Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo

Neutrophil recruitment from blood to extravascular sites of sterile or infectious tissue damage is a hallmark of early innate immune responses, and the molecular events leading to cell exit from the bloodstream have been well defined1,2. Once outside the vessel, individual neutrophils often show extremely coordinated chemotaxis and cluster formation reminiscent of the swarming behaviour of insects3,4,5,6,7,8,9,10,11. The molecular players that direct this response at the single-cell and population levels within the complexity of an inflamed tissue are unknown. Using two-photon intravital microscopy in mouse models of sterile injury and infection, we show a critical role for intercellular signal relay among neutrophils mediated by the lipid leukotriene B4, which acutely amplifies local cell death signals to enhance the radius of highly directed interstitial neutrophil recruitment. Integrin receptors are dispensable for long-distance migration12, but have a previously unappreciated role in maintaining dense cellular clusters when congregating neutrophils rearrange the collagenous fibre network of the dermis to form a collagen-free zone at the wound centre. In this newly formed environment, integrins, in concert with neutrophil-derived leukotriene B4 and other chemoattractants, promote local neutrophil interaction while forming a tight wound seal. This wound seal has borders that cease to grow in kinetic concert with late recruitment of monocytes and macrophages at the edge of the displaced collagen fibres. Together, these data provide an initial molecular map of the factors that contribute to neutrophil swarming in the extravascular space of a damaged tissue. They reveal how local events are propagated over large-range distances, and how auto-signalling produces coordinated, self-organized neutrophil-swarming behaviour that isolates the wound or infectious site from surrounding viable tissue

Mechanism of the Inhibition of Ca2+-Activated Cl− Currents by Phosphorylation in Pulmonary Arterial Smooth Muscle Cells

The aim of the present study was to provide a mechanistic insight into how phosphatase activity influences calcium-activated chloride channels in rabbit pulmonary artery myocytes. Calcium-dependent Cl− currents (IClCa) were evoked by pipette solutions containing concentrations between 20 and 1000 nM Ca2+ and the calcium and voltage dependence was determined. Under control conditions with pipette solutions containing ATP and 500 nM Ca2+, IClCa was evoked immediately upon membrane rupture but then exhibited marked rundown to ∼20% of initial values. In contrast, when phosphorylation was prohibited by using pipette solutions containing adenosine 5′-(β,γ-imido)-triphosphate (AMP-PNP) or with ATP omitted, the rundown was severely impaired, and after 20 min dialysis, IClCa was ∼100% of initial levels. IClCa recorded with AMP-PNP–containing pipette solutions were significantly larger than control currents and had faster kinetics at positive potentials and slower deactivation kinetics at negative potentials. The marked increase in IClCa was due to a negative shift in the voltage dependence of activation and not due to an increase in the apparent binding affinity for Ca2+. Mathematical simulations were carried out based on gating schemes involving voltage-independent binding of three Ca2+, each binding step resulting in channel opening at fixed calcium but progressively greater “on” rates, and voltage-dependent closing steps (“off” rates). Our model reproduced well the Ca2+ and voltage dependence of IClCa as well as its kinetic properties. The impact of global phosphorylation could be well mimicked by alterations in the magnitude, voltage dependence, and state of the gating variable of the channel closure rates. These data reveal that the phosphorylation status of the Ca2+-activated Cl− channel complex influences current generation dramatically through one or more critical voltage-dependent steps

Deep lithospheric structures along the southern central Chile Margin from wide-angle P-wave modellilng

