Control of intestinal bacterial proliferation in regulation of lifespan in Caenorhabditis elegans

<p>Abstract</p> <p>Background</p> <p>A powerful approach to understanding complex processes such as aging is to use model organisms amenable to genetic manipulation, and to seek relevant phenotypes to measure. <it>Caenorhabditis elegans </it>is particularly suited to studies of aging, since numerous single-gene mutations have been identified that affect its lifespan; it possesses an innate immune system employing evolutionarily conserved signaling pathways affecting longevity. As worms age, bacteria accumulate in the intestinal tract. However, quantitative relationships between worm genotype, lifespan, and intestinal lumen bacterial load have not been examined. We hypothesized that gut immunity is less efficient in older animals, leading to enhanced bacterial accumulation, reducing longevity. To address this question, we evaluated the ability of worms to control bacterial accumulation as a functional marker of intestinal immunity.</p> <p>Results</p> <p>We show that as adult worms age, several <it>C. elegans </it>genotypes show diminished capacity to control intestinal bacterial accumulation. We provide evidence that intestinal bacterial load, regulated by gut immunity, is an important causative factor of lifespan determination; the effects are specified by bacterial strain, worm genotype, and biologic age, all acting in concert.</p> <p>Conclusions</p> <p>In total, these studies focus attention on the worm intestine as a locus that influences longevity in the presence of an accumulating bacterial population. Further studies defining the interplay between bacterial species and host immunity in <it>C. elegans </it>may provide insights into the general mechanisms of aging and age-related diseases.</p

Differences in Demographic, Behavioral, and Biological Variables Between Those With Valid and Invalid Accelerometry Data: Implications for Generalizability

Background: The exclusion of participants with invalid accelerometry data (IAD) may lead to biased results and/or lack of generalizability in large population studies. The purpose of this study was to investigate whether demographic, behavioral, and biological differences occur between those with IAD and valid accelerometry data (VAD) among adults using a representative sample of the civilian noninstitutionalized U.S. population. Methods: Ambulatory participants from NHANES (2003-2004) who were 20-85 years of age were included in the current study and wore an ActiGraph 7164 accelerometer for 7 days. A valid person was defined as those with 4 or more days of at least 10+ hrs of monitoring per day. Among adults (20-85 yrs), 3088 participants provided VAD and 987 provided IAD. Demographic, behavioral, and biological information were obtained from the household interview or from data obtained in a mobile examination center. Results: Differences were observed in age, BMI, ethnicity, education, smoking status, marital status, use of street drugs, current health status, HDL-cholesterol, C-reactive protein, self-reported vigorous physical activity, and plasma glucose levels between those with VAD and IAD. Conclusions: Investigators should take into consideration the potential cut-off bias in interpreting results based on data that excludes IAD participants

Objectively-Measured Physical Activity and C-Reactive Protein: NHANES 2003–2004

The association between physical activity (PA) and C-reactive protein (CRP) is inconsistent, with nearly all studies using self-report measures of PA. The purpose of this study was to examine the association between objectively-measured PA and CRP in U.S. adults and children. Adults (N=2912) and children (N=1643) with valid accelerometer data and CRP data were included in the analyses. Logistic regression analysis was used to assess the odds of meeting physical activity guidelines across CRP quartiles for children and among adults with low, average, and high CRP levels. For adults, after adjustments for age, gender, race, body mass index, smoking, diabetes, and high density lipoprotein cholesterol (HDL-C), compared to those with low CRP levels, odds ratios were 0.59 (CI = 0.45–0.77) and 0.46 (CI = 0.28–0.76) for participants with average and high CRP levels, respectively. For children, after adjustments for age, gender, race, weight status, and HDLC, compared to those in CRP quartile 1, odds ratios were 0.96 (CI = 0.5–1.84), 1.23 (CI = 0.71– 2.12), and 0.79 (CI = 0.33–1.88) for participants in quartiles 2, 3, and 4, respectively. Objectivelymeasured PA is inversely associated with CRP in adults, with PA not related to CRP in children

Ventrolateral Prefrontal Cortex Activation and Attentional Bias in Response to Angry Faces in Adolescents with Generalized Anxiety Disorder

