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Abstract Sequence variants in the HERC2 gene are associated with a significant reduction in HERC2 protein levels and cause a neurodevelopmental disorder known as the HERC2-related disorder, which shares clinical features with Angelman syndrome, including global developmental delay, intellectual disability, autism, and movement disorders. Remarkably, the HERC2 gene is commonly deleted in individuals with Angelman syndrome, suggesting a potential contribution of HERC2 to the pathophysiology of this disease. Given the known critical role of autophagy in brain development and its implication in neurodevelopmental diseases, we undertook different experimental approaches to monitor autophagy in fibroblasts derived from individuals affected by the HERC2-related disorder. Our findings reveal alterations in the levels of the autophagy-related protein LC3. Furthermore, experiments with lysosomal inhibitors provide confirmation of an upregulation of the autophagy pathway in these patient-derived cells. Mechanistically, we corroborate an interaction between HERC2 and the deubiquitylating enzyme USP20; and demonstrate that HERC2 deficiency leads to increased USP20 protein levels. Notably, USP20 upregulation correlates with enhanced stability of the autophagy initiating kinase ULK1, highlighting the role of HERC2 as an autophagy regulator factor through the USP20-ULK1 axis. Moreover, we show that p38 acts as a modulator of this pathway, since p38 activation disrupts HERC2-USP20 interaction, leading to increased USP20 and LC3-II protein levels. Together, these findings uncover a previously unknown role for HERC2 in autophagy regulation and provide insights into the pathomolecular mechanisms underlying the HERC2-related disorder and Angelman syndrome.

Abstract Bone remodeling is a continuous process between bone-forming osteoblasts and bone-resorbing osteoclasts, with any imbalance resulting in metabolic bone disease, including osteopenia. The HERC1 gene encodes an E3 ubiquitin ligase that affects cellular processes by regulating the ubiquitination of target proteins, such as C-RAF. Of interest, an association exists between biallelic pathogenic sequence variants in the HERC1 gene and the neurodevelopmental disorder MDFPMR syndrome (macrocephaly, dysmorphic facies, and psychomotor retardation). Most pathogenic variants cause loss of HERC1 function, and the affected individuals present with features related to altered bone homeostasis. Herc1-knockout mice offer an excellent model in which to study the role of HERC1 in bone remodeling and to understand its role in disease. In this study, we show that HERC1 regulates osteoblastogenesis and osteoclastogenesis, proving that its depletion increases gene expression of osteoblastic makers during the osteogenic differentiation of mesenchymal stem cells. During this process, HERC1 deficiency increases the levels of C-RAF and of phosphorylated ERK and p38. The Herc1-knockout adult mice developed imbalanced bone homeostasis that presented as osteopenia in both sexes of the adult mice. By contrast, only young female knockout mice had osteopenia and increased number of osteoclasts, with the changes associated with reductions in testosterone and dihydrotestosterone levels. Finally, osteocytes isolated from knockout mice showed a higher expression of osteocytic genes and an increase in the Rankl/Opg ratio, indicating a relevant cell-autonomous role of HERC1 when regulating the transcriptional program of bone formation. Overall, these findings present HERC1 as a modulator of bone homeostasis and highlight potential therapeutic targets for individuals affected by pathological HERC1 variants.

The complexity of coastal fisheries, which often involve many gears with cross-impacts on various species and life stages, requires a management system that is able to integrate these multiple interactions in order to gradually achieve sustainability. In this paper, we argue that regional co-management can appropriately address the complex interactions between fisheries, including those with other potentially conflicting human activities. Our results, notably obtained through a questionnaire to local fishers’ representatives mainly on bottom trawl fisheries in the Catalan Sea region, show, however, that improved mutual understanding through effective communication and long-term collaboration between stakeholders, and in particular between fishers and scientists, is essential to ensure the successful implementation of fisheries co-management. In addition to balancing the voices of the many stakeholders, co-management needs to be further improved by developing multi-species, multi-gear and multi-use approaches to the oceans. This improvement could in turn support the effectiveness of co-decisions, as they would be based on the recognised administrative structure of co-management committees and sound scientific guidance that addresses both ecosystem protection and sustainable fisheries profitability. Dynamic management over time and space, using real-time essential fish habitat from operational oceanography, can help to make the co-management process more robust by improving collaboration between stakeholders and the effectiveness of measures in a changing environment. The decision-making, social and ecological components are described as integral and dependent parts of the co-management system, with priority given to mutual understanding between stakeholders. This integrated co-management framework is flexible enough to take into account regional complexity, but also national legislation and the EU Common Fisheries Policy, which all promote sustainable use of the oceans and protection of the ecosystem.

