ABSTRACT IFI16 (interferon-γ-inducible protein 16) is an innate-immune DNA sensor that detects viral dsDNA in the nucleus. It also functions as an antiviral restriction factor, playing a crucial role in regulating the latency/lytic balance of several herpesviruses, including Kaposi’s sarcoma-associated herpesvirus (KSHV). We previously demonstrated that IFI16 achieves this by regulating the deposition of H3K9me3 marks on the KSHV genome. Here, we explored whether IFI16 impacts the KSHV latency/lytic balance through additional mechanisms. Our analysis of the IFI16 interactome revealed that IFI16 binds to the class-I HDACs, HDAC1 and HDAC2, and recruits them to the KSHV major latency protein, latency-associated nuclear antigen (LANA). Previous reports have suggested that LANA undergoes lysine acetylation through unknown mechanisms, which results in the loss of its ability to bind to the KSHV transactivator protein (RTA) promoter. However, how the LANA acetylation-deacetylation cycle is orchestrated and what effect this has on KSHV gene expression remains unknown. Here, we demonstrate that LANA, by default, undergoes post-translational acetylation, and during latency, IFI16 interacts with this acetylated LANA and recruits HDAC1/2 to it. This keeps LANA in a deacetylated form, competent in binding and repressing lytic promoters. However, during lytic reactivation, IFI16 is degraded via the proteasomal pathway, leading to the accumulation of acetylated LANA, which cannot bind to the RTA promoter. This results in the de-repression of the RTA and, subsequently, other lytic promoters, driving reactivation. These findings shed new light on the role of IFI16 in KSHV latency and suggest that KSHV utilizes the cellular IFI16-HDAC1/2 interaction to facilitate its latency. IMPORTANCE Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic γ-herpesviruses etiologically associated with several human malignancies, including Kaposi’s sarcoma, primary effusion B-cell lymphoma, and multicentric Castleman’s disease. Understanding the molecular mechanisms governing the establishment and maintenance of latency in γ-herpesviruses is crucial because latency plays a pivotal role in oncogenesis and disease manifestation post-infection. Here, we have elucidated a new mechanism by which IFI16, a previously discovered antiviral restriction factor, is hijacked by KSHV to recruit class-I HDACs on latency-associated nuclear antigen (LANA), resulting in the latter’s deacetylation. The acetylation status of LANA is critical for KSHV latency because it governs LANA’s binding to the KSHV replication and transcription activator (RTA) promoter, an immediate-early gene crucial for lytic reactivation. Depletion of IFI16 results in the accumulation of acetylated LANA, which is incapable of maintaining latency. These newly discovered interactions between IFI16 and LANA and between IFI16 and HDAC1/2 enhance our understanding of KSHV latency regulations.

• Book : ()
• Pub. Date : 2025
• Page :
• Keyword :

ABSTRACTIn situ leaching (ISL) is an important method for green and efficient development of sandstone‐type uranium ore. It achieves ISL of uranium through the deployment of injection and extraction vertical well patterns. The optimization of parameter matching between injection and extraction wells is key to improving the efficiency of uranium development. However, as the depth of mining and the scale of development increase, the small area controlled by vertical wells leads to a large number of vertical wells and high drilling costs, which severely affect the benefits of mine development. In this paper, taking the development case of the LK mine area in Xinjiang as an example, an extraction method of “horizontal well injection–vertical well extraction” was innovatively proposed for the first time. By using the well‐storage coupling model and particle tracking technology, this study systematically investigated the impact of well types and injection–extraction parameters on the leaching range and the distribution of leaching dead zones. Furthermore, a hybrid multiobjective optimization algorithm was used to complete the parameter optimization of well‐storage coupling for ISL of uranium. The research content of this paper explores the impact of injection–extraction parameters and well spacing on the leaching effect of “horizontal well injection–vertical well extraction,” providing a method and approach for the optimization study of ISL uranium parameters. In addition, the research results of this paper have certain guiding significance for enhancing the leaching and extraction effect of the existing uranium mining plan in the LK mining area.

