Étude de la régulation du facteur de transcription NF-kB dans l'infection par le RSV

L’infection par le Virus Respiratoire Syncytial cause des affections pulmonaires aiguës en pédiatrie caractérisée par une réponse inflammatoire excessive médiée par la production de cytokines par les cellules épithéliales des voies aériennes. Les gènes codant pour ces cytokines sont régulés par le facteur de transcription NF-κB (p50/p65) dont l’activation est classiquement induite par la phosphorylation de son inhibiteur IκBα, ce qui permet l’accumulation de l’hétérodimère au noyau. Par contre, nous avons récemment identifié la phosphorylation en sérine 536 de la sous-unité p65 comme une autre étape essentielle à son activation lors de l’infection des AEC par RSV. Le travail présenté dans ce mémoire a permis de démontrer que l’inhibition de l’expression de RIG-I, de Cardif ou de TRAF6, 3 protéines impliquées dans la reconnaissance cellulaire des virus, conduit à l’inhibition de cette phosphorylation en réponse à RSV. Nous avons également établi à l’aide d’inhibiteurs pharmacologiques et d’ARNi que, parmi les diverses kinases connues pour phosphoryler p65 en réponse à divers stimulus, IKKα/β sont essentielles à cette phosphorylation lors d’une stimulation par RSV. Puisque TRAF6 est bien connu dans la littérature pour activer le complexe IKK, nous proposons que TRAF6, après reconnaissance de l’ARN viral de RSV par RIG-I, active le complexe IKK qui induit la phosphorylation de la sousunité p65 de NF-κB, permettant l’expression de gènes cibles. D’autre part, nous avions précédemment démontré que Nox2, un isoforme de NADPH oxydase, contrôle l’activation de NF-κB en régulant les phosphorylations de IκBα et p65. Nous montrons ici que l’inhibition de Nox2 réduit fortement l’activité du complexe kinase IKK. De plus, la présence au niveau basal de Nox2 est critique pour le niveau d’ARN messager de Cardif. Nous proposons donc que la régulation de la phosphorylation de p65 en ser536 par Nox2 soit via son effet sur Cardif en permettant la fonctionnalité de la voie RIG-I.The infection by the Respiratory Syncytial Virus causes acute respiratory tract affections among children characterized by an excessive inflammatory response mediated by airway epithelial cells production of cytokines. The genes coding for theses cytokines are regulated by the transcription factor NF-κB (p50/p65) which is classically activated by phosphorylation of its inhibitor IκBα, permitting the nuclear accumulation of the heterodimer. The work presented in this master’s thesis allowed demonstrating that the inhibition of either RIG-I, Cardif or TRAF6, 3 proteins implicated in the cellular recognition of virus, leads to the inhibition of this phosphorylation in response to RSV. Moreover, we established with pharmacological inhibitors and siRNA that, among all kinases known to phosphorylate p65 in response to various stimulus, IKKα/β are essential to this phosphorylation in RSV stimulation. Since TRAF6 is a well-known IKK complex activator in the literature, we propose that TRAF6, after the recognition of the RSV viral RNA by RIG-I, activates the IKK complex witch induces the phosphorylation of the NF-κB subunit p65, allowing the expression of targets genes. Furthermore, we had previously demonstrated that Nox2, a NADPH oxydase isoform, controls the activation of NF-κB by regulating the phosphorylation of IκBα and p65. We show here that the inhibition of Nox2 by siRNA reduces strongly the activity of the IKK complex. Moreover, the basal level presence of Nox2 is critic for the messenger RNA level of Cardif. Thus, we propose that the Nox2 regulation of p65 ser536 is done by its effect on Cardif, which allows the integrity of the RIG-I pathway

Machine learning in bail decisions and judges’ trustworthiness

The use of AI algorithms in criminal trials has been the subject of very lively ethical and legal debates recently. While there are concerns over the lack of accuracy and the harmful biases that certain algorithms display, new algorithms seem more promising and might lead to more accurate legal decisions. Algorithms seem especially relevant for bail decisions, because such decisions involve statistical data to which human reasoners struggle to give adequate weight. While getting the right legal outcome is a strong desideratum of criminal trials, advocates of the relational theory of procedural justice give us good reason to think that fairness and perceived fairness of legal procedures have a value that is independent from the outcome. According to this literature, one key aspect of fairness is trustworthiness. In this paper, I argue that using certain algorithms to assist bail decisions could increase three diferent aspects of judges’ trustworthiness: (1) actual trustworthiness, (2) rich trustworthiness, and (3) perceived trustworthiness

Funciones de la inspección de educación: análisis descriptivo-comparativo de la normativa de inspección autonómica

