Touch of chemokines

Chemoattractant cytokines or chemokines constitute a family of structurally related proteins found in vertebrates, bacteria, or viruses. So far, 48 chemokine genes have been identified in humans, which bind to around 20 chemokine receptors These receptors belong to the seven transmembrane G-protein-coupled receptor family. Chemokines and their receptors were originally studied for their role in cellular trafficking of leukocytes during inflammation and immune surveillance. It is now known that they exert different functions under physiological conditions such as homeostasis, development, tissue repair, and angiogenesis but also under pathological disorders including tumorigenesis, cancer metastasis, inflammatory, and autoimmune diseases. Physicochemical properties of chemokines and chernokine receptors confer the ability to homo- and hetero-oligornerize. Many efforts are currently performed in establishing new therapeutically compounds able to target the chemokine/chemokine receptor system. In this review, we are interested in the role of chemokines in inflammatory disease and leukocyte trafficking with a focus on vascular inflammatory diseases, the operating synergism, and the emerging therapeutic approaches of chemokines

Hubble Space Telescope survey of Magellanic Cloud star clusters: photometry and astrometry of 113 clusters and early results

In the past few years, we have undertaken an extensive investigation of star clusters and their stellar populations in the Large and Small Magellanic Clouds (LMC and SMC) based on archival images collected with the Hubble Space Telescope. We present photometry and astrometry of stars in 101 fields observed with the Wide Field Channel of the Advanced Camera for Surveys and the Ultraviolet and Visual Channel and the Near-Infrared Channel of Wide Field Camera 3. These fields comprise 113 star clusters. We provide differential-reddening maps for those clusters with significant reddening variations across the field of view. We illustrate various scientific outcomes that arise from the early inspection of the photometric catalogs. In particular, we provide new insights into the extended main-sequence turnoff (eMSTO) phenomenon: (i) We detected eMSTOs in two clusters, KMHK 361 and NGC 265, which had no previous evidence of multiple populations. This finding corroborates the conclusion that the eMSTO is a widespread phenomenon among clusters younger than ~2 Gyr. (ii) The homogeneous color-magnitude diagrams (CMDs) of 19 LMC clusters reveal that the distribution of stars along the eMSTO depends on cluster age. (iii) We discovered a new feature along the eMSTO of NGC 1783, which consists of a distinct group of stars on the red side of the eMSTO in CMDs composed of UV filters. Furthermore, we derived the proper motions of stars in the fields of view of clusters with multi-epoch images. Proper motions allowed us to separate the bulk of bright field stars from cluster members and investigate the internal kinematics of stellar populations in various LMC and SMC fields. As an example, we analyze the field around NGC 346 to disentangle the motions of its stellar populations, including NGC 364 and BS 90, young and pre-main-sequence stars in the star-forming region associated with NGC 346, and young and old field stellar populations of the SMC. Based on these results and the fields around five additional clusters, we find that young SMC stars exhibit elongated proper-motion distributions that point toward the LMC, thus providing new evidence for a kinematic connection between the LMC and SMC.We thank the anonymous referee for various suggestions that improved the quality of the manuscript. This work has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research innovation programme (Grant Agreement ERC-StG 2016, No. 716082 ’GALFOR’, PI: Milone, http://progetti.dfa.unipd. it/GALFOR) and from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Grant Agreement No. 101034319 and from the European Union – NextGenerationEU, beneficiary: Ziliotto. A.P.M., M.T., and E.D. acknowledge support from MIUR through the FARE project R164RM93XW SEMPLICE (PI: Milone). A.P.M. and M.T. have been supported by MIUR under PRIN program 2017Z2HSMF (PI: Bedin). This research was supported in part by the Australian Research Council Centre of Excellence for All Sky Astrophysics in 3 Dimensions (ASTRO 3D) through project number CE170100013. This work is based on observations made with the NASA/ESA Hubble Space Telescope, obtained from the data archive at the Space Telescope Science Institute (STScI). STScI is operated by the Association of Universities for Research in Astronomy, Inc. under NASA contract NAS 5-26555.Peer ReviewedPostprint (published version

Controlled intramyocardial release of engineered chemokines by biodegradable hydrogels as a treatment approach of myocardial infarction

