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Experimental study of inclusive charmless semileptonic beauty meson decays at Belle II
No full textA measurement of partial branching fractions of charmless semileptonic beauty meson decaysusing an inclusively reconstructed hadronic system is presented. These decays are denoted asB → Xuℓν, where Xu represents a hadronic system containing a u quark produced in the un-derlying quark-level b → u transition. The measurement uses the full Run 1 Belle II samplecorresponding to 365 fb−1 of e+e− → Υ(4S) → B ¯B data. One of the two B mesons is recon-structed in a hadronic decay channel to constrain the signal kinematics. Events containing asignal electron or muon ℓ are selected, while the rest of the event defines the hadronic systemXu associated with the signal. To discriminate the signal from the 50-times larger backgroundoriginating from Cabibbo-favoured semileptonic B → Xcℓν decays, a template fit is performedin both signal and control regions after applying an optimised selection. The control regionsare used to constrain the kinematic properties of B → Xcℓν decays based on data and thereforereduce the dependence of the measurement on their modelling. The partial branching fractionmeasured for lepton energies greater than 1 GeV in the signal B meson rest frame is∆B(B → Xuℓν) = (1.54 ± 0.08 ± 0.12) × 10−3,where the uncertainties are statistical and systematic, respectively. From this measurement,using the Gambino, Giordano, Ossola and Uraltsev theoretical framework, the strength of thebeauty-to-up quark coupling is determined to be|Vub| = (4.01 ± 0.19+0.07−0.08) × 10−3,where the uncertainties are experimental and theoretical, respectively. This value is in goodagreement with the world average of |Vub| = (4.06±0.16)×10−3. Different theoretical predictionsand partial branching fractions measured in other phase-space regions, defined by additionalselections on the Xu and leptonic system masses, are also used to determine |Vub|
Acyclic purine and pyrimidine nucleotide analogs as ecto-5′-nucleotidase (CD73) inhibitors
No full textEcto-5′-nucleotidase (CD73) is a novel target in cancer (immuno)therapy. Its blockade prevents the formation of immunosuppressive and cancer-promoting adenosine from AMP. Here, we report on the development of a series of small molecules that mimic adenine nucleotides, in which the ribose moiety was replaced by an alkyl chain. Its length was found to be crucial for potency. A crystal structure of the N6-disubstituted acyclic ADP analog 26 (N6-benzyl,N6-methyladenine-9-yl)pentyloxydiphosphonate) in complex with human CD73 revealed that the flexible pentyl linker adopts to interdomain rotation angles differing by up to 18.5°. The most potent CD73 inhibitor of the present series was analog 27 (N6-benzyl,N6-methyladenine-9-yl)hexyloxydiphosphonate, PSB-24000) which exhibited submicromolar potency at human CD73 (Ki 563 nM at soluble CD73; Ki 481 nM at membrane-bound CD73 of triple-negative breast cancer cells). Acyclic nucleotide analogs may be advantageous compared to the previously reported nucleotidic CD73 inhibitors due to their high chemical stability, and because less off-target effects are to be expected. The structure-activity relationships discovered in this study provide valuable insights which will be useful for the development of CD73 inhibitors as immunotherapeutic drugs
The GTPase κB-Ras is an essential subunit of the RalGAP tumor suppressor complex
No full textκB-Ras1 and κB-Ras2 are small GTPases with noncanonical features that act as tumor suppressors downstream of Ras. Via interaction with the RalGAP (GTPase-activating protein) complex, they limit activity of Ral GTPases and restrict anchorage-independent proliferation. We here present the crystal structure of κB-Ras1 in complex with the N-terminal domain of RGα2. The structure suggests a mechanism of intrinsic GTP hydrolysis of κB-Ras1 that relies on a scaffolding function of the GTPase rather than on catalytic residues, which we confirm by mutational analysis. The interaction with RGα2 is nucleotide independent and does not involve κB-Ras1 switch regions, which establishes κB-Ras proteins as a constitutive third subunit of RalGAP complexes. Functional studies demonstrate that κB-Ras proteins are not required for RalGAP catalytic activity in vitro but for functionality in vivo. We propose that κB-Ras may thus act as a regulator of RalGAP localization and thereby control the Ras–Ral signaling pathway