Las ocho funciones de la inspección educativa se encuentran recogidas en el art. 151 de la Ley Orgánica 2/2006, de 3 de mayo, de Educación, modificado por la Ley Orgánica 3/2020, de 29 de diciembre. En el presente estudio dichas funciones serán consideradas como aspectos clave y constituirán el punto de partida a fin de comparar las similitudes y diferencias entre las distintas Comunidades Autónomas (en lo sucesivo CCAA) y Ceuta y Melilla, así como de identificar las posibles implicaciones administrativas y de funcionamiento. En este sentido, someteremos a análisis la normativa en relación con la inspección educativa de las 17 CCAA, así como Ceuta y Melilla. Nuestro estudio incluirá una escala de valoración tipo Likert con el fin de determinar cuál es el grado de cumplimiento de los aspectos claves analizados

The dual nature of identity fusion : a unifying force or a source of division?

Identity plays a key role in determining what matters to people and what they are willing to fight for. Identity fusion, an extreme form of identification where one's personal self is unified with an abstraction (a group, cause, or other individual), predicts extreme behaviors in defense of the target of fusion. In the face of a perceived threat to one's fused group, fused individuals often react harshly against the source of the threat, such as by endorsing violence against outgroups. However, identity fusion does not necessitate hostility toward outgroups. Indeed, some work suggests that in the absence of threat, fused individuals can be benign towards outgroup members. The demarcation between when fusion might have prosocial outcomes for the larger society as opposed to antisocial outcomes against perceived outgroup members is in need of further exploration, especially in the highly divided modern American political landscape. Therefore, the purpose of this dissertation is to further investigate the nature of identity fusion and when fusion might have a unifying influence as opposed to a divisive one. Across four lines of research, the current work examined (1) whether identity fusion is a more potent predictor of extreme behaviors in the political sphere than rival constructs such as moral convictions or sacred values (Chapter 2), (2) whether fusion with a partisan identity such as a political party positively predicts extreme behaviors that could potentially increase the power of the partisan group, but may be detrimental to the larger society (Chapters 3-5), and (3) whether fusion with a superordinate group such as one's nation or even all of humanity negatively predicts behaviors that may harm the larger society, even if such behaviors might myopically benefit one's political party. Findings from Chapter 2 provide evidence that identity fusion is the strongest predictor of extreme behavior on behalf of a political cause. Findings from Chapters 3-5 show that fusion with a political party or candidate positively predicts support for authoritarian actions against the opposing party, while fusion with the US negatively predicts the same authoritarianism. In Chapter 5, writing about a patriotic memory increased fusion with the US among Republicans, and fusion with the US marginally interacted with the patriotic prime manipulation to predict decreased support for authoritarianism among both Republicans and Democrats. Taken together, these findings shed valuable insight into the dual nature of identity fusion as both a unifying force and a source of division.Psycholog

EL TRATAMIENTO DE LAS VÍCTIMAS DEL TERRORISMO EN EL CINE: DIFERENCIAS CULTURALES EN DÍAS CONTADOS, JUEGO DE LÁGRIMAS Y BABEL

Terrorism, which has appeared in cinema more than 50 years ago, has generally given priority to perpetrators. However, in the last 30 years, the protagonism of the victims has been increasing, except for those known as collateral victims, which some way have always had a significant appearance. This study analyzes particularly those which fall into this category based on three films: Días contados, Juego de lágrimas, and Babel. As a result of this analysis, it can be concluded that there is a perception of similarities in the representation of the victims, in their protagonism, and their (in-)direct link with terrorism as a consequence of the different narratives on the causes of their victimization.El terrorismo que aparece en el cine hace más de 50 años, por norma general, ha dado prioridad a los perpetradores. Sin embargo, en los últimos 30 años el protagonismo de las víctimas ha ido en aumento, con la excepción de las conocidas como colaterales que de algún modo siempre han tenido una aparición significativa. Este estudio analiza precisamente las de esta categoría atendiendo a tres películas: Días contados, Juego de lágrimas y Babel. Fruto de este análisis, se concluye que hay una percepción de semejanzas en la representación de las víctimas, en su protagonismo y en su vínculo (in-) directo con el terrorismo como consecuencia de las diferentes narrativas sobre las causas de su victimización

Marca Privada, efectos en la gran empresa y pequeño productor en El Salvador.

