Design and Implementation of a Time Predictable Processor: Evaluation With a Space Case Study

Embedded real-time systems like those found in automotive, rail and aerospace, steadily require higher levels of guaranteed computing performance (and hence time predictability) motivated by the increasing number of functionalities provided by software. However, high-performance processor design is driven by the average-performance needs of mainstream market. To make things worse, changing those designs is hard since the embedded real-time market is comparatively a small market. A path to address this mismatch is designing low-complexity hardware features that favor time predictability and can be enabled/disabled not to affect average performance when performance guarantees are not required. In this line, we present the lessons learned designing and implementing LEOPARD, a four-core processor facilitating measurement-based timing analysis (widely used in most domains). LEOPARD has been designed adding low-overhead hardware mechanisms to a LEON3 processor baseline that allow capturing the impact of jittery resources (i.e. with variable latency) in the measurements performed at analysis time. In particular, at core level we handle the jitter of caches, TLBs and variable-latency floating point units; and at the chip level, we deal with contention so that time-composable timing guarantees can be obtained. The result of our applied study with a Space application shows how per-resource jitter is controlled facilitating the computation of high-quality WCET estimates

EPC Enacted: Integration in an Industrial Toolbox and Use against a Railway Application

Measurement-based timing analysis approaches are increasingly making their way into several industrial domains on account of their good cost-benefit ratio. The trustworthiness of those methods, however, suffers from the limitation that their results are only valid for the particular paths and execution conditions that the user is able to explore with the available input vectors. It is generally not possible to guarantee that the collected measurements are fully representative of the worst-case timing behaviour. In the context of measurement-based probabilistic timing analysis, the Extended Path Coverage (EPC) approach has been recently proposed as a means to extend the representativeness of measurement observations, to obtain the same effect of full path coverage. At the time of its first publication, EPC had not reached an implementation maturity that could be trialled industrially. In this work we analyze the practical implications of using EPC with real-world applications, and discuss the challenges in integrating it in an industrial-quality toolchain. We show that we were able to meet EPC requirements and successfully evaluate the technique on a real Railway application, on top of a commercial toolchain and full execution stack.This work has received funding from the European Community’s Seventh Framework Programme [FP7/2007-2013] under grant agreement 611085 (PROXIMA, www.proxima-project.eu). This work has also been partially supported by the Spanish Ministry of Economy and Competitiveness (MINECO) under grant TIN2015-65316-P and the HiPEAC Network of Excellence. Jaume Abella has been partially supported by the MINECO under Ramon y Cajal postdoctoral fellowship number RYC-2013-14717. The authors are grateful to Antoine Colin from Rapita Ltd. for his precious support.Peer ReviewedPostprint (author's final draft

Evaluación de la comunidad de Macroinvertebrados y los grupos funcionales de alimentación como indicadores de calidad ecológica del Río Ambi

Evaluar la comunidad de macroinvertebrados y los grupos funcionales de alimentación como indicadores de calidad ecológica del río Ambi.El control y toma de decisiones de una buena gestión en los ecosistemas fluviales es muy importante para los ciudadanos. Debido a la falta de conocimiento sobre la diversidad y programas de evaluación biológica, la gestión es necesario la evidencia de la contaminación y su impacto en la biodiversidad y la ecología integral. Por esto se realizó la investigación para analizar la calidad ecológica del río Ambi en 7 puntos de muestreo durante dos épocas, utilizando macroinvertebrados como indicadores de la calidad del agua, basados en las clases de índices BMWP/Col, ABI, AAMBI. En los resultados del biomonitoreo espacio temporal indica que el pH, la velocidad del agua, turbidez, saturación de oxígeno disuelto y la conductividad son importantes para la composición de los grupos funcionales de alimentación y los taxones. Los resultados indicaron que la diversidad de las familias y grupos funcionales de alimentación fueron escasos en todas las localidades por la presencia de materia orgánica entre otros factores. Lo colectores-recolectores (CR) fueron en general, los dominantes y abundantes cuando la calidad biológica del agua es mala. Los depredadores (Dp) fueron el segundo grupo más abundante en espacio temporal en los puntos de muestreo de calidad crítica o muy crítica. En el caso de la calidad dudosa al aumentar la presencia de los trituradores (Tr) y la disminución de los demás su calidad a mejorado.Ingenierí

Cocaine-induced behavioral sensitization is associated with changes in the expression of endocannabinoid and glutamatergic signaling systems in the mouse prefrontal cortex

