An analytic and systematic framework for estimating metabolic flux ratios from 13C tracer experiments

<p>Abstract</p> <p>Background</p> <p>Metabolic fluxes provide invaluable insight on the integrated response of a cell to environmental stimuli or genetic modifications. Current computational methods for estimating the metabolic fluxes from ¹³<it>C </it>isotopomer measurement data rely either on manual derivation of analytic equations constraining the fluxes or on the numerical solution of a highly nonlinear system of isotopomer balance equations. In the first approach, analytic equations have to be tediously derived for each organism, substrate or labelling pattern, while in the second approach, the global nature of an optimum solution is difficult to prove and comprehensive measurements of external fluxes to augment the ¹³<it>C </it>isotopomer data are typically needed.</p> <p>Results</p> <p>We present a novel analytic framework for estimating metabolic flux ratios in the cell from ¹³<it>C </it>isotopomer measurement data. In the presented framework, equation systems constraining the fluxes are derived automatically from the model of the metabolism of an organism. The framework is designed to be applicable with all metabolic network topologies, ¹³<it>C </it>isotopomer measurement techniques, substrates and substrate labelling patterns.</p> <p>By analyzing nuclear magnetic resonance (NMR) and mass spectrometry (MS) measurement data obtained from the experiments on glucose with the model micro-organisms <it>Bacillus subtilis </it>and <it>Saccharomyces cerevisiae </it>we show that our framework is able to automatically produce the flux ratios discovered so far by the domain experts with tedious manual analysis. Furthermore, we show by <it>in silico </it>calculability analysis that our framework can rapidly produce flux ratio equations – as well as predict when the flux ratios are unobtainable by linear means – also for substrates not related to glucose.</p> <p>Conclusion</p> <p>The core of ¹³<it>C </it>metabolic flux analysis framework introduced in this article constitutes of flow and independence analysis of metabolic fragments and techniques for manipulating isotopomer measurements with vector space techniques. These methods facilitate efficient, analytic computation of the ratios between the fluxes of pathways that converge to a common junction metabolite. The framework can been seen as a generalization and formalization of existing tradition for computing metabolic flux ratios where equations constraining flux ratios are manually derived, usually without explicitly showing the formal proofs of the validity of the equations.</p

Feasible assessment of recovery and cardiovascular health:accuracy of nocturnal HR and HRV assessed via ring PPG in comparison to medical grade ECG

Abstract Objective: To validate the accuracy of the Oura ring in the quantification of resting heart rate (HR) and heart rate variability (HRV). Background: Wearable devices have become comfortable, lightweight, and technologically advanced for assessing health behavior. As an example, the novel Oura ring integrates daily physical activity and nocturnal cardiovascular measurements. Ring users can follow their autonomic nervous system responses to their daily behavior based on nightly changes in HR and HRV, and adjust their behavior accordingly after self-reflection. As wearable photoplethysmogram (PPG) can be disrupted by several confounding influences, it is crucial to demonstrate the accuracy of ring measurements. Approach: Nocturnal HR and HRV were assessed in 49 adults with simultaneous measurements from the Oura ring and the gold standard ECG measurement. Female and male participants with a wide age range (15—72 years) and physical activity status were included. Regression analysis between ECG and the ring outcomes was performed. Main results: Very high agreement between the ring and ECG was observed for nightly average HR and HRV (r2 = 0.996 and 0.980, respectively) with a mean bias of −0.63 bpm and −1.2 ms. High agreement was also observed across 5 min segments within individual nights in (r2 = 0.869 ± 0.098 and 0.765 ± 0.178 in HR and HRV, respectively). Significance: Present findings indicate high validity of the Oura ring in the assessment of nocturnal HR and HRV in healthy adults. The results show the utility of this miniaturised device as a lifestyle management tool in long-term settings. High quality PPG signal results prompt future studies utilizing ring PPG towards clinically relevant health outcomes

Cost analysis of antibiotic therapy versus appendectomy for treatment of uncomplicated acute appendicitis:5-year results of the APPAC randomized clinical trial

Abstract Background: The efficacy and safety of antibiotic treatment for uncomplicated acute appendicitis has been established at long-term follow-up with the majority of recurrences shown to occur within the first year. Overall costs of antibiotics are significantly lower compared with appendectomy at short-term follow-up, but long-term durability of these cost savings is unclear. The study objective was to compare the long-term overall costs of antibiotic therapy versus appendectomy in the treatment of uncomplicated acute appendicitis in the APPAC (APPendicitis ACuta) trial at 5 years. Methods and findings: This multicentre, non-inferiority randomized clinical trial randomly assigned 530 adult patients with CT-confirmed uncomplicated acute appendicitis to appendectomy or antibiotic treatment at six Finnish hospitals. All major costs during the 5-year follow-up were recorded, whether generated by the initial visit and subsequent treatment or possible recurrent appendicitis. Between November 2009 and June 2012, 273 patients were randomized to appendectomy and 257 to antibiotics. The overall costs of appendectomy were 1.4 times higher (p&lt;0.001) (€5716; 95% CI: €5510 to €5925) compared with antibiotic therapy (€4171; 95% CI: €3879 to €4463) resulting in cost savings of €1545 per patient (95% CI: €1193 to €1899; p&lt;0.001) in the antibiotic group. At 5 years, the majority (61%, n = 156) of antibiotic group patients did not undergo appendectomy. Conclusions: At 5-year follow-up antibiotic treatment resulted in significantly lower overall costs compared with appendectomy. As the majority of appendicitis recurrences occur within the first year after the initial antibiotic treatment, these results suggest that treating uncomplicated acute appendicitis with antibiotics instead of appendectomy results in lower overall costs even at longer-term follow-up

The association between appendicitis severity and patient age with appendiceal neoplasm histology:a population-based study

Abstract Purpose: Recent studies have reported alarming appendiceal tumor rates associated with complicated acute appendicitis, especially in patients presenting with a periappendicular abscess. However, the data on histology of appendiceal tumors among acute appendicitis patients is limited, especially in patient cohorts differentiating between uncomplicated and complicated acute appendicitis. We have previously reported the association of increased appendiceal tumor prevalence with complicated acute appendicitis in this population-based study. The objective of this secondary analysis was to evaluate the association of both appendicitis severity and patient age with appendiceal tumor histology. Methods: This nationwide population-based registry study (The Finnish Cancer Registry) was conducted from 2007 to 2013. All appendiceal tumors (n= 840) and available medical reports (n= 504) of these patients at eight study hospitals were previously evaluated, identifying altogether 250 patients with both acute appendicitis and appendiceal tumor. Results: The severity of acute appendicitis was significantly associated with more malignant tumor histology. The risk of adenocarcinoma or pseudomyxoma was significantly higher among patients with periappendicular abscess (OR 15.05, CI 95% 6.98–32.49, p &lt; 0.001) and patients presenting with perforated acute appendicitis (OR 4.09, CI 95% 1.69–9.90, p = 0.0018) compared to patients with uncomplicated acute appendicitis. Similarly, patient age over 40 years was significantly associated with the risk of adenocarcinoma and pseudomyxoma (OR 26.46, Cl 95% 7.95–88.09, p &lt; 0.001). Patient sex was not associated with a more malignant appendiceal tumor histology (p = 0.67). Conclusion: More malignant appendiceal tumor histology of adenocarcinoma or pseudomyxoma was significantly associated with patient age over 40 years and complicated acute appendicitis, especially periappendicular abscess

Telomere length and physical performance among older people:the Helsinki Birth Cohort study

Abstract Telomere length has been suggested a biomarker of aging and is associated with several chronic diseases. However, the association between telomere length and physical performance is not well known. Using both cross-sectional and longitudinal data, we studied 582 women and 453 men from the Helsinki Birth Cohort Study at two time-points; a baseline examination in 2001–2004 at a mean age of 61 years and a follow-up examination approximately 10 years later in 2011–2013. Telomere length was measured both at baseline and at follow-up using real-time quantitative polymerase chain reaction. Physical performance was evaluated only at follow-up using the Senior Fitness Test (SFT), which assesses strength, flexibility and endurance. In women, shorter telomere length at follow-up (p = 0.044) and greater telomere attrition during follow-up time (p = 0.022) were associated with poorer physical performance after adjusting for covariates (age at baseline, smoking status, body mass index at baseline, follow-up time and educational attainment). No similar associations were found for men. This indicates that, at least in women, telomere length could potentially be used as a biomarker for physical performance, however, more longitudinal studies are needed to confirm this association

Physics-based digital twins merging with machines:cases of mobile log crane and rotating machine

