121 research outputs found
BAFF, APRIL and BAFFR on the pathogenesis of Immunoglobulin-A vasculitis
BAFF, APRIL and BAFF-R are key proteins involved in the development of B-lymphocytes and autoimmunity. Additionally, BAFF, APRIL and BAFFR polymorphisms were associated with immune-mediated conditions, being BAFF GCTGT>A a shared insertion-deletion genetic variant for several autoimmune diseases. Accordingly, we assessed whether BAFF, APRIL and BAFFR represent novel genetic risk factors for Immunoglobulin-A vasculitis (IgAV), a predominantly B-lymphocyte inflammatory condition. BAFF rs374039502, which colocalizes with BAFF GCTGT>A, and two tag variants within APRIL (rs11552708 and rs6608) and BAFFR (rs7290134 and rs77874543) were genotyped in 386 Caucasian IgAV patients and 806 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when BAFF, APRIL and BAFFR variants were analysed independently. Likewise, no statistically significant differences were found in the genotype and allele frequencies of BAFF, APRIL or BAFFR when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when APRIL and BAFFR haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that BAFF, APRIL and BAFFR do not contribute to the genetic network underlying IgAV.Acknowledgements: We are indebted to the patients and healthy controls for their essential collaboration to this study. We also thank the National DNA Bank Repository (Salamanca) for supplying part of the control samples. This study was supported by European Union FEDER funds and `Fondo de Investigaciones Sanitarias´ (grant PI18/00042) from ‘Instituto de Salud Carlos III’ (ISCIII, Health Ministry, Spain). DP-P is a recipient of a RÃo Hortega programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, `Investing in your future´) (grant number CM20/00006). SR-M is supported by funds of the RETICS Program (RD16/0012/0009) (ISCIII, co-funded by the European Regional Development Fund (ERDF)). VP-C is supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). BA-M is a recipient of a `López Albo´ Post-Residency Programme funded by Servicio Cántabro de Salud. LL-G is supported by funds from IDIVAL (INNVAL20/06). OG is staff personnel of Xunta de Galicia (Servizo Galego de Saude (SERGAS)) through a research-staff stabilization contract (ISCIII/SERGAS) and his work is funded by ISCIII and the European Union FEDER fund (grant numbers RD16/0012/0014 (RIER) and PI17/00409). He is beneficiary of project funds from the Research Executive Agency (REA) of the European Union in the framework of MSCA-RISE Action of the H2020 Programme, Project 734899—Olive-Net. RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, cofunded by ESF (`Investing in your future´) (grant number CP16/00033)
Directionality of nuclear recoils in a liquid argon time projection chamber
The direct search for dark matter in the form of weakly interacting massive
particles (WIMP) is performed by detecting nuclear recoils (NR) produced in a
target material from the WIMP elastic scattering. A promising experimental
strategy for direct dark matter search employs argon dual-phase time projection
chambers (TPC). One of the advantages of the TPC is the capability to detect
both the scintillation and charge signals produced by NRs. Furthermore, the
existence of a drift electric field in the TPC breaks the rotational symmetry:
the angle between the drift field and the momentum of the recoiling nucleus can
potentially affect the charge recombination probability in liquid argon and
then the relative balance between the two signal channels. This fact could make
the detector sensitive to the directionality of the WIMP-induced signal,
enabling unmistakable annual and daily modulation signatures for future
searches aiming for discovery. The Recoil Directionality (ReD) experiment was
designed to probe for such directional sensitivity. The TPC of ReD was
irradiated with neutrons at the INFN Laboratori Nazionali del Sud, and data
were taken with 72 keV NRs of known recoil directions. The direction-dependent
liquid argon charge recombination model by Cataudella et al. was adopted and a
likelihood statistical analysis was performed, which gave no indications of
significant dependence of the detector response to the recoil direction. The
aspect ratio R of the initial ionization cloud is estimated to be 1.037 +/-
0.027 and the upper limit is R < 1.072 with 90% confidence levelComment: 20 pages, 10 figures, submitted to Eur. Phys. J.
Study on cosmogenic activation above ground for the DarkSide-20k project
The activation of materials due to the exposure to cosmic rays may become an
important background source for experiments investigating rare event phenomena.
DarkSide-20k is a direct detection experiment for galactic dark matter
particles, using a two-phase liquid argon time projection chamber filled with
49.7 tonnes (active mass) of Underground Argon (UAr) depleted in 39Ar. Here,
the cosmogenic activity of relevant long-lived radioisotopes induced in the
argon and other massive components of the set-up has been estimated; production
of 120 t of radiopure UAr is foreseen. The expected exposure above ground and
production rates, either measured or calculated, have been considered. From the
simulated counting rates in the detector due to cosmogenic isotopes, it is
concluded that activation in copper and stainless steel is not problematic.
