NPJ Aging and Mechanisms of Disease最新文献

{"title":"Erratum: Author Correction: Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD⁺ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study.","authors":"Ryan W Dellinger,&nbsp;Santiago Roel Santos,&nbsp;Mark Morris,&nbsp;Mal Evans,&nbsp;Dan Alminana,&nbsp;Leonard Guarente,&nbsp;Eric Marcotulli","doi":"10.1038/s41514-018-0027-1","DOIUrl":"https://doi.org/10.1038/s41514-018-0027-1","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1038/s41514-017-0016-9.].</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":" ","pages":"8"},"PeriodicalIF":5.0,"publicationDate":"2018-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-018-0027-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36436105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A parthenogenetic quasi-program causes teratoma-like tumors during aging in wild-type <i>C. elegans</i>.","authors":"Hongyuan Wang, Yuan Zhao, Marina Ezcurra, Alexandre Benedetto, Ann F Gilliat, Josephine Hellberg, Ziyu Ren, Evgeniy R Galimov, Trin Athigapanich, Johannes Girstmair, Maximilian J Telford, Colin T Dolphin, Zhizhou Zhang, David Gems","doi":"10.1038/s41514-018-0025-3","DOIUrl":"10.1038/s41514-018-0025-3","url":null,"abstract":"<p><p>A long-standing belief is that aging (senescence) is the result of stochastic damage accumulation. Alternatively, senescent pathology may also result from late-life, wild-type gene action (i.e., antagonistic pleiotropy, as argued by Williams) leading to non-adaptive run-on of developmental programs (or <i>quasi-programs</i>) (as suggested more recently by Blagosklonny). In this study, we use existing and new data to show how uterine tumors, a prominent form of senescent pathology in the nematode <i>Caenorhabditis elegans</i>, likely result from quasi-programs. Such tumors develop from unfertilized oocytes which enter the uterus and become hypertrophic and replete with endoreduplicated chromatin masses. Tumor formation begins with ovulation of unfertilized oocytes immediately after exhaustion of sperm stocks. We show that the timing of this transition between program and quasi-program (i.e., the onset of senescence), and the onset of tumor formation, depends upon the timing of sperm depletion. We identify homology between uterine tumors and mammalian ovarian teratomas, which both develop from oocytes that fail to mature after meiosis I. In teratomas, futile activation of developmental programs leads to the formation of differentiated structures within the tumor. We report that older uterine tumors express markers of later embryogenesis, consistent with teratoma-like activation of developmental programs. We also present evidence of coupling of distal gonad atrophy to oocyte hypertrophy. This study shows how the Williams Blagosklonny model can provide a mechanistic explanation of this component of <i>C. elegans</i> aging. It also suggests etiological similarity between teratoma and some forms of senescent pathology, insofar as both are caused by quasi-programs.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"4 ","pages":"6"},"PeriodicalIF":5.0,"publicationDate":"2018-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-018-0025-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10019727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tissue-specific transcriptome profiling of <i>Drosophila</i> reveals roles for GATA transcription factors in longevity by dietary restriction.","authors":"Adam J Dobson, Xiaoli He, Eric Blanc, Ekin Bolukbasi, Yodit Feseha, Mingyao Yang, Matthew D W Piper","doi":"10.1038/s41514-018-0024-4","DOIUrl":"10.1038/s41514-018-0024-4","url":null,"abstract":"<p><p>Dietary restriction (DR) extends animal lifespan, but imposes fitness costs. This phenomenon depends on dietary essential amino acids (EAAs) and TOR signalling, which exert systemic effects. However, the roles of specific tissues and cell-autonomous transcriptional regulators in diverse aspects of the DR phenotype are unknown. Manipulating relevant transcription factors (TFs) specifically in lifespan-limiting tissues may separate the lifespan benefits of DR from the early-life fitness costs. Here, we systematically analyse transcription across organs of <i>Drosophila</i> subjected to DR or low TOR and predict regulatory TFs. We predict and validate roles for the evolutionarily conserved GATA family of TFs, and identify conservation of this signal in mice. Importantly, restricting knockdown of the GATA TF <i>srp</i> to specific fly tissues recapitulated the benefits but not the costs of DR. Together, our data indicate that the GATA TFs mediate effects of dietary amino acids on lifespan, and that by manipulating them in specific tissues it is possible to reap the fitness benefits of EAAs, decoupled from a cost to longevity.