Targeted Inactivation of the IL-4 Receptor α Chain I4R Motif Promotes Allergic Airway Inflammation

The insulin/interleukin-4 (IL-4) receptor (I4R) motif mediates the association of insulin receptor substrate (IRS)-2 with the interleukin-4 (IL-4)Rα chain and transduces mitogenic signals in response to IL-4. Its physiological functions were analyzed in mice with a germline point mutation that changed the motif's effector tyrosine residue into phenylalanine (Y500F). The Y500F mutation abrogated IRS-2 phosphorylation and impaired IL-4–induced CD4+ T lymphocyte proliferation but left unperturbed Stat6 activation, up-regulation of IL-4-responsive gene products, and Th cell differentiation under Th2 polarizing conditions. However, in vivo the Y500F mutation was associated with increased allergen-induced IgE production, airway responsiveness, tissue eosinophilia, and mucus production. These results define an important role for the I4R motif in regulating allergic inflammation

Factors impacting time to total shoulder arthroplasty among patients with primary glenohumeral osteoarthritis and rotator cuff arthropathy managed conservatively with corticosteroid injections

Background The purpose of this study was to identify predictors of the time from initial presentation to total shoulder arthroplasty (TSA) in patients with primary glenohumeral osteoarthritis (OA) and rotator cuff (RTC) arthropathy who were conservatively managed with corticosteroid injections. Methods We conducted a retrospective cohort study of patients who underwent TSA from 2010 to 2021. Kaplan-Meier survival analysis was used to estimate median time to TSA for primary OA and RTC arthropathy patients. The Cox proportional hazards model was used to identify significant predictors of time to TSA and to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Statistical significance was set at P<0.05. Results The cohort included 160 patients with primary OA and 92 with RTC arthropathy. In the primary OA group, median time to TSA was 15 months. Significant predictors of shorter time to TSA were older age at presentation (HR, 1.02; 95% CI, 1.00–1.04; P=0.03) and presence of moderate or severe acromioclavicular joint arthritis (HR, 1.45; 95% CI, 1.05–2.01; P=0.03). In the RTC arthropathy group, median time to TSA was 14 months, and increased number of corticosteroid injections was associated with longer time to TSA (HR, 0.87; 95% CI, 0.80–0.95; P=0.003). Conclusions There are distinct prognostic factors for progression to TSA between primary OA patients and RTC arthropathy patients managed with corticosteroid injections. Multiple corticosteroid injections are associated with delayed time to TSA in RTC arthropathy patients. Level of evidence III

Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma

Polymorphisms in the interleukin-4 receptor α chain (IL-4Rα) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4Rα has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target– and tissue-specific manner to mediate heightened expression of a subset of IL-4– and IL-13–responsive genes involved in allergic inflammation. Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4Rα–dependent signaling

Digitalisierung: Perspektiven für Arbeitsmodelle der Zukunft in Wirtschaft und Verwaltung

Die Digitalisierung ist derzeit einer der wichtigsten Wandlungstreiber in Wirtschaft und Gesellschaft. Die aus den neuen technischen Möglichkeiten resultierenden Veränderungen wirken sich auch auf das Verhalten von Kunden und Mitarbeitenden aus. In Bezug auf die Zusammenarbeit in Unternehmen und Organisationen sind bestehende Arbeitsmodelle für administrative Arbeit anzupassen und neue Formen digitaler Kollaboration einzuführen. Hiermit verbunden sind Änderungen der Arbeitszeitmodelle, der Organisation der Mitarbeitenden, der Art der Zusammenarbeit und Führung sowie der Gestaltung von Büroräumlichkeiten. In einem vergleichenden Case-Study-Ansatz von zwei Schweizer Großunternehmen und einer großen Verwaltungseinheit des Bundes werden die existierenden Arbeitsmodelle für Büroarbeit analysiert und auf Entwicklungsperspektiven hin untersucht. Ein derzeit vorhandener Mix aus traditionellen und agilen Arbeitsmodellen wird sich in Zukunft im digitalen Kontext voraussichtlich unternehmensspezifisch stärker in Richtung einer höheren Agilität weiterentwickeln

