Lack of Pwcr1/MBII-85 snoRNA is critical for neonatal lethality in Prader–Willi syndrome mouse models

Prader–Willi syndrome (PWS) is a neurobehavioral disorder caused by the lack of paternal expression of imprinted genes in the human chromosome region 15q11–13. Recent studies of rare human translocation patients narrowed the PWS critical genes to a 121-kb region containing PWCR1/HBII-85 and HBII-438 snoRNA genes. The existing mouse models of PWS that lack the expression of multiple genes, including Snrpn, Ube3a, and many intronic snoRNA genes, are characterized by 80%–100% neonatal lethality. To define the candidate region for PWS-like phenotypes in mice, we analyzed the expression of several genetic elements in mice carrying the large radiation-induced p^30PUb deletion that includes the p locus. Mice having inherited this deletion from either parent develop normally into adulthood. By Northern blot and RT-PCR assays of brain tissue, we found that Pwcr1/MBII-85 snoRNAs are expressed normally, while MBII-52 snoRNAs are not expressed when the deletion is paternally inherited. Mapping of the distal deletion breakpoint indicated that the p^30PUb deletion includes the entire MBII-52 snoRNA gene cluster and three previously unmapped EST sequences. The lack of expression of these elements in mice with a paternal p^30PUb deletion indicates that they are not critical for the neonatal lethality observed in PWS mouse models. In addition, we identified MBII-436, the mouse homolog of the HBII-436 snoRNA, confirmed its imprinting status, and mapped it outside of the p^30PUb deletion. Taking together all available data, we conclude that the lack of Pwcr1/MBII-85 snoRNA expression is the most likely cause for the neonatal lethality in PWS model mice.     

Changes in alpha-tocopherol and retinol levels during cardiopulmonary bypass correlate with maximal arterial partial pressure of oxygen

Cardiopulmonary bypass (CPB) is associated with oxidative stress. This study examined antioxidant levels in adults undergoing CPB surgery and their correlation with clinical variables. Arterial blood samples were obtained from 27 patients undergoing CPB. The time-course variation of vitamin C (spectrofluorimetry), alpha-tocopherol and retinol (HPLC) levels were determined. Plasma vitamin C rose initially but gradually decayed during reperfusion until 60% reduction of baseline values post-surgery. alpha-Tocopherol and retinol were reduced along CPB with post-operative values approximately 25% lower than baseline. No significant changes were found for selenium and glutathione peroxidase. PaO(2) values rose steadily throughout CPB. A correlation existed for alpha-tocopherol and retinol depletion vs maximal PaO(2) throughout CPB but no correlation was found for antioxidant consumption vs duration of ischaemia and reperfusion and hypothermia level. In conclusion, consumption of arterial blood antioxidant vitamins occurs with CPB in relation with PaO(2) levels but not for other clinical variables measured in this study.     

Warming shelf seas drive the subtropicalization of European pelagic fish communities

Pelagic fishes are among the most ecologically and economically important fish species in European seas. In principle, these pelagic fishes have potential to demonstrate rapid abundance and distribution shifts in response to climatic variability due to their high adult motility, planktonic larval stages, and low dependence on benthic habitat for food or shelter during their life histories. Here, we provide evidence of substantial climate‐driven changes to the structure of pelagic fish communities in European shelf seas. We investigated the patterns of species‐level change using catch records from 57 870 fisheries‐independent survey trawls from across European continental shelf region between 1965 and 2012. We analysed changes in the distribution and rate of occurrence of the six most common species, and observed a strong subtropicalization of the North Sea and Baltic Sea assemblages. These areas have shifted away from cold‐water assemblages typically characterized by Atlantic herring and European sprat from the 1960s to 1980s, to warmer‐water assemblages including Atlantic mackerel, Atlantic horse mackerel, European pilchard and European anchovy from the 1990s onwards. We next investigated if warming sea temperatures have forced these changes using temporally comprehensive data from the North Sea region. Our models indicated the primary driver of change in these species has been sea surface temperatures in all cases. Together, these analyses highlight how individual species responses have combined to result in a dramatic subtropicalization of the pelagic fish assemblage of the European continental shelf.     

