Biology subjects

Schwartz, C. E.

Publications and source records attributed to Schwartz, C. E..

3 recordsLinked to original sources

bioRxiv2021

Small molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo.

Retinoic acid receptor-related orphan nuclear receptor (ROR) {gamma}t is a member of the RORC nuclear hormone receptor family of transcription factors. ROR{gamma}t functions as a critical regulator of thymopoiesis and immune responses. ROR{gamma}t is expressed in multiple immune cell populations including Th17 cells, where its primary function is regulation of immune responses to bacteria and fungi through IL-17A production. However, excessive IL-17A production has been linked to numerous autoimmune diseases. Moreover, Th17 cells have been shown to elicit both pro- and anti-tumor effects. Thus, modulation of the ROR{gamma}t/IL-17A axis may represent an attractive therapeutic target for the treatment of autoimmune disorders and some cancers. Herein we report the design, synthesis and characterization of three selective allosteric ROR{gamma}t inhibitors in preclinical models of inflammation and tumor growth. We demonstrate that these compounds can inhibit Th17 differentiation and maintenance in vitro and Th17-dependent inflammation and associated gene expression in vivo, in a dose-dependent manner. Finally, ROR{gamma}t inhibitors were shown to inhibit tumor formation in pancreatic ductal adenocarcinoma (PDAC) organoids.

immunology↗

bioRxiv2020

Increased p53 signaling impairs neural differentiation causing HUWE1-promoted intellectual disabilities

Essential E3 ubiquitin ligase HUWE1 (HECT, UBA and WWE domain containing 1) regulates key factors, as p53. Mutations in HUWE1 have been associated with neurodevelopmental X-linked intellectual disabilities (XLIDs), however the pathomechanism at the onset of heterogenous XLIDs remains unknown. In this work, we identify p53 signaling as the process hyperactivated in lymphoblastoid cells from patients with HUWE1-promoted XLIDs. The hiPSCs-based modeling of the severe HUWE1-promoted XLID, the Juberg Marsidi syndrome (JMS), reviled majorly impaired neural differentiation, accompanied by increased p53 signaling. The impaired differentiation results in loss of cortical patterning and overall undergrowth of XLID JMS patient-specific cerebral organoids, thus closely recapitulating key symptoms, as microcephaly. Importantly, the neurodevelopmental potential of JMS hiPSCs is successfully rescued by restoring p53 signaling, upon reduction of p53 levels. In summary, our findings indicate that increased p53 signaling leads to impaired neural differentiation and is the common cause of neurodevelopmental HUWE1-promoted XLIDs.

cell biology↗

bioRxiv2020

Expected impacts of climate change on tree ferns distribution and diversity patterns in subtropical Atlantic Forest

Tree ferns are common elements in the Atlantic Forest domain, sometimes reaching more than half of total dominance at forest sites. Just as most groups, climate change might impact the distribution and diversity of tree ferns. To investigate the extent of these impacts in the subtropical Atlantic Rainforest, we measured the changes in species distribution, - and {beta}-diversity between current climate and future climatic scenarios for 2050. Most tree ferns species tend to lose their distribution area. Hence, species richness tends to decrease in the future, especially in the Rainforest sites. In general, {beta}-diversity tend to not change on the regional scale, but some sites can change its relative singularity in composition. Our results show that climate change can impact distribution and -diversity of tree ferns, but with no trend to cause homogenization in the tree ferns of the study area. Protected Areas (PAs) in our study region manage to withhold more -diversity than areas without PAs -- the same applies to {beta}-diversity. Our study offers a new light into the effects of climate change in tree ferns by integrating the evaluation of its impacts on distribution, - and {beta}-diversity in all study areas and inside PAs.

ecology↗