Que tenga el honor mil ojos. Los dramas de honra de Calderón de la Barca a la luz de la teoría mimética de Réné Girard.

El presente trabajo analiza los tres dramas de la honra conyugal de Calderón de la Barca (a saber, El médico de su honra, A secreto agravio secreta venganza y El pintor de su deshonra) desde los postulados del antropólogo cultural Réné Girard. Las principales teorías de este autor difícilmente clasificable versan sobre el deseo y la violencia pero nacen y han sido aplicadas, básicamente, en el ámbito de los textos literarios canónicos. Consideramos que este punto de vista puede iluminar considerablemente estas crípticas obras sobre las que la crítica ha debatido profusamente sin llegar a consensos claros en lo tocante a su recepción e interpretación. Así, los aspectos más controvertidos de estas piezas (sobre todo la condición de inocencia o culpabilidad de los distintos personajes, la conformación de la violencia como un ritual y, en definitiva, la intención del autor con los incómodos finales de los dramas) cobran una dimensión nueva desde una perspectiva girardiana que podría representar una aportación relevante a la larga tradición de los estudios sobre el honor en el teatro del siglo XVII. Este trabajo presenta la siguiente estructura: se abre con un capítulo que recoge los postulados básicos de Réné Girard que servirán como clave hermenéutica de los dramas de honor a través de una lectura personal de sus obras más relevantes (Mentira romántica, verdad novelesca, La violencia y lo sagrado o Shakespeare y los fuegos de la envidia, principalmente). Proseguimos, en el siguiente capítulo, con una contextualización histórica en torno al concepto de honor y su dramatización en el barroco, así como con un análisis del subgénero del drama de honor conyugal y su marcado corte trágico. El tercer capítulo, elemento central del trabajo, se detiene en los aspectos esenciales y más controvertidos de las piezas de Calderón, combinando un análisis clásico o de carácter más convencional con las teorías girardianas. Así, las tres piezas antes mencionadas se han considerado como un conjunto donde ir trazando progresivamente los caminos que siguen el deseo y la violencia hasta conducir al inexorable ritual sacrificial que cierra estas piezas. Hemos querido hacer especial hincapié en la interpretación de los enigmáticos finales de estas piezas. El cuarto capítulo contrasta este modelo dramatúrgico propio de Calderón con tres piezas de otros autores contemporáneos (a saber, El castigo sin venganza de Lope de Vega, La fuerza de la ley de Moreto y Del rey abajo, ninguno de Rojas Zorrilla) para determinar el alcance e idiosincrasia del modelo de la honra conyugal que fija Calderón. En definitiva, consideramos que estas tres piezas de Calderón (así como el género del honor conyugal del que resulta el máximo exponente) darían cuenta de una estructuración ritual de la violencia encarnada en la honra conyugal dramatizada. Este amplio motivo habría pues servido, sobre las tablas, para revestir de sacralidad los miedos más escondidos y profundos de la escindida subjetividad barroca. Así lo hemos argumentado con un exhaustivo análisis de los aspectos que más debate han generado en el seno de la crítica teatral barroca y a cuya interpretación contribuyen las teorías girardianas de un modo provechoso.This dissertation focuses on the relations between honour and identity in a singularly violent baroque sub-genre called honour plays or wife-murder plays. It is generally admitted amongst scholars that Spanish Golden-Age was obsessed with honour, thus these various pieces, written by many different authors, have been understood as a true reflection of their contemporary society. We claim that they weren't its mere reflection but an identity construction which can be -more easily- understood from a Girardian point of view. Therefore, in this dissertation we want to analyse three Calderonian honour plays (to the extent they symbolise Spanish baroque canon in terms of honour), taking into account both mimetic and sacrificial Girardian theories. Some authors, such as Bandera or Petro del Barrio, have partially studied some of these plays (especially El médico de su honra) following some of Girard's postulates, but this thesis aims to examine the three plays systematically according to Girard as well as verifying their validity in baroque Spain. In this way, concepts such as desire, mimetic triangles, rivalry, double-bind or jealousy clearly appear in those plays in a really similar way. Besides, sacrificial rituals are also shaped in Calderonian's wife-murder plays, which we want to study to a full extent, in order to convey a clear idea of what honour really meant in Baroque Spanish dramaturgy

