Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases （RIPK） associated with the tumor necrosis fact...Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases （RIPK） associated with the tumor necrosis factor-alpha （TNF-a）/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and al- leviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar con- centrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/ kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-u. However, subsequent lower doses （5 mg/kg/day） failed to sustain this neuroprotective effect after 4 days. Dabrafenib bl ocked lipopolysaccharides-induced activation of TNF-ct in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-ct-induced necroptotic pathway after ischemic brain injury. Since Dab- rafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.展开更多
Various resting-state fMRI(R-fMRI) measures have been developed to characterize intrinsic brain activity. While each of these measures has gained a growing presence in the literature, questions remain regarding the co...Various resting-state fMRI(R-fMRI) measures have been developed to characterize intrinsic brain activity. While each of these measures has gained a growing presence in the literature, questions remain regarding the common and unique aspects these indices capture. The present work provided a comprehensive examination of inter-individual variation and intra-individual temporal variation for commonly used measures, including fractional amplitude of low frequency fluctuations, regional homogeneity,voxel-mirrored homotopic connectivity, network centrality and global signal correlation. Regardless of whether examining intra-individual or inter-individual variation, we found that these definitionally distinct R-fMRI indices tend to exhibit a relatively high degree of covariation, which doesn't exist in phase randomized surrogate data. As a measure of intrinsic brain function, concordance for R-fMRI indices was negatively correlated with age across individuals(i.e., concordance among functional indices decreased with age). To understand the functional significance of concordance, we noted that higher concordance was generally associated with higher strengths of R-fMRI indices, regardless of whether looking through the lens of inter-individual(i.e., high vs. low concordance participants) or intra-individual(i.e., high vs.low concordance states identified via temporal dynamic analyses) differences. We also noted a linear increase in functional concordance together with the R-fMRI indices through the scan, which may suggest a decrease in arousal. The current study demonstrated an enriched picture regarding the relationship among the R-fMRI indices, as well as provided new insights in examining dynamic states within and between individuals.展开更多
Arabidopsis MSI1 has fundamental functions in plant development. MSI1 is a subunit of Polycomb group protein complexes and Chromatin assembly factor 1, and it interacts with the Retinoblastoma-related protein 1. Alter...Arabidopsis MSI1 has fundamental functions in plant development. MSI1 is a subunit of Polycomb group protein complexes and Chromatin assembly factor 1, and it interacts with the Retinoblastoma-related protein 1. Altered levels of MSI1 result in pleiotropic phenotypes, reflecting the complexity of MSI1 protein functions. In order to uncover additional functions of MSI1, we performed transcriptional profiling of wild-type and plants with highly reduced MSI1 levels （msil-cs）. Surprisingly, the known functions of MSI1 could only account for a minor part of the transcriptional changes in msil-cs plants. One of the most striking unexpected observations was the up-regulation of a subset of ABA-responsive genes eliciting the response to drought and salt stress. We report that MSI1 can bind to the chromatin of the drought-inducible downstream target RD20 and suggest a new role for MSI1 in the negative regulation of the Arabidopsis drought-stress response.展开更多
People with schizophrenia exhibit impaired social cognitive functions, particularly emotion regulation. Abnormal activations of the ventral medial prefrontal cortex （vMPFC） during emotional tasks have been demonstra...People with schizophrenia exhibit impaired social cognitive functions, particularly emotion regulation. Abnormal activations of the ventral medial prefrontal cortex （vMPFC） during emotional tasks have been demonstrated in schizophrenia, suggesting its important role in emotion processing in patients. We used the resting-state functional connectivity approach, setting a functionally relevant region, the vMPFC, as a seed region to examine the intrinsic functional interactions and communication between the vMPFC and other brain regions in schizophrenic patients. We found hypo-connectivity between the vMPFC and the medial frontal cortex, right middle temporal lobe （MTL）, right hippocampus, parahippocampal cortex （PHC） and amygdala. Further, there was a decreased strength of the negative connectivity （or anticorrelation） between the vMPFC and the bilateral dorsal lateral prefrontal cortex （DLPFC） and pre-supplementary motor areas. Among these connectivity alterations, reduced vMPFC-DLPFC connectivity was positively correlated with positive symptoms on the Positive and Negative Syndrome Scale, while vMPFC-right MTL/PHC/amygdala functional connectivity was positively correlated with the performance of emotional regulation in patients. These findings imply that communication and coordination throughout the brain networks are disrupted in schizophrenia. The emotional correlates of vMPFC connectivity suggest a role of the hypo-connectivity between these regions in the neuropathology of abnormal social cognition in chronic schizophrenia.展开更多
Thousands of resting state functional magnetic resonance imaging(RS-f MRI)articles have been published on brain disorders.For precise localization of abnormal brain activity,a voxel-level comparison is needed.Because ...Thousands of resting state functional magnetic resonance imaging(RS-f MRI)articles have been published on brain disorders.For precise localization of abnormal brain activity,a voxel-level comparison is needed.Because of the large number of voxels in the brain,multiple comparison correction(MCC)must be performed to reduce false positive rates,and a smaller P value(usually including either liberal or stringent MCC)is widely recommended[1].展开更多
