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Background The intestinal microbiota is altered in patients with atopic dermatitis (AD) when compared with those of the healthy population. Some interventions with specific probiotic preparations already demonstrate a change in composition of this microbiota accompanied by improvement in the disease. Objectives This research work was designed to evaluate clinical efficacy of the probiotic preparation, and to measure the effect of the intervention on the total dose of corticosteroids administered to subjects. Methods This double-blind, randomized, placebo-controlled clinical trial including 70 participants with AD aged 4–17 years was designed to evaluate the clinical effect, compared with placebo, of a probiotic mixture of Bifidobacterium lactis, Bifidobacterium longum and Lactobacillus casei at a total daily consumption of 1 × 109 colony-forming units per capsule, over 12 weeks. After randomization and exclusion, 35 patients were allocated to probiotic and 35 to placebo. Clinical variables analysed were SCORAD (SCORing of Atopic Dermatitis) and Investigator Global Assessment (IGA) indices; effect on the amount of topical corticosteroids used; and assessment of safety. Results Mean SCORAD index at 12 weeks showed a statistically significant difference of −5.43 (95% confidence interval −10.65 to −0.21) between probiotic (SCORAD 13.52) and placebo groups (SCORAD 18.96); P = 0.04. Comparison between groups showed a statistically significant difference in the number of patients with IGA score improvement over the 12-week intervention: 29 of 32 (90.5%) in the probiotic group vs. 17 of 30 (56.7%) in the placebo group (P < 0.002). A comparison between groups of the proportions of days using corticosteroids and the total dose (g) of corticosteroids between baseline and end of study showed no significant difference, but between weeks 6 and 12 there was a statistically significant reduction in the probiotic group when compared with the placebo group in both variables. Numbers of adverse events were similar in both groups of treatment. Conclusions The probiotic mix used in this clinical trial demonstrated efficacy on the change in activity index of AD compared with placebo. Furthermore, the total number of days and total amount of topical corticosteroids required by participants in the probiotic group showed a significant reduction compared with placebo between 6 and 12 weeks.

SUMMARYThe currently expanding monkeypox epidemic is caused by a subclade IIb descendant of a monkeypox virus (MPXV) lineage traced back to Nigeria in 1971. In contrast to monkeypox cases caused by clade I and subclade IIa MPXV, the prognosis of current cases is generally favorable, but person-to-person transmission is much more efficient. MPXV evolution is driven by selective pressure from hosts and loss of virus–host interacting genes. However, there is no satisfactory genetic explanation using single-nucleotide polymorphisms (SNPs) for the observed increased MPXV transmissibility. We hypothesized that key genomic changes may occur in the genome’s low-complexity regions (LCRs), which are highly challenging to sequence and have been dismissed as uninformative. Using a combination of highly sensitive techniques, we determined a first high-quality MPXV genome sequence of a representative of the current epidemic with LCRs resolved at unprecedented accuracy. This effort revealed significant variation in short-tandem repeats within LCRs. We demonstrate that LCR entropy in the MPXV genome is significantly higher than that of SNPs and that LCRs are not randomly distributed.In silicoanalyses indicate that expression, translation, stability, or function of MPXV orthologous poxvirus genes (OPGs) 153, 204, and 208 could be affected in a manner consistent with the established “genomic accordion” evolutionary strategies of orthopoxviruses. Consequently, we posit that genomic studies focusing on phenotypic MPXV clade-/subclade-/lineage-/strain differences should change their focus to the study of LCR variability instead of SNP variability.

Propósito: La presente investigación tuvo como objetivo proponer un modelo de planta para la elaboración de Pisco de forma artesanal con estándares de calidad e inocuidad que la normatividad peruana y el mercado internacional exigen. Diseño/metodología/enfoque: La metodología que se utilizó es la exploratoria descriptiva y se inicia con la elaboración de los diagramas de operación y procesos, análisis de los procesos y sus respectivas actividades, desde la recepción de la materia prima hasta el embarque del producto terminado; con énfasis en los puntos de control fisicoquímico e inocuidad. Como parte de las herramientas del modelo se utilizó el diagrama de Muther a fin de establecer la relación entre procesos y actividades. Resultados: Con los resultados obtenidos se elabora la propuesta de plano general de la planta. Para su mejor comprensión del diseño de la planta se elaboran en primer lugar un plano en 2D utilizando el Microsoft Visio profesional 2016 el plano general de la planta y con ayuda del SketchUp se hace el diseño en 3D para obtener una perspectiva general de todo el proceso productivo y poder elaborar una maqueta en detalle. Conclusiones: Se puede una herramienta de fácil aplicación para pequeños y medianos productores de Pisco y de esta manera obtener la certificación denominación de origen.

