A5030146315- Single-cell and spatial transcriptomics
- Cell Image Analysis Techniques
- Advanced Biosensing Techniques and Applications
- Cancer Immunotherapy and Biomarkers
- Microtubule and mitosis dynamics
- Advanced Fluorescence Microscopy Techniques
- Immunotherapy and Immune Responses
- Ovarian cancer diagnosis and treatment
- CAR-T cell therapy research
- Cancer Genomics and Diagnostics
- interferon and immune responses
- Immune cells in cancer
- PARP inhibition in cancer therapy
- Cutaneous Melanoma Detection and Management
- CRISPR and Genetic Engineering
- COVID-19 Clinical Research Studies
- Immune Response and Inflammation
- Genomics and Chromatin Dynamics
- Protein Structure and Dynamics
- RNA modifications and cancer
- Cervical Cancer and HPV Research
- Ubiquitin and proteasome pathways
- Extracellular vesicles in disease
- Long-Term Effects of COVID-19
- SARS-CoV-2 and COVID-19 Research
Center for Systems Biology
2014-2025
Harvard University
2015-2025
Center for Cancer Research
2019-2021
University of Oxford
2019
Imperial College London
2019
Cancer Research UK Scotland Institute
2019
Brigham and Women's Hospital
2019
Max Planck Institute of Molecular Cell Biology and Genetics
2006-2018
Max Planck Institut für Zellbiologie
2012-2018
Max Planck Society
2009-2013
An understanding of protective immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for vaccine and public health strategies aimed at ending the global disease 2019 (COVID-19) pandemic. A key unanswered question whether infection with SARS-CoV-2 results in against reexposure. We developed a rhesus macaque model observed that macaques had high viral loads upper lower tract, humoral cellular immune responses, pathologic evidence pneumonia. After initial...
The MTOC is “speck”-tacular Inflammasome complexes are formed in response to pathogen-associated molecules. They initiate both the maturation of inflammatory cytokines and pyroptosis, a type programmed cell death. One notable feature for inflammasome activation formation single supramolecular punctum (or “speck”) each affected cell. However, location mechanism speck poorly understood. Magupalli et al. report that NLRP3- pyrin-mediated inflammasomes, their assembly downstream functions occur...
Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling highly multiplexed single-cell imaging on tumor samples from patients enrolled a Phase I/II trial of niraparib pembrolizumab cancer (NCT02657889). identify two determinants response; mutational signature 3 reflecting defective homologous recombination DNA repair, positive score as surrogate interferon-primed exhausted...
RNA viruses compartmentalize their replication machinery to evade detection by host pattern recognition receptors and concentrate the of synthesis. For positive-strand viruses, occurs in a virus-induced membrane-associated organelle. NNS compartment is cytoplasmic inclusion that not circumscribed cellular membrane. Such structures were first observed cell bodies neurons from humans infected with rabies virus termed Negri bodies. How forms this remains associated absence membrane has been an...
Highly multiplexed tissue imaging makes detailed molecular analysis of single cells possible in a preserved spatial context. However, reproducible large multichannel images poses substantial computational challenge. Here, we describe modular and open-source pipeline, MCMICRO, for performing the sequential steps needed to transform whole-slide into single-cell data. We demonstrate use MCMICRO on tumor acquired using multiple platforms, thereby providing solid foundation continued development software.
Cutaneous melanoma is a highly immunogenic malignancy that surgically curable at early stages but life-threatening when metastatic. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially resolved microregion transcriptomics to study immune evasion immunoediting in primary melanoma. We find recurrent cellular neighborhoods involving tumor, immune, stromal cells change significantly along progression axis precursor states, situ, invasive tumor. Hallmarks of...
The central portion of the midbody, a cytoplasmic bridge between nascent daughter cells at end cell division, has generally been thought to be retained by one cells, but has, recently, also shown released into extracellular space. significance midbody-retention versus -release is unknown. Here we show, quantitatively analysing midbody-fate in various lines under different growth conditions, that extent midbody-release significantly greater stem than cancer-derived cells. Induction...
Metaphase chromosome positioning depends on Kif18A, a kinesin-8 that accumulates at and suppresses the dynamics of K-MT plus ends. By engineering Kif18A mutants suppress MT but fail to concentrate ends, we identify mechanism allows accumulate ends level required movements. Enrichment its C-terminal tail domain, while ability growth is conferred by N-terminal motor domain. The contains second MT-binding domain diffuses along lattice, suggesting it tethers track. Consistently, enhances...
The majority of high-grade serous ovarian cancers (HGSCs) are deficient in homologous recombination (HR) DNA repair, most commonly due to mutations or hypermethylation the BRCA1/2 genes. We aimed discover how shape cellular phenotypes and spatial interactions tumor microenvironment. Using a highly multiplex immunofluorescence image analysis we generate proteomic data for 21 markers 124,623 single cells from 112 cores originating 31 tumors with mutation (BRCA1/2mut), 13 without alterations HR...
Establishing causal relationships between genetic alterations of human cancers and specific phenotypes malignancy remains a challenge. We sequentially introduced mutations into healthy melanocytes in up to five genes spanning six commonly disrupted melanoma pathways, forming nine genetically distinct cellular models melanoma. connected mutant melanocyte genotypes malignant cell expression programs vitro vivo, replicative immortality, malignancy, rapid tumor growth, pigmentation, metastasis,...
Microcephalic primordial dwarfism (MPD) is a rare, severe form of human growth failure in which restriction evident utero and continues into postnatal life. Single causative gene defects have been identified number patients with MPD, all involve genes fundamental to cellular processes including centrosome functions. The objective the study was find genetic etiology novel presentation MPD. design whole-exome sequencing performed on two affected sisters single family. Molecular functional...
Intra-tumor heterogeneity (ITH) of human tumors is important for tumor progression, treatment response, and drug resistance. However, the spatial distribution ITH remains incompletely understood. Here, we present analysis in lung adenocarcinomas from 147 patients using multi-region mass spectrometry >5,000 regions, single-cell copy number sequencing ∼2,000 single cells, cyclic immunofluorescence >10 million cells. We identified two distinct patterns among tumors, termed clustered random...
Abstract Upcoming technologies enable routine collection of highly multiplexed (20–60 channel), subcellular resolution images mammalian tissues for research and diagnosis. Extracting single cell data from such requires accurate image segmentation, a challenging problem commonly tackled with deep learning. In this paper, we report two findings that substantially improve segmentation using range machine learning architectures. First, unexpectedly find the inclusion intentionally defocused...
Scavenger receptor class B type I (SR-BI) and ABCA1 are structurally dissimilar cell surface proteins that play key roles in HDL metabolism. SR-BI is a binds with high affinity mediates both the selective lipid uptake of cholesteryl esters from lipid-rich to cells efflux unesterified cholesterol HDL. phospholipids lipid-poor apolipoprotein A-I (apoA-I). The activities other ATP binding cassette superfamily members inhibited by drug glyburide, SR-BI-mediated transport blocked small molecule...
A recent crystal structure of monastrol in a ternary complex with the kinesin Eg5 motor domain highlights novel, induced-fit drug binding site at atomic resolution. Mutational obliteration results monastrol-resistant, but otherwise catalytically active domain. However, considering conformational changes this site, it is unclear what specific interactions stabilize interaction between and domain.To study molecular complementarity monastrol-Eg5 interaction, we used combination synthetic...