Notes

Ventral tegmental place serotonin 5-HT1A receptors and also corticolimbic cFos/BDNF/GFAP signaling pathways mediate dextromethorphan/morphine anti-allodynia.
Collectively, these results demonstrate that UCP2 plays a vital role in PDAC, since its aspartate transport activity connects the mitochondrial and cytosolic reactions necessary for KRASmut rewired glutamine metabolism2, and thus it should be considered a key metabolic target for the treatment of this refractory tumour.Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We have previously identified a subset of cancers harbouring homozygous deletion of the glycolytic enzyme enolase (ENO1) that have exceptional sensitivity to inhibition of its redundant paralogue, ENO2, through a therapeutic strategy known as collateral lethality. Here, we show that a small-molecule enolase inhibitor, POMHEX, can selectively kill ENO1-deleted glioma cells at low-nanomolar concentrations and eradicate intracranial orthotopic ENO1-deleted tumours in mice at doses well-tolerated in non-human primates. Our data provide an in vivo proof of principle of the power of collateral lethality in precision oncology and demonstrate the utility of POMHEX for glycolysis inhibition with potential use across a range of therapeutic settings.A Correction to this paper has been published https//doi.org/10.1038/s41587-019-0392-8.Existing technologies for site-specific integration of kilobase-sized DNA sequences in bacteria are limited by low efficiency, a reliance on recombination, the need for multiple vectors, and challenges in multiplexing. Selleckchem CX-5461 To address these shortcomings, we introduce a substantially improved version of our previously reported Tn7-like transposon from Vibrio cholerae, which uses a Type I-F CRISPR-Cas system for programmable, RNA-guided transposition. The optimized insertion of transposable elements by guide RNA-assisted targeting (INTEGRATE) system achieves highly accurate and marker-free DNA integration of up to 10 kilobases at ~100% efficiency in bacteria. Using multi-spacer CRISPR arrays, we achieved simultaneous multiplexed insertions in three genomic loci and facile, multi-loci deletions by combining orthogonal integrases and recombinases. Finally, we demonstrated robust function in biomedically and industrially relevant bacteria and achieved target- and species-specific integration in a complex bacterial community. This work establishes INTEGRATE as a versatile tool for multiplexed, kilobase-scale genome engineering.Metabolomics using nontargeted tandem mass spectrometry can detect thousands of molecules in a biological sample. However, structural molecule annotation is limited to structures present in libraries or databases, restricting analysis and interpretation of experimental data. Here we describe CANOPUS (class assignment and ontology prediction using mass spectrometry), a computational tool for systematic compound class annotation. CANOPUS uses a deep neural network to predict 2,497 compound classes from fragmentation spectra, including all biologically relevant classes. CANOPUS explicitly targets compounds for which neither spectral nor structural reference data are available and predicts classes lacking tandem mass spectrometry training data. In evaluation using reference data, CANOPUS reached very high prediction performance (average accuracy of 99.7% in cross-validation) and outperformed four baseline methods. We demonstrate the broad utility of CANOPUS by investigating the effect of microbial colonization in the mouse digestive system, through analysis of the chemodiversity of different Euphorbia plants and regarding the discovery of a marine natural product, revealing biological insights at the compound class level.Fatty acid translocase (CD36) is a scavenger receptor with multiple ligands and diverse physiological actions. We recently reported that alcohol-induced hepatic retinoid mobilization is impaired in Cd36-/- mice, leading us to hypothesize that CD36 has a novel role in hepatic vitamin A mobilization. Given the central role of the liver in systemic vitamin A homeostasis we also postulated that absence of CD36 would affect whole-body vitamin A homeostasis. We tested this hypothesis in aging wild type and Cd36-/- mice, as well as mice fed a vitamin A-deficient diet. In agreement with our hypothesis, Cd36-/- mice accumulated hepatic retinyl ester stores with age to a greater extent than wild type mice. However, contrary to expectations, Cd36-/- mice consuming a vitamin A-deficient diet mobilized hepatic retinoid similar to wild type mice. Interestingly, we observed that Cd36-/- mice had significantly reduced white adipose tissue retinoid levels compared to wild type mice. In conclusion, we demonstrate that the absence of CD36 alters whole-body vitamin A homeostasis and suggest that this phenotype is secondary to the impaired chylomicron metabolism previously reported in these mice.Lack of standardization and unblinding threaten the research of mechanisms involved in expectancy effects on pain. We evaluated a computer-controlled virtual experimenter (VEx) to avoid these issues. Fifty-four subjects underwent a baseline-retest heat pain protocol. Between sessions, they received an expectancy manipulation (placebo or no-treatment) delivered by VEx or text-only control condition. The VEx provided standardized "social" interaction with the subjects. Pain ratings and psychological state/trait measures were recorded. We found an interaction of expectancy and delivery on pain improvement following the intervention. In the text conditions, placebo was followed by lower pain, whereas in the VEx conditions, placebo and no-treatment were followed by a comparable pain decrease. Secondary analyses indicated that this interaction was mirrored by decreases of negative mood and anxiety. Furthermore, changes in continuous pain were moderated by expectation of pain relief. However, retrospective pain ratings show an effect of expectancy but not of delivery. We conclude that we successfully applied an automated protocol for inducing expectancy effects on pain. The effect of the VEx regardless of treatment may be due to interactions of attention allocation and locus of control. This points to the diversity of expectancy mechanisms, and has implications for research and computer-based treatment applications.
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