Molecular modeling and QSAR studies of a set of indole and benzimidazole derivatives as H(4) receptor antagonists

Histamine is an important biogenic amine, which acts with a group of four G-protein coupled receptors (GPCRs), namely H(1) to H(4) (H(1)R - H(4)R) receptors. The actions of histamine at H(4)R are related to immunological and inflammatory processes, particularly in pathophysiology of asthma, and H(4)R ligands having antagonistic properties could be helpful as antiinflammatory agents. In this work, molecular modeling and QSAR studies of a set of 30 compounds, indole and benzimidazole derivatives, as H(4)R antagonists were performed. The QSAR models were built and optimized using a genetic algorithm function and partial least squares regression (WOLF 5.5 program). The best QSAR model constructed with training set (N = 25) presented the following statistical measures: r (2) = 0.76, q (2) = 0.62, LOF = 0.15, and LSE = 0.07, and was validated using the LNO and y-randomization techniques. Four of five compounds of test set were well predicted by the selected QSAR model, which presented an external prediction power of 80%. These findings can be quite useful to aid the designing of new anti-H(4) compounds with improved biological response.

Influence of Pluronic (R) F68 on Ceftazidime Biological Activity in Parenteral Solutions

beta-Lactam antimicrobials are known to have a low concentration/therapeutic response. However, extending the period in which beta-lactam are free in the plasma does directly influence therapeutic outcomes. The objective of this study was to evaluate the influence of Pluronic (R) F68 on the antimicrobial activity of ceftazidime when admixed with aminophylline in parenteral solutions by the evaluation of its minimal inhibitory concentration (MIC) within 24 h. Ceftazidime, aminophylline, and Pluronics (R) F68 were evaluated using the MIC method against Escherichia coli and Pseudomonas aeruginosa, with these compounds individually and associated in the same parenteral solutions. When Pluronics (R) F68 was admixtured with ceftazidime alone or with ceftazidime and aminophylline, it was possible to observe lower MIC values not only at 24 h but also at 0 h for both microorganisms. This indicates that Pluronics (R) F68 may be able to enhance ceftazidime antimicrobial activity in the presence or absence of aminophylline. This fact suggests that Pluronics (R) F68 can be applied to allow the administration of ceftazidime under continuous infusion in parenteral solutions, beneficiating hospital pharmacotherapy. It may also be possible to reduce ceftazidime doses in formulations achieving the same therapeutic results. (C) 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:715-720, 2011

Photophysical studies and in vitro skin permeation/retention of Foscan (R)/nanoemulsion (NE) applicable to photodynamic therapy skin cancer treatment.

In this work we evaluated the photophysical and in vitro properties of Foscan (R), a second-generation photosensitizer drug (PS) widely used in systemic clinical protocols for cancer therapy based on Photodynamic Therapy (PDT). We employed biodegradable nanoemulsions (NE) as a colloidal vehicle of the oil/water (o/w) type focusing in topical administration of Foscan (R) and other photosensitizer drugs. This formulation was obtained and stabilized by the methodology described by Tabosa do Egito et al.,(30) based on the mixture of two phases: an aqueous solution and an organic medium consisting of nonionic surfactants and oil. The photodynamic potential of the drug incorporated into the NE was studied by steady-state and time-resolved spectroscopic techniques. We also analyzed the in vitro biological behavior carried out in mimetic biological environment protocols based on the animal model. After topical application in a skin animal model, we evaluated the Foscan (R)/NE diffusion flux into the skin layers (stratum corneum and epidermis + dermis) by classical procedures using Franz Diffusion cells. Our results showed that the photophysical properties of PS were maintained after its incorporation into the NE when compared with homogeneous organic medium. The in vitro assays enabled the determination of an adequate profile for the interaction of this system in the different skin layers, with an ideal time lag of 6 h after topical administration in the skin model. The Foscan (R) diffusion flux (J) was increased when this PS was incorporated into the NE, if compared with its flux in physiological medium. These parameters demonstrated that the NE can be potentially applied as a drug delivery system (DDS) for Foscan (R) in both in vitro and in vivo assays, as well as in future clinical applications involving topical skin cancer PDT.

External shower, Sunshine Beach House, Sunshine Coast

View past timber shutter to external shower.

Effect of multiple transverse modes in self-mixing sensors based on vertical-cavity surface-emitting lasers

We investigate the effect of coexisting transverse modes on the operation of self-mixing sensors based on vertical-cavity surface-emitting lasers (VCSELs). The effect of multiple transverse modes on the measurement of displacement and distance were examined by simulation and in laboratory experiment. The simulation model shows that the periodic change in the shape and magnitude of the self-mixing signal with modulation current can be properly explained by the different frequency-modulation coefficients of the respective transverse modes in VCSELs. The simulation results are in excellent agreement with measurements performed on single-mode and multimode VCSELs and on self-mixing sensors based on these VCSELs.

