Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic ...analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains. Multiple functional gene clusters were identified, and full genome-to-genome comparison demonstrated a significant conservation in longevity pathways between yeast and C. elegans. Among the mechanisms of aging identified, deletion of tRNA exporter LOS1 robustly extended lifespan. Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude Los1 from the nucleus in a Rad53-dependent manner. Moreover, lifespan extension from deletion of LOS1 is nonadditive with DR or mTOR inhibition, and results in Gcn4 transcription factor activation. Thus, the DNA damage response and mTOR converge on Los1-mediated nuclear tRNA export to regulate Gcn4 activity and aging.
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•4,698 deletions tested yields the most comprehensive yeast data set on aging•Longevity clusters center on known, conserved biological processes•Enrichment of lifespan-extending C. elegans orthologs suggests conservation•Genome-wide information uncovered aging pathways such as tRNA transport
Analysis of 4,698 viable yeast single-gene deletion strains yielded 238 with increased lifespan, in multiple functional groups, showing a significant conservation in longevity pathways between yeast and C. elegans. Deletion of tRNA exporter LOS1 extended lifespan; DNA damage response and mTOR converge on Los1-mediated tRNA export to regulate Gcn4 activity.
Abstract
Background
In the context of the COVID-19 pandemic, social science research has required recruiting many prospective participants. Many researchers have explicitly taken advantage of ...widespread public interest in COVID-19 to advertise their studies. Leveraging this interest, however, risks creating unrepresentative samples due to differential interest in the topic. In this study, we investigate the design of survey recruitment materials with respect to the views of resultant participants.
Methods
Within a pan-Canadian survey (stratified random mail sampling,
n
= 1969), the design of recruitment invitations to prospective respondents was experimentally varied, with some prospective respondents receiving COVID-specific recruitment messages and others receiving more general recruitment messages (described as research about health and health policy). All respondents participated, however, in the same survey, allowing comparison of both demographic and attitudinal features between these groups.
Results
Respondents recruited via COVID-19 specific postcards were more likely to agree that COVID-19 is serious and believe that they were likely to contract COVID-19 compared to non-COVID respondents (odds = 0.71,
p
= 0.04; odds = 0.74,
p
= 0.03 respectively; comparing health to COVID-19 framed respondents). COVID-19 specific respondents were more likely to disagree that the COVID-19 threat was exaggerated compared to the non-COVID survey respondents (odds = 1.44,
p
= 0.02).
Conclusions
COVID-19 recruitment framing garnered a higher response rate, as well as a sample with greater concern about coronavirus risks and impacts than respondents who received more neutrally framed recruitment materials.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Calorie restriction increases life span in many organisms, including the budding yeast Saccharomyces cerevisiae. From a large-scale analysis of 564 single-genedeletion strains of yeast, we identified ...10 gene deletions that increase replicative life span. Six of these correspond to genes encoding components of the nutrient-responsive TOR and Sch9 pathways. Calorie restriction of tor1Δ or sch9Δ cells failed to further increase life span and, like calorie restriction, deletion of either SCH9 or TOR1 increased life span independent of the Sir2 histone deacetylase. We propose that the TOR and Sch9 kinases define a primary conduit through which excess nutrient intake limits longevity in yeast.
We sought to determine whether temporal changes in the lower airway microbiome are associated with ventilator-associated pneumonia (VAP) in children.Using a multicentre prospective study of children ...aged 31 days to 18 years requiring mechanical ventilation support for >72 h, daily tracheal aspirates were collected and analysed by sequencing of the 16S rRNA gene. VAP was assessed using 2008 Centers for Disease Control and Prevention paediatric criteria. The association between microbial factors and VAP was evaluated using joint longitudinal time-to-event modelling, matched case-control comparisons and unsupervised clustering.Out of 366 eligible subjects, 66 (15%) developed VAP at a median of 5 (interquartile range 3-5) days post intubation. At intubation, there was no difference in total bacterial load (TBL), but Shannon diversity and the relative abundance of
, Lactobacillales and
were lower for VAP subjects
non-VAP subjects. However, higher TBL on each sequential day was associated with a lower hazard (hazard ratio 0.39, 95% CI 0.23-0.64) for developing VAP, but sequential values of diversity were not associated with VAP. Similar findings were observed from the matched analysis and unsupervised clustering. The most common dominant VAP pathogens included
species (19%),
(14%) and
/
(10%).
and
were also identified as dominant organisms in several subjects.In mechanically ventilated children, changes over time in microbial factors were marginally associated with VAP risk, although these changes were not suitable for predicting VAP in individual patients. These findings suggest that focusing exclusively on pathogen burden may not adequately inform VAP diagnosis.
Antibiotics are a known cause of idiosyncratic drug‐induced liver injury (DILI). According to the Centers for Disease Control and Prevention, the five most commonly prescribed antibiotics in the ...United States are azithromycin, ciprofloxacin, cephalexin, amoxicillin, and amoxicillin‐clavulanate. We quantified the frequency of acute DILI for these common antibiotics in the All of Us Research Program, one of the largest electronic health record (EHR)‐linked research cohorts in the United States. Retrospective analyses were conducted applying a standardized phenotyping algorithm to de‐identified clinical data available in the All of Us database for 318,598 study participants. Between February 1984 and December 2022, more than 30% of All of Us participants (n = 119,812 individuals) had been exposed to at least 1 of our 5 study drugs. Initial screening identified 591 potential case patients that met our preselected laboratory‐based phenotyping criteria. Because DILI is a diagnosis of exclusion, we then used phenome scanning to narrow the case counts by (i) scanning all EHRs to identify all alternative diagnostic explanations for the laboratory abnormalities, and (ii) leveraging International Classification of Disease 9th revision (ICD)‐9 and ICD 10th revision (ICD)‐10 codes as exclusion criteria to eliminate misclassification. Our final case counts were 30 DILI cases with amoxicillin‐clavulanate, 24 cases with azithromycin, 24 cases with ciprofloxacin, 22 cases with amoxicillin alone, and < 20 cases with cephalexin. These findings demonstrate that data from EHR‐linked research cohorts can be efficiently mined to identify DILI cases related to the use of common antibiotics.
