Introduction
Variants in the tau gene (MAPT) region are associated with breast cancer in women and Alzheimer's disease (AD) among persons lacking apolipoprotein E ε4 (ε4–).
Methods
To identify novel ...genes associated with tau‐related pathology, we conducted two genome‐wide association studies (GWAS) for AD, one among 10,340 ε4– women in the Alzheimer's Disease Genetics Consortium (ADGC) and another in 31 members (22 women) of a consanguineous Hutterite kindred.
Results
We identified novel associations of AD with MGMT variants in the ADGC (rs12775171, odds ratio OR = 1.4, P = 4.9 × 10–8) and Hutterite (rs12256016 and rs2803456, OR = 2.0, P = 1.9 × 10–14) datasets. Multi‐omics analyses showed that the most significant and largest number of associations among the single nucleotide polymorphisms (SNPs), DNA‐methylated CpGs, MGMT expression, and AD‐related neuropathological traits were observed among women. Furthermore, promoter capture Hi‐C analyses revealed long‐range interactions of the MGMT promoter with MGMT SNPs and CpG sites.
Discussion
These findings suggest that epigenetically regulated MGMT expression is involved in AD pathogenesis, especially in women.
Introduction
The apolipoprotein E (APOE) ɛ2 allele reduces risk against Alzheimer's disease (AD) but mechanisms underlying this effect are largely unknown.
Methods
We conducted a genome‐wide ...association study for AD among 2096 ɛ2 carriers. The potential role of the top‐ranked gene and complement 4 (C4) proteins, which were previously linked to AD in ɛ2 carriers, was investigated using human isogenic APOE allele‐specific induced pluripotent stem cell (iPSC)–derived neurons and astrocytes and in 224 neuropathologically examined human brains.
Results
PPP2CB rs117296832 was the second most significantly associated single nucleotide polymorphism among ɛ2 carriers (P = 1.1 × 10−7) and the AD risk allele increased PPP2CB expression in blood (P = 6.6 × 10−27). PPP2CB expression was correlated with phosphorylated tau231/total tau ratio (P = .01) and expression of C4 protein subunits C4A/B (P = 2.0 × 10−4) in the iPSCs. PPP2CB (subunit of protein phosphatase 2A) and C4b protein levels were correlated in brain (P = 3.3 × 10−7).
Discussion
PP2A may be linked to classical complement activation leading to AD‐related tau pathology.
Non-coding genetic variants outside of protein-coding genome regions play an important role in genetic and epigenetic regulation. It has become increasingly important to understand their roles, as ...non-coding variants often make up the majority of top findings of genome-wide association studies (GWAS). In addition, the growing popularity of disease-specific whole-genome sequencing (WGS) efforts expands the library of and offers unique opportunities for investigating both common and rare non-coding variants, which are typically not detected in more limited GWAS approaches. However, the sheer size and breadth of WGS data introduce additional challenges to predicting functional impacts in terms of data analysis and interpretation. This review focuses on the recent approaches developed for efficient, at-scale annotation and prioritization of non-coding variants uncovered in WGS analyses. In particular, we review the latest scalable annotation tools, databases and functional genomic resources for interpreting the variant findings from WGS based on both experimental data and in silico predictive annotations. We also review machine learning-based predictive models for variant scoring and prioritization. We conclude with a discussion of future research directions which will enhance the data and tools necessary for the effective functional analyses of variants identified by WGS to improve our understanding of disease etiology.
Geochronological, major and trace element, and Sr-Nd-Hf isotopic data are reported for the monzonitic rocks of the Fushan pluton in the Taihang Mountains, central North China Craton, in order to ...investigate their sources, petrogenesis and tectonic implications. Zircon U-Pb dating results reveal that the Fushan pluton was emplaced during the Early Cretaceous (∼126-124 Ma). The monzonites and quartz monzonites are mainly characterized by calc-alkaline and magnesian features and display light rare earth element (LREE) enrichment and flat heavy REE (HREE) patterns with slightly positive Eu anomalies. They have similar whole-rock initial 87Sr/86Sr ratios (0.70653-0.70819), εNd(t) values (-13.6 to -18.6) and zircon εHf(t) values (-21.8 to -17.3). The primary magma of the Fushan pluton was derived from the partial melting of a spinel-facies amphibole-bearing ancient enriched lithospheric mantle. The monzonitic rocks also have high Ba-Sr and low Y and Yb contents, with high Sr/Y and La/Yb ratios. These geochemical features of monzonitic rocks are not only inherited from the magma source but also significantly enhanced by crystal fractionation during magmatic evolution; e.g. hornblende fractionation increased the Ba-Sr concentrations and Sr/Y ratios. During the Early Cretaceous, the slab sinking and roll-back of the Palaeo-Pacific Plate could have created an ancient big mantle wedge beneath East Asia and induced a lithospheric extensional process in the central North China Craton within an intracontinental setting.
