Acetylation of Histone H3K27 Signals the Transcriptional Elongation for Estrogen Receptor Alpha

As approximately 70% of human breast tumors are estrogen receptor α (ERα)-positive, estrogen and ERα play essential roles in breast cancer development. By interrupting the ERα signaling pathway, endocrine therapy has been proven to be an effective therapeutic strategy. In this study, we identified a mechanism by which Transcription Start Site (TSS)-associated histone H3K27 acetylation signals the Super Elongation Complex (SEC) to regulate transcriptional elongation of the ESR1 (ERα) gene. SEC interacts with H3K27ac on ESR1 TSS through its scaffold protein AFF4. Depletion of AFF4 by siRNA or CRISPR/Cas9 dramatically reduces expression of ESR1 and its target genes, consequently inhibiting breast cancer cell growth. More importantly, a AFF4 mutant which lacks H3K27ac interaction failed to rescue ESR1 gene expression, suggesting H3K27 acetylation at TSS region is a key mark bridging the transition from transcriptional initiation to elongation, and perturbing SEC function can be an alternative strategy for targeting ERα signaling pathway at chromatin level

Proteomic characterizations of cGAS and the virus microenvironment to decipher innate immune regulation

The ability of mammalian cells to detect invading pathogens and engage in intra- and inter-cellular host defense signaling cascades is at the core of determining the outcome of infection. Cellular intrinsic and innate immune responses rely on germline-encoded pattern-recognition receptors (PRR) that defend against pathogens by recognizing pathogen-associated molecular patterns (PAMP), thereby stimulating expression of pro-inflammatory cytokines and interferon-induced proteins. This study integrates molecular virology with proteomics to examine intra- and intercellular host responses to viral infection, including PRR signaling and viral countermeasures within the local infected microenvironment. Cyclic GMP-AMP synthase (cGAS) is a PRR that detects pathogenic DNA from DNA viruses including herpesviruses, and synthesizes cyclic GMP-AMP, which activates the STING-TBK1-IRF3 axis to induce cytokines and apoptosis. While this pathway is well-established, how cGAS is homeostatically maintained or regulated upon infection is less clear. We defined cGAS protein-protein interactions upon herpes simplex virus type 1 (HSV-1) infection using immunoaffinity purification coupled to mass spectrometry (IP-MS). We identified an interaction between cGAS and 2ʹ-5ʹ-oligoadenylate synthase-like protein OASL, whose OAS-like domain interacted with the cGAS Mab21 domain, while the ubiquitin-like domain inhibited cGAS-mediated interferon response. By IP-MS and targeted MS, I further identified several critical cGAS phosphorylations and acetylations in human primary fibroblasts, HEK293Ts, and macrophage-like THP-1s. Acetyl-mimic mutations at Lys384 and Lys414 inhibited cGAS-dependent apoptosis, while acetyl-mimic Lys198 increased cGAS-dependent interferon signaling. Moreover, Lys198 acetylation levels were decreased upon infections with HSV-1 or human cytomegalovirus (HCMV), indicating a viral mechanism to inhibit host immunity. As virus-infected cells secrete cytokines to prevent virus spread, viral proteins are secreted to dampen host responses. However, it remains largely unknown how cells either in close or distant proximity to the infected cell respond to infection. I adapted a cell-penetrating mCherry labelling approach paired with cell sorting and MS to isolate and characterize infected, neighboring, and distal cell populations within the HCMV microenvironment. In neighboring compared to distal cells, I discovered lower levels of interferon-inducible proteins, differential cell cycle progression, and higher susceptibility to superinfection with either HCMV or HSV-1. These findings provide insights into how infection reshapes the local microenvironment to facilitate virus spread

Critical area identification and dynamic process simulation for landslide hazard chain formation in the upstream Jinsha River

The upper reaches of the Jinsha River, with their complex terrain and active tectonic movements, are vulnerable to landslide-induced hazard chain events, which endanger the safety of residents and infrastructure construction. Based on the analysis of the development background of the hazard chain in the upstream area of the Jinsha River, five factors, including the lithology, distance to faults, distance to rivers, peak ground acceleration, and slope degree, were selected to identify the critical landslide-prone areas. Principal component and grey correlation analyses were then conducted to determine the contributions of these different factors. Based on ArcGIS, the study zone was categorized into five classes of landslide susceptibility: very high, high, moderate, low, and very low. The identification of the critical target areas for landslide hazard chain formation showed satisfactory accuracy. The very high- and high-susceptibility areas are concentrated along the Jinsha River. The dynamic process of a typical landslide in a very high-susceptibility area was numerically simulated using OpenLISEM. The high-precision Baige landslide data of the study area were used to calibrate the practicality of the input mass parameters, including cohesion, internal friction angle, D50, and D90. The movement and accumulation processes of a typical landslide were then numerically simulated with the verified data. The entire landslide accumulation covers an area of 0.45 km2, with a length of 1,600 m and a width of 270 m. Thus, the OpenLISEM model, which combines mass, topography, and landcover parameters, is feasible for the numerical simulation of landslide dynamic processes. The prediction of the dynamic processes and accumulation morphology of landslides can provide a reference for the formation processes and mechanisms of the landslide-induced hazard chain in the upper Jinsha River.</jats:p