Protein ubiquitylation acts as a complex cell signaling mechanism since the formation of different mono- and polyubiquitin chains determines the substrate’s fate in the cell. E3 ligases define the specificity of this reaction by catalyzing the attachment of ubiquitin to the substrate protein. Thus, they represent an important regulatory component of this process. Large HERC ubiquitin ligases belong to the HECT E3 protein family and comprise HERC1 and HERC2 proteins. The physiological relevance of the Large HERCs is illustrated by their involvement in different pathologies, with a notable implication in cancer and neurological diseases. Understanding how cell signaling is altered in these different pathologies is important for uncovering novel therapeutic targets. To this end, this review summarizes the recent advances in how the Large HERCs regulate the MAPK signaling pathways. In addition, we emphasize the potential therapeutic strategies that could be followed to ameliorate the alterations in MAPK signaling caused by Large HERC deficiencies, focusing on the use of specific inhibitors and proteolysis-targeting chimeras.

This study characterized the fishery dynamics of blue whiting, a bycatch species of the bottom trawl Norway lobster fishery, in the NW Mediterranean. Landings and effort data over the last two decades were combined with current information on the spatial distribution of effort and catch, and with the size and age structure of blue whiting over the year. Recruitment to the demersal habitat occurred from 5 cm total length (TL) over the shelf break in spring (April-May), when discards showed the highest values (>95% of the catch). Adults were located over the upper slope, and large individuals (≥26 cm TL) were abundant during the reproductive period (January-March). A decline in landings has been observed in the last decade, probably related to the absence of intense deep convection processes in winter since 2013, which favour recruitment of the species. The effect of exploitation on the decrease in landings cannot be disregarded considering that the bulk of the catch is made up of immature (age 0) individuals, and the presence of old individuals is very low.

The p53 tumor suppressor protein is a transcription factor that plays a prominent role in protecting cells from malignant transformation. Protein levels of p53 and its transcriptional activity are tightly regulated by the ubiquitin E3 ligase MDM2, the gene expression of which is transcriptionally regulated by p53 in a negative feedback loop. The p53 protein is transcriptionally active as a tetramer, and this oligomerization state is modulated by a complex formed by NEURL4 and the ubiquitin E3 ligase HERC2. Here, we report that MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4. HERC2 knockdown results in a decline in MDM2 protein levels without affecting its protein stability, as it reduces its mRNA expression by inhibition of its promoter activation. DNA damage induced by bleomycin dissociates MDM2 from the p53/HERC2/NEURL4 complex and increases the phosphorylation and acetylation of oligomeric p53 bound to HERC2 and NEURL4. Moreover, the MDM2 promoter, which contains p53‐response elements, competes with HERC2 for binding of oligomeric, phosphorylated and acetylated p53. We integrate these findings in a model showing the pivotal role of HERC2 in p53‐MDM2 loop regulation. Altogether, these new insights in p53 pathway regulation are of great interest in cancer and may provide new therapeutic targets.

