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Item Open Access INVOLVEMENT OF 3′,5′-CYCLIC INOSINE MONOPHOSPHATE IN CYSTATHIONINE Γ-LYASE-DEPENDENT REGULATION OF THE VASCULAR TONE(British Journal of Pharmacology, 2021-04-30) Mitidieri, Emma; Vellecco, Valentina; Brancaleone, Vincenzo; Vanacore, Domenico; Manzo, Onorina L.; Martin, Emil; Sharina, Iraida; Krutsenko, Yekaterina; Monti, Maria Chiara; Morretta, Elva; Papapetropoulos, Andreas; Caliendo, Giuseppe; Frecentese, Francesco; Cirino, Giuseppe; Sorrentino, Raffaella; Bianca, Roberta d'Emmanuele di Villa; Bucci, Mariarosarial-cysteine or hydrogen sulfide (H2S) donors induce a biphasic effect on precontracted isolated vessels. The contractile effect occurs within a concentration range of 10 nM to 3 μM followed by vasodilatation at 30–100 μM. Here, we have investigated the signalling involved in the H2S-induced contraction.Item Open Access GIW and InCoB, two premier bioinformatics conferences in Asia with a combined 40 years of history(BMC, 2015) Schönbach, Christian; Horton, Paul; Yiu, Siu Ming; Tan, Tin Wee; Ranganathan, ShobaKnowledge discovery in bioinformatics thrives on joint and inclusive efforts of stakeholders. Similarly, knowledge dissemination is expected to be more effective and scalable through joint efforts. Therefore, the International Conference on Bioinformatics (InCoB) and the International Conference on Genome Informatics (GIW) were organized as a joint conference for the first time in 13 years of coexistence. The Asia-Pacific Bioinformatics Network (APBioNet) and the Japanese Society for Bioinformatics (JSBi) collaborated to host GIW/InCoB2015 in Tokyo, September 9-11, 2015. The joint endeavour yielded 51 research articles published in seven journals, 78 poster and 89 oral presentations, showcasing bioinformatics research in the Asia-Pacific region. Encouraged by the results and reduced organizational overheads, APBioNet will collaborate with other bioinformatics societies in organizing co-located bKnowledge discovery in bioinformatics thrives on joint and inclusive efforts of stakeholders. Similarly, knowledge dissemination is expected to be more effective and scalable through joint efforts. Therefore, the International Conference on Bioinformatics (InCoB) and the International Conference on Genome Informatics (GIW) were organized as a joint conference for the first time in 13 years of coexistence. The Asia-Pacific Bioinformatics Network (APBioNet) and the Japanese Society for Bioinformatics (JSBi) collaborated to host GIW/InCoB2015 in Tokyo, September 9-11, 2015. The joint endeavour yielded 51 research articles published in seven journals, 78 poster and 89 oral presentations, showcasing bioinformatics research in the Asia-Pacific region. Encouraged by the results and reduced organizational overheads, APBioNet will collaborate with other bioinformatics societies in organizing co-located bioinformatics research and training meetings in the future. InCoB2016 will be hosted in Singapore, September 21-23, 2016.ioinformatics research and training meetings in the future. InCoB2016 will be hosted in Singapore, September 21-23, 2016.Item Open Access InCoB2014: Mining Biological Data From Genomics for Transforming Industry and Health(BMC, 2014) Schönbach, Christian; Tan, Tin Wee; Ranganathan, ShobaThe 13th International Conference on Bioinformatics (InCoB2014) was held for the first time in Australia, at Sydney, July 31-2 August, 2014. InCoB is the annual scientific gathering of the Asia-Pacific Bioinformatics Network (APBioNet), hosted since 2002 in the Asia-Pacific region. Of 106 full papers submitted to the BMC track of InCoB2014, 50 (47.2%) were accepted in BMC Bioinformatics, BMC Genomics and BMC Systems Biology supplements, with three papers in a new BMC Medical Genomics supplement. While the majority of presenters and authors were from Asia and Australia, the increasing number of US and European conference attendees augurs well for the international flavour of InCoB. Next year's InCoB will be held jointly with the Genome Informatics Workshop (GIW), September 9-11, 2015 in Tokyo, Japan, with a view to integrate bioinformatics communities in the region.Item Open Access InCoB2013 introduces Systems Biology as a major conference theme(BMC, 2013-09) Schönbach, Christian; Shen, Bairong; Tan, Tin Wee; Ranganathan, ShobaThe Asia-Pacific Bioinformatics Network (APBioNet) held the first International Conference on Bioinformatics (InCoB) in Bangkok in 2002 to promote North-South networking. Commencing as a forum for Asia-Pacific researchers to interact with and learn from with scientists of developed countries, InCoB has become a major regional bioinformatics conference, with participants from the region as well as North America and Europe. Since 2006, InCoB has selected the best submissions for publication in BMC Bioinformatics. In response to the growth and maturation of data-driven approaches, InCoB added BMC Genomics in 2009 and with the introduction of this conference supplement, BMC Systems Biology to its journal choices for submitting authors. Co-hosting InCoB2013 with the second International Conference for Translational Bioinformatics (ICTBI) is in line with InCoB's support for the current trend in taking bioinformatics to the bedside, along with a systems approach to solving biological problems.Item Open Access Characterization of biochemical properties of an apurinic/apyrimidinic endonuclease from Helicobacter pylori(PLoS ONE, 2018-08-15) Turgimbayeva, Aigerim; Abeldenov, Sailau; Zharkov, Dmitry O.; Ishchenko, Alexander A.; Ramankulov, Yerlan; Saparbaev, Murat; Khassenov, BekbolatApurinic/apyrimidinic (AP) endonucleases play critical roles in the repair of abasic sites and strand breaks in DNA. Complete genome sequences of Helicobacter pylori reveal that this bacterial specie has a single AP endonuclease. An H. pylori homolog of Xth (HpXth) is a member of exonuclease III family, which is represented by Escherichia coli Xth. Currently, it remains unknown whether this single AP endonuclease has DNA repair activities similar to those of its counterpart in E. coli and other bacteria. We report that HpXth possesses efficient AP site cleavage, 3’-repair phosphodiesterase, and 3’-phosphatase activities but not the nucleotide incision repair function...Item Open Access Genetic Diversity of Brucella melitensis in Kazakhstan in Relation to World-Wide Diversity(FRONTIERS MEDIA SA, 2019-08-13) Shevtsova, Elena; Vergnaud, Gilles; Shevtsov, Alexandr; Shustov, Alexandr; Berdimuratova, Kalysh; Mukanov, Kasim; Syzdykov, Marat; Kuznetsov, Andrey; Lukhnova, Larissa; Izbanova, Uinkul; Filipenko, Maxim; Ramankulov, YerlanWe describe the genetic diversity of 1327 Brucella strains from human patients in Kazakhstan using multiple-locus variable-number tandem repeat (VNTR) analysis (MLVA). All strains were assigned to the Brucella melitensis East Mediterranean group and clustered into 16 MLVA11 genotypes, nine of which are reported for the first time. MLVA11 genotype 116 predominates (86.8%) and is present all over Kazakhstan indicating existence and temporary preservation of a "founder effect" among B. melitensis strains circulating in Central Eurasia. The diversity pattern observed in humans is highly similar to the pattern previously reported in animals. The diversity observed by MLVA suggested that the epidemiological status of brucellosis in Kazakhstan is the result of the introduction of a few lineages, which have subsequently diversified at the most unstable tandem repeat loci. This investigation will allow to select the most relevant strains for testing these hypotheses via whole genome sequencing and to subsequently adjust the genotyping scheme to the Kazakhstan epidemiological situation.Item Open Access Autoantibodies to tissue transglutaminase target epitopes dependent on residues in the N-terminal domain(Coeliac UK's Research Conference, 2017-03-24) Kozhakhmetova, A; Wyatt, R; Elvers, K; Emery, D; Williams, C; Annis, P; Lampasona, V; Gillespie, K; Williams, AINTRODUCTION: Tissue transglutaminase (tTG), is the main autoantigen of coeliac disease (CD). Specific tTG epitopes, including N-and C-terminal sites as well as the catalytic triad, have been reported to be targeted by autoantibodies in CD, but the findings are controversial. We aimed to confirm which of the tTG sites, catalytic core, C- or N-terminus, are critical for antibody binding as this could aid the design of more specific assays and inform studies of disease pathogenesis. METHODS: Plasmid DNA encoding human tTG was mutated at sites in the catalytic core (Cys277, His335, Asp358 to alanine), N- (Arg19, Glu153 to serine) and C-terminal domains (Met659 to serine) using PAGE-purified mutagenic primers. Antibody binding to a