Le Zong, Mayuri Tanaka-Yano, Bongsoo Park, Hagai Yanai, Ferda T Turhan, Deborah L Croteau, Jane Tian, Evandro F Fang, Vilhelm A Bohr, Isabel Beerman
{"title":"NAD<sup>+</sup> augmentation with nicotinamide riboside improves lymphoid potential of Atm<sup>-/-</sup> and old mice HSCs.","authors":"Le Zong, Mayuri Tanaka-Yano, Bongsoo Park, Hagai Yanai, Ferda T Turhan, Deborah L Croteau, Jane Tian, Evandro F Fang, Vilhelm A Bohr, Isabel Beerman","doi":"10.1038/s41514-021-00078-3","DOIUrl":"https://doi.org/10.1038/s41514-021-00078-3","url":null,"abstract":"<p><p>NAD<sup>+</sup> supplementation has significant benefits in compromised settings, acting largely through improved mitochondrial function and DNA repair. Elevating NAD<sup>+</sup> to physiological levels has been shown to improve the function of some adult stem cells, with implications that these changes will lead to sustained improvement of the tissue or system. Here, we examined the effect of elevating NAD<sup>+</sup> levels in models with reduced hematopoietic stem cell (HSC) potential, ATM-deficient and aged WT mice, and showed that supplementation of nicotinamide riboside (NR), a NAD<sup>+</sup> precursor, improved lymphoid lineage potential during supplementation. In aged mice, this improved lymphoid potential was maintained in competitive transplants and was associated with transcriptional repression of myeloid gene signatures in stem and lineage-committed progenitor cells after NR treatment. However, the altered transcriptional priming of the stem cells toward lymphoid lineages was not sustained in the aged mice after NR removal. These data characterize significant alterations to the lineage potential of functionally compromised HSCs after short-term exposure to NR treatment.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2021-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39436921","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":"Assessing the cognitive status of Drosophila by the value-based feeding decision.","authors":"Chih-Chieh Yu, Ferng-Chang Chang, Yong-Huei Hong, Jian-Chiuan Li, Po-Lin Chen, Chun-Hong Chen, Tzai-Wen Chiu, Tsai-Te Lu, Yun-Ming Wang, Chih-Fei Kao","doi":"10.1038/s41514-021-00075-6","DOIUrl":"https://doi.org/10.1038/s41514-021-00075-6","url":null,"abstract":"<p><p>Decision-making is considered an important aspect of cognitive function. Impaired decision-making is a consequence of cognitive decline caused by various physiological conditions, such as aging and neurodegenerative diseases. Here we exploited the value-based feeding decision (VBFD) assay, which is a simple sensory-motor task, to determine the cognitive status of Drosophila. Our results indicated the deterioration of VBFD is notably correlated with aging and neurodegenerative disorders. Restriction of the mushroom body (MB) neuronal activity partly blunted the proper VBFD. Furthermore, using the Drosophila polyQ disease model, we demonstrated the impaired VBFD is ameliorated by the dinitrosyl iron complex (DNIC-1), a novel and steady nitric oxide (NO)-releasing compound. Therefore we propose that the VBFD assay provides a robust assessment of Drosophila cognition and can be used to characterize additional neuroprotective interventions.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2021-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39419776","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":"Convergent evolution of a genomic rearrangement may explain cancer resistance in hystrico- and sciuromorpha rodents.","authors":"Yachna Jain, Keerthivasan Raanin Chandradoss, Anjoom A V, Jui Bhattacharya, Mohan Lal, Meenakshi Bagadia, Harpreet Singh, Kuljeet Singh Sandhu","doi":"10.1038/s41514-021-00072-9","DOIUrl":"https://doi.org/10.1038/s41514-021-00072-9","url":null,"abstract":"<p><p>The rodents of hystricomorpha and sciuromorpha suborders exhibit remarkably lower incidence of cancer. The underlying genetic basis remains obscure. We report a convergent evolutionary split of human 3p21.31, a locus hosting a large number of tumour-suppressor genes (TSGs) and frequently deleted in several tumour types, in hystrico- and sciuromorphs. Analysis of 34 vertebrate genomes revealed that the synteny of 3p21.31 cluster is functionally and evolutionarily constrained in most placental mammals, but exhibit large genomic interruptions independently in hystricomorphs and sciuromorphs, owing to relaxation of underlying constraints. Hystrico- and sciuromorphs, therefore, escape from pro-tumorigenic co-deletion of several TSGs in cis. The split 3p21.31 sub-clusters gained proximity to proto-oncogene clusters from elsewhere, which might further nullify pro-tumorigenic impact of copy number variations due to co-deletion or co-amplification of genes with opposing effects. The split of 3p21.31 locus coincided with the accelerated rate of its gene expression and the body mass evolution of ancestral hystrico- and sciuromorphs. The genes near breakpoints were associated with the traits specific to hystrico- and sciuromorphs, implying adaptive significance. We conclude that the convergently evolved chromosomal interruptions of evolutionarily constrained 3p21.31 cluster might have impacted evolution of cancer resistance, body mass variation and ecological adaptations in hystrico- and sciuromorphs.