Meningocele transetmoidal. Diagnóstico en edad adulta: presentación de un caso

La herniación extracraneal de las cubiertas meníngeas, solas o acompañadas de tejido encefálico, a través de un defecto de cierre de los huesos craneales, se define con los términos de meningocele y encefalocele. Estos se pueden clasificar según su contenido o su localización. Los meningoencefaloceles transetmoidales representan el 5% de los meningoencefaloceles, los cuales a su vez constituyen el 8-19% de todos los disrafismos del SNC. Presentamos un caso de una paciente de 54 años de edad con cuadro clínico de rinoliquorrea de 10 años de evolución y meningitis de repetición. Mediante tomografia computadorizada se diagnosticó de un meningocele transetmoidal, que fue tratado satisfactoriamente con cirugía. Ante un paciente con meningitis de repetición, se debe valorar la presencia de rinoliquorrea y, en caso de tenerla, el paciente debe ser sometido a un estudio radiológico exhaustivo, para identificar la solución de continuidad a través de la cual sale el LCR y poder ofrecerle el tratamiento adecuado. Una de las patologías que pueden dar esta manifestación es el meningoencefalocele transetmoidal. El estudio de la fosa anterior con tomografia computadorizada es un buen método para el diagnóstico de esta patología, no obstante, en la actualidad el método de elección es la resonancia magnética

SUMOylation inhibition mediated by disruption of SUMO E1-E2 interactions confers plant susceptibility to necrotrophic fungal pathogens

Protein modification by SUMO modulates essential biological processes in eukaryotes. SUMOylation is facilitated by sequential action of the E1-activating, E2-conjugating, and E3-ligase enzymes. In plants, SUMO regulates plant development and stress responses, which are key determinants in agricultural productivity. To generate additional tools for advancing our knowledge about the SUMO biology, we have developed a strategy for inhibiting in vivo SUMO conjugation based on disruption of SUMO E1-E2 interactions through expression of E1 SAE2UFDCt domain. Targeted mutagenesis and phylogenetic analyses revealed that this inhibition involves a short motif in SAE2UFDCt highly divergent across kingdoms. Transgenic plants expressing the SAE2UFDCt domain displayed dose-dependent inhibition of SUMO conjugation, and have revealed the existence of a post-transcriptional mechanism that regulates SUMO E2 conjugating enzyme levels. Interestingly, these transgenic plants displayed increased susceptibility to necrotrophic fungal infections by Botrytis cinerea and Plectosphaerella cucumerina. Early after fungal inoculation, host SUMO conjugation was post-transcriptionally downregulated, suggesting that targeting SUMOylation machinery could constitute a novel mechanism for fungal pathogenicity. These findings support the role of SUMOylation as a mechanism involved in plant protection from environmental stresses. In addition, the strategy for inhibiting SUMO conjugation in vivo described in this study might be applicable in important crop plants and other non-plant organisms regardless of their genetic complexity

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Dietary α‐Linolenic Acid, Marine ω‐3 Fatty Acids, and Mortality in a Population With High Fish Consumption: Findings From the PREvención con DIeta MEDiterránea (PREDIMED) Study

Background: Epidemiological evidence suggests a cardioprotective role of α‐linolenic acid (ALA), a plant‐derived ω‐3 fatty acid. It is unclear whether ALA is beneficial in a background of high marine ω‐3 fatty acids (long‐chain n‐3 polyunsaturated fatty acids) intake. In persons at high cardiovascular risk from Spain, a country in which fish consumption is customarily high, we investigated whether meeting the International Society for the Study of Fatty Acids and Lipids recommendation for dietary ALA (0.7% of total energy) at baseline was related to all‐cause and cardiovascular disease mortality. We also examined the effect of meeting the society's recommendation for long‐chain n‐3 polyunsaturated fatty acids (≥500 mg/day). Methods and Results: We longitudinally evaluated 7202 participants in the PREvención con DIeta MEDiterránea (PREDIMED) trial. Multivariable‐adjusted Cox regression models were fitted to estimate hazard ratios. ALA intake correlated to walnut consumption (r=0.94). During a 5.9‐y follow‐up, 431 deaths occurred (104 cardiovascular disease, 55 coronary heart disease, 32 sudden cardiac death, 25 stroke). The hazard ratios for meeting ALA recommendation (n=1615, 22.4%) were 0.72 (95% CI 0.56–0.92) for all‐cause mortality and 0.95 (95% CI 0.58–1.57) for fatal cardiovascular disease. The hazard ratios for meeting the recommendation for long‐chain n‐3 polyunsaturated fatty acids (n=5452, 75.7%) were 0.84 (95% CI 0.67–1.05) for all‐cause mortality, 0.61 (95% CI 0.39–0.96) for fatal cardiovascular disease, 0.54 (95% CI 0.29–0.99) for fatal coronary heart disease, and 0.49 (95% CI 0.22–1.01) for sudden cardiac death. The highest reduction in all‐cause mortality occurred in participants meeting both recommendations (hazard ratio 0.63 [95% CI 0.45–0.87]). Conclusions: In participants without prior cardiovascular disease and high fish consumption, dietary ALA, supplied mainly by walnuts and olive oil, relates inversely to all‐cause mortality, whereas protection from cardiac mortality is limited to fish‐derived long‐chain n‐3 polyunsaturated fatty acids. Clinical Trial Registration URL: http://www.Controlled-trials.com/. Unique identifier: ISRCTN35739639

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Kinetic Analysis of Plant SUMO Conjugation Machinery

Plant SUMO conjugation is an essential posttranslational modification involved in plant development and responses to environmental stress. Most likely, this biological diversification is supported by a functional specialization of the different isoforms of the SUMO conjugation machinery. For instance, the two essential Arabidopsis SUMO isoforms, SUMO1/2, display higher conjugation rate than SUMO3 and 5, which are not essential, linking their specific biochemical properties to their biological role. To study the biochemical properties of plant SUMO conjugation systems, quantitative biochemical assays must be performed. We will present a detailed protocol for reconstituting an in vitro SUMO conjugation assay covering all steps from protein preparation to assay development.This work was supported by the European Research Council (grant ERC-2007-StG-205927) and Departament d’Innovació, Universitats i Empresa from the Generalitat de Catalunya (Xarxa de Referència en Biotecnologia and 2014 SGR 447). L.C.M was supported by research contract through the CRAG. This article is based upon work from COST Action (PROTEOSTASIS BM1307), supported by COST (European Cooperation in Science and Technology).Peer reviewe

Distinctive properties of Arabidopsis SUMO paralogues support the in vivo predominant role of AtSUMO1/2 isoforms

Protein modification by SUMO (small ubiquitin-related modifier) has emerged as an essential regulatory mechanism in eukaryotes. Even though the molecular mechanisms of SUMO conjugation/deconjugation are conserved, the number of SUMO machinery components and their degree of conservation are specific to each organism. In the present paper, we show data contributing to the notion that the four expressed Arabidopsis SUMO paralogues, AtSUMO1, 2, 3 and 5, have functionally diverged to a higher extent than their human orthologues. We have explored the degree of conservation of these paralogues and found that the surfaces involved in E1-activating enzyme recognition, and E2-conjugating enzyme and SIM (SUMO-interacting motif) non-covalent interactions are well conserved in AtSUMO1/2 isoforms, whereas AtSUMO3 shows a lower degree of conservation, and AtSUMO5 is the most divergent isoform. These differences are functionally relevant, since AtSUMO3 and 5 are deficient in establishing E2 non-covalent interactions, which has not been reported for any naturally occurring SUMO orthologue. In addition, AtSUMO3 is less efficiently conjugated than AtSUMO1/2, and AtSUMO5 shows the lowest conjugation level. A mutagenesis analysis revealed that decreases in conjugation rate and thioester-bond formation are the result of the non-conserved residues involved in E1-activating enzyme recognition that are present in AtSUMO3 and 5. The results of the present study support a role for the E1-activating enzyme in SUMO paralogue discrimination, providing a new mechanism to favour conjugation of the essential AtSUMO1/2 paralogues.The work was supported by the European Research Council [grant number ERC-2007-StG-205927], and the Spanish Ministry of Education and Science [grant numbers BIO2008-01495, CONSOLIDER CSD 2007-00036]. L.C.M. is supported by a predoctoral contract through the CRAG. J.S. is supported by a predoctoral fellowship from the Ministry of Education and Science [grant number BES-2005-6843]. We also thank the ‘Departament d’Innovació, Universitats i Empresa’ from the Generalitat de Catalunya (Xarxa de Referència en Biotecnologia and 2009SGR 09626) for support.Peer reviewe

