Non-voltage gated Ca2+ channel signaling in glomerular cells in kidney health and disease.

Positioned at the head of the nephron, the renal corpuscle generates a plasma ultrafiltrate to initiate urine formation. Three major cell types within the renal corpuscle, the glomerular mesangial cells, podocytes, and glomerular capillary endothelial cells communicate via endocrine and paracrine signaling mechanisms to maintain structure and function of the glomerular capillary network and filtration barrier. Ca2+ signaling mediated by several distinct plasma membrane Ca2+ channels modulates the functions of all three cell types. The last two decades have witnessed pivotal advances in understanding of Ca2+ channel function and regulation in glomerular cells, particularly non-voltage gated Ca2+ channels, in health and renal disease. This review summarizes the current knowledge of the physiological and pathological impact of non-voltage gated Ca2+ channel signaling in glomerular capillary endothelium, mesangial cells and podocytes. The main focus is on transient receptor potential and store-operated Ca2+ channels, but ionotropic N-methyl-D-aspartate receptors and purinergic 2X receptors also are discussed. This update of Ca2+ channel functions in the renal corpuscle and their cellular signaling cascades is intended to inform development of therapeutic strategies targeting these channels to treat kidney diseases, particularly diabetic nephropathy.

Examining animal testing for risk assessment: A WC-12 workshop report.

In toxicology and regulatory testing, the use of animal methods has been both a cornerstone and a subject of intense debate. To continue this discourse a panel and audience representing scientists from various sectors and countries convened at a workshop held during the 12th World Congress on Alternatives and Animal Use in the Life Sciences (WC-12). The ensuing discussion focused on the scientific and ethical considerations surrounding the necessity and responsibility of defending the creation of new animal data in regulatory testing. The primary aim was to foster an open dialogue between the panel members and the audience while encouraging diverse perspectives on the responsibilities and obligations of various stakeholders (including industry, regulatory bodies, technology developers, research scientists, and animal welfare NGOs) in defending the development and subsequent utilization of new animal data. This workshop summary report captures the key elements from this critical dialogue and collective introspection. It describes the intersection of scientific progress and ethical responsibility as all sectors seek to accelerate the pace of 21st century predictive toxicology and new approach methodologies (NAMs) for the protection of human health and the environment.

Relationships among age, motivation, and exercise among women Veterans.

Physical activity (PA) and exercise are central to maintaining health, however research has shown steep declines in PA and exercise among women Veterans as they age. Though motivation may be an important contributor to initiating and sustaining exercise that may change across the lifespan, little is known about exercise motivation and its relation to age and exercise behavior among women Veterans. This cross-sectional study sought to describe exercise motivations, examine relationships among exercise motivations and age, and explore the degree to which age and motivation predict self-reported exercise behavior among women Veterans. We conducted a secondary data analysis from a regional mail survey of 197 women Veterans (mean age = 51; SD = 10.5) enrolled in Veterans Health Administration primary care in a northeastern region (N = 180 in analysis). Measures included demographics (age, body mass index), self-reported exercise motivation, and an estimate of average weekly exercise. Participants endorsed multiple motivators for exercise, most prominently fitness and health management. Age was significantly negatively related to amount of exercise and with socializing as an exercise motivation. After accounting for body mass index, age was a significant predictor of exercise behavior, and exercise motivations accounted for an additional 7.3% of variance in self-reported weekly exercise. Our results suggest that although motivation is a potentially important predictor of exercise, factors beyond motivation may better predict exercise in women Veterans. Further research is needed on personal and practical facilitators and barriers to exercise in this population.

Niche construction and the environmental term of the price equation: How natural selection changes when organisms alter their environments.

