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We show that bicircular light (BCL) is a versatile way to control magnetic symmetries and topology in materials. The electric field of BCL, which is a superposition of two circularly polarized light waves with frequencies that are integer multiples of each other, traces out a rose pattern in the polarization plane that can be chosen to break selective symmetries, including spatial inversion. Using a realistic low-energy model, we theoretically demonstrate that the three-dimensional Dirac semimetal Cd_{3}As_{2} is a promising platform for BCL Floquet engineering. Without strain, BCL irradiation induces a transition to a noncentrosymmetric magnetic Weyl semimetal phase with tunable energy separation between the Weyl nodes. In the presence of strain, we predict the emergence of a magnetic topological crystalline insulator with exotic unpinned surface Dirac states that are protected by a combination of twofold rotation and time reversal (2^{'}) and can be controlled by light.
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Although the crystal structures of small-molecule compounds are often determined from single-crystal X-ray diffraction (scXRD), recent advances in three-dimensional electron diffraction (3DED) and crystal structure prediction (CSP) methods promise to expand the structure elucidation toolbox available to the crystallographer. Herein, a comparative assessment of scXRD, 3DED, and CSP in combination with powder X-ray diffraction is carried out on two former drug candidate compounds and a multicomponent crystal of a key building block in the synthesis of gefapixant citrate.
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Polvos , Cristalografía por Rayos X , Polvos/química , Difracción de Rayos X , Rayos XRESUMEN
This paper describes the structure-activity-relationships of novel fluoroalkyl substituents at the C2 position of iminothiazine dioxide beta secretase inhibitors. Key discoveries include reduced amidine basicity and its effect on Pgp, cell potency, and efficacy in various preclinical in vivo efficacy animal models. Findings from these structure-activity-relationships are discussed.
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Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Óxidos/farmacología , Tiazinas/farmacología , Administración Oral , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Células HEK293 , Humanos , Estructura Molecular , Óxidos/administración & dosificación , Óxidos/química , Ratas , Relación Estructura-Actividad , Tiazinas/administración & dosificación , Tiazinas/químicaRESUMEN
Strain describes the deformation of a material as a result of applied stress. It has been widely employed to probe transport properties of materials, ranging from semiconductors to correlated materials. In order to understand, and eventually control, transport behavior under strain, it is important to quantify the effects of strain on the electronic bandstructure, carrier density, and mobility. Here, we demonstrate that much information can be obtained by exploring magnetoelastoresistance (MER), which refers to magnetic field-driven changes of the elastoresistance. We use this powerful approach to study the combined effect of strain and magnetic fields on the semimetallic transition metal dichalcogenide [Formula: see text] We discover that WTe2 shows a large and temperature-nonmonotonic elastoresistance, driven by uniaxial stress, that can be tuned by magnetic field. Using first-principle and analytical low-energy model calculations, we provide a semiquantitative understanding of our experimental observations. We show that in [Formula: see text], the strain-induced change of the carrier density dominates the observed elastoresistance. In addition, the change of the mobilities can be directly accessed by using MER. Our analysis also reveals the importance of a heavy-hole band near the Fermi level on the elastoresistance at intermediate temperatures. Systematic understanding of strain effects in single crystals of correlated materials is important for future applications, such as strain tuning of bulk phases and fabrication of devices controlled by strain.
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In classical morphotropic piezoelectric materials, rhombohedral and tetragonal phase variants can energetically compete to form a mixed phase regime with improved functional properties. While the discovery of morphotropic-like phases in multiferroic BiFeO3 films has broadened this definition, accessing these phase spaces is still typically accomplished through isovalent substitution or heteroepitaxial strain which do not allow for continuous modification of phase composition postsynthesis. Here, we show that it is possible to use low-energy helium implantation to tailor morphotropic phases of epitaxial BiFeO3 films postsynthesis in a continuous and iterative manner. Applying this strain doping approach to morphotropic films creates a new phase space based on internal and external lattice stress that can be seen as an analogue to temperature-composition phase diagrams of classical morphotropic ferroelectric systems.
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We study a one-dimensional interacting quantum liquid hosting a pair of mobile impurities causing backscattering. We determine the effective retarded interaction between the two impurities mediated by the liquid. We show that for strong backscattering this interaction gives rise to resonances and antiresonances in the finite-frequency mobility of the impurity pair. At the antiresonances, the two impurities remain at rest even when driven by a (small) external force. At the resonances, their synchronous motion follows the external drive in phase and reaches maximum amplitude. Using a perturbative renormalization group analysis in quantum tunneling across the impurities, we study the range of validity of our model. We predict that these mechanical antiresonances are observable in experiments on ultracold atom gases confined to one dimension.
