Recent changes in the mutational dynamics of the SARS-CoV-2 main protease substantiate the danger of emerging resistance to antiviral drugs

IntroductionThe current coronavirus pandemic is being combated worldwide by nontherapeutic measures and massive vaccination programs. Nevertheless, therapeutic options such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main-protease (Mpro) inhibitors are essential due to the ongoing evolution toward escape from natural or induced immunity. While antiviral strategies are vulnerable to the effects of viral mutation, the relatively conserved Mpro makes an attractive drug target: Nirmatrelvir, an antiviral targeting its active site, has been authorized for conditional or emergency use in several countries since December 2021, and a number of other inhibitors are under clinical evaluation. We analyzed recent SARS-CoV-2 genomic data, since early detection of potential resistances supports a timely counteraction in drug development and deployment, and discovered accelerated mutational dynamics of Mpro since early December 2021.MethodsWe performed a comparative analysis of 10.5 million SARS-CoV-2 genome sequences available by June 2022 at GISAID to the NCBI reference genome sequence NC_045512.2. Amino-acid exchanges within high-quality regions in 69,878 unique Mpro sequences were identified and time- and in-depth sequence analyses including a structural representation of mutational dynamics were performed using in-house software.ResultsThe analysis showed a significant recent event of mutational dynamics in Mpro. We report a remarkable increase in mutational variability in an eight-residue long consecutive region (R188-G195) near the active site since December 2021.DiscussionThe increased mutational variability in close proximity to an antiviral-drug binding site as described herein may suggest the onset of the development of antiviral resistance. This emerging diversity urgently needs to be further monitored and considered in ongoing drug development and lead optimization

Les droits disciplinaires des fonctions publiques : « unification », « harmonisation » ou « distanciation ». A propos de la loi du 26 avril 2016 relative à la déontologie et aux droits et obligations des fonctionnaires

The production of tt‾ , W+bb‾ and W+cc‾ is studied in the forward region of proton–proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98±0.02 fb−1 . The W bosons are reconstructed in the decays W→ℓν , where ℓ denotes muon or electron, while the b and c quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions.The production of $t\overline{t}$, $W+b\overline{b}$ and $W+c\overline{c}$ is studied in the forward region of proton-proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98 $\pm$ 0.02 \mbox{fb}^{-1}. The $W$ bosons are reconstructed in the decays $W\rightarrow\ell\nu$, where $\ell$ denotes muon or electron, while the $b$ and $c$ quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions

Measurement of the B0s→μ+μ− Branching Fraction and Effective Lifetime and Search for B0→μ+μ− Decays

A search for the rare decays Bs0→μ+μ- and B0→μ+μ- is performed at the LHCb experiment using data collected in pp collisions corresponding to a total integrated luminosity of 4.4  fb-1. An excess of Bs0→μ+μ- decays is observed with a significance of 7.8 standard deviations, representing the first observation of this decay in a single experiment. The branching fraction is measured to be B(Bs0→μ+μ-)=(3.0±0.6-0.2+0.3)×10-9, where the first uncertainty is statistical and the second systematic. The first measurement of the Bs0→μ+μ- effective lifetime, τ(Bs0→μ+μ-)=2.04±0.44±0.05  ps, is reported. No significant excess of B0→μ+μ- decays is found, and a 95% confidence level upper limit, B(B0→μ+μ-)<3.4×10-10, is determined. All results are in agreement with the standard model expectations.A search for the rare decays $B^0_s\to\mu^+\mu^-$ and $B^0\to\mu^+\mu^-$ is performed at the LHCb experiment using data collected in $pp$ collisions corresponding to a total integrated luminosity of 4.4 fb$^{-1}$. An excess of $B^0_s\to\mu^+\mu^-$ decays is observed with a significance of 7.8 standard deviations, representing the first observation of this decay in a single experiment. The branching fraction is measured to be ${\cal B}(B^0_s\to\mu^+\mu^-)=\left(3.0\pm 0.6^{+0.3}_{-0.2}\right)\times 10^{-9}$, where the first uncertainty is statistical and the second systematic. The first measurement of the $B^0_s\to\mu^+\mu^-$ effective lifetime, $\tau(B^0_s\to\mu^+\mu^-)=2.04\pm 0.44\pm 0.05$ ps, is reported. No significant excess of $B^0\to\mu^+\mu^-$ decays is found and a 95 % confidence level upper limit, ${\cal B}(B^0\to\mu^+\mu^-)<3.4\times 10^{-10}$, is determined. All results are in agreement with the Standard Model expectations

