Computational analysis of deleterious missense mutations in aspartoacylase that cause Canavan’s disease

In this work, the most detrimental missense mutations of aspartoacylase that cause Canavan??s disease were identified computationally and the substrate binding efficiencies of those missense mutations were analyzed. Out of 30 missense mutations, I-Mutant 2.0, SIFT and PolyPhen programs identified 22 variants that were less stable, deleterious and damaging respectively. Subsequently, modeling of these 22 variants was performed to understand the change in their conformations with respect to the native aspartoacylase by computing their root mean squared deviation (RMSD). Furthermore, the native protein and the 22 mutants were docked with the substrate NAA (N-Acetyl-Aspartic acid) to explain the substrate binding efficiencies of those detrimental missense mutations. Among the 22 mutants, the docking studies identified that 15 mutants caused lower binding affinity for NAA than the native protein. Finally, normal mode analysis determined that the loss of binding affinity of these 15 mutants was caused by altered flexibility in the amino acids that bind to NAA compared with the native protein. Thus, the present study showed that the majority of the substrate-binding amino acids in those 15 mutants displayed loss of flexibility, which could be the theoretical explanation of decreased binding affinity between the mutant aspartoacylases and NAA.     

Glaucoma Pred: Glaucoma prediction based on Myocilin genotype and phenotype information

Glaucoma is the second leading cause of blindness after cataract and is heterogeneous in nature. Employing a genetic approach for the detection of the diseased condition provides an advantage that the gene responsible for the disease can be identified by genetic test. The availability of predictive tests based on the published literature would provide a mechanism for early detection and treatment. The genotype and phenotype information could be a valuable source for predicting the risk of the disease. To this end, a web server has been developed, based on the genotype and phenotype of myocilin mutation, which were identified by familial linkage analysis and case studies. The proposed web server provides clinical data and severity index for a given mutation. The server has several useful options to help clinicians and researchers to identify individuals at a risk of developing the disease. Glaucoma Pred server is available at http://bioserver1.physics.iisc.ac.in/myocilin.     

The stability and oncogenic function of LIN28A are regulated by USP28

RNA-binding protein LIN28A is often highly expressed in human malignant tumors and is involved in tumor metastasis and poor prognosis. Knowledge about post-translational regulatory mechanisms governing LIN28A protein stability and function is scarce. Here, we investigated the role of ubiquitination and deubiquitination on LIN28A protein stability and report that LIN28A protein undergoes ubiquitination. Ubiquitin-specific protease 28 (USP28), a deubiquitinating enzyme, interacts with and stabilizes LIN28A protein to extend its half-life. USP28, through its deubiquitinating activity, antagonizes LIN28A protein turnover by reversing its proteasomal degradation. Our study describes the consequential impacts of USP28-mediated stabilization of LIN28A protein on enhancing cancer cell viability, migration and ultimately augmenting LIN28A-mediated tumor progression. Overall, our data suggest that a synergistic, combinatorial approach of targeting LIN28A with USP28 would contribute to effective cancer therapeutics.     

Molecular modifications of 2-arylidene-1-indanones leading to increased cytotoxic potencies

A series of 2-arylidene-1-indanones, 1, had been shown previously to display cytotoxic properties towards Molt 4/C8, CEM and L1210 cells. In the present study, two series of analogues of 1 were prepared namely various 2-arylidene-1,3-indandiones, 2, and chalcones, 3. In general, the potencies of compounds 2 and 3 were greater than the analogues bearing the same aryl substituents in series 1. Molecular modeling was undertaken in order to seek explanations for the variation in bioactivities.     

Interactions between proteins encoded within the human cytomegalovirus UL133-UL138 locus

We previously described a novel genetic locus within the ULb' region of the human cytomegalovirus (HCMV) genome that, while dispensable for replication in fibroblasts, suppresses replication in hematopoietic progenitors and augments replication in endothelial cells. This locus, referred to as the UL133-UL138 locus, encodes four proteins, pUL133, pUL135, pUL136, and pUL138. In this work, we have mapped the interactions among these proteins. An analysis of all pairwise interactions during transient expression revealed a robust interaction between pUL133 and pUL138. Potential interactions between pUL136 and both pUL133 and pUL138 were also revealed. In addition, each of the UL133-UL138 locus proteins self-associated, suggesting a potential to form higher-order homomeric complexes. As both pUL133 and pUL138 function in promoting viral latency in CD34(+) hematopoietic progenitor cells (HPCs) infected in vitro, we further focused on this interaction. pUL133 and pUL138 are the predominant complex detected when all proteins are expressed together and require no other proteins in the locus for their association. During infection, the interaction between pUL133 and pUL138 or pUL136 can be detected. A recombinant virus that fails to express both pUL133 and pUL138 exhibited a latency phenotype similar to that of viruses that fail to express either pUL133 or pUL138, indicating that these proteins function cooperatively in latency and do not have independent functions that additively contribute to HCMV latency. These studies identify protein interactions among proteins encoded by the UL133-UL138 locus and demonstrate an important interaction impacting the outcome of HCMV infection.     

