31 results on '"Venkatarajan S. Mathura"'
Search Results
2. Plasma Lipidomic Profiling in a Military Population of Mild Traumatic Brain Injury and Post-Traumatic Stress Disorder with Apolipoprotein E ɛ4–Dependent Effect
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Scott Ferguson, Tanja Emmerich, Hannah Montague, Justin Martin, Robert Pelot, Gogce Crynen, Alex Bishop, Fiona Crawford, Laila Abdullah, John Phillips, Helena Chaytow, Jon Reed, James E. Evans, Michael Mullan, Michael N. Dretsch, Ghania Ait-Ghezala, and Venkatarajan S. Mathura
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Adult ,Male ,0301 basic medicine ,Apolipoprotein E ,medicine.medical_specialty ,Traumatic brain injury ,Apolipoprotein E4 ,Population ,Comorbidity ,Severity of Illness Index ,behavioral disciplines and activities ,Stress Disorders, Post-Traumatic ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,mental disorders ,Severity of illness ,medicine ,Humans ,Young adult ,education ,Brain Concussion ,Phospholipids ,education.field_of_study ,Traumatic stress ,medicine.disease ,Cross-Sectional Studies ,Military Personnel ,030104 developmental biology ,Neurology (clinical) ,Psychology ,030217 neurology & neurosurgery ,Psychological trauma ,Clinical psychology - Abstract
In the military population, there is high comorbidity between mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) due to the inherent risk of psychological trauma associated with combat. These disorders present with long-term neurological dysfunction and remain difficult to diagnose due to their comorbidity and overlapping clinical presentation. Therefore, we performed cross-sectional analysis of blood samples from demographically matched soldiers (total, n = 120) with mTBI, PTSD, and mTBI+PTSD and those who were considered cognitively and psychologically normal. Soldiers were genotyped for apolipoprotein E (APOE) ɛ4, and phospholipids (PL) were examined using liquid chromatography/mass spectrometry analysis. We observed significantly lower levels of several major PL classes in TBI, PTSD, and TBI+PTSD, compared with controls. PTSD severity analysis revealed that significant PL decreases were primarily restricted to the moderate-to-severe PTSD group. An examination of the degree of unsaturation showed that monounsaturated fatty acid-containing phosphatidylcholine (PC) and phosphatidylinositol (PI) species were lower in the TBI and TBI+PTSD groups. However, these PLs were unaltered among PTSD subjects, compared with controls. Similarly, ether PC (ePC) levels were lower in PTSD and TBI+PTSD subjects, relative to controls. Ratios of arachidonic acid (AA) to docosahexaenoic acid (DHA)-containing species were significantly decreased within PC and phosphatidylethanolamine (PE) classes. APOE ɛ4 (+) subjects exhibited higher PL levels than their APOE ɛ4 (-) counterparts within the same diagnostic groups. These findings suggest that PL profiles, together with APOE genotyping, could potentially aid to differentiate diagnosis of mTBI and PTSD and warrant further validation. In conclusion, PL profiling may facilitate clinical diagnosis of mTBI and PTSD currently hindered by comorbid pathology and overlapping symptomology of these two conditions.
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- 2016
3. Identification of Plasma Biomarkers of TBI Outcome Using Proteomic Approaches in an APOE Mouse Model
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Benjamin Katz, Venkatarajan S. Mathura, Benoit Mouzon, John P. Phillips, Michael Mullan, Fiona Crawford, Alex Bishop, Allen Roses, Vani Ganapathi, Scott Ferguson, Jon Reed, and Gogce Crynen
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Male ,Proteomics ,Apolipoprotein E ,Genetically modified mouse ,Traumatic brain injury ,Apolipoprotein E4 ,Quantitative proteomics ,Population ,Apolipoprotein E3 ,Mice, Transgenic ,Bioinformatics ,Plasma biomarkers ,Mice ,medicine ,Animals ,Humans ,education ,education.field_of_study ,Blood Proteins ,Recovery of Function ,Prognosis ,medicine.disease ,nervous system diseases ,Disease Models, Animal ,nervous system ,Brain Injuries ,Neurology (clinical) ,Psychology ,Biomarkers - Abstract
The current lack of diagnostic and prognostic biomarkers for traumatic brain injury (TBI) confounds treatment and management of patients and is of increasing concern as the TBI population grows. We have generated plasma proteomic profiles from mice receiving TBI by controlled cortical impact at either 1.3 mm or 1.8 mm depth, comparing these against those of sham injured-animals to identify plasma biomarkers specific to mild or severe TBI at 24 hours, 1 month, or 3 months post-injury. To identify possible prognostic biomarkers, we used apolipoprotein E (APOE)3 and APOE4 transgenic mice, which demonstrate relatively favorable and unfavorable outcomes respectively, following TBI. Using a quantitative proteomics approach (isobaric tagging for relative and absolute quantitation--iTRAQ) we have identified proteins that are significantly modulated as a function of TBI and also in response to the TBI*APOE genotype interaction, the latter representing potential prognostic biomarkers. These preliminary data clearly demonstrate plasma protein changes that are not only injury dependent but also interaction dependent. Importantly, these results demonstrate the presence of TBI-dependent and interaction-dependent plasma proteins at a 3-month time point, which is a considerable time post-injury in the mouse model, and will potentially be of significance for combat veterans receiving assessment at extended periods post-injury. Furthermore, our identification of clusters of functionally related proteins indicates disturbance of particular biological modules, which potentially increases their value beyond that of solitary biomarkers.
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- 2012
4. A 3D-QSAR model based screen for dihydropyridine-like compound library to identify inhibitors of amyloid beta (Aβ) production
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Venkatarajan S. Mathura, Michael Mullan, Daniel Paris, Corbin Bachmeier, and Nikunj Patel
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chemistry.chemical_classification ,Quantitative structure–activity relationship ,Training set ,biology ,business.industry ,Amyloid beta ,β-amyloid ,dihydropyridine ,In silico ,Dihydropyridine ,in silico screening ,Peptide ,General Medicine ,Computational biology ,Hypothesis ,Bioinformatics ,Alzheimer's Disease ,Bottle neck ,chemistry ,biology.protein ,Medicine ,Model set ,business ,medicine.drug ,3D-QSAR - Abstract
Abnormal accumulation of amyloid beta peptide (Aβ) is one of the hallmarks of Alzheimer's disease progression. Practical limitations such as cost , poor hit rates and a lack of well characterized targets are a major bottle neck in the in vitro screening of a large number of chemical libraries and profiling them to identify Aβ inhibitors. We used a limited set of 1,4 dihydropyridine (DHP)-like compounds from our model set (MS) of 24 compounds which inhibit Aβ as a training set and built 3D-QSAR (Three-dimensional Quantitative Structure-Activity Relationship) models using the Phase program (SchrOdinger, USA). We developed a 3D-QSAR model that showed the best prediction for Aβ inhibition in the test set of compounds and used this model to screen a 1,043 DHP-like small library set of (LS) compounds. We found that our model can effectively predict potent hits at a very high rate and result in significant cost savings when screening larger libraries. We describe here our in silico model building strategy, model selection parameters and the chemical features that are useful for successful screening of DHP and DHP-like chemical libraries for Aβ inhibitors.
