A5056640918- Neuroinflammation and Neurodegeneration Mechanisms
- Neuroscience and Neuropharmacology Research
- Neurogenesis and neuroplasticity mechanisms
- Retinal Development and Disorders
- Axon Guidance and Neuronal Signaling
- Single-cell and spatial transcriptomics
- CRISPR and Genetic Engineering
- Cancer-related molecular mechanisms research
- RNA Research and Splicing
- Amyotrophic Lateral Sclerosis Research
- MicroRNA in disease regulation
- Glaucoma and retinal disorders
- Pluripotent Stem Cells Research
- Genetics and Neurodevelopmental Disorders
- Glioma Diagnosis and Treatment
- Alzheimer's disease research and treatments
- Immune cells in cancer
- Meningioma and schwannoma management
- Circular RNAs in diseases
- Mycobacterium research and diagnosis
- Photoreceptor and optogenetics research
- Protein Tyrosine Phosphatases
- RNA regulation and disease
- Mosquito-borne diseases and control
- COVID-19 Impact on Reproduction
University of California, San Francisco
2016-2025
City College of San Francisco
2022
University of Copenhagen
2017
Ophthalmology Associates (United States)
2008-2016
The University of Texas at San Antonio
2012
Czech Academy of Sciences, Institute of Physiology
2008
Stanford University
1998-2004
Stanford Medicine
2004
Although astrocytes constitute nearly half of the cells in our brain, their function is a long-standing neurobiological mystery. Here we show by quantal analyses, FM1-43 imaging, immunostaining, and electron microscopy that few synapses form absence glial do are functionally immature. Astrocytes increase number mature, functional on central nervous system (CNS) neurons sevenfold required for synaptic maintenance vitro. We also most generated concurrently with development glia vivo. These...
The rapid spread of Zika virus (ZIKV) and its association with abnormal brain development constitute a global health emergency. Congenital ZIKV infection produces range mild to severe pathologies, including microcephaly. To understand the pathophysiology infection, we used models developing that faithfully recapitulate tissue architecture in early midgestation. We identify cell populations are most susceptible primary human tissue, provide evidence for mechanism viral entry, show commonly...
To investigate the role of Dicer and microRNAs in mammalian CNS, we used mice which second RNase III domain was conditionally floxed. Conditional were bred with expressing an α-calmodulin kinase II Cre to selectively inactivate excitatory forebrain neurons vivo . Inactivation results array phenotypes including microcephaly, reduced dendritic branch elaboration, large increases spine length no concomitant change density. Microcephaly is likely caused by a 5.5-fold increase early postnatal...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function vital organ systems, with particularly impact on function. Neurological symptoms, which range in severity, accompany as many one-third COVID-19 cases, indicating potential vulnerability neural types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized stem-cell-derived organoids well primary tissue, both from developmental and...
Using machine learning (ML), we interrogated the function of all human-chimpanzee variants in 2,645 human accelerated regions (HARs), finding 43% HARs have with large opposing effects on chromatin state and 14% neurodevelopmental enhancer activity. This pattern, consistent compensatory evolution, was confirmed using massively parallel reporter assays chimpanzee neural progenitor cells. The species-specific activity accurately predicted from presence absence transcription factor footprints...
Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer's disease (AD), with recent proteomic studies highlighting disrupted glial in AD. We report that inhibition indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN), rescues hippocampal memory function mouse preclinical models AD by restoring astrocyte metabolism. Activation astrocytic IDO1 amyloid β and tau oligomers increases KYN suppresses glycolysis an aryl hydrocarbon...
MicroRNAs (miRNAs) are small noncoding RNAs that can act to repress target mRNAs by suppressing translation and/or reducing mRNA stability. Although it is clear miRNAs and Dicer, an RNase III enzyme central the production of mature miRNAs, have a role in early development neurons, their roles postmitotic neuron vivo largely unknown. To determine Dicer we ablated dopaminoceptive neurons. Mice lost these cells display range phenotypes including ataxia, front hind limb clasping, reduced brain...
Diversified neurons are essential for sensorimotor function, but whether astrocytes become specialized to optimize circuit performance remains unclear. Large fast α-motor (FαMNs) of spinal cord innervate fast-twitch muscles that generate peak strength. We report ventral horn express the inward-rectifying K+ channel Kir4.1 (a.k.a. Kcnj10) around MNs in a VGLUT1-dependent manner. Loss astrocyte-encoded selectively altered FαMN size and function led reduced Overexpression was sufficient...
Hypoxia can injure brain white matter tracts, comprised of axons and myelinating oligodendrocytes, leading to cerebral palsy in neonates delayed post-hypoxic leukoencephalopathy (DPHL) adults. In these conditions, injury be followed by myelin regeneration, but myelination often fails is a significant contributor fixed demyelinated lesions, with ensuing permanent neurological injury. Non-myelinating oligodendrocyte precursor cells are found lesions plentiful numbers, fail mature, suggesting...
Abstract Background Long non-coding RNAs (lncRNAs) exhibit highly cell type-specific expression and function, making this class of transcript attractive for targeted cancer therapy. However, the vast majority lncRNAs have not been tested as potential therapeutic targets, particularly in context currently used treatments. Malignant glioma is rapidly fatal, ionizing radiation part current standard-of-care to slow tumor growth both adult pediatric patients. Results We use CRISPR interference...
Abstract Meningiomas are the most common primary intracranial tumors, but molecular drivers of meningioma tumorigenesis poorly understood. We hypothesized that investigating intratumor heterogeneity in meningiomas would elucidate biologic and reveal new targets for therapy. To test this hypothesis, here we perform multiplatform profiling 86 spatially-distinct samples from 13 human meningiomas. Our data regional alterations chromosome structure underlie clonal transcriptomic, epigenomic,...
Loss of function (LoF) TAR-DNA binding protein 43 (TDP-43) and mis-localization, together with TDP-43-positive hyperphosphorylated inclusions, are found in post-mortem tissue amyotrophic lateral sclerosis (ALS) frontotemporal dementia (FTD) patients, including those carrying LoF variants the progranulin gene (GRN). Modeling TDP-43 pathology has been challenging vivo vitro. We present a three-dimensional induced pluripotent stem cell (iPSC)-derived paradigm-mature brain organoids...
The complexity of the human brain makes it challenging to understand molecular mechanisms underlying function. Genome-wide association studies have uncovered variants associated with neurological phenotypes. Single-cell transcriptomics provided descriptions changes cells undergo during disease. However, these approaches do not establish mechanism. To facilitate scalable interrogation causal in cell types, we developed a 3D co-culture system induced pluripotent stem (iPSC)-derived neurons and...