Biology subjects

Hill, N. S.

Publications and source records attributed to Hill, N. S..

5 recordsLinked to original sources

bioRxiv2026

Metabolomic Network Analysis Reveals Reorganization of Lipid and Steroid Programs Linked to Right Ventricular-Pulmonary Vascular Function in Pulmonary Hypertension

BackgroundPulmonary arterial hypertension (PAH) is characterized by circulating metabolic alterations, but whether these reflect disease-specific metabolic programs or reorganization of normal metabolic architecture, and how they relate to right ventricular-pulmonary vascular function (RV-PV), remains unclear. We hypothesized that the PAH metabolome is organized into biologically coherent, co-regulated metabolic modules whose relationships to RV-PV function would provide insight into known and novel metabolic pathways. MethodsWe applied weighted gene co-expression network analysis (WGCNA) to untargeted metabolomic data from 412 PAH patients enrolled in the multicenter PVDOMICS study. Module preservation analysis was performed in 85 healthy controls, with external replication in an independent single-center pulmonary hypertension cohort of 89 patients. ResultsWGCNA identified 16 distinct metabolic modules organized around biologically coherent programs. A coherent fatty acid axis, spanning substrate pools, {beta}-oxidation intermediates, and conjugated fatty acid disposal products, formed a central organizing structure, with downstream fatty acid oxidation modules strongly associated with adverse hemodynamics and worse RV-pulmonary artery (PA) coupling. Acylcholine-enriched and 5-reduced androgen metabolite modules were associated with favorable hemodynamic indices. Module architecture was largely preserved in healthy controls, with subtle disease-associated modular reorganization, rather than emergence of novel modules, observed in PAH. Core modules were recovered in the replication cohort with conserved hub metabolites. ConclusionsThese findings establish a systems-level framework demonstrating that PAH involves structured intensification and reorganization of interconnected metabolic programs associated with favorable and adverse RV-PV phenotypes. This work provides new insight into the metabolic architecture underlying PAH and identifies coordinated metabolic pathways linked to pulmonary vascular and right ventricular function.

physiology↗

bioRxiv2025

AreTomoLive: Automated reconstruction of comprehensively-corrected and denoised cryo-electron tomograms in real-time and at high throughput

A high throughput processing pipeline that performs comprehensive corrections is needed to realize the full potential of cryo-electron tomography and subtomogram averaging. The fields fragmented software landscape remains a significant hurdle to this end. Here we present AreTomoLive, an automated real-time pipeline composed of two GPU-accelerated packages. The first, AreTomo3, streamlines tomographic alignment and reconstruction, with new features to fully account for sample geometry, locally correct the contrast transfer function, and curate data for downstream tasks. The second package, DenoisET, is a new implementation of the machine learning algorithm Noise2Noise and runs in parallel with AreTomo3 to perform contrast enhancement. To reduce barriers to routine use, AreTomoLive prioritizes automation: AreTomo3 autonomously pauses and reactivates processing depending on the status of data collection, while DenoisET algorithmically determines when to transition from training to inference. AreTomoLive endeavors to advance cryoET for in situ structural analysis with its comprehensive corrections and full automation.

cell biology↗

bioRxiv2023

Simultaneous PET and molecular MR imaging of cardiopulmonary fibrosis in a mouse model of left ventricular dysfunction

