallothionein expression, the regulatory factors and pathways that controlled cadmium-inducible transcription of the C. elegans metallothionein gene, mtl-1, were identified. The transcription factor ATF-7 was identified in both ethylmethanesulfonate mutagenesis and candidate gene screens. PMK-1 and members of the insulin signaling pathway, PDK-1 and AKT-1/2, were also identified as mtl-1 regulators. Genetic and previous results support a model for the regulation of cadmium-inducible mtl-1 transcription based on the derepression of the constitutively active transcription factor ELT-2. In addition, knockdown of the mammalian homologs of PDK1 and ATF7 in HEK293 cells resulted in changes in metallothionein expression, suggesting that this pathway was evolutionarily conserved. The insulin signaling pathway is known to influence the aging process; however, various factors responsible for affecting the aging phenotype are unknown. Identification of portions of the insulin signaling pathway as regulators of metallothionein expression supports the hypothesis that longevity is affected by the expression of this efficient ROS scavenger

Role of ATF-7 in regulating <i>mtl-1</i> transcription.

<p>(A) Effect of 10 μM cadmium exposure for 24 h on wild type (p<i>mtl-1</i>::<i>GFP</i>) and two <i>C</i>. <i>elegans</i> stains containing mutant alleles of <i>atf-7</i> (p<i>mtl-1</i>::<i>GFP</i>;<i>atf-7(gk715)</i> and p<i>mtl-1</i>::<i>GFP</i>;<i>atf-7(mt15)</i>) on GFP expression. (B) <i>atf-7</i> gene x cadmium interaction factors were determined by comparing changes in <i>mtl-1</i> mRNA levels after exposure to 100 μM cadmium for 1 (<i>dark gray</i>) h or 5 (<i>light gray</i>) h. * <i>p</i> < 0.05.</p