Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone

Cytosolic HSP90 requires multiple cochaperones in folding client proteins. However, the function of gp96 (HSP90b1, grp94), an HSP90 paralogue in the endoplasmic reticulum (ER), is believed to be independent of cochaperones. Here, we demonstrate that gp96 chaperones multiple Toll-like receptors (TLRs), but not TLR3, in a manner that is dependent on another ER luminal protein, CNPY3. gp96 directly interacts with CNPY3, and the complex dissociates in the presence of adenosine triphosphate (ATP). Genetic disruption of gp96–CNPY3 interaction completely abolishes their TLR chaperone function. Moreover, we demonstrate that TLR9 forms a multimolecular complex with gp96 and CNPY3, and the binding of TLR9 to either molecule requires the presence of the other. We suggest that CNPY3 interacts with the ATP-sensitive conformation of gp96 to promote substrate loading. Our study has thus established CNPY3 as a TLR-specific cochaperone for gp96

INCEPTUS Natural History, Run-in Study for Gene Replacement Clinical Trial in X-Linked Myotubular Myopathy

Supplementary Material: The supplementary material is available in the electronic version of this article: https://doi.org/10.3233/JND-210871.Copyright © 2022 The authors. Background X-linked myotubular myopathy (XLMTM) is a life-threatening congenital myopathy that, in most cases, is characterized by profound muscle weakness, respiratory failure, need for mechanical ventilation and gastrostomy feeding, and early death. Objective We aimed to characterize the neuromuscular, respiratory, and extramuscular burden of XLMTM in a prospective, longitudinal study. Methods Thirty-four participants 16 hours/day); 20% required non-invasive support (6–16 hours/day). Median age at tracheostomy was 3.5 months (95% CI: 2.5, 9.0). Thirty-three participants (97%) required gastrostomy. Thirty-one (91%) participants had histories of hepatic disease and/or prospectively experienced related adverse events or laboratory or imaging abnormalities. CHOP INTEND scores ranged from 19–52 (mean: 35.1). Seven participants (21%) could sit unsupported for≥30 seconds (one later lost this ability); none could pull to stand or walk with or without support. These parameters remained static over time across the INCEPTUS cohort. Conclusions INCEPTUS confirmed high medical impact, static respiratory, motor and feeding difficulties, and early death in boys with XLMTM. Hepatobiliary disease was identified as an under-recognized comorbidity. There are currently no approved disease-modifying treatments.The INCEPTUS and ASPIRO studies are sponsored by Astellas Gene Therapies

Observation of B(s)0→J/ψpp¯ decays and precision measurements of the B(s)0 masses

The first observation of the decays B 0 ( s ) → J / ψ p ¯ p is reported, using proton-proton collision data corresponding to an integrated luminosity of 5.2     fb − 1 , collected with the LHCb detector. These decays are suppressed due to limited available phase space, as well as due to Okubo-Zweig-Iizuka or Cabibbo suppression. The measured branching fractions are B ( B 0 → J / ψ p ¯ p ) = [ 4.51 ± 0.40 ( stat ) ± 0.44 ( syst ) ] × 10 − 7 , B ( B 0 s → J / ψ p ¯ p ) = [ 3.58 ± 0.19 ( stat ) ± 0.39 ( syst ) ] × 10 − 6 . For the B 0 s meson, the result is much higher than the expected value of O ( 10 − 9 ) . The small available phase space in these decays also allows for the most precise single measurement of both the B 0 mass as 5279.74 ± 0.30 ( stat ) ± 0.10 ( syst )     MeV and the B 0 s mass as 5366.85 ± 0.19 ( stat ) ± 0.13 ( syst )     MeV

Measurement of D s ^± production asymmetry in pp collisions at √s=7 and 8 TeV

The inclusive $D_s^{\pm}$ production asymmetry is measured in $pp$ collisions collected by the LHCb experiment at centre-of-mass energies of $\sqrt{s} =7$ and 8 TeV. Promptly produced $D_s^{\pm}$ mesons are used, which decay as $D_s^{\pm}\to\phi\pi^{\pm}$, with $\phi\to K^+K^-$. The measurement is performed in bins of transverse momentum, $p_{\rm T}$, and rapidity, $y$, covering the range $2.5<p_{\rm T}<25.0$ GeV$/c$ and $2.0<y<4.5$. No kinematic dependence is observed. Evidence of nonzero $D_s^{\pm}$ production asymmetry is found with a significance of 3.3 standard deviations.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2018-010.htm

Observation of the decay Λ _b ⁰ → ψ(2S)pπ⁻

International audienceThe Cabibbo-suppressed decay Λ$_{b}^{0}$  → ψ(2S)pπ$^{−}$ is observed for the first time using a data sample collected by the LHCb experiment in proton-proton collisions corresponding to 1.0, 2.0 and 1.9 fb$^{−1}$ of integrated luminosity at centre-of-mass energies of 7, 8 and 13 TeV, respectively. The ψ(2S) mesons are reconstructed in the μ$^{+}$μ$^{−}$ final state. The branching fraction with respect to that of the Λ$_{b}^{0}$  → ψ(2S)pK$^{−}$ decay mode is measured to b

