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Showing papers by "University of Michigan published in 2019"


Journal ArticleDOI
Frank Arute1, Kunal Arya1, Ryan Babbush1, Dave Bacon1, Joseph C. Bardin1, Joseph C. Bardin2, Rami Barends1, Rupak Biswas3, Sergio Boixo1, Fernando G. S. L. Brandão4, Fernando G. S. L. Brandão1, David A. Buell1, B. Burkett1, Yu Chen1, Zijun Chen1, Ben Chiaro5, Roberto Collins1, William Courtney1, Andrew Dunsworth1, Edward Farhi1, Brooks Foxen5, Brooks Foxen1, Austin G. Fowler1, Craig Gidney1, Marissa Giustina1, R. Graff1, Keith Guerin1, Steve Habegger1, Matthew P. Harrigan1, Michael J. Hartmann6, Michael J. Hartmann1, Alan Ho1, Markus R. Hoffmann1, Trent Huang1, Travis S. Humble7, Sergei V. Isakov1, Evan Jeffrey1, Zhang Jiang1, Dvir Kafri1, Kostyantyn Kechedzhi1, Julian Kelly1, Paul V. Klimov1, Sergey Knysh1, Alexander N. Korotkov8, Alexander N. Korotkov1, Fedor Kostritsa1, David Landhuis1, Mike Lindmark1, E. Lucero1, Dmitry I. Lyakh7, Salvatore Mandrà3, Jarrod R. McClean1, Matt McEwen5, Anthony Megrant1, Xiao Mi1, Kristel Michielsen9, Kristel Michielsen10, Masoud Mohseni1, Josh Mutus1, Ofer Naaman1, Matthew Neeley1, Charles Neill1, Murphy Yuezhen Niu1, Eric Ostby1, Andre Petukhov1, John Platt1, Chris Quintana1, Eleanor Rieffel3, Pedram Roushan1, Nicholas C. Rubin1, Daniel Sank1, Kevin J. Satzinger1, Vadim Smelyanskiy1, Kevin J. Sung11, Kevin J. Sung1, Matthew D. Trevithick1, Amit Vainsencher1, Benjamin Villalonga1, Benjamin Villalonga12, Theodore White1, Z. Jamie Yao1, Ping Yeh1, Adam Zalcman1, Hartmut Neven1, John M. Martinis5, John M. Martinis1 
24 Oct 2019-Nature
TL;DR: Quantum supremacy is demonstrated using a programmable superconducting processor known as Sycamore, taking approximately 200 seconds to sample one instance of a quantum circuit a million times, which would take a state-of-the-art supercomputer around ten thousand years to compute.
Abstract: The promise of quantum computers is that certain computational tasks might be executed exponentially faster on a quantum processor than on a classical processor1. A fundamental challenge is to build a high-fidelity processor capable of running quantum algorithms in an exponentially large computational space. Here we report the use of a processor with programmable superconducting qubits2-7 to create quantum states on 53 qubits, corresponding to a computational state-space of dimension 253 (about 1016). Measurements from repeated experiments sample the resulting probability distribution, which we verify using classical simulations. Our Sycamore processor takes about 200 seconds to sample one instance of a quantum circuit a million times-our benchmarks currently indicate that the equivalent task for a state-of-the-art classical supercomputer would take approximately 10,000 years. This dramatic increase in speed compared to all known classical algorithms is an experimental realization of quantum supremacy8-14 for this specific computational task, heralding a much-anticipated computing paradigm.

2,527 citations


Journal ArticleDOI
TL;DR: In patients with severe aortic stenosis who were at low surgical risk, TAVR with a self‐expanding supraannular bioprosthesis was noninferior to surgery with respect to the composite end point of death or disabling stroke at 24 months.
Abstract: Background Transcatheter aortic-valve replacement (TAVR) is an alternative to surgery in patients with severe aortic stenosis who are at increased risk for death from surgery; less is know...

2,240 citations


Journal ArticleDOI
TL;DR: The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study.
Abstract: Background Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study. Methods We conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation. The primary end point was the best overall response rate (i.e., the percentage of patients who had a complete or partial response), as judged by an independent review committee. Results A total of 93 patients received an infusion and were included in the evaluation of efficacy. The median time from infusion to data cutoff was 14 ...

