46 research outputs found
Stress granules as crucibles of ALS pathogenesis
Amyotrophic lateral sclerosis (ALS) is a fatal human neurodegenerative disease affecting primarily motor neurons. Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. This property is critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis. Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis
The Parkinson\u27s Disease Protein α-Synuclein Disrupts Cellular Rab Homeostasis
α-Synuclein (α-syn), a protein of unknown function, is the most abundant protein in Lewy bodies, the histological hallmark of Parkinson\u27s disease (PD). In yeast α-syn inhibits endoplasmic reticulum (ER)-to-Golgi (ER→Golgi) vesicle trafficking, which is rescued by overexpression of a Rab GTPase that regulates ER→Golgi trafficking. The homologous Rab1 rescues α-syn toxicity in dopaminergic neuronal models of PD. Here we investigate this conserved feature of α-syn pathobiology. In a cell-free system with purified transport factors α-syn inhibited ER→Golgi trafficking in an α-syn dose-dependent manner. Vesicles budded efficiently from the ER, but their docking or fusion to Golgi membranes was inhibited. Thus, the in vivo trafficking problem is due to a direct effect of α-syn on the transport machinery. By ultrastructural analysis the earliest in vivo defect was an accumulation of morphologically undocked vesicles, starting near the plasma membrane and growing into massive intracellular vesicular clusters in a dose-dependent manner. By immunofluorescence/immunoelectron microscopy, these clusters were associated both with α-syn and with diverse vesicle markers, suggesting that α-syn can impair multiple trafficking steps. Other Rabs did not ameliorate α-syn toxicity in yeast, but RAB3A, which is highly expressed in neurons and localized to presynaptic termini, and RAB8A, which is localized to post-Golgi vesicles, suppressed toxicity in neuronal models of PD. Thus, α-syn causes general defects in vesicle trafficking, to which dopaminergic neurons are especially sensitive
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Prion-like domain mutations in hnRNPs cause multisystem proteinopathy and ALS
Summary Algorithms designed to identify canonical yeast prions predict that ~250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbor a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here, we define pathogenic mutations in PrLDs of hnRNPA2/B1 and hnRNPA1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and a case of familial ALS. Wild-type hnRNPA2 and hnRNPA1 display an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a ‘steric zipper’ motif in the PrLD, which accelerates formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Importantly, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant ‘steric zipper’ motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs must be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone
Molecular Determinants and Genetic Modifiers of Aggregation and Toxicity for the ALS Disease Protein FUS/TLS
A combination of yeast genetics and protein biochemistry define how the fused in
sarcoma (FUS) protein might contribute to Lou Gehrig's disease
Readout of a quantum processor with high dynamic range Josephson parametric amplifiers
We demonstrate a high dynamic range Josephson parametric amplifier (JPA) in
which the active nonlinear element is implemented using an array of rf-SQUIDs.
The device is matched to the 50 environment with a Klopfenstein-taper
impedance transformer and achieves a bandwidth of 250-300 MHz, with input
saturation powers up to -95 dBm at 20 dB gain. A 54-qubit Sycamore processor
was used to benchmark these devices, providing a calibration for readout power,
an estimate of amplifier added noise, and a platform for comparison against
standard impedance matched parametric amplifiers with a single dc-SQUID. We
find that the high power rf-SQUID array design has no adverse effect on system
noise, readout fidelity, or qubit dephasing, and we estimate an upper bound on
amplifier added noise at 1.6 times the quantum limit. Lastly, amplifiers with
this design show no degradation in readout fidelity due to gain compression,
which can occur in multi-tone multiplexed readout with traditional JPAs.Comment: 9 pages, 8 figure
Measurement-Induced State Transitions in a Superconducting Qubit: Within the Rotating Wave Approximation
Superconducting qubits typically use a dispersive readout scheme, where a
resonator is coupled to a qubit such that its frequency is qubit-state
dependent. Measurement is performed by driving the resonator, where the
transmitted resonator field yields information about the resonator frequency
and thus the qubit state. Ideally, we could use arbitrarily strong resonator
drives to achieve a target signal-to-noise ratio in the shortest possible time.
