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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 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 Pathogen-driven gastrointestinal cancers: Time for a change in treatment paradigm?(Infectious Agents and Cancer, 2012) Aituov, Bauyrzhan; Duisembekova, Assem; Bulenova, Assel; Alibek, KennethThe regulation of cancerous tumor development is converged upon by multiple pathways and factors. Besides environmental factors, gastrointestinal (GI) tract cancer can be caused by chronic inflammation, which is generally induced by bacteria, viruses, and parasites. The role of these inducers in cancer development, cell differentiation and transformation, cell cycle deregulation, and in the expression of tumor-associated genes cannot be ignored. Although Helicobacter pylori activates many oncogenic pathways, particularly those in gastric and colorectal cancers, the role of viruses in tumor development is also significant. Viruses possess significant oncogenic potential to interfere with normal cell cycle control and genome stability, stimulating the growth of deregulated cells. An increasing amount of recent data also implies the association of GI cancers with bacterial colonization and viruses.This review focuses on host-cell interactions that facilitate primary mechanisms of tumorigenesis and provides new insights into novel GI cancer treatments.Item Metadata only Proposal for assessment of the antimicrobial efficacy of undiluted medical honey: Using a standardized phase 2/step 2 in vitro stainless steel disc carrier test model(Wound Medicine, 2013-07-01) Goerdt, Anna-Maria; Assadian, Ojan; Razavi, Behzad; Igelbrink-Holter, Dorothee; Simon, Arne; Hübner, Nils-Olaf; Partecke, Lars Ivo; Zhumadilova, Anara; Heidecke, Claus-Dieter; Kramer, Axel; Anna-Maria, GoerdtAbstract PurposeThe antimicrobial efficacy of medical honeys used for professional wound care was published previously. So far, all in vitro antimicrobial tests performed have been conducted using non-standardized methods and used diluted medical honey. A standardized, reproducible phase 2/step 2 in vitro disc carrier model is proposed allowing testing the antimicrobial efficacy of undiluted medical honey. MethodsUsing a standardized disc carrier model, the log10 Reduction Factor (RF) of undiluted medical honey was determined for MSSA, MRSA, VRE, Pseudomonas aeruginosa, and Candida albicans, with and without protein challenge. ResultsAn antimicrobial efficacy was observed after 1h. Without organic challenge, log10RF >5 within 24h was achieved for all tested microorganisms, except for Staphylococcus aureus (log10RF: 4.8/24h). Challenged with 10% bovine serum albumin, a similar pattern was observed at 24h. The most susceptible organism was C. albicans (log10RF of >3/5min). Over an exposure time of 48h, the tested medical honey's antimicrobial activity under protein challenge achieved log10RFs >6 for C. albicans and >7log10 for all tested bacteria. ConclusionsIt was demonstrated that the proposed standardized phase 2/step 2 in vitro stainless steel disc carrier test model is applicable for testing the antimicrobial activity of highly viscous and undiluted compounds such as medical honey. Undiluted medical honey exhibits a strong antimicrobial efficacy even under protein challenge after 1h, which increases to >6log10 for C. albicans, and >7log10 for Gr+ and Gr− bacteria.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 Metadata only Acceptability and tolerability of liquid versus gel and standard versus virucidal alcohol-based hand rub formulations among dental students(American Journal of Infection Control, 2013-11-01) Stauffer, Fritz; Griess, Marion; Pleininger, Gabriele; Zhumadilova, Anara; Assadian, Ojan; Fritz, StaufferBackgroundHand hygiene is effective to prevent the transmission of microorganisms in health care settings, but compliance remains low, even when easy access to hand cleaning agents is provided. ObjectiveFormulation of alcohol-based hand rub (ABHRs) may influence staff compliance to hand hygiene. The aim of this prospective longitudinal study (1 week) was to investigate possible differences of 4 different gel or liquid ABHR formulations, with or without virucidal claim among dental students. MethodsParticipants were randomly assigned to dental treatment cubicles, equipped with either a gel or a liquid based ABHRs, with our without a virucidal claim. Participants assessed the subjective acceptability and the tolerability of test formulations on their hands over a period of 1 week using the 14 item, 7-point Lickert scale World Health Organization questionnaire. ResultsAll tested ABHRs passed the subjective acceptability criteria of ≥50% above 4 for the items “color and fragrance” and for all other items of >75% above 4 and may be regarded as “good.” Significant differences were observed between the 2 gels but not between the 2 liquid ABHRs. For subjective skin tolerability, no significant difference was observed between the liquid formulations after 1 consecutive week of application. However, the difference between the 2 gels was highly significant. ConclusionVirucidal ABHR formulations may be better accepted and tolerated over prolonged periods by dental students than anticipated. The user acceptability of ABHRs depend more on the specific product's formula than its general category.