The Cellular Mechanism for Water Detection in the Mammalian Taste System

Initiation of drinking behavior relies on both internal state and peripheral water detection. While central neural circuits regulating thirst have been well studied, it is still unclear how mammals recognize external water. Here we show that acid-sensing taste receptor cells (TRCs) that were previously suggested as the sour taste sensors also mediate taste responses to water. Genetic silencing of these TRCs abolished water-evoked responses in taste nerves. Optogenetic self-stimulation of acid-sensing TRCs in thirsty animals induced robust drinking responses toward light even without water. This behavior was only observed when animals were water-deprived but not under food- or salt-depleted conditions, indicating that the hedonic value of water-evoked responses is highly internal-state dependent. Conversely, thirsty animals lacking functional acid-sensing TRCs showed compromised discrimination between water and nonaqueous fluids. Taken together, this study revealed a function of mammalian acid-sensing TRCs that provide a cue for external water

Metabolism of halophilic archaea

In spite of their common hypersaline environment, halophilic archaea are surprisingly different in their nutritional demands and metabolic pathways. The metabolic diversity of halophilic archaea was investigated at the genomic level through systematic metabolic reconstruction and comparative analysis of four completely sequenced species: Halobacterium salinarum, Haloarcula marismortui, Haloquadratum walsbyi, and the haloalkaliphile Natronomonas pharaonis. The comparative study reveals different sets of enzyme genes amongst halophilic archaea, e.g. in glycerol degradation, pentose metabolism, and folate synthesis. The carefully assessed metabolic data represent a reliable resource for future system biology approaches as it also links to current experimental data on (halo)archaea from the literature

Caspase-2-mediated cell death is required for deleting aneuploid cells

Caspase-2, one of the most evolutionarily conserved of the caspase family, has been implicated in maintenance of chromosomal stability and tumour suppression. Caspase-2 deficient (Casp2-/-) mice develop normally but show premature ageing-related traits and when challenged by certain stressors, succumb to enhanced tumour development and aneuploidy. To test how caspase-2 protects against chromosomal instability, we utilized an ex vivo system for aneuploidy where primary splenocytes from Casp2-/- mice were exposed to anti-mitotic drugs and followed up by live cell imaging. Our data show that caspase-2 is required for deleting mitotically aberrant cells. Acute silencing of caspase-2 in cultured human cells recapitulated these results. We further generated Casp2C320S mutant mice to demonstrate that caspase-2 catalytic activity is essential for its function in limiting aneuploidy. Our results provide direct evidence that the apoptotic activity of caspase-2 is necessary for deleting cells with mitotic aberrations to limit aneuploidy.S Dawar, Y Lim, J Puccini, M White, P Thomas, L Bouchier-Hayes, D R Green, L Dorstyn and S Kuma

Discovering functional linkages and uncharacterized cellular pathways using phylogenetic profile comparisons: a comprehensive assessment

