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More than 1 in 8 people potentially live with a mental health disorder, yet fewer than half receive treatment. Poor mental health awareness may contribute to this treatment gap, and digital health technologies, like wearables and their associated phone- and web-based applications, have the potential to reduce the mental health awareness gap due to their ease of adoption, objective feedback, and high rate of engagement. This study aimed to better understand the relationships between mental health and objective wearable-derived metrics. We examined the longitudinal results of monthly mental health surveys (Patient Health Questionnaire-2, Generalized Anxiety Disorder 2-item, and Perceived Stress Scale) delivered over 13 months to 181,574 individuals wearing a device (WHOOP, Inc.) that measures sleep, cardiorespiratory parameters, and physical activity (up to 307,860 survey responses and 7,942,176 days of total wear time). Generalized linear mixed models, cross-lag analyses, and intrapersonal scaling were used to assess interpersonal and intrapersonal associations between wearable-derived metrics and mental health outcomes. Age, gender, BMI, and time of year were used as covariates in the models. Interpersonal associations between wearable-derived metrics and mental health outcomes indicate that individuals with better sleep characteristics (ie, longer sleep durations and more consistent wake and sleep times), higher heart rate variabilities (HRV), lower resting heart rates (RHR), and higher levels of physical activity report lower levels of depression, anxiety, and stress. Intrapersonal associations between wearable-derived metrics and mental health outcomes displayed similar results as the between-person analyses, with higher HRVs, lower RHRs, and more physical activity generally coinciding with improved mental health outcomes. However, intrapersonal wearable-derived sleep metric associations diverged from the interpersonal association findings when specifically looking at sleep duration and depression, whereby increased sleep durations within an individual were associated with higher levels of depression. In interpersonal analyses, the largest association observed was between the Perceived Stress Scale scores and RHR, with a standardized coefficient of 0.09 (P<.001); in intrapersonal analyses, the largest association observed was between the Patient Health Questionnaire-2 scores and summated heart rate zones-a proxy for physical activity-with a standardized coefficient of -0.04 (P<.001). Cross-lagged models demonstrated that higher levels of reported stress preceded higher RHRs, respiratory rates, and sleep duration variabilities, as well as lower HRVs. Overall, this investigation reveals that numerous physiological variables measured by wearables are associated with mental state in free-living environments. These findings underscore the potential of wearable-derived physiological and behavioral monitoring to serve as objective complements to traditional subjective assessments in mental health research and care. However, given the complex nature of mental health disorders, further research is needed to determine how these metrics can be effectively integrated into clinical practice.

Wearable devices are increasingly used for health monitoring, yet the impact of consistent wear on physiological and behavioral outcomes is unclear. Leveraging nearly a million days and nights of longitudinal data from 11,914 subscribers, we examined the associations between the frequency of wearing a wrist-worn wearable device (WHOOP Inc., Boston, MA, USA) and 12-week changes in biometric, sleep, and activity profiles, modeling both between- and within-person effects. Higher average wear frequency and week-to-week increases in wear were associated with a lower resting heart rate (RHR), higher heart rate variability (HRV), longer and more consistent sleep, and greater weekly and daily physical activity duration (Ps < 0.01). A within-person multiple mediation analysis indicated that increased sleep duration partially mediated the association between wear frequency and a standardized (z-scored) RHR (indirect effect = −0.0387 [95% CI: −0.0464, −0.0326]), whereas physical activity minutes did not (indirect effect = 0.0003 [95% CI: −0.0036, 0.0040]). A Granger causality analysis revealed a modest but notable association between prior wear frequency and future RHR in participants averaging ≤5 days of weekly wear (p < 0.05 in 10.92% of tests). While further research is needed, our findings provide real-world evidence that sustained wearable engagement may support healthier habits and improved physiological outcomes over time.

