First Gaia Dynamics of the Andromeda System: DR2 Proper Motions, Orbits, and Rotation of M31 and M33

The 3D velocities of M31 and M33 are important for understanding the evolution and cosmological context of the Local Group. Their most massive stars are detected by Gaia, and we use Data Release 2 (DR2) to determine the galaxy proper motions (PMs). We select galaxy members based on, e.g., parallax, PM, color-magnitude-diagram location, and local stellar density. The PM rotation of both galaxies is confidently detected, consistent with the known line-of-sight rotation curves: $V_{\rm rot} = -206\pm86$ km s$^{-1}$ (counter-clockwise) for M31, and $V_{\rm rot} = 80\pm52$ km s$^{-1}$ (clockwise) for M33. We measure the center-of-mass PM of each galaxy relative to surrounding background quasars in DR2. This yields that $({\mu}_{\alpha*},{\mu}_{\delta})$ equals $(65 \pm 18 , -57 \pm 15)$ $\mu$as yr$^{-1}$ for M31, and $(31 \pm 19 , -29 \pm 16)$ $\mu$as yr$^{-1}$ for M33. In addition to the listed random errors, each component has an additional residual systematic error of 16 $\mu$as yr$^{-1}$. These results are consistent at 0.8$\sigma$ and 1.0$\sigma$ with the (2 and 3 times higher-accuracy) measurements already available from Hubble Space Telescope (HST) optical imaging and VLBA water maser observations, respectively. This lends confidence that all these measurements are robust. The new results imply that the M31 orbit towards the Milky Way is somewhat less radial than previously inferred, $V_{\rm tan, DR2+HST} = 57^{+35}_{-31}$ km s$^{-1}$, and strengthen arguments that M33 may be on its first infall into M31. The results highlight the future potential of Gaia for PM studies beyond the Milky Way satellite system.Comment: 15 pages, 7 figures, ApJ, in pres

The SUMO project I. A survey of multiple populations in globular clusters

We present a general overview and the first results of the SUMO project (a SUrvey of Multiple pOpulations in Globular Clusters). The objective of this survey is the study of multiple stellar populations in the largest sample of globular clusters homogeneously analysed to date. To this aim we obtained high signal-to-noise (S/N>50) photometry for main sequence stars with mass down to ~0.5 M_SUN in a large sample of clusters using both archival and proprietary U, B, V, and I data from ground-based telescopes. In this paper, we focus on the occurrence of multiple stellar populations in twenty three clusters. We have defined a new photometric index cubi= (U-B)-(B-I), that turns out to be very effective for identifying multiple sequences along the red giant branch (RGB). We found that in the V-cubi diagram all clusters presented in this paper show broadened or multimodal RGBs, with the presence of two or more components. We found a direct connection with the chemical properties of different sequences, that display different abundances of light elements (O, Na, C, N, and Al). The cubi index is also a powerful tool to identify distinct sequences of stars along the horizontal branch and, for the first time in the case of NGC104 (47 Tuc), along the asymptotic giant branch. Our results demonstrate that i) the presence of more than two stellar populations is a common feature among globular clusters, as already highlighted in previous work; ii) multiple sequences with different chemical contents can be easily identified by using standard Johnson photometry obtained with ground-based facilities; iii) in the study of GC multiple stellar populations the cubi index is alternative to spectroscopy, and has the advantage of larger statistics.Comment: 23 pages, 20 figures, accepted for publication in MNRA

HPV-negative Penile Intraepithelial Neoplasia (PeIN) With Basaloid Features.

Most human papillomavirus (HPV)-independent penile squamous cell carcinomas (PSCCs) originate from an intraepithelial precursor called differentiated penile intraepithelial neoplasia, characterized by atypia limited to the basal layer with marked superficial maturation. Previous studies in vulvar cancer, which has a similar dual etiopathogenesis, have shown that about one fifth of HPV-independent precursors are morphologically indistinguishable from high-grade squamous intraepithelial lesions (HSILs), the precursor of HPV-asssociated carcinomas. However, such lesions have not been described in PSCC. From 2000 to 2021, 55 surgical specimens of PSCC were identified. In all cases, thorough morphologic evaluation, HPV DNA detection, and p16, p53, and Ki-67 immunohistochemical (IHC) staining was performed. HPV-independent status was assigned based on both negative results for p16 IHC and HPV DNA. Thirty-six of the 55 PSCC (65%) were HPV-independent. An intraepithelial precursor was identified in 26/36 cases (72%). Five of them (19%) had basaloid features, morphologically indistinguishable from HPV-associated HSIL. The median age of the 5 patients was 74 years (range: 67 to 83 y). All 5 cases were p16 and DNA HPV-negative. Immunohistochemically, 3 cases showed an abnormal p53 pattern, and 2 showed wild-type p53 staining. The associated invasive carcinoma was basaloid in 4 cases and the usual (keratinizing) type in 1. In conclusion, a small proportion of HPV-independent PSCC may arise on adjacent intraepithelial lesions morphologically identical to HPV-associated HSIL. This unusual histologic pattern has not been previously characterized in detail in PSCC. p16 IHC is a valuable tool to identify these lesions and differentiate them from HPV-associated HSIL

Research-based flow cytometry assays for pathogenic assessment in the human B-cell biology of gene variants revealed in the diagnosis of inborn errors of immunity: a Bruton’s tyrosine kinase case-study

IntroductionInborn errors of immunity (IEI) are an expanding group of rare diseases whose field has been boosted by next-generation sequencing (NGS), revealing several new entities, accelerating routine diagnoses, expanding the number of atypical presentations and generating uncertainties regarding the pathogenic relevance of several novel variants.MethodsResearch laboratories that diagnose and provide support for IEI require accurate, reproducible and sustainable phenotypic, cellular and molecular functional assays to explore the pathogenic consequences of human leukocyte gene variants and contribute to their assessment. We have implemented a set of advanced flow cytometry-based assays to better dissect human B-cell biology in a translational research laboratory. We illustrate the utility of these techniques for the in-depth characterization of a novel (c.1685G>A, p.R562Q) de novo gene variant predicted as probably pathogenic but with no previous insights into the protein and cellular effects, located in the tyrosine kinase domain of the Bruton’s tyrosine kinase (BTK) gene, in an apparently healthy 14-year-old male patient referred to our clinic for an incidental finding of low immunoglobulin (Ig) M levels with no history of recurrent infections.Results and discussionA phenotypic analysis of bone marrow (BM) revealed a slightly high percentage of pre-B-I subset in BM, with no blockage at this stage, as typically observed in classical X-linked agammaglobulinemia (XLA) patients. The phenotypic analysis in peripheral blood also revealed reduced absolute numbers of B cells, all pre-germinal center maturation stages, together with reduced but detectable numbers of different memory and plasma cell isotypes. The R562Q variant allows Btk expression and normal activation of anti-IgM-induced phosphorylation of Y551 but diminished autophosphorylation at Y223 after anti IgM and CXCL12 stimulation. Lastly, we explored the potential impact of the variant protein for downstream Btk signaling in B cells. Within the canonical nuclear factor kappa B (NF-κB) activation pathway, normal IκBα degradation occurs after CD40L stimulation in patient and control cells. In contrast, disturbed IκBα degradation and reduced calcium ion (Ca2+) influx occurs on anti-IgM stimulation in the patient’s B cells, suggesting an enzymatic impairment of the mutated tyrosine kinase domain

Delineating Human B Cell Precursor Development With Genetically Identified PID Cases as a Model