Abstract Real-world products and physics-based simulations are becoming interconnected. In particular, real-time capable dynamic simulation has made it possible for simulation models to run in parallel and simultaneously with operating machinery. This capability combined with state observer techniques such as Kalman filtering have enabled the synchronization between simulation and the real world. State estimator techniques can be applied to estimate unmeasured quantities, also referred as virtual sensing, or to enhance the quality of measured signals. Although synchronized models could be used in a number of ways, value creation and business model development are currently defining the most practical and beneficial use cases from a business perspective. The research reported here reveals the communication and collaboration methods that lead to economically relevant technology solutions. Two case examples are given that demonstrate the proposed methodology. The work benefited from the broad perspective of researchers from different backgrounds and the joint effort to drive the technology development towards business relevant cases

Search for CP violation using tt‾ \textrm{t}\overline{\textrm{t}} events in the lepton+jets channel in pp collisions at s \sqrt{s} = 13 TeV

Results are presented on a search for CP violation in the production and decay of top quark-antiquark pairs in the lepton+jets channel. The search is based on data from proton-proton collisions at $\sqrt{s}$ = 13 TeV, collected with the CMS detector, corresponding to an integrated luminosity of 138 fb$^{−1}$. Possible CP violation effects are evaluated by measuring asymmetries in observables constructed from linearly independent four-momentum vectors of the final-state particles. The dimensionless chromoelectric dipole moment of the top quark obtained from the observed asymmetries is measured to be 0.04 ± 0.10 (stat) ± 0.07(syst), and the asymmetries exhibit no evidence for CP-violating effects, consistent with expectations from the standard model.[graphic not available: see fulltext

Search for Higgs boson decays to a Z boson and a photon in proton-proton collisions at s \sqrt{s} = 13 TeV

Results are presented from a search for the Higgs boson decay H$\to$Z$\gamma$, where Z$\to\ell^+\ell^-$ with $\ell$ = e or $\mu$. The search is performed using a sample of proton-proton (pp) collision data at a center-of-mass energy of 13 TeV, recorded by the CMS experiment at the LHC, corresponding to an integrated luminosity of 138 fb$^{-1}$. Events are assigned to mutually exclusive categories, which exploit differences in both event topology and kinematics of distinct Higgs production mechanisms to enhance signal sensitivity. The signal strength $\mu$, defined as the product of the cross section and the branching fraction [$\sigma($pp$\to$H$)\mathcal{B}($H$\to$Z$\gamma)$] relative to the standard model prediction, is extracted from a simultaneous fit to the $\ell^+\ell^-\gamma$ invariant mass distributions in all categories and is found to be $\mu$=2.4$\pm$0.9 for a Higgs boson mass of 125.38 GeV. The statistical significance of the observed excess of events is 2.7 standard deviations. This measurement corresponds to $\sigma($pp$\to$H$)\mathcal{B}($H$\to$Z$\gamma)$ = 0.21$\pm$0.08 pb. The observed (expected) upper limit at 95% confidence level on $\mu$ is 4.1 (1.8). The ratio of branching fractions $\mathcal{B}($H$\to$Z$\gamma)/\mathcal{B}($H$\to\gamma\gamma)$ is measured to be 1.5$^{+0.7}_{-0.6}$, which agrees with the standard model prediction of 0.69 $\pm$ 0.04 at the 1.5 standard deviation level

Search for top squarks in the four-body decay mode with single lepton final states in proton-proton collisions at s= \sqrt{s}= 13 TeV