<p>Abstract</p> <p>Background</p> <p>A widely-used approach for discovering functional and physical interactions among proteins involves phylogenetic profile comparisons (PPCs). Here, proteins with similar profiles are inferred to be functionally related under the assumption that proteins involved in the same metabolic pathway or cellular system are likely to have been co-inherited during evolution.</p> <p>Results</p> <p>Our experimentation with <it>E. coli </it>and yeast proteins with 16 different carefully composed reference sets of genomes revealed that the phyletic patterns of proteins in prokaryotes alone could be adequate enough to make reasonably accurate functional linkage predictions. A slight improvement in performance is observed on adding few eukaryotes into the reference set, but a noticeable drop-off in performance is observed with increased number of eukaryotes. Inclusion of most parasitic, pathogenic or vertebrate genomes and multiple strains of the same species into the reference set do not necessarily contribute to an improved sensitivity or accuracy. Interestingly, we also found that evolutionary histories of individual pathways have a significant affect on the performance of the PPC approach with respect to a particular reference set. For example, to accurately predict functional links in carbohydrate or lipid metabolism, a reference set solely composed of prokaryotic (or bacterial) genomes performed among the best compared to one composed of genomes from all three super-kingdoms; this is in contrast to predicting functional links in translation for which a reference set composed of prokaryotic (or bacterial) genomes performed the worst. We also demonstrate that the widely used random null model to quantify the statistical significance of profile similarity is incomplete, which could result in an increased number of false-positives.</p> <p>Conclusion</p> <p>Contrary to previous proposals, it is not merely the number of genomes but a careful selection of informative genomes in the reference set that influences the prediction accuracy of the PPC approach. We note that the predictive power of the PPC approach, especially in eukaryotes, is heavily influenced by the primary endosymbiosis and subsequent bacterial contributions. The over-representation of parasitic unicellular eukaryotes and vertebrates additionally make eukaryotes less useful in the reference sets. Reference sets composed of highly non-redundant set of genomes from all three super-kingdoms fare better with pathways showing considerable vertical inheritance and strong conservation (e.g. translation apparatus), while reference sets solely composed of prokaryotic genomes fare better for more variable pathways like carbohydrate metabolism. Differential performance of the PPC approach on various pathways, and a weak positive correlation between functional and profile similarities suggest that caution should be exercised while interpreting functional linkages inferred from genome-wide large-scale profile comparisons using a single reference set.</p

The tumor-modulatory effects of Caspase-2 and Pidd1 do not require the scaffold protein Raidd

The receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD/CRADD) functions as a dual adaptor and is a constituent of different multi-protein complexes implicated in the regulation of inflammation and cell death. Within the PIDDosome complex, RAIDD connects the cell death-related protease, Caspase-2, with the p53-induced protein with a death domain 1 (PIDD1). As such, RAIDD has been implicated in DNA-damage-induced apoptosis as well as in tumorigenesis. As loss of Caspase-2 leads to an acceleration of tumor onset in the Eμ-Myc mouse lymphoma model, whereas loss of Pidd1 actually delays onset of this disease, we set out to interrogate the role of Raidd in cancer in more detail. Our data obtained analyzing Eμ-Myc/Raidd(-/-) mice indicate that Raidd is unable to protect from c-Myc-driven lymphomagenesis. Similarly, we failed to observe a modulatory effect of Raidd deficiency on DNA-damage-driven cancer. The role of Caspase-2 as a tumor suppressor and that of Pidd1 as a tumor promoter can therefore be uncoupled from their ability to interact with the Raidd scaffold, pointing toward the existence of alternative signaling modules engaging these two proteins in this context.L Peintner, L Dorstyn, S Kumar, T Aneichyk, A Villunger, and C Manz

Corruption, inequality and population perception of healthcare quality in Europe

Background Evaluating the quality of healthcare and patient safety using general population questionnaires is important from research and policy perspective. Using a special wave of the Eurobarometer survey, we analysed the general population’s perception of health care quality and patient safety in a cross-country setting. Methods We used ordered probit, ordinary least squares and probit analysis to estimate the determinants of health care quality, and ordered logit analysis to analyse the likelihood of being harmed by a specific medical procedure. The models used population weights as well as country-clustered standard errors. Results We found robust evidence for the impact of socio-demographic variables on the perception of quality of health care. More specifically, we found a non-linear impact of age on the perception of quality of health care and patient safety, as well as a negative impact of poverty on both perception of quality and patient safety. We also found robust evidence that countries with higher corruption levels were associated with worse perceptions of quality of health care. Finally, we found evidence that income inequality affects patients’ perception vis-à-vis safety, thus feeding into the poverty/health care quality nexus. Conclusions Socio-demographic factors and two macro variables (corruption and income inequality) explain the perception of quality of health care and likelihood of being harmed by adverse events. The results carry significant policy weight and could explain why targeting only the health care sector (without an overall reform of the public sector) could potentially be challenging