Loss of Grem1-lineage chondrogenic progenitor cells causes osteoarthritis

Published online: 31 October 2023Osteoarthritis (OA) is characterised by an irreversible degeneration of articular cartilage. Here we show that the BMP-antagonist Gremlin 1 (Grem1) marks a bipotent chondrogenic and osteogenic progenitor cell population within the articular surface. Notably, these progenitors are depleted by injury-induced OA and increasing age. OA is also caused by ablation of Grem1 cells in mice. Transcriptomic and functional analysis in mice found that articular surface Grem1-lineage cells are dependent on Foxo1 and ablation of Foxo1 in Grem1-lineage cells caused OA. FGFR3 signalling was confirmed as a promising therapeutic pathway by administration of pathway activator, FGF18, resulting in Grem1-lineage chondrocyte progenitor cell proliferation, increased cartilage thickness and reduced OA. These findings suggest that OA, in part, is caused by mechanical, developmental or age-related attrition of Grem1 expressing articular cartilage progenitor cells. These cells, and the FGFR3 signalling pathway that sustains them, may be effective future targets for biological management of OA.Jia Q. Ng, Toghrul H. Jafarov, Christopher B. Little, Tongtong Wang, Abdullah M. Ali, YanMa, Georgette A. Radford, Laura Vrbanac, Mari Ichinose, Samuel Whittle, David J. Hunter, Tamsin R. M. Lannagan, Nobumi Suzuki, JarradM. Goyne, Hiroki Kobayashi, Timothy C. Wang, David R. Haynes, Danijela Menicanin, Stan Gronthos, Daniel L. Worthley, Susan L. Woods and Siddhartha Mukherje

Petrophysical, Geochemical, and Hydrological Evidence for Extensive Fracture-Mediated Fluid and Heat Transport in the Alpine Fault's Hanging-Wall Damage Zone

Fault rock assemblages reflect interaction between deformation, stress, temperature, fluid, and chemical regimes on distinct spatial and temporal scales at various positions in the crust. Here we interpret measurements made in the hanging-wall of the Alpine Fault during the second stage of the Deep Fault Drilling Project (DFDP-2). We present observational evidence for extensive fracturing and high hanging-wall hydraulic conductivity (∼10−9 to 10−7 m/s, corresponding to permeability of ∼10−16 to 10−14 m2) extending several hundred meters from the fault's principal slip zone. Mud losses, gas chemistry anomalies, and petrophysical data indicate that a subset of fractures intersected by the borehole are capable of transmitting fluid volumes of several cubic meters on time scales of hours. DFDP-2 observations and other data suggest that this hydrogeologically active portion of the fault zone in the hanging-wall is several kilometers wide in the uppermost crust. This finding is consistent with numerical models of earthquake rupture and off-fault damage. We conclude that the mechanically and hydrogeologically active part of the Alpine Fault is a more dynamic and extensive feature than commonly described in models based on exhumed faults. We propose that the hydrogeologically active damage zone of the Alpine Fault and other large active faults in areas of high topographic relief can be subdivided into an inner zone in which damage is controlled principally by earthquake rupture processes and an outer zone in which damage reflects coseismic shaking, strain accumulation and release on interseismic timescales, and inherited fracturing related to exhumation

Stress testing and non-invasive coronary angiography in patients with suspected coronary artery disease: time for a new paradigm

Diagnosis and management of coronary artery disease represents major challenges to our health care system, affecting millions of patients each year. Until recently, the diagnosis of coronary artery disease was possible only through cardiac catheterization and invasive coronary angiography. To avoid the risks of an invasive procedure, stress testing is often employed for an initial assessment of patients with suspected coronary artery disease, serving as a gatekeeper for cardiac catheterization. With the emergence of non-invasive coronary angiography, the question arises if such a strategy is still sensible, particularly, in view of only a modest agreement between stress testing results and the presence of coronary artery disease established by cardiac catheterization. Much data in support of the diagnostic accuracy and prognostic value of non-invasive coronary angiography by computed tomography have emerged within the last few years. These data challenge the role of stress testing as the initial imaging modality in patients with suspected coronary artery disease. This article reviews the clinical utility, limitations, as well as the hazards of stress testing compared with non-invasive coronary artery imaging by computed tomography. Finally, the implications of this review are discussed in relation to clinical practice

Search for invisible Higgs boson decays in vector boson fusion at √s = 13 TeV with the ATLAS detector

