Computational Biology Approach for Therapeutic Intervention of Alexander Disease by Post Transcriptional Gene Silencing

Alexander disease (AxD) primarily affects the white matter of the central nervous system (CNS). It is an astrogliopathy in which Astroglial cells involved in maintenance homeostasis and providing defence to the brain are affected. Therefore their dysfunction has been implicated in a number of neurological, neuropsychiatric and neurodegerative disorders. GFAP (Glial fibrillary acidic protein) is the major intermediate filament protein present in astrocytes whose heterozygous missense mutations have been reported to be a cause of AxD. In the absence of any effective therapeutic intervention of AxD, in the present study PTGS (Post transcriptional gene silencing) approach to knock down mutant gfap gene. Various mutations causing AxD were checked for their pathogenicity using various in silico tools and 13 mutations were shortlisted based on their pathogenicity and probability of occurrence. Thereafter siRNA were designed against the mutant genes to silence them and thereby preventing the accumulation of mutant gfap that causes the pathophysiology of AxD

In-silico design of an Epitope-based peptide vaccine: A Computational Biology Approach

Lymphocytic choriomeningitis, is a rodent-borne viral infectious disease caused by Lymphocytic choriomeningitis virus (LCMV), a member of the family Arenaviridae, that was initially isolated in 1933. Acquired postnatal infection ranges from asymptomatic to a brief, nonspecific flu-like illness to critical self-resolving neurological disease, predominantly consisting of aseptic meningitis or meningoencephalitis. This study was undertaken to design an epitope-based peptide vaccine against Lymphocytic choriomeningitis virus using a computational biology approach. Twenty four sequences of LCMV were retrieved from UniProt database and analyzed with various in silico tools. VaxiJen was used to identify immunogenic peptides and T-cell epitopes were analysed using NetCTL server to identify T-cell epitopes. Out of 15 immunogenic peptides analysed using NetCTL server, a conservancy of 64.28% amongst all epitopes was observed. The peptide sequence VVQNLDQLY, a non-allergen, was found to be a potent T-cell epitope that interacted with 28 human leukocyte antigens (HLAs) and its interaction with HLA-A*02:06 was studied using protein-protein docking analysis. The HLA allele and the epitope VVQNLDQLY were found to effectively interact with each other and this epitope may be used as a vaccine against LCMV. Thus immunoinformatics based approaches can be used to predict vaccine candidates against pathogens in a timely manner and usher us into an era of T-cell based novel vaccinomics approach

Investigation of Mutant GFAP Protein Associated with Alexander Disease and its Therapeutic Intervention: Structure Based Drug Design Approach

Systems Biology approach involves integration of experimental and computational research to understand complex biological systems. Alexander's Disease (AxD) was first described by W. S. Alexander in 1949, and is a rare, but often fatal neurological disorder that has been divided into three subtypes based on the age of onset: the infantile, juvenile and adult forms that are shown to be caused by mutations in the gfap gene. The infantile form, with onset between birth and about two years of age, is currently the most common form of the disease. The characteristic neuropathological feature of all forms of AxD is the presence of Rosenthal fibers. In present study, the mutant GFAP protein associated with AxD was investigated by predicting the structure of wild type and mutant GFAP protein. It was found that due to the reported single point mutation, the mutant protein adopted a left handed α-helix structure in sharp contrast to the predicted right handed α-helix of the wt GFAP indicating large conformational change which may be the cause of aggregation of GFAP forming Rosenthal Fibers. In the absence of any commercially available drug to alleviate the symptoms of AxD, the therapeutic intervention of mutant GFAP protein was done using structure based drug design approach. The drug dibutyryl cyclic AMP identified through data mining from STITCH 4.0 was found to be toxic and therefore its structural analogs were generated using GAUSSIAN 09. Each of the 20 structural analogs of dbcAMP were docked with mutant GFAP using Discovery Studio 2.5 and analysed for their toxicity potential using OSIRIS Property Explorer. Three structural analogs i.e. DBCM12, DBCM17 and DBCM20 were found to have favourable docking, druglikeness and did not pose any toxicity risk. These structural analogs identified may be further analysed for therapeutic intervention of AxD by their role in prevention of aggregation of mutant GFAP.

