Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aβo–PrPC binding and downstream pathways

Amyloid β oligomers (Aβo) are the main toxic species in Alzheimer's disease, which have been targeted for single drug treatment with very little success. In this work we report a new approach for identifying functional Aβo binding compounds. A tailored library of 971 fluorine containing compounds was selected by a computational method, developed to generate molecular diversity. These compounds were screened for Aβo binding by a combined 19F and STD NMR technique. Six hits were evaluated in three parallel biochemical and functional assays. Two compounds disrupted Aβo binding to its receptor PrPC in HEK293 cells. They reduced the pFyn levels triggered by Aβo treatment in neuroprogenitor cells derived from human induced pluripotent stem cells (hiPSC). Inhibitory effects on pTau production in cortical neurons derived from hiPSC were also observed. These drug-like compounds connect three of the pillars in Alzheimer's disease pathology, i.e. prion, Aβ and Tau, affecting three different pathways through specific binding to Aβo and are, indeed, promising candidates for further development

Combination of searches for Higgs boson pairs in pp collisions at \sqrts = 13 TeV with the ATLAS detector

This letter presents a combination of searches for Higgs boson pair production using up to 36.1 fb(-1) of proton-proton collision data at a centre-of-mass energy root s = 13 TeV recorded with the ATLAS detector at the LHC. The combination is performed using six analyses searching for Higgs boson pairs decaying into the b (b) over barb (b) over bar, b (b) over barW(+)W(-), b (b) over bar tau(+)tau(-), W+W-W+W-, b (b) over bar gamma gamma and W+W-gamma gamma final states. Results are presented for non-resonant and resonant Higgs boson pair production modes. No statistically significant excess in data above the Standard Model predictions is found. The combined observed (expected) limit at 95% confidence level on the non-resonant Higgs boson pair production cross-section is 6.9 (10) times the predicted Standard Model cross-section. Limits are also set on the ratio (kappa(lambda)) of the Higgs boson self-coupling to its Standard Model value. This ratio is constrained at 95% confidence level in observation (expectation) to -5.0 &lt; kappa(lambda) &lt; 12.0 (-5.8 &lt; kappa(lambda) &lt; 12.0). In addition, limits are set on the production of narrow scalar resonances and spin-2 Kaluza-Klein Randall-Sundrum gravitons. Exclusion regions are also provided in the parameter space of the habemus Minimal Supersymmetric Standard Model and the Electroweak Singlet Model. For complete list of authors see http://dx.doi.org/10.1016/j.physletb.2019.135103</p

Searches for lepton-flavour-violating decays of the Higgs boson in s=13\sqrt{s}=13 TeV pp\mathit{pp} collisions with the ATLAS detector

This Letter presents direct searches for lepton flavour violation in Higgs boson decays, H → eτ and H → μτ , performed with the ATLAS detector at the LHC. The searches are based on a data sample of proton–proton collisions at a centre-of-mass energy √s = 13 TeV, corresponding to an integrated luminosity of 36.1 fb−1. No significant excess is observed above the expected background from Standard Model processes. The observed (median expected) 95% confidence-level upper limits on the leptonflavour-violating branching ratios are 0.47% (0.34+0.13−0.10%) and 0.28% (0.37+0.14−0.10%) for H → eτ and H → μτ , respectively.publishedVersio

Search for flavour-changing neutral currents in processes with one top quark and a photon using 81 fb⁻¹ of pp collisions at \sqrts = 13 TeV with the ATLAS experiment

A search for flavour-changing neutral current (FCNC) events via the coupling of a top quark, a photon, and an up or charm quark is presented using 81 fb−1 of proton–proton collision data taken at a centre-of-mass energy of 13 TeV with the ATLAS detector at the LHC. Events with a photon, an electron or muon, a b-tagged jet, and missing transverse momentum are selected. A neural network based on kinematic variables differentiates between events from signal and background processes. The data are consistent with the background-only hypothesis, and limits are set on the strength of the tqγ coupling in an effective field theory. These are also interpreted as 95% CL upper limits on the cross section for FCNC tγ production via a left-handed (right-handed) tuγ coupling of 36 fb (78 fb) and on the branching ratio for t→γu of 2.8×10−5 (6.1×10−5). In addition, they are interpreted as 95% CL upper limits on the cross section for FCNC tγ production via a left-handed (right-handed) tcγ coupling of 40 fb (33 fb) and on the branching ratio for t→γc of 22×10−5 (18×10−5). © 2019 The Author(s

Evidence for the production of three massive vector bosons with the ATLAS detector

A search for the production of three massive vector bosons in proton-proton collisions is performed using data at $\sqrt{s} = 13$ TeV recorded with the ATLAS detector at the Large Hadron Collider in the years 2015-2017, corresponding to an integrated luminosity of $79.8$ fb$^{-1}$. Events with two same-sign leptons $\ell$ (electrons or muons) and at least two reconstructed jets are selected to search for $WWW \to \ell \nu \ell \nu qq$. Events with three leptons without any same-flavour opposite-sign lepton pairs are used to search for $WWW \to \ell \nu \ell\nu \ell \nu$, while events with three leptons and at least one same-flavour opposite-sign lepton pair and one or more reconstructed jets are used to search for $WWZ \to \ell \nu qq \ell \ell$. Finally, events with four leptons are analysed to search for $WWZ \to \ell \nu \ell \nu \ell \ell$ and $WZZ \to qq \ell \ell \ell \ell$. Evidence for the joint production of three massive vector bosons is observed with a significance of 4.1 standard deviations, where the expectation is 3.1 standard deviations.Comment: 38 pages in total, author list starting page 22, 6 figures, 5 tables, matching published paper in Phys. Lett. B. All figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-2