A study of CP violation in B-+/- -&gt; DK +/- and B-+/- -&gt; D pi(+/-) decays with D -&gt; (KSK +/-)-K-0 pi(-/+) final states

A first study of CP violation in the decay modes $B^\pm\to [K^0_{\rm S} K^\pm \pi^\mp]_D h^\pm$ and $B^\pm\to [K^0_{\rm S} K^\mp \pi^\pm]_D h^\pm$, where $h$ labels a $K$ or $\pi$ meson and $D$ labels a $D^0$ or $\overline{D}^0$ meson, is performed. The analysis uses the LHCb data set collected in $pp$ collisions, corresponding to an integrated luminosity of 3 fb$^{-1}$. The analysis is sensitive to the CP-violating CKM phase $\gamma$ through seven observables: one charge asymmetry in each of the four modes and three ratios of the charge-integrated yields. The results are consistent with measurements of $\gamma$ using other decay modes

Search for the lepton flavour violating decay tau(-) -&gt; mu(-)mu(+)mu(-)

A search for the lepton flavour violating decay $\tau^-\rightarrow\mu^-\mu^+\mu^-$ is performed with the LHCb experiment. The data sample corresponds to an integrated luminosity of 1.0 fb$^{−1}$ of proton-proton collisions at a centre-of-mass energy of 7 TeV and 2.0 fb$^{−1}$ at 8 TeV. No evidence is found for a signal, and a limit is set at 90% confidence level on the branching fraction, $\mathcal{B}(\tau^-\rightarrow\mu^-\mu^+\mu^-)<4.6\times10^{−8}$.A search for the lepton flavour violating decay τ$^{−}$ → μ$^{−}$ μ$^{+}$ μ$^{−}$ is performed with the LHCb experiment. The data sample corresponds to an integrated luminosity of 1.0 fb$^{−1}$ of proton-proton collisions at a centre-of-mass energy of 7 TeV and 2.0 fb$^{−1}$ at 8 TeV. No evidence is found for a signal, and a limit is set at 90% confidence level on the branching fraction, $\mathrm{\mathcal{B}}\left({\tau}^{-}\to {\mu}^{-}{\mu}^{+}{\mu}^{-}\right)<4.6\times {10}^{-8}$ .A search for the lepton flavour violating decay $\tau^-\to \mu^-\mu^+\mu^-$ is performed with the LHCb experiment. The data sample corresponds to an integrated luminosity of $1.0\mathrm{\,fb}^{-1}$ of proton-proton collisions at a centre-of-mass energy of $7\mathrm{\,Te\kern -0.1em V}$ and $2.0\mathrm{\,fb}^{-1}$ at $8\mathrm{\,Te\kern -0.1em V}$. No evidence is found for a signal, and a limit is set at $90\%$ confidence level on the branching fraction, $\mathcal{B}(\tau^-\to \mu^-\mu^+\mu^-) < 4.6 \times 10^{-8}$

Measurement of Upsilon production in collisions at root s=2.76 TeV

The production of $\Upsilon(1S)$, $\Upsilon(2S)$ and $\Upsilon(3S)$ mesons decaying into the dimuon final state is studied with the LHCb detector using a data sample corresponding to an integrated luminosity of 3.3 $pb^{-1}$ collected in proton-proton collisions at a centre-of-mass energy of $\sqrt{s}=2.76$ TeV. The differential production cross-sections times dimuon branching fractions are measured as functions of the $\Upsilon$ transverse momentum and rapidity, over the ranges $p_{\rm T} Upsilon(1S) X) x B(Upsilon(1S) -> mu+mu-) = 1.111 +/- 0.043 +/- 0.044 nb, sigma(pp -> Upsilon(2S) X) x B(Upsilon(2S) -> mu+mu-) = 0.264 +/- 0.023 +/- 0.011 nb, sigma(pp -> Upsilon(3S) X) x B(Upsilon(3S) -> mu+mu-) = 0.159 +/- 0.020 +/- 0.007 nb, where the first uncertainty is statistical and the second systematic

