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Showing papers by "University of Tokyo published in 2014"


Journal ArticleDOI
Marie Ng1, Tom P Fleming1, Margaret Robinson1, Blake Thomson1, Nicholas Graetz1, Christopher Margono1, Erin C Mullany1, Stan Biryukov1, Cristiana Abbafati2, Semaw Ferede Abera3, Jerry Abraham4, Niveen M E Abu-Rmeileh, Tom Achoki1, Fadia AlBuhairan5, Zewdie Aderaw Alemu6, Rafael Alfonso1, Mohammed K. Ali7, Raghib Ali8, Nelson Alvis Guzmán9, Walid Ammar, Palwasha Anwari10, Amitava Banerjee11, Simón Barquera, Sanjay Basu12, Derrick A Bennett8, Zulfiqar A Bhutta13, Jed D. Blore14, N Cabral, Ismael Ricardo Campos Nonato, Jung-Chen Chang15, Rajiv Chowdhury16, Karen J. Courville, Michael H. Criqui17, David K. Cundiff, Kaustubh Dabhadkar7, Lalit Dandona1, Lalit Dandona18, Adrian Davis19, Anand Dayama7, Samath D Dharmaratne20, Eric L. Ding21, Adnan M. Durrani22, Alireza Esteghamati23, Farshad Farzadfar23, Derek F J Fay19, Valery L. Feigin24, Abraham D. Flaxman1, Mohammad H. Forouzanfar1, Atsushi Goto, Mark A. Green25, Rajeev Gupta, Nima Hafezi-Nejad23, Graeme J. Hankey26, Heather Harewood, Rasmus Havmoeller27, Simon I. Hay8, Lucia Hernandez, Abdullatif Husseini28, Bulat Idrisov29, Nayu Ikeda, Farhad Islami30, Eiman Jahangir31, Simerjot K. Jassal17, Sun Ha Jee32, Mona Jeffreys33, Jost B. Jonas34, Edmond K. Kabagambe35, Shams Eldin Ali Hassan Khalifa, Andre Pascal Kengne36, Yousef Khader37, Young-Ho Khang38, Daniel Kim39, Ruth W Kimokoti40, Jonas Minet Kinge41, Yoshihiro Kokubo, Soewarta Kosen, Gene F. Kwan42, Taavi Lai, Mall Leinsalu22, Yichong Li, Xiaofeng Liang43, Shiwei Liu43, Giancarlo Logroscino44, Paulo A. Lotufo45, Yuan Qiang Lu21, Jixiang Ma43, Nana Kwaku Mainoo, George A. Mensah22, Tony R. Merriman46, Ali H. Mokdad1, Joanna Moschandreas47, Mohsen Naghavi1, Aliya Naheed48, Devina Nand, K.M. Venkat Narayan7, Erica Leigh Nelson1, Marian L. Neuhouser49, Muhammad Imran Nisar13, Takayoshi Ohkubo50, Samuel Oti, Andrea Pedroza, Dorairaj Prabhakaran, Nobhojit Roy51, Uchechukwu K.A. Sampson35, Hyeyoung Seo, Sadaf G. Sepanlou23, Kenji Shibuya52, Rahman Shiri53, Ivy Shiue54, Gitanjali M Singh21, Jasvinder A. Singh55, Vegard Skirbekk41, Nicolas J. C. Stapelberg56, Lela Sturua57, Bryan L. Sykes58, Martin Tobias1, Bach Xuan Tran59, Leonardo Trasande60, Hideaki Toyoshima, Steven van de Vijver, Tommi Vasankari, J. Lennert Veerman61, Gustavo Velasquez-Melendez62, Vasiliy Victorovich Vlassov63, Stein Emil Vollset64, Stein Emil Vollset41, Theo Vos1, Claire L. Wang65, Xiao Rong Wang66, Elisabete Weiderpass, Andrea Werdecker, Jonathan L. Wright1, Y Claire Yang67, Hiroshi Yatsuya68, Jihyun Yoon, Seok Jun Yoon69, Yong Zhao70, Maigeng Zhou, Shankuan Zhu71, Alan D. Lopez14, Christopher J L Murray1, Emmanuela Gakidou1 
University of Washington1, Sapienza University of Rome2, Mekelle University3, University of Texas at San Antonio4, King Saud bin Abdulaziz University for Health Sciences5, Debre markos University6, Emory University7, University of Oxford8, University of Cartagena9, United Nations Population Fund10, University of Birmingham11, Stanford University12, Aga Khan University13, University of Melbourne14, National Taiwan University15, University of Cambridge16, University of California, San Diego17, Public Health Foundation of India18, Public Health England19, University of Peradeniya20, Harvard University21, National Institutes of Health22, Tehran University of Medical Sciences23, Auckland University of Technology24, University of Sheffield25, University of Western Australia26, Karolinska Institutet27, Birzeit University28, Brandeis University29, American Cancer Society30, Ochsner Medical Center31, Yonsei University32, University of Bristol33, Heidelberg University34, Vanderbilt University35, South African Medical Research Council36, Jordan University of Science and Technology37, New Generation University College38, Northeastern University39, Simmons College40, Norwegian Institute of Public Health41, Boston University42, Chinese Center for Disease Control and Prevention43, University of Bari44, University of São Paulo45, University of Otago46, University of Crete47, International Centre for Diarrhoeal Disease Research, Bangladesh48, Fred Hutchinson Cancer Research Center49, Teikyo University50, Bhabha Atomic Research Centre51, University of Tokyo52, Finnish Institute of Occupational Health53, Heriot-Watt University54, University of Alabama at Birmingham55, Griffith University56, National Center for Disease Control and Public Health57, University of California, Irvine58, Johns Hopkins University59, New York University60, University of Queensland61, Universidade Federal de Minas Gerais62, National Research University – Higher School of Economics63, University of Bergen64, Columbia University65, Shandong University66, University of North Carolina at Chapel Hill67, Fujita Health University68, Korea University69, Chongqing Medical University70, Zhejiang University71
TL;DR: The global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013 is estimated using a spatiotemporal Gaussian process regression model to estimate prevalence with 95% uncertainty intervals (UIs).