panel of 35S-labelled tTG mutant antigens synthesized in vitro was assessed by radioimmunoassay in sera from 111 TGA-positive individuals (mean age 40 years, range 1.1-80 years) out of 445 patients sent for measurement of CD-associated autoantibodies to the Cork University Hospital, Eire. Wilcoxon signed-ranks test (SPSS) was used for statistical analysis. RESULTS: Showed that single mutation of catalytic core amino acids C277A, D358A, H335A had little effect on the relative binding (RB) of antibodies to antigen compared with native tTG (median RB; p-values: 100%; 0.723, 93%; 6.1E-5, 106%; 0.019, respectively for each mutant, while the triple Cys277/His335/Asp358 mutation slightly decreased RB (85%; 3.7E-16). Single mutation of the N-terminal amino acids, Arg19 or Glu153, elicited significantly decreased RB in ≥90% of sera (66%; 4.2E-17, 76%; 1.0E-11, respectively), as well as for the double Arg19/Glu153 (48%; 3.1E-17) and triple Arg19/Glu153/Met659 (48%; 1.1E—15) mutants. Mutation of Met659 alone had a variable effect, decreasing binding in others (102%; 0.004). The combined Cys277/His335/Asp358 and Arg19/Glu153/Met659 tTG mutations reduced binding in 96% of sera (60%; 2.2E-19). DISCUSSION: The N-terminal domain of tTG involving amino acids Arg19 and Glu153 is important to the integrity of tTG autoantibody epitopes in CD. Simultaneous mutation of these two amino acids has the highest impact on antibody-binding to tTG, while modifying catalytic core previously reported as being important, had little effect on binding. Effect of C-terminal mutation is more variable. These findings suggest that a major epitope is located in the N-terminal, but additional regions of the antigen are likely to contribute to antibody-binding. Characterization of mechanisms and epitopes involved in anti-tTG autoimmunity is important for development of targeted therapeutic manipulations in CD patients or at-risk individuals.Item Open Access Type 1 Diabetes: Current Perspectives(Methods in Molecular Biology, 2016) Kozhakhmetova, A; Gillespie, KMType 1 diabetes, resulting from the autoimmune destruction of insulin producing islet beta cells is caused by genetic and environmental determinants. Recent studies agree that counterintuitively, the major genetic susceptibility factors are decreasing in frequency as the incidence of the condition increases. This suggests a growing role for environmental determinants but these have been difficult to identify and our understanding of gene/environment effects are limited. Individuals "at-risk" can be identified accurately through the presence of multiple islet autoantibodies and current efforts in type 1 diabetes research focus on improved biomarkers and strategies to prevent or reverse the condition through immunotherapy.Item Open Access A quarter of patients with type 1 diabetes have co-existing non-islet autoimmunity: the findings of a UK population-based family study.(Clinical and Experimental Immunology, 2018-03-24) Kozhakhmetova, A; Wyatt, RC; Caygill, C; Williams, C; Long, AE; Chandler, K; Aitken, RJ; Wenzlau, JM; Davidson, HW; Gillespie, KM; Williams, AJKIndividuals with type 1 diabetes (T1D) are at increased risk of coeliac disease (CD), autoimmune thyroiditis and autoimmune gastritis, but the absolute risks are unclear. The aim of this study was to investigate the prevalence of autoantibodies to tissue transglutaminase (TGA), thyroid peroxidase (TPOA) and gastric H+ /K+ -ATPase (ATPA) and their genetic associations in a well-characterized population-based cohort of individuals with T1D from the Bart's-Oxford family study for whom islet autoantibody prevalence data were already available. Autoantibodies in sera from 1072 patients (males/females 604/468; median age 11·8 years, median T1D duration 2·7 months) were measured by radioimmunoassays; HLA class II risk genotype was analysed in 973 (91%) using polymerase chain reaction with sequence specific primers (PCR-SSP). The prevalence of TGA (and/or history of CD), TPOA and ATPA in patients was 9·0, 9·6 and 8·2%, respectively; 3·1% had two or more autoantibodies. Females were at higher risk of multiple autoimmunity; TGA/CD were associated with younger age and TPOA with older age. ATPA were uncommon in patients under 5 years, and more common in older patients. Anti-glutamate decarboxylase autoantibodies were predictive of co-existing TPOA/ATPA. TGA/CD were associated with human leucocyte antigen (HLA) DR3-DQ2, with the DR3-DQ2/DR3-DQ2 genotype conferring the highest risk, followed by DR4-DQ8/DR4-DQ8. ATPA were associated with DR3-DQ2, DRB1*0404 (in males) and the DR3-DQ2/DR4-DQ8 genotype. TPOA were associated with the DR3-DQ2/DR3-DQ2 genotype. Almost one-quarter of patients diagnosed with T1D aged under 21 years have at least one other organ-specific autoantibody. HLA class II genetic profiling may be useful in identifying those at risk of multiple autoimmunity.Item Open Access A Scorpion Defensin BmKDfsin4 Inhibits Hepatitis B Virus Replication in Vitro(MDPI, 2016-04-27) Zeng, Zhengyang; Zhang, Qian; Hong, Wei; Xie, Yingqiu; Liu, Yun; Li, Wenxin; Wu, Yingliang; Cao, Zhijian; Markland, Frank S.Hepatitis B virus (HBV) infection is a major worldwide health problem which can cause acute and chronic hepatitis and can significantly increase the risk of liver cirrhosis and primary hepatocellular carcinoma (HCC). Nowadays, clinical therapies of HBV infection still mainly rely on nucleotide analogs and interferons, the usage of which is limited by drug-resistant mutation or side effects. Defensins had been reported to effectively inhibit the proliferation of bacteria, fungi, parasites and viruses. Here, we screened the anti-HBV activity of 25 scorpion-derived peptides most recently characterized by our group. Through evaluating anti-HBV activity and cytotoxicity, we found that BmKDfsin4, a scorpion defensin with antibacterial and Kv1.3-blocking activities, has a comparable high inhibitory rate of both HBeAg and HBsAg in HepG2.2.15 culture medium and low cytotoxicity to HepG2.2.15. Then, our experimental results further showed that BmKDfsin4 can dose-dependently decrease the production of HBV DNA and HBV viral proteins in both culture medium and cell lysate. Interestingly, BmKDfsin4 exerted high serum stability. Together, this study indicates that the scorpion defensin BmKDfsin4 also has inhibitory activity against HBV replication along with its antibacterial and potassium ion channel Kv1.3-blocking activities, which shows that BmKDfsin4 is a uniquely multifunctional defensin molecule. Our work also provides a good molecule material which will be used to investigate the link or relationship of its antiviral, antibacterial and ion channel–modulating activities in the future.Item Open Access CFD Modeling of Chamber Filling in a Micro- Biosensor for Protein Detection(Biosensors, 2017-10) Islamov, Meiirbek; Sypabekova, Marzhan; Kanayeva, Damira; Rojas-Solórzano, LuisTuberculosis (TB) remains one of the main causes of human death around the globe. The mortality rate for patients infected with active TB goes beyond 50% when not diagnosed. Rapid and accurate diagnostics coupled with further prompt treatment of the disease is the cornerstone for controlling TB outbreaks. To reduce this burden, the existing gap between detection and treatment must be addressed, and dedicated diagnostic tools such as biosensors should be developed. A biosensor is a sensing micro-device that consists of a biological sensing element and a transducer part to produce signals in proportion to quantitative information about the binding event. The micro-biosensor cell considered in this investigation is designed to operate based on aptamers as recognition elements against Mycobacterium tuberculosis secreted protein MPT64, combined in a microfluidic-chamber with inlet and outlet connections. The microfluidic cell is a miniaturized platform with valuable advantages such as low cost of analysis with low reagent consumption, reduced sample volume, and shortened processing time with enhanced analytical capability. The main purpose of this study is to assess the flooding characteristics of the encapsulated microfluidic cell of an existing micro-biosensor using Computational Fluid Dynamics (CFD) techniques. The main challenge in the design of the microfluidic cell lies in the extraction of entrained air bubbles, which may remain after the filling process is completed, dramatically affecting the performance of the sensing element. In this work, a CFD model was developed on the platform ANSYS-CFX using the finite volume method to discretize the domain and solving the Navier–Stokes equations for both air and water in a Eulerian framework. Second-order space discretization scheme and second-order Euler Backward time discretization