The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a s...The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a significant pathomechanism in AD,supported by results of recent clinical trials using anti-Aβantibodies.Nonetheless,the cognitive benefits of the current treatments are limited.The etiology of AD is multifactorial,encompassing Aβand tau accumulation,neuroinflammation,demyelination,vascular dysfunction,and comorbidities,which collectively lead to widespread neurodegeneration in the brain and cognitive impairment.Hence,solely removing Aβfrom the brain may be insufficient to combat neurodegeneration and preserve cognition.To attain effective treatment for AD,it is necessary to(1)conduct extensive research on various mechanisms that cause neurodegeneration,including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level;(2)identify neuroprotective intervention targets against different neurodegeneration mechanisms;and(3)discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients.The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated,multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD.The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD,with the goal of halting or even reversing cognitive decline.展开更多
Objective To compare the cognitive effects of guqin （the oldest Chinese instrument） music and piano music. Methods Behavioral and event-related potential （ERP） data in a standard two-stimulus auditory oddball task...Objective To compare the cognitive effects of guqin （the oldest Chinese instrument） music and piano music. Methods Behavioral and event-related potential （ERP） data in a standard two-stimulus auditory oddball task were recorded and analyzed. Results This study replicated the previous results of culture-familiar music effect on Chinese subjects： the greater P300 amplitude in frontal areas in a culture-familiar music environment. At the same time, the difference between guqin music and piano music was observed in NI and later positive complex （LPC： including P300 and P500）： a relatively higher participation of right anterior-temporal areas in Chinese subjects. Conclusion The results suggest that the special features of ERP responses to guqin music are the outcome of Chinese tonal language environments given the similarity between Guqin＇s tones and Mandarin lexical tones.展开更多
随着中国进入老龄化社会,人口生育政策逐步放开,揭示脑与行为毕生发展的一般规律和常规模式(常模)正成为公共卫生和人口健康领域的重大基础需求.本文介绍"中国彩巢计划"(Chinese Color Nest Project—CCNP)这一在全国范围内...随着中国进入老龄化社会,人口生育政策逐步放开,揭示脑与行为毕生发展的一般规律和常规模式(常模)正成为公共卫生和人口健康领域的重大基础需求.本文介绍"中国彩巢计划"(Chinese Color Nest Project—CCNP)这一在全国范围内分期分步地开展的项目规划,在10年(2013~2022年:http://zuolab.psych.ac.cn/colornest.html)内CCNP将积累毕生发展各年龄段的心理行为与脑影像样本,基于加速纵向实验设计方法建立中国人脑毕生发展的常模轨线.作为CCNP的发育项目"成长在中国"(dev CCNP:Growing Up in China)这一学龄儿童青少年脑与行为生长曲线项目,dev CCNP已经完成对重庆北碚区192名健康儿童青少年(6~18岁)的5年追踪.初步的研究结果表明,dev CCNP在实验设计、样本采集策略、数据获取和存储、初步发现和数据共享等方面具备长期实施的可行性,我国应及早部署开展儿童青少年的脑与认知生长曲线常模的大规模脑科学研究计划,提升中国在脑科学与医疗健康研究领域的国际实力和影响力,革新脑疾病临床实践.展开更多
Human brain mapping (HBM)is increasingly becoming a multidisciplinary field where some scientific issues are fundamental for all scientists and applications of using the technology to investigate individual difference...Human brain mapping (HBM)is increasingly becoming a multidisciplinary field where some scientific issues are fundamental for all scientists and applications of using the technology to investigate individual differences.Reliability represents a significant issue for all scientific fields and has particularly been overlooked for decades by the HBM field [1].Meanwhile,recent advances in open science have offered the field big data for developing novel methodological frameworks as well as performing largescale investigations of the brain-mind associations based upon the individual differences assessed with HBM [2].A systematic investigation of reliability seems still far behind these HBM developments. It is critical that reliability is evaluated ahead of these applications, motivating the current commentary on delineation of the anatomy of reliability for future HBM.展开更多
Brain growth charts and age-normed brain templates are essential resources for researchers to eventually contribute to the care of individuals with atypical developmental trajectories.The present work generates age-no...Brain growth charts and age-normed brain templates are essential resources for researchers to eventually contribute to the care of individuals with atypical developmental trajectories.The present work generates age-normed brain templates for children and adolescents at one-year intervals and the corresponding growth charts to investigate the influences of age and ethnicity using a common pediatric neuroimaging protocol.Two accelerated longitudinal cohorts with the identical experimental design were implemented in the United States and China.Anatomical magnetic resonance imaging(MRI)of typically developing school-age children(TDC)was obtained up to three times at nominal intervals of1.25 years.The protocol generated and compared population-and age-specific brain templates and growth charts,respectively.A total of 674 Chinese pediatric MRI scans were obtained from 457 Chinese TDC and 190 American pediatric MRI scans were obtained from 133 American TDC.Population-and age-specific brain templates were used to quantify warp cost,the differences between individual brains and brain templates.Volumetric growth charts for labeled brain network areas were generated.Shape analyses of cost functions supported the necessity of age-specific and ethnicitymatched brain templates,which was confirmed by growth chart analyses.These analyses revealed volumetric growth differences between the two ethnicities primarily in lateral frontal and parietal areas,regions which are most variable across individuals in regard to their structure and function.Age-and ethnicity-specific brain templates facilitate establishing unbiased pediatric brain growth charts,indicating the necessity of the brain charts and brain templates generated in tandem.These templates and growth charts as well as related codes have been made freely available to the public for open neuroscience(https://github.com/zuoxinian/CCS/tree/master/H3/Growth Charts).展开更多
