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The adult intestinal homeostasis is tightly controlled by proper proliferation and differentiation of intestinal stem cells. The JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription) signaling pathway is essential for the regulation of adult stem cell activities and maintenance of intestinal homeostasis. Currently, it remains largely unknown how JAK/STAT signaling activities are regulated in these processes. Here we have identified windpipe (wdp) as a novel component of the JAK/STAT pathway. We demonstrate that Wdp is positively regulated by JAK/STAT signaling in Drosophila adult intestines. Loss of wdp activity results in the disruption of midgut homeostasis under normal and regenerative conditions. Conversely, ectopic expression of Wdp inhibits JAK/STAT signaling activity. Importantly, we show that Wdp interacts with the receptor Domeless (Dome), and promotes its internalization for subsequent lysosomal degradation. Together, these data led us to propose that Wdp acts as a novel negative feedback regulator of the JAK/STAT pathway in regulating intestinal homeostasis.

Virtual machine logs are generated in large quantities. Virtual machine logs may contain some abnormal logs that indicate security risks or system failures of the virtual machine platform. Therefore, using unsupervised anomaly detection methods to identify abnormal logs is a meaningful task. However, collecting accurate anomaly logs in the real world is often challenging, and there is inherent noise in the log information. Parsing logs and anomaly alerts can be time-consuming, making it important to improve their effectiveness and accuracy. To address these challenges, this paper proposes a method called LADSVM(Long Short-Term Memory + Autoencoder-Decoder + SVM). Firstly, the log parsing algorithm is used to parse the logs. Then, the feature extraction algorithm, which combines Long Short-Term Memory and Autoencoder-Decoder, is applied to extract features. Autoencoder-Decoder reduces the dimensionality of the data by mapping the high-dimensional input to a low-dimensional latent space. This helps eliminate redundant information and noise, extract key features, and increase robustness. Finally, the Support Vector Machine is utilized to detect different feature vector signals. Experimental results demonstrate that compared to traditional methods, this approach is capable of learning better features without any prior knowledge, while also exhibiting superior noise robustness and performance. The LADSVM approach excels at detecting anomalies in virtual machine logs characterized by strong sequential patterns and noise. However, its performance may vary when applied to disordered log data. This highlights the necessity of carefully selecting detection methods that align with the specific characteristics of different log data types.

This study was designed to identify immune-related biomarkers associated with allergic rhinitis (AR) and construct a robust a diagnostic model. Two datasets (GSE5010 and GSE50223) were downloaded from the NCBI GEO database, containing 38 and 84 blood CD4 + T cell samples, respectively. To eliminate batch effects, the surrogate variable analysis (sva) R package (version 3.38.0) was employed, enabling the integration of data for subsequent analysis. Immune cell infiltration profiles were assessed using the Gene Set Variation Analysis (GSVA) R package (version 1.36.3). A gene co-expression network was constructed via the Weighted Gene Co-Expression Network Analysis (WGCNA) algorithm to identify disease-related modules. Differentially expressed genes (DEGs) were identified using the linear models for microarray data (limma) R package (version 3.34.7), followed by functional enrichment analysis using DAVID. Protein-protein interaction (PPI) networks were constructed based on the STRING database to highlight key genes. A diagnostic model was subsequently developed utilizing the Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithm and Support Vector Machine (SVM) method, with its discriminative capacity assessed via Receiver Operating Characteristic (ROC) curves. A total of twenty-eight immune cell types were analyzed, revealing significant differences in eight types between the AR and control groups. Through WGCNA, three disease-related modules comprising 4278 candidate genes were identified. Differential expression analysis identified 326 significant DEGs, of which 257 overlapped with WGCNA-selected genes. These genes exhibited significant enrichment in immune-related pathways, including “cytokine-cytokine receptor interaction” and “chemokine signaling pathway.” Gene Set Enrichment Analysis (GSEA) further uncovered 12 KEGG pathways significantly associated with disease risk scores. Drug screening identified 24 small molecule drugs related to key genes. A diagnostic model incorporating five genes (RFC4, LYN, IL3, TNFRSF1B, and RBBP7) was constructed, demonstrating diagnostic efficiencies of 0.843 and 0.739 in the training and validation sets, respectively. An AR mouse model was successfully established, and the expression levels of relevant genes were validated through RT-qPCR experiments. The five-gene diagnostic model established in this study exhibits strong predictive ability in distinguishing AR patients from healthy controls, with potential clinical applications in diagnosing AR and advancing novel diagnostic and therapeutic strategies.