Pre-sleep nutrition habits in elite female athletes have yet to be evaluated. A retrospective analysis was performed with 14 NCAA Division I female soccer players who wore a WHOOP, Inc. band - a wearable device that quantifies recovery by measuring sleep, activity, and heart rate metrics through actigraphy and photoplethysmography, respectively - 24 h a day for an entire competitive season to measure sleep and recovery. Pre-sleep food consumption data were collected via surveys every 3 days. Average pre-sleep nutritional intake (mean ± sd: kcals 330 ± 284; cho 46.2 ± 40.5 g; pro 7.6 ± 7.3 g; fat 12 ± 10.5 g) was recorded. Macronutrients and kcals were grouped into high and low categories based upon the 50 percentile of the mean to compare the impact of a high versus low pre-sleep intake on sleep and recovery variables. Sleep duration (  = 0.10, 0.69, 0.16, 0.17) and sleep disturbances (  = 0.42, 0.65, 0.81, 0.81) were not affected by high versus low kcal, PRO, fat, CHO intake, respectively. Recovery (  = 0.81, 0.06, 0.81, 0.92), RHR (  = 0.84, 0.64, 0.26, 0.66), or HRV (  = 0.84, 0.70, 0.76, 0.93) were also not affected by high versus low kcal, PRO, fat, or CHO consumption, respectively. Consuming a small meal before bed may have no impact on sleep or recovery.

Insulin-like growth factor-binding protein 2 (IGFBP2) is increasingly recognized as a glioma oncogene, emerging as a target for therapeutic intervention. In this study, we used an integrative approach to characterizing the IGFBP2 network, combining transcriptional profiling of human glioma with validation in glial cells and the replication-competent ASLV long terminal repeat with a splice acceptor/tv-a glioma mouse system. We demonstrated that IGFBP2 expression is closely linked to genes in the integrin and integrin-linked kinase (ILK) pathways and that these genes are associated with prognosis. We further showed that IGFBP2 activates integrin β1 and downstream invasion pathways, requires ILK to induce cell motility, and activates NF-κB. Most significantly, the IGFBP2/integrin/ILK/NF-κB network functions as a physiologically active signaling pathway in vivo by driving glioma progression; interfering with any point in the pathway markedly inhibits progression. The results of this study reveal a signaling pathway that is both targetable and highly relevant to improving the survival of glioma patients.

Among 30,000 new wearable device users (11.6 million person-days), self-reported alcohol consumption significantly declined over 72 weeks, with the daily probability of drinking decreasing by 5.8 percentage points (P<.001) and reductions across age and biological sex.

Alcohol consumption acutely disrupts physiology and behavior. Yet, the modifying effects of age, biological sex, and health behaviors are not well understood. In this retrospective cohort study, we analyzed 5,109,185 person-days from 20,968 participants and fit generalized additive models to estimate within-person associations between alcohol intake and nocturnal resting heart rate (RHR), heart rate variability (HRV), sleep duration, and next-day physical activity. Models were stratified by age and sex, and adjusted for drinking frequency, body mass index, weekday/weekend, and season, and accounted for between-person differences via person-mean centering. We also assessed whether drinking earlier in the day, longer post-drinking sleep, and reducing physical activity attenuated disruptions. Acute alcohol consumption was associated with dose-dependent increases in nocturnal RHR and reductions in HRV, alongside decreases in sleep duration and next-day physical activity. These changes were more pronounced in females than males and in younger than older adults: consuming one drink more than personal average, compared with one less, was associated with an increase in RHR by 2.8 bpm (99.9% CI: 2.7, 2.9) in females and 2.4 bpm (99.9% CI: 2.3, 2.4) in males, while HRV declined by 3.8 ms (99.9% CI: -4.1, -3.5) in females and 3.3 ms (99.9% CI: -3.5, -3.1) in males. Drinking earlier in the day, obtaining longer post-drinking sleep, and reducing activity each reduced these effects. Alcohol consumption acutely disrupts cardiovascular regulation, sleep duration, and next-day physical activity, with stronger disruptions in females and younger adults. Behavioral modifications may mitigate these disruptions.

RNA binding proteins (RBPs) are vital to the regulation of mRNA transcripts, and can alter mRNA localization, degradation, translation, and storage. Whi3 was originally identified in a screen for small cell size mutants, and has since been characterized as an RBP. The identification of Whi3-interacting mRNAs involved in mediating cellular responses to stress suggested that Whi3 might be involved in stress-responsive RNA processing. We show that Whi3 localizes to stress granules in response to glucose deprivation or heat shock. The kinetics and pattern of Whi3 localization in response to a range of temperatures were subtly but distinctly different from those of known components of RNA processing granules. Deletion of Whi3 resulted in an increase in the relative abundance of Whi3 target RNAs, either in the presence or absence of heat shock. Increased levels of the CLN3 mRNA in whi3Δ cells may explain their decreased cell size. Another mRNA target of Whi3 encodes the zinc-responsive transcription factor Zap1, suggesting a role for Whi3 in response to zinc stress. Indeed, we found that whi3Δ cells have enhanced sensitivity to zinc toxicity. Together our results suggest an expanded model for Whi3 function: in addition to its role as a regulator of the cell cycle, Whi3 may have a role in stress-dependent RNA processing and responses to a variety of stress conditions.