While early investigations into the physiological effects of spaceflight suggest the body’s ability to reversibly adapt,the corresponding effects of long-term spaceflight(>6months)aremuch less conclusive.Prolonged...While early investigations into the physiological effects of spaceflight suggest the body’s ability to reversibly adapt,the corresponding effects of long-term spaceflight(>6months)aremuch less conclusive.Prolonged exposure to microgravity and radiation yields profound effects on the cardiovascular system,including a massive cephalad fluid translocation and altered arterial pressure,which attenuate blood pressure regulatory mechanisms and increase cardiac output.Also,central venous pressure decreases as a result of the loss of venous compression.The stimulation of baroreceptors by the cephalad shift results in an approximately 10%–15%reduction in plasma volume,with fluid translocating from the vascular lumen to the interstitium.Despite possible increases in cardiac workload,myocyte atrophy and notable,yet unexplained,alterations in hematocrit have been observed.Atrophy is postulated to result from shunting of protein synthesis from the endoplasmic reticulum to the mitochondria via mortalin-mediated action.While data are scarce regarding their causative agents,arrhythmias have been frequently reported,albeit sublethal,during both Russian and American expeditions,with QT interval prolongation observed in long,but not short duration,spaceflight.Exposure of the heart to the proton and heavy ion radiation of deep space has also been shown to result in coronary artery degeneration,aortic stiffness,carotid intima thickening via collagen-mediated action,accelerated atherosclerosis,and induction of a pro-inflammatory state.Upon return,long-term spaceflight frequently results in orthostatic intolerance and altered sympathetic responses,which can prove hazardous should any rapidmobilization or evacuation be required,and indicates that these cardiac risks should be especially monitored for future missions.展开更多
It is of great scientific and translational promise to formulate a normative reference for the lifespan development of human brain to precisely quantify individual differences.By aggregating more than 120,000 brain im...It is of great scientific and translational promise to formulate a normative reference for the lifespan development of human brain to precisely quantify individual differences.By aggregating more than 120,000 brain imaging scans across the world,the Lifespan Brain Chart Consortium(LBCC)recently published brain charts for the human lifespan in Nature[1].展开更多
Sleep benefits the restoration of energy metabolism and thereby suppo rts neuronal plasticity and cognitive behaviors.Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of...Sleep benefits the restoration of energy metabolism and thereby suppo rts neuronal plasticity and cognitive behaviors.Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of energy metabolism because it modulates various transcriptional regulators and metabolic enzymes.The aim of this study was to investigate the influence of Sirt6 on cerebral function after chronic sleep deprivation(CSD).We assigned C57BL/6J mice to control or two CSD groups and subjected them to AAV2/9-CMV-EGFP or AAV2/9-CMV-Sirt6-EGFP infection in the prelimbic cortex(PrL).We then assessed cerebral functional connectivity(FC) using resting-state functional MRI,neuron/astrocyte metabolism using a metabolic kinetics analysis;dendritic spine densities using sparse-labeling;and miniature excitato ry postsynaptic currents(mEPSCs) and action potential(AP) firing rates using whole-cell patchclamp recordings.In addition,we evaluated cognition via a comprehensive set of behavioral tests.Compared with controls,Sirt6 was significantly decreased(P<0.05) in the PrL after CSD,accompanied by cognitive deficits and decreased FC between the PrL and accumbens nucleus,piriform cortex,motor co rtex,somatosensory co rtex,olfactory tubercle,insular cortex,and cerebellum.Sirt6 ove rexpression reve rsed CSD-induced cognitive impairment and reduced FC.Our analysis of metabolic kinetics using [1-13C] glucose and [2-13C] acetate showed that CSD reduced neuronal Glu4and GABA2synthesis,which could be fully restored via forced Sirt6 expression.Furthermore,Sirt6 ove rexpression reversed CSD-induced decreases in AP firing rates as well as the frequency and amplitude of mEPSCs in PrL pyramidal neurons.These data indicate that Sirt6 can improve cognitive impairment after CSD by regulating the PrL-associated FC network,neuronal glucose metabolism,and glutamatergic neurotransmission.Thus,Sirt6 activation may have potential as a novel strategy for treating sleep disorder-related diseases.展开更多
Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebr...Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available today.Since most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism.However,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders.Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders.These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted therapy.In this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.展开更多
Primate sanctuaries across Africa play a pivotal role in the rescue and rehabilitation of confiscated and rescued wild primates, many of whom have had extensive contact with humans prior to their arrival and throughou...Primate sanctuaries across Africa play a pivotal role in the rescue and rehabilitation of confiscated and rescued wild primates, many of whom have had extensive contact with humans prior to their arrival and throughout the rehabilitation process, heightening the risk of disease transmission. While tuberculosis is not naturally occurring in free-living chimpanzees, it has been extensively observed in captive primates that have been in close proximity to humans or other captive primates infected with Mycobacterium tuberculosis. This case report delves into an outbreak of extra-pulmonary tuberculosis among juvenile chimpanzees within a sanctuary, detailing the associated diagnostic challenges and treatment approaches. The five cases had close contact with a caregiver infected with tuberculosis, subsequently transmitting the infection to other in-contact chimpanzees. Prolonged treatment, employing the human protocol of quadri-therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol), followed by bi-therapy (rifampicin and isoniazid), resulted in complete resolution for all five cases. These cases underscore the critical importance of maintaining high levels of biosecurity, implementing effective quarantine measures, and adhering to strict hygiene practices when working with non-human primates.展开更多
Background The Inspiration4(I4)mission,the first all-civilian orbital flight mission,investigated the physiological effects of short-duration spaceflight through a multi-omic approach.Despite advances,there remains mu...Background The Inspiration4(I4)mission,the first all-civilian orbital flight mission,investigated the physiological effects of short-duration spaceflight through a multi-omic approach.Despite advances,there remains much to learn about human adaptation to spaceflight's unique challenges,including microgravity,immune system perturbations,and radiation exposure.Methods To provide a detailed genetics analysis of the mission,we collected dried blood spots pre-,during,and post-flight for DNA extraction.Telomere length was measured by quantitative PCR,while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations.A robust bioinformatic pipeline was used for data analysis,including variant calling to assess mutational burden.Result Telomere elongation occurred during spaceflight and shortened after return to Earth.Cell-free DNA analysis revealed increased immune cell signatures post-flight.No significant clonal hematopoiesis of indeterminate potential(CHIP)or whole-genome instability was observed.The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight.Conclusion Our findings provide valuable insights into the physiological consequences of short-duration spaceflight,with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth.CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts,an understudied phenomenon as previous studies have focused on career astronauts.This study will serve as a reference point for future commercial and non-commercial spaceflight,low Earth orbit(LEO)missions,and deep-space exploration.展开更多
Frontotemporal dementia(FTD) and amyotrophic lateral sclerosis(ALS) are neurodegenerative diseases that belong to the same disease spectrum,with overlapping of genetic and pathological features.Genetic mutations in TA...Frontotemporal dementia(FTD) and amyotrophic lateral sclerosis(ALS) are neurodegenerative diseases that belong to the same disease spectrum,with overlapping of genetic and pathological features.Genetic mutations in TARDBP,C9ORF72,MAPT,and GRN have been identified in these diseases.展开更多
The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of ...The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.展开更多
AIM: To examine DNA methylation profiles in a longitudinal comparison of pre-diabetes mellitus(Pre-DM) subjects who transitioned to type 2 diabetes mellitus(T2DM).METHODS: We performed DNA methylation study in bisulph...AIM: To examine DNA methylation profiles in a longitudinal comparison of pre-diabetes mellitus(Pre-DM) subjects who transitioned to type 2 diabetes mellitus(T2DM).METHODS: We performed DNA methylation study in bisulphite converted DNA from Pre-DM(n = 11) at baseline and at their transition to T2 DM using Illumina Infinium Human Methylation27 Bead Chip, that enables the query of 27578 individual cytosines at Cp G loci throughout the genome, which are focused on the promoter regions of 14495 genes.RESULTS: There were 694 Cp G sites hypomethylated and 174 Cp G sites hypermethylated in progression from Pre-DM to T2 DM, representing putative genes involved in glucose and fructose metabolism, inflammation, oxidative and mitochondrial stress, and fatty acid metabolism. These results suggest that this high throughput platform is able to identify hundreds of prospective Cp G sites associated with diverse genes that may reflect differences in Pre-DM compared with T2 DM. In addition, there were Cp G hypomethylation changes associated with a number of genes that may be associated with development of complications of diabetes, such as nephropathy. These hypomethylation changes were observed in all of the subjects.CONCLUSION: These data suggest that some epigenomic changes that may be involved in the progression of diabetes and/or the development of complications may be apparent at the Pre-DM state or during the transition to diabetes. Hypomethylation of a number of genes related to kidney function may be an early marker for developing diabetic nephropathy.展开更多
基金supported by grants from the Heart and Stroke Foundation of Canada(HHC,AFRS)the Canadian Institutes of Health Research(to HHC and AFRS)supported by a Mid-Career Investigator Award from the Heart and Stroke Foundation of Ontario
文摘Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases （RIPK） associated with the tumor necrosis factor-alpha （TNF-a）/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and al- leviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar con- centrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/ kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-u. However, subsequent lower doses （5 mg/kg/day） failed to sustain this neuroprotective effect after 4 days. Dabrafenib bl ocked lipopolysaccharides-induced activation of TNF-ct in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-ct-induced necroptotic pathway after ischemic brain injury. Since Dab- rafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.
基金supported by the National Key R&D Program of China (2017YFC1309902 to CGY)National Basic Research Program (2015CB351702 to XNZ)+4 种基金the Natural Science Foundation of China (81671774 and 81630031 to CGY, 81471740, 81220108014 to XNZ)the Hundred Talents Program of the Chinese Academy of Sciences (Y5CX072006 to CGY)Beijing Municipal Science & Technology Commission (Z161100000216152 to CGY)the National Institutes of Health (U01MH099059 to MPM)the Child Mind Institute (1FDN2012-1 to MPM)
文摘Various resting-state fMRI(R-fMRI) measures have been developed to characterize intrinsic brain activity. While each of these measures has gained a growing presence in the literature, questions remain regarding the common and unique aspects these indices capture. The present work provided a comprehensive examination of inter-individual variation and intra-individual temporal variation for commonly used measures, including fractional amplitude of low frequency fluctuations, regional homogeneity,voxel-mirrored homotopic connectivity, network centrality and global signal correlation. Regardless of whether examining intra-individual or inter-individual variation, we found that these definitionally distinct R-fMRI indices tend to exhibit a relatively high degree of covariation, which doesn't exist in phase randomized surrogate data. As a measure of intrinsic brain function, concordance for R-fMRI indices was negatively correlated with age across individuals(i.e., concordance among functional indices decreased with age). To understand the functional significance of concordance, we noted that higher concordance was generally associated with higher strengths of R-fMRI indices, regardless of whether looking through the lens of inter-individual(i.e., high vs. low concordance participants) or intra-individual(i.e., high vs.low concordance states identified via temporal dynamic analyses) differences. We also noted a linear increase in functional concordance together with the R-fMRI indices through the scan, which may suggest a decrease in arousal. The current study demonstrated an enriched picture regarding the relationship among the R-fMRI indices, as well as provided new insights in examining dynamic states within and between individuals.