OpenAPI has become a dominant standard for documentation in the service-oriented software industry. OpenAPI is used in many analysis and reengineering approaches for RESTful service and microservice-based systems. An OpenAPI document has several components that are usually filled by humans using natural language (e.g. description of a certain functionality). Thus, subjectivity may lead to inconsistencies and ambiguities. Understanding what an API does is a challenging question. As a consequence, this issue could hinder developers from identifying the functionality of APIs, after reading all its components. Along this line, we argue that developers will be provided with supportive tools to find those APIs that better suit their needs. In this paper, we propose a step towards creating these kinds of tools by empirically analyzing a set of 2 000 OpenAPI documents with the goal of extracting the main topics of an API using three topic modeling algorithms. To address this issue, we focus on three tasks: i) determine which component of an OpenAPI document provides the most meaningful information, ii) compare three state-of-the-art topic modeling algorithms, and iii) determine the optimal number of topics to represent an API. Our findings show that the best results could be obtained from the Description component by using the Non-negative Matrix Factorization (NMF) or Latent Semantic Indexing (LSI) algorithms. To help developers find services in the OpenAPI directory, we also propose a prototype tool to explore the OpenAPI documents and analyze extracted topics to assess if the APIs meet developers needs.

International audience; Cross-site Scripting (XSS) is one of the most common and impactful software vulnerabilities (ranked second in the CWE 's top 25 in 2021). Several approaches have focused on automatically detecting software vulnerabilities through machine learning models. To build a model, it is necessary to have a dataset of vulnerable and non-vulnerable examples and to represent the source code in a computer understandable way. In this work, we explore the impact of predicting XSS using representations based on single-tier and multi-tier languages. We built 144 models trained on Javascript-based multitier code -i.e. which includes server code and HTML, Javascript and CSS as client code - and 144 models trained on single-tier code, which include server code and client-side code as text. Despite the lower precision, our results show a better recall with a multitier language than a single-tier language, implying an insignificant impact on XSS detectors based on deep learning.; Le Cross-site Scripting (XSS) est l'une des vulnérabilités logicielles les plus courantes et les plus percutantes (classé deuxième dans le top 25 du CWE en 2021). Plusieurs approches se sont concentrées sur la détection automatique des vulnérabilités logicielles via des modèles d'apprentissage automatique. Pour construire un modèle, il est nécessaire de disposer d'un ensemble de données d'exemples vulnérables et non vulnérables et de représenter le code source de manière compréhensible par ordinateur. Dans ce travail, nous explorons l'impact de la prédiction de XSS à l'aide de représentations basées sur des langages à un ou plusieurs niveaux. Nous avons construit 144 modèles formés sur du code multi-niveau basé sur Javascript - c'est-à-dire, qui inclut le code serveur et HTML, Javascript et CSS comme code client - et 144 modèles formés sur du code à un niveau - qui incluent le code serveur et le code côté client sous forme de texte. Malgré une faible précision, nos résultats montrent un meilleur rappel avec un langage multi-niveaux qu'avec un langage mono-niveau, impliquant un impact insignifiant sur les détecteurs XSS basés sur l'apprentissage en profondeur.

One of the key aspects of photodynamic therapy is the light source that is used to irradiate the lesion to be treated. The devices used must ensure that their emission spectrum matches the absorption spectrum of the photosensitizer, so that treatment radiation is delivered only on the target area, without irradiating healthy tissue at superficial or deep levels. Irradiance values must be adequate in order to avoid thermal damage, exceed the oxygen replenishment rate and avoid long treatment times. Furthermore, the device should be user-friendly, inexpensive, and able to be adapted to different photosensitizers. We have developed an easy-to-use and highly customizable device based on LED technology. Its innovative geometric design allows radiation to be delivered to a small treatment surface, since the LEDs are arranged in three arms, the configuration of which directs their radiation on the treatment point. Different high-power color LEDs are disposed on the arms, and can be independently selected based on the most effective wavelengths for exciting the different photodynamic therapy photosensitizers. We have tested the prototype in 5 different patients (1 actinic keratose, 1 actinic cheilitis, 1 superficial basal cell carcinoma and 2 Bowen's disease) and after 1-2 sessions of total cumulative dose of 25-50 J / cm2, 100% clearance of lesions were obtained. Our device can be used by any professional in the field, whether for medical or research purposes. It facilitates the development of treatment protocols and trials with different photosensitizers.

The phosphatidylinositol-3-kinase (PI3K)/AKT pathway is a major regulator of metabolism, migration, survival, proliferation, and antiviral immunity. Both an overactivation and an inhibition of the PI3K/AKT pathway are related to different pathologies. Activation of this signaling pathway is tightly controlled through a multistep process and its deregulation can be associated with aberrant post-translational modifications including SUMOylation. Here, we review the complex modulation of the PI3K/AKT pathway by SUMOylation and we discuss its putative involvement in human disease.