Crustal- and upper-mantle structures of the subduction zone in south central Chile, between 42 degrees S and 46 degrees S, are determined from seismic wide-angle reflection and refraction data, using the seismic ray tracing method to calculate minimum parameter models. Three profiles along differently aged segments of the subducting Nazca Plate were analysed in order to study subduction zone structure dependencies related to the age, that is, thermal state, of the incoming plate. The age of the oceanic crust at the trench ranges from 3 Ma on the southernmost profile, immediately north of the Chile triple junction, to 6.5 Ma old about 100 km to the north, and to 14.5 Ma old another 200 km further north, off the Island of Chiloe. Remarkable similarities appear in the structures of both the incoming as well as the overriding plate. The oceanic Nazca Plate is around 5 km thick, with a slightly increasing thickness northward, reflecting temperature changes at the time of crustal generation. The trench basin is about 2 km thick except in the south where the Chile Ridge is close to the deformation front and only a small, 800-m-thick trench infill could develop. In south central Chile, typically three quarters (1.5 km) of the trench sediments subduct below the decollement in the subduction channel. To the north and south of the study area, only about one quarter to one third of the sediments subducts, the rest is accreted above. Similarities in the overriding plate are the width of the active accretionary prism, 35-50 km, and a strong lateral crustal velocity gradient zone about 75-80 km landward from the deformation front, where landward upper-crustal velocities of over 5.0-5.4 km s<SU-1</SU decrease seaward to around 4.5 km s<SU-1</SU within about 10 km, which possibly represents a palaeo-backstop. This zone is also accompanied by strong intraplate seismicity. Differences in the subduction zone structures exist in the outer rise region, where the northern profile exhibits a clear bulge of uplifted oceanic lithosphere prior to subduction whereas the younger structures have a less developed outer rise. This plate bending is accompanied by strongly reduced rock velocities on the northern profile due to fracturing and possible hydration of the crust and upper mantle. The southern profiles do not exhibit such a strong alteration of the lithosphere, although this effect may be counteracted by plate cooling effects, which are reflected in increasing rock velocities away from the spreading centre. Overall there appears little influence of incoming plate age on the subduction zone structure which may explain why the M-w = 9.5 great Chile earthquake from 1960 ruptured through all these differing age segments. The rupture area, however, appears to coincide with a relatively thick subduction channel

Sodium-glucose co-transporter 2 inhibition in patients hospitalized for acute decompensated heart failure:rationale for and design of the EMPULSE trial

Aims Treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors improves outcomes in patients with chronic heart failure (HF) with reduced ejection fraction. There is limited experience with the in-hospital initiation of SGLT2 inhibitors in patients with acute HF (AHF) with or without diabetes. EMPULSE is designed to assess the clinical benefit and safety of the SGLT2 inhibitor empagliflozin compared with placebo in patients hospitalized with AHF. Methods EMPULSE is a randomized, double-blind, parallel-group, placebo-controlled multinational trial comparing the in-hospital initiation of empagliflozin (10 mg once daily) with placebo. Approximately 500 patients admitted for AHF with dyspnoea, signs of fluid overload, and elevated natriuretic peptides will be randomized 1:1 stratified to HF status (de-novo and decompensated chronic HF) to either empagliflozin or placebo at approximately 165 sites across North America, Europe and Asia. Patients will be enrolled regardless of ejection fraction and diabetes status and will be randomized during hospitalization and after stabilization (between 24 h and 5 days after admission), with treatment continued up to 90 days after initiation. The primary outcome is clinical benefit at 90 days, consisting of a composite of all-cause death, HF events, and >= 5 point change from baseline in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), assessed using a 'win-ratio' approach. Secondary outcomes include assessments of safety, change in KCCQ-TSS from baseline to 90 days and change in natriuretic peptides from baseline to 30 days. Conclusion The EMPULSE trial will evaluate the clinical benefit and safety of empagliflozin in patients hospitalized for AHF

Asperities and barriers on the seismogenic zone in North Chile: state-of-the-art after the 2007 Mw 7.7 Tocopilla earthquake inferred by GPS and InSAR data

The Mw 7.7 2007 November 14 earthquake had an epicentre located close to the city of Tocopilla, at the southern end of a known seismic gap in North Chile. Through modelling of Global Positioning System (GPS) and radar interferometry (InSAR) data, we show that this event ruptured the deeper part of the seismogenic interface (30–50 km) and did not reach the surface. The earthquake initiated at the hypocentre and was arrested ~150 km south, beneath the Mejillones Peninsula, an area already identified as an important structural barrier between two segments of the Peru–Chile subduction zone. Our preferred models for the Tocopilla main shock show slip concentrated in two main asperities, consistent with previous inversions of seismological data. Slip appears to have propagated towards relatively shallow depths at its southern extremity, under the Mejillones Peninsula. Our analysis of post-seismic deformation suggests that small but still significant post-seismic slip occurred within the first 10 d after the main shock, and that it was mostly concentrated at the southern end of the rupture. The post-seismic deformation occurring in this period represents ~12–19 per cent of the coseismic deformation, of which ~30–55 per cent has been released aseismically. Post-seismic slip appears to concentrate within regions that exhibit low coseismic slip, suggesting that the afterslip distribution during the first month of the post-seismic interval complements the coseismic slip. The 2007 Tocopilla earthquake released only ~2.5 per cent of the moment deficit accumulated on the interface during the past 130 yr and may be regarded as a possible precursor of a larger subduction earthquake rupturing partially or completely the 500-km-long North Chile seismic gap

