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Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In cells, DL001 efficiently represses elevated mTORC1 activity and restores normal gene expression to cells lacking a functional tuberous sclerosis complex. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that selective inhibition of mTORC1 significantly reduces the side effects associated with conventional rapalogs. Rapamycin extends lifespan in model organisms by targeting mTORC1, but exerts off-target side effects via inhibition of mTORC2. Here, the authors report the identification of a selective mTORC1 inhibitor, and show that it inhibits mTORC1 activity both in vitro and in vivo, with reduced side effects on glucose homeostasis, lipid metabolism, and the immune system.

The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved protein kinase that regulates growth and metabolism. mTOR is found in two protein complexes, mTORC1 and mTORC2, that have distinct components and substrates and are both inhibited by rapamycin, a macrolide drug that robustly extends lifespan in multiple species including worms and mice. Although the beneficial effect of rapamycin on longevity is generally attributed to reduced mTORC1 signaling, disruption of mTORC2 signaling can also influence the longevity of worms, either positively or negatively depending on the temperature and food source. Here, we show that loss of hypothalamic mTORC2 signaling in mice decreases activity level, increases the set point for adiposity, and renders the animals susceptible to diet‐induced obesity. Hypothalamic mTORC2 signaling normally increases with age, and mice lacking this pathway display higher fat mass and impaired glucose homeostasis throughout life, become more frail with age, and have decreased overall survival. We conclude that hypothalamic mTORC2 is essential for the normal metabolic health, fitness, and lifespan of mice. Our results have implications for the use of mTORC2‐inhibiting pharmaceuticals in the treatment of brain cancer and diseases of aging. The hypothalamic activity of the protein kinase mTORC2 (mechanistic target of rapamycin complex 2) increases with age. Genetic disruption of hypothalamic mTORC2 leads to a lifelong increase in adiposity, as well as decreased spontaneous activity and increased frailty. Mice lacking hypothalamic mTORC2 have decreased lifespan. These findings demonstrate that hypothalamic mTORC2 is essential for the metabolic health, fitness, and lifespan of mice.

Clinical trials worldwide were disrupted when the COVID-19 pandemic began in early 2020. Most intervention trials moved to some form of remote implementation due to restrictions on in-person research activities. Although the proportion of remote trials is growing, they remain the vast minority of studies in part due to few successful examples. Our team transitioned Goals for Reaching Optimal Wellness (GROWell), an NIH-funded (R01NR017659) randomized control trial (RCT; ClinicalTrials.gov identifier NCT04449432) originally designed as a hybrid intervention, into a fully remote clinical trial. GROWell is a digital dietary intervention for people who enter pregnancy with overweight or obesity. Primary outcomes include gestational weight gain and six-month postpartum weight retention. Strategies that we have tested, refined, and deployed include: (a) use of a HIPAA-compliant, web-based participant recruitment and engagement platform; (b) use of a HIPAA-compliant digital health platform to disseminate GROWell and conduct study visits (c) interconnectivity of these two platforms for seamless recruitment, consent, enrollment, intervention delivery, follow-up, and study team blinding; (d) detailed SMS messages to address initial challenges with protocol adherence; (e) email notifications alerting the study team about missed participant surveys so they can follow-up; (f) remuneration using email gift cards with recipient choice of vendor; and (g) geotargeting social media campaigns to improve participation of Black Indigenous and People of Color Communities. These strategies have resulted in screen failure rates improving by 7%, study task adherence improving by an average of 20–30% across study visits, and study completion rates of 82%. Researchers may consider some or all of these approaches in future remote mHealth trials.

