Multiple Signaling Research Articles

Immune Response and Transcriptome Analysis of the Head Kidney to Different Concentrations of Aeromonas veronii in Common Carp (Cyprinus carpio)

The common carp (Cyprinus carpio), a major economic freshwater fish, is suffering from a variety of bacterial infectious diseases because of its high-density, factory and intensive farming patterns. Aeromonas veronii is the causative agent of high mortality in common carp, causing severe economic losses in aquaculture. However, the regulatory mechanisms involved in the response of common carp to this bacterial infection remain poorly understood. In this study, we compared mortality, blood serum LZM (Lysozyme) and IgM (Immunoglobulin M) levels and transcriptome patterns of head kidney tissues after infection with different concentrations of Aeromonas veronii. We observed that mortality increased progressively with an increasing pathogen concentration. The concentrations of blood serum LZM and IgM significantly increased after infection. A total of 13 and 925 differentially expressed genes (DEGs) were identified after infection with low (T4) and high (T9) concentrations of bacterial suspension, respectively. KEGG and GO analyses of the DEGs highlighted multiple immune-related signaling pathways. Weighted gene co-expression network analysis (WGCNA) revealed that 136 and 83 hub genes were related to blood serum LZM and IgM, respectively. Finally, the gene expression in the head kidney was validated via RT–qPCR to be consistent with the transcriptome. These results provide insights into the mechanisms of the immune response to infection with different concentrations of Aeromonas veronii and offer useful information for further studies on immune defense mechanisms in common carp.

Lactate dehydrogenase A is a diagnostic biomarker associated with immune infiltration, m6A modification and ferroptosis in endometrial cancer

BackgroundLactate dehydrogenase A (LDHA) has been confirmed as a tumor promoter in various cancers, but its role in endometrial cancer remains unclear.MethodsThe Cancer Genome Atlas (TCGA), quantitative real-time polymerase chain reaction and the Human Protein Atlas were utilized to analyzed the LDHA expression in EC. The LDHA levels of patients with different clinical features were compared based on the TCGA cohort. The Genome Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis of LDHA-related genes were conducted by R language. The influence of LDHA knockdown on cell proliferation, apoptosis, migration and invasion was detected by in vitro experiment. The relationship between LDHA expression and immune infiltration was explored by Tumor Immune Estimation Resource 2.0 and Gene Expression Profiling Interactive Analysis. The association of LDHA level with N6-methyladenosine (m6A) modification and ferroptosis was investigated based on the TCGA-UCEC and the GEO cohort.ResultsThe LDHA was overexpressed in EC tissues and EC cell lines, and had high predictive accuracy for the EC diagnosis. The LDHA level was associated with age, histological type, histologic grade, and radiation therapy. LDHA-related genes participated in multiple biological functions and signaling pathways. LDHA downregulation significantly promoted cell apoptosis and inhibited the proliferation, migration, and invasion of EC cells. LDHA expression was connected to multiple tumor-infiltrating lymphocytes (TILs), m6A-related genes, and ferroptosis-related genes.ConclusionLDHA has the potential to work as an EC biomarker associated with TILs, m6A modification, and ferroptosis in EC.

Distributed Passive Positioning and Sorting Method for Multi-Network Frequency-Hopping Time Division Multiple Access Signals

When there are time division multiple access (TDMA) signals with large bandwidth, waveform aliasing, and fast frequency-hopping in space, current methods have difficulty achieving the accurate localization of radiation sources and signal-sorting from multiple network stations. To solve the above problems, a distributed passive positioning and network stations sorting method for broadband frequency-hopping signals based on two-level parameter estimation and joint clustering is proposed in this paper. Firstly, a two-stage filtering structure is designed to achieve control filtering for each frequency point. After narrowing down the parameter estimation range through adaptive threshold detection, the time difference of arrival (TDOA) and the velocity difference of arrival (VDOA) can be obtained via coherent accumulating based on the cross ambiguity function (CAF). Then, a multi-station positioning method based on the TDOA/VDOA is used to estimate the position of the target. Finally, the distributed joint eigenvectors of the multi-stations are constructed, and the signals belonging to different network stations are effectively classified using the improved K-means method. Numerical simulations indicate that the proposed method has a better positioning and sorting effect in low signal-to-noise (SNR) and low snapshot conditions compared with current methods.

Atg2 controls Drosophila hematopoiesis through the PVR/TOR signaling pathways

The hematopoietic system of Drosophila is a well‐established genetic model for studying hematopoiesis mechanisms, which are strictly regulated by multiple signaling pathways. Autophagy‐related 2 (Atg2) protein is involved in autophagosome formation through its lipid transfer function; however, other functions in animal development, especially the role of Atg2 in maintaining hematopoietic homeostasis, are unclear. Here, we show that Atg2 knockdown in the cortical zone (CZ) induced the proliferation and differentiation of mature plasmatocytes and disrupted progenitor maintenance in the medullary zone (MZ). We also observed the differentiation of lamellocytes among circulating hemocytes and in the lymph gland, which is rarely observed in healthy larvae. The above results on hematopoiesis disorders are due to Atg2 regulating the Drosophila PDGF/VEGF receptor (PVR) and target of rapamycin (TOR) in the CZ of lymph gland. In conclusion, we identified Atg2 as a previously undescribed regulator of hematopoiesis. Understanding the mechanism of maintenance of hematopoietic homeostasis in Drosophila will help us better evaluate human blood disorder‐related diseases.

