A5058152266- Immune cells in cancer
- Immune Cell Function and Interaction
- Adipose Tissue and Metabolism
- T-cell and B-cell Immunology
- Mitochondrial Function and Pathology
- Cancer Immunotherapy and Biomarkers
- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- Neuroinflammation and Neurodegeneration Mechanisms
- ATP Synthase and ATPases Research
- CAR-T cell therapy research
- Epigenetics and DNA Methylation
- Phagocytosis and Immune Regulation
- PARP inhibition in cancer therapy
- Cancer, Hypoxia, and Metabolism
- Exercise and Physiological Responses
- Atherosclerosis and Cardiovascular Diseases
- DNA and Nucleic Acid Chemistry
- Immune Response and Inflammation
- Coenzyme Q10 studies and effects
- Hippo pathway signaling and YAP/TAZ
- Cancer-related gene regulation
- Cancer Cells and Metastasis
- Immunotherapy and Immune Responses
- Sulfur Compounds in Biology
University of California, San Francisco
2022-2024
California Institute for Regenerative Medicine
2024
University of California, Berkeley
2013-2021
University of Colorado Boulder
2006
Hydrogen peroxide (H2O2) is a central reactive oxygen species (ROS) that contributes to diseases from obesity cancer neurodegeneration but also emerging as an important signaling molecule. We now report versatile histochemical approach for detection of H2O2 can be employed across broad range cell and tissue specimens in both healthy disease states. have developed first-generation H2O2-responsive analogue named Peroxymycin-1, which based on the classic cell-staining molecule puromycin enables...
Abstract Coenzyme Q (CoQ) is essential for mitochondrial respiration and required thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences specific tissues, such as BAT, remain poorly understood. Here, we show that pharmacological or genetic BAT stress signals causing accumulation cytosolic RNAs activation the eIF2α kinase PKR, resulting integrated response (ISR) with suppression UCP1 induction...
Foxo1 is a critical, direct regulator of Rag (recombination activating gene) transcription during B cell development and thus essential for the generation diverse repertoire antigen receptors. Although regulation has been widely studied in many types, pathways regulating cells have not fully elucidated. By screening panel mutants, we identified serine 215 on as novel phosphorylation site that activation transcription. Mutation S215 strongly attenuated transactivation but did affect most...
Abstract The temporal control of RAG (Rag) expression in developing lymphocytes prevents DNA breaks during periods proliferation that could threaten genomic integrity. In B cells, the IL-7R and precursor cell Ag receptor (pre-BCR) synergize to induce repression Rag at protein mRNA levels for a brief period following successful Ig H chain gene rearrangement. Whereas mechanism RAG2 downregulation is well defined, little known about pathways transcription factors mediate transcriptional Rag....
V(D)J recombination creates antibody light chain diversity by joining a Vκ gene segment with one of four Jκ segments. Two germline-transcript (GT) promoters control Vκ-Jκ joining, but the mechanisms that govern choice are unclear. Here, we show in gene-targeted mice proximal GT promoter helps targeting rearrangements to Jκ1 preventing premature DNA breaks at Jκ2. Consequently, cells lacking biased utilization downstream segments, resulting diminished potential for receptor editing....
Developing B lymphocytes undergo clonal expansion following successful immunoglobulin heavy chain gene rearrangement. During this proliferative burst, expression of the Rag genes is transiently repressed to prevent generation double-stranded DNA (dsDNA) breaks in cycling large pre-B cells. The are then reexpressed small, resting cells for light We previously identified c-Myb as a repressor transcription during using Abelson murine leukemia virus-transformed Nevertheless, molecular mechanisms...
Abstract Tumor progression is accompanied by fibrosis, which associated with diminished anti-tumor immune infiltrate. Here, we demonstrate that tumor infiltrating myeloid cells respond to the stiffened fibrotic microenvironment (TME) initiating a TGF-beta (TGFβ)-directed, collagen biosynthesis program. A collateral effect of this programming an untenable metabolic milieu for productive CD8 T cell responses, as collagen-synthesizing macrophages consume environmental arginine, synthesize...