Glucosylpolyphenols as inhibitors of Aβ-induced Fyn kinase activation and Tau phosphorylation: synthesis, membrane permeability, and exploratory target assessment within the scope of type 2 diabetes and Alzheimer’s disease

Despite the rapidly increasing number of patients suffering from type 2 diabetes, Alzheimer’s disease, and diabetes-induced dementia, there are no disease-modifying therapies able to prevent or block disease progress. In this work, we investigate the potential of nature-inspired glucosylpolyphenols against relevant targets, including islet amyloid polypeptide, glucosidases and cholinesterases. Moreover, with the premise of Fyn kinase as a paradigm-shifting target in Alzheimer’s drug discovery, we explore glucosylpolyphenols as blockers of Aβ-induced Fyn kinase activation, while looking into downstream effects leading to Tau hyperphosphorylation. Several compounds inhibit Aβ-induced Fyn kinase activation and decrease pTau levels at 10 μM concentration, particularly the per-O-methylated glucosylacetophloroglucinol and the 4-glucosylcatechol dibenzoate, the latter inhibiting also butyrylcholinesterase and β-glucosidase. Both compounds are non-toxic with ideal pharmacokinetic properties for further development. This work ultimately highlights the multitarget nature, fine structural tuning capacity and valuable therapeutic significance of glucosylpolyphenols in the context of these metabolic and neurodegenerative disorders

Search for the Higgs boson decays H → ee and H → eμ in pp collisions at s=13TeV with the ATLAS detector

Searches for the Higgs boson decays H→ee and H→eμ are performed using data corresponding to an integrated luminosity of 139fb−1 collected with the ATLAS detector in pp collisions at s=13 TeV at the LHC. No significant signals are observed, in agreement with the Standard Model expectation. For a Higgs boson mass of 125 GeV, the observed (expected) upper limit at the 95% confidence level on the branching fraction B(H→ee) is 3.6×10−4 (3.5×10−4) and on B(H→eμ) is 6.2×10−5 (5.9×10−5). These results represent improvements by factors of about five and six on the previous best limits on B(H→ee) and B(H→eμ) respectively. © 2019 The Autho

Search for non-resonant Higgs boson pair production in the bbl nu l nu final state with the ATLAS detector in pp collisions at root s=13 TeV

A search for non-resonant Higgs boson pair production, as predicted by the Standard Model, is presented, where one of the Higgs bosons decays via the channel and the other via one of the ⁎ ⁎ channels. The analysis selection requires events to have at least two b-tagged jets and exactly two leptons (electrons or muons) with opposite electric charge in the final state. Candidate events consistent with Higgs boson pair production are selected using a multi-class neural network discriminant. The analysis uses 139 fb−1 of pp collision data recorded at a centre-of-mass energy of 13 TeV by the ATLAS detector at the Large Hadron Collider. An observed (expected) upper limit of 1.2 ( ) pb is set on the non-resonant Higgs boson pair production cross-section at 95% confidence level, which is equivalent to 40 ( ) times the value predicted in the Standard Model

Search for the Higgs boson decays H -> ee and H -> e mu in pp collisions at root s=13 TeV with the ATLAS detector

Searches for the Higgs boson decays and are performed using data corresponding to an integrated luminosity of collected with the ATLAS detector in pp collisions at TeV at the LHC. No significant signals are observed, in agreement with the Standard Model expectation. For a Higgs boson mass of 125 GeV, the observed (expected) upper limit at the 95% confidence level on the branching fraction is ( ) and on is ( ). These results represent improvements by factors of about five and six on the previous best limits on and respectively

Search for high-mass dilepton resonances using 139 fb−1 of pp collision data collected at √s=13 TeV with the ATLAS detector

A search for high-mass dielectron and dimuon resonances in the mass range of 250 GeV to 6 TeV is presented. The data were recorded by the ATLAS experiment in proton–proton collisions at a centre-of-mass energy of √s=13 TeV during Run 2 of the Large Hadron Collider and correspond to an integrated luminosity of 139 fb−1. A functional form is fitted to the dilepton invariant-mass distribution to model the contribution from background processes, and a generic signal shape is used to determine the significance of observed deviations from this background estimate. No significant deviation is observed and upper limits are placed at the 95% confidence level on the fiducial cross-section times branching ratio for various resonance width hypotheses. The derived limits are shown to be applicable to spin-0, spin-1 and spin-2 signal hypotheses. For a set of benchmark models, the limits are converted into lower limits on the resonance mass and reach 4.5 TeV for the E6-motivated Z'ψ boson. Also presented are limits on Heavy Vector Triplet model couplings