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- 2010
5. Proteomic Analysis of Human Neuronal Cells Treated with the Gulf War Agent Pyridostigmine Bromide
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Venkatarajan S. Mathura, Gogce Kayihan, Jon Reed, Benoit Mouzon, Laila Abdullah, Fiona Crawford, and Michael Mullan
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Gel electrophoresis ,Two-dimensional gel electrophoresis ,Central nervous system ,Cell Biology ,Biology ,Pharmacology ,Gulf war ,Bioinformatics ,Proteomics ,Biochemistry ,Computer Science Applications ,Neuroblastoma cell ,Neuronal signaling ,medicine.anatomical_structure ,medicine ,Pyridostigmine Bromide ,Molecular Biology - Abstract
Gulf War Illness (GWI) is characterized by a wide array of symptomology, which is possibly linked to the prophylactic treatment with pyridostigmine bromide (PB) against neurotoxins. It is now hypothesized that the pathological origin of this multi-symptom illness lies within the central nervous system and is caused by irregular activation of neuronal signaling pathways. To investigate this possibility, a proteomic-based approach was applied to characterize cellular responses of neuronal cells to PB exposure. Protein extracts from cultured neuroblastoma cells treated with 700nM PB for 10 days, as well as extracts from control cells were separated using two-dimensional gel electrophoresis. Twenty two differentially-expressed proteins were identified by MALDI-TOF mass spectrometry (MS). Ingenuity Pathways Analysis (IPA) software was then used to determine the biological functions and canonical pathways associated with the PB-responsive proteins.
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- 2009
6. A Novel Physico-Chemical Property Based Model for Studying the Effects of Mutation on the Aggregation of Peptides
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Daniel Paris, Michael Mullan, and Venkatarajan S. Mathura
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chemistry.chemical_classification ,Mutation ,Protein Conformation ,Chemistry ,Muscles ,Point mutation ,Proteins ,General Medicine ,Structural Classification of Proteins database ,Protein aggregation ,medicine.disease_cause ,Models, Biological ,Biochemistry ,Acid Anhydride Hydrolases ,Amino acid ,Protein structure ,Structural Biology ,Linear regression ,medicine ,Humans ,Point Mutation ,Average Linkage Cluster Analysis ,Neural Networks, Computer ,Protein Multimerization - Abstract
Macromolecular events like protein aggregation are complex processes involving physico-chemical properties of their constituting residues. In this study, we used 5-dimensional physico-chemical property (PCP-descriptors) descriptors of amino acids, derived from 237 physico-chemical properties, to develop linear (LM) and neural network (NM) based regression models. We demonstrate their prediction performance in log values of aggregation rates (psi) for 15 human muscle acyl-phosphatase (AcP) mutants. The correlation coefficient between the predicted and the observed psi-values of the point mutations by LM and NM was 0.81 (p-value
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- 2009
7. Potent anti-angiogenic motifs within the Alzheimer β-amyloid peptide
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Venkatarajan S. Mathura, Amita Quadros, Steven Brem, Michael Mullan, Marguerite Wotoczek-Obadia, Nikunj Patel, Vincent Laporte, and Daniel Paris
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Umbilical Veins ,Amyloid ,Angiogenesis ,Amino Acid Motifs ,Angiogenesis Inhibitors ,Peptide ,Biology ,Alzheimer Disease ,In vivo ,Internal Medicine ,Animals ,Humans ,Corneal Neovascularization ,Senile plaques ,Cells, Cultured ,chemistry.chemical_classification ,Matrigel ,Amyloid beta-Peptides ,P3 peptide ,Brain ,Endothelial Cells ,Peptide Fragments ,In vitro ,Rats ,Cell biology ,Biochemistry ,chemistry ,Mutation ,Oligopeptides - Abstract
Abeta peptides are the major constituents of senile plaques and cerebrovascular deposits in the brains of patients with Alzheimer's disease. We have shown previously that Abeta1-40 and Abeta1-42 peptides are potently anti-angiogenic both in vitro and in vivo. The current study characterizes important sequences within the Abeta peptide that are required to exert its anti-angiogenic activity. We have used human umbilical vein endothelial cells to assess the anti-angiogenic activity of short fragments of Abetain vitro in a Matrigel network assay and in vivo in a rat corneal model of angiogenesis. The anti-angiogenic activity of these short peptide fragments is not related to effects on apoptosis or necrosis. Using normal and mutated peptide fragments, we show that the sequence VHHQKLVFF is sufficient to exhibit potent anti-angiogenic effects. This small peptide may therefore have clinical relevance as an anti-angiogenic agent.
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- 2008
8. Cocaine induced inflammatory response in human neuronal progenitor cells
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Tyler R. Hollen, Marcie Wood, Fiona Crawford, Deepak N. Kolippakkam, Venkatarajan S. Mathura, Freya Geall, Sarah E. Wilson, and Michael Mullan
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Microarray ,Inflammation ,Biology ,Biochemistry ,Cell biology ,Cellular and Molecular Neuroscience ,medicine.anatomical_structure ,Immune system ,Cell culture ,Gene expression ,Immunology ,Gene chip analysis ,medicine ,Neuron ,medicine.symptom ,Progenitor cell - Abstract
We have employed a genomic approach in homogenous cell culture to investigate the fundamental transcriptional responses which occur in neurons over time as a consequence of a single 30-min exposure to cocaine. Data from 24 Affymetrix microarrays, representing eight treatment groups, were analyzed by GeneChip Operating Software and then further mined by hierarchical clustering, anova, and Ingenuity Pathway Analysis software to examine known molecular pathways impacted by the observed transcriptional changes. For each time point under investigation, the data sets of genes exhibiting altered expression in treated cells compared with control were interrogated with a specific focus on differential expression of genes involved in immunomodulation and inflammation. The existing literature on the effects of cocaine in a diverse array of experimental paradigms demonstrates a significant modulation of inflammation and immune mechanisms, but these have typically been studies of chronic exposure in immune-competent cells. Our data show a time-dependent up-regulation of genes associated with pro-inflammatory and immune responses, peaking at 24 h as confirmed by all methods of analysis, suggesting a specific neuronal immunomodulatory response to acute cocaine exposure.
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- 2006
9. Model of Alzheimer’s disease amyloid-β peptide based on a RNA binding protein
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Venkatarajan S. Mathura, Amita Quadros, Michael Mullan, Ghania Ait-Ghezala, Daniel Paris, Deepak N. Kolippakkam, Claude-Henry Volmar, and Nikunj Patel
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Models, Molecular ,Protein Conformation ,Archaeal Proteins ,Molecular Sequence Data ,Biophysics ,Protein Data Bank (RCSB PDB) ,RNA-binding protein ,Peptide ,Biology ,Biochemistry ,Protein structure ,Sequence Analysis, Protein ,Computer Simulation ,Amino Acid Sequence ,Binding site ,Molecular Biology ,Peptide sequence ,Ribonucleoprotein ,chemistry.chemical_classification ,Amyloid beta-Peptides ,Binding Sites ,Sequence Homology, Amino Acid ,RNA-Binding Proteins ,RNA ,Cell Biology ,Ribonucleoproteins, Small Nuclear ,Models, Chemical ,chemistry ,Multiprotein Complexes ,Dimerization ,Protein Binding - Abstract
Although Alzheimer's Abeta peptide has been shown to form beta-sheet structure, a high-resolution molecular structure is still unavailable to date. A search for a sequence neighbor using Abeta(10-42) as the query in the Protein Data-Bank (PDB) revealed that an RNA binding protein, AF-Sm1 from Archaeoglobus fulgidus (PDB entry: 1i4k chain Z), shared 36% identical residues. Using AF-Sm1 as a template, we built a molecular model of Abeta(10-42) by applying comparative modeling methods. The model of Abeta(10-42) contains an antiparallel beta-sheet formed by residues 16-23 and 32-41. Hydrophobic surface constituted by residues 17-20 (LVFF) separates distinctly charged regions. Residues that interact with RNA in the AF-Sm1 crystal structure were found to be conserved in Abeta. Using a native gel we demonstrate for the first time that RNA can interact with Abeta and selectively retard the formation of fibrils or higher-order oligomers. We hypothesize that in a similar fashion to AF-Sm1, RNA interacts with Abeta in the beta-hairpin (beta-turn-beta) structure and prevents fibril formation.
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- 2005
10. Anti-angiogenic activity of the mutant Dutch Aβ peptide on human brain microvascular endothelial cells
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Daniel Paris, Venkatarajan S. Mathura, Nikunj Patel, Vincent Laporte, Michael Mullan, Ghania Ait-Ghezala, and Amita Quadros
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Models, Molecular ,Amyloid ,Angiogenesis ,Blotting, Western ,Biology ,Cellular and Molecular Neuroscience ,Morphogenesis ,medicine ,Cluster Analysis ,Humans ,Computer Simulation ,Molecular Biology ,Cells, Cultured ,Cell Aggregation ,Cell Proliferation ,Oligonucleotide Array Sequence Analysis ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,Neovascularization, Pathologic ,Wild type ,Brain ,Endothelial Cells ,Congo Red ,Cell migration ,Human brain ,medicine.disease ,Peptide Fragments ,In vitro ,Cell biology ,Endothelial stem cell ,medicine.anatomical_structure ,Mutation ,Immunology ,Endothelium, Vascular ,Cerebral amyloid angiopathy ,Signal Transduction - Abstract
Cerebral amyloid angiopathy is a common pathological feature of patients with Alzheimer's disease (AD) and it is also the hallmark of individuals with a rare autosomal dominant disorder known as hereditary cerebral hemorrhage with amyloidosis-Dutch type. We have shown previously that wild type A(beta) peptides are anti-angiogenic both in vitro and in vivo and could contribute to the compromised cerebrovascular architecture observed in AD. In the present study, we investigated the potential anti-angiogenic activity of the Dutch A(beta)(1-40) (E22Q) peptide. We show that compared to wild type A(beta), freshly solubilized Dutch A(beta) peptide more potently inhibits the formation of capillary structures induced by plating human brain microvascular endothelial cells onto a reconstituted basement membrane. Aggregated/fibrillar preparations of wild type A(beta) and Dutch A(beta) do not appear to be anti-angiogenic in this assay. The stronger anti-angiogenic activity of the Dutch A(beta) compared to wild type A(beta) appears to be related to the increased formation of low molecular weight A(beta) oligomers in the culture medium surrounding human brain microvascular endothelial cells. Using oligonucleotide microarray analysis of human brain microvascular endothelial cells, followed by a genome-scale computational analysis with the Ingenuity Pathways Knowledge Base, networks of genes affected by an anti-angiogenic dose of Dutch A(beta) were identified. This analysis highlights that several biological networks involved in angiogenesis, tumorigenesis, atherosclerosis, cellular migration and proliferation are disrupted in human brain microvascular endothelial cells exposed to Dutch A(beta). Altogether, these data provide new molecular clues regarding the pathological activity of Dutch A(beta) peptide in the cerebrovasculature.
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- 2005
11. Identification of a Zinc Finger Domain in the Human NEIL2 (Nei-like-2) Protein
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Venkatarajan S. Mathura, Sankar Mitra, Aditi Das, Lavanya Rajagopalan, Samuel J. Rigby, and Tapas K. Hazra
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Models, Molecular ,Amino Acid Motifs ,Blotting, Western ,Molecular Sequence Data ,Mutant ,chemistry.chemical_element ,Zinc ,Biology ,Arginine ,Biochemistry ,Mass Spectrometry ,DNA Glycosylases ,DNA-(Apurinic or Apyrimidinic Site) Lyase ,Escherichia coli ,Humans ,Histidine ,Amino Acid Sequence ,Cysteine ,Uracil ,Molecular Biology ,Zinc finger ,Sequence Homology, Amino Acid ,Circular Dichroism ,C-terminus ,Zinc Fingers ,DNA ,Cell Biology ,Lyase ,Zinc finger nuclease ,Molecular biology ,Protein Structure, Tertiary ,Oxygen ,RING finger domain ,chemistry ,DNA glycosylase ,Mutation ,Mutagenesis, Site-Directed ,Peptides ,Protein Binding - Abstract
The recently identified human NEIL2 (Nei-like-2) protein, a DNA glycosylase/AP lyase specific for oxidatively damaged bases, shares structural features and reaction mechanism with the Escherichia coli DNA glycosylases, Nei and Fpg. Amino acid sequence analysis of NEIL2 suggested it to have a zinc finger-like Nei/Fpg. However, the Cys-X2-His-X16-Cys-X2-Cys (CHCC) motif present near the C terminus of NEIL2 is distinct from the zinc finger motifs of Nei/Fpg, which are of the C4 type. Here we show the presence of an equimolar amount of zinc in NEIL2 by inductively coupled plasma mass spectrometry. Individual mutations of Cys-291, His-295, Cys-315, and Cys-318, candidate residues for coordinating zinc, inactivated the enzyme by abolishing its DNA binding activity. H295A and C318S mutants were also shown to lack bound zinc, and a significant change in their secondary structure was revealed by CD spectra analysis. Molecular modeling revealed Arg-310 of NEIL2 to be a critical residue in its zinc binding pocket, which is highly conserved throughout the Fpg/Nei family. A R310Q mutation significantly reduced the activity of NEIL2. We thereby conclude that the zinc finger motif in NEIL2 is essential for its structural integrity and enzyme activity.
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- 2004
12. Compression of functional space in HLA-A sequence diversity
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Meena Kishore Sakharkar, Venkatarajan S. Mathura, Adrian Eak H Png, Prasanna R. Kolatkar, Bing Zhao, Ee Chee Ren, and Pandjassarame Kangueane
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Models, Molecular ,Molecular Sequence Data ,Immunology ,Peptide ,Peptide binding ,Crystallography, X-Ray ,Major histocompatibility complex ,Compression (functional analysis) ,Functional space ,Humans ,Immunology and Allergy ,Amino Acid Sequence ,Amino Acids ,Allele ,Alleles ,Sequence (medicine) ,Genetics ,chemistry.chemical_classification ,Binding Sites ,HLA-A Antigens ,biology ,General Medicine ,HLA-A ,chemistry ,biology.protein ,Peptides ,Protein Binding - Abstract
The major histocompatibility complex (MHC) is highly polymorphic and more than 1500 human MHC alleles are known to date. These alleles do not bind to a given peptide with identical affinity. Although MHC alleles are functionally related, it is difficult to quantify the functional variation between them. Three-dimensional structures of known MHC-peptide (MHCp) complexes suggest that specific peptide residues bind selectively to functional pockets in the binding groove. From a set of known MHCp structures we identified 21 critical polymorphic functional residue positions (CPFRP) that significantly reduced functional pocket variability to just 189 among 212 HLA-A alleles. Interestingly 101 HLA-A alleles clustered into 29 clusters such that the six functional pockets formed by the CPFRPs are identical within the cluster.
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- 2003
13. Complementary proteomic approaches reveal mitochondrial dysfunction, immune and inflammatory dysregulation in a mouse model of Gulf War Illness
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Venkatarajan S. Mathura, Jon Reed, Zuchra Zakirova, Fiona Crawford, Lauren Horne, Michael Mullan, Ghania Ait-Ghezala, Samira Hassan, and Gogce Crynen
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Male ,Proteomics ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Clinical Biochemistry ,Pharmacology ,Biology ,Gulf war ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,mitochondrial dysfunction ,MS/MS ,medicine ,Animals ,Persian Gulf Syndrome ,Research Articles ,SIDL ,Inflammation ,Protein level ,Gulf War ,Mitochondria ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,iTRAQ ,Cytokines ,Inflammatory pathways ,Pyridostigmine Bromide ,030217 neurology & neurosurgery ,Function (biology) ,Research Article - Abstract
Purpose Long-term consequences of combined pyridostigmine bromide (PB) and permethrin (PER) exposure in C57BL6/J mice using a well-characterized mouse model of exposure to these Gulf War (GW) agents were explored at the protein level. Experimental design We used orthogonal proteomic approaches to identify pathways that are chronically impacted in the mouse CNS due to semiacute GW agent exposure early in life. These analyses were performed on soluble and membrane-bound protein fractions from brain samples using two orthogonal isotopic labeling LC-MS/MS proteomic approaches—stable isotope dimethyl labeling and iTRAQ. Results The use of these approaches allowed for greater coverage of proteins than was possible by either one alone and revealed both distinct and overlapping datasets. This combined analysis identified changes in several mitochondrial, as well as immune and inflammatory pathways after GW agent exposure. Conclusions and clinical relevance The work discussed here provides insight into GW agent exposure dependent mechanisms that adversely affect mitochondrial function and immune and inflammatory regulation. Collectively, our work identified key pathways which were chronically impacted in the mouse CNS following acute GW agent exposure, this may lead to the identification of potential targets for therapeutic intervention in the future. Long-term consequences of combined PB and PER exposure in C57BL6/J mice using a well-characterized mouse model of exposure to these GW agents were explored at the protein level. Expanding on earlier work, we used orthogonal proteomic approaches to identify pathways that are chronically impacted in the mouse CNS due to semiacute GW agent exposure early in life. These analyses were performed on soluble and membrane-bound protein fractions from brain samples using two orthogonal isotopic labeling LC-MS/MS proteomic approaches—stable isotope dimethyl labeling and iTRAQ. The use of these approaches allowed for greater coverage of proteins than was possible by either one alone and revealed both distinct and overlapping datasets. This combined analysis identified changes in several mitochondrial, as well as immune and inflammatory pathways after GW agent exposure. The work discussed here provides insight into GW agent exposure dependent mechanisms that adversely affect mitochondrial function and immune and inflammatory regulation at 5 months postexposure to PB + PER.
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- 2017
14. CliniProteus: A flexible clinical trials information management system
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Mahendiranath Rangareddy, Michael Mullan, Pankaj Gupta, and Venkatarajan S. Mathura
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Electronic data capture ,business.industry ,Test data generation ,computer.internet_protocol ,Data management ,Automatic identification and data capture ,clinical trial ,General Medicine ,Hypothesis ,XML ,Patient registration ,NET ,World Wide Web ,Clinical trial ,Management information systems ,Medicine ,eCRF ,business ,computer - Abstract
Clinical trials involve multi-site heterogeneous data generation with complex data input-formats and forms. The data should be captured and queried in an integrated fashion to facilitate further analysis. Electronic case-report forms (eCRF) are gaining popularity since it allows capture of clinical information in a rapid manner. We have designed and developed an XML based flexible clinical trials data management framework in .NET environment that can be used for efficient design and deployment of eCRFs to efficiently collate data and analyze information from multi-site clinical trials. The main components of our system include an XML form designer, a Patient registration eForm, reusable eForms, multiple-visit data capture and consolidated reports. A unique id is used for tracking the trial, site of occurrence, the patient and the year of recruitment. Availability http://www.rfdn.org/bioinfo/CTMS/ctms.html.