B-cell precursors (BCP) arise from hematopoietic stem cells in bone marrow (BM). Identification and characterization of the different BCP subsets has contributed to the understanding of normal B-cell development. BCP first rearrange their immunoglobulin (Ig) heavy chain (IGH) genes to form the pre-B-cell receptor (pre-BCR) complex together with surrogate light chains. Appropriate signaling via this pre-BCR complex is followed by rearrangement of the Ig light chain genes, resulting in the formation, and selection of functional BCR molecules. Consecutive production, expression, and functional selection of the pre-BCR and BCR complexes guide the BCP differentiation process that coincides with corresponding immunophenotypic changes. We studied BCP differentiation in human BM samples from healthy controls and patients with a known genetic defect in V(D)J recombination or pre-BCR signaling to unravel normal immunophenotypic changes and to determine the effect of differentiation blocks caused by the specific genetic defects. Accordingly, we designed a 10-color antibody panel to study human BCP development in BM by flow cytometry, which allows identification of classical preB-I, preB-II, and mature B-cells as defined via BCR-related markers with further characterization by additional markers. We observed heterogeneous phenotypes associated with more than one B-cell maturation pathway, particularly for the preB-I and preB-II stages in which V(D)J recombination takes place, with asynchronous marker expression patterns. Next Generation Sequencing of complete IGH gene rearrangements in sorted BCP subsets unraveled their rearrangement status, indicating that BCP differentiation does not follow a single linear pathway. In conclusion, B-cell development in human BM is not a linear process, but a rather complex network of parallel pathways dictated by V(D)J-recombination-driven checkpoints and pre-BCR/BCR mediated-signaling occurring during B-cell production and selection. It can also be described as asynchronous, because precursor B-cells do not differentiate as full population between the different stages, but rather transit as a continuum, which seems influenced (in part) by V-D-J recombination-driven checkpoints

Dissection of the pre-germinal center B-cell maturation pathway in common variable immunodeficiency based on standardized flow cytometric EuroFlow tools

Copyright © 2021 del Pino-Molina, López-Granados, Lecrevisse, Torres Canizales, Pérez-Andrés, Blanco, Wentink, Bonroy, Nechvatalova, Milota, Kienzler, Philippé, Sousa, van der Burg, Kalina, van Dongen and Orfao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Introduction: Common Variable Immunodeficiency (CVID) is characterized by defective antibody production and hypogammaglobulinemia. Flow cytometry immunophenotyping of blood lymphocytes has become of great relevance for the diagnosis and classification of CVID, due to an impaired differentiation of mature post-germinal-center (GC) class-switched memory B-cells (MBC) and severely decreased plasmablast/plasma cell (Pb) counts. Here, we investigated in detail the pre-GC B-cell maturation compartment in blood of CVID patients. Methods: In this collaborative multicentric study the EuroFlow PID 8-color Pre-GC B-cell tube, standardized sample preparation procedures (SOPs) and innovative data analysis tools, were used to characterize the maturation profile of pre-GC B-cells in 100 CVID patients, vs 62 age-matched healthy donors (HD). Results: The Pre-GC B-cell tube allowed identification within pre-GC B-cells of three subsets of maturation associated immature B-cells and three subpopulations of mature naïve B-lymphocytes. CVID patients showed overall reduced median absolute counts (vs HD) of the two more advanced stages of maturation of both CD5+ CD38+/++ CD21het CD24++ (2.7 vs 5.6 cells/µl, p=0.0004) and CD5+ CD38het CD21+ CD24+ (6.5 vs 17 cells/µl, p1 (CD38, CD5, CD19, CD21, CD24, and/or smIgM) phenotypic marker (57/88 patients; 65%) for a total of 3 distinct CVID patient profiles (group 1: 42/88 patients, 48%; group 2: 8/88, 9%; and group 3: 7/88, 8%) and ii) CVID patients with a clearly altered pre-GC B cell maturation pathway in blood (group 4: 31/88 cases, 35%). Conclusion: Our results show that maturation of pre-GC B-cells in blood of CVID is systematically altered with up to four distinctly altered maturation profiles. Further studies, are necessary to better understand the impact of such alterations on the post-GC defects and the clinical heterogeneity of CVID.The coordination and innovation processes of this study were supported by the EuroFlow Consortium (Chairmen: MB and AO). LP-M was supported by FIS PI16/01605 and JTC by FIS PI13/02296 (Fondo de Investigación Sanitaria Instituto de Salud Carlos III, Madrid, Spain). The work was partially supported by grant PI20/01712-FEDER (Fondo de Investigación Sanitaria Instituto de Salud Carlos III, Madrid, Spain) and a grant from Fundación Mutua Madrileña (MMA, Madrid, Spain).info:eu-repo/semantics/publishedVersio

