6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile as cathepsin S inhibitors

6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile analogues were identified as potent and selective cathepsin S inhibitor against both purified enzyme and in human JY cell based cellular assays. This core has a very stable thio-trapping nitrile war-head in comparison with the well reported pyrimidine-2-carbonitrile cysteine cathepsin inhibitors. Compound 47 is also very potent in in vivo mouse spleenic Lip10 accumulation assays.     

Macrocyclic BACE-1 inhibitors acutely reduce Aβ in brain after po application

A series of macrocyclic peptidic BACE-1 inhibitors was designed. While potency on BACE-1 was rather high, the first set of compounds showed poor brain permeation and high efflux in the MDRI–MDCK assay. The replacement of the secondary benzylamino group with a phenylcyclopropylamino group maintained potency on BACE-1, while P-glycoprotein-mediated efflux was significantly reduced and brain permeation improved. Several compounds from this series demonstrated acute reduction of Aβ in human APP-wildtype transgenic (APP51/16) mice after oral administration.     

Rural health centres, communities and malaria case detection in Zambia using mobile telephones: a means to detect potential reservoirs of infection in unstable transmission conditions

Background

Zoonotic malaria caused by Plasmodium knowlesi is an important, but newly recognized, human pathogen. For the first time, post-mortem findings from a fatal case of knowlesi malaria are reported here.

Case presentation

A formerly healthy 40 year-old male became symptomatic 10 days after spending time in the jungle of North Borneo. Four days later, he presented to hospital in a state of collapse and died within two hours. He was hyponatraemic and had elevated blood urea, potassium, lactate dehydrogenase and amino transferase values; he was also thrombocytopenic and eosinophilic. Dengue haemorrhagic shock was suspected and a post-mortem examination performed. Investigations for dengue virus were negative. Blood for malaria parasites indicated hyperparasitaemia and single species P. knowlesi infection was confirmed by nested-PCR. Macroscopic pathology of the brain and endocardium showed multiple petechial haemorrhages, the liver and spleen were enlarged and lungs had features consistent with ARDS. Microscopic pathology showed sequestration of pigmented parasitized red blood cells in the vessels of the cerebrum, cerebellum, heart and kidney without evidence of chronic inflammatory reaction in the brain or any other organ examined. Brain sections were negative for intracellular adhesion molecule-1. The spleen and liver had abundant pigment containing macrophages and parasitized red blood cells. The kidney had evidence of acute tubular necrosis and endothelial cells in heart sections were prominent.

Conclusions

The overall picture in this case was one of systemic malaria infection that fit the WHO classification for severe malaria. Post-mortem findings in this case were unexpectedly similar to those that define fatal falciparum malaria, including cerebral pathology. There were important differences including the absence of coma despite petechial haemorrhages and parasite sequestration in the brain. These results suggest that further study of knowlesi malaria will aid the interpretation of, often conflicting, information on malaria pathophysiology in humans.     

Characterization of airborne molds, endotoxins, and glucans in homes in New Orleans after Hurricanes Katrina and Rita

In August and September 2005, Hurricanes Katrina and Rita caused breeches in the New Orleans, LA, levee system, resulting in catastrophic flooding. The city remained flooded for several weeks, leading to extraordinary mold growth in homes. To characterize the potential risks of mold exposures, we measured airborne molds and markers of molds and bacteria in New Orleans area homes. In October 2005, we collected air samples from 5 mildly water-damaged houses, 15 moderately to heavily water-damaged houses, and 11 outdoor locations. The air filters were analyzed for culturable fungi, spores, (1-->3,1-->6)-beta-D-glucans, and endotoxins. Culturable fungi were significantly higher in the moderately/heavily water-damaged houses (geometric mean=67,000 CFU/m3) than in the mildly water-damaged houses (geometric mean=3,700 CFU/m3) (P=0.02). The predominant molds found were Aspergillus niger, Penicillium spp., Trichoderma, and Paecilomyces. The indoor and outdoor geometric means for endotoxins were 22.3 endotoxin units (EU)/m3 and 10.5 EU/m3, respectively, and for (1-->3,1-->6)-beta-D-glucans were 1.7 microg/m3 and 0.9 microg/m3, respectively. In the moderately/heavily water-damaged houses, the geometric means were 31.3 EU/m3 for endotoxins and 1.8 microg/m3 for (1-->3,1-->6)-beta-D-glucans. Molds, endotoxins, and fungal glucans were detected in the environment after Hurricanes Katrina and Rita in New Orleans at concentrations that have been associated with health effects. The species and concentrations were different from those previously reported for non-water-damaged buildings in the southeastern United States.     

Rapid ecological turnover and its impact on Neanderthal and other human populations

The latter part of the last glaciation, 50,000-12,000 years ago (kya), was characterized by a rapidly changing climate, cold conditions and corresponding vegetation and faunal turnover. It also coincided with the extinction of the Neanderthals and the expansion of modern human populations. Established views of modern human superiority over Neanderthals as the cause of their extinction are under attack as recent work shows that Neanderthals were capable of behaviour that is regarded as modern. As we discuss here, the exact nature of biological and cultural interactions between Neanderthals and other human groups between 50 kya and 30 kya is currently hotly contested. The extinction of the Neanderthals, and other modern human lineages, now appears to have been a drawn-out, climate-related affair.     

Observations on the calcium dependence and reversibility of cobalamin transport across the outer membrane of Escherichia coli

The calcium dependence of cobalamin (Cbl) binding to the BtuB protein of Escherichia coli and the reversibility of its function in the transport of Cbl across the outer membrane have been examined. The results show that the two calcium-binding sites in BtuB that were identified previously by others are responsible for the calcium dependence of high affinity Cbl binding. The affinity of the pure BtuB protein for Cbl was approximately 1000-fold higher in the presence of saturating levels of calcium than in its absence. The affinities of BtuB for both Cbl and calcium were decreased by insertion of alanine residues at position 51 of the mature protein and were increased by several mutations and deletions in the TonB box. Experiments on the uptake of Cbl into the periplasmic space showed that this process is reversible and that the exit of Cbl back into the medium does not require the protonmotive force. Our interpretation of these results is that the role of the TonB-ExbB-ExbD complex, potentiated by the protonmotive force, is to reduce the affinity of the Cbl-binding site, thus increasing the rate of Cbl release into the periplasmic space. The evidence also indicates that access of the Cbl-binding site of BtuB to the periplasmic space does not require removal of the hatch domain from the barrel.     

Selective perturbation of the myosin recovery stroke by point mutations at the base of the lever arm affects ATP hydrolysis and phosphate release

After ATP binding the myosin head undergoes a large structural rearrangement called the recovery stroke. This transition brings catalytic residues into place to enable ATP hydrolysis, and at the same time it causes a swing of the myosin lever arm into a primed state, which is a prerequisite for the power stroke. By introducing point mutations into a subdomain interface at the base of the myosin lever arm at positions Lys(84) and Arg(704), we caused modulatory changes in the equilibrium constant of the recovery stroke, which we could accurately resolve using the fluorescence signal of single tryptophan Dictyostelium myosin II constructs. Our results shed light on a novel role of the recovery stroke: fine-tuning of this reversible equilibrium influences the functional properties of myosin through controlling the effective rates of ATP hydrolysis and phosphate release.