Homologous to the E6AP carboxyl terminus (HECT) and regulator of chromosome condensation 1 (RCC1)-like domain-containing proteins (HERCs) belong to the superfamily of ubiquitin ligases. HERC proteins are divided into two subfamilies, Large and Small HERCs. Despite their similarities in terms of both structure and domains, these subfamilies are evolutionarily very distant and result from a convergence phenomenon rather than from a common origin. Large HERC genes, HERC1 and HERC2, are present in most metazoan taxa. They encode very large proteins (approximately 5,000 amino acid residues in a single polypeptide chain) that contain more than one RCC1-like domain as a structural characteristic. Accumulating evidences show that these unusually large proteins play key roles in a wide range of cellular functions which include neurodevelopment, DNA damage repair, and cell proliferation. To better understand the origin, evolution, and function of the Large HERC family, this minireview provides with an integrated overview of their structure and function and details their physiological implications. This study also highlights and discusses how dysregulation of these proteins is associated with severe human diseases such as neurological disorders and cancer.

Objetivos: Analizar las actitudes y las percepciones de pacientes, médicos y enfermeros respecto a los derechos de los pacientes en el ámbito de los hospitales públicos del sector sanitario de Reus (Tarragona). Métodos: Análisis cualitativo, mediante grupos focales de profesionales sanitarios (médicos y enfermeros) y usuarios dados de alta, seguido de 3 encuestas dirigidas a cada uno de estos colectivos. Se realizó un análisis descriptivo de los resultados y de las diferencias entre colectivos. Se utilizó el análisis de componentes principales categóricos para reducir el número de dimensiones y revelar las relaciones existentes entre las diversas variables. Resultados: Ex pacientes y enfermeros identifican los «derechos a la información» y «autonomía del paciente» como los más importantes, mientras que para los médicos las 2 dimensiones más importantes son «derecho a la autonomía» y «derecho a la formulación de la opinión del paciente». Una minoría de pacientes es refractaria a la toma de decisiones. Las mujeres, los más jóvenes y los niveles de educación altos son más favorables al respeto a la autonomía del paciente. Hay posiciones menos favorables a las visiones «autonomistas» por parte de los pacientes, en comparación con las visiones más favorables por parte de los médicos y radicalmente partidarias por parte de los enfermeros. Conclusiones: Los derechos de los pacientes no son suficientemente conocidos y el derecho a la información es valorado como más importante que el derecho al ejercicio de la autonomía. Ex pacientes, médicos y enfermeros tienen actitudes y percepciones diferentes frente a situaciones similares.Objectives: To analyze patients', physicians' and nurses' attitudes to and perceptions of patient rights in the public hospitals of the Reus health district in Catalonia (Spain). Methods: We performed a qualitative analysis, through focus groups composed of health professionals (physicians and nurses) and discharged patients, followed by three surveys aimed at physicians, nurses, and patients. A descriptive analysis was performed of the results and of the differences among the three collectives. A principal components analysis for categorical data was used to reduce the number of dimensions and to reveal the associations among the different variables. Results: Among discharged patients and nurses, the most important patient rights were «the right to information» and «patient autonomy», whereas among physicians, the most important dimensions were the «right to autonomy» and «the patient's right to form an opinion». A minority of patients was reluctant to participate in decision-making. The groups with the most favorable attitudes to exercising patient autonomy were women, younger patients, and those with the highest educational level. Patients were less in favor of patient autonomy than physicians while nurses had the most radical attitudes in favor of patient autonomy. Conclusions: Patient's rights are not sufficiently well known, and the right to information is valued more highly than the right to exercise autonomy. Discharged patients, physicians and nurses have different attitudes to and perceptions of the same issue.

