Components Of Pathway Research Articles

Transcription factor BbCDR1 regulates the orchestration between conidial formation and maturation in the entomopathogenic fungus Beauveria bassiana.

The entomopathogenic fungus Beauveria bassiana has been widely used for pest biocontrol with conidia serving as the main active agents. Conidial yield and quality are two important characteristics in fungal conidia development, however, the regulatory mechanisms that orchestrate conidial formation and development are not well understood. In this study, we identified a Zn2Cys6 transcription factor BbCDR1 that inhibits conidial production while promoting conidial maturation. Compared with the wild type, the ΔBbCDR1 mutant exhibited a 1.88-fold increase in conidial yield but a reduction in conidial quality, including decreased cell wall integrity and trehalose synthesis. The deletion of BbCDR1 also led to reduced conidial germination rates under oxidative, osmotic, conidial wall disruption and UV stresses. Interestingly, ΔBbCDR1 exhibited an increase of fungal virulence with a 12.5% decrease in LT50 compared to the wild type. Further analysis revealed that BbCDR1 represses the expression of BbbrlA and activates BbwetA, two components of the central developmental pathway (CDP) that regulate conidial initiation and maturation, respectively. These findings suggest that BbCDR1 plays a crucial role in conidial development and a new target gene for the genetic engineering of highly active fungal insecticides. © 2025 Society of Chemical Industry.

Suppression of chemically induced mammary cancer by early-life oral administration of cholera toxin in mice is associated with aberrant regulation of Bmp and Notch signaling pathways.

Lately, significant attention has been drawn towards the potential efficacy of cholera toxin (CT)-an exotoxin produced by the small intestine pathogenic bacterium Vibrio cholera-in modulating cancer-promoting events. In a recent study, we demonstrated that early-life oral administration of non-pathogenic doses of CT in mice suppressed chemically-induced carcinogenesis in tissues distantly located from the gut. In the mammary gland, CT pretreatment was shown to reduce tumor multiplicity, increase apoptosis and alter the expression of several cancer-related molecules. In the present work we investigated the protumorigenic mammary microenvironment for possible associations between early life CT administration and the expression of key components of the Bmp and Notch signaling pathways. Total RNA from mammary tissue samples were retrieved from a recent experiment where FVB/N female mice were preconditioned with CT and later treated with the carcinogen 7,12-dimethylbenzanthracene (DMBA). Real-time PCR was used for relative quantification of gene expression. Our results revealed that CT anti-tumor effects significantly correlated with deregulation of crucial BMP pathway elements, with downregulation of Bmp7 ligand and upregulation of inhibitory Smad6 being the most prominent alterations observed. Concerning Notch signaling pathway, significantly elevated gene expression levels in the CT-treated DMBA mice, as compared to their non-treated counterparts, were also identified at the ligand-receptor level. These findings suggest that CT tumor protective effects in the mammary gland are associated with discerning deregulation of components of both Bmp and Notch signaling pathways and provide insights into the mechanisms underlying CT's anti-cancer outcome.

Plasmodium falciparum raf kinase inhibitor is a lipid binding protein that interacts with and regulates the activity of PfCDPK1, an essential plant-like kinase required for red blood cell invasion.

Raf Kinase Inhibitor Protein (RKIP) is an important regulator of the MAPK signaling pathway in multicellular eukaryotes. Plasmodium falciparum RKIP (PfRKIP) is a putative phosphatidylethanolamine binding protein (PEBP) that shares limited similarity with Homo sapiens RKIP (HsRKIP). Interestingly, critical components of the MAPK pathway are not expressed in malaria parasites and the physiological function of PfRKIP remains unknown. PfRKIP is expressed throughout the asexual schizogony with maximum expression in late schizonts. Interestingly, PfRKIP and HsRKIP show pH-dependent differential interaction profiles with various lipids. At physiological pH, PfRKIP shows interaction with phosphatidic acid and lipids containing phosphorylated phosphatidylinositol group; however, HsRKIP shows no interaction under the same conditions. Mutation of conserved residues in the PEBP domain of PfRKIP decreases its interaction with PtdIns(3)P. Additionally, in silico docking and mutagenesis studies identified a unique IKK motif within the PEBP domain of PfRKIP that is important for its interaction with the lipids. Using ELISA, we demonstrate the interaction of PfRKIP with PfCDPK1. Importantly, we establish the interaction of PfRKIP and PfCDPK1 within the parasites using immunofluorescence assay and proximity biotinylation technique. Furthermore, our results suggest that PfRKIP regulates the kinase activity of PfCDPK1. In the presence of its substrate, PfCDPK1 hyper-phosphorylates PfRKIP which leads to its dissociation from PfCDPK1. Dissociation of PfRKIP allows PfCDPK1 to trans-phosphorylate its substrates. The molecular mechanism of interaction between PfRKIP and PfCDPK1 may be explored further to identify novel anti-malarial compounds.

