Biology subjects

Baron, R.

Publications and source records attributed to Baron, R..

3 recordsLinked to original sources

bioRxiv2020

Individualized System for Augmenting Ventilator Efficacy (iSAVE):A Rapidly deployable system to expand ventilator capacity

The COVID-19 pandemic is overwhelming healthcare systems worldwide. A significant portion of COVID-19 patients develop pneumonia and acute respiratory distress syndrome (ARDS), necessitating ventilator support. Some health systems do not have the capacity to accommodate this surge in ventilator demand, leading to shortages and inevitable mortality. Some clinicians have, of necessity, jerry-rigged ventilators to support multiple patients, but these devices lack protected air streams or individualized controls for each patient. Moreover, some have not been tested under conditions of ARDS. We have developed the Individualized System for Augmenting Ventilator Efficacy (iSAVE), a rapidly deployable platform to more safely use a single ventilator to simultaneously support multiple critically-ill patients. The iSAVE enables patient-specific volume and pressure control and incorporates safety features to mitigate cross-contamination between patients and flow changes due to patient interdependencies within the respiratory circuit. Here we demonstrate through simulated and in vivo pig evaluation the capacity of the iSAVE to support a range of respiratory clinical states. By leveraging off-the-shelf components that are readily available to intensive care unit (ICU) caregivers, the iSAVE could potentially be translated for human application to expand the ventilation capacity of hospitals using existing ventilators, minimizing the need to procure additional ventilators.

physiology↗

bioRxiv2020

Pharmacological inhibition of longevity regulator PAPP-A restrains mesenchymal stromal cell activity

Reducing insulin-like growth factor (IGF) signaling is one of the best conserved and characterized mechanisms to extend longevity. Pregnancy associated plasma protein A (PAPP-A) is a secreted metalloprotease that increases IGF availability by cleaving IGF binding proteins. PAPP-A inhibition reduces local IGF signaling, limits the progression of multiple age-related diseases, and extends lifespan, but the mechanisms behind these pleiotropic effects remains unknown. Here, we developed and utilized a PAPP-A neutralizing antibody to discover that adulthood inhibition of this protease reduced collagen and extracellular matrix (ECM) gene expression in multiple tissues in mice. Using bone marrow to explore this effect, we identified mesenchymal stromal cells (MSCs) as the source of PAPP-A and primary responders to PAPP-A inhibition. Short-term treatment with anti-PAPP-A reduced IGF signaling in MSCs, altered MSC expression of collagen/ECM, and decreased MSC number. This affected MSC-dependent functions, decreasing myelopoiesis and osteogenesis. Our data demonstrate that PAPP-A inhibition reduces the activity and number of IGF-dependent mesenchymal progenitor cells and their differentiated progeny, and that this reduction leads to functional changes at the tissue level. MSC-like cells are present in virtually all tissues, and aberrant collagen and ECM production from mesenchymal cells drives aspects of aging and age-related diseases, thus this may be a mechanism by which PAPP-A deficiency enhances lifespan and healthspan. SummaryInhibition of PAPP-A, a regulator of IGF signaling, decreases multi-tissue collagen and extracellular matrix gene expression and modulates mesenchymal stromal cell activity in murine bone marrow.

physiology↗

bioRxiv2020

Propranolol and parathyroid hormone synergistically improve bone volume fraction by suppressing resorption

Although the non-selective {beta}-blocker, propranolol, improves bone density with PTH treatment in mice, the mechanism of this effect is unclear. To address this, we used a combination of in vitro and in vivo approaches to address how propranolol influences bone remodeling in the context of PTH treatment. In female C57BL/6J mice, intermittent PTH and propranolol had complementary effects in the trabecular bone of the distal femur and L5 vertebra, with combination treatment achieving micro-architectural parameters beyond that of PTH alone. Combined treatment improved the serum bone formation marker, P1NP, but did not impact other histomorphometric parameters relating to osteoblast function at the L5. In vitro, propranolol amplified the acute, PTH-induced, intracellular calcium signal in osteoblast-like cells. The most striking finding, however, was suppression of PTH-induced bone resorption. Despite this, PTH-induced receptor activator of nuclear factor kappa-B ligand (RANKL) mRNA and protein levels were unaltered by propranolol, which led us to hypothesize that propranolol could act directly on osteoclasts. Using in situ methods, we found Adrb2 expression in osteoclasts in vivo, suggesting {beta}-blockers may directly impact osteoclasts. Taken together, this work suggests a strong anti-osteoclastic effect of non-selective {beta}-blockers in vivo, indicating that combining propranolol with PTH could be beneficial to patients with extremely low bone density.

physiology↗