RNA molecules fold into complex three-dimensional shapes, guided by the pattern of hydrogen bonding between nucleotides. This pattern of base pairing, known as RNA secondary structure, is critical to ...their cellular function. Recently several diverse methods have been developed to assay RNA secondary structure on a transcriptome-wide scale using high-throughput sequencing. Each approach has its own strengths and caveats, however there is no widely available tool for visualizing and comparing the results from these varied methods.
To address this, we have developed Structure Surfer, a database and visualization tool for inspecting RNA secondary structure in six transcriptome-wide data sets from human and mouse ( http://tesla.pcbi.upenn.edu/strucuturesurfer/ ). The data sets were generated using four different high-throughput sequencing based methods. Each one was analyzed with a scoring pipeline specific to its experimental design. Users of Structure Surfer have the ability to query individual loci as well as detect trends across multiple sites.
Here, we describe the included data sets and their differences. We illustrate the database's function by examining known structural elements and we explore example use cases in which combined data is used to detect structural trends.
In total, Structure Surfer provides an easy-to-use database and visualization interface for allowing users to interrogate the currently available transcriptome-wide RNA secondary structure information for mammals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Although neuritic plaques and neurofibrillary tangles in older adults are correlated with cognitive impairment and severity of dementia, it has long been recognized that the relationship is ...imperfect, as some people exhibit normal cognition despite high levels of Alzheimer's disease (AD) pathology. We compared the cellular, synaptic, and biochemical composition of midfrontal cortices in female subjects from the Religious Orders Study who were stratified into three subgroups: (1) pathological AD with normal cognition (“AD-Resilient”), (2) pathological AD with AD-typical dementia (“AD-Dementia”), and (3) pathologically normal with normal cognition (“Normal Comparison”). The AD-Resilient group exhibited preserved densities of synaptophysin-labeled presynaptic terminals and synaptopodin-labeled dendritic spines compared with the AD-Dementia group, and increased densities of glial fibrillary acidic protein astrocytes compared with both the AD-Dementia and Normal Comparison groups. Further, in a discovery-type antibody microarray protein analysis, we identified a number of candidate protein abnormalities that were associated with a particular diagnostic group. These data characterize cellular and synaptic features and identify novel biochemical targets that may be associated with resilient cognitive brain aging in the setting of pathological AD.