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- 2007
15. APDbase: Amino acid Physico-chemical properties Database
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Deepak Kolippakkam and Venkatarajan S. Mathura
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folding ,chemistry.chemical_classification ,amino acids ,function ,Information retrieval ,Database ,Sequence database ,Computer science ,homology ,Web Database ,General Medicine ,computer.software_genre ,Physico-chemical properties ,Amino acid ,Database index ,Protein sequencing ,chemistry ,Property value ,computer - Abstract
UNLABELLED Physico-chemical properties of amino acids can be used to study protein sequence profiles, folding and function. We collated 242 properties for the 20 naturally occurring amino acids and created a dataset. The dataset is available as a database named APDbase( Amino acid Physico-chemical properties Data base). The database can be queried using either key words describing physico-chemical properties or pre-assigned database index number. The database contains corresponding references for each property value and facilitates deposition of new property values for processing and inclusion in the database. AVAILABILITY The database is available for free at http://www.rfdn.org/bioinfo/APDbase.php.
- Published
- 2005
16. Proteomic CNS profile of delayed cognitive impairment in mice exposed to Gulf War agents
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Myles Mullan, Venkatarajan S. Mathura, Benoit Mouzon, John Phillips, Jon Reed, Scott Ferguson, Fiona Crawford, Alex Bishop, Michael Mullan, Ghania Ait-Ghezala, Gogce Crynen, and Laila Abdullah
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Central Nervous System ,Male ,Proteomics ,medicine.medical_specialty ,Insecticides ,Neurology ,Central nervous system ,Endocrine System ,Biology ,Anxiety ,Cellular and Molecular Neuroscience ,Mice ,Immune system ,medicine ,Endocrine system ,Animals ,Persian Gulf Syndrome ,Enzyme Inhibitors ,Permethrin ,Veterans ,Lipid metabolism ,Biological Transport ,medicine.disease ,Lipid Metabolism ,Astrogliosis ,medicine.anatomical_structure ,Immune System ,Immunology ,Acute Disease ,Etiology ,Molecular Medicine ,Pyridostigmine Bromide ,Cognition Disorders ,Psychomotor Performance - Abstract
Gulf War Illness (GWI) is a chronic multisymptom condition with a central nervous system (CNS) component, for which there is no treatment available. It is now believed that the combined exposure to Gulf War (GW) agents, including pyridostigmine bromide (PB) and pesticides, such as permethrin (PER), was a key contributor to the etiology of GWI. In this study, a proteomic approach was used to characterize the biomolecular disturbances that accompany neurobehavioral and neuropathological changes associated with combined exposure to PB and PER. Mice acutely exposed to PB and PER over 10 days showed an increase in anxiety-like behavior, psychomotor problems and delayed cognitive impairment compared to control mice that received vehicle only. Proteomic analysis showed changes in proteins associated with lipid metabolism and molecular transport in the brains of GW agent-exposed mice compared to controls. Proteins associated with the endocrine and immune systems were also altered, and dysfunction of these systems is a prominent feature of GWI. The presence of astrogliosis in the GW agent-exposed mice compared to control mice further suggests an immune system imbalance, as is observed in GWI. These studies provide a broad perspective of the molecular disturbances driving the late pathology of this complex illness. Evaluation of the potential role of these biological functions in GWI will be useful in identifying molecular pathways that can be targeted for the development of novel therapeutics against GWI.
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- 2011
17. Impaired orthotopic glioma growth and vascularization in transgenic mouse models of Alzheimer's disease
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Christopher Ganey, Venkatarajan S. Mathura, Nowel Ganey, Nikunj Patel, Michael Mullan, Vincent Laporte, Myles Mullan, Gi-Taek Yee, Daniel Paris, Susan F. Murphy, Steven Brem, Corbin Bachmeier, Magdalena Banasiak, and David Beaulieu-Abdelahad
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Genetically modified mouse ,Pathology ,medicine.medical_specialty ,Angiogenesis ,Mice, Transgenic ,Disease ,Biology ,Article ,Mice ,Alzheimer Disease ,Glioma ,Cell Line, Tumor ,Cricetinae ,medicine ,Dementia ,Animals ,Humans ,Cells, Cultured ,Matrigel ,Neovascularization, Pathologic ,Brain Neoplasms ,General Neuroscience ,Human brain ,medicine.disease ,Coculture Techniques ,Disease Models, Animal ,medicine.anatomical_structure ,Cancer research ,Endostatin ,Neoplasm Transplantation - Abstract
Alzheimer's disease (AD) is the most common form of dementia among the aging population and is characterized pathologically by the progressive intracerebral accumulation of β-amyloid (Aβ) peptides and neurofibrillary tangles. The level of proangiogenic growth factors and inflammatory mediators with proangiogenic activity is known to be elevated in AD brains which has led to the supposition that the cerebrovasculature of AD patients is in a proangiogenic state. However, angiogenesis depends on the balance between proangiogenic and antiangiogenic factors and the brains of AD patients also show an accumulation of endostatin and Aβ peptides which have been shown to be antiangiogenic. To determine whether angiogenesis is compromised in the brains of two transgenic mouse models of AD overproducing Aβ peptides (Tg APPsw and Tg PS1/APPsw mice), we assessed the growth and vascularization of orthotopically implanted murine gliomas since they require a high degree of angiogenesis to sustain their growth. Our data reveal that intracranial tumor growth and angiogenesis is significantly reduced in Tg APPsw and Tg PS1/APPsw mice compared with their wild-type littermates. In addition, we show that Aβ inhibits the angiogenesis stimulated by glioma cells when cocultured with human brain microvascular cells on a Matrigel layer. Altogether our data suggest that the brain of transgenic mouse models of AD does not constitute a favorable environment to support neoangiogenesis and may explain why vascular insults synergistically precipitate the cognitive presentation of AD.
