Institution
University of Cambridge
Education•Cambridge, United Kingdom•
About: University of Cambridge is a education organization based out in Cambridge, United Kingdom. It is known for research contribution in the topics: Population & Galaxy. The organization has 118293 authors who have published 282289 publications receiving 14497093 citations. The organization is also known as: Cambridge University & Cambridge.
Topics: Population, Galaxy, Context (language use), Gene, Transplantation
Papers published on a yearly basis
Papers
More filters
TL;DR: It is shown that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis, establishing the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.
Abstract: Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies1. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction2, 3. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC2, 3 and the polymerase-associated factor complex (PAFc)4, 5, are associated with the BET family of acetyl-lysine recognizing, chromatin ‘adaptor’ proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL–AF9 and human MLL–AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.
1,388 citations
University of Rochester1, French Institute of Health and Medical Research2, Institute for Health Metrics and Evaluation3, Cairo University4, University of Extremadura5, Debre Berhan University6, University of Cambridge7, Seoul National University Hospital8, Autonomous University of Chile9, University of Pennsylvania10, Haramaya University11, Humboldt University of Berlin12, Karolinska Institutet13, McGill University14, Imperial College London15, West Virginia University16, University of Western Australia17, Hawassa University18, Tehran University of Medical Sciences19, Jordan University of Science and Technology20, Seoul National University21, Xiamen University22, University of Bari23, University of Porto24, National University of Malaysia25, University of Sydney26, Baqiyatallah University of Medical Sciences27, Iran University of Medical Sciences28, Mekelle University29, University of Western Sydney30, University of Ibadan31, La Trobe University32, Deakin University33, Ahvaz Jundishapur University of Medical Sciences34, University of Maragheh35, Utkal University36, University of North Carolina at Charlotte37, New York University38
TL;DR: Over the past generation, the global burden of Parkinson's disease has more than doubled as a result of increasing numbers of older people, with potential contributions from longer disease duration and environmental factors.
Abstract: Summary Background Neurological disorders are now the leading source of disability globally, and ageing is increasing the burden of neurodegenerative disorders, including Parkinson's disease. We aimed to determine the global burden of Parkinson's disease between 1990 and 2016 to identify trends and to enable appropriate public health, medical, and scientific responses. Methods Through a systematic analysis of epidemiological studies, we estimated global, regional, and country-specific prevalence and years of life lived with disability for Parkinson's disease from 1990 to 2016. We estimated the proportion of mild, moderate, and severe Parkinson's disease on the basis of studies that used the Hoehn and Yahr scale and assigned disability weights to each level. We jointly modelled prevalence and excess mortality risk in a natural history model to derive estimates of deaths due to Parkinson's disease. Death counts were multiplied by values from the Global Burden of Disease study's standard life expectancy to compute years of life lost. Disability-adjusted life-years (DALYs) were computed as the sum of years lived with disability and years of life lost. We also analysed results based on the Socio-demographic Index, a compound measure of income per capita, education, and fertility. Findings In 2016, 6·1 million (95% uncertainty interval [UI] 5·0–7·3) individuals had Parkinson's disease globally, compared with 2·5 million (2·0–3·0) in 1990. This increase was not solely due to increasing numbers of older people, because age-standardised prevalence rates increased by 21·7% (95% UI 18·1–25·3) over the same period (compared with an increase of 74·3%, 95% UI 69·2–79·6, for crude prevalence rates). Parkinson's disease caused 3·2 million (95% UI 2·6–4·0) DALYs and 211 296 deaths (95% UI 167 771–265 160) in 2016. The male-to-female ratios of age-standardised prevalence rates were similar in 2016 (1·40, 95% UI 1·36–1·43) and 1990 (1·37, 1·34–1·40). From 1990 to 2016, age-standardised prevalence, DALY rates, and death rates increased for all global burden of disease regions except for southern Latin America, eastern Europe, and Oceania. In addition, age-standardised DALY rates generally increased across the Socio-demographic Index. Interpretation Over the past generation, the global burden of Parkinson's disease has more than doubled as a result of increasing numbers of older people, with potential contributions from longer disease duration and environmental factors. Demographic and potentially other factors are poised to increase the future burden of Parkinson's disease substantially. Funding Bill & Melinda Gates Foundation.
1,388 citations
Broad Institute1, University of Amsterdam2, University of California, Riverside3, University of Arizona4, Université Paris-Saclay5, University of Córdoba (Spain)6, Oregon State University7, Aix-Marseille University8, Pennsylvania State University9, Texas A&M University10, Purdue University11, University of California, Irvine12, Rothamsted Research13, Pacific Northwest National Laboratory14, University of Minnesota15, United States Department of Agriculture16, Centre national de la recherche scientifique17, University of Texas Southwestern Medical Center18, University of California, Los Angeles19, Commonwealth Scientific and Industrial Research Organisation20, Seoul National University21, University of Texas at Dallas22, University of Cambridge23, University of Wisconsin-Madison24, Cornell University25
TL;DR: Comparison of genomes of three phenotypically diverse Fusarium species revealed lineage-specific genomic regions in F. oxysporum that include four entire chromosomes and account for more than one-quarter of the genome, putting the evolution of fungal pathogenicity into a new perspective.