• Book : ()
• Pub. Date : 2025
• Page :
• Keyword :

An effective neural network system for monitoring sensors in helicopter turboshaft engines has been developed based on a hybrid architecture combining LSTM and GRU. This system enables sequential data processing while ensuring high accuracy in anomaly detection. Using recurrent layers (LSTM/GRU) is critical for dependencies among data time series analysis and identification, facilitating key information retention from previous states. Modules such as SensorFailClean and SensorFailNorm implement adaptive discretization and quantisation techniques, enhancing the data input quality and contributing to more accurate predictions. The developed system demonstrated anomaly detection accuracy at 99.327% after 200 training epochs, with a reduction in loss from 2.5 to 0.5%, indicating stability in anomaly processing. A training algorithm incorporating temporal regularization and a combined optimization method (SGD with RMSProp) accelerated neural network convergence, reducing the training time to 4 min and 13 s while achieving an accuracy of 0.993. Comparisons with alternative methods indicate superior performance for the proposed approach across key metrics, including accuracy at 0.993 compared to 0.981 and 0.982. Computational experiments confirmed the presence of the highly correlated sensor and demonstrated the method’s effectiveness in fault detection, highlighting the system’s capability to minimize omissions.

• Book : 25(4)
• Pub. Date : 2025
• Page : pp.990-990
• Keyword :

Abstract Background JCOG1212 is a dose-finding and efficacy confirmatory study of concurrent superselective intra-arterial infusion of cisplatin and radiotherapy (RADPLAT) for locally advanced primary squamous cell carcinoma of the maxillary sinus (cT4a,bN0M0). In this study, we report the results of the final analysis of the efficacy confirmation phase for the T4a cohort with 5-year follow-up data to evaluate the late adverse events and long-term efficacy. Methods Based on the results of the dose-finding phase, the efficacy confirmation phase consisted of seven weekly intra-arterial infusions of cisplatin 100 mg/m2 combined with radiotherapy (70 Gy). The 5-year prognosis and late adverse events were evaluated. Results Between April 2014 and August 2018, 64 patients were included in the analysis (one ineligible patient was excluded); 31 patients were treated with three-dimensional conformal radiation therapy (3D-CRT) and 33 with intensity modulated radiation therapy (IMRT). The 5-year overall survival, event-free survival, and local event-free survival was 71.9, 54.7, and 57.5%, respectively. In terms of late adverse events, grade 3 or higher non-hematologic toxicity was observed in 42.9% of 63 patients (retinopathy: 12, cataract: 10, osteonecrosis of mandible: 4, etc.). Grade 3 and 4 cataracts of affected side appeared in 22.6% (7/31) of the 3D-CRT group compared to 3.1% (1/32) in the IMRT group. Twenty-one patients had died, with 15 from the primary disease, 5 from other causes, and 1 from treatment-related cause. Conclusion The prognosis of RADPLAT was favorable after 5-year follow-up with acceptable late adverse events and low proportion of treatment related death.

• Book : ()
• Pub. Date : 2025
• Page :
• Keyword :

Glioblastoma (GBM) tumors exhibit extensive genomic, epigenomic, and transcriptional diversity, with significant intratumoral heterogeneity, complicating standard treatment approaches involving radiation (RT) and the DNA-alkylating agent temozolomide (TMZ). In this study, we employed an integrative multi-omics approach, including targeted proteomics, transcriptomics, genomics, and DNA methylation profiling, to investigate the response of a representative panel of GBM patient-derived cancer stem cells (CSCs) to astrocytic differentiation and RT and TMZ treatments. Differentiated CSC progenies retained the expression of key stemness genes and survival pathways, while activating the BMP-Smad signaling pathway and upregulating extracellular matrix components. This was associated with increased resistance to TMZ, though not to RT, across all models. We identified TP53 status as a critical determinant of transcriptional response to both RT and TMZ, which was also modulated by the differentiation state and treatment modality in wildtype (wt) p53 GBM cells. Both mutant and wt p53 models exhibited significant activation of the DNA-damage associated interferon (IFN) response in CSCs and differentiated cells, implicating this pathway in the GBM response to therapy. We observed that activation of NF-κB was positively correlated with the levels of O-6-methylguanine-DNA methyltransferase (MGMT) protein, a direct DNA repair enzyme leading to TMZ resistance, regardless of MGMT promoter methylation status, further supporting the clinical potential for inhibition of NF-kB signaling in GBM treatment. Our integrative analysis of the impact of GBM cell developmental states, in the context of genomic and molecular diversity of patient-derived models, provides valuable insights for pre-clinical studies aimed at optimizing treatment strategies.

