A5013753659- Trypanosoma species research and implications
- SARS-CoV-2 and COVID-19 Research
- CRISPR and Genetic Engineering
- vaccines and immunoinformatics approaches
- Insect symbiosis and bacterial influences
- Computational Drug Discovery Methods
- Mosquito-borne diseases and control
- Monoclonal and Polyclonal Antibodies Research
- Protein Structure and Dynamics
- Research on Leishmaniasis Studies
- Calcium signaling and nucleotide metabolism
- Bacteriophages and microbial interactions
- Cytomegalovirus and herpesvirus research
- Virus-based gene therapy research
- Viral Infections and Outbreaks Research
- Biochemical and Molecular Research
- Animal Virus Infections Studies
- Advanced biosensing and bioanalysis techniques
- Gene Regulatory Network Analysis
- Lysosomal Storage Disorders Research
- Viral Infections and Immunology Research
- Genetic Syndromes and Imprinting
- Studies on Chitinases and Chitosanases
- Fungal Plant Pathogen Control
- Clinical Nutrition and Gastroenterology
Lawrence Livermore National Laboratory
2021-2024
Sandia National Laboratories California
2017-2023
University of California, Los Angeles
2011-2020
The flagellum of African trypanosomes is an essential and multifunctional organelle that functions in motility, cell morphogenesis, host-parasite interaction. Previous studies the trypanosome have been limited by inability to purify flagella without first removing flagellar membrane. This limitation particularly relevant context studying signaling, as signaling requires surface-exposed proteins membrane soluble matrix. Here we employ a combination genetic mechanical approaches intact from...
The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs
Increasing evidence indicates that the Trypanosoma brucei flagellum (synonymous with cilium) plays important roles in host-parasite interactions. Several studies have identified virulence factors and signaling proteins flagellar membrane of bloodstream-stage T. brucei, but less is known about procyclic, insect-stage parasites. Here we report on identification several receptor-type adenylate cyclases (ACs) are specifically upregulated procyclic Identification insect stage-specific ACs novel,...
Sophisticated systems for cell-cell communication enable unicellular microbes to act as multicellular entities capable of group-level behaviors that are not evident in individuals. These group influence microbe physiology, and the underlying signaling pathways considered potential drug targets microbial pathogens. Trypanosoma brucei is a protozoan parasite causes substantial human suffering economic hardship some most impoverished regions world. T. lives on host tissue surfaces during...
ABSTRACT The protozoan parasite Trypanosoma brucei engages in surface-induced social behavior, termed motility, characterized by single cells assembling into multicellular groups that coordinate their movements response to extracellular signals. Social motility requires sensing and responding signals, but the underlying mechanisms are unknown. Here we report T. depends on cyclic AMP (cAMP) signaling systems parasite's flagellum (synonymous with cilium). Pharmacological inhibition of...
African trypanosomes are devastating human and animal pathogens transmitted by tsetse flies between mammalian hosts. The trypanosome surface forms a critical host interface that is essential for sensing adapting to diverse environments. However, protein composition diversity remain largely unknown. Here, we use labeling, affinity purification, proteomic analyses describe cell proteomes from insect-stage bloodstream-stage Trypanosoma brucei. contain most previously characterized proteins. We...
Members of the eIF4E mRNA cap-binding family are involved in translation and modulation transcript availability other systems as part a three-component complex including eIF4G eIF4A. The kinetoplastids possess four described five homologs. We have identified two new proteins Trypanosoma brucei , define distinct complexes associated with fifth member, TbEIF4E5. cytosolic TbEIF4E5 protein binds cap 0 vitro. was found association TbEIF4Gs. TbIF4EG1 bound TbEIF4E5, 47.5-kDa RNA-binding domains,...
Significance We combine genetics, biochemistry, cell biology, and proteomics to define Bardet–Biedl Syndrome complex (BBSome) composition, location, function in the deadly parasite Trypanosoma brucei . BBSome mutants have reduced infectivity mice, quantitative identified surface proteome changes that may underlie virulence. To our knowledge, this work presents first comprehensive study of any microbial pathogen. T. is also among earliest organisms diverged from other eukaryotes, showing deep...
ABSTRACT Trypanosomes lack the transcriptional control characteristic of majority eukaryotes that is mediated by gene-specific promoters in a one-gene–one-promoter arrangement. Rather, their genomes are transcribed large polycistrons with no obvious functional linkage. Posttranscriptional regulation gene expression must thus play larger role these organisms. The eIF4E homolog TbEIF4E6 binds mRNA cap analogs vitro and part complex vivo may fulfill such role. Knockdown tagged protein A-tobacco...
Abstract Emerging and re-emerging viral pathogens present a unique challenge for anti-viral therapeutic development. Anti-viral approaches with high flexibility rapid production times are essential combating these high-pandemic risk viruses. CRISPR-Cas technologies have been extensively repurposed to treat variety of diseases, recent work expanding into potential applications against infections. However, delivery still presents major technologies. Lipid-coated mesoporous silica nanoparticles...