9,180 citations


Journal ArticleDOI
Keith A. Olive1, Kaustubh Agashe2, Claude Amsler3, Mario Antonelli  +222 moreInstitutions (107)
TL;DR: The review as discussed by the authors summarizes much of particle physics and cosmology using data from previous editions, plus 3,283 new measurements from 899 Japers, including the recently discovered Higgs boson, leptons, quarks, mesons and baryons.
Abstract: The Review summarizes much of particle physics and cosmology. Using data from previous editions, plus 3,283 new measurements from 899 Japers, we list, evaluate, and average measured properties of gauge bosons and the recently discovered Higgs boson, leptons, quarks, mesons, and baryons. We summarize searches for hypothetical particles such as heavy neutrinos, supersymmetric and technicolor particles, axions, dark photons, etc. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as Supersymmetry, Extra Dimensions, Particle Detectors, Probability, and Statistics. Among the 112 reviews are many that are new or heavily revised including those on: Dark Energy, Higgs Boson Physics, Electroweak Model, Neutrino Cross Section Measurements, Monte Carlo Neutrino Generators, Top Quark, Dark Matter, Dynamical Electroweak Symmetry Breaking, Accelerator Physics of Colliders, High-Energy Collider Parameters, Big Bang Nucleosynthesis, Astrophysical Constants and Cosmological Parameters.

7,337 citations


Journal ArticleDOI
TL;DR: This introductory review covers the fundamental aspects of photocatalytic and photoelectrochemical water splitting and recent advances in the water splitting reaction under visible light will be presented with a focus on non-oxide semiconductor materials to give an overview of the various problems and solutions.
Abstract: Photocatalytic and photoelectrochemical water splitting under irradiation by sunlight has received much attention for production of renewable hydrogen from water on a large scale. Many challenges still remain in improving energy conversion efficiency, such as utilizing longer-wavelength photons for hydrogen production, enhancing the reaction efficiency at any given wavelength, and increasing the lifetime of the semiconductor materials. This introductory review covers the fundamental aspects of photocatalytic and photoelectrochemical water splitting. Controlling the semiconducting properties of photocatalysts and photoelectrode materials is the primary concern in developing materials for solar water splitting, because they determine how much photoexcitation occurs in a semiconductor under solar illumination and how many photoexcited carriers reach the surface where water splitting takes place. Given a specific semiconductor material, surface modifications are important not only to activate the semiconductor for water splitting but also to facilitate charge separation and to upgrade the stability of the material under photoexcitation. In addition, reducing resistance loss and forming p-n junction have a significant impact on the efficiency of photoelectrochemical water splitting. Correct evaluation of the photocatalytic and photoelectrochemical activity for water splitting is becoming more important in enabling an accurate comparison of a number of studies based on different systems. In the latter part, recent advances in the water splitting reaction under visible light will be presented with a focus on non-oxide semiconductor materials to give an overview of the various problems and solutions.

3,470 citations


Journal ArticleDOI
TL;DR: The AWGS consensus report is believed to promote more Asian sarcopenia research, and most important of all, to focus on sarc Openia intervention studies and the implementation of sarcopenian in clinical practice to improve health care outcomes of older people in the communities and the healthcare settings in Asia.

2,976 citations


Journal ArticleDOI
TL;DR: These evidence-based consensus recommendations provide guidance to patients and practitioners on treatments applicable to all individuals with knee OA, as well as therapies that can be considered according to individualized patient needs and preferences.

2,467 citations


Journal ArticleDOI
TL;DR: In this article, the authors presented cosmological constraints from a joint analysis of type Ia supernova (SN Ia) observations obtained by the SDSS-II and SNLS collaborations.
Abstract: Aims. We present cosmological constraints from a joint analysis of type Ia supernova (SN Ia) observations obtained by the SDSS-II and SNLS collaborations. The dataset includes several low-redshift samples (z< 0.1), all three seasons from the SDSS-II (0.05

1,939 citations


Journal ArticleDOI
Yukinori Okada1, Yukinori Okada2, Di Wu2, Di Wu1, Di Wu3, Gosia Trynka1, Gosia Trynka2, Towfique Raj2, Towfique Raj1, Chikashi Terao4, Katsunori Ikari, Yuta Kochi, Koichiro Ohmura4, Akari Suzuki, Shinji Yoshida, Robert R. Graham5, A. Manoharan5, Ward Ortmann5, Tushar Bhangale5, Joshua C. Denny6, Robert J. Carroll6, Anne E. Eyler6, Jeff Greenberg7, Joel M. Kremer, Dimitrios A. Pappas8, Lei Jiang9, Jian Yin9, Lingying Ye9, Ding Feng Su9, Jian Yang10, Gang Xie11, E.C. Keystone11, Harm-Jan Westra12, Tõnu Esko2, Tõnu Esko1, Tõnu Esko13, Andres Metspalu13, Xuezhong Zhou14, Namrata Gupta1, Daniel B. Mirel1, Eli A. Stahl15, Dorothee Diogo1, Dorothee Diogo2, Jing Cui1, Jing Cui2, Katherine P. Liao2, Katherine P. Liao1, Michael H. Guo1, Michael H. Guo2, Keiko Myouzen, Takahisa Kawaguchi4, Marieke J H Coenen16, Piet L. C. M. van Riel16, Mart A F J van de Laar17, Henk-Jan Guchelaar18, Tom W J Huizinga18, Philippe Dieudé19, Xavier Mariette20, S. Louis Bridges21, Alexandra Zhernakova18, Alexandra Zhernakova12, René E. M. Toes18, Paul P. Tak22, Paul P. Tak23, Paul P. Tak24, Corinne Miceli-Richard20, So Young Bang25, Hye Soon Lee25, Javier Martin26, Miguel A. Gonzalez-Gay, Luis Rodriguez-Rodriguez27, Solbritt Rantapää-Dahlqvist28, Lisbeth Ärlestig28, Hyon K. Choi2, Hyon K. Choi29, Yoichiro Kamatani30, Pilar Galan19, Mark Lathrop31, Steve Eyre32, Steve Eyre33, John Bowes33, John Bowes32, Anne Barton33, Niek de Vries24, Larry W. Moreland34, Lindsey A. Criswell35, Elizabeth W. Karlson2, Atsuo Taniguchi, Ryo Yamada4, Michiaki Kubo, Jun Liu2, Sang Cheol Bae25, Jane Worthington33, Jane Worthington32, Leonid Padyukov36, Lars Klareskog36, Peter K. Gregersen37, Soumya Raychaudhuri2, Soumya Raychaudhuri1, Barbara E. Stranger38, Philip L. De Jager1, Philip L. De Jager2, Lude Franke12, Peter M. Visscher10, Matthew A. Brown10, Hisashi Yamanaka, Tsuneyo Mimori4, Atsushi Takahashi, Huji Xu9, Timothy W. Behrens5, Katherine A. Siminovitch11, Shigeki Momohara, Fumihiko Matsuda4, Kazuhiko Yamamoto39, Robert M. Plenge2, Robert M. Plenge1 
20 Feb 2014-Nature
TL;DR: A genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries provides empirical evidence that the genetics of RA can provide important information for drug discovery, and sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis.
Abstract: A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

1,910 citations


Journal ArticleDOI
27 Mar 2014-Nature
TL;DR: For example, the authors mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body.
Abstract: Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research

1,715 citations


Journal ArticleDOI
27 Feb 2014-Cell
TL;DR: In this article, the crystal structure of the CRISPR-associated endonuclease Cas9 in complex with sgRNA and its target DNA at 2.5-A resolution was reported.