BackgroundAging-associated left ventricular (LV) dysfunction promotes cardiopulmonary fibrogenic remodeling, Group 2 pulmonary hypertension (PH), and right ventricular failure. At the time of diagnosis, cardiac function has declined, and cardiopulmonary fibrosis has often developed. Here, we sought to develop a molecular positron emission tomography (PET)-magnetic resonance imaging (MRI) protocol to detect both cardiopulmonary fibrosis and fibrotic disease activity in an LV dysfunction model. MethodsLV dysfunction was induced by transverse aortic constriction (TAC) in 6-month-old senescence-accelerated prone (SAMP8) mice, a subset of mice received sham surgery. Three weeks post-surgery, mice underwent simultaneous PET-MR imaging at 4.7 T. Collagen-targeted PET and fibrogenesis MR probes were intravenously administered. PET signal was computed as myocardium- or lung-to-muscle ratio (MMR, LMR). Percent signal increase (%SI) and {Delta}LMR were computed from the pre-/post-injection MR images. Tissue specimens were analyzed for hydroxyproline (Hyp) and allysine content. Ventricular structure and function were measured by echocardiography and hemodynamic pressure-volume (PV) loop analysis. ResultsAllysine in the heart (22{+/-}5 (TAC), 13{+/-}5 (sham) nmol/g, P=0.02) and lungs (7.5{+/-}4 (TAC), 5.8{+/-}2 (sham) nmol/lung, P=0.17) of TAC mice corresponded to an increase in myocardial MRI %SI (29{+/-}15 (TAC), 6.1{+/-}4 (sham), P<0.0001) and {Delta}LMR (0.3{+/-}0.1 (TAC), 0.08{+/-}0.1 (sham), P<0.0001). Hyp in the heart (555{+/-}90 (TAC), 400{+/-}80 (sham) {micro}g/g, P<0.0001) and lungs (189{+/-}63 (TAC), 143{+/-}31 (sham) {micro}g/lung, P<0.01) were elevated in TAC mice, which corresponded to an increase in PET signal (MMR: 1.8{+/-}0.1 (TAC), 1.6{+/-}0.2 (sham), P=0.02; LMR: 1.5{+/-}0.1 (TAC), 1.2{+/-}0.1 (sham), P<0.001). PV loop and echocardiography demonstrated adverse LV remodeling, function, and increased right ventricular systolic pressure in TAC mice. ConclusionsAdministration of collagen-targeted PET and allysine-targeted MR probes led to elevated PET-MRI signals in the myocardium and lungs of TAC mice. The study demonstrates the potential to detect fibrosis and fibrogenesis in cardiopulmonary disease through a dual molecular PET-MR imaging protocol.

molecular biology↗

bioRxiv2021

A mycobacterial glycine-rich protein governs actin-based motility

Mycobacterium marinum, a close relative of the significant human pathogen Mycobacterium tuberculosis, polymerizes host actin at the bacterial surface to drive intracellular movement and cell-to-cell spread during infection. Here, we report the identification and characterization of MirA, the M. marinum actin-based motility factor. MirA is a member of the glycine-rich PE_PGRS family of ESX-5-secreted proteins. MirA uses an amphipathic helix to anchor into the mycobacterial outer membrane and, surprisingly, also the surface of host lipid droplet organelles. The glycine-rich PGRS domain in MirA directly binds and activates host N-WASP to stimulate actin polymerization through the Arp2/3 complex, directing both bacterial and lipid droplet actin- based motility. MirA is dissimilar to known N-WASP activating ligands and may represent a new class of microbial and host actin regulator. Additionally, the MirA-N-WASP interaction represents a model to understand how the enigmatic PE_PGRS proteins contribute to mycobacterial pathogenesis.

microbiology↗

bioRxiv2017

A nutrient-dependent division antagonist is regulated post-translationally by the Clp proteases in Bacillus subtilis

Changes in nutrient availability have dramatic and well-defined impacts on both transcription and translation in bacterial cells. At the same time, the role of post-translational control in adaptation to nutrient-poor environments is poorly understood. Here we report a role for the bacterial Clp proteases in degradation of the division inhibitor UgtP during growth in nutrient-poor medium. Under nutrient-rich conditions, interactions with its substrate UDP-glucose promote interactions between UgtP and the tubulin-like cell division protein FtsZ in Bacillus subtilis, inhibiting maturation of the cytokinetic ring and increasing cell size. In nutrient-poor medium, reductions in UDP-glucose availability favor UgtP oligomerization, sequestering it from FtsZ and allowing division to occur at a smaller cell mass. Intriguingly, in nutrient-poor conditions UgtP levels are reduced [~] 3-fold independent of UDP-glucose, suggesting an additional layer of regulation. B. subtilis cells cultured under different nutrient conditions indicate that UgtP accumulation is controlled through a nutrient-dependent post-translational mechanism dependent on the Clp proteases. Notably, all three B. subtilis Clp chaperones appeared able to target UgtP for degradation during growth in nutrient-poor conditions. Together these findings highlight conditional proteolysis as a mechanism for bacterial adaptation to a rapidly changing nutritional landscape.

microbiology↗