Objective: While adolescent anxiety disorders represent prevalent, debilitating conditions, few studies explore their brain physiology. Using event-related functional MRI (fMRI) and a behavioral measure of attention to angry faces, we evaluated differences in response between healthy adolescents and adolescents with generalized anxiety disorder (GAD). Method: In the primary trials of interest, 18 adolescents with GAD and 15 comparisons of equivalent age/gender/IQ viewed angry/neutral face pairs during fMRI acquisition. Following the presentation of each face pair, subjects pressed a button to a probe that was either on the same (congruent) or opposite (incongruent) side as the angry face. Reaction time differences between congruent and incongruent face-trials provided a measure of attention bias to angry faces. Results: Relative to controls, patients with GAD manifested greater right ventrolateral prefrontal cortex (VLPFC) activation to trials containing angry faces. Compared with controls, patients with GAD also showed greater attentional bias away from angry faces. VLPFC activation differences were independent of differences in attentional bias. Conclusions: Adolescents with GAD show greater right VLPFC activation and attentional bias away from angry faces than controls. Enhanced VLPFC engagement may directly relate to anxiety, or may regulate abnormal functioning in another region

A formative study exploring perceptions of physical activity and physical activity monitoring among children and young people with cystic fibrosis and health care professionals

Background: Physical activity (PA) is associated with reduced hospitalisations and maintenance of lung function in patients with Cystic Fibrosis (CF). PA is therefore recommended as part of standard care. Despite this, there is no consensus for monitoring of PA and little is known about perceptions of PA monitoring among children and young people with CF. Therefore, the research aimed to explore patients’ perceptions of PA and the acceptability of using PA monitoring devices with children and young people with CF. Methods: An action research approach was utilised, whereby findings from earlier research phases informed subsequent phases. Four phases were utilised, including patient interviews, PA monitoring, follow-up patient interviews and health care professional (HCP) interviews. Subsequently, an expert panel discussed the study to develop recommendations for practice and future research. Results: Findings suggest that experiences of PA in children and young people with CF are largely comparable to their non-CF peers, with individuals engaging in a variety of activities. CF was not perceived as a barrier per se, although participants acknowledged that they could be limited by their symptoms. Maintenance of health emerged as a key facilitator, in some cases PA offered patients the opportunity to ‘normalise’ their condition. Participants reported enjoying wearing the monitoring devices and had good compliance. Wrist-worn devices and devices providing feedback were preferred. HCPs recognised the potential benefits of the devices in clinical practice. Recommendations based on these findings are that interventions to promote PA in children and young people with CF should be individualised and involve families to promote PA as part of an active lifestyle. Patients should receive support alongside the PA data obtained from monitoring devices. Conclusions: PA monitoring devices appear to be an acceptable method for objective assessment of PA among children and young people with CF and their clinicians. Wrist-worn devices, which are unobtrusive and can display feedback, were perceived as most acceptable. By understanding the factors impacting PA, CF health professionals will be better placed to support patients and improve health outcomes

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pulmonary Artery Catheter Use&nbsp;and&nbsp;Mortality in the Cardiac&nbsp;Intensive&nbsp;Care Unit.

BACKGROUND: The appropriate use of pulmonary artery catheters (PACs) in critically ill cardiac patients remains debated. OBJECTIVES: The authors aimed to characterize the current use of PACs in cardiac intensive care units (CICUs) with attention to patient-level and institutional factors influencing their application and explore the association with in-hospital mortality. METHODS: The Critical Care Cardiology Trials Network is a multicenter network of CICUs in North America. Between 2017 and 2021, participating centers contributed annual 2-month snapshots of consecutive CICU admissions. Admission diagnoses, clinical and demographic data, use of PACs, and in-hospital mortality were captured. RESULTS: Among 13,618 admissions at 34 sites, 3,827 were diagnosed with shock, with 2,583 of cardiogenic etiology. The use of mechanical circulatory support and heart failure were the patient-level factors most strongly associated with a greater likelihood of the use of a PAC (OR: 5.99 [95%&nbsp;CI: 5.15-6.98]; P&nbsp;&lt; 0.001 and OR: 3.33 [95%&nbsp;CI: 2.91-3.81]; P&nbsp;&lt;&nbsp;0.001, respectively). The proportion of shock admissions with a PAC varied significantly by study center ranging from 8% to 73%. In analyses adjusted for factors associated with their placement, PAC use was associated with lower mortality in all shock patients admitted to a CICU (OR: 0.79 [95%&nbsp;CI: 0.66-0.96]; P = 0.017). CONCLUSIONS: There is wide variation in the use of PACs that is not fully explained by patient level-factors and appears driven in part by institutional tendency. PAC use was associated with higher survival in cardiac patients with shock presenting to CICUs. Randomized trials are needed to guide the appropriate use of PACs in cardiac critical care

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment