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WRKY transcription factors (TFs) play crucial roles in responses to abiotic and biotic stresses that significantly impact plant growth and development. Advancements in molecular biology and sequencing technologies have elevated WRKY TF studies from merely determining expression patterns and functional characterization to uncovering molecular regulatory networks. Numerous WRKY TFs regulate drought tolerance in plants through various regulatory networks. This review details the physiological and molecular mechanisms of WRKY TFs regulating drought tolerance. The review focuses on the WRKY TFs involved in the phytohormone and metabolic pathways associated with the drought stress response and the multiple functions of these WRKY TFs, including biotic and abiotic stress responses and their participation in plant growth and development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Bromodomain-containing protein 4 (BRD4) has been identified as a promising target in drug discovery, and the development of novel specific BRD4 bromodomain inhibitors will benefit anti-inflammatory drug discovery as well as bromodomain function role disclose. Herein, inspired by marine quinazolinone alkaloid penipanoid C, we designed and synthesized a series of quinazolin-4(3H)-ones with diverse linkers between two aromatic ring systems. Among them, compound 25 possessed good in vitro BRD4 inhibitory activities (IC 50  = 3.64 μM for BRD4 BD1 and IC 50  = 0.12 μM for BRD4 BD2) and anti-inflammatory activity (IC 50  = 1.98 μM for NO production assay). Meantime, 25 obviously suppressed the expression of TNF-α and IL-6 in LPS-stimulated Raw 264.7 and THP-1 cells. Notablely, 25 displayed in vivo therapeutic efficacies in an acute inflammation model without obvious cytotoxicity. These findings suggest that 25 is a selective BRD4 BD2 inhibitor which is a promising anti-inflammatory lead compound worthy for further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Oligodendrocyte precursor cells (OPCs) respond rapidly to demyelination injury. However, the rescuing effects may be hindered by cell death of OPCs, leading to incomplete remyelination. This study aimed to explore the expression of MYC-associated zinc finger protein (MAZ) in demyelinated mice and the effects of MAZ on cell death form and differentiation of OPCs. Mice received demyelinating agent (cuprizone, CZ) for 5 weeks. Histological staining demonstrated that CZ feeding triggered demyelination in the corpus callosum (CC). Detection of iron content and ferroptosis markers indicated that ferroptosis was inducted in the CC of CZ-treated mice. Notably, we found CZ feeding resulted in a reduction of MAZ expression within the CC. Using CCK-8 assay, detection of iron content, MDA level, GSH level, and ferroptosis markers, lipid ROS detection, and immunofluorescence staining for 4-HNE, we found that knockdown of MAZ facilitated OPC ferroptosis. We also evaluated the susceptibility of MAZ-overexpressing OPCs to ferroptosis inducer, erastin, and demonstrated that MAZ-overexpressing OPCs were resistant to erastin-induced ferroptosis. TUNEL staining and western blot analysis indicated that MAZ knockdown promoted apoptosis of OPCs by inhibiting PI3K/Akt activation. Immunofluorescence staining of MBP indicated that knockdown of MAZ inhibited OPC differentiation. Moreover, we elucidate the mechanism responsible for MAZ's protective effects on OPC death and differentiation, which may be achieved through transcriptional activation of SOX2. Our findings introduced MAZ as a beneficial modulator of OPC survival and differentiation, and it could serve as a potential therapeutic target for demyelination diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The aim of this research was to investigate the specific regulatory role of miR-6760-5p in angiogenesis in moyamoya disease., Methods: HUVECs were transfected with miR-6760-5p inhibitor and mimics fragments, then subjected to assays for cell proliferation, migration, and tube formation. Subsequently, downstream target genes of miR-6760-5p were predicted and the protein expression levels of these genes were evaluated. The presence of miR-6760-5p and YAP1 was verified by a dual luciferase reporter gene test, followed by an assessment of the effects of YAP1 and miR-6760-5p on the HUVECs., Results: Comparatively to the control group, increased expression of miR-6760-5p decreased cell growth, movement, and tube formation. YAP1 gene was discovered as a target controlled by miR-6760-5p, with subsequent investigation confirming YAP1 as a gene regulated by miR-6760-5p. Additionally, miR-6760-5p was found to counteract the angiogenesis-promoting effect of YAP1., Conclusion: The results of this research suggest a possible link between the miR-6760-5p gene found in the cerebrospinal fluid of individuals with moyamoya disease and the process of vascularization in this particular condition. The findings indicate that miR-6760-5p may be a new molecular indicator and potential target for the diagnosis of moyamoya disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ovarian cancer is a malignancy gynecologic oncology with high incidence and high mortality rate. M2-like tumor-associated macrophages promote cancer cell migration and metastasis. Ovarian tumor family deubiquitinase 4 (OTUD4) belongs to deubiquitinating enzyme family. The roles of OTUD4 in tumor microenvironments in ovarian cancer remains unknow. In this work, OTUD4 was overexpressed or knocked down in high-grade serous ovarian cancer cells OVCAR8 and CAOV3. Ovarian cells were co-cultured with THP-1 macrophages to simulate the tumor microenvironment. We found that OTUD4-expressed ovarian cells inhibited macrophage chemotaxis and M2 polarization. Besides, in ovarian tumor-bearing mouse model, OTUD4 suppressed tumor metastasis and remodeling tumor-associated macrophages phenotype (pro-tumor M2 to anti-tumor M1). In mechanism, OTUD4 protein bound to YAP1 protein, and downregulation of OTUD4 enhanced K63 ubiquitination and nuclear translocation of YAP1, thus increasing CCL2 transcription and subsequent macrophage recruitment. OTUD4 might inhibit CCL2 expression to regulate tumor-associated macrophages in ovarian tumor microenvironment. Those findings present a potential therapeutic strategy for ovarian cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Pyroptosis, which is accompanied by inflammatory responses, is critical for pathogen clearance. However, the mechanism through which Brucella evades host pyroptosis remains unclear. The transcriptional regulator ArsR6 maintains bacterial intracellular homeostasis and possibly influences host cell death. However, whether ArsR6 acts on cellular pyroptosis is unknown. Therefore, we investigated pathogen-host interactions within macrophages infected with Brucella abortus (B. abortus), and found that ArsR6 is crucial for inhibiting host cell pyroptosis after B. abortus infection. The downstream target gene, BAB_RS28760 of ArsR6 was screened using chromatin immunoprecipitation sequencing. BAB_RS28760 belongs to the BA14K protein family and is strongly immunoreactive and induces humoral and cellular immune responses in the host during infection. Deleting ArsR6 in B. abortuspromotes pyroptosis and enhancs the intracellular survival of B. abortus. In addition, ArsR6 negatively regulated its target gene BAB_RS28760, whereas BAB_RS28760 deletion downregulated cellular pyroptosis by inhibiting endoplasmic reticulum stress and decreasing the intracellular survival of B. abortus. Our results reveal for the first time that Brucella ArsR6 reduces endoplasmic reticulum stress activation by negatively regulating its downstream target genes, thus inhibiting host cell pyroptosis. Our study provides new insights into the pathogenic mechanisms of Brucella, which can provide potential selectivity for the development of anti-Brucella therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.)