Bio-reduction of Cr(VI) by exopolysaccharides (EPS) from indigenous bacterial species of Sukinda chromite mine, India

Chrome mining activity has contributed intensively towards pollution of hexavalent chromium around Sukinda Valley, Orissa, India. In an attempt to study the specific contribution of exopolysaccharides (EPS) extracted from indigenous isolates towards Cr(VI) reduction, three chromium (VI) tolerant strains were isolated from the effluent mining sludge. Based on the tolerance towards Cr(VI) and EPS production capacity, one of them was selected for further work. The taxonomic identity of the selected strain was confirmed to be Enterobacter cloacae (showing 98% similarity in BLAST search to E. cloacae) through 16S rRNA analysis. The EPS production was observed to increase with increasing Cr(VI) concentration in the growth medium, highest being 0.078 at 100?mg/l Cr(VI). The extracted EPS from Enterobacter cloacae SUKCr1D was able to reduce 31.7% of Cr(VI) at 10?mg/l concentration, which was relevant to the prevailing natural concentrations at Sukinda mine effluent sludge. The FT-IR spectral studies confirmed the surface chemical interactions of hexavalent chromium with EPS.     

New conformationally locked thioderivatives of mannose: synthesis, applications, and mechanistic studies

Tetrathiomolybdate has been used as an efficient sulfur-transfer reagent in the synthesis of a number of thiolevomannosan derivatives having an axial-rich 1C4 conformation. An unprecedented synthesis of a novel thioorthoester and its synthetic utility in glycosylation has been demonstrated. This is a general and efficient method for the synthesis of conformationally locked thiosugars.     

Effect of seaweed extracts on the growth and biochemical constituents of Vigna sinensis

The effect of seaweed liquid fertilizers (SLF) of Sargassum wightii and Caulerpa chemnitzia on growth and biochemical constituents of Vigna sinensis was studied. The seeds soaked with aqueous extract of seaweeds performed better when compared to the water soaked controls. Hundred per cent germination was recorded both in aqueous extract soaked and water soaked treatments. The low concentration (20%) of aqueous extracts of S. wightii and C. chemnitzia promoted the seedling growth including the parameters of shoot length (15.87, 14.13 cm/seedling), root length (6.42, 5.38 cm/seedling), fresh weight (4.017, 4.012 g/seedling) and dry weight (0.878, 0.865 g/seedling), chlorophyll (1.599, 1.491 mg g-1 fr. wt.), carotenoids (0.899, 0.875 mg g-1 fr. wt.), protein content of shoot (3.956, 3.474 mg g-1 fr. wt.) and root (2.926, 2.890 mg g-1 fr. wt.), amino acid content of shoot (1.447, 1.429 mg g-1 fr. wt.) and root (0.698, 0.680 mg g-1 fr. wt.), reducing sugar content of shoot (6.426, 6.233 mg g-1 fr. wt.) and root (5.118, 5.103 mg g-1 fr. wt.), total sugar content of shoot (11.846, 11.350 mg g-1 fr. wt.) and root (10.368, 10.102 mg g-1 fr. wt.), alpha-amylase (1.927, 1.819 microg min-1 mg-1 protein) and beta-amylase (1.730, 1.617 microg min-1 mg-1 protein) activities in V. sinensis. Among the two seaweeds tested, S. wightii exhibited better responses.     

Correlation of antibacterial activity of some N-[5-(2-furanyl)-2-methyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl]-carboxamide and 3-substituted-5-(2-furanyl)-2-methyl-3H-thieno[2,3-d]pyrimidin-4-ones with topological indices using Hansch analysis

The antimicrobial activity of the N-[5-(2-furanyl)-2-methyl-4-oxo-4H-theino[2,3-d]pyrimidin-3-y1]-carboxamides and 3-substituted-5-(2-furanyl)-2-methyl-3H-thieno[2,3-d]pyrimidin-4-ones was correlated with different topological indices using Hansch analysis. Good correlations were obtained through a simple regression equation with third order molecular connectivity index (3chi). The developed QSAR models were crossvalidated by leave-one-out technique.