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 Metadata only Histological and biochemical analysis of DNA damage after BNCT in rat model(Applied Radiation and Isotopes, 2014-06-01) Masutani, Mitsuko; Baiseitov, Diaz; Itoh, Tasuku; Hirai, Takahisa; Berikkhanova, Kulzhan; Murakami, Yasufumi; Zhumadilov, Zhaxybay; Imahori, Yoshio; Hoshi, Masaharu; Itami, Jun; Mitsuko, MasutaniAbstract To understand the mechanism of tumor cell death induced by boron neutron capture therapy (BNCT) and to optimize BNCT condition, we used rat tumor graft models and histological and biochemical analyses were carried out focusing on DNA damage response. Rat lymphosarcoma cells were grafted subcutaneously into male Wister rats. The rats with developed tumors were then treated with neutron beam irradiation 45min after injection of 330mg/kg bodyweight boronophenylalanine (10BPA) (+BPA) or saline control (–BPA). BNCT was carried out in the National Nuclear Center of the Republic of Kazakhstan (neutron flux: 1×109nvt/s, fluence: 6×1011nvt) with the presence of background γ-irradiation of 33Gy. 6 and 20h after BNCT treatment, tumors were resected, fixed and subjected to immunohistochemistry and biochemical analyses. Immunostaining of nuclei showed that double strand break (DSB) marker gamma H2AX staining was high in 20h/+BPA sample but not in 20h/–BPA samples. Poly(ADP-ribose), DSB and single strand break markers of DNA, also demonstrated this tendency. These two markers were observed at low levels in unirradiated tissues or 6h after BNCT either under −BPA and +BPA conditions. HMGB1 level increased in 6h/+BPA but not in 6h/−BPA or 20h/+BPA samples. The persistent staining of γH2AX and poly(ADP-ribose) in +BPA group suggests accumulated DSB damage after BNCT. The early HMGB1 upregulation and γH2AX and poly(ADP-ribose) observed later might be the markers for monitoring the DNA damage induced by BNCT.Item Open Access InCoB2014: Bioinformatics to tackle the data to knowledge challenge(BMC Bioinformatics, 2014-12-08) Ranganathan, Shoba; Tan, Tin Wee; Schönbach, ChristianSince 2006, the International Conference on Bioinformatics (InCoB) has been publishing selected papers in BMC Bioinformatics. Papers within the scope of the journal from the 13th InCoB July 31-2 August, 2014 in Sydney, Australia have been compiled in this supplement. These span protein and proteome informatics, structural bioinformatics, software development and bioimaging to pharmacoinformatics and disease informatics, representing the breadth of bioinformatics research in the Asia-Pacific.Item Open Access Computational and Bioinformatics Techniques for Immunology(BioMed Research International, 2014-12-31) Pappalardo, Francesco; Brusic, Vladimir; Castiglione, Filippo; Schönbach, ChristianItem 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 Advances in Computational Immunology(Journal of Immunology Research, 2015) Pappalardo, Francesco; Brusic, Vladimir; Pennisi, Marzio; Zhang, GuanglanItem 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 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 Metadata only Genetic diversity of Brucella abortus and Brucella melitensis in Kazakhstan using MLVA-16(Infection, Genetics and Evolution, 2015-08-01) Shevtsov, Alexandr; Ramanculov, Erlan; Shevtsova, Elena; Kairzhanova, Alma; Tarlykov, Pavel; Filipenko, Maxim; Dymova, Maya; Abisheva, Gulzada; Jailbekova, Aygul; Kamalova, Dinara; Chsherbakov, Andrei; Tulegenov, Samat; Akhmetova, Assel; Sytnik, Igor; Karibaev, Talgat; Mukanov, Kasim; Alexandr, ShevtsovAbstract Brucellosis is an endemic disease in Central Asia characterized by high infection rates in humans and animals. Currently, little is known about the genetic diversity of Brucella spp. circulating in the region, despite the high prevalence of brucellosis. This study aimed to analyze the genetic diversity of Brucella melitensis and Brucella abortus strains circulating in the Republic of Kazakhstan. We genotyped 128 B. melitensis and 124 B. abortus strains collected in regions with the highest prevalence of brucellosis. Genotyping was performed using multi-locus variable-number tandem-repeat analysis (MLVA). Analysis of a subset of 8 loci (MLVA-8) of 128 B. melitensis strains identified genotypes 42 (n=108), 43 (n=2), and 63 (n=19) related to the ‘East Mediterranean’ group. An MLVA-16 assay sorted 128 B. melitensis strains into 25 different genotypes. Excluding one variable locus, MLVA-15 of B. melitensis was distinct from strains originating in the Mediterranean region; however, 77% of them were identical to strains isolated in China. A minimum spanning tree for B. melitensis using MLVA-15 analysis clustered the local strains together with strains previously collected in China. MLVA-8 analysis of 124 B. abortus strains identified them as genotype 36, suggesting Eurasian distribution of this lineage. Complete MLVA-16 assay analysis clustered the strains into five genotypes, revealing little diversity of B. abortus when compared on the global scale. A minimum spanning tree for B. abortus obtained using MLVA-15 