Breslow thickness (BT), a parameter measuring the depth of invasion of abnormally proliferating melanocytes, is a key indicator of melanoma severity and prognosis. However, the mechanisms underlying the increase in BT remain elusive. Utilizing data from The Cancer Genome Atlas (TCGA) human skin cutaneous melanoma (SKCM), we identified a set of BT-related molecules and analyzed their expression and genomic heterogeneity across pan-cancerous and normal tissues. Through consensus clustering, we identified two distinct BT phenotypes in melanoma, which exhibited significant differences in clinical, genomic, and immune infiltration characteristics. High BT molecular expression was associated with reduced CD8+ T cell infiltration and poor immunotherapy response, potentially mediated by the Macrophage Migration Inhibitory Factor (MIF) signaling pathway. In vitro experiments confirmed that BT molecules, including TRIM29, SERPINB5, and RAB25, promoted melanoma development through distinct mechanisms. Notably, fibroblast-derived TRIM29 and B-cell-derived RAB25 interacted with SPP1+ monocytes/macrophages via different pathways. Our findings suggest that genomic variations leading to imbalanced expression of BT molecules across cancers contribute to increased BT, which is closely linked to an immunosuppressive microenvironment. The involvement of multiple cell types and complex intercellular interactions underscores the importance of evaluating dynamic cellular crosstalk in the tumor microenvironment to better understand BT increases and develop more effective immunotherapeutic strategies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare no conflicts of interest. All authors contributed to data analysis, drafting, or revising of the article; agree on the journal to which the article is being submitted; provided final approval of the version to be published; and agree to be accountable for all aspects of the work. Prior to the commencement of data collection, the first author obtained written consent from all participants concerning participation and subsequent publication of the study results., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Tripartite motif-containing proteins (TRIMs), comprising the greatest subfamily of E3 ubiquitin ligases with approximately 80 members of this family, are widely distributed in mammalian cells. TRIMs actively participate in ubiquitination of target proteins, a type of post-translational modification associated with protein degradation and other functions. Tripartite motif-containing protein 29 (TRIM29), a member of the TRIM family, differs from other members of this family in that it lacks the RING finger structural domain containing cysteine and histidine residues that mediates DNA binding, protein-protein interactions, and ubiquitin ligase, at its N-terminus. The expression of TRIM29 was initially found to be associated with cancer and diabetic nephropathy progression, and antiviral immunity which is triggered by virus-derived nucleic acids binding to pattern recognition receptors (PRRs) on immune cells. Recently, TRIM29 has also been explored as a diagnostic biomarker and therapeutic target for some immune-related diseases. Here, we review the functions of TRIM29 in the progression of diseases and the inherent mechanisms, as well as the remaining gaps in the literature. A thorough understanding of the detailed regulatory mechanisms of TRIM29 will ultimately facilitate the development of different therapeutic strategies for various diseases., Competing Interests: Declaration of competing interests The authors declare that they have no known competing interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Astragaloside II (AST II) is one of the principal bioactive components of Astragalus mongholicus Bunge, exhibiting multiple pharmacological properties. However, the therapeutic efficacy of AST II in Chronic Obstructive Pulmonary Disease (COPD) remains to be fully elucidated. The study explored the effects and mechanisms of AST II in a COPD model induced by exposure to cigarette smoke (CS) and lipopolysaccharide (LPS) in mice., Methods: An animal model of COPD was established by intratracheal instillation of LPS and cigarette smoking in mice. Serum samples were collected to determine inflammatory cell infiltration and cytokine levels. Lung tissues were collected for histological, immunofluorescence and Western blot analysis. The RAW264.7 macrophage cell line was employed to investigate the molecular mechanism of AST II in vitro., Results: Lung dysfunction, histopathological damage, inflammatory infiltration, and pro-inflammatory factors secretion in COPD mice induced by CS and LPS were mitigated by AST II. AST II exerted an anti-inflammatory effect by enhancing the activation of the mammalian target of rapamycin complex 1 (mTORC1)/glycogen synthase kinase-3β (GSK-3β) signaling pathway, which promoted the binding of CREB-binding protein (CBP) to CREB, thereby antagonizing the binding to nuclear factor-κB (NF-κB) and inhibiting its transcriptional activity. However, AST II did not demonstrate a protective effect against LPS-induced inflammatory damage to RAW264.7 cells when mTORC1 was inhibited by rapamycin., Conclusion: AST II exhibits potential therapeutic benefits as an alternative medication for COPD and other respiratory inflammatory conditions since it may reduce lung injury and inflammatory response in mice exposed to CS and LPS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The BET family proteins play pleiotropic roles in the tumorigenesis and growth of various human malignancies that have aroused great interests as the cancer therapeutic targets. Therefore, it's significant to develop labeling toolkits for the dynamic monitoring of BET family proteins in living tumor cells and tissue slices. In particular, there are few small-molecule fluorescent probes based on BET family proteins developed for real-time imaging of these proteins in tumor cells and tissues and treatment of breast cancer. In general, antibodies of BET family proteins are chosen for imaging of these proteins. However, the cost of these antibodies is more expensive than small molecules and the operation is relatively complicated. Moreover, the antibodies for imaging are not capable of the therapy for breast cancer. Thus, it's essential to exploit a novel imaging system for BET family proteins which is easy-operating and economical, with achieving therapeutic effects simultaneously. Therefore, a series of fluorescent probes (17-21) targeting BET family proteins were developed. Through the evaluation studies, probe 17 showed advantages in docking studies, analysis of cell viability, and imaging studies. Importantly, probe 17 was capable of distinguishing tumor cells and tissue slices and made a distinction between them by labeling BRD3 and BRD4 proteins. Importantly, probe 17 showed higher resolution in mouse tumor and human tumor slice imaging than BRD3 and BRD4 antibodies. Moreover, compared with these antibodies, probe 17 was more stable, more economical and easier to operate in the imaging assays. In addition, it also played an anti-tumor role by inducing cell apoptosis, proliferation inhibition, and cycle arrest in tumor cells. All these features render probe 17 to perform as an effective labeling toolkit compatible for imaging studies of BRD3/BRD4, as well as an approach to diagnosis and treatment of breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Waterlogging stress is a significant abiotic factor that severely limits plant growth and development. Identifying genes involved in the waterlogging stress response and understanding the mechanisms by which plants resist waterlogging stress are therefore critical. In this study, we identified a specific role for two transcription factors, BPC1 and BPC2, in the waterlogging stress response of Arabidopsis thaliana. Waterlogging stress markedly upregulated the transcripts of BPC1 and BPC2 in Arabidopsis. Loss-of-function mutations in BPC1 and BPC2 decreased tolerance to waterlogging stress during the seedling growth stage. Physiological analyses demonstrated that the mutations of BPC1 and BPC2 aggravated waterlogging-induced increases in electrolyte leakage, malondialdehyde (MDA) content and hydrogen peroxide (H₂O₂) accumulation by modulating POD activity. Furthermore, quantitative real-time PCR (qRT-PCR) and dual-luciferase assays showed that BPC1 and BPC2 up-regulated the expression of peroxidase gene (Prx28). Collectively, our results indicate that BPC1 and BPC2 positively modulate Prx28 expression to affect the POD activity, modulating electrolyte leakage, MDA content and H₂O₂ accumulation under waterlogging stress. This study reveals the molecular mechanisms underlying waterlogging resistance in A. thaliana, providing new insights into this field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Neurodevelopmental abnormalities are significant contributors to a variety of neurological disorders. Ubiquitination is essential for embryonic development and plays a pivotal role in neurodevelopment. Although Cnot4 possesses E3-ubiquitin ligase activity, its function in neurodevelopment and embryonic stem cells (ESCs) remains inadequately understood. This study examined the impact of Cnot4 ubiquitination-deficit in mouse ESCs using flow cytometry, CCK-8 assays, immunofluorescence, western blotting, RNA sequencing (RNA-seq), and intracellular Ca 2+ measurement. Findings demonstrated that the lack of ubiquitination in Cnot4 reduced ESC proliferation rates and facilitated ectodermal differentiation during spontaneous ESC differentiation. RNA-seq analysis identified that the differentially expressed genes were primarily linked to glucose metabolism and Ca 2+ signaling pathways. Additionally, results indicated that the ubiquitination-deficit in Cnot4 caused increased intracellular Ca 2+ levels in mESCs. These findings suggest that Cnot4 plays a critical role in the regulation of proliferation and differentiation of mESCs through ubiquitination, providing a basis for further exploration of its involvement in embryonic and neural development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Myelin is the key structure for high-speed information transmission and is formed by oligodendrocytes (OLs) which are differentiated from oligodendrocyte precursor cells (OPCs) in the central nervous system. Lipid is the main component of myelin and the role of lipid metabolism-related molecules in myelination attach increasing attention. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) mediates the conversion of lysophosphatidylcholine (LPC) to phosphatidylcholine (PC), and its role in myelination draws our interest as LPC is a classical demyelination inducer and PC is a major component of myelin. In this work, LPCAT1 is found expressed in the oligodendrocyte lineage cells during myelination. In vitro experiments showed that the expression level of LPCAT1 gradually increased along with the differentiation process from OPCs to OLs, and over-expression and interference experiments showed that LPCAT1 promoted OPCs differentiation without affecting their proliferation or apoptosis. Mechanistically, the undertaker of LPCAT1's pro-differentiation role is not PC, but the phosphorylated mTOR which is a key regulator in OPCs differentiation. RNA sequencing analysis showed LPCAT1 promoted the expression of ZBTB20 which is an important transcription factor related to lipid metabolism and regulates mTOR phosphorylation. In vivo, complex myelin tomacula involving multiple axons was formed after conditionally knocking out LPCAT1 in oligodendrocyte lineage cells, but no obvious myelin thickness abnormalities were observed. Our results indicate that LPCAT1 is an important regulator of myelination, and lipid metabolism-related molecules may be new valuable targets for the treatment of diseases with myelin abnormalities., (© 2025 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Loz1 is a zinc-responsive transcription factor in fission yeast that maintains cellular zinc homeostasis by repressing the expression of genes required for zinc uptake in high zinc conditions. Previous deletion analysis of Loz1 found a region containing two tandem C 2 H 2 zinc-fingers and an upstream "accessory domain" rich in histidine, lysine, and arginine residues to be sufficient for zinc-dependent DNA binding and gene repression. Here we report unexpected biophysical properties of this pair of seemingly classical C 2 H 2 zinc fingers. Isothermal titration calorimetry and NMR spectroscopy reveal two distinct zinc binding events localized to the zinc fingers. NMR spectra reveal complex dynamic behavior in this zinc-responsive region spanning time scales from fast 10 -12 -10 -10 to slow >10 0  s. Slow exchange due to cis-trans isomerization of the TGERP linker results in the doubling of many signals in the protein. Conformational exchange on the 10 -3  s timescale throughout the first zinc finger distinguishes it from the second and is linked to a weaker affinity for zinc. These findings reveal a mechanism of zinc sensing by Loz1 and illuminate how the protein's rough free-energy landscape enables zinc sensing, DNA binding and regulated gene expression., (© 2025 The Author(s). Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Direct cardiac reprogramming or transdifferentiation is a relatively new and promising area in regenerative therapy, cardiovascular disease modeling, and drug discovery. Effective reprogramming of fibroblasts is limited by their plasticity, that is, their ability to reprogram, and depends on solving several levels of tasks: inducing cardiomyocyte-like cells and obtaining functionally and metabolically mature cardiomyocytes. Currently, in addition to the use of more classical approaches such as overexpression of exogenous transcription factors, activation of endogenous cardiac transcription factors via controlled nucleases, such as CRISPR, represents another interesting way to obtain cardiomyocytes. Therefore, special attention is given to the potential of synthetic biology, in particular the CRISPR system, for the targeted conversion of only certain subpopulations of fibroblasts into cardiomyocytes. However, obtaining functionally and metabolically mature cardiomyocytes remains a challenge despite the range of recently developed approaches. In this review, we summarized current knowledge on the function and diversity of human cardiac fibroblasts and alternative cell sources for in vitro human cardiomyocyte models. We examined in detail the transcription factors that initiate cardiomyogenic reprogramming and their interactions. Additionally, we critically analyzed the strategies used for the metabolic and physiological maturation of induced cardiomyocytes., (© 2025 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Transcription is a key cell process that consists of synthesizing several copies of RNA from a gene DNA sequence. This process is highly regulated and closely linked to the ability of transcription factors to bind specifically to DNA. TFinder is an easy-to-use Python web portal allowing the identification of Individual Motifs (IM) such as Transcription Factor Binding Sites (TFBS). Using the NCBI API, TFinder extracts either promoter or gene terminal regulatory regions, through a simple query of NCBI gene name or ID. It enables simultaneous analysis across five different species for an unlimited number of genes. TFinder searches for Individual Motifs in different formats, including IUPAC codes and JASPAR entries. Moreover, TFinder also allows de novo generations of a Position Weight Matrix (PWM) and the use of already established PWM. Finally, the data are provided in a tabular and a graph format showing the relevance and the P-value of the Individual Motifs found as well as their location relative to the Transcription Start Site (TSS) or the terminal region of the gene. The results are then sent by email to users facilitating the subsequent data analysis and sharing. TFinder is written in Python and freely available on GitHub under the MIT license: https://github.com/Jumitti/TFinder. It can be accessed as a web application implemented in Streamlit at https://tfinder-ipmc.streamlit.app. Resources are available on Streamlit "Resources" tab. TFINDER strength is that it relies on an all-in-one intuitive tool allowing users inexperienced with bioinformatics tools to retrieve gene regulatory regions sequences in multiple species and to search for individual motifs in a huge number of genes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Clade A APSES family transcription factor Swi6 functions alongside Mbp1 to form the MBF (MluI cell cycle box-binding factor) complex in ascomycetes. In the agaricomycete Pleurotus ostreatus, Mbp1 plays a crucial role in regulating β-glucan and chitin synthesis; however, the role of Swi6 has not been explored in this fungus. In this study, its involvement in cell wall synthesis regulation was analysed using swi6 disruption strains in P. ostreatus. The Δswi6 strains exhibited reduced growth rates and shorter aerial hyphae formation in both agar and liquid media, suggesting an essential role of Swi6 in normal vegetative growth. Furthermore, swi6 disruption affected cell wall thickness distribution, the expression of specific chitin synthase genes, the relative percentage of chitin, and sensitivity to calcofluor white, suggesting that Swi6 is required for normal chitin synthesis regulation in P. ostreatus. In contrast, no significant differences were observed between the wild-type and Δswi6 strains in the relative percentage of α- and β-glucan and the expression of α- and β-glucan synthase genes, suggesting its unimportant role in α- and β-glucan synthesis regulation. In conclusion, Swi6 is necessary for normal mycelial growth and chitin synthesis regulation in P. ostreatus. To the best of our knowledge, this study is the first report on the functional differences and overlaps between Mbp1 and Swi6 in the regulation of cell wall synthesis in agaricomycetes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication that affects an increasing number of cancer survivors. However, the current treatment options for CIPN are limited. Paclitaxel (PTX) is a widely used chemotherapeutic drug that induces senescence in cancer cells. While previous studies have demonstrated that Sonic hedgehog (Shh) can counteract cellular dysfunction during aging, its role in CIPN remains unknown., Objectives: Herein, the aim of this study was to investigate whether Shh activation could inhibits neuronal/glial senescence and alleviates CIPN., Methods: We treated ND7/23 neuronal cells and RSC96 Schwann cells with two selective Shh activators (purmorphamine [PUR] and smoothened agonist [SAG]) in the presence of PTX. Additionally, we utilized a CIPN mouse model induced by PTX injection. To assess cellular senescence, we performed a senescence-associated β-galactosidase (SA-β-gal) assay, measured reactive oxygen species (ROS) levels, and examined the expression of P16, P21, and γH2AX. To understand the underlying mechanisms, we conducted ubiquitin assays, LC-MS/MS, H&E staining, and assessed protein expression through Western blotting and immunofluorescence staining., Results: In vitro, we observed that Shh activation significantly alleviated the senescence-related decline in multiple functions included SA-β-gal activity, expression of P16 and P21, cell viability, and ROS accumulation in DRG sensory neurons and Schwann cells after PTX exposure. Furthermore, our in vivo experiments demonstrated that Shh activation significantly reduced axonal degeneration, demyelination, and improved nerve conduction. Mechanistically, we discovered that PTX reduced the protein level of SP1, which was ubiquitinated by the E3 ligase TRIM25 at the lysine 694 (K694), leading to increased CXCL13 expression, and we found that Shh activation inhibited PTX-induced neuronal/glial senescence and CIPN through the TRIM25-SP1-CXCL13 axis., Conclusion: These findings provide evidence for the role of PTX-induced senescence in DRG sensory neurons and Schwann cells, suggesting that Shh could be a potential therapeutic target for CIPN., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Aims: The PEComa family of tumours is defined by spindle/epithelioid cells with myomelanocytic differentiation. A small subset harbours TFE3 fusion; however, YAP1::TEE3 has not been reported. Clear cell stromal tumour of the lung (CCST-L) is an emerging entity characterized by spindle to epithelioid cells with focal cytoplasmic clearing, inflammatory infiltrates, no myomelanocytic differentiation, and YAP1::TFE3 fusion. Herein, we report two cases of lung tumours with myomelanocytic differentiation that showed inflammatory spindle cell histology, focal epithelioid clear cells, as well as YAP1::TFE3 fusion., Methods and Results: The patients were both men, aged 61 and 68 years. The tumours in both cases presented as well-circumscribed solid masses involving the lung hilum. After lobectomy, no recurrence was observed at 7 and 32 months. Both tumours shared storiform to short fascicular growth of long spindle cells, with a minor component of epithelioid cells showing clear cytoplasm in the background of substantial intratumoral chronic inflammation and dilated blood vessels. One tumour showed focal melanin deposition. Both tumours were immunohistochemically positive for HMB45, Melan A, and h-caldesmon. Fluorescence in situ hybridization assays indicated the presence of YAP1::TFE3 fusions, which was confirmed by RNA sequencing in one case tested, and by immunohistochemical TFE3 expression and loss of YAP1 C-terminus staining., Conclusion: We present two cases of inflammatory spindle to epithelioid cell tumours of the lungs with myomelanocytic differentiation and YAP1::TFE3 fusion. This unique morphology and gene fusion suggest that these tumours may constitute a distinct subset of lung PEComa. Furthermore, morphological and molecular overlap with CCST-L gives rise to a hypothesis of a potential inherent relationship between PEComa and CCST-L., (© 2024 John Wiley & Sons Ltd.)

