cDC1s: New Orchestrators of Tissue Innate Immunity

Type-I conventional dendritic cells (cDC1s) are key in inducing adaptive immunity. Using single-cell sequencing, Ginhoux and colleagues (Immunity 2019;50:1069-1083.e8) find that a subset of activated cDC1s in bacteria-infected skin is critical for neutrophil recruitment via the production of VEGF-α. These results reveal a crucial function for cDC1s beyond antigen presentation.C.d.F. is supported by AECC Foundation as recipient of an ‘Ayuda Fundación Científica AECC a personal investigador en cancer’. Work in the D.S. laboratory is funded by the CNIC and grant SAF2016-79040-R from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO), Agencia Estatal de Investigación and FEDER (European Fund for Regional Development); B2017/BMD-3733 Immunothercan-CM from Comunidad de Madrid; RD16/0015/0018-REEM from FIS-Instituto de Salud Carlos III, MINECO and FEDER; Foundation Acteria; Constantes y Vitales prize (Atresmedia); Foundation La Marató de TV3 (201723); the European Commission (635122-PROCROP H2020) and the European Research Council (ERCConsolidator Grant 725091). The CNIC is supported by the MINECO and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505).S

Clec2d Joins the Cell Death Sensor Ranks

Sensing tissue damage is an ancient function of immune cells that is central to the regulation of inflammation, tissue repair, and immunity. In this issue of Immunity, Lai et al. (2020) uncover a role for the C-type lectin receptor Clec2d as a sensor of cell death, which directly detects histones released during necrosis and thus contributes to inflammation and immunopathology.C.d.F. is supported by the AECC Foundation (INVES192DELF). Work in the DS laboratory is funded by the CNIC; the European Research Council (ERC 2016 Consolidator Grant 725091); the European Commission (635122-PROCROP H2020); Ministerio de Ciencia, Innovacion e Universidades (MICINN), Agencia Estatal de Investigacion, and Fondo Europeo de Desarrollo Regional (FEDER) (SAF2016-79040-R); Comunidad de Madrid (B2017/BMD-3733 Immunothercan-CM); FIS-Instituto de Salud Carlos III, MICINN, and FEDER (RD16/0015/0018-REEM); the Acteria Foundation; Atresmedia (Constantes y Vitales prize); and Fundacio La Marato de TV3 (201723). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MICINN, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505)

A Proposal for Nomenclature in Myeloid C-Type Lectin Receptors

Myeloid C-type lectin receptors (CLRs) comprise a family of receptors expressed by immune myeloid cells that share homologous C-type lectin domains. The implication of these CLRs in the regulation of homeostasis and activation of myeloid cells has generated a buoyant growth in the number of studies involving these receptors. Since their first description, diverse nomenclature has been used to refer to each of them, ranging from systematic classifications, such as gene name or cluster of differentiation, to non-systematic ones that include terminology based on gene expression patterns or function. In this review, we aim to summarize the different names used for the main myeloidCLRs and analyzewhich of themhave beenmore frequently used in the literature. In addition, we have examined the evolution of the terminology applied to these myeloid CLRs over time. Based on this analysis, we propose a consensus alias for each of those myeloid CLRs. However, we acknowledge that systematicity is required beyond this terminology based on use frequency. Therefore, we have included gene names as the standardization tool to gather the maximum agreement. We suggest that a standard nomenclature consisting of both gene names and consensus alias should be included at least in scientific abstracts, which would help to identify relevant literature, saving time and effort and fostering the research in this field in a more systematic manner.CF was supported by AECC Foundation (INVES192DELF). Work in the DS laboratory was funded by the CNIC and grant SAF2016-79040-R from Ministerio de Ciencia, Innovacion e Universidades (MCIU), Agencia Estatal de Investigacion and Fondo Europeo de Desarrollo Regional (FEDER); B2017/BMD-3733 Immunothercan-CM from Comunidad de Madrid; RD16/0015/0018-REEM from FIS-Instituto de Salud Carlos III, MICINN, and FEDER; Acteria Foundation; Constantes y Vitales prize (Atresmedia); La Marato de TV3 Foundation (201723); the European Research Council (ERC-2016-Consolidator Grant 725091); and the European Commission (635122-PROCROP H2020). The CNIC is supported by the MCIU and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

