BMP-2 induces ATF4 phosphorylation in chondrocytes through a COX-2/PGE2 dependent signaling pathway

SummaryObjectiveBone morphogenic protein (BMP)-2 is approved for fracture non-union and spine fusion. We aimed to further dissect its downstream signaling events in chondrocytes with the ultimate goal to develop novel therapeutics that can mimic BMP-2 effect but have less complications.MethodsBMP-2 effect on cyclooxygenase (COX)-2 expression was examined using Real time quantitative PCR (RT-PCR) and Western blot analysis. Genetic approach was used to identify the signaling pathway mediating the BMP-2 effect. Similarly, the pathway transducing the PGE2 effect on ATF4 was investigated. Immunoprecipitation (IP) was performed to assess the complex formation after PGE2 binding.ResultsBMP-2 increased COX-2 expression in primary mouse costosternal chondrocytes (PMCSC). The results from the C9 Tet-off system demonstrated that endogenous BMP-2 also upregulated COX-2 expression. Genetic approaches using PMCSC from ALK2fx/fx, ALK3fx/fx, ALK6−/−, and Smad1fx/fx mice established that BMP-2 regulated COX-2 through activation of ALK3–Smad1 signaling. PGE-2 EIA showed that BMP-2 increased PGE2 production in PMCSC. ATF4 is a transcription factor that regulates bone formation. While PGE2 did not have significant effect on ATF4 expression, it induced ATF4 phosphorylation. In addition to stimulating COX-2 expression, BMP-2 also induced phosphorylation of ATF4. Using COX-2 deficient chondrocytes, we demonstrated that the BMP-2 effect on ATF4 was COX-2-dependent. Tibial fracture samples from COX-2−/− mice showed reduced phospho-ATF4 immunoreactivity compared to wild type (WT) ones. PGE2 mediated ATF4 phosphorylation involved signaling primarily through the EP2 and EP4 receptors and PGE2 induced an EP4-ERK1/2-RSK2 complex formation.ConclusionsBMP-2 regulates COX-2 expression through ALK3–Smad1 signaling, and PGE2 induces ATF4 phosphorylation via EP4-ERK1/2-RSK2 axis

Clouds, shadows, or twilight? Mayfly nymphs recognise the difference

1. We examined the relative changes in light intensity that initiate night-time locomotor activity changes in nymphs of the mayfly, Stenonema modestum (Heptageniidae). Tests were carried out in a laboratory stream to examine the hypothesis that nymphs increase their locomotion in response to the large and sustained reductions in relative light intensity that take place during twilight but not to short-term daytime light fluctuations or a minimum light intensity threshold. Ambient light intensity was reduced over a range of values representative of evening twilight. Light was reduced over the same range of intensities either continuously or in discrete intervals while at the same time nymph activity on unglazed tile substrata was video recorded. 2. Nymphs increased their locomotor activity during darkness in response to large, sustained relative light decreases, but not in response to short-term, interrupted periods of light decrease. Nymphs did not recognise darkness unless an adequate light stimulus, such as large and sustained relative decrease in light intensity, had taken place. 3. We show that nymphs perceive light change over time and respond only after a lengthy period of accumulation of light stimulus. The response is much lengthier than reported for other aquatic organisms and is highly adaptive to heterogeneous stream environments

Spatial representation for navigation in animats

This article considers the problem of spatial representation for animat navigation systems. It is proposed that the global navigation task, or "wayfinding, " is best supported by multiple interacting subsystems, each of which builds its own partial representation of relevant world knowledge. Evidence from the study of animal navigation is reviewed to demonstrate that similar principles underlie the wayfinding behavior of animals, including humans. A simulated wayfinding system is described that embodies and illustrates several of the themes identified with animat navigation. This system constructs a network of partial models of the quantitative spatial relations between groups of salient landmarks. Navigation tasks are solved by propagating egocentric view information through this network, using a simple but effective heuristic to arbitrate between multiple solutions

Search for the Zγ decay mode of new high-mass resonances in pp collisions at √s = 13 TeV with the ATLAS detector