文摘Arabidopsis MSI1 has fundamental functions in plant development. MSI1 is a subunit of Polycomb group protein complexes and Chromatin assembly factor 1, and it interacts with the Retinoblastoma-related protein 1. Altered levels of MSI1 result in pleiotropic phenotypes, reflecting the complexity of MSI1 protein functions. In order to uncover additional functions of MSI1, we performed transcriptional profiling of wild-type and plants with highly reduced MSI1 levels （msil-cs）. Surprisingly, the known functions of MSI1 could only account for a minor part of the transcriptional changes in msil-cs plants. One of the most striking unexpected observations was the up-regulation of a subset of ABA-responsive genes eliciting the response to drought and salt stress. We report that MSI1 can bind to the chromatin of the drought-inducible downstream target RD20 and suggest a new role for MSI1 in the negative regulation of the Arabidopsis drought-stress response.
基金supported by grants from the Beijing Municipal Science & Technology Commission(D0906001040191,D101107047810005,D101100050010051)the Beijing Natural Science Foundation(7102086)+3 种基金the Fund for Capital Medical Development and Research(2007-3059)the National Natural Science Foundation of China(81171409)Startup Foundation for Distinguished Research Professors of the Institute for Psychology(Y0CX492S03)Fund for Outstanding Talents in Beijing(2012D003034000003)
文摘People with schizophrenia exhibit impaired social cognitive functions, particularly emotion regulation. Abnormal activations of the ventral medial prefrontal cortex （vMPFC） during emotional tasks have been demonstrated in schizophrenia, suggesting its important role in emotion processing in patients. We used the resting-state functional connectivity approach, setting a functionally relevant region, the vMPFC, as a seed region to examine the intrinsic functional interactions and communication between the vMPFC and other brain regions in schizophrenic patients. We found hypo-connectivity between the vMPFC and the medial frontal cortex, right middle temporal lobe （MTL）, right hippocampus, parahippocampal cortex （PHC） and amygdala. Further, there was a decreased strength of the negative connectivity （or anticorrelation） between the vMPFC and the bilateral dorsal lateral prefrontal cortex （DLPFC） and pre-supplementary motor areas. Among these connectivity alterations, reduced vMPFC-DLPFC connectivity was positively correlated with positive symptoms on the Positive and Negative Syndrome Scale, while vMPFC-right MTL/PHC/amygdala functional connectivity was positively correlated with the performance of emotional regulation in patients. These findings imply that communication and coordination throughout the brain networks are disrupted in schizophrenia. The emotional correlates of vMPFC connectivity suggest a role of the hypo-connectivity between these regions in the neuropathology of abnormal social cognition in chronic schizophrenia.
基金the National Natural Science Foundation of China(81520108016,81661148045,and 31471084 to Yu-Feng Zang81671774 and 81630031 to Chao-Gan Yan+11 种基金81571228 to Tao Wu61571047 to Xia Wu81701664 to Jian Wang,81471654 to Biao Huang81701671 to Wei-Guo Liu82001898 to Xi-Ze Jia81771820,81371519 and 81571654 to Wei Luo)Henry G Leong Endowed Professorship in Neurology to Shu-Leong Ho and Shirley YY Pang,BRC for Mental Health at South London and Maudsley NHS Foundation Trust and by the Sackler Institute to Grainne McAlonan,NIH(2R01AG006457 to Fay B.Horak1RC4NS073008-01 and P50NS062684 to Tara Madhyastha)NINDS Intramural Research Program to Mark HallettStart-up Funds for Leading Talents at Beijing Normal UniversityNational Basic Science Data Center‘‘Chinese Data-sharing Warehouse for In-vivo Imaging Brain”(NBSDC-DB-15)to Xi-Nian ZuoGrant NU20-04-00294 of the Agency for Health Research,Czech Republic to Lenka Krajcovicova and Irena Rektorova。
文摘Thousands of resting state functional magnetic resonance imaging(RS-f MRI)articles have been published on brain disorders.For precise localization of abnormal brain activity,a voxel-level comparison is needed.Because of the large number of voxels in the brain,multiple comparison correction(MCC)must be performed to reduce false positive rates,and a smaller P value(usually including either liberal or stringent MCC)is widely recommended[1].
基金National Natural Science Foundation of China,Grant/Award Numbers:92249305,82120108010,81930028,31921003Academy of Medical Sciences(Newton Advanced Fellowship),Grant/Award Number:NAF/R11/1010National Institutes of Health,Grant/Award Number:R01DA056739。
文摘The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a significant pathomechanism in AD,supported by results of recent clinical trials using anti-Aβantibodies.Nonetheless,the cognitive benefits of the current treatments are limited.The etiology of AD is multifactorial,encompassing Aβand tau accumulation,neuroinflammation,demyelination,vascular dysfunction,and comorbidities,which collectively lead to widespread neurodegeneration in the brain and cognitive impairment.Hence,solely removing Aβfrom the brain may be insufficient to combat neurodegeneration and preserve cognition.To attain effective treatment for AD,it is necessary to(1)conduct extensive research on various mechanisms that cause neurodegeneration,including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level;(2)identify neuroprotective intervention targets against different neurodegeneration mechanisms;and(3)discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients.The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated,multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD.The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD,with the goal of halting or even reversing cognitive decline.
