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Open Access Publications from the University of California

Scholarly Works (7 results)

  • Article
  • Peer Reviewed
UC Riverside Previously Published Works (2015)
Catecholamines and adipokines function as hormones; catecholamines as neurotransmitters in the sympathetic nervous system, and adipokines as mediators of metabolic processes. It has become increasingly clear, however, that both also function as immunomodulators of innate and adaptive immune cells, including macrophages. Macrophages can respond to, as well as produce their own catecholamines. Dopamine, noradrenaline, and adrenaline are the most abundant catecholamines in the body, and can induce both pro-inflammatory and anti-inflammatory immune responses in macrophages, as well as non-immune processes such as thermogenesis. Though they are responsive to adipokines, particularly lipoproteins, leptin, and adiponectin, macrophages generally do not synthesize their own adipokines, with the exception being resistin-like molecules. Adipokines contribute to adverse metabolic and immune responses by stimulating lipid accumulation, foam cell formation and pro-inflammatory cytokine production in macrophages. Adipokines can also promote balance or resolution during metabolic and immune processes by promoting reverse lipid transport and expression of Th2 cytokines. This review will explore the mechanisms by which catecholamines and adipokines influence macrophage function in neural pathways, immunity and metabolism.
    Cover page: Non-traditional cytokines: How catecholamines and adipokines influence macrophages in immunity, metabolism and the central nervous system
    • Article
    • Peer Reviewed
    UC Riverside Previously Published Works (2022)
    Many helminth life cycles, including hookworm, involve a mandatory lung phase, where myeloid and granulocyte subsets interact with the helminth and respond to infection-induced lung injury. To evaluate these innate subsets in Nippostrongylus brasiliensis infection, reporter mice for myeloid cells (CX3CR1GFP ) and granulocytes (PGRPdsRED ) are employed. Nippostrongylus infection induces lung infiltration of reporter cells, including CX3CR1+ myeloid cells and PGRP+ eosinophils. Strikingly, CX3CR1GFP/GFP mice, which are deficient in CX3CR1, are protected from Nippostrongylus infection with reduced weight loss, lung leukocyte infiltration, and worm burden compared to CX3CR1+/+ mice. This protective effect is specific for CX3CR1 as CCR2-deficient mice do not exhibit reduced worm burdens. Nippostrongylus co-culture with lung Ly6C+ monocytes or CD11c+ cells demonstrates that CX3CR1GFP/GFP monocytes secrete more pro-inflammatory cytokines and actively bind the parasites causing reduced motility. RNA sequencing of Ly6C+ or CD11c+ cells shows Nippostrongylus-induced gene expression changes, particularly in monocytes, associated with inflammation, chemotaxis, and extracellular matrix remodeling pathways. Analysis reveals cytotoxic and adhesion molecules as potential effectors against the parasite, such as Gzma and Gzmb, which are elevated in CX3CR1GFP/GFP monocytes. These studies validate a dual innate cell reporter for lung helminth infection and demonstrate that CX3CR1 impairs monocyte-helminth interaction.
      Cover page: CX3CR1‐Expressing Myeloid Cells Regulate Host–Helminth Interaction and Lung Inflammation
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2023)

      Background

      All cancers harbor somatic mutations in their genomes. In principle, mutations affecting between one and fifty base pairs are generally classified as small mutational events. Conversely, large mutational events affect more than fifty base pairs, and, in most cases, they encompass copy-number and structural variants affecting many thousands of base pairs. Prior studies have demonstrated that examining patterns of somatic mutations can be leveraged to provide both biological and clinical insights, thus, resulting in an extensive repertoire of tools for evaluating small mutational events. Recently, classification schemas for examining large-scale mutational events have emerged and shown their utility across the spectrum of human cancers. However, there has been no computationally efficient bioinformatics tool that allows visualizing and exploring these large-scale mutational events.

      Results

      Here, we present a new version of SigProfilerMatrixGenerator that now delivers integrated capabilities for examining large mutational events. The tool provides support for examining copy-number variants and structural variants under two previously developed classification schemas and it supports data from numerous algorithms and data modalities. SigProfilerMatrixGenerator is written in Python with an R wrapper package provided for users that prefer working in an R environment.

      Conclusions

      The new version of SigProfilerMatrixGenerator provides the first standardized bioinformatics tool for optimized exploration and visualization of two previously developed classification schemas for copy number and structural variants. The tool is freely available at https://github.com/AlexandrovLab/SigProfilerMatrixGenerator with an extensive documentation at https://osf.io/s93d5/wiki/home/ .
        Cover page: Visualizing and exploring patterns of large mutational events with SigProfilerMatrixGenerator
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2022)
        Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and multi-base substitutions1-5, diffuse hypermutation termed omikli6, and longer strand-coordinated events termed kataegis3,7-9. Here we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome-sequenced cancers from 30 types of cancer10. Clustered mutations were highly enriched in driver genes and associated with differential gene expression and changes in overall survival. Several distinct mutational processes gave rise to clustered indels, including signatures that were enriched in tobacco smokers and homologous-recombination-deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, whereas most multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, which have previously been attributed to APOBEC3 activity6, accounted for a large proportion of clustered substitutions; however, only 16.2% of omikli matched APOBEC3 patterns. Kataegis was generated by multiple mutational processes, and 76.1% of all kataegic events exhibited mutational patterns that are associated with the activation-induced deaminase (AID) and APOBEC3 family of deaminases. Co-occurrence of APOBEC3 kataegis and extrachromosomal DNA (ecDNA), termed kyklonas (Greek for cyclone), was found in 31% of samples with ecDNA. Multiple distinct kyklonic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kyklonic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fuelling the evolution of ecDNA.
          Cover page: Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA.
          • Article
          • Peer Reviewed
          UC Riverside Previously Published Works (2015)

          Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg- mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology.

            • Article
            • Peer Reviewed
            UC Riverside Previously Published Works (2015)
            Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg- mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology.
              Cover page: Macrophage-Derived Human Resistin Is Induced in Multiple Helminth Infections and Promotes Inflammatory Monocytes and Increased Parasite Burden
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2022)
              Mutational signature analysis is commonly performed in cancer genomic studies. Here, we present SigProfilerExtractor, an automated tool for de novo extraction of mutational signatures, and benchmark it against another 13 bioinformatics tools by using 34 scenarios encompassing 2,500 simulated signatures found in 60,000 synthetic genomes and 20,000 synthetic exomes. For simulations with 5% noise, reflecting high-quality datasets, SigProfilerExtractor outperforms other approaches by elucidating between 20% and 50% more true-positive signatures while yielding 5-fold less false-positive signatures. Applying SigProfilerExtractor to 4,643 whole-genome- and 19,184 whole-exome-sequenced cancers reveals four novel signatures. Two of the signatures are confirmed in independent cohorts, and one of these signatures is associated with tobacco smoking. In summary, this report provides a reference tool for analysis of mutational signatures, a comprehensive benchmarking of bioinformatics tools for extracting signatures, and several novel mutational signatures, including one putatively attributed to direct tobacco smoking mutagenesis in bladder tissues.
                Cover page: Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor
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