Genomic RNA Elements Drive Phase Separation of the SARS-CoV-2 Nucleocapsid.

We report that the SARS-CoV-2 nucleocapsid protein (N-protein) undergoes liquid-liquid phase separation (LLPS) with viral RNA. N-protein condenses with specific RNA genomic elements under physiological buffer conditions and condensation is enhanced at human body temperatures (33°C and 37°C) and reduced at room temperature (22°C). RNA sequence and structure in specific genomic regions regulate N-protein condensation while other genomic regions promote condensate dissolution, potentially preventing aggregation of the large genome. At low concentrations, N-protein preferentially crosslinks to specific regions characterized by single-stranded RNA flanked by structured elements and these features specify the location, number, and strength of N-protein binding sites (valency). Liquid-like N-protein condensates form in mammalian cells in a concentration-dependent manner and can be altered by small molecules. Condensation of N-protein is RNA sequence and structure specific, sensitive to human body temperature, and manipulatable with small molecules, and therefore presents a screenable process for identifying antiviral compounds effective against SARS-CoV-2.

Decoding disease: from genomes to networks to phenotypes.

Interpreting the effects of genetic variants is key to understanding individual susceptibility to disease and designing personalized therapeutic approaches. Modern experimental technologies are enabling the generation of massive compendia of human genome sequence data and associated molecular and phenotypic traits, together with genome-scale expression, epigenomics and other functional genomic data. Integrative computational models can leverage these data to understand variant impact, elucidate the effect of dysregulated genes on biological pathways in specific disease and tissue contexts, and interpret disease risk beyond what is feasible with experiments alone. In this Review, we discuss recent developments in machine learning algorithms for genome interpretation and for integrative molecular-level modelling of cells, tissues and organs relevant to disease. More specifically, we highlight existing methods and key challenges and opportunities in identifying specific disease-causing genetic variants and linking them to molecular pathways and, ultimately, to disease phenotypes.

A platform to induce and mature biomolecular condensates using chemicals and light.

Biomolecular condensates are membraneless compartments that impart spatial and temporal organization to cells. Condensates can undergo maturation, transitioning from dynamic liquid-like states into solid-like states associated with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Huntington's disease. Despite their important roles, many aspects of condensate biology remain incompletely understood, requiring tools for acutely manipulating condensate-relevant processes within cells. Here we used the BCL6 BTB domain and its ligands BI-3802 and BI-3812 to create a chemical genetic platform, BTBolig, allowing inducible condensate formation and dissolution. We also developed optogenetic and chemical methods for controlled induction of condensate maturation, where we surprisingly observed recruitment of chaperones into the condensate core and formation of dynamic biphasic condensates. Our work provides insights into the interaction of condensates with proteostasis pathways and introduces a suite of chemical-genetic approaches to probe the role of biomolecular condensates in health and disease.

Neural Speech Tracking Highlights the Importance of Visual Speech in Multi-speaker Situations.

Visual speech plays a powerful role in facilitating auditory speech processing and has been a publicly noticed topic with the wide usage of face masks during the COVID-19 pandemic. In a previous magnetoencephalography study, we showed that occluding the mouth area significantly impairs neural speech tracking. To rule out the possibility that this deterioration is because of degraded sound quality, in the present follow-up study, we presented participants with audiovisual (AV) and audio-only (A) speech. We further independently manipulated the trials by adding a face mask and a distractor speaker. Our results clearly show that face masks only affect speech tracking in AV conditions, not in A conditions. This shows that face masks indeed primarily impact speech processing by blocking visual speech and not by acoustic degradation. We can further highlight how the spectrogram, lip movements and lexical units are tracked on a sensor level. We can show visual benefits for tracking the spectrogram especially in the multi-speaker condition. While lip movements only show additional improvement and visual benefit over tracking of the spectrogram in clear speech conditions, lexical units (phonemes and word onsets) do not show visual enhancement at all. We hypothesize that in young normal hearing individuals, information from visual input is less used for specific feature extraction, but acts more as a general resource for guiding attention.

Modeling transcriptional regulation of model species with deep learning.