La marca privada dentro de El Salvador significa una oportunidad más para los pequeños empresarios que desarrollan productos con un capital limitado. Es una estrategia que introduce productos en los mercados, con ayuda de distribuidores que hacen llegar el resultado final a los consumidores. En la economía, las empresas representan una gran parte del dinamismo económico, la cooperación entre ellas mismas significa además de un reto, una posibilidad de hacer crecer al país, con un apoyo bidireccional entre las partes. Además, el involucramiento de empresas extranjeras que permita el apoyo de los microempresarios para el crecimiento paulatino de ambos. Dentro del país, en las cadenas de supermercados más fuertes dentro de las cuales se tiene a una extranjera, se encuentran diferentes casos en donde se apoyan de las marcas privadas para crecer dentro del mercado. Este método de crecimiento, no se reduce solamente al beneficio de la gran empresa quien recibe a los consumidores, sino, a través de la tarea de proveer de productos, y la venta de ellos aprovechando el reconocimiento de la marca, el pequeño productor encuentra una forma de desarrollo también. Algunos autores cuestionan la similitud o igualdad del término con otros, sin embargo, es importante saber diferenciar basándose en características que en el trabajo se detallan. Las marcas privadas como clasificación de la estrategia de marca de distribución incursionan en los mercados gracias al valor de marca percibido de los establecimientos que la distribuyen. Que tanto se espera conseguir de esta estrategia y hasta qué punto es técnicamente saludable llevarla a cabo, es lo que se presenta en el siguiente trabajo, considerando todas aquellas ventajas que se atraen y mencionando los retos que trae consigo. Es importante tomar en cuenta que todas las estrategias llevan como por objetivo conseguir algo de forma más rápida pero segura. De este modo, utilizar la misma estrategia durante años, estaría cohibiendo la oportunidad de crecer

Nepafenac 0.3% after Cataract Surgery in Patients with Diabetic Retinopathy: Results of 2 Randomized Phase 3 Studies

Purpose To demonstrate the efficacy and safety of once-daily nepafenac 0.3% ophthalmic suspension versus vehicle, based on clinical outcomes, after cataract surgery in patients with diabetes. Design Two prospective, randomized, multicenter, double-masked, vehicle-controlled phase 3 studies. Participants Total, 615 patients in study 1 and 605 patients in study 2. Methods Patients were randomized (1:1) to topical nepafenac 0.3% or vehicle once-daily starting the day before surgery and continuing for 90 days thereafter. Main Outcome Measures Key efficacy variables were: patients (%) in whom macular edema (ME) developed (≥30% increase from preoperative baseline central subfield macular thickness) within 90 days after cataract surgery and the patients (%) with a best-corrected visual acuity (BCVA) improvement of ≥15 letters from preoperative baseline through day 14 maintained through day 90. Secondary end points included: patients (%) with a BCVA improvement of ≥15 letters from preoperative baseline through days 90 and 60 and safety over 3 months. Results A significantly lower percentage of patients demonstrated ME within 90 days after surgery with nepafenac 0.3% versus vehicle (study 1: 2.3% vs. 17.3%; P P = 0.001; pooled: 4.1% vs. 15.9%; P P P = 0.671) in study 2, and 55.4% versus 46.7% ( P = 0.003) in the pooled analysis. A greater percentage of patients treated with nepafenac 0.3% versus vehicle in study 1 and similar percentage in study 2 had a BCVA improvement of ≥15 letters from preoperative baseline through day 90 (77.2% vs. 67.7% [ P = 0.009] and 65.4% vs. 65.9% [ P = 0.888]) and through day 60 (76.2% vs. 64.7% [ P = 0.002] and 68.9% vs. 62.1% [ P = 0.092]). No unanticipated adverse events were observed. Conclusions These studies demonstrated the clinical benefits of nepafenac 0.3% over vehicle in reducing the risk of postoperative ME, with the integrated analysis showing improved BCVA after cataract surgery in patients with diabetic retinopathy, with no unanticipated safety events

Requirement of NOX2 and Reactive Oxygen Species for Efficient RIG-I-Mediated Antiviral Response through Regulation of MAVS Expression

The innate immune response is essential to the host defense against viruses, through restriction of virus replication and coordination of the adaptive immune response. Induction of antiviral genes is a tightly regulated process initiated mainly through sensing of invading virus nucleic acids in the cytoplasm by RIG-I like helicases, RIG-I or Mda5, which transmit the signal through a common mitochondria-associated adaptor, MAVS. Although major breakthroughs have recently been made, much remains unknown about the mechanisms that translate virus recognition into antiviral genes expression. Beside the reputed detrimental role, reactive oxygen species (ROS) act as modulators of cellular signaling and gene regulation. NADPH oxidase (NOX) enzymes are a main source of deliberate cellular ROS production. Here, we found that NOX2 and ROS are required for the host cell to trigger an efficient RIG-I-mediated IRF-3 activation and downstream antiviral IFNβ and IFIT1 gene expression. Additionally, we provide evidence that NOX2 is critical for the expression of the central mitochondria-associated adaptor MAVS. Taken together these data reveal a new facet to the regulation of the innate host defense against viruses through the identification of an unrecognized role of NOX2 and ROS

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease