LRRK2 is a negative regulator of <em>Mycobacterium tuberculosis</em> phagosome maturation in macrophages

\ua9 2018 EMBO. Mutations in the leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson\u27s disease, chronic inflammation and mycobacterial infections. Although there is evidence supporting the idea that LRRK2 has an immune function, the cellular function of this kinase is still largely unknown. By using genetic, pharmacological and proteomics approaches, we show that LRRK2 kinase activity negatively regulates phagosome maturation via the recruitment of the Class III phosphatidylinositol-3 kinase complex and Rubicon to the phagosome in macrophages. Moreover, inhibition of LRRK2 kinase activity in mouse and human macrophages enhanced Mycobacterium tuberculosis phagosome maturation and mycobacterial control independently of autophagy. In vivo, LRRK2 deficiency in mice resulted in a significant decrease in M. tuberculosis burdens early during the infection. Collectively, our findings provide a molecular mechanism explaining genetic evidence linking LRRK2 to mycobacterial diseases and establish an LRRK2-dependent cellular pathway that controls M. tuberculosis replication by regulating phagosome maturation

Introducing the National Library for Health Skin Conditions Specialist Library

BACKGROUND: This paper introduces the new National Library for Health Skin Conditions Specialist Library . DESCRIPTION: The aims, scope and audience of the new NLH Skin Conditions Specialist Library, and the composition and functions of its core Project Team, Editorial Team and Stakeholders Group are described. The Library's collection building strategy, resource and information types, editorial policies, quality checklist, taxonomy for content indexing, organisation and navigation, and user interface are all presented in detail. The paper also explores the expected impact and utility of the new Library, as well as some possible future directions for further development. CONCLUSION: The Skin Conditions Specialist Library is not just another new Web site that dermatologists might want to add to their Internet favourites then forget about it. It is intended to be a practical, "one-stop shop" dermatology information service for everyday practical use, offering high quality, up-to-date resources, and adopting robust evidence-based and knowledge management approaches

Young Aphids Avoid Erroneous Dropping when Evading Mammalian Herbivores by Combining Input from Two Sensory Modalities

Mammalian herbivores may incidentally ingest plant-dwelling insects while foraging. Adult pea aphids (Acyrthosiphon pisum) avoid this danger by dropping off their host plant after sensing the herbivore's warm and humid breath and the vibrations it causes while feeding. Aphid nymphs may also drop (to escape insect enemies), but because of their slow movement, have a lower chance of finding a new plant. We compared dropping rates of first-instar nymphs with those of adults, after exposing pea aphids to different combinations of simulated mammalian breath and vibrations. We hypothesized that nymphs would compensate for the greater risk they face on the ground by interpreting more conservatively the mammalian herbivore cues they perceive. Most adults dropped in response to breath alone, but nymphs rarely did so. Breath stimulus accompanied by one concurrent vibrational stimulus, caused a minor rise in adult dropping rates. Adding a second vibration during breath had no additional effect on adults. The nymphs, however, relied on a combination of the two types of stimuli, with a threefold increase in dropping rates when the breath was accompanied by one vibration, and a further doubling of dropping rates when the second vibration was added. The age-specificity of the aphids' herbivore detection mechanism is probably an adaptation to the different cost of dropping for the different age groups. Relying on a combination of stimuli from two sensory modalities enables the vulnerable nymphs to avoid costly mistakes. Our findings emphasize the importance of the direct trophic effect of mammalian herbivory for plant-dwelling insects

Aphid Wing Induction and Ecological Costs of Alarm Pheromone Emission under Field Conditions

The pea aphid, Acyrthosiphon pisum Harris, (Homoptera: Aphididae) releases the volatile sesquiterpene (E)-β-farnesene (EBF) when attacked by a predator, triggering escape responses in the aphid colony. Recently, it was shown that this alarm pheromone also mediates the production of the winged dispersal morph under laboratory conditions. The present work tested the wing-inducing effect of EBF under field conditions. Aphid colonies were exposed to two treatments (control and EBF) and tested in two different environmental conditions (field and laboratory). As in previous experiments aphids produced higher proportion of winged morphs among their offspring when exposed to EBF in the laboratory but even under field conditions the proportion of winged offspring was higher after EBF application (6.84±0.98%) compared to the hexane control (1.54±0.25%). In the field, the proportion of adult aphids found on the plant at the end of the experiment was lower in the EBF treatment (58.1±5.5%) than in the control (66.9±4.6%), in contrast to the climate chamber test where the numbers of adult aphids found on the plant at the end of the experiment were, in both treatments, similar to the numbers put on the plant initially. Our results show that the role of EBF in aphid wing induction is also apparent under field conditions and they may indicate a potential cost of EBF emission. They also emphasize the importance of investigating the ecological role of induced defences under field conditions

Do Behavioral Foraging Responses of Prey to Predators Function Similarly in Restored and Pristine Foodwebs?

