Molecular insights into the association of obesity with breast cancer risk: relevance to xenobiotic metabolism and CpG island methylation of tumor suppressor genes

Obesity, genetic polymorphisms of xenobiotic metabolic pathway, hypermethylation of tumor suppressor genes, and hypomethylation of proapoptotic genes are known to be independent risk factors for breast cancer. The objective of this study is to evaluate the combined effect of these environmental, genetic, and epigenetic risk factors on the susceptibility to breast cancer. PCR–RFLP and multiplex PCR were used for the genetic analysis of six variants of xenobiotic metabolic pathway. Methylation-specific PCR was used for the epigenetic analysis of four genetic loci. Multifactor dimensionality reduction analysis revealed a significant interaction between the body mass index (BMI) and catechol-O-methyl transferase H108L variant alone or in combination with cytochrome P450 (CYP) 1A1m1 variant. Women with “Luminal A” breast cancer phenotype had higher BMI compared to other phenotypes and healthy controls. There was no association between the BMI and tumor grade. The post-menopausal obese women exhibited lower glutathione levels. BMI showed a positive association with the methylation of extracellular superoxide dismutase (r = 0.21, p < 0.05), Ras-association (RalGDS/AF-6) domain family member 1 (RASSF1A) (r = 0.31, p < 0.001), and breast cancer type 1 susceptibility protein (r = 0.19, p < 0.05); and inverse association with methylation of BNIP3 (r = ?0.48, p < 0.0001). To conclude based on these results, obesity increases the breast cancer susceptibility by two possible mechanisms: (i) by interacting with xenobiotic genetic polymorphisms in inducing increased oxidative DNA damage and (ii) by altering the methylome of several tumor suppressor genes.     

Eco-geographical diversity of cowpea bradyrhizobia in Senegal is marked by dominance of two genetic types

The genetic diversity of native cowpea rhizobia originating from 60 sites across four eco-geographic zones in Senegal was studied. More than 300 cowpea nodules were analyzed by PCR-RFLP of the 16S–23S rDNA InterGenic Spacer region (IGS). Alignments of IGS sequences indicated that all genotypes were grouping within the Bradyrhizobium genus. The geographical distribution showed that apart from five IGS types, the others were specifically found in only one region. The diversity was significantly higher in the Senegal River valley zone, which presents lower mean annual rainfalls and slightly alkaline soils. Interestingly, two IGS types dominated the Senegalese rhizobial collection, one IGS type (VI) was found on more than half of the nodules collected in the northern Senegal River valley while another IGS type (I) was recovered from the great majority of nodules in the three other regions sampled. Two representative strains from each of these two dominant types were isolated and further analyzed. Multi Locus Sequence Analyses using 6 housekeeping genes indicate that they belong to a new Bradyrhizobium species closely related to B. yuanmingense. Phylogenetic analyses of 2 symbiotic genes nodC and nifH show that they are clustered with B. arachidis. Physiological tests on these strains have shown that under laboratory conditions, the growth of the IGS type VI strains was slightly less affected by a higher osmotic strength in the medium and to alkaline pH, which corroborates the soil physico-chemical parameters.     

Targeted Silencing of Anthrax Toxin Receptors Protects against Anthrax Toxins

Anthrax spores can be aerosolized and dispersed as a bioweapon. Current postexposure treatments are inadequate at later stages of infection, when high levels of anthrax toxins are present. Anthrax toxins enter cells via two identified anthrax toxin receptors: tumor endothelial marker 8 (TEM8) and capillary morphogenesis protein 2 (CMG2). We hypothesized that host cells would be protected from anthrax toxins if anthrax toxin receptor expression was effectively silenced using RNA interference (RNAi) technology. Thus, anthrax toxin receptors in mouse and human macrophages were silenced using targeted siRNAs or blocked with specific antibody prior to challenge with anthrax lethal toxin. Viability assays were used to assess protection in macrophages treated with specific siRNA or antibody as compared with untreated cells. Silencing CMG2 using targeted siRNAs provided almost complete protection against anthrax lethal toxin-induced cytotoxicity and death in murine and human macrophages. The same results were obtained by prebinding cells with specific antibody prior to treatment with anthrax lethal toxin. In addition, TEM8-targeted siRNAs also offered significant protection against lethal toxin in human macrophage-like cells. Furthermore, silencing CMG2, TEM8, or both receptors in combination was also protective against MEK2 cleavage by lethal toxin or adenylyl cyclase activity by edema toxin in human kidney cells. Thus, anthrax toxin receptor-targeted RNAi has the potential to be developed as a life-saving, postexposure therapy against anthrax.     

KIF14 Binds Tightly to Microtubules and Adopts a Rigor-Like Conformation

The mitotic kinesin motor protein KIF14 is essential for cytokinesis during cell division and has been implicated in cerebral development and a variety of human cancers. Here we show that the mouse KIF14 motor domain binds tightly to microtubules and does not display typical nucleotide-dependent changes in this affinity. It also has robust ATPase activity but very slow motility. A crystal structure of the ADP-bound form of the KIF14 motor domain reveals a dramatically opened ATP-binding pocket, as if ready to exchange its bound ADP for Mg·ATP. In this state, the central β-sheet is twisted ~ 10° beyond the maximal amount observed in other kinesins. This configuration has only been seen in the nucleotide-free states of myosins—known as the “rigor-like” state. Fitting of this atomic model to electron density maps from cryo-electron microscopy indicates a distinct binding configuration of the motor domain to microtubules. We postulate that these properties of KIF14 are well suited for stabilizing midbody microtubules during cytokinesis.     

