High-fidelity parallel entangling gates on a neutral-atom quantum computer.

The ability to perform entangling quantum operations with low error rates in a scalable fashion is a central element of useful quantum information processing1. Neutral-atom arrays have recently emerged as a promising quantum computing platform, featuring coherent control over hundreds of qubits2,3 and any-to-any gate connectivity in a flexible, dynamically reconfigurable architecture4. The main outstanding challenge has been to reduce errors in entangling operations mediated through Rydberg interactions5. Here we report the realization of two-qubit entangling gates with 99.5% fidelity on up to 60 atoms in parallel, surpassing the surface-code threshold for error correction6,7. Our method uses fast, single-pulse gates based on optimal control8, atomic dark states to reduce scattering9 and improvements to Rydberg excitation and atom cooling. We benchmark fidelity using several methods based on repeated gate applications10,11, characterize the physical error sources and outline future improvements. Finally, we generalize our method to design entangling gates involving a higher number of qubits, which we demonstrate by realizing low-error three-qubit gates12,13. By enabling high-fidelity operation in a scalable, highly connected system, these advances lay the groundwork for large-scale implementation of quantum algorithms14, error-corrected circuits7 and digital simulations15.

A quantum processor based on coherent transport of entangled atom arrays.

The ability to engineer parallel, programmable operations between desired qubits within a quantum processor is key for building scalable quantum information systems1,2. In most state-of-the-art approaches, qubits interact locally, constrained by the connectivity associated with their fixed spatial layout. Here we demonstrate a quantum processor with dynamic, non-local connectivity, in which entangled qubits are coherently transported in a highly parallel manner across two spatial dimensions, between layers of single- and two-qubit operations. Our approach makes use of neutral atom arrays trapped and transported by optical tweezers; hyperfine states are used for robust quantum information storage, and excitation into Rydberg states is used for entanglement generation3-5. We use this architecture to realize programmable generation of entangled graph states, such as cluster states and a seven-qubit Steane code state6,7. Furthermore, we shuttle entangled ancilla arrays to realize a surface code state with thirteen data and six ancillary qubits8 and a toric code state on a torus with sixteen data and eight ancillary qubits9. Finally, we use this architecture to realize a hybrid analogue-digital evolution2 and use it for measuring entanglement entropy in quantum simulations10-12, experimentally observing non-monotonic entanglement dynamics associated with quantum many-body scars13,14. Realizing a long-standing goal, these results provide a route towards scalable quantum processing and enable applications ranging from simulation to metrology.

Quantum phases of matter on a 256-atom programmable quantum simulator.

Motivated by far-reaching applications ranging from quantum simulations of complex processes in physics and chemistry to quantum information processing1, a broad effort is currently underway to build large-scale programmable quantum systems. Such systems provide insights into strongly correlated quantum matter2-6, while at the same time enabling new methods for computation7-10 and metrology11. Here we demonstrate a programmable quantum simulator based on deterministically prepared two-dimensional arrays of neutral atoms, featuring strong interactions controlled by coherent atomic excitation into Rydberg states12. Using this approach, we realize a quantum spin model with tunable interactions for system sizes ranging from 64 to 256 qubits. We benchmark the system by characterizing high-fidelity antiferromagnetically ordered states and demonstrating quantum critical dynamics consistent with an Ising quantum phase transition in (2 + 1) dimensions13. We then create and study several new quantum phases that arise from the interplay between interactions and coherent laser excitation14, experimentally map the phase diagram and investigate the role of quantum fluctuations. Offering a new lens into the study of complex quantum matter, these observations pave the way for investigations of exotic quantum phases, non-equilibrium entanglement dynamics and hardware-efficient realization of quantum algorithms.

Quantum Kibble-Zurek mechanism and critical dynamics on a programmable Rydberg simulator.

