Biology subjects

Markowitz, J.

Publications and source records attributed to Markowitz, J..

5 recordsLinked to original sources

bioRxiv2026

Spatially resolved multimodal hallmarks of response to neoadjuvant immunotherapies in the melanoma ecosystem in 2D and 3D

Neoadjuvant immunotherapy has transformed cancer treatment, yet the spatial molecular architecture governing response and resistance across distinct immune checkpoint blockade (ICB) regimens remains poorly defined. We assembled the largest neoadjuvant ICB (NICB) spatial multi-omics cohort to date, profiling over 112 million cells at single-cell resolution across three melanoma ICB regimens using MERFISH spatial transcriptomics, multiplexed immunofluorescence, and scRNA-sequencing. These analyses revealed the full multicellular spatial architecture of the NICB tumor microenvironment, including mature TLS with germinal centers, TCF7+ stem-like T cells, myeloid cells organized into spatially distinct cellular neighborhoods with unique intercellular signaling circuits, and CCL19/CCL21-expressing fibroblasts as a previously unrecognized stromal scaffold sustaining these immune hubs. We developed three purpose-built computational tools that together enabled comprehensive quantification of this microenvironment for the first time: SCIRA for whole-slide single-cell receptor-ligand quantification, GCSCAN for molecularly grounded TLS and germinal center structural delineation, and PathNet-TLS for automated TLS detection on H&E images. Applying these tools across the cohort, we defined the immune and stromal composition and cellular neighborhood organization distinguishing responders from non-responders. We also quantified cell-cell interactions and regimen-specific immune architectures, including a markedly stronger mature TLS/germinal center response with IPI-NIVO than NIVO-RELA. Importantly, GCSCAN-quantified TLS and germinal center density each stratified disease-free survival, with responders that lack germinal centers having an elevated risk of relapse. Open-top light-sheet imaging and CODA-based 3D reconstruction further uncovered interconnected germinal center-TLS tunnels invisible to standard 2D histopathology. These findings establish a discovery-to-tool paradigm linking single-cell tumor microenvironment interrogation to clinically deployable computational pathology for biomarker-driven NICB assessment across cancer types.

cancer biology↗

bioRxiv2024

spatialGE: A user-friendly web application to democratize spatial transcriptomics analysis

Spatial transcriptomics (ST) is a powerful tool for understanding tissue biology and disease mechanisms. However, its potential is often underutilized due to the advanced data analysis and programming skills required. To address this, we present spatialGE, a web application that simplifies the analysis of ST data. The application spatialGE provides a user-friendly interface that guides users without programming expertise through various analysis pipelines, including quality control, normalization, domain detection, phenotyping, and multiple spatial analyses. It also enables comparative analysis among samples and supports various ST technologies. We demonstrate the utility of spatialGE through its application in studying the tumor microenvironment of melanoma brain metastasis and Merkel cell carcinoma. Our results highlight the ability of spatialGE to identify spatial gene expression patterns and enrichments, providing valuable insights into the tumor microenvironment and its utility in democratizing ST data analysis for the wider scientific community.

bioinformatics↗

bioRxiv2021

Striatal dopamine explains novelty-induced behavioral dynamics and individual variability in threat prediction

Animals exhibit diverse behavioral responses, such as exploration and avoidance, to novel cues in the environment. However, it remains unclear how dopamine neuron-related novelty responses influence behavior. Here, we characterized dynamics of novelty exploration using multi-point tracking (DeepLabCut) and behavioral segmentation (MoSeq). Novelty elicits a characteristic sequence of behavior, starting with investigatory approach and culminating in object engagement or avoidance. Dopamine in the tail of striatum (TS) suppresses engagement, and dopamine responses were predictive of individual variability in behavior. Behavioral dynamics and individual variability were explained by a novel reinforcement learning (RL) model of threat prediction, in which behavior arises from a novelty-induced initial threat prediction (akin to "shaping bonus"), and a threat prediction that is learned through dopamine-mediated threat prediction errors. These results uncover an algorithmic similarity between reward- and threat-related dopamine sub-systems. HighlightsO_LINovelty-induced behaviors are analyzed using modern machine-learning methods C_LIO_LINovelty induces risk assessment which develops into engagement or avoidance C_LIO_LIDopamine in the tail of striatum correlates with individual behavioral variability C_LIO_LIReinforcement learning with shaping bonus and uncertainty explains the data C_LI

neuroscience↗

bioRxiv2021

Stratification of Risk of Progression to Colectomy in Ulcerative Colitis using Measured and Predicted Gene Expression

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of ulcerative colitis (UC) patients require colectomy within five years of diagnosis, but polygenic risk scores (PRS) utilizing findings from GWAS are unable to provide meaningful prediction of this adverse status. By contrast, in Crohns disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a Transcriptional Risk Score (TRS). Here we demonstrate that both measured (TRS) and polygenic predicted gene expression (PPTRS) identify UC patients at 5-fold elevated risk of colectomy with data from the PROTECT clinical trial and UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with transcriptome-wide association studies to stratify risk of disease complications.

genetics↗

bioRxiv2016

Dynamically controlled light delivery over large brain volumes through tapered optical fibers

Optogenetics promises spatiotemporal precise control of neural processes using light. However, the spatial extent of illumination within the brain is difficult to control and cannot be adjusted using standard fiber optics. We demonstrate that optical fibers with tapered tips can be used to illuminate either large brain volumes or dynamically selectable subregions. Remotely adjusting the light input angle to the fiber varies the light-emitting portion of the taper over several millimeters without movement of the implant. We use this mode to activate dorsal versus ventral striatum of individual mice and reveal different effects of each manipulation on motor behavior. Conversely injecting light over the full numerical aperture of the fiber results in light emission from the entire taper surface, achieving broader and more efficient optogenetic activation of neurons when compared to the standard flat-faced fiber stimulation. Thus, tapered fibers permit focal or broad illumination that can be precisely and dynamically matched to experimental needs.

neuroscience↗