Meta-analysis of massively parallel reporter assays enables prediction of regulatory function across cell types.

Deciphering the potential of noncoding loci to influence gene regulation has been the subject of intense research, with important implications in understanding genetic underpinnings of human diseases. Massively parallel reporter assays (MPRAs) can measure regulatory activity of thousands of DNA sequences and their variants in a single experiment. With increasing number of publically available MPRA data sets, one can now develop data-driven models which, given a DNA sequence, predict its regulatory activity. Here, we performed a comprehensive meta-analysis of several MPRA data sets in a variety of cellular contexts. We first applied an ensemble of methods to predict MPRA output in each context and observed that the most predictive features are consistent across data sets. We then demonstrate that predictive models trained in one cellular context can be used to predict MPRA output in another, with loss of accuracy attributed to cell-type-specific features. Finally, we show that our approach achieves top performance in the Fifth Critical Assessment of Genome Interpretation "Regulation Saturation" Challenge for predicting effects of single-nucleotide variants. Overall, our analysis provides insights into how MPRA data can be leveraged to highlight functional regulatory regions throughout the genome and can guide effective design of future experiments by better prioritizing regions of interest

Integration of multiple epigenomic marks improves prediction of variant impact in saturation mutagenesis reporter assay

The integrative analysis of highâ throughput reporter assays, machine learning, and profiles of epigenomic chromatin state in a broad array of cells and tissues has the potential to significantly improve our understanding of noncoding regulatory element function and its contribution to human disease. Here, we report results from the CAGI 5 regulation saturation challenge where participants were asked to predict the impact of nucleotide substitution at every base pair within five diseaseâ associated human enhancers and nine diseaseâ associated promoters. A library of mutations covering all bases was generated by saturation mutagenesis and altered activity was assessed in a massively parallel reporter assay (MPRA) in relevant cell lines. Reporter expression was measured relative to plasmid DNA to determine the impact of variants. The challenge was to predict the functional effects of variants on reporter expression. Comparative analysis of the full range of submitted prediction results identifies the most successful models of transcription factor binding sites, machine learning algorithms, and ways to choose among or incorporate diverse datatypes and cellâ types for training computational models. These results have the potential to improve the design of future studies on more diverse sets of regulatory elements and aid the interpretation of diseaseâ associated genetic variation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151884/1/humu23797_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151884/2/humu23797.pd

Dynamical alterations of brain function and gut microbiome in weight loss

ObjectiveIntermittent energy restriction (IER) is an effective weight loss strategy. However, little is known about the dynamic effects of IER on the brain-gut-microbiome axis.MethodsIn this study, a total of 25 obese individuals successfully lost weight after a 2-month IER intervention. FMRI was used to determine the activity of brain regions. Metagenomic sequencing was performed to identify differentially abundant gut microbes and pathways in from fecal samples.ResultsOur results showed that IER longitudinally reduced the activity of obese-related brain regions at different timepoints, including the inferior frontal orbital gyrus in the cognitive control circuit, the putamen in the emotion and learning circuit, and the anterior cingulate cortex in the sensory circuit. IER longitudinally reduced E. coli abundance across multiple timepoints while elevating the abundance of obesity-related Faecalibacterium prausnitzii, Parabacteroides distasonis, and Bacterokles uniformis. Correlation analysis revealed longitudinally correlations between gut bacteria abundance alterations and brain activity changes.ConclusionsThere was dynamical alteration of BGM axis (the communication of E. coli with specific brain regions) during the weight loss under the IER

Meta-analysis of massively parallel reporter assays enables prediction of regulatory function across cell types.

Deciphering the potential of noncoding loci to influence gene regulation has been the subject of intense research, with important implications in understanding genetic underpinnings of human diseases. Massively parallel reporter assays (MPRAs) can measure regulatory activity of thousands of DNA sequences and their variants in a single experiment. With increasing number of publically available MPRA data sets, one can now develop data-driven models which, given a DNA sequence, predict its regulatory activity. Here, we performed a comprehensive meta-analysis of several MPRA data sets in a variety of cellular contexts. We first applied an ensemble of methods to predict MPRA output in each context and observed that the most predictive features are consistent across data sets. We then demonstrate that predictive models trained in one cellular context can be used to predict MPRA output in another, with loss of accuracy attributed to cell-type-specific features. Finally, we show that our approach achieves top performance in the Fifth Critical Assessment of Genome Interpretation "Regulation Saturation" Challenge for predicting effects of single-nucleotide variants. Overall, our analysis provides insights into how MPRA data can be leveraged to highlight functional regulatory regions throughout the genome and can guide effective design of future experiments by better prioritizing regions of interest

