Integration across biophysical scales identifies molecular and cellular correlates of person-to-person variability in human brain connectivity.

Brain connectivity arises from interactions across biophysical scales, ranging from molecular to cellular to anatomical to network level. To date, there has been little progress toward integrated analysis across these scales. To bridge this gap, from a unique cohort of 98 individuals, we collected antemortem neuroimaging and genetic data, as well as postmortem dendritic spine morphometric, proteomic and gene expression data from the superior frontal and inferior temporal gyri.

Dendritic spine head diameter predicts episodic memory performance in older adults.

Episodic memory in older adults is varied and perceived to rely on numbers of synapses or dendritic spines. We analyzed 2157 neurons among 128 older individuals from the Religious Orders Study and Rush Memory and Aging Project. Analysis of 55,521 individual dendritic spines by least absolute shrinkage and selection operator regression and nested model cross-validation revealed that the dendritic spine head diameter in the temporal cortex, but not the premotor cortex, improved the prediction of episodic memory performance in models containing β amyloid plaque scores, neurofibrillary tangle pathology, and sex.

Human intestinal stromal cells promote homeostasis in normal mucosa but inflammation in Crohn's disease in a retinoic acid-deficient manner.

Intestinal stromal cells (SCs), which synthesize the extracellular matrix that gives the mucosa its structure, are newly appreciated to play a role in mucosal inflammation. Here, we show that human intestinal vimentinCD90smooth muscle actin SCs synthesize retinoic acid (RA) at levels equivalent to intestinal epithelial cells, a function in the human intestine previously attributed exclusively to epithelial cells. Crohn's disease SCs (Crohn's SCs), however, synthesized markedly less RA than SCs from healthy intestine (normal SCs).

A Molecular Basis of Human Brain Connectivity.

Unlabelled: Neuroimaging is commonly used to infer human brain connectivity, but those measurements are far-removed from the molecular underpinnings at synapses. To uncover the molecular basis of human brain connectivity, we analyzed a unique cohort of 98 individuals who provided neuroimaging and genetic data contemporaneous with dendritic spine morphometric, proteomic, and gene expression data from the superior frontal and inferior temporal gyri. Through cellular contextualization of the molecular data with dendritic spine morphology, we identified hundreds of proteins related to synapses, energy metabolism, and RNA processing that explain between-individual differences in functional connectivity and structural covariation.

l-Carnitine therapy improves right heart dysfunction through Cpt1-dependent fatty acid oxidation.

Pulmonary arterial hypertension (PAH) is a fatal vasculopathy that ultimately leads to elevated pulmonary pressure and death by right ventricular (RV) failure, which occurs in part due to decreased fatty acid oxidation and cytotoxic lipid accumulation. In this study, we tested the hypothesis that decreased fatty acid oxidation and increased lipid accumulation in the failing RV is driven, in part, by a relative carnitine deficiency. We then tested whether supplementation of l-carnitine can reverse lipotoxic RV failure through augmentation of fatty acid oxidation.

Dendritic Spine Remodeling and Synaptic Tau Levels in PS19 Tauopathy Mice.

Synapse or dendritic spine loss is the strongest correlate of cognitive decline in Alzheimer's disease (AD), and neurofibrillary tangles (NFTs), but not amyloid-β plaques, associate more closely with transition to mild cognitive impairment. Yet, how dendritic spine architecture is affected by hyperphosphorylated tau is still an ongoing question. To address this, we combined cell and biochemical analyses of the Tau P301S mouse line (PS19).

Natriuretic peptide receptor C contributes to disproportionate right ventricular hypertrophy in a rodent model of obesity-induced heart failure with preserved ejection fraction with pulmonary hypertension.

Heart failure with preserved ejection fraction (HFpEF) currently has no therapies that improve mortality. Right ventricular dysfunction and pulmonary hypertension are common in HFpEF, and thought to be driven by obesity and metabolic syndrome. Thus, we hypothesized that an animal model of obesity-induced HFpEF with pulmonary hypertension would provide insight into the pathogenesis of right ventricular failure in HFpEF.