Objectives/Goals: To identify lipid signatures associated with adverse pregnancy outcomes (APOs) and postpartum weight retention (PPWR) in women entering pregnancy with overweight or obesity and to explore potential epigenetic mechanisms through ongoing DNA methylation (DNAm) analysis. Methods/Study Population: The GROWell: Goals for Reaching Optimal Wellness study was a blinded, randomized clinical trial to improve dietary support during pregnancy and postpartum. Data were collected via online questionnaires, electronic health records (EHRs), and participant-collected dried blood spots (DBS) at 10–16 weeks, 36–38 weeks, and 3 months postpartum. We analyzed DBS data from 49 participants using three lipidomic analytical techniques: weighted lipid correlation network analysis, differential lipid analysis, and partial least squares discriminant analysis. Lipid profiles were characterized and then tested for associations with APOs and PPWR at all three time points. DNAm analysis from the samples is ongoing to determine the epigenetic mechanisms associated with lipid dysregulation and pregnancy outcomes. Results/Anticipated Results: The lipid network analysis revealed positive correlations between specific lipid types and APOs, particularly at 10–16 weeks and postpartum. Notably, triglycerides and phosphatidylcholine were associated with an increased risk of APOs. Additionally, in the third trimester, triglycerides were positively correlated with weight-related variables. Postpartum analysis also showed a positive correlation between elevated triglyceride levels and a history of APOs. The network analysis also revealed positive associations between triglycerides and PPWR, which were most evident at the 36–38 week and postpartum time points. Ongoing methylation analysis is expected to identify genomic regions associated with pregnancy outcomes. Discussion/Significance of Impact: These findings underscore the significant role of lipids in pregnancy outcomes for individuals with overweight or obesity. Identifying lipidomic and methylome biomarkers of risk for APOs and PPWR may help with early detection and intervention, improving maternal and fetal health.

Summary Inhibition of the mTOR (mechanistic Target Of Rapamycin) signaling pathway robustly extends the lifespan of model organisms including mice. The precise molecular mechanisms and physiological effects that underlie the beneficial effects of rapamycin are an exciting area of research. Surprisingly, while some data suggest that mTOR signaling normally increases with age in mice, the effect of age on mTOR signaling has never been comprehensively assessed. Here, we determine the age-associated changes in mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2) signaling in the liver, muscle, adipose, and heart of C57BL/6J.Nia mice, the lifespan of which can be extended by rapamycin treatment. We find that the effect of age on several different readouts of mTORC1 and mTORC2 activity varies by tissue and sex in C57BL/6J.Nia mice. Intriguingly, we observed increased mTORC1 activity in the liver and heart tissue of young female mice compared to male mice of the same age. Tissue and substrate-specific results were observed in the livers of HET3 and DBA/2 mouse strains, and in liver, muscle and adipose tissue of F344 rats. Our results demonstrate that aging does not result in increased mTOR signaling in most tissues and suggest that rapamycin does not promote lifespan by reversing or blunting such an effect.

Abstract The mechanisms that underlie the β-cell pathophysiology of Type 1 Diabetes (T1D) are not fully understood. Our group has defined the unique heterotrimeric G protein alpha-subunit, Gαz, as a key negative regulator of β-cell signal transduction pathways. Non-obese diabetic (NOD) mice lacking Gαz throughout the body are protected from developing T1D-like hyperglycemia. To determine whether this phenotype is β-cell autonomous, we generated and validated a β-cell-specific Gαz knockout (βKO) on the NOD background and characterized the phenotype of female and male cohorts. Long-term hyperglycemia incidence was lower in Gαz βKO mice as compared to wild-type (WT) controls, but, unlike global Gαz knockout mice, this protection was incomplete. While young male and female Gαz βKO NOD mice had improved glucose tolerance, WT NOD males were significantly less glucose tolerant than females, and only female Gαz βKO mice retained improved glucose tolerance at 28-29 weeks of age. Conversely, β-cell-specific Gαz loss only influenced insulitis in 28-29-week old male NOD mice, a phenotype correlating directly with body burden of glucose during oral glucose challenge. Using surrogates for β-cell function and apoptosis, the partial penetrance of euglycemia in Gαz βKO NOD was best explained by an early failure to up-regulate β-cell proliferation. We conclude β-cell Gαz is an important regulator of the sexually-dimorphic T1D-like phenotype of NOD mice. Yet, other factors must be important in imparting full protection from the disease. Competing Interest Statement The authors have declared no competing interest. Footnotes * Grants/Fellowships: US Department of Veterans Affairs: I01 BX003700 (to M.E.K). US National Institutes of Health: K01 DK080845 (to M.E.K.), R01 DK102598 (to M.E.K.) and F31 DK109698 (to R.J.F.) American Diabetes Association: 1-16-IBS-212 (to M.E.K.), JDRF: 17-2011-608 (to M.E.K.) * Disclosure Summary:The authors declare that they have no real or perceived conflicts of interest with the contents of this article.

