A5061022395- Cellular transport and secretion
- Neuroscience and Neuropharmacology Research
- Lipid Membrane Structure and Behavior
- Liver physiology and pathology
- Pancreatic function and diabetes
- RNA Research and Splicing
- Photoreceptor and optogenetics research
- Retinal Development and Disorders
- Neuroinflammation and Neurodegeneration Mechanisms
- Organ Transplantation Techniques and Outcomes
- Barrier Structure and Function Studies
- Advanced Memory and Neural Computing
- Histone Deacetylase Inhibitors Research
- Erythrocyte Function and Pathophysiology
- RNA regulation and disease
- Cell Image Analysis Techniques
- COVID-19 Clinical Research Studies
- Caveolin-1 and cellular processes
- Amyotrophic Lateral Sclerosis Research
- Nuclear Structure and Function
- Neurogenetic and Muscular Disorders Research
- Advanced Sensor and Energy Harvesting Materials
- Fibroblast Growth Factor Research
- Single-cell and spatial transcriptomics
- SARS-CoV-2 and COVID-19 Research
Harvard University
2020-2024
Massachusetts Institute of Technology
2024
University of Pavia
2020-2022
Allen Institute
2022
Koch Institute for Integrative Cancer Research At MIT
2022
Boston Children's Hospital
2020
We describe here the design and implementation of an in vitro microvascular open model system using human brain endothelial cells. The has several advantages over other traditional closed microfluidic platforms: (1) it enables controlled unidirectional flow media at physiological rates to support vascular function, (2) allows for very small volumes which makes device ideal studies involving biotherapeutics, (3) is amenable multiple high resolution imaging modalities such as transmission...
The active zone of a presynaptic nerve terminal defines sites for neurotransmitter release. Its protein machinery may be organized through liquid-liquid phase separation, mechanism the formation membrane-less subcellular compartments. Here, we show that Liprin-α3 rapidly and reversibly undergoes separation in transfected HEK293T cells. Condensate is triggered by PKC-phosphorylation at serine-760, RIM Munc13 are co-recruited into membrane-attached condensates. Phospho-specific antibodies...
Abstract Deep brain stimulation with implanted electrodes has transformed neuroscience studies and treatment of neurological psychiatric conditions. Discovering less invasive alternatives to deep could expand its clinical research applications. Nanomaterial-mediated transduction magnetic fields into electric potentials been explored as a means for remote neuromodulation. Here we synthesize magnetoelectric nanodiscs (MENDs) core–double-shell Fe 3 O 4 –CoFe 2 –BaTiO architecture (250 nm...
It has long been proposed that leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) are cell-adhesion proteins control synapse assembly. Their synaptic nanoscale localization, however, is not established, and fine structure after knockout of the three vertebrate LAR-RPTPs (PTPδ, PTPσ, LAR) tested. Here, superresolution microscopy reveals PTPδ localizes to cleft precisely apposed postsynaptic scaffolds excitatory inhibitory synapses. We next assessed in newly...
Active zones consist of protein scaffolds that are tightly attached to the presynaptic plasma membrane. They dock and prime synaptic vesicles, couple them voltage-gated Ca 2+ channels, direct neurotransmitter release toward postsynaptic receptor domains. Simultaneous RIM + ELKS ablation disrupts these scaffolds, abolishes vesicle docking, removes active zone-targeted Munc13, but some vesicles remain releasable. To assess whether this enduring vesicular fusogenicity is mediated by non-active...
Bats are tolerant to highly pathogenic viruses such as Marburg, Ebola, and Nipah, suggesting the presence of a unique immune tolerance toward viral infection. Here, we compared severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection human bat ( Rhinolophus ferrumequinum ) pluripotent cells fibroblasts. Since do not express an angiotensin-converting enzyme (ACE2) receptor that allows virus infection, transduced ACE2 (hA) into found can be infected with SARS-CoV-2. Compared...
