Template-Based Modeling of Protein-RNA Interactions

Protein-RNA complexes formed by specific recognition between RNA and RNA-binding proteins play an important role in biological processes. More than a thousand of such proteins in human are curated and many novel RNA-binding proteins are to be discovered. Due to limitations of experimental approaches, computational techniques are needed for characterization of protein-RNA interactions. Although much progress has been made, adequate methodologies reliably providing atomic resolution structural details are still lacking. Although protein-RNA free docking approaches proved to be useful, in general, the template-based approaches provide higher quality of predictions. Templates are key to building a high quality model. Sequence/structure relationships were studied based on a representative set of binary protein-RNA complexes from PDB. Several approaches were tested for pairwise target/template alignment. The analysis revealed a transition point between random and correct binding modes. The results showed that structural alignment is better than sequence alignment in identifying good templates, suitable for generating protein-RNA complexes close to the native structure, and outperforms free docking, successfully predicting complexes where the free docking fails, including cases of significant conformational change upon binding. A template-based protein-RNA interaction modeling protocol PRIME was developed and benchmarked on a representative set of complexes

Genome mining for anti-CRISPR operons using machine learning

Motivation: Encoded by (pro-)viruses, anti-CRISPR (Acr) proteins inhibit the CRISPR-Cas immune system of their prokaryotic hosts. As a result, Acr proteins can be employed to develop more controllable CRISPR-Cas genome editing tools. Recent studies revealed that known acr genes often coexist with other acr genes and with phage structural genes within the same operon. For example, we found that 47 of 98 known acr genes (or their homologs) co-exist in the same operons. None of the current Acr prediction tools have considered this important genomic context feature. We have developed a new software tool AOminer to facilitate the improved discovery of new Acrs by fully exploiting the genomic context of known acr genes and their homologs. Results: AOminer is the first machine learning based tool focused on the discovery of Acr operons (AOs). A two-state HMM (hidden Markov model) was trained to learn the conserved genomic context of operons that contain known acr genes or their homologs, and the learnt features could distinguish AOs and non-AOs. AOminer allows automated mining for potential AOs from query genomes or operons. AOminer outperformed all existing Acr prediction tools with an accuracy¼0.85. AOminer will facilitate the discovery of novel anti-CRISPR operons

Homeobox transcription factor HbxA influences expression of over one thousand genes in the model fungus \u3ci\u3eAspergillus nidulans\u3c/i\u3e

In fungi, conserved homeobox-domain proteins are transcriptional regulators governing development. In Aspergillus species, several homeobox-domain transcription factor genes have been identified, among them, hbxA/hbx1. For instance, in the opportunistic human pathogen Aspergillus fumigatus, hbxA is involved in conidial production and germination, as well as virulence and secondary metabolism, including production of fumigaclavines, fumiquinazolines, and chaetominine. In the agriculturally important fungus Aspergillus flavus, disruption of hbx1 results in fluffy aconidial colonies unable to produce sclerotia. hbx1 also regulates production of aflatoxins, cyclopiazonic acid and aflatrem. Furthermore, transcriptome studies revealed that hbx1 has a broad effect on the A. flavus genome, including numerous genes involved in secondary metabolism. These studies underline the importance of the HbxA/Hbx1 regulator, not only in developmental processes but also in the biosynthesis of a broad number of fungal natural products, including potential medical drugs and mycotoxins. To gain further insight into the regulatory scope of HbxA in Aspergilli, we studied its role in the model fungus Aspergillus nidulans. Our present study of the A. nidulans hbxA-dependent transcriptome revealed that more than one thousand genes are differentially expressed when this regulator was not transcribed at wild-type levels, among them numerous transcription factors, including those involved in development as well as in secondary metabolism regulation. Furthermore, our metabolomics analyses revealed that production of several secondary metabolites, some of them associated with A. nidulans hbxA-dependent gene clusters, was also altered in deletion and overexpression hbxA strains compared to the wild type, including synthesis of nidulanins A, B and D, versicolorin A, sterigmatocystin, austinol, dehydroaustinol, and three unknown novel compounds

pVHL suppresses kinase activity of Akt in a proline-hydroxylation-dependent manner

Activation of the serine-threonine kinase Akt promotes the survival and proliferation of various cancers. Hypoxia promotes the resistance of tumor cells to specific therapies. We therefore explored a possible link between hypoxia and Akt activity. We found that Akt was prolyl-hydroxylated by the oxygen-dependent hydroxylase EglN1. The von Hippel–Lindau protein (pVHL) bound directly to hydroxylated Akt and inhibited Akt activity. In cells lacking oxygen or functional pVHL, Akt was activated to promote cell survival and tumorigenesis. We also identified cancer-associated Akt mutations that impair Akt hydroxylation and subsequent recognition by pVHL, thus leading to Akt hyperactivation. Our results show that microenvironmental changes, such as hypoxia, can affect tumor behaviors by altering Akt activation, which has a critical role in tumor growth and therapeutic resistance

