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Background Inflammatory bowel diseases (IBD) are chronic, heterogeneous, and inflammatory conditions mainly affecting the gastrointestinal tract. Currently, endoscopy is the gold standard test for assessing mucosal activity and healing in clinical practice; however, it is a costly, time-consuming, invasive, and uncomfortable procedure for patients. There is, therefore, a need for sensitive, specific, fast and non-invasive biomarkers for the diagnosis of IBD. Methods Label-free quantification by nanoscale liquid chromatography coupled to tandem mass spectrometry (nLC MS/MS) was performed to profile the urinary and serum proteomes of 100 patients with newly diagnosed IBD, before starting any treatment [50 patients with Crohn′s disease (CD) and 50 patients with ulcerative colitis (UC)] and 50 healthy controls (HC). Data Mining and Pattern Recognition techniques were used to identify hidden relationships that are not detectable by using the classical and most commonly used lineal classifiers; and thus, identifying potential markers able to discriminate the studied cohorts. Finally, we applied Ingenuity Pathway Analysis (IPA) to analyze the pathways and functions of differentially expressed proteins. Results Serum proteomics results revealed 45 differentially expressed proteins in the comparison between UC and HC groups, 32 proteins significantly expressed in CD versus HC, and 12 proteins in CD compared with UC. In urine samples, 110 proteins were significantly changed in UC versus HC, 50 proteins were differentially expressed between CD and HC, and a total of 31 proteins were significantly changed in CD compared with UC patients. Receiver operating characteristic curve (ROC) analysis found multiple proteins with high area under the curve values, up to 0.94, indicating that these serum and urine proteins are of value as new non-invasive diagnostic classifiers of IBD patients. For each study comparative, the 5 most significant classifiers were selected (Figures 1 and 2). IPA revealed multiple signaling pathways, including prothrombin activation, acute phase response signaling, complement and coagulation system and liver X receptor/retinoid X receptor (LXR/RXR) activation, altered in IBD patients compared to HC (p-value < 0.05) (Figures 3 and 4). Conclusion Our findings indicate that analysis of the urine and serum proteome using nLC MS/MS is a feasible approach for biomarker discovery. We identified several serum and urine proteins that could serve as new non-invasive markers for the diagnosis of IBD patients after further validation. After bioinformatic analyses, we found multiple proteins that may play important roles in the pathogenesis of IBD.

Background Inflammatory bowel disease (IBD) is a complex multi-factorial disease characterized by chronic inflammation of the gastrointestinal tract. Despite significant efforts to understand the pathogenetic mechanisms of IBD, the elucidation of its etiopathology and progression is far from fully understood. The direct analysis of the intestinal tissue from the endoscopy which leads to IBD diagnosis (before starting any treatment) would be the ideal sample to elucidate IBD pathogenesis. Methods High-throughput mass-spectrometry-based quantitative proteomic analysis was performed using formalin-fixed paraffin-embedded human intestinal samples from newly diagnosed patients to elucidate the potential mechanisms responsible for gut inflammation in Crohn′s disease (CD) and ulcerative colitis (UC). For this purpose, 192 formalin-fixed paraffin-embedded samples from 40 active UC patients, 67 active CD patients and 46 normal biopsies from healthy controls (HC) were analyzed (Figure 1). Proteins with p-value < 0.05 were considered as significantly dysregulated. Moreover, we used Ingenuity Pathway Analysis (IPA) to analyze the pathways and functions in different locations of the gut (ileum or left colon) that could be related to IBD pathogenesis. Results A total of 2,903 proteins were identified, of which 1,010 were differentially expressed between left colon from CD patients and HC. 1,242 proteins were differentially expressed between left colon from UC patients and HC, and 952 differential proteins discriminated between left colon from CD and UC patients. In the comparative study of ileum biopsies from Crohn's disease patients and healthy controls, 956 proteins were differentially expressed (Figure 2). IPA revealed multiple canonical pathways, including EIF2 signaling, regulation of eIF4 and serine/threonine kinase P7056K signaling, mitochondrial dysfunction, and oxidative phosphorylation altered in ileum biopsies from CD patients compared to HC (Figure 3). Regarding the proteomic study in left colon samples, the main canonical pathways enrichment in the comparison of UC and CD with HC were the following: neutrophil extracellular trap signaling pathways, fatty acid oxidation, sirtuin signaling pathway, tRNA charging, and mitochondrial dysfunction (Figure 4). Conclusion The proteomic results revealed dysregulated proteins and pathways in ileum and left colon biopsies from patients with active CD and UC compared to HC that may unravel key mechanisms contributing to the pathogenesis of these diseases. The results of the study serve as a starting point for hypotheses to understand the pathogenesis and search for therapeutic targets.