文摘Objective To compare the cognitive effects of guqin （the oldest Chinese instrument） music and piano music. Methods Behavioral and event-related potential （ERP） data in a standard two-stimulus auditory oddball task were recorded and analyzed. Results This study replicated the previous results of culture-familiar music effect on Chinese subjects： the greater P300 amplitude in frontal areas in a culture-familiar music environment. At the same time, the difference between guqin music and piano music was observed in NI and later positive complex （LPC： including P300 and P500）： a relatively higher participation of right anterior-temporal areas in Chinese subjects. Conclusion The results suggest that the special features of ERP responses to guqin music are the outcome of Chinese tonal language environments given the similarity between Guqin＇s tones and Mandarin lexical tones.
文摘随着中国进入老龄化社会,人口生育政策逐步放开,揭示脑与行为毕生发展的一般规律和常规模式(常模)正成为公共卫生和人口健康领域的重大基础需求.本文介绍"中国彩巢计划"(Chinese Color Nest Project—CCNP)这一在全国范围内分期分步地开展的项目规划,在10年(2013~2022年:http://zuolab.psych.ac.cn/colornest.html)内CCNP将积累毕生发展各年龄段的心理行为与脑影像样本,基于加速纵向实验设计方法建立中国人脑毕生发展的常模轨线.作为CCNP的发育项目"成长在中国"(dev CCNP:Growing Up in China)这一学龄儿童青少年脑与行为生长曲线项目,dev CCNP已经完成对重庆北碚区192名健康儿童青少年(6~18岁)的5年追踪.初步的研究结果表明,dev CCNP在实验设计、样本采集策略、数据获取和存储、初步发现和数据共享等方面具备长期实施的可行性,我国应及早部署开展儿童青少年的脑与认知生长曲线常模的大规模脑科学研究计划,提升中国在脑科学与医疗健康研究领域的国际实力和影响力,革新脑疾病临床实践.
基金supported by the National Basic Research (973) Program (2015CB351702)the Natural Science Foundation of China (81471740)+3 种基金Beijing Municipal Science and Tech Commission (Z161100002616023, Z171100000117012)the China – Netherlands CAS-NWO Programme (153111KYSB20160020)the Major Project of National Social Science Foundation of China (14ZDB161)the National R&D Infrastructure and Facility Development Program of China, ‘‘Fundamental Science Data Sharing Platform" (DKA2017-12-02-21)
文摘Human brain mapping (HBM)is increasingly becoming a multidisciplinary field where some scientific issues are fundamental for all scientists and applications of using the technology to investigate individual differences.Reliability represents a significant issue for all scientific fields and has particularly been overlooked for decades by the HBM field [1].Meanwhile,recent advances in open science have offered the field big data for developing novel methodological frameworks as well as performing largescale investigations of the brain-mind associations based upon the individual differences assessed with HBM [2].A systematic investigation of reliability seems still far behind these HBM developments. It is critical that reliability is evaluated ahead of these applications, motivating the current commentary on delineation of the anatomy of reliability for future HBM.
基金the Beijing Municipal Science and Tech Commission(Z161100002616023,Z171100000117012,Z181100001518003)the National Natural Science Foundation of China(81220108014)+4 种基金the China-Netherlands CAS-NWO Programme(153111KYSB20160020)the National R&D Infrastructure and Facility Development Program of China,Fundamental Science Data Sharing Platform(DKA2020-12-02-21)the Startup Funds for Leading Talents at Beijing Normal University,Guangxi Ba Gui Scholarship(201621)the Key Realm R&D Program of Guangdong Province(2019B030335001)funded by the Singapore National Research Foundation(NRF)Fellowship(Class of 2017)。
文摘Brain growth charts and age-normed brain templates are essential resources for researchers to eventually contribute to the care of individuals with atypical developmental trajectories.The present work generates age-normed brain templates for children and adolescents at one-year intervals and the corresponding growth charts to investigate the influences of age and ethnicity using a common pediatric neuroimaging protocol.Two accelerated longitudinal cohorts with the identical experimental design were implemented in the United States and China.Anatomical magnetic resonance imaging(MRI)of typically developing school-age children(TDC)was obtained up to three times at nominal intervals of1.25 years.The protocol generated and compared population-and age-specific brain templates and growth charts,respectively.A total of 674 Chinese pediatric MRI scans were obtained from 457 Chinese TDC and 190 American pediatric MRI scans were obtained from 133 American TDC.Population-and age-specific brain templates were used to quantify warp cost,the differences between individual brains and brain templates.Volumetric growth charts for labeled brain network areas were generated.Shape analyses of cost functions supported the necessity of age-specific and ethnicitymatched brain templates,which was confirmed by growth chart analyses.These analyses revealed volumetric growth differences between the two ethnicities primarily in lateral frontal and parietal areas,regions which are most variable across individuals in regard to their structure and function.Age-and ethnicity-specific brain templates facilitate establishing unbiased pediatric brain growth charts,indicating the necessity of the brain charts and brain templates generated in tandem.These templates and growth charts as well as related codes have been made freely available to the public for open neuroscience(https://github.com/zuoxinian/CCS/tree/master/H3/Growth Charts).
基金Thisworkwas funded byNASA(GrantNos.NNX14AH50G and NNX17AB26G)the National Institutes of Health(Grant No.R25EB020393).