Botulinum neurotoxin A mutants with enhanced ganglioside binding show improved potency and altered ganglioside selectivity
No full textBotulinum neurotoxins are the causative agents of botulism, a lethal paralytic disease, but are also one of the most commonly used therapeutics for the treatment of numerous neuromuscular conditions. These toxins recognise motor nerve terminals with high specificity and affinity by using a dual binding mechanism involving gangliosides and protein receptors. The initial recognition of gangliosides is crucial for the toxins’ potency. In this study, we employed a synaptosome-binding screening strategy to identify BoNT/A mutants with enhanced ganglioside-binding which translated into improved potency. X-ray crystallography and receptor-binding assays were used to elucidate the molecular mechanisms underlying the increased affinity or altered ganglioside selectivity of these mutants. Our findings provide a basis for the development of BoNT/A variants with enhanced therapeutic potential
Uptake of fucosylated type I human milk oligosaccharide blocks by Bifidobacterium longum subsp. infantis
No full textHuman milk oligosaccharides (HMOs) are uniquely rich in the type 1 building block disaccharide lacto-N-biose I (LNB; Galβ1,3GlcNAc), as compared to other mammals. Most HMOs are fucosylated, for example, α1,2 and α1,4 fucosylations on LNB blocks, resulting in H type 1 (H1) and Lewis a (Lea) epitopes, respectively. The dominance of Bifidobacterium in breastfed infant guts hinges on the efficient uptake of HMOs by specific ATP-binding cassette (ABC) importers. However, molecular insight into uptake of fucosylated LNB blocks is lacking. Here, we analyzed the uptake of LNB and its fucosylated H1 and Lea trisaccharides, as well as the mucin-derived disaccharide galacto-N-biose (GNB; Galβ1,3GalNAc) by an ABC importer from the HMO-utilization specialist Bifidobacterium longum subsp. infantis. Structural analyses and molecular dynamics simulations explained how fucosylated and non-fucosylated LNB forms are recognized with similar affinities by the binding protein of this importer. Strikingly, we showed that two ABC importers confer to the uptake of LNB, while the Lea trisaccharide is efficiently internalized by a single importer in B. infantis. Phylogenetic and structural analyses of bifidobacterial ABC-associated binding proteins showed that the Lea clade harbors homologs possessing internal cavities, which allows for the accommodation of branched oligosaccharides. Our work provides unique insight into the evolution and molecular basis of capture and uptake of key HMO and host-derived saccharide blocks, highlighting these compounds as hitherto unexplored candidates for fortification of infant formula
Fermi surface and pseudogap in highly doped Sr2IrO4
No full textThe fate of the Fermi surface in bulk electron-doped SrIrO remains elusive, as does the origin and extension of its pseudogap phase. Here, we use high-resolution angle-resolved photoelectron spectroscopy (ARPES) to investigate the electronic structure of SrLaxIrO up to x = 0.2, a factor of two higher than in previous work. We find that the antinodal pseudogap persists up to the highest doping level, and thus beyond the sharp increase in Hall carrier density to ≃ 1 + x recently observed above x* ≃ 0.16. This suggests that doped iridates host a unique phase of matter in which a large Hall density coexists with an anisotropic pseudogap, breaking up the Fermi surface into disconnected arcs. The temperature boundary of the pseudogap is T* ≃ 200 K for x = 0.2, comparable to cuprates and to the energy scale of short range antiferromagnetic correlations in cuprates and iridates
Tuning Li occupancy and local structures for advanced Co-free Ni-rich positive electrodes
No full textStructure evolution and surface reactivity have long been regarded as the most crucial points for studying Ni-rich positive electrodes for Li-ion batteries. Unfortunately, the influence of Li occupancy as a single factor on electro-chemomechanical stability has been overlooked and is missing, owing to the challenge of Li determination in the lattice. Here, a comprehensive analysis reveals different Li occupancies and related structural domains (Ni/Li exchange, LiXO, Li/Mn/X(Ni) ordering domains, X = Nb, W, and Mo) by using a combination of Li-sensitive characterization techniques. By introducing a Li-regulation strategy, the relative ratio of each domain is effectively tuned in the Ni-rich positive electrodes. Through tuning, two specific positive electrodes are designed, exhibiting notable improvement in battery cyclability. The specific Li structural units induce significant changes in redox mechanisms. This Li-occupancy-tuning approach highlights the necessity of focusing on Li distribution and opens up ideas for designing advanced Ni-rich positive electrodes with high durability
