Failures in drug trials strengthen the necessity to further determine the neuropathological events during the development of Alzheimer's disease (AD). We sought to investigate the dynamic changes and ...performance of plasma biomarkers across the entire Alzheimer's continuum in the Chinese population.
Plasma amyloid-β (Αβ)42, Aβ40, Aβ42/Aβ40, phosphorylated tau (p-tau)181, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were measured utilizing the ultrasensitive single-molecule array technology across the AD continuum (n=206), wherein Aβ status was defined by the values of cerebrospinal fluid (CSF) Aβ42 or Aβ positron emission tomography (PET). Their trajectories were compared with those of putative CSF biomarkers.
Plasma GFAP and p-tau181 increased only in Aβ-positive individuals throughout aging, whereas NfL increased with aging regardless of Aβ status. Among the plasma biomarkers studied, GFAP was the one that changed first. It had a prominent elevation early in the cognitively unimpaired (CU) A+T- phase (CU A+T- phase: 97.10±41.29 pg/ml; CU A-T- phase: 49.18±14.39 pg/ml; p<0.001). From preclinical to symptomatic stages of AD, plasma GFAP started to rise sharply as soon as CSF Aβ became abnormal and continued to increase until reaching its highest level during the AD dementia phase. The greatest slope of change was seen in plasma GFAP. This is followed by CSF p-tau181 and total-tau, and, to a lesser extent, then plasma p-tau181. In contrast, the changes in plasma NfL, Aβ42/Aβ40, Aβ42, and Aβ40 were less pronounced. Of note, these plasma biomarkers exhibited smaller dynamic ranges than their CSF counterparts, except for GFAP which was the opposite. Plasma GFAP and p-tau181 were tightly associated with AD pathologies and amyloid tracer uptake in widespread brain areas. Plasma GFAP could accurately identify CSF Aβ42 (area under the curve (AUC)=0.911) and Aβ PET (AUC=0.971) positivity. Plasma p-tau181 also performed well in discriminating Aβ PET status (AUC=0.916), whereas the discriminative accuracy was relatively low for other plasma biomarkers.
This study is the first to delineate the trajectories of plasma biomarkers throughout the Alzheimer's continuum in the Chinese population, providing important implications for future trials targeting plasma GFAP to facilitate AD prevention and treatment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The transition from ordered to noisy is a significant epigenetic signature of aging and age‐related disease. As a paradigm of healthy human aging and longevity, long‐lived individuals (LLI, >90 years ...old) may possess characteristic strategies in coping with the disordered epigenetic regulation. In this study, we constructed high‐resolution blood epigenetic noise landscapes for this cohort by a methylation entropy (ME) method using whole genome bisulfite sequencing (WGBS). Although a universal increase in global ME occurred with chronological age in general control samples, this trend was suppressed in LLIs. Importantly, we identified 38,923 genomic regions with LLI‐specific lower ME (LLI‐specific lower entropy regions, for short, LLI‐specific LERs). These regions were overrepresented in promoters, which likely function in transcriptional noise suppression. Genes associated with LLI‐specific LERs have a considerable impact on SNP‐based heritability of some aging‐related disorders (e.g., asthma and stroke). Furthermore, neutrophil was identified as the primary cell type sustaining LLI‐specific LERs. Our results highlight the stability of epigenetic order in promoters of genes involved with aging and age‐related disorders within LLI epigenomes. This unique epigenetic feature reveals a previously unknown role of epigenetic order maintenance in specific genomic regions of LLIs, which helps open a new avenue on the epigenetic regulation mechanism in human healthy aging and longevity.
Wang et al. constructed high‐resolution methylation entropy (ME) maps in long‐lived individuals (LLIs) using WGBS data. It provides the evidence supporting that a large number of genomic regions, significantly enriched in promoters, displaying significantly lower ME in LLIs (LLI‐specific LERs) than normal aging people. Further analysis revealed a close relationship between these lower entropy regions and age‐related disorders and longevity.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
INTRODUCTION
Amyloid beta (Aβ) deposition, tau accumulation, and brain atrophy occurr in sequence, but the contribution of Alzheimer's disease (AD) pathology to biological and clinical progression ...remains unclear.
METHODS
We included 290 and 70 participants with longitudinal assessment on Aβ‐positron emission tomography (PET), tau‐PET, magnetic resonance imaging, and cognitive function from the Harvard Aging Brain Study (HABS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) datasets, respectively. Partial least squares structural equation modeling (PLS‐SEM) was used to determine the contribution of AD pathology to the biological and clinical longitudinal changes.
