The Role of Activated Protein C in Bone, Arthritis, and Fracture Healing

Activated protein C (APC) is a cytoprotective anticoagulant that stimulates cellular proliferation, suppresses inflammation, and enhances wound healing. These properties of APC are primarily modulated through its receptors, endothelial protein C receptor (EPCR) and protease-activated receptors (PAR)1/2, and subsequent activation of downstream proteins including ERK1/2, Akt, and p38. In this study, APC was investigated for its potential application in bone repair and arthritic bone conditions, including rheumatoid arthritis (RA) and osteoarthritis (OA), through its actions on osteoblasts. APC increased viability of MG-63 and MC3T3-E1 cells through a PAR1 dependent pathway and subsequently upregulated pERK, pAkt, and p-p38. APC augmented bone and tissue volume but not osteoclast numbers in a BMP-2 induced murine ectopic bone formation model. APC, however, did not enhance callus formation in a closed murine mid-tibial fracture model owing to several study limitations. In contrast with its effects in osteoblastic cell lines, APC suppressed cell viability through an EPCR/PAR1/PAR2 dependent mechanism in OA and RA bone derived cells. APC also decreased pERK, increased p27, and modulated IL-6 and MMP-2 secretion in arthritic cells. Collectively, these results demonstrate the diverse actions of APC in normal and arthritic bone biology including the novel potential of APC on bone formation

Statistics of Galactic-Scale Quasar Pairs at Cosmic Noon

The statistics of galactic-scale quasar pairs can elucidate our understanding of the dynamical evolution of supermassive black hole (SMBH) pairs, the duty cycles of quasar activity in mergers, or even the nature of dark matter, but have been challenging to measure at cosmic noon, the prime epoch of massive galaxy and SMBH formation. Here we measure a double quasar fraction of $\sim 6.2\pm0.5\times 10^{-4}$ integrated over $\sim 0.3-3$ arcsec separations (projected physical separations of $\sim 3-30\,{\rm kpc}$ at $z\sim 2$) in luminous ($L_{\rm bol}>10^{45.8}\,{\rm erg\,s^{-1}}$) unobscured quasars at $1.5<z<3.5$, using Gaia EDR3-resolved pairs around SDSS DR16 quasars. The measurement was based on a sample of 60 Gaia-resolved double quasars (out of 487 Gaia pairs dominated by quasar+star superpositions) at these separations, corrected for pair completeness in Gaia, which we quantify as functions of pair separation, magnitude of the primary, and magnitude contrast. The double quasar fraction increases towards smaller separations by a factor of $\sim 5$ over these scales. The division between physical quasar pairs and lensed quasars in our sample is currently unknown, requiring dedicated follow-up observations (in particular, deep, sub-arcsec-resolution IR imaging for the closest pairs). Intriguingly, at this point the observed pair statistics are in rough agreement with theoretical predictions both for the lensed quasar population in mock catalogs and for dual quasars in cosmological hydrodynamic simulations. Upcoming wide-field imaging/spectroscopic space missions such as Euclid, CSST and Roman, combined with targeted follow-up observations, will conclusively measure the abundances and host galaxy properties of galactic-scale quasar pairs, offset AGNs, and sub-arcsec lensed quasars across cosmic time.Comment: 19 pages, 9 figures; submitted to Ap

CIViCdb 2022: Evolution of an open-access cancer variant interpretation knowledgebase

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC\u27s functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing \u3e3200 variants in \u3e470 genes from \u3e3100 publications