A multi-parametric analysis of Trypanosoma cruzi infection: common pathophysiologic patterns beyond extreme heterogeneity of host responses

The extreme genetic diversity of the protozoan Trypanosoma cruzi has been proposed to be associated with the clinical outcomes of the disease it provokes: Chagas disease (CD). To address this question, we analysed the similarities and differences in the CD pathophysiogenesis caused by different parasite strains. Using syngeneic mice infected acutely or chronically with 6 distant parasite strains, we integrated simultaneously 66 parameters: parasite tropism (7 parameters), organ and immune responses (local and systemic; 57 parameters), and clinical presentations of CD (2 parameters). While the parasite genetic background consistently impacts most of these parameters, they remain highly variable, as observed in patients, impeding reliable one-dimensional association with phases, strains, and damage. However, multi-dimensional statistics overcame this extreme intra-group variability for each individual parameter and revealed some pathophysiological patterns that accurately allow defining (i) the infection phase, (ii) the infecting parasite strains, and (iii) organ damage type and intensity. Our results demonstrated a greater variability of clinical outcomes and host responses to T. cruzi infection than previously thought, while our multi-parametric analysis defined common pathophysiological patterns linked to clinical outcome of CD, conserved among the genetically diverse infecting strains

Numerical and Experimental Evaluation of a CFRP Fatigue Strengthening for Stringer-Floor Beam Connections in a 19th Century Riveted Railway Bridge

ABSTRACT: A local and global finite element analysis of the stringer-floor beam connection of a 19th century riveted railway bridge in Spain made of puddle iron were performed to obtain the maximum principal strains in the riveted connecting angles corresponding to bending moments from train loading on the bridge. Due to the anisotropic nature of puddle iron, the connecting angles were modelled using Hill anisotropic plasticity potential and a parametric study in the local FE model of the connection was performed. A laboratory specimen fabricated with original stringers dismantled from the railway bridge was tested to calibrate the numerical models, so the yield stress ratio that best fitted experimental results was obtained. Based on the method of constant fatigue-life diagram and modified Goodman fatigue failure criterion, it was detected that the connecting angles were prone to fatigue crack initiation, as the combination of mean stress and alternating stress amplitude at the toe of the angle fillet remained outside the infinite fatigue-life region. An innovative strengthening system based on adhesively-bonded carbon-fiber reinforced polymer (CFRP) angles was designed to prevent fatigue crack initiation in the connecting angles of the stringer-floor beam connection. Different CFRP laminate layouts were numerically evaluated and a proper configuration was obtained that reduced both the mean stress and the alternating stress amplitude in the connecting angle to shift from finite fatigue-life region to infinite fatigue-life region in the constant fatigue-life diagram. To validate the effectiveness of the proposed CFRP strengthening method, its application on a second laboratory specimen fabricated with original stringers was evaluated experimentally and compared with numerical results. The research study conducted showed that the use of adhesively-bonded CFRP angles was an effective strengthening system in reducing the stress level in the fillet region of the puddle iron connecting angles (where fatigue cracks are prone to initiate) and consequently could increase fatigue life of the stringer-floor beam connection

Clinical phenotype clustering in cardiovascular risk patients for the identification of responsive metabotypes after red wine polyphenol intake

© 2015 Elsevier Inc. This study aims to evaluate the robustness of clinical and metabolic phenotyping through, for the first time, the identification of differential responsiveness to dietary strategies in the improvement of cardiometabolic risk conditions. Clinical phenotyping of 57 volunteers with cardiovascular risk factors was achieved using k-means cluster analysis based on 69 biochemical and anthropometric parameters. Cluster validation based on Dunn and Figure of Merit analysis for internal coherence and external homogeneity were employed. k-Means produced four clusters with particular clinical profiles. Differences on urine metabolomic profiles among clinical phenotypes were explored and validated by multivariate orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) models. OSC-PLS-DA of 1H-NMR data revealed that model comparingPostprint (published version