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with no effective treatment. The Hepatocyte Growth Factor/Scatter Factor (HGF/SF), through its receptor MET, one of the most potent survival-promoting factors for motor neurons (MN) and known as modulator immune cell function. We recently developed novel recombinant MET agonist optimized therapy, designated K1K1. K1K1 was ten times more than HGF/SF in preventing MN loss an vitro model ALS. Treatments delayed onset...
Abstract Liquid-liquid phase separation enables the assembly of membrane-less subcellular compartments, but testing its biological functions has been difficult. The presynaptic active zone, protein machinery in nerve terminals that defines sites for neurotransmitter release, may be organized through separation. Here, we discover zone Liprin-α3 rapidly and reversibly undergoes upon phosphorylation by PKC at a single site. RIM Munc13 are co-recruited to membrane-attached condensates,...
Hepatocyte growth factor/scatter factor (HGF/SF) and its cognate receptor MET play several essential roles in embryogenesis regeneration postnatal life of epithelial organs such as the liver, kidney, lung, pancreas, prompting a strong interest harnessing HGF/SF-MET signalling for after acute or chronic damage. The limited stability tissue diffusion native HGF/SF, however, which reflect tightly controlled, local mechanism action morphogen, have led to major search HGF/SF mimics therapy. In...
Summary Action potentials trigger neurotransmitter release with minimal delay. Active zones mediate this temporal precision by co-organizing primed vesicles Ca V 2 2+ channels. The presumed model is that scaffolding proteins directly tether to 2s. We find clustering and vesicle priming are executed separate machineries. At hippocampal synapses, nanoclusters positioned at variable distances from those of the protein Munc13. active zone organizer RIM anchors both proteins, but distinct...
Abstract It has long been proposed that Leukocyte common Antigen-Related Receptor Protein Tyrosine Phosphatases (LAR-RPTPs) are cell-adhesion proteins for the control of synapse assembly. Their synaptic nanoscale localization, however, not established, and fine structure synapses after knockout three vertebrate genes LAR-RPTPs (PTPδ, PTPσ LAR) tested. Here, we find PTPδ is precisely apposed to postsynaptic scaffolds at excitatory inhibitory using superresolution microscopy. We generated...
ABSTRACT We describe here the design and implementation of an in-vitro BBB-on-a-chip open model system capable reconstituting microenvironment blood brain barrier. This allows controlled unidirectional flow nutrients biologicals on lumen artificial microvessel. is suitable for high resolution electron microscopy it amenable quantitative 3D live fluorescence imaging using spinning confocal disk or lattice light sheet (LLSM) to follow, example transcytosis across BBB-like barrier...
Abstract Hepatocyte Growth Factor/Scatter Factor (HGF/SF) and its cognate receptor MET play several essential roles in embryogenesis regeneration post-natal life of epithelial organs such as liver, kidney, lung, pancreas, prompting a strong interest harnessing HGF/SF-MET signalling for after acute or chronic damage. The limited stability tissue diffusion native HGF/SF, however, which reflect the tightly controlled, local mechanism action morphogen, have led to major search HGF/SF mimics...
Abstract Active zones consist of protein scaffolds that are tightly attached to the presynaptic plasma membrane. They dock and prime synaptic vesicles, couple them Ca 2+ entry, target neurotransmitter release postsynaptic receptor domains. Simultaneous RIM+ELKS ablation disrupts these scaffolds, abolishes vesicle docking removes active zone-targeted Munc13, but some vesicles remain releasable. This enduring vesicular fusogenicity may be Munc13-independent or mediated by non-active...
Abstract Active zones are molecular machines that control neurotransmitter release through synaptic vesicle docking and priming, coupling of these vesicles to Ca 2+ entry. The complexity active zone machinery has made it challenging determine which mechanisms drive roles in release. Here, we induce RIM+ELKS knockout eliminate scaffolding networks, then reconstruct each function. Re-expression RIM1-Zn fingers positioned Munc13 on undocked rendered them release-competent. Reconstitution...