Cross-site Scripting (XSS) is ranked first in the top 25 Most Dangerous Software Weaknesses (2020) of Common Weakness Enumeration (CWE) and places this vulnerability as the most dangerous among programming errors. In this work, we explore static approaches to detect XSS vulnerabilities using neural networks. We compare two different code representations based on Natural Language Processing (NLP) and Programming Language Processing (PLP) and experiment with models based on different neural network architectures for static analysis detection in PHP and Node.js. We train and evaluate the models using synthetic databases. Using the generated PHP and Node.js databases, we compare our results with a well-known static analyzer for PHP code, ProgPilot, and a known scanner for Node.js, AppScan static mode. Our analyzers using neural networks overcome the results of existing tools in all cases., Cross-site Scripting (XSS) est classé au premier rang des 25 faiblesses logicielles les plus dangereuses (2020) de Common Weakness Enumeration (CWE) et place cette vulnérabilité comme la plus dangereuse parmi les erreurs de programmation. Dans ce travail, nous explorons des approches statiques pour détecter les vulnérabilités XSS à l'aide de réseaux de neurones. Nous comparons deux représentations de code différentes basées sur le traitement du langage naturel (NLP) et le traitement du langage de programmation (PLP) et nous expérimentons des modèles basés sur différentes architectures de réseaux neuronaux pour la détection d'analyse statique en PHP et Node.js. Nous formons et évaluons les modèles à l'aide de bases de données synthétiques. En utilisant les bases de données PHP et Node.js générées, nous comparons nos résultats avec un analyseur statique connu pour le code PHP, nommé Progpilot, et le mode statique d'un scanner connu pour Node.js, AppScan. Dans tous les cas, nos analyseurs utilisant des réseaux de neurones surpassent les résultats des outils existants.

Background and objectives Understanding the origin and referral routes of patients seen in teledermatology and in-person dermatology consultations in Spain is of interest from the perspective of health care management. The objective of this study was to describe the referral routes and the frequency and characteristics of teledermatology consultations in Spain. Material and methods We performed a descriptive cross-sectional study of data collected over 6 days from the DIADERM study sample, which included the outpatients diagnosed by 80 Spanish dermatologists, selected by means of stratified random sampling. We studied the source and destination of patients based on funding, type of consultation, and age of the patients. We reported the frequency of teledermatology consultations, their origin and destination, type of funding, age of the patients, and most common diagnoses, and compared them with the same characteristics for in-person consultations. Results In private consultations, most patients were direct clients, whereas the most frequent source in public consultations was primary care and the dermatologist. Sixty-six percent of patients were referred to dermatology and 27% were discharged. No differences in these percentages were found between public and private consultations. The ratio of follow-up to initial visits was 0.8 for public consultations and 0.2 for private consultations. Teledermatology accounts for 1% of consultations. Eighty percent of these come from primary care and 17% are direct visits. Thirty-three percent of these visits are referred to primary care —a greater proportion than in in-person consultations. Galicia, Andalusia, and Catalonia are the regions with the highest percentage of consultations. Conclusions The results suggest that dermatologists in Spain have a considerable ability to resolve cases. Teledermatology accounts for a small percentage of consultations and access to these consultations is direct in a large percentage of cases.

Resumen Antecedentes y objetivos El conocimiento de las rutas de origen y derivacion de los pacientes atendidos en consulta dermatologica presencial y de teledermatologia en Espana tiene interes desde el punto de vista de la gestion sanitaria. El objetivo de este estudio es describir las rutas de derivacion y la frecuencia y caracteristicas de la teledermatologia en Espana. Material y metodos Estudio transversal descriptivo sobre la muestra del estudio DIADERM, que recogio la actividad de 80 dermatologos espanoles, seleccionados mediante muestreo aleatorio estratificado, durante 6 dias. Se estudiaron el origen y destino de los pacientes en funcion de la financiacion, el tipo de consulta y la edad de los pacientes. Se describio la frecuencia de las consultas por teledermatologia, su origen y destino, el tipo de financiacion, la edad de los pacientes y los diagnosticos mas frecuentes, comparandolos con la consulta presencial. Resultados El origen mas frecuente en la consulta privada es el directo, mientras que en la publica es la atencion primaria y el propio dermatologo. Un 66% de los pacientes se derivan a dermatologia y un 27% son dados de alta. No existen diferencias en estos porcentajes entre consulta publica y privada. El indice sucesivas/primeras fue de 0,8 para la consulta publica y de 0,2 para la privada. La teledermatologia representa un 1% de las consultas. El 80% procede de atencion primaria y el 17% tiene origen directo. Se deriva a atencion primaria el 33%, en mayor proporcion que en consulta presencial. Galicia, Andalucia y Cataluna son las regiones donde representa un mayor porcentaje de consultas. Conclusiones Los resultados sugieren una alta capacidad resolutiva de las consultas de dermatologia en Espana. La teledermatologia representa un porcentaje pequeno de las consultas, y el acceso a ella se da en un porcentaje relevante de pacientes por via directa.