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"4 ","pages":"5"},"PeriodicalIF":5.4,"publicationDate":"2018-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9444237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural variation of chronological aging in the <i>Saccharomyces cerevisiae</i> species reveals diet-dependent mechanisms of life span control.","authors":"Paul P Jung,&nbsp;Zhi Zhang,&nbsp;Nicole Paczia,&nbsp;Christian Jaeger,&nbsp;Tomasz Ignac,&nbsp;Patrick May,&nbsp;Carole L Linster","doi":"10.1038/s41514-018-0022-6","DOIUrl":"https://doi.org/10.1038/s41514-018-0022-6","url":null,"abstract":"<p><p>Aging is a complex trait of broad scientific interest, especially because of its intrinsic link with common human diseases. Pioneering work on aging-related mechanisms has been made in <i>Saccharomyces cerevisiae</i>, mainly through the use of deletion collections isogenic to the S288c reference strain. In this study, using a recently published high-throughput approach, we quantified chronological life span (CLS) within a collection of 58 natural strains across seven different conditions. We observed a broad aging variability suggesting the implication of diverse genetic and environmental factors in chronological aging control. Two major Quantitative Trait Loci (QTLs) were identified within a biparental population obtained by crossing two natural isolates with contrasting aging behavior. Detection of these QTLs was dependent upon the nature and concentration of the carbon sources available for growth. In the first QTL, the <i>RIM15</i> gene was identified as major regulator of aging under low glucose condition, lending further support to the importance of nutrient-sensing pathways in longevity control under calorie restriction. In the second QTL, we could show that the <i>SER1</i> gene, encoding a conserved aminotransferase of the serine synthesis pathway not previously linked to aging, is causally associated with CLS regulation, especially under high glucose condition. These findings hint toward a new mechanism of life span control involving a trade-off between serine synthesis and aging, most likely through modulation of acetate and trehalose metabolism. More generally it shows that genetic linkage studies across natural strains represent a promising strategy to further unravel the molecular basis of aging.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":" ","pages":"3"},"PeriodicalIF":5.0,"publicationDate":"2018-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-018-0022-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35933446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physician-initiated clinical study of limb ulcers treated with a functional peptide, SR-0379: from discovery to a randomized, double-blind, placebo-controlled trial.","authors":"Hironori Nakagami,&nbsp;Ken Sugimoto,&nbsp;Takahiro Ishikawa,&nbsp;Taku Fujimoto,&nbsp;Toshifumi Yamaoka,&nbsp;Misa Hayashi,&nbsp;Eiji Kiyohara,&nbsp;Hiroshi Ando,&nbsp;Yuta Terabe,&nbsp;Yoichi Takami,&nbsp;Koichi Yamamoto,&nbsp;Yasushi Takeya,&nbsp;Minoru Takemoto,&nbsp;Masaya Koshizaka,&nbsp;Tamotsu Ebihara,&nbsp;Ayumi Nakamura,&nbsp;Mitsunori Nishikawa,&nbsp;Xiang Jing Yao,&nbsp;Hideki Hanaoka,&nbsp;Ichiro Katayama,&nbsp;Koutaro Yokote,&nbsp;Hiromi Rakugi","doi":"10.1038/s41514-018-0021-7","DOIUrl":"https://doi.org/10.1038/s41514-018-0021-7","url":null,"abstract":"<p><p>SR-0379 is a functional peptide that has wound healing effect with anti-microbial action, making it an ideal drug to prevent infection. To evaluate the safety, efficacy, and pharmacokinetics of SR-0379 for the treatment of leg ulcers, a physician-initiated, phase I/IIa, first-in-patient clinical study was designed. A multi-center, double-blind, randomized clinical study was conducted from October 2015 to September 2016. The inclusion criteria for leg ulcers were (1) diabetes or critical limb ischemia and (2) wound size <6 cm in diameter. Twelve patients were randomized into four groups and administered 0.02%, 0.1%, or 0.5% SR-0379 or placebo treatment on skin ulcers once per day for 28 days. Efficiency was evaluated by determining the rate of wound size reduction as a primary endpoint at 4 weeks after the first treatment compared with the pre-treatment wound size. As a secondary endpoint, the DESIGN-R score index, time to wound closure, and the 50% wound size reduction ratio were also evaluated. The safety of SR-0379 was evaluated during the study period. In the evaluation of efficiency, the skin ulcer reduction rates at the last evaluation were 44.73% for the 0.02% SR-0379 group, 68.25% for the 0.1% group, and 71.61% for the 0.5% group, compared with 9.95% for the placebo group. Six adverse events were reported in four patients, of which one occurred in the placebo group, and causal relationships to study drugs were denied for all six events. Treatment with SR-0379 for chronic leg ulcers was safe, well tolerated, and effective.