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Biomedical subjects

Nikolai Petrovsky

Publications and source records attributed to Nikolai Petrovsky.

At least 19 recordsLinked to original sources
PubMed2006

PRED(TAP): a system for prediction of peptide binding to the human transporter associated with antigen processing.

BACKGROUND: The transporter associated with antigen processing (TAP) is a critical component of the major histocompatibility complex (MHC) class I antigen processing and presentation pathway. TAP transports antigenic peptides into the endoplasmic reticulum where it loads them into the binding groove of MHC class I molecules. Because peptides must first be transported by TAP in order to be presented on MHC class I, TAP binding preferences should impact significantly on T-cell epitope selection. DESCRIPTION: PRED(TAP) is a computational system that predicts peptide binding to human TAP. It uses artificial neural networks and hidden Markov models as predictive engines. Extensive testing was performed to valid the prediction models. The results showed that PRED(TAP) was both sensitive and specific and had good predictive ability (area under the receiver operating characteristic curve Aroc>0.85). CONCLUSION: PRED(TAP) can be integrated with prediction systems for MHC class I binding peptides for improved performance of in silico prediction of T-cell epitopes. PRED(TAP) is available for public use at [1].

Journal Article↗
PubMed2006

Novel human polysaccharide adjuvants with dual Th1 and Th2 potentiating activity.

Pure soluble, recombinant and synthetic antigens, despite their better tolerability, are unfortunately often much less immunogenic than live or killed whole organism vaccines. Thus, the move towards the development of safer subunit vaccines has created a major need for more potent adjuvants. In particular, there is an urgent need for adjuvants capable of boosting cellular (Th1) immunity but without unacceptable toxicity. The adjuvant activity of aluminium compounds (aluminium phosphate or hydroxide) was first described by Glenny and colleagues in 1926. Surprisingly, despite the description of over one hundred adjuvants in the scientific literature, alum remains the only adjuvant approved for human use in the USA. Unfortunately, alum has no effect on cellular immunity and is faced with increasing concerns regarding potential for cumulative aluminium toxicity. Why then has alum not been replaced in human vaccines? Despite the enormous number of candidates, potency has invariably been associated with increased toxicity, and this more than anything else has precluded their use, particularly in prophylactic vaccines where safety issues are paramount. Hence, there is a major unmet need for a safe efficacious adjuvant capable of boosting cellular plus humoral immunity. The extensive data on inulin-based adjuvants indicate that these are excellent candidates to replace alum as the adjuvant of choice for many vaccines. Particular advantages offered by inulin-based adjuvants is that they induce cellular in addition to humoral immunity and offer excellent safety, tolerability, ease of manufacture and formulation. Thus, adjuvants based on inulin have enormous potential for use in vaccines against both pathogens and cancer.

Adjuvants, Immunologic↗
PubMed2006

Fat aussie--a new Alström syndrome mouse showing a critical role for ALMS1 in obesity, diabetes, and spermatogenesis.

Mutations in the human ALMS1 gene are responsible for Alström syndrome, a disorder in which key metabolic and endocrinological features include childhood-onset obesity, metabolic syndrome, and diabetes, as well as infertility. ALMS1 localizes to the basal bodies of cilia and plays a role in intracellular trafficking, but the biological functions of ALMS1 and how these relate to the pathogenesis of obesity, diabetes, and infertility remain unclear. Here we describe a new mouse model of Alström syndrome, fat aussie, caused by a spontaneous mutation in the Alms1 gene. Fat aussie (Alms1 foz/foz) mice are of normal weight when young but, by 120 d of age, they become obese and hyperinsulinemic. Diabetes develops in Alms1 foz/foz mice accompanied by pancreatic islet hyperplasia and islet cysts. Female mice are fertile before the onset of obesity and metabolic syndrome; however, male fat aussie mice are sterile due to a progressive germ cell loss followed by an almost complete block of development at the round-to-elongating spermatid stage of spermatogenesis. In conclusion, Alms1 foz/foz mouse is a new animal model in which to study the pathogenesis of the metabolic and fertility defects of Alström syndrome, including the role of ALMS1 in appetite regulation, pathogenesis of the metabolic syndrome, pancreatic islet physiology, and spermatogenesis.

