Wartime research on malaria chemotherapy

Malaria was a major problem for the opposing forces in World War II. During the first year of operations in the South West Pacific the casualties caused by this disease greatly exceeded the numbers of battle casualties. In response to this situation comprehensive research and development programs to discover new antimalarial drugs were undertaken in the United States and Britain. In both countries compounds synthesised by co-operating chemical laboratories were screened against bird malaria and those with high activity and low toxicity were tested in man. The wartime program in America was funded by the Office of Scientific Research and Development and co-ordinated through a specially designated body under the Committee on Medical Research of the National Research Council. It was an enormous undertaking involving a massive co-operative effort between pharmacologists, chemists, and clinical research scientists from American universities, the US Public Health Service, and the laboratories of commercial pharmaceutical companies. The British program, on a much smaller scale, was based on a co-operative arrangement between the research laboratories of Imperial Chemical Industries at Manchester, the Liverpool School of Tropical Medicine and the British Medical Research Council. The wartime programs in both countries identified a number of promising leads but lacked the resources to permit their rapid clinical evaluation against field strains of human malaria. This deficiency was overcome by experiments conducted by the Land Headquarters Medical Research Unit of the Australian Army in Cairns, Queensland with the use of army volunteers. Large scale clinical trials of the most promising compounds which emerged from the American and British programs were carried out in Australia. This co-operative endeavour among allied scientists resulted in a range of new drugs which have had an enduring influence on malaria chemotherapy.     

Dap160/intersectin scaffolds the periactive zone to achieve high-fidelity endocytosis and normal synaptic growth

Dap160/Intersectin is a multidomain adaptor protein that colocalizes with endocytic machinery in the periactive zone at the Drosophila NMJ. We have generated severe loss-of-function mutations that eliminate Dap160 protein from the NMJ. dap160 mutant synapses have decreased levels of essential endocytic proteins, including dynamin, endophilin, synaptojanin, and AP180, while other markers of the active zone and periactive zone are generally unaltered. Functional analyses demonstrate that dap160 mutant synapses are unable to sustain high-frequency transmitter release, show impaired FM4-64 loading, and show a dramatic increase in presynaptic quantal size consistent with defects in synaptic vesicle recycling. The dap160 mutant synapse is grossly malformed with abundant, highly ramified, small synaptic boutons. We present a model in which Dap160 scaffolds both endocytic machinery and essential synaptic signaling systems to the periactive zone to coordinately control structural and functional synapse development.     

Breeding bird communities of second‐rotation plantations at different stages of the forest cycle

Capsule Early stages of the plantation forest cycle have distinct bird communities and bird density was significantly higher in the second rotation than in the first for a given age class.

Aims To characterize the bird communities in Irish second-rotation plantations and to compare them with those of first-rotation plantations.

Methods Point counts were used to survey 20 plantation forests in four age classes (Pre-thicket; Thicket; Mid‐rotation; and Mature) in the breeding season of 2007. distance software was used to generate bird densities. Ordination, indicator species analysis, and glm were used to analyse the bird communities.

Results Bird communities of Pre‐thicket and, to a lesser extent, Thicket age classes were distinct from those of more mature forests. Bird communities of Mid‐rotation and Mature age classes were indistinguishable from each other and were therefore combined into a single age class (Closed canopy). Pre‐thicket held significantly lower total bird density, but significantly higher migrant bird density, than this Closed canopy age class. Bird density was significantly higher in the second rotation in all age classes except for Pre‐thicket, but migrant density was significantly higher in Pre‐thicket in the second rotation. There was no difference in species richness between the first and second rotation.

Conclusions Differences between rotations are probably due to changes in vegetation structure, and the increase in second‐rotation forests in Ireland is likely to be a positive development for bird communities. Especially encouraging is the higher migrant bird density in second‐rotation Pre‐thicket, as some of these species are in decline throughout Europe. However, the largest differences in population density between rotations were exhibited by common species and such species will likely benefit most from future increases in the area of second‐rotation plantation forests.     

Reactivity-based analysis of domain structures in native replication protein A

Replication protein A (RPA) is an essential heterotrimeric ssDNA binding protein that participates in DNA repair, replication, and recombination. Though X-ray and NMR experiments have been used to determine three-dimensional structure models of the protein's domain fragments, a complete RPA structural model has not been reported. To test whether the fragment structures faithfully represent the same portions in the native solution-state protein, we have examined the structure of RPA under biologically relevant conditions. We have probed the location of multiple amino acids within the native RPA three-dimensional structure using reactivity of these amino acids toward proteolytic and chemical modification reagents. In turn, we evaluated different structural models by comparing the observed native RPA reactivities with anticipated reactivities based on candidate structural models. Our results show that our reactivity analysis approach is capable of critically assessing structure models and can be a basis for selecting the most relevant from among alternate models of a protein structure. Using this analytical approach, we verified the relevance of RPA fragment models to the native protein structure. Our results further indicate several important features of native RPA's structure in solution, such as flexibility at specific locations in RPA, particularly in the C-terminal region of RPA70. Our findings are consistent with reported DNA-free structural models and support the role of conformational change in the ssDNA binding mechanism of RPA.     