Twisted quantum affine superalgebra Uq[gl(m|n)(2)] and new Uq[osp(m|n)] invariant R-matrices

The minimal irreducible representations of U-q[gl(m|n)], i.e. those irreducible representations that are also irreducible under U-q[osp(m|n)] are investigated and shown to be affinizable to give irreducible representations of the twisted quantum affine superalgebra U-q[gl(m|n)((2))]. The U-q[osp(m|n)] invariant R-matrices corresponding to the tensor product of any two minimal representations are constructed, thus extending our twisted tensor product graph method to the supersymmetric case. These give new solutions to the spectral-dependent graded Yang-Baxter equation arising from U-q[gl(m|n)((2))], which exhibit novel features not previously seen in the untwisted or non-super cases.

XSophe-Sophe-XeprView (R). A computer simulation software suite (v. 1.1.3) for the analysis of continuous wave EPR spectra

The XSophe-Sophe-XeprView((R)) computer simulation software suite enables scientists to easily determine spin Hamiltonian parameters from isotropic, randomly oriented and single crystal continuous wave electron paramagnetic resonance (CW EPR) spectra from radicals and isolated paramagnetic metal ion centers or clusters found in metalloproteins, chemical systems and materials science. XSophe provides an X-windows graphical user interface to the Sophe programme and allows: creation of multiple input files, local and remote execution of Sophe, the display of sophelog (output from Sophe) and input parameters/files. Sophe is a sophisticated computer simulation software programme employing a number of innovative technologies including; the Sydney OPera HousE (SOPHE) partition and interpolation schemes, a field segmentation algorithm, the mosaic misorientation linewidth model, parallelization and spectral optimisation. In conjunction with the SOPHE partition scheme and the field segmentation algorithm, the SOPHE interpolation scheme and the mosaic misorientation linewidth model greatly increase the speed of simulations for most spin systems. Employing brute force matrix diagonalization in the simulation of an EPR spectrum from a high spin Cr(III) complex with the spin Hamiltonian parameters g(e) = 2.00, D = 0.10 cm(-1), E/D = 0.25, A(x) = 120.0, A(y) = 120.0, A(z) = 240.0 x 10(-4) cm(-1) requires a SOPHE grid size of N = 400 (to produce a good signal to noise ratio) and takes 229.47 s. In contrast the use of either the SOPHE interpolation scheme or the mosaic misorientation linewidth model requires a SOPHE grid size of only N = 18 and takes 44.08 and 0.79 s, respectively. Results from Sophe are transferred via the Common Object Request Broker Architecture (CORBA) to XSophe and subsequently to XeprView((R)) where the simulated CW EPR spectra (1D and 2D) can be compared to the experimental spectra. Energy level diagrams, transition roadmaps and transition surfaces aid the interpretation of complicated randomly oriented CW EPR spectra and can be viewed with a web browser and an OpenInventor scene graph viewer.

Transformation of external sensilla to chordotonal sensilla in the cut mutant of Drosophila assessed by single-cell marking in the embryo and larva

The cut gene of Drosophila melanogaster is an identity selector gene that establishes the program of development and differentiation of external sense organs. Mutations in the cut gene cause a transformation of the external sense organs into chordotonal organs, originally assessed by the use of immunostaining methods [Bodmer et al. (1987): Cell, 51:293-307]. Because of evidence that axonal projections of the transformed neurons within the central nervous system are not completely switched in cut mutants, the transformation of the four cells making up a sense organ was reassessed using single-cell staining with fluorescent dye and differential interface contrast (DIC) microscopy of the embryo and larva. The results provide strong evidence that all cells of the sense organs are completely transformed, exhibiting the morphologies and organelles characteristic of chordotonal sense organs. A comparison of the structures of external sense organs and chordotonal organs indicates that a number of the differences could be due to the degree of development of common structures, and that cut or downstream genes modulate effector genes that are normally utilized in both receptor types. The possible derivation of insect chordotonal and external sense organs from a receptor type found in crustaceans is discussed in the light of arthropod phylogenetics and the molecular genetics of sense organ development. (C) 1997 Wiley-Liss, Inc.

Improving wheat simulation capabilities in Australia from a cropping systems perspective - III. The integrated wheat model (I_WHEAT)

