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A premature termination codon (PTC) in the ORF of an mRNA generally leads to production of a truncated polypeptide, accelerated degradation of the mRNA, and depression of overall mRNA expression. Accordingly, nonsense mutations cause some of the most severe forms of inherited disorders. The small-molecule drug ataluren promotes therapeutic nonsense suppression and has been thought to mediate the insertion of near-cognate tRNAs at PTCs. However, direct evidence for this activity has been lacking. Here, we expressed multiple nonsense mutation reporters in human cells and yeast and identified the amino acids inserted when a PTC occupies the ribosomal A site in control, ataluren-treated, and aminoglycoside-treated cells. We find that ataluren’s likely target is the ribosome and that it produces full-length protein by promoting insertion of near-cognate tRNAs at the site of the nonsense codon without apparent effects on transcription, mRNA processing, mRNA stability, or protein stability. The resulting readthrough proteins retain function and contain amino acid replacements similar to those derived from endogenous readthrough, namely Gln, Lys, or Tyr at UAA or UAG PTCs and Trp, Arg, or Cys at UGA PTCs. These insertion biases arise primarily from mRNA:tRNA mispairing at codon positions 1 and 3 and reflect, in part, the preferred use of certain nonstandard base pairs, e.g., U-G. Ataluren’s retention of similar specificity of near-cognate tRNA insertion as occurs endogenously has important implications for its general use in therapeutic nonsense suppression.

Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin ( HTT ) gene. Consequently, the mutant protein is ubiquitously expressed and drives pathogenesis of HD through a toxic gain-of-function mechanism. Animal models of HD have demonstrated that reducing huntingtin (HTT) protein levels alleviates motor and neuropathological abnormalities. Investigational drugs aim to reduce HTT levels by repressing HTT transcription, stability or translation. These drugs require invasive procedures to reach the central nervous system (CNS) and do not achieve broad CNS distribution. Here, we describe the identification of orally bioavailable small molecules with broad distribution throughout the CNS, which lower HTT expression consistently throughout the CNS and periphery through selective modulation of pre-messenger RNA splicing. These compounds act by promoting the inclusion of a pseudoexon containing a premature termination codon (stop-codon psiExon), leading to HTT mRNA degradation and reduction of HTT levels. Here the authors describe the discovery of a class of small molecule splicing modifiers which are orally bioavailable, cross the blood-brain barrier, and lower levels of huntingtin in a mouse model of Huntington’s disease (HD).

Pre-mRNA splicing is a key controller of human gene expression. Disturbances in splicing due to mutation lead to dysregulated protein expression and contribute to a substantial fraction of human disease. Several classes of splicing modulator compounds (SMCs) have been recently identified and establish that pre-mRNA splicing represents a target for therapy. We describe herein the identification of BPN-15477, a SMC that restores correct splicing of ELP1 exon 20. Using transcriptome sequencing from treated fibroblast cells and a machine learning approach, we identify BPN-15477 responsive sequence signatures. We then leverage this model to discover 155 human disease genes harboring ClinVar mutations predicted to alter pre-mRNA splicing as targets for BPN-15477. Splicing assays confirm successful correction of splicing defects caused by mutations in CFTR , LIPA , MLH1 and MAPT . Subsequent validations in two disease-relevant cellular models demonstrate that BPN-15477 increases functional protein, confirming the clinical potential of our predictions. Drugs that modify RNA splicing are promising treatments for many genetic diseases. Here the authors show that deep learning strategies can predict drug targets, strongly supporting the use of in silico approaches to expand the therapeutic potential of drugs that modulate RNA splicing.

A light-hole exciton is a quasiparticle formed from a single electron bound to a single light hole. This type of fundamental excitation, if confined inside a semiconductor quantum dot, could be advantageous in quantum information science and technology. However, it has been difficult to access it so far, because confinement and strain in conventional quantum dots favour a ground-state single-particle hole with a predominantly heavy-hole character. Here we demonstrate the creation of a light-hole exciton ground state by applying elastic stress to an initially unstrained quantum dot. Its signature is clearly distinct from that of the well-known heavy-hole exciton and consists of three orthogonally polarized bright optical transitions and a fine-structure splitting of hundreds of microelectronvolts between in-plane and out-of-plane components. This work paves the way for the exploration of the fundamental properties and of the potential relevance of three-dimensionally confined light-hole states in quantum technologies. An electron and a hole trapped in the same quantum dot couple together to form an exciton. Conventionally the hole involved is a heavy hole. Light-hole excitons are now observed by applying elastic stress to initially unstrained gallium arsenide-based dots. The quasiparticles are identified by their optical emission signature, and could be used in future quantum technologies.

Efficient all-photonic quantum teleportation requires fast and deterministic sources of highly indistinguishable and entangled photons. Solid-state-based quantum emitters—notably semiconductor quantum dots—are a promising candidate for the role. However, despite the remarkable progress in nanofabrication, proof-of-concept demonstrations of quantum teleportation have highlighted that imperfections of the emitter still place a major roadblock in the way of applications. Here, rather than focusing on source optimization strategies, we deal with imperfections and study different teleportation protocols with the goal of identifying the one with maximal teleportation fidelity. Using a quantum dot with sub-par values of entanglement and photon indistinguishability, we show that the average teleportation fidelity can be raised from below the classical limit to 0.842(14), adopting a polarization-selective Bell state measurement and moderate spectral filtering. Our results, which are backed by a theoretical model that quantitatively explains the experimental findings, loosen the very stringent requirements set on the ideal entangled-photon source and highlight that imperfect quantum dots can still have a say in teleportation-based quantum communication architectures.

