Microbiota Sensing by Mincle-Syk Axis in Dendritic Cells Regulates Interleukin-17 and -22 Production and Promotes Intestinal Barrier Integrity.

Production of interleukin-17 (IL-17) and IL-22 by T helper 17 (Th17) cells and group 3 innate lymphoid cells (ILC3s) in response to the gut microbiota ensures maintenance of intestinal barrier function. Here, we examined the mechanisms whereby the immune system detects microbiota in the steady state. A Syk-kinase-coupled signaling pathway in dendritic cells (DCs) was critical for commensal-dependent production of IL-17 and IL-22 by CD4+ T cells. The Syk-coupled C-type lectin receptor Mincle detected mucosal-resident commensals in the Peyer's patches (PPs), triggered IL-6 and IL-23p19 expression, and thereby regulated function of intestinal Th17- and IL-17-secreting ILCs. Mice deficient in Mincle or with selective depletion of Syk in CD11c+ cells had impaired production of intestinal RegIIIγ and IgA and increased systemic translocation of gut microbiota. Consequently, Mincle deficiency led to liver inflammation and deregulated lipid metabolism. Thus, sensing of commensals by Mincle and Syk signaling in CD11c+ cells reinforces intestinal immune barrier and promotes host-microbiota mutualism, preventing systemic inflammation.

Optimal Generation of Tissue-Resident but Not Circulating Memory T Cells during Viral Infection Requires Crosspriming by DNGR-1+ Dendritic Cells.

Despite the crucial role of tissue-resident memory T (Trm) cells in protective immunity, their priming remains poorly understood. Here, we have shown differential priming requirements for Trm versus circulating memory CD8+ T cells. In vaccinia cutaneous-infected mice, DNGR-1-mediated crosspresentation was required for optimal Trm cell priming but not for their skin differentiation or for circulating memory T cell generation. DNGR-1+ dendritic cells (DCs) promoted T-bet transcription-factor induction and retention of CD8+ T cells in the lymph nodes (LNs). Inhibition of LN egress enhanced Trm cell generation, whereas genetic or antibody blockade of DNGR-1 or specific signals provided during priming by DNGR-1+ DCs, such as interleukin-12 (IL-12), IL-15, or CD24, impaired Trm cell priming. DNGR-1 also regulated Trm cell generation during influenza infection. Moreover, protective immunity depended on optimal Trm cell induction by DNGR-1+ DCs. Our results reveal specific priming requirements for CD8+ Trm cells during viral infection and vaccination.

Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection.

C-type lectin receptors sense a diversity of endogenous and exogenous ligands that may trigger differential responses. Here, we have found that human and mouse Mincle bind to a ligand released by Leishmania, a eukaryote parasite that evades an effective immune response. Mincle-deficient mice had milder dermal pathology and a tenth of the parasite burden compared to wild-type mice after Leishmania major intradermal ear infection. Mincle deficiency enhanced adaptive immunity against the parasite, correlating with increased activation, migration, and priming by Mincle-deficient dendritic cells (DCs). Leishmania triggered a Mincle-dependent inhibitory axis characterized by SHP1 coupling to the FcRγ chain. Selective loss of SHP1 in CD11c+ cells phenocopies enhanced adaptive immunity to Leishmania. In conclusion, Leishmania shifts Mincle to an inhibitory ITAM (ITAMi) configuration that impairs DC activation. Thus, ITAMi can be exploited for immune evasion by a pathogen and may represent a paradigm for ITAM-coupled receptors sensing self and non-self.

Mapping trust relationships in organ donation and transplantation: a conceptual model.

The organ donation and transplantation (ODT) system heavily relies on the willingness of individuals to donate their organs. While it is widely believed that public trust plays a crucial role in shaping donation rates, the empirical support for this assumption remains limited. In order to bridge this knowledge gap, this article takes a foundational approach by elucidating the concept of trust within the context of ODT. By examining the stakeholders involved, identifying influential factors, and mapping the intricate trust relationships among trustors, trustees, and objects of trust, we aim to provide a comprehensive understanding of trust dynamics in ODT. We employ maps and graphs to illustrate the functioning of these trust relationships, enabling a visual representation of the complex interactions within the ODT system. Through this conceptual groundwork, we pave the way for future empirical research to investigate the link between trust and organ donation rates, informed by a clarified understanding of trust in ODT. This study can also provide valuable insights to inform interventions and policies aimed at enhancing organ donation rates.

Upadacitinib in refractory ulcerative colitis.

We report the first clinical-practice case to date of treatment with upadacitinib for ulcerative colitis, prior refractoriness to all therapeutic options, and preventing proctocolectomy as of today after treatment for 14 months.

Flow Cytometry Data Preparation Guidelines for Improved Automated Phenotypic Analysis.

Advances in flow cytometry (FCM) increasingly demand adoption of computational analysis tools to tackle the ever-growing data dimensionality. In this study, we tested different data input modes to evaluate how cytometry acquisition configuration and data compensation procedures affect the performance of unsupervised phenotyping tools. An analysis workflow was set up and tested for the detection of changes in reference bead subsets and in a rare subpopulation of murine lymph node CD103+ dendritic cells acquired by conventional or spectral cytometry. Raw spectral data or pseudospectral data acquired with the full set of available detectors by conventional cytometry consistently outperformed datasets acquired and compensated according to FCM standards. Our results thus challenge the paradigm of one-fluorochrome/one-parameter acquisition in FCM for unsupervised cluster-based analysis. Instead, we propose to configure instrument acquisition to use all available fluorescence detectors and to avoid integration and compensation procedures, thereby using raw spectral or pseudospectral data for improved automated phenotypic analysis.

Ionizing diagnostic radiation exposure in patients with Crohn's disease: A retrospective study in a medium hospital and its predictive factors. / Exposición a radiación diagnóstica en pacientes con enfermedad de Crohn: estudio retrospectivo en un hospital medio y sus factores predictivos.

INTRODUCTION: It is estimated that diagnostic medical radiation exposure may be responsable for 0.5-2% of cancers worldwide. Because of the relapsing course of Crohn's disease (CD), these patients usually requiere multiple ionizing radiation test. OBJECTIVE: Stimating the total cumulative effective dose received by our CD patients and identifying the risk factors associated with the exposure to a cumulative effective dose due to the disease (CEED) > 50mSv. MATERIALS AND METHODS: Retrospective cohort study (2001-2014). POPULATION: patients with CD. Risk dose >50mSv. For calculating de cumulative effective dose and the CEED, all the ionizing test done were taken. For identifying predictive factors for receiving a CEDD >50mSv, an univariate and a multivariate logistic regression analyses were performed using a >50mSv dose as dependent variable. RESULTS: Of the 267 patients analyzed the 24.6% of them received a cumulative effective dose > 50mSv and the 15.2% a CEED>50mSv. In the multivariate analysis, the following variables were identified as independent predictors associated with a CEDD >50mSv: major surgery (OR= 2.1; IC95% [1.1-3.8]; p=.019) and severity (OR= 20.6; IC95% [4.5-94.8]; p<.01). CONCLUSIONS: Patients with CD are more at risk of receiving risk CEED, so it would be advisable to monitor the cumulative effective dose received to anticipate our intervention in order to avoid reaching that dose. The ultrasounds and abdominal resonance enterography are alternatives in these cases, although their accessibility is limited in some centers.

Batf3-dependent CD103+ dendritic cells are major producers of IL-12 that drive local Th1 immunity against Leishmania major infection in mice.

The role of different DC subsets in priming and maintenance of immunity against Leishmania major (L. major) infection is debated. The transcription factor basic leucine zipper transcription factor, ATF-like 3 (Batf3) is essential for the development of mouse CD103(+) DCs and some functions of CD8α(+) DCs. We found that CD103(+) DCs were significantly reduced in the dermis of Batf3-deficient C57BL/6 mice. Batf3(-/-) mice developed exacerbated and unresolved cutaneous pathology following a low dose of intradermal L. major infection in the ear pinnae. Parasite load was increased 1000-fold locally and expanded systemically. Batf3 deficiency did not affect L. major antigen presentation to T cells, which was directly exerted by CD8α(-) conventional DCs (cDCs) in the skin draining LN. However, CD4(+) T-cell differentiation in the LN and skin was skewed to nonprotective Treg- and Th2-cell subtypes. CD103(+) DCs are major IL-12 producers during L. major infection. Local Th1 immunity was severely hindered, correlating with impaired IL-12 production and reduction in CD103(+) DC numbers. Adoptive transfer of WT but not IL-12p40(-/-) Batf3-dependent DCs significantly improved anti-L. major response in infected Batf3(-/-) mice. Our results suggest that IL-12 production by Batf3-dependent CD103(+) DCs is crucial for maintenance of local Th1 immunity against L. major infection.

Prophylactic mesh does not prevent parastomal hernia in long-term: Meta-analysis and trial sequential analysis.

BACKGROUND: Previous randomized clinical trials, systematic reviews, and meta-analyses evaluating parastomal hernia prevention with mesh placement during end colostomy formation have reported contradictory results. This review aimed to assess the efficacy of this strategy in long-term follow-up according to the latest available data. METHODS: Medline, EMBASE, Cochrane Library, Web of Science, and Google Scholar were searched. Randomized clinical trials were included if they compared mesh with no mesh during initial end colostomy creation in adult patients to prevent parastomal hernia with a follow-up longer than 2 years. A meta-analysis was performed to evaluate parastomal hernia incidence (primary outcome), parastomal hernia repair rate, and mortality. Subgroup analysis included surgical approach and mesh position, and trial sequential analysis was performed. RESULTS: Eight randomized clinical trials involving 537 patients met the inclusion criteria. Based on long-term follow-up, the incidence of parastomal hernia was not reduced when a prophylactic mesh was placed (relative risk = 0.68 [95% confidence interval:0.46-1.02]; I2 = 81%, P =.06). The parastomal hernia repair rate was low; however, no difference was found between the groups (relative risk = 0.90 [95% confidence interval:0.51-1.56]; I2 = 0%; P = .70), and no difference was detected between the groups when mortality was assessed (relative risk = 1.03 [95% confidence interval: 0.77-1.39]; I2 = 21%; P = .83). Subgroup analyses did not show differences according to the surgical approach or mesh position used. Regarding trial sequential analysis, an optimal information size was not achieved. CONCLUSION: Prophylactic mesh placement during end colostomy formation does not prevent parastomal hernia in the long term. The parastomal hernia repair rate and mortality rate did not vary between the included groups. Heterogeneity among the included randomized clinical trials might restrict the reliability of the results.

Regulating Chemisorption and Electrosorption Activity for Efficient Uptake of Rare Earth Elements in Low Concentration on Oxygen-Doped Molybdenum Disulfide.

Recovery of rare earth elements (REEs) with trace amount in environmental applications and nuclear energy is becoming an increasingly urgent issue due to their genotoxicity and important role in society. Here, highly efficient recovery of low-concentration REEs from aqueous solutions by an enhanced chemisorption and electrosorption process of oxygen-doped molybdenum disulfide (O-doped MoS2) electrodes is performed. All REEs could be extremely recovered through a chemisorption and electrosorption coupling (CEC) method, and sorption behaviors were related with their outer-shell electrons. Light, medium, and heavy ((La(III), Gd(III), and Y(III)) rare earth elements were chosen for further investigating the adsorption and recovery performances under low-concentration conditions. Recovery of REEs could approach 100% under a low initial concentration condition where different recovery behaviors occurred with variable chemisorption interactions between REEs and O-doped MoS2. Experimental and theoretical results proved that doping O in MoS2 not only reduced the transfer resistance and improved the electrical double layer thickness of ion storage but also enhanced the chemical interaction of REEs and MoS2. Various outer-shell electrons of REEs performed different surficial chemisorption interactions with exposed sulfur and oxygen atoms of O-doped MoS2. Effects of variants including environmental conditions and operating parameters, such as applied voltage, initial concentration, pH condition, and electrode distance on adsorption capacity and recovery of REEs were examined to optimize the recovery process in order to achieve an ideal selective recovery of REEs. The total desorption of REEs from the O-doped MoS2 electrode was realized within 120 min while the electrode demonstrated a good cycling performance. This work presented a prospective way in establishing a CEC process with a two-dimensional metal sulfide electrode through structure engineering for efficient recovery of REEs within a low concentration range.

Family bereavement and organ donation in Spain: a mixed method, prospective cohort study protocol.

INTRODUCTION: There is a discrepancy in the literature as to whether authorising or refusing the recovery of organs for transplantation is of direct benefit to families in their subsequent grieving process. This study aims to explore the impact of the family interview to pose the option of posthumous donation and the decision to authorise or refuse organ recovery on the grieving process of potential donors' relatives. METHODS AND ANALYSIS: A protocol for mixed methods, prospective cohort longitudinal study is proposed. Researchers do not randomly assign participants to groups. Instead, participants are considered to belong to one of three groups based on factors related to their experiences at the hospital. In this regard, families in G1, G2 and G3 would be those who authorised organ donation, declined organ donation or were not asked about organ donation, respectively. Their grieving process is monitored at three points in time: 1 month after the patient's death, when a semistructured interview focused on the lived experience during the donation process is carried out, 3 months and 9 months after the death. At the second and third time points, relatives' grieving process is assessed using six psychometric tests: State-Trait Anxiety Inventory, Beck Depression Inventory-II, Inventory of Complicated Grief, The Impact of Event Scale: Revised, Posttraumatic Growth Inventory and Connor-Davidson Resilience Scale. Descriptive statistics (means, SDs and frequencies) are computed for each group and time point. Through a series of regression models, differences between groups in the evolution of bereavement are estimated. Additionally, qualitative analyses of the semistructured interviews are conducted using the ATLAS.ti software. ETHICS AND DISSEMINATION: This study involves human participants and was approved by Comité Coordinador de Ética de la Investigación Biomédica de Andalucía (CCEIBA) ID:1052-N-21. The results will be disseminated at congresses and ordinary academic forums. Participants gave informed consent to participate in the study before taking part.

Brownian motion on an out-of-thermal-equilibrium surface.

The motion of colloidal species on an out-of-thermal equilibrium surface is studied experimentally by optical microscopy. Water droplets of size in the micrometer range, spontaneously formed at a spherical-like interface between water and oil, are the colloidal species. The interface appears as a convex meniscus when putting water on oil with an added nonionic surfactant. Since the water density is greater than that of oil, the interface is produced into the oil. The spontaneously formed water droplets move attached to the interface while still growing from submicrometer sizes to a few micrometers. Although the dynamic nature of the process, with both the interface and the particles still changing, produces heterogeneities in the system, anomalous diffusion was not observed. The motion of the droplets has a well-identified Brownian component with a Gaussian distribution of steps due to the thermal agitation of the media surrounding the droplets and a drift component due to the effect of gravity.

[Feminist public health, another view on the pandemic.] / Por una salud pública feminista, otra lectura sobre la pandemia.

Theorists of the ethics and politics of care, with their feminist and intersectional analyses, have spent decades trying to leave their mark on clinical practice and political structures . In them, extensive processes of humanization of the relationship between professionals and people who need their care are required, without neglecting inequalities due to gender, social class or belonging to vulnerable minority groups that go through health and disease experiences in the community. society. It is evident that our institutions must be extensively rethought in their foundations; from nursing homes to highly technological ICUs; from the saturation of primary care to the lack of specialized personnel. In areas such as nursing, great emphasis is placed on models based on interdependence and the particular context to generate another care framework , while fighting for hierarchies and invisibilities related to highly feminized professions . Not surprisingly, the reflections that follow are signed by three women with hybrid profiles who have dedicated part of our working life to the field of primary and hospital care (both in nursing and in physiotherapy) and, in turn, to research and teaching in bioethics, philosophy and humanities. We have experienced in our flesh the contradictions between a will to serve and some axes of oppression connatural to the institutions.

Las teóricas de las éticas y políticas del cuidado, con sus análisis en clave feminista e interseccional, llevan décadas intentando dejar huella en la práctica clínica y en las estructuras políticas . En ellas, se requieren amplios procesos de humanización de la relación entre profesionales y personas que necesitan su atención, sin dejar de lado las desigualdades por motivos de género, clase social o pertenencia a colectivos vulnerables minoritarios que atraviesan las vivencias de salud y enfermedad en la sociedad. Es evidente que nuestras instituciones deben ser ampliamente repensadas en sus fundamentos; desde las residencias de ancianos a las UCI altamente tecnologizadas; desde la saturación de la atención primaria a la falta de personal especializado. En ámbitos como la enfermería se hace gran hincapié en los modelos basados en la interdependencia y el contexto particular para generar otro marco de asistencia , a la vez que se lucha por las jerarquías e invisibilidades relacionadas con las profesiones altamente feminizadas . No en vano las reflexiones que siguen las firman tres mujeres con perfiles híbridos que hemos dedicado parte de nuestra vida laboral al ámbito de la atención primaria y hospitalaria (tanto en enfermería como en fisioterapia) y, a su vez, a la investigación y la docencia en bioética, filosofía y humanidades. Hemos vivido en nuestras carnes las contradicciones entre una voluntad de servicio y unos ejes de opresión connaturales a las instituciones.

Evaluation of a Program of Aquatic Motor Games in the Improvement of Motor Competence in Children from 4 to 5 Years Old.

The present study aimed to verify whether a program of initiation to the aquatic environment composed of motor games (motor stories, learning environments and motor circuits) is more effective in the acquisition of aquatic skills in early childhood education than a traditional program. For this purpose, the Escala de Competencia Motriz Acuática for 4-5 year-old children was used before and after both programs. This scale has two factors, one named Familiarization, linked to more elementary aquatic abilities, and the Immersion factor, which integrates more advanced aquatic abilities. The two programs were used as independent variables, and there was a sample of 17 children over six weeks. The results show that both programs improved the acquisition of aquatic skills. The program that integrated motor games impacted the improvement of skills related to the Immersion factor significantly more.

Macrophage cytokine responses to commensal Gram-positive Lactobacillus salivarius strains are TLR2-independent and Myd88-dependent.

The mechanisms through which cells of the host innate immune system distinguish commensal bacteria from pathogens are currently unclear. Toll-like receptors (TLRs) are a class of pattern recognition receptors (PRRs) expressed by host cells which recognize microbe-associated molecular patterns (MAMPs) common to both commensal and pathogenic bacteria. Of the different TLRs, TLR2/6 recognize bacterial lipopeptides and trigger cytokines responses, especially to Gram-positive and Gram-negative pathogens. We report here that TLR2 is dispensable for triggering macrophage cytokine responses to different strains of the Gram-positive commensal bacterial species Lactobacillus salivarius. The L. salivarius UCC118 strain strongly upregulated expression of the PRRs, Mincle (Clec4e), TLR1 and TLR2 in macrophages while downregulating other TLR pathways. Cytokine responses triggered by L. salivarius UCC118 were predominantly TLR2-independent but MyD88-dependent. However, macrophage cytokine responses triggered by another Gram-positive commensal bacteria, Bifidobacterium breve UCC2003 were predominantly TLR2-dependent. Thus, we report a differential requirement for TLR2-dependency in triggering macrophage cytokine responses to different commensal Gram-positive bacteria. Furthermore, TNF-α responses to the TLR2 ligand FSL-1 and L. salivarius UCC118 were partially Mincle-dependent suggesting that PRR pathways such as Mincle contribute to the recognition of MAMPs on distinct Gram-positive commensal bacteria. Ultimately, integration of signals from these different PRR pathways and other MyD88-dependent pathways may determine immune responses to commensal bacteria at the host-microbe interface.

SHP-1 Regulates Antigen Cross-Presentation and Is Exploited by Leishmania to Evade Immunity.

Intracellular pathogens have evolved strategies to evade detection by cytotoxic CD8+ T lymphocytes (CTLs). Here, we ask whether Leishmania parasites trigger the SHP-1-FcRγ chain inhibitory axis to dampen antigen cross-presentation in dendritic cells expressing the C-type lectin receptor Mincle. We find increased cross-priming of CTLs in Leishmania-infected mice deficient for Mincle or with a selective loss of SHP-1 in CD11c+ cells. The latter also shows improved cross-presentation of cell-associated viral antigens. CTL activation in vitro reveals increased MHC class I-peptide complex expression in Mincle- or SHP-1-deficient CD11c+ cells. Neuraminidase treatment also boosts cross-presentation, suggesting that Leishmania triggers SHP-1-associated sialic-acid-binding receptors. Mechanistically, enhanced antigen processing correlates with reduced endosomal acidification in the absence of SHP-1. Finally, we demonstrate that SHP-1 inhibition improves CD11c+ cell-based vaccination against the parasite. Thus, SHP-1-mediated impairment of cross-presentation can be exploited by pathogens to evade CTLs, and SHP-1 inhibition improves CTL responses during vaccination.

Leishmania Hijacks Myeloid Cells for Immune Escape.

Protozoan parasites of the Leishmania genus are the causative agents of leishmaniasis, a group of neglected tropical diseases whose clinical manifestations vary depending on the infectious Leishmania species but also on host factors. Recognition of the parasite by host myeloid immune cells is a key to trigger an effective Leishmania-specific immunity. However, the parasite is able to persist in host myeloid cells by evading, delaying and manipulating host immunity in order to escape host resistance and ensure its transmission. Neutrophils are first in infiltrating infection sites and could act either favoring or protecting against infection, depending on factors such as the genetic background of the host or the parasite species. Macrophages are the main host cells where the parasites grow and divide. However, macrophages are also the main effector population involved in parasite clearance. Parasite elimination by macrophages requires the priming and development of an effector Th1 adaptive immunity driven by specific subtypes of dendritic cells. Herein, we will provide a comprehensive outline of how myeloid cells regulate innate and adaptive immunity against Leishmania, and the mechanisms used by the parasites to promote their evasion and sabotage. Understanding the interactions between Leishmania and the host myeloid cells may lead to the development of new therapeutic approaches and improved vaccination to leishmaniases, an important worldwide health problem in which current therapeutic or preventive approaches are limited.

Flexible Signaling of Myeloid C-Type Lectin Receptors in Immunity and Inflammation.

Myeloid C-type lectin receptors (CLRs) are important sensors of self and non-self that work in concert with other pattern recognition receptors (PRRs). CLRs have been previously classified based on their signaling motifs as activating or inhibitory receptors. However, specific features of the ligand binding process may result in distinct signaling through a single motif, resulting in the triggering of non-canonical pathways. In addition, CLR ligands are frequently exposed in complex structures that simultaneously bind different CLRs and other PRRs, which lead to integration of heterologous signaling among diverse receptors. Herein, we will review how sensing by myeloid CLRs and crosstalk with heterologous receptors is modulated by many factors affecting their signaling and resulting in differential outcomes for immunity and inflammation. Finding common features among those flexible responses initiated by diverse CLR-ligand partners will help to harness CLR function in immunity and inflammation.