Comparative Validation of Polyp Detection Methods in Video Colonoscopy: Results from the MICCAI 2015 Endoscopic Vision Challenge

Colonoscopy is the gold standard for colon cancer screening though still some polyps are missed, thus preventing early disease detection and treatment. Several computational systems have been proposed to assist polyp detection during colonoscopy but so far without consistent evaluation. The lack of publicly available annotated databases has made it difficult to compare methods and to assess if they achieve performance levels acceptable for clinical use. The Automatic Polyp Detection subchallenge, conducted as part of the Endoscopic Vision Challenge (http://endovis.grand-challenge.org) at the international conference on Medical Image Computing and Computer Assisted Intervention (MICCAI) in 2015, was an effort to address this need. In this paper, we report the results of this comparative evaluation of polyp detection methods, as well as describe additional experiments to further explore differences between methods. We define performance metrics and provide evaluation databases that allow comparison of multiple methodologies. Results show that convolutional neural networks (CNNs) are the state of the art. Nevertheless it is also demonstrated that combining different methodologies can lead to an improved overall performance

A finite difference method for pricing European and American options under a geometric Lévy process

In this paper we develop a numerical approach to a fractional-order differential Linear Complementarity Problem (LCP) arising in pricing European and American options under a geometric Lévy process. The LCP is first approximated by a nonlinear penalty fractional Black-Scholes (fBS) equation. We then propose a finite difference scheme for the penalty fBS equation. We show that both the continuous and the discretized fBS equations are uniquely solvable and establish the convergence of the numerical solution to the viscosity solution of the penalty fBS equation by proving the consistency, stability and monotonicity of the numerical scheme. We also show that the discretization has the 2nd-order truncation error in both the spatial and time mesh sizes. Numerical results are presented to demonstrate the accuracy and usefulness of the numerical method for pricing both European and American options under the geometric Lévy process

Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses

Correlates of immune-mediated protection to most viral and cancer vaccines are still unknown. This impedes the development of novel vaccines to incurable diseases such as HIV and cancer. In this study, we have used functional genomics and polychromatic flow cytometry to define the signature of the immune response to the yellow fever (YF) vaccine 17D (YF17D) in a cohort of 40 volunteers followed for up to 1 yr after vaccination. We show that immunization with YF17D leads to an integrated immune response that includes several effector arms of innate immunity, including complement, the inflammasome, and interferons, as well as adaptive immunity as shown by an early T cell response followed by a brisk and variable B cell response. Development of these responses is preceded, as demonstrated in three independent vaccination trials and in a novel in vitro system of primary immune responses (modular immune in vitro construct [MIMIC] system), by the coordinated up-regulation of transcripts for specific transcription factors, including STAT1, IRF7, and ETS2, which are upstream of the different effector arms of the immune response. These results clearly show that the immune response to a strong vaccine is preceded by coordinated induction of master transcription factors that lead to the development of a broad, polyfunctional, and persistent immune response that integrates all effector cells of the immune system

Cardiovascular Mortality Can Be Predicted by Heart Rate Turbulence in Hemodialysis Patients

Background: Excess mortality in hemodialysis patients is mostly of cardiovascular origin. We examined the association of heart rate turbulence (HRT), a marker of baroreflex sensitivity, with cardiovascular mortality in hemodialysis patients. Methods: A population of 290 prevalent hemodialysis patients was followed up for a median of 3 years. HRT categories 0 (both turbulence onset [TO] and slope [TS] normal), 1 (TO or TS abnormal), and 2 (both TO and TS abnormal) were obtained from 24 h Holter recordings. The primary end-point was cardiovascular mortality. Associations of HRT categories with the endpoints were analyzed by multivariable Cox regression models including HRT, age, albumin, and the improved Charlson Comorbidity Index for hemodialysis patients. Multivariable linear regression analysis identified factors associated with TO and TS. Results: During the follow-up period, 20 patients died from cardiovascular causes. In patients with HRT categories 0, 1 and 2, cardiovascular mortality was 1, 10, and 22%, respectively. HRT category 2 showed the strongest independent association with cardiovascular mortality with a hazard ratio of 19.3 (95% confidence interval: 3.69-92.03;P < 0.001). Age, calcium phosphate product, and smoking status were associated with TO and TS. Diabetes mellitus and diastolic blood pressure were only associated with TS. Conclusion: Independent of known risk factors, HRT assessment allows identification of hemodialysis patients with low, intermediate, and high risk of cardiovascular mortality. Future prospective studies are needed to translate risk prediction into risk reduction in hemodialysis patients