Heterocyclic analogues of squamocin as inhibitors of mitochondrial complex I. On the role of the terminal lactone of annonaceous acetogenins

Heterocyclic analogues of squamocin have been semisynthesized by condensation reactions between squamocin-derived alpha-keto esters and heterodinucleophiles. The strong complex I inhibitory potency of squamocin-benzimidazole, a hybrid derivative, illustrates for the first time the functional analogy existing between the terminal butenolide of annonaceous acetogenins and heteroaromatic substructures of classic inhibitors of the enzyme. This finding supports the categorization of this atypical group of inhibitors as antagonists of the ubiquinone substrates. In addition, competition experiments of squamocin-benzimidazole versus squamocin and rolliniastatin-2 suggest that the binding of this hybrid inhibitor is responsible for a negative allosteric effect at the level of the first ubiquinone-binding site (A site) of mitochondrial complex I. This result supports the existence of a large cooperatively regulated inhibitor/ubiquinone-binding pocket located within the catalytic core of the enzyme, consisting of the association of the previously defined affinity sites A and B.     

The residue 179 is involved in product specificity of the <Emphasis Type="Italic">Bacillus circulans</Emphasis> DF 9R cyclodextrin glycosyltransferase

Cyclodextrin glycosyltransferases (CGTases) are important enzymes in biotechnology because of their ability to produce cyclodextrin (CD) mixtures from starch whose relative composition depends on enzyme source. A multiple alignment of 46 CGTases and Shannon entropy analysis allowed us to find differences and similarities that could be related to product specificity. Interestingly, position 179 has Gly in all the CGTases except in that from Bacillus circulans DF 9R which possesses Gln. The absence of a side chain at that position has been considered as a strong requirement for substrate binding and cyclization process. Therefore, we constructed two mutants of this enzyme, Q179L and Q179G. The activity and kinetic parameters of Q179G remained unchanged while the Q179L mutant showed a different CDs ratio, a lower catalytic efficiency, and a decreased ability to convert starch into CDs. We show that position 179 is involved in CGTase product specificity and must be occupied by Gly—without a side chain—or by amino acid residues able to interact with the substrate through hydrogen bonds in a way that the cyclization process occurs efficiently. These findings are also explained on the basis of a structural model.     

Developmental origin of a major difference in sensory patterning between zebrafish and bluefin tuna

The posterior lateral line system (PLL) of teleost fish comprises a number of mechanosensory organs arranged in defined patterns on the body surface. Embryonic patterns are largely conserved among teleosts, yet adult patterns are highly diverse. Although changes in pattern modify the perceptual abilities of the system, their developmental origin remains unknown. Here we compare the processes that underlie the formation of the juvenile PLL pattern in Thunnus thynnus, the bluefin tuna, to the processes that were elucidated in Danio rerio, the zebrafish. In both cases, the embryonic PLL comprises five neuromasts regularly spaced along the horizontal myoseptum, but the juvenile PLL comprises four roughly parallel anteroposterior lines in zebrafish, whereas it is a simple dorsally arched line in tuna fish. We examined whether this difference involves evolutionary novelties, and show that the same mechanisms mediate the transition from embryonic to juvenile patterns in both species. We conclude that the marked difference in juveniles depends on a single change (dorsal vs. ventral migration of neuromasts) in the first days of larval life.     

Social inequalities and mortality in europe - results from a large multi-national cohort

Background

Socio-economic inequalities in mortality are observed at the country level in both North America and Europe. The purpose of this work is to investigate the contribution of specific risk factors to social inequalities in cause-specific mortality using a large multi-country cohort of Europeans.

Methods

A total of 3,456,689 person/years follow-up of the European Prospective Investigation into Cancer and Nutrition (EPIC) was analysed. Educational level of subjects coming from 9 European countries was recorded as proxy for socio-economic status (SES). Cox proportional hazard model''s with a step-wise inclusion of explanatory variables were used to explore the association between SES and mortality; a Relative Index of Inequality (RII) was calculated as measure of relative inequality.

Results

Total mortality among men with the highest education level is reduced by 43% compared to men with the lowest (HR 0.57, 95% C.I. 0.52–0.61); among women by 29% (HR 0.71, 95% C.I. 0.64–0.78). The risk reduction was attenuated by 7% in men and 3% in women by the introduction of smoking and to a lesser extent (2% in men and 3% in women) by introducing body mass index and additional explanatory variables (alcohol consumption, leisure physical activity, fruit and vegetable intake) (3% in men and 5% in women). Social inequalities were highly statistically significant for all causes of death examined in men. In women, social inequalities were less strong, but statistically significant for all causes of death except for cancer-related mortality and injuries.

