Proteomic changes induced by longevity-promoting interventions in mice.

Using mouse models and high-throughput proteomics, we conducted an in-depth analysis of the proteome changes induced in response to seven interventions known to increase mouse lifespan. This included two genetic mutations, a growth hormone receptor knockout (GHRKO mice) and a mutation in the Pit-1 locus (Snell dwarf mice), four drug treatments (rapamycin, acarbose, canagliflozin, and 17α-estradiol), and caloric restriction. Each of the interventions studied induced variable changes in the concentrations of proteins across liver, kidney, and gastrocnemius muscle tissue samples, with the strongest responses in the liver and limited concordance in protein responses across tissues. To the extent that these interventions promote longevity through common biological mechanisms, we anticipated that proteins associated with longevity could be identified by characterizing shared responses across all or multiple interventions. Many of the proteome alterations induced by each intervention were distinct, potentially implicating a variety of biological pathways as being related to lifespan extension. While we found no protein that was affected similarly by every intervention, we identified a set of proteins that responded to multiple interventions. These proteins were functionally diverse but tended to be involved in peroxisomal oxidation and metabolism of fatty acids. These results provide candidate proteins and biological mechanisms related to enhancing longevity that can inform research on therapeutic approaches to promote healthy aging.

Parents' Concerns Are Associated with Early Intervention Evaluation and Eligibility Outcomes.

OBJECTIVE: To test the association of parents' concerns with early intervention (EI) developmental services outcomes including evaluation, eligibility, and enrollment in services. METHOD: We collected survey data on parents' concerns and EI service use data from a sample of 428 children referred to EI from 2016 to 2018 in 6 Oregon primary care clinics serving lower-income families as part of a developmental and autism spectrum disorder screening intervention. We assessed EI service use trajectories and associations of the presence of parent concern, age of child at the time of parents' concerns, number of concerns, and type of provider concern, with EI evaluation, EI eligibility, and enrollment in EI services, using bivariate testing and multivariable logistic regression. RESULTS: Only 22.9% of children referred to EI were enrolled in services 6 months later. Children whose parents had developmental and/or behavioral concerns were more likely to receive an EI evaluation and were also more likely to be eligible for services, compared with children whose parents had no concerns. There was no association between age, number of concerns, and type of concern with EI evaluation, eligibility, or services enrollment. CONCLUSION: Although only a minority of children referred to EI enrolled in services, the presence of parent concern is strongly associated with EI services evaluation and eligibility outcomes. Study results suggest that providers should assess the presence of parent concern when deciding on EI referrals and provide more support to parents who are not concerned at all.

Centella asiatica Alters Metabolic Pathways Associated With Alzheimer's Disease in the 5xFAD Mouse Model of ß-Amyloid Accumulation.

Centella asiatica is an herb used in Ayurvedic and traditional Chinese medicine for its beneficial effects on brain health and cognition. Our group has previously shown that a water extract of Centella asiatica (CAW) elicits cognitive-enhancing effects in animal models of aging and Alzheimer's disease, including a dose-related effect of CAW on memory in the 5xFAD mouse model of ß-amyloid accumulation. Here, we endeavor to elucidate the mechanisms underlying the effects of CAW in the brain by conducting a metabolomic analysis of cortical tissue from 5xFAD mice treated with increasing concentrations of CAW. Tissue was collected from 8-month-old male and female 5xFAD mice and their wild-type littermates treated with CAW (0, 200, 500, or 1,000 mg/kg/d) dissolved in their drinking water for 5 weeks. High-performance liquid chromatography coupled to high-resolution mass spectrometry analysis was performed and relative levels of 120 annotated metabolites were assessed in the treatment groups. Metabolomic analysis revealed sex differences in the effect of the 5xFAD genotype on metabolite levels compared to wild-type mice, and variations in the metabolomic response to CAW depending on sex, genotype, and CAW dose. In at least three of the four treated groups (5xFAD or wild-type, male or female), CAW (500 mg/kg/d) significantly altered metabolic pathways related to purine metabolism, nicotinate and nicotinamide metabolism, and glycerophospholipid metabolism. The results are in line with some of our previous findings regarding specific mechanisms of action of CAW (e.g., improving mitochondrial function, reducing oxidative stress, and increasing synaptic density). Furthermore, these findings provide new information about additional, potential mechanisms for the cognitive-enhancing effect of CAW, including upregulation of nicotinamide adenine dinucleotide in the brain and modulation of brain-derived neurotrophic factor. These metabolic pathways have been implicated in the pathophysiology of Alzheimer's disease, highlighting the therapeutic potential of CAW in this neurodegenerative disease.

