Biology subjects

Raman, C.

Publications and source records attributed to Raman, C..

7 recordsLinked to original sources

bioRxiv2026

The Quagmire of Immunogenicity-Guided Antibody Design: Labels Limit Progress

Generative sequence-based antibody design is increasingly steered by learned property predictors, so a design objective is only as well specified as the labels behind its oracle. Immunogenicity is among the most clinically consequential properties to condition on, and among the least well specified: the supervisory signal is a single anti-drug-antibody percentage (ADA%) per molecule, aggregated from published trials. To analyze that signal, we first extended and corrected the widely used 217-entry dataset to 231 therapeutics with paired sequences, spanning formats from mouse to fully human. Then, we manually reconstructed the clinical evidence for 110 of them from primary sources. We find that an antibody format lookup outperforms every sequence-based learned predictor on the 231-antibody dataset. Apparent accuracy tracks the format composition of the evaluation split rather than sequence signal. Furthermore, the labels understate their own evidence: molecules labeled at [≤]6 ADA% span up to 86% across trials. We recomputed labels from the trial-level measurements and found that the advantage of the format-based approach disappears, while the sequence-based predictors degrade less under the cohort-weighted mean. We conclude that progress is limited by the label itself, and recommend reporting ADA% at the trial level, treating the target as a distribution rather than a point value, and evaluating against a format-based baseline.

bioinformatics↗

bioRxiv2026

Human skin fibrosis with iPSC-derived organoids reveals RUNX2-mediated fibroblast reprogramming

Fibrotic skin diseases are characterized by persistent fibroblast activation and extracellular matrix remodeling, yet the mechanisms governing fibroblast state transitions remain incompletely understood. Here, we established a human iPSC-derived skin organoid model of fibrosis through chronic TGF-{beta} stimulation. Single-cell RNA sequencing combined with immunofluorescence-based spatial analysis revealed dynamic fibroblast state transitions, spatial reorganization, and expansion of activated fibroblast populations during fibrotic remodeling. Integration with human scleroderma single-cell datasets demonstrated conserved fibroblast states and transcriptional programs between organoids and patient tissues. We further identified broad induction of RUNX2 in the dermal compartment during fibrosis, and RUNX2 depletion attenuated fibrotic marker expression. CUT&RUN profiling revealed RUNX2 occupancy at fibrosis-associated loci, including RUNX1 and LOXL2. Using a machine learning-guided screening approach, we identified F0565-0303, a small molecule that suppressed RUNX2-dependent fibrotic programs in vitro and reduced fibrosis in a bleomycin-induced mouse model. Together, these findings establish human skin organoids as a platform for modeling fibrosis and nominate RUNX2 as a potential therapeutic target.

bioengineering↗

bioRxiv2026

A framework for quantifying the mechanics of dexterous grasp

AO_SCPLOWBSTRACTC_SCPLOWA hallmark of primate behavior is the exceptional ability to dexterously grasp and manipulate objects, yet the investigation of the neural mechanisms that support manual dexterity has been hindered by technical challenges. Optical hand tracking is complicated by frequent occlusions, and contact forces are hard to measure with sufficient precision. Furthermore, while monitoring the kinematics during reaching phase, and the contact forces during object manipulation phase is difficult, joint torques are impossible to measure directly. While challenging, the ability to estimate joint torques in the complex primate hand could provide an invaluable continuous mechanical description spanning both phases. With this in mind, we have developed an experimental apparatus and data processing pipeline for quantifying these variables describing prehension. The apparatus presented objects of various sizes and orientations throughout the workspace, evoking different grasping strategies. Object surfaces were instrumented with thousands of pressure-sensitive elements, enabling high-resolution measurement of distributed contact forces. Simultaneously, eight high-speed cameras were used to reconstruct hand and arm movements with markerless tracking, triangulating 3D landmarks, and mapping them onto a musculoskeletal model, enabling estimation of time-varying joint angles. This posture quantification allowed contact forces to be automatically assigned to specific hand segments, in close agreement with manual human annotations. We used the reconstructed movements and contact forces with the musculoskeletal model of the hand to compute inverse dynamics, yielding joint torques throughout behavior, unifying the hand kinematics and grasp forces into a single physical description. Throughout the processing, we identified individual neurons in the motor cortex of monkeys that were related to grasp force, kinematics, and torques. Together, this framework enabled a comprehensive and precise physical characterization of primate manual behavior, providing a foundation for investigating the neural mechanisms of manual dexterity.

