Effect of acute TLR4 inhibition on insulin resistance in humans.

BackgroundStudies in cell cultures and rodents suggest that TLR4 is involved in the pathogenesis of insulin resistance, but direct data in humans are limited. We tested the hypothesis that pharmacologic blockade of TLR4 with the competitive inhibitor eritoran would improve insulin resistance in humans.MethodsIn protocol I, 10 lean, healthy individuals received the following 72-hour i.

Exploration and analysis of R-loop mapping data with RLBase.

R-loops are three-stranded nucleic acid structures formed from the hybridization of RNA and DNA. In 2012, Ginno et al. introduced the first R-loop mapping method.

Dietary Quality and Perceived Barriers to Weight Loss among Older Overweight Veterans with Dysmobility.

Healthier diets are associated with higher muscle mass and physical performance which may reduce the risk of developing frailty and disability later in life. This study examined the dietary quality and self-reported weight loss barriers among older (>60 years), overweight (BMI ≥ 25 kg/m2) Veterans with dysmobility (low gait speed, impaired mobility diagnosis, or a comorbidity that results in impaired mobility). Habitual dietary intake and healthy eating index (HEI-2015) were assessed using 24-h recalls and compared to US nationally representative dietary intake data and national recommendations.

Randomization to Treadmill Training Improves Physical and Metabolic Health in Association With Declines in Oxidative Stress in Stroke.

Objective: To investigate the effect of aerobic exercise vs control (stretching/balance) on inflammatory and oxidative stress biomarkers in stroke survivors and whether these changes are associated with improvements in physical and metabolic health.

Design: Randomized controlled trial.

Setting: The general communities of Baltimore, Maryland, and Atlanta, Georgia.

Intervention in Older Urban-Dwelling Veterans With Dysmobility: Protocol for a Pilot Feasibility Clinical Trial.

Background: The majority of older veterans do not meet the minimum healthy diet or physical activity recommendations despite known benefits. Identifying ways to increase adherence to programs that improve dietary quality and physical activity may reduce the risk of disability in older veterans. Peer-based interventions may be one method for facilitating lasting behavior change because peers often share a common culture and knowledge regarding problems their community experiences.

Arachidonic Acid Cascade and Eicosanoid Production Are Elevated While LTC4 Synthase Modulates the Lipidomics Profile in the Brain of the HIVgp120-Transgenic Mouse Model of NeuroHIV.

Background: Combination antiretroviral therapy (cART) has transformed HIV infection from a terminal disease to a manageable chronic health condition, extending patients' life expectancy to that of the general population. However, the incidence of HIV-associated neurocognitive disorders (HANDs) has persisted despite virological suppression. Patients with HIV display persistent signs of immune activation and inflammation despite cART.

The clinical significance of binge eating among older adult women: an investigation into health correlates, psychological wellbeing, and quality of life.

Background: One type of overnutrition, binge eating (BE; eating an unusually large amount of food with loss of control), is prevalent among older adult women. Yet, little is known about the clinical significance of this eating disorder pathology in older adults, especially in relation to health outcomes used in geriatrics, while controlling for associations with body mass index (BMI).

Method: Women (N = 227) aged 60-94 completed two measures of BE and health/wellness questionnaires online.

Determination of dexamethasone dose for cortisol suppression in adult common marmosets (Callithrix jacchus).

We conducted a dose-response study of dexamethasone to investigate an optimal dexamethasone suppression test for common marmosets. Twelve marmosets received 0.1, 0.

Pharmacological inhibition of ALCAT1 mitigates amyotrophic lateral sclerosis by attenuating SOD1 protein aggregation.

Objective: Mutations in the copper-zinc superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS), a progressive fatal neuromuscular disease characterized by motor neurons death and severe skeletal muscle degeneration. However, there is no effective treatment for this debilitating disease, since the underlying cause for the pathogenesis remains poorly understood. Here, we investigated a role of acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1), an acyltransferase that promotes mitochondrial dysfunction in age-related diseases by catalyzing pathological remodeling of cardiolipin, in promoting the development of ALS in the SOD1 transgenic mice.

Characterizing the Electron Transport Chain: Functional Approach Using Extracellular Flux Analyzer on Mouse Tissue Samples.

The Seahorse Extracellular Flux Analyzer enables the high-throughput characterization of oxidative phosphorylation capacity based on the electron transport chain organization and regulation with relatively small amount of material. This development over the traditional polarographic Clark-type electrode approaches make it possible to analyze the respiratory features of mitochondria isolated from tissue samples of particular animal models. Here we provide a description of an optimized approach to carry out multi-well measurement of O consumption, with the Agilent Seahorse XFe96 analyzer on mouse brain and muscles to determine the tissue-specific oxidative phosphorylation properties.

