Proteolysis of the endothelial cell protein C receptor by neutrophil proteinase 3

BACKGROUND: The endothelial cell protein C receptor (EPCR) presents protein C to the thrombin:thrombomodulin complex on the endothelium of large vessels, and enhances the generation of activated protein C (APC) and activation of protease-activated receptor-1. A previous report has demonstrated binding of soluble (s) EPCR to activated neutrophils via surface proteinase 3 (PR3). METHODS: We now report further characterization of this interaction. Activated neutrophils and purified PR3 both decrease endothelial cell (EC) surface EPCR, suggestive of its proteolysis. RESULTS: When added to purified recombinant sEPCR, PR3 produced multiple cleavages, with early products including 20 kDa N-terminal and C-terminal (after Lys(176)) fragments. The binding of active site blocked PR3 to sEPCR was studied by surface plasmon resonance. Estimates of the K(D) of 18.5–102 nm were obtained with heterogeneous binding, suggestive of more than a single interaction site. CONCLUSIONS: This work demonstrates PR3 binding to and proteolysis of EPCR and suggests a mechanism by which anticoagulant and cell protective pathways can be down-regulated during inflammation

IFN-γ-producing CD4+ T cells promote experimental cerebral malaria by modulating CD8+ T cell accumulation within the brain.

It is well established that IFN-γ is required for the development of experimental cerebral malaria (ECM) during Plasmodium berghei ANKA infection of C57BL/6 mice. However, the temporal and tissue-specific cellular sources of IFN-γ during P. berghei ANKA infection have not been investigated, and it is not known whether IFN-γ production by a single cell type in isolation can induce cerebral pathology. In this study, using IFN-γ reporter mice, we show that NK cells dominate the IFN-γ response during the early stages of infection in the brain, but not in the spleen, before being replaced by CD4(+) and CD8(+) T cells. Importantly, we demonstrate that IFN-γ-producing CD4(+) T cells, but not innate or CD8(+) T cells, can promote the development of ECM in normally resistant IFN-γ(-/-) mice infected with P. berghei ANKA. Adoptively transferred wild-type CD4(+) T cells accumulate within the spleen, lung, and brain of IFN-γ(-/-) mice and induce ECM through active IFN-γ secretion, which increases the accumulation of endogenous IFN-γ(-/-) CD8(+) T cells within the brain. Depletion of endogenous IFN-γ(-/-) CD8(+) T cells abrogates the ability of wild-type CD4(+) T cells to promote ECM. Finally, we show that IFN-γ production, specifically by CD4(+) T cells, is sufficient to induce expression of CXCL9 and CXCL10 within the brain, providing a mechanistic basis for the enhanced CD8(+) T cell accumulation. To our knowledge, these observations demonstrate, for the first time, the importance of and pathways by which IFN-γ-producing CD4(+) T cells promote the development of ECM during P. berghei ANKA infection

Exhausted CD4⁺ T Cells during Malaria Exhibit Reduced mTORc1 Activity Correlated with Loss of T-bet Expression

CD4⁺ T cell functional inhibition (exhaustion) is a hallmark of malaria and correlates with impaired parasite control and infection chronicity. However, the mechanisms of CD4⁺ T cell exhaustion are still poorly understood. In this study, we show that Ag-experienced (Ag-exp) CD4⁺ T cell exhaustion during Plasmodium yoelii nonlethal infection occurs alongside the reduction in mammalian target of rapamycin (mTOR) activity and restriction in CD4+ T cell glycolytic capacity. We demonstrate that the loss of glycolytic metabolism and mTOR activity within the exhausted Ag-expCD4⁺ T cell population during infection coincides with reduction in T-bet expression. T-bet was found to directly bind to and control the transcription of various mTOR and metabolism-related genes within effector CD4⁺ T cells. Consistent with this, Ag-expTh1 cells exhibited significantly higher and sustained mTOR activity than effector T-bet- (non-Th1) Ag-expT cells throughout the course of malaria. We identified mTOR to be redundant for sustaining T-bet expression in activated Th1 cells, whereas mTOR was necessary but not sufficient for maintaining IFN-γ production by Th1 cells. Immunotherapy targeting PD-1, CTLA-4, and IL-27 blocked CD4⁺ T cell exhaustion during malaria infection and was associated with elevated T-bet expression and a concomitant increased CD4⁺ T cell glycolytic metabolism. Collectively, our data suggest that mTOR activity is linked to T-bet in Ag-expCD4⁺ T cells but that reduction in mTOR activity may not directly underpin Ag-expTh1 cell loss and exhaustion during malaria infection. These data have implications for therapeutic reactivation of exhausted CD4⁺ T cells during malaria infection and other chronic conditions

IL-27 receptor signaling regulates CD4+ T cell chemotactic responses during infection.