Animals↗
PubMed2006

Adaptive failure to high-fat diet characterizes steatohepatitis in Alms1 mutant mice.

The biochemical differences between simple steatosis, a benign liver disease, and non-alcoholic steatohepatitis, which leads to cirrhosis, are unclear. Fat aussie is an obese mouse strain with a truncating mutation (foz) in the Alms1 gene. Chow-fed female foz/foz mice develop obesity, diabetes, and simple steatosis. We fed foz/foz and wildtype mice a high-fat diet. Foz/foz mice developed serum ALT elevation and severe steatohepatitis with hepatocyte ballooning, inflammation, and fibrosis; wildtype mice showed simple steatosis. Biochemical pathways favoring hepatocellular lipid accumulation (fatty acid uptake; lipogenesis) and lipid disposal (fatty acid beta-oxidation; triglyceride egress) were both induced by high-fat feeding in wildtype but not foz/foz mice. The resulting extremely high hepatic triglyceride levels were associated with induction of mitochondrial uncoupling protein-2 and adipocyte-specific fatty acid binding protein-2, but not cytochrome P4502e1 or lipid peroxidation. In this model of metabolic syndrome, transition of steatosis to steatohepatitis was associated with hypoadiponectinemia, a mediator of hepatic fatty acid disposal pathways.

Adaptation, Physiological↗
PubMed2006

Bioinformatics for study of autoimmunity.

Recent years have witnessed an explosive growth in available biological data pertaining to autoimmunity research. This includes a tremendous quantity of sequence data (biological structures, genetic and physical maps, pathways, etc.) generated by genome and proteome projects plus extensive clinical and epidemiological data. Autoimmunity research stands to greatly benefit from this data so long as appropriate strategies are available to enable full access to and utilization of this data. The quantity and complexity of this biological data necessitates use of advanced bioinformatics strategies for its efficient retrieval, analysis and interpretation. Major progress has been made in development of specialized tools for storage, analysis and modeling of immunological data, and this has led to development of a whole new field know as immunoinformatics. With advances in novel high-throughput immunology technologies immunoinformatics is transforming understanding of how the immune system functions. This paper reviews advances in the field of immunoinformatics pertinent to autoimmunity research including databases, tools in genomics and proteomics, tools for study of B- and T-cell epitopes, integrative approaches, and web servers.

Allergy and Immunology↗
PubMed2006

PREDNOD, a prediction server for peptide binding to the H-2g7 haplotype of the non-obese diabetic mouse.

The non-obese diabetic (NOD) mouse is a widely used animal model for study of autoimmune diseases, in particular human type 1 diabetes mellitus (T1DM). Identification of the subset of peptides that bind MHC molecules comprising the H-2g7 haplotype of NOD mouse and thereby representing potential NOD T-cell epitopes is important for research into the pathogenesis and immunotherapy of T1DM. The H-2g7 haplotype comprises the MHC class-I molecules Kd and Db and a single class-II molecule I-Ag7. We have developed a prediction system, PREDNOD, for accurate identification of peptides that bind the MHC molecules constituting the H-2g7 haplotype. PREDNOD is accessible at http://antigen.i2r.a-star.edu.sg/Ag7.

Algorithms↗
PubMed2005

Immunome research.

Immunology research has been transformed in the post-genomics era, with high throughput molecular biology and information technologies taking an increasingly central role. This has led to the development of a new area of science termed "Immunomics", that encompasses genomic, high throughput and bioinformatic approaches to immunology. In recognition of the increasing importance of this field, Immunome Research is a new Open Access, online journal, that will publish cutting edge research across the field of Immunomics. Immunome Research will publish a wide range of article types including specialty immunology databases, immunology database tools, immunome epitope research, epitope analysis tools, high-throughput technologies (gene sequencing, microarrays, proteomics), white papers, mathematical and theoretical models, and prediction tools. Immunome Research is the official journal of the International Immunomics Society (IIMMS).

Editorial↗
PubMed2005

Assessment of cardiovascular disease risk factors and diabetes mellitus in Australian prisons: is the prisoner population unhealthier than the rest of the Australian population?