Abstract: Fusarium species are among the most important phytopathogenic and toxigenic fungi. To understand the molecular underpinnings of pathogenicity in the genus Fusarium, we compared the genomes of three phenotypically diverse species: Fusarium graminearum, Fusarium verticillioides and Fusarium oxysporum f. sp. lycopersici. Our analysis revealed lineage-specific (LS) genomic regions in F. oxysporum that include four entire chromosomes and account for more than one-quarter of the genome. LS regions are rich in transposons and genes with distinct evolutionary profiles but related to pathogenicity, indicative of horizontal acquisition. Experimentally, we demonstrate the transfer of two LS chromosomes between strains of F. oxysporum, converting a non-pathogenic strain into a pathogen. Transfer of LS chromosomes between otherwise genetically isolated strains explains the polyphyletic origin of host specificity and the emergence of new pathogenic lineages in F. oxysporum. These findings put the evolution of fungal pathogenicity into a new perspective.
1,386 citations
TL;DR: Compared crop yields and densities of bird and tree species across gradients of agricultural intensity in southwest Ghana and northern India, land sparing is a more promising strategy for minimizing negative impacts of food production, at both current and anticipated future levels of production.
Abstract: The question of how to meet rising food demand at the least cost to biodiversity requires the evaluation of two contrasting alternatives: land sharing, which integrates both objectives on the same land; and land sparing, in which high-yield farming is combined with protecting natural habitats from conversion to agriculture. To test these alternatives, we compared crop yields and densities of bird and tree species across gradients of agricultural intensity in southwest Ghana and northern India. More species were negatively affected by agriculture than benefited from it, particularly among species with small global ranges. For both taxa in both countries, land sparing is a more promising strategy for minimizing negative impacts of food production, at both current and anticipated future levels of production.
1,383 citations
Conservation International1, International Union for Conservation of Nature and Natural Resources2, Sapienza University of Rome3, Texas A&M University4, University of Cambridge5, Instituto Superior Técnico6, Zoological Society of London7, Arizona State University8, Columbia University9, National Scientific and Technical Research Council10, Wildlife Conservation Society11, Imperial College London12, National University of Tucumán13, University of the Philippines Los Baños14, University of Tasmania15, University of Edinburgh16, Earthwatch Institute17, Drexel University18, Universidade Federal de Minas Gerais19, Global Environment Facility20, University of Alberta21, Smithsonian Institution22, Université de Sherbrooke23, University of Virginia24, Minnesota Department of Natural Resources25, University of Calgary26, James Cook University27, NatureServe28, University of St Andrews29, Australian National University30, University of Montana31, General Post Office32, University of Otago33, Field Museum of Natural History34, Wildlife Institute of India35, Tokyo Woman's Christian University36, National Oceanic and Atmospheric Administration37, University of Aberdeen38, University of the Witwatersrand39, University of Oxford40, Norwegian Polar Institute41, University Centre in Svalbard42, Copenhagen Zoo43, San Diego State University44, University of Alaska Fairbanks45, Manchester Metropolitan University46, National Autonomous University of Mexico47, University of Kent48, City University of New York49, Victoria University of Wellington50, California Academy of Sciences51, Mote Marine Laboratory52, Osmania University53, White Oak Conservation54, Aaranyak55, University of California, Davis56, Museu Paraense Emílio Goeldi57, University of Stirling58
TL;DR: In this paper, the authors present a comprehensive assessment of the conservation status and distribution of the world's mammals, including marine mammals, using data collected by 1700+ experts, covering all 5487 species.
Abstract: Knowledge of mammalian diversity is still surprisingly disparate, both regionally and taxonomically. Here, we present a comprehensive assessment of the conservation status and distribution of the world's mammals. Data, compiled by 1700+ experts, cover all 5487 species, including marine mammals. Global macroecological patterns are very different for land and marine species but suggest common mechanisms driving diversity and endemism across systems. Compared with land species, threat levels are higher among marine mammals, driven by different processes (accidental mortality and pollution, rather than habitat loss), and are spatially distinct (peaking in northern oceans, rather than in Southeast Asia). Marine mammals are also disproportionately poorly known. These data are made freely available to support further scientific developments and conservation action.
1,383 citations
Authors
Showing all 119522 results
| Name | H-index | Papers | Citations |
|---|---|---|---|
| Albert Hofman | 267 | 2530 | 321405 |
| Zhong Lin Wang | 245 | 2529 | 259003 |
| Solomon H. Snyder | 232 | 1222 | 200444 |
| Trevor W. Robbins | 231 | 1137 | 164437 |
| George Davey Smith | 224 | 2540 | 248373 |
| Nicholas J. Wareham | 212 | 1657 | 204896 |
| Cyrus Cooper | 204 | 1869 | 206782 |
| Eric B. Rimm | 196 | 988 | 147119 |
| Martin White | 196 | 2038 | 232387 |
| Simon D. M. White | 189 | 795 | 231645 |
| Michael Rutter | 188 | 676 | 151592 |
| George Efstathiou | 187 | 637 | 156228 |
| Mark Hallett | 186 | 1170 | 123741 |
| David H. Weinberg | 183 | 700 | 171424 |
| Paul G. Richardson | 183 | 1533 | 155912 |