RESULTS
Imaging biomarkers and cognitive function were significantly associated in cross‐sectional and longitudinal analyses. At the final time point, the percentage of variance explained by PLS‐SEM was 27% for Aβ, 30% for tau (Aβ accounted for 61%), 29% for brain atrophy (tau accounted for 37%), and 37% for cognitive decline (brain atrophy accounted for 35%).
DISCUSSION
This study highlights distinctive contributing proportions of AD pathology to biological and clinical progression. Treatments targeting Aβ and tau may partially block AD progression.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
ABSTRACT
Innovations in genomics have enabled the development of low‐cost, high‐resolution, single nucleotide polymorphism (SNP) genotyping arrays that accelerate breeding progress and support basic ...research in crop science. Here, we developed and validated the SoySNP618K array (618,888 SNPs) for the important crop soybean. The SNPs were selected from whole‐genome resequencing data containing 2,214 diverse soybean accessions; 29.34% of the SNPs mapped to genic regions representing 86.85% of the 56,044 annotated high‐confidence genes. Identity‐by‐state analyses of 318 soybeans revealed 17 redundant accessions, highlighting the potential of the SoySNP618K array in supporting gene bank management. The patterns of population stratification and genomic regions enriched through domestication were highly consistent with previous findings based on resequencing data, suggesting that the ascertainment bias in the SoySNP618K array was largely compensated for. Genome‐wide association mapping in combination with reported quantitative trait loci enabled fine‐mapping of genes known to influence flowering time, E2 and GmPRR3b, and of a new candidate gene, GmVIP5. Moreover, genomic prediction of flowering and maturity time in 502 recombinant inbred lines was highly accurate (>0.65). Thus, the SoySNP618K array is a valuable genomic tool that can be used to address many questions in applied breeding, germplasm management, and basic crop research.
To accelerate breeding progress and support basic research in soybean, the customized SoySNP618K array contains 618,888 SNPs selected from > 2,000 diverse, re‐sequenced soybean genomes. SoySNP618K is a valuable genomic tool to address questions in applied breeding, germplasm management, and basic research.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Esophageal squamous cell carcinoma (ESCC) has the highest mortality rates in China. The 5-year survival rate of ESCC remains dismal despite improvements in treatments such as surgical resection and ...adjuvant chemoradiation, and current clinical staging approaches are limited in their ability to effectively stratify patients for treatment options. The aim of the present study, therefore, was to develop an immunohistochemistry-based prognostic model to improve clinical risk assessment for patients with ESCC.
We developed a molecular prognostic model based on the combined expression of axis of epidermal growth factor receptor (EGFR), phosphorylated Specificity protein 1 (p-Sp1), and Fascin proteins. The presence of this prognostic model and associated clinical outcomes were analyzed for 130 formalin-fixed, paraffin-embedded esophageal curative resection specimens (generation dataset) and validated using an independent cohort of 185 specimens (validation dataset).
The expression of these three genes at the protein level was used to build a molecular prognostic model that was highly predictive of ESCC survival in both generation and validation datasets (P = 0.001). Regression analysis showed that this molecular prognostic model was strongly and independently predictive of overall survival (hazard ratio = 2.358 95% CI, 1.391-3.996, P = 0.001 in generation dataset; hazard ratio = 1.990 95% CI, 1.256-3.154, P = 0.003 in validation dataset). Furthermore, the predictive ability of these 3 biomarkers in combination was more robust than that of each individual biomarker.
This technically simple immunohistochemistry-based molecular model accurately predicts ESCC patient survival and thus could serve as a complement to current clinical risk stratification approaches.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although it is well known that metabolic control plays a crucial role in regulating the health span and life span of various organisms, little is known for the systems metabolic profile of ...centenarians, the paradigm of human healthy aging and longevity. Meanwhile, how to well characterize the system‐level metabolic states in an organism of interest remains to be a major challenge in systems metabolism research. To address this challenge and better understand the metabolic mechanisms of healthy aging, we developed a method of genome‐wide precision metabolic modeling (GPMM) which is able to quantitatively integrate transcriptome, proteome and kinetome data in predictive modeling of metabolic networks. Benchmarking analysis showed that GPMM successfully characterized metabolic reprogramming in the NCI‐60 cancer cell lines; it dramatically improved the performance of the modeling with an R2 of 0.86 between the predicted and experimental measurements over the performance of existing methods. Using this approach, we examined the metabolic networks of a Chinese centenarian cohort and identified the elevated fatty acid oxidation (FAO) as the most significant metabolic feature in these long‐lived individuals. Evidence from serum metabolomics supports this observation. Given that FAO declines with normal aging and is impaired in many age‐related diseases, our study suggests that the elevated FAO has potential to be a novel signature of healthy aging of humans.