A bstract We present statistically convergent profile likelihood maps obtained via global fits of a phenomenological Minimal Supersymmetric Standard Model with 15 free parameters (the MSSM-15), based on over 250M points. We derive constraints on the model parameters from direct detection limits on dark matter, the Planck relic density measurement and data from accelerator searches. We provide a detailed analysis of the rich phenomenology of this model, and determine the SUSY mass spectrum and dark matter properties that are preferred by current experimental constraints. We evaluate the impact of the measurement of the anomalous magnetic moment of the muon ( g − 2) on our results, and provide an analysis of scenarios in which the lightest neutralino is a subdominant component of the dark matter. The MSSM-15 parameters are relatively weakly constrained by current data sets, with the exception of the parameters related to dark matter phenomenology ( M 1 , M 2 , μ ), which are restricted to the sub-TeV regime, mainly due to the relic density constraint. The mass of the lightest neutralino is found to be < 1.5 TeV at 99% C.L., but can extend up to 3 TeV when excluding the g − 2 constraint from the analysis. Low-mass bino-like neutralinos are strongly favoured, with spin-independent scattering cross-sections extending to very small values, ~ 10 −20 pb. ATLAS SUSY null searches strongly impact on this mass range, and thus rule out a region of parameter space that is outside the reach of any current or future direct detection experiment. The best-fit point obtained after inclusion of all data corresponds to a squark mass of 2.3 TeV, a gluino mass of 2.1 TeV and a 130 GeV neutralino with a spin-independent cross-section of 2.4 × 10 −10 pb, which is within the reach of future multi-ton scale direct detection experiments and of the upcoming LHC run at increased centre-of-mass energy.

The visible world is founded on the proton, the only composite building block of matter that is stable in nature. Consequently, understanding the formation of matter relies on explaining the dynamics and the properties of the proton’s bound state. A fundamental property of the proton involves the response of the system to an external electromagnetic field. It is characterized by the electromagnetic polarizabilities 1 that describe how easily the charge and magnetization distributions inside the system are distorted by the electromagnetic field. Moreover, the generalized polarizabilities 2 map out the resulting deformation of the densities in a proton subject to an electromagnetic field. They disclose essential information about the underlying system dynamics and provide a key for decoding the proton structure in terms of the theory of the strong interaction that binds its elementary quark and gluon constituents. Of particular interest is a puzzle in the electric generalized polarizability of the proton that remains unresolved for two decades 2 . Here we report measurements of the proton’s electromagnetic generalized polarizabilities at low four-momentum transfer squared. We show evidence of an anomaly to the behaviour of the proton’s electric generalized polarizability that contradicts the predictions of nuclear theory and derive its signature in the spatial distribution of the induced polarization in the proton. The reported measurements suggest the presence of a new, not-yet-understood dynamical mechanism in the proton and present notable challenges to the nuclear theory. Measurements of the proton’s electromagnetic structure show enhancement of its electric generalized polarizability compared with theoretical expectations, confirming the presence of a new dynamical mechanism not accounted for by current theories.

60S and 40S ribosomal subunits are assembled in the nucleolus and exported from the nucleus to the cytoplasm independently of each other. We show that in vertebrate cells, transport of both subunits requires the export receptor CRM1 and Ran·GTP. Export of 60S subunits is coupled with that of the nucleo‐ cytoplasmic shuttling protein NMD3. Human NMD3 (hNMD3) contains a CRM‐1‐dependent leucine‐rich nuclear export signal (NES) and a complex, dispersed nuclear localization signal (NLS), the basic region of which is also required for nucleolar accumulation. When present in Xenopus oocytes, both wild‐type and export‐defective mutant hNMD3 proteins bind to newly made nuclear 60S pre‐export particles at a late step of subunit maturation. The export‐defective hNMD3, but not the wild‐type protein, inhibits export of 60S subunits from oocyte nuclei. These results indicate that the NES mutant protein competes with endogenous wild‐type frog NMD3 for binding to nascent 60S subunits, thereby preventing their export. We propose that NMD3 acts as an adaptor for CRM1–Ran·GTP‐mediated 60S subunit export, by a mechanism that is conserved from vertebrates to yeast.

We report new pion electroproduction measurements in the Δ ( 1232 ) resonance, utilizing the SHMS - HMS magnetic spectrometers of Hall C at Jefferson Lab. The data focus on a region that exhibits a strong and rapidly changing interplay of the mesonic cloud and quark-gluon dynamics in the nucleon. The results are in reasonable agreement with models that employ pion cloud effects and chiral effective field theory calculations, but at the same time they suggest that an improvement is required to the theoretical calculations and provide valuable input that will allow their refinements. The data illustrate the potential of the magnetic spectrometers setup in Hall C towards the study the Δ ( 1232 ) resonance. These first reported results will be followed by a series of measurements in Hall C, that will expand the studies of the Δ ( 1232 ) resonance offering a high precision insight within a wide kinematic range from low to high momentum transfers.