Background In recent years, evidence shows that long non-coding RNAs (lncRNAs) are key regulators of gene transcription and play important roles in the pathogenesis of inflammatory bowel diseases. LncRNA are involved in regulation of intestinal epithelial cell apoptosis, cell-cell interactions, enhancing inflammation, among others. Biological therapies, which are considered the most potent for disease control, only benefit one-third of patients. For this reason, a deeper understanding regarding the mechanisms by which biological drugs elicit their effect on intestinal mucosal is needed. Hence, we aimed to unravel the ex vivo modulator effect of infliximab on the lncRNAs expression in intestinal biopsies from patients with Crohn′s Disease (CD). Methods We performed an unbiased transcriptomic analysis of intestinal biopsies from the ileum and colon from 30 patients [active CD = 10, quiescent CD = 10, healthy controls (HC) = 10] to identify lncRNA differentially expressed in the setting of infliximab modulation (Figure 1). Endoscopic biopsies were cultured with or without infliximab, and the transcriptome was determined by stranded total-RNAseq (reagents from Illumina Inc.). We used different databases (Ensembl Biomart, RNAcentral and ToppGene) to search for non-annotated lncRNA information and data on the location (cellular component), biological process and molecular function of differentially expressed lncRNAs. Results Transcriptomic results revealed a widespread dysregulation of lncRNAs in ileum biopsies from patients with active CD, quiescent CD and HC compared to the colon at baseline and after infliximab culture (Figure 2). These differentially expressed lncRNAs were enriched in such pathways as proliferation, apoptosis, migration, inflammatory response of fibroblasts, response to wounding, posttranscriptional regulation of inflammatory genes and activation of the mitogen-activated protein kinase signaling pathways. Regarding the effect of infliximab according to intestinal location, presence of disease and activity, no significant lncRNAs were identified in the different study comparatives. Conclusion We have characterized the basal transcriptomic landscape of lncRNAs in patients with CD (active and quiescent) and HC both in ileum and left colon. However, we have not found differential lncRNA expression due to the effect of infliximab, suggesting that the location (ileum or colon) is more relevant when analyzing differences in lncRNA expression in the intestinal tissue.

Background The etiology and pathogenesis of inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC) are complex and the mechanisms that lead to the development of these diseases remain unclear. Extracellular vesicles (EVs) are small particles covered with a cell membrane, originating from the emitting cell, excreted into the extracellular medium, and subsequently captured by receptor cells. EVs have a role in multiple diseases and they could also have a function in IBD pathogenesis. Therefore, the analysis of EVs isolated from the serum of newly diagnosed IBD patients (before starting any treatment) may represent an appropriate experimental approach to elucidate their role in IBD pathogenesis. We aimed to evaluate EVs’ composition and potential effects in the pathogenesis of IBD. Methods The protein content of EVs isolated by size exclusion chromatography from the 500 µl of serum from 100 patients with IBD (50 patients with CD and 50 patients with UC) recently diagnosed and 50 healthy controls (HC) was characterized by proteomics and their size and concentration in serum by Nanoparticle tracking analysis (NTA). The biological function of EVs and alterations in signaling pathways related to IBD were determined using Ingenuity Pathways Analysis (IPA) to analyze the OMICs results. Results A total of 1,100 proteins have been identified, of which 105 proteins were differentially expressed by patients with CD versus HC, 111 proteins by patients with UC versus HC, and 32 proteins by patients with UC versus CD. IPA analysis revealed that proteins carried in EVs are involved in the dysregulation of immune pathways such as the acute phase response (Figure 1), LXR/RXR activation pathway (Figure 2), and the complement pathway. These pathways were regulated differentially in IBD patients compared with HC, but also when the CU group was compared with the CD group (Figure 3) being upregulated nuclear receptors signaling and cytotoxicity pathways. Conclusion EVs carry proteins that can be involved in the dysregulation of the immune system in IBD; this effect would be different in UC and CD since their EVs show a differential profile. Consequently, EVs may play role in IBD pathogenesis and source of strong biomarkers candidates for diagnosis in UC and CD. Further studies on their specific function during IBD are warranted.