Quantum phase transitions (QPTs) involve transformations between different states of matter that are driven by quantum fluctuations1. These fluctuations play a dominant part in the quantum critical region surrounding the transition point, where the dynamics is governed by the universal properties associated with the QPT. Although time-dependent phenomena associated with classical, thermally driven phase transitions have been extensively studied in systems ranging from the early Universe to Bose-Einstein condensates2-5, understanding critical real-time dynamics in isolated, non-equilibrium quantum systems remains a challenge6. Here we use a Rydberg atom quantum simulator with programmable interactions to study the quantum critical dynamics associated with several distinct QPTs. By studying the growth of spatial correlations when crossing the QPT, we experimentally verify the quantum Kibble-Zurek mechanism (QKZM)7-9 for an Ising-type QPT, explore scaling universality and observe corrections beyond QKZM predictions. This approach is subsequently used to measure the critical exponents associated with chiral clock models10,11, providing new insights into exotic systems that were not previously understood and opening the door to precision studies of critical phenomena, simulations of lattice gauge theories12,13 and applications to quantum optimization14,15.

Probing many-body dynamics on a 51-atom quantum simulator.

Controllable, coherent many-body systems can provide insights into the fundamental properties of quantum matter, enable the realization of new quantum phases and could ultimately lead to computational systems that outperform existing computers based on classical approaches. Here we demonstrate a method for creating controlled many-body quantum matter that combines deterministically prepared, reconfigurable arrays of individually trapped cold atoms with strong, coherent interactions enabled by excitation to Rydberg states. We realize a programmable Ising-type quantum spin model with tunable interactions and system sizes of up to 51 qubits. Within this model, we observe phase transitions into spatially ordered states that break various discrete symmetries, verify the high-fidelity preparation of these states and investigate the dynamics across the phase transition in large arrays of atoms. In particular, we observe robust many-body dynamics corresponding to persistent oscillations of the order after a rapid quantum quench that results from a sudden transition across the phase boundary. Our method provides a way of exploring many-body phenomena on a programmable quantum simulator and could enable realizations of new quantum algorithms.

Alzheimer's protection effect of A673T mutation may be driven by lower Aß oligomer binding affinity.

Several mutations conferring protection against Alzheimer's disease (AD) have been described, none as profound as the A673T mutation, where carriers are four times less likely to get AD compared to noncarriers. This mutation results in reduced amyloid beta (Aß) protein production in vitro and lower lifetime Aß concentration in carriers. Better understanding of the protective mechanisms of the mutation may provide important insights into AD pathophysiology and identify productive therapeutic intervention strategies for disease modification. Aß(1-42) protein forms oligomers that bind saturably to a single receptor site on neuronal synapses, initiating the downstream toxicities observed in AD. Decreased formation, toxicity, or stability of soluble Aß oligomers, or reduction of synaptic binding of these oligomers, may combine with overall lower Aß concentration to underlie A673T's disease protecting mechanism. To investigate these possibilities, we compared the formation rate of soluble oligomers made from Icelandic A673T mutant and wild type (wt) Aß(1-42) synthetic protein, the amount and intensity of oligomer bound to mature primary rat hippocampal/cortical neuronal synapses, and the potency of bound oligomers to impact trafficking rate in neurons in vitro using a physiologically relevant oligomer preparation method. At equal protein concentrations, mutant protein forms approximately 50% or fewer oligomers of high molecular weight (>50 kDa) compared to wt protein. Mutant oligomers are twice as potent at altering the cellular vesicle trafficking rate as wt at equivalent concentrations, however, mutant oligomers have a >4-fold lower binding affinity to synaptic receptors (Kd  = 1,950 vs. 442 nM). The net effect of these differences is a lower overall toxicity at a given concentration. This study demonstrates for the first time that mutant A673T Aß oligomers prepared with this method have fundamentally different assembly characteristics and biological impact from wt protein and indicates that its disease protecting mechanism may result primarily from the mutant protein's much lower binding affinity to synaptic receptors. This suggests that therapeutics that effectively reduce oligomer binding to synapses in the brain may be beneficial in AD.

Exploration of the functionality of sugars in cake-baking, and effects on cake quality.

