Defective Gp130-Mediated Signal Transducer and Activator of Transcription (Stat) Signaling Results in Degenerative Joint Disease, Gastrointestinal Ulceration, and Failure of Uterine Implantation

The receptor subunit gp130 transduces multiple cell type–specific activities of the leukemia inhibitory factor (LIF)/interleukin (IL)-6 family of cytokines through the signal transducer and activator of transcription (STAT) and src homology 2 domain–bearing protein tyrosine phosphatase (SHP)-2/ras/Erk pathways. To define STAT-dependent physiological responses, we generated mice with a COOH-terminal gp130ΔSTAT “knock-in” mutation which deleted all STAT-binding sites. gp130ΔSTAT mice phenocopyed mice deficient for IL-6 (impaired humoral and mucosal immune and hepatic acute phase responses) and LIF (failure of blastocyst implantation). However, unlike mice with null mutations in any of the components in the gp130 signaling pathway, gp130ΔSTAT mice also displayed gastrointestinal ulceration and a severe joint disease with features of chronic synovitis, cartilaginous metaplasia, and degradation of the articular cartilage. Mitogenic hyperresponsiveness of synovial cells to the LIF/IL-6 family of cyto-kines was caused by sustained gp130-mediated SHP-2/ras/Erk activation due to impaired STAT-mediated induction of suppressor of cytokine signaling (SOCS) proteins which normally limits gp130 signaling. Therefore, the joint pathology in gp130ΔSTAT mice is likely to arise from the disturbance of the otherwise balanced activation of the SHP-2/ras/Erk and STAT signaling cascades emanating from gp130

L’anziano attivo. Proposte e riflessioni per la terza e la quarta età

Il problema della senilità si pone ormai in Italia, come in tutte le società avanzate, in termini assai diversi dal passato. I saggi compresi nel presente volume intervengono su tutti gli aspetti della senilità - da quelli psicologici, sanitari e affettivi a quelli assistenziali, economici e giuridici - per suggerire indicazioni operative e possibili soluzioni.- Indice #4- Prefazione, Marcello Pacini #10- Introduzione, Giuliano Urbani #12- Prima parte Per una nuova concezione della condizione anziana #20- L’età del tempo libero, Norberto Bobbio #22- L’anziano protagonista in una società che cambia, Gian Maria Capuani e Giannino Piana #26- La piccola immortalità, Nando dalla Chiesa #36- L’anziano come risorsa sociale: il volontariato dopo la pensione, Fausto Melloni #44- Seconda Parte Aspetti sociali della condizione anziana #62- Psicogerontologia: attualità e nuove prospettive, Maria Antonietta Aveni Casucci #64- L’invecchiamento della popolazione italiana in un contesto internazionale, Antonio Golini e Agostino Lori #82- L’anziano e l’innovazione tecnologica, Francesco Jovane e Roberto Groppetti #114- La tutela giuridica dell’anziano, Luigi Mengoni #128- La salute dell’anziano: valutazione dei meccanismi di plasticità, Renzo Rozzini, Angelo Bianchetti e Marco Trabucchi #140- Lavoratori anziani: ambivalenza e interventi, Harris T. Schrank e Joan M. Waring #156- Il medico e l’anziano, Carlo Vergani #176- La normalità incerta, Virginio Oddone e Fabrizio Fabris #188- Il quadro organizzativo per una corretta assistenza socio-sanitaria alla popolazione anziana, Gaetano Maria Fara #200- Terza Parte Le tendenze della riflessione #216- La condizione degli anziani in Italia, Claudio Calvaruso #218- Anziani attivi: un possibile esempio di nuova centralità del sociale, Vincenzo Cesareo #228- Appendice Un contributo di ricerca #246- Figli adulti e genitori anziani: una nuova relazione tra le generazioni, Giovanna Rossi #24

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Gender studies : terms and debates

This book provides an accessible and interdisciplinary introduction to current debates on gender, exploring the major theorists whose work has produced and inspired feminist analysis in women's/gender studies, cultural studies and sociology. By clarifying and explaining the concepts of gender analysis and by demonstrating ways of working with these concepts, the authors involve the readers directly in the reading process and leave them feeling empowered. Accessible introductions to the work of major theorists help to give difficult concepts a context and the theory is related back to practice and to related fields such as class and race analysis throughout