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":" ","pages":"2"},"PeriodicalIF":5.0,"publicationDate":"2018-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-018-0021-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35837458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fighting against a protean enemy: immunosenescence, vaccines, and healthy aging.","authors":"Giuseppe Del Giudice,&nbsp;Jörg J Goronzy,&nbsp;Beatrix Grubeck-Loebenstein,&nbsp;Paul-Henri Lambert,&nbsp;Tomas Mrkvan,&nbsp;Jeffrey J Stoddard,&nbsp;T Mark Doherty","doi":"10.1038/s41514-017-0020-0","DOIUrl":"https://doi.org/10.1038/s41514-017-0020-0","url":null,"abstract":"<p><p>The progressive increase of the aged population worldwide mandates new strategies to ensure sustained health and well-being with age. The development of better and/or new vaccines against pathogens that affect older adults is one pivotal intervention in approaching this goal. However, the functional decline of various physiological systems, including the immune system, requires novel approaches to counteract immunosenescence. Although important progress has been made in understanding the mechanisms underlying the age-related decline of the immune response to infections and vaccinations, knowledge gaps remain, both in the areas of basic and translational research. In particular, it will be important to better understand how environmental factors, such as diet, physical activity, co-morbidities, and pharmacological treatments, delay or contribute to the decline of the capability of the aging immune system to appropriately respond to infectious diseases and vaccination. Recent findings suggest that successful approaches specifically targeted to the older population can be developed, such as the high-dose and adjuvanted vaccines against seasonal influenza, the adjuvanted subunit vaccine against herpes zoster, as well as experimental interventions with immune-potentiators or immunostimulants. Learning from these first successes may pave the way to developing novel and improved vaccines for the older adults and immunocompromised. With an integrated, holistic vaccination strategy, society will offer the opportunity for an improved quality of life to the segment of the population that is going to increase most significantly in numbers and proportion over future decades.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":" ","pages":"1"},"PeriodicalIF":5.0,"publicationDate":"2017-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-017-0020-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35694916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytochrome b5 protects photoreceptors from light stress-induced lipid peroxidation and retinal degeneration.","authors":"Xinping Chen,&nbsp;Hana Hall,&nbsp;Jeffrey P Simpson,&nbsp;Walter D Leon-Salas,&nbsp;Donald F Ready,&nbsp;Vikki M Weake","doi":"10.1038/s41514-017-0019-6","DOIUrl":"https://doi.org/10.1038/s41514-017-0019-6","url":null,"abstract":"<p><p>Lipid peroxides are generated by oxidative stress in cells, and contribute to ageing and neurodegenerative disease. The eye is at special risk for lipid peroxidation because photoreceptors possess amplified sensory membranes rich in peroxidation-susceptible polyunsaturated fatty acids. Light-induced lipid peroxidation in the retina contributes to retinal degeneration, and lipid peroxidation has been implicated in the progression of age-associated ocular diseases such as age-related macular degeneration (AMD). Here, we show that exposing <i>Drosophila melanogaster</i> to strong blue light induces oxidative stress including lipid peroxidation that results in retinal degeneration. Surprisingly, very young flies are resilient to this acute light stress, suggesting they possess endogenous neuroprotective mechanisms. While lipophilic antioxidants partially suppressed blue light-induced retinal degeneration in older flies, we find that overexpression of cytochrome b5 (Cyt-b5) completely suppressed both blue light-induced lipid peroxidation and retinal degeneration. Our data identify Cyt-b5 as a neuroprotective factor that targets light-induced oxidative damage, particularly lipid peroxidation. Cyt-b5 may function via supporting antioxidant recycling, thereby providing a strategy to prevent oxidative stress in ageing photoreceptors that would be synergistic with dietary antioxidant supplementation.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":" ","pages":"18"},"PeriodicalIF":5.0,"publicationDate":"2017-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-017-0019-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35230820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective role of retinal SIRT3 against acute photo-stress.","authors":"Norimitsu Ban,&nbsp;Yoko Ozawa,&nbsp;Hideto Osada,&nbsp;Jonathan B Lin,&nbsp;Eriko Toda,&nbsp;Mitsuhiro Watanabe,&nbsp;Kenya Yuki,&nbsp;Shunsuke Kubota,&nbsp;Rajendra S Apte,&nbsp;Kazuo Tsubota","doi":"10.1038/s41514-017-0017-8","DOIUrl":"https://doi.org/10.1038/s41514-017-0017-8","url":null,"abstract":"<p><p>SIRT3 is a key regulator of mitochondrial reactive oxygen species as well as mitochondrial function. The retina is one of the highest energy-demanding tissues, in which the regulation of reactive oxygen species is critical to prevent retinal neurodegeneration. Although previous reports have demonstrated that SIRT3 is highly expressed in the retina and important in neuroprotection, function of SIRT3 in regulating reactive oxygen species in the