Sigma-1 receptor recruits LC3 mRNA to ER-associated omegasomes to promote localized LC3 translation enabling functional autophagy.

Autophagosome formation initiated on the endoplasmic reticulum (ER)-associated omegasome requires LC3. Translational regulation of LC3 biosynthesis is unexplored. Here we demonstrate that LC3 mRNA is recruited to omegasomes by directly binding to the ER transmembrane Sigma-1 receptor (S1R). Cell-based and in vitro reconstitution experiments show that S1R interacts with the 3' UTR of LC3 mRNA and ribosomes to promote LC3 translation. Strikingly, the 3' UTR of LC3 is also required for LC3 protein lipidation, thereby linking the mRNA-3' UTR to LC3 function. An autophagy-defective S1R mutant responsible for amyotrophic lateral sclerosis cannot bind LC3 mRNA or induce LC3 translation. We propose a model wherein S1R de-represses LC3 mRNA via its 3' UTR at the ER, enabling LC3 biosynthesis and lipidation. Because several other LC3-related proteins use the same mechanism, our data reveal a conserved pathway for localized translation essential for autophagosome biogenesis with insights illuminating the molecular basis of a neurodegenerative disease.

Intuitive moral bias favors the religiously faithful.

Belief in powerful supernatural agents that enforce moral norms has been theoretically linked with cooperative altruism and prosociality. Correspondingly, prior research reveals an implicit association between atheism and extreme antisociality (e.g., serial murder). However, findings centered on associations between lack of faith and moral transgression do not directly address the hypothesized conceptual association between religious belief and prosociality. Accordingly, we conducted two pre-registered experiments depicting a "serial helper" to assess biases related to extraordinary helpfulness, mirroring designs depicting a serial killer used in prior cross-cultural work. In both a predominantly religious society (the U.S., Study 1) and a predominantly secular society (New Zealand, Study 2), we successfully replicated previous research linking atheism with transgression, and obtained evidence for a substantially stronger conceptual association between religiosity and virtue. The results suggest that stereotypes linking religiosity with prosociality are both real and global in scale.

Mentoring practices that predict doctoral student outcomes in a biological sciences cohort.

Despite the importance of a diversity of backgrounds and perspectives in biological research, women, racial and ethnic minorities, and students from non-traditional academic backgrounds remain underrepresented in the composition of university faculty. Through a study on doctoral students at a research-intensive university, we pinpoint advising from faculty as a critical component of graduate student experiences and productivity. Graduate students from minority backgrounds reported lower levels of support from their advisors and research groups. However, working with an advisor from a similar demographic background substantially improved productivity and well-being of these students. Several other aspects of mentoring practices positively predicted student success and belonging, including frequent one-on-one meetings, empathetic and constructive feedback, and relationships with other peer or faculty mentors. Our study highlights the need to renovate graduate education with a focus on retention-not just recruitment-to best prepare students for success in scientific careers.

BMI/Obesity and consumers' price sensitivity: Implications for food tax policies.

We examine the relationship between BMI and food purchase behavior using a unique dataset that links individual-level food purchases to health data. We find that individuals with higher BMI are significantly more sensitive to price changes in vice categories but do not show similar sensitivity in comparable nonvice categories. We rely on past literature that defines and identifies vice categories as those that are tempting and purchased impulsively. We explore the effectiveness of a 10% price increase on vice food categories, a hypothetical policy similar in spirit to a fat tax or sugar tax. We predict that such a tax would substantially reduce consumption of these foods, and would be particularly effective in reducing consumption by individuals with higher BMI.

Precise and High-Throughput Delivery of Micronutrients in Plants Enabled by Pollen-Inspired Spiny and Biodegradable Microcapsules.

