321034 research outputs found
Sort by
Search for the nonresonant and resonant production of a Higgs boson in association with an additional scalar boson in the final state in proton-proton collisions at = 13 TeV
No full textThe results of a search for the production of two scalar bosons in final states with two photons and two tau leptons are presented. The search considers both nonresonant production of a Higgs boson pair, HH, and resonant production via a new boson X which decays either to HH or to H and a new scalar Y. The analysis uses up to 138 fb of proton-proton collision data, recorded between 2016 and 2018 by the CMS experiment at the LHC at a center-of-mass energy of 13 TeV. No evidence for signal is found in the data. For the nonresonant production, the observed (expected) upper limit at 95% confidence level (CL) on the HH production cross section is set at 930 (740) fb, corresponding to 33 (26) times the standard model prediction. At 95% CL, HH production is observed (expected) to be excluded for values of outside the range between 12 (9.4) and 17 (15). Observed (expected) upper limits at 95% CL for the XHH cross section are found to be within 160 to 2200 (200 to 1800) fb, depending on the mass of X. In the X Y()H() search, the observed (expected) upper limits on the product of the production cross section and decay branching fractions vary between 0.0591.2 fb (0.0870.68 fb). For the X Y()H() search the observed (expected) upper limits on the product of the production cross section and Y branching fraction vary between 0.6915 fb (0.738.3 fb) in the low Y mass search, tightening constraints on the next-to-minimal supersymmetric standard model, and between 0.6410 fb (0.707.6 fb) in the high Y mass search
Measurements of differential cross-sections of production in the dilepton channel in collisions at = 13 TeV using the ATLAS detector
No full textAt the Large Hadron Collider, the final state is expected to be dominated by production with a contribution from single-top processes. Differential cross-sections for production in the dilepton decay channel are measured at the particle level as a function of various kinematic variables. The analysis is based on data from proton-proton collisions at a centre-of-mass energy of TeV, recorded by the ATLAS detector at the Large Hadron Collider over the period from 2015 to 2018, corresponding to an integrated luminosity of 140 fb. Measurements are performed within the fiducial phase-space defined by the presence of two -jets and one electron and one muon of opposite charges. The differential cross-sections are corrected for detector effects and unfolded to the particle level. Results are compared with predictions from Monte Carlo event generators at next-to-leading order in perturbative quantum chromodynamics. These measurements provide valuable constraints on the modelling of production and the interference between doubly resonant and singly resonant production
Exploration of chemical probes and conformational flexibility of GID4 - the substrate receptor of human CTLH E3 ligase complex
No full textThe application of targeted protein degradation (TPD) is currently constrained by the limited availability of low-molecular-weight molecules that can recruit E3 ligases other than CRBN (Cereblon) or VHL (Von Hippel-Lindau ligase). In this study, we present the structure-based drug design (SBDD) of high-affinity ligands that engage E3 ligase GID4 (Glucose-induced degradation protein 4) in biophysical and cellular experiments. Through structural studies and molecular modeling, we identified three groups (clusters) of compounds that induce distinct conformations of GID4. We identified potential exit vectors and used the most promising ligand as a building block to prepare bifunctional degraders in the form of proteolysis-targeting chimeras (PROTACs). Although ternary complex formation was successful in vitro, degradation of BRD4 was not observed, highlighting the need for further optimization of the degraders. We also theoretically investigated the likelihood of the identified GID4 conformations participating in protein-protein interactions mediated by molecular glue mechanisms. We believe the expanded ligand diversity discovered in this study may pave the way for tuning the selectivity and efficacy of protein-protein interactions involving GID4 and its neosubstrates
CryoRhodopsins: A comprehensive characterization of a group of microbial rhodopsins from cold environments
No full textMicrobial rhodopsins are omnipresent on Earth; however, the vast majority of them remain uncharacterized. Here, we describe a rhodopsin group found in microorganisms from cold environments, such as glaciers, denoted as CryoRhodopsins (CryoRs). A distinguishing feature of the group is the presence of a buried arginine residue close to the cytoplasmic face. Combining single-particle cryo–electron microscopy and x-ray crystallography with rhodopsin activation by light, we demonstrate that the arginine stabilizes an ultraviolet (UV)–absorbing intermediate of an extremely slow CryoRhodopsin photocycle. Together with extensive spectroscopic characterization, our investigations on CryoR1 and CryoR2 proteins reveal mechanisms of photoswitching in the identified group. Our data suggest that CryoRs are sensors for UV irradiation and are also capable of inward proton translocation modulated by UV light
Interfacing B‐DNA and DNA Mimic Foldamers
No full textA linker unit was designed and synthesized that can serve both as a hairpin turn in a DNA duplex and anchor point for an aromatic helical foldamer mimicking the shape and surface properties of B-DNA. Methods were developed to synthesize natural/non-natural chimeric molecules combining foldamer and DNA segments. The ability of the linker to position the foldamer helix and the duplex DNA so that their rims and grooves are in register, despite their completely different chemical nature, was demonstrated using single crystal X-ray diffraction, circular dichroism and molecular models. Bio-layer interferometry confirmed that artificial hairpin DNA duplexes keep their ability to bind to DNA binding proteins. The chimeric molecules may pave the way to competitive inhibitors of protein-DNA interactions involving sequence-selective DNA-binding proteins