Objective: The characteristics of the 36 item Medical Outcome Short Form Health Study Survey (SF-36) questionnaire, designed as a generic indicator of health status for the general population, allow it to be self-administered or used in personal or telephone interviews. The main objective of the study was to compare the telephone and self-administered modes of SF-36 for a population from Girona (Spain). Methods: A randomized crossover administration of the questionnaire design was used in a cardiovascular risk factor survey. Of 385 people invited to participate in the survey, 351 agreed to do so and were randomly assigned to two orders of administration (i.e., telephone-self and self-telephone); 261 completed both questionnaires. Scores were compared between administration modes using a paired t test. Internal consistency and agreement between modalities were analyzed by respectively applying Chronbach's alpha and intraclass correlation coefficients. The effect of the order of administration on the test-retest difference was analyzed by one-way ANOVA for repeated measurements. Results: Physical function, physical role and social functioning received significantly lower scores when the self-administered questionnaire was used prior to the telephone survey. When the initial survey was conducted by telephone, all Chronbach's alpha coefficients (except social functioning) scored over 0.70 in the self-administered modality. The intraclass correlation coefficient ranged from 0.41 to 0.83 for the telephone-self order and from 0.32 to 0.73 for the self-telephone order. No clinically significant effect was observed for the order of application. Conclusions: The results of the present study suggest that the telephone-administration mode of SF-36 is equivalent to and as valid as the self-administered mode.Objetivo: El cuestionario de salud SF-36 puede ser autoaplicado o utilizado en entrevistas personales o telefónicas. El objetivo principal de este trabajo fue comparar la aplicación telefónica del cuestionario y la versión autoaplicada en una población de Girona (España). Métodos: Diseño cruzado y aleatorizado para la aplicación de las dos formas del cuestionario. Se asignaron dos órdenes de aplicación de las encuestas (telefónica-autoaplicada y autoaplicada-telefónica). Un total de 261 personas completaron los cuestionarios. Las comparaciones entre modos de aplicación se realizaron mediante la prueba de la t de Student para datos apareados. La consistencia interna y la concordancia entre modos de aplicación se analizaron mediante los coeficientes * de Chronbach y de correlación intraclase, respectivamente. Su utilizó un modelo lineal general para medidas repetidas para evaluar el efecto del orden de la aplicación de los cuestionarios. Resultados: Cuando se utilizó primero el cuestionario autoaplicado, las escalas de función física, rol físico y función social resultaron en una menor puntuación. Todos los coeficientes * de Chronbach fueron superiores a 0,70, excepto para la escala de función social en la modalidad autoaplicada cuando se aplicó primero la encuesta telefónica. El rango de los coeficientes de correlación intraclase fue de 0,41 a 0,83 en la modalidad telefónica-autoaplicada y de 0,32 a 0,73 en la modalidad autoaplicada-telefónica. No se observó un efecto relevante del orden de aplicación.

Background and objectiveCoronary heart disease (CHD) is the leading cause of death, and smoking its strongest modifiable risk factor. Our aim was to determine the impact of the Spanish 2006 partial smoke-free legislation on acute myocardial infarction (AMI) incidence, hospitalization and mortality rates, and 28-day case-fatality in Girona, Spain.MethodsUsing a population-based registry (the REGICOR Study), we compared population incidence, hospitalization, and mortality rates, and 28-day case-fatality in the pre- and post-ban periods (2002-2005 and 2006-2008, respectively) by binomial regression analysis adjusted for confounding factors. We also analyzed the ban's impact on the outcomes of interest using the AMI definitions of the American Heart Association (AHA)/European Society of Cardiology (ESC) and the World Health Organization (WHO)-Monitoring trends and determinants in cardiovascular diseases (MONICA).ResultsIn the post-ban period, AMI incidence and mortality rates significantly decreased (relative risk [RR] = 0.89; 95% confidence interval [CI] = 0.81-0.97 and RR = 0.82; 95% CI = 0.71-0.94, respectively). Incidence and mortality rates decreased in both sexes, especially in women, and in people aged 65-74 years. Former and non-smokers (passive smokers) showed diminished incidence rates. Implementation of the ban was not associated with AMI case-fatality. Models tended to be more significant with the WHO-MONICA than with the AHA/ESC definition.ConclusionsThe 2006 Spanish partial smoke-free legislation was associated with a decrease in population AMI incidence and mortality, particularly in women, in people aged 65-74 years, and in passive smokers. These results clarify the association between AMI mortality and the enactment of a partial smoke-free legislation and reinforce the effectiveness of smoking regulations in preventing CHD.