Previous work has identified several short-comings in the ability of four spring wheat and one barley model to simulate crop processes and resource utilization. This can have important implications when such models are used within systems models where final soil water and nitrogen conditions of one crop define the starting conditions of the following crop. In an attempt to overcome these limitations and to reconcile a range of modelling approaches, existing model components that worked demonstrably well were combined with new components for aspects where existing capabilities were inadequate. This resulted in the Integrated Wheat Model (I_WHEAT), which was developed as a module of the cropping systems model APSIM. To increase predictive capability of the model, process detail was reduced, where possible, by replacing groups of processes with conservative, biologically meaningful parameters. I_WHEAT does not contain a soil water or soil nitrogen balance. These are present as other modules of APSIM. In I_WHEAT, yield is simulated using a linear increase in harvest index whereby nitrogen or water limitations can lead to early termination of grainfilling and hence cessation of harvest index increase. Dry matter increase is calculated either from the amount of intercepted radiation and radiation conversion efficiency or from the amount of water transpired and transpiration efficiency, depending on the most limiting resource. Leaf area and tiller formation are calculated from thermal time and a cultivar specific phyllochron interval. Nitrogen limitation first reduces leaf area and then affects radiation conversion efficiency as it becomes more severe. Water or nitrogen limitations result in reduced leaf expansion, accelerated leaf senescence or tiller death. This reduces the radiation load on the crop canopy (i.e. demand for water) and can make nitrogen available for translocation to other organs. Sensitive feedbacks between light interception and dry matter accumulation are avoided by having environmental effects acting directly on leaf area development, rather than via biomass production. This makes the model more stable across environments without losing the interactions between the different external influences. When comparing model output with models tested previously using data from a wide range of agro-climatic conditions, yield and biomass predictions were equal to the best of those models, but improvements could be demonstrated for simulating leaf area dynamics in response to water and nitrogen supply, kernel nitrogen content, and total water and nitrogen use. I_WHEAT does not require calibration for any of the environments tested. Further model improvement should concentrate on improving phenology simulations, a more thorough derivation of coefficients to describe leaf area development and a better quantification of some processes related to nitrogen dynamics. (C) 1998 Elsevier Science B.V.

Bimanual co-ordination in Parkinson's disease

The basal ganglia may be involved in bimanual co-ordination. Parkinson's disease (which impairs basal ganglia output) is clinically reported to cause difficulties in the performance of co-ordinated bimanual movements. Nevertheless, any bimanual co-ordination difficulties may be task specific, as experimental observations are equivocal. To infer the role of the basal ganglia in co-ordinating the two arms, this study investigated the bimanual co-ordination of patients with Parkinson's disease. Sixteen Parkinson's disease patients and matched control subjects performed a bimanual cranking task, at different speeds (1 and 2 Hz) and phase relationships. All subjects performed the required bimanual in-phase movement on a pair of cranks, at fast (2 Hz) and slow (1 Hz) speeds. However the Parkinson's disease patients were unable to perform the asymmetrical anti-phase movement, in which rotation of the cranks differed by 180 degrees, at either speed; but instead reverted to the in-phase symmetrical movement. For Parkinson's disease patients, performance of the in-phase movement was more accurate and stable when an external timing cue was used; however for anti-phase movement, the external cue accentuated the tendency for patients to revert to more symmetrical, in-phase movements.

The Australian mortality decline: cause-specific mortality 1907-1990

This review describes the changes in composition of mortality by major attributed cause during the Australian mortality decline this century. The principal categories employed were: infectious diseases, nonrheumatic cardiovascular disease, external causes, cancer,'other' causes and ill-defined conditions. The data were age-adjusted. Besides registration problems (which also affect all-cause mortality) artefacts due to changes in diagnostic designation and coding-are evident. The most obvious trends over the period are the decline in infectious disease mortality (half the decline 1907-1990 occurs before 1949), and the epidemic of circulatory disease mortality which appears to commence around 1930, peaks during the 1950s and 1960s, and declines from 1970 to 1990 (to a rate half that at the peak). Mortality for cancer remains static for females after 1907, but increases steadily for males, reaching a plateau in the mid-1980s (owing to trends in lung cancer); trends in cancers of individual sites are diverse. External cause mortality declines after 1970. The decline in total mortality to 1930 is associated with decline in infection and 'other' causes, Stagnation of mortality decline in 1930-1940 and 1946-1970 for males is a consequence of contemporaneous movements in opposite directions of infection mortality (decrease) and circulatory disease and cancer mortality (increase). In females, declines in infections and 'other' causes of death exceed the increase in circulatory disease mortality until 1960, then stability in all major causes of death to 1970. The overall mortality decline since 1970 is a consequence of a reduction in circulatory disease,'other' cause, external cause and infection mortality, despite the increase in cancer mortality (for males).

Influence of field-based nutrient enrichment on the photobiology of the giant clam Tridacna maxima

Nutrients were added to 12 microatolls in One Tree Island lagoon every low tide for 13 mo to an initial concentration of 10 mu M (ammonium, N) and 2 mu M (phosphate, P). These concentrations remained above background for 2 to 3 h after addition. The addition of ammonium (N and NI-P but not P alone) significantly increased P, (gross photosynthesis) P,, (net photosynthesis) and R (respiration) per unit wet-tissue weight and cc (photosynthetic efficiency) in Tridacna maxima after 3 mo nutrient enrichment. These responses to small and transient changes in ammonium concentrations suggest that symbiotic clams are not nutrient-replete, and that even subtle changes in nutrients can have a measurable effect on photosynthesis. The same clams did not show significant differences in photosynthetic parameters 6 mo after the beginning of nutrient enrichment, suggesting that their previous responses had either been seasonal or that symbiotic clams such as T. maxima are able to adjust their photophysiology following external changes in nutrient concentrations.