Small molecule inhibitors target multiple neuropathological signaling to exert novel neuroprotection in intracranial aneurysms

Small molecule inhibitors target multiple neuropathological signaling to exert novel neuroprotection in intracranial aneurysms

Efficacy of L-arabinose in managing cucumber Fusarium wilt and the underlying mechanism of action.

Cucumber Fusarium wilt (CFW), triggered by Fusarium oxysporum f. sp. cucumerinum, leads to substantial yield reductions in global cucumber (Cucumis sativus L.) production. Common management strategies for CFW include soil fumigation, grafting, and crop rotation. However, these methods have limitations regarding safety and efficacy stability, necessitating the development of new, cost-effective, and eco-friendly control strategies. Our prior research demonstrated that L-arabinose, an inexpensive and safe sugar commonly used in food and beverages, effectively suppressed bacterial wilt in tomatoes. This study explores the potential of L-arabinose in managing CFW and investigates its mechanism of action. Soil applications of L-arabinose, ranging from 0.00001 to 0.01%, effectively suppressed CFW. The most significant suppressive effect was observed at 0.01%, reducing the disease severity index by 67.5% compared to the control treatment. Microscopic examination of transverse root sections showed that pathogen hyphae colonized the epidermis but seldom penetrated the cortical layer of roots in L-arabinose-treated seedlings. In contrast, the entire root tissue of control seedlings was colonized by the pathogen. Quantitative real-time PCR revealed a significant increase in the expression of defense-related genes dependent on salicylic acid, jasmonic acid, and ethylene in L-arabinose-treated plants compared to control plants, 6 and 10 days post pathogen inoculation. This study demonstrated that soil application of L-arabinose can effectively suppress CFW by priming root tissues for multiple defense signaling pathways. Therefore, L-arabinose holds potential as a new fungicide for managing CFW. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Multi-channel Fused Vision Transformer Network for Bearing Fault Diagnosis under Different Working Conditions

Abstract Many of the current fault diagnosis methods rely on time-domain signals. While the richest information are contained in these signals, their complexity poses challenges to network learning and limits the ability to fully characterize them. To address these issues, a novel Multi-channel Fused Vision Transformer Network (MFVTN) is proposed in this paper. Firstly, the Overlapping Patch Embedding (OPE) module is introduced to overlap the time-domain map with edge information, preserving the global continuous features of the time-domain map and adding positional encoding for sorting. This integration helps the Vision Transformer (ViT) merge detailed features and construct the global mapping. Secondly, multiple dimensional time domain signal features are extracted and fused in parallel, enabling multi-domain fault diagnosis of bearings. In order to enhance the network ability to extract domain-invariant features, an adversarial training strategy combined with Wasserstein distance is utilized. The results demonstrate that the diagnostic accuracy of the proposed MFVTN can reach 98.2%.

TDOA-AOA Localization Algorithm for 5G Intelligent Reflecting Surfaces

5G positioning technology has become deeply integrated into daily life. However, in wireless signal propagation environments, there may exist non-line-of-sight (NLOS) conditions, which lead to signal blockage and subsequently hinder the provision of positioning services. To address this issue, this paper proposes an intelligent reflecting surface (IRS) NLOS time difference of arrival–angle of arrival (TDOA-AOA) localization (INTAL) algorithm. First, the algorithm constructs a system model for 5G IRS localization, effectively overcoming the challenges of positioning in NLOS paths. Then, by applying the multiple signal classification algorithm to estimate the time delay and angle, and using the Chan algorithm to obtain the user’s estimated coordinates, an optimization problem is formulated to minimize the distance between the estimated and actual coordinates. The tent–snake optimization algorithm is employed to solve this optimization problem, thereby reducing localization errors. Finally, simulations demonstrate that the INTAL algorithm outperforms the snake optimization (SO) algorithm and the gray wolf optimization (GWO) algorithm under the same conditions, reducing the localization error by 56% and 60% on average, respectively. Additionally, when the signal-to-noise ratio is 30 dB, the localization error of the INTAL algorithm is only 0.2968 m, while the errors for the SO and GWO algorithms are 0.6733 m and 0.7398 m, respectively. This further proves the significant improvement of the algorithm in terms of localization accuracy.