A rapid response is necessary to contain emergent biological outbreaks before they can become pandemics. The novel coronavirus (SARS-CoV-2) that causes COVID-19 was first reported in December of 2019 Wuhan, China and reached most corners the globe less than two months. In just over a year since initial infections, infected almost 100 million people worldwide. Although similar SARS-CoV MERS-CoV, SARS-CoV-2 has resisted treatments are effective against other coronaviruses. Crystal structures...
To complete its infectious cycle, the protozoan parasite Trypanosoma brucei must navigate through diverse tissue environments in both tsetse fly and mammalian hosts. This is hypothesized to be driven by yet unidentified chemotactic cues. Prior work has shown that parasites engaging social motility vitro alter their trajectory avoid other groups of parasites, an example negative chemotaxis. However, movement T. toward a stimulus, positive chemotaxis, so far not been reported. Here, we show...
The respiratory virus responsible for coronavirus disease 2019 (COVID-19), severe acute syndrome 2 (SARS-CoV-2), has affected nearly every aspect of life worldwide, claiming the lives over 3.9 million people globally, at time this publication. Neutralizing humanized nanobody (VHH)-based antibodies (VHH-huFc) represent a promising therapeutic intervention strategy to address current SARS-CoV-2 pandemic and provide powerful toolkit future outbreaks. Using synthetic, high-diversity VHH...
The high-affinity receptor for IgE expressed on the surface of mast cells and basophils interacts with antigens, via bound antibody, triggers secretion inflammatory mediators that contribute to allergic reactions. To understand how past inputs (memory) influence future responses in cells, a microfluidic device was used precisely control exposure alternating stimulatory non-stimulatory inputs. We determined response subsequent stimulation depends interval signaling quiescence. For shorter...
The RNA-guided DNA nuclease Cas9 is now widely used for the targeted modification of genomes human cells and various organisms. Despite extensive use Clustered Regularly Interspaced Palindromic Repeats (CRISPR) systems genome engineering rapid discovery new CRISPR-associated nucleases, there are no high-throughput assays measuring enzymatic activity. current laboratory future therapeutic uses CRISPR technology have a significant risk accidental exposure or clinical off-target effects,...
Structure-based Deep Fusion models were recently shown to outperform several physics- and machine learning-based protein-ligand binding affinity prediction methods. As part of a multi-institutional COVID-19 pandemic response, over 500 million small molecules computationally screened against four protein structures from the novel coronavirus (SARS-CoV-2), which causes COVID-19. Three enhancements made in order evaluate more than 5 billion docked poses on SARS-CoV-2 targets. First, concept was...
ABSTRACT The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs 1–3 , but also revealed how quickly viral escape can curtail effective options 4, 5 . With emergence SARS-CoV-2 Omicron variant in late 2021, many clinically used antibody drug products lost potency, including Evusheld TM its constituent, cilgavimab 6 Cilgavimab, like progenitor COV2-2130, is a class 3 that compatible with other antibodies combination 4 challenging to...
Viral populations in natural infections can have a high degree of sequence diversity, which directly impact immune escape. However, antibody potency is often tested vitro with relatively clonal viral populations, such as laboratory virus or pseudotyped stocks, may not accurately represent the genetic diversity circulating genotypes. This affect validity phenotype assays, neutralization assays. To address this issue, we whether recombinant carrying SARS-CoV-2 spike (VSV-SARS-CoV-2-S) stocks...
Abstract To complete its infectious cycle, the protozoan parasite, Trypanosoma brucei , must navigate through diverse tissue environments in both tsetse fly and mammalian hosts. This is hypothesized to be driven by yet unidentified chemotactic cues. Prior work has shown that parasites engaging social motility vitro alter their trajectory avoid other groups of parasites, an example negative chemotaxis. However, movement T. toward a stimulus, positive chemotaxis, so far not been reported. Here...
Targeting host factors for anti-viral development offers several potential advantages over traditional countermeasures that include broad-spectrum activity and prevention of resistance. Characterization in animal models provides strong evidence their involvement disease pathogenesis, but the feasibility performing high-throughput vivo analyses on lists genes is problematic. To begin addressing challenges screening candidate vivo, we combined advances CRISPR-Cas9 genome editing with an...
Structure-based Deep Fusion models were recently shown to outperform several physics- and machine learning-based protein-ligand binding affinity prediction methods. As part of a multi-institutional COVID-19 pandemic response, over 500 million small molecules computationally screened against four protein structures from the novel coronavirus (SARS-CoV-2), which causes COVID-19. Three enhancements made in order evaluate more than 5 billion docked poses on SARS-CoV-2 targets. First, concept was...