Bone remodelling in the mouse tibia is spatio-temporally modulated by oestrogen deficiency and external mechanical loading: A combined in vivo/in silico study

Osteoporosis disrupts the healthy remodelling process in bone and affects its mechanical properties. Mechanical loading has been shown to be effective in stimulating bone formation to mitigate initial bone loss. However, no study has investigated the effects of repeated mechanical loading, with a pause of one week in between, in the mouse tibia with oestrogen deficiency. This study uses a combined experimental and computational approach, through longitudinal monitoring with micro-computed tomography, to evaluate the effects of loading on bone adaptation in the tibiae of ovariectomised (OVX) C57BL/6 mice from 14 to 22 weeks of age. Micro-FE models coupled with bone adaptation algorithms were used to estimate changes in local tissue strains due to OVX and mechanical loading, and to quantify the relationship between local strain and remodelling. The first in vivo mechanical loading increased apposition, by 50–150%, while resorption decreased by 50–60%. Both endosteal and periosteal resorption increased despite the second mechanical loading, and periosteal resorption was up to 70% higher than that after the first loading. This was found to correlate with an initial decrease in average strain energy density after the first loading, which was lower and more localised after the second loading. Predictions of bone adaptation showed that between 50 and 90% of the load-induced bone apposition is linearly strain driven at the organ-level, but resorption is more biologically driven at the local level. The results imply that a systematic increase in peak load or loading rate may be required to achieve a similar bone adaptation rate in specific regions of interests

A novel algorithm to predict bone changes in the mouse tibia properties under physiological conditions

Understanding how bone adapts to mechanical stimuli is fundamental for optimising treatments against musculoskeletal diseases in preclinical studies, but the contribution of physiological loading to bone adaptation in mouse tibia has not been quantified so far. In this study, a novel mechanistic model to predict bone adaptation based on physiological loading was developed and its outputs were compared with longitudinal scans of the mouse tibia. Bone remodelling was driven by the mechanical stimuli estimated from micro-FEA models constructed from micro-CT scans of C57BL/6 female mice (N = 5) from weeks 14 and 20 of age, to predict bone changes in week 16 or 22. Parametric analysis was conducted to evaluate the sensitivity of the models to subject-specific or averaged parameters, parameters from week 14 or week 20, and to strain energy density (SED) or maximum principal strain (εmaxprinc). The results at week 20 showed no significant difference in bone densitometric properties between experimental and predicted images across the tibia for both stimuli, and 59% and 47% of the predicted voxels matched with the experimental sites in apposition and resorption, respectively. The model was able to reproduce regions of bone apposition in both periosteal and endosteal surfaces (70% and 40% for SED and εmaxprinc, respectively), but it under-predicted the experimental sites of resorption by over 85%. This study shows for the first time the potential of a subject-specific mechanoregulation algorithm to predict bone changes in a mouse model under physiological loading. Nevertheless, the weak predictions of resorption suggest that a combined stimulus or biological stimuli should be accounted for in the model

The role of the loading condition in predictions of bone adaptation in a mouse tibial loading model

The in vivo mouse tibial loading model is used to evaluate the effectiveness of mechanical loading treatment against skeletal diseases. Although studies have correlated bone adaptation with the induced mechanical stimulus, predictions of bone remodeling remained poor, and the interaction between external and physiological loading in engendering bone changes have not been determined. The aim of this study was to determine the effect of passive mechanical loading on the strain distribution in the mouse tibia and its predictions of bone adaptation. Longitudinal micro-computed tomography (micro-CT) imaging was performed over 2 weeks of cyclic loading from weeks 18 to 22 of age, to quantify the shape change, remodeling, and changes in densitometric properties. Micro-CT based finite element analysis coupled with an optimization algorithm for bone remodeling was used to predict bone adaptation under physiological loads, nominal 12N axial load and combined nominal 12N axial load superimposed to the physiological load. The results showed that despite large differences in the strain energy density magnitudes and distributions across the tibial length, the overall accuracy of the model and the spatial match were similar for all evaluated loading conditions. Predictions of densitometric properties were most similar to the experimental data for combined loading, followed closely by physiological loading conditions, despite no significant difference between these two predicted groups. However, all predicted densitometric properties were significantly different for the 12N and the combined loading conditions. The results suggest that computational modeling of bone’s adaptive response to passive mechanical loading should include the contribution of daily physiological load

