Entanglement-free Heisenberg-limited phase estimation

Measurement underpins all quantitative science. A key example is the measurement of optical phase, used in length metrology and many other applications. Advances in precision measurement have consistently led to important scientific discoveries. At the fundamental level, measurement precision is limited by the number N of quantum resources (such as photons) that are used. Standard measurement schemes, using each resource independently, lead to a phase uncertainty that scales as 1/sqrt(N) - known as the standard quantum limit. However, it has long been conjectured that it should be possible to achieve a precision limited only by the Heisenberg uncertainty principle, dramatically improving the scaling to 1/N. It is commonly thought that achieving this improvement requires the use of exotic quantum entangled states, such as the NOON state. These states are extremely difficult to generate. Measurement schemes with counted photons or ions have been performed with N <= 6, but few have surpassed the standard quantum limit and none have shown Heisenberg-limited scaling. Here we demonstrate experimentally a Heisenberg-limited phase estimation procedure. We replace entangled input states with multiple applications of the phase shift on unentangled single-photon states. We generalize Kitaev's phase estimation algorithm using adaptive measurement theory to achieve a standard deviation scaling at the Heisenberg limit. For the largest number of resources used (N = 378), we estimate an unknown phase with a variance more than 10 dB below the standard quantum limit; achieving this variance would require more than 4,000 resources using standard interferometry. Our results represent a drastic reduction in the complexity of achieving quantum-enhanced measurement precision.Comment: Published in Nature. This is the final versio

Quantum feedback control of a superconducting qubit: Persistent Rabi oscillations

The act of measurement bridges the quantum and classical worlds by projecting a superposition of possible states into a single, albeit probabilistic, outcome. The time-scale of this "instantaneous" process can be stretched using weak measurements so that it takes the form of a gradual random walk towards a final state. Remarkably, the interim measurement record is sufficient to continuously track and steer the quantum state using feedback. We monitor the dynamics of a resonantly driven quantum two-level system -- a superconducting quantum bit --using a near-noiseless parametric amplifier. The high-fidelity measurement output is used to actively stabilize the phase of Rabi oscillations, enabling them to persist indefinitely. This new functionality shows promise for fighting decoherence and defines a path for continuous quantum error correction.Comment: Manuscript: 5 Pages and 3 figures ; Supplementary Information: 9 pages and 3 figure

Holographic Renormalization of general dilaton-axion gravity

We consider a very general dilaton-axion system coupled to Einstein-Hilbert gravity in arbitrary dimension and we carry out holographic renormalization for any dimension up to and including five dimensions. This is achieved by developing a new systematic algorithm for iteratively solving the radial Hamilton-Jacobi equation in a derivative expansion. The boundary term derived is valid not only for asymptotically AdS backgrounds, but also for more general asymptotics, including non-conformal branes and Improved Holographic QCD. In the second half of the paper, we apply the general result to Improved Holographic QCD with arbitrary dilaton potential. In particular, we derive the generalized Fefferman-Graham asymptotic expansions and provide a proof of the holographic Ward identities.Comment: 42 pages. v2: two references added. Version published in JHEP. v3: fixed minor typos in eqs. (1.6), (2.3), (3.20), (A.3), (B.8), (B.12) and (B.22

ATF6 is essential for human cone photoreceptor development

Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR regulator Activating Transcription Factor 6 (ATF6) cause severe congenital vision loss diseases such as achromatopsia by unclear pathomechanisms. To investigate this, we generated retinal organoids from achromatopsia patient induced pluripotent stem cells carrying ATF6 disease variants and from gene-edited ATF6 null hESCs. We found that achromatopsia patient and ATF6 null retinal organoids failed to form cone structures concomitant with loss of cone phototransduction gene expression, while rod photoreceptors developed normally. Adaptive optics retinal imaging of achromatopsia patients carrying ATF6 variants also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the defect in cone formation observed in our retinal organoids. These results establish that ATF6 is essential for human cone development. Interestingly, we find that a selective small molecule ATF6 signaling agonist restores the transcriptional activity of some ATF6 disease-causing variants and stimulates cone growth and gene expression in patient retinal organoids carrying these variants. These findings support that pharmacologic targeting of the ATF6 pathway can promote human cone development and should be further explored for blinding retinal diseases

Spatial quantitation of drugs in tissues using liquid extraction surface analysis mass spectrometry imaging

Liquid extraction surface analysis mass spectrometry imaging (LESA-MSI) has been shown to be an effective tissue profiling and imaging technique, producing robust and reliable qualitative distribution images of an analyte or analytes in tissue sections. Here, we expand the use of LESA-MSI beyond qualitative analysis to a quantitative analytical technique by employing a mimetic tissue model previously shown to be applicable for MALDI-MSI quantitation. Liver homogenate was used to generate a viable and molecularly relevant control matrix for spiked drug standards which can be frozen, sectioned and subsequently analyzed for the generation of calibration curves to quantify unknown tissue section samples. The effects of extraction solvent composition, tissue thickness and solvent/tissue contact time were explored prior to any quantitative studies in order to optimize the LESA-MSI method across several different chemical entities. The use of a internal standard to normalize regional differences in ionization response across tissue sections was also investigated. Data are presented comparing quantitative results generated by LESA-MSI to LC-MS/MS. Subsequent analysis of adjacent tissue sections using DESI-MSI is also reported

