Mathematical model of a telomerase transcriptional regulatory network developed by cell-based screening: analysis of inhibitor effects and telomerase expression mechanisms

Cancer cells depend on transcription of telomerase reverse transcriptase (TERT). Many transcription factors affect TERT, though regulation occurs in context of a broader network. Network effects on telomerase regulation have not been investigated, though deeper understanding of TERT transcription requires a systems view. However, control over individual interactions in complex networks is not easily achievable. Mathematical modelling provides an attractive approach for analysis of complex systems and some models may prove useful in systems pharmacology approaches to drug discovery. In this report, we used transfection screening to test interactions among 14 TERT regulatory transcription factors and their respective promoters in ovarian cancer cells. The results were used to generate a network model of TERT transcription and to implement a dynamic Boolean model whose steady states were analysed. Modelled effects of signal transduction inhibitors successfully predicted TERT repression by Src-family inhibitor SU6656 and lack of repression by ERK inhibitor FR180204, results confirmed by RT-QPCR analysis of endogenous TERT expression in treated cells. Modelled effects of GSK3 inhibitor 6-bromoindirubin-3′-oxime (BIO) predicted unstable TERT repression dependent on noise and expression of JUN, corresponding with observations from a previous study. MYC expression is critical in TERT activation in the model, consistent with its well known function in endogenous TERT regulation. Loss of MYC caused complete TERT suppression in our model, substantially rescued only by co-suppression of AR. Interestingly expression was easily rescued under modelled Ets-factor gain of function, as occurs in TERT promoter mutation. RNAi targeting AR, JUN, MXD1, SP3, or TP53, showed that AR suppression does rescue endogenous TERT expression following MYC knockdown in these cells and SP3 or TP53 siRNA also cause partial recovery. The model therefore successfully predicted several aspects of TERT regulation including previously unknown mechanisms. An extrapolation suggests that a dominant stimulatory system may programme TERT for transcriptional stability

Updated measurements of exclusive J/ψ and ψ(2S) production cross-sections in pp collisions at √s = 7 TeV

The differential cross-section as a function of rapidity has been measured for the exclusive production of J/ψ and ψ(2S) mesons in proton–proton collisions at √s = 7 TeV, using data collected by the LHCb experiment, corresponding to an integrated luminosity of 930 pb−1. The cross-sections times branching fractions to two muons having pseudorapidities between 2.0 and 4.5 are measured to be where the first uncertainty is statistical and the second is systematic. The measurements agree with next-to-leading order QCD predictions as well as with models that include saturation effects

Observation of Two New Excited Ξb0 States Decaying to Λb0 K-π+

Two narrow resonant states are observed in the Λb0K-π+ mass spectrum using a data sample of proton-proton collisions at a center-of-mass energy of 13 TeV, collected by the LHCb experiment and corresponding to an integrated luminosity of 6 fb-1. The minimal quark content of the Λb0K-π+ system indicates that these are excited Ξb0 baryons. The masses of the Ξb(6327)0 and Ξb(6333)0 states are m[Ξb(6327)0]=6327.28-0.21+0.23±0.12±0.24 and m[Ξb(6333)0]=6332.69-0.18+0.17±0.03±0.22 MeV, respectively, with a mass splitting of Δm=5.41-0.27+0.26±0.12 MeV, where the uncertainties are statistical, systematic, and due to the Λb0 mass measurement. The measured natural widths of these states are consistent with zero, with upper limits of Γ[Ξb(6327)0]<2.20(2.56) and Γ[Ξb(6333)0]<1.60(1.92) MeV at a 90% (95%) credibility level. The significance of the two-peak hypothesis is larger than nine (five) Gaussian standard deviations compared to the no-peak (one-peak) hypothesis. The masses, widths, and resonant structure of the new states are in good agreement with the expectations for a doublet of 1D Ξb0 resonances

Predicting attitudinal and behavioral responses to COVID-19 pandemic using machine learning

