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A mechanistic link between the marine Si cycle and off-axis H2 production requires a reevaluation of the processes that supplied H2 to prebiotic and early microbial systems, as well as those that balanced ocean-atmosphere redox through time.Whether G protein-coupled receptors signal from endosomes to control important pathophysiological processes and are therapeutic targets is uncertain. We report that opioids from the inflamed colon activate δ-opioid receptors (DOPr) in endosomes of nociceptors. Biopsy samples of inflamed colonic mucosa from patients and mice with colitis released opioids that activated DOPr on nociceptors to cause a sustained decrease in excitability. DOPr agonists inhibited mechanically sensitive colonic nociceptors. DOPr endocytosis and endosomal signaling by protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) pathways mediated the sustained inhibitory actions of endogenous opioids and DOPr agonists. DOPr agonists stimulated the recruitment of Gαi/o and β-arrestin1/2 to endosomes. Analysis of compartmentalized signaling revealed a requirement of DOPr endocytosis for activation of PKC at the plasma membrane and in the cytosol and ERK in the nucleus. We explored a nanoparticle delivery strategy to evaluate whether endosomal DOPr might be a therapeutic target for pain. The DOPr agonist DADLE was coupled to a liposome shell for targeting DOPr-positive nociceptors and incorporated into a mesoporous silica core for release in the acidic and reducing endosomal environment. Nanoparticles activated DOPr at the plasma membrane, were preferentially endocytosed by DOPr-expressing cells, and were delivered to DOPr-positive early endosomes. Nanoparticles caused a long-lasting activation of DOPr in endosomes, which provided sustained inhibition of nociceptor excitability and relief from inflammatory pain. Conversely, nanoparticles containing a DOPr antagonist abolished the sustained inhibitory effects of DADLE. TEPP-46 cell line Thus, DOPr in endosomes is an endogenous mechanism and a therapeutic target for relief from chronic inflammatory pain.The ice shell on Enceladus, an icy moon of Saturn, exhibits strong asymmetry between the northern and southern hemispheres, with all known geysers concentrated over the south pole, even though the expected pattern of tidal forced deformation should be symmetric between the north and south poles. Using an idealized ice-evolution model, we demonstrate that this asymmetry may form spontaneously, without any noticeable a priori asymmetry (such as a giant impact or a monopole structure of geological activity), in contrast to previous studies. Infinitesimal asymmetry in the ice shell thickness due to random perturbations are found to be able to grow indefinitely, ending up significantly thinning the ice shell at one of the poles, thereby allowing fracture formation there. Necessary conditions to trigger this hemispheric symmetry-breaking mechanism are found analytically. A rule of thumb we find is that, for Galilean and Saturnian icy moons, the ice shell can undergo hemispheric symmetry breaking only if the mean shell thickness is around 10 to 30 km.We sequenced the genome of a Neandertal from Chagyrskaya Cave in the Altai Mountains, Russia, to 27-fold genomic coverage. We show that this Neandertal was a female and that she was more related to Neandertals in western Eurasia [Prüfer et al., Science 358, 655-658 (2017); Hajdinjak et al., Nature 555, 652-656 (2018)] than to Neandertals who lived earlier in Denisova Cave [Prüfer et al., Nature 505, 43-49 (2014)], which is located about 100 km away. About 12.9% of the Chagyrskaya genome is spanned by homozygous regions that are between 2.5 and 10 centiMorgans (cM) long. This is consistent with the fact that Siberian Neandertals lived in relatively isolated populations of less than 60 individuals. In contrast, a Neandertal from Europe, a Denisovan from the Altai Mountains, and ancient modern humans seem to have lived in populations of larger sizes. The availability of three Neandertal genomes of high quality allows a view of genetic features that were unique to Neandertals and that are likely to have been at high frequency among them. We find that genes highly expressed in the striatum in the basal ganglia of the brain carry more amino-acid-changing substitutions than genes expressed elsewhere in the brain, suggesting that the striatum may have evolved unique functions in Neandertals.We report a patient with cat-scratch disease presenting with meningitis and neuroretinitis. This condition, caused by Bartonella henselae, has a worldwide distribution and is among the most common infective causes of neuroretinitis. Bartonella neuroretinitis is a rare but under-recognised mimic of optic neuritis; it should be suspected in a patient with an infective prodrome whose fundus shows optic disc oedema and a macular star. A low-positive initial serological test for Bartonella henselae does not exclude cat-scratch disease if there is high clinical suspicion, and repeat testing is recommended to look for titre rise.Background Junior doctors at the Royal Devon and Exeter Hospital spend hours every day creating and updating patient lists for all surgical specialties on Microsoft Excel spreadsheets. This not only consumes time that should be spent on clinical tasks, it allows for human errors, system errors and patient safety concerns. Our aim was to reduce time spent on the list and reduce the chance for error. Methods We measured the time junior doctors spent creating and updating the surgical lists for one specialty, and on-call shifts. Our first Plan-Do-Study-Act (PDSA) cycle was to introduce clinical secretaries; this reduced the time spent by ward teams on the list but had no effect on the on-call team. We then worked with the hospital application developer to adapt software currently used to suit all surgical teams. Once completed, this software was rolled out alongside the existing spreadsheet method with a view to a switch after a transition period. Results The introduction of clinical secretaries reduced the time spent on the colorectal surgery list from 99.22 min a day to 43.38 min. The on-call team however did not benefit from this intervention. Following the introduction of the new software, the day on-call team time spent on the list changed from 121 min a day to 4.66 min. The night on-call team time changed from 91 min to 7.38 min. Conclusion Reducing the time juniors spend compiling surgical lists has clear benefits to patients with extra time for junior doctors to clerk patients. The use of an automated system removes the chance of error in transcription of blood results. Due to the success of this project, colorectal, upper gastrointestinal, urology, vascular and on-call teams have adopted the new list permanently.