A5042082069- Lysosomal Storage Disorders Research
- Cellular transport and secretion
- Lipid Membrane Structure and Behavior
- Calcium signaling and nucleotide metabolism
- Yeasts and Rust Fungi Studies
- HIV Research and Treatment
- Fungal and yeast genetics research
- Fungal Plant Pathogen Control
- Chromosomal and Genetic Variations
- Cancer, Hypoxia, and Metabolism
- CRISPR and Genetic Engineering
- Lipoproteins and Cardiovascular Health
- Quantum-Dot Cellular Automata
- Probiotics and Fermented Foods
- Pancreatic function and diabetes
- Blood Pressure and Hypertension Studies
- Renal Transplantation Outcomes and Treatments
- Tuberculosis Research and Epidemiology
- Endoplasmic Reticulum Stress and Disease
- Carbohydrate Chemistry and Synthesis
- Nutrition, Genetics, and Disease
- Pineapple and bromelain studies
- Genetic Associations and Epidemiology
- RNA modifications and cancer
- Gut microbiota and health
Massachusetts General Hospital
2023-2025
Harvard University
2023-2025
Broad Institute
2023-2024
University of Toronto
2021-2023
McGovern Institute for Brain Research
2023
Massachusetts Institute of Technology
2023
Thermo Fisher Scientific (United States)
2023
The University of Texas Southwestern Medical Center
2016-2022
National Institutes of Health
2017
Significance Feedback control of cholesterol metabolism is essential for cell viability and prevention heart attacks. Cells acquire from receptor-mediated uptake low-density lipoprotein, which delivers to lysosomes. To exert feedback control, must reach the endoplasmic reticulum (ER). Here we use a CRISPR screen show that lysosome-derived moves first plasma membrane then ER. The last movement requires an enzyme produces phosphatidylserine. This demonstrates transmembrane one lipid...
Significance The Niemann–Pick C1 (NPC1) protein is responsible for transporting LDL-derived cholesterol out of late endosomes. Mutations in NPC1 lead to the fatal Type C disease. We present here an improved structure at 3.3 Å and decipher details its C-terminal luminal domain (CTD), which could not be resolved previous structures. In particular, a loop stabilized by pair disulfide bonds CTD binds N-terminal through loop–loop interaction. show that this interaction important transport...
Significance In animal cells, cholesterol is essential for the assembly of membranes and production steroid hormones bile acids. Cells obtain through receptor-mediated endocytosis LDL into lysosomes. After lysosomal degradation, LDL-derived must cross membrane to execute its functions. Lysosomal export mediated by Niemann–Pick C1 (NPC1), a protein. Here we show that triazole drugs posaconazole itraconazole inhibit export. A photoactivatable derivative cross-links NPC1 in intact cells...
Significance Cholesterol constitutes 50% of lipids in the plasma membrane (PM) animal cells. Sensors endoplasmic reticulum (ER) maintain this level by adjusting cholesterol uptake, synthesis, and storage. Uptake is mediated LDL receptors, which deliver cholesterol-carrying to lysosomes from moves PM then ER. We report PM-to-ER transport requires cholesterol-binding Aster proteins anchored ER phosphatidylserine embedded PM. Asters are known bind phosphatidylserine, accounts for part...
Niemann-Pick C1 (NPC1) is a polytopic membrane protein with 13 transmembrane helices that exports LDL-derived cholesterol from lysosomes by carrying it through the 80 Å glycocalyx and 40 lipid bilayer. Transport begins when binds to N-terminal domain (NTD) of NPC1, which projects surface glycocalyx. Here, we reconstitute transport expressing NTD as fragment separate remaining portion NPC1. When co-expressed, two NPC1 fragments transport, indicating has flexibility interact parts even not...
Abstract Increasing accessibility to genetic screening for cancer risk can lead earlier surveillance and prevention, but with this comes the caveat of incidental identification germline pathogenic gene variants. Here, we report a single institution case series 6 otherwise healthy individuals “incidental” Von Hippel Lindau (VHL) disease. These patients were found have variants in VHL gene, after undergoing testing other purposes (5 familial breast 1 determine ancestry) no disease-associated...
Urine CXCL10 (C-X-C motif chemokine ligand 10, interferon gamma-induced protein 10 [IP10]) outperforms standard-of-care monitoring for detecting subclinical and early clinical T-cell-mediated rejection (TCMR) may advance TCMR therapy development through biomarker-enriched trials. The goal was to perform an international multicenter validation of a bead-based immunoassay (Luminex) transplant surveillance compare with electrochemiluminescence-based (Meso Scale Discovery [MSD]) assay used in...
Abstract TnpB proteins are RNA-guided nucleases that broadly associated with IS200/605 family transposons in prokaryotes. homologs, named Fanzors, have been detected genomes of some eukaryotes and large viruses, but their activity functions remain unknown. We searched diverse viruses for homologs identified numerous putative often various transposases, suggesting they encoded mobile genetic elements. Reconstruction the evolution these nucleases, which we rename Horizontally-transferred...
Abstract Rare coding alleles play crucial roles in the molecular diagnosis of genetic diseases. However, systemic identification these has been challenging due to their scarcity general population. Here, we discovered and characterized rare contributing dyslipidemia, a principal risk for coronary artery disease, among over million individuals combining three large contemporary datasets (the Million Veteran Program, n = 634,535, UK Biobank, 431,178, All Us Research 92,304) totaling 1,158,017...
Background: Inherited hypercholesterolemia is an important Mendelian condition associated with early onset myocardial infarction. However, current genetic diagnostic criteria only partially explain severe clinical hypercholesterolemia. Furthermore, pathogenicity categorizations do not consistently inform prognosis, but quantification limited by scarcity of such rare variants. Aim: Exploiting populations scale genotype/phenotype data, to determine the architecture variants associating blood...
Introduction: Widespread practices of over-prescribing antibiotic, antiviral, and antifungal drugs have sparked concern over the risk antimicrobial resistance arising in bacterial, viral, fungal pathogens. This threatens to jeopardize efficacy many being prescribed today for said infections. Azoles are a major class drugs, presenting need research efforts on mechanisms azole resistance. My objective was perform genomic sequencing variant profiling Baker’s Yeast (Saccharomyces cerevisiae)...
Introduction: Widespread practices of over-prescribing antibiotic, antiviral, and antifungal drugs have sparked concern over the risk antimicrobial resistance arising in bacterial, viral, fungal pathogens. This threatens to jeopardize efficacy many being prescribed today for said infections. Azoles are a major class drugs, presenting need research efforts on mechanisms azole resistance. My objective was perform genomic sequencing variant profiling Baker’s Yeast (Saccharomyces cerevisiae)...