We report a search for Higgs bosons that are produced via vector boson fusion and subsequently decay into invisible particles. The experimental signature is an energetic jet pair with invariant mass of O(1) TeV and O(100) GeV missing transverse momentum. The analysis uses 36.1 fb−1 of pp collision data at √s=13 TeV recorded by the ATLAS detector at the LHC. In the signal region the 2252 observed events are consistent with the background estimation. Assuming a 125 GeV scalar particle with Standard Model cross sections, the upper limit on the branching fraction of the Higgs boson decay into invisible particles is 0.37 at 95% confidence level where 0.28 was expected. This limit is interpreted in Higgs portal models to set bounds on the wimp–nucleon scattering cross section. We also consider invisible decays of additional scalar bosons with masses up to 3 TeV for which the upper limits on the cross section times branching fraction are in the range of 0.3–1.7 pb

Comparison between simulated and observed LHC beam backgrounds in the ATLAS experiment at Ebeam =4 TeV

Results of dedicated Monte Carlo simulations of beam-induced background (BIB) in the ATLAS experiment at the Large Hadron Collider (LHC) are presented and compared with data recorded in 2012. During normal physics operation this background arises mainly from scattering of the 4 TeV protons on residual gas in the beam pipe. Methods of reconstructing the BIB signals in the ATLAS detector, developed and implemented in the simulation chain based on the \textscFluka Monte Carlo simulation package, are described. The interaction rates are determined from the residual gas pressure distribution in the LHC ring in order to set an absolute scale on the predicted rates of BIB so that they can be compared quantitatively with data. Through these comparisons the origins of the BIB leading to different observables in the ATLAS detectors are analysed. The level of agreement between simulation results and BIB measurements by ATLAS in 2012 demonstrates that a good understanding of the origin of BIB has been reached

Observation of photon-induced W⁺W⁻ production in pp collisions at √s=13 TeV using the ATLAS detector

This letter reports the observation of photon-induced production of W-boson pairs, γγ→ WW. The analysis uses 139 fb-1 of LHC proton-proton collision data taken at √s=13 TeV recorded by the ATLAS experiment during the years 2015-2018. The measurement is performed selecting one electron and one muon, corresponding to the decay of the diboson system as WW→e±νμ∓ν final state. The background-only hypothesis is rejected with a significance of well above 5 standard deviations consistent with the expectation from Monte Carlo simulation. A cross section for the γγ→ WW process of 3.13±0.31(stat.)±0.28(syst.) fb is measured in a fiducial volume close to the acceptance of the detector, by requiring an electron and a muon of opposite signs with large dilepton transverse momentum and exactly zero additional charged particles. This is found to be in agreement with the Standard Model prediction

Searches for lepton-flavour-violating decays of the Higgs boson in s=13\sqrt{s}=13 TeV pp\mathit{pp} collisions with the ATLAS detector

This Letter presents direct searches for lepton flavour violation in Higgs boson decays, H → eτ and H → μτ , performed with the ATLAS detector at the LHC. The searches are based on a data sample of proton–proton collisions at a centre-of-mass energy √s = 13 TeV, corresponding to an integrated luminosity of 36.1 fb−1. No significant excess is observed above the expected background from Standard Model processes. The observed (median expected) 95% confidence-level upper limits on the leptonflavour-violating branching ratios are 0.47% (0.34+0.13−0.10%) and 0.28% (0.37+0.14−0.10%) for H → eτ and H → μτ , respectively.publishedVersio

Measurement of the total cross section and ρ -parameter from elastic scattering in pp collisions at √s=13 TeV with the ATLAS detector

In a special run of the LHC with β⋆=2.5 km, proton–proton elastic-scattering events were recorded at s√=13 TeV with an integrated luminosity of 340 μb−1 using the ALFA subdetector of ATLAS in 2016. The elastic cross section was measured differentially in the Mandelstam t variable in the range from −t=2.5⋅10−4 GeV2 to −t=0.46 GeV2 using 6.9 million elastic-scattering candidates. This paper presents measurements of the total cross section σtot, parameters of the nuclear slope, and the ρ-parameter defined as the ratio of the real part to the imaginary part of the elastic-scattering amplitude in the limit t→0. These parameters are determined from a fit to the differential elastic cross section using the optical theorem and different parameterizations of the t-dependence. The results for σtot and ρ are σtot(pp→X)=104.7±1.1 mb ,ρ=0.098±0.011. The uncertainty in σtot is dominated by the luminosity measurement, and in ρ by imperfect knowledge of the detector alignment and by modelling of the nuclear amplitude.publishedVersio