Diversity and environmental adaptation of phagocytic cell metabolism

Phagocytes are cells of the immune system that play important roles in phagocytosis, respiratory burst and degranulation-key components of innate immunity and response to infection. This diverse group of cells includes monocytes, macrophages, dendritic cells, neutrophils, eosinophils, and basophils-heterogeneous cell populations possessing cell and tissue-specific functions of which cellular metabolism comprises a critical underpinning. Core functions of phagocytic cells are diverse and sensitive to alterations in environmental- and tissue-specific nutrients and growth factors. As phagocytic cells adapt to these extracellular cues, cellular processes are altered and may contribute to pathogenesis. The considerable degree of functional heterogeneity among monocyte, neutrophil, and other phagocytic cell populations necessitates diverse metabolism. As we review our current understanding of metabolism in phagocytic cells, gaps are focused on to highlight the need for additional studies that hopefully enable improved cell-based strategies for counteracting cancer and other diseases

Density of critical points for a Gaussian random function

Critical points of a scalar quantitiy are either extremal points or saddle points. The character of the critical points is determined by the sign distribution of the eigenvalues of the Hessian matrix. For a two-dimensional homogeneous and isotropic random function topological arguments are sufficient to show that all possible sign combinations are equidistributed or with other words, the density of the saddle points and extrema agree. This argument breaks down in three dimensions. All ratios of the densities of saddle points and extrema larger than one are possible. For a homogeneous Gaussian random field one finds no longer an equidistribution of signs, saddle points are slightly more frequent.Comment: 11 pages 1 figure, changes in list of references, corrected typo

Common health conditions in childhood and adolescence, school absence, and educational attainment: Mendelian randomization study

Good health is positively related to children’s educational outcomes, but relationships may not be causal. Demonstrating a causal influence would strongly support childhood and adolescent health as important for education policy. We applied genetic causal inference methods to assess the causal relationship of common health conditions at age 10 (primary/elementary school) and 13 (mid-secondary/mid-high school) with educational attainment at 16 and school absence at 14–16. Participants were 6113 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Exposures were symptoms of attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depression, asthma, migraines and BMI. Genetic liability for these conditions and BMI was indexed by polygenic scores. In non-genetic, multivariate-adjusted models, all health conditions except asthma and migraines were associated with poorer attainment and greater school absence. School absence substantially mediated effects of BMI (39.9% for BMI at 13) and migraines (72.0% at 10), on attainment with more modest mediation for emotional and neurodevelopmental conditions. In genetic models, a unit increase in standardized BMI at 10 predicted a 0.19 S.D. decrease (95% CI: 0.11, 0.28) in attainment at 16, equivalent to around a 1/3 grade lower in all subjects, and 8.7% more school absence (95% CI:1.8%,16.1%). Associations were similar at 13. Genetic liability for ADHD predicted lower attainment but not more absence. Triangulation across multiple approaches supports a causal, negative influence on educational outcomes of BMI and ADHD, but not of ASD, depression, asthma or migraine. Higher BMI in childhood and adolescence may causally impair educational outcomes

Peritoneal tissue-resident macrophages are metabolically poised to engage microbes using tissue-niche fuels

The importance of metabolism in macrophage function has been reported, but the in vivo relevance of the in vitro observations is still unclear. Here we show that macrophage metabolites are defined in a specific tissue context, and these metabolites are crucially linked to tissue-resident macrophage functions. We find the peritoneum to be rich in glutamate, a glutaminolysis-fuel that is exploited by peritoneal-resident macrophages to maintain respiratory burst during phagocytosis via enhancing mitochondrial complex-II metabolism. This niche-supported, inducible mitochondrial function is dependent on protein kinase C activity, and is required to fine-tune the cytokine responses that control inflammation. In addition, we find that peritoneal-resident macrophage mitochondria are recruited to phagosomes and produce mitochondrially derived reactive oxygen species, which are necessary for microbial killing. We propose that tissue-resident macrophages are metabolically poised in situ to protect and exploit their tissue-niche by utilising locally available fuels to implement specific metabolic programmes upon microbial sensing

Gas dynamics of the central few parsec region of NGC 1068 fuelled by the evolving nuclear star cluster

High resolution observations with the NIR adaptive optics integral field spectrograph SINFONI at the VLT proved the existence of massive and young nuclear star clusters in the centres of a sample of Seyfert galaxies. With the help of three-dimensional high resolution hydrodynamical simulations with the Pluto code, we follow the evolution of such clusters, focusing on stellar mass loss. This leads to clumpy or filamentary inflow of gas on large scales (tens of parsec), whereas a turbulent and very dense disc builds up on the parsec scale. In order to capture the relevant physics in the inner region, we treat this disc separately by viscously evolving the radial surface density distribution. This enables us to link the tens of parsec scale region (accessible via SINFONI observations) to the (sub-)parsec scale region (observable with the MIDI instrument and via water maser emission). In this work, we concentrate on the effects of a parametrised turbulent viscosity to generate angular momentum and mass transfer in the disc and additionally take star formation into account. Input parameters are constrained by observations of the nearby Seyfert 2 galaxy NGC 1068. At the current age of its nuclear starburst of 250 Myr, our simulations yield disc sizes of the order of 0.8 to 0.9 pc, gas masses of 1.0e6 solar masses and mass transfer rates of 0.025 solar masses per year through the inner rim of the disc. This shows that our large scale torus model is able to approximately account for the disc size as inferred from interferometric observations in the mid-infrared and compares well to the extent and mass of a rotating disc structure as inferred from water maser observations. Several other observational constraints are discussed as well.Comment: 13 pages, 11 figures, accepted for publication in MNRAS, updated author list and reference