1,694 citations


Journal ArticleDOI
TL;DR: The Japanese Society of Hypertension Guidelines for the Management ofhypertension (JSH 2009) provide guidelines for the management ofpertension in patients with high blood pressure.
Abstract: The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009)

1,409 citations


Journal ArticleDOI
TL;DR: Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability in patients with mild Alzheimer's disease.
Abstract: BackgroundAlzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain. MethodsIn two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study–Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary...

Journal ArticleDOI
TL;DR: Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015, with evidence of continued acceleration in the MMR, and MMR was highest in the oldest age groups in both 1990 and 2013.

Journal ArticleDOI
TL;DR: In this article, the authors investigate the evolution of the star-forming galaxy (SFG) main sequence (MS) in stellar mass and star formation rate (SFR) out to z ~ 6.4 Gyr.
Abstract: Using a compilation of 25 studies from the literature, we investigate the evolution of the star-forming galaxy (SFG) main sequence (MS) in stellar mass and star formation rate (SFR) out to z ~ 6. After converting all observations to a common set of calibrations, we find a remarkable consensus among MS observations (~0.1 dex 1σ interpublication scatter). By fitting for time evolution of the MS in bins of constant mass, we deconvolve the observed scatter about the MS within each observed redshift bin. After accounting for observed scatter between different SFR indicators, we find the width of the MS distribution is ~0.2 dex and remains constant over cosmic time. Our best fits indicate the slope of the MS is likely time-dependent, with our best-fit log SFR(M_*, t) = (0.84 ± 0.02 – 0.026 ± 0.003 × t)log M_* – (6.51 ± 0.24 – 0.11 ± 0.03 × t), where t is the age of the universe in Gyr. We use our fits to create empirical evolutionary tracks in order to constrain MS galaxy star formation histories (SFHs), finding that (1) the most accurate representations of MS SFHs are given by delayed-τ models, (2) the decline in fractional stellar mass growth for a "typical" MS galaxy today is approximately linear for most of its lifetime, and (3) scatter about the MS can be generated by galaxies evolving along identical evolutionary tracks assuming an initial 1σ spread in formation times of ~1.4 Gyr.

Journal ArticleDOI
TL;DR: It is shown that climate change is likely to exacerbate regional and global water scarcity considerably and GHM uncertainty is particularly dominant in many regions affected by declining water resources, suggesting a high potential for improved water resource projections through hydrological model development.
Abstract: Water scarcity severely impairs food security and economic prosperity in many countries today. Expected future population changes will, in many countries as well as globally, increase the pressure on available water resources. On the supply side, renewable water resources will be affected by projected changes in precipitation patterns, temperature, and other climate variables. Here we use a large ensemble of global hydrological models (GHMs) forced by five global climate models and the latest greenhouse-gas concentration scenarios (Representative Concentration Pathways) to synthesize the current knowledge about climate change impacts on water resources. We show that climate change is likely to exacerbate regional and global water scarcity considerably. In particular, the ensemble average projects that a global warming of 2 °C above present (approximately 2.7 °C above preindustrial) will confront an additional approximate 15% of the global population with a severe decrease in water resources and will increase the number of people living under absolute water scarcity (<500 m3 per capita per year) by another 40% (according to some models, more than 100%) compared with the effect of population growth alone. For some indicators of moderate impacts, the steepest increase is seen between the present day and 2 °C, whereas indicators of very severe impacts increase unabated beyond 2 °C. At the same time, the study highlights large uncertainties associated with these estimates, with both global climate models and GHMs contributing to the spread. GHM uncertainty is particularly dominant in many regions affected by declining water resources, suggesting a high potential for improved water resource projections through hydrological model development.

