Dyclonine rescues frataxin deficiency in animal models and buccal cells of patients with Friedreich's ataxia.

Inherited deficiency in the mitochondrial protein frataxin (FXN) causes the rare disease Friedreich's ataxia (FA), for which there is no successful treatment. We identified a redox deficiency in FA cells and used this to model the disease. We screened a 1600-compound library to identify existing drugs, which could be of therapeutic benefit. We identified the topical anesthetic dyclonine as protective. Dyclonine increased FXN transcript and FXN protein dose-dependently in FA cells and brains of animal models. Dyclonine also rescued FXN-dependent enzyme deficiencies in the iron-sulfur enzymes, aconitase and succinate dehydrogenase. Dyclonine induces the Nrf2 [nuclear factor (erythroid-derived 2)-like 2] transcription factor, which we show binds an upstream response element in the FXN locus. Additionally, dyclonine also inhibited the activity of histone methyltransferase G9a, known to methylate histone H3K9 to silence FA chromatin. Chronic dosing in a FA mouse model prevented a performance decline in balance beam studies. A human clinical proof-of-concept study was completed in eight FA patients dosed twice daily using a 1% dyclonine rinse for 1 week. Six of the eight patients showed an increase in buccal cell FXN levels, and fold induction was significantly correlated with disease severity. Dyclonine represents a novel therapeutic strategy that can potentially be repurposed for the treatment of FA

Modeling for assessment of long-term behavior of prestressed concrete box-girder bridges

Large-span prestressed concrete (PC) box-girder bridges suffer excessive vertical deflections and cracking. Recent serviceability failures in China show that the current Chinese standard modeling approach fails to accurately predict long-term deformations of large box-girder bridges. This hinders the efforts of inspectors to conduct satisfactory structural assessments and make decisions on potential repair and strengthening. This study presents a model-updating approach that aims to assess the models used in the current Chinese standard and improve the accuracy of numerical modeling of the long-term behavior of box-girder bridges, calibrated against data obtained from a bridge in service. A three-dimensional finite-element model representing the long-term behavior of box-girder sections is initially established. Parametric studies are then conducted to determine the relevant influencing parameters and to quantify the relationships between those and the behavior of box-girder bridges. Genetic algorithm optimization, based on the response-surface method (RSM), is used to determine realistic creep and shrinkage levels and prestress losses. The modeling results correspond well with the measured historic deflections and the observed cracks. This approach can lead to more accurate bridge assessments, which result in safer strengthening and more economic maintenance plans

Parallel momentum distribution of the 28^{28}Si fragments from 29^{29}P

Distribution of the parallel momentum of $^{28}$Si fragments from the breakup of 30.7 MeV/nucleon $^{29}$P has been measured on C targets. The distribution has the FWHM with the value of 110.5 $\pm$ 23.5 MeV/c which is consistent quantitatively with Galuber model calculation assuming by a valence proton in $^{29}$P. The density distribution is also predicted by Skyrme-Hartree-Fock calculation. Results show that there might exist the proton-skin structure in $^{29}$P.Comment: 4 pages, 4 figure

A Unified Description of Cuprate and Iron Arsenide Superconductors

We propose a unified description of cuprate and iron-based superconductivity. Consistency with magnetic structure inferred from neutron scattering implies significant constraints on the symmetry of the pairing gap for the iron-based superconductors. We find that this unification requires the orbital pairing formfactors for the iron arsenides to differ fundamentally from those for cuprates at the microscopic level.Comment: 12 pages, 10 figures, 2 table

Deep learning radiomic nomogram can predict the number of lymph node metastasis in locally advanced gastric cancer: an international multi-center study.

BACKGROUND: Preoperative evaluation of the number of lymph node metastasis (LNM) is the basis of individual treatment of locally advanced gastric cancer (LAGC). However, the routinely used preoperative determination method is not accurate enough. PATIENTS AND METHODS: We enrolled 730 LAGC patients from 5 centers in China and 1 center in Italy, and divided them into 1 primary cohort, 3 external validation cohorts, and 1 international validation cohort. A deep learning radiomic nomogram (DLRN) was built based on the images from multi-phase computed tomography (CT) for preoperatively determining the number of LNM in LAGC. We comprehensively tested the DLRN and compared it with three state-of-the-art methods. Moreover, we investigated the value of the DLRN in survival analysis. RESULTS: The DLRN showed good discrimination of the number of LNM on all cohorts (overall C-indexes: 0.821, 95% CI: 0.785-0.858 in the primary cohort; 0.797, 95% CI: 0.771-0.823 in the external validation cohorts; and 0.822, 95% CI: 0.756-0.887 in the international validation cohort). The nomogram performed significantly better than the routinely used clinical N stages, tumor size, and clinical model (p<0.05). Besides, DLRN is significantly associated with the overall survival of LAGC patients (n=271). CONCLUSION: A deep learning-based radiomic nomogram had good predictive value for LNM in LAGC. In staging-oriented treatment of gastric cancer, this preoperative nomogram could provide baseline information for individual treatment of LAGC

Effect of transport-induced charge inhomogeneity on point-contact Andreev reflection spectra at ferromagnet-superconductor interfaces