Critical Filling Height of Embankment over Soft Soil: A Three-Dimensional Upper-Bound Limit Analysis

This paper investigates the critical filling height of embankments over soft soil using three-dimensional (3D) upper-bound limit analysis based on a rotational log-spiral failure mechanism. Soft soils are characterized by low shear strength and high compressibility, making the accurate determination of critical filling height essential for evaluating embankment stability. Unlike conventional two-dimensional (2D) analyses, the proposed 3D method captures the true failure mechanism of embankments, providing more realistic and reliable results. The upper-bound analysis equations are derived using the principle of virtual work and solved efficiently through the genetic algorithm (GA), which avoids the limitations of traditional loop and random searching algorithms. The proposed solution is validated by comparing it with existing studies on slope stability and demonstrates higher accuracy and computational efficiency. Parametric studies are conducted to evaluate the influence of the depth–height ratio (the ratio of soft soil depth to embankment height) on the failure width of the embankment, the critical failure surface, and the critical filling height. Results show that the critical failure surface is tangential to the bottom of the soft soil layer and the critical filling height increases as the depth–height ratio decreases. The findings provide a set of critical filling heights calculated under various soft soil depths, strength parameters, and embankment geometries, offering practical guidance for embankment design

Post-translational modification control of viral DNA sensors and innate immune signaling

The vertebrate innate immune system confers host cells with mechanisms to protect against both evolutionarily ancient pathogens and newly emerging pathogenic strains. Innate immunity relies on the host cell’s ability to distinguish between self and pathogen-derived molecules. To achieve this, the innate immune system uses germline encoded receptors called pattern recognition receptors (PRRs), which recognize various molecular signatures, including nucleic acids, proteins, lipids, glycans and glycolipids. Among these molecules, the recognition of pathogenic, mislocalized, or damaged DNA by cellular protein receptors, commonly called DNA sensors, represents a major surveillance pathway for initiating immune signaling. The ability of cells to temporally regulate DNA sensor activation and subsequent signal termination is critical for effective immune signaling. These same mechanisms are also co-opted by pathogens to promote their replication. Therefore, there is significant interest in understanding DNA sensor regulatory networks during microbial infections and autoimmune disease. One emerging aspect of DNA sensor regulation is through post-translational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, ADP-ribosylation, SUMOylation, methylation, deamidation, glutamylation. In this chapter, we discuss how PTMs have been shown to positively or negatively impact DNA sensor functions via diverse mechanisms, including direct regulation of enzymatic activity, protein-protein and protein-DNA interactions, protein translocations and protein turnover. In addition, we highlight the ability of virus-induced PTMs to promote immune evasion. We also discuss the recent evidence linking PTMs on DNA sensors with human diseases and more broadly, highlight promising directions for future research on PTM-mediated regulation of DNA sensor-dependent immune signaling

New Discoveries in the Maijishan Grottoes: Identification of Blue-Green Pigments and Insights into Green Pigment Application Techniques

The application techniques and composition of green and blue-green pigments in the Maijishan Grottoes were explored by utilizing microscopic observation, Raman spectroscopy, and SEM-EDX analysis. For the first time, lavendulan and high-purity botallackite were identified in these grottoes, in addition to the commonly found malachite and atacamite. These discoveries suggest that several caves in the Maijishan Grottoes were originally painted in blue-green tones, which have since altered to the current green or dark green hues. It was also revealed that the application of green mixed pigments involved layering malachite over basic copper chloride, rather than blending them together. Moreover, variations in the composition and placement of white ash layers indicate that the use of mixed pigments was likely due to repainting rather than initial decorative purposes. These findings significantly enhance our understanding of ancient painting techniques and provide crucial data for the conservation and restoration of cultural heritage in the Maijishan Grottoes

Recent Advances in ZnO Nanomaterial-Mediated Biological Applications and Action Mechanisms

In recent years, with the deepening research, metal zinc oxide (ZnO) nanomaterials have become a popular research object in the biological field, particularly in biomedicine and food safety, which is attributed to their unique physicochemical properties such as high surface area and volume ratio, luminescence effect, surface characteristics and biological activities. Herein, this review provides a detailed overview of the ZnO nanomaterial-mediated biological applications that involve anti-bacterial, anti-tumor, anti-inflammation, skin care, biological imaging and food packaging applications. Importantly, the corresponding action mechanisms of ZnO nanomaterials are pointed. Additionally, the structure and structure-dependent physicochemical properties, the common synthesis methods and the biosafety of ZnO nanoparticles are revealed in brief. Finally, the significance and future challenges of ZnO nanomaterial applications are concluded