Ownership-dependent mating tactics of minor males of the beetle Librodor japonicus (Nitidulidae) with intra-sexual dimorphism of mandibles

Intra-sexual dimorphism is found in the weapons of many male beetles. Different behavioral tactics to access females between major and minor males, which adopt fighting and alternative tactics, respectively, are thought to maintain the male dimorphism. In these species major males have enlarged weapons that they use in fights with rival males. Minor males also have small weapons in some of these species, and it is unclear why these males possess weapons. We examined the hypothesis that minor males might adopt a fighting tactic when their status was relatively high in comparison with that of other males (e.g., ownership of a territory). We observed the behavioral tactics of major and minor males of the beetle Librodor japonicus, whose males have a dimorphism of their mandibles. Major males fought for resources, whereas minor males adopted two status-dependent tactics, fighting and sneaking, to access females, depending on their ownership of a sap site. We suggest that ownership status-dependent mating tactics in minor males may maintain the intra-sexual dimorphism in this beetle.</p

Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase.

Profound metabolic changes are characteristic of macrophages during classical activation and have been implicated in this phenotype. Here we demonstrate that nitric oxide (NO) produced by murine macrophages is responsible for TCA cycle alterations and citrate accumulation associated with polarization. 13C tracing and mitochondrial respiration experiments map NO-mediated suppression of metabolism to mitochondrial aconitase (ACO2). Moreover, we find that inflammatory macrophages reroute pyruvate away from pyruvate dehydrogenase (PDH) in an NO-dependent and hypoxia-inducible factor 1α (Hif1α)-independent manner, thereby promoting glutamine-based anaplerosis. Ultimately, NO accumulation leads to suppression and loss of mitochondrial electron transport chain (ETC) complexes. Our data reveal that macrophages metabolic rewiring, in vitro and in vivo, is dependent on NO targeting specific pathways, resulting in reduced production of inflammatory mediators. Our findings require modification to current models of macrophage biology and demonstrate that reprogramming of metabolism should be considered a result rather than a mediator of inflammatory polarization

Non-pharmacological interventions to reduce psychological distress in patients undergoing diagnostic cardiac catheterization: a rapid review

Abstract Background: Cardiac catheterization is the standard procedure for the diagnosis of coronary heart disease. The threat physically and emotionally from this procedure can effect the patient’s perception of their health. The heightened psychological distress associated with this diagnostic procedure can cause adverse patient outcomes. Non-pharmacologic interventions have been implemented to reduce psychological distress associated with cardiac catheterization. Aims: The objective of this rapid review is to assess the efficacy of non-pharmacologic interventions (procedural education, relaxation techniques, psychological preparation) on psychological distress experienced by patients as they undergo a cardiac catheterization. Methods: Published, peer-reviewed, English-language intervention studies from 1981 to 2014 were identified in a search of CINAHL, Medline, and Cochrane Library. Eligible studies included adults undergoing cardiac catheterization. Studies included in this review used experimental and quasi-experimental designs and assessed at least one primary outcome: anxiety, depression, and pain to test non-pharmacologic interventions pre and post-cardiac catheterization. Researchers independently extracted data from included studies and completed a quality assessment using a published tool. Data was synthesised as a narrative. Results: There were 29 eligible experimental and quasi-experimental studies that tested the 3 interventions (n=2504). Findings suggest that non-pharmacologic interventions were able to effectively reduce psychological distress in some patients undergoing cardiac catheterization. Conclusion: Evidence is stronger in recent studies that non-pharmacologic interventions of procedural education and psychological preparation can reduce psychological distress in patients undergoing cardiac catheterization. Further research is needed to define the various relaxation techniques that can be effectively implemented for patients undergoing cardiac catheterization

Human neutrophil clearance of bacterial pathogens triggers anti-microbial gamma delta T cell responses in early infection

Human blood Vc9/Vd2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vc9/Vd2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vc9/Vd2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-c and tumor necrosis factor (TNF)-a. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vc9/Vd2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-a dependent proliferation of Vc9/Vd2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting cd T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis – characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity – show a selective activation of local Vc9/Vd2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The cd T celldriven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of cd T cells and TNF-a and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive cd T cells in early infection and suggest novel diagnostic and therapeutic approaches.Martin S. Davey, Chan-Yu Lin, Gareth W. Roberts, Sinéad Heuston, Amanda C. Brown, James A. Chess, Mark A. Toleman, Cormac G.M. Gahan, Colin Hill, Tanya Parish, John D. Williams, Simon J. Davies, David W. Johnson, Nicholas Topley, Bernhard Moser and Matthias Eber