Journal ArticleDOI
01 Feb 2014-Leukemia
TL;DR: Large-scale genetic and molecular profiling of multiple target genes is invaluable for subclassification and prognostication in MDS patients.
Abstract: High-throughput DNA sequencing significantly contributed to diagnosis and prognostication in patients with myelodysplastic syndromes (MDS). We determined the biological and prognostic significance of genetic aberrations in MDS. In total, 944 patients with various MDS subtypes were screened for known/putative mutations/deletions in 104 genes using targeted deep sequencing and array-based genomic hybridization. In total, 845/944 patients (89.5%) harbored at least one mutation (median, 3 per patient; range, 0-12). Forty-seven genes were significantly mutated with TET2, SF3B1, ASXL1, SRSF2, DNMT3A, and RUNX1 mutated in >10% of cases. Many mutations were associated with higher risk groups and/or blast elevation. Survival was investigated in 875 patients. By univariate analysis, 25/48 genes (resulting from 47 genes tested significantly plus PRPF8) affected survival (P<0.05). The status of 14 genes combined with conventional factors revealed a novel prognostic model ('Model-1') separating patients into four risk groups ('low', 'intermediate', 'high', 'very high risk') with 3-year survival of 95.2, 69.3, 32.8, and 5.3% (P<0.001). Subsequently, a 'gene-only model' ('Model-2') was constructed based on 14 genes also yielding four significant risk groups (P<0.001). Both models were reproducible in the validation cohort (n=175 patients; P<0.001 each). Thus, large-scale genetic and molecular profiling of multiple target genes is invaluable for subclassification and prognostication in MDS patients.

Journal ArticleDOI
01 Jan 2014
TL;DR: In this paper, the authors present a comprehensive state-of-the-art survey on SM-MIMO research, to provide a critical appraisal of its potential advantages, and to promote the discussion of its beneficial application areas and their research challenges.
Abstract: A key challenge of future mobile communication research is to strike an attractive compromise between wireless network's area spectral efficiency and energy efficiency. This necessitates a clean-slate approach to wireless system design, embracing the rich body of existing knowledge, especially on multiple-input-multiple-ouput (MIMO) technologies. This motivates the proposal of an emerging wireless communications concept conceived for single-radio-frequency (RF) large-scale MIMO communications, which is termed as SM. The concept of SM has established itself as a beneficial transmission paradigm, subsuming numerous members of the MIMO system family. The research of SM has reached sufficient maturity to motivate its comparison to state-of-the-art MIMO communications, as well as to inspire its application to other emerging wireless systems such as relay-aided, cooperative, small-cell, optical wireless, and power-efficient communications. Furthermore, it has received sufficient research attention to be implemented in testbeds, and it holds the promise of stimulating further vigorous interdisciplinary research in the years to come. This tutorial paper is intended to offer a comprehensive state-of-the-art survey on SM-MIMO research, to provide a critical appraisal of its potential advantages, and to promote the discussion of its beneficial application areas and their research challenges leading to the analysis of the technological issues associated with the implementation of SM-MIMO. The paper is concluded with the description of the world's first experimental activities in this vibrant research field.

Journal ArticleDOI
30 Apr 2014-Nature
TL;DR: The results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity, and demonstrate that phosphorylated ubiquit in is a parkin activator.
Abstract: Ubiquitin, known for its role in post-translational modification of other proteins, undergoes post-translational modification itself; after a decrease in mitochondrial membrane potential, the kinase enzyme PINK1 phosphorylates ubiquitin at Ser 65, and the phosphorylated ubiquitin then interacts with ubiquitin ligase (E3) enzyme parkin, which is also phosphorylated by PINK1, and this process is sufficient for full activation of parkin enzymatic activity. The small protein ubiquitin, familiar for its role in post-translational modification of other proteins by binding to them and regulating their activity or stability, is shown here to be the substrate of the kinase PINK1, which together with the ubiquitin ligase parkin is a causal gene for hereditary recessive Parkinsonism. Noriyuki Matsuda and colleagues show that following a decrease in mitochondrial membrane potential, PINK1 phosphorylates ubiquitin at serine residue 65; the phosphorylated ubiquitin then interacts with parkin, which is also phosphorylated by PINK1. This interaction allows full activation of parkin enzymatic activity, which involves tagging mitochondrial substrates with ubiquitin. PINK1 (PTEN induced putative kinase 1) and PARKIN (also known as PARK2) have been identified as the causal genes responsible for hereditary recessive early-onset Parkinsonism1,2. PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates3,4,5. PINK1 acts as an upstream factor for parkin6,7 and is essential both for the activation of latent E3 parkin activity8 and for recruiting parkin onto depolarized mitochondria8,9,10,11,12. Recently, mechanistic insights into mitochondrial quality control mediated by PINK1 and parkin have been revealed3,4,5, and PINK1-dependent phosphorylation of parkin has been reported13,14,15. However, the requirement of PINK1 for parkin activation was not bypassed by phosphomimetic parkin mutation15, and how PINK1 accelerates the E3 activity of parkin on damaged mitochondria is still obscure. Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential. Unexpectedly, phosphomimetic ubiquitin bypassed PINK1-dependent activation of a phosphomimetic parkin mutant in cells. Furthermore, phosphomimetic ubiquitin accelerates discharge of the thioester conjugate formed by UBCH7 (also known as UBE2L3) and ubiquitin (UBCH7∼ubiquitin) in the presence of parkin in vitro, indicating that it acts allosterically. The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator.