TAR DNA-binding protein 43 (TDP-43) is normally a nuclear RNA-binding protein that exhibits a range of functions including regulation of alternative splicing, RNA trafficking, and RNA stability. ...However, in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved, and is mislocalized to the cytoplasm where it forms distinctive aggregates. We previously developed a mouse model expressing human TDP-43 with a mutation in its nuclear localization signal (ΔNLS-hTDP-43) so that the protein preferentially localizes to the cytoplasm. These mice did not exhibit a significant number of cytoplasmic aggregates, but did display dramatic changes in gene expression as measured by microarray, suggesting that cytoplasmic TDP-43 may be associated with a toxic gain-of-function. Here, we analyze new RNA-sequencing data from the ΔNLS-hTDP-43 mouse model, together with published RNA-sequencing data obtained previously from TDP-43 antisense oligonucleotide (ASO) knockdown mice to investigate further the dysregulation of gene expression in the ΔNLS model. This analysis reveals that the transcriptomic effects of the overexpression of the ΔNLS-hTDP-43 transgene are likely due to a gain of cytoplasmic function. Moreover, cytoplasmic TDP-43 expression alters transcripts that regulate chromatin assembly, the nucleolus, lysosomal function, and histone 3' untranslated region (UTR) processing. These transcriptomic alterations correlate with observed histologic abnormalities in heterochromatin structure and nuclear size in transgenic mouse and human brains.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The poor outcomes in infant acute lymphoblastic leukemia (ALL) necessitate new treatments. Here we discover that EIF4E protein is elevated in most cases of infant ALL and test EIF4E targeting by the ...repurposed antiviral agent ribavirin, which has anticancer properties through EIF4E inhibition, as a potential treatment. We find that ribavirin treatment of actively dividing infant ALL cells on bone marrow stromal cells (BMSCs) at clinically achievable concentrations causes robust proliferation inhibition in proportion with EIF4E expression. Further, we find that ribavirin treatment of KMT2A-rearranged (KMT2A-R) infant ALL cells and the KMT2A-AFF1 cell line RS4:11 inhibits EIF4E, leading to decreases in oncogenic EIF4E-regulated cell growth and survival proteins. In ribavirin-sensitive KMT2A-R infant ALL cells and RS4:11 cells, EIF4E-regulated proteins with reduced levels of expression following ribavirin treatment include MYC, MCL1, NBN, BCL2 and BIRC5. Ribavirin-treated RS4:11 cells exhibit impaired EIF4E-dependent nuclear to cytoplasmic export and/or translation of the corresponding mRNAs, as well as reduced phosphorylation of the p-AKT1, p-EIF4EBP1, p-RPS6 and p-EIF4E signaling proteins. This leads to an S-phase cell cycle arrest in RS4:11 cells corresponding to the decreased proliferation. Ribavirin causes nuclear EIF4E to re-localize to the cytoplasm in KMT2A-AFF1 infant ALL and RS4:11 cells, providing further evidence for EIF4E inhibition. Ribavirin slows increases in peripheral blasts in KMT2A-R infant ALL xenograft-bearing mice. Ribavirin cooperates with chemotherapy, particularly L-asparaginase, in reducing live KMT2A-AFF1 infant ALL cells in BMSC co-cultures. This work establishes that EIF4E is broadly elevated across infant ALL and that clinically relevant ribavirin exposures have preclinical activity and effectively inhibit EIF4E in KMT2A-R cases, suggesting promise in EIF4E targeting using ribavirin as a means of treatment.
We implemented a high-throughput identification pipeline for promoter interacting enhancer element to streamline the workflow from mapping raw Hi-C reads, identifying DNA-DNA interacting fragments ...with high confidence and quality control, detecting histone modifications and DNase hypersensitive enrichments in putative enhancer elements, to ultimately extracting possible intra- and inter-chromosomal enhancer-target gene relationships.
This software package is designed to run on high-performance computing clusters with Oracle Grid Engine. The source code is freely available under the MIT license for academic and nonprofit use. The source code and instructions are available at the Wang lab website (http://wanglab.pcbi.upenn.edu/hippie/). It is also provided as an Amazon Machine Image to be used directly on Amazon Cloud with minimal installation.
lswang@mail.med.upenn.edu or bdgregor@sas.upenn.edu
Supplementary Material is available at Bioinformatics online.
In order to improve the measuring accuracy of the Hemispherical Resonator Gyro under variable temperature, aiming at the problem of "external temperature is unavailable and internal temperature is ...unmeasurable," a multiple regression based method is proposed for compensating temperature error in the gyro. The relationship between the internal temperature and the resonant frequency of the gyro is analyzed theoretically. According to a constant temperature experiment, a linear relationship between them is derived based on the least square method. The analysis of a temperature-rising experiment shows that the correlation of the gyro output with the internal temperature is much higher than that with the external temperature. Therefore, taking the resonant frequency as an independent variable, a multiple regression model is established for compensating the temperature error. The compensation effect of the model is verified by temperature-rising and temperature-dropping experiments, which show that the output sequence before compensation is not stable, while it is stable after compensation. After compensation, the drift of the gyro decreases by 62.76% and 48.48%, respectively, and its measuring accuracy becomes equivalent to that at the constant temperature. The experimental results verify the feasibility and effectiveness of the model developed for indirect compensation of temperature error.
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