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With the development of the global navigation satellite system(GNSS), the hourly ultra-rapid products of GNSS are attracting more attention due to their low latency and high accuracy. A new strategy and method was applied by the Shanghai Astronomical Observatory (SHAO) Analysis Center (AC) of the international GNSS Monitoring and Assessment Service (iGMAS) for generating 6-hourly and 1-hourly GNSS products, which mainly include the American Global Positioning System (GPS), the Russian Global’naya Navigatsionnaya Sputnikova Sistema (GLONASS), the European Union’s Galileo, and the Chinese BeiDou navigation satellite system (BDS). The 6-hourly and 1-hourly GNSS orbit and clock ultra-rapid products included a 24-h observation session which is determined by 24-h observation data from global tracking stations, and a 24-h prediction session which is predicted from the observation session. The accuracy of the 1-hourly orbit product improved about 1%, 31%, 13%, 11%, 23%, and 9% for the observation session and 18%, 43%, 45%, 34%, 53%, and 15% for the prediction session of GPS, GLONASS, Galileo, BDS Medium Earth Orbit (MEO), Inclined Geosynchronous Orbit (IGSO), and GEO orbit, when compared with reference products with high accuracy from the International GNSS service (IGS).The precision of the 1-hourly clock products can also be seen better than the 6-hourly clock products. The accuracy and precision of the 6-hourly and 1-hourly orbit and clock verify the availability and reliability of the hourly ultra-rapid products, which can be used for real-time or near-real-time applications, and show encouraging prospects.

Histone lysine methylations have primarily been linked to selective recruitment of reader or effector proteins that subsequently modify chromatin regions and mediate genome functions. Here, we describe a divergent role for histone H4 lysine 20 mono-methylation (H4K20me1) and demonstrate that it directly facilitates chromatin openness and accessibility by disrupting chromatin folding. Thus, accumulation of H4K20me1 demarcates highly accessible chromatin at genes, and this is maintained throughout the cell cycle. In vitro, H4K20me1-containing nucleosomal arrays with nucleosome repeat lengths (NRL) of 187 and 197 are less compact than unmethylated (H4K20me0) or trimethylated (H4K20me3) arrays. Concordantly, and in contrast to trimethylated and unmethylated tails, solid-state NMR data shows that H4K20 mono-methylation changes the H4 conformational state and leads to more dynamic histone H4-tails. Notably, the increased chromatin accessibility mediated by H4K20me1 facilitates gene expression, particularly of housekeeping genes. Altogether, we show how the methylation state of a single histone H4 residue operates as a focal point in chromatin structure control. While H4K20me1 directly promotes chromatin openness at highly transcribed genes, it also serves as a stepping-stone for H4K20me3-dependent chromatin compaction. The effect of histone H4 lysine 20 methylation (H4K20me) on chromatin accessibility are not well established. Here the authors show how H4K20 methylation regulates chromatin structure and accessibility to ensure precise transcriptional outputs through the cell cycle using genome-wide approaches, in vitro biophysical assays, and NMR.

It is well known that chromatin structure is highly sensitive to the ionic environment. However, the combined effects of a physiologically relevant mixed ionic environment of K + , Mg 2+ and Na + , which are the main cations of the cell cytoplasm, has not been systematically investigated. We studied folding and self-association (aggregation) of recombinant 12-mer nucleosome arrays with 177 bp DNA repeat length in solutions of mixtures of K + and Mg 2+ or Na + and Mg 2+ . In the presence of Mg 2+ , the addition of sodium ions promotes folding of array into 30-nm fibres, whereas in mixtures of K + and Mg 2+ , potassium ions abrogate folding. We found that self-association of nucleosome arrays in mixed salt solutions is synergistically promoted by Mg 2+ and monovalent ions, with sodium being slightly more efficient than potassium in amplifying the self-association. The results highlight the importance of a mixed ionic environment for the compaction of chromatin under physiological conditions and demonstrate the complicated nature of the various factors that determine and regulate chromatin compaction in vivo .