A search for the pair production of the lightest supersymmetric partner of the top quark, the top squark ($\tilde{\mathrm{t}}_{1}$), is presented. The search targets the four-body decay of the $\tilde{\mathrm{t}}_{1}$, which is preferred when the mass difference between the top squark and the lightest supersymmetric particle is smaller than the mass of the W boson. This decay mode consists of a bottom quark, two other fermions, and the lightest neutralino ($\tilde{\chi}_{1}^{0}$), which is assumed to be the lightest supersymmetric particle. The data correspond to an integrated luminosity of 138 fb$^{-1}$ of proton-proton collisions at a center-of-mass energy of 13 TeV collected by the CMS experiment at the CERN LHC. Events are selected using the presence of a high-momentum jet, an electron or muon with low transverse momentum, and a significant missing transverse momentum. The signal is selected based on a multivariate approach that is optimized for the difference between $m(\tilde{\mathrm{t}}_{1})$ and $m(\tilde{\chi}_{1}^{0})$. The contribution from leading background processes is estimated from data. No significant excess is observed above the expectation from standard model processes. The results of this search exclude top squarks at 95% confidence level for masses up to 480 and 700 GeV for $m(\tilde{\mathrm{t}}_{1}) - m(\tilde{\chi}_{1}^{0}) =$ 10 and 80 GeV, respectively.A search for the pair production of the lightest supersymmetric partner of the top quark, the top squark (${\overset{\sim }{\textrm{t}}}_1$), is presented. The search targets the four-body decay of the ${\overset{\sim }{\textrm{t}}}_1$, which is preferred when the mass difference between the top squark and the lightest supersymmetric particle is smaller than the mass of the W boson. This decay mode consists of a bottom quark, two other fermions, and the lightest neutralino (${\overset{\sim }{\chi}}_1^0$), which is assumed to be the lightest supersymmetric particle. The data correspond to an integrated luminosity of 138 fb$^{−1}$ of proton-proton collisions at a center-of-mass energy of 13 TeV collected by the CMS experiment at the CERN LHC. Events are selected using the presence of a high-momentum jet, an electron or muon with low transverse momentum, and a significant missing transverse momentum. The signal is selected based on a multivariate approach that is optimized for the difference between m(${\overset{\sim }{\textrm{t}}}_1$) and m(${\overset{\sim }{\chi}}_1^0$). The contribution from leading background processes is estimated from data. No significant excess is observed above the expectation from standard model processes. The results of this search exclude top squarks at 95% confidence level for masses up to 480 and 700 GeV for m(${\overset{\sim }{\textrm{t}}}_1$) − m(${\overset{\sim }{\chi}}_1^0$) = 10 and 80 GeV, respectively.[graphic not available: see fulltext]A search for the pair production of the lightest supersymmetric partner of the top quark, the top squark ($\tilde{\mathrm{t}}_1$), is presented. The search targets the four-body decay of the $\tilde{\mathrm{t}}_1$, which is preferred when the mass difference between the top squark and the lightest supersymmetric particle is smaller than the mass of the W boson. This decay mode consists of a bottom quark, two other fermions, and the lightest neutralino ($\tilde{\chi}^0_1$), which is assumed to be the lightest supersymmetric particle. The data correspond to an integrated luminosity of 138 fb$^{-1}$ of proton-proton collisions at a center-of-mass energy of 13 TeV collected by the CMS experiment at the CERN LHC. Events are selected using the presence of a high-momentum jet, an electron or muon with low transverse momentum, and a significant missing transverse momentum. The signal is selected based on a multivariate approach that is optimized for the difference between $m(\tilde{\mathrm{t}}_1)$ and $m(\tilde{\chi}^0_1)$. The contribution from leading background processes is estimated from data. No significant excess is observed above the expectation from standard model processes. The results of this search exclude top squarks at 95% confidence level for masses up to 480 and 700 GeV for $m(\tilde{\mathrm{t}}_1) - m(\tilde{\chi}^0_1$) = 10 and 80 GeV, respectively

Search for nonresonant Higgs boson pair production in the four leptons plus twob jets final state in proton-proton collisions at s \sqrt{s} = 13 TeV

The first search for nonresonant production of Higgs boson pairs (HH) with one H decaying into four leptons and the other into a pair of b quarks is presented, using proton-proton collisions recorded at a center-of-mass energy of $\sqrt{s}$ = 13 TeV by the CMS experiment. The analyzed data correspond to an integrated luminosity of 138 fb$^{−1}$. A 95% confidence level upper limit of 32.4 is set on the signal strength modifier μ, defined as the ratio of the observed HH production rate in the $\textrm{HH}\to {\textrm{ZZ}}^{\ast}\textrm{b}\overline{\textrm{b}}\to 4\ell \textrm{b}\overline{\textrm{b}}$ decay channel to the standard model (SM) expectation. Possible modifications of the H trilinear coupling λ$_{HHH}$ with respect to the SM value are investigated. The coupling modifier κ$_{λ}$, defined as λ$_{HHH}$ divided by its SM prediction, is constrained to be within the observed (expected) range −8.8 (−9.8) < κ$_{λ}$< 13.4 (15.0) at 95% confidence level.[graphic not available: see fulltext