Discovery of small molecule guanylyl cyclase A receptor positive allosteric modulators.

The particulate guanylyl cyclase A receptor (GC-A), via activation by its endogenous ligands atrial natriuretic peptide (ANP) and b-type natriuretic peptide (BNP), possesses beneficial biological properties such as blood pressure regulation, natriuresis, suppression of adverse remodeling, inhibition of the renin-angiotensin-aldosterone system, and favorable metabolic actions through the generation of its second messenger cyclic guanosine monophosphate (cGMP). Thus, the GC-A represents an important molecular therapeutic target for cardiovascular disease and its associated risk factors. However, a small molecule that is orally bioavailable and directly targets the GC-A to potentiate cGMP has yet to be discovered. Here, we performed a cell-based high-throughput screening campaign of the NIH Molecular Libraries Small Molecule Repository, and we successfully identified small molecule GC-A positive allosteric modulator (PAM) scaffolds. Further medicinal chemistry structure-activity relationship efforts of the lead scaffold resulted in the development of a GC-A PAM, MCUF-651, which enhanced ANP-mediated cGMP generation in human cardiac, renal, and fat cells and inhibited cardiomyocyte hypertrophy in vitro. Further, binding analysis confirmed MCUF-651 binds to GC-A and selectively enhances the binding of ANP to GC-A. Moreover, MCUF-651 is orally bioavailable in mice and enhances the ability of endogenous ANP and BNP, found in the plasma of normal subjects and patients with hypertension or heart failure, to generate GC-A-mediated cGMP ex vivo. In this work, we report the discovery and development of an oral, small molecule GC-A PAM that holds great potential as a therapeutic for cardiovascular, renal, and metabolic diseases.

The Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) for serious mental illness in community mental health part 2: study protocol for a hybrid type 2 effectiveness-implementation cluster-randomized trial using train-the-trainer.

BACKGROUND: Train-the-trainer (TTT) is a promising method for implementing evidence-based psychological treatments (EBPTs) in community mental health centers (CMHCs). In TTT, expert trainers train locally embedded individuals (i.e., Generation 1 providers) to deliver an EBPT, who then train others (i.e., Generation 2 providers). The present study will evaluate implementation and effectiveness outcomes of an EBPT for sleep and circadian dysfunction-the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C)-delivered to CMHC patients with serious mental illness by Generation 2 providers (i.e., trained and supervised within CMHCs via TTT). Specifically, we will investigate whether adapting TranS-C to fit CMHC contexts improves Generation 2 (a) patient outcomes and (b) providers' perceptions of fit. METHODS: TTT will be implemented in nine CMHCs in California, USA (N = 60 providers; N = 130 patients) via facilitation. CMHCs are cluster-randomized by county to Adapted TranS-C or Standard TranS-C. Within each CMHC, patients are randomized to immediate TranS-C or usual care followed by delayed treatment with TranS-C (UC-DT). Aim 1 will assess the effectiveness of TranS-C (combined Adapted and Standard), compared to UC-DT, on improvements in sleep and circadian problems, functional impairment, and psychiatric symptoms for Generation 2 patients. Aim 2 will evaluate whether Adapted TranS-C is superior to Standard TranS-C with respect to Generation 2 providers' perceptions of fit. Aim 3 will evaluate whether Generation 2 providers' perceived fit mediates the relation between TranS-C treatment condition and patient outcomes. Exploratory analyses will (1) evaluate whether the effectiveness of TranS-C for patient outcomes is moderated by generation, (2) compare Adapted and Standard TranS-C on patient perceptions of credibility/improvement and PhenX Toolkit outcomes (e.g., substance use, suicidality), and (3) evaluate other possible moderators. DISCUSSION: This trial has potential to (a) inform the process of embedding local trainers and supervisors to expand delivery of a promising transdiagnostic treatment for sleep and circadian dysfunction, (b) add to the growing body of TTT literature by evaluating TTT outcomes with a novel treatment and population, and (c) advance our understanding of providers' perceptions of EBPT "fit" across TTT generations. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05805657 . Registered on April 10, 2023.

The Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) for serious mental illness in community mental health part 2: Study protocol for a hybrid type 2 effectiveness-implementation cluster- randomized trial using train-the-trainer.