Journal ArticleDOI
10 Jan 2014-Science
TL;DR: Exome sequencing of exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution.
Abstract: Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in TP53, ATRX, SMARCA4, and BRAF; this suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis.

Journal ArticleDOI
TL;DR: MaNGA (Mapping Nearby Galaxies at Apache Point Observatory) as mentioned in this paper employs dithered observations with 17 fiber-bundle integral field units that vary in diameter from 12'' (19 fibers) to 32'' (127 fibers).
Abstract: We present an overview of a new integral field spectroscopic survey called MaNGA (Mapping Nearby Galaxies at Apache Point Observatory), one of three core programs in the fourth-generation Sloan Digital Sky Survey (SDSS-IV) that began on 2014 July 1. MaNGA will investigate the internal kinematic structure and composition of gas and stars in an unprecedented sample of 10,000 nearby galaxies. We summarize essential characteristics of the instrument and survey design in the context of MaNGA's key science goals and present prototype observations to demonstrate MaNGA's scientific potential. MaNGA employs dithered observations with 17 fiber-bundle integral field units that vary in diameter from 12'' (19 fibers) to 32'' (127 fibers). Two dual-channel spectrographs provide simultaneous wavelength coverage over 3600-10300 A at R ~ 2000. With a typical integration time of 3 hr, MaNGA reaches a target r-band signal-to-noise ratio of 4-8 (A–1 per 2'' fiber) at 23 AB mag arcsec–2, which is typical for the outskirts of MaNGA galaxies. Targets are selected with M * 109 M ☉ using SDSS-I redshifts and i-band luminosity to achieve uniform radial coverage in terms of the effective radius, an approximately flat distribution in stellar mass, and a sample spanning a wide range of environments. Analysis of our prototype observations demonstrates MaNGA's ability to probe gas ionization, shed light on recent star formation and quenching, enable dynamical modeling, decompose constituent components, and map the composition of stellar populations. MaNGA's spatially resolved spectra will enable an unprecedented study of the astrophysics of nearby galaxies in the coming 6 yr.

Journal ArticleDOI
24 Apr 2014-Cell
TL;DR: CUBIC enables time-course expression profiling of whole adult brains with single-cell resolution and develops a whole-brain cell-nuclear counterstaining protocol and a computational image analysis pipeline that enable the visualization and quantification of neural activities induced by environmental stimulation.

Journal ArticleDOI
TL;DR: Kazuaki SHIMAMOTO, Katsuyuki ANDO, Toshiro FUJITA, Naoyuki HASEBE, Jitsuo HIGAKI, Masatsugu HORIUCHI, Yutaka IMAI, Tsutomu IMAIZUMI, Toshihiko ISHIMITSU, Masaaki ITO, Sadayoshi ITO and Hiroshi ITOH are presented.
Abstract: Kazuaki SHIMAMOTO, Katsuyuki ANDO, Toshiro FUJITA, Naoyuki HASEBE, Jitsuo HIGAKI, Masatsugu HORIUCHI, Yutaka IMAI, Tsutomu IMAIZUMI, Toshihiko ISHIMITSU, Masaaki ITO, Sadayoshi ITO, Hiroshi ITOH, Hiroshi IWAO, Hisashi KAI, Kazuomi KARIO, Naoki KASHIHARA, Yuhei KAWANO, Shokei KIM-MITSUYAMA, Genjiro KIMURA, Katsuhiko KOHARA, Issei KOMURO, Hiroo KUMAGAI, Hideo MATSUURA, Katsuyuki MIURA, Ryuichi MORISHITA, Mitsuhide NARUSE, Koichi NODE, Yusuke OHYA, Hiromi RAKUGI, Ikuo SAITO, Shigeyuki SAITOH, Kazuyuki SHIMADA, Tatsuo SHIMOSAWA, Hiromichi SUZUKI, Kouichi TAMURA, Norio TANAHASHI, Takuya TSUCHIHASHI, Makoto UCHIYAMA, Shinichiro UEDA, Satoshi UMEMURA, on behalf of The Japanese Society of Hypertension Committee for Guidelines for the Management of Hypertension

