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Purpose in life has been linked with better health (mental and physical) and health behaviors, but its link with patterns of health care use are understudied. We hypothesized that people with higher purpose would be more proactive in taking care of their health, as indicated by a higher likelihood of using preventive health care services. We also hypothesized that people with higher purpose would spend fewer nights in the hospital. Participants ( n = 7,168) were drawn from the Health and Retirement Study, a nationally representative panel study of American adults over the age of 50, and tracked for 6 y. After adjusting for sociodemographic factors, each unit increase in purpose (on a six-point scale) was associated with a higher likelihood that people would obtain a cholesterol test [odds ratio (OR) = 1.18, 95% confidence interval (CI) = 1.08–1.29] or colonoscopy (OR = 1.06, 95% CI = 0.99–1.14). Furthermore, females were more likely to receive a mammogram/X-ray (OR = 1.27, 95% CI = 1.16–1.39) or pap smear (OR = 1.16, 95% CI = 1.06–1.28), and males were more likely to receive a prostate examination (OR = 1.31, 95% CI = 1.18–1.45). Each unit increase in purpose was also associated with 17% fewer nights spent in the hospital (rate ratio = 0.83, 95% CI = 0.77–0.89). An increasing number of randomized controlled trials show that purpose in life can be raised. Therefore, with additional research, findings from this study may inform the development of new strategies that increase the use of preventive health care services, offset the burden of rising health care costs, and enhance the quality of life among people moving into the ranks of our aging society. Significance Less than 50% of people over the age of 65 are up-to-date with core preventive services. Identifying modifiable factors linked with preventive services are important targets for research and practice. Purpose in life, recently the focus of multiple intervention studies, has been linked with better health (mental and physical) as well as improved health behaviors. However, its association with health care use has been understudied. We found that higher purpose was linked with greater use of several preventive health care services and also fewer nights spent hospitalized. These results may facilitate the development of new strategies to increase use of preventive health care services and improve health, thereby offsetting the burden of rising health care costs in our aging society.

\"This book presents recent advancements in positive psychology, specifically its application across broad areas of current interest. Chapters include submissions from various international authors in the field and cover discussion and presentation of relevant research, theories, and applications. The volume covers topics such as CBT, Psychotherapy, Coaching, Workplaces, Aging, Education, Leadership, Emotion, Interventions, Measurement, Technology, Design, Health, Relationships, Experiences, Communities. With the growing interest in the applications of positive psychology across diverse fields within psychology and beyond, this book will make a worthwhile contribution to the field. It will also fill the current need for a volume that highlights specifically the various recent advancements in positive psychology into diverse fields and as such will be of benefit to a wide range of professionals, including psychologists, educators, clinicians, therapists, and many others.\" -- Publisher's website.

Defining cellular and molecular identities within the kidney is necessary to understand its organization and function in health and disease. Here we demonstrate a reproducible method with minimal artifacts for single-nucleus Droplet-based RNA sequencing (snDrop-Seq) that we use to resolve thirty distinct cell populations in human adult kidney. We define molecular transition states along more than ten nephron segments spanning two major kidney regions. We further delineate cell type-specific expression of genes associated with chronic kidney disease, diabetes and hypertension, providing insight into possible targeted therapies. This includes expression of a hypertension-associated mechano-sensory ion channel in mesangial cells, and identification of proximal tubule cell populations defined by pathogenic expression signatures. Our fully optimized, quality-controlled transcriptomic profiling pipeline constitutes a tool for the generation of healthy and diseased molecular atlases applicable to clinical samples. Single-cell studies in solid tissues remain challenging and have benefited from the development of single-nuclei RNA sequencing strategies. Here Lake et al. apply single-nucleus RNA sequencing to human kidney tissues to provide a comprehensive molecular and cellular atlas of the human kidney, with potential implications for the understanding of kidney physiology and disease.