Background The response rate to hepatitis B virus (HBV) vaccination in the general population is about 90%. However, the response rate to the vaccine in patients with inflammatory bowel disease (IBD) is significantly lower. IBD is a multifactorial disease so, it is important to study which cell subsets are involved in the failure of the HBV vaccine. Therefore, our main objective was to study the differences between the circulating immune system of responders and not responders to the vaccine. Methods Observational clinical practice study on the factors associated with the immunogenicity of the HBV vaccine in patients with IBD. Per clinical practice, 19 IBD patients vaccinated for the first time against HBV were included. Patients were divided according to their vaccination response after three doses of the vaccine at 0, 1, and 6 months as responders (≥ 100 anti-HBV) and non-responders (< 100 anti-HBV). Blood was collected before and after vaccination to characterize the different immune subsets by flow cytometry. Data were analyzed manually and by high dimensional data analysis (UMAP and FlowSOM). Results Non-responders displayed a lower percentage of naïve T cells compared with those who responded while responders had a lower percentage of Th2 and CD4 central memory subsets before vaccination. According to the high dimensional data analysis, 22 different T-cell metaclusters were identified (Fig. 1). Indeed, the percentage of type 2 conventional dendritic cells was increased following vaccination in both responders and non-responders, allowing us to identify 11 submetacluster (Fig. 2). Finally, The percentage of IgG class switch and IgG plasmablasts were increased following vaccination in the responders group, while the percentage of IgM plasmablast was increased in non-responders. Using the high dimensional data analysis 26 different subpopulations, were identified (Fig. 3). Conclusion The proportion of circulating T cell subsets can be used as predictor markers of the response to the HBV vaccine in IBD patients: while non-responders showed a lower percentage of naïve T cells, responders presented a lower percentage of Th2 T cells compared with their counterparts. The analysis of the data reveals that high-resolution and high-dimensional data, show several clusters containing events that evade the canonical definition.

Biological therapies only benefit one-third of patients with Crohn’s disease (CD). For this reason, a deeper understanding of the mechanisms by which biologics elicit their effect on intestinal mucosa is needed. Increasing evidence points toward the involvement of long noncoding RNAs (lncRNAs) in the pathogenesis of CD, although their role remains poorly studied. We aimed to characterize lncRNA profiles in the ileum and colon from CD patients and evaluate the effect of anti-TNF-α treatment on their transcription. Terminal ileum and left colon samples from 30 patients (active CD = 10, quiescent CD = 10, and healthy controls (HCs) = 10) were collected for RNA-seq. The patients were classified according to endoscopic activity. Furthermore, biopsies were cultured with infliximab, and their transcriptome was determined by Illumina gene expression array. A total of 678 differentially expressed lncRNAs between the terminal ileum and left colon were identified in HCs, 438 in patients with quiescent CD, and 468 in patients with active CD. Additionally, we identified three new lncRNAs in the ileum associated with CD activity. No differences were observed when comparing the effect of infliximab according to intestinal location, presence of disease (CD vs. HC), and activity (active vs. quiescent). The expression profiles of lncRNAs are associated with the location of intestinal tissue, being very different in the ileum and colon. The presence of CD and disease activity are associated with the differential expression of lncRNAs. No modulatory effect of infliximab has been observed in the lncRNA transcriptome., Depto. de Nutrición y Ciencia de los Alimentos, Fac. de Farmacia, TRUE, pub

This paper describes two new helical arrays of magnetic coils recently installed inside the TJ-II vacuum vessel. Their main objective is the precise measurement of the spatial periodicity of the magnetohydrodynamic perturbations usually found in the TJ-II plasmas. Given the high probability of coil failures due to the harsh plasma environment and in view of the extremely difficult access to the TJ-II vessel interior for maintenance, the coil system has been divided in two quasi-identical helical arrays. Both arrays consist of 32 triaxial sensors measuring orthogonal components of the local magnetic field along an ideal helical path whose trajectory runs close to the plasma edge. A description of the main characteristics of coils and arrays as well as their nominal positioning along an ideal helical path, inside the vessel, is given. A precise experimental determination of the real spatial orientation of the coils is performed by comparing the signals measured in current ramp-up and ramp-down experiments with calculations based on a filamentary model for the TJ-II magnetic coils. After this fine calibration procedure, it is possible to analyze the dependence of the amplitude of the measured magnetic field and its fluctuations as a function of the coil distance to the last closed flux surface. The study of the phase evolution of the parallel and perpendicular oscillatory components is also enabled. Finally, two examples of mode number determination are shown. One corresponds to a low frequency mode appearing in pure electron cyclotron resonance heating plasma, and the other one shows several modes observed during combined injection of both co and counter neutral beams and identified as shear Alfvén waves.