Little is known for the systems metabolic profile of centenarians, the paradigm of human healthy aging and longevity. Here, we developed a method of genome‐wide precision metabolic modeling (GPMM) to systematically analyze human metabolic networks. We used GPMM to examine the metabolic networks of centenarian and demonstrated the elevated fatty acid oxidation as a novel signature of healthy aging of humans.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Purpose
This systematic review aimed to evaluate the effect of implant length on peri‐implant marginal bone loss (MBL) and its associated influencing factors.
Material and methods
An electronic ...search of the PubMed and MEDLINE databases for relevant studies published in English from November 2006 to July 2012 was performed by one examiner (AM). Selected studies were randomized clinical trials, human experimental clinical trials or prospective studies (e.g., cohort as well as case series) with a clear aim of investigating marginal bone loss of short dental implants (<10 mm) supporting fixed prostheses. A random‐effect meta‐regression model was used to determine the relationship between the effect size mean MBL and the covariate “implant length.” Additionally, a subgroup analysis, by means of a random‐effect one‐way ANOVA model, comparing mean MBL values at different levels of each factor (“type of connection” and “type of prostheses”) was also performed.
Results
The meta‐regression of mean MBL on the moderator “implant length” was found to be insignificant (P = 0.633). Therefore, it could not be concluded that implant length had an effect on peri‐implant MBL. In addition, standardized differences in mean MBL on the subgroups short (<10 mm) and standard (≥10 mm) implants, as determined by the meta‐analysis (random‐effect model), were found to be statistically insignificant (P = 0.222).
Conclusions
Within limitations of the present systematic review, it could be concluded that short dental implants (<10 mm) had similar peri‐implant MBL as standard implants (≥10 mm) for implant‐supported fixed prostheses.
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BFBNIB, CMK, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Genome-wide association studies have identified more than 30 Alzheimer's disease (AD) risk genes, although the detailed mechanism through which all these genes are associated with AD pathogenesis ...remains unknown. We comprehensively evaluate the roles of the variants in top 30 non-APOE AD risk genes, based on whether these variants were associated with altered mRNA transcript levels, as well as brain amyloidosis, tauopathy, and neurodegeneration.
Human brain gene expression data were obtained from the UK Brain Expression Consortium (UKBEC), while other data used in our study were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We examined the association of AD risk allele carrier status with the levels of gene expression in blood and brain regions and tested the association with brain amyloidosis, tauopathy, and neurodegeneration at baseline, using a multivariable linear regression model. Next, we analyzed the longitudinal effects of these variants on the change rates of pathology using a mixed effect model.
Altogether, 27 variants were detected to be associated with the altered expression of 21 nearby genes in blood and brain regions. Eleven variants (especially novel variants in ADAM10, IGHV1-68, and SLC24A4/RIN3) were associated with brain amyloidosis, 7 variants (especially in INPP5D, PTK2B) with brain tauopathy, and 8 variants (especially in ECHDC3, HS3ST1) with brain neurodegeneration. Variants in ADAMTS1, BZRAP1-AS1, CELF1, CD2AP, and SLC24A4/RIN3 participated in more than one cerebral pathological process.
Genetic variants might play functional roles and suggest potential mechanisms in AD pathogenesis, which opens doors to uncover novel targets for AD treatment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Somatic mutations accumulate with age and are associated closely with human health, their characterization in longevity cohorts remains largely unknown. Here, by analyzing whole genome somatic ...mutation profiles in 73 centenarians and 51 younger controls in China, we found that centenarian genomes are characterized by a markedly skewed distribution of somatic mutations, with many genomic regions being specifically conserved but displaying a high function potential. This, together with the observed more efficient DNA repair ability in the long‐lived individuals, supports the existence of key genomic regions for human survival during aging, with their integrity being of essential to human longevity.
By systematically analyzing the somatic mutation landscapes of 73 centenarians and 51 controls using whole genome sequencing, Wang et al. identified a number of genomic regions (viz., CSM‐FRs) that are free of any somatic mutations in the centenarians but are always mutated in the general older people. Importantly, the high conservation and function potential of these genomic regions indicate the necessity of their integrity for human longevity.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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