In vitro effects of recombinant human Neuritin on hair cell recovery post-gentamicin injury in SC lineage-tracing models: Involvement of notch and FGFR signaling.

Hair cell (HC) loss, frequently induced by ototoxic agents such as gentamicin, leads to irreversible hearing loss. Because of the restricted regenerative capabilities of the mammalian inner ear, the exploration of therapeutic strategies to restore damaged HCs is critically needed. Recombinant human Neuritin (rhNeuritin), a neurotrophic factor with established roles in promoting cell survival and regeneration across various systems, presents itself as a promising therapeutic candidate for HC repair. In this study, we elucidate the protective effects of rhNeuritin on injured HCs and its capacity to facilitate HC regeneration post-damage. Through the use of cochlear Supporting Cell (SC) lineage-tracing models in neonatal mice, we demonstrate that SC trans-differentiation serves as the origin of HC regeneration following damage. Simultaneously, we uncover that rhNeuritin potentiates the proliferation of SC precursor cells. Mechanistic insights reveal that rhNeuritin-induced cochleae exhibit downregulation of the critical Notch pathway mediator, Hes1, and upregulation of the essential FGFR pathway component Erm, which together may underpin HC regeneration and the proliferation of SC precursors. Notably, rhNeuritin demonstrates significant preservation of HC structural integrity. These findings collectively highlight the therapeutic potential of rhNeuritin in addressing hearing loss resulting from HC damage, thereby opening a new avenue for the restoration of auditory function.

Screening a library of temperature-sensitive mutants to identify secretion factors in Staphylococcus aureus.

Protein secretion is an essential cell process in bacteria, required for cell envelope biogenesis, export of virulence factors, and acquisition of nutrients, among other important functions. In the Sec secretion pathway, signal peptide-bearing precursors are recognized by the SecA ATPase and pushed across the membrane through a translocon channel made of the proteins SecY, SecE, and SecG. The Sec pathway has been extensively studied in the model organism Escherichia coli, but the Sec pathways of other bacteria such as the human pathogen Staphylococcus aureus differ in important ways from this model. Unlike in E. coli, a subset of precursors in S. aureus contains a YSIRK/GXXS (YSIRK) motif in an extended signal peptide. These proteins are secreted into the cross-wall compartment bounded by invaginating septal membranes during cell division. To gain insights into the factor(s) and mechanism(s) enabling protein secretion and spatial specificity in S. aureus, we isolated and screened a collection of temperature-sensitive (ts) mutants. These efforts identified at least one secA(ts) allele as well as mutations in the secG and pepV genes. A SecA pull-down experiment identified SecDF, all ribosomal proteins, several chaperones and proteases, as well as PepV, validating the genetic screen in identifying candidate cofactors of SecA in S. aureus.IMPORTANCEAll organisms use the Sec pathway for protein secretion, and key components of this pathway are essential for viability. The discovery of conditional loss-of-function mutants played an important role in defining the genetic basis of protein secretion in model organisms. In turn, the identification of Sec components facilitated mechanistic studies and revealed general rules for protein secretion but did not answer species-specific intricacies. Gram-positive bacteria, such as Staphylococcus aureus, restrict the secretion of some proteins into the septal membranes that bind their division site at mid-cell. Here, we screen a library of conditional temperature-sensitive mutants to define components of the Sec pathway of S. aureus and factors that may regulate its activity.