Organisms construct their own environments and phenotypes through the adaptive processes of habitat choice, habitat construction, and phenotypic plasticity. We examine how these processes affect the dynamics of mean fitness change through the environmental change term of the Price Equation. This tends to be ignored in evolutionary theory, owing to the emphasis on the first term describing the effect of natural selection on mean fitness (the additive genetic variance for fitness of Fisher's Fundamental Theorem). Using population genetic models and the Price Equation, we show how adaptive niche constructing traits favorably alter the distribution of environments that organisms encounter and thereby increase population mean fitness. Because niche-constructing traits increase the frequency of higher-fitness environments, selection favors their evolution. Furthermore, their alteration of the actual or experienced environmental distribution creates selective feedback between niche constructing traits and other traits, especially those with genotype-by-environment interaction for fitness. By altering the distribution of experienced environments, niche constructing traits can increase the additive genetic variance for such traits. This effect accelerates the process of overall adaption to the niche-constructed environmental distribution and can contribute to the rapid refinement of alternative phenotypic adaptations to different environments. Our findings suggest that evolutionary biologists revisit and reevaluate the environmental term of the Price Equation: owing to adaptive niche construction, it contributes directly to positive change in mean fitness; its magnitude can be comparable to that of natural selection; and, when there is fitness G × E, it increases the additive genetic variance for fitness, the much-celebrated first term.

Relaxed Selection and the Rapid Evolution of Reproductive Genes.

Evolutionary genomic studies find that reproductive protein genes, those directly involved in reproductive processes, diversify more rapidly than most other gene categories. Strong postcopulatory sexual selection acting within species is the predominant hypothesis proposed to account for the observed pattern. Recently, relaxed selection due to sex-specific gene expression has also been put forward to explain the relatively rapid diversification. We contend that relaxed selection due to sex-limited gene expression is the correct null model for tests of molecular evolution of reproductive genes and argue that it may play a more significant role in the evolutionary diversification of reproductive genes than previously recognized. We advocate for a re-evaluation of adaptive explanations for the rapid diversification of reproductive genes.

A Randomized Clinical Trial of Clinician-Supported PTSD Coach in VA Primary Care Patients.

BACKGROUND: Posttraumatic stress disorder (PTSD) is common in primary care patients; however, evidence-based treatments are typically only available in specialty mental healthcare settings and often not accessed. OBJECTIVE: To test the effectiveness of a brief primary care-based treatment, Clinician-Supported PTSD Coach (CS PTSD Coach) was compared with Primary Care Mental Health Integration-Treatment as Usual (PCMHI-TAU) in (1) reducing PTSD severity, (2) engaging veterans in specialty mental health care, and (3) patient satisfaction with care. DESIGN: Multi-site randomized pragmatic clinical trial. PARTICIPANTS: A total of 234 veterans with PTSD symptoms who were not currently accessing PTSD treatment. INTERVENTION: CS PTSD Coach was designed to be implemented in Veterans Affairs PCMHI and combines mental health clinician support with the "PTSD Coach" mobile app. Four 30-min sessions encourage daily use of symptom management strategies. MAIN MEASURES: PTSD severity was measured by clinician-rated interviews pre- and post-treatment (8 weeks). Self-report measures assessed PTSD, depression, and quality of life at pretreatment, posttreatment, and 16- and 24-week follow-ups, and patient satisfaction at post-treatment. Mental healthcare utilization was extracted from medical records. KEY RESULTS: Clinician-rated PTSD severity did not differ by condition at post-treatment. CS PTSD Coach participants improved more on patient-reported PTSD severity at post-treatment than TAU participants (D = .28, p = .021). Coach participants who continued to have problematic PTSD symptoms at post-treatment were not more likely to engage in 2 sessions of specialty mental health treatment than TAU participants. Coach participants engaged in 74% more sessions in the intervention and reported higher treatment satisfaction than TAU participants (p < .001). CONCLUSIONS: A structured 4-session intervention designed to align with patient preferences for care resulted in more patient-reported PTSD symptom relief, greater utilization of mental health treatment, and overall treatment satisfaction than TAU, but not more clinician-rated PTSD symptom relief or engagement in specialty mental health.

Health service utilization among women veterans who report eating disorder symptoms.