Correction of Distortion in Flattened Representations of the Cortical Surface Allows Prediction of V1-V3 Functional Organization from Anatomy

Several domains of neuroscience offer map-like models that link location on the cortical surface to properties of sensory representation. Within cortical visual areas V1, V2, and V3, algebraic transformations can relate position in the visual field to the retinotopic representation on the flattened cortical sheet. A limit to the practical application of this structure-function model is that the cortex, while topologically a two-dimensional surface, is curved. Flattening of the curved surface to a plane unavoidably introduces local geometric distortions that are not accounted for in idealized models. Here, we show that this limitation is overcome by correcting the geometric distortion induced by cortical flattening. We use a mass-spring-damper simulation to create a registration between functional MRI retinotopic mapping data of visual areas V1, V2, and V3 and an algebraic model of retinotopy. This registration is then applied to the flattened cortical surface anatomy to create an anatomical template that is linked to the algebraic retinotopic model. This registered cortical template can be used to accurately predict the location and retinotopic organization of these early visual areas from cortical anatomy alone. Moreover, we show that prediction accuracy remains when extrapolating beyond the range of data used to inform the model, indicating that the registration reflects the retinotopic organization of visual cortex. We provide code for the mass-spring-damper technique, which has general utility for the registration of cortical structure and function beyond the visual cortex.     

Importance de la Mérione de Shaw Meriones shawii au sein des composantes trophiques de la Chouette effraie Tyto alba en milieux steppiques de l’Algérie

The study of the diet of the Barn Owl in two steppic regions (M'Sila and Djelfa) located in the Algerian highlands is based on the analysis of the pellets of rejections collected in six stations. The analysis of 706 pellets resulting from the various stations made it possible to count 1380 individuals, represented by seven classes, 12 orders, 32 families, and 76 species of preys. The mammals are consumed with variable abundance rates between 59.1 % and 90.0 % whose predominance is assigned to the rodents (relative abundance: AR > 58 %). The latter constitute the most advantageous preys in biomass (61.4 ≤ B % ≤ 99.2). The most consumed prey is Meriones shawii, with variable rates between 31.9 % and 76.6 %. Generally, Tyto alba presents a diversified diet in the majority of the stations (0.69 ≤ E ≤ 0.76), except the station of Ain El-Hadjel (E = 0.35), with a low diversity and dominance of M. shawii (AR = 76.6 %).     

Role of plasma membrane lipid composition on cellular homeostasis： learning from cell line models expressing fatty acid desaturases

Experimental evidence has suggested that plasma membrane （PM）-associated signaling and hence cell metabolism and viability depend on lipid composition and organization. The aim of the present work is to develop a cell model to study the endogenous polyunsaturated fatty acids （PUFAs） effect on PM properties and analyze its influence on cholesterol （Chol） homeostasis. We have previously shown that by using a cell line overexpressing stearoyl-CoA-desaturase, membrane composition and organization coordinate cellular pathways involved in Chol efflux and ceil viability by different mechanisms. Now, we expanded our studies to a cell model overexpressing both A5 and A6 desaturases, which resulted in a permanently higher PUFA content in PM. Furthermore, this cell line showed increased PM fluidity, Chol storage, and mitochondrial activity. In addition, human apolipoprotein AI-mediated Chol removal was less efficient in these cells than in the corresponding control. Taken together, our results suggested that the ceil functionality is preserved by regulating PM organization and Chol exportation and homeostasis.     

Caloric restriction reveals a metabolomic and lipidomic signature in liver of male mice

Lipid composition, particularly membrane unsaturation, has been proposed as being a lifespan determinant, but it is currently unknown whether caloric restriction (CR), an accepted life‐extending intervention, affects cellular lipid profiles. In this study, we employ a liquid chromatography quadrupole time‐of‐flight‐based methodology to demonstrate that CR in the liver of male C57BL/6 mice: (i) induces marked changes in the cellular lipidome, (ii) specifically reduces levels of a phospholipid peroxidation product, 1‐palmitoyl‐2‐glutaryl‐sn‐glycero‐3‐phosphatidylcholine, (iii) alters cellular phosphoethanolamine and triglyceride distributional profiles, (iv) affects mitochondrial electron transport chain complexes, increasing complex II and decreasing complex III and (v) is associated with specific changes in liver metabolic pathways. These data demonstrate that CR induces a specific lipidome and metabolome reprogramming event in mouse liver which is associated with lower protein oxidative damage, as assessed by mass spectrometry‐based measurements. Such changes may be critical to the increased lifespan and healthspan observed in C57BL/6 mice following CR.     

Neoechinorhynchus qatarensis sp. n. (Acanthocephala: Neoechinorhynchidae) from the blue-barred flame parrot fish,Scarus ghobban Forsskål, 1775, in Qatari waters of the Arabian Gulf

Neoechinorhynchus qatarensis sp. n. (Acanthocephala: Neoechinorhynchidae) is described from the marine blue-barred flame parrot fish Scarus ghobban Forssk?l, 1775 in the Arabian Gulf waters off the coast of Qatar. The new species is distinguished from all other species of the genus Neoechinorhynchus by its unique reproductive system and a glandular structure associated with the proboscis receptacle in both males and females. Other uncommon features of N. qatarensis are also discussed.