Structure of astacin and implications for activation of astacins and zinc-ligation of collagenases.

Astacin, a digestive zinc-endopeptidase from the crayfish Astacus astacus L., is the prototype for the 'astacin family', which includes mammalian metallo-endopeptidases and developmentally regulated proteins of man, fruitfly, frog and sea urchin. Here we report the X-ray crystal structure of astacin, which reveals a deep active-site cleft, with the zinc at its bottom ligated by three histidines, a water molecule and a more remote tyrosine. The third histidine (His 102) forms part of a consensus sequence, shared not only by the members of the astacin family, but also by otherwise sequentially unrelated proteinases, such as vertebrate collagenases. It may therefore represent the elusive 'third' zinc ligand in these enzymes. The amino terminus of astacin is buried forming an internal salt-bridge with Glu 103, adjacent to His 102. Astacin pro-forms extended at the N terminus, as observed for some 'latent' mammalian astacin homologues, did not exhibit this 'active' conformation, indicating an activation mechanism reminiscent of trypsin-like serine proteinases.     

Morphological,biochemical and molecular changes during ectomycorrhiza development

Summary An ectomycorrhiza, a specialized root organ, is the result of a complex interaction leading to a finely-tuned symbiosis between a plant and a compatible ectomycorrhizal fungus. Ultrastructural observations combined with cytochemical and biochemical studies reveal that structural and metabolic changes in the symbiont cells lead to the final phenotype of the active ectomycorrhiza. In the present review these changes are interpreted as changes in gene expression and discussed within the context of ectomycorrhiza development. Recent genetic data indicate that the continued vegetative growth of the ectomycorrhizal hyphae and the root tissues, and their ability to switch to symbiotic organ formation, is basically controlled by developmentally critical genes. The activity of these symbiotic genes during the differentiation of ectomycorrhizas is associated with extensive changes in the concentration of particular polypeptides and protein biosynthesis. The present state of knowledge about the developmental biology of ectomycorrhizas allows only speculation about the events during their development.Puisant mes forces aux sources des galaxies En buvant la sève des arbres M. Jonasz     

Error rates in quadratic discrimination with constraints on the covariance matrices

In multivariate discrimination of several normal populations, the optimal classification procedure is based on quadratic discriminant functions. We compare expected error rates of the quadratic classification procedure if the covariance matrices are estimated under the following four models: (i) arbitrary covariance matrices, (ii) common principal components, (iii) proportional covariance matrices, and (iv) identical covariance matrices. Using Monte Carlo simulation to estimate expected error rates, we study the performance of the four discrimination procedures for five different parameter setups corresponding to standard situations that have been used in the literature. The procedures are examined for sample sizes ranging from 10 to 60, and for two to four groups. Our results quantify the extent to which a parsimonious method reduces error rates, and demonstrate that choosing a simple method of discrimination is often beneficial even if the underlying model assumptions are wrong.The authors wish to thank the editor and three referees for their helpful comments on the first draft of this article. M. J. Schmid supported by grants no. 2.724-0.85 and 2.038-0.86 of the Swiss National Science Foundation.     

A cannabinoid with cardiovascular activity but no overt behavioral effects

Summary Abnormal-⁸-tetrahydrocannabidiol (ABN-⁸-THC) failed to elicit central nervous system and cardiovascular effects in laboratory animals. Abnormal-cannabidiol (ABN-CBD) was also devoid of overt behavioral effects but produced marked hypotension with only slight bradycardia in anesthesized dogs.Acknowledgment. This work was supported by NIDA (grant No. DA-00574-01 and DA-00490) and Virginia Heart Society (grant No. RR-05697)     

Algae acquire vitamin B12 through a symbiotic relationship with bacteria

Vitamin B12 (cobalamin) was identified nearly 80 years ago as the anti-pernicious anaemia factor in liver, and its importance in human health and disease has resulted in much work on its uptake, cellular transport and utilization. Plants do not contain cobalamin because they have no cobalamin-dependent enzymes. Deficiencies are therefore common in strict vegetarians, and in the elderly, who are susceptible to an autoimmune disorder that prevents its efficient uptake. In contrast, many algae are rich in vitamin B12, with some species, such as Porphyra yezoensis (Nori), containing as much cobalamin as liver. Despite this, the role of the cofactor in algal metabolism remains unknown, as does the source of the vitamin for these organisms. A survey of 326 algal species revealed that 171 species require exogenous vitamin B12 for growth, implying that more than half of the algal kingdom are cobalamin auxotrophs. Here we show that the role of vitamin B12 in algal metabolism is primarily as a cofactor for vitamin B12-dependent methionine synthase, and that cobalamin auxotrophy has arisen numerous times throughout evolution, probably owing to the loss of the vitamin B12-independent form of the enzyme. The source of cobalamin seems to be bacteria, indicating an important and unsuspected symbiosis.     

Common Molecular Mechanisms of Mammary Gland Development and Breast Cancer

During its lifetime, the mammary gland undergoes many phases of development and differentiation. Much of this occurs during puberty, when the ductal epithelium expands by branching morphogenesis, invading the surrounding fat pad to form an organised mammary tree. Throughout its existence, the epithelium will go through several cycles of proliferation and cell death during pregnancy, lactation and involution. Many of the signalling mechanisms which control the initial invasion of the fat pad by the epithelium, and regulate its continuing plasticity, can be harnessed or corrupted by tumour cells in order to support their aberrant growth and progression towards invasion. This is true not just for the epithelial cells themselves but also for cells in the surrounding microenvironment, including fibroblasts, macrophages and adipocytes. This review examines the complex web of signalling and adhesion interactions controlling branching morphogenesis, and how their alteration can promote malignancy. Current in vivo and in vitro mammary gland models are also discussed. (Part of a Multi-author Review)     

A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21

We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5' of IL21; meta-analysis P = 1.3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease.     

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.     

Network Motif Detection： Algorithms, Parallel and Cloud Computing,and Related Tools

Network motif is defined as a frequent and unique subgraph pattern in a network, and the search involves counting all the possible instances or listing all patterns, testing isomorphism known as NP-hard and large amounts of repeated processes for statistical evaluation. Although many efficient algorithms have been introduced, exhaustive search methods are still infeasible and feasible approximation methods are yet implausible.Additionally, the fast and continual growth of biological networks makes the problem more challenging. As a consequence, parallel algorithms have been developed and distributed computing has been tested in the cloud computing environment as well. In this paper, we survey current algorithms for network motif detection and existing software tools. Then, we show that some methods have been utilized for parallel network motif search algorithms with static or dynamic load balancing techniques. With the advent of cloud computing services, network motif search has been implemented with MapReduce in Hadoop Distributed File System(HDFS), and with Storm, but without statistical testing. In this paper, we survey network motif search algorithms in general, including existing parallel methods as well as cloud computing based search, and show the promising potentials for the cloud computing based motif search methods.