Decarbonizing food production and mitigating agriculture's environmental impact require new technologies for precise delivery of fertilizers and pesticides to plants. The cuticle, a waxy barrier that protects the surface of leaves, causes 60%-90% runoff of fertilizers and pesticides, leading to the wastage of intensive resources, soil depletion, and water bodies pollution. Solutions to mitigate runoff include adding chemicals (e.g., surfactants) to decrease surface tension and enhance cuticles' permeability but have low efficacy. In this study, vapor-induced synergistic differentiation (VISDi) is used to nanomanufacture echinate pollen-like, high payload content (≈50 wt%) microcapsules decorated with robust spines that mechanically disrupt the cuticle and adhere to the leaf. VISDi induces a core-shell structure in the spines, enabling the release of agrochemicals from the microparticles' body into the leaf. As proof of concept, precise and highthroughput delivery of iron fertilizer in Fe-deficient spinach plants is demonstrated. Spray of spiny microparticles improves leaf adhesion by mechanical interlocking, reduces wash-off by an ≈12.5 fold, and enhances chlorophyll content by ≈7.3 times compared to the application of spherical counterparts. Together, these results show that spiny microparticles can mitigate agricultural runoff and provide a high-throughput tool for precise plant drug delivery.

How Are We Teaching Advocacy? A National Survey of Internal Medicine Residency Program Directors.

BACKGROUND: Although internal medicine (IM) physicians accept public advocacy as a professional responsibility, there is little evidence that IM training programs teach advocacy skills. The prevalence and characteristics of public advocacy curricula in US IM residency programs are unknown. OBJECTIVES: To describe the prevalence and characteristics of curricula in US IM residencies addressing public advocacy for communities and populations; to describe barriers to the provision of such curricula. DESIGN: Nationally representative, web-based, cross-sectional survey of IM residency program directors with membership in an academic professional association. PARTICIPANTS: A total of 276 IM residency program directors (61%) responded between August and December 2022. MAIN MEASUREMENTS: Percentage of US IM residency programs that teach advocacy curricula; characteristics of advocacy curricula; perceptions of barriers to teaching advocacy. KEY RESULTS: More than half of respondents reported that their programs offer no advocacy curricula (148/276, 53.6%). Ninety-five programs (95/276, 34.4%) reported required advocacy curricula; 33 programs (33/276, 12%) provided curricula as elective only. The content, structure, and teaching methods of advocacy curricula in IM programs were heterogeneous; experiential learning in required curricula was low (23/95, 24.2%) compared to that in elective curricula (51/65, 78.5%). The most highly reported barriers to implementing or improving upon advocacy curricula (multiple responses allowed) were lack of faculty expertise in advocacy (200/276, 72%), inadequate faculty time (190/276, 69%), and limited curricular flexibility (148/276, 54%). CONCLUSION: Over half of US IM residency programs offer no formal training in public advocacy skills and many reported lack of faculty expertise in public advocacy as a barrier. These findings suggest many IM residents are not taught how to advocate for communities and populations. Further, less than one-quarter of required curricula in public advocacy involves experiential learning.

Spesolimab: A Review of the First IL-36 Blocker Approved for Generalized Pustular Psoriasis.

OBJECTIVE: This article reviews clinical trial data that assesses the safety, efficacy, and clinical application of spesolimab, an interleukin-36 (IL-36) blocker, for the treatment of generalized pustular psoriasis (GPP). DATA SOURCES: A review of the literature was conducted using the search terms: "spesolimab," "BI 655130," and "spevigo" in MEDLINE (PubMed) and Clinicaltrials.gov from January 1, 1950 to October 31, 2023. STUDY SELECTION AND DATA EXTRACTION: Relevant articles in English relating to the pharmacodynamics, pharmacokinetics, efficacy, and safety of spesolimab were included. DATA SYNTHESIS: In one phase 2 clinical trial evaluating single dose IV spesolimab for GPP flares at day 8, 54% of patients receiving spesolimab had a GPP physician global assessment (GPPGA) pustulation subscore of 0, and 43% had a GPPGA total score of 0 compared with 6% and 11% for the placebo group, respectively. Another phase 2 clinical trial assessing subcutaneous spesolimab found 23% of patients in low-dose, 29% in medium-dose, and 10% of high-dose spesolimab had flares by week 48 compared with 52% of the placebo group. Hazard ratios for time to GPP flare compared with placebo were 0.16 (P = 0.0005), 0.35 (P = 0.0057), and 0.47 (P = 0.027) for the spesolimab groups, respectively. Infection rates were similar across treatment and placebo groups, and severe adverse events such as drug reactions with eosinophilia and systemic symptom (DRESS), cholelithiasis, and breast cancer occurred with spesolimab. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS: Spesolimab is a first-in-class IL-36 monoclonal antibody receptor antagonist approved for the treatment of acute GPP flares. It is a safe and effective therapeutic agent in preventing future GPP flares, with no current comparator trials with other GPP agents. CONCLUSION: Spesolimab is a safe and effective treatment for acute GPP flares in adults. Future clinical trials can establish safety and efficacy compared with other agents.