文摘While early investigations into the physiological effects of spaceflight suggest the body’s ability to reversibly adapt,the corresponding effects of long-term spaceflight(>6months)aremuch less conclusive.Prolonged exposure to microgravity and radiation yields profound effects on the cardiovascular system,including a massive cephalad fluid translocation and altered arterial pressure,which attenuate blood pressure regulatory mechanisms and increase cardiac output.Also,central venous pressure decreases as a result of the loss of venous compression.The stimulation of baroreceptors by the cephalad shift results in an approximately 10%–15%reduction in plasma volume,with fluid translocating from the vascular lumen to the interstitium.Despite possible increases in cardiac workload,myocyte atrophy and notable,yet unexplained,alterations in hematocrit have been observed.Atrophy is postulated to result from shunting of protein synthesis from the endoplasmic reticulum to the mitochondria via mortalin-mediated action.While data are scarce regarding their causative agents,arrhythmias have been frequently reported,albeit sublethal,during both Russian and American expeditions,with QT interval prolongation observed in long,but not short duration,spaceflight.Exposure of the heart to the proton and heavy ion radiation of deep space has also been shown to result in coronary artery degeneration,aortic stiffness,carotid intima thickening via collagen-mediated action,accelerated atherosclerosis,and induction of a pro-inflammatory state.Upon return,long-term spaceflight frequently results in orthostatic intolerance and altered sympathetic responses,which can prove hazardous should any rapidmobilization or evacuation be required,and indicates that these cardiac risks should be especially monitored for future missions.
基金supported by the STI 2030–the major project of the Brain Science and Brain-Inspired Intelligence Technology(2021ZD0200500)。
文摘It is of great scientific and translational promise to formulate a normative reference for the lifespan development of human brain to precisely quantify individual differences.By aggregating more than 120,000 brain imaging scans across the world,the Lifespan Brain Chart Consortium(LBCC)recently published brain charts for the human lifespan in Nature[1].
基金National Natural Science Foundation of China,Nos.81771160 (to ZZ),81671060 (to CC),31970973 (to JW),21921004 (to FX)Translational Medicine and In terdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University,No.ZNJC201934 (to ZZ)。
文摘Sleep benefits the restoration of energy metabolism and thereby suppo rts neuronal plasticity and cognitive behaviors.Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of energy metabolism because it modulates various transcriptional regulators and metabolic enzymes.The aim of this study was to investigate the influence of Sirt6 on cerebral function after chronic sleep deprivation(CSD).We assigned C57BL/6J mice to control or two CSD groups and subjected them to AAV2/9-CMV-EGFP or AAV2/9-CMV-Sirt6-EGFP infection in the prelimbic cortex(PrL).We then assessed cerebral functional connectivity(FC) using resting-state functional MRI,neuron/astrocyte metabolism using a metabolic kinetics analysis;dendritic spine densities using sparse-labeling;and miniature excitato ry postsynaptic currents(mEPSCs) and action potential(AP) firing rates using whole-cell patchclamp recordings.In addition,we evaluated cognition via a comprehensive set of behavioral tests.Compared with controls,Sirt6 was significantly decreased(P<0.05) in the PrL after CSD,accompanied by cognitive deficits and decreased FC between the PrL and accumbens nucleus,piriform cortex,motor co rtex,somatosensory co rtex,olfactory tubercle,insular cortex,and cerebellum.Sirt6 ove rexpression reve rsed CSD-induced cognitive impairment and reduced FC.Our analysis of metabolic kinetics using [1-13C] glucose and [2-13C] acetate showed that CSD reduced neuronal Glu4and GABA2synthesis,which could be fully restored via forced Sirt6 expression.Furthermore,Sirt6 ove rexpression reversed CSD-induced decreases in AP firing rates as well as the frequency and amplitude of mEPSCs in PrL pyramidal neurons.These data indicate that Sirt6 can improve cognitive impairment after CSD by regulating the PrL-associated FC network,neuronal glucose metabolism,and glutamatergic neurotransmission.Thus,Sirt6 activation may have potential as a novel strategy for treating sleep disorder-related diseases.
文摘Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available today.Since most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism.However,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders.Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders.These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted therapy.In this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.
文摘Primate sanctuaries across Africa play a pivotal role in the rescue and rehabilitation of confiscated and rescued wild primates, many of whom have had extensive contact with humans prior to their arrival and throughout the rehabilitation process, heightening the risk of disease transmission. While tuberculosis is not naturally occurring in free-living chimpanzees, it has been extensively observed in captive primates that have been in close proximity to humans or other captive primates infected with Mycobacterium tuberculosis. This case report delves into an outbreak of extra-pulmonary tuberculosis among juvenile chimpanzees within a sanctuary, detailing the associated diagnostic challenges and treatment approaches. The five cases had close contact with a caregiver infected with tuberculosis, subsequently transmitting the infection to other in-contact chimpanzees. Prolonged treatment, employing the human protocol of quadri-therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol), followed by bi-therapy (rifampicin and isoniazid), resulted in complete resolution for all five cases. These cases underscore the critical importance of maintaining high levels of biosecurity, implementing effective quarantine measures, and adhering to strict hygiene practices when working with non-human primates.
基金supported by the Leukemia and Lymphoma Society (Grants No.LLS 9238-16 and MCL7001-18)the National Institutes of Health (Grants No.P01CA214274,R01CA249054 and R01MH117406)the WorldQuant Foundation,NASA (Grants No.80NSSC19K0432,80NSSC22K0254,NNH18ZTT001N-FG2,NNX13AE45G,NNX14AH50G,NNX17AB26G).
