PCA based population generation for genetic network optimization

A gene regulatory network (GRN) represents a set of genes and its regulatory interactions. The inference of the regulatory interactions between genes is usually carried out using an appropriate mathematical model and the available gene expression profile. Among the various models proposed for GRN inference, our recently proposed Michaelis–Menten based ODE model provides a good trade-off between the computational complexity and biological relevance. This model, like other known GRN models, also uses an evolutionary algorithm for parameter estimation. Considering various issues associated with such population based stochastic optimization approaches (e.g. diversity, premature convergence due to local optima, accuracy, etc.), it becomes important to seed the initial population with good individuals which are closer to the optimal solution. In this paper, we exploit the inherent strength of principal component analysis (PCA) in a novel manner to initialize the population for GRN optimization. The benefit of the proposed method is validated by reconstructing in silico and in vivo networks of various sizes. For the same level of accuracy, the approach with PCA based initialization shows improved convergence speed.     

Bidens pilosa L.: Exclusive report of vivipary in a non-mangrove taxa from the eastern Himalayas

Vivipary is an extremely evolved type of epigeal germination in seed plants and very common in tropical estuarine plant communities (mangroves), ensuring a greater number of viable settings of offspring. In addition to this, there are some other non-mangrove angiosperm taxa that have a successful existence, and because of their invasive nature, vivipary has been reported as an attribute of their uncongenial abiotic stress. The present observation confirms the incidence of true vivipary in Bidens pilosa L. (a member of the family Asteraceae) from the eastern Himalayan region.     

Identification of potent,selective and orally bioavailable phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone analogues as RORγt inverse agonists

An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.     

Design and utility of temperature-sensitive Gal4 mutants for conditional gene expression in Drosophila

Temperature-sensitive (ts) mutants are valuable tools to study the function of essential genes in vivo. Despite their widespread use, little is known about mechanisms responsible for the temperature-sensitive (ts) phenotype, or of the transferability of ts mutants of a specific gene between organisms. Since ts mutants are typically generated by random mutagenesis it is difficult to isolate such mutants without efficient screening procedures. We have recently shown that it is possible to obtain ts mutants at high frequency by targeted mutations at either predicted, buried residues important for protein stability or at functional, ligand binding residues. The former class of residues can be identified solely from amino acid sequence and the latter from Ala scanning mutagenesis or from a structure of the protein:ligand complex. Several ts mutants of Gal4 in yeast were generated by mutating both categories of residues. Two of these ts mutants were also shown to result in tight and rapid ts reporter gene-expression in Drosophila when driven by either the elav or GMR promoters. We suggest possible mechanisms that might be responsible for such transferable ts phenotypes and also discuss some of the limitations and difficulties involved in rational design of ts mutants.     

ExoS and ExoT ADP ribosyltransferase activities mediate Pseudomonas aeruginosa keratitis by promoting neutrophil apoptosis and bacterial survival

Pseudomonas aeruginosa is a leading cause of blinding corneal ulcers worldwide. To determine the role of type III secretion in the pathogenesis of P. aeruginosa keratitis, corneas of C57BL/6 mice were infected with P. aeruginosa strain PAO1 or PAK, which expresses ExoS, ExoT, and ExoY, but not ExoU. PAO1- and PAK-infected corneas developed severe disease with pronounced opacification and rapid bacterial growth. In contrast, corneas infected with ΔpscD or ΔpscJ mutants that cannot assemble a type III secretion system, or with mutants lacking the translocator proteins, do not develop clinical disease, and bacteria are rapidly killed by infiltrating neutrophils. Furthermore, survival of PAO1 and PAK strains in the cornea and development of corneal disease was impaired in ΔexoS, ΔexoT, and ΔexoST mutants of both strains, but not in a ΔexoY mutant. ΔexoST mutants were also rapidly killed in neutrophils in vitro and were impaired in their ability to promote neutrophil apoptosis in vivo compared with PAO1. Point mutations in the ADP ribosyltransferase (ADPR) regions of ExoS or ExoT also impaired proapoptotic activity in infected neutrophils, and exoST(ADPR-) mutants replicated the ΔexoST phenotype in vitro and in vivo, whereas mutations in rho-GTPase-activating protein showed the same phenotype as PAO1. Together, these findings demonstrate that the pathogenesis of P. aeruginosa keratitis in ExoS- and ExoT-producing strains is almost entirely due to their ADPR activities, which subvert the host response by targeting the antibacterial activity of infiltrating neutrophils.     

Identification and optimization of small molecule antagonists of vasoactive intestinal peptide receptor-1 (VIPR1)

Identification, synthesis and structure-activity relationship of small-molecule VIPR1 antagonists encompassing two chemical series are described.     

Focus on antivirally active sulfated polysaccharides: from structure-activity analysis to clinical evaluation

In recent years, many compounds having potent antiviral activityin cell culture have been detected and some of these compoundsare currently undergoing either preclinical or clinical evaluation.Among these antiviral substances, naturally occurring sulfatedpolysaccharides and those from synthetic origin are noteworthy.Recently, several controversies over the molecular structuresof sulfated polysaccharides, viral glycoproteins, and cell-surfacereceptors have been resolved, and many aspects of their antiviralactivity have been elucidated. It has become clear that theantiviral properties of sulfated polysaccharides are not onlya simple function of their charge density and chain length butalso their detailed structural features. The in vivo efficacyof these compounds mostly corresponds to their ability to inhibitthe attachment of the virion to the host cell surface althoughin some cases virucidal activity plays an additional role. Thisreview summarizes experimental evidence indicating that sulfatedpolysaccharides might become increasingly important in drugdevelopment for the prevention of sexually transmitted diseasesin the near future.