Haematological phenotypes in relation to the C1797T beta-adducin polymorphism in a Caucasian population

beta-Adducin plays a role in maintaining the structural integrity of the red blood cell (erythrocyte) membrane. Moreover, beta-adducin-deficient knock-out mice show a phenotype characterized by mild anaemia and compensated haemolysis. We therefore investigated whether, in humans, common haematological phenotypes of red blood cells were associated with a polymorphism in exon 15 of the human beta-adducin gene (C1797T). We studied 802 unrelated individuals and 294 families (459 parents and 609 offspring) randomly selected from a Caucasian population. We employed generalized estimating equations to allow for the non-independence of the observations within families, while controlling for co-variables. In 917 men, with adjustments applied for age, body mass index, serum total cholesterol, smoking and alcohol intake, CC homozygotes had significantly ( P =0.02) lower values for red blood cell count (4.93 x 10(12)/l compared with 4.86 x 10(12)/l), haemoglobin level (9.30 compared with 9.18 mmol/l) and haematocrit (45.0% compared with 44.4%) than T allele carriers. In the 329 men who consumed alcohol, the differences between CC homozygotes and T allele carriers were 0.13 x 10(12)/l ( P =0.02) for red blood cell count, 0.23 mmol/l ( P =0.005) for haemoglobin and 1.08% ( P =0.02) for haematocrit. In 953 women, none of these associations was significant ( P >/=0.06), regardless of alcohol intake [13.3% of women ( n =127) consmued alcohol]. In conclusion, in men consuming alcohol, the beta-adducin CC genotype was associated with lower red blood cell count, haemoglobin level and haematocrit. We hypothesize that, in CC homozygotes, alcohol consumption may unveil the greater fragility of the red blood cell membrane. This genotype may slightly potentiate the structural and functional haematological disturbances associated with alcohol intake

Re-education of Tumor-Associated Macrophages by CXCR2 Blockade Drives Senescence and Tumor Inhibition in Advanced Prostate Cancer

Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment supporting tumorigenesis. TAMs re-education has been proposed as a strategy to promote tumor inhibition. However, whether this approach may work in prostate cancer is unknown. Here we find that Pten-null prostate tumors are strongly infiltrated by TAMs expressing C-X-C chemokine receptor type 2 (CXCR2), and activation of this receptor through CXCL2 polarizes macrophages toward an anti-inflammatory phenotype. Notably, pharmacological blockade of CXCR2 receptor by a selective antagonist promoted the re-education of TAMs toward a pro-inflammatory phenotype. Strikingly, CXCR2 knockout monocytes infused in Ptenpc−/−; Trp53pc−/− mice differentiated in tumor necrosis factor alpha (TNF-α)-releasing pro-inflammatory macrophages, leading to senescence and tumor inhibition. Mechanistically, PTEN-deficient tumor cells are vulnerable to TNF-α-induced senescence, because of an increase of TNFR1. Our results identify TAMs as targets in prostate cancer and describe a therapeutic strategy based on CXCR2 blockade to harness anti-tumorigenic potential of macrophages against this disease. © 2019 The Author(s) Di Mitri et al. show that CXCR2 blockade in prostate cancer triggers TAMs re-education, leading to tumor inhibition. CXCR2-KO monocytes infused in Ptenpc−/−; Trp53pc−/− tumor-bearing mice differentiate into TNFα-releasing pro-inflammatory macrophages that induce senescence in tumor cells. PTEN-null tumors display higher sensitivity to TNF-α-induced senescence because of TNFR1 upregulation

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

The ALICE experiment at the CERN LHC

ALICE (A Large Ion Collider Experiment) is a general-purpose, heavy-ion detector at the CERN LHC which focuses on QCD, the strong-interaction sector of the Standard Model. It is designed to address the physics of strongly interacting matter and the quark-gluon plasma at extreme values of energy density and temperature in nucleus-nucleus collisions. Besides running with Pb ions, the physics programme includes collisions with lighter ions, lower energy running and dedicated proton-nucleus runs. ALICE will also take data with proton beams at the top LHC energy to collect reference data for the heavy-ion programme and to address several QCD topics for which ALICE is complementary to the other LHC detectors. The ALICE detector has been built by a collaboration including currently over 1000 physicists and engineers from 105 Institutes in 30 countries. Its overall dimensions are 161626 m3 with a total weight of approximately 10 000 t. The experiment consists of 18 different detector systems each with its own specific technology choice and design constraints, driven both by the physics requirements and the experimental conditions expected at LHC. The most stringent design constraint is to cope with the extreme particle multiplicity anticipated in central Pb-Pb collisions. The different subsystems were optimized to provide high-momentum resolution as well as excellent Particle Identification (PID) over a broad range in momentum, up to the highest multiplicities predicted for LHC. This will allow for comprehensive studies of hadrons, electrons, muons, and photons produced in the collision of heavy nuclei. Most detector systems are scheduled to be installed and ready for data taking by mid-2008 when the LHC is scheduled to start operation, with the exception of parts of the Photon Spectrometer (PHOS), Transition Radiation Detector (TRD) and Electro Magnetic Calorimeter (EMCal). These detectors will be completed for the high-luminosity ion run expected in 2010. This paper describes in detail the detector components as installed for the first data taking in the summer of 2008

La protezione dell'identità culturale dei popoli indigeni oggetto di una norma di diritto internazionale generale?

francese-inglese-portoghese-spagmolo. L'ultimo decennio è stato caratterizzato da una crescente attenzione per i diritti dei poopoli indigeni, a livello genrale ma soprattutto regionale americano. Il saggio si interroga sul se, alla luce di nuovi strumenti e della giurisprudenza della corte americnaa dei diritti dell'uomo, sia lecito parlare ormai dell'esistenza di una norma di diritto itnernaizonale generale che obbliga al rispetto dell'identità culturale indigena. L'autore conclude che, malgrado i segnali positivi in tale direzione, una tale conclusione risulta allo stato prematura

Il trasferimento di dati personali verso Stati terzi: esiti (in parte sorprendenti) dell'unilateralismo giuridico CE

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