Histone H2A and H2B Are Monoubiquitinated at AID-Targeted Loci

Background: Somatic hypermutation introduces base substitutions into the rearranged and expressed immunoglobulin (Ig) variable regions to promote immunity. This pathway requires and is initiated by the Activation Induced Deaminase (AID) protein, which deaminates cytidine to produce uracils and UG mismatches at the Ig genes. Subsequent processing of uracil by mismatch repair and base excision repair factors contributes to mutagenesis. While selective for certain genomic targets, the chromatin modifications which distinguish hypermutating from non-hypermutating loci are not defined. Methodology/Principal Findings: Here, we show that AID-targeted loci in mammalian B cells contain ubiquitinated chromatin. Chromatin immunoprecipitation (ChIP) analysis of a constitutively hypermutating Burkitt\u27s B cell line, Ramos, revealed the presence of monoubiquitinated forms of both histone H2A and H2B at two AID-associated loci, but not at control loci which are expressed but not hypermutated. Similar analysis using LPS activated primary murine splenocytes showed enrichment of the expressed V(H) and S gamma 3 switch regions upon ChIP with antibody specific to AID and to monoubiquitinated H2A and H2B. In the mechanism of mammalian hypermutation, AID may interact with ubiquitinated chromatin because confocal immunofluorescence microscopy visualized AID colocalized with monoubiquitinated H2B within discrete nuclear foci. Conclusions/Significance: Our results indicate that monoubiquitinated histones accompany active somatic hypermutation, revealing part of the histone code marking AID-targeted loci. This expands the current view of the chromatin state during hypermutation by identifying a specific nucleosome architecture associated with somatic hypermutation

Human Skeletal Muscle Possesses an Epigenetic Memory of Hypertrophy

It is unknown if adult human skeletal muscle has an epigenetic memory of earlier encounters with growth. We report, for the first time in humans, genome-wide DNA methylation (850,000 CpGs) and gene expression analysis after muscle hypertrophy (loading), return of muscle mass to baseline (unloading), followed by later hypertrophy (reloading). We discovered increased frequency of hypomethylation across the genome after reloading (18,816 CpGs) versus earlier loading (9,153 CpG sites). We also identified AXIN1, GRIK2, CAMK4, TRAF1 as hypomethylated genes with enhanced expression after loading that maintained their hypomethylated status even during unloading where muscle mass returned to control levels, indicating a memory of these genes methylation signatures following earlier hypertrophy. Further, UBR5, RPL35a, HEG1, PLA2G16, SETD3 displayed hypomethylation and enhanced gene expression following loading, and demonstrated the largest increases in hypomethylation, gene expression and muscle mass after later reloading, indicating an epigenetic memory in these genes. Finally, genes; GRIK2, TRAF1, BICC1, STAG1 were epigenetically sensitive to acute exercise demonstrating hypomethylation after a single bout of resistance exercise that was maintained 22 weeks later with the largest increase in gene expression and muscle mass after reloading. Overall, we identify an important epigenetic role for a number of largely unstudied genes in muscle hypertrophy/memory

Prostaglandin E2 Signals Through PTGER2 to Regulate Sclerostin Expression

The Wnt signaling pathway is a robust regulator of skeletal homeostasis. Gain-of-function mutations promote high bone mass, whereas loss of Lrp5 or Lrp6 co-receptors decrease bone mass. Similarly, mutations in antagonists of Wnt signaling influence skeletal integrity, in an inverse relation to Lrp receptor mutations. Loss of the Wnt antagonist Sclerostin (Sost) produces the generalized skeletal hyperostotic condition of sclerosteosis, which is characterized by increased bone mass and density due to hyperactive osteoblast function. Here we demonstrate that prostaglandin E2 (PGE2), a paracrine factor with pleiotropic effects on osteoblasts and osteoclasts, decreases Sclerostin expression in osteoblastic UMR106.01 cells. Decreased Sost expression correlates with increased expression of Wnt/TCF target genes Axin2 and Tcf3. We also show that the suppressive effect of PGE2 is mediated through a cyclic AMP/PKA pathway. Furthermore, selective agonists for the PGE2 receptor EP2 mimic the effect of PGE2 upon Sost, and siRNA reduction in Ptger2 prevents PGE2-induced Sost repression. These results indicate a functional relationship between prostaglandins and the Wnt/β-catenin signaling pathway in bone