Identifying specific prefrontal neurons that contribute to autism-associated abnormalities in physiology and social behavior.

Functional imaging and gene expression studies both implicate the medial prefrontal cortex (mPFC), particularly deep-layer projection neurons, as a potential locus for autism pathology. Here, we explored how specific deep-layer prefrontal neurons contribute to abnormal physiology and behavior in mouse models of autism. First, we find that across three etiologically distinct models-in utero valproic acid (VPA) exposure, CNTNAP2 knockout and FMR1 knockout-layer 5 subcortically projecting (SC) neurons consistently exhibit reduced input resistance and action potential firing. To explore how altered SC neuron physiology might impact behavior, we took advantage of the fact that in deep layers of the mPFC, dopamine D2 receptors (D2Rs) are mainly expressed by SC neurons, and used D2-Cre mice to label D2R+ neurons for calcium imaging or optogenetics. We found that social exploration preferentially recruits mPFC D2R+ cells, but that this recruitment is attenuated in VPA-exposed mice. Stimulating mPFC D2R+ neurons disrupts normal social interaction. Conversely, inhibiting these cells enhances social behavior in VPA-exposed mice. Importantly, this effect was not reproduced by nonspecifically inhibiting mPFC neurons in VPA-exposed mice, or by inhibiting D2R+ neurons in wild-type mice. These findings suggest that multiple forms of autism may alter the physiology of specific deep-layer prefrontal neurons that project to subcortical targets. Furthermore, a highly overlapping population-prefrontal D2R+ neurons-plays an important role in both normal and abnormal social behavior, such that targeting these cells can elicit potentially therapeutic effects

Correlation between vitamin A, E, coenzyme Q10 and degree of insulin resistance in obese and non-obese subjects

The aim of the present study was to investigate correlation between plasma vitamin A, vitamin E, serum coenzyme Q10 levels and degree of insulin resistance in obese and normal weight people. The study was performed on 98 (21 Male, 77 Female) obese people and 78 (20 Male, 58 Female) control subjects. Vitamin A, E and coenzyme Q10 levels were adjusted to the lipid levels. Adjusted vitamin A and E and coenzyme Q10 levels of the obese female group were significantly lower than those of the control female group. Adjusted vitamin A and coenzyme Q10 levels of the obese male group were significantly lower than those of the control male group. Insulin resistance level of the obese female and male groups were significantly higher than that of the control female and male groups. There were no significant correlations between serum coenzyme Q10, plasma vitamin A and E levels and insulin resistance in obese and control subjects. Our findings show that it is essential to use the lipid adjusted levels of lipid soluble nutrients in obesity. Also, we have found no association between insulin resistance and vitamin A, vitamin E and coenzyme Q10 levels in obese subjects

Nitric oxide availability is increased in contracting skeletal muscle from aged mice, but does not differentially decrease muscle superoxide

Reactive oxygen and nitrogen species have been implicated in the loss of skeletal muscle mass and function that occurs during aging. Nitric oxide (NO) and superoxide are generated by skeletal muscle and where these are generated in proximity their chemical reaction to form peroxynitrite can compete with the superoxide dismutation to hydrogen peroxide. Changes in NO availability may therefore theoretically modify superoxide and peroxynitrite activities in tissues, but published data are contradictory regarding aging effects on muscle NO availability. We hypothesised that an age-related increase in NO generation might increase peroxynitrite generation in muscles from old mice, leading to an increased nitration of muscle proteins and decreased superoxide availability. This was examined using fluorescent probes and an isolated fiber preparation to examine NO content and superoxide in the cytosol and mitochondria of muscle fibers from adult and old mice both at rest and following contractile activity. We also examined the 3-nitrotyrosine (3-NT) and peroxiredoxin 5 (Prx5) content of muscles from mice as markers of peroxynitrite activity. Data indicate that a substantial age-related increase in NO levels occurred in muscle fibers during contractile activity and this was associated with an increase in muscle eNOS. Muscle proteins from old mice also showed an increased 3-NT content. Inhibition of NOS indicated that NO decreased superoxide bioavailability in muscle mitochondria, although this effect was not age related. Thus increased NO in muscles of old mice was associated with an increased 3-NT content that may potentially contribute to age-related degenerative changes in skeletal muscle

Microbiota modulating nutritional approaches to countering the effects of viral respiratory infections including SARS-CoV-2 through promoting metabolic and immune fitness with probiotics and plant bioactives