Nrf2 Regulates Basal Glutathione Production in Astrocytes.

Astrocytes produce and export glutathione (GSH), an important thiol antioxidant essential for protecting neural cells from oxidative stress and maintaining optimal brain health. While it has been established that oxidative stress increases GSH production in astrocytes, with Nrf2 acting as a critical transcription factor regulating key components of the GSH synthetic pathway, the role of Nrf2 in controlling constitutive GSH synthetic and release mechanisms remains incompletely investigated. Our data show that naïve primary mouse astrocytes cultured from the cerebral cortices of Nrf2 knockout (Nrf2-/-) pups have significantly less intracellular and extracellular GSH levels when compared to astrocytes cultured from Nrf2 wild-type (Nrf2+/+) pups. Key components of the GSH synthetic pathway, including xCT (the substrate-specific light chain of the substrate-importing transporter, system xc-), glutamate-cysteine ligase [catalytic (GCLc) and modifying (GCLm) subunits], were affected. To wit: qRT-PCR analysis demonstrates that naïve Nrf2-/- astrocytes have significantly lower basal mRNA levels of xCT and both GCL subunits compared to naïve Nrf2+/+ astrocytes. No change in mRNA levels of glutathione synthetase (GS) or the GSH exporting transporter, Mrp1, was found. Western blot analysis reveals reduced protein levels of both subunits of GCL, while (seleno)cystine uptake into Nrf2-/- astrocytes was reduced compared to Nrf2+/+ astrocytes, confirming decreased system xc- activity. These findings suggest that Nrf2 regulates the basal production of GSH in astrocytes through constitutive transcriptional regulation of GCL and xCT.

Multi-tissue characterization of the constitutive heterochromatin proteome in Drosophila identifies a link between satellite DNA organization and transposon repression.

Noncoding satellite DNA repeats are abundant at the pericentromeric heterochromatin of eukaryotic chromosomes. During interphase, sequence-specific DNA-binding proteins cluster these repeats from multiple chromosomes into nuclear foci known as chromocenters. Despite the pivotal role of chromocenters in cellular processes like genome encapsulation and gene repression, the associated proteins remain incompletely characterized. Here, we use 2 satellite DNA-binding proteins, D1 and Prod, as baits to characterize the chromocenter-associated proteome in Drosophila embryos, ovaries, and testes through quantitative mass spectrometry. We identify D1- and Prod-associated proteins, including known heterochromatin proteins as well as proteins previously unlinked to satellite DNA or chromocenters, thereby laying the foundation for a comprehensive understanding of cellular functions enabled by satellite DNA repeats and their associated proteins. Interestingly, we find that multiple components of the transposon-silencing piRNA pathway are associated with D1 and Prod in embryos. Using genetics, transcriptomics, and small RNA profiling, we show that flies lacking D1 during embryogenesis exhibit transposon expression and gonadal atrophy as adults. We further demonstrate that this gonadal atrophy can be rescued by mutating the checkpoint kinase, Chk2, which mediates germ cell arrest in response to transposon mobilization. Thus, we reveal that a satellite DNA-binding protein functions during embryogenesis to silence transposons, in a manner that is heritable across later stages of development.

VEGFA, MYC, and JUN are abnormally elevated in the synovial tissue of patients with advanced osteoarthritis

Osteoarthritis (OA), affecting > 500 million people worldwide, profoundly affects the quality of life and ability to work. The mitogen-activated protein kinase (MAPK) signaling pathway plays an essential role in OA. To address the lack of studies focused on synovial cells in OA, we evaluated the expression patterns and roles of the MAPK signaling pathway components in OA synovial tissues using bioinformatics. The JUN, MYC, and VEGFA expression levels were significantly higher in the synovial tissues of patients with OA than in control tissues. These loci were closely related to abnormal proliferation, inflammation, and angiogenesis in the synovial tissues of patients with OA. We speculate that Myc and VEGFA activate the p38-MAPK signaling pathway to further activate Jun, thereby promoting abnormal inflammation, proliferation, and angiogenesis in OA synovial tissue. The high MYC, JUN, and VEGFA expression was positively correlated with the patients’ K-L score, pain time, and synovial score. Furthermore, the high p38-MAPK and P-p38-MAPK expression confirmed that the abnormal expression and activation of the MAPK signaling pathway occurred in the synovial tissue of patients with OA. Our findings may provide a new direction for the clinical diagnosis and treatment of OA and insights into its pathogenesis.

