Epigenetic silencing of nucleolar rRNA genes in Alzheimer\u27s disease

BACKGROUND: Ribosomal deficits are documented in mild cognitive impairment (MCI), which often represents an early stage Alzheimer\u27s disease (AD), as well as in advanced AD. The nucleolar rRNA genes (rDNA), transcription of which is critical for ribosomal biogenesis, are regulated by epigenetic silencing including promoter CpG methylation. METHODOLOGY/PRINCIPAL FINDINGS: To assess whether CpG methylation of the rDNA promoter was dysregulated across the AD spectrum, we analyzed brain samples from 10 MCI-, 23 AD-, and, 24 age-matched control individuals using bisulfite mapping. The rDNA promoter became hypermethylated in cerebro-cortical samples from MCI and AD groups. In parietal cortex, the rDNA promoter was hypermethylated more in MCI than in advanced AD. The cytosine methylation of total genomic DNA was similar in AD, MCI, and control samples. Consistent with a notion that hypermethylation-mediated silencing of the nucleolar chromatin stabilizes rDNA loci, preventing their senescence-associated loss, genomic rDNA content was elevated in cerebrocortical samples from MCI and AD groups. CONCLUSIONS/SIGNIFICANCE: In conclusion, rDNA hypermethylation could be a new epigenetic marker of AD. Moreover, silencing of nucleolar chromatin may occur during early stages of AD pathology and play a role in AD-related ribosomal deficits and, ultimately, dementia

Late Preterm Infants' Social Competence, Motor Development, and Cognition

The aim of this study was to compare the social competence, motor development, and cognition of late preterm infants (LPIs) with full-term infants. Several studies in the recent past indicated that LPIs are at high risk of social development problems. We compared the development of motor skills, cognition, and social competency of LPIs with full-term infants at between 2 and 2.5 years old. The Chinese versions of the Gesell Development Diagnosis scale and the Normal Development of Social Skills from Infants to Junior High School Children scale were used for the assessment. LPIs were not more socially competent than their full-term counterparts. Each skill—namely, adaptability, gross motor, fine motor, language, and personal-social responses—was separately associated with the total level of social skills. It was found that gross motor skills had a positive correlation with the self-help and locomotive abilities, and fine motor skills had a positive association with locomotion abilities. LPIs had risk factors due to their delayed social skills in areas including motor disorders and physiological and perinatal factors. LPIs under three were at a higher risk of impairment in social competency. Therefore, it is recommended that they be monitored regularly to identify the development of social and cognitive disorders at an early stage

A many-objective evolutionary algorithm based on rotation and decomposition

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Evolutionary algorithms have shown their promise in addressing multiobjective problems (MOPs). However, the Pareto dominance used in multiobjective optimization loses its effectiveness when addressing many-objective problems (MaOPs), which are defined as having more than three objectives. This is because the Pareto dominance loses its ability to distinguish between individuals. In this paper, a many-objective evolutionary algorithm based on rotation and decomposition is proposed (MaOEA-RD) to overcome the shortcoming of insufficient selection pressure caused by the Pareto dominance. First, the coordinates system is rotated and a hyperplane is established to distinguish between the nondominated individuals. Then, a novel individual selection mechanism incorporating decomposition is adopted to maintain the diversity of the population. In order to compensate for the deficiency of the predefined reference vectors, a reference vector adjustment mechanism is proposed. Experimental studies on several well-known benchmark problems show that the proposed algorithm is competitive compared with seven state-of-the-art many-objective algorithms

Tris­[3,3′-(p-phenyl­enedimethyl­ene)diimidazol-1-ium] bis(phosphatododeca­molybdate)

In the title compound, (C14H16N4)3[PMo12O40]2, the asymmetric unit contains one [PMo12O40]3− anion and one and a half 3,3′-(p-phenyl­enedimethyl­ene)diimidazol-1-ium cations. Each cation links two [PMo12O40]3− anions, which link three cations through N—H⋯O hydrogen bonds, generating an infinite supra­molecular chain-like structure

Nucleolar Enrichment of Brain Proteins with Critical Roles in Human Neurodevelopment*

To study nucleolar involvement in brain development, the nuclear and nucleolar proteomes from the rat cerebral cortex at postnatal day 7 were analyzed using LC-MS/iTRAQ methodology. Data of the analysis are available via ProteomeXchange with identifier PXD002188. Among 504 candidate nucleolar proteins, the overrepresented gene ontology terms included such cellular compartmentcategories as “nucleolus”, “ribosome” and “chromatin”. Consistent with such classification, the most overrepresented functional gene ontology terms were related to RNA metabolism/ribosomal biogenesis, translation, and chromatin organization. Sixteen putative nucleolar proteins were associated with neurodevelopmental phenotypes in humans. Microcephaly and/or cognitive impairment were the most common phenotypic manifestations. Although several such proteins have links to ribosomal biogenesis and/or genomic stability/chromatin structure (e.g. EMG1, RPL10, DKC1, EIF4A3, FLNA, SMC1, ATRX, MCM4, NSD1, LMNA, or CUL4B), others including ADAR, LARP7, GTF2I, or TCF4 have no such connections known. Although neither the Alazami syndrome-associated LARP7nor the Pitt-Hopkins syndrome-associated TCF4 were reported in nucleoli of non-neural cells, in neurons, their nucleolar localization was confirmed by immunostaining. In cultured rat hippocampal neurons, knockdown of LARP7 reduced both perikaryal ribosome content and general protein synthesis. Similar anti-ribosomal/anti-translation effects were observed after knockdown of the ribosomal biogenesis factor EMG1 whose deficiency underlies Bowen-Conradi syndrome. Finally, moderate reduction of ribosome content and general protein synthesis followed overexpression of two Pitt-Hopkins syndrome mutant variants of TCF4. Therefore, dysregulation of ribosomal biogenesis and/or other functions of the nucleolus may disrupt neurodevelopment resulting in such phenotypes as microcephaly and/or cognitive impairment

