Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis

Neutrophil influx into the intestinal lumen is a critical response to infectious agents, but is also associated with severe intestinal damage observed in idiopathic inflammatory bowel disease. The chemoattractant hepoxilin A3, an eicosanoid secreted from intestinal epithelial cells by the apically restricted efflux pump multidrug resistance protein 2 (MRP2), mediates this neutrophil influx. Information about a possible counterbalance pathway that could signal the lack of or resolution of an apical inflammatory signal, however, has yet to be described. We now report a system with such hallmarks. Specifically, we identify endocannabinoids as the first known endogenous substrates of the apically restricted multidrug resistance transporter P-glycoprotein (P-gp) and reveal a mechanism, which we believe is novel, for endocannabinoid secretion into the intestinal lumen. Knockdown or inhibition of P-gp reduced luminal secretion levels of N-acyl ethanolamine-type endocannabinoids, which correlated with increased neutrophil transmigration in vitro and in vivo. Additionally, loss of CB2, the peripheral cannabinoid receptor, led to increased pathology and neutrophil influx in models of acute intestinal inflammation. These results define a key role for epithelial cells in balancing the constitutive secretion of antiinflammatory lipids with the stimulated secretion of proinflammatory lipids via surface efflux pumps in order to control neutrophil infiltration into the intestinal lumen and maintain homeostasis in the healthy intestine

A lower bound on the right-handed neutrino mass from leptogenesis

In the seesaw model, the baryon asymmetry of the Universe can be generated by the decay of the lightest right-handed neutrino, nu_R. For a hierarchical spectrum of right-handed neutrinos, we show that there is a model independent upper bound on the CP asymmetry produced in these decays: epsilon < 3 m_{nu_3} M_{nu_R}/(8 pi ^2). This implies that epsilon and the mass M_{nu_R} of the lightest right-handed neutrino are not independent parameters, as is commonly assumed. If m_{nu_3} = sqrt{Delta m^2_{atm}} and the nu_R are produced thermally, then leptogenesis requires a reheat temperature of the Universe T_{reh} > M_{nu_R} > 10^8 GeV. Reasonable estimates of nu_R production and the subsequent washout of the asymmetry, as made by Buchmuller and Plumacher, imply M_{nu_R} > 10^9 GeV, and T_{reh} > 10^{10} GeV. Implications for the gravitino problem are also discussed.Comment: 9 pages. References added. Version to appear in Phys. Lett.

Saving lives beyond 2020: The next steps

Road safety analysis can be used to understand what has been successful in the past and what needs to be changed in order to be successful to reduce severe road trauma going forward and ultimately what\u27s needed to achieve zero. This chapter covers some of the tools used to retrospectively evaluate real-life benefits of road safety measures and methods used to predict the combined effects of interventions in a road safety action plan as well as to estimate if they are sufficient to achieve targets near-term and long-term. Included are also a brief overview of methods to develop boundary conditions on what constitutes a Safe System for different road users. Further to that, the chapter lists some arguments for the need of high-quality mass and in-depth data to ensure confidence in the results and conclusions from road safety analysis. Finally, a few key messages are summarized

Synergistic warm inflation

We consider an alternative warm inflationary scenario in which $n$ scalar fields coupled to a dissipative matter fluid cooperate to produce power--law inflation. The scalar fields are driven by an exponential potential and the bulk dissipative pressure coefficient is linear in the expansion rate. We find that the entropy of the fluid attains its asymptotic value in a characteristic time proportional to the square of the number of fields. This scenario remains nearly isothermal along the inflationary stage. The perturbations in energy density and entropy are studied in the long--wavelength regime and seen to grow roughly as the square of the scale factor. They are shown to be compatible with COBE measurements of the fluctuations in temperature of the CMB.Comment: 13 pages, Revtex 3 To be published in Physical Review

ESTUDIO EXPLORATORIO SOBRE LA ASOCIACIÓN DE METALES PESADOS Y LA NEFROPATÍA DE ETIOLOGÍA DESCONOCIDA EN EL PONIENTE DEL ESTADO DE MÉXICO