OBJECTIVE: Describe health service utilization in women veterans with eating disorder symptoms and characterize the nature of mental health services received. METHOD: Women veterans (N = 191) in a northeastern Veterans Health Administration region completed the Eating Disorders Examination Questionnaire. Health service utilization was then observed for 5 years across multiple domains (i.e., mental health, primary care, telephone consultations, emergency services); negative binomial or zero-inflated negative binomial regression models (mental health) estimated the relative impact of reported eating disorder symptoms on health service utilization. RESULTS: After adjusting for the effects of age and body mass index, higher eating disorder symptoms were associated with higher primary care, mental health services, and telephone consultations. Eating disorder diagnoses were infrequent across the sample. DISCUSSION: Women veterans with higher self-reported eating disorder symptoms evidence higher health service utilization across common healthcare domains. Encounter data suggest that eating disorder symptoms are rarely identified or clinically addressed by providers. Existing mental health visits may represent an opportunity for selective screening for eating disorder symptoms, particularly among women who evidence known risk factors. PUBLIC SIGNIFICANCE: This study reveals that women veterans with higher levels of eating disorder symptoms (e.g., dietary restriction, poor body image) use more primary care, mental health, and telephone consultations than others, but may not receive services that target disordered eating. Opportunities may exist to better identify eating disorder symptoms in the context of existing mental health visits, or potentially to combine treatment for eating disorder symptoms into their mental health care.

Increased gut serotonin production in response to bisphenol A structural analogs may contribute to their obesogenic effects.

Obesogens are synthetic, environmental chemicals that can disrupt endocrine control of metabolism and contribute to the risk of obesity and metabolic disease. Bisphenol A (BPA) is one of the most studied obesogens. There is considerable evidence that BPA exposure is associated with weight gain, increased adiposity, poor blood glucose control, and nonalcoholic fatty liver disease in animal models and human populations. Increased usage of structural analogs of BPA has occurred in response to legislation banning their use in some commercial products. However, BPA analogs may also cause some of the same metabolic impairments because of common mechanisms of action. One key effector that is altered by BPA and its analogs is serotonin, however, it is unknown if BPA-induced changes in peripheral serotonin pathways underlie metabolic perturbations seen with BPA exposure. Upon ingestion, BPA and its analogs act as endocrine-disrupting chemicals in the gastrointestinal tract to influence serotonin production by the gut, where over 95% of serotonin is produced. The purpose of this review is to evaluate how BPA and its analogs alter gut serotonin regulation and then discuss how disruption of serotonergic networks influences host metabolism. We also provide evidence that BPA and its analogs enhance serotonin production in gut enterochromaffin cells. Taken together, we propose that BPA and many BPA analogs represent endocrine-disrupting chemicals that can influence host metabolism through the endogenous production of gut-derived factors, such as serotonin.

Niche construction in quantitative traits: heritability and response to selection.

A central tenet of niche construction (NC) theory is that organisms can alter their environments in heritable and evolutionarily important ways, often altering selection pressures. We suggest that the physical changes niche constructors make to their environments may also alter trait heritability and the response of phenotypes to selection. This effect might change evolution, over and above the effect of NC acting via selection alone. We develop models of trait evolution that allow us to partition the effects of NC on trait heritability from those on selection to better investigate their distinct effects. We show that the response of a phenotype to selection and so the pace of phenotypic change can be considerably altered in the presence of NC and that this effect is compounded when trans-generational interactions are included. We argue that novel mathematical approaches are needed to describe the simultaneous effects of NC on trait evolution via selection and heritability. Just as indirect genetic effects have been shown to significantly increase trait heritability, the effects of NC on heritability in our model suggest a need for further theoretical development of the concept of heritability.

Generating and testing the efficacy of transgenic Cas9 in Tribolium castaneum.

CRISPR/Cas9 genome editing has now expanded to many insect species, including Tribolium castaneum. However, compared to Drosophila melanogaster, the CRISPR toolkit of T. castaneum is limited. A particularly apparent gap is the lack of Cas9 transgenic animals, which generally offer higher editing efficiency. We address this by creating and testing transgenic beetles expressing Cas9. We generated two different constructs bearing basal heat shock promoter-driven Cas9, two distinct 3' UTRs, and one containing Cas9 fused to EGFP by a T2A peptide. Analyses of Cas9 activity in each transgenic line demonstrated that both designs are capable of inducing CRISPR- mediated changes in the genome in the absence of heat induction. Overall, these resources enhance the accessibility of CRISPR/Cas9 genome editing for the Tribolium research community and provide a benchmark against which to compare future transgenic Cas9 lines.

