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"Smith, Daniel L"
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A Microarray-Based Genetic Screen for Yeast Chronological Aging Factors
Model organisms have played an important role in the elucidation of multiple genes and cellular processes that regulate aging. In this study we utilized the budding yeast, Saccharomyces cerevisiae, in a large-scale screen for genes that function in the regulation of chronological lifespan, which is defined by the number of days that non-dividing cells remain viable. A pooled collection of viable haploid gene deletion mutants, each tagged with unique identifying DNA \"bar-code\" sequences was chronologically aged in liquid culture. Viable mutants in the aging population were selected at several time points and then detected using a microarray DNA hybridization technique that quantifies abundance of the barcode tags. Multiple short- and long-lived mutants were identified using this approach. Among the confirmed short-lived mutants were those defective for autophagy, indicating a key requirement for the recycling of cellular organelles in longevity. Defects in autophagy also prevented lifespan extension induced by limitation of amino acids in the growth media. Among the confirmed long-lived mutants were those defective in the highly conserved de novo purine biosynthesis pathway (the ADE genes), which ultimately produces IMP and AMP. Blocking this pathway extended lifespan to the same degree as calorie (glucose) restriction. A recently discovered cell-extrinsic mechanism of chronological aging involving acetic acid secretion and toxicity was suppressed in a long-lived ade4Delta mutant and exacerbated by a short-lived atg16Delta autophagy mutant. The identification of multiple novel effectors of yeast chronological lifespan will greatly aid in the elucidation of mechanisms that cells and organisms utilize in slowing down the aging process.
Journal Article
Fat mass loss correlates with faster disease progression in amyotrophic lateral sclerosis patients: Exploring the utility of dual-energy x-ray absorptiometry in a prospective study
Weight loss is a predictor of shorter survival in amyotrophic lateral sclerosis (ALS). We performed serial measures of body composition using Dual-energy X-ray Absorptiometry (DEXA) in ALS patients to explore its utility as a biomarker of disease progression.
DEXA data were obtained from participants with ALS (enrollment, at 6- and 12- months follow ups) and Parkinson's disease (enrollment and at 4-month follow up) as a comparator group. Body mass index, total lean mass index, appendicular lean mass index, total fat mass index, and percentage body fat at enrollment were compared between the ALS and PD cohorts and age-matched normative data obtained from the National Health and Nutrition Examination Survey database. Estimated monthly changes of body composition measures in the ALS cohort were compared to those of the PD cohort and were correlated with disease progression measured by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).
The ALS cohort (N = 20) had lower baseline total and appendicular lean mass indices compared to the PD cohort (N = 20) and general population. Loss in total and appendicular lean masses were found to be significantly associated with follow-up time. Low baseline percentage body fat (r = 0.72, p = 0.04), loss of percentage body fat (r = 0.81, p = 0.01), and total fat mass index (r = 0.73, p = 0.04) during follow up correlated significantly with monthly decline of ALSFRS-R scores in ALS cohort who had 2 or more follow-ups (N = 8).
Measurement of body composition with DEXA might serve as a biomarker for rapid disease progression in ALS.
Journal Article
Myths, Presumptions, and Facts about Obesity
This commentary reviews common myths and presumptions about obesity and also provides some useful evidence-based concepts about overweight and obesity.
Passionate interests, the human tendency to seek explanations for observed phenomena, and everyday experience appear to contribute to strong convictions about obesity, despite the absence of supporting data. When the public, mass media, government agencies, and even academic scientists espouse unsupported beliefs, the result may be ineffective policy, unhelpful or unsafe clinical and public health recommendations, and an unproductive allocation of resources. In this article, we review some common beliefs about obesity that are not supported by scientific evidence and also provide some useful evidence-based concepts. We define myths as beliefs held to be true despite substantial refuting evidence, presumptions . . .
Journal Article
Prediction accuracy and repeatability of UAV based biomass estimation in wheat variety trials as affected by variable type, modelling strategy and sampling location
Background
This study explores the use of Unmanned Aerial Vehicles (UAVs) for estimating wheat biomass, focusing on the impact of phenotyping and analytical protocols in the context of late-stage variety selection programs. It emphasizes the importance of variable selection, model specificity, and sampling location within the experimental plot in predicting biomass, aiming to refine UAV-based estimation techniques for enhanced selection accuracy and throughput in variety testing programs.
