Discrete latent embedding of single-cell chromatin accessibility sequencing data for uncovering cell heterogeneity.

Single-cell epigenomic data has been growing continuously at an unprecedented pace, but their characteristics such as high dimensionality and sparsity pose substantial challenges to downstream analysis. Although deep learning models-especially variational autoencoders-have been widely used to capture low-dimensional feature embeddings, the prevalent Gaussian assumption somewhat disagrees with real data, and these models tend to struggle to incorporate reference information from abundant cell atlases. Here we propose CASTLE, a deep generative model based on the vector-quantized variational autoencoder framework to extract discrete latent embeddings that interpretably characterize single-cell chromatin accessibility sequencing data. We validate the performance and robustness of CASTLE for accurate cell-type identification and reasonable visualization compared with state-of-the-art methods. We demonstrate the advantages of CASTLE for effective incorporation of existing massive reference datasets in a weakly supervised or supervised manner. We further demonstrate CASTLE's capacity for intuitively distilling cell-type-specific feature spectra that unveil cell heterogeneity and biological implications quantitatively.

OpenAnnotateApi: Python and R packages to efficiently annotate and analyze chromatin accessibility of genomic regions.

Summary: Chromatin accessibility serves as a critical measurement of physical contact between nuclear macromolecules and DNA sequence, providing valuable insights into the comprehensive landscape of regulatory mechanisms, thus we previously developed the OpenAnnotate web server. However, as an increasing number of epigenomic analysis software tools emerged, web-based annotation often faced limitations and inconveniences when integrated into these software pipelines. To address these issues, we here develop two software packages named OpenAnnotatePy and OpenAnnotateR. In addition to web-based functionalities, these packages encompass supplementary features, including the capability for simultaneous annotation across multiple cell types, advanced searching of systems, tissues and cell types, and converting the result to the data structure of mainstream tools. Moreover, we applied the packages to various scenarios, including cell type revealing, regulatory element prediction, and integration into mainstream single-cell ATAC-seq analysis pipelines including EpiScanpy, Signac, and ArchR. We anticipate that OpenAnnotateApi will significantly facilitate the deciphering of gene regulatory mechanisms, and offer crucial assistance in the field of epigenomic studies. Availability and implementation: OpenAnnotateApi for R is available at https://github.com/ZjGaothu/OpenAnnotateR and for Python is available at https://github.com/ZjGaothu/OpenAnnotatePy.

EpiGePT: a Pretrained Transformer model for epigenomics.

The inherent similarities between natural language and biological sequences have given rise to great interest in adapting the transformer-based large language models (LLMs) underlying recent breakthroughs in natural language processing (references), for applications in genomics. However, current LLMs for genomics suffer from several limitations such as the inability to include chromatin interactions in the training data, and the inability to make prediction in new cellular contexts not represented in the training data. To mitigate these problems, we propose EpiGePT, a transformer-based pretrained language model for predicting context-specific epigenomic signals and chromatin contacts. By taking the context-specific activities of transcription factors (TFs) and 3D genome interactions into consideration, EpiGePT offers wider applicability and deeper biological insights than models trained on DNA sequence only. In a series of experiments, EpiGePT demonstrates superior performance in a diverse set of epigenomic signals prediction tasks when compared to existing methods. In particular, our model enables cross-cell-type prediction of long-range interactions and offers insight on the functional impact of genetic variants under different cellular contexts. These new capabilities will enhance the usefulness of LLM in the study of gene regulatory mechanisms. We provide free online prediction service of EpiGePT through http://health.tsinghua.edu.cn/epigept/.

Enhanced effect and mechanism of nano Fe-Ca bimetallic oxide modified substrate on Cu(II) and Ni(II) removal in constructed wetland.

In this study, Fe2O3 nanoparticles (Fe2O3 NPs) and CaO NPs were loaded on the zeolite sphere carrier to create nano Fe-Ca bimetallic oxide (Fe-Ca-NBMO) modified substrate, which was introduced into constructed wetland (CW) to remove Cu(II) and Ni(II) via constructing "substrate-microorganism" system. Adsorption experiments showed that the equilibrium adsorption capacities of Fe-Ca-NBMO modified substrate for Cu(II) and Ni(II) were respectively 706.48 and 410.59 mg/kg at an initial concentration of 20 mg/L, 2.45 and 2.39 times of gravel. The Cu(II) and Ni(II) removal efficiencies in CW with Fe-Ca-NBMO modified substrate respectively reached 99.7% and 99.9% at an influent concentration of 100 mg/L, significantly higher than those in gravel-based CW (47.0% and 34.3%). Fe-Ca-NBMO modified substrate could promote Cu(II) and Ni(II) removal by increasing electrostatic adsorption, chemical precipitation, as well as the abundances of resistant microorganisms (Geobacter, Desulfuromonas, Zoogloea, Dechloromonas, and Desulfobacter) and functional genes (copA, cusABC, ABC.CD.P, gshB, and exbB). This study provided an effective method to enhance Cu(II) and Ni(II) removal of electroplating wastewater by CW with Fe-Ca-NBMO modified substrate.