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Recent experiments in iron pnictide superconductors reveal that, as the putative magnetic quantum critical point is approached, different types of magnetic order coexist over a narrow region of the phase diagram. Although these magnetic configurations share the same wave vectors, they break distinct symmetries of the lattice. Importantly, the highest superconducting transition temperature takes place close to this proliferation of near-degenerate magnetic states. In this Letter, we employ a renormalization group calculation to show that such a behavior naturally arises due to the effects of spin-orbit coupling on the quantum magnetic fluctuations. Formally, the enhanced magnetic degeneracy near the quantum critical point is manifested as a stable Gaussian fixed point with a large basin of attraction. Implications of our findings to the superconductivity of the iron pnictides are also discussed.
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Stimulated by experimental advances in electrolyte gating methods, we investigate theoretically percolation in thin films of inhomogeneous complex oxides, such as La_{1-x}Sr_{x}CoO_{3} (LSCO), induced by a combination of bulk chemical and surface electrostatic doping. Using numerical and analytical methods, we identify two mechanisms that describe how bulk dopants reduce the amount of electrostatic surface charge required to reach percolation: (i) bulk-assisted surface percolation and (ii) surface-assisted bulk percolation. We show that the critical surface charge strongly depends on the film thickness when the film is close to the chemical percolation threshold. In particular, thin films can be driven across the percolation transition by modest surface charge densities. If percolation is associated with the onset of ferromagnetism, as in LSCO, we further demonstrate that the presence of critical magnetic clusters extending from the film surface into the bulk results in considerable enhancement of the saturation magnetization, with pronounced experimental consequences. These results should significantly guide experimental work seeking to verify gate-induced percolation transitions in such materials.
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We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors containing a pendant fused bi-heteroaryl group, which demonstrate sub-nanomolar potency (Ki), excellent activity in human whole blood assay, and improved DMPK profiles over prior series.
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Proteína ADAM17/antagonistas & inhibidores , Hidantoínas/química , Inhibidores de Proteasas/química , Proteína ADAM17/metabolismo , Animales , Área Bajo la Curva , Perros , Activación Enzimática/efectos de los fármacos , Semivida , Haplorrinos , Humanos , Hidantoínas/síntesis química , Hidantoínas/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Curva ROC , Ratas , Relación Estructura-ActividadRESUMEN
The symptoms of Clostridium difficile infections are caused by two exotoxins, TcdA and TcdB, which target host colonocytes by binding to unknown cell surface receptors, at least in part via their combined repetitive oligopeptide (CROP) domains. A combination of the anti-TcdA antibody actoxumab and the anti-TcdB antibody bezlotoxumab is currently under development for the prevention of recurrent C. difficile infections. We demonstrate here through various biophysical approaches that bezlotoxumab binds to specific regions within the N-terminal half of the TcdB CROP domain. Based on this information, we solved the x-ray structure of the N-terminal half of the TcdB CROP domain bound to Fab fragments of bezlotoxumab. The structure reveals that the TcdB CROP domain adopts a ß-solenoid fold consisting of long and short repeats and that bezlotoxumab binds to two homologous sites within the CROP domain, partially occluding two of the four putative carbohydrate binding pockets located in TcdB. We also show that bezlotoxumab neutralizes TcdB by blocking binding of TcdB to mammalian cells. Overall, our data are consistent with a model wherein a single molecule of bezlotoxumab neutralizes TcdB by binding via its two Fab regions to two epitopes within the N-terminal half of the TcdB CROP domain, partially blocking the carbohydrate binding pockets of the toxin and preventing toxin binding to host cells.
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Anticuerpos Antibacterianos/inmunología , Anticuerpos Neutralizantes/inmunología , Proteínas Bacterianas/química , Proteínas Bacterianas/inmunología , Toxinas Bacterianas/química , Toxinas Bacterianas/inmunología , Clostridioides difficile/inmunología , Epítopos/inmunología , Secuencia de Aminoácidos , Anticuerpos Antibacterianos/química , Anticuerpos Monoclonales , Anticuerpos Neutralizantes/química , Proteínas Bacterianas/genética , Toxinas Bacterianas/genética , Sitios de Unión , Anticuerpos ampliamente neutralizantes , Clostridioides difficile/química , Clostridioides difficile/genética , Cristalografía por Rayos X , Mapeo Epitopo , Epítopos/química , Epítopos/genética , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Terciaria de ProteínaRESUMEN
In an extensive computational experiment, we test Polyakov's conjecture that under certain circumstances an isotropic Heisenberg model can develop algebraic spin correlations. We demonstrate the emergence of a multispin U(1) order parameter in a Heisenberg antiferromagnet on interpenetrating honeycomb and triangular lattices. The correlations of this relative phase angle are observed to decay algebraically at intermediate temperatures in an extended critical phase. Using finite-size scaling we show that both phase transitions are of the Berezinskii-Kosterlitz-Thouless type, and at lower temperatures we find long-range Z(6) order.
