Regulation of differentiation to the infective stage of the protozoan parasite Leishmania major by tetrahydrobiopterin

A critical step in the infectious cycle of Leishmania is the differentiation of parasites within the sand fly vector to the highly infective metacyclic promastigote stage. Here, we establish tetrahydrobiopterin (H4B) levels as an important factor controlling the extent of metacyclogenesis. H4B levels decline substantially during normal development, and genetic or nutritional manipulations showed that low H4B caused elevated metacyclogenesis. Mutants lacking pteridine reductase 1 (PTR1) had low levels of H4B, remained infectious to mice, and induced larger cutaneous lesions (hypervirulence). Thus, the control of pteridine metabolism has relevance to the mechanism of Leishmania differentiation and the limitation of virulence during evolution.     

Saline culture of crops: a genetic approach

Increasing salinity of soil and water threatens agriculture in arid and semiarid regions. By itself, the traditional engineering approach to the problem is no longer adequate. Genetic science offers the possibility of developing salt-tolerant crops, which, in conjunction with environmental manipulation, could improve agricultural production in saline regions and extend agriculture to previously unsuited regions.     

Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule

Human growth hormone (hGH) forms a 1:2 complex with the extracellular domain of its receptor-binding protein (hGHbp) as studied by crystallization, size exclusion chromatography, calorimetry, and a previously undescribed fluorescence quenching assay. These and other experiments with protein engineered variants of hGH have led to the identification of the binding determinants for two distinct but adjacent sites on hGH for the hGHbp, and the data indicated that there are two overlapping binding sites on the hGHbp for hGH. Furthermore, the binding of hGH to the hGHbp occurred sequentially; a first hGHbp molecule bound to site 1 on hGH and then a second hGHbp bound to site 2. Hormone-induced receptor dimerization is proposed to be relevant to the signal transduction mechanism for the hGH receptor and other related cytokine receptors.     

Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein

Leukotrienes are proinflammatory products of arachidonic acid oxidation by 5-lipoxygenase that have been shown to be involved in respiratory and cardiovascular diseases. The integral membrane protein FLAP is essential for leukotriene biosynthesis. We describe the x-ray crystal structures of human FLAP in complex with two leukotriene biosynthesis inhibitors at 4.0 and 4.2 angstrom resolution, respectively. The structures show that inhibitors bind in membrane-embedded pockets of FLAP, which suggests how these inhibitors prevent arachidonic acid from binding to FLAP and subsequently being transferred to 5-lipoxygenase, thereby preventing leukotriene biosynthesis. This structural information provides a platform for the development of therapeutics for respiratory and cardiovascular diseases.     

Review: The strobilurin fungicides

The original article to which this Correction refers was published in Pest Management Science 58 (7): 649–662 (2002).Copyright © 2004 Society of Chemical Industry     

East coast fever: 3. Chemoprophylactic immunization of cattle using oxytetracycline and a combination of theilerial strains

In the first of two experiments performed, 29 animals were immunized by chemoprophylaxis against either a combination of three theilerial strains, Theileria parva (Muguga), T. parva (Kiambu 5) and T. lawrencei (Serengeti transformed), or against one or two elements of the combination separately, and then challenged with either T. parva (Kiambu 1) or T. lawrencei (Solio KB1), both of which were known to be heterologous to T. parva (Muguga). The animals immunized against the combination had mild or inapparent reactions to challenge, whilst the susceptible control cattle and many of those immunized against one or two strains either had severe reactions of died.In the second experiment, 17 cattle immunized by chemoprophylaxis against the combination were challenged with lethal doses of three theilerial strains, T. parva (Entebbe 1), T. parva (Entebbe 2) and T. parva (Ukunda), recently isolated from two widely separated areas of East Africa. They had mild or inapparent reactions whilst 13 of 15 susceptible control cattle died.Chemoprophylaxis using a combination of theilerial strains and a limited oxytetracycline regimen was shown to be an effective means of immunizing cattle against East African theilerioses. The use of this technique as a method of immunizing cattle before exposure in the field is proposed.