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- 2010
18. Alzheimer's beta-amyloid peptide blocks vascular endothelial growth factor mediated signaling via direct interaction with VEGFR-2
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Ophelia Weeks, Daniel Paris, Corbin Bachmeier, David Beaulieu-Abdelahad, Venkatarajan S. Mathura, Nikunj Patel, Vincent Laporte, and Michael Mullan
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Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Angiogenesis ,medicine.medical_treatment ,Angiogenesis Inhibitors ,Mice, Transgenic ,Biology ,Biochemistry ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Mice ,Alzheimer Disease ,Cell Movement ,Internal medicine ,medicine ,Animals ,Humans ,Senile plaques ,Cells, Cultured ,Amyloid beta-Peptides ,Growth factor ,Kinase insert domain receptor ,Tyrosine phosphorylation ,Vascular Endothelial Growth Factor Receptor-2 ,Peptide Fragments ,Cell biology ,Vascular endothelial growth factor ,Endothelial stem cell ,Endocrinology ,chemistry ,Endothelium, Vascular ,Signal transduction ,Protein Binding ,Signal Transduction - Abstract
J. Neurochem. (2010) 112, 66–76. Abstract Beta-amyloid peptides (Aβ) are the major constituents of senile plaques and cerebrovascular deposits in the brains of Alzheimer’s disease patients. We have shown previously that soluble forms of Aβ are anti-angiogenic both in vitro and in vivo. However, the mechanism of the anti-angiogenic activity of Aβ peptides is unclear. In this study, we examined the effects of Aβ1–42 on vascular endothelial growth factor receptor 2 (VEGFR-2) signaling, which plays a key role in angiogenesis. Aβ inhibited VEGF-induced migration of endothelial cells, as well as VEGF-induced permeability of an in vitro model of the blood brain barrier. Consistently, exogenous VEGF dose-dependently antagonized the anti-angiogenic activity of Aβ in a capillary network assay. Aβ1–42 also blocked VEGF-induced tyrosine phosphorylation of VEGFR-2 in two types of primary endothelial cells, suggesting an antagonistic action of Aβ toward VEGFR-2 signaling in cells. Moreover, Aβ was able to directly interact with the extracellular domain of VEGFR-2 and to compete with the binding of VEGF to its receptor in a cell-free assay. Co-immunoprecipitation experiments confirmed that Aβ can bind VEGFR-2 both in vitro and in vivo. Altogether, our data suggest that Aβ acts as an antagonist of VEGFR-2 and provide a mechanism explaining the anti-angiogenic activity of Aβ peptides.
- Published
- 2009
19. Introduction to Algorithms
- Author
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Senthilkumar Radhakrishnan, Deepak Kolippakkam, and Venkatarajan S. Mathura
- Subjects
Sequence ,Artificial neural network ,Computer science ,business.industry ,Bayesian probability ,Decision tree ,Machine learning ,computer.software_genre ,Support vector machine ,Artificial intelligence ,Cluster analysis ,business ,Complex problems ,computer ,Selection (genetic algorithm) - Abstract
Computational methods are designed to solve complex problems systematically and efficiently. Classification and selection procedures are often used in biological sequence and other data analysis. This chapter provides an introduction to different methods like clustering, hypothesis -testing, and classification methods.
- Published
- 2008
20. Introduction to Proteomics
- Author
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Venkatarajan S. Mathura and Fai Poon
- Subjects
Proteome ,Identification (biology) ,Protein profile ,Computational biology ,Biology ,Peptide-mass fingerprint ,Proteomics ,Protein spot ,Organism - Abstract
Proteome is defined as the total set of proteins expressed in a given cell or biological sample at a given time. The study of proteome is termed “proteomics”. Proteomics research includes the separation, identification, qualitative, quantitative, and functional characterization of the entire protein profile of a given cell, tissue, and/or organism. In this chapter, we describe the processes of commonly used proteomics techniques like gel-based separation and mass-spectrometry.
- Published
- 2008
21. Biological Sequence Search and Analysis
- Author
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Venkatarajan S. Mathura
- Subjects
Computer science ,Sequence analysis ,Protein sequence analysis ,Computational biology ,Sequence motif ,Gene ,Sequence search ,Genomic databases ,Function (biology) ,Sequence (medicine) - Abstract
Protein and genomic sequence analyses helps in understanding the structure, function, and organization of cellular systems. Important features of genes include identifying promoter regions, protein-coding regions, and intron-exon boundaries. Protein sequence analysis involves identifying functional motifs and patterns. Sequence search tools help in identifying similar sequences in protein and genomic databases. Here, we will discuss bioinformatics tools that help in biological sequence searches and analyses.
- Published
- 2008
22. Introduction to Biological Systems
- Author
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Michael Mullan, Daniel Paris, Amita Quadros, Nikunj Patel, Claude-Henry Volmar, and Venkatarajan S. Mathura
- Subjects
chemistry.chemical_classification ,Cell signaling ,chemistry.chemical_compound ,Biochemistry ,Chemistry ,RNA ,Biological process ,DNA ,Macromolecule ,Amino acid - Abstract
Living organisms are composed of macromolecules like DNA, RNA, proteins, and carbohydrates that dictate various processes. This chapter provides a glimpse of biological macromolecules and their interplay resulting in biological process or pathways.
- Published
- 2008
23. Protein-Protein Interaction and Macromolecular Visualization
- Author
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Venkatarajan S. Mathura, Cui Zhanhua, Arun K. Ramani, and Pandjassarame Kangueane
- Subjects
Chemistry ,Docking (molecular) ,Theoretical methods ,A protein ,Computational biology ,Signal transduction ,Protein–protein interaction ,Macromolecule ,Visualization - Abstract
Large-scale prediction and understanding of protein-protein interaction is important to elucidate biological function. Protein interactions play a key role in signaling pathways, transportation, and other structural/functional roles in a cell. Several experimental and theoretical methods have been developed to predict a protein’s interacting partners. Protein-protein docking is also gaining importance. A brief introduction to visualization tools for proteins is provided here.
- Published
- 2008
24. Computer Programming Fundamentals and Concepts
- Author
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Venkatarajan S. Mathura, Deepak Kolippakkam, and Pankaj Gupta
- Subjects
Symbolic programming ,Computer science ,Programming language ,business.industry ,Interpreted language ,Computer programming ,computer.software_genre ,Inductive programming ,Open source ,Relational database management system ,Perl ,business ,computer ,Programming language theory ,computer.programming_language - Abstract
This chapter introduces programming methods and languages that help beginners to learn essentials of computer programming. Two interpreted languages: Perl and PHP are introduced with examples. A popular open source database, MySQL is also included. Additional web-pointers are provided.
- Published
- 2008
25. Biological Sequence Databases
- Author
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Meena Kishore Sakharkar, Pandjassarame Kangueane, and Venkatarajan S. Mathura
- Subjects
World Wide Web ,Sequence ,Biological data ,Sequence profiling tool ,Computer science ,End user ,Biological database ,Gateway (computer program) ,UniProt ,Dissemination - Abstract
Biological data available today surpasses information content in several fields. It is critical to logically organize and disseminate these contents to end users. In this chapter, we learn about biological databases that serve as the gateway for researchers.