An early step in triploblastic embryo differentiation is the formation of the three germ layers. Maternal pioneer transcription factors (TFs) bind to embryonic enhancers before zygotic genome activation, initiating germ layer specification. While maternal TFs' role in establishing epigenetic marks is known, how early pluripotent cells gain spatially restricted epigenetic identities remains unclear. We show that by the early gastrula stage, H3K4me1-marked regions become distinct in each germ layer, with certain chromatin regions forming high density H3K4me1 marked regions (HDRs). Genes associated with these HDRs are more robustly expressed compared to those associated with low density H3K4me1 marked regions (LDRs) in the genome. This process is driven by the sequential actions of maternal and zygotic factors. Knockdown of key maternal endodermal TFs (Otx1, Vegt and Foxh1) leads to a loss of endodermal H3K4me1 marks in endoderm, with a concurrent emergence of ectodermal and mesodermal marks, indicating a shift in chromatin state. This work highlights the importance of coordinated activities of maternal and zygotic TFs in defining the regionally-resolved and dynamic process of chromatin modification conferred by H3K4me1 in the early Xenopus embryo., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cold stress can limit the growth and development of grapevines, which can ultimately reduce productivity. However, the mechanisms by which grapevines respond to cold stress are not yet fully understood. Here, we characterized an APETALA2/ethylene response factor (AP2/ERF) which was shown to be a target gene of our previously identified VaMYB4a from Amur grape. We further investigated the molecular interactions between VaMYB4a and VaERF054-like transcription factors in grapes and their role in cold stress tolerance. Our results demonstrated that VaMYB4a directly binds to and activates the VaERF054-like gene promoter, leading to its enhanced expression. Moreover, we also explored the influence of ethylene precursors and inhibitors on VaERF054-like expression and grape cold tolerance. Our findings indicate that VaERF054-like contribute to cold tolerance in grapes through modulation of the ethylene pathway and the CBF signal pathway. Overexpression of VaERF054-like in Vitis vinifera 'Chardonnay' calli and transgenic grape lines resulted in increased freezing stress tolerance, confirming its role in the cold stress response. We further confirmed the interaction between VaMYB4a and VaERF054-like in vivo and in vitro. The co-transformation of VaMYB4a and VaERF054-like in grape calli demonstrates a synergistic interaction, enhancing the cold tolerance through a regulatory feedback mechanism. Our finding provides new insights into grape cold tolerance mechanisms, potentially contributing to the development of cold-resistant grape varieties., (© 2024 John Wiley & Sons Ltd.)

Antigen-presenting cells (APCs) are a heterogenous group of immune cells composed by dendritic cells (DCs) and macrophages (Mϕ), which are critical for orchestrating immunity against cancer or infections. Several strategies have been explored to generate APC subsets, including enrichment from peripheral blood and differentiation from pluripotent or multipotent cells. During development, the generation of APC subsets is instructed by transcription factors (TFs). Direct cell reprogramming, also known as transdifferentiation, offers an approach to harness combinations of TFs to generate APCs from unrelated somatic cells, including cancer cells. In this review, we summarize the transcriptional specification of DC subsets, highlight transcriptional networks for their generation, and discuss future applications of DC reprogramming in cancer immunotherapy., Competing Interests: Declaration of Competing Interest C.-F.P. has equity interest and serves in management positions at Asgard Therapeutics AB, which develops cancer immunotherapies based on in vivo DC reprogramming technologies. C.-F.P. is an inventor on granted patents U.S. 11345891, JP 7303743, CN ZL201880005047.3, patent application WO 2018/185709, and patent application WO 2022/243448 (together with E.A.) held by Asgard Therapeutics that covers the direct cell reprogramming approach described here., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The process of mating induces significant shifts in female reproductive behavior across various species, with the postmating behavioral switch playing a crucial role in insect reproduction. Previous studies have demonstrated the regulatory role of GATA transcription factors in vitellogenin transcription and egg formation in insects, while miRNAs have been implicated in modulating GATA expression and insect reproductive processes. Nevertheless, the precise regulatory mechanism underlying the interaction between miRNAs and GATA transcription factors in the postmating behavioral switch remains largely unexplored., Results: In this study, we identified two key GATA transcription factors, HaGATAa and HaGATAb, as central players in orchestrating the postmating behavior of H. armigera using transcriptomics and RNAi technologies. HaGATAa was found to act upstream of HaGATAb, regulating its expression. Furthermore, we observed a postmating increase in miR-282 levels in females, targeting HaGATAa to regulate egg-laying capacity. Conversely, the decreased expression of miR-2 following mating functioned as a negative feedback regulator, influencing the expression of HaGATAb and thus impacting the postmating behavior of female individuals., Conclusion: Our results revealed a signal-mediated feedback regulatory mechanism that sustains female postmating behavior in H. armigera. These findings not only establish a strong basis for understanding the postmating behavior mechanisms in female moths, but also offer valuable insights for identifying potential targets for pest control strategies. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Breast cancer has become the leading cause of death in women. Membrane associated ring-CH-type finger 1 (MARCHF1) is associated with the development of various types of cancer, but the exact role of MARCHF1 in breast cancer remains unclear. In our study, the higher MARCHF1 expression was observed in tumor samples of patients with breast cancer and then the role of MARCHF1 in breast cancer was further evaluated. Overexpression of MARCHF1 contributed to proliferation of cancer cells and inhibition of oxidative stress. Knockdown of MARCHF1 reduced breast cancer cell proliferation, increased mitochondrial dysfunction induced by oxidative stress, eventually aggravating cell death. In vivo, MARCHF1 promoted the tumor growth and oppositely, MARCHF1 silencing suppressed the tumor development. Moreover, MARCHF1 interacted with repressor Element-1 silencing transcription factor (REST) and facilitated its ubiquitylation and degradation. Subsequently, REST negatively regulated the transcription of mitochondrial transcription factor A (TFAM). The subcutaneous tumor formation assay in nude mice also supported these conclusions. In details, knockdown of MARCHF1 upregulated the protein expression of REST and downregulated the mRNA level of TFAM. On the contrary, MARCHF1 overexpression exhibited opposite effects. Thus, MARCHF1 is conducive to the progression of breast cancer via promoting the ubiquitylation and degradation of RSET and then the transcription of TFAM. Downregulating MARCHF1 could provide a novel direction for treating breast cancer., (© 2024 International Federation for Cell Biology.)

Transcription factors often contain several different functional regions, including DNA-binding domains, and play an important regulatory role in plant growth, development, and the response to external stimuli. YABYY transcription factors are plant-specific and contain two special domains (N-terminal C 2 C 2 zinc-finger and C-terminal helix-loop-helix domains) that are indispensable. Specifically, YABBY transcription factors play key roles in maintaining the polarity of the adaxial-abaxial axis of leaves, as well as in regulating: vegetative and reproductive growth, hormone response, stress resistance, and secondary metabolite synthesis in plants. Recently, the identification and functional verification of YABBY transcription factors in different plants has increased. On this basis, we summarize recent advances in the: identification, classification, expression patterns, and functions of the YABBY transcription factor family. The normal expression and function of YABBY transcription factors rely on a regulatory network that is established through the interaction of YABBY family members with other genes. We discuss the interaction network of YABBY transcription factors during leaf polarity establishment and floral organ development. This article provides a reference for research on YABBY function, plant genetic improvement, and molecular breeding.