were used in the numerical treatment of the equations. For a given inlet–outlet diameter and dimensions of an in-house built cell chamber, different inlet liquid flow rates were explored to determine an appropriate flow condition to guarantee an effective venting of the air while filling the chamber. The numerical model depicted free surface waves as promoters of air entrainment that ultimately may explain the significant amount of air content in the chamber observed in preliminary tests after the filling process is completed. Results demonstrated that for the present design, against the intuition, the chamber must be filled with liquid at a modest flow rate to minimize free surface waviness during the flooding stage of the chamber.Item Open Access Discovery and Characterization of an Endogenous CXCR4 Antagonist(Cell Reports, 2015-05-05) O., Zirafi; K-A., Kim; L., Ständker; K. B., Mohr; D., Sauter; A., Heigele; S. F., Kluge; E., Wiercinska; D., Chudziak; R., Richter; B., Moepps; P., Gierschik; V., Vas; H., Geiger; M., Lamla; T., Weil; T., Burster; A., Zgraja; F., Daubeuf; N., Frossard; Timo, Burster; Timo, BursterCXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPIX4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.Item Open Access Immune phenotypes predict survival in patients with glioblastoma multiforme(Journal of Hematology and Oncology, 2016-09-01) Mostafa, Haouraa; Pala, Andrej; Högel, Josef; Hlavac, Michal; Dietrich, Elvira; Westhoff, M. Andrew; Nonnenmacher, Lisa; Burster, Timo; Georgieff, Michael; Wirtz, C. Rainer; Schneider, E. MarionBackground: Glioblastoma multiforme (GBM), a common primary malignant brain tumor, rarely disseminates beyond the central nervous system and has a very bad prognosis. The current study aimed at the analysis of immunological control in individual patients with GBM. Methods: Immune phenotypes and plasma biomarkers of GBM patients were determined at the time of diagnosis using flow cytometry and ELISA, respectively. Results: Using descriptive statistics, we found that immune anomalies were distinct in individual patients. Defined marker profiles proved highly relevant for survival. A remarkable relation between activated NK cells and improved survival in GBM patients was in contrast to increased CD39 and IL-10 in patients with a detrimental course and very short survival. Recursive partitioning analysis (RPA) and Cox proportional hazards models substantiated the relevance of absolute numbers of CD8 cells and low numbers of CD39 cells for better survival. Conclusions: Defined alterations of the immune system may guide the course of disease in patients with GBM and may be prognostically valuable for longitudinal studies or can be applied for immune intervention.Item Open Access CK1δ in lymphoma: gene expression and mutation analyses and validation of CK1δ kinase activity for therapeutic application(Frontiers in Cell and Developmental Biology, 2015-02-20) Winkler, B.Sophia; Oltmer, Franziska; Richter, Julia; Bischof, Joachim; Xu, Pengfei; Burster, Timo; Leithäuser, Frank; Knippschild, UweThe prognosis of lymphoid neoplasms has improved considerably during the last decades. However, treatment response for some lymphoid neoplasms is still poor, indicating the need for new therapeutic approaches. One promising new strategy is the inhibition of kinases regulating key signal transduction pathways, which are of central importance in tumorigenesis. Kinases of the CK1 family may represent an attractive drug target since CK1 expression and/or activity are associated with the pathogenesis of malignant diseases. Over the last years efforts were taken to develop highly potent and selective CK1-specific inhibitor compounds and their therapeutic potential has now to be proved in pre-clinical trials. Therefore, we analyzed expression and mutational status of CK1δ in several cell lines representing established lymphoma entities, and also measured the mRNA expression level in primary lymphoma tissue as well as in non-neoplastic blood cells. For a selection of lymphoma cell lines we furthermore determined CK1δ kinase activity and demonstrated therapeutic potential of CK1-specific inhibitors as a putative therapeutic option in the treatment of lymphoid neoplasmsItem Open Access Lactoferrin Is an Allosteric Enhancer of the Proteolytic Activity of Cathepsin G(PLOS ONE, 