Overexpression of Polo-like kinase1 (PLK1) in chondrosarcoma and its implications for cancer progression

Polo-like kinase1 (PLK1) is a new therapeutic target for osteosarcoma with good application prospects. Whether PLK1 is highly expressed in chondrosarcoma and whether PLK1 can be a potential therapeutic target for chondrosarcoma are worth exploring. However, PLK1 expression in chondrosarcoma is scarcely investigated. Therefore, we collected 11 cases of chondrosarcoma and 26 cases of osteochondroma with complete clinical pathological data and used immunohistochemical staining to detect the expression of PLK1 in chondrosarcoma and osteochondroma and then studied its significance and relationship with clinical pathological parameters. Our results showed that the positive expression rate of PLK1 in chondrosarcoma tissue (90.91%, 10/11) was significantly higher than the rate of osteochondroma tissues (53.85%, 14/26) (

The deubiquitinase USP6 affects memory and synaptic plasticity through modulating NMDA receptor stability

人类与其他动物相比的重要区别在于人类拥有高等认知能力，这种能力集中体现在学习记忆和语言表达方面。厦门大学医学院神经科学研究所王鑫教授团队发现人科动物特异性基因USP6作为一个新的NMDA受体调控因子，可通过去泛素化途径调节NMDA型谷氨酸受体的降解和稳定性，进而调控突触可塑性和学习记忆能力。 本研究工作由王鑫教授指导完成，博士生曾凡伟、马学海与硕士生朱琳为共同第一作者，王鑫教授为通讯作者。Ubiquitin-specific protease (USP) 6 is a hominoid deubiquitinating enzyme previously implicated in intellectual disability and autism spectrum disorder. Although these findings link USP6 to higher brain function, potential roles for USP6 in cognition have not been investigated. Here, we report that USP6 is highly expressed in induced human neurons and that neuron-specific expression of USP6 enhances learning and memory in a transgenic mouse model. Similarly, USP6 expression regulates N-methyl-D-aspartate-type glutamate receptor (NMDAR)-dependent long-term potentiation and long-term depression in USP6 transgenic mouse hippocampi. Proteomic characterization of transgenic USP6 mouse cortex reveals attenuated NMDAR ubiquitination, with concomitant elevation in NMDAR expression, stability, and cell surface distribution with USP6 overexpression. USP6 positively modulates GluN1 expression in transfected cells, and USP6 down-regulation impedes focal GluN1 distribution at postsynaptic densities and impairs synaptic function in neurons derived from human embryonic stem cells. Together, these results indicate that USP6 enhances NMDAR stability to promote synaptic function and cognition.This work was partially supported by the National Natural Science Foundation of China (31871077, 81822014, 81571176 to XW; 81701349 to Hongfeng Z.; 81701130 to QZ; and 81471160 to HS), the National Key R&D Program of China (2016YFC1305900 to XW and HS), the Natural Science Foundation of Fujian Province of China (2017J06021 to XW), the Fundamental Research Funds for the Chinese Central Universities (20720150061 to XW and 20720180040 to ZS), Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University (SKLCSB2019KF012 to QZ), and China Postdoctoral Science Foundation (2017M612130 to QZ).该研究得到了国家自然科学基金面上项目和优秀青年基金项目的支持

Innate Lymphoid Cells and Intestinal Inflammatory Disorders

Innate lymphoid cells (ILCs) are a population of lymphoid cells that do not express T cell or B cell antigen-specific receptors. They are largely tissue-resident and enriched at mucosal sites to play a protective role against pathogens. ILCs mimic the functions of CD4 T helper (Th) subsets. Type 1 innate lymphoid cells (ILC1s) are defined by the expression of signature cytokine IFN-γ and the master transcription factor T-bet, involving in the type 1 immune response; ILC2s are characterized by the expression of signature cytokine IL-5/IL-13 and the master transcription factor GATA3, participating in the type 2 immune response; ILC3s are RORγt-expressing cells and are capable of producing IL-22 and IL-17 to maintain intestinal homeostasis. The discovery and investigation of ILCs over the past decades extends our knowledge beyond classical adaptive and innate immunology. In this review, we will focus on the roles of ILCs in intestinal inflammation and related disorders

Template-free synthesis of mesoporous N-doped SrTiO3 perovskite with high visible-light-driven photocatalytic activity

An effective, template-free synthesis methodology has been developed for preparing mesoporous nitrogen-doped SrTiO3 (meso-STON) using glycine as both a nitrogen source and a mesopore creator. The N-doping, large surface area and developed porosity endow meso-STON with excellent activity in visible-light-responsive photodegradation of organic dyes