Faculty Bibliography

Protease-activated receptor 2 (PAR₂) is a central regulator of intestinal barrier function, inflammation, and pain. Upregulated intestinal proteolysis and PAR₂ signaling are implicated in inflammatory bowel diseases (IBDs) and irritable bowel syndrome (IBS), conditions often associated with gut microbiome alterations. To identify potential bacterial regulators of PAR₂ activity, we developed a functional assay for PAR₂ processing to screen a library of diverse gut microbes. We identify multiple bacteria that secrete proteases capable of cleaving host PAR₂. Using chemoproteomic profiling with a covalent irreversible inhibitor, we uncovered a previously uncharacterized Bacteroides fragilis serine protease 1 (Bfp1) and show that it cleaves and activates PAR₂ in multicellular and murine models. PAR₂ cleavage by Bfp1 disrupts the intestinal barrier, sensitizes nociceptors, and triggers colonic inflammation and abdominal pain. Collectively, our findings uncover Bfp1-mediated PAR₂ processing as an axis of host-commensal interaction in the gut that has the potential to be targeted for therapeutic intervention in IBD or IBS.

Neurons process information by integrating thousands of synaptic inputs along their dendrites. Understanding the computational principles underlying neuronal information processing requires a reliable measure of synaptic conductance dynamics that accurately represents the input sources before signal integration and processing. Prevailing approaches to measuring synaptic conductances typically employ a voltage clamp at the soma of a neuron and assume the neuron as an isopotential point when processing electrical signals. However, owing to the presence of the well-known space clamp effect, the measurement of synaptic conductances through these methods often leads to significant errors, impeding the elucidation of dendritic signal features and subsequent signal integration processes. To address this issue, here we first develop a two-step clamp method at the soma that separately recovers the mean and time constant information of local synaptic conductance on the dendrite with high accuracy when a neuron receives a single synaptic input. Furthermore, under in vivo conditions of multiple synaptic inputs, we propose an intercept method to extract effective net excitatory and inhibitory synaptic conductances from measurements of synaptic currents at the soma. Both methods are grounded in mathematical perturbation analyses of a conductance-based passive cable model and are validated across multiple biologically detailed multicompartment neuron models with active channels, including Purkinje neuron, pyramidal neuron, and fast-spiking interneuron. Results demonstrate that our methods effectively circumvent the space clamp effect, offering reliable means to assess the role of measured conductances and synaptic activity in neuronal information processing.

Mothers exhibit an increased appetite to cope with the energetic demands of lactation. A new study has identified a neural circuit that interfaces between food seeking and pup caring.

Serial Magnetic Resonance Imaging (MRI) exams are often performed in clinical practice, offering shared anatomical and motion information across imaging sessions. However, existing reconstruction methods process each session independently without leveraging this valuable longitudinal information. In this work, we propose a novel concept of longitudinal dynamic MRI, which incorporates patient-specific prior images to exploit temporal correlations across sessions. This framework enables progressive acceleration of data acquisition and reduction of scan time as more imaging sessions become available. The concept is demonstrated using the 4D Golden-angle RAdial Sparse Parallel (GRASP) MRI, a state-of-the-art dynamic imaging technique. Longitudinal reconstruction is performed by concatenating multi-session time-resolved 4D GRASP datasets into an extended dynamic series, followed by a low-rank subspace-based reconstruction algorithm. A series of experiments were conducted to evaluate the feasibility and performance of the proposed method. Results show that longitudinal 4D GRASP reconstruction consistently outperforms standard single-session reconstruction in image quality, while preserving inter-session variations. The approach demonstrated robustness to changes in anatomy, imaging intervals, and body contour, highlighting its potential for improving imaging efficiency and consistency in longitudinal MRI applications. More generally, this work suggests a new context-aware imaging paradigm in which the more we see a patient, the faster we can image.