SUMO activation across evolution

Trabajo presentado al EMBO Workshop: The ubiquitin system: Biology, mechanisms and roles in disease, celebrado en Cavtat (Croacia) del 13 al 17 de septiembre de 2019

Meningocele transetmoidal. Diagnóstico en edad adulta: presentación de un caso

La herniación extracraneal de las cubiertas meníngeas, solas o acompañadas de tejido encefálico, a través de un defecto de cierre de los huesos craneales, se define con los términos de meningocele y encefalocele. Estos se pueden clasificar según su contenido o su localización. Los meningoencefaloceles transetmoidales representan el 5% de los meningoencefaloceles, los cuales a su vez constituyen el 8-19% de todos los disrafismos del SNC. Presentamos un caso de una paciente de 54 años de edad con cuadro clínico de rinoliquorrea de 10 años de evolución y meningitis de repetición. Mediante tomografia computadorizada se diagnosticó de un meningocele transetmoidal, que fue tratado satisfactoriamente con cirugía. Ante un paciente con meningitis de repetición, se debe valorar la presencia de rinoliquorrea y, en caso de tenerla, el paciente debe ser sometido a un estudio radiológico exhaustivo, para identificar la solución de continuidad a través de la cual sale el LCR y poder ofrecerle el tratamiento adecuado. Una de las patologías que pueden dar esta manifestación es el meningoencefalocele transetmoidal. El estudio de la fosa anterior con tomografia computadorizada es un buen método para el diagnóstico de esta patología, no obstante, en la actualidad el método de elección es la resonancia magnética

SUMOylation inhibition mediated by disruption of SUMO E1-E2 interactions confers plant susceptibility to necrotrophic fungal pathogens

Protein modification by SUMO modulates essential biological processes in eukaryotes. SUMOylation is facilitated by sequential action of the E1-activating, E2-conjugating, and E3-ligase enzymes. In plants, SUMO regulates plant development and stress responses, which are key determinants in agricultural productivity. To generate additional tools for advancing our knowledge about the SUMO biology, we have developed a strategy for inhibiting in vivo SUMO conjugation based on disruption of SUMO E1-E2 interactions through expression of E1 SAE2UFDCt domain. Targeted mutagenesis and phylogenetic analyses revealed that this inhibition involves a short motif in SAE2UFDCt highly divergent across kingdoms. Transgenic plants expressing the SAE2UFDCt domain displayed dose-dependent inhibition of SUMO conjugation, and have revealed the existence of a post-transcriptional mechanism that regulates SUMO E2 conjugating enzyme levels. Interestingly, these transgenic plants displayed increased susceptibility to necrotrophic fungal infections by Botrytis cinerea and Plectosphaerella cucumerina. Early after fungal inoculation, host SUMO conjugation was post-transcriptionally downregulated, suggesting that targeting SUMOylation machinery could constitute a novel mechanism for fungal pathogenicity. These findings support the role of SUMOylation as a mechanism involved in plant protection from environmental stresses. In addition, the strategy for inhibiting SUMO conjugation in vivo described in this study might be applicable in important crop plants and other non-plant organisms regardless of their genetic complexity