At the beginning of 2020, COVID-19 became a global problem. Despite all the efforts to emphasize the relevance of preventive measures, not everyone adhered to them. Thus, learning more about the characteristics determining attitudinal and behavioral responses to the pandemic is crucial to improving future interventions. In this study, we applied machine learning on the multinational data collected by the International Collaboration on the Social and Moral Psychology of COVID-19 (N = 51,404) to test the predictive efficacy of constructs from social, moral, cognitive, and personality psychology, as well as socio-demographic factors, in the attitudinal and behavioral responses to the pandemic. The results point to several valuable insights. Internalized moral identity provided the most consistent predictive contribution-individuals perceiving moral traits as central to their self-concept reported higher adherence to preventive measures. Similar results were found for morality as cooperation, symbolized moral identity, self-control, open-mindedness, and collective narcissism, while the inverse relationship was evident for the endorsement of conspiracy theories. However, we also found a non-neglible variability in the explained variance and predictive contributions with respect to macro-level factors such as the pandemic stage or cultural region. Overall, the results underscore the importance of morality-related and contextual factors in understanding adherence to public health recommendations during the pandemic.Published versio

Studies of beauty baryon decays to D0ph− and Λ+ch− final states

Decays of beauty baryons to the D0ph− and Λ+ch− final states (where h indicates a pion or a kaon) are studied using a data sample of pp collisions, corresponding to an integrated luminosity of 1.0  fb−1, collected by the LHCb detector. The Cabibbo-suppressed decays Λ0b→D0pK− and Λ0b→Λ+cK− are observed, and their branching fractions are measured with respect to the decays Λ0b→D0pπ− and Λ0b→Λ+cπ−. In addition, the first observation is reported of the decay of the neutral beauty-strange baryon Ξ0b to the D0pK− final state, and a measurement of the Ξ0b mass is performed. Evidence of the Ξ0b→Λ+cK− decay is also reported

Measurement of the CKM angle γ\gamma using B0→DK∗0B^0 \rightarrow D K^{*0} with D→KS0π+π−D \rightarrow K^0_S \pi^+ \pi^- decays

A model-dependent amplitude analysis of the decay $B^0\rightarrow D(K^0_S\pi^+\pi^-) K^{*0}$ is performed using proton-proton collision data corresponding to an integrated luminosity of 3.0fb$^{-1}$, recorded at $\sqrt{s}=7$ and $8 TeV$ by the LHCb experiment. The CP violation observables $x_{\pm}$ and $y_{\pm}$, sensitive to the CKM angle $\gamma$, are measured to be \begin{eqnarray*} x_- &=& -0.15 \pm 0.14 \pm 0.03 \pm 0.01, y_- &=& 0.25 \pm 0.15 \pm 0.06 \pm 0.01, x_+ &=& 0.05 \pm 0.24 \pm 0.04 \pm 0.01, y_+ &=& -0.65^{+0.24}_{-0.23} \pm 0.08 \pm 0.01, \end{eqnarray*} where the first uncertainties are statistical, the second systematic and the third arise from the uncertainty on the $D\rightarrow K^0_S \pi^+\pi^-$ amplitude model. These are the most precise measurements of these observables. They correspond to $\gamma=(80^{+21}_{-22})^{\circ}$ and $r_{B^0}=0.39\pm0.13$, where $r_{B^0}$ is the magnitude of the ratio of the suppressed and favoured $B^0\rightarrow D K^+ \pi^-$ decay amplitudes, in a $K\pi$ mass region of $\pm50 MeV$ around the $K^*(892)^0$ mass and for an absolute value of the cosine of the $K^{*0}$ decay angle larger than $0.4$.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-007.htm

Model-independent measurement of mixing parameters in D0 → K S 0 π+π− decays

The first model-independent measurement of the charm mixing parameters in the decay D 0 → K S 0 π + π − is reported, using a sample of pp collision data recorded by the LHCb experiment, corresponding to an integrated luminosity of 1.0 fb−1 at a centre-of-mass energy of 7 TeV. The measured values are x=(−0.86±0.53±0.17)×10−2,y=(+0.03±0.46±0.13)×10−2, x=(−0.86±0.53±0.17)×10−2,y=(+0.03±0.46±0.13)×10−2, where the first uncertainties are statistical and include small contributions due to the external input for the strong phase measured by the CLEO collaboration, and the second uncertainties are systematic