IL-27 exerts pleiotropic suppressive effects on naive and effector T cell populations during infection and inflammation. Surprisingly, however, the role of IL-27 in restricting or shaping effector CD4(+) T cell chemotactic responses, as a mechanism to reduce T cell-dependent tissue inflammation, is unknown. In this study, using Plasmodium berghei NK65 as a model of a systemic, proinflammatory infection, we demonstrate that IL-27R signaling represses chemotaxis of infection-derived splenic CD4(+) T cells in response to the CCR5 ligands, CCL4 and CCL5. Consistent with these observations, CCR5 was expressed on significantly higher frequencies of splenic CD4(+) T cells from malaria-infected, IL-27R-deficient (WSX-1(-/-)) mice than from infected wild-type mice. We find that IL-27 signaling suppresses splenic CD4(+) T cell CCR5-dependent chemotactic responses during infection by restricting CCR5 expression on CD4(+) T cell subtypes, including Th1 cells, and also by controlling the overall composition of the CD4(+) T cell compartment. Diminution of the Th1 response in infected WSX-1(-/-) mice in vivo by neutralization of IL-12p40 attenuated CCR5 expression by infection-derived CD4(+) T cells and also reduced splenic CD4(+) T cell chemotaxis toward CCL4 and CCL5. These data reveal a previously unappreciated role for IL-27 in modulating CD4(+) T cell chemotactic pathways during infection, which is related to its capacity to repress Th1 effector cell development. Thus, IL-27 appears to be a key cytokine that limits the CCR5-CCL4/CCL5 axis during inflammatory settings

New stable by construction autonomous aerial vehicle: configuration and dynamic model.