Proceedings ArticleDOI
06 Jul 2014
TL;DR: L-SHADE is proposed, which further extends SHADE with Linear Population Size Reduction (LPSR), which continually decreases the population size according to a linear function and is quite competitive with state-of-the-art evolutionary algorithms.
Abstract: SHADE is an adaptive DE which incorporates success-history based parameter adaptation and one of the state-of-the-art DE algorithms. This paper proposes L-SHADE, which further extends SHADE with Linear Population Size Reduction (LPSR), which continually decreases the population size according to a linear function. We evaluated the performance of L-SHADE on CEC2014 benchmarks and compared its search performance with state-of-the-art DE algorithms, as well as the state-of-the-art restart CMA-ES variants. The experimental results show that L-SHADE is quite competitive with state-of-the-art evolutionary algorithms.

Journal ArticleDOI
Anubha Mahajan1, Min Jin Go, Weihua Zhang2, Jennifer E. Below3  +392 moreInstitutions (104)
TL;DR: In this paper, the authors aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry.
Abstract: To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

Proceedings ArticleDOI
TL;DR: In this paper, the authors present a method to analyze the powers of a given trilinear form (a special kind of algebraic constructions also called a tensor) and obtain upper bounds on the asymptotic complexity of matrix multiplication.
Abstract: This paper presents a method to analyze the powers of a given trilinear form (a special kind of algebraic constructions also called a tensor) and obtain upper bounds on the asymptotic complexity of matrix multiplication. Compared with existing approaches, this method is based on convex optimization, and thus has polynomial-time complexity. As an application, we use this method to study powers of the construction given by Coppersmith and Winograd [Journal of Symbolic Computation, 1990] and obtain the upper bound $\omega<2.3728639$ on the exponent of square matrix multiplication, which slightly improves the best known upper bound.

Journal ArticleDOI
TL;DR: Enhanced reductive stability of a superconcentrated AN solution is reported and, for the first time, reversible lithium intercalation into a graphite electrode in a reduction-vulnerable AN solvent is demonstrated.
Abstract: The development of a stable, functional electrolyte is urgently required for fast-charging and high-voltage lithium-ion batteries as well as next-generation advanced batteries (e.g., Li–O2 systems). Acetonitrile (AN) solutions are one of the most promising electrolytes with remarkably high chemical and oxidative stability as well as high ionic conductivity, but its low stability against reduction is a critical problem that hinders its extensive applications. Herein, we report enhanced reductive stability of a superconcentrated AN solution (>4 mol dm–3). Applying it to a battery electrolyte, we demonstrate, for the first time, reversible lithium intercalation into a graphite electrode in a reduction-vulnerable AN solvent. Moreover, the reaction kinetics is much faster than in a currently used commercial electrolyte. First-principle calculations combined with spectroscopic analyses reveal that the peculiar reductive stability arises from modified frontier orbital characters unique to such superconcentrated ...

Journal ArticleDOI
TL;DR: A systematic review and pooled analysis of individual patient data from prospective cohort studies and a risk prediction chart to estimate 5-year aneurysm rupture risk by risk factor status found the PHASES score is an easily applicable aid for prediction of the risk of rupture of incidental intracranialAneurysms.
Abstract: Summary Background The decision of whether to treat incidental intracranial saccular aneurysms is complicated by limitations in current knowledge of their natural history. We combined individual patient data from prospective cohort studies to determine predictors of aneurysm rupture and to construct a risk prediction chart to estimate 5-year aneurysm rupture risk by risk factor status. Methods We did a systematic review and pooled analysis of individual patient data from 8382 participants in six prospective cohort studies with subarachnoid haemorrhage as outcome. We analysed cumulative rupture rates with Kaplan-Meier curves and assessed predictors with Cox proportional-hazard regression analysis. Findings Rupture occurred in 230 patients during 29 166 person-years of follow-up. The mean observed 1-year risk of aneurysm rupture was 1·4% (95% CI 1·1–1·6) and the 5-year risk was 3·4% (2·9–4·0). Predictors were age, hypertension, history of subarachnoid haemorrhage, aneurysm size, aneurysm location, and geographical region. In study populations from North America and European countries other than Finland, the estimated 5-year absolute risk of aneurysm rupture ranged from 0·25% in individuals younger than 70 years without vascular risk factors with a small-sized ( 20 mm) posterior circulation aneurysm. By comparison with populations from North America and European countries other than Finland, Finnish people had a 3·6-times increased risk of aneurysm rupture and Japanese people a 2·8-times increased risk. Interpretation The PHASES score is an easily applicable aid for prediction of the risk of rupture of incidental intracranial aneurysms. Funding Netherlands Organisation for Health Research and Development.

