LRP1 Has a Predominant Role in Production over Clearance of Aβ in a Mouse Model of Alzheimer's Disease.

The low-density lipoprotein receptor-related protein-1 (LRP1) has a dual role in the metabolism of the amyloid precursor protein (APP). In cellular models, LRP1 enhances amyloid-β (Aβ) generation via APP internalization and thus its amyloidogenic processing. However, conditional knock-out studies in mice define LRP1 as an important mediator for the clearance of extracellular Aβ from brain via cellular degradation or transcytosis across the blood-brain barrier (BBB). In order to analyze the net effect of LRP1 on production and clearance of Aβ in vivo, we crossed mice with impaired LRP1 function with a mouse model of Alzheimer's disease (AD). Analysis of Aβ metabolism showed that, despite reduced Aβ clearance due to LRP1 inactivation in vivo, less Aβ was found in cerebrospinal fluid (CSF) and brain interstitial fluid (ISF). Further analysis of APP metabolism revealed that impairment of LRP1 in vivo shifted APP processing from the Aβ-generating amyloidogenic cleavage by beta-secretase to the non-amyloidogenic processing by alpha-secretase as shown by a decrease in extracellular Aβ and an increase of soluble APP-α (sAPP-α). This shift in APP processing resulted in overall lower Aβ levels and a reduction in plaque burden. Here, we present for the first time clear in vivo evidence that global impairment of LRP1's endocytosis function favors non-amyloidogenic processing of APP due to its reduced internalization and subsequently, reduced amyloidogenic processing. By inactivation of LRP1, the inhibitory effect on Aβ generation overrules the simultaneous impaired Aβ clearance, resulting in less extracellular Aβ and reduced plaque deposition in a mouse model of AD

Coherent quantum state storage and transfer between two phase qubits via a resonant cavity

A network of quantum-mechanical systems showing long lived phase coherence of its quantum states could be used for processing quantum information. As with classical information processing, a quantum processor requires information bits (qubits) that can be independently addressed and read out, long-term memory elements to store arbitrary quantum states, and the ability to transfer quantum information through a coherent communication bus accessible to a large number of qubits. Superconducting qubits made with scalable microfabrication techniques are a promising candidate for the realization of a large scale quantum information processor. Although these systems have successfully passed tests of coherent coupling for up to four qubits, communication of individual quantum states between qubits via a quantum bus has not yet been demonstrated. Here, we perform an experiment demonstrating the ability to coherently transfer quantum states between two superconducting Josephson phase qubits through a rudimentary quantum bus formed by a single, on chip, superconducting transmission line resonant cavity of length 7 mm. After preparing an initial quantum state with the first qubit, this quantum information is transferred and stored as a nonclassical photon state of the resonant cavity, then retrieved at a later time by the second qubit connected to the opposite end of the cavity. Beyond simple communication, these results suggest that a high quality factor superconducting cavity could also function as a long term memory element. The basic architecture presented here is scalable, offering the possibility for the coherent communication between a large number of superconducting qubits.Comment: 17 pages, 4 figures (to appear in Nature

Effects of steady state free precession parameters on cardiac mass, function, and volumes

G0400444/Medical Research Council/United Kingdom Wellcome Trust/United Kingdo

Geometrical Insights for Implicit Generative Modeling

Learning algorithms for implicit generative models can optimize a variety of criteria that measure how the data distribution differs from the implicit model distribution, including the Wasserstein distance, the Energy distance, and the Maximum Mean Discrepancy criterion. A careful look at the geometries induced by these distances on the space of probability measures reveals interesting differences. In particular, we can establish surprising approximate global convergence guarantees for the $1$-Wasserstein distance,even when the parametric generator has a nonconvex parametrization.Comment: this version fixes a typo in a definitio

Transit Timing and Duration Variations for the Discovery and Characterization of Exoplanets

Transiting exoplanets in multi-planet systems have non-Keplerian orbits which can cause the times and durations of transits to vary. The theory and observations of transit timing variations (TTV) and transit duration variations (TDV) are reviewed. Since the last review, the Kepler spacecraft has detected several hundred perturbed planets. In a few cases, these data have been used to discover additional planets, similar to the historical discovery of Neptune in our own Solar System. However, the more impactful aspect of TTV and TDV studies has been characterization of planetary systems in which multiple planets transit. After addressing the equations of motion and parameter scalings, the main dynamical mechanisms for TTV and TDV are described, with citations to the observational literature for real examples. We describe parameter constraints, particularly the origin of the mass/eccentricity degeneracy and how it is overcome by the high-frequency component of the signal. On the observational side, derivation of timing precision and introduction to the timing diagram are given. Science results are reviewed, with an emphasis on mass measurements of transiting sub-Neptunes and super-Earths, from which bulk compositions may be inferred.Comment: Revised version. Invited review submitted to 'Handbook of Exoplanets,' Exoplanet Discovery Methods section, Springer Reference Works, Juan Antonio Belmonte and Hans Deeg, Eds. TeX and figures may be found at https://github.com/ericagol/TTV_revie

Tripartite interactions between two phase qubits and a resonant cavity

The creation and manipulation of multipartite entangled states is important for advancements in quantum computation and communication, and for testing our fundamental understanding of quantum mechanics and precision measurements. Multipartite entanglement has been achieved by use of various forms of quantum bits (qubits), such as trapped ions, photons, and atoms passing through microwave cavities. Quantum systems based on superconducting circuits have been used to control pair-wise interactions of qubits, either directly, through a quantum bus, or via controllable coupling. Here, we describe the first demonstration of coherent interactions of three directly coupled superconducting quantum systems, two phase qubits and a resonant cavity. We introduce a simple Bloch-sphere-like representation to help one visualize the unitary evolution of this tripartite system as it shares a single microwave photon. With careful control and timing of the initial conditions, this leads to a protocol for creating a rich variety of entangled states. Experimentally, we provide evidence for the deterministic evolution from a simple product state, through a tripartite W-state, into a bipartite Bell-state. These experiments are another step towards deterministically generating multipartite entanglement in superconducting systems with more than two qubits

Implementation of a Toffoli Gate with Superconducting Circuits

The quantum Toffoli gate allows universal reversible classical computation. It is also an important primitive in many quantum circuits and quantum error correction schemes. Here we demonstrate the realization of a Toffoli gate with three superconducting transmon qubits coupled to a microwave resonator. By exploiting the third energy level of the transmon qubit, the number of elementary gates needed for the implementation of the Toffoli gate, as well as the total gate time can be reduced significantly in comparison to theoretical proposals using two-level systems only. We characterize the performance of the gate by full process tomography and Monte Carlo process certification. The gate fidelity is found to be $68.5\pm0.5$%.Comment: 4 pages, 5figure

Preparation and Measurement of Three-Qubit Entanglement in a Superconducting Circuit

Traditionally, quantum entanglement has played a central role in foundational discussions of quantum mechanics. The measurement of correlations between entangled particles can exhibit results at odds with classical behavior. These discrepancies increase exponentially with the number of entangled particles. When entanglement is extended from just two quantum bits (qubits) to three, the incompatibilities between classical and quantum correlation properties can change from a violation of inequalities involving statistical averages to sign differences in deterministic observations. With the ample confirmation of quantum mechanical predictions by experiments, entanglement has evolved from a philosophical conundrum to a key resource for quantum-based technologies, like quantum cryptography and computation. In particular, maximal entanglement of more than two qubits is crucial to the implementation of quantum error correction protocols. While entanglement of up to 3, 5, and 8 qubits has been demonstrated among spins, photons, and ions, respectively, entanglement in engineered solid-state systems has been limited to two qubits. Here, we demonstrate three-qubit entanglement in a superconducting circuit, creating Greenberger-Horne-Zeilinger (GHZ) states with fidelity of 88%, measured with quantum state tomography. Several entanglement witnesses show violation of bi-separable bounds by 830\pm80%. Our entangling sequence realizes the first step of basic quantum error correction, namely the encoding of a logical qubit into a manifold of GHZ-like states using a repetition code. The integration of encoding, decoding and error-correcting steps in a feedback loop will be the next milestone for quantum computing with integrated circuits.Comment: 7 pages, 4 figures, and Supplementary Information (4 figures)

An online international comparison of palliative care identification in primary care using the Surprise Question.

BACKGROUND The Surprise Question ('Would I be surprised if this patient died within 12 months?') identifies patients in the last year of life. It is unclear if 'surprised' means the same for each clinician, and whether their responses are internally consistent. AIM To determine the consistency with which the Surprise Question is used. DESIGN A cross-sectional online study of participants located in Belgium, Germany, Italy, The Netherlands, Switzerland and UK. Participants completed 20 hypothetical patient summaries ('vignettes'). Primary outcome measure: continuous estimate of probability of death within 12 months (0% [certain survival]-100% [certain death]). A threshold (probability estimate above which Surprise Question responses were consistently 'no') and an inconsistency range (range of probability estimates where respondents vacillated between responses) were calculated. Univariable and multivariable linear regression explored differences in consistency. Trial registration: NCT03697213. SETTING/PARTICIPANTS Registered General Practitioners (GPs). Of the 307 GPs who started the study, 250 completed 15 or more vignettes. RESULTS Participants had a consistency threshold of 49.8% (SD 22.7) and inconsistency range of 17% (SD 22.4). Italy had a significantly higher threshold than other countries (p = 0.002). There was also a difference in threshold levels depending on age of clinician, for every yearly increase, participants had a higher threshold. There was no difference in inconsistency between countries (p = 0.53). CONCLUSIONS There is variation between clinicians regarding the use of the Surprise Question. Over half of GPs were not internally consistent in their responses to the Surprise Question. Future research with standardised terms and real patients is warranted

Quantum non-demolition measurement of a superconducting two-level system

In quantum mechanics, the process of measurement is a subtle interplay between extraction of information and disturbance of the state of the quantum system. A quantum non-demolition (QND) measurement minimizes this disturbance by using a particular system - detector interaction which preserves the eigenstates of a suitable operator of the quantum system. This leads to an ideal projective measurement. We present experiments in which we perform two consecutive measurements on a quantum two -level system, a superconducting flux qubit, by probing the hysteretic behaviour of a coupled nonlinear resonator. The large correlation between the results of the two measurements demonstrates the QND nature of the readout method. The fact that a QND measurement is possible for superconducting qubits strengthens the notion that these fabricated mesoscopic systems are to be regarded as fundamental quantum objects. Our results are also relevant for quantum information processing, where projective measurements are used for protocols like state preparation and error correction.Comment: 14 pages, 4 figure