Publications

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64 Publications visible to you, out of a total of 64
Antibody-Fab and -Fc features promote Mycobacterium tuberculosis restriction.

Abstract (Expand)

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), a leading cause of death by an infectious disease globally, has no efficacious vaccine. Antibodies are implicated in M. tuberculosis … control, but the mechanisms of action remain poorly understood. We assembled a library of monoclonal antibodies (mAb) and screened for M. tuberculosis-restrictive activity in mice, identifying protective antibodies targeting diverse antigens. To dissect the mechanism of mAb-mediated M. tuberculosis restriction, we optimized a protective lipoarabinomannan-specific mAb, generating Fc variants. In vivo analysis of these Fc variants revealed a role for Fc-effector function in M. tuberculosis restriction. Restrictive Fc variants altered distribution of M. tuberculosis across innate immune cells. Single-cell transcriptomics highlighted distinctly activated pathways within innate immune cell subpopulations, identifying early activation of neutrophils as a key signature of mAb-mediated M. tuberculosis restriction. Therefore, antibody-mediated restriction of M. tuberculosis is associated with reorganization of the tissue-level immune response to infection and depends on the collaboration of antibody Fab and Fc.

Authors: P. S. Grace, J. M. Peters, J. Sixsmith, R. Lu, E. B. Irvine, C. Luedeman, B. A. Fenderson, A. Vickers, M. D. Slein, T. McKitrick, M. H. Wei, R. D. Cummings, A. Wallace, L. A. Cavacini, A. Choudhary, M. K. Proulx, C. Sundling, G. Kallenius, R. Reljic, J. D. Ernst, A. Casadevall, C. Locht, A. Pinter, C. M. Sassetti, B. D. Bryson, S. M. Fortune, G. Alter

Date Published: 10th Jun 2025

Publication Type: Journal Article

Structural and systems characterization of phosphorylation on metabolic enzymes identifies sex-specific metabolic reprogramming in obesity.

Abstract (Expand)

Coordination of adaptive metabolism through signaling networks is essential for cellular bioenergetics and homeostasis. Phosphorylation of metabolic enzymes provides a rapid, efficient, and dynamic … mechanism to regulate metabolic networks. Our structural analysis stratified phosphosites on metabolic enzymes based on proximity to functional and dimerization domains. Most phosphosites occur on oxidoreductases and are enriched near substrate, cofactor, active sites, or dimer interfaces. Despite low stoichiometry, phosphotyrosine (pY) is overrepresented in functional domains. Using high-fat diet (HFD)-induced obesity in C57BL/6J mice and multiomics, we measured HFD-induced sex-specific dysregulation of pY and metabolites, which was reversible with the antioxidant butylated hydroxyanisole (BHA). Computational modeling revealed predictive pY sites for HFD- or BHA-induced metabolite changes. We characterized functional roles for predictive pY sites on glutathione S-transferase pi 1 (GSTP1), isocitrate dehydrogenase 1 (IDH1), and uridine monophosphate synthase (UMPS) using CRISPR interference (CRISPRi) rescue and stable isotope tracing. Our findings reveal mechanisms whereby cellular signaling fine-tunes enzyme activity and metabolism.

Authors: T. Y. Tamir, S. Chaudhary, A. X. Li, S. E. Trojan, C. T. Flower, P. Vo, Y. Cui, J. C. Davis, R. Mukkamala, F. N. Venditti, A. L. Hillis, A. Toker, M. G. Vander Heiden, J. B. Spinelli, N. J. Kennedy, R. J. Davis, F. M. White

Date Published: 5th Jun 2025

Publication Type: Journal Article

Validation and quantification of peptide antigens presented on MHCs using SureQuant.

Abstract (Expand)

Vaccines and immunotherapies that target peptide-major histocompatibility complexes (peptide-MHCs) have the potential to address multiple unmet medical needs in cancer and infectious disease. Designing … vaccines and immunotherapies to target peptide-MHCs requires accurate identification of target peptides in infected or cancerous cells or tissue, and may require absolute or relative quantification to identify abundant targets and measure changes in presentation under different treatment conditions. Internal standard parallel reaction monitoring (also known as 'SureQuant') can be used to validate and/or quantify MHC peptides previously identified by using untargeted methods such as data-dependent acquisition. SureQuant MHC has three main use cases: (i) conclusive confirmation of the identities of putative MHC peptides via comparison with an internal synthetic stable isotope labeled (SIL) peptide standard; (ii) accurate relative quantification by using pre-formed heavy isotope-labeled peptide-MHC complexes (hipMHCs) containing SIL peptides as internal controls for technical variation; and (iii) absolute quantification of each target peptide by using different amounts of hipMHCs loaded with synthetic peptides containing one, two or three SIL amino acids to provide an internal standard curve. Absolute quantification can help determine whether the abundance of a peptide-MHC is sufficient for certain therapeutic modalities. SureQuant MHC therefore provides unique advantages for immunologists seeking to confidently validate antigenic targets and understand the dynamics of the MHC repertoire. After synthetic standards are ordered (3-4 weeks), this protocol can be carried out in 3-4 days and is suitable for individuals with mass spectrometry experience who are comfortable with customizing instrument methods.

