β7 Integrin Inhibition Can Increase Intestinal Inflammation by Impairing Homing of CD25hiFoxP3+ Regulatory T Cells.

Background & aimsIntegrin α4β7 mediates lymphocyte trafficking to the gut and gut-associated lymphoid tissues, a process critical for recruitment of effector lymphocytes from the circulation to the gut mucosa in inflammatory bowel disease (IBD) and murine models of intestinal inflammation. Antibody blockade of β7 integrins generally is efficacious in IBD; however, some patients fail to respond, and a few patients can experience exacerbations. This study examined the effects of loss of β7 integrin function in murine models of IBD.MethodsIn a mouse IBD model caused by lack of interleukin 10, a cytokine important in CD25hiFoxP3+ regulatory T cell (Treg) function, genetic deletion of β7 integrin or antibody blockade of α4β7-mucosal addressin cell adhesion molecule-1 interaction paradoxically exacerbated colitis.ResultsLoss of β7 impaired the capacity of Tregs homing to the gut and therefore suppress intestinal inflammation in an adoptive T-cell transfer model; however, the intrinsic suppressive function of β7-deficient Tregs remained intact, indicating that the β7 deficiency selectively impacts gut homing. Deletion of β7 integrin did not worsen colitis in an acute dextran sodium sulfate model in which Treg number and function were normal.ConclusionsIn Integrin subunit beta (Itgb)7-/-Il10-/- mice, loss of β7-dependent Treg homing to gut-associated lymphoid tissues combined with loss of intrinsic Treg function exacerbated intestinal inflammation. These results suggest that IBD patients with reduced CD25hiFoxP3+ Treg numbers or function or lack of interleukin 10 could be at risk for failure of α4β7 blocking therapy

On the components of the unstable set of isolated invariant sets

The aim of this note is to shed some light on the topological structure of the unstable set of an isolated invariant set K. We give a bound on the number of essential quasicomponents of the unstable set of K in terms of the homological Conley index of K. The proof relies on an explicit pairing between Čech homology classes and Alexander–Spanier cohomology classes that takes the form of an integral.Depto. de Álgebra, Geometría y TopologíaFac. de Ciencias MatemáticasTRUEMinisterio de Ciencia, Innovación y Universidadespu

Retrieval of canopy water content of different crop types with two new hyperspectral indices: Water Absorption Area Index and Depth Water Index

Crop canopy water content (CWC) is an essential indicator of the crop's physiological state. While a diverse range of vegetation indices have earlier been developed for the remote estimation of CWC, most of them are defined for specific crop types and areas, making them less universally applicable. We propose two new water content indices applicable to a wide variety of crop types, allowing to derive CWC maps at a large spatial scale. These indices were developed based on PROSAIL simulations and then optimized with an experimental dataset (SPARC03; Barrax, Spain). This dataset consists of water content and other biophysical variables for five common crop types (lucerne, corn, potato, sugar beet and onion) and corresponding top-of-canopy (TOC) reflectance spectra acquired by the hyperspectral HyMap airborne sensor. First, commonly used water content index formulations were analysed and validated for the variety of crops, overall resulting in a R2 lower than 0.6. In an attempt to move towards more generically applicable indices, the two new CWC indices exploit the principal water absorption features in the near-infrared by using multiple bands sensitive to water content. We propose the Water Absorption Area Index (WAAI) as the difference between the area under the null water content of TOC reflectance (reference line) simulated with PROSAIL and the area under measured TOC reflectance between 911 and 1271 nm. We also propose the Depth Water Index (DWI), a simplified four-band index based on the spectral depths produced by the water absorption at 970 and 1200 nm and two reference bands. Both the WAAI and DWI outperform established indices in predicting CWC when applied to heterogeneous croplands, with a R2 of 0.8 and 0.7, respectively, using an exponential fit. However, these indices did not perform well for species with a low fractional vegetation cover (<30%). HyMap CWC maps calculated with both indices are shown for the Barrax region. The results confirmed the potential of using generically applicable indices for calculating CWC over a great variety of crops

