HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis.

Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples.

Regulation of senescence traits by MAPKs.

A phenotype of indefinite growth arrest acquired in response to sublethal damage, cellular senescence affects normal aging and age-related disease. Mitogen-activated protein kinases (MAPKs) are capable of sensing changes in cellular conditions, and in turn elicit adaptive responses including cell senescence. MAPKs modulate the levels and function of many proteins, including proinflammatory factors and factors in the p21/p53 and p16/RB pathways, the main senescence-regulatory axes.

Noncoding RNAs Controlling Telomere Homeostasis in Senescence and Aging.

Aging is a universal and time-dependent biological decline associated with progressive deterioration of cells, tissues, and organs. Age-related decay can eventually lead to pathology such as cardiovascular and neurodegenerative diseases, cancer, and diabetes. A prominent molecular process underlying aging is the progressive shortening of telomeres, the structures that protect the ends of chromosomes, eventually triggering cellular senescence.

RNA-Binding Protein HuR Promotes Th17 Cell Differentiation and Can Be Targeted to Reduce Autoimmune Neuroinflammation.

Dysregulated Th17 cell differentiation is associated with autoimmune diseases such as multiple sclerosis, which has no curative treatment. Understanding the molecular mechanisms of regulating Th17 cell differentiation will help find a novel therapeutic target for treating Th17 cell-mediated diseases. In this study, we investigated the cell-intrinsic processes by which RNA-binding protein HuR orchestrates Th17 cell fate decisions by posttranscriptionally regulating transcription factors and and receptor expression, in turn promoting Th17 cell and Th1-like Th17 cell differentiation in C57BL/6J mice.

Survey of senescent cell markers with age in human tissues.

Cellular senescence, triggered by sublethal damage, is characterized by indefinite growth arrest, altered gene expression patterns, and a senescence-associated secretory phenotype. While the accumulation of senescent cells during aging decreases tissue function and promotes many age-related diseases, at present there is no universal marker to detect senescent cells in tissues. Cyclin-dependent kinase inhibitors 2A (p16/CDKN2A) and 1A (p21/CDKN1A) can identify senescent cells, but few studies have examined the numbers of cells expressing these markers in different organs as a function of age.

Comparing Analytical Methods for the Gut Microbiome and Aging: Gut Microbial Communities and Body Weight in the Osteoporotic Fractures in Men (MrOS) Study.

Determining the role of gut microbial communities in aging-related phenotypes, including weight loss, is an emerging gerontology research priority. Gut microbiome datasets comprise relative abundances of microbial taxa that necessarily sum to 1; analysis ignoring this feature may produce misleading results. Using data from the Osteoporotic Fractures in Men (MrOS) study (n = 530; mean [SD] age = 84.

Relations of Executive Function and Physical Performance in Middle Adulthood: A Prospective Investigation in African American and White Adults.

Objectives: Previous studies in older adults found robust associations between executive functions (EF) and physical performance, as well as sociodemographic variation in physical performance decline. To examine these associations earlier in the adult lifespan, we investigated relations of EF, race, and sex with age-related physical performance decline during middle adulthood.

Method: Participants were 2,084 urban-dwelling adults (57.

circSamd4 represses myogenic transcriptional activity of PUR proteins.

By interacting with proteins and nucleic acids, the vast family of mammalian circRNAs is proposed to influence many biological processes. Here, RNA sequencing analysis of circRNAs differentially expressed during myogenesis revealed that circSamd4 expression increased robustly in mouse C2C12 myoblasts differentiating into myotubes. Moreover, silencing circSamd4, which is conserved between human and mouse, delayed myogenesis and lowered the expression of myogenic markers in cultured myoblasts from both species.

Ribonucleoprotein Immunoprecipitation (RIP) Analysis.

RNAs and RNA-binding proteins (RBPs) can interact dynamically in ribonucleoprotein (RNP) complexes that play important roles in controlling gene expression programs. One of the powerful ways to investigate changes in the association of RNAs with an RBP of interest is by immunoprecipitation (IP) analysis of native RNPs. RIP (RNP immunoprecipitation) analysis enables the rapid identification of endogenous RNAs bound to an RBP and to monitor time-dependent changes in this association, as well as changes in response to different metabolic and stress conditions.

Interaction between HuR and Modulates Autophagy in the Intestinal Epithelium by Altering ATG16L1 Translation.

Intestinal epithelial autophagy is crucial for host defense against invasive pathogens, and defects in this process occur frequently in patients with inflammatory bowel disease (IBD) and other mucosal disorders, but the exact mechanism that activates autophagy is poorly defined. Here, we investigated the role of RNA-binding protein HuR (human antigen R) in the posttranscriptional control of autophagy-related genes (ATGs) in the intestinal epithelium. We found that targeted deletion of HuR in intestinal epithelial cells (IECs) specifically decreased the levels of ATG16L1 in the intestinal mucosa.

Impact of Stiffer Arteries on the Response to Antihypertensive Treatment: A Longitudinal Study of the SardiNIA Cohort.

Objectives: Carotid-femoral pulse wave velocity (PWV), an index of arterial stiffness and a proxy of arterial aging, has been reported to be an independent determinant of cardiovascular health. Whether the effects of antihypertensive treatment vary in the presence of accelerated arterial aging (stiffer artery, ie, PWV >10 m/s) has not been established. We tested this hypothesis in a longitudinal study in a large community-dwelling population.

Long Noncoding RNA H19 Impairs the Intestinal Barrier by Suppressing Autophagy and Lowering Paneth and Goblet Cell Function.

Background & Aims: The protective intestinal mucosal barrier consists of multiple elements including mucus and epithelial layers and immune defense; nonetheless, barrier dysfunction is common in various disorders. The imprinted and developmentally regulated long noncoding RNA H19 is involved in many cell processes and diseases. Here, we investigated the role of H19 in regulating Paneth and goblet cells and autophagy, and its impact on intestinal barrier dysfunction induced by septic stress.