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-021-00072-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39375386","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":"Social perception of young adults prolongs the lifespan of aged Drosophila.","authors":"Li-Chun Cho, Chih-Chieh Yu, Chih-Fei Kao","doi":"10.1038/s41514-021-00073-8","DOIUrl":"https://doi.org/10.1038/s41514-021-00073-8","url":null,"abstract":"<p><p>Lifespan is modulated at distinct levels by multiple factors, including genetic backgrounds, the environment, behavior traits, metabolic status, and more interestingly, sensory perceptions. However, the effects of social perception between individuals living in the same space remain less clear. Here, we used the Drosophila model to study the influences of social perception on the lifespan of aged fruit flies. We found the lifespan of aged Drosophila is markedly prolonged after being co-housed with young adults of the same gender. Moreover, the changes of lifespan were affected by several experimental contexts: (1) the ratios of aged and young adults co-housed, (2) the chronological ages of two populations, and (3) the integrity of sensory modalities. Together, we hypothesize the chemical/physical stimuli derived from the interacting young adults are capable of interfering with the physiology and behavior of aged flies, ultimately leading to the alteration of lifespan.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-021-00073-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39378275","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}
Subhashis Banerjee, Sarbani Ghoshal, Clemence Girardet, Kelly M DeMars, Changjun Yang, Michael L Niehoff, Andrew D Nguyen, Prerana Jayanth, Brittany A Hoelscher, Fenglian Xu, William A Banks, Kim M Hansen, Jinsong Zhang, Eduardo Candelario-Jalil, Susan A Farr, Andrew A Butler
{"title":"Adropin correlates with aging-related neuropathology in humans and improves cognitive function in aging mice.","authors":"Subhashis Banerjee, Sarbani Ghoshal, Clemence Girardet, Kelly M DeMars, Changjun Yang, Michael L Niehoff, Andrew D Nguyen, Prerana Jayanth, Brittany A Hoelscher, Fenglian Xu, William A Banks, Kim M Hansen, Jinsong Zhang, Eduardo Candelario-Jalil, Susan A Farr, Andrew A Butler","doi":"10.1038/s41514-021-00076-5","DOIUrl":"https://doi.org/10.1038/s41514-021-00076-5","url":null,"abstract":"<p><p>The neural functions of adropin, a secreted peptide highly expressed in the brain, have not been investigated. In humans, adropin is highly expressed in astrocytes and peaks during critical postnatal periods of brain development. Gene enrichment analysis of transcripts correlating with adropin expression suggests processes relevant to aging-related neurodegenerative diseases that vary with age and dementia state, possibly indicating survivor bias. In people aged <40 y and 'old-old' (>75 y) diagnosed with dementia, adropin correlates positively with genes involved in mitochondrial processes. In the 'old-old' without dementia adropin expression correlates positively with morphogenesis and synapse function. Potent neurotrophic responses in primary cultured neurons are consistent with adropin supporting the development and function of neural networks. Adropin expression in the 'old-old' also correlates positively with protein markers of tau-related neuropathologies and inflammation, particularly in those without dementia. How variation in brain adropin expression affects neurological aging was investigated using old (18-month) C57BL/6J mice. In mice adropin is expressed in neurons, oligodendrocyte progenitor cells, oligodendrocytes, and microglia and shows correlative relationships with groups of genes involved in neurodegeneration and cellular metabolism. Increasing adropin expression using transgenesis improved spatial learning and memory, novel object recognition, resilience to exposure to new environments, and reduced mRNA markers of inflammation in old mice. Treatment with synthetic adropin peptide also reversed age-related declines in cognitive functions and affected expression of genes involved in morphogenesis and cellular metabolism. Collectively, these results establish a link between adropin expression and neural energy metabolism and indicate a potential therapy against neurological aging.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2021-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-021-00076-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10648759","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}
Sophie Vanhunsel, Steven Bergmans, An Beckers, Isabelle Etienne, Jolien Van Houcke, Eve Seuntjens, Lut Arckens, Lies De Groef, Lieve Moons