NEOWISE Observations of Near-Earth Objects: Preliminary Results

With the NEOWISE portion of the \emph{Wide-field Infrared Survey Explorer} (WISE) project, we have carried out a highly uniform survey of the near-Earth object (NEO) population at thermal infrared wavelengths ranging from 3 to 22 $\mu$m, allowing us to refine estimates of their numbers, sizes, and albedos. The NEOWISE survey detected NEOs the same way whether they were previously known or not, subject to the availability of ground-based follow-up observations, resulting in the discovery of more than 130 new NEOs. The survey's uniformity in sensitivity, observing cadence, and image quality have permitted extrapolation of the 428 near-Earth asteroids (NEAs) detected by NEOWISE during the fully cryogenic portion of the WISE mission to the larger population. We find that there are 981$\pm$19 NEAs larger than 1 km and 20,500$\pm$3000 NEAs larger than 100 m. We show that the Spaceguard goal of detecting 90% of all 1 km NEAs has been met, and that the cumulative size distribution is best represented by a broken power law with a slope of 1.32$\pm$0.14 below 1.5 km. This power law slope produces $\sim13,200\pm$1,900 NEAs with $D>$140 m. Although previous studies predict another break in the cumulative size distribution below $D\sim$50-100 m, resulting in an increase in the number of NEOs in this size range and smaller, we did not detect enough objects to comment on this increase. The overall number for the NEA population between 100-1000 m are lower than previous estimates. The numbers of near-Earth comets will be the subject of future work.Comment: Accepted to Ap

Social Models for Dealing with Inequalities

Production of INCASI Project H2020-MSCA-RISE-2015 GA 691004This chapter compares social models in Europe and Latin America. The goal is to study the interaction between two institutions: on the one hand, pre-distributive (ex ante) institutions, such as the structure and coverage of collective bargaining and, on the other hand, post-distributive (ex post) institutions, such as unemployment protection and social policy. Pre-distributive institutions are important for correcting inequalities in the labour market, because they introduce guidelines for egalitarian wage structures. Post-distributive institutions help to mitigate inequalities generated in the labour market. The methodology is based on statistical analysis of a series of indicators related to pre and post-distributive policies. The results present three types of model: (1) coordinated economies, typical of neo-corporatist Scandinavian countries; (2) mixed economies, typical of Mediterranean systems, and (3) uncoordinated economies, which equate to liberalism and the Latin American 'structural heterogeneity' model. It is neo-corporatist coordinated economies that generate the most pre and post-distributive equality. In turn, uncoordinated economies, and Latin American ones in particular, generate more inequalities due to highly informal employment and the weakness of their post-distributive institutions

Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses

Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, displays impaired terminal B-cell differentiation and defective antibody responses. Incomplete genetic penetrance and ample phenotypic expressivity in CVID suggest the participation of additional pathogenic mechanisms. Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease. Here, we generate a single-cell epigenomics and transcriptomics census of naïve-to-memory B cell differentiation in a CVID-discordant MZ twin pair. Our analysis identifies DNA methylation, chromatin accessibility and transcriptional defects in memory B-cells mirroring defective cell-cell communication upon activation. These findings are validated in a cohort of CVID patients and healthy donors. Our findings provide a comprehensive multi-omics map of alterations in naïve-to-memory B-cell transition in CVID and indicate links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, gives insight into future diagnosis and treatments of CVID patients

Unemployment benefits : discursive convergence, distant realities

Production of INCASI Project H2020-MSCA-RISE-2015 GA 691004Unemployment protection systems have certain characteristics in common in Argentina, Uruguay, Spain and Italy: they are compulsory and contributory-proportional, although in Uruguay, it also has a capitalisation supplement. Despite the similarities, they work differently because the context of informal employment chiefly, and unemployment, low salaries and precariousness differ greatly. Consequently, the unemployment protection coverage rate varies. Theories of the Active Welfare State, the Investor State and the reforms of unemployment protection systems have led to a certain modernising language being adopted in these countries: activation, employability, conditionality, lifelong learning, flexibility, which are, among others, words shared with Europe. However, the meanings of these words differ according to the institutional context of each country. In Latin America the welfare state is low institutionalised even almost non-existent, while in Europe it is a diverse institution. Despite this, the four countries share an upward trend in benefit policies, in accordance with the increase in poverty risk