Vegetation type and seasonality promote changes in the species composition and abundance of parasite hosts. However, it is poorly known how these variables affect host–parasite interaction networks. This information is important to understand the dynamics of parasite–host relationships according to biotic and abiotic changes. We compared the specialization of host–bat fly interaction networks, as well as bat fly and host species composition between upland dry forest and riparian forest and between dry and rainy seasons in a tropical dry forest in Jalisco, Mexico. Bat flies were surveyed by direct collection from bats. Our results showed that host–bat fly interaction networks were more specialized in upland dry forest compared to riparian forest. Bat fly species composition was different between the dry and rainy seasons, while host species composition was different between upland dry forest and riparian forest. The higher specialization in upland dry forest could be related to the differences in bat host species composition and their respective roosting habits. Variation in the composition of bat fly species between dry and rainy seasons coincides with the seasonal shifts in their species richness. Our study confirms the high specialization of host–bat fly interactions and shows the importance of biotic and abiotic factors to understand the dynamics of parasite–host interactions.

Riparian forests (RF) provide shelter, feeding resources and commuting areas and are fundamental for local fauna during long drought periods in tropical dry forests. Nevertheless, information regarding vertebrate ecology in tropical RF is scarce. The studies of bats in riparian habitats have been mostly focused on insectivorous assemblages in non-tropical regions. We contrasted the occurrence of frugivorous bats between RF and upland dry forest (UDF) in a Neotropical dry forest region and evaluated how vegetation structure modulates frugivorous bat presence and abundance. We sampled bat ensembles and vegetation structure in three UDF and three RF sites in Jalisco, Mexico. Bat ensembles and populations were analysed with generalized linear models, including as independent factors: (1) habitat and (2) vegetation attributes. In 72 nights we captured 840 bats belonging to seven species. No effect of habitat type or vegetation structure on species richness was found, but habitat type did affect bat species composition and abundance. Moreover, vegetation structural traits affected frugivorous bat abundance. Frugivore abundance was higher in RF than in UDF probably because RF provides greater resources and more roosting sites. Riparian forests also present more canopy cover and accessible flight spaces. Our results support the importance of RF for frugivorous bats in terms of abundance and composition. Additionally, the lack of differences in species richness between UDF and RF highlights the importance of both habitats for maintaining frugivorous bats, as well as the related ecosystem processes and services in tropical dry forest landscapes.

Emergency medical service (EMS) professionals have a stressful vocation, inarguably worsened by the COVID-19 pandemic, which affects their mental health and makes them a vulnerable population warranting further study. However, to date, no published research has compared non-treatment and treatment-seeking EMS professionals in the same greater metropolitan area. In this study, we examined differences and similarities among the non-treatment-seeking EMS professionals (n = 57) from a local EMS agency and treatment-seeking EMS personnel (n = 53) from a non-profit community treatment center on six assessment instruments that measure attachment avoidance, attachment anxiety, resilience, depression, generalized anxiety, posttraumatic stress disorder (PTSD), and suicidality. The Mann-Whitney U test revealed attachment avoidance, attachment anxiety, depression, generalized anxiety, and posttraumatic stress disorder (PTSD) were significantly higher in the treatment-seeking sample compared to the non-treatment-seeking group. Resilience and suicide did not significantly differ. Correlational analyses revealed that the most consistent findings for both samples were PTSD, depression, and generalized anxiety. Findings suggest that negative affect may underlie these three constructs, regardless of whether the individual is treatment-seeking or not. These findings are conceptualized through three different theoretical frameworks: attachment, resilience, and negative affect. We also make recommendations for EMS agencies and suggest future scholarship based on these preliminary findings.