Esta obra presenta las investigaciones desarrolladas a lo largo del proyecto europeo de investigación, financiado por el Programa de Justicia de la Union Europea (2014-2020): “RE-TREAT: Reshaping treatment approaches towards victims of sexual crimes within criminal proceedings”. Los objetivos perseguidos por este proyecto de investigación son, entre otros, el análisis de las barreras, recursos y prácticas nocivas en el tratamiento de las víctimas de delitos sexuales a lo largo de las diversas fases del proceso penal, identificación de mejores prácticas en este ámbito que pueden ser aplicadas por los operadores jurídicos, o bien, la sensibilización de los actores que abordan este fenómeno. Se presentan en el primer Capítulo los obstáculos que enfrentan las víctimas de delitos sexuales en las diversas etapas del proceso penal español, se describen los estándares prácticos para profesionales del sistema de justicia que trabajan con víctimas de violencia sexual en el Capítulo II de la obra. En el Capítulo III se incluyen recomendaciones políticas que permiten garantizar un mejor tratamiento hacia las víctimas de violencia sexual por parte del sistema de justicia en España y en el Capítulo IV el informe comparativo de la situación con Grecia e Italia. Esta obra presenta las investigaciones desarrolladas a lo largo del proyecto europeo de investigación, financiado por el Programa de Justicia de la Union Europea (2014-2020): “RE-TREAT: Reshaping treatment approaches towards victims of sexual crimes within criminal proceedings” Financed by The European Union Justice Program (2014-2020). RE-TREAT: Reshaping treatment approaches towards victims of sexual violence within criminal proceedings. JUST-JACC-AG-2019 - 878566 - RETREAT Obstáculos que enfrentan las víctimas de delito sexual en las etapas del proceso penal / Helena Soleto, Sabela Oubiña Barbolla, Jessica Jullien de Asís, Aurea Grané Chávez, Margarita Diges Junco, Candela Galán González, Nieves Pérez-Mata, Anna Fiodorova, Federico González Barrera, Iván Navarro Papic, Rosa Gómez de Liaño, Raquel López Jiménez, Daniel Rodríguez Horcajo, Soledad Torrecuadrada García Lozano, Ignacio de Torres Guajardo, Belén Hernández Moura, Emiliano Carretero Morales, Irene de Lamo Velado, Rocío Zafra Espinosa de los Monteros, Cristina Ruiz López, Miriam Peláez Devesa (pp. 7-92). -- Guía para profesionales de la justicia que trabajan con mujeres víctimas de violencia sexual / Monique Anderson, Evelien Claes (pp. 93-116). -- Recomendaciones políticas / Monique Anderson, Evelien Claes, Anna Fiodorova, Helena Soleto (p. 117-165). -- Estudio comparativo sobre tratamiento procesal a víctimas de violencia sexual en España, Grecia e Italia / Sabela Oubiña Barbolla, Helena Soleto Muñoz, Nieves Pérez-Mata, Daniel Rodríguez Horcajo, Margarita Diges Junco, Miriam Peláez Devesa, Jessica Jullien de Asís, Aurea Grané, Candela Galán González, Manuel Cancio Meliá, Jose Alberto Revilla González (pp. 166-229)

El Proyecto Víctima nace como un estudio de la realidad social que enfrentan las víctimas de violencia sexual, así como del tratamiento procesal que les dispensa nuestro sistema judicial. Todo ello con el fin de determinar el nivel de eficacia del sistema español a la hora de reparar el daño causado a las víctimas e identificar los perjuicios que, eventualmente, puedan derivarse de esa relación de la víctima con el propio sistema. El presente trabajo, que se enmarca dentro del mencionado Proyecto, constituye una obra colectiva que pretende profundizar en la situación actual de las víctimas de violencia sexual y la protección que les proporciona el sistema judicial. Así, partiendo de la contextualización del delito sexual, víctimas y victimarios, se realiza un estudio de los factores que influyen en la reparación a las víctimas, situación actual y deficiencias detectadas, identificando