A geological cross-section along the Basque Pyrenees and the Parentis Basin (Western Pyrenees)

A new geological cross- section along the North Iberian Margin shows a complete image of the Western Pyrenees and the Parentis Basin as well as the geometric differences and age constraints between both Pyrenean fronts. The South Pyrenean front, developed during Uppermost Cretaceous- Middle Miocene, is represented by a major thrust which accumulates around 20 km of southward displacement. The Basque- Cantabrian basin is a mesozoic extensional basin which was inverted during Paleogene times as a consequence of the Pyrenean orogeny. A basement- involved thrust wedge with an upper south- directed back- thrust characterizes the North Pyrenean Frontal Thrust. The main thrust, emplaced during Late Eocene- Miocene times, shows a displacement around 2 km whereas the back- thrust detached in Paleocene materials shows a displacement about 1.5 km. Northwards, the Landes High, is interpreted as an uplifted plateau where a thick wedge of Upper Cretaceous- Cenozoic synorogenic deposits overlay unconformably the Hercinian basement. This package corresponds with the North Pyrenean foreland basin. More to the north, the Landes fault is the southern margin of the Mesozoic Parentis Basin, a semigraben infilled with a thick package of Triassic to Albian synrift sequence overlied by Cretaceous and Cenozoic deposits. There, inversion structures were poorly developed

Type III secretion inhibitors for the management of bacterial plant diseases

Altres ajuts: COST Action SUSTAIN (FA1208) from the European Union.The identification of chemical compounds that prevent and combat bacterial diseases is fundamental for crop production. Bacterial virulence inhibitors are a promising alternative to classical control treatments, because they have a low environmental impact and are less likely to generate bacterial resistance. The major virulence determinant of most animal and plant bacterial pathogens is the type III secretion system (T3SS). In this work, we screened nine plant extracts and 12 isolated compounds-including molecules effective against human pathogens-for their capacity to inhibit the T3SS of plant pathogens and for their applicability as virulence inhibitors for crop protection. The screen was performed using a luminescent reporter system developed in the model pathogenic bacterium Ralstonia solanacearum. Five synthetic molecules, one natural product and two plant extracts were found to down-regulate T3SS transcription, most through the inhibition of the regulator hrpB. In addition, for three of the molecules, corresponding to salicylidene acylhydrazide derivatives, the inhibitory effect caused a dramatic decrease in the secretion capacity, which was translated into impaired plant responses. These candidate virulence inhibitors were then tested for their ability to protect plants. We demonstrated that salicylidene acylhydrazides can limit R. solanacearum multiplication in planta and protect tomato plants from bacterial speck caused by Pseudomonas syringae pv. tomato. Our work validates the efficiency of transcription reporters to discover compounds or natural product extracts that can be potentially applied to prevent bacterial plant disease

The antimalarial drug amodiaquine stabilizes p53 through ribosome biogenesis stress, independently of its autophagy-inhibitory activity

Pharmacological inhibition of ribosome biogenesis is a promising avenue for cancer therapy. Herein, we report a novel activity of the FDA-approved antimalarial drug amodiaquine which inhibits rRNA transcription, a rate-limiting step for ribosome biogenesis, in a dose-dependent manner. Amodiaquine triggers degradation of the catalytic subunit of RNA polymerase I (Pol I), with ensuing RPL5/RPL11-dependent stabilization of p53. Pol I shutdown occurs in the absence of DNA damage and without the subsequent ATM-dependent inhibition of rRNA transcription. RNAseq analysis revealed mechanistic similarities of amodiaquine with BMH-21, the first-in-class Pol I inhibitor, and with chloroquine, the antimalarial analog of amodiaquine, with well-established autophagy-inhibitory activity. Interestingly, autophagy inhibition caused by amodiaquine is not involved in the inhibition of rRNA transcription, suggesting two independent anticancer mechanisms. In vitro, amodiaquine is more efficient than chloroquine in restraining the proliferation of human cell lines derived from colorectal carcinomas, a cancer type with predicted susceptibility to ribosome biogenesis stress. Taken together, our data reveal an unsuspected activity of a drug approved and used in the clinics for over 30 years, and provide rationale for repurposing amodiaquine in cancer therapy

Global phosphoproteome profiling reveals unanticipated networks responsive to cisplatin treatment of embryonic stem cells