BeiDou global navigation satellite system (BDS) began to provide positioning, navigation, and timing (PNT) services to global users officially on 31 July, 2020. BDS constellations consist of regional (BDS-2) and global navigation satellites (BDS-3). Due to the difference of modulations and characteristics for the BDS-2 and BDS-3 default civil service signals (B1I/B3I) and the increase of new signals (B1C/B2a) for BDS-3, a systemically bias exists in the receiver-end when receiving and processing BDS-2 and BDS-3 signals, which leads to the inter-system bias (ISB) between BDS-2 and BDS-3 on the receiver side. To fully utilize BDS, the BDS-2 and BDS-3 combined precise time and frequency transfer are investigated considering the effect of the ISB. Four kinds of ISB stochastic models are presented, which are ignoring ISB (ISBNO), estimating ISB as random constant (ISBCV), random walk process (ISBRW), and white noise process (ISBWN). The results demonstrate that the datum of receiver clock offsets can be unified and the ISB deduced datum confusion can be avoided by estimating the ISB. The ISBCV and ISBRW models are superior to ISBWN. For the BDS-2 and BDS-3 combined precise time and frequency transfer using ISBNO, ISBCV, ISBRW, and ISBWN, the stability of clock differences of old signals can be enhanced by 20.18%, 23.89%, 23.96%, and 11.46% over BDS-2-only, respectively. For new signals, the enhancements are −50.77%, 20.22%, 17.53%, and −3.69%, respectively. Moreover, ISBCV and ISBRW models have the better frequency transfer stability. Consequently, we recommended the optimal ISBCV or suboptimal ISBRW model for BDS-2 and BDS-3 combined precise time and frequency transfer when processing the old as well as the new signals.