aquellos aspectos que es necesario mejorar en aras de alcanzar el ideal de justicia restaurativa. Proyecto Nacional (Ministerio de Ciencia, Innovación y Universidades) RTI2018-099170-B-100 Tratamiento procesal de la víctima de violencia sexual: participación, objeto de prueba e interpretación social en las redes, 2019-2021. Prólogo / Soleto, Helena - Grané, Aurea (p. 3). -- CONTEXTO SOCIAL, IMPACTO E INTERPRETACIÓN (pp. 37-260). -- El impacto social de los delitos sexuales y su tramitación procesal / Donas Aguilera, Álvaro (pp.37-83). -- Impacto mediático del delito sexual / García Peña, Alejandro (pp- 84-122). -- La protección de la víctima del delito sexual en el ámbito familiar / Delgado Villar, Cristina (pp. 123-187). -- La menor migrante víctima de delito sexual / Luján Zato, Ana Isabel (pp. 188-231). -- Influencia de las redes sociales y los medios en la victimización secundaria en delitos sexuales / Andrés Alonso, Isabel (pp. 232-260). -- VICTIMIZACIÓN (pp. 261-779). -- El consentimiento en los delitos de abuso y agresión sexual / Azuara Berrozpe, Helena (pp. 261-303). -- El delito sexual en los círculos de confianza / Fernández Mañas, Miguel (pp. 304-356). -- Los delitos sexuales en el ámbito familiar y la comisión por omisión / Andrés Peral (pp. 357-395). -- Obstáculos para la persecución del delito sexual contra menores en el ámbito intrafamiliar / Perales Díaz, Adrián (pp. 396-435). -- Obstáculos en la persecución del abuso sexual intrafamiliar entre menores / Revuelto Hernández, Laura (pp. 436-496). -- Victimización sexual en grupo / Bescós Hernando, Laura (pp. 497-548). -- Victimización sexual en grupo y el delito sexual continuado / Berceruelo Cámara, Jonathan (pp. 549-586). -- La victimización sexual a través de las redes sociales / Villanueva González, Adrián (pp. 587-629). -- La victimización sexual online en mujeres adolescentes y jóvenes / Fernández Senac, Gloria (pp. 630-673). -- La victimización sexual de menores en línea / Cañamares Mateo, Carlos (pp. 674-696). -- Análisis jurídico y estadístico del menor como víctima de violencia sexual / Gómez Gavarrón, Beatriz Soledad (pp. 697-738). -- Personas en situación de prostitución como víctimas especialmente vulnerables / Peláez Morales, Olaya (pp. 739-779). -- MARCO DE JUSTICIA (pp. 780-972). -- La especialización del sistema de justicia frente a la violencia sexual / Delgado García, Blanca (pp. 780-831). -- Los mitos de la violación en la jurisprudencia española / Cuesta Pérez, Lydia (pp. 832-863). -- Tardanza en la justicia penal por delito sexual: desincentivo e impunidad / López López, Paula (pp. 864-899). -- La prescripción en la persecución de los delitos sexuales / Villalobos Silva, María (pp. 900-925). -- Tratamiento y rehabilitación de los delincuentes sexuales / Aramburu González, Almudena (pp. 926-972). -- FASE DE INSTRUCCIÓN (pp. 973-1138). -- The influence of the security forces in sexual crime reports / Cibrian Ejido, Olatz (pp. 973-994). -- La actuación del ministerio fiscal en delitos contra la libertad e indemnidad sexual / Gutiérrez Pericacho, Celia (pp. 995-1036). -- Las denuncias por violencia sexual: problemática entorno a los obstáculos y oportunidades para una persecución adecuada / Pascual Merino, Marta (pp. 1037-1072). -- La victimización sexual por sumisión química en el sistema de justicia / Laso Martínez, Irene Pilar (pp. 1073-1138). -- EL JUICIO ORAL: PRÁCTICA DE PRUEBA (1139-1411). -- Valoración de la declaración de las víctimas de delitos sexuales / Fernández Luna, Francisco Javier (pp. 1139-1182). -- Las corroboraciones periféricas del testimonio de la víctima de violencia sexual / Cascos Rodríguez, Inmaculada (pp. 1183-1220). -- La prueba indiciaria en los delitos sexuales. La importancia de las corroboraciones periféricas del testimonio de la víctima / Fernández Gómez, Yolanda (pp. 1221-1264). -- La