Results of the MAJORANA DEMONSTRATOR's Search for Double-Beta Decay of 76Ge to Excited States of 76Se

The MAJORANA DEMONSTRATOR is searching for double-beta decay of 76Ge to excited states (E.S.) in 76Se using a modular array of high purity Germanium detectors. 76Ge can decay into three E.S.s of 76Se. The E.S. decays have a clear event signature consisting of a ββ-decay with the prompt emission of one or two γ-rays, resulting in with high probability in a multi-site event. The granularity of the DEMONSTRATOR detector array enables powerful discrimination of this event signature from backgrounds. Using 21.3 kg-y of isotopic exposure, the DEMONSTRATOR has set world leading limits for each E.S. decay, with 90% CL lower half-life limits in the range of (0.56 2.1) ⋅ 1024 y. In particular, for the 2v transition to the first 0+ E.S. of 76Se, a lower half-life limit of 0.68 ⋅ 1024 at 90% CL was achieved

Long-term complete responses after 131I-tositumomab therapy for relapsed or refractory indolent non-Hodgkin's lymphoma

We present the long-term results of 18 chemotherapy relapsed indolent (N=12) or transformed (N=6) NHL patients of a phase II anti-CD20 131I-tositumomab (Bexxar®) therapy study. The biphasic therapy included two injections of 450 mg unlabelled antibody combined with 131I-tositumomab once as dosimetric and once as therapeutic activity delivering 75 or 65 cGy whole-body radiation dose to patients with normal or reduced platelet counts, respectively. Two patients were not treated due to disease progression during dosimetry. The overall response rate was 81% in the 16 patients treated, including 50% CR/CRu and 31% PR. Median progression free survival of the 16 patients was 22.5 months. Median overall survival has not been reached after a median observation of 48 months. Median PFS of complete responders (CR/CRu) has not been reached and will be greater than 51 months. Short-term side effects were mainly haematological and transient. Among the relevant long-term side effects, one patient previously treated with CHOP chemotherapy died from secondary myelodysplasia. Four patients developed HAMA. In conclusion, 131I-tositumomab RIT demonstrated durable responses especially in those patients who achieved a complete response. Six of eight CR/CRu are ongoing after 46–70 months

ADC Nonlinearity Correction for the Majorana Demonstrator

Imperfections in analog-to-digital conversion (ADC) cannot be ignored when signal digitization requirements demand both wide dynamic range and high resolution, as is the case for the Majorana Demonstrator 76Ge neutrinoless double-beta decay search. Enabling the experiment's high-resolution spectral analysis and efficient pulse shape discrimination required careful measurement and correction of ADC nonlinearities. A simple measurement protocol was developed that did not require sophisticated equipment or lengthy data-taking campaigns. A slope-dependent hysteresis was observed and characterized. A correction applied to digitized waveforms prior to signal processing reduced the differential and integral nonlinearities by an order of magnitude, eliminating these as dominant contributions to the systematic energy uncertainty at the double-beta decay Q value

Inference of hidden structures in complex physical systems by multi-scale clustering

We survey the application of a relatively new branch of statistical physics--"community detection"-- to data mining. In particular, we focus on the diagnosis of materials and automated image segmentation. Community detection describes the quest of partitioning a complex system involving many elements into optimally decoupled subsets or communities of such elements. We review a multiresolution variant which is used to ascertain structures at different spatial and temporal scales. Significant patterns are obtained by examining the correlations between different independent solvers. Similar to other combinatorial optimization problems in the NP complexity class, community detection exhibits several phases. Typically, illuminating orders are revealed by choosing parameters that lead to extremal information theory correlations.Comment: 25 pages, 16 Figures; a review of earlier work

Iodine Atoms: A New Molecular Feature for the Design of Potent Transthyretin Fibrillogenesis Inhibitors

The thyroid hormone and retinol transporter protein known as transthyretin (TTR) is in the origin of one of the 20 or so known amyloid diseases. TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites. The aggregation pathway of TTR into amiloid fibrils is not yet well characterized but in vitro binding of thyroid hormones and other small organic molecules to TTR binding channel results in tetramer stabilization which prevents amyloid formation in an extent which is proportional to the binding constant. Up to now, TTR aggregation inhibitors have been designed looking at various structural features of this binding channel others than its ability to host iodine atoms. In the present work, greatly improved inhibitors have been designed and tested by taking into account that thyroid hormones are unique in human biochemistry owing to the presence of multiple iodine atoms in their molecules which are probed to interact with specific halogen binding domains sitting at the TTR binding channel. The new TTR fibrillogenesis inhibitors are based on the diflunisal core structure because diflunisal is a registered salicylate drug with NSAID activity now undergoing clinical trials for TTR amyloid diseases. Biochemical and biophysical evidence confirms that iodine atoms can be an important design feature in the search for candidate drugs for TTR related amyloidosis