This review paper describes our exploratory experimental studies on the functionality of sucrose and other sugars in cake-baking, and effects on cake quality. We have used the American Association of Cereal Chemists Method 10-90.01 as a base cake-baking method, and have applied Differential Scanning Calorimetry, Rapid Visco-Analyzer, and time-lapse photography analyses in experimental design studies of the effects of the following ingredient and formulation variables on cake quality (e.g. texture, color, moisture content) and other finished-product properties (e.g. shape, dimensions): (a) cake formula levels of sucrose and water, in terms of %Sucrose and Total Solvent; (b) concentration of sucrose or other sugars (e.g. xylose, ribose, fructose, glucose, maltose, polydextrose) vs. wheat flour starch gelatinization temperature and starch pasting during baking and gluten development during mixing; (c) unchlorinated flour vs. chlorinated flours (of varying pH); (d) cake formula %Sucrose and TS vs. cake color, shape, and dimensions; (e) cakes formulated with sucrose or other sugars (i.e. xylose, fructose, glucose), and variable %S and TS, and unchlorinated or chlorinated flour (pH 4.6), vs. cake color, shape, and dimensions.

Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer's disease modification.

INTRODUCTION: Amyloid beta (Aß) oligomers are one of the most toxic structural forms of the Aß protein and are hypothesized to cause synaptotoxicity and memory failure as they build up in Alzheimer's disease (AD) patients' brain tissue. We previously demonstrated that antagonists of the sigma-2 receptor complex effectively block Aß oligomer toxicity. CT1812 is an orally bioavailable, brain penetrant small molecule antagonist of the sigma-2 receptor complex that appears safe and well tolerated in healthy elderly volunteers. We tested CT1812's effect on Aß oligomer pathobiology in preclinical AD models and evaluated CT1812's impact on cerebrospinal fluid (CSF) protein biomarkers in mild to moderate AD patients in a clinical trial (ClinicalTrials.gov NCT02907567). METHODS: Experiments were performed to measure the impact of CT1812 versus vehicle on Aß oligomer binding to synapses in vitro, to human AD patient post mortem brain tissue ex vivo, and in living APPSwe /PS1dE9 transgenic mice in vivo. Additional experiments were performed to measure the impact of CT1812 versus vehicle on Aß oligomer-induced deficits in membrane trafficking rate, synapse number, and protein expression in mature hippocampal/cortical neurons in vitro. The impact of CT1812 on cognitive function was measured in transgenic Thy1 huAPPSwe/Lnd+ and wild-type littermates. A multicenter, double-blind, placebo-controlled parallel group trial was performed to evaluate the safety, tolerability, and impact on protein biomarker expression of CT1812 or placebo given once daily for 28 days to AD patients (Mini-Mental State Examination 18-26). CSF protein expression was measured by liquid chromatography with tandem mass spectrometry or enzyme-linked immunosorbent assay in samples drawn prior to dosing (Day 0) and at end of dosing (Day 28) and compared within each patient and between pooled treated versus placebo-treated dosing groups. RESULTS: CT1812 significantly and dose-dependently displaced Aß oligomers bound to synaptic receptors in three independent preclinical models of AD, facilitated oligomer clearance into the CSF, increased synaptic number and protein expression in neurons, and improved cognitive performance in transgenic mice. CT1812 significantly increased CSF concentrations of Aß oligomers in AD patient CSF, reduced concentrations of synaptic proteins and phosphorylated tau fragments, and reversed expression of many AD-related proteins dysregulated in CSF. DISCUSSION: These preclinical studies demonstrate the novel disease-modifying mechanism of action of CT1812 against AD and Aß oligomers. The clinical results are consistent with preclinical data and provide evidence of target engagement and impact on fundamental disease-related signaling pathways in AD patients, supporting further development of CT1812.

Large-scale uniform optical focus array generation with a phase spatial light modulator.

In this Letter, to the best of our knowledge, we report a new method to generate uniform large-scale optical focus arrays (LOFAs). By identifying and removing undesired phase rotation in the iterative Fourier transform algorithm (IFTA), our approach rapidly produces computer-generated holograms of highly uniform LOFAs. The new algorithm also shows a faster compensation of system-induced LOFA intensity inhomogeneity than the conventional IFTA. After only three adaptive correction steps, we demonstrate LOFAs consisting of O(103) optical foci with an intensity uniformity greater than 98%.