2,086 citations


Journal ArticleDOI
TL;DR: Although some recommendations remain unchanged from the 2007 guideline, the availability of results from new therapeutic trials and epidemiological investigations led to revised recommendations for empiric treatment strategies and additional management decisions.
Abstract: Background: This document provides evidence-based clinical practice guidelines on the management of adult patients with community-acquired pneumonia.Methods: A multidisciplinary panel conducted pra...

1,708 citations


Journal ArticleDOI
01 May 2019-Nature
TL;DR: Investigation of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNγ and CD8 and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach.
Abstract: Cancer immunotherapy restores or enhances the effector function of CD8+ T cells in the tumour microenvironment1,2. CD8+ T cells activated by cancer immunotherapy clear tumours mainly by inducing cell death through perforin-granzyme and Fas-Fas ligand pathways3,4. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent accumulation of lipid peroxide5,6. Although it has been investigated in vitro7,8, there is emerging evidence that ferroptosis might be implicated in a variety of pathological scenarios9,10. It is unclear whether, and how, ferroptosis is involved in T cell immunity and cancer immunotherapy. Here we show that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased ferroptosis contributes to the anti-tumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFNγ) released from CD8+ T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system xc-, impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced ferroptosis in tumour cells. Expression of system xc- was negatively associated, in cancer patients, with CD8+ T cell signature, IFNγ expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNγ and CD8. Thus, T cell-promoted tumour ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach.

1,222 citations


Journal ArticleDOI
TL;DR: The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer.
Abstract: The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer. The portions of the guidelines included herein focus on the roles of germline and somatic genetic testing, risk stratification with nomograms and tumor multigene molecular testing, androgen deprivation therapy, secondary hormonal therapy, chemotherapy, and immunotherapy in patients with prostate cancer.

1,218 citations


Book
28 Aug 2019
TL;DR: New Directions in Social Psychology: Violence and honor in the Southern United States as mentioned in this paper, Homicide Rate Differences between North and South, Differences Between Northerners and Southerners in Attitudes Toward Violence, Insult, Anger, and Aggression: An "Experimental Ethnography" of the Culture of Honor, Collective Expressions of the culture of honor: Violence, Social Policy, and the Law.
Abstract: New Directions in Social Psychology -- Introduction -- Violence and Honor in the Southern United States -- Homicide Rate Differences Between North and South -- Differences Between Northerners and Southerners in Attitudes Toward Violence -- Insult, Anger, and Aggression: An "Experimental Ethnography" of the Culture of Honor -- Collective Expressions of the Culture of Honor: Violence, Social Policy, and the Law -- Culture of Honor: Manifestations, Explanations, and Destinations -- Appendix A -- Appendix B -- Appendix C -- About the Book and Authors

1,193 citations


Journal ArticleDOI
TL;DR: Blood eosinophils are recommended as a biomarker to support clinical decisions regarding the use of inhaled corticosteroids in chronic obstructive pulmonary disease patients, based on recent evidence from clinical trials.
Abstract: Precision medicine is a patient-specific approach that integrates all relevant clinical, genetic and biological information in order to optimise the therapeutic benefit relative to the possibility of side-effects for each individual. Recent clinical trials have shown that higher blood eosinophil counts are associated with a greater efficacy of inhaled corticosteroids (ICSs) in chronic obstructive pulmonary disease (COPD) patients. Blood eosinophil counts are a biomarker with potential to be used in clinical practice, to help target ICS treatment with more precision in COPD patients with a history of exacerbations despite appropriate bronchodilator treatment. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 pharmacological treatment algorithms, based on the ABCD assessment, can be applied relatively easily to treatment-naive individuals at initial presentation. However, their use is more problematic during follow-up in patients who are already on maintenance treatment. There is a need for a different system to guide COPD pharmacological management during follow-up. Recent large randomised controlled trials have provided important new information concerning the therapeutic effects of ICSs and long-acting bronchodilators on exacerbations. The new evidence regarding blood eosinophils and inhaled treatments, and the need to distinguish between initial and follow-up pharmacological management, led to changes in the GOLD pharmacological treatment recommendations. This article explains the evidence and rationale for the GOLD 2019 pharmacological treatment recommendations.

