Search

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.

Inflammatory bowel disease (IBD) is a chronic condition which includes ulcerative colitis (UC) and Crohn’s disease (CD), the origins of which are not yet fully understood. Both conditions involve an exacerbated immune response in the intestinal tract, leading to tissue inflammation. Dendritic cells (DCs) are antigen-presenting cells crucial for maintaining tolerance in the gastrointestinal mucosa. Previous research has indicated that DC recruitment to the intestinal mucosa is more pronounced in individuals with IBD, but the specific mechanisms governing this migration remain unclear. This study aimed to assess the expression of various homing markers and the migratory abilities of circulating DC subsets in response to intestinal chemotactic signals. Additionally, this study examined how golimumab and ustekinumab impact these characteristics in individuals with IBD compared to healthy controls. The findings revealed that a particular subset of DCs known as type 2 conventional DCs (cDC2) displayed a more pronounced migratory profile compared to other DC subsets. Furthermore, the study observed that golimumab and ustekinumab had varying effects on the migratory profile of cDC1 in individuals with CD and UC. While CCL2 did not exert a chemoattractant effect on DC subsets in this patient cohort, treatment with golimumab and ustekinumab enhanced their migratory capacity towards CCL2 and CCL25 while reducing their migration towards MadCam1. In conclusion, this study highlights that cDC2 exhibits a heightened migratory profile towards the gastrointestinal mucosa compared to other DC subsets. This finding could be explored further for the development of new diagnostic biomarkers or the identification of potential immunomodulatory targets in the context of IBD.

The article aims to put together the historical basis of the organization of the conflict resolution systems and the judicial procedural systems. It considers the Pound Conference of 1976 and its predecessor of 1906 and the relevant lessons given by Professor Sander to the integration of the alternative dispute resolution systems in the light of a large concept of the judicial systems in the 21st century. The study takes into consideration the quality of the judicial systems and highlights that each alternative dispute resolution method, such mediation, has different rates of quality and quantity. Finally, the article points out the trend of expansion of the multidoor courthouses, considered more adequate and with a higher level of quality, especially in advanced countries.

JT-60SA is the superconducting tokamak that will be operated at the Naka Fusion Institute of QST (the National Institutes for Quantum and Radiological Science and Technology) in Japan. The project is being developed under the framework of the Broader Approach Agreement between the EU and Japan (started in 2007) for an early realization of the fusion energy, aimed at conducting supportive and complementary work for the ITER experimental program towards DEMO. The assembly of the tokamak components as well as the related equipment was completed last year and the device is currently undergoing the integrated commissioning phase.Within the European contribution, Spain was one of the stakeholders that committed it, as a Voluntary Contributor, to design and manufacture one of the main components of the device: the cryostat. The cryostat is a large stainless steel vacuum vessel, 14 m diameter, 16 m high, which encloses the tokamak and provides the vacuum boundary (10−3 Pa) necessary to limit the heat loads on the magnets operated at cryogenic temperatures. The component is made up of the Cryostat Base (CB), the Cryostat Vessel Body Cylindrical Section (CVBCS), both designed and fabricated in Spain (through the National Fusion Laboratory at Ciemat), as well as the cryostat top lid (CTL) designed and procured by Japan (through QST).Within the manufacturing phases of the CB and CVBCS an extensive test program was carried out at Ciemat that focussed on the characterization of the welding processes selected for the manufacturing before their final approval. The aim of this paper is to present the results of the mechanical and microstructural tests performed on the welded joints.

