| 1. |
- Ajibola Omotesho, Quadri, et al.
(författare)
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Epigenetic targets to enhance antitumor immune response through the induction of tertiary lymphoid structures
- 2024
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 15
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Forskningsöversikt (refereegranskat)abstract
- Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates found in sites of chronic inflammation such as tumors and autoimmune diseases. The discovery that TLS formation at tumor sites correlated with good patient prognosis has triggered extensive research into various techniques to induce their formation at the tumor microenvironment (TME). One strategy is the exogenous induction of specific cytokines and chemokine expression in murine models. However, applying such systemic chemokine expression can result in significant toxicity and damage to healthy tissues. Also, the TLS formed from exogenous chemokine induction is heterogeneous and different from the ones associated with favorable prognosis. Therefore, there is a need to optimize additional approaches like immune cell engineering with lentiviral transduction to improve the TLS formation in vivo. Similarly, the genetic and epigenetic regulation of the different phases of TLS neogenesis are still unknown. Understanding these molecular regulations could help identify novel targets to induce tissue-specific TLS in the TME. This review offers a unique insight into the molecular checkpoints of the different stages and mechanisms involved in TLS formation. This review also highlights potential epigenetic targets to induce TLS neogenesis. The review further explores epigenetic therapies (epi-therapy) and ongoing clinical trials using epi-therapy in cancers. In addition, it builds upon the current knowledge of tools to generate TLS and TLS phenotyping biomarkers with predictive and prognostic clinical potential.
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| 2. |
- Barragan, Antonio
(författare)
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Carbohydrate-mediated adhesion in Plasmodium falciparum malaria
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Characterization of virulence factors in P. falciparum malaria is essential in order to identify new therapeutic and prophylactic targets. Rosette formation, the binding of uninfected red blood cells to parasite-infected red blood cells, is a P. falciparum virulence phenotype associated with severe clinical manifestations, e. g. cerebral malaria and severe anemia. Humoral responses to rosetting epitopes seem to confer protective immunity and we have shown in these studies that individuals living in malaria endemic areas build up age-related humoral responses to rosetting epitopes that parallel the development of clinical immunity. Furthermore, epitopes that mediate the rosetting phenotype appear to be diverse but conserved between distant regions in Africa. We have performed a detailed study of the cell-cell binding mechanisms that govern rosetting. Polysaccharides belonging to the glycosaminoglycan family, especially heparin and heparan sulfate, inhibit rosette formation and treatments of host cells indicate that heparan sulfate-like glycans support adhesion. In addition, the ABO blood group phenotype of the infected host modulates rosetting and blood group A and B antigens have been shown to function as co-receptors to other receptors in rosetting. The parasite-derived adhesion molecule that mediates rosetting has been identified as a Plasmodium falciparum erythrocyte membrane protein I (PfEMP1) variant, a product of the vast family of var genes. PfEMP1 mediates adhesion by interacting with host cell glycan receptors, such as heparan sulfate and blood group A antigen. We have characterized the binding of heparan sulfate and heparin to the rosetting domain of PfEMP1. Important molecular features of oligosaccharides required for optimal binding, such as molecular size (12-mer oligosaccharide chain or larger) and N-sulfation, have thus been identified. In field studies, the heparin-binding phenotype of P. falciparum was found to be more common among patients with severe malaria. Furthermore, the clinical isolates had the ability to adhere to multiple receptors. We have characterized the binding properties of PfEMP1. to multiple host receptors, which may explain the poly-adhesive P. falciparum phenotype associated with severe disease in these studies. The present investigation contributes to the molecular elucidation of virulent adhesive phenotypes in P. falciparum malaria. The identified molecules involved in the cell-cell adherence may serve as targets for prophylactic and therapeutic measures.
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| 3. |
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| 4. |
- Barragan, Antonio, et al.
(författare)
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Erythrocyte Glycans as Plasmodium falciparum Rosetting Receptors : Molecular Background of Strain Specific Rosette Disruption by Glycosaminoglycans and Sulfated Glycoconjugates
- 1999
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Ingår i: Experimental parasitology. - : Elsevier BV. - 0014-4894 .- 1090-2449. ; 91:2, s. 133-143
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Tidskriftsartikel (refereegranskat)abstract
- Rosetting, the adhesion of Plasmodium falciparum-infected erythrocytes to uninfected erythrocytes, is a virulent parasite phenotype associated with the occurrence of severe malaria, e.g., cerebral malaria. Compounds with specific anti-rosetting activity are potential therapeutic agents. Glycosaminoglycans and sulfated glycoconjugates were found to disrupt rosettes in a strain- and isolate-specific manner. Rosette disruption was strongly connected to the presence of N-sulfate groups in heparin/heparan sulfate as demonstrated by modified heparin preparations. This finding was corroborated by the disruption of rosettes with mono- and disaccharides derived from heparin/heparan sulfate that contained N-sulfated glucosamine. Furthermore, heparinase III treatment of erythrocyte cultures infected by FCR3S1 (and to some extent TM 284) P. falciparum strains abolished rosetting. Heparinase III treatment of the uninfected erythrocytes prior to mixing with the infected culture impeded formation of rosettes, indicating that the rosetting receptors at least partially are of glycosaminoglycan nature.