Determination of the sequence specificity of XIAP BIR domains by screening a combinatorial peptide library

Inhibitor of apoptosis (IAP) proteins regulate programmed cell death by inhibiting members of the caspase family of proteases. The X-chromosome-linked IAP (XIAP) contains three baculovirus IAP repeat (BIR) domains, which bind directly to the N-termini of target proteins including those of caspases-3, -7, and -9. In the present study, we defined the consensus sequences of the motifs that interact with the three BIR domains in an unbiased manner. A combinatorial peptide library containing four random residues at the N-terminus was constructed and screened using BIR domains as probes. We found that the BIR3 domain binds a highly specific motif containing an alanine or valine at the N-terminus (P1 position), an arginine or proline at the P3 position, and a hydrophobic residue (Phe, Ile, and Tyr) at the P4 position. The BIR2-binding motif is less stringent. Although it still requires an N-terminal alanine, it tolerates a wide variety of amino acids at P2-P4 positions. The BIR1 failed to bind to any peptides in the library. SPR analysis of individually synthesized peptides confirmed the library screening results. Database searches with the BIR2- and BIR3-binding consensus sequences revealed a large number of potential target proteins. The combinatorial library method should be readily applicable to other BIR domains or other types of protein modular domains.     

Development of the adhesive pad on climbing fig (Ficus pumila) stems from clusters of adventitious roots

Vines have different climbing strategies; one type, called clinging vines, has developed a specialized structure, the adhesive pad that secretes a sticky substance that adheres to almost any substrate. In this study on the climbing fig, Ficus pumila L., we report on the developmental anatomy of clusters of adventitious roots that become transformed into this unique structure. Clustered adventitious roots in F. pumila are initiated in pairs on either side of a vascular bundle at the 2nd to 3rd internodes of young stems. After emergence through the cortex and epidermis, root hairs form, which secrete a substance that stains positively for polysaccharide and protein. The adventitious roots and root hairs stick together forming the adhesive pad. Pads stick to almost any substrate. If the adventitious roots do not touch a substrate they usually dry up, if they touch moist soil they tend to branch and change to a terrestrial form. We discuss experiments on the shoot developmental behavior leading to adhesive pad formation and the possible roles of auxin.     

Preparation of novel anthranilic acids as antibacterial agents. Extensive evaluation of alternative amide bioisosteres connecting the A- and the B-rings

In the past few years, a significant effort has been devoted by Pharmacia toward the discovery of novel antibiotics. We have recently described the identification of an anthranilic acid lead 1 and the optimization resulting in the advanced lead 2. In this report, we describe the preparation of several selected amide bioisosteres connecting the A- and the B-rings. The E-alkene provided a rigid analog with equal potency to the corresponding amide. This indicates that the amide is not a recognition element rather acts as an appropriate spatial linker of the two important aryl A and B rings. The work here clearly demonstrates that the amide linker can be replaced with several functionalities without significant deterioration in the MIC activity.     

The influence of a native tree species mix component on bird communities in non‐native coniferous plantations in Ireland

Capsule Norway Spruce plantations with Scots Pine as a secondary tree species had higher bird densities than pure Norway Spruce. Shrub cover was the most important structural variable, influencing bird density, species richness and Simpson’s diversity.

Aims To investigate whether incorporating a native tree component into non‐native coniferous plantations had any effect on bird communities or vegetation structure.

Methods Birds were surveyed in plantations of Norway Spruce mixed with Oak and Scots Pine, each paired with a plantation of pure Norway Spruce. distance was used to generate bird densities. Bird density, species richness and Simpson’s diversity were compared between each mix type and pure Norway Spruce. glms were used to investigate relationships between structural components of plantations and bird data.

Results Bird communities of mixed plantations differed only slightly in their composition from pure Norway Spruce. Bird density was significantly higher in Scots Pine mixes than in Oak mixes or pure Norway Spruce. Neither species richness nor Simpson’s diversity differed significantly between the plantation types. Some vegetation components differed between the plantations and shrub cover was positively associated with bird density, species richness and Simpson’s diversity. The presence of rides also increased bird density.

Conclusions There is a positive effect on bird communities of including a native tree species in non‐native coniferous plantations, but the magnitude of the effect is small. The influence of shrub cover on birds suggests that forest management may play an important role in determining the utility of plantations for birds. We recommend the establishment of mixed tree species plantations where possible, although, in the case of Oak mixes, the Norway Spruce appeared to suppress growth of the Oak and thus may be restricting its effect on birds. Changes in management, such as planting Oaks in clumps or heavier thinning of the coniferous component, could address this problem.     

New Staphylinidae (Coleoptera) records with new collection data from New Brunswick and an addition to the fauna of Quebec: Staphylininae

Forty-four species of Staphylininae are newly reported from New Brunswick, bringing the total number of species known from the province to 126. Quedius criddlei (Casey) is reported for the first time from Quebec. Bisnius cephalotes (Gravenhorst) is removed from the faunal list of New Brunswick due to a lack of supporting voucher specimens. Additional locality data are presented for seven species either recently recorded from the province or with few previous records and little habitat data. We provide the first documented records of Atrecus americanus (Casey), Quedius erythrogaster Mannerheim, Quedius labradorensis labradorensis Smetana, Quedius plagiatus (Mannerheim), and Neobisnius terminalis (LeConte) from New Brunswick. Collection and habitat data are presented and discussed for all species.     

Dam inactivation in <Emphasis Type="Italic">Neisseria meningitidis</Emphasis>: prevalence among diverse hyperinvasive lineages

Background  

DNA adenine methyltransferase (Dam) activity is absent in many, but not all, disease isolates of Neisseria meningitidis, as a consequence of the insertion of a restriction endonuclease-encoding gene, the 'dam replacing gene' (drg) at the dam locus. Here, we report the results of a survey to assess the prevalence of drg in a globally representative panel of disease-associated meningococci.