Background Neuroblastoma (NB) is the most common extracranial solid tumor in children and is characterized by marked clinical heterogeneity and poor prognosis. MYCN amplification drives NB tumorigenesis through epigenetic reprogramming and is frequently accompanied by a copy-number gain of the long arm of chromosome 17 (17q). Epigenetic dysregulation of enhancer landscapes—particularly large regulatory elements termed super‑enhancers (SEs), which are enriched for H3K27ac and bound by lineage-specific master transcription factors (TFs)—establishes distinct NB cellular identities and states. These SE domains demarcate oncogenes that function as critical regulators of cell proliferation and apoptosis. Therefore, SE-driven genes represent tumor vulnerabilities, offering selective therapeutic opportunities. Methods By integrating ATAC-seq data from 22 NB cell lines, the intratumoral heterogeneity of MYCN-amplified NB was characterized at the level of chromatin accessibility. Subsequently, based on H3K27ac ChIP-seq data from 38 NB cell lines, the ROSE algorithm was employed to identify SE-driven oncogenes. The synergistic mechanism between MYCN amplification and the 17q SE-driven gene MSI2 was investigated through genome‑wide CRISPR/Cas9 loss‑of‑function screens. At single‑cell resolution, we conducted a comprehensive analysis of the characteristics of heterogeneous tumor subpopulations and their immune microenvironment features. This analysis was performed using multiple bioinformatics workflows, including AUCell scoring, SCENIC analysis, copy‑number inference, cell differentiation‑state evaluation, neighborhood abundance tests, and separability tests. Finally, functional validation was performed using NB cell lines (MYCN‑amplified and non‑amplified) to assess gene perturbations. Results Pronounced epigenetic heterogeneity was observed within MYCN-amplified NB. MSI2 is an SE‑driven oncogene and is highly expressed in MYCN‑amplified NB. MSI2 and MYCN are co-expressed, may be mutually dependent, and are both correlated with cell cycle-related pathways. At the single-cell level, we identified and redefined an NB-MSI2 + MYCN+ subtype characterized by malignant transcriptional features, an immunosuppressive microenvironment, and poor patient prognosis. Building on this, combined targeting of MSI2 and MYCN markedly reduced proliferation and migration in MYCN‑amplified NB cells. Conclusions The NB‑MSI2 + MYCN+ subtype defines a clinically aggressive, therapy‑refractory state characterized by high proliferation, metabolic reprogramming, and immunosuppression. For patients with MYCN-amplified NB, MSI2 is both a prognostic biomarker and a candidate therapeutic target.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a group of chronic intestinal inflammatory diseases. Its incidence and prevalence have been on the rise globally, imposing a heavy burden on patients' health and social medical resources. Intestinal microbiota dysbiosis is believed to play a crucial role in the occurrence and development of IBD, but the association between them and the global disease burden growth trend remains unclear. By searching the Global Burden of Disease (GBD) study database, we collected IBD disease burden data from 180 countries and regions between 1990 and 2023, including key indicators such as incidence, prevalence, mortality, and disability-adjusted life years (DALYs). Intestinal microbiota data were sourced from two parts: (1) Independent collection: A total of 20,000 healthy individuals and IBD patients were selected as research subjects from 180 countries and regions using a stratified random sampling method. Fecal samples (2-5 grams per person) were collected and immediately stored in a -80 °C ultra-low temperature refrigerator to avoid changes in the microbial community structure; (2) Supplementary data from public databases: Published intestinal microbiota sequencing data of corresponding regions from 1990 to 2023 were extracted from the MGnify (https://www.ebi.ac.uk/metagenomics/), Human Microbiome Project (HMP), and GMrepo (https://gmrepo.humangut.info/) databases. The sample size for each country and region was no less than 500 to cover populations of different ages (18-70 years), genders (male/female ratio approximately 1:1), and dietary habits (high-fiber diet, high-sugar and high-fat diet). Technologies like metagenomic sequencing and 16S rRNA gene sequencing were used to obtain data on the composition, abundance, and diversity of the intestinal microbiota of the corresponding regional populations. For metagenomic sequencing, the Illumina HiSeq or NovaSeq platform was used. Linear regression models, time-series analysis, and causal inference methods were applied to evaluate the correlation between intestinal microbiota dysbiosis and the growth trends of various disease burden indicators, and to explore the potential impact mechanisms. The global incidence of IBD increased from 12.3 per 100,000 in 1990 to 25.6 per 100,000 in 2023, the prevalence rose from 396 per 100,000 to 523 per 100,000, and the DALY value also increased significantly (from 230 per 100,000 in 1990 to 380 per 100,000 in 2023). The average annual growth rates of the above indicators were 2.8% (95% CI: 2.5-3.1%, < 0.001), 1.0% (95% CI: 0.8-1.2%, < 0.001), and 1.5% (95% CI: 1.3-1.7%, < 0.001), respectively. Further analysis showed that intestinal microbiota dysbiosis was closely related to the growth of the disease burden. In regions with severe microbiota dysbiosis, the annual growth rate of the IBD incidence was 3.2 times higher than that in balanced regions ( = 3.2, 95% CI: 2.8-3.6, < 0.001); when the average abundance of beneficial bacteria such as and in the intestine decreased by 40% (relative to the average abundance of healthy populations) and the abundance of harmful bacteria such as increased by 60%, the annual growth rate of IBD incidence in this region was as high as 8.5% (95% CI: 7.9-9.1%, < 0.001); in regions where the Shannon index decreased by 10%, the incidence of IBD increased by an average of 15% ( = 0.15, 95% CI: 0.12-0.18, < 0.001). A positive correlation was observed between the degree of intestinal microbiota dysbiosis and disease severity (measured by DALYs): in regions where the intestinal F/B ratio deviated from the normal range by more than 30%, DALYs were 40% higher than those in regions with a normal ratio ( = 0.40, 95% CI: 0.35-0.45, < 0.001); in regions where the content of short-chain fatty acids (SCFAs) decreased by 20%, DALYs increased by approximately 25% ( = 0.25, 95% CI: 0.21-0.29, < 0.001). Among IBD patients with different severity levels in the Asian region, the abundance of specific bacterial genera related to inflammation regulation (e.g., ) in the intestines of severe patients decreased by more than 50% compared with healthy populations, and their DALY values were 60% higher than those of mild patients (95% CI: 55-65%, < 0.001). Additionally, the SCFA levels of severe patients were significantly lower than those of mild patients and healthy populations (median SCFA level: 2.1 mmol/L in severe patients; 4.5 mmol/L in mild patients; 6.8 mmol/L in healthy populations, < 0.001). This study confirms a close association between intestinal microbiota dysbiosis in inflammatory bowel disease and the global disease burden growth trend. Intestinal microbiota dysbiosis can be used as a key indicator to predict the growth of the IBD disease burden, providing an important theoretical basis for formulating targeted prevention, control strategies, and treatment methods.