Abstract Efforts to identify anti-cancer therapeutics and understand tumor-immune interactions are built with in vitro models that do not match the microenvironmental characteristics of human tissues. Using which mimic physical properties healthy or cancerous tissues a physiologically relevant culture medium, we demonstrate chemical microenvironment regulate composition topology glycocalyx. Remarkably, find cancer age-related changes sufficient adjust immune surveillance via glycocalyx,...
Abstract Mitochondria control eukaryotic cell fate by producing the energy needed to support life and signals required execute programmed death. The biochemical milieu is known affect mitochondrial function contribute dysfunctional phenotypes implicated in cancer morbidities of ageing. However, physical characteristics extracellular matrix are also altered aging tissues. We demonstrate that cells sense properties activate a stress response adaptively tunes via SLC9A1-dependent ion exchange...
Abstract Toll-like receptor (TLR)-dependent macrophage responses rely on acute increases in oxidative mitochondrial glucose metabolism that epigenetically support rapid proinflammatory transcriptional programming via histone acetylation. Subsequent suppression of restrains this metabolic-epigenetic gene transcription to enforce tolerance, an immunosuppressed state innate immune memory. Identifying biology promotes or counters these changes will inform therapeutic approaches influence...
Summary Efforts to identify anti-cancer therapeutics and understand tumor-immune interactions are built with in vitro models that do not match the microenvironmental characteristics of human tissues. Using which mimic physical properties healthy or cancerous tissues a physiologically relevant culture medium, we demonstrate chemical microenvironment regulate composition topology glycocalyx. Remarkably, find cancer age-related changes sufficient adjust immune surveillance via glycocalyx,...
<title>Abstract</title> Tumor progression is accompanied by fibrosis, which associated with diminished anti-tumor immune infiltrate. Here, we demonstrate that tumor infiltrating myeloid cells respond to the stiffened fibrotic microenvironment (TME) initiating a TGF-beta (TGFβ)-directed, collagen biosynthesis program. A collateral effect of this programming an untenable metabolic milieu for productive CD8 T cell responses, as collagen-synthesizing macrophages consume environmental arginine,...
A key question regarding DNA and RNA polymerase mechanisms is how they discriminate between right wrong (d)NTPs. Even after extensive study, the answer(s) to this remain unclear controversial. We have addressed using specific series of modified (d)NTPs 3 enzymes: Human primase, an X family that exhibits very low fidelity (average error frequency 1:100); Herpes extremely 1:30), and; human α, a B moderately high 1:5000). Both primases only efficiently polymerize NTP if it can form Watson-Crick...
Abstract Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether stress caused by these molecules impacts macrophage function is unknown. Here we demonstrate that both pharmacologically- lipopolysaccharide (LPS)-driven in macrophages triggers a response called mitohormesis. LPS-driven mitohormetic adaptations occur transition from an LPS-responsive to LPS-tolerant...
Abstract Aim Excessive microglial inflammation has emerged as a key player in mediating the effects of aging and neurodegeneration on brain dysfunction. Thus, there is great interest discovering transcriptional repressors that can control this process. We aimed to examine whether Phf15 —one top differentially expressed genes microglia during humans—could regulate transcription pro-inflammatory mediators microglia. Methods RT-qPCR was used assess mRNA expression mouse aging. Loss-of-function...
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Abstract Coenzyme Q (CoQ) is an essential component of mitochondrial respiration 1 and required for thermogenic activity in brown adipose tissues 2 (BAT). CoQ deficiency leads to a wide range pathological manifestations 3 but mechanistic consequences specific such as BAT remain poorly understood. Here we show that pharmacological or genetic (50-75% reduction) accumulation cytosolic RNAs (mtRNAs) activation the eIF2α kinase PKR resulting induction integrated stress response (ISR) suppression...
Abstract Women with aggressive DCIS are at high risk of progression to invasive breast cancer. Invasive disease is accompanied by extensive collagen remodeling and crosslinking that contributes tissue fibrosis stiffness. Fibrotic tumors associated an immune desert or excluded tumor microenvironment (TME) functions promote progression. In particular, tumor-associated macrophages (TAMs) invasion metastasis and, drive suppression allowing evade intrinsic anti-tumor responses. Here, we show...