Nanoscopic Study of Water Uptake on Glass Surfaces with Organic Thin Films and Particles from Exposure to Indoor Cooking Activities: Comparison to Model Systems.

Water uptake by thin organic films and organic particles on glass substrates at 80% relative humidity was investigated using atomic force microscopy-infrared (AFM-IR) spectroscopy. Glass surfaces exposed to kitchen cooking activities show a wide variability of coverages from organic particles and organic thin films. Water uptake, as measured by changes in the volume of the films and particles, was also quite variable. A comparison of glass surfaces exposed to kitchen activities to model systems shows that they can be largely represented by oxidized oleic acid and carboxylate groups on long and medium hydrocarbon chains (i.e., fatty acids). Overall, we demonstrate that organic particles and thin films that cover glass surfaces can take up water under indoor-relevant conditions but that the water content is not uniform. The spatial heterogeneity of the changes in these aged glass surfaces under dry (5%) and wet (80%) conditions is quite marked, highlighting the need for studies at the nano- and microscale.

Disruption by stealth - Interference of endocrine disrupting chemicals on hormonal crosstalk with thyroid axis function in humans and other animals.

Thyroid hormones (THs) are important regulators of growth, development, and homeostasis of all vertebrates. There are many environmental contaminants that are known to disrupt TH action, yet their mechanisms are only partially understood. While the effects of Endocrine Disrupting Chemicals (EDCs) are mostly studied as "hormone system silos", the present critical review highlights the complexity of EDCs interfering with TH function through their interactions with other hormonal axes involved in reproduction, stress, and energy metabolism. The impact of EDCs on components that are shared between hormone signaling pathways or intersect between pathways can thus extend beyond the molecular ramifications to cellular, physiological, behavioral, and whole-body consequences for exposed organisms. The comparatively more extensive studies conducted in mammalian models provides encouraging support for expanded investigation and highlight the paucity of data generated in other non-mammalian vertebrate classes. As greater genomics-based resources become available across vertebrate classes, better identification and delineation of EDC effects, modes of action, and identification of effective biomarkers suitable for HPT disruption is possible. EDC-derived effects are likely to cascade into a plurality of physiological effects far more complex than the few variables tested within any research studies. The field should move towards understanding a system of hormonal systems' interactions rather than maintaining hormone system silos.

Maternal-Offspring Interactions: Reciprocally Coevolving Social Environments.

Maternal-zygotic co-evolution is one of the most common examples of indirect genetic effects. I investigate how maternal-zygotic gene interactions affect rates of evolution and adaptation. Using comparably parameterized population genetic models, I compare evolution to an abiotic environment with genotype-by-environment interaction (G × E) to evolution to a maternal environment with offspring genotype-by-maternal environment interaction (G × Gmaternal). There are strong parallels between the 2 models in the components of fitness variance but they differ in their rates of evolution measured in terms of ∆p, gene frequency change, or of ∆W, change in mean fitness. The Price Equation is used to partition ∆W into 2 components, one owing to the genetic variance in fitness by natural selection and a second owing to change in environment. Adaptive evolution is faster in the 2-locus model with G × Gmaternal with free recombination, than it is in the 1-locus model with G × E, because in the former the maternal genetic environment coevolves with the zygotic phenotype adapting to it. I discuss the relevance of these findings for the evolution of genes with indirect genetic effects.

When is Offspring Viability Fitness a Measure of Paternal Fitness and When is it not?

