Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

MANIPULATING ENHANCER RNA ACTIVITY TO STUDY THEIR ROLES IN GENE REGULATION AND CANCER

Enhancers are essential regulatory elements that precisely control gene transcription during development and disease. Especially in cancer, enhancers modulate tumor gene expression, and in some cases directly drive tumorigenesis. With the recent advances in next-generation sequencing, researchers discovered that active enhancers are pervasively transcribed into RNAs, which are named enhancer RNAs (eRNAs). Studies have suggested that eRNAs have a functional role in the enhancer action mechanism. Studying their roles will provide a new understanding of gene regulation and cancer development. In my MS study, I focused on using novel methods to study eRNA functions. Using a breast-cancer-specific eRNA, I have conducted effective knockdown with both antisense oligos and CRISPR inhibition. I also explored in situ enhancer RNA activation by CRISPR mediated epigenetic activator. For some eRNAs, my data showed that individual knockdown of a single eRNA sometimes causes strong phenotypical changes of cancer cells, providing important novel targets for cancer therapeutics. To further validate and understand the functional role of specific eRNAs, I conducted ChIRP-Seq to identify its potential location in the genome to regulate target genes. Our work by using several novel methods to manipulate eRNAs has provided important knowledge of enhancer functions in gene regulation and cancer development

Impaired bone morphogenetic protein (BMP) signaling pathways disrupt decidualization in endometriosis

Abstract Endometriosis is linked to increased infertility and pregnancy complications due to defective endometrial decidualization. We hypothesized that identification of altered signaling pathways during decidualization could identify the underlying cause of infertility and pregnancy complications. Our study reveals that transforming growth factor β (TGFβ) pathways are impaired in the endometrium of individuals with endometriosis, leading to defective decidualization. Through detailed transcriptomic analyses, we discovered abnormalities in TGFβ signaling pathways and key regulators, such as SMAD4, in the endometrium of affected individuals. We also observed compromised activity of bone morphogenetic proteins (BMP), a subset of the TGFβ family, that control endometrial receptivity. Using 3-dimensional models of endometrial stromal and epithelial assembloids, we showed that exogenous BMP2 improved decidual marker expression in individuals with endometriosis. Our findings reveal dysfunction of BMP/SMAD signaling in the endometrium of individuals with endometriosis, explaining decidualization defects and subsequent pregnancy complications in these individuals

Two Facile Aniline-Based Hypercrosslinked Polymer Adsorbents for Highly Efficient Iodine Capture and Removal

Effective capture and safe disposal of radioactive iodine (129I or 131I) during nuclear power generation processes have always been a worldwide environmental concern. Low-cost and high-efficiency iodine removal materials are urgently needed. In this study, we synthesized two aniline-based hypercrosslinked polymers (AHCPs), AHCP-1 and AHCP-2, for iodine capture in both aqueous and gaseous phases. They are obtained by aniline polymerization through Friedel–Crafts alkylation and Scholl coupling reaction, respectively, with high chemical and thermal stability. Notably, AHCP-1 exhibits record-high static iodine adsorption (250 wt%) in aqueous solution. In the iodine vapor adsorption, AHCP-2 presents an excellent total iodine capture (596 wt%), surpassing the most reported amorphous polymer adsorbents. The rich primary amine groups of AHCPs promote the rapid physical capture of iodine from iodine water and iodine vapor. Intrinsic features such as low-cost preparation, good recyclability, as well as excellent performance in iodine capture indicate that the AHCPs can be used as potential candidates for the removal of iodine from radioactive wastewater and gas mixtures

A GREB1-steroid receptor feedforward mechanism governs differential GREB1 action in endometrial function and endometriosis

Abstract Cellular responses to the steroid hormones, estrogen (E2), and progesterone (P4) are governed by their cognate receptor’s transcriptional output. However, the feed-forward mechanisms that shape cell-type-specific transcriptional fulcrums for steroid receptors are unidentified. Herein, we found that a common feed-forward mechanism between GREB1 and steroid receptors regulates the differential effect of GREB1 on steroid hormones in a physiological or pathological context. In physiological (receptive) endometrium, GREB1 controls P4-responses in uterine stroma, affecting endometrial receptivity and decidualization, while not affecting E2-mediated epithelial proliferation. Of mechanism, progesterone-induced GREB1 physically interacts with the progesterone receptor, acting as a cofactor in a positive feedback mechanism to regulate P4-responsive genes. Conversely, in endometrial pathology (endometriosis), E2-induced GREB1 modulates E2-dependent gene expression to promote the growth of endometriotic lesions in mice. This differential action of GREB1 exerted by a common feed-forward mechanism with steroid receptors advances our understanding of mechanisms that underlie cell- and tissue-specific steroid hormone actions

Enhancer RNA m6A methylation facilitates transcriptional condensate formation and gene activation

The mechanistic understanding of nascent RNAs in transcriptional control remains limited. Here, by a high sensitivity method methylation-inscribed nascent transcripts sequencing (MINT-seq), we characterized the landscapes of N6-methyladenosine (m6A) on nascent RNAs. We uncover heavy but selective m6A deposition on nascent RNAs produced by transcription regulatory elements, including promoter upstream antisense RNAs and enhancer RNAs (eRNAs), which positively correlates with their length, inclusion of m6A motif, and RNA abundances. m6A-eRNAs mark highly active enhancers, where they recruit nuclear m6A reader YTHDC1 to phase separate into liquid-like condensates, in a manner dependent on its C terminus intrinsically disordered region and arginine residues. The m6A-eRNA/YTHDC1 condensate co-mixes with and facilitates the formation of BRD4 coactivator condensate. Consequently, YTHDC1 depletion diminished BRD4 condensate and its recruitment to enhancers, resulting in inhibited enhancer and gene activation. We propose that chemical modifications of eRNAs together with reader proteins play broad roles in enhancer activation and gene transcriptional control

Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation

The dysregulation of the m6A epitranscriptomic networks have been reported to contribute to the development of gliomas. Here, the authors utilize induced pluripotent stem cell-derived astrocytes with a p53 mutation and demonstrate that mutant p53 upregulates the m6A reader YTHDF2, resulting in the initiation of gliomas

CEPC Conceptual Design Report: Volume 2 - Physics & Detector

The Circular Electron Positron Collider (CEPC) is a large international scientific facility proposed by the Chinese particle physics community to explore the Higgs boson and provide critical tests of the underlying fundamental physics principles of the Standard Model that might reveal new physics. The CEPC, to be hosted in China in a circular underground tunnel of approximately 100 km in circumference, is designed to operate as a Higgs factory producing electron-positron collisions with a center-of-mass energy of 240 GeV. The collider will also operate at around 91.2 GeV, as a Z factory, and at the WW production threshold (around 160 GeV). The CEPC will produce close to one trillion Z bosons, 100 million W bosons and over one million Higgs bosons. The vast amount of bottom quarks, charm quarks and tau-leptons produced in the decays of the Z bosons also makes the CEPC an effective B-factory and tau-charm factory. The CEPC will have two interaction points where two large detectors will be located. This document is the second volume of the CEPC Conceptual Design Report (CDR). It presents the physics case for the CEPC, describes conceptual designs of possible detectors and their technological options, highlights the expected detector and physics performance, and discusses future plans for detector R&D and physics investigations. The final CEPC detectors will be proposed and built by international collaborations but they are likely to be composed of the detector technologies included in the conceptual designs described in this document. A separate volume, Volume I, recently released, describes the design of the CEPC accelerator complex, its associated civil engineering, and strategic alternative scenarios