Novel Immune Response Evasion Strategy to Redose Adeno-associated Viral Vectors and Prolong Survival in Surfactant Protein-B Deficient Mice.

Surfactant protein-B (SP-B) deficiency is a lethal neonatal respiratory disease with few therapeutic options. Gene therapy using adeno-associated viruses (AAV) to deliver human SFTPB cDNA (AAV-hSPB) can improve survival in a mouse model of SP-B deficiency. However, the effect of this gene therapy wanes. Gene therapy efficacy could be prolonged if AAV vectors were able to be redosed, but readministering vectors is hindered by an immune response which includes toll like receptor 9 (TLR9) recognition of unmethylated CpG DNA motifs in the AAV genome. One strategy to mitigate TLR9 recognition of AAV is to incorporate decoy nucleotide sequences within the AAV genome. This work examined if AAV containing these TLR9 inhibitory oligonucleotide sequences (AAV-hSPBTLR9i) could mitigate the immune response sufficiently to redose AAV in the lungs and prolong the survival of SP-B deficient mice. Indeed, AAV-hSPBTLR9i was able to be redosed multiple times which significantly improved survival in our mouse model. This was partially a result of long-term increased SFTPB RNA and SP-B protein expression. Conversely, redosing AAV-hSPB resulted in the rapid death of SP-B deficient mice after the second AAV dose. TLR9 inhibition enabled readministration by avoiding the broad stimulation of genes belonging to multiple pathways in the host immune and inflammatory responses, including components of the interferon pathways. Thus, redosing of AAV vectors in the lungs using TLR9 inhibitory sequences is a promising strategy for prolonging gene therapy efficacy, with a proof-of-concept for AAV readministration in a clinically relevant mouse model of SP-B deficiency.

Selective Degradation of TEADs by a PROTAC Molecule Exhibited Robust Anticancer Efficacy In Vitro and In Vivo.

Genetic mutations in components of the Hippo pathway frequently lead to the aberrant activation of TEADs, which is often associated with cancer. Consequently, TEADs have been actively pursued as therapeutic targets for diseases driven by TEAD overactivation. In this study, we report two series of TEAD PROTACs based on CRBN binders and VHL binders. Both series yielded potent TEAD degraders, including 19 and 40 (H122), which induced TEAD1 degradation with DC50 < 10 nM. Mechanistic studies demonstrated that the degradation of TEAD1 induced by 40 relied on CRBN binding, TEAD1 binding, E3 ligase activity, and a functional proteasome. RNA-seq analyses indicated that 40 significantly downregulated the expression of Myc target genes, as highlighted by GSEA analysis. More importantly, 40 exhibited robust antitumor efficacy in the MSTO-211H mouse xenograft model. Collectively, our results suggest that TEAD PROTACs have therapeutic potential for the treatment of cancers associated with TEAD overactivation.

Nuclear Argonaute protein NRDE-3 switches small RNA partners during embryogenesis to mediate temporal-specific gene regulatory activity.

RNA interference (RNAi) is a conserved gene regulation mechanism that utilizes the Argonaute protein and their associated small RNAs to exert regulatory function on complementary transcripts. While the majority of germline-expressed RNAi pathway components reside in perinuclear germ granules, it is unknown whether and how RNAi pathways are spatially organized in other cell types. Here we find that the small RNA biogenesis machinery is spatially and temporally organized during embryogenesis. Specifically, the RNAi factor, SIMR-1, forms visible concentrates during mid-embryogenesis that contain an RNA-dependent RNA polymerase, a poly-UG polymerase, and the unloaded nuclear Argonaute protein, NRDE-3. We also observe that many other RNAi factors form foci in embryonic cells distinct from "SIMR granules", including the Argonaute protein CSR-1, underscoring a potential role for cytoplasmic concentrates of RNAi factors to promote gene regulation in embryos. Curiously, coincident with the appearance of the SIMR granules, the small RNAs bound to NRDE-3 switch from predominantly CSR-class 22G-RNAs to ERGO-dependent 22G-RNAs. Prior work has shown that NRDE-3 binds ERGO-dependent 22G-RNAs in the somatic cells of larvae and adults to silence ERGO-target genes; here we demonstrate that NRDE-3-bound, CSR-class 22G-RNAs repress transcription in oocytes. Thus, our study defines two separable roles for NRDE-3, targeting germline-expressed genes during oogenesis to promote global transcriptional repression, and switching during embryogenesis to repress recently duplicated genes and retrotransposons in somatic cells, highlighting the plasticity of Argonaute proteins and the need for more precise temporal characterization of Argonaute-small RNA interactions.