Protocol for a mechanistic study of mindfulness based cognitive therapy during pregnancy.

OBJECTIVE: Preventive interventions for postpartum depression (PPD) are critical for women at elevated risk of PPD. Mindfulness based cognitive therapy - perinatal depression (MBCT-PD) is a preventive intervention that has been shown to reduce risk for PPD in women with a prior history of depression. The objective of this clinical trial is to examine two potential mechanisms of action of MBCT-PD, emotion regulation and cognitive control, using behavioral and neuroimaging methods. METHOD: This baseline protocol describes a randomized control trial (RCT) with two arms, MBCT-PD and treatment as usual (TAU). We plan on enrolling 74 females with a prior history of a major depressive episode, with 37 participants randomized to each arm. Participants in the MBCT-PD arm will receive MBCT-PD during pregnancy, and the TAU group will receive standard prenatal care. All participants will complete the Center for Epidemiological Studies Depression Scale - Revised (CESD-R), Emotion Regulation Questionnaire (ERQ), and classic Stroop task at multiple points from pregnancy through six months postpartum. Participants will also complete an fMRI scan at six weeks postpartum. RESULTS: All primary outcomes are collected at six weeks postpartum. Primary behavioral outcomes include: depressive symptoms on the CESD-R, cognitive reappraisal on the ERQ, and Stroop task performance. In parallel, the primary neurobiological outcomes include whole-brain activation during fMRI tasks when participants 1) regulate emotional responding and 2) engage cognitive control. CONCLUSIONS: This results of this innovative RCT will help identify potential behavioral and neurobiological mechanisms of action of preventive interventions for PPD for in-depth examination in larger scale RCTs. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Opposing effects of impulsivity and mindset on sources of science self-efficacy and STEM interest in adolescents.

Impulsivity has been linked to academic performance in the context of Attention Deficit Hyperactivity Disorder, though its influence on a wider spectrum of students remains largely unexplored, particularly in the context of STEM learning (i.e. science, technology, engineering, and math). STEM learning was hypothesized to be more challenging for impulsive students, since it requires the practice and repetition of tasks as well as concerted attention to task performance. Impulsivity was assessed in a cross-sectional sample of 2,476 students in grades 6-12. Results show impulsivity affects a larger population of students, not limited to students with learning disabilities. Impulsivity was associated with lower sources of self-efficacy for science (SSSE), interest in most STEM domains (particularly math), and self-reported STEM skills. The large negative effect size observed for impulsivity was opposed by higher mindset, which describes a student's belief in the importance of effort when learning is difficult. Mindset had a large positive effect size associated with greater SSSE, STEM interest, and STEM skills. When modeled together, results offer that mindset interventions may benefit impulsive students who struggle with STEM. Together, these data suggest important interconnected roles for impulsivity and mindset that can influence secondary students' STEM trajectories.

Modeling and Cost Benefit Analysis to Guide Deployment of POC Diagnostics for Non-typhoidal Salmonella Infections with Antimicrobial Resistance.

Invasive non-typhoidal Salmonella (NTS) is among the leading causes of blood stream infections in sub-Saharan Africa and other developing regions, especially among pediatric populations. Invasive NTS can be difficult to treat and have high case-fatality rates, in part due to emergence of strains resistant to broad-spectrum antibiotics. Furthermore, improper treatment contributes to increased antibiotic resistance and death. Point of care (POC) diagnostic tests that rapidly identify invasive NTS infection, and differentiate between resistant and non-resistant strains, may greatly improve patient outcomes and decrease resistance at the community level. Here we present for the first time a model for NTS dynamics in high risk populations that can analyze the potential advantages and disadvantages of four strategies involving POC diagnostic deployment, and the resulting impact on antimicrobial treatment for patients. Our analysis strongly supports the use of POC diagnostics coupled with targeted antibiotic use for patients upon arrival in the clinic for optimal patient and public health outcomes. We show that even the use of imperfect POC diagnostics can significantly reduce total costs and number of deaths, provided that the diagnostic gives results quickly enough that patients are likely to return or stay to receive targeted treatment.