Relationship between multiple sequence alignments and quality of protein comparative models

Comparative modeling is the method of choice, whenever applicable, for protein structure prediction, not only because of its higher accuracy compared to alternative methods, but also because it is possible to estimate a priori the quality of the models that it can produce, thereby allowing the usefulness of a model for a given application to be assessed beforehand. By and large, the quality of a comparative model depends on two factors: the extent of structural divergence between the target and the template and the quality of the sequence alignment between the two protein sequences. The latter is usually derived from a multiple sequence alignment (MSA) of as many proteins of the family as possible, and its accuracy depends on the number and similarity distribution of the sequences of the protein family. Here we describe a method to evaluate the expected difficulty, and by extension accuracy, of a comparative model on the basis of the MSA used to build it. The parameter that we derive is used to compare the results obtained in the last two editions of the Critical Assessment of Methods for Structure Prediction (CASP) experiment as a function of the difficulty of the modeling exercise. Our analysis demonstrates that the improvement in the scope and quality of comparative models between the two experiments is largely due to the increased number of available protein sequences and to the consequent increased chance that a large and appropriately spaced set of protein sequences homologous to the proteins of interest is available.     

Neuronal mechanisms for illusory brightness perception in humans

Biological visual systems are extraordinarily capable of recovering the shape and brightness of objects from sparse and fragmentary information. Using functional magnetic imaging, we show that two associative areas of the dorsal pathway--in the caudal region of the intrapariatal sulcus and in the lateral occipital sulcus--respond specifically to the Craik-O'Brien-Cornsweet illusion generated by high-pass filtered edges. Other visual areas, including primary visual cortex, also respond strongly to the retinotopic location of the edge, but these areas respond equally well to a line of matched contrast and detectability, rather than specifically to the brightness illusion. The reconstruction of surface and/or its brightness seems to be achieved by associative areas from the information about visual features provided by the primary visual cortices, even where there is no physical difference in luminance.     

Genetic variation in the HSD17B1 gene and risk of prostate cancer

Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17β-hydroxysteroid dehydrogenase 1, an enzyme that converts dihydroepiandrosterone to the testosterone precursor Δ5-androsterone-3β,17β-diol and converts estrone to estradiol. The Breast and Prostate Cancer Cohort Consortium researchers systematically characterized variation in HSD17B1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,290 prostate cancer cases and 9,367 study-, age-, and ethnicity-matched controls. We found no evidence that HSD17B1 htSNPs (including the nonsynonymous coding SNP S312G) or htSNP haplotypes were associated with risk of prostate cancer or tumor stage in the pooled multiethnic sample or in U.S. and European whites. Analyses stratified by age, body mass index, and family history of disease found no subgroup-specific associations between these HSD17B1 htSNPs and prostate cancer. We found significant evidence of heterogeneity in associations between HSD17B1 haplotypes and prostate cancer across ethnicity: one haplotype had a significant (p < 0.002) inverse association with risk of prostate cancer in Latinos and Japanese Americans but showed no evidence of association in African Americans, Native Hawaiians, or whites. However, the smaller numbers of Latinos and Japanese Americans in this study makes these subgroup analyses less reliable. These results suggest that the germline variants in HSD17B1 characterized by these htSNPs do not substantially influence the risk of prostate cancer in U.S. and European whites.     

Ten years of predictions ... and counting

The CASP experiment has been run every other year since 1994. Its objective is to subject the available structure prediction methods to a blind test. This is a short report of the highlights of its last edition. 'Men who wish to know about the world must learn about it in its particular details' (Heraclitus of Ephesus, 535-475 bc).     

Innate immunity and inflammation in ageing: a key for understanding age-related diseases

The process of maintaining life for the individual is a constant struggle to preserve his/her integrity. This can come at a price when immunity is involved, namely systemic inflammation. Inflammation is not per se a negative phenomenon: it is the response of the immune system to the invasion of viruses or bacteria and other pathogens. During evolution the human organism was set to live 40 or 50 years; today, however, the immune system must remain active for much a longer time. This very long activity leads to a chronic inflammation that slowly but inexorably damages one or several organs: this is a typical phenomenon linked to ageing and it is considered the major risk factor for age-related chronic diseases. Alzheimer's disease, atherosclerosis, diabetes and even sarcopenia and cancer, just to mention a few – have an important inflammatory component, though disease progression seems also dependent on the genetic background of individuals. Emerging evidence suggests that pro-inflammatory genotypes are related to unsuccessful ageing, and, reciprocally, controlling inflammatory status may allow a better chance of successful ageing. In other words, age-related diseases are "the price we pay" for a life-long active immune system: this system has also the potential to harm us later, as its fine tuning becomes compromised. Our immune system has evolved to control pathogens, so pro-inflammatory responses are likely to be evolutionarily programmed to resist fatal infections with pathogens aggressively. Thus, inflammatory genotypes are an important and necessary part of the normal host responses to pathogens in early life, but the overproduction of inflammatory molecules might also cause immune-related inflammatory diseases and eventually death later. Therefore, low responder genotypes involved in regulation of innate defence mechanisms, might better control inflammatory responses and age-related disease development, resulting in an increased chance of long life survival in a "permissive" environment with reduced pathogen load, medical care and increased quality of life.     

Porin and cytochrome oxidase containing contact sites involved in the oxidation of cytosolic NADH

Cytochrome c (cyto-c) added to isolated mitochondria promotes the oxidation of extra-mitochondrial NADH and the reduction of molecular oxygen associated to the generation of an electrochemical membrane potential available for ATP synthesis. The electron transport pathway activated by exogenous cyto-c molecules is completely distinct from the one catalyzed by the respiratory chain. Dextran sulfate (500 kDa), known to interact with porin (the voltage-dependent anion channel), other than to inhibit the release of ATP synthesized inside the mitochondria, greatly decreases the activity of exogenous NADH/cyto-c system of intact mitochondria but has no effect on the reconstituted system made of mitoplasts and external membrane preparations. The results obtained are consistent with the existence of specific contact sites containing cytochrome oxidase and porin, as components of the inner and the outer membrane respectively, involved in the oxidation of cytosolic NADH. The proposal is put forward that the bi-trans-membrane electron transport chain activated by cytosolic cyto-c becomes, in physio-pathological conditions: (i) functional in removing the excess of cytosolic NADH; (ii) essential for cell survival in the presence of an impairment of the first three respiratory complexes; and (iii) an additional source of energy at the beginning of apoptosis.