Background: Train-the-trainer (TTT) is a promising method for implementing evidence-based psychological treatments (EBPTs) in community mental health centers (CMHCs). In TTT, expert trainers train locally embedded individuals (i.e., Generation 1 providers) to deliver an EBPT, who then train others (i.e., Generation 2 providers). The present study will evaluate implementation and effectiveness outcomes of an EBPT for sleep and circadian dysfunction-the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C)-delivered to CMHC patients with serious mental illness by Generation 2 providers (i.e., trained and supervised within CMHCs via TTT). Specifically, we will investigate whether adapting TranS-C to fit CMHC contexts improves Generation 2 (a) patient outcomes (b) providers' perceptions of fit. Methods: TTT will be implemented in nine CMHCs in California, United States (N= 60 providers; N= 130 patients) via facilitation. CMHCs are cluster-randomized by county to Adapted TranS-C or Standard TranS-C. Within each CMHC, patients are randomized to immediate TranS-C or usual care followed by delayed treatment with TranS-C (UC-DT). Aim 1 will assess the effectiveness of TranS-C (combined Adapted and Standard), compared to UC-DT, on improvements in sleep and circadian problems, functional impairment, and psychiatric symptoms for Generation 2 patients. Aim 2 will evaluate whether Adapted TranS-C is superior to Standard TranS-C with respect to Generation 2 providers' perceptions of fit. Aim 3 will evaluate whether Generation 2 providers' perceived fit mediates the relation between TranS-C treatment condition and patient outcomes. Exploratory analyses will: (1) evaluate whether the effectiveness of TranS-C for patient outcomes is moderated by generation, (2) compare Adapted and Standard TranS-C on patient perceptions of credibility/improvement and PhenX Toolkit outcomes (e.g., substance use, suicidality); and (3) evaluate other possible moderators. Discussion: This trial has potential to inform the process of (a) embedding local trainers and supervisors to expand delivery of a promising transdiagnostic treatment for sleep and circadian dysfunction, (b) adding to the growing body of TTT literature by evaluating TTT outcomes with a novel treatment and population, and (c) advancing our understanding of providers' perceptions of EBPT 'fit' across TTT generations. Trial registration: Clinicaltrials.gov identifier: NCT05805657. Registered on April 10, 2023. https://clinicaltrials.gov/ct2/show/NCT05805657.

Using crossover breakpoints in recombinant inbred lines to identify quantitative trait loci controlling the global recombination frequency.

Recombination is a crucial component of evolution and breeding, producing new genetic combinations on which selection can act. Rates of recombination vary tremendously, not only between species but also within species and for specific chromosomal segments. In this study, by examining recombination events captured in recombinant inbred mapping populations previously created for maize, wheat, Arabidopsis, and mouse, we demonstrate that substantial variation exists for genomewide crossover rates in both outcrossed and inbred plant and animal species. We also identify quantitative trait loci (QTL) that control this variation. The method that we developed and employed here holds promise for elucidating factors that regulate meiotic recombination and for creation of hyperrecombinogenic lines, which can help overcome limited recombination that hampers breeding progress.

Dietary restraint and heightened reactivity to food.

Previously, studies have explored the relationship between dietary behavior and salivary reactivity to food. Despite this, it remains unclear which behaviors are associated with enhanced reactivity. One problem is that measures of behavior have not been compared directly. In particular, it is unclear whether elevated reactivity is associated with measures of dietary restraint or with measures of failed dietary control and a tendency to overeat. To address this problem, we compared the association between salivary reactivity and scores on the subscales of the Three-Factor Eating Questionnaire (restraint, disinhibition, and hunger). Estimates of reactivity were derived from the difference between a baseline saliva measure and a similar measure taken in close proximity to hot pizza. Our second aim was to explore how salivary reactivity changes after a meal. Female participants (N=40) were tested before and after a lunch (cheese sandwiches). All tended to show reactivity to pizza before but not after lunch. No significant differences were associated with the disinhibition or hunger subscales. However, prelunch reactivity was significantly greater in those participants with high scores on the restraint scale. This does not appear to be related to reported levels of hunger before lunch. Rather, it may reveal an intrinsic difference between the reaction of restrained and unrestrained eaters to food.

Risky business: risk behaviors in adolescents with type 1 diabetes.

PURPOSE: The purpose of this article is to review risk behaviors and their health consequences in adolescents with type 1 diabetes. The existing literature on common risk behaviors in adolescents is examined, with a focus on illicit drug use, alcohol use, smoking, unprotected sexual activity, and disordered eating behaviors. CONCLUSIONS: A review of the literature highlights the lack of studies of risk behaviors in this population. Much of what is known comes from studies with adolescents in the general population or from studies of adults with type 1 diabetes. Known risk and protective factors for risk behaviors and health outcomes are noted. Based on these findings, suggestions are provided for diabetes educators and health care providers to assess for and prevent risk behaviors in adolescents with type 1 diabetes. Directions for future research in this population are indicated, including the need to develop and test standardized prevention programs.

