Extracellular RNA in a single droplet of human serum reflects physiologic and disease states.

Extracellular RNAs (exRNAs) are present in human serum. It remains unclear to what extent these circulating exRNAs may reflect human physiologic and disease states. Here, we developed SILVER-seq (Small Input Liquid Volume Extracellular RNA Sequencing) to efficiently sequence both integral and fragmented exRNAs from a small droplet (5 μL to 7 μL) of liquid biopsy. We calibrated SILVER-seq in reference to other RNA sequencing methods based on milliliters of input serum and quantified droplet-to-droplet and donor-to-donor variations. We carried out SILVER-seq on more than 150 serum droplets from male and female donors ranging from 18 y to 48 y of age. SILVER-seq detected exRNAs from more than a quarter of the human genes, including small RNAs and fragments of mRNAs and long noncoding RNAs (lncRNAs). The detected exRNAs included those derived from genes with tissue (e.g., brain)-specific expression. The exRNA expression levels separated the male and female samples and were correlated with chronological age. Noncancer and breast cancer donors exhibited pronounced differences, whereas donors with or without cancer recurrence exhibited moderate differences in exRNA expression patterns. Even without using differentially expressed exRNAs as features, nearly all cancer and noncancer samples and a large portion of the recurrence and nonrecurrence samples could be correctly classified by exRNA expression values. These data suggest the potential of using exRNAs in a single droplet of serum for liquid biopsy-based diagnostics

GIVE: portable genome browsers for personal websites.

Growing popularity and diversity of genomic data demand portable and versatile genome browsers. Here, we present an open source programming library called GIVE that facilitates the creation of personalized genome browsers without requiring a system administrator. By inserting HTML tags, one can add to a personal webpage interactive visualization of multiple types of genomics data, including genome annotation, "linear" quantitative data, and genome interaction data. GIVE includes a graphical interface called HUG (HTML Universal Generator) that automatically generates HTML code for displaying user chosen data, which can be copy-pasted into user's personal website or saved and shared with collaborators. GIVE is available at: https://www.givengine.org/

Genome-wide Analysis of the Interplay Between Chromatin-associated Rna and 3d Genome Organization in Human Cells

The interphase genome is dynamically organized in the nucleus and decorated with chromatin-associated RNA (caRNA). It remains unclear whether the genome architecture modulates the spatial distribution of caRNA and vice versa. Here, we generate a resource of genome-wide RNA-DNA and DNA-DNA contact maps in human cells. These maps reveal the chromosomal domains demarcated by locally transcribed RNA, hereafter termed RNA-defined chromosomal domains. Further, the spreading of caRNA is constrained by the boundaries of topologically associating domains (TADs), demonstrating the role of the 3D genome structure in modulating the spatial distribution of RNA. Conversely, stopping transcription or acute depletion of RNA induces thousands of chromatin loops genome-wide. Activation or suppression of the transcription of specific genes suppresses or creates chromatin loops straddling these genes. Deletion of a specific caRNA-producing genomic sequence promotes chromatin loops that straddle the interchromosomal target sequences of this caRNA. These data suggest a feedback loop where the 3D genome modulates the spatial distribution of RNA, which in turn affects the dynamic 3D genome organization

High Accordance in Prognosis Prediction of Colorectal Cancer across Independent Datasets by Multi-Gene Module Expression Profiles

A considerable portion of patients with colorectal cancer have a high risk of disease recurrence after surgery. These patients can be identified by analyzing the expression profiles of signature genes in tumors. But there is no consensus on which genes should be used and the performance of specific set of signature genes varies greatly with different datasets, impeding their implementation in the routine clinical application. Instead of using individual genes, here we identified functional multi-gene modules with significant expression changes between recurrent and recurrence-free tumors, used them as the signatures for predicting colorectal cancer recurrence in multiple datasets that were collected independently and profiled on different microarray platforms. The multi-gene modules we identified have a significant enrichment of known genes and biological processes relevant to cancer development, including genes from the chemokine pathway. Most strikingly, they recruited a significant enrichment of somatic mutations found in colorectal cancer. These results confirmed the functional relevance of these modules for colorectal cancer development. Further, these functional modules from different datasets overlapped significantly. Finally, we demonstrated that, leveraging above information of these modules, our module based classifier avoided arbitrary fitting the classifier function and screening the signatures using the training data, and achieved more consistency in prognosis prediction across three independent datasets, which holds even using very small training sets of tumors

Attenuation of epigenetic regulator SMARCA4 and ERK-ETS signaling suppresses aging-related dopaminergic degeneration

How complex interactions of genetic, environmental factors and aging jointly contribute to dopaminergic degeneration in Parkinson's disease (PD) is largely unclear. Here, we applied frequent gene co‐expression analysis on human patient substantia nigra‐specific microarray datasets to identify potential novel disease‐related genes. In vivo Drosophila studies validated two of 32 candidate genes, a chromatin‐remodeling factor SMARCA4 and a biliverdin reductase BLVRA. Inhibition of SMARCA4 was able to prevent aging‐dependent dopaminergic degeneration not only caused by overexpression of BLVRA but also in four most common Drosophila PD models. Furthermore, down‐regulation of SMARCA4 specifically in the dopaminergic neurons prevented shortening of life span caused by α‐synuclein and LRRK2. Mechanistically, aberrant SMARCA4 and BLVRA converged on elevated ERK‐ETS activity, attenuation of which by either genetic or pharmacological manipulation effectively suppressed dopaminergic degeneration in Drosophila in vivo. Down‐regulation of SMARCA4 or drug inhibition of MEK/ERK also mitigated mitochondrial defects in PINK1 (a PD‐associated gene)‐deficient human cells. Our findings underscore the important role of epigenetic regulators and implicate a common signaling axis for therapeutic intervention in normal aging and a broad range of age‐related disorders including PD

Real-time Monitoring for the Next Core-Collapse Supernova in JUNO

Core-collapse supernova (CCSN) is one of the most energetic astrophysical events in the Universe. The early and prompt detection of neutrinos before (pre-SN) and during the SN burst is a unique opportunity to realize the multi-messenger observation of the CCSN events. In this work, we describe the monitoring concept and present the sensitivity of the system to the pre-SN and SN neutrinos at the Jiangmen Underground Neutrino Observatory (JUNO), which is a 20 kton liquid scintillator detector under construction in South China. The real-time monitoring system is designed with both the prompt monitors on the electronic board and online monitors at the data acquisition stage, in order to ensure both the alert speed and alert coverage of progenitor stars. By assuming a false alert rate of 1 per year, this monitoring system can be sensitive to the pre-SN neutrinos up to the distance of about 1.6 (0.9) kpc and SN neutrinos up to about 370 (360) kpc for a progenitor mass of 30$M_{\odot}$ for the case of normal (inverted) mass ordering. The pointing ability of the CCSN is evaluated by using the accumulated event anisotropy of the inverse beta decay interactions from pre-SN or SN neutrinos, which, along with the early alert, can play important roles for the followup multi-messenger observations of the next Galactic or nearby extragalactic CCSN.Comment: 24 pages, 9 figure