However, experiments have shown that when the average resonator photon number
exceeds a certain threshold, the qubit is excited out of its computational
subspace, which we refer to as a measurement-induced state transition. These
transitions degrade readout fidelity, and constitute leakage which precludes
further operation of the qubit in, for example, error correction. Here we study
these transitions using a transmon qubit by experimentally measuring their
dependence on qubit frequency, average photon number, and qubit state, in the
regime where the resonator frequency is lower than the qubit frequency. We
observe signatures of resonant transitions between levels in the coupled
qubit-resonator system that exhibit noisy behavior when measured repeatedly in
time. We provide a semi-classical model of these transitions based on the
rotating wave approximation and use it to predict the onset of state
transitions in our experiments. Our results suggest the transmon is excited to
levels near the top of its cosine potential following a state transition, where
the charge dispersion of higher transmon levels explains the observed noisy
behavior of state transitions. Moreover, occupation in these higher energy
levels poses a major challenge for fast qubit reset
Overcoming leakage in scalable quantum error correction
Leakage of quantum information out of computational states into higher energy
states represents a major challenge in the pursuit of quantum error correction
(QEC). In a QEC circuit, leakage builds over time and spreads through
multi-qubit interactions. This leads to correlated errors that degrade the
exponential suppression of logical error with scale, challenging the
feasibility of QEC as a path towards fault-tolerant quantum computation. Here,
we demonstrate the execution of a distance-3 surface code and distance-21
bit-flip code on a Sycamore quantum processor where leakage is removed from all
qubits in each cycle. This shortens the lifetime of leakage and curtails its
ability to spread and induce correlated errors. We report a ten-fold reduction
in steady-state leakage population on the data qubits encoding the logical
state and an average leakage population of less than
throughout the entire device. The leakage removal process itself efficiently
returns leakage population back to the computational basis, and adding it to a
code circuit prevents leakage from inducing correlated error across cycles,
restoring a fundamental assumption of QEC. With this demonstration that leakage
can be contained, we resolve a key challenge for practical QEC at scale.Comment: Main text: 7 pages, 5 figure
Suppressing quantum errors by scaling a surface code logical qubit
Practical quantum computing will require error rates that are well below what
is achievable with physical qubits. Quantum error correction offers a path to
algorithmically-relevant error rates by encoding logical qubits within many
physical qubits, where increasing the number of physical qubits enhances
protection against physical errors. However, introducing more qubits also
increases the number of error sources, so the density of errors must be
sufficiently low in order for logical performance to improve with increasing
code size. Here, we report the measurement of logical qubit performance scaling
across multiple code sizes, and demonstrate that our system of superconducting
qubits has sufficient performance to overcome the additional errors from
increasing qubit number. We find our distance-5 surface code logical qubit
modestly outperforms an ensemble of distance-3 logical qubits on average, both
in terms of logical error probability over 25 cycles and logical error per
cycle ( compared to ). To investigate
damaging, low-probability error sources, we run a distance-25 repetition code
and observe a logical error per round floor set by a single
high-energy event ( when excluding this event). We are able
to accurately model our experiment, and from this model we can extract error
budgets that highlight the biggest challenges for future systems. These results
mark the first experimental demonstration where quantum error correction begins
to improve performance with increasing qubit number, illuminating the path to
reaching the logical error rates required for computation.Comment: Main text: 6 pages, 4 figures. v2: Update author list, references,
Fig. S12, Table I
Measurement-induced entanglement and teleportation on a noisy quantum processor
Measurement has a special role in quantum theory: by collapsing the
wavefunction it can enable phenomena such as teleportation and thereby alter
the "arrow of time" that constrains unitary evolution. When integrated in
many-body dynamics, measurements can lead to emergent patterns of quantum
information in space-time that go beyond established paradigms for
characterizing phases, either in or out of equilibrium. On present-day NISQ
processors, the experimental realization of this physics is challenging due to
noise, hardware limitations, and the stochastic nature of quantum measurement.
Here we address each of these experimental challenges and investigate
measurement-induced quantum information phases on up to 70 superconducting
qubits. By leveraging the interchangeability of space and time, we use a
duality mapping, to avoid mid-circuit measurement and access different
manifestations of the underlying phases -- from entanglement scaling to
measurement-induced teleportation -- in a unified way. We obtain finite-size
signatures of a phase transition with a decoding protocol that correlates the
experimental measurement record with classical simulation data. The phases
display sharply different sensitivity to noise, which we exploit to turn an
inherent hardware limitation into a useful diagnostic. Our work demonstrates an
approach to realize measurement-induced physics at scales that are at the
limits of current NISQ processors
Non-Abelian braiding of graph vertices in a superconducting processor
Indistinguishability of particles is a fundamental principle of quantum
mechanics. For all elementary and quasiparticles observed to date - including
fermions, bosons, and Abelian anyons - this principle guarantees that the
braiding of identical particles leaves the system unchanged. However, in two
spatial dimensions, an intriguing possibility exists: braiding of non-Abelian
anyons causes rotations in a space of topologically degenerate wavefunctions.
Hence, it can change the observables of the system without violating the
principle of indistinguishability. Despite the well developed mathematical
description of non-Abelian anyons and numerous theoretical proposals, the
experimental observation of their exchange statistics has remained elusive for
decades. Controllable many-body quantum states generated on quantum processors
offer another path for exploring these fundamental phenomena. While efforts on
conventional solid-state platforms typically involve Hamiltonian dynamics of
quasi-particles, superconducting quantum processors allow for directly
manipulating the many-body wavefunction via unitary gates. Building on
predictions that stabilizer codes can host projective non-Abelian Ising anyons,
we implement a generalized stabilizer code and unitary protocol to create and
braid them. This allows us to experimentally verify the fusion rules of the
anyons and braid them to realize their statistics. We then study the prospect
of employing the anyons for quantum computation and utilize braiding to create
an entangled state of anyons encoding three logical qubits. Our work provides
new insights about non-Abelian braiding and - through the future inclusion of
error correction to achieve topological protection - could open a path toward
fault-tolerant quantum computing