To enable large-scale analyses of transcription regulation in model species, we developed DeepArk, a set of deep learning models of the cis-regulatory activities for four widely studied species: Caenorhabditis elegans, Danio rerio, Drosophila melanogaster, and Mus musculus DeepArk accurately predicts the presence of thousands of different context-specific regulatory features, including chromatin states, histone marks, and transcription factors. In vivo studies show that DeepArk can predict the regulatory impact of any genomic variant (including rare or not previously observed) and enables the regulatory annotation of understudied model species.

Modeling molecular development of breast cancer in canine mammary tumors.

Understanding the changes in diverse molecular pathways underlying the development of breast tumors is critical for improving diagnosis, treatment, and drug development. Here, we used RNA-profiling of canine mammary tumors (CMTs) coupled with a robust analysis framework to model molecular changes in human breast cancer. Our study leveraged a key advantage of the canine model, the frequent presence of multiple naturally occurring tumors at diagnosis, thus providing samples spanning normal tissue and benign and malignant tumors from each patient. We showed human breast cancer signals, at both expression and mutation level, are evident in CMTs. Profiling multiple tumors per patient enabled by the CMT model allowed us to resolve statistically robust transcription patterns and biological pathways specific to malignant tumors versus those arising in benign tumors or shared with normal tissues. We showed that multiple histological samples per patient is necessary to effectively capture these progression-related signatures, and that carcinoma-specific signatures are predictive of survival for human breast cancer patients. To catalyze and support similar analyses and use of the CMT model by other biomedical researchers, we provide FREYA, a robust data processing pipeline and statistical analyses framework.

Food security status and cardiometabolic health by sex/gender and race/ethnicity among adults in the United States.

BACKGROUND: Minoritized racial/ethnic groups and women in the United States (US) are disproportionately burdened by food insecurity, which likely contributes to disparities in cardiovascular health (CVH). Disparities are projected to widen due to the worsening climate crisis that is straining the agricultural system including food supplies. Nonetheless, studies have not investigated the relationship between food security status and 'ideal' CVH in a large, nationally-representative and racially/ethnically diverse US sample. METHODS AND RESULTS: We investigated household food security status in relation to 'ideal' CVH among US adults (N = 157,001) using 2014-2018/2020 National Health Interview Survey data. Food security status was defined as very low, low, marginal, or high. A summed score of 4 health behaviors and 3 clinical factors totaling 7 different measures was dichotomized (yes/no) to assess modified 'ideal' CVH (mICVH). Using Poisson regression with robust variance, we estimated prevalence ratios (PRs) and 95% CIs of mICVH by household food security status. We stratified models by sex/gender and race/ethnicity. Very low food security prevalence was higher among non-Hispanic (NH)-Black (8.0%) compared to Hispanic/Latinx (5.1%), NH-White (3.1%) and NH-Asian (1.7%) adults. The association between very low versus high food security and mICVH was stronger among women (PR = 0.23 [95% CI: 0.17-0.31]) than men (PR = 0.48 [95% CI: 0.35-0.66]). Compared to NH-White adults with high food security, racially/ethnically minoritized groups with very low to high food security were generally less likely (range: [PRvery low = 0.25[95% CI: 0.14-0.44] - [PRhigh = 0.88 [95% CI: 0.79-0.97]) to meet mICVH criteria. CONCLUSIONS: Food insecurity was associated with lower mICVH prevalence and racially/ethnically minoritized groups were disproportionately burdened.

Multiple forms of perceived job discrimination and hypertension risk among employed women: Findings from the Sister Study.

BACKGROUND: Hypertension has been linked to socially patterned stressors, including discrimination. Few studies have quantified the risk of hypertension associated with exposure to perceived job discrimination. METHODS: We used prospective cohort data from the Sister Study (enrollment from 2003-2009) to estimate self-reported incident hypertension associated with perceived job discrimination based on race, gender, age, sexual orientation, or health status. Job discrimination in the prior 5 years was assessed in 2008-2012, and incident doctor-diagnosed hypertension was ascertained in previously hypertension-free participants. RESULTS: Among the 16,770 eligible participants aged 37-78 years at the start of follow-up, 10.5% reported job discrimination in the past 5 years, and 19.2% (n = 3226) reported incident hypertension during a median follow-up of 9.7 years (interquartile range 8.2-11.0 years). Self-reported poor health or inclusion in minoritized groups based on race/ethnicity or sexual orientation were more frequent among those reporting job discrimination. In a Cox proportional hazards model adjusting for covariates, report of at least one type of job discrimination (compared to none) was associated with a 14% (hazard ratio = 1.14 [95% confidence: 1.02-1.27]) higher hypertension risk. Results from sensitivity analyses reinforced the findings. CONCLUSIONS: Results suggest that interventions addressing job discrimination could have workplace equity and health benefits.