A novel long noncoding RNA Linc-ASEN represses cellular senescence through multileveled reduction of p21 expression.

Long noncoding RNAs (lncRNAs) regulating diverse cellular processes implicate in many diseases. However, the function of lncRNAs in cellular senescence remains largely unknown. Here we identify a novel long intergenic noncoding RNA Linc-ASEN expresses in prematurely senescent cells.

SIRT3 Haploinsufficiency Aggravates Loss of GABAergic Interneurons and Neuronal Network Hyperexcitability in an Alzheimer's Disease Model.

Impaired mitochondrial function and aberrant neuronal network activity are believed to be early events in the pathogenesis of Alzheimer's disease (AD), but how mitochondrial alterations contribute to aberrant activity in neuronal circuits is unknown. In this study, we examined the function of mitochondrial protein deacetylase sirtuin 3 (SIRT3) in the pathogenesis of AD. Compared with AppPs1 mice, Sirt3-haploinsufficient AppPs1 mice (Sirt3AppPs1) exhibit early epileptiform EEG activity and seizure.

A mitochondrial uncoupler prodrug protects dopaminergic neurons and improves functional outcome in a mouse model of Parkinson's disease.

Dopaminergic neuronal cell loss in the substantia nigra is responsible for the motor symptoms that are the clinical hallmark of Parkinson's disease (PD). As of yet there are no treatments that slow or prevent the degeneration of dopaminergic neurons in PD patients. Here we tested the hypothesis that dopaminergic neurons can be protected by treatment with the mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) and the novel DNP prodrug MP201.

Telomere length and cognitive function: Differential patterns across sociodemographic groups.

Objective: The present study investigates whether associations between telomere length (TL) and cognitive performance across multiple domains are moderated by poverty status and race.

Method: Participants were 325 African American and White urban-dwelling adults (M age = 47.9 years; 49.

High-potency ligands for DREADD imaging and activation in rodents and monkeys.

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated F positron emission tomography (PET) DREADD radiotracer, [F]JHU37107.

The Interplay of Diet Quality and Alzheimer's Disease Genetic Risk Score in Relation to Cognitive Performance Among Urban African Americans.

We examined the interactive associations of poor diet quality and Alzheimer's Disease (AD) genetic risk with cognitive performance among 304 African American adults (mean age~57 years) from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. In this cross-sectional study, selected participants had complete predictors and covariate data with 13 cognitive test scores as outcomes. Healthy Eating Index-2010 (HEI-2010), Dietary Approaches to Stop Hypertension (DASH), and mean adequacy ratio (MAR) were measured.

Intergenerational Metabolic Syndrome and Neuronal Network Hyperexcitability in Autism.

We review evidence that suggests a role for excessive consumption of energy-dense foods, particularly fructose, and consequent obesity and insulin resistance (metabolic syndrome) in the recent increase in prevalence of autism spectrum disorders (ASD). Maternal insulin resistance, obesity, and diabetes may predispose offspring to ASD by mechanisms involving chronic activation of anabolic cellular pathways and a lack of metabolic switching to ketosis resulting in a deficit in GABAergic signaling and neuronal network hyperexcitability. Metabolic reprogramming by epigenetic DNA and chromatin modifications may contribute to alterations in gene expression that result in ASD.

Skewed macrophage polarization in aging skeletal muscle.

Skeletal muscle aging is a major cause of disability and frailty in the elderly. The progressive impairment of skeletal muscle function with aging was recently linked to a disequilibrium between damage and repair. Macrophages participate in muscle tissue repair, first as pro-inflammatory M1 subtype and then as anti-inflammatory M2 subtype.

Arterial stiffness and multiple organ damage: a longitudinal study in population.

Aims: Previous cross-sectional observation identified arterial aging, indexed as pulse-wave velocity (PWV), as a key determinant of the simultaneous multiple organ damage (heart, carotid artery, and kidney). The aim of the present cohort study is to investigate trajectories of repeated measures of PWV and traditional CV risk factors in subjects who eventually presented clinical evidence of multiple organ damage in the SardiNIA study.

Methods And Results: Organ damage was measured in the heart (left ventricular hypertrophy, LVH), the common carotid artery (intima-media thickness > 0.

Disparities in Diffuse Cortical White Matter Integrity Between Socioeconomic Groups.

There is a growing literature demonstrating a link between lower socioeconomic status (SES) and poorer neuroanatomical health, such as smaller total and regional gray and white matter volumes, as well as greater white matter lesion volumes. Little is known, however, about the relation between SES and white matter integrity. Here we examined the relation between SES and white matter integrity of the brain's primary cortical regions, and evaluated potential moderating influences of age and self-identified race.

A Novel Apolipoprotein E Antagonist Functionally Blocks Apolipoprotein E Interaction With N-terminal Amyloid Precursor Protein, Reduces β-Amyloid-Associated Pathology, and Improves Cognition.

Background: The ɛ4 isoform of apolipoprotein E (apoE4) is a major genetic risk factor for the development of sporadic Alzheimer's disease (AD), and its modification has been an intense focus for treatment of AD during recent years.

Methods: We investigated the binding of apoE, a peptide corresponding to its low-density lipoprotein receptor binding domain (amino acids 133-152; ApoEp), and modified ApoEp to amyloid precursor protein (APP) and their effects on amyloid-β (Aβ) production in cultured cells. Having discovered a peptide (6KApoEp) that blocks the interaction of apoE with N-terminal APP, we investigated the effects of this peptide and ApoEp on AD-like pathology and behavioral impairment in 3XTg-AD and 5XFAD transgenic mice.