[ES] En los últimos años, diferentes estrategias y modelos matemáticos se han desarrollado para el análisis y control de vehículos aéreos no tripulados. El presente artículo amplía este panorama al enfocarse en un sistema aéreo no tripulado estable por construcción. Gracias a su diseño, el sistema reportado disipa la energía que recibe por la acción de perturbaciones externas. El sistema propuesto cuenta con un rotor único para el desarrollo de diferentes tipos de vuelo. Este artículo reporta el concepto de diseño del sistema aéreo no tripulado, la estructura de su modelo dinámico de nueve grados de libertad, un conjunto de simulaciones numéricas que permiten analizar el comportamiento del modelo desarrollado y los primeros resultados experimentales que validan la estabilidad por construcción del vehículo aéreo autónomo. Los dos aspectos más significativos e innovadores reportados en este artículo son el uso de un rotor único orientable para la ejecución de diferentes modos de vuelo y la propiedad inherente del sistema tal que sus estructuras, externa e interna, son estables por construcción.[EN] In recent years, different strategies and mathematical models have been developed in order to analyze and control unmanned aerial vehicles. This article expands this panorama by focusing on a, stable by construction, unmanned aerial system. Thanks to its design, the reported system dissipates the energy received by the action of external disturbances. The proposed vehicle has a unique rotor in order to perform different flight modes. This article reports the design concept of the aerial system, the mathematical structure of its nine degrees of freedom dynamic model, a set of numerical simulations allowing the analysis of the behavior of the developed model and the first experimental results that validate the stability, by construction, of the aerial vehicle. The two most significant and innovative aspects reported in this article are the use of a single orientable rotor to perform different flight modes and the inherent property of the system that makes it stable by construction.Este trabajo fue apoyado por la Universidad Autónoma del Estado de México bajo el proyecto de investigación: Desarrollo de un Vehículo Esférico Aéreo Autónomo con clave 3818/2014/CIB. Eduardo Sánchez Fontes agradece el financiamiento por la beca CONACYT CVU 553663.Sánchez-Fontes, E.; Avila Vilchis, JC.; Vilchis-González, AH.; Saldivar, B.; Jacinto-Villegas, JM.; Martínez-Mendez, R. (2020). 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Chinese Journal of Aeronautics 30 (1), 135-148. https://doi.org/https://doi.org/10.1016/j.cja.2016.11.001Lozano, R., 2013. Unmanned Aerial Vehicles: Embedded Control. Vol. 42 of ISTE. Wiley. https://doi.org/10.1002/esp.4142Mendelow, B., Muir, P., Boshielo, B., Robertson, J., 2007. Development of e-juba, a preliminary proof of concept unmanned aerial vehicle designed to facilitate the transportation of microbiological test samples from remote rural clinics to national health laboratory service laboratories. South African Medical Journal 15, 1021-1030. https://doi.org/10.1002/lom3.10222Mohamed, M. K., Lanzon, A., 2012. Design and control of novel tri-rotor uav. In: Proceedings of 2012 UKACC International Conference on Control. pp. 304-309. https://doi.org/10.1109/CONTROL.2012.6334647Motlagh, N. H., Bagaa, M., Taleb, T., Feb. 2017. UAV-based iot platform: A crowd surveillance use case. IEEE Communications Magazine 55 (2), 128-134. https://doi.org/10.1109/MCOM.2017.1600587CMNex, F., Remondino, F., Mar. 2014. UAV for 3d mapping applications: A review. Applied Geomatics 6 (1), 1-15. https://doi.org/10.1007/s12518-013-0120-xPerlo, P., Bollea, D., Finizio, R., Carvignese, C., Balocco, E., Dec. 2005. VTOL micro-aircraft. Patent US 6,976,653 B2, C.R.F Societa Consortile per Azioni, Washington, DC: US.Prouty, R., Jan. 2003. Helicopter performance, Stability, and Control. Krieger.Remondino, F., Barazzetti, L., Nex, F., Scaioni, M., Sarazzi, D., Jan. 2011. UAV photogrammetry for mapping and 3d modeling-current status and future perspectives. In: ISPRS - International Archives of the Photogrammetry, Remote Sensing and Spatial Information Sciences. Vol. XXXVIII-1/C22. pp. 25-31. https://doi.org/10.5194/isprsarchives-xxxviii-1-c22-25-2011Sanchez, A., Escareño, J., Garcia, O., Lozano, R., 2008. Autonomous hovering of a noncyclic tiltrotor UAV: Modeling, control and implementation. IFAC Proceedings Volumes 41 (2), 803 - 808. https://doi.org/https://doi.org/10.3182/20080706-5-KR-1001.00138Sanchez-Fontes, E., Jan. 2016. Diseño y modelado de un vehículo esférico aéreo autónomo. Master's thesis, Facultad de Ingeniería de la Universidad Autónoma del Estado de México, Toluca, México.Segui-Gasco, P., Al-Rihani, Y., Shin, H. S., Savvaris, A., May 2014. A novel actuation concept for a multi rotor uav. In: International Conference on Unmanned Aircraft Systems (ICUAS). Vol. 74. pp. 173-191. https://doi.org/10.1007/s10846-013-9987-3Senkul, A. F., Altug, E., 2016. System design of a novel tilt-roll rotor quadrotor UAV. Journal of Intelligent & Robotic Systems 84 (1), 575-599. https://doi.org/10.1007/s10846-015-0301-4Shames, I. H., Apr. 1996. Engineering Mechanics: Statics and Dynamics, 4th Edition. Prentice Hall.Tilli, A., Montanari, M., Jan. 2001. 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Chasing extreme planetary architectures: I- HD196885Ab, a super-Jupiter dancing with two stars?

Planet(s) in binaries are unique architectures for testing predictions of planetary formation and evolution theories in very hostile environments. We used the IRDIS dual-band imager of SPHERE at VLT, and the speckle interferometric camera HRCAM of SOAR, to acquire high-angular resolution images of HD 196885 AB between 2015 and 2020. Radial velocity observations have been extended over almost 40 yr extending the radial velocity measurements HD 196885 A and resolving both the binary companion and the inner giant planet HD 196885 Ab. Finally, we took advantage of the exquisite astrometric precision of the dual-field mode of VLTI/GRAVITY (down to 30 {\mu}as) to monitor the relative position of HD 196885 A and B to search for the 3.6 yr astrometric wobble of the circumprimary planet Ab imprinted on the binary separation. Our observations enable to accurately constrain the orbital properties of the binary HD 196885 AB, seen on an inclined and retrograde orbit (iAB = 120.43 deg) with a semi-major axis of 19.78 au, and an eccentricity of 0.417. The GRAVITY measurements confirm for the first time the nature of the inner planet HD 196885 Ab by rejecting all families of pole-on solutions in the stellar or brown dwarf masses. The most favored island of solutions is associated with a Jupiter-like planet (MAb = 3.39 MJup), with moderate eccentricity (eAaAb = 0.44), and inclination close to 143.04 deg. This results points toward a significant mutual inclination (Phi = 24.36 deg) between the orbital planes (relative to the star) of the binary companion B and the planet Ab. Our dynamical simulations indicate that the system is dynamically stable over time. Eccentricity and mutual inclination variations could be expected for moderate von Zipele Kozai Lidov cycles that may affect the inner planet.Comment: 12 pages, 6 figures, accepted in A&