neuroscience↗

bioRxiv2026

Metabolic Repression of Autophagy Drives Inflammation, Pain, and Malodor in Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a debilitating and underdiagnosed inflammatory skin disease with limited therapeutic options due to an incomplete understanding of its molecular and immunopathogenic basis. Using an integrated multi-omics approach, we delineate convergent pathways linking dysregulated autophagy, malodour, and pain in HS. Lesional tissues exhibited sustained autophagy repression, marked by increased expression and activation of mTOR and ZKSCAN3, reduced levels of autolysosome-promoting metabolites {beta}-hydroxybutyrate and nicotinamide riboside, and accumulation of fructose-1,6-bisphosphate, a negative regulator of AMPK. Transcriptomic analyses identified cadaverine derivatives as key metabolic drivers of keratinocyte reprogramming, inducing gene networks associated with hyperproliferation, inflammation, fibrosis, nociception, and the characteristic carrion-like odour of HS. Concordantly, ATAC-seq revealed increased chromatin accessibility at loci encoding TRP channels and histamine receptors, consistent with heightened nociceptive signalling. Multi-layered proteomics, phospho-proteomics, kinomics, and spatial proteomics analyses, validated by high-resolution confocal imaging, demonstrated elevated mTOR (Ser2448), ZKSCAN3, and P62, alongside reduced LAMP1, across keratinocytes and immune cell populations including CD4 T cells, CD56 NK cells, and CD68 macrophages. Inhibition of mTOR normalized transcriptional programs and cytokine production linked to NLRP3 inflammasome, restoring tissue homeostasis. Collectively, these findings identify a metabolically reinforced mTOR-ZKSCAN3 axis in autophagy dysregulation and cadaverine-driven epithelial reprogramming as central mechanisms sustaining inflammation, pain, and fibrosis in HS. HighlightsO_LIWe identified BCAAs, BHB, NR, and FBP as key metabolites linked to mTOR activation and autophagy dysregulation in HS. C_LIO_LIPolyamines like cadaverine and putrescine, their acetylated derivatives, LPCs, and endocannabinoid dysregulation likely drive malodor and pain in HS. C_LIO_LICadaverine treatment of Ker-CT cells induces HS-associated gene signatures of inflammation, fibrosis, and pain. C_LIO_LIIdentification of an HS macrophage subpopulation expressing ZKSCAN3 with activated mTOR and impaired autophagy. C_LI

immunology↗

bioRxiv2023

NK and NKT cells in the pathogenesis of Hidradenitis suppurativa: Novel therapeutic strategy through targeting of CD2

Hidradenitis suppurativa (HS) is a chronic debilitating inflammatory skin disease with poorly understood pathogenesis. Single-cell RNAseq analysis of HS lesional and healthy individual skins revealed that NKT and NK cell populations were greatly expanded in HS, and they expressed elevated CD2, an activation receptor. Immunohistochemistry analyses confirmed significantly expanded numbers of CD2+ cells distributed throughout HS lesional tissue, and many co-expressed the NK marker, CD56. While CD4+ T cells were expanded in HS, CD8 T cells were rare. CD20+ B cells in HS were localized within tertiary follicle like structures. Immunofluorescence microscopy showed that NK cells (CD2+CD56dim) expressing perforin, granzymes A and B were enriched within the hyperplastic follicular epidermis and tunnels of HS and juxtaposed with apoptotic cells. In contrast, NKT cells (CD2+CD3+CD56bright) primarily expressed granzyme A and were associated with -SMA expressing fibroblasts within the fibrotic regions of the hypodermis. Keratinocytes and fibroblasts expressed high levels of CD58 (CD2 ligand) and they interacted with CD2 expressing NKT and NK cells. The NKT/NK maturation and activating cytokines, IL-12, IL-15 and IL-18, were significantly elevated in HS. Inhibition of cognate CD2-CD58 interaction with blocking anti-CD2 mAb in HS skin organotypic cultures resulted in a profound reduction of the inflammatory gene signature and secretion of inflammatory cytokines and chemokines in the culture supernate. In summary, we show that a cellular network of heterogenous NKT and NK cell populations drives inflammation, tunnel formation and fibrosis in the pathogenesis of HS. Furthermore, CD2 blockade is a viable immunotherapeutic approach for the management of HS.

