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

Quantitative Analysis of Immune Response and Erythropoiesis during Rodent Malarial Infection

Malarial infection is associated with complex immune and erythropoietic responses in the host. A quantitative understanding of these processes is essential to help inform malaria therapy and for the design of effective vaccines. In this study, we use a statistical model-fitting approach to investigate the immune and erythropoietic responses in Plasmodium chabaudi infections of mice. Three mouse phenotypes (wildtype, T-cell-deficient nude mice, and nude mice reconstituted with T-cells taken from wildtype mice) were infected with one of two parasite clones (AS or AJ). Under a Bayesian framework, we use an adaptive population-based Markov chain Monte Carlo method and fit a set of dynamical models to observed data on parasite and red blood cell (RBC) densities. Model fits are compared using Bayes' factors and parameter estimates obtained. We consider three independent immune mechanisms: clearance of parasitised RBCs (pRBC), clearance of unparasitised RBCs (uRBC), and clearance of parasites that burst from RBCs (merozoites). Our results suggest that the immune response of wildtype mice is associated with less destruction of uRBCs, compared to the immune response of nude mice. There is a greater degree of synchronisation between pRBC and uRBC clearance than between either mechanism and merozoite clearance. In all three mouse phenotypes, control of the peak of parasite density is associated with pRBC clearance. In wildtype mice and AS-infected nude mice, control of the peak is also associated with uRBC clearance. Our results suggest that uRBC clearance, rather than RBC infection, is the major determinant of RBC dynamics from approximately day 12 post-innoculation. During the first 2–3 weeks of blood-stage infection, immune-mediated clearance of pRBCs and uRBCs appears to have a much stronger effect than immune-mediated merozoite clearance. Upregulation of erythropoiesis is dependent on mouse phenotype and is greater in wildtype and reconstitited mice. Our study highlights the informative power of statistically rigorous model-fitting techniques in elucidating biological systems

Quantitative Analysis of Mechanisms That Govern Red Blood Cell Age Structure and Dynamics during Anaemia

Mathematical modelling has proven an important tool in elucidating and quantifying mechanisms that govern the age structure and population dynamics of red blood cells (RBCs). Here we synthesise ideas from previous experimental data and the mathematical modelling literature with new data in order to test hypotheses and generate new predictions about these mechanisms. The result is a set of competing hypotheses about three intrinsic mechanisms: the feedback from circulating RBC concentration to production rate of immature RBCs (reticulocytes) in bone marrow, the release of reticulocytes from bone marrow into the circulation, and their subsequent ageing and clearance. In addition we examine two mechanisms specific to our experimental system: the effect of phenylhydrazine (PHZ) and blood sampling on RBC dynamics. We performed a set of experiments to quantify the dynamics of reticulocyte proportion, RBC concentration, and erythropoietin concentration in PHZ-induced anaemic mice. By quantifying experimental error we are able to fit and assess each hypothesis against our data and recover parameter estimates using Markov chain Monte Carlo based Bayesian inference. We find that, under normal conditions, about 3% of reticulocytes are released early from bone marrow and upon maturation all cells are released immediately. In the circulation, RBCs undergo random clearance but have a maximum lifespan of about 50 days. Under anaemic conditions reticulocyte production rate is linearly correlated with the difference between normal and anaemic RBC concentrations, and their release rate is exponentially correlated with the same. PHZ appears to age rather than kill RBCs, and younger RBCs are affected more than older RBCs. Blood sampling caused short aperiodic spikes in the proportion of reticulocytes which appear to have a different developmental pathway than normal reticulocytes. We also provide evidence of large diurnal oscillations in serum erythropoietin levels during anaemia

Woodland Recovery after Suppression of Deer: Cascade effects for Small Mammals, Wood Mice (Apodemus sylvaticus) and Bank Voles (Myodes glareolus)