Journal ArticleDOI
28 Jan 2014-ACS Nano
TL;DR: The introduction of hydrogen in the reaction chamber helps to activate the selenization of WO3, where large-size WSe2 monolayer flakes or thin films can be successfully grown and the resistor-loaded inverter based on a WSe 2 film, with a gain of ∼13, further demonstrates its applicability for logic-circuit integrations.
Abstract: The monolayer transition metal dichalcogenides have recently attracted much attention owing to their potential in valleytronics, flexible and low-power electronics, and optoelectronic devices. Recent reports have demonstrated the growth of large-size two-dimensional MoS2 layers by the sulfurization of molybdenum oxides. However, the growth of a transition metal selenide monolayer has still been a challenge. Here we report that the introduction of hydrogen in the reaction chamber helps to activate the selenization of WO3, where large-size WSe2 monolayer flakes or thin films can be successfully grown. The top-gated field-effect transistors based on WSe2 monolayers using ionic gels as the dielectrics exhibit ambipolar characteristics, where the hole and electron mobility values are up to 90 and 7 cm2/Vs, respectively. These films can be transferred onto arbitrary substrates, which may inspire research efforts to explore their properties and applications. The resistor-loaded inverter based on a WSe2 film, wit...

Journal ArticleDOI
TL;DR: It is shown that TH17 cells originating from Foxp3+ T cells have a key role in the pathogenesis of autoimmune arthritis.
Abstract: Autoimmune diseases often result from an imbalance between regulatory T (Treg) cells and interleukin-17 (IL-17)-producing T helper (TH17) cells; the origin of the latter cells remains largely unknown. Foxp3 is indispensable for the suppressive function of Treg cells, but the stability of Foxp3 has been under debate. Here we show that TH17 cells originating from Foxp3(+) T cells have a key role in the pathogenesis of autoimmune arthritis. Under arthritic conditions, CD25(lo)Foxp3(+)CD4(+) T cells lose Foxp3 expression (herein called exFoxp3 cells) and undergo transdifferentiation into TH17 cells. Fate mapping analysis showed that IL-17-expressing exFoxp3 T (exFoxp3 TH17) cells accumulated in inflamed joints. The conversion of Foxp3(+)CD4(+) T cells to TH17 cells was mediated by synovial fibroblast-derived IL-6. These exFoxp3 TH17 cells were more potent osteoclastogenic T cells than were naive CD4(+) T cell-derived TH17 cells. Notably, exFoxp3 TH17 cells were characterized by the expression of Sox4, chemokine (C-C motif) receptor 6 (CCR6), chemokine (C-C motif) ligand 20 (CCL20), IL-23 receptor (IL-23R) and receptor activator of NF-κB ligand (RANKL, also called TNFSF11). Adoptive transfer of autoreactive, antigen-experienced CD25(lo)Foxp3(+)CD4(+) T cells into mice followed by secondary immunization with collagen accelerated the onset and increased the severity of arthritis and was associated with the loss of Foxp3 expression in the majority of transferred T cells. We observed IL-17(+)Foxp3(+) T cells in the synovium of subjects with active rheumatoid arthritis (RA), which suggests that plastic Foxp3(+) T cells contribute to the pathogenesis of RA. These findings establish the pathological importance of Foxp3 instability in the generation of pathogenic TH17 cells in autoimmunity.

Journal ArticleDOI
TL;DR: The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration.

Proceedings ArticleDOI
02 Dec 2014
TL;DR: It is demonstrated that autoencoders are able to detect subtle anomalies which linear PCA fails and can be useful as nonlinear techniques without complex computation as kernel PCA requires.
Abstract: This paper proposes to use autoencoders with nonlinear dimensionality reduction in the anomaly detection task. The authors apply dimensionality reduction by using an autoencoder onto both artificial data and real data, and compare it with linear PCA and kernel PCA to clarify its property. The artificial data is generated from Lorenz system, and the real data is the spacecrafts' telemetry data. This paper demonstrates that autoencoders are able to detect subtle anomalies which linear PCA fails. Also, autoencoders can increase their accuracy by extending them to denoising autoenconders. Moreover, autoencoders can be useful as nonlinear techniques without complex computation as kernel PCA requires. Finaly, the authors examine the learned features in the hidden layer of autoencoders, and present that autoencoders learn the normal state properly and activate differently with anomalous input.