Sleep-Disordered Breathing and Cardiac Arrhythmias in Adults: Mechanistic Insights and Clinical Implications: A Scientific Statement From the American Heart Association.

Sleep-disordered breathing (SDB), characterized by specific underlying physiological mechanisms, comprises obstructive and central pathophysiology, affects nearly 1 billion individuals worldwide, and is associated with excessive cardiopulmonary morbidity. Strong evidence implicates SDB in cardiac arrhythmogenesis. Immediate consequences of SDB include autonomic nervous system fluctuations, recurrent hypoxia, alterations in carbon dioxide/acid-base status, disrupted sleep architecture, and accompanying increases in negative intrathoracic pressures directly affecting cardiac function. Day-night patterning and circadian biology of SDB-induced pathophysiological sequelae collectively influence the structural and electrophysiological cardiac substrate, thereby creating an ideal milieu for arrhythmogenic propensity. Cohort studies support strong associations of SDB and cardiac arrhythmia, with evidence that discrete respiratory events trigger atrial and ventricular arrhythmic events. Observational studies suggest that SDB treatment reduces atrial fibrillation recurrence after rhythm control interventions. However, high-level evidence from clinical trials that supports a role for SDB intervention on rhythm control is not available. The goals of this scientific statement are to increase knowledge and awareness of the existing science relating SDB to cardiac arrhythmias (atrial fibrillation, ventricular tachyarrhythmias, sudden cardiac death, and bradyarrhythmias), synthesizing data relevant for clinical practice and identifying current knowledge gaps, presenting best practice consensus statements, and prioritizing future scientific directions. Key opportunities identified that are specific to cardiac arrhythmia include optimizing SDB screening, characterizing SDB predictive metrics and underlying pathophysiology, elucidating sex-specific and background-related influences in SDB, assessing the role of mobile health innovations, and prioritizing the conduct of rigorous and adequately powered clinical trials.

Cystic fibrosis macrophage function and clinical outcomes after elexacaftor/tezacaftor/ivacaftor.

BACKGROUND: Abnormal macrophage function caused by dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is a critical contributor to chronic airway infections and inflammation in people with cystic fibrosis (PWCF). Elexacaftor/tezacaftor/ivacaftor (ETI) is a new CFTR modulator therapy for PWCF. Host-pathogen and clinical responses to CFTR modulators are poorly described. We sought to determine how ETI impacts macrophage CFTR function, resulting effector functions and relationships to clinical outcome changes. METHODS: Clinical information and/or biospecimens were obtained at ETI initiation and 3, 6, 9 and 12 months post-ETI in 56 PWCF and compared with non-CF controls. Peripheral blood monocyte-derived macrophages (MDMs) were isolated and functional assays performed. RESULTS: ETI treatment was associated with increased CF MDM CFTR expression, function and localisation to the plasma membrane. CF MDM phagocytosis, intracellular killing of CF pathogens and efferocytosis of apoptotic neutrophils were partially restored by ETI, but inflammatory cytokine production remained unchanged. Clinical outcomes including increased forced expiratory volume in 1 s (+10%) and body mass index (+1.0 kg·m-2) showed fluctuations over time and were highly individualised. Significant correlations between post-ETI MDM CFTR function and sweat chloride levels were observed. However, MDM CFTR function correlated with clinical outcomes better than sweat chloride. CONCLUSION: ETI is associated with unique changes in innate immune function and clinical outcomes.

Perceived neighborhood social cohesion and type 2 diabetes mellitus by age, sex/gender, and race/ethnicity in the United States.

In prior research, perceived low neighborhood social cohesion (nSC) has been associated with prevalence of type 2 diabetes mellitus (T2DM); however, few studies have investigated the nSC-T2DM relationship among a large, racially/ethnically diverse, and nationally representative sample of the U.S. population. We used National Health Interview Survey (2013-2018) data to determine overall, age-, sex/gender-, and racial/ethnic-specific associations between nSC and T2DM among 170,432 adults. Self-reported nSC was categorized as low, medium, and high. T2DM was determined by participants being told they had diabetes by a health professional. We used Poisson regression with robust variance to estimate prevalence ratios (PRs) and 95% confidence intervals (CI) while adjusting for confounders. Mean age was 47.4 ±â€¯0.1 years, 52% were women, and 69% self-identified as Non-Hispanic (NH)-White. Low vs. high nSC was associated with a higher prevalence of T2DM (PR = 1.22 [95% CI: 1.16-1.27]), after adjustment. A higher prevalence of T2DM was observed among participants 31-49 years old who perceived low vs. high nSC (PR = 1.36 [95% CI: 1.20-1.54]) and among participants ≥50 years old (PR = 1.18 [95% CI: 1.13-1.24]). Hispanic/Latinx women 18-30 years old in neighborhoods with low vs. high social cohesion had a higher prevalence of T2DM (PR = 3.70 [95% CI: 1.40-9.80]), whereas NH-Black women 18-30 years old in neighborhoods with medium vs. high social cohesion had a lower prevalence of T2DM (PR = 0.35 [95% CI: 0.14-0.89]). Our findings support the literature by demonstrating an association between neighborhood environment and T2DM as well as extend it by identifying determinants for intervention for T2DM.

Knowledge Gaps, Challenges, and Opportunities in Health and Prevention Research for Asian Americans, Native Hawaiians, and Pacific Islanders: A Report From the 2021 National Institutes of Health Workshop.

Asian Americans (AsA), Native Hawaiians, and Pacific Islanders (NHPI) comprise 7.7% of the U.S. population, and AsA have had the fastest growth rate since 2010. Yet the National Institutes of Health (NIH) has invested only 0.17% of its budget on AsA and NHPI research between 1992 and 2018. More than 40 ethnic subgroups are included within AsA and NHPI (with no majority subpopulation), which are highly diverse culturally, demographically, linguistically, and socioeconomically. However, data for these groups are often aggregated, masking critical health disparities and their drivers. To address these issues, in March 2021, the National Heart, Lung, and Blood Institute, in partnership with 8 other NIH institutes, convened a multidisciplinary workshop to review current research, knowledge gaps, opportunities, barriers, and approaches for prevention research for AsA and NHPI populations. The workshop covered 5 domains: 1) sociocultural, environmental, psychological health, and lifestyle dimensions; 2) metabolic disorders; 3) cardiovascular and lung diseases; 4) cancer; and 5) cognitive function and healthy aging. Two recurring themes emerged: Very limited data on the epidemiology, risk factors, and outcomes for most conditions are available, and most existing data are not disaggregated by subgroup, masking variation in risk factors, disease occurrence, and trajectories. Leveraging the vast phenotypic differences among AsA and NHPI groups was identified as a key opportunity to yield novel clues into etiologic and prognostic factors to inform prevention efforts and intervention strategies. Promising approaches for future research include developing collaborations with community partners, investing in infrastructure support for cohort studies, enhancing existing data sources to enable data disaggregation, and incorporating novel technology for objective measurement. Research on AsA and NHPI subgroups is urgently needed to eliminate disparities and promote health equity in these populations.

Invited Commentary: The Need for Repeated Measures and Other Methodological Considerations When Investigating Discrimination as a Contributor to Health.

To determine potential measurement error related to the assessment of lifetime discrimination, Van Dyke et al. (Am J Epidemiol. 2022;191(3):370-378) investigated inconsistencies in reporting of racial, socioeconomic status, and sex discrimination over time among Black and White adults enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The authors found that "ever" reports of discrimination (as assessed by the Experiences of Discrimination Scale) decreased over time and that populations who most experience discrimination (i.e., Black/African-American people, younger persons, persons of low socioeconomic status, and women) were often also the most likely to inconsistently report discrimination over the course of the study period (from 1992 to 2010). The authors have raised an important issue related to the potential underestimation of lifetime discrimination that may depend on when discrimination is assessed, as well as the social identity of individuals surveyed. With implications for health inequities, these findings highlight study design and methodological issues that should be addressed to accurately estimate the true burden discrimination places on health. In this commentary, we further illuminate potential methodological challenges and opportunities to consider when investigating the impact of discrimination on health.