Abstract Background: Endocannabinoids modulate the glutamatergic excitatory transmission by acting as retrograde messengers. A growing body of studies has reported that both signaling systems in the mesocorticolimbic neural circuitry are involved in the neurobiological mechanisms underlying drug addiction. Methods: We investigated whether the expression of both endocannabinoid and glutamatergic systems in the prefrontal cortex (PFC) were altered by an acute and/or repeated cocaine administration schedule that resulted in behavioral sensitization. We measured the protein and mRNA expression of the main endocannabinoid metabolic enzymes and the cannabinoid receptor type 1 (CB1). We also analyzed the mRNA expression of relevant components of the glutamatesignaling system, including glutamate-synthesizing enzymes, metabotropic receptors, and ionotropic receptors. Results: Although acute cocaine (10 mg/kg) produced no significant changes in the endocannabinoid-related proteins, repeated cocaine administration (20 mg/kg daily) induced a pronounced increase in the CB1 receptor expression. In addition, acute cocaine administration (10 mg/kg) in cocaine-sensitized mice (referred to as cocaine priming) induced a selective increase in the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). These protein changes were accompanied by an overall decrease in the ratios of endocannabinoid synthesis/degradation, especially the N-acyl phosphatidylethanolamine phospholipase D/FAAH and diacylglycerol lipase alpha/MAGL ratios.Regarding mRNA expression, while acute cocaine administration produced a decrease in CB1 receptors and N-acyl phosphatidylethanolamine phospholipase D, repeated cocaine treatment enhanced CB1 receptor expression. Cocaine sensitized mice that were administered priming injections of cocaine mainly displayed an increased FAAH expression. These endocannabinoid changes were associated with modifications in glutamatergic transmission-related genes. An overall decrease was observed in the mRNA expression of the glutamate-synthesizing gene kidney-type glutaminase (KGA), the metabotropic glutamate receptors (mGluR3 and GluR), and subunits of NMDA ionotropic receptors (NR1, NR2A, NR2B and NR2C) after acute cocaine administration, while mice repeatedly exposed to cocaine only displayed an increase in NR2C. However, in cocaine-sensitized mice primed with cocaine, this inhibition was reversed and a strong increase was detected in the mGluR5, NR2 subunits, and both GluR1 and GluR3. Conclusions: These findings indicate that cocaine sensitization is associated with an endocannabinoid downregulation and a hyperglutamatergic state in the PFC that, overall, contribute to an enhanced glutamatergic input into PFC-projecting areasThis work was supported by Ministerio de Ciencia e Innovación (PI13/02261 and SAF 2010–20521), Instituto de Salud Carlos III (ISCIII), Ministerio de Economía y Competitividad, Red de Trastornos Adictivos (RD12/0028/0001), Plan Nacional Sobre Drogas, Ministerio de Sanidad y Consumo (PNSD2013/049), Consejería de Economía, Innovación y Ciencia, Junta de Andalucía, UE/ERDF (CTS-433 and P-11-CVI-07637), Consejería de Salud, and Junta de Andalucía (PI0232/2008, PI0029/2008 and SAS111224). Dr Suárez is the recipient of a Miguel Servet research contract from ISCIII (CP12/03109). We thank Mariam Vázquez for English language assistance

Enfermedades autoinmunes sistémicas en pacientes con infección por el virus de la hepatitis C: caracterización de 1020 casos (Registro HISPAMEC).

Objective. To describe the clinical and immunologic characteristics of a large series of patients with systemic autoimmune diseases (SAD) associated with chronic hepatitis C virus (HCV) infection. Methods. The HISPAMEC Registry is a multicenter international study group dedicated to collecting data on patients diagnosed with SAD with serological evidence of chronic HCV infection. The information sources are cases reported by physicians of the HISPAMEC Study Group and periodic surveillance of reported cases by a Medline search updated up to December 31, 2007. Results. One thousand twenty HCV patients with SAD were included in the registry. Patients were reported from Southern Europe (60%), North America (15%), Asia (14%), Northern Europe (9%), South America (1%), and Australia (1%). Countries reporting the most cases were Spain (236 cases), France (222 cases), Italy (144 cases), USA (120 cases), and Japan (95 cases). The most frequently reported SAD were Sjögren’s syndrome (SS; 483 cases), rheumatoid arthritis (RA; 150 cases), systemic lupus erythematosus (SLE; 129 cases), polyarteritis nodosa (78 cases), antiphospholipid syndrome (59 cases), inflammatory myopathies (39 cases), and sarcoidosis (28 cases). Twenty patients had 2 or more SAD. Epidemiological data were available in 677 cases. Four hundred eighty-seven (72%) patients were female and 186 (28%) male, with a mean age of 49.5 ± 1.0 years at SAD diagnosis and 50.5 ± 1.1 years at diagnosis of HCV infection. The main immunologic features were antinuclear antibody (ANA) in 61% of patients, rheumatoid factor (RF) in 57%, hypocomplementemia in 52%, and cryoglobulins in 52%. The main differential aspect between primary and HCV-related SAD was the predominance of cryoglobulinemic-related markers (cryoglobulins, RF, hypocomplementemia) over specific SAD-related markers (anti-ENA antibodies, anti-dsDNA, anti-cyclic citrullinated peptide) in patients with HCV. Conclusion. In the selected cohort, the SAD most commonly reported in association with chronic HCV infection were SS (nearly half the cases), RA and SLE. Nearly two thirds of SAD-HCV cases were reported from the Mediterranean area. In these patients, ANA, RF and cryoglobulins are the predominant immunological features. (First Release April 15 2009; J Rheumatol 2009;36:1442–8; doi:10.3899/jrheum.080874)

Probabilistic timing analysis on time-randomized platforms for the space domain

Timing Verification is a fundamental step in real-time embedded systems, with measurement-based timing analysis (MBTA) being the most common approach used to that end. We present a Space case study on a real platform that has been modified to support a probabilistic variant of MBTA called MBPTA. Our platform provides the properties required by MBPTA with the predicted WCET estimates with MBPTA being competitive to those with current MBTA practice while providing more solid evidence on their correctness for certification.The research leading to these results has received funding from the European Community’s FP7 [FP7/2007-2013] under the PROXIMA Project (www.proxima-project.eu), grant agreement no 611085. This work has also been partially supported by the Spanish Ministry of Science and Innovation under grant TIN2015-65316-P and the HiPEAC Network of Excellence. Jaume Abella has been partially supported by the Ministry of Economy and Competitiveness under Ramon y Cajal postdoctoral fellowship number RYC-2013-14717. Carles Hernandez is jointly funded by the Spanish Ministry of Economy and Competitiveness and FEDER funds through grant TIN2014-60404-JIN.Peer ReviewedPostprint (author's final draft

Sex-specific behavioral and neurogenic responses to cocaine in mice lacking and blocking dopamine D1 or dopamine D2 receptors

Adult neurogenesis in rodents is modulated by dopaminergic signaling and inhibited by cocaine. However, the sex-specific role of dopamine D1 and D2 receptors (D1R, D2R) in the deleterious effect of cocaine on adult neurogenesis has not been described yet. Here, we explored sex differences in (a) cell proliferation (5′-bromo-2′-deoxyuridine [BrdU]), (b) neural precursor (nestin), (c) neuronal phenotype (BrdU/β3-tubulin), and (d) neuronal maturity (NeuN) in the subventricular zone (SVZ) of the lateral ventricles and striatum of mice with genetic deletion (D1, D2) or pharmacological blockage (SCH23390: 0.1 mg/kg/day/5 days; Raclopride: 0.3 mg/kg/day/5 days) of D1R and D2R, and treated (10 mg/kg/day/5 days) and then challenged (5 mg/kg, 48 hr later) with cocaine. Results indicated that hyperactivity responses to cocaine were absent in D1 mice and reduced in SCH23390-treated mice. Activity responses to cocaine were reduced in D2 males, but absent in D2 females and increased in Raclopride-treated females. D1R deletion blocked the deleterious effect of cocaine on SVZ cell proliferation in males. Cocaine-exposed D1 males also had reduced neuronal phenotype of SVZ newborn cells and increased striatal neuronal maturity. D2 mice had lower proliferative and neural precursor responses. Cocaine in D2 females or coadministered with Raclopride in wild-type females improved SVZ cell proliferation, an effect that positively correlated with plasma brain-derived neurotrophic factor (BDNF) concentrations. In conclusion, the sex-specific D1R and D2R signaling on SVZ cell proliferation, neural progenitor and neuronal maturity is differentially perturbed by cocaine, and BDNF may be required to link D2R to neuroplasticity in cocaine addiction in females.Consejería de Salud, Junta de Andalucía, Grant/Award Number: C1-0049-2019; Instituto de Salud Carlos III, Grant/Award Numbers: CP19/00068, CPII17/00024, CPII19/00022, CPII19/00031, PI19/01577, PI19/00886, PI17/02026, RD16/0017/0001; Ministerio de Sanidad, Servicios Sociales e Igualdad, Grant/Award Numbers: PND2017/043, PND2018/033, PND2018/044, PND2019/04

Oleoylethanolamide, Neuroinflammation, and Alcohol Abuse

Neuroinflammation is a complex process involved in the physiopathology of many central nervous system diseases, including addiction. Alcohol abuse is characterized by induction of peripheral inflammation and neuroinflammation, which hallmark is the activation of innate immunity toll-like receptors 4 (TLR4). In the last years, lipid transmitters have generated attention as modulators of parts of the addictive process. Specifically, the bioactive lipid oleoylethanolamide (OEA), which is an endogenous acylethanolamide, has shown a beneficial profile for alcohol abuse. Preclinical studies have shown that OEA is a potent anti-inflammatory and antioxidant compound that exerts neuroprotective effects in alcohol abuse. Exogenous administration of OEA blocks the alcohol-induced TLR4-mediated pro-inflammatory cascade, reducing the release of proinflammatory cytokines and chemokines, oxidative and nitrosative stress, and ultimately, preventing the neural damage in frontal cortex of rodents. The mechanisms of action of OEA are discussed in this review, including a protective action in the intestinal barrier. Additionally, OEA blocks cue-induced reinstatement of alcohol-seeking behavior and reduces the severity of withdrawal symptoms in animals, together with the modulation of alcohol-induced depression-like behavior and other negative motivational states associated with the abstinence, such as the anhedonia. Finally, exposure to alcohol induces OEA release in blood and brain of rodents. Clinical evidences will be highlighted, including the OEA release and the correlation of plasma OEA levels with TLR4-dependent peripheral inflammatory markers in alcohol abusers. In base of these evidences we hypothesize that the endogenous release of OEA could be a homeostatic signal to counteract the toxic action of alcohol and we propose the exploration of OEA-based pharmacotherapies to treat alcohol-use disorders