Effects of Speaking Rate Changes on Speech Motor Variability in Adults.

The relationship between speaking rate and speech motor variability was examined in three groups of neurotypical adults, n = 40; 15 young adults (18-30 years), 13 adults (31-40 years), and 12 middle-aged adults (41-50 years). Participants completed a connected speech task at three speaking rates (habitual, fast, and slow) where kinematic (lower lip movement) and acoustic data were obtained. Duration and variability were measured at each speaking rate. Findings revealed a complex relationship between speaking rate and variability. Adults from the middle age range (31-40 years) demonstrated shorter acoustic and kinematic durations compared with the oldest age group (41-50 years) during the habitual speaking rate condition. All adults demonstrated the greatest variability in the slow speaking rate condition, with no significant differences in variability between habitual and fast speaking rates. Interestingly, lip aperture variability was significantly lower in the youngest age group (18-30 years) compared with the two older groups during the fast speaking rate condition. Differences in measures of acoustic variability were not observed across the age levels. Strong negative correlations between kinematic/acoustic duration and lip aperture/acoustic variability in the youngest age group were revealed. Therefore, while a slow speaking rate does result in greater variability compared with habitual and fast speaking rates, longer durations of productions by the different age groups were not linked to higher spatiotemporal index (STI) values, suggesting that timing influences speech motor variability, but is not the sole contributor.

Racial, Ethnic, and Geographic Differences in Vaginal Birth After Cesarean Delivery in the US, 2011-2021.

This cross-sectional study examines racial, ethnic, and geographic differences in vaginal birth after cesarean delivery in the US, from 2011 to 2021.

Fmo induction as a tool to screen for pro-longevity drugs.

Dietary restriction (DR) and hypoxia (low oxygen) extend lifespan in Caenorhabditis elegans through the induction of a convergent downstream longevity gene, fmo-2. Flavin-containing monooxygenases (FMOs) are highly conserved xenobiotic-metabolizing enzymes with a clear role in promoting longevity in nematodes and a plausible similar role in mammals. This makes them an attractive potential target of small molecule drugs to stimulate the health-promoting effects of longevity pathways. Here, we utilize an fmo-2 fluorescent transcriptional reporter in C. elegans to screen a set of 80 compounds previously shown to improve stress resistance in mouse fibroblasts. Our data show that 19 compounds significantly induce fmo-2, and 10 of the compounds induce fmo-2 more than twofold. Interestingly, 9 of the 10 high fmo-2 inducers also extend lifespan in C. elegans. Two of these drugs, mitochondrial respiration chain complex inhibitors, interact with the hypoxia pathway to induce fmo-2, whereas two dopamine receptor type 2 (DRD2) antagonists interact with the DR pathway to induce fmo-2, indicating that dopamine signaling is involved in DR-mediated fmo-2 induction. Together, our data identify nine drugs that each (1) increase stress resistance in mouse fibroblasts, (2) induce fmo-2 in C. elegans, and (3) extend nematode lifespan, some through known longevity pathways. These results define fmo-2 induction as a viable approach to identifying and understanding mechanisms of putative longevity compounds.

Fmo5 plays a sex-specific role in goblet cell maturation and mucus barrier formation.

The intestine plays a key role in metabolism, nutrient and water absorption, and provides both physical and immunological defense against dietary and luminal antigens. The protective mucus lining in the intestine is a critical component of intestinal barrier function that when compromised, can lead to dysfunctional intestinal barriers that are a defining characteristic of inflammatory bowel disease (IBD), among other intestinal diseases. Here, we define a new role for the flavin-containing monooxygenase family of enzymes in maintaining a healthy intestinal epithelium. In nematodes, we find that Cefmo-2 is necessary and sufficient for proper intestinal barrier function, intestinal actin expression, and is induced by intestinal damage. In mice, we utilize an intestine-specific, inducible knockout model of the prevalent gut Fmo (Fmo5) and find striking phenotypes within two weeks of knockout. These phenotypes include sex-dependent changes in colon epithelial histology, goblet cell localization and maturation factors, and mucus barrier formation. Each of these changes are significantly more severe in female mice, plausibly mirroring differences observed in some types of IBD in humans. Looking further at these phenotypes, we find increased protein folding stress in Fmo5 knockout animals and successfully rescue the severe female phenotype with addition of a chemical ER chaperone. Together, our results identify a new role for Fmo5 in the mammalian intestine and support a key role for Fmo5 in maintenance of ER/protein homeostasis and proper mucus barrier formation.