Vitamin D concentrations and breast cancer incidence among Black/African American and non-Black Hispanic/Latina women.

BACKGROUND: Vitamin D may protect against breast cancer. Although Black/African American women and Hispanic/Latina women have lower circulating vitamin D levels than non-Hispanic White women, few studies have examined the association between vitamin D and breast cancer within these racial/ethnic groups. METHODS: The vitamin D-breast cancer association was evaluated using a case-cohort sample of self-identified Black/African American and non-Black Hispanic/Latina women participating in the US-wide Sister Study cohort. Circulating 25-hydroxyvitamin D (25(OH)D) and 24,25-dihydroxyvitamin D (24,25(OH)2D) were measured using liquid chromatography-tandem mass spectrometry in blood samples collected at the baseline from 415 women (290 Black/African American women and 125 non-Black Hispanic/Latina women) who developed breast cancer. These were compared to concentrations in 1545 women (1084 Black/African American women and 461 Hispanic/Latina women) randomly selected from the cohort. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Over a mean follow-up of 9.2 years, women with circulating 25(OH)D concentrations above the clinical cut point for deficiency (20.0 ng/mL) had lower breast cancer rates than women with concentrations ≤ 20 ng/mL (HR, 0.79; 95% CI, 0.61-1.02). The inverse association was strongest among Hispanic/Latina women (HR, 0.52; 95% CI, 0.29-0.93), with a weaker association observed among Black/African American women (HR, 0.89; 95% CI, 0.68-1.18; P for heterogeneity = 0.13). There were no clear differences by menopausal status, follow-up time, estrogen receptor status, or invasiveness. Neither 24,25(OH)2 D nor the 24,25(OH)2 D to 25(OH)D ratio were independently associated with breast cancer risk. CONCLUSIONS: This prospective study supports the hypothesis that vitamin D may be protective against breast cancer incidence in women, including non-Black Hispanic/Latina and Black/African American women. LAY SUMMARY: Vitamin D may protect against breast cancer. Although women of color have lower average vitamin D levels than non-Hispanic White women, few studies have considered the role of race/ethnicity. In a sample of self-identified Black/African American and Hispanic/Latina women, we observed that vitamin D concentrations measured in blood were inversely associated with breast cancer, particularly among Latinas. These findings indicate that vitamin D may protect women against breast cancer, including those in racial/ethnic groups with low average circulating levels.

Latent Class Models of Early-life Trauma and Incident Breast Cancer.

BACKGROUND: Psychosocial trauma has been hypothesized to influence breast cancer risk, but little is known about how co-occurring traumas-particularly during early life-may impact incidence. We examine the relationship between multiple measures of early-life trauma and incident breast cancer. METHODS: The Sister Study is a prospective cohort study of US women (n = 50,884; enrollment 2003-2009; ages 35-74). Of 45,961 eligible participants, 3,070 developed invasive breast cancer or ductal carcinoma in situ through 2017. We assessed trauma before age 18 using previously studied measures (cumulative score, individual trauma type, and substantive domain) and a six-class latent variable to evaluate co-occurring traumas. We accounted for missing data using multiple imputation and estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional-hazards models. RESULTS: Approximately 49% of participants reported early-life trauma. Using the latent class variable approach, breast cancer hazard was higher among participants who had sexual trauma or household dysfunction (HR = 1.1; CI = 0.93, 1.3) or moderate (HR = 1.2; CI = 0.99, 1.4) but not high trauma (HR = 0.66; CI = 0.44, 0.99) compared to low trauma. Breast cancer HRs associated with sexual early-life trauma or household dysfunction were elevated for pre- and postmenopausal breast cancer and by estrogen receptor status. We found no effect modification by race-ethnicity. Estimated effects were attenuated with report of constant childhood social support. CONCLUSIONS: Breast cancer incidence varied by latent patterns of co-occurring early-life trauma. Models capturing childhood social support and trauma patterning, rather than cumulative or discrete indicators, may be more meaningful in breast cancer risk assessment.

