Prediction of caspase-3 inhibitory activity of 1,3-dioxo-4-methyl-2,3-dihydro-1h-pyrrolo[3,4-c] quinolines: QSAR study

Neurodegenerative disorders are consequences of progressive and irreversible loss of neurons due to unwanted apoptosis which involves caspases, a group of cysteine proteases that cleave other proteins and inactivate them. Among several different groups of caspase enzymes, caspases-3 plays a key role in apoptosis and are a therapeutic target for their inhibition. In pursuit of better caspase-3 inhibitors, a quantitative structure-activity relationship (QSAR) analysis was performed on a series of 1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c] quinolines as caspase-3 inhibitors using WIN CAChe 6.1 and Medicinal Chemistry Regression Machine. The best QSAR model was selected and validated by internal and external validation method. The values of statistical data are r = 0.955, F = 72.95, SEE = 0.397, q² = 0.885, S_PRESS = 0.44. The present study reveals that when the conformational minimum energy is increased, and lowest unoccupied molecular orbital energy and highest occupied molecular orbital energy are decreased the biological activity can be increased. On the basis of a selected QSAR model, we designed a new series of 1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines compounds, calculated their caspases inhibitory activity and found that the designed compounds were more potent than the existing compounds.     

Historical trends in frog populations in New Zealand based on public perceptions

Surveys were distributed to New Zealand land users in 1998 and 2008 to acquire information about New Zealand frogs with the aim of compiling and mapping their distribution and inferred population trends without costly and time-consuming field surveys. The overall frog population trend was reported as declining, with possible causes reported as an increase in agriculture, an increase in the distribution of predatory fish and disease. The resultant maps could be used for four main purposes: 1) to identify regions where Litoria populations are known to occur, which can be eliminated when considering suitable regions for translocation of Leiopelma; 2) to identify growing or stable populations of Litoria species, which may assist future disease surveys, population monitoring and to identify sources of genetic material that may serve as an Ark for declining Australian populations; 3) to highlight populations that are in decline to enable effective targeting of detailed disease studies; and 4) to approximate the stability of amphibian populations in the absence of more accurate, but costly, scientific monitoring.     

QSAR-based prediction of anti-HCV activity of thiourea derivatives

Quantitative structure–activity relationship (QSAR) studies were performed on a series of thioureas to explore the physico-chemical parameters responsible for their activity against the hepatitis C virus (HCV)-infected AVa5 cell. The physico-chemical parameters were calculated using WIN CAChe 6.1. Multiple linear regression analysis, after the variables selection by factor analysis, was performed to derive QSAR models which were further evaluated for their statistical significance and predictive power by internal and external validation. The developed QSAR model had the correlation coefficient (R) = 0.928 and cross-validated squared correlation coefficient (Q ²) = 0.751. The selected significant QSAR model indicates that hydrophobicity, dielectric energy, valence connectivity index (order 1), conformational minimum energy and highest occupied molecular orbital of the whole molecule play an important role in the anti-HCV activity of thioureas.     

A novel harmony search-K means hybrid algorithm for clustering gene expression data

Recent progress in bioinformatics research has led to the accumulation of huge quantities of biological data at various data sources. The DNA microarray technology makes it possible to simultaneously analyze large number of genes across different samples. Clustering of microarray data can reveal the hidden gene expression patterns from large quantities of expression data that in turn offers tremendous possibilities in functional genomics, comparative genomics, disease diagnosis and drug development. The k- ¬means clustering algorithm is widely used for many practical applications. But the original k-¬means algorithm has several drawbacks. It is computationally expensive and generates locally optimal solutions based on the random choice of the initial centroids. Several methods have been proposed in the literature for improving the performance of the k-¬means algorithm. A meta-heuristic optimization algorithm named harmony search helps find out near-global optimal solutions by searching the entire solution space. Low clustering accuracy of the existing algorithms limits their use in many crucial applications of life sciences. In this paper we propose a novel Harmony Search-K means Hybrid (HSKH) algorithm for clustering the gene expression data. Experimental results show that the proposed algorithm produces clusters with better accuracy in comparison with the existing algorithms.     