The potential for indirect effects between co‐flowering plants via shared pollinators depends on resource abundance,accessibility and relatedness

Co‐flowering plant species commonly share flower visitors, and thus have the potential to influence each other's pollination. In this study we analysed 750 quantitative plant–pollinator networks from 28 studies representing diverse biomes worldwide. We show that the potential for one plant species to influence another indirectly via shared pollinators was greater for plants whose resources were more abundant (higher floral unit number and nectar sugar content) and more accessible. The potential indirect influence was also stronger between phylogenetically closer plant species and was independent of plant geographic origin (native vs. non‐native). The positive effect of nectar sugar content and phylogenetic proximity was much more accentuated for bees than for other groups. Consequently, the impact of these factors depends on the pollination mode of plants, e.g. bee or fly pollinated. Our findings may help predict which plant species have the greatest importance in the functioning of plant–pollination networks.     

A model of an autocatalytic network formed by error-prone self-replicative species

A generalized model ofn catalytically-coupled self-replicative molecules witherror-prone replication is presented. A generalized mathematical formulation of this model and the outline of its asymptotic behaviour have been developed. Due to the complexity of the model, only in simple situations is it possible to draw general conclusions from the standard analysis. Some complex situations are illustrated by means of numerical integration of particular examples.     

Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells

Inhibitors of the lipogenic enzyme fatty acid synthase (FASN) have attracted much attention in the last decade as potential targeted cancer therapies. However, little is known about the molecular determinants of cancer cell sensitivity to FASN inhibitors (FASNis), which is a major roadblock to their therapeutic application. Here, we find that pharmacological starvation of endogenously produced FAs is a previously unrecognized metabolic stress that heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors. Evaluation of the death decision circuits controlled by the BCL-2 family of proteins revealed that FASN inhibition is accompanied by the upregulation of the pro-death BH3-only proteins BIM, PUMA, and NOXA. Cell death triggered by FASN inhibition, which causally involves a palmitate/NADPH-related redox imbalance, is markedly diminished by concurrent loss of BIM or PUMA, suggesting that FASN activity controls cancer cell survival by fine-tuning the BH3 only proteins-dependent mitochondrial threshold for apoptosis. FASN inhibition results in a heightened mitochondrial apoptosis priming, shifting cells toward a primed-for-death state “addicted” to the anti-apoptotic protein BCL-2. Accordingly, co-administration of a FASNi synergistically augments the apoptosis-inducing activity of the dual BCL-X_L/BCL-2 inhibitor ABT-263 (navitoclax) and the BCL-2 specific BH3-mimetic ABT-199 (venetoclax). FASN inhibition, however, fails to sensitize breast cancer cells to MCL-1- and BCL-X_L-selective inhibitors such as {"type":"entrez-nucleotide","attrs":{"text":"S63845","term_id":"400540"}}S63845 and A1331852. A human breast cancer xenograft model evidenced that oral administration of the only clinically available FASNi drastically sensitizes FASN-addicted breast tumors to ineffective single-agents navitoclax and venetoclax in vivo. In summary, a novel FASN-driven facet of the mitochondrial priming mechanistically links the redox-buffering mechanism of FASN activity to the intrinsic apoptotic threshold in breast cancer cells. Combining next-generation FASNis with BCL-2-specific BH3 mimetics that directly activate the apoptotic machinery might generate more potent and longer-lasting antitumor responses in a clinical setting.Subject terms: Cancer metabolism, Lipid signalling     

Modification of the lysine residues of histones H1 and H5: Effects on structure and on the binding to chromatin

The extensive modification of histone H1 from calf thymus with the amino-group reagent dimethylmaleic anhydride (over 35 lysine residues modified per molecule) produces no effect on its secondary structure detectable by circular dichroism (far UV). Fluorescence and circular dichroism (near-UV) of the modified histone show variations in the local environment of its sole tyrosine residue. These changes are reversed on regeneration of the modified amino groups. While histone H1 is easily dissociated with this reagent from calf thymus or chicken erythrocyte chromatin, a much stronger treatment is needed to liberate histone H5 from erythrocyte chromatin. This difference appears to be related to the higher arginine content of histone H5.     

Morphometric study of the LH-immunoreactive gonadotrophic cells of rats following treatment with methoclopramide.

The LH-immunoreactive cells of the adult rat hypophysis were studied morphometrically after chronic treatment with methoclopramide. The morphological features of these cells showed modifications in both male and female rats, after treatment. Additionally, morphometric changes revealed a significant decrease (p less than 0.05) in both cytoplasmic area, which was more evident in the female rats, and nuclear area, with respect to the normal and control animals. These findings suggest that chronic inhibition of the dopaminergic system in rats atrophies LH-immunoreactive gonadotrophic cells of rats.