Combining PTH(1‐34) and mechanical loading has increased benefit to tibia bone mechanics in ovariectomised mice

Combined treatment with PTH(1-34) and mechanical loading confers increased structural benefits to bone than monotherapies. However, it remains unclear how this longitudinal adaptation affects the bone mechanics. This study quantified the individual and combined longitudinal effects of PTH(1-34) and mechanical loading on the bone stiffness and strength evaluated in vivo with validated micro-finite element (microFE) models. C57BL/6 mice were ovariectomised at 14-week-old and treated either with injections of PTH(1-34), compressive tibia loading or both interventions concurrently. Right tibiae were in vivo microCT-scanned every 2 weeks from 14 until 24-week-old. MicroCT images were rigidly registered to reference tibia and the cortical organ level (whole bone) and tissue level (midshaft) morphometric properties and bone mineral content were quantified. MicroCT images were converted into voxel-based homogeneous, linear elastic microFE models to estimate the bone stiffness and strength. This approach allowed us for the first time to quantify the longitudinal changes in mechanical properties induced by combined treatments in a model of accelerated bone resorption. Both changes of stiffness and strength were higher with co-treatment than with individual therapies, consistent with increased benefits with the tibia bone mineral content and cortical area, properties strongly associated with the tibia mechanics. The longitudinal data shows that the two bone anabolics, both individually and combined, had persistent benefit on estimated mechanical properties, and that benefits (increased stiffness and strength) remained after treatment was withdrawn

Study of Z → llγ decays at √s = 8 TeV with the ATLAS detector

This paper presents a study of Z → llγ decays with the ATLAS detector at the Large Hadron Collider. The analysis uses a proton–proton data sample corresponding to an integrated luminosity of 20.2 fb−1 collected at a centre-ofmass energy √s = 8 TeV. Integrated fiducial cross-sections together with normalised differential fiducial cross-sections, sensitive to the kinematics of final-state QED radiation, are obtained. The results are found to be in agreement with stateof-the-art predictions for final-state QED radiation. First measurements of Z → llγ γ decays are also reported

Software performance of the ATLAS track reconstruction for LHC run 3

Charged particle reconstruction in the presence of many simultaneous proton–proton (pp) collisions in the LHC is a challenging task for the ATLAS experiment’s reconstruction software due to the combinatorial complexity. This paper describes the major changes made to adapt the software to reconstruct high-activity collisions with an average of 50 or more simultaneous pp interactions per bunch crossing (pileup) promptly using the available computing resources. The performance of the key components of the track reconstruction chain and its dependence on pile-up are evaluated, and the improvement achieved compared to the previous software version is quantified. For events with an average of 60 pp collisions per bunch crossing, the updated track reconstruction is twice as fast as the previous version, without significant reduction in reconstruction efficiency and while reducing the rate of combinatorial fake tracks by more than a factor two

Observation of four-top-quark production in the multilepton final state with the ATLAS detector

This paper presents the observation of four-top-quark (tt¯tt¯) production in proton-proton collisions at the LHC. The analysis is performed using an integrated luminosity of 140 fb−1 at a centre-of-mass energy of 13 TeV collected using the ATLAS detector. Events containing two leptons with the same electric charge or at least three leptons (electrons or muons) are selected. Event kinematics are used to separate signal from background through a multivariate discriminant, and dedicated control regions are used to constrain the dominant backgrounds. The observed (expected) significance of the measured tt¯tt¯ signal with respect to the standard model (SM) background-only hypothesis is 6.1 (4.3) standard deviations. The tt¯tt¯ production cross section is measured to be 22.5+6.6−5.5 fb, consistent with the SM prediction of 12.0±2.4 fb within 1.8 standard deviations. Data are also used to set limits on the three-top-quark production cross section, being an irreducible background not measured previously, and to constrain the top-Higgs Yukawa coupling and effective field theory operator coefficients that affect tt¯tt¯ production