Annual Long-Distance Migration Strategies and Home Range of Chinese Sparrowhawk (Accipiter soloensis) from South China.

From 2018 to 2019, two Chinese Sparrowhawks (Bird 01, male; Bird 02, female), Accipiter soloensis, were captured and fitted with Global Positioning System (GPS) loggers in order to identify summering and wintering sites, migration routes, and stop-over sites. The Chinese Sparrowhawks were first fitted with backpack solar GPS satellite trackers in China in order to explore their migration routes. The two Chinese Sparrowhawks successfully completed their migration from southern China, through Nanning city of Guangxi province, China, to Vietnam, Laos, Myanmar, Thailand, Malaysia, and Singapore and finally arriving in Indonesia, where they stayed until the March of the following year. They then returned to China along the original route, arriving in Changsha city, Hunan province, China. The two individuals traveled more than 4000-5000 km. For the first time, telemetry data demonstrate, the linkages between their Indonesia wintering sites, their stop-over sites in Southeast Asia, and their breeding/summering sites near south Yangtze River in the south-central part of China. During this long-distance migration, 2653 bird satellite sites were received. The autumn migration durations for the two Chinese Sparrowhawks were 84 days and 50 days, respectively, compared to 83 days and 49 days in spring. The median stop-over duration was 12.7 and 9.3 days, respectively and the median speed of travel was 74.2 km/day during the autumn migration and 73.9 km/day during the spring migration. Furthermore, two and one stop-over sites and one and three stop-over sites were used during the autumn and spring migrations of Chinese Sparrowhawks 01 and 02, respectively. The Chinese Sparrowhawks migrated long distances and used stop-over sites during their migration. Based on the home range analysis, we can conclude that Chinese Sparrowhawks reach their maximum home range in the summer and have multiple nuclear domains.

SilencerDB: a comprehensive database of silencers.

Gene regulatory elements, including promoters, enhancers, silencers, etc., control transcriptional programs in a spatiotemporal manner. Though these elements are known to be able to induce either positive or negative transcriptional control, the community has been mostly studying enhancers which amplify transcription initiation, with less emphasis given to silencers which repress gene expression. To facilitate the study of silencers and the investigation of their potential roles in transcriptional control, we developed SilencerDB (http://health.tsinghua.edu.cn/silencerdb/), a comprehensive database of silencers by manually curating silencers from 2300 published articles. The current version, SilencerDB 1.0, contains (1) 33 060 validated silencers from experimental methods, and (ii) 5 045 547 predicted silencers from state-of-the-art machine learning methods. The functionality of SilencerDB includes (a) standardized categorization of silencers in a tree-structured class hierarchy based on species, organ, tissue and cell line and (b) comprehensive annotations of silencers with the nearest gene and potential regulatory genes. SilencerDB, to the best of our knowledge, is the first comprehensive database at this scale dedicated to silencers, with reliable annotations and user-friendly interactive database features. We believe this database has the potential to enable advanced understanding of silencers in regulatory mechanisms and to empower researchers to devise diverse applications of silencers in disease development.

Metal-Organic Framework in Situ Post-Encapsulating DNA-Enzyme Composites on a Magnetic Carrier with High Stability and Reusability.

In recent years, metal-organic frameworks (MOFs) have been extensively studied as candidate enzyme immobilization platforms. However, conventional MOF-enzyme composites usually exhibit low controllability and reusability. In this study, a novel and stable strategy for enzyme immobilization was designed by use of ZIF-8 to encapsulate in situ DNA-enzyme composites on the surface of magnetic particles (MPs). The mechanism of in situ encapsulation was discussed in detail. It was found that immobilized enzymes were involved in the growth of ZIF-8, and the DNA cross-linking agents promoted the growth of ZIF-8 on the surface of MP. The thermal, chemical, and physical stabilities of horseradish peroxidase (HRP) were all significantly enhanced after in situ encapsulation. Most importantly, this strategy was proven to be a general platform that can be used to stabilize various proteins. The in situ encapsulation strategy was expanded to immobilize a cascade of enzymes, and ZIF-8@MPGOx-HRP possessed high selectivity and a wide linear range (25-500 µM) for glucose detection.