Over the past century, increases in both density and distribution of deer species in the Northern Hemisphere have resulted in major changes in ground flora and undergrowth vegetation of woodland habitats, and consequentially the animal communities that inhabit them. In this study, we tested whether recovery in the vegetative habitat of a woodland due to effective deer management (from a peak of 0.4–1.5 to <0.17 deer per ha) had translated to the small mammal community as an example of a higher order cascade effect. We compared deer-free exclosures with neighboring open woodland using capture-mark-recapture (CMR) methods to see if the significant difference in bank vole (Myodes glareolus) and wood mouse (Apodemus sylvaticus) numbers between these environments from 2001–2003 persisted in 2010. Using the multi-state Robust Design method in program MARK we found survival and abundance of both voles and mice to be equivalent between the open woodland and the experimental exclosures with no differences in various metrics of population structure (age structure, sex composition, reproductive activity) and individual fitness (weight), although the vole population showed variation both locally and temporally. This suggests that the vegetative habitat - having passed some threshold of complexity due to lowered deer density - has allowed recovery of the small mammal community, although patch dynamics associated with vegetation complexity still remain. We conclude that the response of small mammal communities to environmental disturbance such as intense browsing pressure can be rapidly reversed once the disturbing agent has been removed and the vegetative habitat is allowed to increase in density and complexity, although we encourage caution, as a source/sink dynamic may emerge between old growth patches and the recently disturbed habitat under harsh conditions

CD36 Inhibitors Reduce Postprandial Hypertriglyceridemia and Protect against Diabetic Dyslipidemia and Atherosclerosis

CD36 is recognized as a lipid and fatty acid receptor and plays an important role in the metabolic syndrome and associated cardiac events. The pleiotropic activity and the multiple molecular associations of this scavenger receptor with membrane associated molecules in different cells and tissues have however questioned its potential as a therapeutic target. The present study shows that it is possible to identify low molecular weight chemicals that can block the CD36 binding and uptake functions. These inhibitors were able to reduce arterial lipid deposition, fatty acid intestinal transit, plasma concentration of triglycerides and glucose, to improve insulin sensitivity, glucose tolerance and to reduce the plasma concentration of HbAc1 in different and independent rodent models. Correlation between the anti-CD36 activity of these inhibitors and the known pathophysiological activity of this scavenger receptor in the development of atherosclerosis and diabetes were observed at pharmacological doses. Thus, CD36 might represent an attractive therapeutic target

Apoptotic Engulfment Pathway and Schizophrenia

Background: Apoptosis has been speculated to be involved in schizophrenia. In a previously study, we reported the association of the MEGF10 gene with the disease. In this study, we followed the apoptotic engulfment pathway involving the MEGF10, GULP1, ABCA1 and ABCA7 genes and tested their association with the disease. Methodology/Principal Findings: Ten, eleven and five SNPs were genotyped in the GULP1, ABCA1 and ABCA7 genes respectively for the ISHDSF and ICCSS samples. In all 3 genes, we observed nominally significant associations. Rs2004888 at GULP1 was significant in both ISHDSF and ICCSS samples (p = 0.0083 and 0.0437 respectively). We sought replication in independent samples for this marker and found highly significant association (p = 0.0003) in 3 Caucasian replication samples. But it was not significant in the 2 Chinese replication samples. In addition, we found a significant 2-marker (rs2242436 * rs3858075) interaction between the ABCA1 and ABCA7 genes in the ISHDSF sample (p = 0.0022) and a 3-marker interaction (rs246896 * rs4522565 * rs3858075) amongst the MEGF10, GULP1 and ABCA1 genes in the ICCSS sample (p = 0.0120). Rs3858075 in the ABCA1 gene was involved in both 2- and 3-marker interactions in the two samples. Conclusions/Significance: From these data, we concluded that the GULP1 gene and the apoptotic engulfment pathway are involved in schizophrenia in subjects of European ancestry and multiple genes in the pathway may interactively increase the risks to the disease. © 2009 Chen et al

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Charge-carrier dynamics in hybrid metal halide perovskites for next-generation solar cells