A 40 Gbps QAM-16 communication link using a 130 nm SiGe BiCMOS process

In this work a high data rate transmitter and receiver link is presented using a 130 nm SiGe BiCMOS process. The communication link has demonstrated transmissions up to 40 Gbps QAM-16 at D-band (110-170 GHz) over a one meter polymer microwave fiber (PMF). The peak output power of the transmitter (Tx) is 3 dBm at 135 GHz and the 3-dB bandwidth of both Tx and receiver (Rx) is between 115 - 145 GHz, resulting in a 30 GHz bandwidth. Total chip area for Tx and Rx combined, including pads, is 4.2 mm2

Daintain/AIF-1 Plays Roles in Coronary Heart Disease via Affecting the Blood Composition and Promoting Macrophage Uptake and Foam Cell Formation

Background: Daintain/AIF-1 is an inflammatory polypeptide factor/allograft inflammatory factor 1 derived from macrophages. It is characterized in APOE-/- mice as a novel inflammatory factor associated with atherosclerosis. The purpose of this study was to characterize its function in human atherosclerosis. Methods: Immunohistochemistry was used to identify the expression of daintain/AIF-1 in vessel segments within and far from atherosclerotic plaques; High-performance liquid chromatography (HPLC) was used to display the effects of daintain/AIF-1 on C-reactive protein (CRP), oxidative capacity and superoxide dismutase (SOD) in vivo; Oil Red O Staining was used to show the effects of daintain/AIF-1 on uptake of oxidized low density lipoprotein (ox-LDL) into U937 cells, a macrophage line; Western Blot was used to test scavenger receptor A (SRA) expression. Results: A high density of daintain/AIF-1 was observed in the tunica intima and media of coronary artery with atherosclerotic plaque, and fewer daintain/AIF-1 in the vessels without atherosclerotic plaque; Daintain/AIF-1 injected intravenously into BALB/c mice boosted oxidative capacity, significantly impaired SOD activities and augmented the CRP level in blood. According to the oil red O test, daintain/AIF-1 profoundly facilitated the uptake of ox-LDL in U937 macrophages and formation of foam cells in the endothelium. We also found that the molecular mechanisms are effective by promoting overexpression of SRA on macrophages. Conclusion: These findings implicate that the inflammatory factor daintain/AIF-1 is closely associated with atherogenesis, and could be further characterized as a novel risk factor for atherosclerosi

Association between Dietary Inflammatory Index, C-Reactive Protein and Metabolic Syndrome: A Cross-Sectional Study

Increased prevalence of metabolic syndrome (MetS) has become a global major public health problem. Chronic low-grade inflammation associated with diet was found to play an import role in the development of MetS, although further studies are needed. The main purpose of this study was to explore the association between the dietary inflammatory index (DII), C-reactive protein (CRP) as a sign of inflammation status, and MetS. A total of 1712 participants from eight cities in China were included. Sociodemographic and health-related information was collected by a self-administrated questionnaire. Anthropometric information and fasting blood samples were collected for identification of MetS. DII scores were computed based on one time 24-h dietary recall. No significant association between MetS and DII was observed except for the blood pressure component of MetS (OR T3 versus T1 = 1.40; 95% CI: 1.03 to 1.89). A significant increased prevalence for MetS was observed for higher CRP (OR = 1.66; 95% CI: 1.26 to 2.18), as well as four out of five of MetS components. In stratified analyses by sex, the associations between DII/CRP and MetS among women, but not men, are comparable to the whole sample. In addition, Both the 2nd and 3rd tertile of the DII had a higher CRP level (β-Coefficients T2 versus T1 = 0.086, 95% CI: 0.004 to 0.167; β-Coefficients T3 versus T1 = 0.145, 95% CI: 0.045 to 0.245) among subjects with MetS. Participants with higher DII scores reported a higher degree of “Shanghuo” (p = 0.007), which is a traditional concept characterized by “redness, swelling, fever and pain” in Chinese Medicine. This study suggested a close association between CRP and MetS, while the association between the DII and MetS was limited. DII was only specifically associated with CRP at a higher level among participants with MetS