The Interspace Afocal Module (IAM) is one integral component of the ITER Visible/Infrared Wide Angle Viewing System (WAVS), which is an optical diagnostic aimed at monitoring the ITER plasma facing components for machine protection. The diagnostic comprises 15 lines of sight (LoS), strategically distributed in the ITER Equatorial Ports (EP) 3, 9, 12 and 17. Design of WAVS in EP12 is critical, since it has to be fully operational for the first plasma of ITER; it is at its Preliminary stage, carried out by the Consortium constituted by CEA, CIEMAT and Bertin Technologies, within the Framework Partnership Agreement financed by F4E.The WAVS in EP12 comprises three LoS that pass through the IAM, consisting in a refractive optical system that relays the pupil forward and controls the beam diameter. It includes two doublets of lenses for each LoS, made of Shappire and Calcium Fluoride, with diameters up to 128 mm. The afocal sets (up to 1.9 m in length) are tightly held in place by the support structure of the IAM, which is directly attached to the Interspace Support Structure (ISS).The IAM structural requirements are highly demanding, given the optical performance that has to be assured under thermal and inertial loads in normal operation, including seismic SL1. In addition, it also has to withstand loads in Category III and IV, including higher seismic events SMHV and SL2, or accidental loads such as the loss of coolant or fire events, since the IAM structure is classified as ITER Safety Relevant, due to its attachment to the ISS.The paper summarizes the structural analyses performed by CIEMAT to validate the mechanical behaviour of the IAM Preliminary design in EP12, to guarantee both the structural integrity and the optical performance, in accordance with the RCC-MR Code.

CD38 is a multifunctional molecule that functions both as a transmembrane signaling receptor and as an ectoenzyme with important roles in cell adhesion, calcium regulation and signal transduction. Within the B cell linage, CD38 is expressed in diverse murine B cell subsets, with highest levels in innate B cell subpopulations such as marginal zone (MZ) B cells or B1 cells. In humans, however, CD38 is transiently expressed on early lymphocyte precursors, is lost on mature B cells and is consistently expressed on terminally differentiated plasma cells. In the present work, we have identified two homologues of mammalian CD38 in rainbow trout (Oncorhynchus mykiss), designating them as CD38A and CD38B. Although constitutively transcribed throughout different tissues in homeostasis, both CD38A and CD38B mRNA levels were significantly up-regulated in head kidney (HK) in response to a viral infection. In this organ, after the generation of a specific monoclonal antibody (mAb) against CD38A, the presence of CD38A+ populations among IgM+ B cells and IgM- leukocytes was investigated by flow cytometry. Interestingly, the percentage of IgM+CD38A+ B cells increased in response to an in vitro stimulation with inactivated Aeromonas salmonicida. Finally, we demonstrated that HK IgM+CD38A+ B cells had an increased IgM secreting capacity than that of cells lacking CD38A on the cell surface, also showing increased transcription levels of genes associated with B cell differentiation. This study strongly suggests a role for CD38 on the B cell differentiation process in teleosts, and provides us with novel tools to discern between B cell subsets in these species.

Inflammatory bowel disease (IBD) is an idiopathic and chronic disorder that includes ulcerative colitis (UC) and Crohn’s disease (CD). Both diseases show an uncontrolled intestinal immune response that generates tissue inflammation. Dendritic cells (DCs) are antigen-presenting cells that play a key role in tolerance maintenance in the gastrointestinal mucosa. Although it has been reported that DC recruitment by the intestinal mucosa is more prominent in IBD patients, the specific mechanisms governing this migration are currently unknown. In this study, the expression of several homing markers and the migratory profile of circulating DC subsets towards intestinal chemo-attractants were evaluated and the effect of biological drugs with different mechanisms of action, such as anti-TNFα or anti-integrin α4β7 (vedolizumab), on this mechanism in healthy controls (HCs) and IBD patients was also assessed. Our results revealed that type 2 conventional DCs (cDC2) express differential homing marker profiles in UC and CD patients compared to HCs. Indeed, integrin β7 was differentially modulated by vedolizumab in CD and UC. Additionally, although CCL2 displayed a chemo-attractant effect over cDC2, while biological therapies did not modulate the expression of the homing markers, we paradoxically found that anti-TNF-treated cDC2 increased their migratory capacity towards CCL2 in HCs and IBD. Our results therefore suggest a key role for cDC2 migration towards the intestinal mucosa in IBD, something that could be explored in order to develop novel diagnostic biomarkers or to unravel new immunomodulatory targets in IBD.

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. [ABSTRACT FROM AUTHOR]

This study aimed to determine the top performing K to 3 pupils' unfamiliarity with the Ibanag words used in modules as described by the teachers. Specifically, this study aimed to answer the description of teacher participants on the experiences of the said pupils using the modules written in Ibanag, explain the reasons behind the pupils' unfamiliarity with the vocabulary used in the module, and their teaching strategies in teaching the modules. Schema Theory was used to determine the background knowledge of the top performing k to 3 pupils with the Ibanag words used in the modules. The Researcher used a phenomenological qualitative method of Moustakas (1994) to explore the phenomenon on the top performing K to 3 pupils' unfamiliarity with the Ibanag words used in modules as described by the teachers. The study was conducted during the School Year 2021-2022 in Angancasilian Elementary School. The teacher participants of the study were four (4) teachers from kindergarten, Grade 1, Grade 2, and Grade 3. Purposive sampling was applied by the Researcher since there was only one (1) teacher per grade level with the total of four (4) teacher participants from the said Grade levels. In this design, bracketing or epoche, horizontalization, textural description, structural description and essence were done. The study revealed that top performing K to 3 pupils had vocabulary problems in answering the modules written in Ibanag as described by teachers. They could not fully grasp Ibanag terms used in the modules. Meanwhile, teachers gave clearer instructions to aid the difficult terminologies used in the modules written in Ibanag. Thus, definition of terms should be included in each module and module writers should use simple Ibanag terms in crafting the modules. [ABSTRACT FROM AUTHOR]

Abstract Background Salmonella enterica subsp. diarizonae (IIIb) is frequently isolated from the environment, cold-blooded reptiles, sheep and humans; however only a few studies describe the isolation of this subspecies from invasive human infections. The factors contributing to this unusual behavior are currently unknown. Results We report here the genome features of two diarizonae strains, SBO13 and SBO27, isolated from endocervical tissue collected post-abortion and from cerebrospinal fluid of a newborn child, respectively, in the city of Santa Cruz, Bolivia. Although isolated six years apart, SBO27 in 2008 and SBO13 in 2014, both strains belong to the same sequence type 1256 (ST1256) and show a high degree of genome conservation sharing more than 99% of their genes, including the conservation of a ~ 10 kb plasmid. A prominent feature of the two genomes is the presence of 24 genomic islands (GIs), in addition to 10 complete Salmonella pathogenicity islands (SPI) and fragments of SPI-7, a pathogenicity island first reported in the human-adapted serovar Typhi. Some of the GIs identified in SBO13 and SBO27 harbor genes putatively encoding auto-transporters involved in adhesion, lipopolysaccharide modifying enzymes, putative toxins, pili-related proteins, efflux pumps, and several putative membrane cation transport related-genes, among others. These two Bolivian isolates also share genes encoding the type-III secretion system effector proteins SseK2, SseK3 and SlrP with other diarizonae sequence types (ST) mainly-associated with infections in humans. The sseK2, sseK3 and slrP genes were either absent or showing frameshift mutations in a significant proportion of genomes from environmental diarizonae isolates. Conclusions The comparative genomic study of two diarizonae strains isolated in Bolivia from human patients uncovered the presence of many genes putatively related to virulence. The statistically-significant acquisition of a unique combination of these functions by diarizonae strains isolated from humans may have impacted the ability of these isolates to successfully infect the human host.

In mammals, Blimp1 (B lymphocyte-induced maturation protein 1) encoded by the prdm1 gene and its homolog Hobit (homolog of Blimp1 in T cells) encoded by znf683, represent key transcriptional factors that control the development and differentiation of both B and T cells. Despite their essential role in the regulation of acquired immunity, this gene family has been largely unexplored in teleosts to date. Until now, one prdm1 gene has been identified in most teleost species, whereas a znf683 homolog has not yet been reported in any of these species. Focusing our analysis on rainbow trout (Oncorhynchus mykiss), an in silico identification and characterization of prdm1-like genes has been undertaken, confirming that prdm1 and znf683 evolved from a common ancestor gene, acquiring three gene copies after the teleost-specific whole genome duplication event (WGD) and six genes after the salmonid-specific WGD. Additional transcriptional studies to study how each of these genes are regulated in homeostasis, in response to a viral infection or in B cells in different differentiation stages, provide novel insights as to how this gene family evolved and how their encoded products might be implicated in the lymphocyte differentiation process in teleosts.