This letter presents a search for narrow, high-mass resonances in the Zγ final state with the Z boson decaying into a pair of electrons or muons. The √s = 13 TeV pp collision data were recorded by the ATLAS detector at the CERN Large Hadron Collider and have an integrated luminosity of 140 fb−1. The data are found to be in agreement with the Standard Model background expectation. Upper limits are set on the resonance production cross section times the decay branching ratio into Zγ. For spin-0 resonances produced via gluon–gluon fusion, the observed limits at 95% confidence level vary between 65.5 fb and 0.6 fb, while for spin-2 resonances produced via gluon–gluon fusion (or quark–antiquark initial states) limits vary between 77.4 (76.1) fb and 0.6 (0.5) fb, for the mass range from 220 GeV to 3400 GeV

Measurement of the cross-sections of the electroweak and total production of a Zγ pair in association with two jets in pp collisions at √s = 13 TeV with the ATLAS detector

This Letter presents the measurement of the fiducial and differential cross-sections of the electroweak production of a Zγ pair in association with two jets. The analysis uses 140 fb−1 of LHC proton–proton collision data taken at √s = 13 TeV recorded by the ATLAS detector during the years 2015–2018. Events with a Z boson candidate decaying into either an e+e− or μ+μ− pair, a photon and two jets are selected. The electroweak component is extracted by requiring a large dijet invariant mass and by using the information about the centrality of the system and is measured with an observed and expected significance well above five standard deviations. The fiducial pp → Zγ jj cross-section for the electroweak production is measured to be 3.6 ± 0.5 fb. The total fiducial cross-section that also includes contributions where the jets arise from strong interactions is measured to be 16.8+2.0 −1.8 fb. The results are consistent with the Standard Model predictions. Differential cross-sections are also measured using the same events and are compared with parton-shower Monte Carlo simulations. Good agreement is observed between data and predictions

Measurement of the charge asymmetry in top-quark pair production in association with a photon with the ATLAS experiment

A measurement of the charge asymmetry in top-quark pair (tt¯) production in association with a photon is presented. The measurement is performed in the single-lepton tt¯ decay channel using proton–proton collision data collected with the ATLAS detector at the Large Hadron Collider at CERN at a centre-of-massenergy of 13 TeV during the years 2015–2018, corresponding to an integrated luminosity of 139 fb−1. The charge asymmetry is obtained from the distribution of the difference of the absolute rapidities of the top quark and antiquark using a profile likelihood unfolding approach. It is measured to be AC = −0.003 ± 0.029 in agreement with the Standard Model expectation

Search for non-resonant production of semi-visible jets using Run 2 data in ATLAS

Semi-visible jets, with a significant contribution to the event's missing transverse momentum, can arise in strongly interacting dark sectors. This results in an event topology where one of the jets can be aligned with the direction of the missing transverse momentum. The first search for semi-visible jets produced via a t-channel mediator exchange is presented. The analysis uses proton-proton collisions with an integrated luminosity of 139 fb−1 and a centre-of-mass energy of 13 TeV, collected with the ATLAS detector during the Run 2 of the LHC. No excess over Standard Model predictions is observed. Assuming a coupling strength of unity between the mediator, a Standard Model quark and a dark quark, mediator masses up to 2.7 TeV are excluded at the 95% confidence level. Upper limits on the coupling strength are also derived

Observation of Wγγ triboson production in proton-proton collisions at √s = 13 TeV with the ATLAS detector

This letter reports the observation of W(ℓν)γγ production in proton-proton collisions. This measurement uses the full Run 2 sample of events recorded at a center-of-mass energy of √s = 13 TeV by the ATLAS detector at the LHC, corresponding to an integrated luminosity of 140 fb−1. Events with a leptonically-decaying W boson and at least two photons are considered. The background-only hypothesis is rejected with an observed and expected significance of 5.6 standard deviations. The inclusive fiducial production cross section of W(eν)γγ and W(μν)γγ events is measured to be σfid=13.8±1.1(stat)+2.1−2.0(syst)±0.1(lumi) fb, in agreement with the Standard Model prediction