Direct structural investigation of pH responsiveness in mRNA lipid nanoparticles: Refining paradigms
No full textUsing small angle X-ray scattering measurements, structural coherencies in lipid nanoparticle (LNP) formulations comprising messenger RNA (mRNA) were elucidated in response to pH changes and as a function of RNA to lipid ratio. Formulations were assembled using selected ionizable lipids with well-known activity from previous experiments, with otherwise identical composition. Several structural parameters were determined, including internal organization, fraction of ordered material, the underlying repeating distance, and the fractal dimension of the overall particles. Repeat distances increased with increasing pH, with profiles similar to the shape of pKa curves, therefore allowing to directly reveal the structural implication of the pH responsiveness inside the particles. The fractal dimension, which so far had not been in the center of attention for quality control, was correlated with biological activity. Such systematic data on structure-function coherencies in LNPs can serve as complementary methods to standard lab-based quality control measures. This can help to facilitate and accelerate the rational formulation development of new RNA therapeutics
Insights into the solution structure of the actin-binding tail domain of metavinculin by small angle X-ray scattering and molecular dynamics simulations
No full textVinculin is a ubiquitously expressed focal adhesion protein that plays an important role in cell-matrix and cell-to-cell junctions. Metavinculin, a muscle-specific splice variant of vinculin, contains a 68-amino acid disordered insert region in its actin binding tail domain (MVt). Mutations in this insert are linked to cardiomyopathies. This study investigates the solution structures and structural ensembles of wild-type (WT) and two mutant MVts, ΔLeu954 and R975W, which have been associated with cardiomyopathies, using small-angle X-ray scattering (SAXS) and molecular dynamics (MD) simulations. SAXS analyses revealed subtle differences in the estimated maximum dimensions and corroborated the elongated shape of the MVts. Quantitative comparisons of SAXS profiles indicated similarity between the WT and ΔLeu954, whereas R975W exhibited differences in the small-angle region. MD simulations demonstrated reduced conformational flexibility and greater packing of the insert in WT compared to mutants. Notably, a salt-bridge observed between R975 and D907 in a WT simulation provides a structural basis for the destabilization caused by the R975W mutation. These findings provide insights into the structure and dynamics of WT and mutant MVt, reflecting the promise of SAXS combined with MD simulations to elucidate the structural properties of proteins with structural disorder
In-situ synchrotron X-ray study on the deformation behavior at each stage of strain aging process in bake-hardenable low-carbon steel under tensile loading
No full textn this study, we comparatively analyzed the deformation behavior of the bake-hardenable steel across the strain aging stages using in-situ synchrotron X-ray diffraction (SXRD) experiments. The lattice strain and dislocation density evolutions evaluated from the in-situ SXRD patterns elucidated the diverse elastic and plastic deformation behaviors of the initial, pre-strained, and strain-aged states. This research, by leveraging a powerful real-time technique, enhances our understanding of strain aging and provides valuable insights for its future applications
Measurement of photonuclear jet production in ultraperipheral Pb+Pb collisions at = 5.02 TeV with the ATLAS detector
No full textIn ultrarelativistic heavy ion collisions at the LHC, each nucleus acts a sources of high-energy real photons that can scatter off the opposing nucleus in ultraperipheral photonuclear (γ+A) collisions. Hard scattering processes initiated by the photons in such collisions provide a novel method for probing nuclear parton distributions in a kinematic region not easily accessible to other measurements. ATLAS has measured production of dijet and multijet final states in ultraperipheral Pb+Pb collisions at =5.02 TeV using a dataset recorded in 2018 with an integrated luminosity of 1.72 nb. Photonuclear final states are selected by requiring a rapidity gap in the photon direction; this selects events where one of the outgoing nuclei remains intact. Jets are reconstructed using the anti-kt algorithm with radius parameter, R=0.4. Triple-differential cross sections, unfolded for detector response, are measured and presented using two sets of kinematic variables. The first set consists of the total transverse momentum (H), rapidity, and mass of the jet system. The second set uses H and particle-level nuclear and photon parton momentum fractions, x and z, respectively. The results are compared with leading-order perturbative QCD calculations of photonuclear jet production cross sections, where all leading order predictions using existing fits fall below the data in the shadowing region. More detailed theoretical comparisons will allow these results to strongly constrain nuclear parton distributions, and these data provide results from the LHC directly comparable to early physics results at the planned Electron-Ion Collider
Search for light neutral particles decaying promptly into collimated pairs of electrons or muons in pp collisions at = 13 with the ATLAS detector
No full textA search for a dark photon, a new light neutral particle, which decays promptly into collimated pairs of electrons or muons is presented. The search targets dark photons resulting from the exotic decay of the Standard Model Higgs boson, assuming its production via the dominant gluon-gluon fusion mode. The analysis is based on of data collected with the ATLAS detector at the Large Hadron Collider from proton-proton collisions at a center-of-mass energy of 13 . Events with collimated pairs of electrons or muons are analysed and background contributions are estimated using data-driven techniques. No significant excess in the data above the Standard Model background is observed. Upper limits are set at 95% confidence level on the branching ratio of the Higgs boson decay into dark photons between 0.001% and 5%, depending on the assumed dark photon mass and signal model