Context: A common practice in JavaScript development is to ship and deploy an application as a large file, called bundle, which is the result of combining the application code along with the code of all the libraries the application depends on. Despite the benefits of having a single bundle per application, this approach leads to applications being shipped with significant portions of code that are actually not used, which unnecessarily inflates the JavaScript bundles and could slow down website loading because of the extra unused code. Although some static analysis techniques exist for removing unused code, our investigations suggest that there is still room for improvements. Objective: The goal of this paper is to address the problem of reducing the size of bundle files in JavaScript applications. Method: In this context, we define the notion of Unused Foreign Function (UFF) to denote a JavaScript function contained in dependent libraries that is not needed at runtime. Furthermore, we propose an approach based on dynamic analysis that assists developers to identify and remove UFFs from JavaScript bundles. Results: We report on a case-study performed over 22 JavaScript applications, showing evidence that our approach can produce size reductions of 26% on average (with reductions going up to 66% in some applications). Conclusion: It is concluded that removing unused foreign functions from JavaScript bundles helps reduce their size, and thus, it can boost the results of existing static analysis techniques. Fil: Vázquez, Hernán Ceferino. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina Fil: Bergel, Alexandre. Universidad de Chile; Chile Fil: Vidal, Santiago Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina Fil: Diaz Pace, Jorge Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina Fil: Marcos, Claudia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina

Ebola virus (EBOV) VP24 protein is a nucleocapsid-associated protein that inhibits interferon (IFN) gene expression and counteracts the IFN-mediated antiviral response, preventing nuclear import of signal transducer and activator of transcription 1 (STAT1). Proteomic studies to identify additional EBOV VP24 partners have pointed to the nuclear membrane component emerin as a potential element of the VP24 cellular interactome. Here, we have further studied this interaction and its impact on cell biology. We demonstrate that VP24 interacts with emerin but also with other components of the inner nuclear membrane, such as lamin A/C and lamin B. We also show that VP24 diminishes the interaction between emerin and lamin A/C and compromises the integrity of the nuclear membrane. This disruption is associated with nuclear morphological abnormalities, activation of a DNA damage response, the phosphorylation of extracellular signal-regulated kinase (ERK), and the induction of interferon-stimulated gene 15 (ISG15). Interestingly, expression of VP24 also promoted the cytoplasmic translocation and downmodulation of barrier-to-autointegration factor (BAF), a common interactor of lamin A/C and emerin, leading to repression of the BAF-regulated CSF1 gene. Importantly, we found that EBOV infection results in the activation of pathways associated with nuclear envelope damage, consistent with our observations in cells expressing VP24. In summary, here we demonstrate that VP24 acts at the nuclear membrane, causing morphological and functional changes in cells that recapitulate several of the hallmarks of laminopathy diseases. IMPORTANCE The Ebola virus (EBOV) VP24 protein is a nucleocapsid-associated protein with multiple functions. Proteomic studies have identified the cellular nuclear membrane component emerin as a potential VP24 interactor. Here, we demonstrate that VP24 not only interacts with emerin but also with lamin A/C and lamin B, prompting nuclear membrane disruption. This disruption is associated with nuclear morphological abnormalities, activation of a DNA damage response, the phosphorylation of extracellular signal-regulated kinase (ERK), and the induction of interferon-stimulated gene 15 (ISG15). Interestingly, VP24 also promotes the cytoplasmic translocation and downmodulation of barrier-to-autointegration factor (BAF), leading to repression of the BAF-regulated CSF1 gene. Finally, we show that EBOV infection also results in the activation of pathways associated with nuclear envelope damage, consistent with our observations in cells expressing VP24. These results reveal novel activities of EBOV VP24 protein, resulting in a cell phenotype similar to that of most laminopathies, with potential impact on EBOV replication.

Class I PI3K are heterodimers composed of a p85 regulatory subunit and a p110 catalytic subunit involved in multiple cellular functions. Recently, the catalytic subunit p110β has emerged as a class I PI3K isoform playing a major role in tumorigenesis. Understanding its regulation is crucial for the control of the PI3K pathway in p110β-driven cancers. Here we sought to evaluate the putative regulation of p110β by SUMO. Our data show that p110β can be modified by SUMO1 and SUMO2 in vitro, in transfected cells and under completely endogenous conditions, supporting the physiological relevance of p110β SUMOylation. We identify lysine residue 952, located at the activation loop of p110β, as essential for SUMOylation. SUMOylation of p110β stabilizes the protein increasing its activation of AKT which promotes cell growth and oncogenic transformation. Finally, we show that the regulatory subunit p85β counteracts the conjugation of SUMO to p110β. In summary, our data reveal that SUMO is a novel p110β interacting partner with a positive effect on the activation of the PI3K pathway., Funding at the laboratory of CR is provided by Ministry of Science, Innovation and Universities and FEDER (BFU-2017–88,880-P) and Xunta de Galicia (ED431G 2019/02). SV and RS are predoctoral fellows funded by Xunta de Galicia-Consellería de Cultura, Educación y Ordenación Universitaria (ED481A-2018/110 and ED481A-2020/160, respectively)