Myocardial infarction (MI) induces a complex inflammatory immune response, followed by the remodelling of the heart muscle and scar formation. The rapid regeneration of the blood vessel network system by the attraction of hematopoietic stem cells is beneficial for heart function. Despite the important role of chemokines in these processes, their use in clinical practice has so far been limited by their limited availability over a long time-span in vivo. Here, a method is presented to increase physiological availability of chemokines at the site of injury over a defined time-span and simultaneously control their release using biodegradable hydrogels. Two different biodegradable hydrogels were implemented, a fast degradable hydrogel (FDH) for delivering Met-CCL5 over 24hrs and a slow degradable hydrogel (SDH) for a gradual release of protease-resistant CXCL12 (S4V) over 4weeks. We demonstrate that the time-controlled release using Met-CCL5-FDH and CXCL12 (S4V)-SDH suppressed initial neutrophil infiltration, promoted neovascularization and reduced apoptosis in the infarcted myocardium. Thus, we were able to significantly preserve the cardiac function after MI. This study demonstrates that time-controlled, biopolymer-mediated delivery of chemokines represents a novel and feasible strategy to support the endogenous reparatory mechanisms after MI and may compliment cell-based therapies

Aesthetic caries infiltration - Long-term masking efficacy after 6 years.

OBJECTIVES This study aimed to evaluate the masking efficacy of caries infiltration technique of initial caries lesions (ICL) six years after debonding and single treatment. METHODS In 10 adolescents, 74 ICL (ICDAS 2) in 74 teeth were treated by resin infiltration (Icon, DMG) at a mean (SD) of 1.2 (1.2) months after bracket removal. The etching procedure was performed up to 3 times. Standardized digital images were taken before treatment (T0), seven days (T7) and 6 years (T2190) after treatment. Outcomes included the evaluation of the color differences between carious and healthy enamel at T0, T7 and T2190 by quantitative colorimetric analysis (ΔE), ICDAS scores, quantitative light-induced fluorescence (QLF; ΔF,ΔQ,WS Area) and qualitative visual evaluation (5-point Likert-scale [deteriorated (1), unchanged (2), improved, but not satisfying (3), improved and no further treatment required (4), completely masked (5)). RESULTS The median color difference ΔΕ0 (25th/75th percentiles) at T0 was 10.3 (8.56/13.0). At T7 a significant decrease was observed (ΔΕ7=3.7 (2.0/5.8); p<0.001; Friedmann-test; ICDAS p<0.001; Chi-square test). No significant changes based on ΔΕ (p=0.972; Friedmann-test) and ICDAS grading (p=0.511, chi-square test) were observed between T7 and T2190 (ΔΕ2190=2.9 (1.8/4.2)). Furthermore, at T2190 four experienced dentists classified 50% and 37% of the lesions as "improved and no further treatment required" and "completely masked", respectively (Fleiss kappa: T2190: 0.782 (substantial agreement)). CONCLUSION Aesthetic caries infiltration can effectively mask post-orthodontic initial caries lesions for at least 6 years. These results for most of the teeth could not only be observed by quantitative but also by qualitative analysis. CLINICAL SIGNIFICANCE Resin infiltration efficaciously masks post-orthodontic initial carious lesions. The optical improvement can be observed directly after treatment and remains stable for at six years

MAL Protein Controls Protein Sorting at the Supramolecular Activation Cluster of Human T Lymphocytes

T cell membrane receptors and signaling molecules assemble at the immunological synapse (IS) in a supramolecular activation cluster (SMAC), organized into two differentiated subdomains: the central SMAC (cSMAC), with the TCR, Lck, and linker for activation of T cells (LAT), and the peripheral SMAC (pSMAC), with adhesion molecules. The mechanism of protein sorting to the SMAC subdomains is still unknown. MAL forms part of the machinery for protein targeting to the plasma membrane by specialized mechanisms involving condensed membranes or rafts. In this article, we report our investigation of the dynamics of MAL during the formation of the IS and its role in SMAC assembly in the Jurkat T cell line and human primary T cells. We observed that under normal conditions, a pool of MAL rapidly accumulates at the cSMAC, where it colocalized with condensed membranes, as visualized with the membrane fluorescent probe Laurdan. Mislocalization of MAL to the pSMAC greatly reduced membrane condensation at the cSMAC and redistributed machinery involved in docking microtubules or transport vesicles from the cSMAC to the pSMAC. As a consequence of these alterations, the raft-associated molecules Lck and LAT, but not the TCR, were missorted to the pSMAC. MAL, therefore, regulates membrane order and the distribution of microtubule and transport vesicle docking machinery at the IS and, by doing so, ensures correct protein sorting of Lck and LAT to the cSMAC.This work was supported by Grants BFU2009-07886 and CONSOLIDER CSD2009-00016 (to M.A.A.) from the Ministerio de Ciencia e Innovación, Spain.Peer reviewe