Introduction: Obesity, one of the most frequent health problems in the adult population, is a condition characterized by excessive white adipose tissue accumulation and accompanied by the increased risk to develop other disorders such as type II diabetes, cardiovascular disorders, physical disability, frailty and sarcopenia. Total fat mass frequently increases during aging, often coexisting with sarcopenia, thus resulting in an emerging condition defined sarcopenic obesity (SO). Our previous data demonstrated the relevant role of the bromo and extra-terminal domain (BET) proteins inhibitor JQ1 in attenuating inflammation and fibrosis in sarcopenic mice. Moreover, we preliminarily observed that JQ1 administration markedly reduces white adipose tissue mass, suggesting a potential role of BET proteins on visceral fat deposition during aging., Objectives: Starting from those observations, the aim of this study was to investigate the ability of JQ1 to reduce adiposity in a chronic diet-induced obesity (DIO) mouse model mimicking the human metabolic syndrome., Methods: Male C57BL/6J mice were divided in subgroups, either fed a standard diet or a high fat diet for 22 or 12 weeks, treated over the last 14 days with JQ1 or with vehicle., Results: The results showed that JQ1 administration reduces fat mass, preserving skeletal muscle mass and function. A direct JQ1 lipolytic effect was demonstrated on mature adipocyte cultures. JQ1-mediated loss of adipose tissue mass was not associated with systemic inflammation or with lipid accumulation in muscle and liver. JQ1 administration did not impinge on skeletal muscle metabolism and oxidative capability, as shown by the lack of significant impact on mitochondrial mass and biogenesis., Conclusion: In conclusion, the current data highlight a potential benefit of JQ1 administration to counteract obesity, suggesting epigenetic modulation as a prospective target in the treatment of obesity and sarcopenic obesity, despite the underlying multiorgan molecular mechanism is still not completely elucidated., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Eukaryotic transcription is a complex process regulated by transcription factors (TFs), coactivators, and RNA polymerase machineries, many of which contain sizable intrinsically disordered regions (IDRs). Many TFs activate transcription through multivalent IDR-IDR interactions. Optimal levels of such multivalent interactions associated with appropriate IDR concentrations, interaction strengths, or interaction valencies are required for effective transcriptional activation. The interaction selectivity of IDRs is crucial for the precise regulation of transcription, and this selectivity is dependent on the IDR sequences. Furthermore, IDRs modulate gene expression by bringing chromatin sites together to form transcriptionally active chromatin hubs. Mutations in IDRs may cause dysregulation of their multivalent interactions, contributing to diseases, including cancers and neurodegenerative disorders. Understanding the effects of IDR-related mutations on transcription control and genome organization opens new opportunities for developing targeted therapeutic strategies. In this review, we discuss recent reports documenting important functions of IDRs in transcriptional regulation and their implications for human health and disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The intake of selenium (Se) in the human body is negatively correlated with the risk of colorectal cancer (CRC), but its mechanism in the occurrence and development of CRC is not clear. This study aimed to evaluate the therapeutic effect of Se on CRC, and explore the anti-tumor effect of Se supplementation on CRC and its molecular mechanism. In this study, we utilized colony formation assay, cell scratch test, Transwell migration, and flow cytometry to assess cell proliferation, migration, and apoptosis. Our findings demonstrate that Se effectively suppresses the growth and proliferation of CRC cell lines HCT116 and SW480 and promoting cellular apoptosis. In vivo experiments demonstrated a significant inhibitory effect of Se on tumor growth. CRC-related datasets were extracted from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases for differential expression analysis of TRIM32 and survival analysis. We found that TRIM32 was highly expressed in tumor tissues of CRC patients and correlated with a poor prognosis. Furthermore, through RNA sequencing analysis, we identified TRIM32 as a gene that was significantly decreased after Se treatment in HCT116 cells. This finding was subsequently validated by Western blot results. Moreover, TRIM32 knockdown combined with Se treatment significantly inhibited cell growth proliferation and migration and further induced apoptosis of colorectal cancer cells. In conclusion, our findings provided evidence that Se inhibited the growth of colorectal cancer cells by down-regulating TRIM32., Competing Interests: Declarations. Ethics Approval: The study was reviewed and approved by the Medical Ethics Committee of Southern Medical University (no. 2021–0024) and the Experimental Animal Ethics Committee of Southern Medical University (L2019074). Consent to Participate: All study participants signed informed consent. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pollen formation and development during the life cycle of flowering plant are crucial for maintaining reproductive and genetic diversity. In this study, an R2R3MYB family transcription factor, SlTDF1 (SlMYB35), was predominantly expressed in stamens. Repressed expression of SlTDF1 results in a delay in the degradation of the anther tapetum in tomatoes, which in turn leads to the formation of abnormal pollen, including a reduction in the number of single-fruit seeds and fertility when compared to wild-type plants. Analysis of paraffin sections demonstrated that SlTDF1 is a crucial factor in the maturation of tomato pollen. Further analysis of the transcriptomic data revealed that downregulation of the SlTDF1 gene significantly suppressed the expression of genes related to sugar metabolism and anther development. The findings of this study indicated that SlTDF1 plays a pivotal role in regulating tomato pollen development. Moreover, these findings provide a genetic resource for male sterility in tomato plants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Plants, being immobile, are exposed to environmental adversities such as wind, snow and animals that damage their structure, making regeneration essential for their survival. The adventitious roots (ARs) primarily emerge from a detached explant to uptake nutrients; therefore, the molecular network involved in their regeneration needs to be explored. DNA methylation, a key epigenetic mark, influences molecular pathways, and recent studies suggested its role in regeneration. In our research, the application of 5-azacytidine (5-azaC), an inhibitor of DNA methylation, caused the earlier initiation and development of root primordia and consequently enhanced the AR regeneration rate in Robinia psuedoacacia L (black locust). The whole-genome bisulfite sequencing (WGBS) revealed a decrease in global methylation and an increase in hypomethylated cytosine sites and regions across all contexts including CHH, CHG and mergedCG caused transcriptional variations in 5-azaC-treated sample. The yeast two-hybrid (Y2H) assay revealed a RpMYB2-centred network of transcriptionally activated transcription factors (TFs) including RpWRKY23, RpGATA23, RpSPL16 and other genes like RpSDP, RpSS1, RpBEN1, RpGULL05 and RpCUV with nuclear localization suggesting their potential co-localization. Additionally, yeast one-hybrid (Y1H) assay showed the interaction of RpMYB2 interactors, RpGATA23 and RpWRKY23, with promoters of RpSK6 and RpCDC48, and luciferase reporting assay (LRA) validated their binding with RpSK6. Our results revealed that hypomethylation-mediated transcriptomic modifications activated the RpMYB2-centred gene network to enhance AR regeneration in black locust hypocotyl cuttings. These findings pave the way for genetic modification to improve plant regeneration ability and increase wood production while withstanding environmental damage., (© 2024 John Wiley & Sons Ltd.)