Policy Points Several intergovernmental organizations (Organisation for Economic Co‐operation and Development, World Health Organization, United Nations) are urging countries to use well‐being indicators (e.g., life satisfaction) in addition to traditional economic indicators when making important policy decisions. As the number of governments implementing this new approach grows, so does the need to continue evaluating the health and well‐being outcomes we might observe from policies aimed at improving life satisfaction. The results of this study suggest that life satisfaction is a valuable target for policies aiming to enhance several indicators of psychosocial well‐being, health behaviors, and physical health outcomes. Context Several intergovernmental organizations (Organisation for Economic Co‐operation and Development, World Health Organization, United Nations) are urging countries to use well‐being indicators (e.g., life satisfaction) in addition to traditional economic indicators when making important policy decisions. As the number of governments implementing this new approach grows, so does the need to continue evaluating the health and well‐being outcomes we might observe from policies aimed at improving life satisfaction. Methods We evaluated whether positive change in life satisfaction (between t0;2006/2008 and t1;2010/2012) was associated with better outcomes on 35 indicators of physical, behavioral, and psychosocial health and well‐being (in t2;2014/2016). Data were from 12,998 participants in the University of Michigan's Health and Retirement Study—a prospective and nationally representative cohort of US adults over age 50. Findings Participants with the highest (versus lowest) life satisfaction had better subsequent outcomes on some physical health indicators (lower risk of pain, physical functioning limitations, and mortality; lower number of chronic conditions; and higher self‐rated health) and health behaviors (lower risk of sleep problems and more frequent physical activity), and nearly all psychosocial indicators (higher positive affect, optimism, purpose in life, mastery, health mastery, financial mastery, and likelihood of living with spouse/partner; and lower depression, depressive symptoms, hopelessness, negative affect, perceived constraints, and loneliness) over the 4‐year follow‐up period. However, life satisfaction was not subsequently associated with many specific health conditions (i.e., diabetes, hypertension, stroke, cancer, heart disease, lung disease, arthritis, overweight/obesity, or cognitive impairment), other health behaviors (i.e., binge drinking or smoking), or frequency of contact with children, family, or friends. Conclusions These results suggest that life satisfaction is a valuable target for policies aiming to enhance several indicators of psychosocial well‐being, health behaviors, and physical health outcomes.

Protein-protein interactions (PPIs) are ubiquitous biomolecular processes that are central to virtually all aspects of cellular function. Identifying small molecules that modulate specific disease-related PPIs is a strategy with enormous promise for drug discovery. The design of drugs to disrupt PPIs is challenging, however, because many potential drug-binding sites at PPI interfaces are “cryptic”: When unoccupied by a ligand, cryptic sites are often flat and featureless, and thus not readily recognizable in crystal structures, with the geometric and chemical characteristics of typical small-molecule binding sites only emerging upon ligand binding. The rational design of small molecules to inhibit specific PPIs would benefit from a better understanding of how such molecules bind at PPI interfaces. To this end, we have conducted unbiased, all-atom MD simulations of the binding of four small-molecule inhibitors (SP4206 and three SP4206 analogs) to interleukin 2 (IL2)—which performs its function by forming a PPI with its receptor—without incorporating any prior structural information about the ligands’ binding. In multiple binding events, a small molecule settled into a stable binding pose at the PPI interface of IL2, resulting in a protein–small-molecule binding site and pose virtually identical to that observed in an existing crystal structure of the IL2-SP4206 complex. Binding of the small molecule stabilized the IL2 binding groove, which when the small molecule was not bound emerged only transiently and incompletely. Moreover, free energy perturbation (FEP) calculations successfully distinguished between the native and non-native IL2–small-molecule binding poses found in the simulations, suggesting that binding simulations in combination with FEP may provide an effective tool for identifying cryptic binding sites and determining the binding poses of small molecules designed to disrupt PPI interfaces by binding to such sites.

The standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which is typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. Here, we sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis. We applied urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq), a targeted next-generation sequencing (NGS) method for detecting utDNA, to urine cell-free DNA (cfDNA) samples acquired between April 2019 and November 2020 on the day of curative-intent radical cystectomy from 42 patients with localized bladder cancer. The average age of patients was 69 years (range: 50 to 86), of whom 76% (32/42) were male, 64% (27/42) were smokers, and 76% (32/42) had a confirmed diagnosis of MIBC. Among MIBC patients, 59% (19/32) received neoadjuvant chemotherapy. utDNA variant calling was performed noninvasively without prior sequencing of tumor tissue. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. utDNA analysis revealed a median utDNA level of 0% in healthy adults and 2.4% in bladder cancer patients. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (pCR; n = 26), median utDNA levels were 4.3% vs. 0%, respectively (p = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD detection was highly correlated with the absence of pCR (p < 0.001) with a sensitivity of 81% and specificity of 81%. Leave-one-out cross-validation applied to the prediction of pathologic response based on utDNA MRD detection in our cohort yielded a highly significant accuracy of 81% (p = 0.007). Moreover, utDNA MRD-positive patients exhibited significantly worse progression-free survival (PFS; HR = 7.4; 95% CI: 1.4-38.9; p = 0.02) compared to utDNA MRD-negative patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 85%. Tumor mutational burden (TMB) in utDNA MRD-positive patients was inferred from the number of non-silent mutations detected in urine cfDNA by applying a linear relationship derived from The Cancer Genome Atlas (TCGA) whole exome sequencing of 409 MIBC tumors. We suggest that about 58% of these patients with high inferred TMB might have been candidates for treatment with early immune checkpoint blockade. Study limitations included an analysis restricted only to single-nucleotide variants (SNVs), survival differences diminished by surgery, and a low number of DNA damage response (DRR) mutations detected after neoadjuvant chemotherapy at the MRD time point. utDNA MRD detection prior to curative-intent radical cystectomy for bladder cancer correlated significantly with pathologic response, which may help select patients for bladder-sparing treatment. utDNA MRD detection also correlated significantly with PFS. Furthermore, utDNA can be used to noninvasively infer TMB, which could facilitate personalized immunotherapy for bladder cancer in the future.

