INFIMA leverages multi-omics model organism data to identify effector genes of human GWAS variants.

Genome-wide association studies reveal many non-coding variants associated with complex traits. However, model organism studies largely remain as an untapped resource for unveiling the effector genes of non-coding variants. We develop INFIMA, Integrative Fine-Mapping, to pinpoint causal SNPs for diversity outbred (DO) mice eQTL by integrating founder mice multi-omics data including ATAC-seq, RNA-seq, footprinting, and in silico mutation analysis. We demonstrate INFIMA\u27s superior performance compared to alternatives with human and mouse chromatin conformation capture datasets. We apply INFIMA to identify novel effector genes for GWAS variants associated with diabetes. The results of the application are available at http://www.statlab.wisc.edu/shiny/INFIMA/

HiView: an integrative genome browser to leverage Hi-C results for the interpretation of GWAS variants

Abstract Background Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with complex traits and diseases. However, most of them are located in the non-protein coding regions, and therefore it is challenging to hypothesize the functions of these non-coding GWAS variants. Recent large efforts such as the ENCODE and Roadmap Epigenomics projects have predicted a large number of regulatory elements. However, the target genes of these regulatory elements remain largely unknown. Chromatin conformation capture based technologies such as Hi-C can directly measure the chromatin interactions and have generated an increasingly comprehensive catalog of the interactome between the distal regulatory elements and their potential target genes. Leveraging such information revealed by Hi-C holds the promise of elucidating the functions of genetic variants in human diseases. Results In this work, we present HiView, the first integrative genome browser to leverage Hi-C results for the interpretation of GWAS variants. HiView is able to display Hi-C data and statistical evidence for chromatin interactions in genomic regions surrounding any given GWAS variant, enabling straightforward visualization and interpretation. Conclusions We believe that as the first GWAS variants-centered Hi-C genome browser, HiView is a useful tool guiding post-GWAS functional genomics studies. HiView is freely accessible at: http://www.unc.edu/~yunmli/HiView

Integrative functional genomic analysis of human brain development and neuropsychiatric risks

INTRODUCTION The brain is responsible for cognition, behavior, and much of what makes us uniquely human. The development of the brain is a highly complex process, and this process is reliant on precise regulation of molecular and cellular events grounded in the spatiotemporal regulation of the transcriptome. Disruption of this regulation can lead to neuropsychiatric disorders. RATIONALE The regulatory, epigenomic, and transcriptomic features of the human brain have not been comprehensively compiled across time, regions, or cell types. Understanding the etiology of neuropsychiatric disorders requires knowledge not just of endpoint differences between healthy and diseased brains but also of the developmental and cellular contexts in which these differences arise. Moreover, an emerging body of research indicates that many aspects of the development and physiology of the human brain are not well recapitulated in model organisms, and therefore it is necessary that neuropsychiatric disorders be understood in the broader context of the developing and adult human brain. RESULTS Here we describe the generation and analysis of a variety of genomic data modalities at the tissue and single-cell levels, including transcriptome, DNA methylation, and histone modifications across multiple brain regions ranging in age from embryonic development through adulthood. We observed a widespread transcriptomic transition beginning during late fetal development and consisting of sharply decreased regional differences. This reduction coincided with increases in the transcriptional signatures of mature neurons and the expression of genes associated with dendrite development, synapse development, and neuronal activity, all of which were temporally synchronous across neocortical areas, as well as myelination and oligodendrocytes, which were asynchronous. Moreover, genes including MEF2C, SATB2, and TCF4, with genetic associations to multiple brain-related traits and disorders, converged in a small number of modules exhibiting spatial or spatiotemporal specificity. CONCLUSION We generated and applied our dataset to document transcriptomic and epigenetic changes across human development and then related those changes to major neuropsychiatric disorders. These data allowed us to identify genes, cell types, gene coexpression modules, and spatiotemporal loci where disease risk might converge, demonstrating the utility of the dataset and providing new insights into human development and disease

Enhancers: Multi-dimensional signal integrators

Enhancers play a critical role in regulating tissue-specific gene expression, but their molecular mechanisms of function have not been fully characterized. It is now increasingly clear that enhancers associate with specific protein factors and chromatin modifications and also produce non-coding RNAs known as eRNAs. These predictive signatures have facilitated genomic identification of enhancers and helped characterize tissue-specific gene expression mechanisms. Herein we review recent studies investigating enhancers in mammalian cells, and propose that enhancers function as a central platform integrating lineage-specific transcription factors and epigenetic states with ubiquitous yet signal-dependent transcriptional inputs, culminating in highly specific gene expression programs