Although elevated ambient temperature causes many effects on plant growth and development, the mechanisms of plant high-ambient temperature sensing remain unknown. In this study, we show that GLYCOGEN SYNTHASE KINASE 3s (GSK3s) negatively regulate high-ambient temperature response and oligomerize upon high-temperature treatment. We demonstrate that GSK3 kinase BIN2 specifically interacts with the high-temperature sensor phytochrome B (phyB) but not the high-temperature sensor EARLY FLOWER 3 (ELF3) to phosphorylate and promote phyB photobody formation. Furthermore, we show that phosphorylation of phyB by GSK3s promotes its interaction with ELF3. Subsequently, we find that ELF3 recruits the phyB photobody facilitator HEMERA (HMR) to promote its association with phyB. Taken together, our data reveal a mechanism that GSK3s promote the phyB-ELF3-HMR complex formation in regulating plant thermomorphogenesis., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Urothelial carcinoma and prostatic adenocarcinoma can have overlapping histologic features and in some instances pose challenges to pathologists. GATA binding protein 3 (GATA3) immunohistochemistry (IHC) is a well-established tool to aid in this specific diagnostic dilemma as it has been shown to be a sensitive marker for urothelial carcinoma and a putatively specific marker in excluding prostatic adenocarcinoma. However, in encountering an index tumor of prostatic adenosquamous carcinoma positive for GATA3, herein we sought to investigate this potential diagnostic pitfall in a larger series of tumors. In this study, we retrospectively reviewed prostatic adenosquamous carcinomas diagnosed in 17 patients across the authors' institutions and personal consult collections in the past 10 years. GATA3 IHC was either reviewed or performed on tumors not previously tested. We also recorded other immunostains that were performed at initial diagnosis. Positivity for GATA3 was found in 9 of 17 (53%) tumors, all within squamous regions (2 tumors also showed concomitant moderate GATA3 positivity within glandular elements). The GATA3 positive tumors were all positive for p63 in the 7 tumors where p63 was also performed. Of all tumors tested, NKX3.1 was positive in 100% (13/13) of the glandular elements (3 tumors also showed NKX3.1 concomitant positivity within squamous regions). In summary, when encountering a carcinoma with mixed glandular/squamous features in which prostatic origin is being considered, awareness of GATA3 immunoreactivity in a subset of prostatic adenosquamous carcinoma is critical to avoid diagnostic pitfalls., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Renal cell carcinoma (RCC) is a malignant tumor with highly heterogeneous and complex molecular mechanisms. Through systematic analysis of TCGA, COSMIC and other databases, 24 mutated genes closely related to RCC were screened, including VHL, PBRM1, BAP1 and SETD2, which play key roles in signaling pathway transduction, chromatin remodeling and DNA repair. The PI3K/AKT/mTOR signaling pathway is particularly important in the pathogenesis of RCC. Mutations in genes such as PIK3CA, MTOR and PTEN are closely associated with metabolic abnormalities and tumor cell proliferation. Clinically, mTOR inhibitors and VEGF-targeted drugs have shown significant efficacy in personalized therapy. Abnormal regulation of metabolic reprogramming, especially glycolysis and glutamine metabolic pathways, provides tumor cells with continuous energy supply and survival advantages, and GLS1 inhibitors have shown promising results in preclinical studies. This paper also explores the potential of immune checkpoint inhibitors in combination with other targeted drugs, as well as the promising application of nanotechnology in drug delivery and targeted therapy. In addition, unique molecular mechanisms are revealed and individualized therapeutic strategies are explored for specific subtypes such as TFE3, TFEB rearrangement type and SDHB mutant type. The review summarizes the common gene mutations in RCC and their molecular mechanisms, emphasizes their important roles in tumor diagnosis, treatment and prognosis, and looks forward to the application prospects of multi-pathway targeted therapy, metabolic targeted therapy, immunotherapy and nanotechnology in RCC treatment, providing theoretical support and clinical guidance for individualized treatment and new drug development., Competing Interests: Conflict of interest The authors declare that there were no commercial or financial relationships during this study that could be considered conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In recent decades, chronic wounds have become an increasingly significant clinical concern because of their increasing morbidity and socioeconomic toll. However, there is currently no product available on the market that specifically targets this intricate process. One clear indicator of delayed wound repair is the inhibition of reepithelialization. Yes-associated protein (YAP), which is a potential focal point for tissue repair and regeneration, has been shown to be prominent in several studies. In this context, the authors have identified the pharmacologic product TT-10, which is a YAP activator, as a potential candidate for the treatment of various forms of chronic wounds., Methods: The role of TT-10 in regulating YAP activity and subcellular localization was determined by Western blotting and immunofluorescence staining. The effect of TT-10 on the biological functions of keratinocytes was assessed by proliferation, wound healing, and apoptosis assays. The impairment of YAP activity in chronic wounds was measured in human and mouse tissues. The in vivo efficacy of TT-10 was examined by gross examination; hematoxylin and eosin staining; and measuring wound areas and gaps in normal, diabetic, and ischemic wounds., Results: The authors' findings suggest that TT-10 facilitates the nuclear transport of YAP, consequently increasing YAP activity, which in turn increases the proliferation and migration of keratinocytes. Moreover, the authors showed that intracutaneous injection of TT-10 along the wound periphery promoted reepithelialization by means of YAP activation in the epidermis, culminating in accelerated wound closure in several chronic wound healing models., Conclusion: The authors' research highlights the potential of TT-10 to treat chronic wounds, which is a persistent challenge in tissue repair., Clinical Relevance Statement: The authors' research identifies TT-10, a small molecule YAP activator, as a novel therapeutic candidate that enhances keratinocyte function and promotes reepithelialization, offering plastic surgeons an innovative approach to addressing chronic wound challenges., (Copyright © 2024 by the American Society of Plastic Surgeons.)

The enhancement of complex physiological functions such as cognition and exercise performance in healthy individuals represents a challenging goal. Adaptive transcription programs that are naturally activated in animals to mediate cellular plasticity in response to stimulation can be leveraged to enhance physiological function above wild-type levels in young organisms and counteract complex functional decline in aging. In processes such as learning and memory and exercise-dependent muscle remodeling, a relatively small number of molecules such as certain stimulus-responsive transcription factors and immediate early genes coordinate widespread changes in cellular physiology. Adaptive transcription can be targeted by various methods including pharmaceutical compounds and gene transfer technologies. Important problems for leveraging adaptive transcription programs for physiological enhancement include a better understanding of their dynamical organization, more precise methods to influence the underlying molecular components, and the integration of adaptive transcription into multi-scale physiological enhancement concepts., Competing Interests: Declarations. Competing interests: The author declares no competing interests., (© 2024. The Author(s).)

Introduction: Abnormal alternative splicing (AS) contributes to aggressive intrahepatic invasion and metastatic spread, leading to the high lethality of hepatocellular carcinoma (HCC)., Objectives: This study aims to investigate the functional implications of UPF3B-S (a truncated oncogenic splice variant) in HCC metastasis., Methods: Basescope assay was performed to analyze the expression of UPF3B-S mRNA in tissues and cells. RNA immunoprecipitation, and in vitro and in vivo models were used to explore the role of UPF3B-S and the underlying mechanisms., Results: We show that splicing factor HnRNPR binds to the pre-mRNA of UPF3B via its RRM2 domain to generate an exon 8 exclusion truncated splice variant UPF3B-S. High expression of UPF3B-S is correlated with tumor metastasis and unfavorable overall survival in patients with HCC. The knockdown of UPF3B-S markedly suppresses the invasive and migratory capacities of HCC cells in vitro and in vivo. Mechanistically, UPF3B-S protein targets the 3'-UTR of CDH1 mRNA to enhance the degradation of CDH1 mRNA, which results in the downregulation of E-cadherin and the activation of epithelial-mesenchymal transition. Overexpression of UPF3B-S enhances the dephosphorylation of LATS1 and the nuclear accumulation of YAP1 to trigger the Hippo signaling pathway., Conclusion: Our findings suggest that HnRNPR-induced UPF3B-S promotes HCC invasion and metastasis by exhausting CDH1 mRNA and modulating YAP1-Hippo signaling. UPF3B-S could potentially serve as a promising biomarker for the clinical management of invasive HCC., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: Glioblastoma multiforme (GBM) poses significant challenges in treatment due to its aggressive nature and immune escape mechanisms. Despite recent advances in immune checkpoint blockade therapies, GBM prognosis remains poor. The role of bromodomain and extraterminal domain (BET) protein BRD4 in GBM, especially its interaction with immune checkpoints, is not well understood. Our study