Genetic properties of the maize nested association mapping population.

Maize genetic diversity has been used to understand the molecular basis of phenotypic variation and to improve agricultural efficiency and sustainability. We crossed 25 diverse inbred maize lines to the B73 reference line, capturing a total of 136,000 recombination events. Variation for recombination frequencies was observed among families, influenced by local (cis) genetic variation. We identified evidence for numerous minor single-locus effects but little two-locus linkage disequilibrium or segregation distortion, which indicated a limited role for genes with large effects and epistatic interactions on fitness. We observed excess residual heterozygosity in pericentromeric regions, which suggested that selection in inbred lines has been less efficient in these regions because of reduced recombination frequency. This implies that pericentromeric regions may contribute disproportionally to heterosis.

The genetic architecture of maize flowering time.

Flowering time is a complex trait that controls adaptation of plants to their local environment in the outcrossing species Zea mays (maize). We dissected variation for flowering time with a set of 5000 recombinant inbred lines (maize Nested Association Mapping population, NAM). Nearly a million plants were assayed in eight environments but showed no evidence for any single large-effect quantitative trait loci (QTLs). Instead, we identified evidence for numerous small-effect QTLs shared among families; however, allelic effects differ across founder lines. We identified no individual QTLs at which allelic effects are determined by geographic origin or large effects for epistasis or environmental interactions. Thus, a simple additive model accurately predicts flowering time for maize, in contrast to the genetic architecture observed in the selfing plant species rice and Arabidopsis.

Photocatalytic antimicrobial activity of thin surface films of TiO(2), CuO and TiO (2)/CuO dual layers on Escherichia coli and bacteriophage T4.

TiO(2)-coated surfaces are increasingly studied for their ability to inactivate microorganisms. The activity of glass coated with thin films of TiO(2), CuO and hybrid CuO/TiO(2) prepared by atmospheric Chemical Vapour Deposition (Ap-CVD) and TiO(2) prepared by a sol-gel process was investigated using the inactivation of bacteriophage T4 as a model for inactivation of viruses. The chemical oxidising activity was also determined by measuring stearic acid oxidation. The results showed that the rate of inactivation of bacteriophage T4 increased with increasing chemical oxidising activity with the maximum rate obtained on highly active sol-gel preparations. However, these were delicate and easily damaged unlike the Ap-CVD coatings. Inactivation rates were highest on CuO and CuO/TiO(2) which had the lowest chemical oxidising activities. The inactivation of T4 was higher than that of Escherichia coli on low activity surfaces. The combination of photocatalysis and toxicity of copper acted synergistically to inactivate bacteriophage T4 and retained some self-cleaning activity. The presence of phosphate ions slowed inactivation but NaCl had no effect. The results show that TiO(2)/CuO coated surfaces are highly antiviral and may have applications in the food and healthcare industries.

Clinical experience of a carbohydrate-restricted diet for the metabolic syndrome.

BACKGROUND: Our objective was to analyze a restricted carbohydrate dietary approach compared to a standard low-fat diet plus medication plan as treatment for weight loss and the metabolic syndrome. METHODS: This was a retrospective analysis of patients attending an outpatient weight and metabolism management program, including periodic individual visits combined with either a carbohydrate-restricted diet (with multivitamin and essential fatty acids supplementation) or low-fat/low-calorie diet + phentermine/fenfluramine. The main outcome measurements were total body weight and fasting serum lipid profiles. Clinical data were maintained on standardized flow sheets. RESULTS: One hundred twenty-two patients had complete baseline and follow-up information. Sixty-six were treated with a carbohydrate-restricted diet without medication, and 56 were treated with a combination of low-fat/low-calorie diet and medication. Weight loss occurred in both groups, but was greater in the medication group: the carbohydrate-restricted group lost a mean of 9.5 kg over 15.0 weeks (0.63 kg/week); the low-fat/low-calorie diet + medication group lost a mean of 14.1 kg over a mean duration of 20.2 weeks (0.70 kg/week), p < 0.01. The carbohydrate-restricted group had a greater reduction in triglycerides (p = 0.02) and triglyceride/HDL ratio (p = 0.01), and a greater increase in HDL (p < 0.001) than the medication group. CONCLUSIONS: In this outpatient program, a carbohydrate-restricted diet and a low-fat/low-calorie diet + medication led to weight loss, but the carbohydrate-restricted diet had a more favorable effect on triglycerides and HDL. Because of the effects on weight, triglycerides, and HDL, a carbohydrate-restricted diet may be useful for the treatment of metabolic syndrome.