Tanshinone IIA (Tan IIA) is an important characteristic component and active ingredient in Salvia miltiorrhiza , and its various aspects of research are constantly being updated to explore its potential application. In this paper, we review the recent progress on pharmacological activities and the therapeutic mechanisms of Tan IIA according to literature during the years 2015–2021. Tan IIA shows multiple pharmacological effects, including anticarcinogenic, cardiovascular, nervous, respiratory, urinary, digestive, and motor systems activities. Tan IIA modulates multi-targets referring to Nrf2, AMPK, GSK-3β, EGFR, CD36, HO-1, NOX4, Beclin-1, TLR4, TNF-α, STAT3, Caspase-3, and bcl-2 proteins and multi-pathways including NF-κB, SIRT1/PGC1α, MAPK, SREBP-2/Pcsk9, Wnt, PI3K/Akt/mTOR pathways, TGF-β/Smad and Hippo/YAP pathways, etc., which directly or indirectly influence disease course. Further, with the reported targets, the potential effects and possible mechanisms of Tan IIA against diseases were predicted by bioinformatic analysis. This paper provides new insights into the therapeutic effects and mechanisms of Tan IIA against diseases.

Alternative splicing is an important mechanism that enhances protein functional diversity. To date, our understanding of alternative splicing variants has been based on mRNA transcript data, but due to the difficulty in predicting protein structures, protein tertiary structures have been largely unexplored. However, with the release of AlphaFold, which predicts three-dimensional models of proteins, this challenge is rapidly being overcome. Here, we present a dataset of 315 predicted structures of abnormal isoforms in 18 uveal melanoma patients based on second- and third-generation transcriptome-sequencing data. This information comprises a high-quality set of structural data on recurrent aberrant isoforms that can be used in multiple types of studies, from those aimed at revealing potential therapeutic targets to those aimed at recognizing of cancer neoantigens at the atomic level.

Background The combination of drug delivery with immune checkpoint targeting has been extensively studied in cancer therapy. However, the clinical benefit for patients from this strategy is still limited. B7 homolog 3 protein (B7-H3), also known as CD276 (B7-H3/CD276), is a promising therapeutic target for anti-cancer treatment. It is widely overexpressed on the surface of malignant cells and tumor vasculature, and its overexpression is associated with poor prognosis. Herein, we report B7H3 targeting doxorubicin (Dox)-conjugated gold nanocages (B7H3/Dox@GNCs) with pH-responsive drug release as a selective, precise, and synergistic chemotherapy-photothermal therapy agent against non-small-cell lung cancer (NSCLC). Results In vitro, B7H3/Dox@GNCs exhibited a responsive release of Dox in the tumor acidic microenvironment. We also demonstrated enhanced intracellular uptake, induced cell cycle arrest, and increased apoptosis in B7H3 overexpressing NSCLC cells. In xenograft tumor models, B7H3/Dox@GNCs exhibited tumor tissue targeting and sustained drug release in response to the acidic environment. Wherein they synchronously destroyed B7H3 positive tumor cells, tumor-associated vasculature, and stromal fibroblasts. Conclusion This study presents a dual-compartment targeted B7H3 multifunctional gold conjugate system that can precisely control Dox exposure in a spatio-temporal manner without evident toxicity and suggests a general strategy for synergistic therapy against NSCLC.