We use population genetics to model the evolution of a gene with an indirect effect owing to paternal care and with a second pleiotropic, direct effect on offspring viability. We use the model to illustrate how the common empirical practice of considering offspring viability as a component of parent fitness can confound a gene's direct and indirect fitness effects. We investigate when this confounding results in a distorted picture of overall evolution and when it does not. We find that the practice has no effect on mean fitness, W, but it does have an effect on the dynamics of gene frequency change, ∆q. We also find that, for some regions of parameter space associated with fitness trade-offs, the distortion is not only quantitative but also qualitative, obscuring the direction of gene frequency change. Because it affects the evolutionary dynamics, it also affects the expected amount of genetic variation at mutation-selection balance, an important consideration in molecular evolution. We discuss empirical techniques for separating direct from indirect effects and how field studies measuring the value of male paternal care might be improved by using them.

Web-Based Problem-solving Training With and Without Peer Support in Veterans With Unmet Mental Health Needs: Pilot Study of Feasibility, User Acceptability, and Participant Engagement.

BACKGROUND: eHealth tools have the potential to meet the mental health needs of individuals who experience barriers to accessing in-person treatment. However, most users have less than optimal engagement with eHealth tools. Coaching from peer specialists may increase their engagement with eHealth. OBJECTIVE: This pilot study aims to test the feasibility and acceptability of a novel, completely automated web-based system to recruit, screen, enroll, assess, randomize, and then deliver an intervention to a national sample of military veterans with unmet mental health needs; investigate whether phone-based peer support increases the use of web-based problem-solving training compared with self-directed use; and generate hypotheses about potential mechanisms of action for problem-solving and peer support for future full-scale research. METHODS: Veterans (N=81) with unmet mental health needs were recruited via social media advertising and enrolled and randomized to the self-directed use of a web-based problem-solving training called Moving Forward (28/81, 35%), peer-supported Moving Forward (27/81, 33%), or waitlist control (26/81, 32%). The objective use of Moving Forward was measured with the number of log-ins. Participants completed pre- and poststudy measures of mental health symptoms and problem-solving confidence. Satisfaction was also assessed post treatment. RESULTS: Automated recruitment, enrollment, and initial assessment methods were feasible and resulted in a diverse sample of veterans with unmet mental health needs from 38 states. Automated follow-up methods resulted in 46% (37/81) of participants completing follow-up assessments. Peer support was delivered with high fidelity and was associated with favorable participant satisfaction. Participants randomized to receive peer support had significantly more Moving Forward log-ins than those of self-directed Moving Forward participants, and those who received peer support had a greater decrease in depression. Problem-solving confidence was associated with greater Moving Forward use and improvements in mental health symptoms among participants both with and without peer support. CONCLUSIONS: Enrolling and assessing individuals in eHealth studies without human contact is feasible; however, different methods or designs are necessary to achieve acceptable participant engagement and follow-up rates. Peer support shows potential for increasing engagement in web-based interventions and reducing symptoms. Future research should investigate when and for whom peer support for eHealth is helpful. Problem-solving confidence should be further investigated as a mechanism of action for web-based problem-solving training. TRIAL REGISTRATION: ClinicalTrials.gov NCT03555435; http://clinicaltrials.gov/ct2/show/NCT03555435.

When mother knows best: A population genetic model of transgenerational versus intragenerational plasticity.

Many organisms exhibit phenotypic plasticity; producing alternate phenotypes depending on the environment. Individuals can be plastic (intragenerational or direct plasticity), wherein individuals of the same genotype produce different phenotypes in response to the environments they experience. Alternatively, an individual's phenotype may be under the control of its parents, usually the mother (transgenerational or indirect plasticity), so that mother's genotype determines the phenotype produced by a given genotype of her offspring. Under what conditions does plasticity evolve to have intragenerational as opposed to transgenerational genetic control? To explore this question, we present a population genetic model for the evolution of transgenerational and intragenerational plasticity. We hypothesize that the capacity for plasticity incurs a fitness cost, which is borne either by the individual developing the plastic phenotype or by its mother. We also hypothesize that individuals are imperfect predictors of future environments and their capacity for plasticity can lead them occasionally to make a low-fitness phenotype for a particular environment. When the cost, benefit and error parameters are equal, we show that there is no evolutionary advantage to intragenerational over transgenerational plasticity, although the rate of evolution of transgenerational plasticity is half the rate for intragenerational plasticity, as predicted by theory on indirect genetic effects. We find that transgenerational plasticity evolves when mothers are better predictors of future environments than offspring or when the fitness cost of the capacity for plasticity is more readily borne by a mother than by her developing offspring. We discuss different natural systems with either direct intragenerational plasticity or indirect transgenerational plasticity and find a pattern qualitatively in accord with the predictions of our model.