Hybrid metal halide perovskites have emerged over the last decade as highly promising materials for use in solar cells. Their advantages include low production costs, and rapidly increasing efficiencies to compete with those of commercially dominant silicon cells. Recently, increasing attention has been devoted to the use of perovskites in next-generation photovoltaic devices in order to overcome the efficiency limit for conventional single-junction cells. Work is still needed to identify the most promising perovskite materials for these applications, and to fully understand their relevant properties. This thesis contributes to both goals. The challenge of identifying the true timescale of charge-carrier cooling in metal halide perovskites, and whether certain compositions in fact show exceptionally slow cooling, is addressed. This is central to assessing the viability of hot-carrier extraction in perovskite solar cells. Key sources of error in previous approaches to determine charge-carrier temperature, which have produced an orders-of-magnitude range of reported cooling times, are identified. An improved model, which accounts for the full photoluminescence lineshape and enables a consistent approach that can be applied to studies across different perovskite compositions, is then described. Applying this improved model, charge-carrier cooling in FASnI3 is studied, revealing that observations of a secondary regime of slow charge-carrier cooling are in fact attributable to electronic relaxation, state-filling and recombination in this energetically disordered material. This result highlights that careful analysis of charge-carrier cooling dynamics is vital to assessing the realistic prospects for hot-carrier solar cells. Photoluminescence polarisation memory in FASnI3 is also examined, finding no persistent polarisation anisotropy within 270 fs. This points to a need for further study to identify the factors that lead such memory to arise from structural changes in certain perovskite compositions. Finally, the effects of the SnF2 additive commonly used to improve material quality of tin-containing perovskites are explored for FA0.83Cs0.17SnxPb1-xI3 across the lead-tin range. Significant beneficial effects from the suppression of tin oxidation and associated background hole doping, including reduced energetic disorder and increased charge-carrier mobilities and lifetimes, are found with as little as 1 mol% SnF2 added. The larger amounts of additive that have commonly been used are found to contribute to detrimental non-radiative recombination. These results, unravelling the impacts of SnF2 on both structural and optoelectronic properties, provide a foundation for control over the properties of mixed tin-lead perovskites for use as low-bandgap absorbers in all-perovskite tandem cells.</p

Optoelectronic properties of tin-lead halide perovskites

Mixed tin–lead halide perovskites have recently emerged as highly promising materials for efficient single- and multi-junction photovoltaic devices. This Focus Review discusses the optoelectronic properties that underpin this performance, clearly differentiating between intrinsic and defect-mediated mechanisms. We show that from a fundamental perspective, increasing tin fraction may cause increases in attainable charge-carrier mobilities, decreases in exciton binding energies, and potentially a slowing of charge-carrier cooling, all beneficial for photovoltaic applications. We discuss the mechanisms leading to significant bandgap bowing along the tin–lead series, which enables attractive near-infrared bandgaps at intermediate tin content. However, tin-rich stoichiometries still suffer from tin oxidation and vacancy formation which often obscures the fundamentally achievable performance, causing high background hole densities, accelerating charge-carrier recombination, lowering charge-carrier mobilities, and blue-shifting absorption onsets through the Burstein–Moss effect. We evaluate impacts on photovoltaic device performance, and conclude with an outlook on remaining challenges and promising future directions in this area

Charge-carrier cooling and polarization memory loss in formamidinium tin triiodide

Combination of a cryogenic ion-trap machine, operated at 4.7 K, with the free-electron-laser FELIX allows the first experimental characterization of the unusually bright antisymmetric stretch (ν3) and π-bending (ν2) fundamentals of the He–X+–He (X = H, D) chromophore of the in situ prepared HHen+ and DHen+ (n = 3–6) complexes. The band origins obtained are fully supported by first-principles quantum-chemical computations, performed at the MP2, the CCSD(T), and occasionally the CCSDTQ levels employing extended basis sets. Both the experiments and the computations are consistent with structures for the species with n = 3 and 6 being of T-shaped C2v and of D4h symmetry, respectively, while the species with n = 4 are suggested to exhibit interesting dynamical phenomena related to large-amplitude motions.</p