Autoreactivity to Glucose Regulated Protein 78 Links Emphysema and Osteoporosis in Smokers

Rationale: Emphysema and osteoporosis are epidemiologically associated diseases of cigarette smokers. The causal mechanism(s) linking these illnesses is unknown. We hypothesized autoimmune responses may be involved in both disorders. Objectives: To discover an antigen-specific autoimmune response associated with both emphysema and osteoporosis among smokers. Methods: Replicate nonbiased discovery assays indicated that autoimmunity to glucose regulated protein 78 (GRP78), an endoplasmic reticulum chaperone and cell surface signaling receptor, is present in many smokers. Subject assessments included spirometry, chest CT scans, dual x-ray absorptiometry, and immunoblots for anti-GRP78 IgG. Anti-GRP78 autoantibodies were isolated from patient plasma by affinity chromatography, leukocyte functions assessed by flow cytometry, and soluble metabolites and mediators measured by immunoassays. Measurements and Main Results Circulating anti-GRP78 IgG autoantibodies were detected in plasma specimens from 86 (32%) of the 265 smoking subjects. Anti-GRP78 autoantibodies were singularly prevalent among subjects with radiographic emphysema (OR 3.1, 95%CI 1.7–5.7, p = 0.003). Anti-GRP78 autoantibodies were also associated with osteoporosis (OR 4.7, 95%CI 1.7–13.3, p = 0.002), and increased circulating bone metabolites (p = 0.006). Among emphysematous subjects, GRP78 protein was an autoantigen of CD4 T-cells, stimulating lymphocyte proliferation (p = 0.0002) and IFN-gamma production (p = 0.03). Patient-derived anti-GRP78 autoantibodies had avidities for osteoclasts and macrophages, and increased macrophage NFkB phosphorylation (p = 0.005) and productions of IL-8, CCL-2, and MMP9 (p = 0.005, 0.007, 0.03, respectively). Conclusions: Humoral and cellular GRP78 autoimmune responses in smokers have numerous biologically-relevant pro-inflammatory and other deleterious actions, and are associated with emphysema and osteoporosis. These findings may have relevance for the pathogenesis of smoking-associated diseases, and development of biomarker immunoassays and/or novel treatments for these disorders

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Partie II : analyse comparative des politiques de logement.

In occasione del cinquecentenario della morte di Raffaello Sanzio (1483-1520) si propone un testo agile e informato per scoprire dipinti e architetture eseguiti a Roma dall\u2019arrivo nell\u2019Urbe nel 1508 alla morte nel 1520. Aggiornate e complete dei dati essenziali, le schede esplicative illustrano l\u2019ampio ventaglio della produzione matura del Raffaello pittore, dagli affreschi alle pale d\u2019altare ai ritratti eseguiti per Roma o oggi l\uec conservati, e permettono di individuare e di comprendere le tracce dell\u2019attivit\ue0 del Raffaello architetto. Si svolge attraverso le opere il racconto dell\u2019appassionante stagione romana dell\u2019artista, impegnato nel continuo rinnovamento del proprio linguaggio di pittore nel dialogo travolgente con Michelangelo, nella gara con Sebastiano del Piombo, nella spinta possente delle sollecitazioni fornite dal repertorio antico della scultura, nel nuovo impegno come caposcuola, alla guida di una bottega che far\ue0 da modello per tutto il secolo e oltre, e si segue il definirsi proprio a Roma dei suoi interessi di architetto e degli obiettivi che egli matura sul fronte dell\u2019architettura moderna su sollecitazione di Bramante e poi di altri, nella sfida costituita dal confronto con i resti degli edifici antichi, in uno scambio costante con gli umanisti, come Pietro Bembo e Fra Giocondo, suoi ferventi interlocutori, committenti, sostenitori. Il testo non trascura di segnalare le opere non accessibili legate all\u2019operato del Sanzio, quali, in Vaticano, le Logge o l\u2019Appartamento del cardinal Bibbiena, o quelle che da architetto egli non pot\ue9 realizzare ma di cui ci restano suoi progetti, o che vennero distrutte (Palazzo Branconio dell\u2019Aquila), e dedica un\u2019attenzione speciale, per la forza del suo rapporto con il presente, alla lettera a Leone X scritta da Raffaello e da Baldassarre Castiglione, riconosciuta come primo documento di una consapevole riflessione sull\u2019urgenza della conservazione dell\u2019architettura e dell\u2019arte del passato alla quale oggi pi\uf9 di allora siamo chiamati a rispondere

CMOS active pixel sensors response to low energy light ions

International audienceRecently CMOS active pixel sensors have been used in Hadrontherapy ions fragmentation cross section measurements. Their main goal is to reconstruct tracks generated by the non interacting primary ions or by the produced fragments. In this framework the sensors, unexpectedly, demonstrated the possibility to obtain also some informations that could contribute to the ion type identification. The present analysis shows a clear dependency in charge and number of pixels per cluster (pixels with a collected amount of charge above a given threshold) with both fragment atomic number Z and energy loss in the sensor. This information, in the FIRST (F ragmentation of I ons R elevant for S pace and T herapy) experiment, has been used in the overall particle identification analysis algorithm. The aim of this paper is to present the data analysis and the obtained results. An empirical model was developed, in this paper, that reproduce the cluster size as function of the deposited energy in the sensor

Dispositifs acoustiques pour la furtivité et la discrétion

International audienc

Dispositifs acoustiques pour la furtivité et la discrétion

International audienc

Dispositifs acoustiques pour la furtivité et la discrétion

International audienc