Characterizing the Electron Transport Chain: Structural Approach.

The mitochondrial respiratory chain which carries out the oxidative phosphorylation (OXPHOS) consists of five multi-subunit protein complexes. Emerging evidences suggest that the supercomplexes which further consist of multiple respiratory complexes play important role in regulating OXPHOS function. Dysfunction of the respiratory chain and its regulation has been implicated in various human diseases including neurodegenerative diseases and muscular disorders.

Quality-controlled R-loop meta-analysis reveals the characteristics of R-loop consensus regions.

R-loops are three-stranded nucleic acid structures formed from the hybridization of RNA and DNA. While the pathological consequences of R-loops have been well-studied to date, the locations, classes, and dynamics of physiological R-loops remain poorly understood. R-loop mapping studies provide insight into R-loop dynamics, but their findings are challenging to generalize.

Matrix-bound Cyr61/CCN1 is required to retain the properties of the bone marrow mesenchymal stem cell niche but is depleted with aging.

Previously, we showed that extracellular matrices (ECMs), produced ex vivo by various types of stromal cells, direct bone marrow mesenchymal stem cells (BM-MSCs) in a tissue-specific manner and recapitulate physiologic changes characteristic of the aging microenvironment. In particular, BM-MSCs obtained from elderly donors and cultured on ECM produced by young BM stromal cells showed improved quantity, quality and osteogenic differentiation. In the present study, we searched for matrix components that are required for a functional BM-MSC niche by comparing ECMs produced by BM stromal cells from "young" (≤25 y/o) versus "elderly" (≥60 y/o) donors.

In Search of the Holy Grail: Toward a Unified Hypothesis on Mitochondrial Dysfunction in Age-Related Diseases.

Cardiolipin (CL) is a mitochondrial signature phospholipid that plays a pivotal role in mitochondrial dynamics, membrane structure, oxidative phosphorylation, mtDNA bioenergetics, and mitophagy. The depletion or abnormal acyl composition of CL causes mitochondrial dysfunction, which is implicated in the pathogenesis of aging and age-related disorders. However, the molecular mechanisms by which mitochondrial dysfunction causes age-related diseases remain poorly understood.

Retraction: Gonzalez, G.; Chen, L. EFA6 in Axon Regeneration, as a Microtubule Regulator and as a Guanine Nucleotide Exchange Factor. 2021, , 1325.

The journal retracts the article "Retraction: Gonzalez, G.; Chen, L. EFA6 in Axon Regeneration, as a Microtubule Regulator and as a Guanine Nucleotide Exchange Factor" [.

Inhibition of ATR Reverses a Mitochondrial Respiratory Insufficiency.

Diseases that affect the mitochondrial electron transport chain (ETC) often manifest as threshold effect disorders, meaning patients only become symptomatic once a certain level of ETC dysfunction is reached. Cells can invoke mechanisms to circumvent reaching their critical ETC threshold, but it is an ongoing challenge to identify such processes. In the nematode , severe reduction of mitochondrial ETC activity shortens life, but mild reduction actually extends it, providing an opportunity to identify threshold circumvention mechanisms.

Genetic and pharmacologic proteasome augmentation ameliorates Alzheimer's-like pathology in mouse and fly APP overexpression models.

The proteasome has key roles in neuronal proteostasis, including the removal of misfolded and oxidized proteins, presynaptic protein turnover, and synaptic efficacy and plasticity. Proteasome dysfunction is a prominent feature of Alzheimer's disease (AD). We show that prevention of proteasome dysfunction by genetic manipulation delays mortality, cell death, and cognitive deficits in fly and cell culture AD models.

Mental health and quality of life in postmenopausal women as a function of retrospective menopause symptom severity.

Objectives: Perimenopause is commonly viewed as a window of vulnerability for developing psychiatric and eating disorders, especially for women who experience severe symptoms. However, menopausal symptoms may have a lasting effect on older women's mental health and quality of life (QOL) into postmenopause. The current study examined older (60+) postmenopausal women's mental health and QOL as a function of retrospective menopausal symptom severity.

Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease.

We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts.

Mitochondrial TrxR2 regulates metabolism and protects from metabolic disease through enhanced TCA and ETC function.

Mitochondrial dysfunction is a key driver of diabetes and other metabolic diseases. Mitochondrial redox state is highly impactful to metabolic function but the mechanism driving this is unclear. We generated a transgenic mouse which overexpressed the redox enzyme Thioredoxin Reductase 2 (TrxR2), the rate limiting enzyme in the mitochondrial thioredoxin system.