Critical role of endothelial P-selectin glycoprotein ligand 1 in chronic murine ileitis

L-selectin ligands might be relevant for inflammatory cell trafficking into the small intestine in a spontaneous model of chronic ileitis (i.e., SAMP1/YitFc mice). Immunoblockade of peripheral node addressin or mucosal addressin cell adhesion molecule 1 failed to ameliorate ileitis, whereas P-selectin glycoprotein ligand 1 (PSGL-1) neutralization attenuated both the adoptively transferred and spontaneous disease. PSGL-1 was detected in venules of mesenteric lymph node and small intestine by immunohistochemistry and confirmed by real-time reverse transcription polymerase chain reaction and flow cytometry. In addition, reconstitution of wild-type mice with PSGL-1−/− bone marrow demonstrated that PSGL-1 messenger RNA and PSGL-1 protein expression remained on endothelium, localized within mesenteric lymph node and small intestine. Endothelial PSGL-1 bound P-selectin–IgG and its blockade or genetic deletion altered the recruitment of lymphocytes to the small intestine, as revealed by intravital microscopy and homing studies. Endothelial expression of PSGL-1 adds a new dimension to the various cellular interactions involved in small intestinal recruitment. Thus, the multiple roles of PSGL-1 may explain why targeting this single adhesion molecule results in attenuation of chronic murine ileitis, a disease previously resistant to antiadhesion molecule strategies

Targeting Cytokine Signaling and Lymphocyte Traffic via Small Molecules in Inflammatory Bowel Disease: JAK Inhibitors and S1PR Agonists

The inflammatory Bowel diseases (IBDs) are a chronic, relapsing inflammatory diseases of the gastrointestinal tract with heterogeneous behavior and prognosis. The introduction of biological therapies including anti-TNF, anti-IL-12/23, and anti-integrins, has revolutionized the treatment of IBD, but these drugs are not universally effective. Due to the complex molecular structures of biologics, they are uniformly immunogenic. New discoveries concerning the underlying mechanisms involved in the pathogenesis of IBD have allowed for progress in the development of new treatment options. The advantage of small molecules (SMs) over biological therapies includes their lack of immunogenicity, short half-life, oral administration, and low manufacturing cost. Among these, the Janus Kinases (JAKs) inhibition has emerged as a novel strategy to modulate downstream cytokine signaling during immune-mediated diseases. These drugs target various cytokine signaling pathways that participate in the pathogenesis of IBD. Tofacitinib, a JAK inhibitor targeting predominantly JAK1 and JAK3, has been approved for the treatment of ulcerative colitis (UC), and there are other specific JAK inhibitors under development that may be effective in Crohn’s. Similarly, the traffic of lymphocytes can now be targeted by another SM. Sphingosine-1-phosphate receptor (S1PR) agonism is a novel strategy that acts, in part, by interfering with lymphocyte recirculation, through blockade of lymphocyte egress from lymph nodes. S1PR agonists are being studied in IBD and other immune-mediated disorders. This review will focus on SM drugs approved and under development, including JAK inhibitors (tofacitinib, filgotinib, upadacitinib, peficitinib) and S1PR agonists (KRP-203, fingolimod, ozanimod, etrasimod, amiselimod), and their mechanism of action

Effectiveness and safety of integrase strand transfer inhibitors in Spain: a prospective real-world study

IntroductionSecond-generation integrase strand transfer inhibitors (INSTIs) are preferred treatment options worldwide, and dolutegravir (DTG) is the treatment of choice in resource-limited settings. Nevertheless, in some resource-limited settings, these drugs are not always available. An analysis of the experience with the use of INSTIs in unselected adults living with HIV may be of help to make therapeutic decisions when second-generation INSTIs are not available. This study aimed to evaluate the real-life effectiveness and safety of dolutegravir (DTG), elvitegravir/cobicistat (EVG/c), and raltegravir (RAL) in a large Spanish cohort of HIV-1-infected patients. MethodsReal-world study of adults living with HIV who initiated integrase INSTIs DTG, EVG/c, and RAL-based regimens in three settings (ART-naive patients, ART-switching, and ART-salvage patients). The primary endpoint was the median time to treatment discontinuation after INSTI-based regimen initiation. Proportion of patients experiencing virological failure (VF) (defined as two consecutive viral loads (VL) & GE;200 copies/mL at 24 weeks or as a single determination of VL & GE;1,000 copies/mL while receiving DTG, EVG/c or RAL, and at least 3 months after INSTI initiation) and time to VF were also evaluated. ResultsVirological effectiveness of EVG/c- and RAL-based regimens was similar to that of DTG when given as first-line and salvage therapy. Treatment switching for reasons other than virological failure was more frequent in subjects receiving EVG/c and, in particular, RAL. Naive patients with CD4+ nadir <100 cells/& mu;L were more likely to develop VF, particularly if they initiated RAL or EVG/c. In the ART switching population, initiation of RAL and EVG/c was associated with both VF and INSTI discontinuation. There were no differences in the time to VF and INSTI discontinuation between DTG, EVG/c and RAL. Immunological parameters improved in the three groups and for the three drugs assessed. Safety and tolerability were consistent with expected safety profiles. DiscussionWhereas second-generation INSTIs are preferred treatment options worldwide, and DTG is one of the treatment of choices in resource-limited settings, first-generation INSTIs may still provide high virological and immunological effectiveness when DTG is not available

Deep-sea habitat characterization using acoustic data and underwater imagery in Gazul mud volcano (Gulf of Cádiz, NE Atlantic)

Gazul is the shallowest mud volcano (MV) within the Shallow Field of Fluid Expulsion (SFFE) of the northeastern Gulf of Cádiz (NE Atlantic; 300–1200 m depth). The SFFE represents an important geo- and biodiversity area that was designated as a Site of Community Importance under the European Habitats Directive in 2014. In this study, geological features, habitats and associated biodiversity, as well as anthropogenic impacts, were characterized at Gazul MV from underwater imagery and multibeam bathymetry. Multivariate methods using the Bray-Curtis similarity index identified six main habitats, each of which harbored a characteristic faunal assemblage that included: (1) sandy ripple bottoms typified by the actiniarian Actinauge richardi; (2) sandy, muddy, coarse sand and bioclastic bottoms dominated by the solitary coral Flabellum chunii; (3) coarse sand and bioclastic bottoms, together with soft sediments covered by scattered methane-derived authigenic carbonates (MDACs) (mixed bottoms), characterized by the echinoid Cidaris cidaris; (4) hard bottoms comprising MDACs dominated by a wide variety of sponges and gorgonians; (5) coral-rubble bottoms typified by the presence of colonial scleractinian communities dominated by Madrepora oculata; and (6) mixed bottoms characterized by the presence of a styelid ascidian. Slope and water depth were the main factors explaining assemblages’ distribution, which was also supported by the presence of MDACs such as slabs, crusts and chimneys on the seafloor, as well as by the geomorphologic diversity of Gazul MV. The results highlight Gazul MV as an eco-biologically important area harboring different vulnerable marine ecosystem (VME) elements with indicator taxa such as scleractinians, sponges, gorgonians and black corals. ROV images revealed abandoned or lost fishing gears and marine debris on the seafloor, indicating anthropogenic impacts in Gazul MV and adjacent areas. Indeed trawling fisheries activities have also been detected in Vessel Monitoring System datasets. A fishery restricted area is recommended in Gazul MV due to the occurrence of diverse VMEs and species included in different conservation directives and conventions.Postprin

Análisis de la opinión de estudiantes sobre conductas de riesgo de jóvenes en Puerto Rico

The main purpose of the study was to analyze the opinion that students of the University of Puerto Rico, Río Piedras Campus (UPRRP) have about some risk behaviors in teenagers of both genders between the ages of 13-18. We administered an online survey, which was taken by 1,836 students enrolled during the first semester of the 2017-18 academic year. We used mixed methods: descriptive statistics analysis and content analysis. The findings reveal that the opinion of students is that youth is a stage of confusion and turbulence; that some risk behaviors have increased during the past five years and that it tends to be associated to male youth. These results suggest that university students tend to reproduce the dominant social imaginary in terms of risk behavior in youth. Further investigations should take into consideration the consequences of youth stigmatization, since this is a heterogeneous and diverse group.El objetivo de nuestro estudio fue analizar la opinión que tienen los/as estudiantes de la Universidad de Puerto Rico, Recinto de Río Piedras (UPRRP), sobre algunas conductas de riesgo en jóvenes de ambos géneros, de 13-18 años.&nbsp; Administramos un cuestionario en línea que fue contestado por 1,836 estudiantes matriculados/as durante el primer semestre del año académico 2017-18. Utilizamos un método mixto: análisis estadístico descriptivo y análisis de contenido. Los hallazgos revelan que la opinión de la mayoría de los/as estudiantes universitarios/as es que la juventud es una etapa de confusión y turbulencia; que algunas conductas de riesgo han aumentado durante los pasados cinco años y que se asocian más con los jóvenes que con las jóvenes. Estos hallazgos sugieren que los/as estudiantes tienden a reproducir los imaginarios sociales dominantes sobre la conducta de riesgo en jóvenes entre las edades de 13-18 años. Futuros trabajos deben considerar las consecuencias de la estigmatización hacia los/as jóvenes, ya que este es un grupo heterogéneo y variado

CARB-ES-19 Multicenter Study of Carbapenemase-Producing Klebsiella pneumoniae and Escherichia coli From All Spanish Provinces Reveals Interregional Spread of High-Risk Clones Such as ST307/OXA-48 and ST512/KPC-3.

CARB-ES-19 is a comprehensive, multicenter, nationwide study integrating whole-genome sequencing (WGS) in the surveillance of carbapenemase-producing K. pneumoniae (CP-Kpn) and E. coli (CP-Eco) to determine their incidence, geographical distribution, phylogeny, and resistance mechanisms in Spain. Methods: In total, 71 hospitals, representing all 50 Spanish provinces, collected the first 10 isolates per hospital (February to May 2019); CPE isolates were first identified according to EUCAST (meropenem MIC > 0.12 mg/L with immunochromatography, colorimetric tests, carbapenem inactivation, or carbapenem hydrolysis with MALDI-TOF). Prevalence and incidence were calculated according to population denominators. Antibiotic susceptibility testing was performed using the microdilution method (EUCAST). All 403 isolates collected were sequenced for high-resolution single-nucleotide polymorphism (SNP) typing, core genome multilocus sequence typing (cgMLST), and resistome analysis. Results: In total, 377 (93.5%) CP-Kpn and 26 (6.5%) CP-Eco isolates were collected from 62 (87.3%) hospitals in 46 (92%) provinces. CP-Kpn was more prevalent in the blood (5.8%, 50/853) than in the urine (1.4%, 201/14,464). The cumulative incidence for both CP-Kpn and CP-Eco was 0.05 per 100 admitted patients. The main carbapenemase genes identified in CP-Kpn were bla OXA-48 (263/377), bla KPC-3 (62/377), bla VIM-1 (28/377), and bla NDM-1 (12/377). All isolates were susceptible to at least two antibiotics. Interregional dissemination of eight high-risk CP-Kpn clones was detected, mainly ST307/OXA-48 (16.4%), ST11/OXA-48 (16.4%), and ST512-ST258/KPC (13.8%). ST512/KPC and ST15/OXA-48 were the most frequent bacteremia-causative clones. The average number of acquired resistance genes was higher in CP-Kpn (7.9) than in CP-Eco (5.5). Conclusion: This study serves as a first step toward WGS integration in the surveillance of carbapenemase-producing Enterobacterales in Spain. We detected important epidemiological changes, including increased CP-Kpn and CP-Eco prevalence and incidence compared to previous studies, wide interregional dissemination, and increased dissemination of high-risk clones, such as ST307/OXA-48 and ST512/KPC-3