Condensed Layer Deposition of Nanoscopic TiO2 Overlayers on High-Surface-Area Electrocatalysts.

Encapsulating an electrocatalytic material with a semipermeable, nanoscopic oxide overlayer offers a promising approach to enhancing its stability, activity, and/or selectivity compared to an unencapsulated electrocatalyst. However, applying nanoscopic oxide encapsulation layers to high-surface-area electrodes such as nanoparticle-supported porous electrodes is a challenging task. This study demonstrates that the recently developed condensed layer deposition (CLD) method can be used for depositing nanoscopic (sub-10 nm thick) titanium dioxide (TiO2) overlayers onto high-surface-area platinized carbon foam electrodes. Characterization of the overlayers by transmission electron microscopy (TEM) and electron energy loss spectroscopy (EELS) showed that the films are amorphous, while X-ray photoelectron spectroscopy confirmed that they exhibit TiO2 stoichiometry. Electrodes were also characterized by hydrogen underpotential deposition (Hupd) and carbon monoxide (CO) stripping, demonstrating that the Pt electrocatalysts remain electrochemically active after encapsulation. Additionally, copper underpotential deposition (Cuupd) measurements revealed that TiO2 overlayers are effective at blocking Cu2+ from reaching the TiO2/Pt buried interface and were used to estimate that between 43 and 98% of Pt surface sites were encapsulated. Overall, this study shows that CLD is a promising approach for depositing nanoscopic protective overlayers on high-surface-area electrodes.

A diet of oxidative stress-adapted bacteria improves stress resistance and lifespan in C. elegans via p38-MAPK.

Organisms across taxa face stresses including variable temperature, redox imbalance, and xenobiotics. Successfully responding to stress and restoring homeostasis are crucial for survival. Aging is associated with a decreased stress response and alterations in the microbiome, which contribute to disease development. Animals and their microbiota share their environment; however, microbes have short generation time and can rapidly evolve and potentially affect host physiology during stress. Here, we leverage Caenorhabditis elegans and its simplified bacterial diet to demonstrate how microbial adaptation to oxidative stress affects the host's lifespan and stress response. We find that worms fed stress-evolved bacteria exhibit enhanced stress resistance and an extended lifespan. Through comprehensive genetic and metabolic analysis, we find that iron in stress-evolved bacteria enhances worm stress resistance and lifespan via activation of the mitogen-activated protein kinase pathway. In conclusion, our study provides evidence that understanding microbial stress-mediated adaptations could be used to slow aging and alleviate age-related health decline.

Neuroendocrine effects of the duper mutation in Syrian hamsters: a role for Cryptochrome 1.

Molecular and physiological determinants of the timing of reproductive events, including the pre-ovulatory LH surge and seasonal fluctuations in fertility, are incompletely understood. We used the Cryptochrome 1-deficient duper mutant to examine the role of this core circadian clock gene in Syrian hamsters. We find that the phase of the LH surge and its stability upon shifts of the light: dark cycle are altered in duper mutants. The intensity of immunoreactive PER1 in GnRH cells of the preoptic area peaks earlier in the day in duper than wild type hamsters. We note that GnRH fibers coursing through the suprachiasmatic nucleus (SCN) contact vasopressin- and VIP-immunoreactive cells, suggesting a possible locus of circadian control of the LH surge. Unlike wild types, duper hamsters do not regress their gonads within 8 weeks of constant darkness, despite evidence of melatonin secretion during the subjective night. In light of the finding that the duper allele is a stop codon in Cryptochrome 1, our results suggest important neuroendocrine functions of this core circadian clock gene.

Efficacy, Safety, and Tolerability of Tivozanib in Heavily Pretreated Patients With Advanced Clear Cell Renal Cell Carcinoma.