We investigate the transport properties of a ferromagnet-superconductor interface within the framework of a modified three-dimensional Blonder-Tinkham-Klapwijk formalism. In particular, we propose that charge inhomogeneity forms via two unique transport mechanisms, namely, evanescent Andreev reflection and evanescent quasiparticle transmission. Furthermore, we take into account the influence of charge inhomogeneity on the interfacial barrier potential and calculate the conductance as a function of bias voltage. Point-contact Andreev reflection (PCAR) spectra often show dip structures, large zero-bias conductance enhancement, and additional zero-bias conductance peak. Our results indicate that transport-induced charge inhomogeneity could be a source of all these anomalous characteristics of the PCAR spectra.Comment: 9 pages, 6 figure

X-ray Structures of the Signal Recognition Particle Receptor Reveal Targeting Cycle Intermediates

The signal recognition particle (SRP) and its conjugate receptor (SR) mediate cotranslational targeting of a subclass of proteins destined for secretion to the endoplasmic reticulum membrane in eukaryotes or to the plasma membrane in prokaryotes. Conserved active site residues in the GTPase domains of both SRP and SR mediate discrete conformational changes during formation and dissociation of the SRP·SR complex. Here, we describe structures of the prokaryotic SR, FtsY, as an apo protein and in two different complexes with a non-hydrolysable GTP analog (GMPPNP). These structures reveal intermediate conformations of FtsY containing GMPPNP and explain how the conserved active site residues position the nucleotide into a non-catalytic conformation. The basis for the lower specificity of binding of nucleotide in FtsY prior to heterodimerization with the SRP conjugate Ffh is also shown. We propose that these structural changes represent discrete conformational states assumed by FtsY during targeting complex formation and dissociation

Observation of Ds+→pnˉD^+_s\rightarrow p\bar{n} and confirmation of its large branching fraction

The baryonic decay $D^+_s\rightarrow p\bar{n}$ is observed, and the corresponding branching fraction is measured to be $(1.21\pm0.10\pm0.05)\times10^{-3}$, where the first uncertainty is statistical and second systematic. The data sample used in this analysis was collected with the BESIII detector operating at the BEPCII $e^+e^-$ double-ring collider with a center-of-mass energy of 4.178~GeV and an integrated luminosity of 3.19~fb$^{-1}$. The result confirms the previous measurement by the CLEO Collaboration and is of greatly improved precision, which may deepen our understanding of the dynamical enhancement of the W-annihilation topology in the charmed meson decays

Observation and study of the decay J/ψ→ϕηη′J/\psi\rightarrow\phi\eta\eta'

We report the observation and study of the decay $J/\psi\rightarrow\phi\eta\eta'$ using $1.3\times{10^9}$ $J/\psi$ events collected with the BESIII detector. Its branching fraction, including all possible intermediate states, is measured to be $(2.32\pm0.06\pm0.16)\times{10^{-4}}$. We also report evidence for a structure, denoted as $X$, in the $\phi\eta'$ mass spectrum in the $2.0-2.1$ GeV/$c^2$ region. Using two decay modes of the $\eta'$ meson ($\gamma\pi^+\pi^-$ and $\eta\pi^+\pi^-$), a simultaneous fit to the $\phi\eta'$ mass spectra is performed. Assuming the quantum numbers of the $X$ to be $J^P = 1^-$, its significance is found to be 4.4$\sigma$, with a mass and width of $(2002.1 \pm 27.5 \pm 21.4)$ MeV/$c^2$ and $(129 \pm 17 \pm 9)$ MeV, respectively, and a product branching fraction $\mathcal{B}(J/\psi\rightarrow\eta{}X)\times{}\mathcal{B}(X\rightarrow\phi\eta')=(9.8 \pm 1.2 \pm 1.7)\times10^{-5}$. Alternatively, assuming $J^P = 1^+$, the significance is 3.8$\sigma$, with a mass and width of $(2062.8 \pm 13.1 \pm 7.2)$ MeV/$c^2$ and $(177 \pm 36 \pm 35)$ MeV, respectively, and a product branching fraction $\mathcal{B}(J/\psi\rightarrow\eta{}X)\times{}\mathcal{B}(X\rightarrow\phi\eta')=(9.6 \pm 1.4 \pm 2.0)\times10^{-5}$. The angular distribution of $J/\psi\rightarrow\eta{}X$ is studied and the two $J^P$ assumptions of the $X$ cannot be clearly distinguished due to the limited statistics. In all measurements the first uncertainties are statistical and the second systematic.Comment: 10 pages, 6 figures and 4 table

Observation of ηc→ωω\eta_c\to\omega\omega in J/ψ→γωωJ/\psi\to\gamma\omega\omega

Using a sample of $(1310.6\pm7.0)\times10^6$ $J/\psi$ events recorded with the BESIII detector at the symmetric electron positron collider BEPCII, we report the observation of the decay of the $(1^1 S_0)$ charmonium state $\eta_c$ into a pair of $\omega$ mesons in the process $J/\psi\to\gamma\omega\omega$. The branching fraction is measured for the first time to be $\mathcal{B}(\eta_c\to\omega\omega)= (2.88\pm0.10\pm0.46\pm0.68)\times10^{-3}$, where the first uncertainty is statistical, the second systematic and the third is from the uncertainty of $\mathcal{B}(J/\psi\to\gamma\eta_c)$. The mass and width of the $\eta_c$ are determined as $M=(2985.9\pm0.7\pm2.1)\,$MeV/$c^2$ and $\Gamma=(33.8\pm1.6\pm4.1)\,$MeV.Comment: 13 pages, 6 figure