retina is largely unknown. In this study, we investigated the role of retinal SIRT3 in a light-induced retinal degeneration model using SIRT3 knockout mice. We demonstrate that SIRT3 deficiency causes acute reactive oxygen species accumulation and endoplasmic reticulum stress in the retina after the light exposure, which leads to increased photoreceptor death, retinal thinning, and decreased retinal function. Using a photoreceptor-derived cell line, we revealed that reactive oxygen species were the upstream initiators of endoplasmic reticulum stress. Under SIRT3 knockdown condition, we demonstrated that decreased superoxide dismutase 2 activity led to elevated intracellular reactive oxygen species. These studies have helped to elucidate the critical role of SIRT3 in photoreceptor neuronal survival, and suggest that SIRT3 might be a therapeutic target for oxidative stress-induced retinal disorders.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":" ","pages":"19"},"PeriodicalIF":5.0,"publicationDate":"2017-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-017-0017-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35231291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD⁺ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study.","authors":"Ryan W Dellinger,&nbsp;Santiago Roel Santos,&nbsp;Mark Morris,&nbsp;Mal Evans,&nbsp;Dan Alminana,&nbsp;Leonard Guarente,&nbsp;Eric Marcotulli","doi":"10.1038/s41514-017-0016-9","DOIUrl":"https://doi.org/10.1038/s41514-017-0016-9","url":null,"abstract":"<p><p>NRPT is a combination of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD⁺⁾ precursor vitamin found in milk, and pterostilbene (PT), a polyphenol found in blueberries. Here, we report this first-in-humans clinical trial designed to assess the safety and efficacy of a repeat dose of NRPT (commercially known as Basis). NRPT was evaluated in a randomized, double-blind, and placebo-controlled study in a population of 120 healthy adults between the ages of 60 and 80 years. The study consisted of three treatment arms: placebo, recommended dose of NRPT (NRPT 1X), and double dose of NRPT (NRPT 2X). All subjects took their blinded supplement daily for eight weeks. Analysis of NAD⁺ in whole blood demonstrated that NRPT significantly increases the concentration of NAD⁺ in a dose-dependent manner. NAD⁺ levels increased by approximately 40% in the NRPT 1X group and approximately 90% in the NRPT 2X group after 4 weeks as compared to placebo and baseline. Furthermore, this significant increase in NAD⁺ levels was sustained throughout the entire 8-week trial. NAD⁺ levels did not increase for the placebo group during the trial. No serious adverse events were reported in this study. This study shows that a repeat dose of NRPT is a safe and effective way to increase NAD⁺ levels sustainably.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":" ","pages":"17"},"PeriodicalIF":5.0,"publicationDate":"2017-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-017-0016-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35598151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Health benefits of late-onset metformin treatment every other week in mice.","authors":"Irene Alfaras,&nbsp;Sarah J Mitchell,&nbsp;Hector Mora,&nbsp;Darisbeth Rosario Lugo,&nbsp;Alessandra Warren,&nbsp;Ignacio Navas-Enamorado,&nbsp;Vickie Hoffmann,&nbsp;Christopher Hine,&nbsp;James R Mitchell,&nbsp;David G Le Couteur,&nbsp;Victoria C Cogger,&nbsp;Michel Bernier,&nbsp;Rafael de Cabo","doi":"10.1038/s41514-017-0018-7","DOIUrl":"https://doi.org/10.1038/s41514-017-0018-7","url":null,"abstract":"<p><p>Chronic 1% metformin treatment is nephrotoxic in mice, but this dose may nonetheless confer health benefits if given intermittently rather than continuously. Here, we examined the effects of 1% metformin given every-other week (EOW) or two consecutive weeks per month (2WM) on survival of 2-year-old male mice fed standard chow. EOW and 2WM mice had comparable life span compared with control mice. A significant reduction in body weight within the first few weeks of metformin treatment was observed without impact on food consumption and energy expenditure. Moreover, there were differences in the action of metformin on metabolic markers between the EOW and 2WM groups, with EOW metformin conferring greater benefits. Age-associated kidney lesions became more pronounced with metformin, although without pathological consequences. In the liver, metformin treatment led to an overall reduction in steatosis and was accompanied by distinct transcriptomic and metabolomic signatures in response to EOW versus 2WM regimens. Thus, the absence of adverse outcomes associated with chronic, intermittent use of 1% metformin in old mice has clinical translatability into the biology of aging in humans.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":" ","pages":"16"},"PeriodicalIF":5.0,"publicationDate":"2017-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-017-0018-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35632245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}