High-temperature compression induced α to γ phase transformation and related phase morphology transition in TiAl alloy
No full textTitanium aluminide (TiAl) alloys are promising for aerospace and automotive applications due to their lowdensity, high strength and excellent oxidation and creep resistance. Among them, the β-solidifying TNM (Ti-Al-Nb-Mo-B) alloys exhibit remarkable mechanical properties and thermal stability. Hot deformation is commonlyused to shape these alloys, typically below the (α + β) phase region (below the γ-solvus temperature). In thisstudy, hot compression was performed at 1280 ◦C (in the (α + β) phase region) with two thickness reductions at astrain rate of 10-2 s-1. Unexpectedly, the γ phase resurged abnormally from the α phase despite its thermodynamicinstability at equilibrium. The formed γ phase follows the Blackburn orientation relationship (OR) and exhibitslamellar and nodular morphologies. Crystallographic analysis reveals that the activation of the basal slip in the αphase under the compression triggered this transformation. The early formed γ lamellae then evolved throughfragmentation, spheroidization, coarsening and boundary sliding, leading to the morphology change fromlamellae to nodules. These insights advance the understanding of TNM alloys for high-performance and hightemperatureapplications
Using the as a Standard Candle to Reach the Top: Calibrating Energy Correlator Based Top Mass Measurements
No full textThe top quark mass plays a central role in our understanding of the Standard Model and its extrapolation to high energies. However, precision measurements of the top quark mass at hadron colliders are notoriously difficult, motivating the development of qualitatively new approaches to take advantage of the enormous datasets of top quarks at the Large Hadron Collider (LHC). Recent advances in jet substructure have enabled the precise theoretical description of angular correlations in energy flux. However, their application to precision mass measurements is less direct since they measure a dimensionless angular scale. Inspired by the use of standard candles in cosmology, we introduce a single energy correlator-based observable that reflects the characteristic angular scales of both the -boson and the top quark masses. This gives direct access to the dimensionless quantity , from which can be extracted in a well-defined short-distance mass scheme as a function of the well-known (our LHC Cepheid variable). We perform a Monte-Carlo-based study to demonstrate the properties of our observable and the statistical feasibility of its extraction from the Run 2 and 3 and High-Luminosity LHC data sets. The resulting has remarkably small uncertainties from non-perturbative effects and is insensitive to the parton distribution functions. We believe that our proposed observable provides a road map for a rich program to achieve a record precision top quark mass measurement at the LHC
How austenite improves the fatigue behavior of high-speed steels
No full textOptimizing the fatigue performance of tool materials, such as high-speed steels, is crucial for increasing the service life of parts and metalworking tools. An important property in this respect is a material’s resistance to the propagation of short cracks, evident in cyclic R-curve behavior. The potential to improve the fatigue crack propagation resistance by transformation-induced crack closure was studied for a high-speed steel grade in which significant fractions of metastable austenite were retained. The austenite’s resistance to martensitic transformation under cyclic thermal loads was evaluated. Transformation-induced plasticity was studied using tensile tests with in situ determination of austenite content by X-ray diffraction using synchrotron radiation. The cyclic R–curve behavior and the threshold for fatigue crack propagation were determined for stress ratios of R = 0.1, −1, and −5. Critical parameters regarding fatigue behavior, such as the slope of the cyclic R-curve and the long crack threshold of the stress intensity factor range, were significantly improved relative to comparable industry-relevant material states