Viral respiratory infections (VRIs) can spread quickly and cause enormous morbidityand mortality worldwide. These events pose serious threats to public health due to time lags indeveloping vaccines to activate the acquired immune system. The high variability of people’ssymptomatic responses to viral infections, as illustrated in the current COVID-19 pandemic, indicatesthe potential to moderate the severity of morbidity from VRIs. Growing evidence supports rolesfor probiotic bacteria (PB) and prebiotic dietary fiber (DF) and other plant nutritional bioactivesin modulating immune functions. While human studies help to understand the epidemiology andimmunopathology of VRIs, the chaotic nature of viral transmissions makes it difficult to undertakemechanistic study where the pre-conditioning of the metabolic and immune system could bebeneficial. However, recent experimental studies have significantly enhanced our understanding ofhow PB and DF, along with plant bioactives, can significantly modulate innate and acquired immunityresponses to VRIs. Synbiotic combinations of PB and DF potentiate increased benefits primarilythrough augmenting the production of short-chain fatty acids (SCFAs) such as butyrate. These andspecific plant polyphenolics help to regulate immune responses to both restrain VRIs and temperthe neutrophil response that can lead to acute respiratory distress syndrome (ARDS). This reviewhighlights the current understanding of the potential impact of targeted nutritional strategies insetting a balanced immune tone for viral clearance and reinforcing homeostasis. This knowledge mayguide the development of public health tactics and the application of functional foods with PB andDF components as a nutritional approach to support countering VRI morbidit

Impact of Deleterious Mutations on Structure, Function and Stability of Serum/Glucocorticoid Regulated Kinase 1: A Gene to Diseases Correlation.

Serum and glucocorticoid-regulated kinase 1 (SGK1) is a Ser/Thr protein kinase involved in regulating cell survival, growth, proliferation, and migration. Its elevated expression and dysfunction are reported in breast, prostate, hepatocellular, lung adenoma, and renal carcinomas. We have analyzed the SGK1 mutations to explore their impact at the sequence and structure level by utilizing state-of-the-art computational approaches. Several pathogenic and destabilizing mutations were identified based on their impact on SGK1 and analyzed in detail. Three amino acid substitutions, K127M, T256A, and Y298A, in the kinase domain of SGK1 were identified and incorporated structurally into original coordinates of SGK1 to explore their time evolution impact using all-atom molecular dynamic (MD) simulations for 200 ns. MD results indicate substantial conformational alterations in SGK1, thus its functional loss, particularly upon T256A mutation. This study provides meaningful insights into SGK1 dysfunction upon mutation, leading to disease progression, including cancer, and neurodegeneration

Separation of breast cancer and organ microenvironment transcriptomes in metastases

Background: The seed and soil hypothesis was proposed over a century ago to describe why cancer cells (seeds) grow in certain organs (soil). Since then, the genetic properties that define the cancer cells have been heavily investigated; however, genomic mediators within the organ microenvironment that mediate successful metastatic growth are less understood. These studies sought to identify cancer- and organ-specific genomic programs that mediate metastasis. Methods: In these studies, a set of 14 human breast cancer patient-derived xenograft (PDX) metastasis models was developed and then tested for metastatic tropism with two approaches: spontaneous metastases from mammary tumors and intravenous injection of PDX cells. The transcriptomes of the cancer cells when growing as tumors or metastases were separated from the transcriptomes of the microenvironment via species-specific separation of the genomes. Drug treatment of PDX spheroids was performed to determine if genes activated in metastases may identify targetable mediators of viability. Results: The experimental approaches that generated metastases in PDX models were identified. RNA sequencing of 134 tumors, metastases, and normal non-metastatic organs identified cancer- and organ-specific genomic properties that mediated metastasis. A common genomic response of the liver microenvironment was found to occur in reaction to the invading PDX cells. Genes within the cancer cells were found to be either transiently regulated by the microenvironment or permanently altered due to clonal selection of metastatic sublines. Gene Set Enrichment Analyses identified more than 400 gene signatures that were commonly activated in metastases across basal-like PDXs. A Src signaling signature was found to be extensively upregulated in metastases, and Src inhibitors were found to be cytotoxic to PDX spheroids. Conclusions: These studies identified that during the growth of breast cancer metastases, there were genomic changes that occurred within both the cancer cells and the organ microenvironment. We hypothesize that pathways upregulated in metastases are mediators of viability and that simultaneously targeting changes within different cancer cell pathways and/or different tissue compartments may be needed for inhibition of disease progression

3D CFD Model of a Tubular Porous-Metal Supported Solid Oxide Electrolysis Cell

Currently there is strong interest in the large-scale production of hydrogen as an energy carrier for the non-electrical market [1, 2, and 3]. High-temperature nuclear reactors have the potential for substantially increasing the efficiency of hydrogen production from water splitting, with no consumption of fossil fuels, no production of greenhouse gases, and no other forms of air pollution. A high-temperature advanced nuclear reactor coupled with a high-efficiency high-temperature electrolyzer could achieve a competitive thermal-to-hydrogen conversion efficiency of 45 to 55%. A research program is under way at the INL to simultaneously address the research and scale-up issues associated with the implementation of solid-oxide electrolysis cell technology for hydrogen production from steam. The future SOEC market includes the 1200MW GEN4 reactor which has projected 40-50% efficiency, 400 tones H2 production per day (at 5kg H2/car/300 mile day this corresponds to 80,000 cars/day). DOE is planning for 26GW of nuclear hydrogen production by 2025

