cAMP Attenuates TGF-β\u27s Profibrotic Responses in Osteoarthritic Synoviocytes: Involvement of Hyaluronan and PRG4

Osteoarthritis (OA) is characterized by synovitis and synovial fibrosis. Synoviocytes are fibroblast-like resident cells of the synovium that are activated by transforming growth factor (TGF)-β to proliferate, migrate, and produce extracellular matrix. Synoviocytes secrete hyaluronan (HA) and proteoglycan-4 (PRG4). HA reduces synovial fibrosis in vivo, and the Prg4−/− mouse exhibits synovial hyperplasia. We investigated the antifibrotic effects of increased intracellular cAMP in TGF-β-stimulated human OA synoviocytes. TGF-β1 stimulated collagen I (COL1A1), α-smooth muscle actin (α-SMA), tissue inhibitor of metalloproteinase (TIMP)-1, and procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) expression, and procollagen I, α-SMA, HA, and PRG4 production, migration, and proliferation of OA synoviocytes were measured. Treatment of OA synoviocytes with forskolin (10 μM) increased intracellular cAMP levels and reduced TGF-β1-stimulated COL1A1, α-SMA, and TIMP-1 expression, with no change in PLOD2 expression. Forskolin also reduced TGF-β1-stimulated procollagen I and α-SMA content as well as synoviocyte migration and proliferation. Forskolin (10 μM) increased HA secretion and PRG4 expression and production. A cell-permeant cAMP analog reduced COL1A1 and α-SMA expression and enhanced HA and PRG4 secretion by OA synoviocytes. HA and PRG4 reduced α-SMA expression and content, and PRG4 reduced COL1A1 expression and procollagen I content in OA synoviocytes. Prg4−/− synovium exhibited increased α-SMA, COL1A1, and TIMP-1 expression compared with Prg4+/+ synovium. Prg4−/− synoviocytes demonstrated strong α-SMA and collagen type I staining, whereas these were undetected in Prg4+/+ synoviocytes and were reduced with PRG4 treatment. We conclude that increasing intracellular cAMP levels in synoviocytes mitigates synovial fibrosis through enhanced production of HA and PRG4, possibly representing a novel approach for treatment of OA synovial fibrosis

Seriously personal:The reasons that motivate entrepreneurs to address climate change

This is the author accepted manuscript. The final version is freely available from Springer Verlag via the DOI in this record.Scholars increasingly argue that entrepreneurs and their small- and medium-sized enterprises should play a central role in reducing the rate and magnitude of climate change. However, evidence suggests that while some entrepreneurs recognize their crucial role in addressing climate change, most do not. Why some entrepreneurs nevertheless concern themselves with climate change has largely been overlooked. Some initial work in this area tentatively suggests that these entrepreneurs may engage with climate change because of their personal values, which either focus on financial or socio-ecological reasons, or a combination of both. Yet, it is unclear if all for-profit entrepreneurs engage with climate change for the same reasons, or if indeed their motivations vary across business types. Over a period of four years, we examined entrepreneurs’ motivations to engage with climate change through a variety of qualitative research methods. Our findings illustrate how entrepreneurs who address climate change have motivations specific to their business activity/industry and level of maturity. In each instance, we link these motivations to distinct conceptualizations of time and place. We contend that, through a more differentiated understanding of entrepreneurial motivations, policy-makers can draft climate change-related policies tailored to entrepreneurial needs. Policies could both increase the number of entrepreneurs who already engage in climate change mitigation and leverage the impact of those entrepreneurs already mitigating climate change.This study was funded by the European Social Fund (09099NCO5). We acknowledge with thanks the participation of the entrepreneurs and the support of Business Leaders for Low Carbon, Cornwall Council, and Cornwall Sustainable Tourism Project. The authors wish to thank Professor John Amis, Professor Kenneth Amaeshi and the anonymous reviewers who provided useful feedback on earlier versions of the article

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Is American Public Administration Detached From Historical Context?: On the Nature of Time and the Need to Understand It in Government and Its Study

The study of public administration pays little attention to history. Most publications are focused on current problems (the present) and desired solutions (the future) and are concerned mainly with organizational structure (a substantive issue) and output targets (an aggregative issue that involves measures of both individual performance and organizational productivity/services). There is much less consideration of how public administration (i.e., organization, policy, the study, etc.) unfolds over time. History, and so administrative history, is regarded as a “past” that can be recorded for its own sake but has little relevance to contemporary challenges. This view of history is the product of a diminished and anemic sense of time, resulting from organizing the past as a series of events that inexorably lead up to the present in a linear fashion. To improve the understanding of government’s role and position in society, public administration scholarship needs to reacquaint itself with the nature of time.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Theropod Fauna from Southern Australia Indicates High Polar Diversity and Climate-Driven Dinosaur Provinciality

The Early Cretaceous fauna of Victoria, Australia, provides unique data on the composition of high latitude southern hemisphere dinosaurs. We describe and review theropod dinosaur postcranial remains from the Aptian–Albian Otway and Strzelecki groups, based on at least 37 isolated bones, and more than 90 teeth from the Flat Rocks locality. Several specimens of medium- and large-bodied individuals (estimated up to ∼8.5 metres long) represent allosauroids. Tyrannosauroids are represented by elements indicating medium body sizes (∼3 metres long), likely including the holotype femur of Timimus hermani, and a single cervical vertebra represents a juvenile spinosaurid. Single specimens representing medium- and small-bodied theropods may be referrable to Ceratosauria, Ornithomimosauria, a basal coelurosaur, and at least three taxa within Maniraptora. Thus, nine theropod taxa may have been present. Alternatively, four distinct dorsal vertebrae indicate a minimum of four taxa. However, because most taxa are known from single bones, it is likely that small-bodied theropod diversity remains underestimated. The high abundance of allosauroids and basal coelurosaurs (including tyrannosauroids and possibly ornithomimosaurs), and the relative rarity of ceratosaurs, is strikingly dissimilar to penecontemporaneous dinosaur faunas of Africa and South America, which represent an arid, lower-latitude biome. Similarities between dinosaur faunas of Victoria and the northern continents concern the proportional representatation of higher clades, and may result from the prevailing temperate–polar climate of Australia, especially at high latitudes in Victoria, which is similar to the predominant warm–temperate climate of Laurasia, but distinct from the arid climate zone that covered extensive areas of Gondwana. Most dinosaur groups probably attained a near-cosmopolitan distribution in the Jurassic, prior to fragmentation of the Pangaean supercontinent, and some aspects of the hallmark ‘Gondwanan’ fauna of South America and Africa may therefore reflect climate-driven provinciality, not vicariant evolution driven by continental fragmentation. However, vicariance may still be detected at lower phylogenetic levels