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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.

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.

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 whi3 Delta 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 whi3 Delta 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.

British voters are heading to the polls Thursday for a crucialgeneral election that is being seen as a referendum on 14 years ofConservative rule. President Joe Biden has privately acknowledged thatthe next few days are critical to whether he can salvage hisreelection campaign. Hurricane Beryl brushed by Jamaica on Wednesdayafternoon, unleashing 140 miles per hour winds and sending storm surgeonto the island's shores. A group of Democratic governors say they arestanding behind President Joe Biden amid increasing calls from some intheir party for him to leave the presidential race. Donald Trumpappears to be showing relative restraint as he watches PresidentBidens candidacy self-destruct. One Trump confidant says, quote, \"LetBiden twist\". The National Hurricane Center reports that HurricaneBeryl is headed towards the Cayman Islands now after lashing Jamaicawith high winds and heavy rain. Police in India are investigatingTuesday's deadly crowd crush at a religious festival. It happened asfemale devotees rushed towards the stage to touch the feet of thepreacher who led the event. Japan's banks have been stocking theirshiny new yen notes. They're sourced from a fairly unlikely source,the paperbush shrubs that grow on the Himalayan Mountains in Nepal. GUESTS: Freddy Gray, Caroline Heldman

Israel vowing to retaliate after Iran launches a major strike,firing about 200 ballistic missiles at Israel. A strike Iran insistwas only a, quote, \"portion of their power.\" Israel vows\"consequences\" for Iran, says they have plans. United NationsSecretary General Antonio Guterres said, \"I condemn the broadening ofthe Middle East conflict with escalation after escalation. This muststop. We absolutely need a cease fire.\" Former Israeli prime minister,Naftali Bennet, responds that it's time for him to quit if he cannotcondemn Iran. Democrat Tim Walz and Republican J.D. Vance are set tomeet Tuesday night in the only vice presidential debate of the 2024election and in what might be the last time the two campaigns squareoff onstage. GUESTS: Eyal Hulata, Mark Hertling, Seth Jones, Naftali Bennett, JoshShapiro, Brad Todd

Joe Biden and President Trump continue to disagree onseriousness of the problem as COVID-19 deaths are rising with almost400,000 total deaths predicted by February according to one model.Trump unconvincingly called himself the least racist at last night'sdebate and did not address past issues like his condemnation of theCentral Park Five. Delta Airlines has banned over 400 people for notfollowing mask policy.

It's now in the judge's hands, lawyers for the former presidentjust filed their answer to special counsel Jack Smith's call for a gagorder in the classified documents case. The Sandy Hook families getone step closer to finally collecting at least some damages fromconspiracy pusher Alex Jones. Catherine, Princess of Wales, announcedon Friday she will make her first public appearance in six months thisweekend after \"making good progress\" in treatment for cancer. PamelaSmart, who is serving life in prison for plotting with her teenagestudent to have her husband killed in 1990, accepted fullresponsibility for his death for the first time in a videotapedstatement released Tuesday as part of her latest sentence reductionrequest. Joey Chestnut, defending champion of the annual July Fourthhot-dog eating competition on New York City's Coney Island, isexcluded from this year's event because he is sponsoring an all-veggiefrankfurter of another brand, organizers said on June 11. GUESTS: Shira Scheindlin, Richard Blumenthal

Infections caused by Gram-negative pathogens are increasingly prevalent and are typically treated with broad-spectrum antibiotics, resulting in disruption of the gut microbiome and susceptibility to secondary infections 1 – 3 . There is a critical need for antibiotics that are selective both for Gram-negative bacteria over Gram-positive bacteria, as well as for pathogenic bacteria over commensal bacteria. Here we report the design and discovery of lolamicin, a Gram-negative-specific antibiotic targeting the lipoprotein transport system. Lolamicin has activity against a panel of more than 130 multidrug-resistant clinical isolates, shows efficacy in multiple mouse models of acute pneumonia and septicaemia infection, and spares the gut microbiome in mice, preventing secondary infection with Clostridioides difficile . The selective killing of pathogenic Gram-negative bacteria by lolamicin is a consequence of low sequence homology for the target in pathogenic bacteria versus commensals; this doubly selective strategy can be a blueprint for the development of other microbiome-sparing antibiotics. Lolamicin, a novel antibiotic developed from a pyridinepyrazole precursor, exhibits potent activity against a broad range of Gram-negative multidrug-resistant clinical isolates, and good efficacy in mouse models of infection without inducing gut dysbiosis.

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.