Capacity strengthening in malaria research: the Gates Malaria Partnership

The Gates Malaria Partnership (GMP) includes five African and four European partner institutions. Its research programme has five priority areas involving an extensive range of field-based studies. GMP research has contributed significantly to the development of new research consortia investigating strategies for improving means of malaria control, and has already had an impact on policy and practice. A substantial investment in innovative training activities in malaria has enhanced knowledge and practice of malaria control at all levels from policy making to local community involvement. Capacity development, notably through a PhD programme, has been an underlying feature of all aspects of the programme.     

Small efficient cell-penetrating peptides derived from scorpion toxin maurocalcine

Maurocalcine is the first demonstrated example of an animal toxin peptide with efficient cell penetration properties. Although it is a highly competitive cell-penetrating peptide (CPP), its relatively large size of 33 amino acids and the presence of three internal disulfide bridges may hamper its development for in vitro and in vivo applications. Here, we demonstrate that several efficient CPPs can be derived from maurocalcine by replacing Cys residues by isosteric 2-aminobutyric acid residues and sequence truncation down to peptides of up to 9 residues in length. A surprising finding is that all of the truncated maurocalcine analogues possessed cell penetration properties, indicating that the maurocalcine is a highly specialized CPP. Careful examination of the cell penetration properties of the truncated analogues indicates that several maurocalcine-derived peptides should be of great interest for cell delivery applications where peptide size matters.     

Novel mechanisms of early upper and lower urinary tract patterning regulated by RetY1015 docking tyrosine in mice

Mutations in the receptor tyrosine kinase RET are associated with congenital anomalies of kidneys or urinary tract (CAKUT). RET tyrosine Y1015 is the docking site for PLCγ, a major regulator of RET signaling. Abrogating signaling via Y1015 causes CAKUT that are markedly different than renal agenesis in Ret-null or RetY1062F mutant mice. We performed analysis of Y1015F mutant upper and lower urinary tracts in mice to delineate its molecular and developmental roles during early urinary tract formation. We found that the degeneration of the common nephric ducts (CND), the caudal-most Wolffian duct (WD) segment, depends on Y1015 signals. The CNDs in Y1015F mutants persist owing to increased proliferation and reduced apoptosis, and showed abundance of phospho-ERK-positive cells. In the upper urinary tract, the Y1015 signals are required for proper patterning of the mesonephros and metanephros. Timely regression of mesonephric mesenchyme and proper demarcation of mesonephric and metanephric mesenchyme from the WD depends on RetY1015 signaling. We show that the mechanism of de novo ectopic budding is via increased ERK activity due to abnormal mesenchymal GDNF expression. Although reduction in GDNF dosage improved CAKUT it did not affect delayed mesenchyme regression. Experiments using whole-mount immunofluorescence confocal microscopy and explants cultures of early embryos with ERK-specific inhibitors suggest an imbalance between increased proliferation, decreased apoptosis and increased ERK activity as a mechanism for WD defects in RetY1015F mice. Our work demonstrates novel inhibitory roles of RetY1015 and provides a possible mechanistic explanation for some of the confounding broad range phenotypes in individuals with CAKUT.     

Overcoming fluconazole resistance in Candida albicans clinical isolates with tetracyclic indoles

Continuing efforts to discover novel means of combating fluconazole resistance in Candida albicans have identified an indole derivative that sensitizes strains demonstrating resistance to fluconazole. This tetracycle (3, ML229) does not appear to act through established Hsp90 or calcineurin pathways to chemosensitize C. albicans, as determined in Saccharomyces cerevisiae models, and may be a useful probe to uncover alternative resistance pathways.     

4-Piperidin-4-ylidenemethyl-benzamides as δ-opioid receptor agonists for CNS indications: identifying clinical candidates

A series of 4-piperidin-4-ylidenemethyl-benzamide δ-opioid receptor agonists is described with an emphasis on balancing the potency, subtype selectivity and in vitro ADME and safety properties. The three sites impacting SAR are substitutions on the aryl group (R(1)), the piperidine nitrogen (R(2)), and the amide (R(3)). Each region contributes to the balance of properties for δ opioid activity and a desirable CNS profile, and two clinical candidates (20 and 24) were advanced.     

Differential changes of fat-soluble vitamins and pollutants during lactation in northern elephant seal mother-pup pairs

We investigated the changes of vitamins A and E as well as PCBs and DDTs during lactation in northern elephant seal (Mirounga angustirostris) mother-pup pairs. On average, milk vitamin A concentrations were 6 times higher during late lactation than during early lactation, a pattern that differs dramatically from terrestrial mammals. Vitamin A concentrations also significantly increased in the inner blubber throughout lactation, whereas they remained constant in the outer blubber. Similar dynamics were observed for PCBs and DDTs in maternal blubber and milk. Blubber appears to be an important storage site for vitamin A and organochlorines in seals and a direct transfer of those molecules to the mammary gland may occur. The dynamics of vitamin A, PCBs and DDTs differed from those of vitamin E. There was a significant drop in milk vitamin E concentrations between early and late lactation, which is the usual pattern observed in terrestrial mammals. The dynamics of vitamin E in the blubber layers also differed from those of vitamin A, suggesting different mechanisms of mobilization and transfer into the milk.     

Corridor network design in hinterland transportation systems

In this paper the design of the service network in intermodal barge transport is studied. The network of inland barge terminals is modelled to demonstrate potential cooperations in a corridor network. Cooperation between inland terminals leads to bundling of freight flows in the hinterland of major ports. A service network design model for intermodal barge transport is developed and applied to the hinterland network of the port of Antwerp in Belgium. Selected cooperation schemes are simulated by means of a discrete event simulation model for intermodal barge transport and compared with simulation results of bundling in the port area. Cooperation between inland terminals offers an opportunity to attain economies of scale, but may not be perceived as a sole solution for reducing waiting times of inland barges at sea terminals. A combination of bundling measures in the port area and in the hinterland may be necessary to improve the intermodal transport chain.     

American social psychology: Examining the contours of the 1970s crisis

Throughout the 1960s and 1970s, social psychologists diagnosed their field as suffering a state of disciplinary crisis. The crisis was a multifaceted one, but issues of methodology, social relevance, and disciplinary, philosophical, and theoretical orientation were the primary areas of concern. Given that these issues have been prominent ones throughout the history of the social and behavioral sciences, it becomes necessary to look to the immediate context of the 1970s crisis to understand how and why a disciplinary crisis came to be diagnosed. The present analysis suggests that the crisis reflected the larger crisis in American society and also drew on the language of crisis prevalent at the time. Employing this language may have offered the field a method of making sense of, reframing, and redirecting internal and external critiques of the discipline.