Directing LRRK2 to membranes of the endolysosomal pathway triggers RAB phosphorylation and JIP4 recruitment

Coding mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene, which are associated with dominantly inherited Parkinson's disease (PD), lead to an increased activity of the encoded LRRK2 protein kinase. As such, kinase inhibitors are being considered as therapeutic agents for PD. It is therefore of interest to understand the mechanism(s) by which LRRK2 is activated during cellular signaling. Lysosomal membrane damage represents one way of activating LRRK2 and leads to phosphorylation of downstream RAB substrates and recruitment of the motor adaptor protein JIP4. However, it is unclear whether the activation of LRRK2 would be seen at other membranes of the endolysosomal system, where LRRK2 has also shown to be localized, or whether these signaling events can be induced without membrane damage. Here, we use a rapamycin-dependent oligomerization system to direct LRRK2 to various endomembranes including the Golgi apparatus, lysosomes, the plasma membrane, recycling, early, and late endosomes. Irrespective of membrane location, the recruitment of LRRK2 to membranes results in local accumulation of phosphorylated RAB10, RAB12, and JIP4. We also show that endogenous RAB29, previously nominated as an activator of LRRK2 based on overexpression, is not required for activation of LRRK2 at the Golgi nor lysosome. We therefore conclude that LRRK2 signaling to RAB10, RAB12, and JIP4 can be activated once LRRK2 is accumulated at any cellular organelle along the endolysosomal pathway

Lysosomal positioning regulates Rab10 phosphorylation at LRRK2+ lysosomes

Genetic variation at the leucine-rich repeat kinase 2 (LRRK2) locus contributes to an enhanced risk of familial and sporadic Parkinson’s disease. Previous data have demonstrated that recruitment to various membranes of the endolysosomal system results in LRRK2 activation. However, the mechanism(s) underlying LRRK2 activation at endolysosomal membranes and the cellular consequences of these events are still poorly understood. Here, we directed LRRK2 to lysosomes and early endosomes, triggering both LRRK2 autophosphorylation and phosphorylation of the direct LRRK2 substrates Rab10 and Rab12. However, when directed to the lysosomal membrane, pRab10 was restricted to perinuclear lysosomes, whereas pRab12 was visualized on both peripheral and perinuclear LRRK2+ lysosomes, suggesting that lysosomal positioning provides additional regulation of LRRK2-dependent Rab phosphorylation. Anterograde transport of lysosomes to the cell periphery by increasing the expression of ARL8B and SKIP or by knockdown of JIP4 blocked the recruitment and phosphorylation of Rab10 by LRRK2. The absence of pRab10 from the lysosomal membrane prevented the formation of a lysosomal tubulation and sorting process we previously named LYTL. Conversely, overexpression of RILP resulted in lysosomal clustering within the perinuclear area and increased LRRK2-dependent Rab10 recruitment and phosphorylation. The regulation of Rab10 phosphorylation in the perinuclear area depends on counteracting phosphatases, as the knockdown of phosphatase PPM1H significantly increased pRab10 signal and lysosomal tubulation in the perinuclear region. Our findings suggest that LRRK2 can be activated at multiple cellular membranes, including lysosomes, and that lysosomal positioning further provides the regulation of some Rab substrates likely via differential phosphatase activity or effector protein presence in nearby cellular compartments

Spatial dynamics of soil fungal communities after forest clearcutting in a Pinus sylvestris forest

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Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson disease (PD), while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a is poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a to lysosomes in overexpression cell models, while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive association of endocytosed transferrin with Rab8a-positive lysosomes. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in postmortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show a significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild-type mice, accompanied by striatal accumulation of ferritin. Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia

Mortality and biochemical recurrence after surgery, brachytherapy, or external radiotherapy for localized prostate cancer: a 10-year follow-up cohort study