By improving the delivery and tumor retention of chemotherapeutics, nanomedicines hold potential for cancer treatment. The usefulness of nanoparticle (NP)-encapsulated analgesics for the cancer pain treatment is comparatively unexplored. We investigated whether NPs encapsulating olcegepant (OCP), an antagonist of the calcitonin receptor-like receptor (CLR) for the calcitonin gene-related peptide (CGRP), effectively relieved oral cancer pain in mice. Because persistent endosomal CLR signaling in Schwann cells mediates craniofacial pain, we reasoned that the predisposition of NPs to accumulate in endosomes could be leveraged to effectively relieve oral cancer pain. By expressing biosensors for activated CLR, Gα proteins and β-arrestins in HEK293T and Schwann cells, we found that CGRP activates CLR signaling first at the plasma membrane and then in early, late and recycling endosomes and the cis- and trans-Golgi apparatus. We synthesized biocompatible NPs encapsulating OCP and fluorophores by integrating hydrophobic ion pairing nanoformulation with Flash NanoPrecipitation. NPs slowly released OCP and accumulated in early endosomes, leading to sustained inhibition of endosomal CLR signaling in HEK293T and Schwann cells. Oral cancers were established in mice, which led to heightened pain-like responses. After intra-tumoral injection, NPs were retained in tumors for at least one week. OCP-loaded NPs almost completely reversed allodynia and hyperalgesia for a prolonged period, whereas unencapsulated OCP had small and transient effects. The NP accumulation in endosomal sites of pain signaling, the sustained release of antagonist, and the retention of NPs in tumors explain their beneficial actions. Thus, NP-encapsulation holds promise for the relief of painful cancers that are inadequately treated by opioids.

OBJECTIVES/OBJECTIVE:Magnetization-prepared rapid gradient-echo (MP-RAGE) sequences are routinely acquired for brain exams, providing high conspicuity for enhancing lesions. Vessels, however, also appear bright, which can complicate the detection of small lesions. T1RESS (T1 relaxation-enhanced steady-state) sequences have been proposed as an alternative to MP-RAGE, offering improved lesion conspicuity and suppression of blood vessels. This work aims to evaluate the performance of radial T1RESS variants for motion-robust contrast-enhanced brain MRI. MATERIALS AND METHODS/METHODS:Radial stack-of-stars sampling was implemented for steady-state free-precession-based rapid T1RESS acquisition with saturation recovery preparation. Three variants were developed using a balanced steady-state free-precession readout (bT1RESS), an unbalanced fast imaging steady precession (FISP) readout (uT1RESS-FISP), and an unbalanced reversed FISP readout (uT1RESS-PSIF). Image contrast was evaluated in numerical simulations and phantom experiments. The motion robustness of radial T1RESS was demonstrated with a motion phantom. Four patients and six healthy volunteers were scanned at 3 T and 0.55 T. Extensions were developed combining T1RESS with GRASP for dynamic imaging, with GRAPPA for accelerated scans, and with Dixon for fat/water separation. RESULTS:In simulations and phantom scans, uT1RESS-FISP provided higher signal intensity for regions with lower T1 values (<500 ms) compared with MP-RAGE. In motion experiments, radial uT1RESS-FISP showed fewer artifacts than MP-RAGE and Cartesian uT1RESS-FISP. In patients, both unbalanced uT1RESS variants provided higher lesion conspicuity than MP-RAGE. Blood vessels appeared bright with MP-RAGE, gray with uT1RESS-FISP, and dark with uT1RESS-PSIF. At 0.55 T, bT1RESS provided high signal-to-noise ratio T1-weighted images without banding artifacts. Lastly, dynamic T1RESS images with a temporal resolution of 10.14 seconds/frame were generated using the GRASP algorithm. CONCLUSIONS:Radial T1RESS sequences offer improved lesion conspicuity and motion robustness and enable dynamic imaging for contrast-enhanced brain MRI. Both uT1RESS variants showed higher tumor-to-brain contrast than MP-RAGE and may find application as alternative techniques for imaging uncooperative patients with small brain lesions.