Memory CD8 + T cells exhibit tissue imprinting and non‐stable exposure‐dependent reactivation characteristics following blood‐stage Plasmodium berghei ANKA infections

From Wiley via Jisc Publications RouterHistory: received 2020-11-02, rev-recd 2021-08-09, accepted 2021-08-13, pub-electronic 2021-08-27Article version: VoRPublication status: PublishedFunder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100000265; Grant(s): G0900487, MR/R010099/1Abstract: Experimental cerebral malaria (ECM) is a severe complication of Plasmodium berghei ANKA (PbA) infection in mice, characterized by CD8+ T‐cell accumulation within the brain. Whilst the dynamics of CD8+ T‐cell activation and migration during extant primary PbA infection have been extensively researched, the fate of the parasite‐specific CD8+ T cells upon resolution of ECM is not understood. In this study, we show that memory OT‐I cells persist systemically within the spleen, lung and brain following recovery from ECM after primary PbA‐OVA infection. Whereas memory OT‐I cells within the spleen and lung exhibited canonical central memory (Tcm) and effector memory (Tem) phenotypes, respectively, memory OT‐I cells within the brain post‐PbA‐OVA infection displayed an enriched CD69+CD103− profile and expressed low levels of T‐bet. OT‐I cells within the brain were excluded from short‐term intravascular antibody labelling but were targeted effectively by longer‐term systemically administered antibodies. Thus, the memory OT‐I cells were extravascular within the brain post‐ECM but were potentially not resident memory cells. Importantly, whilst memory OT‐I cells exhibited strong reactivation during secondary PbA‐OVA infection, preventing activation of new primary effector T cells, they had dampened reactivation during a fourth PbA‐OVA infection. Overall, our results demonstrate that memory CD8+ T cells are systemically distributed but exhibit a unique phenotype within the brain post‐ECM, and that their reactivation characteristics are shaped by infection history. Our results raise important questions regarding the role of distinct memory CD8+ T‐cell populations within the brain and other tissues during repeat Plasmodium infections

Real-Time Imaging Reveals the Dynamics of Leukocyte Behaviour during Experimental Cerebral Malaria Pathogenesis

During experimental cerebral malaria (ECM) mice develop a lethal neuropathological syndrome associated with microcirculatory dysfunction and intravascular leukocyte sequestration. The precise spatio-temporal context in which the intravascular immune response unfolds is incompletely understood. We developed a 2-photon intravital microscopy (2P-IVM)-based brain-imaging model to monitor the real-time behaviour of leukocytes directly within the brain vasculature during ECM. Ly6Chi monocytes, but not neutrophils, started to accumulate in the blood vessels of Plasmodium berghei ANKA (PbA)-infected MacGreen mice, in which myeloid cells express GFP, one to two days prior to the onset of the neurological signs (NS). A decrease in the rolling speed of monocytes, a measure of endothelial cell activation, was associated with progressive worsening of clinical symptoms. Adoptive transfer experiments with defined immune cell subsets in recombinase activating gene (RAG)-1-deficient mice showed that these changes were mediated by Plasmodium-specific CD8+ T lymphocytes. A critical number of CD8+ T effectors was required to induce disease and monocyte adherence to the vasculature. Depletion of monocytes at the onset of disease symptoms resulted in decreased lymphocyte accumulation, suggesting reciprocal effects of monocytes and T cells on their recruitment within the brain. Together, our studies define the real-time kinetics of leukocyte behaviour in the central nervous system during ECM, and reveal a significant role for Plasmodium-specific CD8+ T lymphocytes in regulating vascular pathology in this disease. © 2014 Pai et al

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112