2016-03-17) Eipper, Steffen; Steiner, Robin; Lesner, Adam; Sienczyk, Marcin; Palesch, David; Halatsch, Marc- Eric; Zaczynska, Ewa; Heim, Christopher; Hartmann, Marcus D.; Zimecki, Michal; Rainer Wirtz, Christian; Burster, TimoProtease-mediated degradation of proteins is critical in a plethora of physiological processes. Neutrophils secrete serine proteases including cathepsin G (CatG), neutrophile elastase (NE), and proteinase 3 (PR3) together with lactoferrin (LF) as a first cellular immune response against pathogens. Here, we demonstrate that LF increases the catalytic activity of CatG at physiological concentration, with its highest enhancing capacity under acidic (pH 5.0) conditions, and broadens the substrate selectivity of CatG. On a functional level, the enzymatic activity of CatG was increased in the presence of LF in granulocytederived supernatant. Furthermore, LF enhanced CatG-induced activation of platelets as determined by cell surface expression of CD62P. Consequently, LF-mediated enhancement of CatG activity might promote innate immunity during acute inflammation.Item Open Access Characterization of Legumain(Biological Chemistry, 2002-11) Schwarz, Gerold; Brandenburg, Jens; Reich, Michael; Burster, Timo; Driessen, Christoph; Kalbacher, HubertThe mammalian legumain, also called asparaginyl endopeptidase (AEP), is critically involved in the processing of bacterial antigens for MHC class II presentation. In order to investigate the substrate specificity of AEP in the P1’ position, we created a peptide library and digested it with purified pig kidney AEP. Digestion was less efficient only when proline was in the P1’ position. Maximum AEP activity was found in lysosomal fractions of different types of antigen presenting cells (APC). When the multiple sclerosis-associated autoantigen myelin basic protein (MBP) was digested with AEP, the immunodominant epitope 83 – 99 was destroyed. Myoglobin as an alternative substrate was AEP resistant. These results suggest an important, but not necessarily critical role for AEP in lysosomal antigen degradationItem Open Access Exogenous cathepsin G upregulates cell surface MHC class I molecules on immune and glioblastoma cells(Oncotarget, 2016-10-28) Giese, Madleen; Turiello, Nadine; Molenda, Nicole; Palesch, David; Meid, Annika; Schroeder, Roman; Basilico, Paola; Benarafa, Charaf; Halatsch, Marc-Eric; Zimecki, Michal; Westhoff, Mike-Andrew; Rainer Wirtz, Christian; Burster, TimoMajor histocompatibility complex (MHC) class I molecules present antigenic peptides to cytotoxic T cells. During an adaptive immune response, MHC molecules are regulated by several mechanisms including lipopolysaccharide (LPS) and interferon gamma (IFN-g). However, it is unclear whether the serine protease cathepsin G (CatG), which is generally secreted by neutrophils at the site of inflammation, might regulate MHC I molecules. We identified CatG, and to a higher extend CatG and lactoferrin (LF), as an exogenous regulator of cell surface MHC I expression of immune cells and glioblastoma stem cells. In addition, levels of MHC I molecules are reduced on dendritic cells from CatG deficient mice compared to their wild type counterparts. Furthermore, cell surface CatG on immune cells, including T cells, B cells, and NK cells triggers MHC I on THP-1 monocytes suggesting a novel mechanism for CatG to facilitate intercellular communication between infiltrating cells and the respective target cell. Subsequently, our findings highlight the pivotal role of CatG as a checkpoint protease which might force target cells to display their intracellular MHC I:antigen repertoireItem Open Access Regulation of Cathepsin G Reduces the Activation of Proinsulin-Reactive T Cells from Type 1 Diabetes Patients(PLoS ONE, 2011-08-05) Zou, Fang; Schafer, Nadja; Palesch, David; Brucken, Ruth; Beck, Alexander; Sienczyk, Marcin; Kalbacher, Hubert; Sun, ZiLin; Boehm, Bernhard O.; Burster, Timo; Herrath, Matthias G.Autoantigenic peptides resulting from self-proteins such as proinsulin are important players in the development of type 1 diabetes mellitus (T1D). Self-proteins can be processed by cathepsins (Cats) within endocytic compartments and loaded to major histocompatibility complex (MHC) class II molecules for CD4+ T cell inspection. However, the processing and presentation of proinsulin by antigen-presenting cells (APC) in humans is only partially understood. Here we demonstrate