Interferons (IFNs) orchestrate antiviral responses in jawed vertebrates and can be classified into three types based on different aspects of their genomic organization, structure and receptors through which they signal and function. Generally, type I and type III IFNs include cytokines that directly induce an antiviral response, whereas type II IFNs are well-known for their immunomodulatory role during viral infections. In mammals, type I IFNs have been shown to also regulate many aspects of B cell development and differentiation. Yet, these functions have been only faintly investigated for teleost IFNs. Thus, in the current study, we have examined the effects of a model type I rainbow trout IFN molecule (IFNa) on blood naïve (IgM+IgD+) B cells, comparing them to those exerted by type II IFN (IFNγ). Our results demonstrate that IFNa increases the survival of naïve rainbow trout B cells, in the absence of lymphoproliferative effects, by rescuing them from spontaneous apoptosis. Additionally, IFNa increased the phagocytic capacity of blood IgM+IgD+ B cells and augmented the number of IgM-secreting cells in blood leukocyte cultures. IFNγ, on the other hand, had only minor effects up-regulating IgM secretion, whereas it increased the phagocytic capacity of IgM− cells in the cultures. Finally, given the recent identification of 9 mx genes in rainbow trout, we have also established which of these genes were transcriptionally regulated in blood naïve B cells in response to IFNa. This study points to a previously undescribed role for teleost type I IFNs in the regulation of B cell responses.

La reparación económica a las víctimas de delito es uno de los objetivos del sistema de justicia español. Este trabajo analiza si el sistema español es eficaz en la reparación económica de las víctimas de violencia sexual a través de los dos mecanismos destinados a tal fin: por un lado, el pago de las indemnizaciones establecidas en sentencias condenatorias y, por otro, las ayudas directas otorgadas por el Estado a las víctimas. Los resultados del análisis evidencian la ineficacia del sistema procesal -que es generalizada para todo tipo de delitos- y, especialmente, la falta de interés por parte del Estado en la reparación a estas víctimas mediante las ayudas públicas. Ante este escenario, el trabajo evalúa algunas propuestas normativas y procedimentales encaminadas a mejorar la situación, entre ellas la denominada justicia restaurativa

Summary: Immunoglobulin D (IgD) is an ancient antibody with dual membrane-bound and fluid-phase antigen receptor functions. The biology of secreted IgD remains elusive. Here, we demonstrate that teleost IgD+IgM− plasmablasts constitute a major lymphocyte population in some mucosal surfaces, including the gut mucosa. Remarkably, secreted IgD binds to gut commensal bacteria, which in turn stimulate IgD gene transcription in gut B cells. Accordingly, secreted IgD from gut as well as gill mucosae, but not the spleen, show a V(D)J gene configuration consistent with microbiota-driven clonal expansion and diversification, including mild somatic hypermutation. By showing that secreted IgD establishes a mutualistic relationship with commensals, our findings suggest that secreted IgD may play an evolutionary conserved role in mucosal homeostasis. : Perdiguero et al. show that IgD+IgM− plasmablasts constitute a major lymphocyte population in the teleost intestine, as in gills. In these two tissues, IgD molecular signatures reflect a clonal expansion not detected in the spleen. Finally, secreted IgD in the intestine establishes a two-way interaction with the local microbiota. Keywords: IgD, teleost fish, intestine, gills, microbiota, B cells, clonal expansion, somatic hypermutation, SHM

In the absence of class switch recombination and germinal centers, the mechanisms through which B cells from teleost fish mount extrafollicular immunoglobulin M (IgM) memory responses remains mostly unexplored. In this report, we demonstrate that teleost IgM+ B cells respond to CD40L, a thymus-dependent activation signal, similarly to mammalian B2 cells. However, when stimulated with different types of antigens, fish IgM+ B cells only reach a general activation state in response to antigens cataloged as thymus-independent 1 (TI-1) in mammals, as established through both functional assays and RNA sequencing. Interestingly, fish IgM+ B cells remained completely unresponsive to TI-2 antigens, suggesting that the engagement of innate receptors provided by TI-1 antigens is required for the activation of teleost B cells. Finally, a synergy between CD40L and TI-1 antigens was also demonstrated, further supporting that there is no clear dichotomy between thymus-dependent and TI responses in teleost fish.