Structural basis of signal sequence surveillance and selection by the SRP–FtsY complex

Signal-recognition particle (SRP)-dependent targeting of translating ribosomes to membranes is a multistep quality-control process. Ribosomes that are translating weakly hydrophobic signal sequences can be rejected from the targeting reaction even after they are bound to the SRP. Here we show that the early complex, formed by Escherichia coli SRP and its receptor FtsY with ribosomes translating the incorrect cargo EspP, is unstable and rearranges inefficiently into subsequent conformational states, such that FtsY dissociation is favored over successful targeting. The N-terminal extension of EspP is responsible for these defects in the early targeting complex. The cryo-electron microscopy structure of this 'false' early complex with EspP revealed an ordered M domain of SRP protein Ffh making two ribosomal contacts, and the NG domains of Ffh and FtsY forming a distorted, flexible heterodimer. Our results provide a structural basis for SRP-mediated signal-sequence selection during recruitment of the SRP receptor

Impact of COVID-19 on vascular patients worldwide: analysis of the COVIDSurg data

BACKGROUND: The COVIDSurg collaborative was an international multicenter prospective analysis of perioperative data from 235 hospitals in 24 countries. It found that perioperative COVID-19 infection was associated with a mortality rate of 24%. At the same time, the COVER study demonstrated similarly high perioperative mortality rates in vascular surgical patients undergoing vascular interventions even without COVID-19, likely associated with the high burden of comorbidity associated with vascular patients. This is a vascular subgroup analysis of the COVIDSurg cohort. // METHODS: All patients with a suspected or confirmed diagnosis of COVID-19 in the 7 days prior to, or in the 30 days following a vascular procedure were included. The primary outcome was 30-day mortality. Secondary outcomes were pulmonary complications (adult respiratory distress syndrome, pulmonary embolism, pneumonia and respiratory failure). Logistic regression was undertaken for dichotomous outcomes. // RESULTS: Overall, 602 patients were included in this subgroup analysis, of which 88.4% were emergencies. The most common operations performed were for vascular-related dialysis access procedures (20.1%, N.=121). The combined 30-day mortality rate was 27.2%. Composite secondary pulmonary outcomes occurred in half of the vascular patients (N.=275, 45.7%). // CONCLUSIONS: Mortality following vascular surgery in COVID positive patients was significantly higher than levels reported pre-pandemic, and similar to that seen in other specialties in the COVIDSurg cohort. Initiatives and surgical pathways that ensure vascular patients are protected from exposure to COVID-19 in the peri-operative period are vital to protect against excess mortality

Elective surgery cancellations due to the COVID-19 pandemic: global predictive modelling to inform surgical recovery plans.

BACKGROUND: The COVID-19 pandemic has disrupted routine hospital services globally. This study estimated the total number of adult elective operations that would be cancelled worldwide during the 12 weeks of peak disruption due to COVID-19. METHODS: A global expert response study was conducted to elicit projections for the proportion of elective surgery that would be cancelled or postponed during the 12 weeks of peak disruption. A Bayesian β-regression model was used to estimate 12-week cancellation rates for 190 countries. Elective surgical case-mix data, stratified by specialty and indication (surgery for cancer versus benign disease), were determined. This case mix was applied to country-level surgical volumes. The 12-week cancellation rates were then applied to these figures to calculate the total number of cancelled operations. RESULTS: The best estimate was that 28 404 603 operations would be cancelled or postponed during the peak 12 weeks of disruption due to COVID-19 (2 367 050 operations per week). Most would be operations for benign disease (90·2 per cent, 25 638 922 of 28 404 603). The overall 12-week cancellation rate would be 72·3 per cent. Globally, 81·7 per cent of operations for benign conditions (25 638 922 of 31 378 062), 37·7 per cent of cancer operations (2 324 070 of 6 162 311) and 25·4 per cent of elective caesarean sections (441 611 of 1 735 483) would be cancelled or postponed. If countries increased their normal surgical volume by 20 per cent after the pandemic, it would take a median of 45 weeks to clear the backlog of operations resulting from COVID-19 disruption. CONCLUSION: A very large number of operations will be cancelled or postponed owing to disruption caused by COVID-19. Governments should mitigate against this major burden on patients by developing recovery plans and implementing strategies to restore surgical activity safely

Measurement of D0−D‾0D^0-\overline{D}^0 mixing and search for CPCP violation with D0→K+π−D^0\rightarrow K^+\pi^- decays