- Published
- 2008
26. Protein Structure Prediction
- Author
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Venkatarajan S. Mathura, Yaoqi Zhou, and Hongyi Zhou
- Subjects
0303 health sciences ,Sequence ,Protein function ,Computer science ,LiveBench ,030303 biophysics ,Drug design ,MODELLER ,Protein structure prediction ,Data science ,03 medical and health sciences ,ComputingMethodologies_PATTERNRECOGNITION ,Functional annotation ,CASP ,030304 developmental biology - Abstract
Genomic projects have provided large number of sequence information. In order to obtain tangible benefit of this information, structural and functional annotation of the sequences is a must. Understanding the structural basis for protein function enables rational drug design and novel interventions for various diseases. This chapter describes protein-modeling packages and services that integrate various tools to facilitate rapid large-scale modeling of proteins.
- Published
- 2008
27. Diagnostic utility of APOE, soluble CD40, CD40L, and Abeta1-40 levels in plasma in Alzheimer's disease
- Author
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Laila Abdullah, Daniel Paris, Cheryl A. Luis, Venkatarajan S. Mathura, Julia Parrish, Benoit Mouzon, Michael Mullan, Claude-Henry Volmar, Ghania Ait-Ghezala, Fiona Crawford, Amita Quadros, Andrew P. Keegan, and Myles Mullan
- Subjects
Apolipoprotein E ,Amyloid ,Amyloid beta ,Immunology ,CD40 Ligand ,Disease ,Neuropsychological Tests ,Biochemistry ,Sensitivity and Specificity ,Proinflammatory cytokine ,Pathogenesis ,Apolipoproteins E ,Alzheimer Disease ,Immunology and Allergy ,Medicine ,Humans ,CD40 Antigens ,Molecular Biology ,Aged ,CD40 ,Amyloid beta-Peptides ,biology ,business.industry ,Hematology ,Peptide Fragments ,Peripheral ,biology.protein ,Female ,business ,Biomarkers - Abstract
A continuous inflammatory state is associated with Alzheimer's disease (AD) evidenced by an increase in proinflammatory cytokines around beta-amyloid (Abeta) deposits. In addition, functional loss of CD40L is shown to result in diminished Amyloid precursor proton (APP) processing and microglial activation, supporting a prominent role of CD40-CD40L in AD etiology. We therefore hypothesize that a peripheral increase in Abeta may result in corresponding increase of sCD40 and sCD40L further contributing to AD pathogenesis. We measured plasma Abeta, sCD40 and sCD40L levels in 73 AD patients and compared to 102 controls matched on general demographics. We demonstrated that Abeta(1-40), levels of sCD40 and sCD40L are increased in AD and declining MMSE scores correlated with increasing sCD40L, which in turn, correlated positively with Abeta(1-42). We then combined sCD40, sCD40L, Abeta and APOE and found that this biomarker panel has high sensitivity and specificity (90%) as a predictor of clinical AD diagnosis. Given the imminent availability of potentially disease modifying therapies for AD, a great need exists for peripheral diagnostic markers of AD. Thus, we present preliminary evidence for potential usefulness for combination of plasma sCD40, sCD40L along with Abeta(1-40) and APOE epsilon4 in improving the clinical diagnosis of AD.
- Published
- 2008
28. Genomic analysis of response to traumatic brain injury in a mouse model of Alzheimer's disease (APPsw)
- Author
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Ronald L. Hayes, Brandon Faza, Barbara O'Steen, Tao Fan, Marcie Wood, Fiona Crawford, Michael Mullan, Ghania Ait-Ghezala, Venkatarajan S. Mathura, Sarah E. Wilson, and Scott Ferguson
- Subjects
Genetically modified mouse ,Programmed cell death ,Traumatic brain injury ,Gene Expression ,Inflammation ,Mice, Transgenic ,Amyloid beta-Protein Precursor ,Mice ,Alzheimer Disease ,medicine ,Animals ,Molecular Biology ,Amyloid beta-Peptides ,Genome ,General Neuroscience ,Head injury ,Neurodegeneration ,medicine.disease ,Microarray Analysis ,nervous system diseases ,Disease Models, Animal ,Brain Injuries ,Immunology ,Disease Progression ,Neurology (clinical) ,Animal studies ,Alzheimer's disease ,medicine.symptom ,Psychology ,Neuroscience ,Developmental Biology - Abstract
Numerous studies have shown that the beta-amyloid peptide (Abeta) or beta-amyloid deposits impact many processes that can contribute to neurodegeneration, ranging from immune and inflammatory processes to cell death and apoptosis, processes characteristic of both Alzheimer's disease and head injury. Human and animal studies of traumatic brain injury (TBI) have shown that Abeta production is increased acutely following injury, and there is evidence for increased amyloid deposition and risk for Alzheimer's disease following TBI. Given the poorer outcome after injury observed both in transgenic mice overproducing Abeta, as well as in humans subjected to repetitive head injury, one may conclude that the presence of elevated brain levels of Abeta, whether endogenous or as a consequence of previous injury, exacerbates many of the deleterious processes triggered by TBI. We sought to test this hypothesis by examining the genomic response to injury in wild-type mice and in transgenic mice (APPsw) overexpressing and accumulating cerebral Abeta/beta-amyloid. Gene expression was investigated by microarray 24 h after controlled cortical impact (CCI) injury or sham injury in aged APPsw transgenic mice and wild-type controls. Stringent statistical analysis revealed differential expression of a total of 129 genes in the transgenic TBI vs. sham comparison and 119 genes in the wild-type TBI vs. sham comparison. Of these, only 28 genes were common to both comparisons, suggesting considerable differences in response to injury in the Alzheimer models compared to wild-type mice. We focused our analyses by creating a "genotype-dependent" data set of response to injury which contained the genes that were uniquely altered in response to injury in either wild-type or APPsw mice, as well as those which were significantly differently modulated following TBI in one genotype compared to the other. The cellular functions predicted to be influenced by these changes in gene expression thus indicate the adverse pathways triggered by increased levels of Abeta, and the potentially favorable (recovery) pathways which are activated in wild-type mice but suppressed when Abeta levels are high. The results show that the cellular functions most influenced by the cerebral Abeta levels following TBI include inflammation, immune response, and cell death, which suggest a particular vulnerability to head injury in the Alzheimer brain.
