RGNNV and SJNNV reassortants produce mortality and replicate in gilthead seabream larvae

Nervous Necrosis Virus (NNV) is one of the most challenging pathogens for aquaculture development nowadays, mainly affecting marine teleost fish of major interest to the aquaculture industry and causing great economic losses. NNV consist in four genotypes, which seem to have a tropism for certain teleost fish species. Among them, gilthead seabream (Sparus aurata) has been considered as a non-susceptible species to the disease produced by traditional NNV genotypes. However, there are some evidences that indicate seabream is able to develop the disease in the presence of certain reassortant strains of NNV, called RGNNV/SJNNV, which possesses the RNA1 segment of the RGNNV genotype and the RNA2 segment of the SJNNV genotype, which may cause a new threat to aquaculture. Therefore, the main objective of this study was to evaluate the susceptibility of gilthead seabream larvae to the reassortant strains RGNNV/SJNNV and SJNNV/RGNNV. For this purpose, larvae were exposed to 104 TCDI50/mL in triplicate tanks with the reassortant strains. Samples of 5 individual larvae were collected at different days post-infection and used for gene expression and infective NNV isolation. Our data show that both reassortants produced mortalities, although the RGNNV/SJNNV was the one which produced the highest mortality and viral gene transcription, which significantly increased from 1 to 7 days post-infection. In conclusion, our study demonstrate that seabream larvae are susceptible to both RGNNV/SJNNV and SJNNV/RGNNV reassortants under laboratory conditions. Further studies should be performed to understand the pathogenicity of the NNV reassortant strains to prevent and control future outbreaks in aquaculture farms

Histopathological study of JNK in venous wall of patients with chronic venous insufficiency related to osteogenesis process

Chronic venous insufficiency (CVI) is one of the most common vascular pathologies worldwide. One of the risk factors for the development of CVI is aging, which is why it is related to senile changes. The main trigger of the changes that occur in the venous walls in CVI is blood flow reflux, which produces increased hydrostatic pressure, leading to valve incompetence. The cellular response is one of the fundamental processes in vascular diseases, causing the activation of cell signalling pathways such as c-Jun N-terminal kinase (JNK). Metabolic changes and calcifications occur in vascular pathology as a result of pathophysiological processes. The aim of this study was to determine the expression of JNK in venous disease and its relationship with the role played by the molecules involved in the osteogenic processes in venous tissue calcification. This was a cross-sectional study that analyzed the greater saphenous vein wall in 110 patients with (R) and without venous reflux (NR), classified according to age. Histopathological techniques were used and protein expression was analysed using immunohistochemistry techniques for JNK and markers of osteogenesis (RUNX2, osteocalcin (OCN), osteopontin (OPN)). Significantly increased JNK, RUNX2, OCN, OPN and pigment epithelium-derived factor (PEDF) protein expression and the presence of osseous metaplasia and amorphous calcification were observed in younger patients (<50 years) with venous reflux. This study shows for the first time the existence of an osteogenesis process related to the expression of JNK in the venous wall.This study (FIS-PI18/00912) was supported by the Instituto de Salud Carlos III (Plan Estatal de I+D+i 2013-2016) and cofinanced by the European Development Regional Fund ‘‘A way to achieve Europe’’ (ERDF) and B2017/BMD-3804 MITIC-C

Potential Impacts in the Gilthead Seabream Larviculture by Nodavirus

The nervous necrosis virus (NNV) leads to viral encephalopathy and retinopathy (VER) disease in more than 170 fish species, mainly from marine habitats. It replicates in the central nervous tissues, reaching up to 100% mortalities after a few days of infection, mainly in the larvae and juvenile stages. This is continuously spreading and affecting more species, both wild and cultured, posing a risk to the development of the aquaculture industry. In the Mediterranean Sea, it mainly affects European sea bass (Dicentrarchus labrax) and some grouper species (Epinephelus spp.). Interestingly, in the gilthead seabream (Sparus aurata), typically resistant to common NNV strains, great mortalities in hatcheries associated with typical clinical signs of VER have been confirmed to be caused by RGNNV/SJNNV reassortants. Thus, we have evaluated the susceptibility of seabream larvae to either RGNNV/SJNNV or SJNNV/RGNNV reassortants, as well as the larval immunity. Based on our results we can conclude that: (i) gilthead seabream larvae are susceptible to infection with both NNV reassortant genotypes, but mainly to RGNNV/SJNNV; (ii) virus replicated and infective particles were isolated; (iii) larval immunity was correlated with larval survival; and (iv) larval resistance and immunity were correlated with age of the larvae. Further investigations should be carried out to ascertain the risks of these new pathogens to Mediterranean larviculture

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Mar Menor: una laguna singular y sensible. Evaluación científica de su estado.