Several intergovernmental organizations, including the World Health Organization and United Nations, are urging countries to use well-being indicators for policymaking. This trend, coupled with increasing recognition that positive affect is beneficial for health/well-being, opens new avenues for intervening on positive affect to improve outcomes. However, it remains unclear if positive affect in adolescence shapes health/well-being in adulthood. We examined if increases in positive affect during adolescence were associated with better health/well-being in adulthood across 41 outcomes. We conducted a longitudinal cohort study using data from Add Health-a prospective and nationally representative cohort of community-dwelling U.S. adolescents. Using regression models, we evaluated if increases in positive affect over 1 year (between Wave I; 1994 to 1995 and Wave II; 1995 to 1996) were associated with better health/well-being 11.37 years later (in Wave IV; 2008; N = 11,040) or 20.64 years later (in Wave V; 2016 to 2018; N = 9,003). Participants were aged 15.28 years at study onset, and aged 28.17 or 37.20 years-during the final assessment. Participants with the highest (versus lowest) positive affect had better outcomes on 3 (of 13) physical health outcomes (e.g., higher cognition (β = 0·12, 95% CI = 0·05, 0·19, p = 0.002)), 3 (of 9) health behavior outcomes (e.g., lower physical inactivity (RR = 0·80, CI = 0·66, 0·98, p = 0.029)), 6 (of 7) mental health outcomes (e.g., lower anxiety (RR = 0·81, CI = 0·71, 0·93, p = 0.003)), 2 (of 3) psychological well-being (e.g., higher optimism (β = 0·20, 95% CI = 0·12, 0·28, p < 0.001)), 4 (of 7) social outcomes (e.g., lower loneliness (β = -0·09, 95% CI = -0·16, -0·02, p = 0.015)), and 1 (of 2) civic/prosocial outcomes (e.g., more voting (RR = 1·25, 95% CI = 1·16, 1·36, p < 0.001)). Study limitations include potential unmeasured confounding and reverse causality. Enhanced positive affect during adolescence is linked with a range of improved health/well-being outcomes in adulthood. These findings suggest the promise of testing scalable positive affect interventions and policies to more definitively assess their impact on outcomes.

Transcriptome engineering applications in living cells with RNA-targeting CRISPR effectors depend on accurate prediction of on-target activity and off-target avoidance. Here we design and test ~200,000 Rfx Cas13d guide RNAs targeting essential genes in human cells with systematically designed mismatches and insertions and deletions (indels). We find that mismatches and indels have a position- and context-dependent impact on Cas13d activity, and mismatches that result in G–U wobble pairings are better tolerated than other single-base mismatches. Using this large-scale dataset, we train a convolutional neural network that we term targeted inhibition of gene expression via gRNA design (TIGER) to predict efficacy from guide sequence and context. TIGER outperforms the existing models at predicting on-target and off-target activity on our dataset and published datasets. We show that TIGER scoring combined with specific mismatches yields the first general framework to modulate transcript expression, enabling the use of RNA-targeting CRISPRs to precisely control gene dosage. A machine learning model predicts on-target and off-target activity of Cas13d in human cells.

Background Although higher psychological well-being has been linked with a range of positive biological processes and health outcomes, the prospective association between psychological well-being and physical activity among older adults has been understudied. Purpose We tested whether higher baseline psychological well-being predicted higher levels of physical activity over time. Methods Prospective data were from the English Longitudinal Study of Aging, a nationally representative sample of English adults over the age of 50. Our sample included 9986 adults who were assessed up to six times across an average of 11 years. Results After adjusting for sociodemographic factors, each standard deviation increase in baseline psychological well-being was associated with higher median physical activity in linear regression models that examined physical activity across all six waves ( β  = 0.20; 95% confidence interval [CI] 0.18–0.21) and in linear mixed effect models that examined repeated measures of physical activity over the entire follow-up period ( β  = 0.20; 95% CI 0.19–0.21). Further, higher baseline psychological well-being was associated with a slower rate of decline in physical activity among people who were active at baseline (hazard ratio [HR] = 0.79, 95% CI 0.76–0.82) and increasing physical activity among people who were inactive at baseline (HR = 1.28, 95% CI 1.22–1.35). Findings were maintained after adjusting for baseline health status and depression. Conclusions Psychological well-being was independently associated with attaining and maintaining higher physical activity levels over 11 years, suggesting that it may be a valuable target for interventions aimed at helping older adults acquire more physical activity.