INTRODUCTION: This paper compares the prevalence estimates of diabetes and cardiovascular disease (CVD) risk factors in the Indigenous and non-Indigenous New South Wales (NSW) prisoner population in 1996 and 2001, and also compares the 2001 prevalence estimates with Australian population data. METHODS: In 1996 and 2001, 789 and 916 prisoners, respectively, in NSW underwent a face-to-face interview covering behavioural risks and physical and mental health. Weight, height and blood pressure were recorded and blood was taken for measurement of cholesterol and random blood sugar. RESULTS: The prevalence of hypertension, hypercholesterolaemia and smoking were lower in the 2001 prison survey as compared with the 1996 survey but the prevalence of smoking was extremely high in both the prison surveys (88% in 1996 and 79% in 2001). There were no differences in the age and sex-adjusted prevalence estimates for any condition except that the prison sample had a higher standardised morbidity ratio for angina than the AusDiab population. CONCLUSION: This study highlights the high prevalence of CVD risk factors, particularly in younger prisoners, when compared with the Australian non-prison population. IMPLICATIONS: Programs should be put in place to routinely screen for chronic disease conditions and to educate Australian prisoners regarding CVD and diabetes risk factors and their long-term management.

Adolescent↗
PubMed2005

Dexamethasone infusion testing in the diagnosis of Cushing's syndrome.

Cushing's syndrome and its various aetiologies is a markedly difficult diagnosis to make given its subtle signs, sometime cyclical nature, and the lack of a single definitive diagnostic test. Although a great variety of diagnostic tests have been developed to assist in the diagnosis, even with the best clinical acumen, biochemistry and medical imaging the diagnosis can remain elusive. The long low and high dose oral dexamethasone suppression test is cumbersome, costly and often requiring an extended inpatient stay. The utility of the dexamethasone suppression test would be greatly enhanced if it could be performed as a short outpatient procedure. In this study we sought to confirm and refine the clinical utility of the high dose 4 mg intravenous dexamethasone suppression test as an alternative diagnostic test for Cushing's syndrome. There were a total of 31 subjects: 8 patients with proven pituitary Cushing's disease, 3 with primary adrenal tumors, 10 with pseudo-Cushing's syndrome and 10 healthy controls. All subjects with pseudo-Cushing's syndrome suppress serum cortisol at +5 and at +24 hours. In subjects with pituitary Cushing's disease, 7 out of 8 (88%) had serum cortisol suppressed at +5 hours but rebounded at +24 hours to at least 70% of the original serum level. Primary adrenal tumors showed a pattern of non-suppression throughout. The 4 mg intravenous dexamethasone suppression test is excellent in ruling out pseudo-Cushing's syndrome. This test is much simpler and more convenient than the oral dexamethasone suppression test in confirming clinical suspicion of pituitary Cushing's disease.

Adrenal Gland Neoplasms↗
PubMed2005

Information technologies for vaccine research.

Vaccinology is a combinatorial science which studies the diversity of pathogens and the human immune system, and formulations that can modulate immune responses and prevent or cure disease. Huge amounts of data are produced by genomics and proteomics projects and large-scale screening of pathogen-host and antigen-host interactions. Current developments in computational vaccinology mainly support the analysis of antigen processing and presentation and the characterization of targets of immune response. Future development will also include systemic models of vaccine responses. Immunomics, the large-scale screening of immune processes which includes powerful immunoinformatic tools, offers great promise for future translation of basic immunology research advances into successful vaccines.

Animals↗
PubMed2004

Identification of "pathologs" (disease-related genes) from the RIKEN mouse cDNA dataset using human curation plus FACTS, a new biological information extraction system.

BACKGROUND: A major goal in the post-genomic era is to identify and characterise disease susceptibility genes and to apply this knowledge to disease prevention and treatment. Rodents and humans have remarkably similar genomes and share closely related biochemical, physiological and pathological pathways. In this work we utilised the latest information on the mouse transcriptome as revealed by the RIKEN FANTOM2 project to identify novel human disease-related candidate genes. We define a new term "patholog" to mean a homolog of a human disease-related gene encoding a product (transcript, anti-sense or protein) potentially relevant to disease. Rather than just focus on Mendelian inheritance, we applied the analysis to all potential pathologs regardless of their inheritance pattern. RESULTS: Bioinformatic analysis and human curation of 60,770 RIKEN full-length mouse cDNA clones produced 2,578 sequences that showed similarity (70-85% identity) to known human-disease genes. Using a newly developed biological information extraction and annotation tool (FACTS) in parallel with human expert analysis of 17,051 MEDLINE scientific abstracts we identified 182 novel potential pathologs. Of these, 36 were identified by computational tools only, 49 by human expert analysis only and 97 by both methods. These pathologs were related to neoplastic (53%), hereditary (24%), immunological (5%), cardio-vascular (4%), or other (14%), disorders. CONCLUSIONS: Large scale genome projects continue to produce a vast amount of data with potential application to the study of human disease. For this potential to be realised we need intelligent strategies for data categorisation and the ability to link sequence data with relevant literature. This paper demonstrates the power of combining human expert annotation with FACTS, a newly developed bioinformatics tool, to identify novel pathologs from within large-scale mouse transcript datasets.