1,122 citations


Journal ArticleDOI
TL;DR: In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo.
Abstract: Background Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the ef...

1,113 citations


Journal ArticleDOI
Eli A. Stahl1, Eli A. Stahl2, Gerome Breen3, Andreas J. Forstner  +339 moreInstitutions (107)
TL;DR: Genome-wide analysis identifies 30 loci associated with bipolar disorder, allowing for comparisons of shared genes and pathways with other psychiatric disorders, including schizophrenia and depression.
Abstract: Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

1,090 citations


Journal ArticleDOI
Peter A. R. Ade1, James E. Aguirre2, Z. Ahmed3, Simone Aiola4  +276 moreInstitutions (53)
TL;DR: The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s as mentioned in this paper.
Abstract: The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s. We describe the scientific goals of the experiment, motivate the design, and forecast its performance. SO will measure the temperature and polarization anisotropy of the cosmic microwave background in six frequency bands centered at: 27, 39, 93, 145, 225 and 280 GHz. The initial configuration of SO will have three small-aperture 0.5-m telescopes and one large-aperture 6-m telescope, with a total of 60,000 cryogenic bolometers. Our key science goals are to characterize the primordial perturbations, measure the number of relativistic species and the mass of neutrinos, test for deviations from a cosmological constant, improve our understanding of galaxy evolution, and constrain the duration of reionization. The small aperture telescopes will target the largest angular scales observable from Chile, mapping ≈ 10% of the sky to a white noise level of 2 μK-arcmin in combined 93 and 145 GHz bands, to measure the primordial tensor-to-scalar ratio, r, at a target level of σ(r)=0.003. The large aperture telescope will map ≈ 40% of the sky at arcminute angular resolution to an expected white noise level of 6 μK-arcmin in combined 93 and 145 GHz bands, overlapping with the majority of the Large Synoptic Survey Telescope sky region and partially with the Dark Energy Spectroscopic Instrument. With up to an order of magnitude lower polarization noise than maps from the Planck satellite, the high-resolution sky maps will constrain cosmological parameters derived from the damping tail, gravitational lensing of the microwave background, the primordial bispectrum, and the thermal and kinematic Sunyaev-Zel'dovich effects, and will aid in delensing the large-angle polarization signal to measure the tensor-to-scalar ratio. The survey will also provide a legacy catalog of 16,000 galaxy clusters and more than 20,000 extragalactic sources.

Journal ArticleDOI
TL;DR: To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism and the American College of Rheumatology (ACR).
Abstract: Objective To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). Methods This international initiative had four phases. 1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort, and a patient survey. 2) Criteria reduction by Delphi and nominal group technique exercises. 3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. 4) Refinement of weights and threshold scores in a new derivation cohort of 1,001 subjects and validation compared with previous criteria in a new validation cohort of 1,270 subjects. Results The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. Conclusion These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered, and weighted criteria reflects current thinking about SLE and provides an improved foundation for SLE research.

Journal ArticleDOI
TL;DR: The role of PT symmetry and non-Hermitian dynamics for synthesizing and controlling the flow of light in optical structures is highlighted and a roadmap for future studies and potential applications is provided.
Abstract: Exploiting the interplay between gain, loss and the coupling strength between different optical components creates a variety of new opportunities in photonics to generate, control and transmit light. Inspired by the discovery of real eigenfrequencies for non-Hermitian Hamiltonians obeying parity–time (PT) symmetry, many counterintuitive aspects are being explored, particularly close to the associated degeneracies also known as ‘exceptional points’. This Review explains the underlying physical principles and discusses the progress in the experimental investigation of PT-symmetric photonic systems. We highlight the role of PT symmetry and non-Hermitian dynamics for synthesizing and controlling the flow of light in optical structures and provide a roadmap for future studies and potential applications. This Review discusses recent developments in the area of non-Hermitian physics, and more specifically the special case of non-Hermitian optical systems with parity–time symmetry.

