A Dominant-Negative Approach That Prevents Diphthamide Formation Confers Resistance to Pseudomonas Exotoxin A and Diphtheria Toxin

Diphtheria toxin (DT), Pseudomonas aeruginosa Exotoxin A (ETA) and cholix toxin from Vibrio cholerae share the same mechanism of toxicity; these enzymes ADP-rybosylate elongation factor-2 (EF-2) on a modified histidine residue called diphthamide, leading to a block in protein synthesis. Mutant Chinese hamster ovary cells that are defective in the formation of diphthamide have no distinct phenotype except their resistance to DT and ETA. These observations led us to predict that a strategy that prevents the formation of diphthamide to confer DT and ETA resistance is likely to be safe. It is well documented that Dph1 and Dph2 are involved in the first biochemical step of diphthamide formation and that these two proteins interact with each other. We hypothesized that we could block diphthamide formation with a dominant negative mutant of either Dph1 or Dph2. We report in this study the first cellular-targeted strategy that protects against DT and ETA toxicity. We have generated Dph2(C-), a dominant-negative mutant of Dph2, that could block very efficiently the formation of diphthamide. Cells expressing Dph2(C-) were 1000-fold more resistant to DT than parental cells, and a similar protection against Pseudomonas exotoxin A was also obtained. The targeting of a cellular component with this approach should have a reduced risk of generating resistance as it is commonly seen with antibiotic treatments

Paracellular absorption is relatively low in the herbivorous Egyptian spiny-tailed lizard, Uromastyx aegyptia

Extent: 9 p.Absorption of small water-soluble nutrients in vertebrate intestines occurs both by specific, mediated transport and by nonspecific, passive, paracellular transport. Although it is apparent that paracellular absorption represents a significant route for nutrient absorption in many birds and mammals, especially small, flying species, its importance in ectothermic vertebrates has not previously been explored. Therefore, we measured fractional absorption (e) and absorption rate of three paracellular probes (arabinose, L-rhamnose, cellobiose) and of 3-O-methyl D-glucose (absorbed by both mediated and paracellular pathways) by the large herbivorous lizard, Uromastyx aegyptia, to explore the relative importance of paracellular and mediated transport in an ectothermic, terrestrial vertebrate. Fractional absorption of 3-O-methyl D-glucose was high (e = 0.7360.04) and similar to other vertebrates; e of the paracellular probes was relatively low (arabinose e = 0.3160.03, Lrhamnose e = 0.1960.02, and cellobiose e = 0.1460.02), and decreased with molecular mass, a pattern consistent with other vertebrates. Paracellular absorption accounted for approximately 24% of total 3-O-methyl D-glucose uptake, indicating low reliance on this pathway for these herbivorous lizards, a pattern similar to that found in other terrestrial vertebrates, and different from small flying endotherms (both birds and bats).Todd J. McWhorter, Berry Pinshow, William H. Karasov and Christopher R. Trac

The endothelial glycocalyx: composition, functions, and visualization

This review aims at presenting state-of-the-art knowledge on the composition and functions of the endothelial glycocalyx. The endothelial glycocalyx is a network of membrane-bound proteoglycans and glycoproteins, covering the endothelium luminally. Both endothelium- and plasma-derived soluble molecules integrate into this mesh. Over the past decade, insight has been gained into the role of the glycocalyx in vascular physiology and pathology, including mechanotransduction, hemostasis, signaling, and blood cell–vessel wall interactions. The contribution of the glycocalyx to diabetes, ischemia/reperfusion, and atherosclerosis is also reviewed. Experimental data from the micro- and macrocirculation alludes at a vasculoprotective role for the glycocalyx. Assessing this possible role of the endothelial glycocalyx requires reliable visualization of this delicate layer, which is a great challenge. An overview is given of the various ways in which the endothelial glycocalyx has been visualized up to now, including first data from two-photon microscopic imaging

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

Study of the ψ2(3823)ψ_2(3823) and χc1(3872)χ_{c1}(3872) states in B+→(Jψπ+π−)K+B^+ \rightarrow \left( Jψπ^+π^-\right)K^+ decays