The dynamic regulation of the physical states of chromatin in the cell nucleus is crucial for maintaining cellular homeostasis. Chromatin can exist in solid- or liquid-like forms depending on the surrounding ions, binding proteins, post-translational modifications and many other factors. Several recent studies suggested that chromatin undergoes liquid–liquid phase separation (LLPS) in vitro and also in vivo; yet, controversial conclusions about the nature of chromatin LLPS were also observed from the in vitro studies. These inconsistencies are partially due to deviations in the in vitro buffer conditions that induce the condensation/aggregation of chromatin as well as to differences in chromatin (nucleosome array) constructs used in the studies. In this work, we present a detailed characterization of the effects of K+, Mg2+ and nucleosome fiber length on the physical state and property of reconstituted nucleosome arrays. LLPS was generally observed for shorter nucleosome arrays (15-197-601, reconstituted from 15 repeats of the Widom 601 DNA with 197 bp nucleosome repeat length) at physiological ion concentrations. In contrast, gel- or solid-like condensates were detected for the considerably longer 62-202-601 and lambda DNA (~48.5 kbp) nucleosome arrays under the same conditions. In addition, we demonstrated that the presence of reduced BSA and acetate buffer is not essential for the chromatin LLPS process. Overall, this study provides a comprehensive understanding of several factors regarding chromatin physical states and sheds light on the mechanism and biological relevance of chromatin phase separation in vivo.

Large topologically associated domains (TADs) contain irregularly spaced nucleosome clutches, and interactions between such clutches are thought to aid the compaction of these domains. Here, we reconstituted TAD-sized chromatin fibers containing hundreds of nucleosomes on native source human and lambda-phage DNA and compared their mechanical properties at the single-molecule level with shorter ‘601’ arrays with various nucleosome repeat lengths. Fluorescent imaging showed increased compaction upon saturation of the DNA with histones and increasing magnesium concentration. Nucleosome clusters and their structural fluctuations were visualized in confined nanochannels. Force spectroscopy revealed not only similar mechanical properties of the TAD-sized fibers as shorter fibers but also large rupture events, consistent with breaking the interactions between distant clutches of nucleosomes. Though the arrays of native human DNA, lambda-phage and ‘601’ DNA featured minor differences in reconstitution yield and nucleosome stability, the fibers’ global structural and mechanical properties were similar, including the interactions between nucleosome clutches. These single-molecule experiments quantify the mechanical forces that stabilize large TAD-sized chromatin domains consisting of disordered, dynamically interacting nucleosome clutches and their effect on the condensation of large chromatin domains.

The tropospheric delay is one of the main error sources for radio navigation technologies and other ground-or space-based earth observation systems. In this paper, the spatial and temporal variations of the zenith tropospheric delay （ZTD）, especially their dependence on altitude over China region, are analyzed using ECMWF （European Centre for Medium-Range Weather Forecast） pressure-level atmospheric data in 2004 and the ZTD series in 1999–2007 measured at 28 GPS stations from the Crustal Movement Observation Network of China （CMONC）. A new tropospheric delay correction model （SHAO） is derived and a regional realization of this model for China region named SHAO-C is established. In SHAO-C model, ZTD is modeled directly by a cosine function together with an initial value and an amplitude at a reference height in each grid, and the variation of ZTD along altitude is fitted with a second-order polynomial. The coefficients of SHAO-C are generated using the meteorology data in China area and given at two degree latitude and longitude interval, featuring regional characteristics in order to facilitate a wide range of navigation and other surveying applications in and around China. Compared with the EGNOS （European Geostationary Navigation Overlay Service） model, which has been used globally and recommended by the European Union Wide Area Augmentation System, the ZTD prediction （in form of spatial and temporal projection） accuracy of the SHAO-C model is significantly improved over China region, especially at stations of higher altitudes. The reasons for the improvement are： （1） the reference altitude of SHAO-C parameters are given at the average height of each grid, and （2） more detailed description of complicated terrain variations in China is incorporated in the model. Therefore, the accumulated error at higher altitude can be reduced considerably. In contrast, the ZTD has to be calculated from the mean sea level with EGNOS and other models. Compared with the direct estimation of ZTD from the 28 GPS stations, the accuracy of the derived ZTD using the SHAO-C model can be improved by 60.5% averagely compared with the EGNOS model. The overall bias and rms are 2.0 and 4.5 cm, respectively, which should be sufficient to satisfy the requirements of most GNSS navigation or positioning applications in terms of the tropospheric delay correction.