Coupling of ventricular action potential duration and local strain patterns during reverse remodeling in responders and non-responders to cardiac resynchronization therapy

BACKGROUND: The high risk of ventricular arrhythmias in heart failure patients remains despite the benefit of cardiac resynchronization therapy (CRT). An electromechanical interaction between regional myocardial strain patterns and the electrophysiological substrate is thought to be important. OBJECTIVE: We investigated the in-vivo relation between left ventricular (LV) activation recovery interval (ARI), as a surrogate measure of activation potential duration (APD), and local myocardial strain patterns in responders and non-responders to CRT. METHODS: ARI were recorded from the left ventricular epicardium in 20 CRT patients 6 weeks and 6 months post implant. Two-dimensional speckle tracking echocardiography was performed at the same time to assess myocardial strains. Patients with ≥15% reduction in end-systolic volume at 6-months were classified as responders. RESULTS: ARI reduced in responders, 263±46ms vs. 246±47ms, p145ms and QRS shortening with biventricular pacing was associated with ARI shortening during CRT. CONCLUSIONS: Changes in ventricular wall mechanics predict local APD lengthening or shortening during CRT. Non-responders have a worsening of myocardial strain and local APD. Baseline QRS >145ms and QRS shortening on biventricular pacing identified patients who exhibited improvement in APD

A multicenter prospective randomized controlled trial of cardiac resynchronization therapy guided by invasive dP/dt

Background: No periprocedural metric has demonstrated improved cardiac resynchronization therapy (CRT) outcomes in a multicenter setting. Objective: We sought to determine if left ventricular (LV) lead placement targeted to the coronary sinus (CS) branch generating the best acute hemodynamic response (AHR) results in improved outcomes at 6 months. Methods: In this multicenter randomized controlled trial, patients were randomized to guided CRT or conventional CRT. Patients in the guided arm had LV dP/dtmax measured during biventricular (BIV) pacing. Target CS branches were identified and the final LV lead position was the branch with the best AHR and acceptable threshold values. The primary endpoint was the proportion of patients with a reduction in LV end-systolic volume (LVESV) of ≥15% at 6 months. Results: A total of 281 patients were recruited across 12 centers. Mean age was 70.8 ± 10.9 years and 54% had ischemic etiology. Seventy-three percent of patients in the guided arm demonstrated a reduction in LVESV of ≥15% at 6 months vs 60% in the conventional arm (P = .02). Patients with AHR ≥ 10% were more likely to demonstrate a reduction of ESV ≥ 15% (84% of patients with an AHR ≥10% vs 28% with an AHR <10%; P < 0.001). Procedure duration and fluoroscopy times were longer in the pressure wire-guided arm (104 ± 39 minutes vs 142 ± 39 minutes; P < .001 and 20 ±16 minutes vs 28 ± 15 minutes; P = .002). Conclusions: AHR determined by invasively measuring LV dP/dtmax during BIV pacing predicts reverse remodeling 6 months after CRT. Patients in whom LV dP/dtmax was used to guide LV lead placement demonstrated better rates of reverse remodeling

Vessel-Associated Transforming Growth Factor-Beta1 (TGF-β1) Is Increased in the Bronchial Reticular Basement Membrane in COPD and Normal Smokers

BACKGROUND: Transforming growth factor-beta1 (TGF-β1) is a multipotential cytokine with angiogenic activity. There are only limited data about its role in airway remodeling in COPD. We have previously shown that the reticular basement membrane (Rbm) is hypervascular in the airways of current smokers either with or without chronic obstructive pulmonary disease (COPD). This study evaluated TGF-β1 immunostaining in the Rbm and its relationship to vascularity in smokers with or without COPD. METHODOLOGY/PRINCIPAL FINDINGS: Bronchial biopsies from 15 smokers with normal lung function, 19 current and 14 ex-smokers with COPD were immunostained for TGF-β1 antibody and compared to 17 healthy controls. The percentage area of tissue and also number and area of vessels staining positively for TGF-β1 were measured and compared between groups. Some bronchial biopsies from current smoking COPD subjects were also stained for phosphorylated (active) Smad2/3. Epithelial TGF- β1 staining was not different between COPD current smokers and normal controls. TGF-β1 stained vessels in the Rbm were increased in smokers with normal lung function, current smoking COPD and ex-smokers with COPD compared to controls [median (range) for number of vessels/mm Rbm 2.5 (0.0-12.7), 3.4 (0.0-8.1) and 1.0 (0.0-6.3) vs. 0.0 (0.0-7.0), p<0.05]. Percentage of vessels stained was also increased in these clinical groups. Preliminary data suggest that in current smoking COPD subjects endothelial cells and cells in the Rbm stain positively for phosphorylated Smad2/3 suggesting TGF-β1 is functionally active in this situation. CONCLUSIONS/SIGNIFICANCE: Vessel-associated TGF-β1 activity is increased in the bronchial Rbm in smokers and especially those with COPD