The levels of insulin-like growth factor-binding protein 2 (IGFBP2) are elevated during progression of many human cancers. By using a glial-specific transgenic mouse system (RCAS/Ntv-a), we reported previously that IGFBP2 is an oncogenic factor for glioma progression in combination with platelet-derived growth factor-β (PDGFB). Because the INK4a-ARF locus is often deleted in high-grade gliomas (anaplastic oligodendroglioma and glioblastoma), we investigated the effect of the Ink4a-Arf-null background on IGFBP2-mediated progression of PDGFB-initiated oligodendroglioma. We demonstrate here that homozygous deletion of Ink4a-Arf bypasses the requirement of exogenously introduced IGFBP2 for glioma progression. Instead, absence of Ink4a-Arf resulted in elevated endogenous tumor cell IGFBP2. An inverse relationship between p16INK⁴a and IGFBP2 expression was also observed in human glioma tissue samples and in 90 different cancer cell lines by using Western blotting and reverse-phase protein lysate arrays. When endogenous IGFBP2 expression was attenuated by an RCAS vector expressing antisense IGFBP2 in our mouse model, a decreased incidence of anaplastic oligodendroglioma as well as prolonged survival was observed. Thus, p16INK⁴a is a negative regulator of the IGFBP2 oncogene. Loss of Ink4a-Arf results in increased IGFBP2, which contributes to glioma progression, thereby implicating IGFBP2 as a marker and potential therapeutic target for Ink4a-Arf-deleted gliomas.

Despite widespread advances in DNA sequencing, the functional consequences of most genetic variants remain poorly understood. Multiplexed Assays of Variant Effect (MAVEs) can measure the function of variants at scale, and are beginning to address this problem. However, MAVEs cannot readily be applied to the ~10% of human genes encoding secreted proteins. We developed a flexible, scalable human cell surface display method, Multiplexed Surface Tethering of Extracellular Proteins (MultiSTEP), to measure secreted protein variant effects. We used MultiSTEP to study the consequences of missense variation in coagulation factor IX (FIX), a serine protease where genetic variation can cause hemophilia B. We combined MultiSTEP with a panel of antibodies to detect FIX secretion and post-translational modification, measuring a total of 44,816 effects for 436 synonymous variants and 8,528 of the 8,759 possible missense variants. 49.6% of possible missense variants impacted secretion, post-translational modification, or both. We also identified functional constraints on secretion within the signal peptide and for nearly all variants that caused gain or loss of cysteine. Secretion scores correlated strongly with FIX levels in hemophilia B and revealed that loss of secretion variants are particularly likely to cause severe disease. Integration of the secretion and post-translational modification scores enabled reclassification of 63.1% of variants of uncertain significance in the hemophilia genotyping project. Lastly, we showed that MultiSTEP can be applied to a wide variety of secreted proteins. Thus, MultiSTEP is a multiplexed, multimodal, and generalizable method for systematically assessing variant effects in secreted proteins at scale.

Mass Transport Deposits (MTDs) are seen in seismic images as an area with chaoticreflections or no reflections, bounded by laterally consistent reflectors. There are a wide range of known causes for these types of submarine landslides. By focusing on MTDs that are Quaternary in age, and that are located within the Atlantis region of the Gulf of Mexico, the most likely cause for the MTDs in this study was hypothesized to be variations in sea level. With the use of 2-D sub-bottom profile data from the study area, it was possible to map out the MTDs in relation to age horizons provided by core analysis done in another study. Once an age was determined, each MTD was linked to specific sea level trends during that time. It was concluded that there was a strong relationship between changes in sea level and the occurrence of mass transport events. The study area was highly affected by minor changes in sea level due to the origin of its sediment supply, the Mississippi River drainage system. Analysis suggests that the MTDs in the Atlantis region could all be caused by the effect of sea level changes on rates in sedimentation.