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Factors controlling the position and strength of the surface winds during the Last Glacial Maximum (LGM) are examined using a global, multilevel, moist, atmospheric model. The idealized aquaplanet model is bounded below by a prescribed axisymmetric temperature distribution that corresponds to an ocean-covered surface. Various forms of this distribution are used to examine the influence of changes in the surface cooling and baroclinicity rates. The model omits seasonal variations. Increasing the cooling lowers the tropopause and greatly reduces the moist convection in the Tropics, thereby causing a weakening and equatorward contraction of the Hadley cell. Such a cooling also weakens the surface westerlies and shifts the peak westerly stress equatorward. An extra surface baroclinicity in midlatitudes—implicitly associated with an increase in the polar sea ice—also shifts the peak westerly stress equatorward, but strengthens the surface westerlies. Thus, calculations with combined surface cooling and baroclinicity increases, representative of the Last Glacial Maximum, reveal an absence of change in the amplitude of the peak westerly stress but exhibit a substantial equatorward shift in its position, 7° for a 3-K cooling and 11° for a 6-K cooling. The easterlies, however, always increase in strength when the surface westerlies move equatorward. The application of these results to the LGM must take into account the model’s assumption of symmetry between the two hemispheres. Any changes in the climate’s hemispheric asymmetry could also cause comparable latitudinal shifts in the westerlies, probably of opposite sign in the two hemispheres. Published coupled-model simulations for the LGM give an equatorward shift for the peak westerlies in the Northern Hemisphere but give contradictory results for the Southern Hemisphere. [ABSTRACT FROM AUTHOR]

A correction to the article by Williams and Bryan about the description of Hadley cell behavior that was published in the previous issue of the periodical is presented.

Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose to screen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs. Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (Hs1 and Hs2) and for broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. Analysis of the screening results has shown that structure-activity relationships (SAR) for Leishmania NMT are divergent from all other NMTs tested, a finding not predicted by sequence similarity calculations, resulting in the identification of four novel series of Leishmania-selective NMT inhibitors. We found a strong overlap between the SARs for Plasmodium NMT and both human NMTs, suggesting that achieving an appropriate selectivity profile will be more challenging. However, we did discover two novel series with selectivity for Plasmodium NMT over the other NMT orthologues in this study, and an additional two structurally distinct series with selectivity over Leishmania NMT. We believe that release of results from this study into the public domain will accelerate the discovery of NMT inhibitors to treat malaria and leishmaniasis. Our screening initiative is another example of how a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/non-governmental organisations such as Medical Research Council and Wellcome Trust can stimulate research for neglected diseases. Author Summary: Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose to screen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs. Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (HsNMT1 and HsNMT2) and for broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. We have identified eight series of protozoan NMT inhibitors, six having good selectivity for either Plasmodium or Leishmania NMTs over the other orthologues in this study. We believe that all of these series could form the basis of medicinal chemistry programs to deliver drug candidates against either malaria or leishmaniasis. Our screening initiative is another example of how a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/non-governmental organisations such as the UK Medical Research Council and Wellcome Trust can stimulate research for neglected diseases. [ABSTRACT FROM AUTHOR]

Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose to screen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs. Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (Hs1 and Hs2) and for broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. Analysis of the screening results has shown that structure-activity relationships (SAR) for Leishmania NMT are divergent from all other NMTs tested, a finding not predicted by sequence similarity calculations, resulting in the identification of four novel series of Leishmania-selective NMT inhibitors. We found a strong overlap between the SARs for Plasmodium NMT and both human NMTs, suggesting that achieving an appropriate selectivity profile will be more challenging. However, we did discover two novel series with selectivity for Plasmodium NMT over the other NMT orthologues in this study, and an additional two structurally distinct series with selectivity over Leishmania NMT. We believe that release of results from this study into the public domain will accelerate the discovery of NMT inhibitors to treat malaria and leishmaniasis. Our screening initiative is another example of how a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/nongovernmental organisations such as Medical Research Council and Wellcome Trust can stimulate research for neglected diseases. [ABSTRACT FROM AUTHOR]