A phylogenetic model for understanding the effect of gene duplication on cancer progression

As biotechnology advances rapidly, a tremendous amount of cancer genetic data has become available, providing an unprecedented opportunity for understanding the genetic mechanisms of cancer. To understand the effects of duplications and deletions on cancer progression, two genomes (normal and tumor) were sequenced from each of five stomach cancer patients in different stages (I, II, III and IV). We developed a phylogenetic model for analyzing stomach cancer data. The model assumes that duplication and deletion occur in accordance with a continuous time Markov Chain along the branches of a phylogenetic tree attached with five extended branches leading to the tumor genomes. Moreover, coalescence times of the phylogenetic tree follow a coalescence process. The simulation study suggests that the maximum likelihood approach can accurately estimate parameters in the phylogenetic model. The phylogenetic model was applied to the stomach cancer data. We found that the expected number of changes (duplication and deletion) per gene for the tumor genomes is significantly higher than that for the normal genomes. The goodness-of-fit test suggests that the phylogenetic model with constant duplication and deletion rates can adequately fit the duplication data for the normal genomes. The analysis found nine duplicated genes that are significantly associated with stomach cancer

Acupuncture for chronic, stable angina pectoris and an investigation of the characteristics of acupoint specificity: study protocol for a multicenter randomized controlled trial

BACKGROUND: Chronic stable angina pectoris (CSAP) is a common cardiovascular condition that endangers a patient’s life quality and longevity. As demonstrated in several clinical trials, acupuncture is attested to be effective for CSAP. Current trials are not adequate enough to provide high-quality evidence for clinical decision making, as a result of inadequate methodology design and small sample size. Notably, stark controversy toward acupoint specificity also exists in the clinical acupuncture trials for CSAP. Therefore, we designed the present study as a randomized controlled trial primarily to investigate the effectiveness of acupuncture in addition to routine care among patients with CSAP. Meanwhile, we examined whether acupoint on the disease-affected meridian (DAM) is superior to either acupoint on the non-affected meridian (NAM) or non-acupoint (NA), to further investigate the meridian-based characteristics of acupoint specificity. METHODS/DESIGN: This study was a multicenter, assessor and statistician blinded, randomized controlled trial in China. In this study, 404 participants in sum will be randomly assigned to four groups through central randomization in a 1:1:1:1 ratio. The whole study period is 20 weeks including a 4-week baseline period, a 4-week treatment period and a 12-week follow-up. Participants in the DAM group receive acupuncture stimulation at acupoints on the disease-affected meridian, and three different control groups will undergo acupuncture stimulation at the NAM, the non-acupoint and no intervention respectively, in addition to basic treatment. Participants in the acupuncture groups will receive 12 sessions of acupuncture treatment over 4 weeks, while the wait-listed (WL) group would receive free acupuncture treatment after the completion of the study. The outcome measures in this trial include the frequency of angina attack during 4 weeks as the primary outcome and eight other secondary outcomes. DISCUSSION: This trial will provide new and relatively high-quality evidence in acupuncture treatment for CSAP. Moreover, this trial may further validate the meridian-based characteristics of acupoint specificity by comparing the strength of acupoints on the disease-affected meridian versus that of the non-affected meridian, to further inspire optimization of acupuncture therapy for CSAP. TRIAL REGISTRATION: Clinical Trials.gov NCT0168623

Multiaxial fatigue life prediction using an improved Smith‐Watson‐Topper model

AbstractIn this paper, the SWT model was improved by incorporating the Walker equation into the strain–life curve. The established model takes into account the material's sensitivity to mean stress by introducing the Walker exponent, w. Under uniaxial loading condition, the proposed model can reduce to the SWT model, Manson‐Coffin equation, and Walker model for w values of 0.5, 1, and 0, respectively. Under multiaxial symmetric loading, when w = 0.5, the proposed model can be simplified as another SWT correction model (CXH) proposed by Chen et al. The prediction accuracy of the established model was validated using about 200 data points collected from literature. These data points were obtained from tests conducted on eight different kinds of metals under various multiaxial loading paths. The verification results indicate that 96.8% and 97.9% of the data points fall within the factor‐of‐three boundary for the loading paths without and with mean stresses, respectively.</jats:p