[EN] Higher education is continuously evolving to keep up with the challenges posed by the introduction of information and communication technologies (ICT) to education. In this sense, distance learning is booming, with an increasing number of higher education students taking advantage of the flexibility remote learning provides. The School of Agricultural Engineering and Environment (ETSIAMN) of Universitat Politècnica de València (UPV) has been gradually incorporating ICT tools in its bachelor and master degrees for the last two decades. As a result, many college students and university instructors are familiar with ICT techniques. However, the unprecedented COVID-19 crisis has put distance learning in the spotlight like never before, forcing students, faculty, and staff to adapt to the new situation with hardly any preparation time. For that reason, it is convenient to analyse in depth the results and impact of the teaching and evaluation methodologies developed and applied during this critical period, as a way to detect and amend potential inefficiencies in the learning process. The specific goal of this study was to analyse the teaching period during the COVID-19 crisis in ETSIAMN, which covered the spring semester of the academic year 2019-2020. To this purpose, 114 instructors and 274 students were surveyed in July 2020, belonging to four bachelor degrees (agricultural and biological engineering; forestry engineering; food engineering; and biotechnology), and three master degrees (agricultural and biological engineering; forestry engineering, and oenology). Regarding the experimental design for the survey, three main blocks were identified: the first block corresponds to teaching methodologies, comparing students and faculty preferences for distance lecturing; the second block focuses on evaluation modalities and exam configurations; and the final block centers on the difficulties found by both students and lecturers along the adaptation process from conventional to distance teaching. Results showed that instructors and students preferred a combination of live streaming with recorded lectures, being multiple choice the favourite examination type, although many students rated first a project-based evaluation. Overall, students rejected tests with no possibilities to go back on already answered questions, and instructors mostly preferred limiting the time to complete the on-line tests. The lack of motivation was the main barrier encountered by students to achieve an effective learning. Finally, a set of counterweighting measures to improve and promote the successful implementation of distance learning in engineering colleges is proposed.

To characterize the building blocks of a legacy software system (e.g., structure, dependencies), programmers usually spend a long time navigating its source code. Yet, modern integrated development environments (IDEs) do not provide appropriate means to efficiently achieve complex software comprehension tasks. To deal with this unfulfilled need, we present Hunter, a tool for the visualization of JavaScript applications. Hunter visualizes source code through a set of coordinated views that include a node-link diagram that depicts the dependencies among the components of a system, and a treemap that helps programmers to orientate when navigating its structure. In this paper, we report on a controlled experiment that evaluates Hunter. We asked 16 participants to solve a set of software comprehension tasks, and assessed their effectiveness in terms of (i) user performance (i.e., completion time, accuracy, and attention), and (ii) user experience (i.e., emotions, usability). We found that when using Hunter programmers required significantly less time to complete various software comprehension tasks and achieved a significantly higher accuracy. We also found that the node-link diagram panel of Hunter gets most of the attention of programmers, whereas the source code panel does so in Visual Studio Code. Moreover, programmers considered that Hunter exhibits a good user experience.

SUMO is a ubiquitin-like protein that covalently binds to lysine residues of target proteins and regulates many biological processes such as protein subcellular localization or stability, transcription, DNA repair, innate immunity, or antiviral defense. SUMO has a critical role in the signaling pathway governing type I interferon (IFN) production, and among the SUMOylation substrates are many IFN-induced proteins. The overall effect of IFN is increasing global SUMOylation, pointing to SUMO as part of the antiviral stress response. Viral agents have developed different mechanisms to counteract the antiviral activities exerted by SUMO, and some viruses have evolved to exploit the host SUMOylation machinery to modify their own proteins. The exploitation of SUMO has been mainly linked to nuclear replicating viruses due to the predominant nuclear localization of SUMO proteins and enzymes involved in SUMOylation. However, SUMOylation of numerous viral proteins encoded by RNA viruses replicating at the cytoplasm has been lately described. Whether nuclear localization of these viral proteins is required for their SUMOylation is unclear. Here, we summarize the studies on exploitation of SUMOylation by cytoplasmic RNA viruses and discuss about the requirement for nuclear localization of their proteins.

