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

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

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

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

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

Exact Hybrid Particle/Population Simulation of Rule-Based Models of Biochemical Systems

Detailed modeling and simulation of biochemical systems is complicated by the problem of combinatorial complexity, an explosion in the number of species and reactions due to myriad protein-protein interactions and post-translational modifications. Rule-based modeling overcomes this problem by representing molecules as structured objects and encoding their interactions as pattern-based rules. This greatly simplifies the process of model specification, avoiding the tedious and error prone task of manually enumerating all species and reactions that can potentially exist in a system. From a simulation perspective, rule-based models can be expanded algorithmically into fully-enumerated reaction networks and simulated using a variety of network-based simulation methods, such as ordinary differential equations or Gillespie's algorithm, provided that the network is not exceedingly large. Alternatively, rule-based models can be simulated directly using particle-based kinetic Monte Carlo methods. This "network-free" approach produces exact stochastic trajectories with a computational cost that is independent of network size. However, memory and run time costs increase with the number of particles, limiting the size of system that can be feasibly simulated. Here, we present a hybrid particle/population simulation method that combines the best attributes of both the network-based and network-free approaches. The method takes as input a rule-based model and a user-specified subset of species to treat as population variables rather than as particles. The model is then transformed by a process of "partial network expansion" into a dynamically equivalent form that can be simulated using a population-adapted network-free simulator. The transformation method has been implemented within the open-source rule-based modeling platform BioNetGen, and resulting hybrid models can be simulated using the particle-based simulator NFsim. Performance tests show that significant memory savings can be achieved using the new approach and a monetary cost analysis provides a practical measure of its utility. © 2014 Hogg et al

Upper lithospheric structure of the subduction zone offshore of southern Arauco peninsula, Chile, at ~38°S

A joint interpretation of swath bathymetric, seismic refraction, wide-angle reflection, and multichannel seismic data was used to derive a detailed tomographic image of the Nazca-South America subduction zone system offshore southern Arauco peninsula, Chile at similar to 38 degrees S. Here, the trench basin is filled with up to 2.2 km of sediments, and the Mocha Fracture Zone (FZ) is obliquely subducting underneath the South American plate. The velocity model derived from the tomographic inversion consists of a similar to 7-km-thick oceanic crust and shows P wave velocities typical for mature fast spreading crust in the seaward section of the profile, with uppermost mantle velocities >8.4 km s(-1). In the trench-outer rise area, the top of incoming oceanic plate is pervasively fractured and likely hydrated as shown by extensional faults, horst-and-graben structures, and a reduction of both crustal and mantle velocities. These slow velocities are interpreted in terms of extensional bending-related faulting leading to fracturing and hydration in the upper part of the oceanic lithosphere. The incoming Mocha FZ coincides with an area of even slower velocities and thinning of the oceanic crust (10-15% thinning), suggesting that the incoming fracture zone may enhance the flux of chemically bound water into the subduction zone. Slow mantle velocities occur down to a maximum depth of 6-8 km into the upper mantle, where mantle temperatures are estimated to be 400-430 degrees C. In the overriding plate, the tomographic model reveals two prominent velocity transition zones characterized by steep lateral velocity gradients, resulting in a seismic segmentation of the marine fore arc. The margin is composed of three main domains: (1) a similar to 20 km wide frontal prism below the continental slope with Vp <= 3.5 km s(-1), (2) a similar to 50 km area with Vp = 4.5-5.5 km s(-1), interpreted as a paleoaccretionary complex, and (3) the seaward edge of the Paleozoic continental framework with Vp >= 6.0 km s(-1). Frontal prism velocities are noticeably lower than those found in the northern erosional Chile margin, confirming recent accretionary processes in south central Chile

Treatment effects of empagliflozin in hospitalized heart failure patients across the range of left ventricular ejection fraction :Results from the EMPULSE trial

Aim: The EMPULSE (EMPagliflozin in patients hospitalised with acUte heart faiLure who have been StabilizEd) trial showed that, compared to placebo, the sodium–glucose cotransporter 2 inhibitor empagliflozin (10 mg/day) improved clinical outcomes of patients hospitalized for acute heart failure (HF). We investigated whether efficacy and safety of empagliflozin were consistent across the spectrum of left ventricular ejection fraction (LVEF). Methods and results: A total of 530 patients hospitalized for acute de novo or decompensated HF were included irrespective of LVEF. For the present analysis, patients were classified as HF with reduced (HFrEF, LVEF ≤40%), mildly reduced (HFmrEF, LVEF 41–49%) or preserved (HFpEF, LVEF ≥50%) ejection fraction at baseline. The primary endpoint was a hierarchical outcome of death, worsening HF events (HFE) and quality of life over 90 days, assessed by the win ratio. Secondary endpoints included individual components of the primary endpoint and safety. Out of 523 patients with baseline data, 354 (67.7%) had HFrEF, 54 (10.3%) had HFmrEF and 115 (22.0%) had HFpEF. The clinical benefit (hierarchical composite of all-cause death, HFE and Kansas City Cardiomyopathy Questionnaire total symptom score) of empagliflozin at 90 days compared to placebo was consistent across LVEF categories (≤40%: win ratio 1.35 [95% confidence interval 1.04, 1.75]; 41–49%: win ratio 1.25 [0.66, 2.37)] and ≥50%: win ratio 1.40 [0.87, 2.23], pinteraction = 0.96) with a favourable safety profile. Results were consistent across individual components of the hierarchical primary endpoint. Conclusion: The clinical benefit of empagliflozin proved consistent across LVEF categories in the EMPULSE trial. These results support early in-hospital initiation of empagliflozin regardless of LVEF.</p

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