Lung development generates a complex tree-like architecture through proximal-distal patterning and branching morphogenesis. However, the gene regulatory programs governing embryonic lung development remain poorly understood. Here, we present a comprehensive single-cell multi-omics atlas of mouse embryonic lungs, integrating gene expression and chromatin accessibility profiles. Through systematic analysis, we identify 13 distinct cell types and map cis-regulatory elements, peak-to-gene linkages, and transcription factors underlying lung development. Leveraging this multi-modal dataset, we uncover lineage-determining transcription factors driving cell differentiation, including the Activated Protein-1 complex. We further delineate gene regulatory networks involving diverse transcription regulators, including CCCTC-binding factor (CTCF). Using the Ctcf conditional knockout mouse, coupled with histological and multi-omics analyses, we demonstrate that CTCF orchestrates lung progenitor maintenance and branching morphogenesis by modulating both gene expression and chromatin accessibility. Thus, our study provides a multi-omics resource and mechanistic insights for transcriptional regulation of lung morphogenesis. Lung development generates a complex tree-like architecture through branching and proximal-distal patterning. Here, Sun et al. provide a multi-omics resource and mechanistic insights into the transcriptional regulation of lung morphogenesis.

Programmed Cell Death (PCD) or apoptosis is a highly conserved biological process and plays essential roles both in the development and stress context. In Drosophila , expression of pro-apoptotic genes, including reaper (rpr) , head involution defective (hid) , grim , and sickle ( skl ), is sufficient to induce cell death. Here, we demonstrate that the chromatin remodeler Dmp18, the homolog of mammalian Znhit1, plays a crucial role in regulating apoptosis in eye and wing development. We showed that loss of Dmp18 disrupted eye and wing development, up-regulated transcription of pro-apoptotic genes, and induced apoptosis. Inhibition of apoptosis suppressed the eye defects caused by Dmp18 deletion. Furthermore, loss of Dmp18 disrupted H2Av incorporation into chromatin, promoted H3K4me3, but reduced H3K27me3 modifications on the TSS regions of pro-apoptotic genes. These results indicate that Dmp18 negatively regulates apoptosis by mediating H2Av incorporation and histone H3 modifications at pro-apoptotic gene loci for transcriptional regulation. Our study uncovers the role of Dmp18 in regulating apoptosis in Drosophila eye and wing development and provides insights into chromatin remodeling regulating apoptosis at the epigenetic levels.

Drosophila Wingless （Wg） acts as a morphogen during development. Wg secretion is controlled by a seven- pass transmembrane cargo Wntless （Wls）. We have recently identified retromer as a key regulator involved in Wls trafficking. As sorting nexin （SNX） molecules are essential components of the retromer complex, we hypothesized that specific SNX（s） is required for retromer-mediated Wnt secretion. Here, we generated Drosophila mutants for all of the eight snx members, and identified Drosophila SNX3 （DSNX3） as an essential molecule required for Wg secretion. We show that Wg secretion and its signaling activity are defective in Dsnx3 mutant clones in wing discs. Wg levels in the culture medium of Dsnx3-depleted S2 cells are also markedly reduced. Importantly, Wls levels are strikingly reduced in Dsnx3 mutant cells, and overexpression of Wls can rescue the Wg secretion defect observed in Dsnx3 mutant cells. Moreover, DSNX3 can interact with the retromer component Vps35, and co-localize with Vps35 in early endosomes. These data indicate that DSNX3 regulates Wg secretion via retromer-dependent Wls recycling. In contrast, we found that Wg secretion is not defective in cells mutant for Drosophila snxl and snx6, two components of the classical retromer complex. Ectopic expression of DSNXI or DSNX6 fails to rescue the Wg secretion defect in Dsnx3 mutant wing discs and in Dsnx3 dsRNA-treated S2 cells. These data demonstrate the specificity of the DSNX3- retromer complex in Wls recycling. Together, our findings suggest that DSNX3 acts as a cargo-specific component of retromer, which is required for endocytic recycling of Wls and Wg/Wnt secretion.