Artículo publicado en: Rev. Int. Contam. Ambie. 34 (4) 555-564, 2018 DOI: 10.20937/RICA.2018.34.04.01En el occidente del Estado de México, la mitad de los ingresos hospitalarios por insuficiencia renal crónica (IRC) no asociada a diabetes mellitus ni a hipertensión arterial corresponden a personas menores de 40 años. Por lo tanto, esta IRC se considera de causas desconocidas (IRCd). En este trabajo se estudió la asociación entre la presencia de metales y factores de riesgo para IRCd. Se realizó un estudio transversal analítico de 100 casos y 100 testigos. Se aplicó un cuestionario para conocer las adicciones y exposiciones (alimentarias, ocupacionales y medicamentosas) de los sujetos. En 50 casos y 50 testigos se determinó la concentración de los metales arsénico, cadmio, mercurio y plomo en muestras de cabello. Finalmente, se construyó un mapa con la posición de la vivienda de los 100 pacientes. Con base en una regresión logística bivariada se determinó que existe una asociación estadísticamente significativa entre la IRCd y el consumo de tabaco, exposición ocupacional a la construcción y herrería, y exposición a arsénico. Es necesaria una muestra mayor para comprobar la exposición ocupacional a la industria del papel, al consumo de paracetamol, naproxeno y cadmio. Los valores obtenidos en este trabajo para estas variables mencionadas son sólo informativos. Los casos estudiados se localizan en la cuenca del Rio Lerma, uno de los más contaminados del país. La IRCd presente en el Estado de México parece ser muy similar a la de Siri Lanka y la del Pacífico centroamericano, por lo que se requieren estudios a mayor escala.Fondo de Fomento y Desarrollo de la Investigación Científica y Tecnológica de la Universidad Autónoma del Estado de México, proyecto con clave 3896/2015E

Leptogenesis and low-energy phases

In supersymmetric models, the CP asymmetry produced in the decay of the lightest right-handed neutrino, $\equiv epsilon$, can be written as a function of weak scale parameters. We introduce a way of separating epsilon into contributions from the various weak-scale phases, and study the contribution of potentially measurable neutrino phases to leptogenesis. We find that the Majorana phase phi', which could have observable effects on neutrinoless double beta decay, is important for epsilon unless there are cancellations among phases. If the phase delta can be measured at a neutrino factory, then it contributes significantly to epsilon over much of parameter space.Comment: amplified discussion, minor comments added (33 pages, 3 figures

Combined technique as first approach in mechanical thrombectomy: Efficacy and safety of REACT catheter combined with stent retriever

Acute stroke; Endovascular treatment; Mechanical thrombectomyAccidente cerebrovascular agudo; Tratamiento endovascular; Trombectomía mecánicaAccident cerebrovascular agut; Tractament endovascular; Trombectomia mecànicaIntroduction Mechanical thrombectomy (MT) with combined treatment including both a stent retriever and distal aspiration catheter may improve recanalization rates in patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO). Here, we evaluated the effectiveness and safety of the REACT aspiration catheter used with a stent retriever. Methods This prospective study included consecutive adult patients who underwent MT with a combined technique using REACT 68 and/or 71 between June 2020 and July 2021. The primary endpoints were final and first pass mTICI 2b-3 and mTICI 2c-3 recanalization. Analysis was performed after first pass and after each attempt. Secondary safety outcomes included procedural complications, symptomatic intracranial hemorrhage (sICH) at 24 h, in-hospital mortality, and 90-day functional independence (modified Rankin Scale [mRS] 0–2). Results A total of 102 patients were included (median age 78; IQR: 73–87; 50.0% female). At baseline, median NIHSS score was 19 (IQR: 11–21), and ASPECTS was 9 (IQR: 8–10). Final mTICI 2b-3 recanalization was achieved in 91 (89.2%) patients and mTICI 2c-3 was achieved in 66 (64.7%). At first pass, mTICI 2b-3 was achieved in 55 (53.9%) patients, and mTICI 2c-3 in 37 (36.3%). The rate of procedural complications was 3.9% (4/102), sICH was 6.8% (7/102), in-hospital mortality was 12.7% (13/102), and 90-day functional independence was 35.6% (36/102). Conclusion A combined MT technique using a stent retriever and REACT catheter resulted in a high rate of successful recanalization and first pass recanalization in a sample of consecutive patients with AIS due to LVO in clinical use

Granulocytes-Rich Thrombi in Cerebral Large Vessel Occlusion Are Associated with Increased Stiffness and Poorer Revascularization Outcomes

