Ascariasis on screening colonoscopy.
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Biomedical subjects
Vishal Jain
Publications and source records attributed to Vishal Jain.
A phage antibody to the active site of human placental alkaline phosphatase with higher affinity to the enzyme-substrate complex.
Selection of specific antibodies from large repertoires is of importance in generating antibodies to specific structural determinants and in studying structure-function relationships. Alkaline phosphatase (AP) has several isozymes with various degrees of homology and a range of common synthetic substrates. We have previously reported the generation of isozyme specific anti-enzyme antibodies to an oncofetal antigen, placental alkaline phosphatase (PLAP) by using a specific uncompetitive inhibitor, L-Phe-Gly-Gly along with the substrate para-nitrophenyl phosphate (pNPP), to elute scFvs from a phage-displayed immunoglobulin library. These antibodies were directed to the active site and inhibited enzyme activity. An uncompetitive inhibitor acts by stabilizing the enzyme-substrate (ES) complex. In the present work, we report the characteristics of a clone VE5, selected by the same method. This clone has a higher binding affinity for ES complex than for enzyme alone. This is true for all the three isozymes (placental, bone and intestinal) tested. However, the other synthetic small molecular substrate, disodium phenyl phosphate inhibits phage binding. The clone possibly binds to the conserved structures of the active site of the AP isozymes and the higher affinity binding to AP-pNPP complex reflects the method of selection. Such anti-enzyme antibodies have a possible potential role in dissecting structure-function relationship of enzymatic antigens.
Alkaline Phosphatase↗
Bilateral facial paralysis: case presentation and discussion of differential diagnosis.
Bilateral facial paralysis is a rare condition and therefore represents a diagnostic challenge. We report the case of a 34-year-old healthy woman with sequential bilateral facial paralysis as a sole manifestation of sarcoidosis. She initially presented with an isolated left sided Bell's palsy without any symptoms to suggest alternative diagnoses. Within a month there was progression to peripheral facial paresis on the contra lateral side, prompting a diagnosis of Lyme disease. Her physical examination and chest x-ray did not reveal any clinical evidence of sarcoidosis. After failing to respond to an empiric trial of intravenous ceftriaxone for a presumptive diagnosis of Lyme disease, computed tomography scan of the chest was ordered which demonstrated bilateral hilar lymphadenopathy. Bronchoscopic biopsy confirmed a diagnosis of sarcoidosis. The patient then made a complete recovery on steroid therapy. We discuss the differential diagnosis of facial diplegia and focus on the clinical presentation, diagnosis and treatment of neurosarcoidosis.
Adult↗
Computational neurogenetic modelling: a pathway to new discoveries in genetic neuroscience.
The paper presents a methodology for using computational neurogenetic modelling (CNGM) to bring new original insights into how genes influence the dynamics of brain neural networks. CNGM is a novel computational approach to brain neural network modelling that integrates dynamic gene networks with artificial neural network model (ANN). Interaction of genes in neurons affects the dynamics of the whole ANN model through neuronal parameters, which are no longer constant but change as a function of gene expression. Through optimization of interactions within the internal gene regulatory network (GRN), initial gene/protein expression values and ANN parameters, particular target states of the neural network behaviour can be achieved, and statistics about gene interactions can be extracted. In such a way, we have obtained an abstract GRN that contains predictions about particular gene interactions in neurons for subunit genes of AMPA, GABAA and NMDA neuro-receptors. The extent of sequence conservation for 20 subunit proteins of all these receptors was analysed using standard bioinformatics multiple alignment procedures. We have observed abundance of conserved residues but the most interesting observation has been the consistent conservation of phenylalanine (F at position 269) and leucine (L at position 353) in all 20 proteins with no mutations. We hypothesise that these regions can be the basis for mutual interactions. Existing knowledge on evolutionary linkage of their protein families and analysis at molecular level indicate that the expression of these individual subunits should be coordinated, which provides the biological justification for our optimized GRN.
Algorithms↗
Targeting the active site of the placental isozyme of alkaline phosphatase by phage-displayed scFv antibodies selected by a specific uncompetitive inhibitor.
BACKGROUND: The isozymes of alkaline phosphatase, the tissue non-specific, intestinal and placental, have similar properties and a high degree of identity. The placental isozyme (PLAP) is an oncofetal antigen expressed in several malignancies including choriocarcinoma, seminoma and ovarian carcinoma. We had earlier attempted to isolate PLAP-specific scFv from a synthetic human immunoglobulin library but were unable to do so, presumably because of the similarity between the isozymes. In this work, we have employed a PLAP-specific uncompetitive inhibitor, L-Phe-Gly-Gly, to select isozyme specific scFvs. An uncompetitive inhibitor binds to the enzyme in the presence of substrate and stabilizes the enzyme-substrate complex. Several uncompetitive inhibitors have varying degrees of isozyme specificity for human alkaline phosphatase isozymes. A specific uncompetitive inhibitor would be able to unmask conformational differences between the otherwise very similar molecules. Also, such inhibitors would be directed to regions at/close to the active site of the enzyme. In this work, the library was first incubated with PLAP and the bound clones then eluted by incubation with L-Phe-Gly-Gly along with the substrate, para-nitro phenyl phosphate (pNPP). The scFvs were then studied with regard to the biochemical modulation of their binding, isozyme specificity and effect on enzyme activity. RESULTS: Of 13 clones studied initially, the binding of 9 was inhibited by L-Phe-Gly-Gly (with pNPP) and 2 clones were inhibited by pNPP alone. Two clones had absolute and 2 clones had partial specificity to PLAP. Two clones were cross-reactive with only one other isozyme. Three scFv clones, having an accessible His6-tag, were purified and studied for their modulation of enzyme activity. All the three scFvs inhibited PLAP activity with the kinetics of competitive inhibition. Cell ELISA could demonstrate binding of the specific scFvs to the cell surface expressed PLAP. CONCLUSION: The results demonstrate the biochemical modulation of scFv binding. Also, the scFvs bound to the active site and denied the access to the substrate. The selection strategy could generate specific anti-enzyme antibodies to PLAP that can potentially be used for targeting, for modulating enzyme activity in in vitro and in vivo and as probes for the active site. This strategy also has a general application in selecting antibodies from combinatorial libraries to closely related molecules and conformations.
Alkaline Phosphatase↗