- Published
- 2007
29. Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease
- Author
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Fiona Crawford, Michael Mullan, Venkatarajan S. Mathura, Amita Quadros, Nikunj Patel, and Daniel Paris
- Subjects
Genetically modified mouse ,medicine.medical_specialty ,Neurology ,Amyloid ,business.industry ,Research ,General Neuroscience ,medicine.medical_treatment ,Transgene ,Immunology ,Inflammation ,Cytokine Expression Profile ,lcsh:RC346-429 ,Cellular and Molecular Neuroscience ,Slice preparation ,Cytokine ,medicine ,medicine.symptom ,business ,lcsh:Neurology. Diseases of the nervous system - Abstract
BackgroundInflammation is believed to play an important role in the pathology of Alzheimer's disease (AD) and cytokine production is a key pathologic event in the progression of inflammatory cascades. The current study characterizes the cytokine expression profile in the brain of two transgenic mouse models of AD (TgAPPsw and PS1/APPsw) and explores the correlations between cytokine production and the level of soluble and insoluble forms of Aβ.MethodsOrganotypic brain slice cultures from 15-month-old mice (TgAPPsw, PS1/APPsw and control littermates) were established and multiple cytokine levels were analyzed using the Bio-plex multiple cytokine assay system. Soluble and insoluble forms of Aβ were quantified and Aβ-cytokine relationships were analyzed.ResultsCompared to control littermates, transgenic mice showed a significant increase in the following pro-inflammatory cytokines: TNF-α, IL-6, IL-12p40, IL-1β, IL-1α and GM-CSF. TNF-α, IL-6, IL-1α and GM-CSF showed a sequential increase from control to TgAPPsw to PS1/APPsw suggesting that the amplitude of this cytokine response is dependent on brain Aβ levels, since PS1/APPsw mouse brains accumulate more Aβ than TgAPPsw mouse brains. Quantification of Aβ levels in the same slices showed a wide range of Aβ soluble:insoluble ratio values across TgAPPsw and PS1/APPsw brain slices. Aβ-cytokine correlations revealed significant relationships between Aβ1–40, 1–42 (both soluble and insoluble) and all the above cytokines that changed in the brain slices.ConclusionOur data confirm that the brains of transgenic APPsw and PS1/APPsw mice are under an active inflammatory stress, and that the levels of particular cytokines may be directly related to the amount of soluble and insoluble Aβ present in the brain suggesting that pathological accumulation of Aβ is a key driver of the neuroinflammatory response.
- Published
- 2005
30. Genomic regulation after CD40 stimulation in microglia: relevance to Alzheimer's disease
- Author
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Claude-Henry Volmar, Nikunj Patel, Vincent Laporte, Venkatarajan S. Mathura, Fiona Crawford, Amita Quadros, Daniel Paris, Deepak N. Kolippakkam, Michael Mullan, and Ghania Ait-Ghezala
- Subjects
Cytoplasm ,Amyloid beta ,CD40 Ligand ,Hyperphosphorylation ,Biology ,Models, Biological ,Cellular and Molecular Neuroscience ,Alzheimer Disease ,medicine ,Humans ,CD40 Antigens ,Molecular Biology ,Cells, Cultured ,Oligonucleotide Array Sequence Analysis ,Regulation of gene expression ,Cell Nucleus ,B-Lymphocytes ,Amyloid beta-Peptides ,Microglia ,Interleukin-6 ,Nucleic Acid Hybridization ,medicine.disease ,medicine.anatomical_structure ,Gliosis ,Gene Expression Regulation ,biology.protein ,Neuroglia ,Alzheimer's disease ,Signal transduction ,medicine.symptom ,Neuroscience ,Signal Transduction - Abstract
Key pathological processes in Alzheimer's disease (AD) include the accumulation of amyloid beta peptide (Abeta) which, in excess, triggers pathological cascades including widespread inflammation, partly reflected by chronic microglial activation. It has previously been suggested that CD40/CD40L interaction promotes AD like pathology in transgenic mice. Thus, amyloid burden, gliosis and hyperphosphorylation of tau are all reduced in transgenic models of AD lacking functional CD40L. We therefore hypothesized that cellular events leading to altered APP metabolism, inflammation and increased tau phosphorylation underlying these observations would be regulated at the genomic level. In the present report, we used the Affymetrix (GeneChip) oligonucleotide microarray U133A to gain insight into the global and simultaneous transcriptomic changes in response to microglia activation after CD40/CD40L ligation. As expected, regulation of elements of the NF-kappaB signaling, chemokine and B cell signaling pathways was observed. Taken together, our data also suggest that CD40 ligation in human microglia specifically perturbs many genes associated with APP processing.
- Published
- 2005
31. A multimeric model for murine anti-apoptotic protein Bcl-2 and structural insights for its regulation by post-translational modification.
- Author
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Venkatarajan S. Mathura, Kizhake V. Soman, Tushar K. Varma, and Werner Braun
- Subjects
PROTEINS ,MOLECULAR dynamics ,DYNAMICS ,DIMERS - Abstract
A monomeric model for murine antiapoptotic protein Bcl-2 was constructed by comparative modeling with the software suite MPACK (EXDIS/DIAMOD/FANTOM) using human Bcl-xL as a template. The monomeric model shows that murine Bcl-2 is an all a-helical protein with a central (helix 5) hydrophobic helix surrounded by amphipathic helices and an unstructured loop of 30 residues connecting helices 1 and 2. It has been previously shown that phosphorylation of Ser 70 located in this loop region regulates the anti-apoptotic activity of Bcl-2. Based on our current model, we propose that this phosphorylation may result in a conformational change that aids multimer formation. We constructed a model for the Bcl-2 homodimer based on the experimentally determined 3D structure of the Bcl-xL: Bad peptide complex. The model shows that it will require approximately a half turn in helix 2 to expose hydrophobic residues important for the formation of a multimer. Helices 5 and 6 of the monomeric subunit Bcl-2 have been proposed to form an ion-channel by associating with helices 5 and 6 of another monomeric subunit in the higher-order complex. In the multimeric model of Bcl-2, helices 5 and 6 of each subunit were placed distantly apart. From our model, we conclude that a global conformational change may be required to bring helices 5 and 6 together during ion-channel formation. Figure Hydrophobic interactions in the dimerization groove are shown. Helix 2' of monomer B interacts through residues V90, H91, L94, A97, G98, F101 and Y105 with the hydrophobic surface formed by residues in helices 3, 4, and 5 of the monomer A. Shown here is a lateral view of monomer A depicted in a surface model with hydrophobic regions in red. The backbone of the helix is shown using a neon representation in yellow and the interacting side chains are in blue. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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