Activation of titanium, considered in early designs but not used in the final
design, is discussed. The activity of 39Ar induced during extraction,
purification and transport on surface, in baseline conditions, is evaluated to
be 2.8% of the activity measured in UAr from the same source, and thus
considered acceptable. Other products in the UAr such as 37Ar and 3H are shown
to not be relevant due to short half-life and assumed purification methods
Strategies to inhibit tumour associated integrin receptors: rationale for dual and multi-antagonists
YesThe integrins are a family of 24 heterodimeric transmembrane cell surface receptors. Involvement in cell attachment to the extracellular matrix, motility, and proliferation identifies integrins as therapeutic targets in cancer and associated conditions; thrombosis, angiogenesis and osteoporosis. The most reported strategy for drug development is synthesis of an agent that is highly selective for a single integrin receptor. However, the ability of cancer cells to change their integrin repertoire in response to drug treatment renders this approach vulnerable to the development of resistance and paradoxical promotion of tumor growth. Here, we review progress towards development of antagonists targeting two or more members of the RGD-binding integrins, notably αvβ3, αvβ5, αvβ6, αvβ8, α5β1, and αIIbβ3, as anticancer therapeutics
Measurement of isotopic separation of argon with the prototype of the cryogenic distillation plant Aria for dark matter searches
The Aria cryogenic distillation plant, located in Sardinia, Italy, is a key component of the DarkSide-20k experimental program for WIMP dark matter searches at the INFN Laboratori Nazionali del Gran Sasso, Italy. Aria is designed to purify the argon, extracted from underground wells in Colorado, USA, and used as the DarkSide-20k target material, to detector-grade quality. In this paper, we report the first measurement of argon isotopic separation by distillation with the 26 m tall Aria prototype. We discuss the measurement of the operating parameters of the column and the observation of the simultaneous separation of the three stable argon isotopes: 36Ar , 38Ar , and 40Ar . We also provide a detailed comparison of the experimental results with commercial process simulation software. This measurement of isotopic separation of argon is a significant achievement for the project, building on the success of the initial demonstration of isotopic separation of nitrogen using the same equipment in 2019
A Genome-Wide Association Scan on the Levels of Markers of Inflammation in Sardinians Reveals Associations That Underpin Its Complex Regulation
Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals—5 of which were identified only with the custom arrays—and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10−29); for ESR, at the HBB (rs4910472, p = 2.31×10−11) and UCN119B/SPPL3 (rs11829037, p = 8.91×10−10) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10−13) and in CADM3 (rs3026968, p = 7.63×10−13); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10−21), near DARC (rs3845624, p = 1.43×10−10), UNC119B/SPPL3 (rs11829037, p = 1.50×10−14), and ICOSLG/AIRE (rs113459440, p = 1.54×10−08) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process
Sensitivity projections for a dual-phase argon TPC optimized for light dark matter searches through the ionization channel
Dark matter lighter than 10 GeV/c encompasses a promising range of
candidates. A conceptual design for a new detector, DarkSide-LowMass, is
presented, based on the DarkSide-50 detector and progress toward DarkSide-20k,
optimized for a low-threshold electron-counting measurement. Sensitivity to
light dark matter is explored for various potential energy thresholds and
background rates. These studies show that DarkSide-LowMass can achieve
sensitivity to light dark matter down to the solar neutrino floor for GeV-scale
masses and significant sensitivity down to 10 MeV/c considering the Migdal
effect or interactions with electrons. Requirements for optimizing the
detector's sensitivity are explored, as are potential sensitivity gains from
modeling and mitigating spurious electron backgrounds that may dominate the
signal at the lowest energies
Sensitivity projections for a dual-phase argon TPC optimized for light dark matter searches through the ionization channel
Dark matter lighter than 10  GeV/c2 encompasses a promising range of candidates. A conceptual design for a new detector, DarkSide-LowMass, is presented, based on the DarkSide-50 detector and progress toward DarkSide-20k, optimized for a low-threshold electron-counting measurement. Sensitivity to light dark matter is explored for various potential energy thresholds and background rates. These studies show that DarkSide-LowMass can achieve sensitivity to light dark matter down to the solar neutrino fog for GeV-scale masses and significant sensitivity down to 10  MeV/c2 considering the Migdal effect or interactions with electrons. Requirements for optimizing the detector’s sensitivity are explored, as are potential sensitivity gains from modeling and mitigating spurious electron backgrounds that may dominate the signal at the lowest energies
Antagonizing Integrin β3 Increases Immunosuppression in Cancer
Integrin β3 is critical for tumor invasion, neoangiogenesis, and inflammation, making it a promising cancer target. However, preclinical and clinical data of integrin β3 antagonists have demonstrated no benefit or worse outcomes. We hypothesized that integrin β3 could affect tumor immunity and evaluated tumors in mice with deletion of integrin β3 in macrophage lineage cells (β3KOM). β3KOM mice had increased melanoma and breast cancer growth with increased tumor-promoting M2 macrophages and decreased CD8+ T cells. Integrin β3 antagonist, cilengitide, also enhanced tumor growth and increased M2 function. We uncovered a negative feedback loop in M2 myeloid cells, wherein integrin β3 signaling favored STAT1 activation, an M1-polarizing signal, and suppressed M2-polarizing STAT6 activation. Finally, disruption of CD8+ T cells, macrophages, or macrophage integrin β3 signaling blocked the tumor-promoting effects of integrin β3 antagonism. These results suggest that effects of integrin β3 therapies on immune cells should be considered to improve outcomes. Cancer Res; 76(12); 3484–95. ©2016 AACR
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