Integrating Neural Networks with a Quantum Simulator for State Reconstruction.

We demonstrate quantum many-body state reconstruction from experimental data generated by a programmable quantum simulator by means of a neural-network model incorporating known experimental errors. Specifically, we extract restricted Boltzmann machine wave functions from data produced by a Rydberg quantum simulator with eight and nine atoms in a single measurement basis and apply a novel regularization technique to mitigate the effects of measurement errors in the training data. Reconstructions of modest complexity are able to capture one- and two-body observables not accessible to experimentalists, as well as more sophisticated observables such as the Rényi mutual information. Our results open the door to integration of machine learning architectures with intermediate-scale quantum hardware.

Parallel Implementation of High-Fidelity Multiqubit Gates with Neutral Atoms.

We report the implementation of universal two- and three-qubit entangling gates on neutral-atom qubits encoded in long-lived hyperfine ground states. The gates are mediated by excitation to strongly interacting Rydberg states and are implemented in parallel on several clusters of atoms in a one-dimensional array of optical tweezers. Specifically, we realize the controlled-phase gate, enacted by a novel, fast protocol involving only global coupling of two qubits to Rydberg states. We benchmark this operation by preparing Bell states with fidelity F≥95.0(2)%, and extract gate fidelity ≥97.4(3)%, averaged across five atom pairs. In addition, we report a proof-of-principle implementation of the three-qubit Toffoli gate, in which two control atoms simultaneously constrain the behavior of one target atom. These experiments demonstrate key ingredients for high-fidelity quantum information processing in a scalable neutral-atom platform.

High-Fidelity Control and Entanglement of Rydberg-Atom Qubits.

Individual neutral atoms excited to Rydberg states are a promising platform for quantum simulation and quantum information processing. However, experimental progress to date has been limited by short coherence times and relatively low gate fidelities associated with such Rydberg excitations. We report progress towards high-fidelity quantum control of Rydberg-atom qubits. Enabled by a reduction in laser phase noise, our approach yields a significant improvement in coherence properties of individual qubits. We further show that this high-fidelity control extends to the multi-particle case by preparing a two-atom entangled state with a fidelity exceeding 0.97(3), and extending its lifetime with a two-atom dynamical decoupling protocol. These advances open up new prospects for scalable quantum simulation and quantum computation with neutral atoms.

Detection and Imaging of Aß1-42 and Tau Fibrils by Redesigned Fluorescent X-34 Analogues.

We revisited the Congo red analogue 2,5-bis(4'-hydroxy-3'-carboxy-styryl)benzene (X-34) to develop this highly fluorescent amyloid dye for imaging Alzheimer's disease (AD) pathology comprising Aß and Tau fibrils. A selection of ligands with distinct optical properties were synthesized by replacing the central benzene unit of X-34, with other heterocyclic moieties. Full photophysical characterization was performed, including recording absorbance and fluorescence spectra, Stokes shift, quantum yield and fluorescence lifetimes. All ligands displayed high affinity towards recombinant amyloid fibrils of Aß1-42 (13-300 nm Kd ) and Tau (16-200 nm Kd ) as well as selectivity towards the corresponding disease-associated protein aggregates in AD tissue. We observed that these ligands efficiently displaced X-34, but not Pittsburgh compound B (PiB) from recombinant Aß1-42 amyloid fibrils, arguing for retained targeting of the Congo red type binding site. We foresee that the X-34 scaffold offers the possibility to develop novel high-affinity ligands for Aß pathology found in human AD brain in a different mode compared with PiB, potentially recognizing different polymorphs of Aß fibrils.

Intramolecular Proton and Charge Transfer of Pyrene-based trans-Stilbene Salicylic Acids Applied to Detection of Aggregated Proteins.