How to manage salinity in irrigated lands: a selective review with particular reference to irrigation in developing countries

Irrigation management / Irrigable land / Soil salinity / Water use efficiency / Soil degradation / Irrigated farming / Policy making / Developing countries

Error caused by carbon dioxide in determination of ammonium by direct steam distillation of tropical wetland rice soils

Abstract A study was made with eight Philippine wetland rice soils to quantify the possible error caused by the CO2 evolved during direct distillation of soil suspensions in aerobic and anaerobic conditions with MgO. The error caused by CO2 was eliminated by absorbing the ammonia distilled in H2SO4, which was gently boiled to derive off the CO2 absorbed. The possible error caused by CO2 was not eliminated when boric acid was used for absorbing ammonia. The difference in NH4 + values determined by using sulfuric acid and boric acid methods gave an estimate of the error caused by CO2. It was found that CO2 evolved caused negative error in the NH4 + values obtained using the direct distillation of soil suspensions with MgO in presence of KCl. The magnitude of error was higher and significant with anaerobic soil samples but this error was negligible with aerobic soils

The role of tolerant genotypes and plant nutrients in reducing acid-soil infertility in upland rice ecosystem: an appraisal

Acid-soil-related infertility is a major constraint in the humid tropical regions. Soil infertility problems result from low pH, aluminum toxicity, phosphorus deficiency, low silicon and low base saturation, and the interactions between various deficiencies and toxicities. Phosphorus (P) deficiency is identified as a major nutrient deficiency in acid upland soils; and not only are the soils are low in P but also the applied soluble P is rendered unavailable due to reactions with iron and aluminum oxides. Upland rice cultivars differ in tolerance for and adaptation to acid soil conditions. In this paper, recent research on the role of tolerant genotypes adapted to acid soil conditions and plant nutrients, especially P, in reducing acid soil infertility in upland rice is reviewed. Synergy between genetic tolerance and P nutrition seems critical for sustainable productivity enhancement

Direct and residual phosphorus effects on grain yield-phosphorus uptake relationships in upland rice on an ultisol in West Africa

Phosphorus (P) deficiency is a major constraint to crop production on highly weathered, low-activity clay soils in the humid zone of West Africa. Past research suggested a linear relationship between grain yield and P uptake over a range of fertilizer P applied to upland rice cultivars. However, there is lack of information on how these relationships are affected by the long-term fertilizer P effects, although such information is needed for developing P management strategies because phosphate fertilization effects last for several seasons. Results from a long-term field experiment (1993-1998) conducted to determine the response of four improved upland rice cultivars to fertilizer P (0, 45, 90, 135 and 180 kg P ha-1) applied only once in 1993 and to its residues in 1994, 1995, 1996 and 1998, were used to determine grain yield and P uptake relationships. The soil at the experimental site, in the humid forest zone of Côte d'Ivoire (West Africa), was an Ultisol with acidic pH and low in available P. Significant linear relationships (R varying between 0.796 and 0.956) were observed between grain yield and total P uptake for each of the crops grown during 1993-1998. The results indicate that P uptake based models can be used to determine P requirements of rice cultivars under direct and residual P

Effect of carbofuran on transformation of urea nitrogen in soil

THE effect of Carbofuran at 10 and 50 ppm of soil on transformation of urea nitrogen in a sandy loam (PH 7-7) was studied in laboratory. The insecticide had no effect on urea hydrolysis but moderately inhibited both conversion of NH4+ to N02- and N02- to N03-, the effect being pronounced at the higher rate but lasted upto 2 weeks only. The results 0'£ the study along with other evidences suggest that under normal field application rates, carbofuran may have little effect on the hydrolysis as well as nitrification of urea nitrogen in soils with pH in the alkaline rang

Soil and Plant Testing for Iron: An Appraisal

Iron (Fe) deficiency chlorosis in crops is common in high-pH calcareous soils. Soil and plant testing is routinely used for diagnosing iron (Fe) deficiency chlorosis in crops, with mixed results. This article presents an overview of the factors that influence soil and plant tissue testing results. It is clear that soil tests for Fe are dominantly influenced by soil pH, bicarbonate, and moisture regime rather soil test result per se. This is because the solubility of Fe is more regulated by soil pH and moisture regime. Plant tissue testing for Fe can complement the results of soil testing for Fe. But at times, especially in calcareous soils, total Fe in plant tissue is not related to Fe deficiency, but metabolically active Fe is better at diagnosing the occurrence of the disorder. A combined use of soil and plant tissue testing seems more helpful in diagnosing Fe deficiency chlorosis disorder in crops

Effects of parathion and malathion on transformations of urea and ammonium sulfate nitrogen in soils

A study of the effects of malathion and parathion applied at 10 and 50 g/g of soil on transformations of urea and (NH4)2SO4–N in a sandy loam showed that the insecticides retarded urea hydrolysis as well as nitrification of urea and (NH4)2SO4–N. At 50 parts/106 rate of the insecticides, inhibition of urea hydrolysis ranged from 44 to 61% after 0.5 week and from 7 to 21% after 3 weeks of application. The insecticides inhibited the conversion of NH4 + to NO2 – without appreciably affecting the subsequent oxidation of NO2 – to NO3 – –N. This resulted in accumulation of higher amounts of NH4 +–N in soil samples treated with ammonium sulfate or urea N. The results suggest that transformations of urea and NH4 + fertilizers in soils may be influenced by the amount of organophosphorus insecticide present and this may affect plant nutrition and fertilizer use