{"title":"The killifish visual system as an in vivo model to study brain aging and rejuvenation.","authors":"Sophie Vanhunsel, Steven Bergmans, An Beckers, Isabelle Etienne, Jolien Van Houcke, Eve Seuntjens, Lut Arckens, Lies De Groef, Lieve Moons","doi":"10.1038/s41514-021-00077-4","DOIUrl":"10.1038/s41514-021-00077-4","url":null,"abstract":"<p><p>Worldwide, people are getting older, and this prolonged lifespan unfortunately also results in an increased prevalence of age-related neurodegenerative diseases, contributing to a diminished life quality of elderly. Age-associated neuropathies typically include diseases leading to dementia (Alzheimer's and Parkinson's disease), as well as eye diseases such as glaucoma and age-related macular degeneration. Despite many research attempts aiming to unravel aging processes and their involvement in neurodegeneration and functional decline, achieving healthy brain aging remains a challenge. The African turquoise killifish (Nothobranchius furzeri) is the shortest-lived reported vertebrate that can be bred in captivity and displays many of the aging hallmarks that have been described for human aging, which makes it a very promising biogerontology model. As vision decline is an important hallmark of aging as well as a manifestation of many neurodegenerative diseases, we performed a comprehensive characterization of this fish's aging visual system. Our work reveals several aging hallmarks in the killifish retina and brain that eventually result in a diminished visual performance. Moreover, we found evidence for the occurrence of neurodegenerative events in the old killifish retina. Altogether, we introduce the visual system of the fast-aging killifish as a valuable model to understand the cellular and molecular mechanisms underlying aging in the vertebrate central nervous system. These findings put forward the killifish for target validation as well as drug discovery for rejuvenating or neuroprotective therapies ensuring healthy aging.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2021-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-021-00077-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10646619","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}
Nicholas Don-Doncow, Lotte Vanherle, Frank Matthes, Sine Kragh Petersen, Hana Matuskova, Sara Rattik, Anetta Härtlova, Anja Meissner
{"title":"Simvastatin therapy attenuates memory deficits that associate with brain monocyte infiltration in chronic hypercholesterolemia.","authors":"Nicholas Don-Doncow, Lotte Vanherle, Frank Matthes, Sine Kragh Petersen, Hana Matuskova, Sara Rattik, Anetta Härtlova, Anja Meissner","doi":"10.1038/s41514-021-00071-w","DOIUrl":"https://doi.org/10.1038/s41514-021-00071-w","url":null,"abstract":"<p><p>Evidence associates cardiovascular risk factors with unfavorable systemic and neuro-inflammation and cognitive decline in the elderly. Cardiovascular therapeutics (e.g., statins and anti-hypertensives) possess immune-modulatory functions in parallel to their cholesterol- or blood pressure (BP)-lowering properties. How their ability to modify immune responses affects cognitive function is unknown. Here, we examined the effect of chronic hypercholesterolemia on inflammation and memory function in Apolipoprotein E (ApoE) knockout mice and normocholesterolemic wild-type mice. Chronic hypercholesterolemia that was accompanied by moderate blood pressure elevations associated with apparent immune system activation characterized by increases in circulating pro-inflammatory Ly6Chi monocytes in ApoE<sup>-/-</sup> mice. The persistent low-grade immune activation that is associated with chronic hypercholesterolemia facilitates the infiltration of pro-inflammatory Ly6Chi monocytes into the brain of aged ApoE<sup>-/-</sup> but not wild-type mice, and links to memory dysfunction. Therapeutic cholesterol-lowering through simvastatin reduced systemic and neuro-inflammation, and the occurrence of memory deficits in aged ApoE<sup>-/-</sup> mice with chronic hypercholesterolemia. BP-lowering therapy alone (i.e., hydralazine) attenuated some neuro-inflammatory signatures but not the occurrence of memory deficits. Our study suggests a link between chronic hypercholesterolemia, myeloid cell activation and neuro-inflammation with memory impairment and encourages cholesterol-lowering therapy as safe strategy to control hypercholesterolemia-associated memory decline during ageing.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2021-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-021-00071-w","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39276356","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}
Mohammed R Shaker, Julio Aguado, Harman Kaur Chaggar, Ernst J Wolvetang
