Pyruvate kinase deficiency in mice protects against malaria

The global health impact of malaria is enormous, with an estimated 300-500 million clinical cases and 1 million annual deaths. In humans, initial susceptibility to infection with Plasmodium species, disease severity and ultimate outcome of malaria (self-healing or lethal) are under complex genetic control. Alleles associated with sickle cell anemia, beta-thalassemia and deficiency in glucose-6-phosphate dehydrogenase have a protective effect against malaria and may have been retained by positive selection in areas of endemic malaria. Likewise, genetic variations in erythrocyte antigens and levels of host cytokines affect type and severity of disease. A mouse model of infection with Plasmodium chabaudi was used to study the genetic component of malaria susceptibility. Segregation analyses in informative F2 crosses derived from resistant C57BL/6J and susceptible A/J, C3H and SJL strains using extent of blood stage replication of the parasite and survival as traits mapped three P. chabaudi resistance (Char) loci on chromosomes 9 (Char1), 8 (Char2) and 17 (Char3, MHC-linked). Recombinant congenic strains AcB55 and AcB61 are unusually resistant to malaria despite carrying susceptibility alleles at Char1 and Char2. Malaria resistance in AcB55 and AcB61 is associated with splenomegaly and constitutive reticulocytosis, is inherited in an autosomal recessive fashion and is controlled by a locus on chromosome 3 (Char4). Sequencing of candidate genes from the Char4 region identified a loss-of-function mutation (269T-->A, resulting in the amino acid substitution I90N) in the pyruvate kinase gene (Pklr) that underlies the malaria resistance in AcB55 and AcB61. These results suggest that pyruvate kinase deficiency may similarly protect humans against malaria.     

In silico simulations reveal that replicators with limited dispersal evolve towards higher efficiency and fidelity

The emergence of functional replicases, acting quickly and with high accuracy, was crucial to the origin of life. Although where the first RNA molecules came from is still unknown, it is nevertheless assumed that catalytic RNA enzymes (ribozymes) with replicase function emerged at some early stage of evolution. The fidelity of copying is especially important because the mutation load limits the length of replicating templates that can be maintained by natural selection. An increase in template length is disadvantageous for a fixed digit copying fidelity, however, longer molecules are expected to be better replicases. An iteration for longer molecules with better replicase function has been suggested and analysed mathematically. Here we show that more efficient replicases can spread, provided they are adsorbed to a prebiotic mineral surface. A cellular automaton simulation reveals that copying fidelity, replicase speed and template efficiency all increase with evolution, despite the presence of molecular parasites, essentially because of reciprocal atruism ('within-species mutualism') on the surface, thus making a gradual improvement of replicase function more plausible.     

Toxicity of the common puffer fish in Hong Kong

Résumé L'origine et la nature probable de la toxicité chez deux espèces de poissons (Fugu etLagocephalus) a été étudiée. Les tissus énumérés dans l'ordre de toxicité décroissant sont les gonades, le foie et les muscles, avec une différence entre les deux sexes, les tissus mâle étant plus toxiques que les tissus femelles. On a éliminé la toxicité par un traitement thermique prolongé et maintenu à 120 °C.

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This work was financially supported by the Chinese University of Hong Kong, and the mice were generously supplied by Dr. {pcD. Huang}.     

Structural characterization of the molecular platform for type III secretion system assembly

Type III secretion systems (TTSSs) are multi-protein macromolecular 'machines' that have a central function in the virulence of many Gram-negative pathogens by directly mediating the secretion and translocation of bacterial proteins (termed effectors) into the cytoplasm of eukaryotic cells. Most of the 20 unique structural components constituting this secretion apparatus are highly conserved among animal and plant pathogens and are also evolutionarily related to proteins in the flagellar-specific export system. Recent electron microscopy experiments have revealed the gross 'needle-shaped' morphology of the TTSS, yet a detailed understanding of the structural characteristics and organization of these protein components within the bacterial membranes is lacking. Here we report the 1.8-A crystal structure of EscJ from enteropathogenic Escherichia coli (EPEC), a member of the YscJ/PrgK family whose oligomerization represents one of the earliest events in TTSS assembly. Crystal packing analysis and molecular modelling indicate that EscJ could form a large 24-subunit 'ring' superstructure with extensive grooves, ridges and electrostatic features. Electron microscopy, labelling and mass spectrometry studies on the orthologous Salmonella typhimurium PrgK within the context of the assembled TTSS support the stoichiometry, membrane association and surface accessibility of the modelled ring. We propose that the YscJ/PrgK protein family functions as an essential molecular platform for TTSS assembly.     

Passive harmonic mode locking of gain-guided solitons in erbium-doped fiber lasers

We report the experimental observation of passive harmonic mode locking of gain-guided solitons in erbium-doped fiber lasers either made of purely normal dispersion fibers or operating in the net normal cavity dispersion regime. Harmonic-2 and harmonic-3 mode locking states of the gain-guided solitons with supermode suppression larger than 35 dB have been obtained.     

水稻转基因表达的诱导因子麦黄酮的合成

麦黄酮广泛存在于单子叶植物中,最近已证明,麦黄酮及其甙是水稻转基因表达的主要诱导因子［１］,这一发现显示了麦黄酮在转基因研究和利用生物工程技术培育水稻新品种方面有重要价值．然而,麦黄酮在自然界中存在较微量,难于满足深入研究的需要,也限制了它在培育水稻...     

Systematic identification of genomic markers of drug sensitivity in cancer cells

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.     

Use of Data Mining to Support the Development of Knowledge Intensive CAD

In order to compete in the global manufacturing mar ke t, agility is the only possible solution to response to the fragmented market se gments and frequently changed customer requirements. However, manufacturing agil ity can only be attained through the deployment of knowledge. To embed knowledge into a CAD system to form a knowledge intensive CAD (KIC) system is one of way to enhance the design compatibility of a manufacturing company. The most difficu lt phase to develop a KIC system is to capitalize a ...     

Comparison of two non‐parametric models for daily traffic forecasting in Hong Kong

The most up‐to‐date annual average daily traffic (AADT) is always required for transport model development and calibration. However, the current‐year AADT data are not always available. The short‐term traffic flow forecasting models can be used to predict the traffic flows for the current year. In this paper, two non‐parametric models, non‐parametric regression (NPR) and Gaussian maximum likelihood (GML), are chosen for short‐term traffic forecasting based on historical data collected for the annual traffic census (ATC) in Hong Kong. These models are adapted as they are more flexible and efficient in forecasting the daily vehicular flows in the Hong Kong ATC core stations (in total of 87 stations). The daily vehicular flows predicted by these models are then used to calculate the AADT of the current year, 1999. The overall prediction and comparison results show that the NPR model produces better forecasts than the GML model using the ATC data in Hong Kong. Copyright © 2006 John Wiley _ Sons, Ltd.