Some viruses take advantage of conjugation of ubiquitin or ubiquitin-like proteins to enhance their own replication. One example is Ebola virus, which has evolved strategies to utilize these modification pathways to regulate the viral proteins VP40 and VP35 and to counteract the host defenses. Here, we show a novel mechanism by which Ebola virus exploits the ubiquitin and SUMO pathways. Our data reveal that minor matrix protein VP24 of Ebola virus is a bona fide SUMO target. Analysis of a SUMOylation-defective VP24 mutant revealed a reduced ability to block the type I interferon (IFN) pathway and to inhibit IFN-mediated STAT1 nuclear translocation, exhibiting a weaker interaction with karyopherin 5 and significantly diminished stability. Using glutathione S-transferase (GST) pulldown assay, we found that VP24 also interacts with SUMO in a noncovalent manner through a SIM domain. Mutation of the SIM domain in VP24 resulted in a complete inability of the protein to downmodulate the IFN pathway and in the monoubiquitination of the protein. We identified SUMO deubiquitinating enzyme ubiquitin-specific-processing protease 7 (USP7) as an interactor and a negative modulator of VP24 ubiquitination. Finally, we show that mutation of one ubiquitination site in VP24 potentiates the IFN modulatory activity of the viral protein and its ability to block IFN-mediated STAT1 nuclear translocation, pointing to the ubiquitination of VP24 as a negative modulator of the VP24 activity. Altogether, these results indicate that SUMO interacts with VP24 and promotes its USP7-mediated deubiquitination, playing a key role in the interference with the innate immune response mediated by the viral protein.IMPORTANCE The Ebola virus VP24 protein plays a critical role in escape of the virus from the host innate immune response. Therefore, deciphering the molecular mechanisms modulating VP24 activity may be useful to identify potential targets amenable to therapeutics. Here, we identify the cellular proteins USP7, SUMO, and ubiquitin as novel interactors and regulators of VP24. These interactions may represent novel potential targets to design new antivirals with the ability to modulate Ebola virus replication., Funding at the laboratory of C.R. is provided by Ministry of Science, Innovation and Universities and FEDER (BFU-2017-88880-P). C.R. also acknowledges grants GRC GI-2119 (Xunta de Galicia) and SAF2017-90900-REDT (UBIRed Program). S.V. is a predoctoral fellow funded by Xunta de Galicia. M.B.-M. is a postdoctoral fellow funded by Xunta de Galicia (Consellería de Cultura, Educación e Ordenación Universitaria). A.E.M. is the recipient of a fellowship of the Spanish FPI program. This work was partially funded by the German Center for Infection Research (DZIF TTU 01.702_00 to C.M.-F.). R.B. and J.D.S. acknowledge grants BFU2017-84653-P (MINECO/FEDER, EU), SEV-2016-0644 (Severo Ochoa Excellence Program), 765445-EU (UbiCODE Program), and SAF2017- 90900-REDT (UBIRed Program). C.S.M. acknowledges grant BFU2016-74868-P.

Code smells are a popular mechanism for identifying structural design problems in software systems. Several tools have emerged to support the detection of code smells and propose some refactorings. However, existing tools do not guarantee that a smell will be automatically fixed by means of refactorings. This article presents Bandago, an automated approach to fix a specific type of code smell called Brain Method. A Brain Method centralizes the intelligence of a class and manifests itself as a long and complex method that is difficult to understand and maintain by developers. For each Brain Method, Bandago recommends several refactoring solutions to remove the smell using a search strategy based on simulated annealing. Our approach has been evaluated with several open-source Java applications, and the results show that Bandago can automatically fix more than 60% of Brain Methods. Furthermore, we conducted a survey with 35 industrial developers that showed evidence about the usefulness of the refactorings proposed by Bandago. Also, we compared the performance of the Bandago against that of a third-party refactoring tool. Fil: Vidal, Santiago Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina Fil: Berra, Iñaki. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Exactas; Argentina Fil: Zuliani Held, Santiago. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Exactas; Argentina Fil: Marcos, Claudia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina Fil: Diaz Pace, Jorge Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina

A code smell is a symptom in the source code that helps to identify a design problem. Several tools for detecting and ranking code smells according to their criticality to the system have been developed. However, existing works assume a centralized development approach, which does not consider systems being developed in a distributed fashion. The main problem in a distributed group of developers is that a tool cannot always ensure a global vision of (smells of) the system, and thus inconsistencies among the rankings provided by each developer are likely to happen. These inconsistencies often cause unnecessary refactorings and might not focus the whole team on the critical smells system-wide. Along this line, this work proposes a multi-agent tool, called D-JSpIRIT, which helps individual developers to reach a consensus on their smell rankings by means of distributed optimization techniques. Fil: Vázquez, Hernán Ceferino. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina Fil: Marcos, Claudia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina Fil: Vidal, Santiago Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina Fil: Diaz Pace, Jorge Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina

Java access modifiers regulate interactions among software components. In particular, class modifiers specify which classes from a component are publicly exposed and therefore belong to the component public interface. Restricting the accessibility as specified by a programmer is key to ensure a proper software modularity. It has been said that failing to do so is likely to produce maintenance problems, poor system quality, and architecture decay. However, how developers uses class access modifiers or how inadequate access modifiers affect software systems has not been investigated yet in the literature. In this work, we empirically analyze the use of class access modifiers across a collection of 15 Java libraries and 15 applications, totaling over 3.6M lines of code. We have found that an average of 25% of classes are over-exposed, i.e., classes defined with an accessibility that is broader than necessary. A number of code patterns involving over-exposed classes have been formalized, characterizing programmers' habits. Furthermore, we propose an Eclipse plugin to make component public interfaces match with the programmer's intent. Fil: Vidal, Santiago Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina Fil: Bergel, Alexandre. Universidad de Chile; Chile Fil: Diaz Pace, Jorge Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina Fil: Marcos, Claudia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Exactas; Argentina

Code smells are symptoms in the source code that could help to identify architectural problems. However, developers may feel discouraged to analyze multiple smells if they are not able to focus their attention on a small set of source code locations. Unfortunately, current techniques fall short in assisting developers to prioritize smelly locations that are likely to indicate architectural problems. Furthermore, developers often have trouble analyzing interconnected smells that contribute together to realize an architectural problem. To deal with these issues, this work presents and evaluates a suite of five criteria for ranking groups of code smells as indicators of architectural problems in evolving systems. These criteria were implemented in a tool called JSpIRIT. In a first experiment, we have assessed the criteria in the context of 23 versions of 4 systems and analyzed their effectiveness for revealing architectural problem locations. In addition, we conducted a second experiment for analyzing similarities between the prioritization provided by developers and the prioritization provided by our best performing criterion. The results provide evidence that one of the proposed criteria helped to correctly prioritize more than 80 code locations of architectural problems, alleviating tedious manual inspection of the source code vis-a-vis with the architecture. Fil: Vidal, Santiago Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina Fil: Oizumi, Willian. Pontifícia Universidade Católica do Rio de Janeiro; Brasil Fil: Garcia, Alessandro. Pontifícia Universidade Católica do Rio de Janeiro; Brasil Fil: Diaz Pace, Jorge Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina Fil: Marcos, Claudia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina

The ribosomal protein L11 (RPL11) integrates different types of stress into a p53-mediated response. Here, we analyzed the impact of the ubiquitin-like protein SUMO on the RPL11-mouse double-minute 2 homolog-p53 signaling. We show that small ubiquitin-related modifier (SUMO)1 and SUMO2 covalently modify RPL11. We find that SUMO negatively modulates the conjugation of the ubiquitin-like protein neural precursor cell-expressed developmentally downregulated 8 (NEDD8) to RPL11 and promotes the translocation of the RP outside of the nucleoli. Moreover, the SUMO-conjugating enzyme, Ubc9, is required for RPL11-mediated activation of p53. SUMOylation of RPL11 is triggered by ribosomal stress, as well as by alternate reading frame protein upregulation. Collectively, our data identify SUMO protein conjugation to RPL11 as a new regulator of the p53-mediated cellular response to different types of stress and reveal a previously unknown SUMO-NEDD8 interplay.-El Motiam, A, Vidal, S., de la Cruz-Herrera, C. F., Da Silva-Álvarez, S., Baz-Martínez, M., Seoane, R., Vidal, A., Rodríguez, M. S., Xirodimas, D. P., Carvalho, A. S., Beck, H. C., Matthiesen, R., Collado, M., Rivas, C. Interplay between SUMOylation and NEDDylation regulates RPL11 localization and function.

Las universidades españolas están trabajando para que sus egresados posean competencias transversales, altamente demandadas hoy en día para comenzar su vida laboral, cuando concluyan sus estudios de grado. Pero, para que el alumnado esté formado en tales competencias, hay que trabajarlas. En el presente artículo se presenta la acción que se ha realizado con las TIC, en concreto un blog, dentro de la asignatura Estadística, en el que los estudiantes trabajan diferentes competencias transversales. A partir de un blog colaborativo (son autores tanto la profesora como sus alumnos y alumnas que así lo desean), creado para divulgar aplicaciones prácticas de la materia que se estudia, se ha llegado a un entorno en el que se desarrollan diferentes competencias transversales.

[EN] A comparison among widely used multivariate latent variable-based techniques for supervised process fault diagnosis was carried out. In order to assess their overall performance several diagnosis criteria were proposed (C-1: most suspected fault assignment; C-2: threshold-based fault assignment). Additionally, it was evaluated i) how the size of the training set used to build the latent variable models affected the diagnosis ability of the methods under study, ii) how they behaved under new types of failures not included in the original list of fault candidates and iii) which of them were more suitable for either early or late diagnosis. To accomplish all these objectives, the approaches were tested in different scenarios. Two datasets were analysed: the first was generated by a Simulink-based model of a binary distillation column, while the second relates to a pasteurisation process performed in a laboratory-scale plant., This research work was partially supported by the Spanish Ministry of Economy and Competitiveness under the project DPI2017-82896-C2-1-R and Shell Global Solutions International B.V. (Amsterdam, The Netherlands).

