Biology subjects

Grant, J. L.

Publications and source records attributed to Grant, J. L..

3 recordsLinked to original sources

bioRxiv2025

Identification of Omaveloxolone as An Endoplasmic Reticulum Associated Degradation Inhibitor That Induces Early Apoptotic Signaling in Multiple Myeloma

Endoplasmic reticulum-associated degradation (ERAD) is essential for maintaining protein homeostasis, yet its regulatory mechanisms remain poorly understood. A major challenge in studying ERAD is the lack of specific inhibitors targeting the ERAD complex. To address this, we conducted a cell-based high-throughput screen using the FDA-repurposing library and identified omaveloxolone (RTA408) as a potent ERAD inhibitor that selectively impairs the degradation of ER luminal and membrane substrates. Beyond its utility in identifying ERAD substrates, RTA408 exhibits strong cytotoxic effects in multiple myeloma (MM), an incurable plasma cell malignancy. RTA408 inhibits ERAD activity and rapidly induces apoptotic signaling via caspase 8 and the death-inducing signaling complex (DISC). Notably, RTA408 is cytotoxic to malignant plasma cells, including those resistant to proteasome inhibitors, and demonstrates in vivo anti-myeloma activity. Our findings establish ERAD inhibitors as valuable tools for dissecting ERAD regulation while also highlighting their potential as therapeutic agents for MM. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/646787v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@96254aorg.highwire.dtl.DTLVardef@16a3f6dorg.highwire.dtl.DTLVardef@6a1503org.highwire.dtl.DTLVardef@897c45_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIWe developed a cell-based screening approach to identify novel modulators of endoplasmic reticulum associated degradation (ERAD), with implications in studying ERAD biology and targeting plasma cell neoplasms. C_LIO_LIScreening of the FDA-repurposing library identified Omaveloxolone (RTA408) as an inhibitor of luminal and membrane ERAD substrate degradation, which can be leveraged to identify ERAD substrates. C_LIO_LImaveloxolone treatment rapidly induces the unfolded protein response and apoptosis that is dependent on caspase 8 and death-inducing signaling complex (DISC) in multiple myeloma cells. C_LIO_LImaveloxolone exhibits cytotoxic effects against multiple myeloma cells in vitro and in vivo and induces apoptosis in primary plasma cells from patients with relapsed/refractory myeloma C_LI

cell biology↗

bioRxiv2025

Evaluation of distal facial nerve branches contribution to facial nerve paralysis in rodents

Introduction/AimsFacial nerve paralysis is a complex and devastating condition. Translational research of facial paralysis recovery remains largely limited to animal studies, for which there are many potential models employed. When studying facial nerve regeneration in rodents, it is important to understand the converging contributions of the motor supply into the whisker pad. A consensus surgical approach and animal model has yet to be defined. Of particular interest for movement of the nose and whiskers are the buccal and marginal mandibular nerves. This study aims to evaluate how these distal nerve branches contribute to facial nerve paralysis and identify key morphological changes at the neuromuscular junctions (NMJs) in the whisker pad of rodents. MethodsAdult rats underwent isolated transection of the buccal branch of the facial nerve, both the buccal and marginal mandibular branches of the facial nerve, or control sham surgery. ResultsHistological, electrophysiological, and behavior assessments confirmed that the transection of the buccal branch alone did not cease whisker movement in rats, but when combined with a transection of the marginal mandibular branch, it resulted in full paralysis of the whisker and nose movement. DiscussionThese results are indicative of the distinct roles of these nerves branches in facial paralysis repair following a transection injury. Further, our results suggest additional targets for facial nerve repair treatments.

neuroscience↗

bioRxiv2020

Investigating the dynamics of microbial consortia in spatially structured environments

The spatial organization of microbial communities arises from a complex interplay of biotic and abiotic interactions and is a major determinant of ecosystem functions. We design a microfluidic platform to investigate how the spatial arrangement of microbes impacts gene expression and growth. We elucidate key biochemical parameters that dictate the mapping between spatial positioning and gene expression patterns. We show that distance can establish a low-pass filter to periodic inputs, and can enhance the fidelity of information processing. Positive and negative feedback can play disparate roles in the synchronization and robustness of a genetic oscillator distributed between two strains to spatial separation. Quantification of growth and metabolite release in an amino-acid auxotroph community demonstrates that the interaction network and stability of the community are highly sensitive to temporal perturbations and spatial arrangements. In sum, our microfluidic platform can quantify spatiotemporal parameters influencing diffusion-mediated interactions in microbial consortia.

systems biology↗