The association between distance to water pipes and water bodies positive for anopheline mosquitoes (Diptera: Culicidae) in the urban community of Malindi, Kenya.

The increasing risk of mosquito-borne diseases in African urban environments has been partly attributed to failed planning and resource underdevelopment. Though engineered systems may reduce mosquito proliferation, there are few studies describing this relationship. This study investigates how engineered systems such as roads and piped water systems affect the odds of anopheline immatures (i.e., larvae and pupae) occurring in water bodies located in Malindi, Kenya. Anopheles gambiae s.s. (Giles), An. arabiensis (Patton), and An. merus (Dointz) were identified in urban Malindi, with Anopheles gambiae s.s. being the predominant species identified. The Breslow-Day test was used to explore interactions among independent variables. Logistic regression was used to test whether water bodies positive for anopheline immatures are associated with engineered systems, while controlling for potential confounding and interaction effects associated with urban water body characteristics. Water bodies more than 100 m from water pipes were 13 times more likely to have anopheline immatures present, compared to water bodies that were less than 100 m from water pipes (OR = 13.54, 95% CI: 3.15-58.23). Roads were not significantly associated with water bodies positive for anopheline immatures. Statistical interaction was detected between water body substrate type and distance to water pipes. This study provides insight into how water pipes influence the distribution of water bodies positive with immature anophelines in urban environments.     

Luteolytic action of two antiprogestational agents (RU-38486 and ZK-98734) in the rat

RU-38486 or ZK-98734 treatment (3 mg/day, s.c.) to intact or hysterectomized adult female rats on Days 5-7 post coitum induced changes characteristic of luteolysis. Ultrastructurally, the luteal cells exhibited an extensive vacuolization of the cytoplasm and perinuclear areas, degeneration of mitochondrial cristae, massive accumulation of lipid droplets, increase in number of lysosome like granules and heterochromatinization of the nucleus. In general, RU-38486 induced more marked degeneration of the luteal cells than did ZK-98734. There was also a significant decrease in peripheral plasma progesterone concentrations in treated rats. We suggest that these antiprogestagens act via inhibition of luteal function in addition to their antagonism at the uterine progesterone receptor level.     

Synthesis and biological evaluation of 4-quinazolinones as Rho kinase inhibitors

Rho kinase (ROCK) is an attractive therapeutic target for various diseases including glaucoma, hypertension, and spinal cord injury. Herein, we report the development of a series of ROCK-II inhibitors based on 4-quinazolinone and quinazoline scaffolds. SAR studies at three positions of the quinazoline core led to the identification of analogs with high potency against ROCK-II and good selectivity over protein kinase A (PKA).     

CXCL10 Is Critical for the Generation of Protective CD8 T Cell Response Induced by Antigen Pulsed CpG-ODN Activated Dendritic Cells

The visceral form of leishmaniasis is the most severe form of the disease and of particular concern due to the emerging problem of HIV/visceral leishmaniasis (VL) co-infection in the tropics. Till date miltefosine, amphotericin B and pentavalent antimony compounds remain the main treatment regimens for leishmaniasis. However, because of severe side effects, there is an urgent need for alternative improved therapies to combat this dreaded disease. In the present study, we have used the murine model of leishmaniasis to evaluate the potential role played by soluble leishmanial antigen (SLA) pulsed-CpG-ODN stimulated dendritic cells (SLA-CpG-DCs) in restricting the intracellular leishmanial growth. We found that mice vaccinated with a single dose of SLA-pulsed DC stimulated by CpG-ODN were protected against a subsequent leishmanial challenge and had a dramatic reduction in parasite burden along with the generation of parasite specific cytotoxic T lymphocytes. Moreover, we demonstrate that the induction of protective immunity conferred by SLA-CpG-DCs depends entirely on the CXC chemokine IFN-γ-inducible protein 10 (CXCL10; IP-10). CXCL10 is directly involved in the generation of a parasite specific CD8⁺ T cell-mediated immune response. We observed significant reduction of CD8⁺ T cells in mice depleted of CXCL10 suggesting a direct role of CXCL10 in the generation of CD8⁺ T cells in SLA-CpG-DCs vaccinated mice. CXCL10 also contributed towards the generation of perforin and granzyme B, two important cytolytic mediators of CD8⁺ T cells, following SLA-CpG-DCs vaccination. Together, these findings strongly demonstrate that CXCL10 is critical for rendering a protective cellular immunity during SLA-CpG-DC vaccination that confers protection against Leishmania donovani infection.     

Protein-Protein Docking with F2Dock 2.0 and GB-Rerank

Motivation

Computational simulation of protein-protein docking can expedite the process of molecular modeling and drug discovery. This paper reports on our new F² Dock protocol which improves the state of the art in initial stage rigid body exhaustive docking search, scoring and ranking by introducing improvements in the shape-complementarity and electrostatics affinity functions, a new knowledge-based interface propensity term with FFT formulation, a set of novel knowledge-based filters and finally a solvation energy (GBSA) based reranking technique. Our algorithms are based on highly efficient data structures including the dynamic packing grids and octrees which significantly speed up the computations and also provide guaranteed bounds on approximation error.

Results

The improved affinity functions show superior performance compared to their traditional counterparts in finding correct docking poses at higher ranks. We found that the new filters and the GBSA based reranking individually and in combination significantly improve the accuracy of docking predictions with only minor increase in computation time. We compared F² Dock 2.0 with ZDock 3.0.2 and found improvements over it, specifically among 176 complexes in ZLab Benchmark 4.0, F² Dock 2.0 finds a near-native solution as the top prediction for 22 complexes; where ZDock 3.0.2 does so for 13 complexes. F² Dock 2.0 finds a near-native solution within the top 1000 predictions for 106 complexes as opposed to 104 complexes for ZDock 3.0.2. However, there are 17 and 15 complexes where F² Dock 2.0 finds a solution but ZDock 3.0.2 does not and vice versa; which indicates that the two docking protocols can also complement each other.

Availability

The docking protocol has been implemented as a server with a graphical client (TexMol) which allows the user to manage multiple docking jobs, and visualize the docked poses and interfaces. Both the server and client are available for download. Server: http://www.cs.utexas.edu/~bajaj/cvc/software/f2dock.shtml. Client: http://www.cs.utexas.edu/~bajaj/cvc/software/f2dockclient.shtml.     

Phenylalanine catabolism in Archaeoglobus fulgidus VC-16

Evidence is presented for a pathway of phenylalanine catabolism in the hyperthermophilic archaeon Archaeoglobus fulgidus involving the following enzymes—phenylalanine:2-oxoglutarate aminotransferase, phenyllactate dehydrogenase, radical iron–sulphur 3-phenyllactyl-CoA dehydratase, phenylpropionyl-CoA dehydrogenase, aryl pyruvate ferredoxin oxidoreductase, ADP-forming acetyl-CoA synthetase and family III CoA-transferase. Hitherto amino acid degradation pathways involving radical iron–sulphur dehydratases have been characterised only in mesophilic clostridia and related bacteria. The difference here is that the pathway is not fermentative but coupled to sulphate reduction. Initial experiments also show the utilisation of tryptophan as a growth substrate and the decarboxylation of caffeate by cell extracts, suggesting the potential to catabolise different classes of aromatic compounds.     

Signaling function of dehydroabietinal in plant defense and development

Plants provide the bulk of the nearly 12,000 diterpenoid natural products, which include diterpene resin acids that have important medicinal and industrial applications. However, the biological function of these terpenoids in plants is poorly understood. Here, we highlight recent work that implicates a signaling function in angiosperms for some of these diterpenoids. In particular, this review will focus on the involvement of an abietane diterpenoid, dehydroabietinal, in the activation of systemic acquired resistance, and draw attention to new evidence that supports a role for dehydroabietinal in the transition from the vegetative phase of growth to reproductive development in the crucifer plant Arabidopsis thaliana.     

Synthesis of a novel family of diterpenes and their evaluation as anti-inflammatory agents

The synthesis and biological evaluation of a new family of diterpenes, represented by structures 2 and 3, is presented. These compounds constitute isomeric analogues of acanthoic acid (1) and were examined as potent anti-inflammatory agents. Among them, methyl ester 12 exhibited a low non-specific cytotoxicity, inhibited TNF-alpha synthesis and displayed good specificity in suppressing cytokine expression.