Search for CP violation using T-odd correlations in D-0 -&gt; K+K-pi(+)pi(-) decays

A search for $CP$ violation using $T$-odd correlations is performed using the four-body $D^0 \to K^+K^-\pi^+\pi^-$ decay, selected from semileptonic $B$ decays. The data sample corresponds to integrated luminosities of $1.0\,\text{fb}^{-1}$ and $2.0\,\text{fb}^{-1}$ recorded at the centre-of-mass energies of 7 TeV and 8 TeV, respectively. The $CP$-violating asymmetry $a_{CP}^{T\text{-odd}}$ is measured to be $(0.18\pm 0.29\text{(stat)}\pm 0.04\text{(syst)})\%$. Searches for $CP$ violation in different regions of phase space of the four-body decay, and as a function of the $D^0$ decay time, are also presented. No significant deviation from the $CP$ conservation hypothesis is found

Measurement of CP asymmetry in B-s(0) -&gt; D-s(-/+) K--/+ decays

We report on measurements of the time-dependent CP violating observables in $B^0_s\rightarrow D^{\mp}_s K^{\pm}$ decays using a dataset corresponding to 1.0 fb$^{-1}$ of pp collisions recorded with the LHCb detector. We find the CP violating observables $C_f=0.53\pm0.25\pm0.04$, $A^{\Delta\Gamma}_f=0.37\pm0.42\pm0.20$, $A^{\Delta\Gamma}_{\bar{f}}=0.20\pm0.41\pm0.20$, $S_f=-1.09\pm0.33\pm0.08$, $S_{\bar{f}}=-0.36\pm0.34\pm0.08$, where the uncertainties are statistical and systematic, respectively. We use these observables to make the first measurement of the CKM angle $\gamma$ in $B^0_s\rightarrow D^{\mp}_s K^{\pm}$ decays, finding $\gamma$ = (115$_{-43}^{+28}$)$^\circ$ modulo 180$^\circ$ at 68% CL, where the error contains both statistical and systematic uncertainties.We report on measurements of the time-dependent CP violating observables in B$_{s}^{0}$  → D$_{s}^{∓}$ K$^{±}$ decays using a dataset corresponding to 1.0 fb$^{−1}$ of pp collisions recorded with the LHCb detector. We find the CP violating observables C$_{f}$ = 0.53±0.25±0.04, A$_{f}^{ΔΓ}$  = 0.37 ± 0.42 ± 0.20, ${A}_{\overline{f}}^{\varDelta \varGamma }=0.20\pm 0.41\pm 0.20$ , S$_{f}$ = −1.09±0.33±0.08, ${S}_{\overline{f}}=-0.36\pm 0.34\pm 0.08$ , where the uncertainties are statistical and systematic, respectively. Using these observables together with a recent measurement of the B$_{s}^{0}$ mixing phase −2β$_{s}$ leads to the first extraction of the CKM angle γ from B$_{s}^{0}$  → D$_{s}^{∓}$ K$^{±}$ decays, finding γ = (115$_{− 43}^{+ 28}$ )° modulo 180° at 68% CL, where the error contains both statistical and systematic uncertainties.We report on measurements of the time-dependent CP violating observables in $B^0_s\rightarrow D^{\mp}_s K^{\pm}$ decays using a dataset corresponding to 1.0 fb$^{-1}$ of pp collisions recorded with the LHCb detector. We find the CP violating observables $C_f=0.53\pm0.25\pm0.04$, $A^{\Delta\Gamma}_f=0.37\pm0.42\pm0.20$, $A^{\Delta\Gamma}_{\bar{f}}=0.20\pm0.41\pm0.20$, $S_f=-1.09\pm0.33\pm0.08$, $S_{\bar{f}}=-0.36\pm0.34\pm0.08$, where the uncertainties are statistical and systematic, respectively. Using these observables together with a recent measurement of the $B^0_s$ mixing phase $-2\beta_s$ leads to the first extraction of the CKM angle $\gamma$ from $B^0_s \rightarrow D^{\mp}_s K^{\pm}$ decays, finding $\gamma$ = (115$_{-43}^{+28}$)$^\circ$ modulo 180$^\circ$ at 68% CL, where the error contains both statistical and systematic uncertainties