Search for heavy Majorana or Dirac neutrinos and right-handed W gauge bosons in final states with charged leptons and jets in pp collisions at √s = 13 TeV with the ATLAS detector

A search for heavy right-handed Majorana or Dirac neutrinos NR and heavy right-handed gauge bosons WR is performed in events with energetic electrons or muons, with the same or opposite electric charge, and energetic jets. The search is carried out separately for topologies of clearly separated final-state products (“resolved” channel) and topologies with boosted final states with hadronic and/or leptonic products partially overlapping and reconstructed as a large-radius jet (“boosted” channel). The events are selected from pp collision data at the LHC with an integrated luminosity of 139 fb−1 collected by the ATLAS detector at √s = 13 TeV. No significant deviations from the Standard Model predictions are observed. The results are interpreted within the theoretical framework of a left-right symmetric model, and lower limits are set on masses in the heavy righthanded WR boson and NR plane. The excluded region extends to about m(WR) = 6.4 TeV for both Majorana and Dirac NR neutrinos at m(NR) < 1 TeV. NR with masses of less than 3.5 (3.6) TeV are excluded in the electron (muon) channel at m(WR) = 4.8 TeV for the Majorana neutrinos, and limits of m(NR) up to 3.6 TeV for m(WR) = 5.2 (5.0) TeV in the electron (muon) channel are set for the Dirac neutrinos. These constitute the most stringent exclusion limits to date for the model considered

Search for third-generation vector-like leptons in pp collisions at s√ = 13 TeV with the ATLAS detector

A search for vector-like leptons in multilepton (two, three, or four-or-more electrons plus muons) final states with zero or more hadronic τ-lepton decays is presented. The search is performed using a dataset corresponding to an integrated luminosity of 139 fb−1 of proton-proton collisions at a centre-of-mass energy of 13 TeV recorded by the ATLAS detector at the LHC. To maximize the separation of signal and background, a machine-learning classifier is used. No excess of events is observed beyond the Standard Model expectation. Using a doublet vector-like lepton model, vector-like leptons coupling to third-generation Standard Model leptons are excluded in the mass range from 130 GeV to 900 GeV at the 95% confidence level, while the highest excluded mass is expected to be 970 GeV

Search for heavy Higgs bosons with flavour-violating couplings in multi-lepton plus b-jets final states in pp collisions at 13 TeV with the ATLAS detector

A search for new heavy scalars with flavour-violating decays in final states with multiple leptons and b-tagged jets is presented. The results are interpreted in terms of a general two-Higgs-doublet model involving an additional scalar with couplings to the top-quark and the three up-type quarks (ρtt, ρtc, and ρtu). The targeted signals lead to final states with either a same-sign top-quark pair, three top-quarks, or four top-quarks. The search is based on a data sample of proton-proton collisions at √s = 13 TeV recorded with the ATLAS detector during Run 2 of the Large Hadron Collider, corresponding to an integrated luminosity of 139 fb−1. Events are categorised depending on the multiplicity of light charged leptons (electrons or muons), total lepton charge, and a deep-neural-network output to enhance the purity of each of the signals. Masses of an additional scalar boson mH between 200 − 630 GeV with couplings ρtt = 0.4, ρtc = 0.2, and ρtu = 0.2 are excluded at 95% confidence level. Additional interpretations are provided in models of R-parity violating supersymmetry, motivated by the recent flavour and (g − 2)μ anomalies