declaración del menor víctima de delitos sexuales / Ruiz Fernández, Sara (pp. 1265-1312). -- La prueba de descargo frente al testimonio de la víctima de delito sexual / Calderón Argüello, María del Mar (pp. 1313-1382). -- La problemática en torno a la declaración de la víctima adulta en delitos sexuales: derecho de defensa versus derecho a la no revictimización / Tapia Martínez, María (pp. 1383-1411). -- REPARACIÓN A LAS VÍCTIMAS (pp. 1412-1564). -- La justicia restaurativa y las víctimas de violencia sexual / Andrés Ayuso, María (pp. 1412-1457). -- Las indemnizaciones a las víctimas de delitos sexuales en el proceso penal: análisis jurídico y estudio de campo / Mañas Soto, Alberto (pp. 1458-1514). -- Adecuación y especialidad de la justicia restaurativa en delitos sexuales / Lanzas Iniesta, Marta (pp. 1515-1564).

This Manual is a guidebook for trainers who will lead and facilitate training on restorative justice to judges and public prosecutors in learning about restorative justice. It is a result of a joint effort of several partners and multidisciplinary professionals within the context of project RE-JUSTICE. RE-JUSTICE is a 30-month project, co-funded by the European Union’s Justice Programme, led by Catholic University of Leuven (KU Leuven) and carried out between November 2019 and April 2022. Through a process of desk and field research and consultation with experts, RE-JUSTICE has developed this training Manual and a training package (handouts, video materials, resources) that were used to provide training on restorative justice to judges and public prosecutors in pilot training sessions in Greece, Italy and Spain. This project involves partners from Belgium, Greece, Italy and Spain. Belgium sees cooperation between KU Leuven, the National Institute for Judicial Training (IGO) and Moderator Forum for Restorative Justice and Mediation, to provide together their technical support through the well-established knowledge and capacities on training and implementation of restorative justice practices. For each of the countries in which the pilot training was given, a partnership between an academic institute and the national judicial training school ensured country-specificity and the long-term sustainability of the training provided. Additionally, endorsement by the national training school confers a level of credibility to the training that is necessary to engage with such judicial professionals. The country-specific knowledge and perspective is supported and coupled by the European expertise brought by the European Forum for Restorative Justice and the European Judicial Training Network.As part of the specialised set of training needs presented by judges and public prosecutors in the context of the Victim’s Directive, this training project focuses on the specific training needs connected to the referral of cases to restorative justice services considering the specific needs of victims (Art. 12, par. 2), and the appropriate, respectful and safe communication with victims, providing them with key information about the availability of restorative justice (Art. 4, par. 1, al. j). The goal of the project is thus, through training, to contribute in a sustainable way to the process of raising awareness, building knowledge and developing skills and attitudes amongst the target groups. Initially and directly, this is done in the three Southern EU MS partners. Ultimately, on the basis of gained experience, RE-JUSTICE aims to contribute to the promotion of the same process across the EU. For approximately 20 years multiple European bodies and actors have highlighted the importance of judges and public prosecutors receiving training on restorative justice. The RE-JUSTICE project addresses this training need, with a specific focus on the topic of criminal law and the implementation of the Victim’s Directive 2012/29/EU.