No abstract

No abstract

No abstract

The neural cell adhesion molecule, NCAM, mediates Ca(2+)-independent cell-cell and cell-substratum adhesion via homophilic (NCAM-NCAM) and heterophilic (NCAM-non-NCAM molecules) binding. NCAM plays a key role in neural development, regeneration, and synaptic plasticity, including learning and memory consolidation. The crystal structure of a fragment comprising the three N-terminal Ig modules of rat NCAM has been determined to 2.0 A resolution. Based on crystallographic data and biological experiments we present a novel model for NCAM homophilic binding. The Ig1 and Ig2 modules mediate dimerization of NCAM molecules situated on the same cell surface (cis interactions), whereas the Ig3 module mediates interactions between NCAM molecules expressed on the surface of opposing cells (trans interactions) through simultaneous binding to the Ig1 and Ig2 modules. This arrangement results in two perpendicular zippers forming a double zipper-like NCAM adhesion complex.

Colorectal cancer (CRC) is the second most common cause of death due to cancer causing death in Europe, accounting for more than 200,000 deaths per year. Prognosis strongly depends on stage at diagnosis, and the disease can be cured in most cases if diagnosed at an early stage. We aimed to assess trends and recent developments in 5-year relative survival in European countries, with a special focus on age, stage at diagnosis and anatomical cancer subsite. Data from 25 population-based cancer registries from 16 European countries collected in the context of the EUROCARE-4 project were analyzed. Using period analysis, age-adjusted and age-specific 5-year relative survival was calculated by country, European region, stage and cancer subsite for time periods from 1988-1990 to 2000-2002. Survival substantially increased over time in all European regions. In general, increases were more pronounced in younger than in older patients, for earlier than for more advanced cancer stages and for rectum than for colon cancer. Substantial variation of CRC survival between European countries and between age groups persisted and even tentatively increased over time. There is a huge potential for reducing the burden of CRC in Europe by more widespread and equal delivery of existing options of effective early detection and curative treatment to the European population.With an estimated number of 436,000 new cases and 212,000 deaths in 2008, colorectal cancer (CRC) has become the most common cancer and the second most common cancer causing death in Europe.1 Incidence rates in European countries, which are likely to reflect risk factors associated with ''Western lifestyle'' are among the highest in the world.

No abstract

Ionotropic glutamate receptors (iGluRs) constitute a family of ligand-gated ion channels that are essential for mediating fast synaptic transmission in the central nervous system. This study presents a high-resolution X-ray structure of the competitive antagonist (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid (ATPO) in complex with the ligand-binding core of the receptor. Comparison with the only previous structure of the ligand-binding core in complex with an antagonist, 6,7-dinitro-2,3-quinoxalinedione (DNQX) (Armstrong, N.; Gouaux, E. Neuron 2000, 28, 165-181), reveals that ATPO and DNQX stabilize an open form of the ligand-binding core by different sets of interactions. Computational techniques are used to quantify the differences between these two ligands and to map the binding site. The isoxazole moiety of ATPO acts primarily as a spacer, and other scaffolds could potentially be used. Whereas agonists induce substantial domain closures compared to the apo structure, ATPO only induces minor conformational changes. These results are consistent with the hypothesis that domain closure is related to receptor activation. To facilitate the design of novel AMPA receptor antagonists, we present a modified model of the binding site that includes key residues involved in ligand recognition.

Several studies report varying incidence rates of cancer in subsites of the colorectum, as an increasing proportion appears to develop in the proximal colon. Varying incidence trends together with biological differences between the colorectal segments raise questions of whether lifestyle factors impact on the risk of cancer differently at colorectal subsites. We provide an updated overview of the risk of cancer at different colorectal subsites (proximal colon, distal colon, and rectum) according to BMI and physical activity to shed light on this issue. Cohort studies of colorectal cancer, published in English throughout 2010, were identified using PubMed. The risk estimates from 30 eligible studies were summarized for BMI and physical activity. A positive relationship was found between BMI and cancer for all colorectal subsites, but most pronounced for the distal colon [relative risk (RR) 1.59, 95% confidence interval (CI) 1.34-1.89]. For the proximal colon and rectum, the risk estimates were 1.24 (95% CI 1.08-1.42) and 1.23 (95% CI 1.02-1.48), respectively. Physical activity was related inversely to the risk of cancer at the proximal (RR 0.76, 95% CI 0.70-0.83) and distal colon (RR 0.77, 95% CI 0.71-0.83). Such a relationship could not be established for the rectum (RR 0.98, 95% CI 0.88-1.08). In conclusion, the results suggest minor differences in the associations of BMI and the risk of cancer between the colorectal subsites. For physical activity, the association does not seem to differ between the colonic subsites, but a difference was observed between the colon and the rectum, perhaps indicating that different mechanisms are operating in the development of colon and rectal cancer.