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The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.
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Inhibidores Enzimáticos/farmacología , Iminas/farmacología , Pirimidinonas/farmacología , Renina/antagonistas & inhibidores , Administración Oral , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Iminas/síntesis química , Iminas/química , Modelos Moleculares , Estructura Molecular , Pirimidinonas/síntesis química , Pirimidinonas/química , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
We investigate the photon statistics, entanglement, and squeezing of a p-n junction sandwiched between two superconducting leads and show that such an electrically driven photon pump generates correlated and entangled pairs of photons. In particular, we demonstrate that the squeezing of the fluctuations in the quadrature amplitudes of the emitted light can be manipulated by changing the relative phase of the order parameters of the superconductors. This reveals how macroscopic coherence of the superconducting state can be used to tailor the properties of a two-photon state.
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We consider an open system near a quantum critical point that is suddenly moved towards the critical point. The bath-dominated diffusive nonequilibrium dynamics after the quench is shown to follow scaling behavior, governed by a critical exponent that emerges in addition to the known equilibrium critical exponents. We determine this exponent and show that it describes universal prethermalized coarsening dynamics of the order parameter in an intermediate time regime. Implications of this quantum critical prethermalization are: (i) a power law rise of order and correlations after an initial collapse of the equilibrium state and (ii) a crossover to thermalization that occurs arbitrarily late for sufficiently shallow quenches.
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The synthesis of a series of iminoheterocycles and their structure-activity relationships (SAR) as inhibitors of the aspartyl protease BACE1 will be detailed. An effort to access the S3 subsite directly from the S1 subsite initially yielded compounds with sub-micromolar potency. A subset of compounds from this effort unexpectedly occupied a different binding site and displayed excellent BACE1 affinities. Select compounds from this subset acutely lowered Aß40 levels upon subcutaneous and oral administration to rats.
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Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/uso terapéutico , Ácido Aspártico Endopeptidasas/uso terapéutico , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Diseño de Fármacos , Descubrimiento de Drogas , Modelos Moleculares , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
Oncogenic mutations in the RAS gene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously "undruggable" target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRASG12C covalent inhibitor currently in phase I clinical trials (NCT05067283). We leveraged structure-based drug design to identify a macrocyclic core structure, and hypothesis-driven optimization of biopharmaceutical properties to further improve metabolic stability and tolerability.
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Descubrimiento de Drogas , Proteínas Proto-Oncogénicas p21(ras) , Animales , Perros , Humanos , Ratones , Ratas , Administración Oral , Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Antineoplásicos/química , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Relación Estructura-ActividadRESUMEN
Quantum geometry in condensed-matter physics has two components: the real part quantum metric and the imaginary part Berry curvature. Whereas the effects of Berry curvature have been observed through phenomena such as the quantum Hall effect in two-dimensional electron gases and the anomalous Hall effect (AHE) in ferromagnets, the quantum metric has rarely been explored. Here, we report a nonlinear Hall effect induced by the quantum metric dipole by interfacing even-layered MnBi2Te4 with black phosphorus. The quantum metric nonlinear Hall effect switches direction upon reversing the antiferromagnetic (AFM) spins and exhibits distinct scaling that is independent of the scattering time. Our results open the door to discovering quantum metric responses predicted theoretically and pave the way for applications that bridge nonlinear electronics with AFM spintronics.
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We introduce a two-dimensional frustrated Heisenberg antiferromagnet on interpenetrating honeycomb and triangular lattices. Classically the two sublattices decouple, and "order from disorder" drives them into a coplanar state. Applying Friedan's geometric approach to nonlinear sigma models, we obtain the scaling of the spin stiffnesses governed by the Ricci flow of a four-dimensional metric tensor. At low temperatures, the relative phase between the spins on the two sublattices is described by a six-state clock model with an emergent critical phase.
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We consider the time-reversal-invariant Hofstadter-Hubbard model which can be realized in cold-atom experiments. In these experiments, an additional staggered potential and an artificial Rashba-type spin-orbit coupling are available. Without interactions, the system exhibits various phases such as topological and normal insulator, metal as well as semi-metal phases with two or even more Dirac cones. Using a combination of real-space dynamical mean-field theory and analytical techniques, we discuss the effect of on-site interactions and determine the corresponding phase diagram. In particular, we investigate the semi-metal to antiferromagnetic insulator transition and the stability of different topological insulator phases in the presence of strong interactions. We compute spectral functions which allow us to study the edge states of the strongly correlated topological phases.