Acute stroke; Flow cytometry; Mechanical thrombectomyIctus agut; Citometria de flux; Trombectomia mecànicaIctus agudo; Citometría de flujo; Trombectomía mecánicaWe aim to identify a profile of intracranial thrombus resistant to recanalization by mechanical thrombectomy (MT) in acute stroke treatment. The first extracted clot of each MT was analyzed by flow cytometry obtaining the composition of the main leukocyte populations: granulocytes, monocytes, and lymphocytes. Demographics, reperfusion treatment, and grade of recanalization were registered. MT failure (MTF) was defined as final thrombolysis in cerebral infarction score IIa or lower and/or need of permanent intracranial stenting as a rescue therapy. To explore the relationship between stiffness of intracranial clots and cellular composition, unconfined compression tests were performed in other cohorts of cases. Thrombi obtained in 225 patients were analyzed. MTF were observed in 30 cases (13%). MTF was associated with atherosclerosis etiology (33.3% vs. 15.9%; p = 0.021) and higher number of passes (3 vs. 2; p < 0.001). Clot analysis of MTF showed higher percentage of granulocytes [82.46 vs. 68.90% p < 0.001] and lower percentage of monocytes [9.18% vs.17.34%, p < 0.001] in comparison to successful MT cases. The proportion of clot granulocytes (aOR 1.07; 95% CI 1.01–1.14) remained an independent marker of MTF. Among thirty-eight clots mechanically tested, there was a positive correlation between granulocyte proportion and thrombi stiffness (Pearson’s r = 0.35, p = 0.032), with a median clot stiffness of 30.2 (IQR, 18.9–42.7) kPa. Granulocytes-rich thrombi are harder to capture by mechanical thrombectomy due to increased stiffness, so a proportion of intracranial granulocytes might be useful to guide personalized endovascular procedures in acute stroke treatment.Open Access Funding provided by Universitat Autonoma de Barcelona. This work was supported by “Project 355/C/2017, Fundació La Marató de TV3 in Strokes and Traumatic Spinal Cord and Brain Injury, 2017 Call of Projects.

Vitruvius+: An area-efficient RISC-V decoupled vector coprocessor for high performance computing applications

The maturity level of RISC-V and the availability of domain-specific instruction set extensions, like vector processing, make RISC-V a good candidate for supporting the integration of specialized hardware in processor cores for the High Performance Computing (HPC) application domain. In this article,1 we present Vitruvius+, the vector processing acceleration engine that represents the core of vector instruction execution in the HPC challenge that comes within the EuroHPC initiative. It implements the RISC-V vector extension (RVV) 0.7.1 and can be easily connected to a scalar core using the Open Vector Interface standard. Vitruvius+ natively supports long vectors: 256 double precision floating-point elements in a single vector register. It is composed of a set of identical vector pipelines (lanes), each containing a slice of the Vector Register File and functional units (one integer, one floating point). The vector instruction execution scheme is hybrid in-order/out-of-order and is supported by register renaming and arithmetic/memory instruction decoupling. On a stand-alone synthesis, Vitruvius+ reaches a maximum frequency of 1.4 GHz in typical conditions (TT/0.80V/25°C) using GlobalFoundries 22FDX FD-SOI. The silicon implementation has a total area of 1.3 mm2 and maximum estimated power of ~920 mW for one instance of Vitruvius+ equipped with eight vector lanes.This research has received funding from the European High Performance Computing Joint Undertaking (JU) under Framework Partnership Agreement No 800928 (European Processor Initiative) and Specific Grant Agreement No 101036168 (EPI SGA2). The JU receives support from the European Union’s Horizon 2020 research and innovation programme and from Croatia, France, Germany, Greece, Italy, Netherlands, Portugal, Spain, Sweden, and Switzerland. The EPI-SGA2 project, PCI2022-132935 is also co-funded by MCIN/AEI/10.13039/501100011033 and by the UE NextGen- erationEU/PRTR. This work has also been partially supported by the Spanish Ministry of Science and Innovation (PID2019-107255GB-C21/AEI/10.13039/501100011033).Peer ReviewedPostprint (author's final draft

Flavour-changing top decays in the aligned two-Higgs-doublet model

We perform a complete one-loop computation of the two-body flavour-changing top decays t --> ch and t --> cV (V = gamma, Z), within the aligned two-Higgs-doublet model. We evaluate the impact of the model parameters on the associated branching ratios, taking into account constraints from flavour data and measurements of the Higgs properties. Assuming that the 125 GeV Higgs corresponds to the lightest CP-even scalar of the CP-conserving aligned two-Higgs-doublet model, we find that the rates for such flavour-changing top decays lie below the expected sensitivity of the future high-luminosity phase of the LHC. Measurements of the Higgs signal strength in the di-photon channel are found to play an important role in limiting the size of the t --> ch decay rate when the charged scalar of the model is light