First experimental study of photon polarization in radiative B-s(0) decays

The polarization of photons produced in radiative B0s decays is studied for the first time. The data are recorded by the LHCb experiment in pp collisions corresponding to an integrated luminosity of 3  fb−1 at center-of-mass energies of 7 and 8 TeV. A time-dependent analysis of the B0s→ϕγ decay rate is conducted to determine the parameter AΔ, which is related to the ratio of right- over left-handed photon polarization amplitudes in b→sγ transitions. A value of AΔ=−0.98+0.46−0.52+0.23−0.20 is measured. This result is consistent with the standard model prediction within 2 standard deviations

Measurement of J/ψ -pair production in pp collisions at √s = 13 TeV and study of gluon transverse-momentum dependent PDFs

The production cross-section of J/ψ pairs in proton-proton collisions at a centre-of-mass energy of √s = 13 TeV is measured using a data sample corresponding to an integrated luminosity of 4.2 fb−1 collected by the LHCb experiment. The measurement is performed with both J/ψ mesons in the transverse momentum range 0 < pT< 14 GeV/c and rapidity range 2.0 < y < 4.5. The cross-section of this process is measured to be 16.36 ± 0.28 (stat) ± 0.88 (syst) nb. The contributions from single-parton scattering and double-parton scattering are separated based on the dependence of the cross-section on the absolute rapidity difference ∆y between the two J/ψ mesons. The effective cross-section of double-parton scattering is measured to be σeff = 13.1 ± 1.8 (stat) ± 2.3 (syst) mb. The distribution of the azimuthal angle ϕCS of one of the J/ψ mesons in the Collins-Soper frame and the pT-spectrum of the J/ψ pairs are also measured for the study of the gluon transverse-momentum dependent distributions inside protons. The extracted values of ⟨cos 2ϕCS⟩ and ⟨cos 4ϕCS⟩ are consistent with zero, but the presence of azimuthal asymmetry at a few percent level is allowed

The effect of consuming Palmaria palmata-enriched bread on inflammatory markers, antioxidant status, lipid profile and thyroid function in a randomised placebo-controlled intervention trial in healthy adults

Purpose Palmaria palmata (P. Palmata) is reported to contain anti-inflammatory and antioxidant compounds albeit no study has investigated these effects in humans. Methods A randomised parallel placebo-controlled human intervention study was carried out to investigate the effect of consuming P. Palmata (5 g/day) incorporated into a bread on serum markers of inflammation [C-reactive protein (CRP); cytokine analysis] with secondary analysis investigating changes in lipids (cholesterol, triglycerides), thyroid function [thyroid-stimulating hormone (TSH)] and antioxidant status ferric reducing antioxidant power. ANCOVA with baseline values as covariates, controlling for age, BMI, sex and smoking status, was used to compare differences between treatment groups over time . In vitro studies investigated the inflammatory activity of P. Palmata extracts (hot water, cold water and ethanol extract), protein extracts and associated protein hydrolysates using a Caco-2 inflammation cell model. Results Consumption of P. Palmata-enriched bread significantly increased serum CRP (+16.1 %, P = 0.011), triglycerides (+31.9 %, P = 0.001) and TSH (+17.2 %, P = 0.017) when compared to the control group. In vitro evaluation of P. palmata extracts and protein hydrolysates identified a significant induction of IL-8 secretion by Caco-2 cells, and the hot water P. palmata extract was shown to increase adipocyte glycerol release (P < 0.05). Conclusion Evidence from this human study suggests that P. palmata stimulates inflammation, increases serum triglycerides and alters thyroid function; however, these changes are not likely to impact health as changes remained within the normal clinical range. The data from the in vitro study provided indications that IL-8 may contribute to the apparent immunostimulation noted in the human study