Este libro recopila las aportaciones que equipos de investigación de la Universidad de Murcia, Universidad Politécnica de Cartagena, Instituto Geológico-Minero de España, Universidad de Alicante, el Instituto Español de Oceanografía y otros organismos hicieron en las Jornadas Científicas del Mar Menor, celebradas en diciembre de 2014.La información recogida en este libro se estructura en dos grandes bloques, uno de Biología y Ecología del Mar Menor (capítulos 1 al 8) y otro de Condiciones fisicoquímicas e impacto de actividades humanas en la laguna (capítulos 9 al 14). El primer bloque resume buena parte de los estudios ecológicos realizados en el Mar Menor, que han servido para mejorar su conocimiento y también para cambiar antiguas asunciones sobre la naturaleza y el funcionamiento de estos ecosistemas lagunares (Capítulo 1). El segundo capítulo muestra que esta laguna alberga en zonas someras de su perímetro hábitats fundamentales para mantener y conservar tanto especies migratorias como residentes, que es necesario conocer para paliar el impacto de las actividades humanas que les afectan. En este sentido la reducción de la carga de nutrientes y contaminantes orgánicos e inorgánicos que fluyen hacia el Mar Menor puede ayudar a preservar la laguna en mejores condiciones, bien sea tratando las escorrentías (plantas de tratamiento, humedales artificiales u otras técnicas) y recuperar este agua para uso agrícola o evitar su descarga en la laguna (Capítulo 3). Estas actuaciones serán clave para la conservación de especies emblemáticas como el caballito de mar (Capítulo 4) y reducir el impacto de las proliferaciones masivas de medusas que se producen en la laguna desde 1993 (Capítulo 5). En este mismo sentido los cambios acaecidos en la laguna han favorecido la incursión de invertebrados marinos alóctonos (Capítulo 6) y han afectado a la respuesta de la dinámica poblacional de las aves acuáticas a distintas escalas (Capítulo 7). Para completar este bloque se ofrece una perspectiva histórica de la importancia que ha tenido la investigación sobre acuicultura realizada en esta laguna, que ha servido de base para su gran desarrollo actual (Capítulo 8). El segundo bloque se inicia con una evaluación del origen y evolución del Mar Menor desde el punto de vista geológico, y evidencia su vulnerabilidad ante el deterioro que puede sufrir la desaparición de la barrera de cierre y/o su colmatación (Capítulo 9). En el Capítulo 10 se describe la relevancia que tiene la interacción de los acuíferos del Campo de Cartagena con la laguna, que se produce no sólo a nivel superficial sino también subterráneo. Esta interacción permite el acceso de nutrientes a la laguna, a pesar de la cierta capacidad de depuración de los humedales que le circundan, y también de metales traza por los aportes de residuos mineros (Capítulo 11). De hecho los metales traza están presentes en los sedimentos de la laguna, y su distribución se ha caracterizado en la columna sedimentaria relacionándola con la granulometría y el contenido de materia orgánica del sedimento (Capítulo 12). Posteriormente se describe la entrada de diversos contaminantes orgánicos, incluyendo pesticidas y fármacos a través de la rambla del Albujón, y su distribución estacional en agua y sedimento de la laguna (Capítulo 13). Este segundo bloque finaliza con el Capítulo 14 en el que se describe la bioacumulación de hidrocarburos aromáticos policíclicos, pesticidas y fármacos en moluscos y peces del Mar Menor, así como los efectos biológicos que la carga contaminante que accede a través de la rambla del Albujón produce en los organismos que allí habitan. El libro concluye con un breve epílogo redactado por los editores de este libro.Versión del edito

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

Betanodavirus reassortants replicate and produce mortality in gilthead seabream larvae