Efforts to restore top predators in human-altered systems raise the question of whether rebounds in predator populations are sufficient to restore pristine foodweb dynamics. Ocean ecosystems provide an ideal system to test this question. Removal of fishing in marine reserves often reverses declines in predator densities and size. However, whether this leads to restoration of key functional characteristics of foodwebs, especially prey foraging behavior, is unclear. The question of whether restored and pristine foodwebs function similarly is nonetheless critically important for management and restoration efforts. We explored this question in light of one important determinant of ecosystem function and structure – herbivorous prey foraging behavior. We compared these responses for two functionally distinct herbivorous prey fishes (the damselfish Plectroglyphidodon dickii and the parrotfish Chlorurus sordidus) within pairs of coral reefs in pristine and restored ecosystems in two regions of these species' biogeographic ranges, allowing us to quantify the magnitude and temporal scale of this key ecosystem variable's recovery. We demonstrate that restoration of top predator abundances also restored prey foraging excursion behaviors to a condition closely resembling those of a pristine ecosystem. Increased understanding of behavioral aspects of ecosystem change will greatly improve our ability to predict the cascading consequences of conservation tools aimed at ecological restoration, such as marine reserves

Water and sodium intake habits and status of ultra-endurance runners during a multi-stage ultra-marathon conducted in a hot ambient environment: an observational field based study

<p>Abstract</p> <p>Background</p> <p>Anecdotal evidence suggests ultra-runners may not be consuming sufficient water through foods and fluids to maintenance euhydration, and present sub-optimal sodium intakes, throughout multi-stage ultra-marathon (MSUM) competitions in the heat. Subsequently, the aims were primarily to assess water and sodium intake habits of recreational ultra-runners during a five stage 225 km semi self-sufficient MSUM conducted in a hot ambient environment (T_max range: 32°C to 40°C); simultaneously to monitor serum sodium concentration, and hydration status using multiple hydration assessment techniques.</p> <p>Methods</p> <p>Total daily, pre-stage, during running, and post-stage water and sodium ingestion of ultra-endurance runners (UER, <it>n</it> = 74) and control (CON, <it>n</it> = 12) through foods and fluids were recorded on Stages 1 to 4 by trained dietetic researchers using dietary recall interview technique, and analysed through dietary analysis software. Body mass (BM), hydration status, and serum sodium concentration were determined pre- and post-Stages 1 to 5.</p> <p>Results</p> <p>Water (overall mean (SD): total daily 7.7 (1.5) L/day, during running 732 (183) ml/h) and sodium (total daily 3.9 (1.3) g/day, during running 270 (151) mg/L) ingestion did not differ between stages in UER (<it>p</it> < 0.001 <it>vs</it>. CON). Exercise-induced BM loss was 2.4 (1.2)% (<it>p</it> < 0.001). Pre- to post-stage BM gains were observed in 26% of UER along competition. Pre- and post-stage plasma osmolality remained within normal clinical reference range (280 to 303 mOsmol/kg) in the majority of UER (<it>p</it> > 0.05 <it>vs</it>. CON pre-stage). Asymptomatic hyponatraemia (<135 mmol/L) was evident pre- and post-stage in <it>n</it> = 8 UER, corresponding to 42% of sampled participants. Pre- and post-stage urine colour, urine osmolality and urine/plasma osmolality ratio increased (<it>p</it> < 0.001) as competition progressed in UER, with no change in CON. Plasma volume and extra-cellular water increased (<it>p</it> < 0.001) 22.8% and 9.2%, respectively, from pre-Stage 1 to 5 in UER, with no change in CON.</p> <p>Conclusion</p> <p>Water intake habits of ultra-runners during MSUM conducted in hot ambient conditions appear to be sufficient to maintain baseline euhydration levels. However, fluid over-consumption behaviours were evident along competition, irrespective of running speed and gender. Normonatraemia was observed in the majority of ultra-runners throughout MSUM, despite sodium ingestion under benchmark recommendations.</p

A Linear Framework for Time-Scale Separation in Nonlinear Biochemical Systems

Cellular physiology is implemented by formidably complex biochemical systems with highly nonlinear dynamics, presenting a challenge for both experiment and theory. Time-scale separation has been one of the few theoretical methods for distilling general principles from such complexity. It has provided essential insights in areas such as enzyme kinetics, allosteric enzymes, G-protein coupled receptors, ion channels, gene regulation and post-translational modification. In each case, internal molecular complexity has been eliminated, leading to rational algebraic expressions among the remaining components. This has yielded familiar formulas such as those of Michaelis-Menten in enzyme kinetics, Monod-Wyman-Changeux in allostery and Ackers-Johnson-Shea in gene regulation. Here we show that these calculations are all instances of a single graph-theoretic framework. Despite the biochemical nonlinearity to which it is applied, this framework is entirely linear, yet requires no approximation. We show that elimination of internal complexity is feasible when the relevant graph is strongly connected. The framework provides a new methodology with the potential to subdue combinatorial explosion at the molecular level

The Type VI secretion system deploys anti-fungal effectors against microbial competitors

This work was supported by the Wellcome Trust (Senior Research Fellowship in Basic Biomedical Science to S.J.C., 104556; 097377, J.Q.; 101873 & 200208, N.A.R.G.), the MRC (MR/K000111X/1, S.J .C; MC_UU_12016/5, M.T.), and the BBSRC (BB/K016393/1 & BB/P020119/1, J.Q.). We thank Maximilian Fritsch, Mario López Martín and Birte Hollmann for help with strain construction; Gary Eitzen for construction of pGED1; Donna MacCallum for the gift of Candida glabrata ATCC2001; Joachim Morschhäuser for the gift of pNIM1; Gillian Milne (Microscopy and Histology facility, University of Aberdeen) for assistance with TEM; and Peter Taylor, Michael Porter, Laura Monlezun and Colin Rickman for advice and technical assistance.Peer reviewedPostprin