Characterization of the CD14⁺⁺CD16⁺ Monocyte Population in Human Bone Marrow

Numerous studies have divided blood monocytes according to their expression of the surface markers CD14 and CD16 into following subsets: classical CD14(++)CD16(-), intermediate CD14(++)CD16(+) and nonclassical CD14(+)CD16(++) monocytes. These subsets differ in phenotype and function and are further correlated to cardiovascular disease, inflammation and cancer. However, the CD14/CD16 nature of resident monocytes in human bone marrow remains largely unknown. In the present study, we identified a major population of CD14(++)CD16(+) monocytes by using cryopreserved bone marrow mononuclear cells from healthy donors. These cells express essential monocyte-related antigens and chemokine receptors such as CD11a, CD18, CD44, HLA-DR, Ccr2, Ccr5, Cx3cr1, Cxcr2 and Cxcr4. Notably, the expression of Ccr2 was inducible during culture. Furthermore, sorted CD14(++)CD16(+) bone marrow cells show typical macrophage morphology, phagocytic activity, angiogenic features and generation of intracellular oxygen species. Side-by-side comparison of the chemokine receptor profile with unpaired blood samples also demonstrated that these rather premature medullar monocytes mainly match the phenotype of intermediate and partially of (non) classical monocytes. Together, human monocytes obviously acquire their definitive CD14/CD16 signature in the bloodstream and the medullar monocytes probably transform into CD14(++)CD16(-) and CD14(+)CD16(++) subsets which appear enriched in the periphery

The “central state” and the almighty Dollar

New methods to determine the titanium (Ti) mass-dependent isotope fractionation of solar system materials to high precision were developed by combining internally normalised Ti isotope data with double-spike analyses utilising a 47Ti-49Ti double spike. The procedure includes a three-stage ion-exchange separation procedure to isolate Ti from the sample matrix that provides high-purity Ti fractions that are necessary for high-precision Ti isotope analyses. Analyses of sample aliquots that were spiked before and after the ion-exchange separation procedure demonstrate that Ti isotope fractionation can be induced by the separation procedure. This outcome requires the addition of the double spike before the ion exchange separation procedure in order to accurately determine the natural mass-dependent Ti isotope fractionation of samples. Multiple double spike analyses of an Alfa Aesar Ti standard performed over eight months yielded a reproducibility (2σ standard deviation) of 0.033‰ for δ49/47Ti (differences in 49Ti/47Ti relative to the OL-Ti standard). Terrestrial sample analyses display a 2σ reproducibility of 0.018 to 0.031‰ for δ49/47Ti. Titanium isotope results for three terrestrial USGS magmatic reference samples (AGV-2, BHVO-2 and BCR-2) agree well with literature data and therefore demonstrate the accuracy and precision of the presented methodologies. Achondritic meteorites display an overall range of 0.75‰ for δ49/47Ti. The ungrouped achondrite NWA 7325 has a more positive composition by 0.64‰ for δ49/47Ti compared to all other investigated samples likely reflecting Ti isotope fractionation induced by magmatic differentiation associated with highly reducing conditions and potentially associated with oxide and plagioclase formation. In contrast, eucrites with δ49/47Ti of -0.020 ± 0.070 and -0.003 ± 0.033 and the first mass-dependent Ti isotope data for an acapulcoite (Dhofar 125; δ49/47Ti = 0.094 ± 0.033) show only limited magmatic Ti isotope fractionation. Chondrites also display a relatively restricted range of 0.085‰ for δ49/47Ti, including one calcium‑aluminum rich inclusion (CAI) from Allende and the first mass-dependent Ti isotope data for two Rumuruti chondrites (NWA 753 and NWA 755). Furthermore, the mass-dependent Ti isotope composition of chondrites overlaps with that of eucrites and the acapulcoite Dhofar 125 indicating that nebular processes induce only limited Ti isotope fractionation. Additionally, the Ti isotope data indicate that thermal metamorphism also produced marginal Ti isotope fractionation at the bulk sample scale for chondrites. Small mass-dependent Ti isotope variations between different bulk meteorite samples are also evident, which might reflect sample heterogeneity. Importantly, the mass-dependent Ti isotope composition of the Earth and Moon overlap with the composition of the investigated chondrites, eucrites and acapulcoites within the 2 standard deviation uncertainties

Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity Evidence From Mouse and Human Studies