Among the pathogens that most affect Mediterranean aquaculture, betanodavirus (NNV), a non-enveloped icosahedral RNA virus with a genome composed of two single-stranded positive-sense RNA segments known as RNA1 and RNA2, stands out. Apart from the traditional NNV genotypes, there are two reassortant genotypes called RGNNV/SJNNV and SJNNV/RGNNV, due to the origin of the RNA genome. It has been confirmed that gilthead seabream, a species resistant to traditional NNV genotypes, is susceptible to developing NNV disease in larval stages when infected by the RGNNV/SJNNV genotype, bringing a new focus to the prevention of infection in aquaculture farms. Therefore, the main objective of this research was to examine the susceptibility of 37 and 86 days post-hatching (dph) seabream larvae against RGNNV/SJNNV an SJNNV/RGNNV reassortants and the infective capacity of both viruses. Our results confirmed that both genotypes induced mortality in seabream larvae of both ages, being higher for RGNNV/SJNNV genotype and in 36 dph larvae. For both ages, the mortality rates were related to the replicative capacity of the virus. In 36 dph larvae, the high mortality can be explained by the high mRNA levels of viral genes from the beginning of the infection, increasing exponentially until the end of the infection, being always higher for RGNNV/SJNNV. In addition, we were able to recover viral particles for both genotypes, again higher for RGNNV/SJNNV. In contrast, the low, but statistically significant, mortality rate for 86 dph larvae might be due to the low replicative capacity of both viruses at this age. This issue together with a low expression level of viral genes and the failure in recovering infective particles seems to indicate that, even when the virus is initially competent to infect cells, its growth is dismissed or even blocked by different immune mechanisms and, therefore, the virus loses its pathogenic capacity. Further studies are needed to understand the host-viral interactions for NNV reassortants since they are threatening marine larviculture. Funded by Ministerio de Ciencia e Innovación-Agencia Estatal de Investigación [MCIN/AEI/10.13039/501100011033, grant PID2019-105522GB-I00 to AC], Ministerio de Economía y Competitividad and FEDER [grant RTI2018-096625-B-C33 to ECP and MA] and Fundación Séneca, Grupo de Excelencia de la Región de Murcia [19883/GERM/15]

Biotechnological tools for the research and control of nodavirus in aquaculture

Introduction. Nodavirus (NNV) is the most threatening marine virus in the Mediterranean area, and it is spreading in the number and type of viral isolates and host fish species, either wild or culture. In our research group we have been studying the immune response of fish against NNV for 2 decades, focusing on gilthead seabream and European sea bass models. While European sea bass is highly susceptible to some classical NNV genotypes the gilthead seabream acts as a resistant and reservoir species. However, their potential vertical transmission, the emergence of new natural NNV recombinants, producing high mortalities to traditionally-resistant species such as gilthead seabream, the climate change and the aquaculture diversification might increase the deleterious effects of NNV infection in the aquaculture sector. Based on this, we are now increasing our knowledge about fish-NNV interactions in the following topics: 1. Generation of biotechnological tools to study NNV and the fish immune response. We have developed several fish cell lines (from seabream, sea bass, European eel or Senegalese sole) susceptible to NNV, antibodies for localization studies and transcriptomic databases, useful as research and diagnostic tools. These tools allow us to increase their applications to other host, marine viruses or, even, other fields. 2. Deepening of the antiviral immune response of fish. We are identifying and characterizing, among others, the involvement of antimicrobial peptides (AMPs) and cell-mediated cytotoxicity as two of the most important antiviral immune mechanisms. Thus, we are able to analyze levels of antibodies and AMPs, or the adaptive cellular cytotoxic activity in fish, novel techniques that are routinely applied in our laboratory. 3. Effect of culture conditions and welfare on susceptibility to NNV. We are characterizing the lethality and presence of the virus in survivors and its success on vertical transmission under different culture conditions, size, or sex of different species susceptible to NNV. We have evidence that survival is more dependent on size than on culture conditions, but the presence of the virus in survivors is not. 4. Design and generation of treatments against NNV. We have developed several effective NNV vaccines in previous projects. We are currently developing the application of sea bass AMPs as antiviral treatments in aquaculture. So far, we have already shown that 4 AMPs derived from sea bass can be applied both as preventive and therapeutics of the disease produced by NNV in sea bass fingerlings. 5. Study of the impact of emerging contaminants on the antiviral immune response. We have evaluated the possible effect that some contaminants, mainly nanoplastics, may have on the immune response of fish and their resistance to NNV infections. Conclusions. In short, our group aims to investigate the fish health status and well-being with interests for the aquaculture sector. We mainly focus on the prevention and improvement of the resistance against nodavirus infections. To this end, we have generated various very interesting biotechnological tools that are exploited through material transfer agreements with research centers and companies, which clearly and decisively adhere to the objectives of the ThinkInAzul programFunding. MCIN/AEI/10.13039/501100011033 (PID2019-105522GB-I00 to A.C.), FPI contract (PRE2020-093771 a L.C.), Juan de la Cierva-Incorporación contract (IJC2020-042733-I a Y.V. y JC2019-040510-I a C.G-F.), OWI TWO (cofunded by EMFF and IEO-CSIC), and the program ThinkInAzul (PRTR-C17.I1 to M.A.E. and E.C-P.)