Cellular responses to DNA-damaging agents involve the activation of various DNA damage signaling and transduction pathways. Using quantitative and high-resolution tandem mass spectrometry, we determined global changes in protein level and phosphorylation site profiles following treatment of SILAC (stable isotope labeling by amino acids in cell culture)-labeled murine embryonic stem cells with the anticancer drug cisplatin. Network and pathway analyses indicated that processes related to the DNA damage response and cytoskeleton organization were significantly affected. Although the ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) consensus sequence (S/T-Q motif) was significantly overrepresented among hyperphosphorylated peptides, about half of the >2-fold-upregulated phosphorylation sites based on the consensus sequence were not direct substrates of ATM and ATR. Eleven protein kinases mainly belonging to the mitogen-activated protein kinase (MAPK) family were identified as being regulated in their kinase domain activation loop. The biological importance of three of these kinases (cyclin-dependent kinase 7 [CDK7], Plk1, and KPCD1) in the protection against cisplatin-induced cytotoxicity was demonstrated by small interfering RNA (siRNA)-mediated knockdown. Our results indicate that the cellular response to cisplatin involves a variety of kinases and phosphatases not only acting in the nucleus but also regulating cytoplasmic targets, resulting in extensive cytoskeletal rearrangements. Integration of transcriptomic and proteomic data revealed a poor correlation between changes in the relative levels of transcripts and their corresponding proteins, but a large overlap in affected pathways at the levels of mRNA, protein, and phosphoprotein. This study provides an integrated view of pathways activated by genotoxic stress and deciphers kinases that play a pivotal role in regulating cellular processes other than the DNA damage response

The plant metacaspase AtMC1 in pathogen-triggered programmed cell death and aging: functional linkage with autophagy

Autophagy is a major nutrient recycling mechanism in plants. However, its functional connection with programmed cell death (PCD) is a topic of active debate and remains not well understood. Our previous studies established the plant metacaspase AtMC1 as a positive regulator of pathogen-triggered PCD. Here, we explored the linkage between plant autophagy and AtMC1 function in the context of pathogen-triggered PCD and aging. We observed that autophagy acts as a positive regulator of pathogen-triggered PCD in a parallel pathway to AtMC1. In addition, we unveiled an additional, pro-survival homeostatic function of AtMC1 in aging plants that acts in parallel to a similar pro-survival function of autophagy. This novel pro-survival role of AtMC1 may be functionally related to its prodomain-mediated aggregate localization and potential clearance, in agreement with recent findings using the single budding yeast metacaspase YCA1. We propose a unifying model whereby autophagy and AtMC1 are part of parallel pathways, both positively regulating HR cell death in young plants, when these functions are not masked by the cumulative stresses of aging, and negatively regulating senescence in older plants

Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease:a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice

Recently, the European Medicines Agency approved the use of the vasopressin V2 receptor antagonist tolvaptan to slow the progression of cyst development and renal insufficiency of autosomal dominant polycystic kidney disease (ADPKD) in adult patients with chronic kidney disease stages 1-3 at initiation of treatment with evidence of rapidly progressing disease. In this paper, on behalf of the ERA-EDTA Working Groups of Inherited Kidney Disorders and European Renal Best Practice, we aim to provide guidance for making the decision as to which ADPKD patients to treat with tolvaptan. The present position statement includes a series of recommendations resulting in a hierarchical decision algorithm that encompasses a sequence of risk-factor assessments in a descending order of reliability. By examining the best-validated markers first, we aim to identify ADPKD patients who have documented rapid disease progression or are likely to have rapid disease progression. We believe that this procedure offers the best opportunity to select patients who are most likely to benefit from tolvaptan, thus improving the benefit-to-risk ratio and cost-effectiveness of this treatment. It is important to emphasize that the decision to initiate treatment requires the consideration of many factors besides eligibility, such as contraindications, potential adverse events, as well as patient motivation and lifestyle factors, and requires shared decision-making with the patient.</p

La educación inclusiva frente a las desigualdades sociales: un estado de la cuestion y algunas reflexiones geograficas

Este artículo establece un estado de la cuestión e la educación inclusiva en el mundo y sugiere algunas reflexiones al respecto. El primer apartado recuerda las conexiones ineludibles entre las preocupaciones educativas por la educación inclusiva y las preocupaciones más generales por la desigualdad. El segundo consigna los criterios de búsqueda de las publicaciones académicas, y observa dos grandes temas en sus contenidos: sobre todo, el cambio interno de las escuelas atrae las miradas, pero en segundo plano también el entorno territorial despierta algunas inquietudes. El tercero anota los criterios de búsqueda de la documentación del Banco Mundial, la OCDE y la UNESCO. En este ámbito los simposios de la Oficina Internacional de la Educación de UNESCO revelan una interpretación dispar, aunque convergente, del concepto de educación inclusiva en las distintas regiones mundiales. Asimismo, todas las publicaciones oficiales muestran una atención prioritaria a las dinámicas internas de las escuelas, puesto que apenas algunas esbozan ciertas relaciones entre la educación inclusiva y las políticas públicas. El último apartado adelanta varios argumentos a favor de una mayor consideración de las escalas local y estatal de la educación inclusiva. Las principales razones para atender a la dimensión local provienen de la causalidad acumulativa de las privaciones sociales, de la necesidad de articular la acción de las escuelas y de la posibilidad de abrir un espacio significativo para la participación ciudadana. Asimismo, las principales razones para atender a la dimensión estatal surgen de las posibles sinergias entre la educación inclusiva y la expansión educativa (p. ej. ¿es correlativo el avance de la escolarización en los distintos ciclos escolares?) como también entre la educación inclusiva y la protección social (p. ej. ¿tienen una implicación pedagógica consistente las abundantes condiciones educativas de las transferencias sociales?