Background: Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (HAT), expresses two proteins with homology to human glycogen synthase kinase 3β (HsGSK-3) designated TbruGSK-3 short and TbruGSK-3 long. TbruGSK-3 short has previously been validated as a potential drug target and since this enzyme has also been pursued as a human drug target, a large number of inhibitors are available for screening against the parasite enzyme. A collaborative industrial/academic partnership facilitated by the World Health Organisation Tropical Diseases Research division (WHO TDR) was initiated to stimulate research aimed at identifying new drugs for treating HAT. Methodology/Principal Findings: A subset of over 16,000 inhibitors of HsGSK-3 β from the Pfizer compound collection was screened against the shorter of two orthologues of TbruGSK-3. The resulting active compounds were tested for selectivity versus HsGSK-3β and a panel of human kinases, as well as in vitro anti-trypanosomal activity. Structural analysis of the human and trypanosomal enzymes was also performed. Conclusions/Significance: We identified potent and selective compounds representing potential attractive starting points for a drug discovery program. Structural analysis of the human and trypanosomal enzymes also revealed hypotheses for further improving selectivity of the compounds. Author Summary: Over 60 million people in sub-Saharan Africa are at risk of infection with the parasite Trypanosoma brucei which causes Human African Trypanosomiasis (HAT), also known as sleeping sickness. The disease results in systemic and neurological disability to its victims. At present, only four drugs are available for treatment of HAT. However, these drugs are expensive, limited in efficacy and are severely toxic, hence the need to develop new therapies. Previously, the short TbruGSK-3 short has been validated as a potential target for developing new drugs against HAT. Because this enzyme has also been pursued as a drug target for other diseases, several inhibitors are available for screening against the parasite enzyme. Here we present the results of screening over 16,000 inhibitors of human GSK-3β (HsGSK-3) from the Pfizer compound collection against TbruGSK-3 short. The resulting active compounds were tested for selectivity versus HsGSK-3β and a panel of human kinases, as well as their ability to inhibit proliferation of the parasite in vitro. We have identified attractive compounds that now form potential starting points for drug discovery against HAT. This is an example of how a tripartite partnership involving pharmaceutical industries, academic institutions and non-government organisations such as WHO TDR, can stimulate research for neglected diseases. [ABSTRACT FROM AUTHOR]

Background: Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (HAT), expresses two proteins with homology to human glycogen synthase kinase 3b (HsGSK-3) designated TbruGSK-3 short and TbruGSK-3 long. TbruGSK- 3 short has previously been validated as a potential drug target and since this enzyme has also been pursued as a human drug target, a large number of inhibitors are available for screening against the parasite enzyme. A collaborative industrial/ academic partnership facilitated by the World Health Organisation Tropical Diseases Research division (WHO TDR) was initiated to stimulate research aimed at identifying new drugs for treating HAT. Methodology/Principal Findings: A subset of over 16,000 inhibitors of HsGSK-3 b from the Pfizer compound collection was screened against the shorter of two orthologues of TbruGSK-3. The resulting active compounds were tested for selectivity versus HsGSK-3b and a panel of human kinases, as well as in vitro anti-trypanosomal activity. Structural analysis of the human and trypanosomal enzymes was also performed. Conclusions/Significance: We identified potent and selective compounds representing potential attractive starting points for a drug discovery program. Structural analysis of the human and trypanosomal enzymes also revealed hypotheses for further improving selectivity of the compounds. [ABSTRACT FROM AUTHOR]

Linear interpolation is the standard image blending method used in image compositing. By averaging in the dynamic range, it reduces contrast and visibly degrades the quality of composite imagery. We demonstrate how to correct linear interpolation to resolve this longstanding problem. To provide visually meaningful, high level control over the compositing process, we introduce three novel image blending operators that are designed to preserve key visual characteristics of their inputs. Our contrast preserving method applies a linear color mapping to recover the contrast lost due to linear interpolation. Our salience preserving method retains the most informative regions of the input images by balancing their relative opacity with their relative saliency. Our color preserving method extends homomorphic image processing by establishing an isomorphism between the image colors and the real numbers, allowing any mathematical operation defined on real numbers to be applied to colors without losing its algebraic properties or mapping colors out of gamut. These approaches to image blending have artistic uses in image editing and video production as well as technical applications such as image morphing and mipmapping. Categories and Subject Descriptors (according to ACM CCS): I.3.3 [Computer Graphics]: Picture/Image Generation [ABSTRACT FROM AUTHOR]