immunology↗

bioRxiv2021

Dysregulated Protein Translation Control in Hidradenitis Suppurativa: Implication for Lesion-associated Squamous Cell Carcinoma Development

Hidradenitis Suppurativa (HS) is a proinflammatory painful skin disorder. This chronic disease is often associated with aggressive squamous cell carcinoma (SCC). The molecular pathogenesis of this disease progression remains undefined. The translation initiation factor eIF4E/4G/4A1 complex is overexpressed in a variety of human malignancies. In this study, we found that the expression of eIF4E/4G/4A1 as well as phosphorylated eIF4E were upregulated in HS skin. In the global transcription profiles derived from two public database, we were able to enrich 734 eIF4F-related genes. GSEA pathway enrichment analysis further demonstrated that RAS/MEK/ERK oncogene signaling pathway associated with inflammation signaling were significantly activated in HS lesion. The increase expression of eIF4 protein components was associated with enhanced eIF4E translation targets Cyclin D1 and c-Myc. Confocal fluorescence microscopy analysis further revealed that Cyclin D1 and c-Myc specifically co-localized in nuclei of certain cells in HS epithelium. We also found that many of the PCNA positive hyperproliferative cells were also positive for c-Myc expression. These data demonstrate that 5-cap{square}dependent translation is a potential pathway underlying the SCC pathogenesis in chronic HS lesions. Furthermore, being a druggable target, inhibition of eIF4F may block lesion-associated lethal SCCs in HS patients.

cancer biology↗

bioRxiv2019

A Systems Immunology Approach Identifies Cytokine-Induced STAT Signaling Pathways Critical to Rheumatoid Arthritis Disease Activity and Treatment Response

Rheumatoid arthritis (RA), a chronic autoimmune disease characterized by circulating autoantibodies, involves many cytokine-mediated signaling pathways in multiple immune cell subsets. Most studies of immune cells in RA have limitations, such as analysis of a small number of cell subsets or pathways, and limited longitudinal data on patient phenotypes. In this study, we used an innovative systems immunology approach to simultaneously quantify up to 882 signaling nodes (Jak/STAT signaling readouts modulated by cytokines and other stimuli) in 21 immune cell subsets. We studied 194 RA patients and 41 controls, including 146 well-characterized RA patients prior to, and 6 months after, initiation of methotrexate or biologic agents from the Treatment Efficacy and Toxicity in RA Database and Repository (TETRAD). There was strikingly attenuated signaling capacity in RA patients in IFN stimulation followed by measurement of phosphorylated STAT1 [IFN[->]p-STAT1] in six immune cell subsets. Multiple nodes showed negative association with disease activity, including IFN[->]STAT5 signaling in naive and memory B cells. In contrast, IL-6-induced STAT1 and STAT3 activation in central memory CD4-negative T cells showed a positive association with disease activity. Multiple nodes were associated with treatment response, including IFN[->]STAT1 in monocytes and IL-6[->]STAT3 in CD4+ naive T cells. Decision tree analysis identified a model combining these two nodes as a high-performing classifier of treatment response to TNF inhibitors. Our study provides novel information on RA disease mechanisms and serves as a framework for the discovery and validation of biomarkers of treatment response in RA.

immunology↗