A5088512981- Alzheimer's disease research and treatments
- Epigenetics and DNA Methylation
- Genetic Associations and Epidemiology
- Single-cell and spatial transcriptomics
- Neuroinflammation and Neurodegeneration Mechanisms
- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- Genomics and Chromatin Dynamics
- Air Quality and Health Impacts
- Microtubule and mitosis dynamics
- Bioinformatics and Genomic Networks
- HIV Research and Treatment
- Neurogenesis and neuroplasticity mechanisms
- Neuroscience and Neuropharmacology Research
- RNA Research and Splicing
- RNA modifications and cancer
- Neurological disorders and treatments
- Prenatal Substance Exposure Effects
- Marriage and Sexual Relationships
- Amyotrophic Lateral Sclerosis Research
- Mercury impact and mitigation studies
- Noise Effects and Management
- Genetics and Neurodevelopmental Disorders
- Dementia and Cognitive Impairment Research
- Parkinson's Disease Mechanisms and Treatments
University of Miami
2014-2024
Allen Institute for Brain Science
2022
Stanford University
2019-2020
Thermo Fisher Scientific (Sweden)
2020
University of Southern California
2013-2016
University of Colorado Anschutz Medical Campus
2015
University of Colorado Health
2015
Biomedical Primate Research Centre
2013-2015
Mercer University Health Sciences Center
2015
University of California, Davis
2002-2011
Neurofibrillary tangles (NFT) and β-amyloid plaques are the neurological hallmarks of both Alzheimer's disease an unusual paralytic illness suffered by Chamorro villagers on Pacific island Guam. Many Chamorros with suffer dementia, in some villages one-quarter adults perished from disease. Like Alzheimer's, causal factors Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) poorly understood. In replicated experiments, we found that chronic dietary exposure to a...
Abstract Single-cell DNA methylome profiling has enabled the study of epigenomic heterogeneity in complex tissues and during cellular reprogramming. However, broader applications method have been impeded by modest quality sequencing libraries. Here we report snmC-seq2, which provides improved read mapping, reduced artifactual reads, enhanced throughput, as well increased library complexity coverage uniformity compared to snmC-seq. snmC-seq2 is an efficient strategy suited for large-scale...
Single-cell technologies measure unique cellular signatures but are typically limited to a single modality. Computational approaches allow the fusion of diverse single-cell data types, their efficacy is difficult validate in absence authentic multi-omic measurements. To comprehensively assess molecular phenotypes cells, we devised single-nucleus methylcytosine, chromatin accessibility, and transcriptome sequencing (snmCAT-seq) applied it postmortem human frontal cortex tissue. We developed...
Abstract Brain region-specific degeneration and somatic expansions of the mutant Huntingtin ( mHTT ) CAG tract are key features Huntington’s disease (HD). However, relationships among expansions, death specific cell types molecular events associated with these processes not established. Here, we used fluorescence-activated nuclear sorting (FANS) deep profiling to gain insight into properties human striatum cerebellum in HD control donors. arise at striatal medium spiny neurons (MSNs),...
The properties of the cell types that are selectively vulnerable in Huntington's disease (HD) cortex, nature somatic CAG expansions mHTT these cells, and their importance CNS circuitry have not been delineated. Here, we employed serial fluorescence-activated nuclear sorting (sFANS), deep molecular profiling, single-nucleus RNA sequencing (snRNA-seq) motor-cortex samples from thirteen predominantly early stage, clinically diagnosed HD donors selected cingulate, visual, insular, prefrontal...
Parkinson's disease (PD) is characterized pathologically by the loss of dopaminergic (DA) neurons in substantia nigra (SN). Whether cell types beyond DA SN show vulnerability PD remains unclear. Through transcriptomic profiling 315,867 high-quality single nuclei from individuals with and without PD, we identified clusters representing various neuron types, glia, endothelial cells, pericytes, fibroblasts, T cells investigated type-dependent alterations gene expression PD. Notably, a unique...
Inhalation of airborne particulate matter (PM) derived from urban traffic is associated with pathology in the arteries, heart, and lung; effects on brain are also indicated but less documented.We evaluated rodent responses to nanoscale (< 200 nm) PM (nPM).Ambient nPM collected near an freeway was transferred aqueous suspension reaerosolized for 10-week inhalation exposure mice or directly applied rat cell cultures.Free radicals were detected by electron paramagnetic resonance 30 days after...
Emerging evidence suggests that excessive exposure to traffic-derived air pollution during pregnancy may increase the vulnerability neurodevelopmental alterations underlie a broad array of neuropsychiatric disorders. We present mouse model for prenatal urban freeway nanoparticulate matter (nPM). In prior studies, we developed adult rodent re-aerosolized nPM which caused inflammatory brain responses with altered neuronal glutamatergic functions. nPMs are collected continuously one month from...
Cetaceans are well-regarded as sentinels for toxin exposure. Emerging studies suggest that cetaceans can also develop neuropathological changes associated with neurodegenerative disease. The occurrence of neuropathology makes an ideal species examining the impact marine toxins on brain across lifespan. Here, we describe TAR DNA-binding protein 43 (TDP-43) proteinopathy and Alzheimer's disease (AD) in a beached harbor porpoise (
The membrane proximal external region (MPER) of the HIV-1 glycoprotein gp41 is targeted by broadly neutralizing antibodies 2F5 and 4E10. To date, no immunization regimen in animals or humans has produced MPER-specific antibodies. We immunized llamas with gp41-MPER proteoliposomes selected a single chain antibody (VHH), 2H10, whose epitope overlaps that mAb 2F5. Bi-2H10, bivalent form which displayed an approximately 20-fold increased affinity compared to monovalent neutralized various...