Pulmonary biocompatibility assessment of inhaled single-wall and multiwall carbon nanotubes in BALB/c mice

With the widespread application of carbon nanotubes (CNTs) in diverse commercial processes, scientists are now concerned about the potential health risk of occupational exposures. In this study, CNT-induced pulmonary toxicity was investigated by exposing BALB/c mice to aerosolized single-wall (SW) CNT and multiwall (MW) CNT (5 μg/g of mice) for 7 consecutive days in a nose-only exposure system. Microscopic studies showed that inhaled CNTs were homogeneously distributed in the mouse lung. The total number of bronchoalveolar lavage polymorphonuclear leukocytes recovered from the mice exposed to SWCNT and MWCNT (1.2 × 10(6) ± 0.52 and 9.87 × 10(5) ± 1.45; respectively) was significantly greater than control mice (5.46 × 10(5) ± 0.78). Rapid development of pulmonary fibrosis in mice that inhaled CNT was also confirmed by significant increases in the collagen level. The lactate dehydrogenase levels were increased nearly 2- and 2.4-fold in mice that inhaled SWCNT and MWCNT, respectively, as compared with control mice. In addition, exposure of CNTs to mice showed a significant (p < 0.05) reduction of antioxidants (glutathione, superoxide dismutase, and catalase) and induction of oxidants (myloperoxidase, oxidative stress, and lipid peroxidation) compared with control. Apoptosis-related proteins such as caspase-3 and -8 activities were also significantly increased in mice that inhaled CNT than in control mice. Together, this study shows that inhaled CNTs induce inflammation, fibrosis, alteration of oxidant and antioxidant levels, and induction of apoptosis-related proteins in the lung tissues to trigger cell death.     

Impact of cypermethrin on the functional response, predatory and mating behaviour of a non-target potential biological control agent Acanthaspis pedestris (Stål) (Het., Reduviidae)

Abstract:  The impact of the insecticide cypermethrin on the functional response, predatory behaviour and mating behaviour was studied in a non-target potential reduviid biological control agent Acanthaspis pedestris (Stål). The intensity of abnormal behaviour increased as the concentration of cypermethrin was increased. The insecticide negatively affected the functional response events such as attack ratio, handling time and rate of discovery. Cypermethrin also reduced the predatory efficiency and prolonged the mating events in A. pedestris . The type II (decelerating curve) of functional response was altered into a type IV (dome-shaped curve) by cypermethrin.     

Loss of the RhoGAP SRGP-1 promotes the clearance of dead and injured cells in Caenorhabditis elegans

Multicellular animals rapidly clear dying cells from their bodies. Many of the pathways that mediate this cell removal are conserved through evolution. Here, we identify srgp-1 as a negative regulator of cell clearance in both Caenorhabditis elegans and mammalian cells. Loss of srgp-1 function results in improved engulfment of apoptotic cells, whereas srgp-1 overexpression inhibits apoptotic cell corpse removal. We show that SRGP-1 functions in engulfing cells and functions as a GTPase activating protein (GAP) for CED-10 (Rac1). Interestingly, loss of srgp-1 function promotes not only the clearance of already dead cells, but also the removal of cells that have been brought to the verge of death through sublethal apoptotic, necrotic or cytotoxic insults. In contrast, impaired engulfment allows damaged cells to escape clearance, which results in increased long-term survival. We propose that C. elegans uses the engulfment machinery as part of a primitive, but evolutionarily conserved, survey mechanism that identifies and removes unfit cells within a tissue.     

Effect of Experimental Temperature on the Permeation of Model Diffusants Across Porcine Buccal Mucosa

The influence of experimental temperature on the permeability of model diffusants across porcine buccal mucosa was investigated in vitro. The permeability increased significantly as the experimental temperature was increased in increments of approximately 7°C. It was observed that the apparent permeability and temperature were related by an exponential relationship that conformed to the Arrhenius equation. Diffusants with higher lipophilicities—buspirone and bupivacaine—had lower activation energies for diffusion when compared to hydrophilic diffusants—antipyrine and caffeine. The activation energy for diffusion of the model diffusants decreased linearly with increasing distribution coefficients across porcine buccal mucosa. The results suggested that the buccal mucosa acts as a stronger barrier to the diffusion of hydrophilic diffusants than the lipophilic ones. The log-linear relationship between permeability and temperature indicates that temperature should be carefully controlled in diffusion experiments. These results also point to the possibility of developing heat-generating buccal delivery devices, especially for hydrophobic diffusants.