Mechanisms of regulated cell death during plant infection by the rice blast fungus Magnaporthe oryzae.

Fungi are the most important group of plant pathogens, responsible for many of the world's most devastating crop diseases. One of the reasons they are such successful pathogens is because several fungi have evolved the capacity to breach the tough outer cuticle of plants using specialized infection structures called appressoria. This is exemplified by the filamentous ascomycete fungus Magnaporthe oryzae, causal agent of rice blast, one of the most serious diseases affecting rice cultivation globally. M. oryzae develops a pressurized dome-shaped appressorium that uses mechanical force to rupture the rice leaf cuticle. Appressoria form in response to the hydrophobic leaf surface, which requires the Pmk1 MAP kinase signalling pathway, coupled to a series of cell-cycle checkpoints that are necessary for regulated cell death of the fungal conidium and development of a functionally competent appressorium. Conidial cell death requires autophagy, which occurs within each cell of the spore, and is regulated by components of the cargo-independent autophagy pathway. This results in trafficking of the contents of all three cells to the incipient appressorium, which develops enormous turgor of up to 8.0 MPa, due to glycerol accumulation, and differentiates a thickened, melanin-lined cell wall. The appressorium then re-polarizes, re-orienting the actin and microtubule cytoskeleton to enable development of a penetration peg in a perpendicular orientation, that ruptures the leaf surface using mechanical force. Re-polarization requires septin GTPases which form a ring structure at the base of the appressorium, which delineates the point of plant infection, and acts as a scaffold for actin re-localization, enhances cortical rigidity, and forms a lateral diffusion barrier to focus polarity determinants that regulate penetration peg formation. Here we review the mechanism of regulated cell death in M. oryzae, which requires autophagy but may also involve ferroptosis. We critically evaluate the role of regulated cell death in appressorium morphogenesis and examine how it is initiated and regulated, both temporally and spatially, during plant infection. We then use this synopsis to present a testable model for control of regulated cell death during appressorium-dependent plant infection by the blast fungus.

Antidepressant effects of fisetin: Identifying molecular mechanisms by network pharmacology and molecular docking

Major depressive disorder (MDD) is a heterogeneous condition influenced by a complex interplay of social, psychological, and biological factors. Fisetin (FT), a flavonoid polyphenol found in various plants, has demonstrated neuroprotective properties that may be beneficial in treating MDD. This research aims to evaluate the potential molecular mechanisms of FT in treating MDD using network pharmacology analysis, with validation through molecular docking methods. We assessed the drug-like properties of FT using the TCMSP and SwissADME platforms. Potential drug targets for FT were identified through SuperPred and SwissTargetPrediction. We compiled MDD-associated targets from established databases and identified common genes shared between FT and MDD. The common targets were analyzed for protein-protein interactions using the STRING database to identify essential targets. Consequently, these key targets were further investigated through Kyoto Encyclopedia of Genes and Genomes and Gene Ontology (GO) enrichment analyses with the help of ShinyGO software. The results indicated that FT targets are linked to specific pathways involved in the pathogenesis of MDD, with the IL-17 signaling pathway emerging as a significant pathway of interest. Strong binding affinities were found between FT and key proteins, including glycogen synthase kinase 3 beta, monoamine oxidase A, acetylcholinesterase, matrix metalloproteinase 9, and myeloperoxidase, suggesting that FT may serve as a promising therapeutic agent for MDD by targeting components of the IL-17 pathway. In conclusion, this research successfully employed computational methods to elucidate the potential effectiveness of FT in managing MDD. It offered important perspectives on the regulatory mechanisms involved and emphasized the IL-17 signaling pathway as a possible target for MDD therapy.