Animals↗
PubMed2004

FREP: a database of functional repeats in mouse cDNAs.

The FREP database (http://facts.gsc.riken.go.jp/FREP/) contains 31 396 RepeatMasker-identified non-redundant variant repeat sequences derived from 16,527 mouse cDNAs with protein-coding potential. The repeats were computationally associated with potential effects on transcriptional variation, translation, protein function or involvement in disease to identify Functional REPeats (FREPs). FREPs are defined by the (i) occurrence of exon-exon boundaries in repeats, (ii) presence of polyadenylation sites in 3'UTR-located repeats, (iii) effect on translation, (iv) position in the protein- coding region or protein domains or (v) conditional association with disease MeSH terms. Currently the database contains 9261 (29.5%) inferred FREPs derived from 6861 (41.5%) mouse cDNAs. Integrated evidence of the functional assignments and dynamically generated sequence similarity search results support the exploration and annotation of functional, ancestral or taxon-specific repeats. Keyword and pre-selected feature searches (e.g. coding sequence-repeat or splice site-repeat relations) support intuitive database querying as well as the retrieval of repeat sequences. Integrated sequence search and alignment tools allow the analysis of known or identification of new functional repeat candidates. FREP is a unique resource for illuminating the role of transposons and repetitive sequences in shaping the coding part of the mouse transcriptome and for selecting the appropriate experimental model to study diseases with suspected repeat etiology contributions.

Animals↗
PubMed2004

Virtual models of the HLA class I antigen processing pathway.

Antigen recognition by cytotoxic CD8 T cells is dependent upon a number of critical steps in MHC class I antigen processing including proteosomal cleavage, TAP transport into the endoplasmic reticulum, and MHC class I binding. Based on extensive experimental data relating to each of these steps there is now the capacity to model individual antigen processing steps with a high degree of accuracy. This paper demonstrates the potential to bring together models of individual antigen processing steps, for example proteosome cleavage, TAP transport, and MHC binding, to build highly informative models of functional pathways. In particular, we demonstrate how an artificial neural network model of TAP transport was used to mine a HLA-binding database so as to identify HLA-binding peptides transported by TAP. This integrated model of antigen processing provided the unique insight that HLA class I alleles apparently constitute two separate classes: those that are TAP-efficient for peptide loading (HLA-B27, -A3, and -A24) and those that are TAP-inefficient (HLA-A2, -B7, and -B8). Hence, using this integrated model we were able to generate novel hypotheses regarding antigen processing, and these hypotheses are now capable of being tested experimentally. This model confirms the feasibility of constructing a virtual immune system, whereby each additional step in antigen processing is incorporated into a single modular model. Accurate models of antigen processing have implications for the study of basic immunology as well as for the design of peptide-based vaccines and other immunotherapies.

Animals↗
PubMed2004

Computational methods for prediction of T-cell epitopes--a framework for modelling, testing, and applications.

Computational models complement laboratory experimentation for efficient identification of MHC-binding peptides and T-cell epitopes. Methods for prediction of MHC-binding peptides include binding motifs, quantitative matrices, artificial neural networks, hidden Markov models, and molecular modelling. Models derived by these methods have been successfully used for prediction of T-cell epitopes in cancer, autoimmunity, infectious disease, and allergy. For maximum benefit, the use of computer models must be treated as experiments analogous to standard laboratory procedures and performed according to strict standards. This requires careful selection of data for model building, and adequate testing and validation. A range of web-based databases and MHC-binding prediction programs are available. Although some available prediction programs for particular MHC alleles have reasonable accuracy, there is no guarantee that all models produce good quality predictions. In this article, we present and discuss a framework for modelling, testing, and applications of computational methods used in predictions of T-cell epitopes.