{"title":"Klotho inhibits neuronal senescence in human brain organoids.","authors":"Mohammed R Shaker, Julio Aguado, Harman Kaur Chaggar, Ernst J Wolvetang","doi":"10.1038/s41514-021-00070-x","DOIUrl":"https://doi.org/10.1038/s41514-021-00070-x","url":null,"abstract":"<p><p>Aging is a major risk factor for many neurodegenerative diseases. Klotho (KL) is a glycosylated transmembrane protein that is expressed in the choroid plexus and neurons of the brain. KL exerts potent anti-aging effects on multiple cell types in the body but its role in human brain cells remains largely unclear. Here we show that human cortical neurons, derived from human pluripotent stem cells in 2D cultures or in cortical organoids, develop the typical hallmarks of senescent cells when maintained in vitro for prolonged periods of time, and that moderate upregulation or repression of endogenous KL expression in cortical organoids inhibits and accelerates senescence, respectively. We further demonstrate that KL expression alters the expression of senescence-associated genes including, extracellular matrix genes, and proteoglycans, and can act in a paracrine fashion to inhibit neuronal senescence. In summary, our results establish an important role for KL in the regulation of human neuronal senescence and offer new mechanistic insight into its role in human brain aging.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2021-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10634824","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}
Fatin N Zainul Abidin, Helena R R Wells, Andre Altmann, Sally J Dawson
{"title":"Hearing difficulty is linked to Alzheimer's disease by common genetic vulnerability, not shared genetic architecture.","authors":"Fatin N Zainul Abidin, Helena R R Wells, Andre Altmann, Sally J Dawson","doi":"10.1038/s41514-021-00069-4","DOIUrl":"https://doi.org/10.1038/s41514-021-00069-4","url":null,"abstract":"<p><p>Age-related hearing loss was recently established as the largest modifiable risk factor for Alzheimer's disease (AD), however, the reasons for this link remain unclear. We investigate shared underlying genetic associations using results from recent large genome-wide association studies (GWAS) on adult hearing difficulty and AD. Genetic correlation and Mendelian randomization (MR) analysis do not support a genetic correlation between the disorders, but suggest a direct causal link from AD genetic risk to hearing difficulty, driven by APOE. Systematic MR analyses on the effect of other traits revealed shared effects of glutamine, gamma-glutamylglutamine, and citrate levels on reduced risk of both hearing difficulty and AD. In addition, pathway analysis on GWAS risk variants suggests shared function in neuronal signalling pathways as well as etiology of diabetes and cardiovascular disease. However, after multiple testing corrections, neither analysis led to statistically significant associations. Altogether, our genetic-driven analysis suggests hearing difficulty and AD are linked by a shared vulnerability in molecular pathways rather than by a shared genetic architecture.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2021-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-021-00069-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39209988","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":"Bcl-2-dependent autophagy disruption during aging impairs amino acid utilization that is restored by hochuekkito.","authors":"Miwa Nahata, Sachiko Mogami, Hitomi Sekine, Seiichi Iizuka, Naoto Okubo, Naoki Fujitsuka, Hiroshi Takeda","doi":"10.1038/s41514-021-00065-8","DOIUrl":"https://doi.org/10.1038/s41514-021-00065-8","url":null,"abstract":"<p><p>Chronic undernutrition contributes to the increase in frailty observed among elderly adults, which is a pressing issue in the sector of health care for older people worldwide. Autophagy, an intracellular recycling system, is closely associated with age-related pathologies. Therefore, decreased autophagy in aging could be involved in the disruption of energy homeostasis that occurs during undernutrition; however, the physiological mechanisms underlying this process remain unknown. Here, we showed that 70% daily food restriction (FR) induced fatal hypoglycemia in 23-26-month-old (aged) mice, which exhibited significantly lower hepatic autophagy than 9-week-old (young) mice. The liver expressions of Bcl-2, an autophagy-negative regulator, and Beclin1-Bcl-2 binding, were increased in aged mice compared with young mice. The autophagy inducer Tat-Beclin1 D11, not the mTOR inhibitor rapamycin, decreased the plasma levels of the glucogenic amino acid and restored the blood glucose levels in aged FR mice. Decreased liver gluconeogenesis, body temperature, physical activity, amino acid metabolism, and hepatic mitochondrial dynamics were observed in the aged FR mice. These changes were restored by treatment with hochuekkito that is a herbal formula containing several autophagy-activating ingredients. Our results indicate that Bcl-2 upregulation in the liver during the aging process disturbs autophagy activation, which increases the vulnerability to undernutrition. The promotion of liver autophagy may offer clinical therapeutic benefits to frail elderly patients.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-021-00065-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39140854","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}