Vitamin A enhances PI3K/Akt signaling and mitigates enterocyte apoptosis in a mouse model of necrotizing enterocolitis.

This study aims to elucidate the roles of the PI3K-Akt signaling pathway and enterocyte apoptosis in necrotizing enterocolitis (NEC) pathogenesis and investigate the impact of vitamin A intervention on these factors. We employed an NEC mouse model and administered vitamin A treatment. Retinol levels in mouse blood were quantified using ELISA. Intestinal cell apoptosis in NEC mice was assessed via the TUNEL assay. We evaluated mRNA and protein expressions of Bcl-2, Bax, cytochrome C (CytoC), Caspase 3, and PI3K/Akt signaling pathway components using qPCR and western blotting. In NEC models, PI3K, Akt, and Bcl-2 were downregulated, accompanied by upregulated Bax, CytoC, and Caspase 3 at both mRNA and protein levels. These molecular changes were associated with an increase in enterocyte apoptosis in the NEC models. Vitamin A supplementation increased PI3K, Akt, and Bcl-2 expression while decreasing Bax, CytoC, and Caspase 3 levels in the NEC models, resulting in reduced apoptosis. Vitamin A has the potential to mitigate enterocyte apoptosis in NEC by upregulating the PI3K/Akt signaling pathway and modulating apoptotic signals, providing new insights into the inhibitory effect of vitamin A on enterocyte apoptosis in NEC.

KAE ameliorates LPS-mediated acute lung injury by inhibiting PANoptosis through the intracellular DNA-cGAS-STING axis.

Acute lung injury (ALI) is a severe condition characterized by inflammation, tissue damage, and persistent activation of the cyclic GMP-AMP (cGAS)-stimulator of interferon genes (STING) pathway, which exacerbates the production of pro-inflammatory mediators and promotes the progression of ALI. Specific inhibition of this pathway has been shown to alleviate ALI symptoms. Kaempferol-3-O-α-L-(4″-E-p-coumaroyl)-rhamnoside (KAE), an active compound found in the flowers of Angelica acutiloba Kitagawa, exhibits anti-inflammatory and antioxidant properties. This study aimed to investigate the molecular mechanisms through which KAE regulates the cGAS-STING pathway in the context of ALI. ALI was induced using LPS. Lung damage and anti-inflammatory/antioxidant effects were assessed by H&E staining, lung edema index, and SOD, MDA, and ELISA assays. NO release and mitochondrial membrane potential (MMP) were measured by JC-1 and Griess methods. The impact of KAE on the cGAS-STING pathway and PANoptosis was analyzed using flow cytometry, Western blot, and immunofluorescence. KAE significantly alleviated lipopolysaccharide-induced pulmonary injury by reducing inflammatory cell infiltration, alleviating pulmonary edema, enhancing antioxidant capacity, and decreasing levels of inflammatory cytokines in mouse lung tissues. In both in vitro and in vivo analyses, KAE downregulated the expression of key components of the cGAS-STING pathway, including cGAS, STING, p-TBK1, and nuclear factor-κB. KAE also reduced the assembly and activation of the PANoptosome, thereby attenuating apoptosis, necroptosis, and pyroptosis. Additionally, KAE inhibited cGAS activation by restoring the MMP, which reduced the release of cytosolic DNA. KAE improve ALI by inhibiting the release of cytosolic DNA and suppressing cGAS-STING pathway activation, thereby protecting cells from PANoptosis. Our findings provide valuable insights for the development and application of novel therapeutic strategies for ALI.

Evaluation of exo-long noncoding RNA MALAT1 in OSCC in comparison to dysplastic and normal: A cross-sectional study.