analysis clustered the 2 most prevalent genotypes (n=117) together with strains previously collected in China. Thus, MLVA analysis was used to characterize 252 strains of Brucella collected in Kazakhstan. The analysis revealed genetic homogeneity among the strains. Interestingly, identical MLVA-15 profiles were found in seemingly unrelated outbreaks in China, Turkey, and Kazakhstan. Further analysis is needed for better understanding of the epidemiology of brucellosis in Asia.Item Open Access GIW and InCoB are advancing bioinformatics in the Asia-Pacific(BMC Bioinformatics, 2015-12-18) Schönbach, Christian; Horton, Paul; Yiu, Siu Ming; Tan, Tin Wee; Ranganathan, ShobaGIW/InCoB2015 the joint 26th International Conference on Genome Informatics (GIW) and 14th International Conference on Bioinformatics (InCoB) held in Tokyo, September 9-11, 2015 was attended by over 200 delegates. Fifty-one out of 89 oral presentations were based on research articles accepted for publication in four BMC journal supplements and three other journals. Sixteen articles in this supplement and six articles in the BMC Systems Biology GIW/InCoB2015 Supplement are covered by this introduction. The topics range from genome informatics, protein structure informatics, image analysis to biological networks and biomarker discovery.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 Restricted Oral administration of chitosan/DNA nanoparticles containing DNA coding for FVIII and FC IgG fragment or IL-10 for the modulation of immune responses to FVIII in hemophilia mice(Nazarbayev University School of Science and Technology, 2016) Yerkesh, ZhadyraHemophilia A is an X-linked bleeding disorder, which occurs due to deficiency of clotting protein FVIII. Current treatment involves regular lifelong infusion of recombinant or plasma-derived FVIII protein, which is suboptimal, invasive and very expensive. One of the biggest challenges of the current therapy is the recognition of FVIII by immune system as a foreign substance, leading to the development of neutralizing antibodies, which makes further administration of FVIII ineffective. Therefore, an alternative cost effective and safe treatment to Hemophilia A is highly desirable. We propose chitosan-mediated oral non-viral gene therapy as a safe and costeffective strategy for immune modulation in severe hemophilia A cases. Having a strong affinity for DNA and forming nanoparticles, chitosan-DNA complexes protect plasmid DNA fi-om degradation by the low pH envu-onment of the stomach and from nucleases in the GI tract; further, safe re-administration of nanoparticles is possible. We also propose to include in the plasmid DNA coding for the Fc fragment of IgG heavy chain region, which contains Tregitope sequences, T cell epitopes that specifically activate regulatory T cells or anti-inflammatory cytokine IL-10 that may modulate the immune response against FVIII protein. Therefore, it is hypothesized that orally administered chitosan/DNA nanoparticles will lead to clinically relevant amount of FVIII in the host without an immune response, providing long term, cost-effective and safe treatment for hemophilia A. For this study we aimed to: I) optimize nanoparticles in terms of effective gene expression in vitro; 2) treat hemophilic mice orally with chitosan nanoparticles containing DNA coding for FVIII and for immunomodulatory elements (Fc fragment of IgG and IL-10) to induce tolerance to FVIII. We found that the key factors contributing to the effectiveness of gene expression in chitosan/DNA nanoparticles are the type of chitosan, the charge ratio (N/P) and the DNA concentration. In vivo, the optimized nanoparticles containing FVIII+Fc DNA significantly decreased antibody formation specific to F V I I I in prophylactic group of mice, and in 4/6 mice receiving nanoparticles containing FVIII+IL-10. It is tempting to hypothesize that this strategy might also be extended to modulate immune responses to other antigens.Item Restricted Morphometric characteristics of cancer cells grown in embryonic microenvironment and under antiviral treatment(Nazarbayev University School of Science and Technology, 2016) Shaimerdenova, MadinaWe describe here that both embryonic microenvironment treatment and antiviral treatment have the potential to serve as effective factors in changing morphometric characteristics of two highly aggressive cancer cell lines, with proven capability to decrease viability of cancer cells, reduce amount of colonies formed after treatment, alter intracellular features of cell such as nucleus and cytoskeleton and diminish aldehyde dehydrogenase activity after treatmentItem Restricted Co-expression of FVIII with human IGG FC Fragment or mouse IL-10 in encapsulated G8 myoblast cells as a potential treatment of hemophilia A(Nazarbayev University School of Science and Technology, 2016) Kanketayeva, ZhansayaIn this master thesis study we have shown that recombination G8 myoblasts, encapsulated in alginate-PLL microcapsules can successfully secrete detectable levels of both Fc and IL-10 out of the capsules and sustain good viability, showing the potential of co-delivering FVIII by encapsulated cells.
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