Targeting SHIP-1 in Myeloid Cells Enhances Trained Immunity and Boosts Response to Infection

beta-Glucan-induced trained immunity in myeloid cells leads to long-term protection against secondary infections. Although previous studies have characterized this phenomenon, strategies to boost trained immunity remain undefined. We found that beta-glucan-trained macrophages from mice with a myeloid-specific deletion of the phosphatase SHIP-1 (LysM Delta SHIP-1) showed enhanced proinflammatory cytokine production in response to lipopolysaccharide. Following beta-glucan training, SHIP-1-deficient macrophages exhibited increased phosphorylation of Akt and mTOR targets, correlating with augmented glycolytic metabolism. Enhanced training in the absence of SHIP-1 relied on histone methylation and acetylation. Trained LysM Delta SHIP-1 mice produced increased amounts of proinflammatory cytokines upon rechallenge in vivo and were better protected against Candida albicans infection compared with control littermates. Pharmacological inhibition of SHIP-1 enhanced trained immunity against Candida infection in mouse macrophages and human peripheral blood mononuclear cells. Our data establish proof of concept for improvement of trained immunity and a strategy to achieve it by targeting SHIP-1.We thank the members of the Immunobiology Lab for useful discussions. We thank the CNIC facilities and personnel, particularly Santiago Rodriguez and Ruben Mota, for their support. P.S.-L. is funded by grant BES-2015-072699 (´´Ayudas para Contratos Predoctorales para la Formacion de Doctores 2015´´) from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO). C.d.F. is supported by the Asociacion Espanola Contra el Cancer (AECC) Foundation as a recipient of an ``Ayuda Fundacion Cientifica AECC a Personal Investigador en Cancer´´ grant. Work in the Sancho laboratory is funded by CNIC and grant SAF2016-79040-R from MINECO, Agencia Estatal de Investigacion, and FEDER (European Fund for Regional Development); grant B2017/BMD-3733 Immunothercan-CM from Comunidad de Madrid; grant RD16/0015/0018-REEM from FIS-Instituto de Salud Carlos III, MINECO, and FEDER; Foundation Acteria; a Constantes y Vitales prize (Atresmedia); Foundation La Marato de TV3 (grant 201723); the European Commission (grant 635122-PROCROP H2020); and the European Research Council (ERC-2016-Consolidator Grant 725091). CNIC is supported by MINECO and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). W.G.K. is an Empire Scholar of the State of New York, the Murphy Family Professor of Children's Oncology Research, and is supported by funds from the Paige Arnold Butterfly Run.S

Clinical Phenotype Clustering in Cardiovascular risk patients for the identification of Responsive Metabotypes after red Wine Polyphenol intake

This study aims to evaluate the robustness of clinical and metabolic phenotyping through, for the first time, the identification of differential responsiveness to dietary strategies in the improvement of cardiometabolic risk conditions. Clinical phenotyping of 57 volunteers with cardiovascular risk factors was achieved using k-means cluster analysis based on 69 biochemical and anthropometric parameters. Cluster validation based on Dunn and FOM analysis for internal coherence and external homogeneity were employed. k-means produced four clusters with particular clinical profiles. Differences on urine metabolomic profiles among clinical phenotypes were explored and validated by multivariate OSC-PLS-DA models. OSC-PLS-DA of 1H-NMR data revealed that model comparing 'obese and diabetic cluster' (OD-c) against 'healthier cluster' (H-c) showed the best predictability and robustness in terms of explaining the pairwise differences between clusters. Considering these two clusters, distinct groups of metabolites were observed following an intervention with wine polyphenol intake (WPI, 733 equivalents of gallic acid/day) per 28 days. Glucose was significantly linked to OD-c metabotype (p<0.01), and lactate, betaine and dimethylamine showed a significant trend. Whereas, associated to wine polyphenol intervention (OD-c_WPI and H-c_WPI) was tartrate (p<0.001), and mannitol, threonine methanol, fucose and 3-hydroxyphenylacetate showed a significant trend. Interestingly, 4-hydroxyphenylacetate significantly increased in H-c_WPI (p<0.05) compared to OD-c_WPI and to basal groups (gut microbial derived metabolite after polyphenol intake), thereby exhibiting a clear metabotypic intervention effect. Results revealed gut microbiota responsive phenotypes to wine polyphenols intervention. Overall, this study illustrates a novel metabolomic strategy for characterizing inter-individual responsiveness to dietary intervention and identification of health benefits

Is Covid-19 Severity Associated With ACE2 Degradation?