This study explores the role of MALAT1 as a valuable target for creating minimally-invasive diagnostic methods and personalized treatments in the management of OSCC. It focuses on evaluating the role of exosomal MALAT1 in the progression of dysplasia to OSCC by influencing the PI3K/AKT pathway. This cross-sectional study evaluated MALAT1 expression and PI3K/AKT pathway components in exosomes derived from plasma samples of patients with various stages of oral dysplasia, OSCC and compared with normal. RNA concentration was estimated, real-time polymerase chain reaction (qPCR) was used for quantitative analysis. Gene expression levels of MALAT1, PI3K, AKT1, and PTEN were analysed and compared across groups using one way ANOVA and Post-hoc Tukey analysis was performed for pairwise comparisons to assess correlations between MALAT1 expression and PI3K/AKT pathway components. MALAT1 was found to be overexpressed in OSCC in comparison to normal, significantly (p<0.001∗). There was no significant change in expression pattern of MALAT1 between dysplastic patients and normal, yet, significant association was found on corelation analysis between expression pattern of MALAT1 and PI3K/AKT/PTEN (p 0.001∗) among individuals of dysplasia and OSCC. As well pairwise comparisons of MALAT1 expression levels between all three stages of dysplasia showed significant association (p<0.001∗). MALAT1 stands out as a key player in the complex landscape of OSCC pathogenesis, impacting tumorigenesis, metastasis, and treatment outcomes through multifaceted molecular mechanisms. Continued research into MALAT1's regulatory roles and its interactions within the tumor microenvironment holds promise for uncovering novel therapeutic targets and biomarkers that could redefine the management of OSCC in the future.

Experimentally Manipulating the Thyroid Hormone Axis in Zebrafish.

Thyroid hormone (TH) is an endocrine factor with a diverse array of developmental, metamorphic, and metabolic functions conserved across vertebrates. Zebrafish (Danio rerio) are a tractable model for endocrinology research, and recent research efforts focus on the roles of TH in zebrafish morphogenesis, growth and behavior. Several powerful approacheshave been developed in zebrafish to modulatethe TH axis and peripheral sensitivity to the hormone. These approaches include gain- and loss-of-function mutations that target components of the TH signaling pathways, as well as pharmacological treatments to modulate TH synthesis andavailability. Here, we review some of these approaches for generating hypo- and hyperthyroid physiology and phenotypes during post-embryonic zebrafish development. In particular, we focus on a transgenic method of producing hypothyroid fish via metronidazole-based thyroid ablation. This approach can straightforwardly generate large numbers of hypothyroid individuals along with euthyroid sibling controls, and we survey some of the research applications in which this system has been used.

Evolution and response of flood disaster network public opinion based on an event logic graph: A case study of rainstorms in Henan, China

Social media takes the center stage as the primary information and opinion-sharing platform for the public during disaster events. Related topics quickly spread, and multiple public opinion events exhibit clear coupling phenomena, leading to the formation of network public opinion. By creating a network public opinion event logic graph, our study illustrates the development and evolution of network public opinion during disaster events and provides the government with a crucial foundation for action. For this study, we selected tweets on Sina Weibo regarding the "Henan rainstorm" between July 19, 2021, and August 2, 2021. To construct a network public opinion event logic graph, pattern matching was used to discover event relationships and extract causal event pairs and sequential event pairs. Moreover, the term frequency-inverse document frequency+K-means clustering algorithm (TF-IDF+K-Means) clustering algorithm was used to group event pairs with high similarity into one category. The critical nodes and evolution pathways in the event logic graph were then thoroughly examined. Our findings demonstrated that the topic evolution of network public opinion was multidirectional in nature, covering topics such as disaster events, emergency rescue, public sentiment, media opinion, and livelihood-related events. The two main components of the evolutionary pathway of network public opinion are the evolution of the disaster itself and its evolution in the social sphere. Our study provides a technique for determining the dynamic evolution of network public opinion and provides useful consultation for the government's upcoming response to network public opinion during disaster events.

SQYC formula improves the efficacy of PD-1 monoclonal antibodies in MSS colorectal cancer by regulating dendritic cell mitophagy via the PINK1-Parkin pathway.