Animals↗
PubMed2004

Vaccine adjuvants: current state and future trends.

The problem with pure recombinant or synthetic antigens used in modern day vaccines is that they are generally far less immunogenic than older style live or killed whole organism vaccines. This has created a major need for improved and more powerful adjuvants for use in these vaccines. With few exceptions, alum remains the sole adjuvant approved for human use in the majority of countries worldwide. Although alum is able to induce a good antibody (Th2) response, it has little capacity to stimulate cellular (Th1) immune responses which are so important for protection against many pathogens. In addition, alum has the potential to cause severe local and systemic side-effects including sterile abscesses, eosinophilia and myofascitis, although fortunately most of the more serious side-effects are relatively rare. There is also community concern regarding the possible role of aluminium in neurodegenerative diseases such as Alzheimer's disease. Consequently, there is a major unmet need for safer and more effective adjuvants suitable for human use. In particular, there is demand for safe and non-toxic adjuvants able to stimulate cellular (Th1) immunity. Other needs in light of new vaccine technologies are adjuvants suitable for use with mucosally-delivered vaccines, DNA vaccines, cancer and autoimmunity vaccines. Each of these areas are highly specialized with their own unique needs in respect of suitable adjuvant technology. This paper reviews the state of the art in the adjuvant field, explores future directions of adjuvant development and finally examines some of the impediments and barriers to development and registration of new human adjuvants.

Adjuvants, Immunologic↗
PubMed2004

Addison's disease presenting in four adolescents with type 1 diabetes.

Primary adrenocortical insufficiency (Addison's disease) is a potentially fatal condition that often develops insidiously and can be easily overlooked. Although rare in the general population, it is more common in patients with type 1 diabetes mellitus (T1DM). The combination of Addison's disease with T1DM and/or autoimmune thyroid disease is known as autoimmune polyendocrine syndrome type-2 (APS-2). T1DM commonly precedes the development of adrenocortical insufficiency in most patients with APS-2. We, in this study, present four cases of Addison's disease developing in adolescents with pre-existing T1DM. Risk factors for Addison's disease in this population include a history of other organ-specific autoimmunity, particularly thyroid, and a positive family history. In addition to the 'classic' Addisonian features, the development of unexplained recurrent hypoglycemia, reduction in total insulin requirement, improvement in glycemic control, or abnormal pigmentation should arouse suspicion of adrenocortical insufficiency. Adrenal antibodies have been proposed as a screening tool for Addison's disease in the T1DM population, but doubts remain about their specificity and sensitivity. The addition of specific HLA DRB1 subtyping has been proposed to improve predictive value.

Addison Disease↗
PubMed2004

Inulin-derived adjuvants efficiently promote both Th1 and Th2 immune responses.

There has been a recent resurgence of interest into new and improved vaccine adjuvants. This interest has been stimulated by the need for new vaccines to combat problematic pathogens such as SARS and HIV, and to counter potential bioterrorist attacks. A major bottleneck in vaccine development is the low immunogenicity of purified subunit or recombinant proteins, creating the need for safe human adjuvants with high potency. A major problem in the search for the ideal adjuvant is that adjuvants that promote cell-mediated (Th1) immunity (e.g. Freund's complete adjuvant) generally have unacceptable local or systemic toxicity that precludes their use in human vaccines. There is a need for a safe, non-toxic adjuvant that is able to stimulate both cell-mediated and humoral immunity. Inulin-derived adjuvants that principally stimulate the innate immune system through their ability to activate the alternative complement pathway have proven ability to induce both cellular and humoral immunity. With their excellent tolerability, long shelf-life, low cost and easy manufacture, they offer great potential for use in a broad range of prophylactic and therapeutic vaccines. Based on successful animal studies in a broad range of species, human trials are about to get underway to validate the use of inulin-based adjuvants in prophylactic vaccines against hepatitis B, malaria and other pathogens. If such trials are successful, then it is possible that inulin-derived adjuvants will one day replace alum as the adjuvant of choice in most human prophylactic vaccines.

Adjuvants, Immunologic↗