Two analogues to the fluorescent amyloid probe 2,5-bis(4'-hydroxy-3'-carboxy-styryl)benzene (X-34) were synthesized based on the trans-stilbene pyrene scaffold (Py1SA and Py2SA). The compounds show strikingly different emission spectra when bound to preformed Aß1-42 fibrils. This remarkable emission difference is retained when bound to amyloid fibrils of four distinct proteins, suggesting a common binding configuration for each molecule. Density functional theory calculations show that Py1SA is twisted, while Py2SA is more planar. Still, an analysis of the highest occupied molecular orbitals (HOMOs) and lowest unoccupied molecular orbitals (LUMOs) of the two compounds indicates that the degree of electronic coupling between the pyrene and salicylic acid (SA) moieties is larger in Py1SA than in Py2SA. Excited state intramolecular proton transfer (ESIPT) coupled-charge transfer (ICT) was observed for the anionic form in polar solvents. We conclude that ICT properties of trans-stilbene derivatives can be utilized for amyloid probe design with large changes in emission spectra and decay times from analogous chemical structures depending on the detailed physical nature of the binding site.

The "Food Polymer Science" approach to the practice of industrial R&D, leading to patent estates based on fundamental starch science and technology.

This article reviews the application of the "Food Polymer Science" approach to the practice of industrial R&D, leading to patent estates based on fundamental starch science and technology. The areas of patents and patented technologies reviewed here include: (a) soft-from-the-freezer ice creams and freezer-storage-stable frozen bread dough products, based on "cryostabilization technology" of frozen foods, utilizing commercial starch hydrolysis products (SHPs); (b) glassy-matrix encapsulation technology for flavors and other volatiles, based on structure-function relationships for commercial SHPs;

Aß40 Reduces P-Glycoprotein at the Blood-Brain Barrier through the Ubiquitin-Proteasome Pathway.

Failure to clear amyloid-ß (Aß) from the brain is in part responsible for Aß brain accumulation in Alzheimer's disease (AD). A critical protein for clearing Aß across the blood-brain barrier is the efflux transporter P-glycoprotein (P-gp) in the luminal plasma membrane of the brain capillary endothelium. P-gp is reduced at the blood-brain barrier in AD, which has been shown to be associated with Aß brain accumulation. However, the mechanism responsible for P-gp reduction in AD is not well understood. Here we focused on identifying critical mechanistic steps involved in reducing P-gp in AD. We exposed isolated rat brain capillaries to 100 nm Aß40, Aß40, aggregated Aß40, and Aß42. We observed that only Aß40 triggered reduction of P-gp protein expression and transport activity levels; this occurred in a dose- and time-dependent manner. To identify the steps involved in Aß-mediated P-gp reduction, we inhibited protein ubiquitination, protein trafficking, and the ubiquitin-proteasome system, and monitored P-gp protein expression, transport activity, and P-gp-ubiquitin levels. Thus, exposing brain capillaries to Aß40 triggers ubiquitination, internalization, and proteasomal degradation of P-gp. These findings may provide potential therapeutic targets within the blood-brain barrier to limit P-gp degradation in AD and improve Aß brain clearance. SIGNIFICANCE STATEMENT: The mechanism reducing blood-brain barrier P-glycoprotein (P-gp) in Alzheimer's disease is poorly understood. In the present study, we focused on defining this mechanism. We demonstrate that Aß40 drives P-gp ubiquitination, internalization, and proteasome-dependent degradation, reducing P-gp protein expression and transport activity in isolated brain capillaries. These findings may provide potential therapeutic avenues within the blood-brain barrier to limit P-gp degradation in Alzheimer's disease and improve Aß brain clearance.

Pathological Tau Promotes Neuronal Damage by Impairing Ribosomal Function and Decreasing Protein Synthesis.