Authors: O. Leddy, Y. Cui, R. Ahn, L. Stopfer, E. Choe, D. H. Kim, M. Roerden, S. Spranger, B. D. Bryson, F. M. White

Date Published: 13th May 2025

Publication Type: Journal Article

Signaling and transcriptional dynamics underlying early adaptation to oncogenic BRAF inhibition.

Abstract (Expand)

A major contributor to poor sensitivity to anti-cancer kinase inhibitor therapy is drug-induced cellular adaptation, whereby remodeling of signaling and gene regulatory networks permits a drug-tolerant … phenotype. Here, we resolve the scale and kinetics of critical subcellular events following oncogenic kinase inhibition and preceding cell cycle re-entry, using mass spectrometry-based phosphoproteomics and RNA sequencing (RNA-seq) to monitor the dynamics of thousands of growth- and survival-related signals over the first minutes, hours, and days of oncogenic BRAF inhibition in human melanoma cells. We observed sustained inhibition of the BRAF-ERK axis, gradual downregulation of cell cycle signaling, and three distinct, reversible phase transitions toward quiescence. Statistical inference of kinetically defined regulatory modules revealed a dominant compensatory induction of SRC family kinase (SFK) signaling, promoted in part by excess reactive oxygen species, rendering cells sensitive to co-treatment with an SFK inhibitor in vitro and in vivo, underscoring the translational potential for assessing early drug-induced adaptive signaling. A record of this paper's transparent peer review process is included in the supplemental information.

Authors: C. T. Flower, C. Liu, H. Y. Chuang, X. Ye, H. Cheng, J. R. Heath, W. Wei, F. M. White

Date Published: 16th Apr 2025

Publication Type: Journal Article

Remodeling of self-assembled microvascular networks under long term flow.

Abstract (Expand)

The incorporation of a functional perfusable microvascular network (MVN) is a common requirement for most organ on-chip-models. Long-term perfusion of MVNs is often required for the maturation of organ … phenotypes and disease pathologies and to model the transport of cells and drugs entering organs. In our microphysiological system, we observe that flow can recover perfusion in regressed MVNs and maintain perfusable MVNs for at least 51 days. Throughout the 51 days, however, the MVNs are continuously remodeling to align with the direction of bulk flow and only appear to attain morphological homeostasis with the use of maintenance medium without growth factors. We observed that the flow resistance of the MVNs decreases over time, and using a computational model, we show that stable vessels have higher flow rates and velocities compared to regressing vessels. Cytokine analysis suggests that static conditions generate an inflammatory state, and that continuous flow reduces inflammation over an extended period. Finally, through bulk RNA sequencing we identify that both the endothelial and fibroblast cells are actively engaged in vascular and matrix remodeling due to flow and that these effects persist for at least 2 weeks. This MPS can be applied to study hemodynamically driven processes, such as metastatic dissemination or drug distribution, or to model long-term diseases previously not captured by MPS, such as chronic inflammation or aging-associated diseases.

Authors: M. Floryan, E. Cambria, A. Blazeski, M. F. Coughlin, Z. Wan, G. Offeddu, V. Vinayak, A. Kant, V. Shenoy, R. D. Kamm

Date Published: 18th Mar 2025

Publication Type: Journal Article

Remodeling of self-assembled microvascular networks under long term flow

Abstract

Not specified

Authors: Marie Floryan, Elena Cambria, Adriana Blazeski, Mark F. Coughlin, Zhengpeng Wan, Giovanni Offeddu, Vinayak Vinayak, Aayush Kant, Vivek Shenoy, Roger D. Kamm

Date Published: 1st Mar 2025

Publication Type: Journal Article

Reversible Electrochemical Sensor for NDMA: Leveraging Molecularly Imprinted Polymers for Enhanced Sensitivity and Selectivity.

Abstract (Expand)

Herein, we present the development and evaluation of a molecularly imprinted polymer (MIP) sensor for the sensitive and selective detection of N-nitrosodimethylamine (NDMA) in aqueous environments. MIP … coatings over electrochemically active electrodes enable NDMA detection with a notably low detection limit of 1.16 ppb. Our findings demonstrate that the dual-monomer system employed in the MIP fabrication enhances both the selectivity and sensitivity toward NDMA. Additionally, the reversibility of the sensor was confirmed via a chronoamperometry regeneration process. Furthermore, the sensor's robustness was demonstrated across various water samples, as well as on different electrode materials, highlighting its potential for practical and reliable water quality monitoring applications.

Authors: Z. Guo, H. Feng, T. M. Swager

Date Published: 28th Feb 2025

Publication Type: Journal Article

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