Vitamin D Supplement Use and Risk of Breast Cancer by Race-Ethnicity.

BACKGROUND: Vitamin D has anticarcinogenic properties, but a relationship between vitamin D supplement use and breast cancer is not established. Few studies have accounted for changes in supplement use over time or evaluated racial-ethnic differences. METHODS: The Sister Study is a prospective cohort of 50,884 women with 35-74 years of age who had a sister with breast cancer, but no breast cancer themselves at enrollment (2003-2009). We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between vitamin D supplement use and incident breast cancer (3,502 cases; median follow-up 10.5 years). RESULTS: Vitamin D supplement use was common, with 64% reporting ever use (at least once per month) in the year before enrollment. Considering supplement use over time, ever use of vitamin D supplements was not meaningfully associated with breast cancer (HR = 0.96, 95% CI = 0.88, 1.0), relative to never use. However, after adjusting for prior use, recent use of vitamin D supplements ≥1/month was inversely associated with breast cancer (HR = 0.88, 95% CI = 0.78, 1.0), relative to nonrecent use. The inverse association was stronger for ductal carcinoma in situ (HR = 0.67, 95% CI = 0.52, 0.87) than invasive breast cancer (HR = 0.94, 95% CI = 0.72, 1.1, p-for-heterogeneity = 0.02). Supplement use was less common among African American/Black (56%) and non-Black Hispanic/Latina (50%) women than non-Hispanic White women (66%), but there was limited evidence of racial-ethnic differences in HRs (p-for-heterogeneity = 0.16 for ever use, P = 0.55 for recent). CONCLUSIONS: Our findings are consistent with the hypothesis that recent vitamin D use is inversely associated with breast cancer risk.

Research Priorities for Patients with Heart Failure and Central Sleep Apnea. An Official American Thoracic Society Research Statement.

Background: Central sleep apnea (CSA) is common among patients with heart failure and has been strongly linked to adverse outcomes. However, progress toward improving outcomes for such patients has been limited. The purpose of this official statement from the American Thoracic Society is to identify key areas to prioritize for future research regarding CSA in heart failure.Methods: An international multidisciplinary group with expertise in sleep medicine, pulmonary medicine, heart failure, clinical research, and health outcomes was convened. The group met at the American Thoracic Society 2019 International Conference to determine research priority areas. A statement summarizing the findings of the group was subsequently authored using input from all members.Results: The workgroup identified 11 specific research priorities in several key areas: 1) control of breathing and pathophysiology leading to CSA, 2) variability across individuals and over time, 3) techniques to examine CSA pathogenesis and outcomes, 4) impact of device and pharmacological treatment, and 5) implementing CSA treatment for all individualsConclusions: Advancing care for patients with CSA in the context of heart failure will require progress in the arenas of translational (basic through clinical), epidemiological, and patient-centered outcome research. Given the increasing prevalence of heart failure and its associated substantial burden to individuals, society, and the healthcare system, targeted research to improve knowledge of CSA pathogenesis and treatment is a priority.

Neighborhood social cohesion and serious psychological distress among Asian, Black, Hispanic/Latinx, and White adults in the United States: a cross-sectional study.