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| 5. |
- Barragan, Antonio, et al.
(författare)
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GABAergic signalling in the immune system
- 2015
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 213:4, s. 819-827
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Forskningsöversikt (refereegranskat)abstract
- The GABAergic system is the main inhibitory neurotransmitter system in the central nervous system (CNS) of vertebrates. Signalling of the transmitter c-aminobutyric acid (GABA) via GABA type A receptor channels or G-protein-coupled type B receptors is implicated in multiple CNS functions. Recent findings have implicated the GABAergic system in immune cell functions, inflammatory conditions and diseases in peripheral tissues. Interestingly, the specific effects may vary between immune cell types, with stage of activation and be altered by infectious agents. GABA/GABA-A receptor-mediated immunomodulatory functions have been unveiled in immune cells, being present in T lymphocytes and regulating the migration of Toxoplasma-infected dendritic cells. The GABAergic system may also play a role in the regulation of brain resident immune cells, the microglial cells. Activation of microglia appears to regulate the function of GABAergic neurotransmission in neighbouring neurones through changes induced by secretion of brain-derived neurotrophic factor. The neurotransmitter-driven immunomodulation is a new but rapidly growing field of science. Herein, we review the present knowledge of the GABA signalling in immune cells of the periphery and the CNS and raise questions for future research.
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| 6. |
- Barragan, Carlos Eduardo, et al.
(författare)
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Isolation of Arsenic Resistant and Arsenopyrite Oxidizing Acidithiobacillus Species from pH Neutral Colombian Mine Effluents
- 2020
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Ingår i: Geomicrobiology Journal. - : Taylor & Francis Group. - 0149-0451 .- 1521-0529. ; 37:7, s. 682-689
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Tidskriftsartikel (refereegranskat)abstract
- Inactive mines provide a great source of bacterial diversity for studying acidophilic communities and their biotechnological applications, but prospecting of these anthropogenic environments in Colombia has been limited. Conventional microbiological methods were used to isolate acidophilic bacterial strains from effluents emanating from the Colombian gold mine 'El Zancudo' (Titiribi, Antioquia). Despite the drainage waters having circumneutral pH, all of the isolated strains were phylogenetically related to the extreme acidophile Acidithiobacillus genus. However, based upon 16S rRNA gene sequences the mesophilic sulfur-oxidizing indigenous strains could not be assigned to a species. Pure cultures were selected by screening in medium with soluble inorganic arsenic (III) and their mineral-oxidative activity was evaluated at 30 degrees C in Erlenmeyer flasks with arsenopyrite ore under rotary shaking conditions. The indigenous strains were able to catalyze arsenopyrite oxidation in a mixed culture with a pulp density of 10%, maintaining their growth in the presence of >80 mM leached arsenic. This research provides information regarding the isolation of arsenic resistant bacterial communities from neutral effluents from El Zancudo mine and the possibility of the isolated strains to be useful in the biooxidation pretreatment of refractory gold-bearing arsenopyrite ores and concentrates.
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| 7. |
- Barragan, Carlos Eduardo, et al.
(författare)
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RNA transcript response by an Acidithiobacillus spp. mixed culture reveals adaptations to growth on arsenopyrite
- 2021
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Ingår i: Extremophiles. - : Springer. - 1431-0651 .- 1433-4909. ; 25, s. 143-158
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Tidskriftsartikel (refereegranskat)abstract
- Biooxidation of gold-bearing refractory mineral ores such as arsenopyrite (FeAsS) in stirred tanks produces solutions containing highly toxic arsenic concentrations. In this study, ferrous iron and inorganic sulfur-oxidizing Acidithiobacillus strain IBUN Ppt12 most similar to Acidithiobacillus ferrianus and inorganic sulfur compound oxidizing Acidithiobacillus sp. IBUNS3 were grown in co-culture during biooxidation of refractory FeAsS. Total RNA was extracted and sequenced from the planktonic cells to reveal genes with different transcript counts involved in the response to FeAsS containing medium. The co-culture's response to arsenic release during biooxidation included the ars operon genes that were independently regulated according to the arsenopyrite concentration. Additionally, increased mRNA transcript counts were identified for transmembrane ion transport proteins, stress response mechanisms, accumulation of inorganic polyphosphates, urea catabolic processes, and tryptophan biosynthesis. Acidithiobacillus spp. RNA transcripts also included those encoding the Rus and PetI proteins involved in ferrous iron oxidation and gene clusters annotated as encoding inorganic sulfur compound metabolism enzymes. Finally, mRNA counts of genes related to DNA methylation, management of oxidative stress, chemotaxis, and motility during biooxidation were decreased compared to cells growing without mineral. The results provide insights into the adaptation of Acidithiobacillus spp. to growth during biooxidation of arsenic-bearing sulfides.