BACKGROUND: Tivozanib has been approved as a third-line or later therapy for advanced renal cell carcinoma based on the TIVO-3 trial, which was conducted before immune checkpoint therapies (ICT), cabozantinib, and lenvatinib/everolimus became incorporated in the current sequential treatment paradigm for advanced clear cell RCC (ccRCC). METHODS: We performed a retrospective study of patients with advanced ccRCC treated with tivozanib at MD Anderson Cancer Center during 6/2021-7/2023. A blinded radiologist assessed tumor response by RECIST v1.1. We assessed overall response rate (ORR), clinical benefit rate (CBR) [percentage of all treated patients who achieved radiologic response or stable disease (SD) for ≥ 6 months], progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Of 30 analyzed patients, 23% had performance status ≥ 2; 47% had International Metastatic RCC Database Consortium (IMDC) poor-risk disease. Median number of prior therapies was 4 (range 1-8). All patients received prior ICT, 87% cabozantinib and 60% lenvatinib ± everolimus. Of 26 evaluable patients, 2 patients had confirmed partial response (ORR 7.7%); 5 patients had SD for ≥ 6 months (CBR 23.3%). Median PFS was 3.8 months (range 0.7-13.9); median OS was 14.1 months (range 0.3-28.5). Fifteen patients (50%) had ≥ 1 treatment-related adverse event (TRAE). There were 6 grade ≥ 3 TRAEs [hypertension, congestive heart failure (3), mucositis, and GI perforation (grade 5)]. CONCLUSIONS: In this cohort of heavily pretreated patients with advanced ccRCC, tivozanib yielded a modest clinical benefit in a minority of patients who received prior ICT, cabozantinib, and lenvatinib ± everolimus. TRAEs were consistent with previously published reports.

Identifying incarceration status in the electronic health record using large language models in emergency department settings.

Background: Incarceration is a significant social determinant of health, contributing to high morbidity, mortality, and racialized health inequities. However, incarceration status is largely invisible to health services research due to inadequate clinical electronic health record (EHR) capture. This study aims to develop, train, and validate natural language processing (NLP) techniques to more effectively identify incarceration status in the EHR. Methods: The study population consisted of adult patients (≥ 18 y.o.) who presented to the emergency department between June 2013 and August 2021. The EHR database was filtered for notes for specific incarceration-related terms, and then a random selection of 1,000 notes was annotated for incarceration and further stratified into specific statuses of prior history, recent, and current incarceration. For NLP model development, 80% of the notes were used to train the Longformer-based and RoBERTa algorithms. The remaining 20% of the notes underwent analysis with GPT-4. Results: There were 849 unique patients across 989 visits in the 1000 annotated notes. Manual annotation revealed that 559 of 1000 notes (55.9%) contained evidence of incarceration history. ICD-10 code (sensitivity: 4.8%, specificity: 99.1%, F1-score: 0.09) demonstrated inferior performance to RoBERTa NLP (sensitivity: 78.6%, specificity: 73.3%, F1-score: 0.79), Longformer NLP (sensitivity: 94.6%, specificity: 87.5%, F1-score: 0.93), and GPT-4 (sensitivity: 100%, specificity: 61.1%, F1-score: 0.86). Conclusions: Our advanced NLP models demonstrate a high degree of accuracy in identifying incarceration status from clinical notes. Further research is needed to explore their scaled implementation in population health initiatives and assess their potential to mitigate health disparities through tailored system interventions.

Diabetes Management in Detention Facilities: A Statement of the American Diabetes Association.

This statement provides guidance for diabetes care in detention facilities. It focuses on areas where the processes for delivery of care to people with diabetes in detention facilities may differ from those in the community, and key points are made at the end of each section. Areas of emphasis, which inform multiple aspects discussed in this statement, include 1) timely identification or diagnosis of diabetes treatment needs and continuity of care (at reception/intake, during transfers, and upon discharge), 2) nutrition and physical activity, 3) timely access to diabetes management tools (insulin, blood glucose monitoring, tracking data, current diabetes management technologies, etc.), and 4) treatment of the whole person with diabetes (self-management education, mental health support, monitoring and addressing long-term complications, specialty care, etc.).