Microsatellite stable (MSS) colorectal carcinomas (CRCs) exhibit poor responsiveness to immunotherapy such as immune checkpoint inhibitors (ICIs). In the realm of clinical cancer treatment, traditional Chinese medicines (TCMs) are extensively utilized for their immunomodulatory properties. Shen Qi Yi Chang (SQYC), a clinical prescription for CRC treatment, improve the life quality of CRC patients and enhance their immune function. This study was to reveal the effect and mechanism of SQYC in improving the effect of PD-1 inhibitors in the treatment of MSS-type CRC. CT26-luc in situ CRC tumor model and human CRC organoid model was established to evaluate the anti-tumor efficacy of SQYC combined with PD-1 inhibitor. Flow cytometry analysis was utilized to investigate the effect of SQYC on the infiltration and immune function of TILs and DCs in the immune microenvironment. Following this, RNA sequencing analysis, seahorse, TEM and immunofluorescence were performed to regulation of SQYC on mitophagy in DCs cells. UPLC-Q-TOF/MS and molecular docking were used to reveal the key blood-entering components of SQYC-regulated PINK1-parkin pathway. The SQYC-containing serum improved the efficacy of sintilimab in MSS CRC organoid model. After combined administration of 11.4 g/kg/day SQYC extract and 5 mg/kg α-PD-1, it was observed that SQYC enhanced the efficacy of PD-1 inhibitor against MSS CRC. Flow cytometry and immunofluorescence analysis revealed an augmented infiltration of tumor-infiltrating lymphocytes (TILs) and an improved antigen presentation function of dendritic cells (DCs). Notably, RNA sequencing analysis demonstrated an evident correlation with mitochondrial function related pathways following SQYC treatment. Mechanistically, SQYC promoted mitophagy in DCs via the PINK1-Parkin pathway, thereby improving mitochondrial quality, energy metabolism, and mitochondrial dynamics. Evaluation of the blood components of SQYC coupled with molecular docking, demonstrated good binding affinity with PINK1/PARKIN/LC3. Our findings highlight SQYC as a promising candidate for improving immunotherapy in MSS CRC, suggesting that targeting PINK1-Parkin in DCs could represent a novel strategy for improving the efficacy of ICIs. Furthermore, it provides new theoretical and scientific underpinnings to enhance the clinical efficacy of immunosuppressants.

Asthma Biologics Across the T2 Spectrum of Inflammation in Severe Asthma: Biomarkers and Mechanism of Action.

Airway inflammation, a hallmark feature of asthma, drives many canonical features of the disease, including airflow limitation, mucus plugging, airway remodeling, and hyperresponsiveness. The T2 inflammatory paradigm is firmly established as the dominant mechanism of asthma pathogenesis, largely due to the success of inhaled corticosteroids and biologic therapies targeting components of the T2 pathway, including IL-4, IL-5, IL-13, and thymic stromal lymphopoietin (TSLP). However, up to 30% of patients may lack signatures of meaningful T2 inflammation (ie, T2 low). In T2-low asthma patients, T2 inflammation may be masked due to anti-inflammatory treatments or may be highly variable depending on exposure to common asthma triggers such as allergens, respiratory infections, and smoke or pollution. The epithelium and epithelial cytokines (TSLP, IL-33) are increasingly recognized as upstream drivers of canonical T2 pathways and as modulators of various effector cells, including mast cells, eosinophils, and neutrophils, which impact the pathological manifestations of airway smooth muscle hypertrophy, hypercontractility, and airway hyperresponsiveness. Approved biologics for severe asthma target several distinct mechanisms of action, leading to differential effects on the spectrum of T2 inflammation, inflammatory biomarkers, and treatment efficacy (reducing asthma exacerbations, improving lung function, and diminishing symptoms). The approved anti-asthma biologics primarily target T2 immune pathways, with little evidence suggesting a benefit of targeting non-T2 asthma-associated mediators. Indeed, many negative results challenge current assumptions about the etiology of non-T2 asthma and raise doubts about the viability of targeting popular alternative inflammatory pathways, such as T17. Novel data have emerged from the use of biologics to treat various inflammatory mediators and have furthered our understanding of pathogenic mechanisms that drive asthma. This review discusses inflammatory pathways that contribute to asthma, quantitatively outlines effects of available biologics on biomarkers, and summarizes data and challenges from clinical trials that address non-T2 mechanisms of asthma.