Journal ArticleDOI
Eric C. Bellm1, Shrinivas R. Kulkarni2, Matthew J. Graham2, Richard Dekany2, Roger M. H. Smith2, Reed Riddle2, Frank J. Masci2, George Helou2, Thomas A. Prince2, Scott M. Adams2, Cristina Barbarino3, Tom A. Barlow2, James Bauer4, Ron Beck2, Justin Belicki2, Rahul Biswas3, Nadejda Blagorodnova2, Dennis Bodewits4, Bryce Bolin1, V. Brinnel5, Tim Brooke2, Brian D. Bue2, Mattia Bulla3, Rick Burruss2, S. Bradley Cenko6, S. Bradley Cenko4, Chan-Kao Chang7, Andrew J. Connolly1, Michael W. Coughlin2, John Cromer2, Virginia Cunningham4, Kaushik De2, Alex Delacroix2, Vandana Desai2, Dmitry A. Duev2, Gwendolyn Eadie1, Tony L. Farnham4, Michael Feeney2, Ulrich Feindt3, David Flynn2, Anna Franckowiak, Sara Frederick4, Christoffer Fremling2, Avishay Gal-Yam8, Suvi Gezari4, Matteo Giomi5, Daniel A. Goldstein2, V. Zach Golkhou1, Ariel Goobar3, Steven Groom2, Eugean Hacopians2, David Hale2, John Henning2, Anna Y. Q. Ho2, David Hover2, Justin Howell2, Tiara Hung4, Daniela Huppenkothen1, David Imel2, Wing-Huen Ip9, Wing-Huen Ip7, Željko Ivezić1, Edward Jackson2, Lynne Jones1, Mario Juric1, Mansi M. Kasliwal2, Shai Kaspi10, Stephen Kaye2, Michael S. P. Kelley4, Marek Kowalski5, Emily Kramer2, Thomas Kupfer11, Thomas Kupfer2, Walter Landry2, Russ R. Laher2, Chien De Lee7, Hsing Wen Lin12, Hsing Wen Lin7, Zhong-Yi Lin7, Ragnhild Lunnan3, Ashish Mahabal2, Peter H. Mao2, Adam A. Miller13, Adam A. Miller14, Serge Monkewitz2, Patrick J. Murphy2, Chow-Choong Ngeow7, Jakob Nordin5, Peter Nugent15, Peter Nugent16, Eran O. Ofek8, Maria T. Patterson1, Bryan E. Penprase17, Michael Porter2, L. Rauch, Umaa Rebbapragada2, Daniel J. Reiley2, Mickael Rigault18, Hector P. Rodriguez2, Jan van Roestel19, Ben Rusholme2, J. V. Santen, Steve Schulze8, David L. Shupe2, Leo Singer6, Leo Singer4, Maayane T. Soumagnac8, Robert Stein, Jason Surace2, Jesper Sollerman3, Paula Szkody1, Francesco Taddia3, Scott Terek2, Angela Van Sistine20, Sjoert van Velzen4, W. Thomas Vestrand21, Richard Walters2, Charlotte Ward4, Quanzhi Ye2, Po-Chieh Yu7, Lin Yan2, Jeffry Zolkower2 
TL;DR: The Zwicky Transient Facility (ZTF) as mentioned in this paper is a new optical time-domain survey that uses the Palomar 48 inch Schmidt telescope, which provides a 47 deg^2 field of view and 8 s readout time, yielding more than an order of magnitude improvement in survey speed relative to its predecessor survey.
Abstract: The Zwicky Transient Facility (ZTF) is a new optical time-domain survey that uses the Palomar 48 inch Schmidt telescope. A custom-built wide-field camera provides a 47 deg^2 field of view and 8 s readout time, yielding more than an order of magnitude improvement in survey speed relative to its predecessor survey, the Palomar Transient Factory. We describe the design and implementation of the camera and observing system. The ZTF data system at the Infrared Processing and Analysis Center provides near-real-time reduction to identify moving and varying objects. We outline the analysis pipelines, data products, and associated archive. Finally, we present on-sky performance analysis and first scientific results from commissioning and the early survey. ZTF's public alert stream will serve as a useful precursor for that of the Large Synoptic Survey Telescope.