Search for CP violation in Λb0→pK− and Λb0→pπ− decays

A search for CP violation in Λb0→pK− and Λb0→pπ− decays is presented using a sample of pp collisions collected with the LHCb detector and corresponding to an integrated luminosity of 3.0fb−1. The CP -violating asymmetries are measured to be ACPpK−=−0.020±0.013±0.019 and ACPpπ−=−0.035±0.017±0.020, and their difference ACPpK−−ACPpπ−=0.014±0.022±0.010, where the first uncertainties are statistical and the second systematic. These are the most precise measurements of such asymmetries to date

Evidence for an nc(1S)ff- resonance in B0 yc(1S)K+ decays

A Dalitz plot analysis of B0→ηc(1S)K+π- decays is performed using data samples of pp collisions collected with the LHCb detector at centre-of-mass energies of s=7,8 and 13TeV , corresponding to a total integrated luminosity of 4.7fb-1 . A satisfactory description of the data is obtained when including a contribution representing an exotic ηc(1S)π- resonant state. The significance of this exotic resonance is more than three standard deviations, while its mass and width are 4096±20-22+18MeV and 152±58-35+60MeV , respectively. The spin-parity assignments JP=0+ and JP=1- are both consistent with the data. In addition, the first measurement of the B0→ηc(1S)K+π- branching fraction is performed and gives B(B0→ηc(1S)K+π-)=(5.73±0.24±0.13±0.66)×10-4, where the first uncertainty is statistical, the second systematic, and the third is due to limited knowledge of external branching fractions

Search for dark photons produced in 13 TeV pppp collisions

Searches are performed for both promptlike and long-lived dark photons, A 0 , produced in proton-proton collisions at a center-of-mass energy of 13 TeV, using A 0 → μ þ μ − decays and a data sample corresponding to an integrated luminosity of 1 . 6 fb − 1 collected with the LHCb detector. The promptlike A 0 search covers the mass range from near the dimuon threshold up to 70 GeV, while the long-lived A 0 search is restricted to the low-mass region 214 <m ð A 0 Þ < 350 MeV. No evidence for a signal is found, and 90% confidence level exclusion limits are placed on the γ – A 0 kinetic-mixing strength. The constraints placed on promptlike dark photons are the most stringent to date for the mass range 10 . 6 <m ð A 0 Þ < 70 GeV, and are comparable to the best existing limits for m ð A 0 Þ < 0 . 5 GeV. The search for long-lived dark photons is the first to achieve sensitivity using a displaced-vertex signature

Search for Lepton-Universality Violation in B^{+}→K^{+}ℓ^{+}ℓ^{-} Decays.

A measurement of the ratio of branching fractions of the decays B^{+}→K^{+}μ^{+}μ^{-} and B^{+}→K^{+}e^{+}e^{-} is presented. The proton-proton collision data used correspond to an integrated luminosity of 5.0  fb^{-1} recorded with the LHCb experiment at center-of-mass energies of 7, 8, and 13 TeV. For the dilepton mass-squared range 1.1<q^{2}<6.0  GeV^{2}/c^{4} the ratio of branching fractions is measured to be R_{K}=0.846_{-0.054}^{+0.060}_{-0.014}^{+0.016}, where the first uncertainty is statistical and the second systematic. This is the most precise measurement of R_{K} to date and is compatible with the standard model at the level of 2.5 standard deviations

Amplitude analysis of the B0 (s)! K0K0 decays and measurement of the branching fraction of the B0! K0K0 decay

The $B^0 \to K^{*0} \overline{K}^{*0}$ and $B^0_s \to K^{*0} \overline{K}^{*0}$ decays are studied using proton-proton collision data corresponding to an integrated luminosity of 3fb$^{-1}$. An untagged and time-integrated amplitude analysis of $B^0_{(s)} \to (K^+\pi^-)(K^-\pi^+)$ decays in two-body invariant mass regions of 150 MeV$/c^2$ around the $K^{*0}$ mass is performed. A stronger longitudinal polarisation fraction in the ${B^0 \to K^{*0} \overline{K}^{*0}}$ decay, ${f_L = 0.724 \pm 0.051 \,({\rm stat}) \pm 0.016 \,({\rm syst})}$, is observed as compared to ${f_L = 0.240 \pm 0.031 \,({\rm stat}) \pm 0.025 \,({\rm syst})}$ in the ${B^0_s\to K^{*0} \overline{K}^{*0}}$ decay. The ratio of branching fractions of the two decays is measured and used to determine $\mathcal{B}(B^0 \to K^{*0} \overline{K}^{*0}) = (8.0 \pm 0.9 \,({\rm stat}) \pm 0.4 \,({\rm syst})) \times 10^{-7}$.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2019-004.html (LHCb public pages