Results
The research uncovered that integrating geometric and spectral traits led to an increase in prediction accuracy, whilst a recursive feature elimination (RFE) based variable selection workflowled to slight reductions in accuracy with the benefit of increased interpretability. Models, tailored to specific experiments were more accurate than those modelling all experiments together, while models trained for broad-growth stages did not significantly increase accuracy. The comparison between a permanent and a precise region of interest (ROI) within the plot showed negligible differences in biomass prediction accuracy, indicating the robustness of the approach across different sampling locations within the plot. Significant differences in the within-season repeatability (w
2
) of biomass predictions across different experiments highlighted the need for further investigation into the optimal timing of measurement for prediction.
Conclusions
The study highlights the promising potential of UAV technology in biomass prediction for wheat at a small plot scale. It suggests that the accuracy of biomass predictions can be significantly improved through optimizing analytical and modelling protocols (i.e., variable selection, algorithm selection, stage-specific model development). Future work should focus on exploring the applicability of these findings under a wider variety of conditions and from a more diverse set of genotypes.
Journal Article
Murine genetic models of obesity: type I error rates and the power of commonly used analyses as assessed by plasmode-based simulation
Background/ObjectivesGenetic contributors to obesity are frequently studied in murine models. However, the sample sizes of these studies are often small, and the data may violate assumptions of common statistical tests, such as normality of distributions. We examined whether, in these cases, type I error rates and power are affected by the choice of statistical test.Subjects/MethodsWe conducted “plasmode”-based simulation using empirical data on body mass (weight) from murine genetic models of obesity. For the type I error simulation, the weight distributions were adjusted to ensure no difference in means between control and mutant groups. For the power simulation, the distributions of the mutant groups were shifted to ensure specific effect sizes. Three to twenty mice were resampled from the empirical distributions to create a plasmode. We then computed type I error rates and power for five common tests on the plasmodes: Student’s t test, Welch’s t test, Wilcoxon rank sum test (aka, Mann–Whitney U test), permutation test, and bootstrap test.ResultsWe observed type I error inflation for all tests, except the bootstrap test, with small samples (≤5). Type I error inflation decreased as sample size increased (≥8) but remained. The Wilcoxon test should be avoided because of heterogeneity of distributions. For power, a departure from the reference was observed with small samples for all tests. Compared with the other tests, the bootstrap test had less power with small samples.ConclusionsOverall, the bootstrap test is recommended for small samples to avoid type I error inflation, but this benefit comes at the cost of lower power. When sample size is large enough, Welch’s t test is recommended because of high power with minimal type I error inflation.
Journal Article
Canagliflozin extends life span in genetically heterogeneous male but not female mice
Canagliflozin (Cana) is an FDA-approved diabetes drug that protects against cardiovascular and kidney diseases. It also inhibits the sodium glucose transporter 2 by blocking renal reuptake and intestinal absorption of glucose. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing Cana at 180 ppm at 7 months of age until their death. Cana extended median survival of male mice by 14%. Cana also increased by 9% the age for 90th percentile survival, with parallel effects seen at each of 3 test sites. Neither the distribution of inferred cause of death nor incidental pathology findings at end-of-life necropsies were altered by Cana. Moreover, although no life span benefits were seen in female mice, Cana led to lower fasting glucose and improved glucose tolerance in both sexes, diminishing fat mass in females only. Therefore, the life span benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in male mice given acarbose, a diabetes drug that blocks glucose surges through a distinct mechanism, i.e., slowing breakdown of carbohydrate in the intestine. Interventions that control daily peak glucose levels deserve attention as possible preventive medicines to protect from a wide range of late-life neoplastic and degenerative diseases.