that the processing of proinsulin by B cell or myeloid dendritic cell (mDC1)-derived lysosomal cathepsins resulted in several proinsulin-derived intermediates. These intermediates were similar to those obtained using purified CatG and, to a lesser extent, CatD, S, and V in vitro. Some of these intermediates polarized T cell activation in peripheral blood mononuclear cells (PBMC) from T1D patients indicative for naturally processed T cell epitopes. Furthermore, CatG activity was found to be elevated in PBMC from T1D patients and abrogation of CatG activity resulted in functional inhibition of proinsulin-reactive T cells. Our data suggested the notion that CatG plays a critical role in proinsulin processing and is important in the activation process of diabetogenic T cells.Item Open Access Effects of a Single Escape Mutation on T Cell and HIV-1 Co-adaptation(Cell Reports, 2016-06-07) Sun, Xiaoming; Shi, Yi; Akahoshi, Tomohiro; Fujiwara, Mamoru; Gatanaga, Hiroyuki; Schönbach, Christian; Kuse, Nozomi; Appay, Victor; Gao, George F.; Oka, Shinichi; Takiguchi, Masafumi; Xiaoming, SunSummary The mechanistic basis for the progressive accumulation of Y135F Nef mutant viruses in the HIV-1-infected population remains poorly understood. Y135F viruses carry the 2F mutation within RW8 and RF10, which are two HLA-A∗24:02-restricted superimposed Nef epitopes recognized by distinct and adaptable CD8+ T cell responses. We combined comprehensive analysis of the T cell receptor repertoire and cross-reactive potential of wild-type or 2F RW8- and RF10-specific CD8+ T cells with peptide-MHC complex stability and crystal structure studies. We find that, by affecting direct and water-mediated hydrogen bond networks within the peptide-MHC complex, the 2F mutation reduces both TCR and HLA binding. This suggests an advantage underlying the evolution of the 2F variant with decreased CD8+ T cell efficacy. Our study provides a refined understanding of HIV-1 and CD8+ T cell co-adaptation at the population level.Item Metadata only Extracellular vesicles in gastrointestinal cancer in conjunction with microbiota: On the border of Kingdoms(Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2017-12-01) Barteneva, Natasha S.; Baiken, Yeldar; Fasler-Kan, Elizaveta; Alibek, Kenneth; Wang, Sheng; Maltsev, Natalia; Ponomarev, Eugene D.; Sautbayeva, Zarina; Kauanova, Sholpan; Moore, Anna; Beglinger, Christoph; Vorobjev, Ivan A.; Natasha S., BartenevaAbstract Extracellular vesicle (EV) production is a universal feature of metazoan cells as well as prokaryotes (bMVs - bacterial microvesicles). They are small vesicles with phospholipid membrane carrying proteins, DNA and different classes of RNAs and are heavily involved in intercellular communication acting as vectors of information to target cells. For the last decade, the interest in EV research has exponentially increased though thorough studies of their roles in various pathologies that was not previously possible due to technical limitations. This review focuses on research evaluating the role of EV production in gastrointestinal (GI) cancer development in conjunction with GI microbiota and inflammatory diseases. We also discuss recent studies on the promising role of EVs and their content as biomarkers for early diagnosis of GI cancers.The bMVs have also been implicated in the pathogenesis of GI chronic inflammatory diseases, however, possible role of bMVs in tumorigenesis remains underestimated. We propose that EVs from eukaryotic cells as well as from different microbial, fungi, parasitic species and edible plants in GI tract act as mediators of intracellular and inter-species communication, particularly facilitating tumor cell survival and multi-drug resistance.In conclusion, we suggest that matching sequences from EV proteomes (available from public databases) with known protein sequences of microbiome gut bacteria will be useful in identification of antigen mimicry between evolutionary conservative protein sequences. Using this approach we identified Bacteroides spp. pseudokinase with activation loop and homology to PDGFRα, providing a proof-of-concept strategy. We speculate that existence of microbial pseudokinase that ‘mimics’ PDGFRα may be related to PDGFRα and Bacteroides spp. roles in colorectal carcinogenesis that require further investigation.
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