Journal ArticleDOI
07 Feb 2019-Cell
TL;DR: An exome capture RNA sequencing protocol is used to detect and characterize circRNAs across >2,000 cancer samples and built the most comprehensive catalog of circRNA species to date, MiOncoCirc, the first database to be composed primarily of circ RNAs directly detected in tumor tissues.

Journal ArticleDOI
TL;DR: The ENCODE blacklist is defined- a comprehensive set of regions in the human, mouse, worm, and fly genomes that have anomalous, unstructured, or high signal in next-generation sequencing experiments independent of cell line or experiment.
Abstract: Functional genomics assays based on high-throughput sequencing greatly expand our ability to understand the genome. Here, we define the ENCODE blacklist- a comprehensive set of regions in the human, mouse, worm, and fly genomes that have anomalous, unstructured, or high signal in next-generation sequencing experiments independent of cell line or experiment. The removal of the ENCODE blacklist is an essential quality measure when analyzing functional genomics data.

Journal ArticleDOI
TL;DR: After median follow-up duration of 4·5 years, radiotherapy plus cetuximab did not meet the non-inferiority criteria for overall survival, and patients were stratified by T category (T1-T2 vs T3-T4), N category (N0-N2a vs N2b-N3), Zubrod performance status (0 vs 1), and tobacco smoking history (≤10 pack-years).

Posted Content
TL;DR: This paper extensively reviews 400+ papers of object detection in the light of its technical evolution, spanning over a quarter-century's time (from the 1990s to 2019), and makes an in-deep analysis of their challenges as well as technical improvements in recent years.
Abstract: Object detection, as of one the most fundamental and challenging problems in computer vision, has received great attention in recent years. Its development in the past two decades can be regarded as an epitome of computer vision history. If we think of today's object detection as a technical aesthetics under the power of deep learning, then turning back the clock 20 years we would witness the wisdom of cold weapon era. This paper extensively reviews 400+ papers of object detection in the light of its technical evolution, spanning over a quarter-century's time (from the 1990s to 2019). A number of topics have been covered in this paper, including the milestone detectors in history, detection datasets, metrics, fundamental building blocks of the detection system, speed up techniques, and the recent state of the art detection methods. This paper also reviews some important detection applications, such as pedestrian detection, face detection, text detection, etc, and makes an in-deep analysis of their challenges as well as technical improvements in recent years.

Journal ArticleDOI
01 Mar 2019-Small
TL;DR: These adhesive hemostatic antioxidant conductive photothermal antibacterial hydrogels based on hyaluronic acid-graft-dopamine and reduced graphene oxide using a H2 O2 /HPR (horseradish peroxidase) system are prepared for wound dressing and are an excellent wound dressing for full-thickness skin repair.
Abstract: Developing injectable nanocomposite conductive hydrogel dressings with multifunctions including adhesiveness, antibacterial, and radical scavenging ability and good mechanical property to enhance full-thickness skin wound regeneration is highly desirable in clinical application. Herein, a series of adhesive hemostatic antioxidant conductive photothermal antibacterial hydrogels based on hyaluronic acid-graft-dopamine and reduced graphene oxide (rGO) using a H2 O2 /HPR (horseradish peroxidase) system are prepared for wound dressing. These hydrogels exhibit high swelling, degradability, tunable rheological property, and similar or superior mechanical properties to human skin. The polydopamine endowed antioxidant activity, tissue adhesiveness and hemostatic ability, self-healing ability, conductivity, and NIR irradiation enhanced in vivo antibacterial behavior of the hydrogels are investigated. Moreover, drug release and zone of inhibition tests confirm sustained drug release capacity of the hydrogels. Furthermore, the hydrogel dressings significantly enhance vascularization by upregulating growth factor expression of CD31 and improve the granulation tissue thickness and collagen deposition, all of which promote wound closure and contribute to a better therapeutic effect than the commercial Tegaderm films group in a mouse full-thickness wounds model. In summary, these adhesive hemostatic antioxidative conductive hydrogels with sustained drug release property to promote complete skin regeneration are an excellent wound dressing for full-thickness skin repair.

