Faculty Bibliography

Over the last decade there has been tremendous growth in the development of accelerated MD pathways that allow medical students to graduate in three years. Developing an accelerated pathway program requires commitment from students and faculty with intensive re-thinking and altering of the curriculum to ensure adequate content to achieve competency in an accelerated timeline. A re-visioning of assessment and advising must follow and the application of AI and new technologies can be added to support teaching and learning. We describe the curricular revision to an accelerated pathway at NYU Grossman School of Medicine highlighting our thought process, conceptual framework, assessment methods and outcomes over the last ten years.

Fibroblast Growth Factor-23 (FGF23) is a bone secreted protein widely recognized as a critical regulator of skeletal and mineral metabolism. However, little is known about non-skeletal production of FGF23 and its role in tissues other than bone. Growing evidence indicates that circulating FGF23 levels rise with high fat diet (HFD) and they are positively correlated with body mass index (BMI) in humans. In the present study, we show for the first time that increased circulating FGF23 levels in obese humans correlate with increased expression of adipose Fgf23 and both positively correlate with BMI. To understand the role of adipose-derived Fgf23, we generated adipocyte-specific Fgf23 knockout mice (AdipoqFgf23Δfl/Δfl) using the Adiponectin (Adipoq)-Cre driver, which targets mature white, beige, and brown adipocytes. Our data show that targeted ablation of Fgf23 in adipocytes prevents HFD-fed female mice from gaining body weight and fat mass while preserving lean mass, but has no effect on male mice, indicating the presence of sexual dimorphism. These effects are observed in the absence of changes in food and energy intake. Adipose Fgf23 inactivation also prevents dyslipidemia, hyperglycemia, and hepatic steatosis in female mice. Moreover, these changes are associated with decreased respiratory exchange ratio (RER) and increased brown fat Ucp1 expression in KO mice compared to HFD-fed control mice (Fgf23fl/fl). In conclusion, this is the first study highlighting that targeted inactivation of Fgf23 is a promising therapeutic strategy for weight loss and lean mass preservation in humans.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder, and recent evidence suggests that pathogenesis may be in part mediated by inflammatory processes, the molecular and cellular architectures of which are largely unknown. To identify and characterize selectively vulnerable brain cell populations in PD, we performed single-nucleus transcriptomics and unbiased proteomics to profile the prefrontal cortex from postmortem human brains of six individuals with late-stage PD and six age-matched controls. Analysis of nearly 80,000 nuclei led to the identification of eight major brain cell types, including elevated brain-resident T cells in PD, each with distinct transcriptional changes in agreement with the known genetics of PD. By analyzing Lewy body pathology in the same postmortem brain tissues, we found that α-synuclein pathology was inversely correlated with chaperone expression in excitatory neurons. Examining cell-cell interactions, we found a selective abatement of neuron-astrocyte interactions and enhanced neuroinflammation. Proteomic analyses of the same brains identified synaptic proteins in the prefrontal cortex that were preferentially down-regulated in PD. By comparing this single-cell PD dataset with a published analysis of similar brain regions in Alzheimer's disease (AD), we found no common differentially expressed genes in neurons but identified many shared differentially expressed genes in glial cells, suggesting that the disease etiologies, especially in the context of neuronal vulnerability, in PD and AD are likely distinct.

Neurogenesis occurs in the adult brain in the hippocampal dentate gyrus, an area that contains neurons which are vulnerable to insults and injury, such as severe seizures. Previous studies showed that increasing adult neurogenesis reduced neuronal damage after these seizures. Because the damage typically is followed by chronic life-long seizures (epilepsy), we asked if increasing adult-born neurons would prevent epilepsy. Adult-born neurons were selectively increased by deleting the pro-apoptotic gene Bax from Nestin-expressing progenitors. Tamoxifen was administered at 6 weeks of age to conditionally delete Bax in Nestin-CreER^T2

Systems consolidation relies on coordination between hippocampal sharp-wave ripples (SWRs) and neocortical UP/DOWN states during sleep. However, whether this coupling exists across neocortex and the mechanisms enabling it remain unknown. By combining electrophysiology in mouse hippocampus (HPC) and retrosplenial cortex (RSC) with widefield imaging of dorsal neocortex, we found spatially and temporally precise bidirectional hippocampo-neocortical interaction. HPC multi-unit activity and SWR probability was correlated with UP/DOWN states in mouse default mode network, with highest modulation by RSC in deep sleep. Further, some SWRs were preceded by the high rebound excitation accompanying DMN DOWN→UP transitions, while large-amplitude SWRs were often followed by DOWN states originating in RSC. We explain these electrophysiological results with a model in which HPC and RSC are weakly coupled excitable systems capable of bi-directional perturbation and suggest RSC may act as a gateway through which SWRs can perturb downstream cortical regions via cortico-cortical propagation of DOWN states.