The basis for air pollution-associated neurodegenerative changes in humans is being studied rodent models. We and others find that the ultrafine particulate matter (PM) derived from vehicular exhaust can induce synaptic dysfunction inflammatory responses vivo vitro. In particular, a nano-sized subfraction of (nPM, PM0.2) local urban traffic corridor glial TNFα production mixed glia (astrocytes microglia) neonatal rat cerebral cortex. Here, we examine role neurite dysfunctions induced by nPM...
Given the known strong relationship of DNA methylation with environmental exposure, we investigated whether brain regions affected in Parkinson disease (PD) were differentially methylated between PD cases and controls.DNA chip arrays used to perform a genome-wide screen on dorsal motor nucleus vagus (DMV), substantia nigra (SN), cingulate gyrus (CG) pathologically confirmed controls selected using criteria Beecham et al. Analysis examined (DMRs) for each area. RNA sequencing pathway analysis...
Abstract The early neuropathological features of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) are protein aggregates in motor neurons and microglial activation. Similar pathology characterizes Guamanian ALS/Parkinsonism dementia complex, which may be triggered by the cyanotoxin β-N-methylamino-l-alanine (BMAA). We report here occurrence ALS/MND-type pathological changes vervets (Chlorocebus sabaeus; n = 8) fed oral doses a dry powder BMAA HCl salt (210 mg/kg/day) for 140...
Abstract Opioid use disorder (OUD) is influenced by genetic and environmental factors. While recent research suggests epigenetic disturbances in OUD, this mostly limited to DNA methylation (5mC). hydroxymethylation (5hmC) has been widely understudied. We conducted a multi-omics profiling of OUD male cohort, integrating neuronal-specific 5mC 5hmC as well gene expression profiles from human postmortem orbitofrontal cortex (OUD = 12; non-OUD 26). Single locus methylomic analysis co-methylation...
Abstract Schizophrenia (SCZ) is a complex psychiatric disorder that involves an inflammatory response thought to be characterized by microglial activation. The inflammasome may play critical roles in the pathomechanism of neuroinflammation but how this relates SCZ remains unclear. In study, we performed immunohistochemical (IHC) analysis compare expression proteins brain tissue from donors with (n = 16) and non-psychiatric (NP; n 13) isolated superior frontal cortex (SFC), temporal cortex,...
Airborne particulate matter (PM) from urban vehicular aerosols altered glutamate receptor functions and induced glial inflammatory responses in rodent models after chronic exposure. Potential neurotoxic mechanisms were analyzed vitro. In hippocampal slices, 2 h exposure to aqueous nanosized PM (nPM) selectively post-synaptic proteins cornu ammonis area 1 (CA1) neurons: increased GluA1, GluN2A, GluN2B, but not GluA2, GluN1, or mGlur5; post synaptic density 95 spinophilin, synaptophysin, while...
Dolphin stranding events occur frequently in Florida and Massachusetts. Dolphins are an excellent sentinel species for toxin exposures the marine environment. In this report we examine whether cyanobacterial neurotoxin, β-methylamino-L-alanine (BMAA), is present stranded dolphins. BMAA has been shown to bioaccumulate food web, including muscles fins of sharks. Dietary exposure associated with occurrence neurofibrillary tangles β-amyloid plaques nonhuman primates. The findings protein-bound...
Brain region-specific degeneration and somatic expansions of the mutant Huntingtin (mHTT) CAG tract are key features Huntington's disease (HD). However, relationships between expansions, death specific cell types, molecular events associated with these processes not established. Here we employed fluorescence-activated nuclear sorting (FANS) deep profiling to gain insight into properties types human striatum cerebellum in HD control donors. arise striatal medium spiny neurons (MSNs)...
Sharks have greater risk for bioaccumulation of marine toxins and mercury (Hg), because they are long-lived predators. Shark fins cartilage also contain β-N-methylamino-l-alanine (BMAA), a ubiquitous cyanobacterial toxin linked to neurodegenerative diseases. Today, significant number shark species found their way onto the International Union Conservation Nature (IUCN) Red List Threatened Species. Many large sharks threatened with extinction due in part growing high demand fin soup and,...
ABSTRACT Single-cell technologies enable measure of unique cellular signatures, but are typically limited to a single modality. Computational approaches allow integration diverse single-cell datasets, their efficacy is difficult validate in the absence authentic multi-omic measurements. To comprehensively assess molecular phenotypes cells tissues, we devised single-nucleus methylCytosine, Chromatin accessibility and Transcriptome sequencing (snmC2T-seq) applied it post-mortem human frontal...
Abstract Parkinson’s disease (PD) is a common and complex neurodegenerative disorder. Loss of neuromelanin-containing dopaminergic (DA) neurons in the substantia nigra (SN) hallmark PD neuropathology; etiology remains unclear. Single-cell (-nucleus) RNA sequencing (sc or snRNAseq) has significantly advanced our understanding diseases including Alzheimer’s, but limited progress been made PD. Here we generated by far largest snRNAseq data high-quality 315,867 nuclei from human SN 9 healthy...
Cyanobacterial blooms produce toxins that may become aerosolized, increasing health risks through inhalation exposures. Health related effects on the lower respiratory tract caused by these are becoming better understood. However, nasal exposures to cyanotoxins remain understudied, especially for those with neurotoxic potential. Here, we present a case series study evaluating exposure β-N-methylamino-l-alanine (BMAA), cyanobacterial toxin linked neurodegenerative disease, in postmortem...