A measurement of the time-dependent ratio of the $D^0\rightarrow K^+\pi^-$ to $\overline{D}^0\rightarrow K^+\pi^-$ decay rates is reported. The analysis uses a sample of proton-proton collisions corresponding to an integrated luminosity of 6 fb$^-1$ recorded by the LHCb experiment from 2015 through 2018 at a center-of-mass energy of 13 TeV. The $D^0$ meson is required to originate from a $D^{*+}\rightarrow D^0\pi^+$ decay, such that its flavor at production is inferred from the charge of the accompanying pion. The measurement is performed simultaneously for the $K^+\pi^-$ and $K^-\pi^+$ final states, allowing both mixing and $CP$-violation parameters to be determined. The value of the ratio of the decay rates at production is determined to be $R_{K\pi} = (343.1 \pm 2.0) \times 10^{-5}$. The mixing parameters are measured to be $c_{K\pi} = (51.4 \pm 3.5) \times 10^{-4}$ and $c_{K\pi}^{\prime} = (13 \pm 4) \times 10^{-6}$, where $\sqrt{R_{K\pi}}c_{K\pi}$ is the linear coefficient of the expansion of the ratio as a function of decay time in units of the $D^0$ lifetime, and $c_{K\pi}^{\prime}$ is the quadratic coefficient, both averaged between the $K^+\pi^-$ and $K^-\pi^+$ final states. The precision is improved relative to the previous best measurement by approximately 60%. No evidence for $CP$ violation is found.Comment: All figures and tables, along with machine-readable versions and any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/Publications/LHCbProjectPublic/LHCb-PAPER-2024-008.htm

Measurement of the CKM angle γ in B± → DK*(892)± decays

Measurements of CP observables and the CKM angle γ are performed in B± → DK∗ (892)± decays, where D represents a superposition of D0 and D 0 states, using the LHCb dataset collected during Run 1 (2011–2012) and Run 2 (2015–2018). A study of this channel is presented with the D meson reconstructed in two-body fnal states K±π ∓, K+K− and π +π −; four-body fnal states K±π ∓π ±π ∓ and π +π −π +π −; and threebody fnal states K0 S π +π − and K0 SK+K−. This analysis includes the frst observation of the suppressed B± → [π ±K∓]DK∗± and B± → [π ±K∓π ±π ∓]DK∗± decays. The combined result gives γ = (63 ± 13)◦

Probing the nature of the χc1(3872)\chi_{c1}(3872) state using radiative decays

The radiative decays $\chi_{c1}(3872)\rightarrow\psi(2S)\gamma$ and $\chi_{c1}(3872)\rightarrow J/\psi\gamma$ are used to probe the~nature of the~$\chi_{c1}(3872)$ state using proton-proton collision data collected with the LHCb detector, corresponding to an~integrated luminosity of~9fb$^{-1}$. Using the~$B^+\rightarrow \chi_{c1}(3872)K^+$decay, the $\chi_{c1}(3872)\rightarrow \psi(2S)\gamma$ process is observed for the first time and the ratio of its partial width to that of the $\chi_{c1}(3872)\rightarrow J/\psi\gamma$ decay is measured to be $$\frac{\Gamma_{\chi_{c1}(3872)\rightarrow \psi(2S)\gamma}} {\Gamma_{\chi_{c1}(3872)\rightarrow J/\psi\gamma}} = 1.67 \pm 0.21 \pm 0.12 \pm0.04 ,$$ where the first uncertainty is statistical, the second systematic and the third is due to the uncertainties on the branching fractions of the $\psi(2S)$ and $J/\psi$ mesons. The measured ratio makes the interpretation of the $\chi_{c1}(3872)$ state as a~pure $D^0\bar{D}^{*0}+\bar{D}^0D^{*0}$ molecule questionable and strongly indicates a sizeable compact charmonium or tetraquark component within the $\chi_{c1}(3872)$ state.Comment: 31 pages, 2 figures. All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2024-015.html (LHCb public pages

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Comprehensive analysis of local and nonlocal amplitudes in the B0→ K*0μ+μ− decay

A comprehensive study of the local and nonlocal amplitudes contributing to the decay B0 → K*0(→ K+π−)μ+μ− is performed by analysing the phase-space distribution of the decay products. The analysis is based on pp collision data corresponding to an integrated luminosity of 8.4 fb−1 collected by the LHCb experiment. This measurement employs for the first time a model of both one-particle and two-particle nonlocal amplitudes, and utilises the complete dimuon mass spectrum without any veto regions around the narrow charmonium resonances. In this way it is possible to explicitly isolate the local and nonlocal contributions and capture the interference between them. The results show that interference with nonlocal contributions, although larger than predicted, only has a minor impact on the Wilson Coefficients determined from the fit to the data. For the local contributions, the Wilson Coefficient C9, responsible for vector dimuon currents, exhibits a 2.1σ deviation from the Standard Model expectation. The Wilson Coefficients C10, C9′ and C10′ are all in better agreement than C9 with the Standard Model and the global significance is at the level of 1.5σ. The model used also accounts for nonlocal contributions from B0→ K*0[τ+τ−→ μ+μ−] rescattering, resulting in the first direct measurement of the bsττ vector effective-coupling C9τ

Observation of muonic Dalitz decays of chib mesons and precise spectroscopy of hidden-beauty states

The decays of the χb1(1P), χb2(1P), χb1(2P) and χb2(2P) mesons into the Υ(1S)μ+μ− final state are observed with a high significance using proton-proton collision data collected with the LHCb detector and corresponding to an integrated luminosity of 9 fb−1. The newly observed decays together with the Υ(2S) → Υ(1S)π+π− and Υ(3S) → Υ(2S)π+π− decay modes are used for precision measurements of the mass and mass splittings for the hidden-beauty states