Thanks to recent developments in Cardiovascular magnetic resonance (CMR), cardiac diffusion-weighted magnetic resonance is fast emerging in a range of clinical applications. Cardiac diffusion-weighted imaging (cDWI) and diffusion tensor imaging (cDTI) now enable investigators and clinicians to assess and quantify the 3D microstructure of the heart. Free-contrast DWI is uniquely sensitized to the presence and displacement of water molecules within the myocardial tissue, including the intra-cellular, extra-cellular and intra-vascular spaces. CMR can determine changes in microstructure by quantifying: a) mean diffusivity (MD) -measuring the magnitude of diffusion; b) fractional anisotropy (FA) - specifying the directionality of diffusion; c) helix angle (HA) and transverse angle (TA) -indicating the orientation of the cardiomyocytes; d) E2A and E2A mobility - measuring the alignment and systolic-diastolic mobility of the sheetlets, respectively. This document provides recommendations for both clinical and research cDWI and cDTI, based on published evidence when available and expert consensus when not. It introduces the cardiac microstructure focusing on the cardiomyocytes and their role in cardiac physiology and pathophysiology. It highlights methods, observations and recommendations in terminology, acquisition schemes, post-processing pipelines, data analysis and interpretation of the different biomarkers. Despite the ongoing challenges discussed in the document and the need for ongoing technical improvements, it is clear that cDTI is indeed feasible, can be accurately and reproducibly performed and, most importantly, can provide unique insights into myocardial pathophysiology.

The intricate network of protein-chaperone interactions is crucial for maintaining cellular function. Recent discoveries have unveiled the existence of specialized chaperone assemblies, known as epichaperomes, which serve as scaffolding platforms that orchestrate the reconfiguration of protein-protein interaction networks, thereby enhancing cellular adaptability and proliferation. This study explores the structural and regulatory aspects of epichaperomes, with a particular focus on the role of post-translational modifications (PTMs) in their formation and function. A key finding is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 within an intrinsically disordered region, as critical determinants of epichaperome assembly. Our data demonstrate that phosphorylation of these serine residues enhances HSP90's interactions with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Moreover, we establish a direct link between epichaperome function and cellular physiology, particularly in contexts where robust proliferation and adaptive behavior are essential, such as in cancer and pluripotent stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone assemblies in diseases characterized by epichaperome dysregulation, thereby bridging the gap between fundamental research and precision medicine.

Advances in closed-loop neural interfaces and neuromodulation have offered a potentially effective and non-addictive treatment for chronic pain. These interfaces link neural sensors with device outputs to provide temporally precise stimulation. We discuss challenges and trends of state-of-the-art neural interfaces for treating pain in animal models and human pilot trials.

Legumain is a cysteine protease broadly associated with inflammation. It has been reported to cleave and activate protease-activated receptor 2 to provoke pain associated with oral cancer. Outside of gastric and colon cancer, little has been reported on the roles of legumain within the gastrointestinal tract. Using a legumain-selective activity-based probe, LE28, we report that legumain is activated within colonocytes and macrophages of the murine colon, and that it is upregulated in models of acute experimental colitis. We demonstrated that loss of legumain activity in colonocytes, either through pharmacological inhibition or gene deletion, had no impact on epithelial permeability in vitro. Moreover, legumain inhibition or deletion had no obvious impacts on symptoms or histological features associated with dextran sulfate sodium-induced colitis, suggesting its proteolytic activity is dispensable for colitis initiation. To gain insight into potential functions of legumain within the colon, we performed field asymmetric waveform ion mobility spectrometry-facilitated quantitative proteomics and N-terminomics analyses on naïve and inflamed colon tissue from wild-type and legumain-deficient mice. We identified 16 altered cleavage sites with an asparaginyl endopeptidase signature that may be direct substrates of legumain and a further 16 cleavage sites that may be indirectly mediated by legumain. We also analyzed changes in protein abundance and proteolytic events broadly associated with colitis in the gut, which permitted comparison to recent analyses on mucosal biopsies from patients with inflammatory bowel disease. Collectively, these results shed light on potential functions of legumain and highlight its potential roles in the transition from inflammation to colorectal cancer.

Chronic pain affects one in five adults. It is not only a major cause of disability for individual patients but also a driver of costs for entire healthcare systems. Treatment of pain remains a challenge, and the use of opioids has further led to a concurrent opioid epidemic. In this review, we discuss current standard treatment options for chronic pain, including pharmacological, behavioral, and interventional treatments. In addition, we review ongoing research in different areas that will potentially unlock new therapies.