BACKGROUND: Serious psychological distress (SPD) is common and more prevalent in women, older adults, and individuals with a low-income. Prior studies have highlighted the role of low neighborhood social cohesion (nSC) in potentially contributing to SPD; however, few have investigated this association in a large, nationally representative sample of the United States. Therefore, our objective was to investigate the overall and racial/ethnic-, sex/gender-, self-rated health status-, age-, and household income-specific relationships between nSC and SPD. METHODS: We used data from survey years 2013 to 2018 of the National Health Interview Survey to investigate nSC and SPD among Asian, Non-Hispanic (NH)-Black, Hispanic/Latinx, and NH-White men as well as women in the United States (N = 168,573) and to determine modification by race/ethnicity, sex/gender, self-rated health status, age, and annual household income. nSC was measured by asking participants four questions related to the trustworthiness and dependability of their neighbors. nSC scores were trichotomized into low (< 12), medium (12-14), and high (15-16). SPD was measured using the Kessler 6 psychological distress scale with scores ≥ 13 indicating SPD. After adjusting for sociodemographic, health behavior, and clinical confounders, we used Poisson regression with robust variance to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs). RESULTS: Among 168,573 participants, most were Non-Hispanic (NH)-White (69%), and mean age was 47 ± 0.01 years. After adjustment, low vs. high nSC was associated with a 75% higher prevalence of SPD overall (PR = 1.75 [1.59-1.92]), 4 times the prevalence of SPD among Asian men (PR = 4.06 [1.57-10.50]), 2 times the prevalence of SPD among participants in at least good health (PR = 2.02 [95% CI: 1.74-2.35]), 92% higher prevalence of SPD among participants ≥ 50 years old (PR = 1.92 [1.70-2.18]), and approximately 3 times the prevalence of SPD among Hispanic/Latinx participants with household incomes ≥ $75,000 (PR = 2.97 [1.45-6.08]). CONCLUSIONS: Low nSC was associated with higher SPD in the overall population and the magnitude of the association was higher in Asian men, participants who reported good health, older participants, and Hispanic/Latinx adults with higher household incomes. Future research should continue to examine how neighborhood contexts can affect health across various sociodemographic groups, especially among groups with multiple marginalized social identities.

Accurate genome-wide predictions of spatio-temporal gene expression during embryonic development.

Comprehensive information on the timing and location of gene expression is fundamental to our understanding of embryonic development and tissue formation. While high-throughput in situ hybridization projects provide invaluable information about developmental gene expression patterns for model organisms like Drosophila, the output of these experiments is primarily qualitative, and a high proportion of protein coding genes and most non-coding genes lack any annotation. Accurate data-centric predictions of spatio-temporal gene expression will therefore complement current in situ hybridization efforts. Here, we applied a machine learning approach by training models on all public gene expression and chromatin data, even from whole-organism experiments, to provide genome-wide, quantitative spatio-temporal predictions for all genes. We developed structured in silico nano-dissection, a computational approach that predicts gene expression in >200 tissue-developmental stages. The algorithm integrates expression signals from a compendium of 6,378 genome-wide expression and chromatin profiling experiments in a cell lineage-aware fashion. We systematically evaluated our performance via cross-validation and experimentally confirmed 22 new predictions for four different embryonic tissues. The model also predicts complex, multi-tissue expression and developmental regulation with high accuracy. We further show the potential of applying these genome-wide predictions to extract tissue specificity signals from non-tissue-dissected experiments, and to prioritize tissues and stages for disease modeling. This resource, together with the exploratory tools are freely available at our webserver http://find.princeton.edu, which provides a valuable tool for a range of applications, from predicting spatio-temporal expression patterns to recognizing tissue signatures from differential gene expression profiles.

Use of hair products in relation to ovarian cancer risk.

We evaluated whether hair products, which may contain carcinogens and endocrine disruptors that can be absorbed into the bloodstream, are related to ovarian cancer incidence in a prospective cohort. After excluding women with a history of ovarian cancer or bilateral oophorectomy, 40 559 Sister Study participants ages 35-74 at enrollment (2003-2009) were included. Participants completed questionnaires on hair product use, including hair dyes, straighteners/relaxers and permanents/body waves, in the past 12 months. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between hair products and incident ovarian cancer. We assessed associations stratified by tumor type (serous, non-serous). Over a mean follow-up of 10 years, 241 women were diagnosed with ovarian cancer. Ever use of any of the examined hair products during the past year was not associated with ovarian cancer risk. However, frequent use (>4 times/year) of straighteners/relaxers or pressing products in the past year was associated with an increased risk of ovarian cancer (HR = 2.19, 95% CI: 1.12-4.27). Ever use of permanent hair dye was positively associated with non-serous (HR = 1.94, 95% CI 1.12-3.37), but inversely associated with serous (HR = 0.65, 95% CI: 0.43-0.99) tumors (p-for-heterogeneity = 0.002). Our novel findings suggest that frequent use of hair straighteners/relaxers or pressing products, which are primarily used by African American/Black women, and possibly permanent hair dye, may be associated with the occurrence of ovarian cancers.