Biology subjects

Shulman, M.

Publications and source records attributed to Shulman, M..

5 recordsLinked to original sources

bioRxiv2025

A single-cell cytokine dictionary of human peripheral blood

Cytokines orchestrate immune responses, yet we still lack a comprehensive understanding of their specific effects across human immune cells due to their pleiotropy, context dependence and extensive functional redundancy. Here, we present a Human Cytokine Dictionary, created from high-resolution single-cell transcriptomes of 9,697,974 human peripheral blood mononuclear cells (PBMC) from 12 donors stimulated in vitro with 90 different cytokines. We describe donor-specific response variation and uncover robust consensus cytokine signatures across individuals. We then delineate similarities between cytokine response profiles, and derive cytokine-induced immune programs that organize responsive genes into data-driven, biologically interpretable functional modules. By integrating cell type-specific responses with expression of cytokines, we infer higher-order cell-to-cell and cytokine-to-cytokine communication networks exemplified by an IL-32-{beta}-initiated signaling cascade, which rewires myeloid programs by inducing neutrophil-recruiting factors while suppressing Th1-responses and promoting IL-10-family cytokines. Finally, we show how the Human Cytokine Dictionary enables the interpretation of cytokine-driven immune responses in other studies and disease contexts, including systemic lupus erythematosus, multiple sclerosis, and non-small cell lung carcinoma. Together, the Human Cytokine Dictionary constitutes the first comprehensive cell type-resolved transcriptional screen of human cytokine responses and provides an essential open-access, easy-to-use community resource with accompanying software package to advance our understanding of cytokine biology in human disease and guide therapeutic discovery.

immunology↗

bioRxiv2025

TNF-α disrupts the malate-aspartate shuttle, driving metabolic rewiring in iPSC-derived enteric neural lineages from Parkinson's Disease patients

Gastrointestinal (GI) dysfunction emerges years before motor symptoms in Parkinsons disease (PD), implicating the enteric nervous system (ENS) in early disease progression. However, the mechanisms linking the PD hallmark protein, -synuclein (-syn), to ENS dysfunction - and whether these mechanisms are influenced by inflammation - remains elusive. Using iPSC-derived enteric neural lineages from patients with -syn triplications, we reveal that TNF- increases mitochondrial--syn interactions, disrupts the malate-aspartate shuttle, and forces a metabolic shift toward glutamine oxidation. These alterations drive mitochondrial dysfunction, characterizing metabolic impairment under cytokine stress. Interestingly, targeting glutamate metabolism with Chicago Sky Blue 6B restores mitochondrial function, reversing TNF--driven metabolic disruption. Our findings position the ENS as a central player in PD pathogenesis, establishing a direct link between cytokines, -syn accumulation, metabolic stress and mitochondrial dysfunction. By uncovering a previously unrecognized metabolic vulnerability in the ENS, we highlight its potential as a therapeutic target for early PD intervention.

neuroscience↗

bioRxiv2024

Stepwise Isolation of Diverse Metabolic Cell Populations Using Sorting by Interfacial Tension (SIFT)

We present here a passive and label-free droplet microfluidic platform to sort cells stepwise by lactate and proton secretion from glycolysis. A technology developed in our lab, Sorting by Interfacial Tension (SIFT), sorts droplets containing single cells into two populations based on pH by using interfacial tension. Cellular glycolysis lowers the pH of droplets through proton secretion, enabling passive selection based on interfacial tension and hence single-cell glycolysis. The SIFT technique is expanded here by exploiting the dynamic droplet acidification from surfactant adsorption that leads to a concurrent increase in interfacial tension. This allows multiple microfabricated rails at different downstream positions to isolate cells with distinct glycolytic levels. The device is used to correlate sorted cells with three levels of glycolysis with a conventional surface marker for T-cell activation. As glycolysis is associated with both disease and cell state, this technology facilitates the sorting and analysis of crucial cell subpopulations for applications in oncology, immunology and immunotherapy.

bioengineering↗

bioRxiv2024

Multimodal weakly supervised learning to identify disease-specific changes in single-cell atlases

To deliver clinically relevant insights from large patient cohorts profiled with single-cell technologies, a key challenge is to relate sample-level and single-cell measurements. We present MultiMIL, a deep learning framework that applies attention-based multiple-instance learning for phenotype prediction and cell state identification. We applied MultiMIL to peripheral blood mononuclear cells from COVID-19 patients, the Human Lung Cell Atlas, and a spatial proteomics breast cancer dataset, demonstrating how our model can be utilized to find phenotype-associated cell states, learn phenotype-informed sample representations, and expand disease signatures.

bioinformatics↗

bioRxiv2023

Folliculogenesis and ovulation in fish are controlled by distinct neuropeptides

Life histories of oviparous species dictate high metabolic investment in the process of gonadal development leading to ovulation. In vertebrates, these two distinct processes are controlled by the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH), respectively. While it was suggested that a common secretagogue, gonadotropin-releasing hormone (GnRH), oversees both functions, the generation of loss-of-function fish challenged this view. Here, we reveal that the satiety hormone cholecystokinin (CCK) is the primary regulator of this axis in zebrafish. We found that FSH cells express a CCK receptor, and our findings demonstrate that mutating this receptor results in a severe hindrance to ovarian development. Additionally, it causes a complete shutdown of both gonadotropins secretion. Using in-vivo and ex-vivo calcium imaging of gonadotrophs, we show that GnRH predominantly activates LH cells, whereas FSH cells respond to CCK stimulation, designating CCK as the bona fide FSH secretagogue. These findings indicate that the control of gametogenesis in fish was placed under different neural circuits, that are gated by CCK.

neuroscience↗