The decays $B^+\rightarrow J/\psi \pi^+ \pi^- K^+$ are studied using a data set corresponding to an integrated luminosity of 9fb$^{-1}$ collected with the LHCb detector in proton-proton collisions between 2011 and 2018. Precise measurements of the ratios of branching fractions with the intermediate $\psi_2(3823)$, $\chi_{c1}(3872)$ and $\psi(2S)$ states are reported. The decay of $B^+\rightarrow \psi_2(3823)K^+$ with $\psi_2(3823)\rightarrow J\psi\pi^+\pi^-$ is observed for the first time with a significance of 5.1 standard deviations. The mass differences between the $\psi_2(3823)$, $\chi_{c1}(3872)$ and $\psi(2S)$ states are measured to be $$\begin{array}{rcl} m_{\chi_{c1(3872)}} - m_{\psi_2(3823)} &= & 47.50 \pm 0.53 \pm 0.13\,\mathrm{MeV/}c^2\,, \\ m_{\psi_2(3823)} - m_{\psi(2S)} &= & 137.98 \pm 0.53 \pm 0.14\,\mathrm{MeV/}c^2\,, \\ m_{\chi_{c1}(3872)} - m_{\psi(2S)} &= & 185.49 \pm 0.06 \pm 0.03\,\mathrm{MeV/}c^2\,, \end{array}$$ resulting in the most precise determination of the $\chi_{c1}(3782)$ mass. The width of the $\psi_2(3823)$ state is found to be below 5.2MeV at 90\% confidence level. The Breit-Wigner width of the $\chi_{c1}(3872)$ state is measured to be $$\Gamma^{\mathrm{BW}}_{\chi_{c1}(3872)} = 0.96^{+0.19}_{-0.18}\pm0.21 \mathrm{MeV},$$ which is inconsistent with zero by 5.5 standard deviations

Precise determination of the B-s(0)-B-s(-0) oscillation frequency

Mesons comprising a beauty quark and a strange quark can oscillate between particle (B0s) and antiparticle (B0s) flavour eigenstates, with a frequency given by the mass difference between heavy and light mass eigenstates, deltams. Here we present ameasurement of deltams using B0s2DsPi decays produced in proton-proton collisions collected with the LHCb detector at the Large Hadron Collider. The oscillation frequency is found to be deltams = 17.7683 +- 0.0051 +- 0.0032 ps-1, where the first uncertainty is statistical and the second systematic. This measurement improves upon the current deltams precision by a factor of two. We combine this result with previous LHCb measurements to determine deltams = 17.7656 +- 0.0057 ps-1, which is the legacy measurement of the original LHCb detector.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2021-005.html (LHCb public pages

Angular Analysis of the B+ -> K*(+)mu(+) mu(-) Decay

We present an angular analysis of the B + → K * + ( → K 0 S π + ) μ + μ − decay using 9     fb − 1 of p p collision data collected with the LHCb experiment. For the first time, the full set of C P -averaged angular observables is measured in intervals of the dimuon invariant mass squared. Local deviations from standard model predictions are observed, similar to those in previous LHCb analyses of the isospin-partner B 0 → K * 0 μ + μ − decay. The global tension is dependent on which effective couplings are considered and on the choice of theory nuisance parameters

Search for the doubly heavy baryons Omega(0)(bc) and Xi(0)(bc) decaying to Lambda(+)(c)pi(-) and Xi(+)(c)pi-

Abstract available from publisher's website

Searches for rare B-s(0) and B-0 decays into four muons

Searches for rare $B_s^0$ and $B^0$ decays into four muons are performed using proton-proton collision data recorded by the LHCb experiment, corresponding to an integrated luminosity of 9 $\text{fb}^{-1}$. Direct decays and decays via light scalar and $J/\psi$ resonances are considered. No evidence for the six decays searched for is found and upper limits at the 95% confidence level on their branching fractions ranging between $1.8\times10^{-10}$ and $2.6\times10^{-9}$ are set

Search for time-dependent CPCP violation in D0→K+K−D^0 \to K^+ K^- and D0→π+π−D^0 \to π^+ π^- decays

A search for time-dependent violation of the charge-parity symmetry in $D^0 \to K^+ K^-$ and $D^0 \to \pi^+ \pi^-$ decays is performed at the LHCb experiment using proton-proton collision data recorded from 2015 to 2018 at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 6 fb$^{-1}$. The $D^0$ meson is required to originate from a $D^*(2010)^+ \to D^0 \pi^+$ decay, such that its flavour at production is identified by the charge of the accompanying pion. The slope of the time-dependent asymmetry of the decay rates of $D^0$ and $\bar{D}^0$ mesons into the final states under consideration is measured to be $\Delta Y_{K^+ K^-} = (-2.3 \pm 1.5 \pm 0.3) \times 10^{-4}$, $\Delta Y_{\pi^+ \pi^-} = (-4.0 \pm 2.8 \pm 0.4)\times 10^{-4}$, where the first uncertainties are statistical and the second are systematic. These results are compatible with the conservation of the charge-parity symmetry at the level of 2 standard deviations and improve the precision by nearly a factor of two