An Effective CFO Estimation Method Based on Unitary Transformation for Interleaved OFDMA Uplink Systems

AbstractThis paper presents an effective carrier frequency offset (CFO) algorithm based on unitary transformation and MUSIC technique, for interleaved orthogonal frequency-division multiple-access (OFDMA) uplink systems. Compared with other recently proposed estimation approaches, the proposed method offers several advantages. Firstly, the proposed method reduces the computational complexity significantly by dealing with only real-valued computations. Secondly, the proposed method incorporates the data stacking technology and the unitary transformation, which adds structure to the data model for the implementation of the proposed method, and leads to an improved estimation performance. Simulation results demonstrate the efficacy of the proposed algorithm

An Investigation on the Microstructure and Texture of an AZ80 Cup-Shaped Piece Processed by Rotating Backward Extrusion

The rotating backward extrusion (RBE) process, as a new severe plastic deformation (SPD) process, is based on conventional backward extrusion and rotation, which meets the requirement of modern industrial development with its high performance and production efficiency. However, there is little research on the microstructure evolution and texture modification of the RBE process. Thus, in this study, the effect of different rotating revolutions, e.g., n = 5, n = 10, and n = 50, on the microstructure and texture development for the RBE process based on the AZ80 magnesium (Mg) alloy were investigated at 653 K. The results disclose that the rotating revolution is an influencing processing parameter on the deformation of the RBE process. The grain refining ability is enhanced with the increase of the rotating revolutions, and the minimum grain size of the cup bottom, shearing zone, and cup wall can reach to 16.7 μm, 15.6 μm, and 13.0 μm, respectively, under the condition of n = 50. Furthermore, with the increase in the rotating revolutions, the microstructure of the alloy becomes more uniform and the proportion of dynamic recrystallization (DRX) is also increased. The maximum DRX fractions of the sample for the cup bottom and cup wall are 95.4% and 86.8%, respectively, at n = 50. The DRX mechanism of the RBE process is determined by the continuous DRX and discontinuous DRX. In addition, the texture can be significant weakened during the RBE process, especially at the cup bottom, where the maximum pole intensity can be reduced from 17.6 at n = 10 to 6.5 at n = 50, which can be attributed to the higher proportion of new DRXed grains whose orientations are more random compared with the deformed grains

Anisotropic Low Cycle Behavior of the Extruded 7075 Al Alloy

The quasi-static and low cycle fatigue tests of extruded 7075 Al alloy (Φ200 mm) were investigated in three directions: the extrusion direction (ED), the radial direction (RD), and 45° with ED (45°). Grain morphology analysis, texture measurement, and fatigue fracture characterization were conducted to discuss the relationship between microstructure and mechanical properties. The experimental results showed that the ED specimen had higher ultimate tensile strength (UTS) and low cycle fatigue (LCF) properties, which were mainly attributed to the following three causes. First, the grain boundaries (GBs) had an obvious effect on the crack growth. The number of GBs in the three directions was different due to the shape of the grains elongated along the ED. Second, the sharp <111> texture and the small Schmidt factor along the ED explained the higher ultimate tensile strength (UTS) of the ED specimens. Third, fatigue fracture observation showed that the ED specimen had a narrow fatigue striation spacing, which indicated that the plastic deformation of the ED specimen was the smallest in each cycle. In addition, two fatigue prediction models were established to predict the LCF life of extruded 7075 Al alloy, based on the life response behavior of the three directions under different strains

Effects of ageing on low-cycle fatigue (LCF) properties of AZ80 magnesium alloy wheel hub

A hollow billet Expanding-Reducing Extrusion (ERE) wheel hub forming process was carried out with AZ80 magnesium alloy. The effects of ageing on Low-cycle fatigue (LCF) properties were investigated, and the microstructure was characterized with scanning electronic microscopy (SEM). The LCF testing results exhibited that the stress amplitude increased with increasing ageing time, while the plastic strain decreased with increasing ageing time. Cyclic softening followed by hardening was observed for 0 h and 16 h aged samples; however, there was no obvious cyclic softening or hardening for 36 h aged sample. The tension-compression asymmetry were not obvious due to the low strain, precipitation and the non typical basal texture. Fracture observations indicated that the fatigue cracks were initiated on the surface, and the crack propagation area decreased with increasing ageing time. Thus, it can be concluded that ageing has strong effects on the fatigue life for the studied magnesium alloy