Recent discoveries reveal that post-translational modifications (PTMs) do more than regulate protein activity - they encode conformational states that transform chaperones into epichaperomes: multimeric scaffolds that rewire protein-protein interaction networks. This emerging paradigm expands the framework of chaperone biology in disease and provides a structural basis for systems-level dysfunction in disorders such as cancer and Alzheimer's disease. This review explores how PTMs within intrinsically disordered regions drive epichaperome formation, how these scaffolds selectively regulate disease-enabling functions, and why their disruption normalizes pathological networks. By highlighting PTMs as molecular encoders of supramolecular assemblies, we propose a shift from targeting proteins to targeting network architectures that sustain and perpetuate disease - a concept with broad implications for cell biology, disease propagation, and therapeutic design.

Pooled single-cell CRISPR screens have profiled either gene expression or chromatin accessibility but not both modalities. Here we develop MultiPerturb-seq, a high-throughput CRISPR screening platform with joint single-nucleus chromatin accessibility, transcriptome and guide RNA capture using combinatorial indexing combined with droplet microfluidics to scale throughput and integrate all three modalities. We identify key differentiation genes in a rare pediatric cancer and establish ZNHIT1 as a potential target for cancer reprogramming therapy.

Perineural invasion (PNI) is a well-established factor of poor prognosis in multiple cancer types¹, yet its mechanism remains unclear. Here we provide clinical and mechanistic insights into the role of PNI and cancer-induced nerve injury (CINI) in resistance to anti-PD-1 therapy. Our study demonstrates that PNI and CINI of tumour-associated nerves are associated with poor response to anti-PD-1 therapy among patients with cutaneous squamous cell carcinoma, melanoma and gastric cancer. Electron microscopy and electrical conduction analyses reveal that cancer cells degrade the nerve fibre myelin sheets. The injured neurons respond by autonomously initiating IL-6- and type I interferon-mediated inflammation to promote nerve healing and regeneration. As the tumour grows, the CINI burden increases, and its associated inflammation becomes chronic and skews the general immune tone within the tumour microenvironment into a suppressive and exhaustive state. The CINI-driven anti-PD-1 resistance can be reversed by targeting multiple steps in the CINI signalling process: denervating the tumour, conditional knockout of the transcription factor mediating the injury signal within neurons (Atf3), knockout of interferon-α receptor signalling (Ifnar1^-/-) or by combining anti-PD-1 and anti-IL-6-receptor blockade. Our findings demonstrate the direct immunoregulatory roles of CINI and its therapeutic potential.

INTRODUCTION/BACKGROUND:The New York University Caregiver Intervention plus Enhanced Support Project is a randomized controlled trial of a family-based psychosocial intervention to enhance social support and reduce cardiometabolic risk for Chinese and Korean American dementia caregivers, using culturally tailored recruitment strategies. METHODS:We reviewed reflections from research staff, weekly meeting minutes, debriefing sessions, and progress reports, to identify key challenges and approaches to engaging participants. RESULTS:Key challenges included reluctance to involve family members, dementia stigma, and resistance to involving family. In response, we engaged online communities, partnered with local organizations, participated in events, and adapted recruitment messages to cultural norms. For the Chinese community, we focused on practical skills while for the Korean community, we emphasized caregiving strategies and the personal/social benefits of participation, reducing rejection rates. DISCUSSION/CONCLUSIONS:Our findings underscore the importance of culturally tailored recruitment strategies in dementia research. Respectful, sensitive, and culturally informed approaches can significantly enhance engagement and participation. HIGHLIGHTS/CONCLUSIONS:Culturally adapted recruitment strategies improve study engagement with Chinese and Korean American dementia caregivers. Community partnerships with local social services agencies are essential for recruitment success. Culturally relevant social media applications were integrated to increase accessibility for study participants. This study uniquely targets and recruits Chinese and Korean American dementia caregivers with metabolic syndrome-related symptoms, incorporating a psychological intervention alongside biomarker data collection. The iterative adaptation of recruitment methods and tailored messaging to specific ethnic groups ensure the intervention is culturally aligned, enhancing both participation and relevance to the caregivers' unique health and caregiving contexts.