BACKGROUND: The CXCL12/CXCR4 chemokine ligand/receptor axis controls (progenitor) cell homeostasis and trafficking. So far, an atheroprotective role of CXCL12/CXCR4 has only been implied through pharmacological intervention, in particular, because the somatic deletion of the CXCR4 gene in mice is embryonically lethal. Moreover, cell-specific effects of CXCR4 in the arterial wall and underlying mechanisms remain elusive, prompting us to investigate the relevance of CXCR4 in vascular cell types for atheroprotection. METHODS: We examined the role of vascular CXCR4 in atherosclerosis and plaque composition by inducing an endothelial cell (BmxCreERT2-driven)-specific or smooth muscle cell (SMC, SmmhcCreERT2-or TaglnCre-driven)-specific deficiency of CXCR4 in an apolipoprotein E-deficient mouse model. To identify underlying mechanisms for effects of CXCR4, we studied endothelial permeability, intravital leukocyte adhesion, involvement of the Akt/WNT/beta-catenin signaling pathway and relevant phosphatases in VE-cadherin expression and function, vascular tone in aortic rings, cholesterol efflux from macrophages, and expression of SMC phenotypic markers. Finally, we analyzed associations of common genetic variants at the CXCR4 locus with the risk for coronary heart disease, along with CXCR4 transcript expression in human atherosclerotic plaques. RESULTS: The cell-specific deletion of CXCR4 in arterial endothelial cells (n=1215) or SMCs (n=13-24) markedly increased atherosclerotic lesion formation in hyperlipidemic mice. Endothelial barrier function was promoted by CXCL12/\CXCR4, which triggered Akt/WNT/beta-catenin signaling to drive VE-cadherin expression and stabilized junctional VE-cadherin complexes through associated phosphatases. Conversely, endothelial CXCR4 deficiency caused arterial leakage and inflammatory leukocyte recruitment during atherogenesis. In arterial SMCs, CXCR4 sustained normal vascular reactivity and contractile responses, whereas CXCR4 deficiency favored a synthetic phenotype, the occurrence of macrophage-like SMCs in the lesions, and impaired cholesterol efflux. Regression analyses in humans (n=259 796) identified the C-allele at rs2322864 within the CXCR4 locus to be associated with increased risk for coronary heart disease. In line, C/C risk genotype carriers showed reduced CXCR4 expression in carotid artery plaques (n=188), which was furthermore associated with symptomatic disease. CONCLUSIONS: Our data clearly establish that vascular CXCR4 limits atherosclerosis by maintaining arterial integrity, preserving endothelial barrier function, and a normal contractile SMC phenotype. Enhancing these beneficial functions of arterial CXCR4 by selective modulators might open novel therapeutic options in atherosclerosis

Novel highly emissive non proteinogenic amino acids : synthesis of 1,3,4-thiadiazolyl asparagines and evaluation as fluorimetric chemosensors for biologically relevant transition metal cations

Highly emissive heterocyclic asparagine derivatives bearing a 1,3,4-thiadiazolyl unit at the side chain, functionalised with electron donor or acceptor groups, were synthesised and evaluated as amino acid based fluorimetric chemosensors for metal cations such as Cu2+, Zn2+, Co2+ and Ni2+. The results suggest that there is a strong interaction through the donor heteroatoms at the side chain of the various asparagine derivatives, with high sensitivity towards Cu2+ in a ligand-metal complex with 1:2 stoichiometry. Association constants and detection limits for Cu2+ were calculated. The photophysical and metal ion sensing properties of these asparagine derivatives confirm their potential as fluorimetric chemosensors and suggest that they can be suitable for incorporation into chemosensory peptidic frameworks.Fundação para a Ciência e a Tecnologia (FCT) - PTDC/QUI/66250/2006 (FCOMP-01-0124-FEDER-007428

CoNLL 2017 Shared Task : Multilingual Parsing from Raw Text to Universal Dependencies

The Conference on Computational Natural Language Learning (CoNLL) features a shared task, in which participants train and test their learning systems on the same data sets. In 2017, one of two tasks was devoted to learning dependency parsers for a large number of languages, in a real world setting without any gold-standard annotation on input. All test sets followed a unified annotation scheme, namely that of Universal Dependencies. In this paper, we define the task and evaluation methodology, describe data preparation, report and analyze the main results, and provide a brief categorization of the different approaches of the participating systems.Peer reviewe

Relatório de estágio em farmácia comunitária

Relatório de estágio realizado no âmbito do Mestrado Integrado em Ciências Farmacêuticas, apresentado à Faculdade de Farmácia da Universidade de Coimbr