Discussion

In this European study, substantial social inequalities in mortality among European men and women which cannot be fully explained away by accounting for known common risk factors for chronic diseases are reported.     

Atypical reproductive cycles in a population of Sceloporus grammicus (Squamata: Phrynosomatidae) from the Mexican Plateau

The spiny lizard Sceloporus grammicus (Squamata: Phrynosomatidae) is a small reptile from central México and the southern United States, occurring in a wide geographic area characterized by extensive variation in topographic and climatic regimes. Genetic variation among lineages from central México is substantial, though the extent to which this variation corresponds with life-history traits remains obscure. To address part of this puzzle, we studied a population of S. grammicus from Tepeapulco, Hidalgo, México. Male-biased sexual dimorphism was extensive in this population; males were larger than females overall, and expressed proportionately larger heads and longer limbs. Minimum size at sexual maturity was similar in the sexes (males: 43 mm; females: 42 mm). In contrast to other populations from the Central Plateau, reproductive activity of males and females was synchronous. Testicular recrudescence of adult males was initiated in October-November, and maximum testis size maintained from December to July. Female reproductive activity showed no clear seasonal pattern: females had vitellogenic follicles from October to July, and pregnant females were found throughout the year. Female body size was not related to litter size. Neither male nor female gonadal mass was correlated with any abiotic environmental variable examined. Differences in reproductive characteristics among populations of S. grammicus might be indicative of plasticity in response to local environmental conditions, local adaptation, or complex gene × environment interactions. We consider these results in the context of previously studied populations of S. grammicus from the Central Plateau and elsewhere, and propose directions for future research.     

Relationship between Tumor Cell Invasiveness and Polyploidization

A number of studies have shown that tumor cells fuse with other tumor and non-tumor cells. In the present study on tumor cell lines derived from glioblastoma, breast cancer, and melanoma, we estimated the frequency of fusion between tumor cells by establishing the fraction of cells with whole tumor-genome duplication in each cell line. Together with this, the capacity of the tumor cell lines to spread through a basement membrane scaffold was assessed, in order to test the hypothesis that pericellular proteolysis by enzymatic release in the spaces of intercellular contact could account for differences in the fusogenicity of tumor cells. The difference in invasiveness between the cell lines accounted for their specific amount of cells with tumor-genome duplication, which, depending on the cell line analyzed, ranged from 2% to 25% of the total cells. These results support the hypothesis that cell-to-cell invasion eliciting membrane fusion causes polyploidization in tumor cells.     

The flies of Icarus: science with wings in Crete

Around 100 researchers gathered at the eighteenth EMBO Conference on ‘The Molecular and Developmental Biology of Drosophila’, which took place in Crete in June 2012. Whether deconstructing or integrating at the genetic, cellular or organ level, the talks highlighted the synergy of combining methods, approaches and disciplines in this increasingly versatile model system.     

Relationship between salt tolerance and photosynthetic machinery performance in citrus

In citrus, salt stress has been related to the build up of chloride ions in plant tissues that affect photosynthesis, growth and yield. We investigated the effects of salt stress on the stability of the photosynthetic machinery with respect to the relative salt tolerance of different citrus genotypes including: Swingle Citrumelo, Carrizo citrange, C35 citrange, Cleopatra mandarin and Forner-Alcaide #5. Under identical salt-stress conditions, Forner-Alcaide #5 and Cleopatra mandarin accumulated less chloride ions in leaves than the other genotypes and showed a better plant performance. Chlorophyll fluorescence parameters indicated severe impairments of photosynthetic activity in salt-sensitive Citrumelo and citranges but Cleopatra and Forner-Alcaide #5 were less affected. In addition, differences in photosynthetic responses between these two moderately tolerant genotypes suggested different strategies to cope with salinity. The high tolerance to salinity shown by Forner-Alcaide #5 can be associated to the ability of keeping an active photosynthetic system at elevated saline conditions whereas the tolerance of Cleopatra was linked to rapid reductions of net photosynthetic rate, stomatal conductance, performance of PSII and photosynthetic efficiency.