A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver.

Hepatic steatosis is a central phenotype in multi-system metabolic dysfunction and is increasing in parallel with the obesity pandemic. We use a translational approach integrating clinical phenotyping and outcomes, circulating proteomics, and tissue transcriptomics to identify dynamic, functional biomarkers of hepatic steatosis. Using multi-modality imaging and broad proteomic profiling, we identify proteins implicated in the progression of hepatic steatosis that are largely encoded by genes enriched at the transcriptional level in the human liver.

The extracellular vesicle transcriptome provides tissue-specific functional genomic annotation relevant to disease susceptibility in obesity.

We characterized circulating extracellular vesicles (EVs) in obese and lean humans, identifying transcriptional cargo differentially expressed in obesity. Since circulating EVs may have broad origin, we compared this obesity EV transcriptome to expression from human visceral adipose tissue derived EVs from freshly collected and cultured biopsies from the same obese individuals. Using a comprehensive set of adipose-specific epigenomic and chromatin conformation assays, we found that the differentially expressed transcripts from the EVs were those regulated in adipose by BMI-associated SNPs from a large-scale GWAS.

Clinical-transcriptional prioritization of the circulating proteome in human heart failure.

Given expanding studies in epidemiology and disease-oriented human studies offering hundreds of associations between the human "ome" and disease, prioritizing molecules relevant to disease mechanisms among this growing breadth is important. Here, we link the circulating proteome to human heart failure (HF) propensity (via echocardiographic phenotyping and clinical outcomes) across the lifespan, demonstrating key pathways of fibrosis, inflammation, metabolism, and hypertrophy. We observe a broad array of genes encoding proteins linked to HF phenotypes and outcomes in clinical populations dynamically expressed at a transcriptional level in human myocardium during HF and cardiac recovery (several in a cell-specific fashion).

Comparison of EV characterization by commercial high-sensitivity flow cytometers and a custom single-molecule flow cytometer.

High-sensitivity flow cytometers have been developed for multi-parameter characterization of single extracellular vesicles (EVs), but performance varies among instruments and calibration methods. Here we compare the characterization of identical (split) EV samples derived from human colorectal cancer (DiFi) cells by three high-sensitivity flow cytometers, two commercial instruments, CytoFLEX/CellStream, and a custom single-molecule flow cytometer (SMFC). DiFi EVs were stained with the membrane dye di-8-ANEPPS and with PE-conjugated anti-EGFR or anti-tetraspanin (CD9/CD63/CD81) antibodies for estimation of EV size and surface protein copy numbers.

The subcutaneous adipose transcriptome identifies a molecular signature of insulin resistance shared with visceral adipose.

Objective: The objective of this study was to identify the transcriptional landscape of insulin resistance (IR) in subcutaneous adipose tissue (SAT) in humans across the spectrum of obesity.

Methods: We used SAT RNA sequencing in 220 individuals with metabolic phenotyping.

Results: We identified a 35-gene signature with high predictive accuracy for homeostatic model of IR that was expressed across a variety of non-immune cell populations.

Harvesting Health: Phytochemicals in Cognitive Impairment Therapy.

Mild Cognitive Impairment (MCI) is swiftly emerging as a prevalent clinical concern within the elderly demographic. Willoughby spearheaded the pioneering investigation into the evolution of memory decline spanning from the age of 20 to 70. Employing a computerized substitution examination, he pinpointed a zenith in memory prowess at the age of 22, signifying the shift from infancy, succeeded by a gradual decline in later years in 1929.

The EV antibody database: An interactive database of curated antibodies for extracellular vesicle and nanoparticle research.

Antibodies are critical tools for research into extracellular vesicles (EVs) and other extracellular nanoparticles (ENPs), where they can be used for their identification, characterization, and isolation. However, the lack of a centralized antibody platform where researchers can share validation results thus minimizing wasted personnel time and reagents, has been a significant obstacle. Moreover, because the performance of antibodies varies among assay types and conditions, detailed information on assay variables and protocols is also of value.

A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver.

Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is increasing in parallel with an obesity pandemic, calling for novel strategies for prevention and treatment. We defined a circulating proteome of human MASLD across ≈7000 proteins in ≈5000 individuals from diverse, at-risk populations across the metabolic health spectrum, demonstrating reproducible diagnostic performance and specifying both known and novel metabolic pathways relevant to MASLD (central carbon and amino acid metabolism, hepatocyte regeneration, inflammation, fibrosis, insulin sensitivity). A parsimonious proteomic signature of MASLD was associated with a protection from MASLD and its related multi-system metabolic consequences in >26000 free-living individuals, with an additive effect to polygenic risk.

Expanding the horizon of EV-RNAs: LncRNAs in EVs as biomarkers for disease pathways.

Extracellular vesicles (EVs) are membrane-bound nanoparticles with different types of cargo released by cells and postulated to mediate functions such as intercellular communications. Recent studies have shown that long non-coding RNAs (lncRNAs) or their fragments are present as cargo within EVs. LncRNAs are a heterogeneous group of RNA species with a length exceeding 200 nucleotides with diverse functions in cells based on their localization.

Circulating extracellular vesicles in human cardiorenal syndrome promote renal injury in a kidney-on-chip system.

BACKGROUNDCardiorenal syndrome (CRS) - renal injury during heart failure (HF) - is linked to high morbidity. Whether circulating extracellular vesicles (EVs) and their RNA cargo directly impact its pathogenesis remains unclear.METHODSWe investigated the role of circulating EVs from patients with CRS on renal epithelial/endothelial cells using a microfluidic kidney-on-chip (KOC) model.

Obesity-Related Atrial Fibrillation: Cardiac Manifestation of a Systemic Disease.

Atrial fibrillation (AF) is the most common arrhythmia worldwide and is associated with increased morbidity and mortality. The mechanisms underlying AF are complex and multifactorial. Although it is well known that obesity is a strong risk factor for AF, the mechanisms underlying obesity-related AF are not completely understood.

Single Extracellular VEsicle Nanoscopy.

Extracellular vesicles (EVs) and their cargo constitute novel biomarkers. EV subpopulations have been defined not only by abundant tetraspanins (e.g.

Exomap1 mouse: a transgenic model for studies of exosome biology.

Exosomes are small extracellular vesicles (sEVs) of ~30-150 nm in diameter that have the same topology as the cell, are enriched in selected exosome cargo proteins, and play important roles in health and disease. To address large unanswered questions regarding exosome biology , we created the transgenic mouse model. In response to Cre recombinase, mice express HsCD81mNG, a fusion protein between human CD81, the most highly enriched exosome protein yet described, and the bright green fluorescent protein mNeonGreen.