• Book : 20(2)
• Pub. Date : 2025
• Page : pp.e0315171-e0315171
• Keyword :

• Book : 34()
• Pub. Date : 2025
• Page :
• Keyword :

Abstract In the case of neonates, especially low birth weight preterm and high-risk infants, portable X-rays are frequently used. However, the image quality of portable X-rays is significantly lower compared to standard adult or pediatric X-rays, leading to considerable challenges in identifying abnormalities. Although attempts have been made to introduce deep learning to address these image quality issues, the poor quality of the images themselves hinders the training of deep learning models, further emphasizing the need for image enhancement. Additionally, since neonates have a high cell division rate and are highly sensitive to radiation, increasing radiation exposure to improve image quality is not a viable solution. Therefore, it is crucial to enhance image quality through preprocessing before training deep learning models. While various image enhancement methods have been proposed, Contrast Limited Adaptive Histogram Equalization (CLAHE) has been recognized as an effective technique for contrast-based image improvement. However, despite extensive research, the process of setting CLAHE’s hyperparameters still relies on a brute force, manual approach, making it inefficient. To address this issue, we propose a method called Bayesian Optimization CLAHE(BO-CLAHE), which leverages Bayesian optimization to automatically select the optimal hyperparameters for X-ray images used in diagnosing lung diseases in preterm and high-risk neonates. The images enhanced by BO-CLAHE demonstrated superior performance across several classification models, with particularly notable improvements in diagnosing Transient Tachypnea of the Newborn (TTN). This approach not only reduces radiation exposure but also contributes to the development of AI-based diagnostic tools, playing a crucial role in the early diagnosis and treatment of preterm and high-risk neonates.

• Book : 15(1)
• Pub. Date : 2025
• Page :
• Keyword :

AbstractHair follicle neural crest stem cells reside in the bulge region of the outer root sheath of hair follicles, originate from the ectoderm, and have multidirectional differentiation potential, making them ideal candidates for tissue engineering applications. These cells mainly reside in a hypoxic microenvironment that favors the maintenance of stemness. Recently, many studies have elucidated the involvement of the Hippo pathway in the regulation of stem cell fate. However, few studies have investigated whether the Hippo signaling pathway regulates the growth of hair follicle neural crest stem cells in hypoxic environments. In the present study, we investigated the role of the Hippo pathway in the regulation of hair follicle neural crest stem cells under hypoxic conditions. We identified neural crest‐derived stem cells from single‐cell RNA‐seq data of skin organoids in a public database, and reported that the Hippo pathway was activated in the cell population. Hair follicle neural crest stem cells were isolated from rat hair follicles and cultured under hypoxic (3% oxygen) and normoxic (20% oxygen) conditions. Cell viability was assessed via the CCK8 assay. The expression levels of several key genes, including Hif2α, Nestin, Sox10, Oct4, Nanog, Sox2, and Klf4, were evaluated via quantitative real‐time PCR, after which we treated the cells with verteporfin, a small molecule inhibitor of the Hippo pathway. Changes in the subcellular localization of the hair follicle neural crest stem cell‐specific marker SOX10 were assessed via immunofluorescence. Western blotting was used to analyze the expression levels of proteins associated with stemness and hypoxia responses, including HIF2α, SOX10, OCT4, NANOG, SOX2, and KLF4. The results showed that hypoxic conditions facilitated the maintenance of stemness in hair follicle neural crest stem cells, including the promotion of proliferation and the expression of multipotential markers. Inhibition of the Hippo pathway results in a significant decrease in cell proliferation. The protein expression of HIF2α, SOX10, OCT4, NANOG, SOX2, and KLF4 was also reduced under hypoxic conditions.

• Book : ()
• Pub. Date : 2025
• Page :
• Keyword :

• Book : ()
• Pub. Date : 2025
• Page :
• Keyword :

Non-centrosomal microtubule-organizing centers (ncMTOCs) are important for the function of differentiated cells. Yet, ncMTOCs are poorly understood. Previously, several components of the nuclear envelope (NE)-MTOC have been identified. However, the temporal localization of MTOC proteins and Golgi to the NE and factors controlling the switch from a centrosomal MTOC to a ncMTOC remain elusive. Here, we utilized the in vitro differentiation of C2C12 mouse myoblasts as a model system to study NE-MTOC formation. We find based on longitudinal co-immunofluorescence staining analyses that MTOC proteins are recruited in a sequential and gradual manner to the NE. AKAP9 localizes with the Golgi to the NE after the recruitment of MTOC proteins. Moreover, siRNA-mediated depletion experiments revealed that Mbnl2 is required for proper NE-MTOC formation by regulating the expression levels of AKAP6β. Finally, Mbnl2 depletion affects Pcnt isoform expression. Taken together, our results shed light on how mammals post-transcriptionally control the switch from a centrosomal MTOC to an NE-MTOC and identify Mbnl2 as a novel modulator of ncMTOCs in skeletal muscle cells.

• Book : 14(4)
• Pub. Date : 2025
• Page : pp.237-237
• Keyword :