aimed to explore the role of BRD4 in GBM, especially the immune aspects., Methods: In this study, we performed bioinformatics gene expression and survival analysis of BRD4 using TCGA and CGGA databases. In addition, we investigated the effects of BRD4 on glioma cell proliferation, invasion and migration by clone formation assay, Transwell assay, CCK8 assay and wound healing assay. Chromatin immunoprecipitation (ChIP) assay was conducted to confirm BRD4 binding to the programmed death ligand 1 (PD-L1) promoter. GL261 cells with BRD4 shRNA and/or PD-L1 cDNA were intracranially injected into mice to investigate tumor growth and survival time. Tumor tissue characteristics were analyzed using H&E and IHC staining and immune cell infiltration were assessed by flow cytometry., Results: The results showed that elevated expression of BRD4 in high-grade gliomas was associated with poor patient survival. In addition, we validated the promotional effects of BRD4 on glioma cell proliferation, invasion and migration. The results of ChIP experiments showed that BRD4 is a regulator of PD-L1 at the transcriptional level, implying that it is involved in the immune escape mechanism of glioma cells. In vivo studies showed that BRD4 knockdown inhibited tumor growth and reduced immunosuppression, improving prognosis., Conclusion: BRD4 has the capability to regulate the growth of glioblastoma and enhance immune suppression by promoting PD-L1 expression. Targeting BRD4 represents a promising direction for future research and treatment., Competing Interests: Declarations. Ethics approval and consent to participate: Approval of the research protocol by an institutional review board: The research protocol was approved by the Institutional Review Board of the First Affiliated Hospital of Soochow University. Animal Studies: All animal procedures and experimental methods were approved by the Medical Ethics Committee of the First Affiliated Hospital of Soochow University. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: A number of immunohistochemical stains have been examined for utility in establishing the site of origin for metastatic well-differentiated neuroendocrine tumors (NETs). In the gastrointestinal (GI) tract, distinguishing metastatic duodenal NETs from jejunoileal and other GI NETs is important for clinical work-up, prognosis, and therapy. A recent study indicated that prohormone convertase 2 (PCSK2 or PC2) had broad expression in small intestine and appendiceal NETs. Because the study did not include duodenal NETs, we examined PCSK2 expression in duodenal and other GI NETs., Methods: GI NETs (n = 69) and 13 corresponding lymph node metastases from stomach, duodenum, pancreas, ileum, appendix, and rectum were evaluated for the expression of PCSK2, along with ISL1, NKX2.2, CDX2, SATB2, and PAX8. Expression of each stain was evaluated using the H-score system, and differences in expression by site were evaluated by the chi square test., Results: PCSK2 was expressed at similar frequency in duodenal (50%), pancreatic (59%), and ileal NETs (40%). PCSK2 was infrequently expressed in stomach (0%), appendiceal (8%), and rectal (25%) NETs. However, incorporating PCSK2 into a panel including ISL1, NKX2.2, CDX2, and SATB2 allowed development of an algorithm which had 87% sensitivity and 93% specificity for classification of ileal NETs; and 68% sensitivity and 98% specificity for pancreaticoduodenal NETs., Conclusions: In contrast to previous findings, PCSK2 does not show specificity for any particular GI site. An algorithmic approach incorporating the expression of PCSK2 with that of ISL1, NKX2.2, CDX2, and SATB2 is useful in discriminating pancreatic, duodenal, ileal, appendiceal, and rectal NETs., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Gastric cancer (GC) is one of the leading causes of cancer-related deaths in humans worldwide. Fibroblast growth factor family (FGFs) and the Hippo signaling pathway play an important role in the epithelial-mesenchymal transition (EMT) process of GC. YAP1, a key mediator of the Hippo pathway, plays an important role in tumor genesis. Alternative splicing of human YAP1 mRNA results in two major isoforms: YAP1-1, which contains a single WW domain, and YAP1-2, which contains two WW domains, respectively. There are significant differences in post-transcriptional regulation and function. Basic FGF (bFGF) treatment promoted the EMT process of most GC cell lines, and the proliferation ability was enhanced. This process may be related to the upregulation of YAP1, the proliferation ability of GC was significantly alleviated upon YAP1 knockdown. bFGF treatment can induce EMT of GC through YAP1-2 and enhance their proliferative ability. In this process, bFGF may enhance the nuclear localization of YAP1-2.In the mouse model of intraperitoneal implantation tumorigenesis, it was shown that under the action of bFGF, the expressing YAP1-2 cell lines could form larger tumors than the expressing YAP1-1, but both of them were larger than the YAP1 knockdown. Our results show that YAP1-2 is the main subtype of bFGF-induced EMT and proliferation of GC cells., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Strigolactones (SLs) are plant hormones that play a crucial role in regulating various aspects of plant architecture, such as shoot and root branching. However, the knowledge of SL-responsive genes and transcription factors (TFs) that control the shaping of plant architecture remains elusive. Here, transcriptomic analysis was conducted using the SL-insensitive barley mutant hvd14.d (carried mutation in SL receptor DWARF14, HvD14) and its wild-type (WT) to unravel the differences in gene expression separately in root and shoot tissues. This approach enabled us to select more than six thousand SL-dependent genes that were exclusive to each studied organ or not tissue-specific. The data obtained, along with in silico analyses, found several TFs that exhibited changed expression between the analyzed genotypes and that recognized binding sites in promoters of other identified differentially expressed genes (DEGs). In total, 28 TFs that recognize motifs over-represented in DEG promoters were identified. Moreover, nearly half of the identified TFs were connected in a single network of known and predicted interactions, highlighting the complexity and multidimensionality of SL-related signalling in barley. Finally, the SL control on the expression of one of the identified TFs in HvD14- and dose-dependent manners was proved. Obtained results bring us closer to understanding the signalling pathways regulating SL-dependent plant development., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Cuticular hydrocarbons (CHCs) play pleiotropic roles in insect survival and reproduction. They prevent desiccation and function as pheromones influencing different behaviors. While the genes in the CHC biosynthesis pathway have been extensively studied, the regulatory mechanisms that lead to different CHC compositions received far less attention. In this review, we present an overview of how different hormones and transcriptional factors regulate CHC synthesis genes, leading to different CHC compositions. Future research focusing on the regulatory mechanisms underlying CHC biosynthesis can lead to a better understanding of how insects could produce dynamic chemical profiles in response to different stimuli., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The family of SQUAMOSA promoter binding protein-like (SPL) transcription factors is essential for regulating plant growth and development. While this SPL gene functional research has been limited in Rhododendron molle (R. molle)., Objective: To preliminarily explore the regulatory mechanism of the SPL gene in flower bud development of R. molle., Methods: In this study, for R. molle, the flower bud differentiation period was determined by observing the morphological anatomy of the flower bud. The SPL gene family members were identified based on the R. molle genome, Additionally, the expressions of RmSPL genes at five flower bud differentiation stages were analyzed via Quantitative reverse transcription PCR (RT-qPCR)., Results: We first characterized 20 SPL family members in the reference genome of R. molle. The phylogenetic analysis of plant SPL proteins separated them into eight subfamilies (G1-G8) according to conserved gene structures and protein motifs. Cis-elements of promoter region analysis showed that RmSPL genes were regulated by light, phytohormones, stress response, and plant growth and development and may play a critical role in the photoresponse, abasic acid, anaerobic induction, and meristematic expression. Gene expression analysis showed that 18 RmSPL genes were differentially expressed in different developing flower buds. In particular, RmSPL1/7/8/12/13 exhibited significantly different expressions, suggesting that they were likely essential genes for regulating the differentiation of flower buds., Conclusion: In conclusion, our analysis of RmSPL genes provides a theoretical basis and reference for future functional analysis of RmSPL genes in the flower bud differentiation of R. molle., Competing Interests: Declarations. Conflict of interest: The authors have no competing interests. Ethical approval: Not applicable. Informed consent: Not applicable., (© 2024. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Introduction and Aims: Mitochondrial myopathies are rare genetic disorders for which no effective treatment exists. We previously showed that the pharmacological cyclophilin inhibitor cyclosporine A (CsA) extends the lifespan of fast-twitch skeletal muscle-specific mitochondrial transcription factor A knockout (Tfam KO) mice, lacking the ability to transcribe mitochondrial DNA and displaying lethal mitochondrial myopathy. Our present aim was to assess whether the positive effect of CsA was associated with improved in vivo mitochondrial energy production., Methods: Mice were treated with CsA for 4 weeks, beginning at 12 weeks (i.e., before the terminal disease phase). Hindlimb plantar flexor muscles were fatigued by 80 contractions (40 Hz, 1.5 s on, 6 s off) while measuring force and energy metabolism using phosphorus-31 magnetic resonance spectroscopy., Results: Force decreased at similar rates in Tfam KO mice with and without the CsA treatment, reaching 50% of the baseline value after ~14 ± 1 contractions, which was faster than in control mice (25 ± 1 contractions). Phosphocreatine (PCr) decreased to ~10% of the control concentration in Tfam KO mice, independent of the treatment, which was larger than the ~20% observed in control mice. The time constant of PCr recovery was higher in untreated Tfam KO than that in control muscle (+100%) and similar in untreated and CsA-treated Tfam KO mice., Discussion: The results do not support improved mitochondrial energy production as a mechanism underlying the prolonged lifespan of Tfam KO mitochondrial myopathy mice treated with CsA. Thus, other mechanisms must be involved, such as the previously observed CsA-mediated protection against excessive mitochondrial Ca 2+ accumulation., (© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Recent studies suggest that trichorhinophalangeal syndrome type 1 (TRPS1) is sensitive immunomarker for breast carcinoma (BC). Salivary duct carcinoma (SDC) of salivary gland can share similar morphologic and immunophenotypic features with BC. This study aimed to assess the expression of TRPS1 in SDC and other salivary gland tumors (SGTs). Cytology cases and selected surgical specimens of SGTs were retrieved. Forty-three cases were selected and TRPS1 immunohistochemistry (IHC) was performed on cell blocks and some histologic specimens. Of those 43 cases, all 13 SDC cases showed TRPS1 expression except for one case. The remaining 30 cases include pleomorphic adenoma (n = 7), Warthin tumor (n = 4), basal cell adenoma (n = 3), adenoid cystic carcinoma (n = 2), secretory carcinoma (n = 5), mucoepidermoid carcinoma (n = 4), and acinic cell carcinoma (n = 5). Three of thirty cases were negative for TRPS1 while the remainder showed variable expression of TRPS1 ranging from focal weak to diffuse strong staining. The three negative cases include a case of secretory carcinoma, mucoepidermoid carcinoma and Warthin tumor. Our study confirmed that TRPS1 expression is present in SDC and other SGTs, indicating an overlapping immunoprofile with breast cancer. Additionally, it may not help differentiate SDC or SGTs from each other. Further studies with larger cohorts are needed., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Production of xylitol from agricultural by-products offers a promising approach for the circular bioeconomy. This study investigates the roles of transcription factors XlnR and CreA in xylitol production from wheat bran in Aspergillus niger by generating strains with a constitutively active XlnR (XlnR c , V756F mutation) and/or deletion of creA, in a previously generated xylitol-producing strain. The XlnR c mutation increased the initial rate of xylitol production but lowered the overall accumulation. Deletion of creA in this strain significantly improved both the onset and rate of xylitol production, indicating an inhibitory role of CreA in the PCP. These results demonstrate the complexity of metabolic engineering to generate fungal cell factories for valuable biochemicals, such as xylitol, as not only metabolic but also multiple gene regulation aspects need to be considered., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Bromodomain and extraterminal domain (BET) proteins, including BRD4, bind acetylated chromatin and coactivate gene transcription. A BET inhibitor, JQ1, prevents and reverses pathological cardiac remodeling in preclinical models of heart failure. However, the underlying cellular mechanisms by which JQ1 improves cardiac structure and function remain poorly defined. Here, we demonstrate that BRD4 knockdown reduced expression of genes encoding CC chemokines in cardiac fibroblasts, suggesting a role for this epigenetic reader in controlling fibroblast-immune cell cross talk. Consistent with this, JQ1 dramatically suppressed recruitment of monocytes to the heart in response to stress. Normal mouse hearts were found to have approximately equivalent numbers of major histocompatibility complex (MHC-II) high and MHC-II low resident macrophages, whereas MHC-II low macrophages predominated following JQ1 treatment. Single-cell RNA-seq data confirmed that JQ1 treatment or BRD4 knockout in CX3CR1 + cells reduced MHC-II gene expression in cardiac macrophages, and studies with cultured macrophages further illustrated a cell autonomous role for BET proteins in controlling the MHC-II axis. Bulk RNA-seq analysis demonstrated that JQ1 blocked pro-inflammatory macrophage gene expression through a mechanism that likely involves repression of NF-κB signaling. JQ1 treatment reduced cardiac infarct size in mice subjected to ischemia/reperfusion. Our findings illustrate that BET inhibition affords a powerful pharmacological approach to manipulate monocyte-derived and resident macrophages in the heart. Such an approach has the potential to enhance the reparative phenotype of macrophages to promote wound healing and limit infarct expansion following myocardial ischemia. NEW & NOTEWORTHY BRD4 inhibition blocks stress-induced recruitment of pro-inflammatory monocytes to the heart. BRD4 inhibition reprograms resident cardiac macrophages toward a reparative phenotype marked by reduced NF-κB signaling and diminished MHC-II expression. BRD4 inhibition reduces infarct size in an acute model of ischemia/reperfusion injury in mice.

Grape (Vitis vinifera) production globally faces significant challenges from grape ripe rot (Colletotrichum viniferum). MYB transcription factors (TFs) play a crucial role in mediating plant responses to biotic stresses. However, their involvement in grapevine responses to ripe rot remains unclarified. This study employed bioinformatics to identify MYB TF genes within the grapevine genome and assessed their expression profiles post C. viniferum infection via transcriptome analysis. Among the 121 R2R3-MYB genes identified, VdMYB31, predominantly expressed in mature fruits, was notably downregulated in responding to C. viniferum infection. Heterologous expression of VdMYB31 in tomato (Solanum lycopersicum) fruits increased susceptibility to C. acutatum by suppressing salicylic acid (SA)-related gene expression. Silencing MYB31 in grape berries conferred resistance to C. viniferum. Additionally, exogenous SA application bolstered grape resistance to C. viniferum infection. These findings underscore the involvement of R2R3-MYB TFs in defending against C. viniferum, positioning VdMYB31 as a promising target for breeding grape varieties with improved resistance to ripe rot in viticulture., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Distant metastasis is a primary factor contributing to the low survival rate of patients with nasopharyngeal carcinoma (NPC). Circular RNAs (circRNAs) are increasingly recognized for their roles in cancer initiation and progression. However, the mechanisms underlying the abnormal expression and biological function of circRNA in NPC remain unclear. In this study, we identified a new circRNA, circINADL, which was upregulated in NPC tissues and positively correlated with the clinical stage of NPC. We found that the FUS RNA binding protein (FUS) promoted the transcription of circINADL in NPC cells. Elevated circINADL levels were shown to enhance NPC cells metastasis. Mechanistically, circINADL attenuated the interaction between human antigen R (HuR) and the E3 ubiquitin ligase β-TrCP, thereby inhibited the ubiquitination and degradation of HuR. Consequently, CircINADL enhanced the stability of the HuR target gene Yes1-associated transcriptional regulator (YAP1), leading to the dysregulation of the Hippo signaling pathway. In conclusion, our study reveals the function of circINADL in promoting NPC metastasis and highlights its potential as a biomarker and therapeutic target for NPC treatment., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Arthrobotrys oligospora has been utilized as a model strain to study the interaction between fungi and nematodes owing to its ability to capture nematodes by developing specialized traps. A previous study showed that high-osmolarity glycerol (Hog1) signaling regulates the osmoregulation and nematocidal activity of A. oligospora. However, the function of downstream transcription factors of the Hog1 signaling in the nematode-trapping (NT) fungi remains unclear., Objective: This study aimed to investigate the functions and potential regulatory network of AoMsn2, a downstream transcription factor of the Hog1 signaling pathway in A. oligospora., Methods: The function of AoMsn2 was characterized using targeted gene deletion, phenotypic experiments, real-time quantitative PCR, RNA sequencing, untargeted metabolomics, and yeast two-hybrid analysis., Results: Loss of Aomsn2 significantly enlarged and swollen the hyphae, with an increase in septa and a significant decrease in nuclei. In particular, spore yield, spore germination rate, traps, and nematode predation efficiency were remarkably decreased in the mutants. Phenotypic and transcriptomic analyses revealed that AoMsn2 is essential for fatty acid metabolism and autophagic pathways. Additionally, untargeted metabolomic analysis identified an important function of AoMsn2 in the modulation of secondary metabolites. Furtherly, we analyzed the protein interaction network of AoMsn2 based on the Kyoto Encyclopedia of Genes and Genomes pathway map and the online website STRING. Finally, Hog1 and six putative targeted proteins of AoMsn2 were identified by Y2H analysis., Conclusion: Our study reveals that AoMsn2 plays crucial roles in the growth, conidiation, trap development, fatty acid metabolism, and secondary metabolism, as well as establishes a broad basis for understanding the regulatory mechanisms of trap morphogenesis and environmental adaptation in NT fungi., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)