文摘Background The Inspiration4(I4)mission,the first all-civilian orbital flight mission,investigated the physiological effects of short-duration spaceflight through a multi-omic approach.Despite advances,there remains much to learn about human adaptation to spaceflight's unique challenges,including microgravity,immune system perturbations,and radiation exposure.Methods To provide a detailed genetics analysis of the mission,we collected dried blood spots pre-,during,and post-flight for DNA extraction.Telomere length was measured by quantitative PCR,while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations.A robust bioinformatic pipeline was used for data analysis,including variant calling to assess mutational burden.Result Telomere elongation occurred during spaceflight and shortened after return to Earth.Cell-free DNA analysis revealed increased immune cell signatures post-flight.No significant clonal hematopoiesis of indeterminate potential(CHIP)or whole-genome instability was observed.The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight.Conclusion Our findings provide valuable insights into the physiological consequences of short-duration spaceflight,with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth.CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts,an understudied phenomenon as previous studies have focused on career astronauts.This study will serve as a reference point for future commercial and non-commercial spaceflight,low Earth orbit(LEO)missions,and deep-space exploration.
文摘Frontotemporal dementia(FTD) and amyotrophic lateral sclerosis(ALS) are neurodegenerative diseases that belong to the same disease spectrum,with overlapping of genetic and pathological features.Genetic mutations in TARDBP,C9ORF72,MAPT,and GRN have been identified in these diseases.
基金supported by National Key R&D Program of China(Grant No.2017YFA0205400,China)the National Natural Science Foundation of China(Grant Nos.81530093 and 81773781,China)+20 种基金Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(Grant No.2016-I2M-1-007,China)CAMS Central Public-interest Scientific Institution Basic Research Fund(Grant No.2017PT3104,China)supported by grants of the National Natural Science Foundation of China(Grant No.81874316,China)the CAMS Innovation Fund for Medical Sciences(Grant No.2016-I2M-3-008,China)supported by grants of from the BBSRC and NWCR(Grant Nos.1088 and 1097,UK)supported by grants of NSF(Grant No.IOS-1456023,USA)NIH(Grant No.NIH R21 CA197317,USA)supported by grants of Ministry of Education,Singapore(Grant Nos.MOE2014-T2-1-012 and 2012-T1-001-036,Singapore)supported by grants from the Health Research Council of New Zealandsupported by a Rutherford Discovery Fellowship from the New Zealand government administered by the Royal Society of New Zealandsupported by Funda??o para a Ciência e a Tecnologia(FCT)Research Center Grant UID/BIM/04773/2013 Centre for Biomedical Research 1334a research grant from Liga Portuguesa Contra o Cancro–Núcleo Regional do Sul(LPCC/NRS,Portugal)a FCT 2014 research grant SFRH/BPD/100434/2014a Pro Regem grant PD/BD/114258/2016(Portugal)supported by European Marie Sklodowska Curie ITN Project TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)Innovation Network and the British Heart Foundation(PG/16/44/32146,UK)supported by grants from The Howat Foundation Ltd.(UK),Children with Cancer UK,Bloodwise and the Friends of Paul O'Gorman(UK)supported by grants of P-CREATE from Japan Agency for Medical Research and Developmentsupported by grants from the NIH(NIAID,USA),Alex's Lemonade Stand Foundation(USA)and the Samuel Waxman Cancer Research Foundation(USA)supported by European Marie Sklodowska Curie ITN Project TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)the "Fondation Centaure"(RTRS),whic
文摘The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.
基金Supported by The grants from the National Center for Research Resources,No.5P20RR016480-12The National Institute of General Medical Sciences of the NIH,No.8P20GM103451-12+2 种基金the partial support from the National Center for Advancing Translational Sciences of the National Institutes of Health,No.8UL1TR000041the University of New Mexico Clinical and Translational Science Centerthe cost for clinical phenotyping and payments to participants was supported under a UNM Health Sciences Center-based Cardiovascular and Metabolic Diseases Signature Program
文摘AIM: To examine DNA methylation profiles in a longitudinal comparison of pre-diabetes mellitus(Pre-DM) subjects who transitioned to type 2 diabetes mellitus(T2DM).METHODS: We performed DNA methylation study in bisulphite converted DNA from Pre-DM(n = 11) at baseline and at their transition to T2 DM using Illumina Infinium Human Methylation27 Bead Chip, that enables the query of 27578 individual cytosines at Cp G loci throughout the genome, which are focused on the promoter regions of 14495 genes.RESULTS: There were 694 Cp G sites hypomethylated and 174 Cp G sites hypermethylated in progression from Pre-DM to T2 DM, representing putative genes involved in glucose and fructose metabolism, inflammation, oxidative and mitochondrial stress, and fatty acid metabolism. These results suggest that this high throughput platform is able to identify hundreds of prospective Cp G sites associated with diverse genes that may reflect differences in Pre-DM compared with T2 DM. In addition, there were Cp G hypomethylation changes associated with a number of genes that may be associated with development of complications of diabetes, such as nephropathy. These hypomethylation changes were observed in all of the subjects.CONCLUSION: These data suggest that some epigenomic changes that may be involved in the progression of diabetes and/or the development of complications may be apparent at the Pre-DM state or during the transition to diabetes. Hypomethylation of a number of genes related to kidney function may be an early marker for developing diabetic nephropathy.