[EN] In this work we propose the use of different educational gaming strategies as a tool for learning and working the different generic skills competences. These methodologies have been applied in several statistics subjects delivered in different engineering degrees at the Universitat Politècnica de València (UPV). In order to design the different innovation activities we have chosed the game-based platform Kahoot! based on his straightforward and versatile use. The activities developed by the authors allow to improve the students assistance, the autonomus learning of the students and generic skills development, [ES] En el trabajo se aborda la utilización de las estrategias de juego como herramientas de aprendizaje y de trabajo de competencias en varias asignaturas de Estadística impartidas en diferentes Grados de Ingeniería de la Universitat Politècnica de València (UPV). Para el diseño de las actividades de innovación propuestas se ha utilizado la plataforma Kahoot!, por su sencillez y versatilidad de uso. Estas actividades desarrolladas por los autores permiten establecer diferentes dinámicas de trabajo de los alumnos, motivar la asistencia y el trabajo autónomo de los estudiantes, así como desarrollar diferentes competencias.

Os acidentes com motos têm sido bastante expressivos em nossa sociedade e gerado graves consequências aos cofres públicos, em virtude do elevado índice de morbimortalidade e motivo de preocupação na saúde pública. Este fenômeno é atribuído a diversos fatores devido a sua vulnerabilidade, deixando as vítimas mais expostas a diversos agravos, entretanto, a maioria necessita de um atendimento de urgência e emergência fora do âmbito hospitalar, contribuindo para a crescente demanda de serviços prestados pelo SAMU. Diante desta realidade, percebemos que o Estado deve implantar mais políticas públicas e fortalecer as existentes com o propósito de reduzir esses acidentes. Este estudo aborda os acidentes de motos e a política de saúde no Município de Fortaleza, entre o período de agosto/2012 a julho/2013. O objetivo central é investigar como vem sendo prestados os atendimentos às vítimas de acidentes de moto pelo SAMU e que significado esses atendimentos trazem para a sociedade. A metodologia utilizada foi de caráter empírico; análise documental e bibliográfica; O escopo da pesquisa foi de 10.319 atendimentos prestados pelo SAMU durante um ano e foram consideradas as seguintes variáveis referentes aos atendimentos: idade, sexo, tipo de acidente, horário da ocorrência, dia da semana e a regional. Os dados foram analisados em bases estatísticas e os resultados foram discutidos de acordo com as referências utilizadas. Considerando os resultados desta pesquisa, identificamos a magnitude do problema e a importância do APH, realizado pelo SAMU que presta uma assistência qualificada, visando reduzir os agravos à saúde.

Code smells are a popular mechanism to find structural design problems in software systems. Consequently, several tools have emerged to support the detection of code smells. However, the number of smells returned by current tools usually exceeds the amount of problems that the developer can deal with, particularly when the effort available for performing refactorings is limited. Moreover, not all the code smells are equally relevant to the goals of the system or its health. This article presents a semi-automated approach that helps developers focus on the most critical problems of the system. We have developed a tool that suggests a ranking of code smells, based on a combination of three criteria, namely: past component modifications, important modifiability scenarios for the system, and relevance of the kind of smell. These criteria are complementary and enable our approach to assess the smells from different perspectives. Our approach has been evaluated in two case-studies, and the results show that the suggested code smells are useful to developers. Fil: Vidal, Santiago Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina Fil: Marcos, Claudia Andrea. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Exactas. Instituto de Sistemas Tandil; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina Fil: Diaz Pace, Jorge Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Instituto Superior de Ingeniería del Software. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto Superior de Ingeniería del Software; Argentina

Activated dsRNA-dependent serine/threonine kinase PKR phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2α), resulting in a shut-off of general translation, induction of apoptosis, and inhibition of virus replication. PKR can be activated by binding to dsRNA or cellular proteins such as PACT/RAX, or by its conjugation to ISG15 or SUMO. Here, we demonstrate that PKR also interacts with SUMO in a non-covalent manner. We identify the phosphorylable tyrosine residue 162 in PKR (Y162) as a modulator of the PKR-SUMO non-covalent interaction as well as of the PKR SUMOylation. Finally, we show that the efficient SUMO-mediated eIF2α phosphorylation and inhibition of protein synthesis induced by PKR in response to dsRNA depend on this residue. In summary, our data identify a new mechanism of regulation of PKR activity and reinforce the relevance of both, tyrosine phosphorylation and SUMO interaction in controlling the activity of PKR.