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| 8. |
- Bhandage, Amol, 1988-, et al.
(författare)
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A motogenic GABAergic system of mononuclear phagocytes facilitates dissemination of coccidian parasites
- 2020
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Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Gamma-aminobutyric acid (GABA) serves diverse biological functions in prokaryotes and eukaryotes, including neurotransmission in vertebrates. Yet, the role of GABA in the immune system has remained elusive. Here, a comprehensive characterization of human and murine myeloid mononuclear phagocytes revealed the presence of a conserved and tightly regulated GABAergic machinery with expression of GABA metabolic enzymes and transporters, GABA-A receptors and regulators, and voltage-dependent calcium channels. Infection challenge with the common coccidian parasites Toxoplasma gondii and Neospora caninum activated GABAergic signaling in phagocytes. Using gene silencing and pharmacological modulators in vitro and in vivo in mice, we identify the functional determinants of GABAergic signaling in parasitized phagocytes and demonstrate a link to calcium responses and migratory activation. The findings reveal a regulatory role for a GABAergic signaling machinery in the host-pathogen interplay between phagocytes and invasive coccidian parasites. The co-option of GABA underlies colonization of the host by a Trojan horse mechanism.
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| 9. |
- Bhandage, Amol, 1988-, et al.
(författare)
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Calling in the CaValry-Toxoplasma gondii Hijacks GABAergic Signaling and Voltage-Dependent Calcium Channel Signaling for Trojan horse-Mediated Dissemination
- 2019
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Ingår i: Frontiers in Cellular and Infection Microbiology. - : Frontiers Media S.A.. - 2235-2988. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Dendritic cells (DCs) are regarded as the gatekeepers of the immune system but can also mediate systemic dissemination of the obligate intracellular parasite Toxoplasma gondii. Here, we review the current knowledge on how T. gondii hijacks the migratory machinery of DCs and microglia. Shortly after active invasion by the parasite, infected cells synthesize and secrete the neurotransmitter γ-aminobutyric acid (GABA) and activate GABA-A receptors, which sets on a hypermigratory phenotype in parasitized DCs in vitro and in vivo. The signaling molecule calcium plays a central role for this migratory activation as signal transduction following GABAergic activation is mediated via the L-type voltage-dependent calcium channel (L-VDCC) subtype Cav1.3. These studies have revealed that DCs possess a GABA/L-VDCC/Cav1.3 motogenic signaling axis that triggers migratory activation upon T. gondii infection. Moreover, GABAergic migration can cooperate with chemotactic responses. Additionally, the parasite-derived protein Tg14-3-3 has been associated with hypermigration of DCs and microglia. We discuss the interference of T. gondii infection with host cell signaling pathways that regulate migration. Altogether, T. gondii hijacks non-canonical signaling pathways in infected immune cells to modulate their migratory properties, and thereby promote its own dissemination.
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| 10. |
- Bhandage, Amol, 1988-, et al.
(författare)
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GABAergic signaling by cells of the immune system : more the rule than the exception.
- 2021
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Ingår i: Cellular and Molecular Life Sciences (CMLS). - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 78:15, s. 5667-5679
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Tidskriftsartikel (refereegranskat)abstract
- Gamma-aminobutyric acid (GABA) is best known as an essential neurotransmitter in the evolved central nervous system (CNS) of vertebrates. However, GABA antedates the development of the CNS as a bioactive molecule in metabolism and stress-coupled responses of prokaryotes, invertebrates and plants. Here, we focus on the emerging findings of GABA signaling in the mammalian immune system. Recent reports show that mononuclear phagocytes and lymphocytes, for instance dendritic cells, microglia, T cells and NK cells, express a GABAergic signaling machinery. Mounting evidence shows that GABA receptor signaling impacts central immune functions, such as cell migration, cytokine secretion, immune cell activation and cytotoxic responses. Furthermore, the GABAergic signaling machinery of leukocytes is implicated in responses to microbial infection and is co-opted by protozoan parasites for colonization of the host. Peripheral GABA signaling is also implicated in inflammatory conditions and diseases, such as type 1 diabetes, rheumatoid arthritis and cancer cell metastasis. Adding to its role in neurotransmission, growing evidence shows that the non-proteinogenic amino acid GABA acts as an intercellular signaling molecule in the immune system and, as an interspecies signaling molecule in host-microbe interactions. Altogether, the data raise the assumption of conserved GABA signaling in a broad range of mammalian cells and diversification of function in the immune system.
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