Scientific institutions are increasingly embracing values of inclusivity and public engagement, but how do these two dimensions intersect? Science festivals have rapidly expanded in recent years as ...an outgrowth of these values, aiming to engage and educate the public about scientific topics and research. While resources invested in public engagement by scientists, universities, and governments are admirable in principle; this study indicates that their ambition to broaden the reach of science may be going unrealized in practice. Using data from three major UK science festivals, we demonstrate such events are disproportionately reaching economically privileged and educated audiences already invested in science, as opposed to diverse and broadly representative samples of the general public. Our results demonstrate that these science festivals are falling short of their aims to make science accessible to a broad audience. There is a clear need for improved practices and on-going evaluation to ensure science festivals include those who are not already scientifically converted.
Resveratrol, a small molecule found in red wine, is reported to slow aging in simple eukaryotes and has been suggested as a potential calorie restriction mimetic. Resveratrol has also been reported ...to act as a sirtuin activator, and this property has been proposed to account for its anti-aging effects. We show here that resveratrol is a substrate-specific activator of yeast Sir2 and human SirT1. In particular, we observed that, in vitro, resveratrol enhances binding and deacetylation of peptide substrates that contain Fluor de Lys, a non-physiological fluorescent moiety, but has no effect on binding and deacetylation of acetylated peptides lacking the fluorophore. Consistent with these biochemical data we found that in three different yeast strain backgrounds, resveratrol has no detectable effect on Sir2 activity in vivo, as measured by rDNA recombination, transcriptional silencing near telomeres, and life span. In light of these findings, the mechanism accounting for putative longevity effects of resveratrol should be reexamined.
Shewanella oneidensis MR-1 produced electrically conductive pilus-like appendages called bacterial nanowires in direct response to electron-acceptor limitation. Mutants deficient in genes for c-type ...decaheme cytochromes MtrC and OmcA, and those that lacked a functional Type II secretion pathway displayed nanowires that were poorly conductive. These mutants were also deficient in their ability to reduce hydrous ferric oxide and in their ability to generate current in a microbial fuel cell. Nanowires produced by the oxygenic phototrophic cyanobacterium Synechocystis PCC6803 and the thermophilic, fermentative bacterium Pelotomaculum thermopropionicum reveal that electrically conductive appendages are not exclusive to dissimilatory metal-reducing bacteria and may, in fact, represent a common bacterial strategy for efficient electron transfer and energy distribution.
There have been many advances in our knowledge about different aspects of P2Y receptor signaling since the last review published by our International Union of Pharmacology subcommittee. More receptor ...subtypes have been cloned and characterized and most orphan receptors de-orphanized, so that it is now possible to provide a basis for a future subdivision of P2Y receptor subtypes. More is known about the functional elements of the P2Y receptor molecules and the signaling pathways involved, including interactions with ion channels. There have been substantial developments in the design of selective agonists and antagonists to some of the P2Y receptor subtypes. There are new findings about the mechanisms underlying nucleotide release and ectoenzymatic nucleotide breakdown. Interactions between P2Y receptors and receptors to other signaling molecules have been explored as well as P2Y-mediated control of gene transcription. The distribution and roles of P2Y receptor subtypes in many different cell types are better understood and P2Y receptor-related compounds are being explored for therapeutic purposes. These and other advances are discussed in the present review.
Objective To investigate the impact of an early emergency department (ED) protocol-driven resuscitation (septic shock protocol SSP) on the incidence of acute kidney injury (AKI). Study design This ...was a retrospective pediatric cohort with clinical sepsis admitted to the pediatric intensive care unit (PICU) from the ED before (2009, PRE) and after (2010, POST) implementation of the SSP. AKI was defined by pRIFLE (pediatric version of the Risk of renal dysfunction; Injury to kidney; Failure of kidney function; Loss of kidney function, End-stage renal disease creatinine criteria). Results A total of 202 patients (PRE, n = 98; POST, n = 104) were included (53% male, mean age 7.7 ± 5.6 years, mean Pediatric Logistic Organ Dysfunction PELOD 8.9 ± 12.7, mean Pediatric Risk of Mortality score 5.3 ± 13.9). There were no differences in demographics or illness severity between the PRE and POST groups. POST was associated with decreased AKI (54% vs 29%, P < .001), renal-replacement therapy (4 vs 0, P = .04), PICU, and hospital lengths of stay (LOS) (1.9 ± 2.3 vs 4.5 ± 7.6, P < .01; 6.3 ± 5.1 vs 15.3 ± 16.9, P < .001, respectively), and mortality (10% vs 3%, P = .037). The SSP was independently associated with decreased AKI when we controlled for age, sex, and PELOD (OR 0.27, CI 0.13-0.56). In multivariate analyses, the SSP was independently associated with shorter PICU and hospital LOS when we controlled for AKI and PELOD ( P = .02, P < .001, respectively). Conclusion A protocol-driven implementation of a resuscitation bundle in the pediatric ED decreased AKI and need for renal-replacement therapy, as well as PICU and hospital LOS and mortality.