Validation of an Expanded Measure of Integrated Care Provider Fidelity: PPAQ-2.

This study aimed to validate the factor structure of the expanded Primary Care Behavioral Health Provider Adherence Questionnaire (PPAQ-2), which is designed to assess provider fidelity to both the Primary Care Behavioral Health (PCBH) and collaborative care management (CCM) models of integrated primary care. Two-hundred fifty-three integrated care providers completed self-reports of professional background, perceptions of clinic integration and related practice barriers, and the PPAQ-2. Confirmatory factor analyses were conducted to assess the theorized factor structure and criterion validity was assessed through correlational analysis. Factor analyses demonstrated adequate fit with the data and acceptable to excellent composite reliabilities across five PCBH domains and five CCM domains. Validity was demonstrated by correlations between adherence scores and measures of clinic integration and barriers to fidelity. The PPAQ-2 is a psychometrically sound measure that can be used in future integrated care dismantling studies to identify provider behaviors that best predict patient outcomes.

The promise and peril of CRISPR gene drives: Genetic variation and inbreeding may impede the propagation of gene drives based on the CRISPR genome editing technology.

Gene drives are selfish genetic elements that use a variety of mechanisms to ensure they are transmitted to subsequent generations at greater than expected frequencies. Synthetic gene drives based on the clustered regularly interspersed palindromic repeats (CRISPR) genome editing system have been proposed as a way to alter the genetic characteristics of natural populations of organisms relevant to the goals of public health, conservation, and agriculture. Here, we review the principles and potential applications of CRISPR drives, as well as means proposed to prevent their uncontrolled spread. We also focus on recent work suggesting that factors such as natural genetic variation and inbreeding may represent substantial impediments to the propagation of CRISPR drives.

Toxicity of Flame Retardant Isopropylated Triphenyl Phosphate: Liver, Adrenal, and Metabolic Effects.

The use of organophosphates phosphate flame retardants, particularly isopropylated triphenyl phosphate (IPTPP), has increased in recent years as replacements for polybrominated diphenyl ethers. This is despite limited understanding of the hazards of IPTPP. To examine the general and endocrine toxicity of IPTPP, adult Wistar rats were fed for 90 days on diets containing IPTPP estimated to deliver daily doses of 5 to 140 mg/kg/d. Exposure to IPTPP caused a dose-related increase in liver and adrenal gland weight in both sexes. Cells in the zona fasciculate (ZF) of the adrenal cortex were observed to be filled with droplets that stained with Nile red, suggesting they contained neutral lipid. Despite marked structural changes, there was no change in basal or stress-induced serum levels of their major secreted ZF product corticosterone (B), suggesting cell function was not altered. There were no effects on responses to glucose or insulin challenge, but serum levels of fructosamine were elevated by IPTPP exposure, suggesting a slight tendency of exposed animals to be hyperglycemic. Serum levels of total cholesterol and high-density lipoprotein cholesterol were significantly elevated in both sexes at the 2 highest doses. This study demonstrates that IPTPP exposure causes hypertrophy and neutral lipid accumulation in adrenal cortex ZF cells but does not result in impaired B production.

50-year anniversary of Lloyd's "mean crowding": Ideas on patchy distributions.

This year marks the 50th anniversary of Monte B. Lloyd's "Mean Crowding" (1967) paper, in which he introduced a metric that accounts for an individual's experience of conspecific density. Mean crowding allows ecologists to measure the degree of spatial aggregation of individuals in a manner relevant to intraspecific competition for resources. We take the concept of mean crowding a step beyond its most common usage and that it has a mathematical relationship to many of the most important concepts in ecology and evolutionary biology. Mean crowding, a first-order approximation of the degree of nonrandomness in a distribution, can function as a powerful heuristic that can unify concepts across disciplines in a more general way that Lloyd originally envisioned.