Classic Grounded Theory to Analyse Secondary Data: Reality and Reflections

This paper draws on the experiences of two researchers and discusses how they conducted a secondary data analysis using classic grounded theory. The aim of the primary study was to explore first-time parents’ postnatal educational needs. A subset of the data from the primary study (eight transcripts from interviews with fathers) was used for the secondary data analysis. The objectives of the secondary data analysis were to identify the challenges of using classic grounded theory with secondary data and to explore whether the re-analysis of primary data using a different methodology would yield a different outcome. Through the process of re-analysis a tentative theory emerged on ‘developing competency as a father’. Challenges encountered during this re-analysis included the small dataset, the pre-framed data, and limited ability for theoretical sampling. This re-analysis proved to be a very useful learning tool for author 1(LA), who was a novice with classic grounded theory

Exposure of Solvent-Inaccessible Regions in the Amyloidogenic Protein Human SOD1 Determined by Hydroxyl Radical Footprinting

Solvent-accessibility change plays a critical role in protein misfolding and aggregation, the culprit for several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Mass spectrometry-based hydroxyl radical (·OH) protein footprinting has evolved as a powerful and fast tool in elucidating protein solvent accessibility. In this work, we used fast photochemical oxidation of protein (FPOP) hydroxyl radical (·OH) footprinting to investigate solvent accessibility in human copper-zinc superoxide dismutase (SOD1), misfolded or aggregated forms of which underlie a portion of ALS cases. ·OH-mediated modifications to 56 residues were detected with locations largely as predicted based on X-ray crystallography data, while the interior of SOD1 β-barrel is hydrophobic and solvent-inaccessible and thus protected from modification. There were, however, two notable exceptions-two closely located residues inside the β-barrel, predicted to have minimal or no solvent accessibility, that were found modified by FPOP (Phe20 and Ile112). Molecular dynamics (MD) simulations were consistent with differential access of peroxide versus quencher to SOD1's interior complicating surface accessibility considerations. Modification of these two residues could potentially be explained either by local motions of the β-barrel that increased peroxide/solvent accessibility to the interior or by oxidative events within the interior that might include long-distance radical transfer to buried sites. Overall, comparison of modification patterns for the metal-free apoprotein versus zinc-bound forms demonstrated that binding of zinc protected the electrostatic loop and organized the copper-binding site. Our study highlights SOD1 hydrophobic groups that may contribute to early events in aggregation and discusses caveats to surface accessibility conclusions. Graphical Abstract

Elevated Dnmt3a activity promotes polyposis in ApcMin mice by relaxing extracellular restraints on Wnt signaling

Background & Aims: Aberrant DNA methylation is a common early event in neoplasia, but it is unclear how this relates to dysregulation of DNA (cytosine-5) methyltransferases (Dnmts). Here we use knock-in transgenic mice to investigate the consequences of intestinal epithelium-specific overexpression of de novo Dnmt3a. Methods: A novel gene targeting strategy, based on the intestinal epithelium-specific, uniform expression of the A33 glycoprotein, is employed to restrict Dnmt3a overexpression in homozygous A33 mutant mice. Results: A33 mice infrequently develop spontaneous intestinal polyps. However, when genetically challenged, tumor multiplicity in A33;Apc compound mice is 3-fold higher than in Apc mice. Although we observe a requirement for spontaneous loss of heterozygosity of the adenomatous polyposis coli (Apc) gene to trigger tumorigenesis in Apc mice, lesions in A33;Apc mice frequently retain the wild-type Apc allele. However, epithelia from normal mucosa and polyps of A33;Apc mice show hypermethylation-mediated transcriptional silencing of the Wnt antagonists Sfrp5, and to a lesser extent, Sfrp1 and increased nuclear β-catenin alongside activation of the Wnt-target gene Axin2/Conductin. Conversely, enforced Sfrp5 expression suppresses canonical Wnt-signaling more effectively in wild-type than in Apc cells. Conclusions: Aberrant activation of the canonical Wnt pathway, either by mono-allelic Apc loss or transcriptional silencing of Sfrp5 is largely insufficient to promote polyposis, but epistatic interactions between these genetic and epigenetic events enables initiation and promotion of disease. This mechanism is likely to play a role in human colorectal cancer, because we also show that elevated DNMT3A expression coincides with repressed SFRP5 and enhanced AXIN2/CONDUCTIN expression in paired patient biopsies