Proceedings Article
15 Feb 2019
TL;DR: The Deep Planning Network (PlaNet) is proposed, a purely model-based agent that learns the environment dynamics from images and chooses actions through fast online planning in latent space using a latent dynamics model with both deterministic and stochastic transition components.
Abstract: Planning has been very successful for control tasks with known environment dynamics. To leverage planning in unknown environments, the agent needs to learn the dynamics from interactions with the world. However, learning dynamics models that are accurate enough for planning has been a long-standing challenge, especially in image-based domains. We propose the Deep Planning Network (PlaNet), a purely model-based agent that learns the environment dynamics from images and chooses actions through fast online planning in latent space. To achieve high performance, the dynamics model must accurately predict the rewards ahead for multiple time steps. We approach this using a latent dynamics model with both deterministic and stochastic transition components. Moreover, we propose a multi-step variational inference objective that we name latent overshooting. Using only pixel observations, our agent solves continuous control tasks with contact dynamics, partial observability, and sparse rewards, which exceed the difficulty of tasks that were previously solved by planning with learned models. PlaNet uses substantially fewer episodes and reaches final performance close to and sometimes higher than strong model-free algorithms.

Journal ArticleDOI
TL;DR: It is confirmed that eukaryotes form at least two domains, the loss of monophyly in the Excavata, robust support for the Haptista and Cryptista, and suggested primer sets for DNA sequences from environmental samples that are effective for each clade are provided.
Abstract: This revision of the classification of eukaryotes follows that of Adl et al., 2012 [J. Euk. Microbiol. 59(5)] and retains an emphasis on protists. Changes since have improved the resolution of many ...

Journal ArticleDOI
TL;DR: Among patients with advanced heart failure, a fully magnetically levitated centrifugal‐flow left ventricular assist device was associated with less frequent need for pump replacement than an axial‐flow device and was superior with respect to survival free of disabling stroke or reoperation to replace or remove a malfunctioning device.
Abstract: Background In two interim analyses of this trial, patients with advanced heart failure who were treated with a fully magnetically levitated centrifugal-flow left ventricular assist device ...

Journal ArticleDOI
TL;DR: This protocol provides an overview of all new features of the COBRA Toolbox and can be adapted to generate and analyze constraint-based models in a wide variety of scenarios.
Abstract: Constraint-based reconstruction and analysis (COBRA) provides a molecular mechanistic framework for integrative analysis of experimental molecular systems biology data and quantitative prediction of physicochemically and biochemically feasible phenotypic states. The COBRA Toolbox is a comprehensive desktop software suite of interoperable COBRA methods. It has found widespread application in biology, biomedicine, and biotechnology because its functions can be flexibly combined to implement tailored COBRA protocols for any biochemical network. This protocol is an update to the COBRA Toolbox v.1.0 and v.2.0. Version 3.0 includes new methods for quality-controlled reconstruction, modeling, topological analysis, strain and experimental design, and network visualization, as well as network integration of chemoinformatic, metabolomic, transcriptomic, proteomic, and thermochemical data. New multi-lingual code integration also enables an expansion in COBRA application scope via high-precision, high-performance, and nonlinear numerical optimization solvers for multi-scale, multi-cellular, and reaction kinetic modeling, respectively. This protocol provides an overview of all these new features and can be adapted to generate and analyze constraint-based models in a wide variety of scenarios. The COBRA Toolbox v.3.0 provides an unparalleled depth of COBRA methods.

Journal ArticleDOI
TL;DR: This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.
Abstract: Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.

Journal ArticleDOI
TL;DR: This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.
Abstract: Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.

Journal ArticleDOI
Andrea Cossarizza1, Hyun-Dong Chang, Andreas Radbruch, Andreas Acs2  +459 moreInstitutions (160)
TL;DR: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community providing the theory and key practical aspects offlow cytometry enabling immunologists to avoid the common errors that often undermine immunological data.
Abstract: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.