One of the most common symptoms of Alzheimer's disease (AD) and related tauopathies is memory loss. The exact mechanisms leading to memory loss in tauopathies are not yet known; however, decreased translation due to ribosomal dysfunction has been implicated as a part of this process. Here we use a proteomics approach that incorporates subcellular fractionation and coimmunoprecipitation of tau from human AD and non-demented control brains to identify novel interactions between tau and the endoplasmic reticulum (ER). We show that ribosomes associate more closely with tau in AD than with tau in control brains, and that this abnormal association leads to a decrease in RNA translation. The aberrant tau-ribosome association also impaired synthesis of the synaptic protein PSD-95, suggesting that this phenomenon contributes to synaptic dysfunction. These findings provide novel information about tau-protein interactions in human brains, and they describe, for the first time, a dysfunctional consequence of tau-ribosome associations that directly alters protein synthesis. Significance statement: Despite the identification of abnormal tau-ribosomal interactions in tauopathies >25 years ago, the consequences of this association remained elusive until now. Here, we show that pathological tau associates closely with ribosomes in AD brains, and that this interaction impairs protein synthesis. The overall result is a stark reduction of nascent proteins, including those that participate in synaptic plasticity, which is crucial for learning and memory. These data mechanistically link a common pathologic sign, such as the appearance of pathological tau inside brain cells, with cognitive impairments evident in virtually all tauopathies.

Synthesis and application of ß-carbolines as novel multi-functional anti-Alzheimer's disease agents.

The design, synthesis and assessment of ß-carboline core-based compounds as potential multifunctional agents against several processes that are believed to play a significant role in Alzheimer's disease (AD) pathology, are described. The activity of the compounds was determined in Aß self-assembly (fibril and oligomer formation) and cholinesterase (AChE, BuChE) activity inhibition, and their antioxidant properties were also assessed. To obtain insight into the mode of action of the compounds, HR-MS studies were carried out on the inhibitor-Aß complex formation and molecular docking was performed on inhibitor-BuChE interactions. While several compounds exhibited strong activities in individual assays, compound 14 emerged as a promising multi-target lead for the further structure-activity relationship studies.

Anionic Oligothiophenes Compete for Binding of X-34 but not PIB to Recombinant Aß Amyloid Fibrils and Alzheimer's Disease Brain-Derived Aß.

Deposits comprised of amyloid-ß (Aß) are one of the pathological hallmarks of Alzheimer's disease (AD) and small hydrophobic ligands targeting these aggregated species are used clinically for the diagnosis of AD. Herein, we observed that anionic oligothiophenes efficiently displaced X-34, a Congo Red analogue, but not Pittsburgh compound B (PIB) from recombinant Aß amyloid fibrils and Alzheimer's disease brain-derived Aß. Overall, we foresee that the oligothiophene scaffold offers the possibility to develop novel high-affinity ligands for Aß pathology only found in human AD brain, targeting a different site than PIB.

Mixed oligomers and monomeric amyloid-ß disrupts endothelial cells integrity and reduces monomeric amyloid-ß transport across hCMEC/D3 cell line as an in vitro blood-brain barrier model.

Senile amyloid plaques are one of the diagnostic hallmarks of Alzheimer's disease (AD). However, the severity of clinical symptoms of AD is weakly correlated with the plaque load. AD symptoms severity is reported to be more strongly correlated with the level of soluble amyloid-ß (Aß) assemblies. Formation of soluble Aß assemblies is stimulated by monomeric Aß accumulation in the brain, which has been related to its faulty cerebral clearance. Studies tend to focus on the neurotoxicity of specific Aß species. There are relatively few studies investigating toxic effects of Aß on the endothelial cells of the blood-brain barrier (BBB). We hypothesized that a soluble Aß pool more closely resembling the in vivo situation composed of a mixture of Aß40 monomer and Aß42 oligomer would exert higher toxicity against hCMEC/D3 cells as an in vitro BBB model than either component alone. We observed that, in addition to a disruptive effect on the endothelial cells integrity due to enhancement of the paracellular permeability of the hCMEC/D3 monolayer, the Aß mixture significantly decreased monomeric Aß transport across the cell culture model. Consistent with its effect on Aß transport, Aß mixture treatment for 24h resulted in LRP1 down-regulation and RAGE up-regulation in hCMEC/D3 cells. The individual Aß species separately failed to alter Aß clearance or the cell-based BBB model integrity. Our study offers, for the first time, evidence that a mixture of soluble Aß species, at nanomolar concentrations, disrupts endothelial cells integrity and its own transport across an in vitro model of the BBB.