Secretases as therapeutic targets for Alzheimer's disease

Accumulation of amyloid-β (Aβ) is widely accepted as the key instigator of Alzheimer’s disease (AD). The proposed mechanism is that accumulation of Aβ results in inflammatory responses, oxidative damages, neurofibrillary tangles and, subsequently, neuronal/synaptic dysfunction and neuronal loss. Given the critical role of Aβ in the disease process, the proteases that produce this peptide are obvious targets. The goal would be to develop drugs that can inhibit the activity of these targets. Protease inhibitors have proved very effective for treating other disorders such as AIDS and hypertension. Mutations in APP (amyloid-β precursor protein), which flanks the Aβ sequence, cause early-onset familial AD, and evidence has pointed to the APP-to-Aβ conversion as a possible therapeutic target. Therapies aimed at modifying Aβ-related processes aim higher up the cascade and are therefore more likely to be able to alter the progression of the disease. However, it is not yet fully known whether the increases in Aβ levels are merely a result of earlier events that were already causing the disease.     

Cardiovascular disease mortality in Canada.

During the past two decades approximately one half of all deaths in Canada were due to cardiovascular diseases. Ischemic heart disease and cerebrovascular disease caused more than 60% and 20% of those deaths respectively. The mortality rates for ischemic heart disease in males increased slightly until 1965 and then dropped substantially, whereas the rates for females, which were declining at least since the early 1960s, accelerated in their decline. As a consequence, the rates for males remain almost twice as high as those for females. The reductions were initially observed in males 25 to 34 years old and in all age groups of females, but became apparent in a wider range of ages in the second period reviewed (1969 through 1977). The mortality of cerebrovascular disease has gradually diminished for both sexes since the 1950s, but the decline has been more pronounced among females, who originally had the higher rate. Marked geographic differences in mortality rates still exist in Canada despite the decline in death rates for both ischemic heart disease and cerebrovascular disease in all regions of the country. Surprising regional differences in times of onset of these declines have been demonstrated. For ischemic heart disease Ontario maintains the highest and the Prairies the lowest mortality rates. Quebec, despite a sustained decline, still ranks third, while the Pacific region shows the second-lowest rates in the country. The Atlantic region showed the lowest rates of decline in the period reviewed. The reduction in the mortality of ischemic heart disease in Canada (16.4% between 1969 and 1977) must be considered real for a variety of reasons. Direct evidence is not available to elucidate whether the reduction is the consequence of reduced incidence, increased survival or a combination of the two factors. The potential role of various factors that may have contributed to this decline is briefly discussed in this article.     

Substrate-binding loop interactions with pseudouridine trigger conformational changes that promote catalytic efficiency of pseudouridine kinase PUKI

Pseudouridine, one major RNA modification, is catabolized into uracil and ribose-5′-phosphate by two sequential enzymatic reactions. In the first step, pseudouridine kinase (PUKI) phosphorylates pseudouridine to pseudouridine 5′-monophosphate. High-fidelity catalysis of pseudouridine by PUKI prevents possible disturbance of in vivo pyrimidine homeostasis. However, the molecular basis of how PUKI selectively phosphorylates pseudouridine over uridine with >100-fold greater efficiency despite minor differences in their K_m values has not been elucidated. To investigate this selectivity, in this study we determined the structures of PUKI from Escherichia coli strain B (EcPUKI) in various ligation states. The structure of EcPUKI was determined to be similar to PUKI from Arabidopsis thaliana, including an α/β core domain and β-stranded small domain, with dimerization occurring via the β-stranded small domain. In a binary complex, we show that Ser30 in the substrate-binding loop of the small domain mediates interactions with the hallmark N1 atom of pseudouridine nucleobase, causing conformational changes in its quaternary structure. Kinetic and fluorescence spectroscopic analyses also showed that the Ser30-mediated interaction is a prerequisite for conformational changes and subsequent catalysis by EcPUKI. Furthermore, S30A mutation or EcPUKI complexed with other nucleosides homologous to pseudouridine but lacking the pseudouridine-specific N1 atom did not induce such conformational changes, demonstrating the catalytic significance of the proposed Ser30-mediated interaction. These analyses provide structural and functional evidence for a pseudouridine-dependent conformational change of EcPUKI and its functional linkage to catalysis.     

Pitaya (stenocereus spp., Cactaceae): An ancient and modern fruit crop of Mexico

Pitayasfrom various species were an important edible fruit in semiarid lands of tropical and subtropical Mexico in ancient times. Recently, farmers have been cultivating plants selected from the wild, such as Stenocereus queretaroensis in the Sayula Basin of Jalisco. These cacti can flower and produce fruit before the onset of the summer rainy period. Their fruits have an attractively colored pulp (often dark red) with digestible seeds and without the nasty glochids found on cactus pears. The sugar content is 10 to 11%. The shelf life is only a few days, as the fruits tend to dehisce longitudinally. Pitayas bring a competitive price in local markets, resulting in a substantial financial return with relatively low inputs of water, fertilizer, and pesticides.     

The complete mitochondrial genome of human parasitic roundworm, Ascaris lumbricoides

The genome length of the Ascaris lumbricoides, human parasitic roundworm, is 14,281 bp with a nucleotide composition of 22.1% A, 49.8% T, 7.8% C, and 20.3% G. The genome consists of 12 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and 1 control region.     

Evaluation of a high throughput toxicity biosensor and comparison with a Daphnia magna bioassay

A high throughput toxicity biosensor has been designed and constructed using recombinant Escherichia coli cells, containing stress specific promoters (recA, fabA, or katG) or constitutive promoters (lac) fused to luciferase genes originating from Vibrio fisheri. These genetically engineered cells were immobilized in 96 well plates. By optimizing cell immobilization conditions and the strains' response specificity to toxic chemicals, bioluminescent outputs decreased or increased dose-dependently upon adding test chemicals. However, to date the toxicity data obtained using this biosensor have not been compared with the results of other toxicity tests. Phenolics were chosen to evaluate the correlation between the LD50 and the EC50 (GC2) or EC120 (DPD2540) of Daphnia magna and E. coli, respectively. Toxicity data obtained from constitutive strains by bioluminescent level decrements were compared with the results from D. magna as a standard. LD50 values were used as parameters of D. magna toxicity and EC50 of EC120 values were used for the immobilized biosensor. In the DPD2540 test, phenolics, membrane damaging toxic chemicals, for testing immobilized stress specific bacterial strains trigger dose-dependant bioluminescence increase within specific concentration. Although the stress specific responsiveness from the strains could not be compared with D. magna's LD50 values, these responses offer additional information, such as upon the mode of toxic action in the sample, in addition to the cellular toxicity results as indicated by the EC50. This novel high throughput toxicity biosensor can be implemented to investigate the toxicity of any other soluble materials, and can be used as a standardization tool for the evaluation of toxicity.