Journal ArticleDOI
TL;DR: The regulating networks of TAM polarization and the mechanisms underlying TAM-facilitated metastasis are summarized and the potential applications of TAM-focused therapeutic strategies in clinical cancer treatment at present and in the future are discussed.
Abstract: Tumor metastasis is a major contributor to the death of cancer patients. It is driven not only by the intrinsic alterations in tumor cells, but also by the implicated cross-talk between cancer cells and their altered microenvironment components. Tumor-associated macrophages (TAMs) are the key cells that create an immunosuppressive tumor microenvironment (TME) by producing cytokines, chemokines, growth factors, and triggering the inhibitory immune checkpoint proteins release in T cells. In doing so, TAMs exhibit important functions in facilitating a metastatic cascade of cancer cells and, meanwhile, provide multiple targets of certain checkpoint blockade immunotherapies for opposing tumor progression. In this article, we summarize the regulating networks of TAM polarization and the mechanisms underlying TAM-facilitated metastasis. Based on the overview of current experimental evidence dissecting the critical roles of TAMs in tumor metastasis, we discuss and prospect the potential applications of TAM-focused therapeutic strategies in clinical cancer treatment at present and in the future.

Journal ArticleDOI
TL;DR: The global prevalence was higher in women and increased with age, peaking at the >95 age group among women and men in 2017, and a positive association was found between the age-standardised YLD rate and SDI at the regional and national levels.
Abstract: Objectives To report the level and trends of prevalence, incidence and years lived with disability (YLDs) for osteoarthritis (OA) in 195 countries and territories from 1990 to 2017 by age, sex and Socio-demographic index (SDI; a composite of sociodemographic factors). Methods Publicly available modelled data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 were used. The burden of OA was estimated for 195 countries and territories from 1990 to 2017, through a systematic analysis of prevalence and incidence modelled data using the methods reported in the GBD 2017 Study. All estimates were presented as counts and age-standardised rates per 100 000 population, with uncertainty intervals (UIs). Results Globally, the age-standardised point prevalence and annual incidence rate of OA in 2017 were 3754.2 (95% UI 3389.4 to 4187.6) and 181.2 (95% UI 162.6 to 202.4) per 100 000, an increase of 9.3% (95% UI 8% to 10.7%) and 8.2% (95% UI 7.1% to 9.4%) from 1990, respectively. In addition, global age-standardised YLD rate in 2017 was 118.8 (95% UI 59.5 to 236.2), an increase of 9.6% (95% UI 8.3% to 11.1%) from 1990. The global prevalence was higher in women and increased with age, peaking at the >95 age group among women and men in 2017. Generally, a positive association was found between the age-standardised YLD rate and SDI at the regional and national levels. Age-standardised prevalence of OA in 2017 ranged from 2090.3 to 6128.1 cases per 100 000 population. United States (6128.1 (95% UI 5729.3 to 6582.9)), American Samoa (5281 (95% UI 4688 to 5965.9)) and Kuwait (5234.6 (95% UI 4643.2 to 5953.6)) had the three highest levels of age-standardised prevalence. Oman (29.6% (95% UI 24.8% to 34.9%)), Equatorial Guinea (28.6% (95% UI 24.4% to 33.7%)) and the United States 23.2% (95% UI 16.4% to 30.5%)) showed the highest increase in the age-standardised prevalence during 1990–2017. Conclusions OA is a major public health challenge. While there is remarkable international variation in the prevalence, incidence and YLDs due to OA, the burden is increasing in most countries. It is expected to continue with increased life expectancy and ageing of the global population. Improving population and policy maker awareness of risk factors, including overweight and injury, and the importance and benefits of management of OA, together with providing health services for an increasing number of people living with OA, are recommended for management of the future burden of this condition.

Journal ArticleDOI
TL;DR: The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders.
Abstract: Background The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity. Scope of review In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases. Major conclusions Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders

Posted ContentDOI
Daniel Taliun1, Daniel N. Harris2, Michael D. Kessler2, Jedidiah Carlson3  +191 moreInstitutions (61)
06 Mar 2019-bioRxiv
TL;DR: The nearly complete catalog of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and non-coding sequence variants to phenotypic variation as well as resources and early insights from the sequence data.
Abstract: Summary paragraph The Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, >400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the >400 million variants detected, 97% have frequency