Phosphorylation and SCF-mediated degradation regulate CREB-H transcription of metabolic targets.

CREB‑H, an endoplasmic reticulum–anchored transcription factor, plays a key role in regulating secretion and in metabolic and inflammatory pathways, but how its activity is modulated remains unclear. We examined processing of the nuclear active form and identified a motif around S87–S90 with homology to DSG-type phosphodegrons. We show that this region is subject to multiple phosphorylations, which regulate CREB-H stability by targeting it to the SCF(Fbw1a) E3 ubiquitin ligase. Data from phosphatase treatment, use of phosophospecific antibody, and substitution of serine residues demonstrate phosphorylation of candidate serines in the region, with the core S87/S90 motif representing a critical determinant promoting proteasome-mediated degradation. Candidate kinases CKII and GSK-3b phosphorylate CREB-H in vitro with specificities for different serines. Prior phosphorylation with GSK-3 at one or more of the adjacent serines substantially increases S87/S90-dependent phosphorylation by CKII. In vivo expression of a dominant-negative Cul1 enhances steady-state levels of CREB‑H, an effect augmented by Fbw1a. CREB-H directly interacts with Fbw1a in a phosphorylation-dependent manner. Finally, mutations within the phosphodegron, when incorporated into the full-length protein, result in increased levels of constitutively cleaved nuclear protein and increased transcription and secretion of a key endogenous target gene, apolipoprotein A IV

A Nuclear Localization Signal in Herpesvirus Protein VP1-2 Is Essential for Infection via Capsid Routing to the Nuclear Pore

To initiate infection, herpesviruses must navigate to and transport their genomes across the nuclear pore. VP1-2 is a large structural protein of the virion that is conserved in all herpesviruses and plays multiple essential roles in virus replication, including roles in early entry. VP1-2 contains an N-terminal basic motif which functions as an efficient nuclear localization signal (NLS). In this study, we constructed a mutant HSV strain, K.VP1-2ΔNLS, which contains a 7-residue deletion of the core NLS at position 475. This mutant fails to spread in normal cells but can be propagated in complementing cell lines. Electron microscopy (EM) analysis of infection in noncomplementing cells demonstrated capsid assembly, cytoplasmic envelopment, and the formation of extracellular enveloped virions. Furthermore, extracellular virions isolated from noncomplementing cells had similar profiles and abundances of structural proteins. Virions containing VP1-2ΔNLS were able to enter and be transported within cells. However, further progress of infection was prevented, with at least a 500- to 1,000-fold reduction in the efficiency of initiating gene expression compared to that in the revertant. Ultrastructural and immunofluorescence analyses revealed that the K.VP1-2ΔNLS mutant was blocked at the microtubule organizing center or immediately upstream of nuclear pore docking and prior to gene expression. These results indicate that the VP1-2 NLS is not required for the known assembly functions of the protein but is a key requirement for the early routing to the nuclear pore that is necessary for successful infection. Given its conservation, we propose that this motif may also be critical for entry of other classes of herpesviruses

A compression-based method for detecting anomalies in textual data

Nowadays, information and communications technology systems are fundamental assets of our social and economical model, and thus they should be properly protected against the malicious activity of cybercriminals. Defence mechanisms are generally articulated around tools that trace and store information in several ways, the simplest one being the generation of plain text files coined as security logs. Such log files are usually inspected, in a semi-automatic way, by security analysts to detect events that may affect system integrity, confidentiality and availability. On this basis, we propose a parameter-free method to detect security incidents from structured text regardless its nature. We use the Normalized Compression Distance to obtain a set of features that can be used by a Support Vector Machine to classify events from a heterogeneous cybersecurity environment. In particular, we explore and validate the application of our method in four different cybersecurity domains: HTTP anomaly identification, spam detection, Domain Generation Algorithms tracking and sentiment analysis. The results obtained show the validity and flexibility of our approach in different security scenarios with a low configuration burdenThis research has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 872855 (TRESCA project), from the Comunidad de Madrid (Spain) under the projects CYNAMON (P2018/TCS-4566) and S2017/BMD-3688, co-financed with FSE and FEDER EU funds, by the Consejo Superior de Investigaciones Científicas (CSIC) under the project LINKA20216 (“Advancing in cybersecurity technologies”, i-LINK+ program), and by Spanish project MINECO/FEDER TIN2017-84452-

The C-terminal domain of the pVP2 precursor is essential for the interaction between VP2 and VP3, the capsid polypeptides of infectious bursal disease virus

AbstractThe interaction between the infectious bursal disease virus (IBDV) capsid proteins VP2 and VP3 has been analyzed in vivo using baculovirus expression vectors. Data presented here demonstrate that the 71-amino acid C-terminal-specific domain of pVP2, the VP2 precursor, is essential for the establishment of the VP2–VP3 interaction. Additionally, we show that coexpression of the pVP2 and VP3 polypeptides from independent genes results in the assembly of virus-like particles (VLPs). This observation demonstrates that these two polypeptides contain the minimal information required for capsid assembly, and that this process does not require the presence of the precursor polyprotein

La escuela 2.0: la percepción del docente en torno a su eficacia en los centros educativos de la Rioja.