Journal Article
A paternal methyl donor depleted diet leads to increased anxiety- and depression-like behavior in adult rat offspring
Epigenetic mechanisms such as DNA methylation elicit lasting changes in gene expression and likely mediate gene–environment interactions that shape brain development, behavior, and emotional health. Myriad environmental factors influence DNA methylation, including methyl donor content in the paternal diet, could influence methylation in offspring via changes in the paternal germ line. The present study examines the effects of paternal methyl donor dietary deficiency on offspring’s emotional behaviors, including anxiety, social interaction, and depression-like behavior. We previously found that rats bred to display high levels of anxiety- and depression-like behavior exhibit diminished DNA methylation in the amygdala. We also observed that depleting dietary methyl donor content exacerbated the rats’ already high levels of anxiety- and depression-like behavior. Here we sought to determine whether paternal dietary methyl donor depletion elicits intergenerational effects on first generation (F1) offspring’s behavior (potentially triggering a similar increase in anxiety- and/or depression-like behavior). Thus, adult male rats prone to high anxiety/depression-like behavior, were fed either a methyl donor depleted (DEP) or control (CON) diet for 5 weeks prior to mating. They were paired with females and resultant F1 male offspring were subjected to a behavioral test battery in adulthood. F1-DEP offspring showed a similar behavioral profile to the F0 males, including greater depression-like behavior in the forced swim test (FST) and increased anxiety-like behavior in the open field test (OFT). Future work will interrogate molecular changes in the brains of F1 offspring that mediate these intergenerational effects of paternal methyl donor dietary content on offspring emotional behavior.
Journal Article
The Antidiabetic Agent Acarbose Improves Anti-PD-1 and Rapamycin Efficacy in Preclinical Renal Cancer
Although immune checkpoint inhibitors and targeted therapeutics have changed the landscape of treatment for renal cell carcinoma (RCC), most patients do not experience significant clinical benefits. Emerging preclinical studies report that nutrition-based interventions and glucose-regulating agents can improve therapeutic efficacy. However, the impact of such agents on therapeutic efficacy in metastatic kidney cancer remains unclear. Here, we examined acarbose, an alpha-glucosidase inhibitor and antidiabetic agent, in a preclinical model of metastatic kidney cancer. We found that acarbose blunted postprandial blood glucose elevations in lean, nondiabetic mice and impeded the growth of orthotopic renal tumors, an outcome that was reversed by exogenous glucose administration. Delayed renal tumor outgrowth in mice on acarbose occurred in a CD8 T cell-dependent manner. Tumors from these mice exhibited increased frequencies of CD8 T cells that retained production of IFNγ, TNFα, perforin, and granzyme B. Combining acarbose with either anti-PD-1 or the mammalian target of rapamycin inhibitor, rapamycin, significantly reduced lung metastases relative to control mice on the same therapies. Our findings in mice suggest that combining acarbose with current RCC therapeutics may improve outcomes, warranting further study to determine whether acarbose can achieve similar responses in advanced RCC patients in a safe and likely cost-effective manner.
Journal Article
High Fructose Corn Syrup-Moderate Fat Diet Potentiates Anxio-Depressive Behavior and Alters Ventral Striatal Neuronal Signaling
The neurobiological mechanisms that mediate psychiatric comorbidities associated with metabolic disorders such as obesity, metabolic syndrome and diabetes remain obscure. High fructose corn syrup (HFCS) is widely used in beverages and is often included in food products with moderate or high fat content that have been linked to many serious health issues including diabetes and obesity. However, the impact of such foods on the brain has not been fully characterized. Here, we evaluated the effects of long-term consumption of a HFCS-Moderate Fat diet (HFCS-MFD) on behavior, neuronal signal transduction, gut microbiota, and serum metabolomic profile in mice to better understand how its consumption and resulting obesity and metabolic alterations relate to behavioral dysfunction. Mice fed HFCS-MFD for 16 weeks displayed enhanced anxiogenesis, increased behavioral despair, and impaired social interactions. Furthermore, the HFCS-MFD induced gut microbiota dysbiosis and lowered serum levels of serotonin and its tryptophan-based precursors. Importantly, the HFCS-MFD altered neuronal signaling in the ventral striatum including reduced inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β), increased expression of ΔFosB, increased Cdk5-dependent phosphorylation of DARPP-32, and reduced PKA-dependent phosphorylation of the GluR1 subunit of the AMPA receptor. These findings suggest that HFCS-MFD-induced changes in the gut microbiota and neuroactive metabolites may contribute to maladaptive alterations in ventral striatal function that underlie neurobehavioral impairment. While future studies are essential to further evaluate the interplay between these factors in obesity and metabolic syndrome-associated behavioral comorbidities, these data underscore the important role of peripheral-CNS interactions in diet-induced behavioral and brain function. This study also highlights the clinical need to address neurobehavioral comorbidities associated with obesity and metabolic syndrome.
Journal Article