VA Palo Alto Healthcare System

About: VA Palo Alto Healthcare System is a healthcare organization based out in Palo Alto, California, United States. It is known for research contribution in the topics: Population & Health care. The organization has 2548 authors who have published 4605 publications receiving 209938 citations.

Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1.

Abstract: An aged circulatory environment can activate microglia, reduce neural precursor cell activity and impair cognition in mice. We hypothesized that brain endothelial cells (BECs) mediate at least some of these effects. We observe that BECs in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of vascular cell adhesion molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, levels of the shed, soluble form of VCAM1 are prominently increased in the plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and the hippocampi of young mice. Systemic administration of anti-VCAM1 antibody or genetic ablation of Vcam1 in BECs counteracts the detrimental effects of plasma from aged individuals on young brains and reverses aging aspects, including microglial reactivity and cognitive deficits, in the brains of aged mice. Together, these findings establish brain endothelial VCAM1 at the blood-brain barrier as a possible target to treat age-related neurodegeneration.

Concurrent neuromechanical and functional gains following upper-extremity power training post-stroke

Abstract: Background: Repetitive task practice is argued to drive neural plasticity following stroke. However, current evidence reveals that hemiparetic weakness impairs the capacity to perform, and practice, movements appropriately. Here we investigated how power training (i.e., high-intensity, dynamic resistance training) affects recovery of upper-extremity motor function post-stroke. We hypothesized that power training, as a component of upper-extremity rehabilitation, would promote greater functional gains than functional task practice without deleterious consequences. Method: Nineteen chronic hemiparetic individuals were studied using a crossover design. All participants received both functional task practice (FTP) and HYBRID (combined FTP and power training) in random order. Blinded evaluations performed at baseline, following each intervention block and 6-months post-intervention included: Wolf Motor Function Test (WMFT-FAS, Primary Outcome), upper-extremity Fugl-Meyer Motor Assessment, Ashworth Scale, and Functional Independence Measure. Neuromechanical function was evaluated using isometric and dynamic joint torques and concurrent agonist EMG. Biceps stretch reflex responses were evaluated using passive elbow stretches ranging from 60 to 180o/s and determining: EMG onset position threshold, burst duration, burst intensity and passive torque at each speed. Results: Primary outcome: Improvements in WMFT-FAS were significantly greater following HYBRID vs. FTP (p= .049), regardless of treatment order. These functional improvements were retained 6-months post-intervention

Lysine methylation of the NF-κB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-κB signaling

Abstract: Signaling via the methylation of lysine residues in proteins has been linked to diverse biological and disease processes, yet the catalytic activity and substrate specificity of many human protein lysine methyltransferases (PKMTs) are unknown. We screened over 40 candidate PKMTs and identified SETD6 as a methyltransferase that monomethylated chromatin-associated transcription factor NF-κB subunit RelA at Lys310 (RelAK310me1). SETD6-mediated methylation rendered RelA inert and attenuated RelA-driven transcriptional programs, including inflammatory responses in primary immune cells. RelAK310me1 was recognized by the ankryin repeat of the histone methyltransferase GLP, which under basal conditions promoted a repressed chromatin state at RelA target genes through GLP-mediated methylation of histone H3 Lys9 (H3K9). NF-κB-activation-linked phosphorylation of RelA at Ser311 by protein kinase C-ζ (PKC-ζ) blocked the binding of GLP to RelAK310me1 and relieved repression of the target gene. Our findings establish a previously uncharacterized mechanism by which chromatin signaling regulates inflammation programs.