To compare the effectiveness at ten years of follow-up of radical prostatectomy, brachytherapy and external radiotherapy, in terms of overall survival, prostate cancer-specific mortality and biochemical recurrence. Cohort of men diagnosed with localized prostate cancer (T1/T2 and low/intermediate risk) from ten Spanish hospitals, followed for 10 years. The treatment selection was decided jointly by patients and physicians. Of 704 participants, 192 were treated with open radical retropubic prostatectomy, 317 with I-125 brachytherapy alone, and 195 with 3D external beam radiation. We evaluated overall survival, prostate cancer-specific mortality, and biochemical recurrence. Kaplan-Meier estimators were plotted, and Cox proportional-hazards regression models were constructed to estimate hazard ratios (HR), adjusted by propensity scores. Of the 704 participants, 542 patients were alive ten years after treatment, and a total of 13 patients have been lost during follow-up. After adjusting by propensity score and Gleason score, brachytherapy and external radiotherapy were not associated with decreased 10-year overall survival (aHR = 1.36, p = 0.292 and aHR = 1.44, p = 0.222), but presented higher biochemical recurrence (aHR = 1.93, p = 0.004 and aHR = 2.56, p < 0.001) than radical prostatectomy at ten years of follow-up. Higher prostate cancer-specific mortality was also observed in external radiotherapy (aHR = 9.37, p = 0.015). Novel long-term results are provided on the effectiveness of brachytherapy to control localized prostate cancer ten years after treatment, compared to radical prostatectomy and external radiotherapy, presenting high overall survival, similarly to radical prostatectomy, but higher risk of biochemical progression. These findings provide valuable information to facilitate shared clinical decision-making. Study identifier at ClinicalTrials.gov: NCT01492751

Correction: Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia

[This corrects the article DOI: 10.1371/journal.pbio.3001480.]

Highly sensitive microsatellite instability and immunohistochemistry assessment in endometrial aspirates as a tool for cancer risk individualization in Lynch syndrome

Women with Lynch syndrome (LS) are at increased risk of endometrial cancer (EC), among other tumors, and are characterized by mismatch repair (MMR) deficiency and microsatellite instability (MSI). While risk-reducing gynecologic surgeries effectively decrease EC incidence, doubts arise regarding the appropriate timing of the surgery. We explored the usefulness of highly sensitive MSI (hs-MSI) assessment in endometrial aspirates for individualizing gynecologic surveillance in LS carriers. Ninety-three women with LS, 25 sporadic EC patients (9 MMR-proficient and 16 MMR-deficient), and 30 women with benign gynecologic disease were included in this study. hs-MSI was assessed in prospectively collected endometrial aspirates in 67 LS carriers, EC cases, and controls. MMR, PTEN, ARID1A, and PAX2 protein expression patterns were evaluated in the LS samples. Follow-up aspirates from 8 LS carriers were also analyzed. Elevated hs-MSI scores were detected in all aspirates from MMR-deficient EC cases (3 LS and 16 sporadic) and negative in aspirates from controls and MMR-proficient EC cases. Positive hs-MSI scores were also detected in all 4 LS aspirates reported as complex hyperplasia. High hs-MSI was also present in 10 of 49 aspirates (20%) from LS carriers presenting a morphologically normal endometrium, where MMR protein expression loss was detected in 69% of the samples. Interestingly, the hs-MSI score was positively correlated with MMR-deficient gland density and the presence of MMR-deficient clusters, colocalizing PTEN and ARID1A expression loss. High hs-MSI scores and clonality were evidenced in 2 samples collected up to 4 months before EC diagnosis; hs-MSI scores increased over time in 5 LS carriers, whereas they decreased in a patient with endometrial hyperplasia after progestin therapy. In LS carriers, elevated hs-MSI scores were detected in aspirates from premalignant and malignant lesions and normal endometrium, correlating with MMR protein loss. hs-MSI assessment and MMR immunohistochemistry may help individualize EC risk assessment in women with LS