Covid-19 is particularly mild with children, and its severity escalates with age. Several theories have been proposed to explain these facts. In particular, it was proposed that the lower expression of the viral receptor ACE2 in children protects them from severe Covid-19. However, other works suggested an inverse relationship between ACE2 expression and disease severity. Here we review the seemingly contradicting observations on ACE2 expression at the levels of mRNA, membrane protein and serum protein in humans and rodents and try to reconcile them at the light of the Renin-Angiotensin system (RAS) and bradykinin system, which constitute an integrated inflammatory system connected by common peptidases and interacting receptors. We find that ACE2 level is not monotonically related with age but it reaches a maximum at a young age that depends on the cell type and then decreases, consistently with almost all existing data. The increase with age of the protease Tumor necrosis factor alpha (TNF-α) converting enzyme (TACE), also known as ADAM17 (a disintegrin and metalloproteinase 17) that sheds ACE2 from the cell membrane to the serum predicts that the decrease occurs before and is steeper for ACE2 cell protein than for its mRNA. This negative relation between ACE2 level and Covid-19 severity at old age is not paradoxical but it is consistent with a mathematical model that predicts that higher viral receptor does not necessarily favour virus propagation and it can even slow it down. More importantly, the angiotensin-bradykinin system is characterized by a powerful positive feedback loop that enhances inflammation through the Angiotensin and Bradykinin receptors that upregulate ADAM17, which in turn downregulates ACE2 and upregulates TNF-α and the pro-inflammatory receptor of the cytokine interleukin 6 (IL6). Here we propose that ACE2 contributes essentially to reverse this inflammatory state by downregulating the pro-inflammatory peptides of the angiotensin-bradykinin system, and that failure to do this, possibly induced by the degradation of ACE2 by SARS-COV-2, may underlie both severe CoViD-19 infection and its many post-infection manifestations, including the multi-inflammatory syndrome of children (MIS-C). Within this view, lower severity in children despite lower ACE2 expression may be consistent with their higher expression of the alternative angiotensin II receptor ATR2 and in general of the anti-inflammatory arm of the RAS at young age

Multidimensional Construction Planning and Agile Organized Project Execution?The 5D-PROMPT Method

Although tremendous technological and strategic advances have been developed and implemented in the construction sector in recent years, there is substantial room for improvement in the areas of productivity growth, project performance, and schedule reliability. Thus, the present paper seeks to discover why the currently applied scheduling tools and the latest agile-based project organization approaches have not yet achieved their full potential. A missing interlinkage between the project?s design, cost, and time aspects within the project design phase and its sparse utilization throughout project execution were indicated as the driving contributors responsible for the slow progress in development. To fundamentally change this situation, an extensive and coherent project organization solution is proposed. The key process of this solution utilizes a 5D Building Information Model comprising tight concatenations between the individual model objects and the corresponding construction cost and time effort values. The key dates of a waterfall-based construction process simulation, set during the project planning phase, provide particular information to create a structure for agile organized project execution. The implementation of information feedback loops allows target/actual comparisons and contributes to continual improvements in future planning. A comparative case study was conducted with auspicious results on improvements in the overall project performance, and schedule and cost reliabilityThis research was supported by Heinrich Schmid GmbH&Co.KG regarding the cooperative conduction of two construction projects used for the case-study; RIB Software SE, who provided the BIM software platform iTWO Baseline and the site management software OnSite, and Contelos GmbH for the provision of the 3D Building Information Model