En este artículo se presentan los resultados más relevantes de una investigación centrada en el análisis del Programa Escuela 2.0 en los centros educativos de La Rioja. Entre otros objetivos, se pretende conocer qué recursos de la Escuela 2.0 se utilizan con mayor frecuencia en la realidad educativa investigada, cual es su sentido en los procesos de enseñanza y aprendizaje, la percepción docente con relación a su eficacia en los procesos educativos del centro, así como la opinión del profesorado sobre su propia formación docente para una integración curricular efectiva de estos recursos en los centros donde desarrollan su práctica educativa. Para llevar a cabo la investigación se ha considerado conveniente adoptar un enfoque metodológico de carácter cuantitativo, desarrollado mediante un procedimiento de encuesta online dirigido a todo el profesorado de enseñanza no universitaria de La Rioja. A grandes rasgos, los resultados vienen a confirmar los datos obtenidos por otros autores en investigaciones similares realizadas en otros contextos educativos. En este sentido, cabría destacar la necesidad formativa sentida por el profesorado investigado con relación a los aspectos pedagógicos de las tecnologías de la información y la comunicación (en adelante TIC). No obstante, como reflexión final y prospectiva del estudio, nos inclinamos a pensar que la eficacia de los recursos de la Escuela 2.0 en los procesos educativos del centro no puede quedar supeditada simplemente a la competencia y actuación del profesor, sino también a la situación y al contexto singular donde se desarrolla la acción didáctica, así como al conocimiento y la competencia tecnológica de los propios estudiantes. Desde esta perspectiva, se abren nuevos campos de estudio que complementen, amplíen y enriquezcan este trabajo

Procedimiento para la producción en levaduras de cápsidas virales vacías compuestas por proteínas derivadas de pVP2 del virus causante de la enfermedad de la bursitis infecciosa (IBDV)

Referencia OEPM: P200401044.-- Fecha de solicitud: 30/04/2004.-- Titulares: Consejo Superior de Investigaciones Científicas (CSIC), Bionostra, S.L.Procedimiento para la producción en levaduras de cápsidas virales vacías compuestas por proteínas derivadas de pVP2 del virus causante de la enfermedad de la bursitis infecciosa (IBDV). Las cápsidas vacías del virus causante de la enfermedad de la bursitis infecciosa (IBDV) están constituidas por ensamblaje de proteínas derivadas de la proteína pVP2 de IBDV, de distinto tamaño y tienen aplicación en la producción de vacunas y en la elaboración de vectores para terapia génica.Peer reviewe

Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.

A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D

RARE-Bestpractices: a platform for sharing best practices for the management of rare diseases

From 7th European Conference on Rare Diseases and Orphan Products (ECRD 2014).Rare diseases; clinical practice guidelines; recommendations. RARE-Bestpractices (http://www.rarebestpractices.eu) is a 4-year project (2013-2016) funded by the EC FP7. The project aims at improving clinical management of patients with rare diseases (RD) and at narrowing the existing gap in quality of healthcare among countries. Methods: RARE-Bestpractices (http://www.rarebestpractices.eu) involves 9 EU countries, including 15 partners from academic institutions, governmental bodies, patient organizations and networks, which will exploit the added value of integrating different contributions and viewpoints. The platform is developed involving both experts in RD research as well as experts in clinical practice guidelines (CPG) and systematic reviews. Results: Project expected outputs include: 1) identification of challenges to be considered in deriving high quality standards for CPG on RD; 2) transparent procedures and criteria for the evaluation of CPG and their collection in a publicly searchable database; 3) identification of notation criteria to improve user understandability and implementation of CPG; 4) production of mechanisms to assess RD clinical research needs; 5) development of training activities targeted to key stakeholders to disseminate process and tools for developing and evaluating CPG; 6) the publication of a new scientific journal (http://rarejournal.org). Discussion: RARE-Bestpractices addresses the demands from both patients and health care providers for updated and high quality CPG on RD. The project will meet the requirements laid down by to the Directive 2011/24/EU, which endorses EU MS to develop European Reference Networks (ERNs) for RD; in fact, one main criterion for ERNs should be the competence to produce CPG and actively disseminate them among Centers of Expertise.N