Show Her the Money

Female-founded businesses struggle to attract private investment but seem to attract more within the sport industry. The purpose of this exploratory study was to examine this discrepancy and determine what factors contribute to private funding of female-owned sport businesses. This study examined 440 female-founded sport-related businesses with a founding date between 2010-2020 from the Crunchbase database. There was $2.21 billion invested into 207 female-founded sport companies during the identified period. Using multiple logistic regression and signaling theory, results of the study suggest that female founders in sport should focus capital acquisition efforts on revenue-generating business models and successfully pitching investors, as this leads to greater funding. Social network analysis indicates that the investing environment for female sport businesses is loosely connected with a potential role for start-up accelerators. This study helps to further understand the investment environment surrounding women-owned businesses in sport.

Discovery of novel TANK-Binding Kinase 1 (TBK1) inhibitor against pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, underscoring the urgent need for developing new therapies. The upregulation of TBK1 activity plays a crucial role in multiple pancreatic cancer-related signaling pathways, suggesting that inhibiting the kinase activity of TBK1 could be a promising strategy. Herein, we discovered a novel TBK1 inhibitor, LIB3S0280, using a structure-based virtual screening (SBVS) strategy. In the anti-proliferative and viability assays, LIB3S0280 showed significant inhibition against pancreatic cancer cell lines that highly express TBK1 with the GI50 values of 2.24 and 4.71 μM and IC50 values of 6.64 and 10.98 μM at 96 h. For the downstream targets, LIB3S0280 can inhibit TBK1 downstream signaling by decreasing the phosphorylation of IκBα and AKT better than a known TBK1 inhibitor, BX-795. Furthermore, PDAC cells were arrested in G2/M and underwent apoptosis or senescence with the treatment of LIB3S0280. These findings suggest that TBK1 inhibitor LIB3S0280 has great potential as a lead compound in the further development of a novel treatment for PDAC.

Innovative fluorescent ratiometric probe from Oolong tea dreg for highly sensitive bilirubin detection

Bilirubin, a crucial component in heme degradation, is formed during the breakdown of red blood cells in the liver and spleen. Elevated bilirubin levels are closely associated with jaundice and serve as markers for various blood and liver-related disorders. Detection of BR has been approached through various methods with fluorescent methods gaining prominence due to their exceptional sensitivity, rapid response, and precision. Among the fluorescence methods, carbon dots have emerged as versatile optical probes, known for their unique optical properties, low toxicity, and ease of synthesis. However, carbon dots typically exhibit a single emission peak, limiting accuracy due to vulnerability to external interferences. To overcome this limitation, probes featuring multiple independent emission signals are preferred. Chlorophyll, abundant in nature and sourced from biomass, is recognized for its safe and fluorescent properties, making it a secure choice for fluorescence-based sensing. This study introduces an innovative approach utilizing Oolong tea dreg as a source of chlorophyll for creating a fluorescent probe to detect bilirubin. Chlorophyll was partially converted into carbon dots using a combination of extraction and hydrothermal techniques, producing a ratiometric probe with two emission signals. The fluorescence of the probe was quenched in the presence of the bilirubin through the inner filter effect. The proposed probe exhibited outstanding selectivity and a low limit of detection (0.8 µM) for bilirubin. Furthermore, the probe demonstrated satisfactory recovery rates when tested with artificial urine and human urine samples.

Examining mental workload based on multiple physiological signals: review of the multi-attribute task battery (MATB) technique

Examining mental workload based on multiple physiological signals: review of the multi-attribute task battery (MATB) technique

Evaluation of the Mechanism of Yishan Formula in Treating Breast Cancer Based on Network Pharmacology and Experimental Verification.

Yishan formula (YSF) has a significant effect on the treatment of breast cancer, which can improve the quality of life and prolong the survival of patients with breast cancer; however, its mechanism of action is unknown. In this study, network pharmacology and molecular docking methods have been used to explore the potential pharmacological effects of the YSF, and the predicted targets have been validated by in vitro experiments. Active components and targets of the YSF were obtained from the TCMSP and Swiss target prediction website. Four databases, namely GeneCards, OMIM, TTD, and DisGeNET, were used to search for disease targets. The Cytoscape v3.9.0 software was utilized to draw the network of drug-component-target and selected core targets. DAVID database was used to analyze the biological functions and pathways of key targets. Finally, molecular docking and in vitro experiments have been used to verify the hub genes. Through data collection from the database, 157 active components and 618 genes implicated in breast cancer were obtained and treated using the YSF. After screening, the main active components (kaempferol, quercetin, isorhamnetin, dinatin, luteolin, and tamarixetin) and key genes (AKT1, TP53, TNF, IL6, EGFR, SRC, VEGFA, STAT3, MAPK3, and JUN) were obtained. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that the YSF could affect the progression of breast cancer by regulating biological processes, such as signal transduction, cell proliferation and apoptosis, protein phosphorylation, as well as PI3K-Akt, Rap1, MAPK, FOXO, HIF-1, and other related signaling pathways. Molecular docking suggested that IL6 with isorhamnetin, MAPK3 with kaempferol, and EGFR with luteolin have strong binding energy. The experiment further verified that YSF can control the development of breast cancer by inhibiting the expression of the hub genes. This study showed that resistance to breast cancer may be achieved by the synergy of multiple active components, target genes, and signal pathways, which can provide new avenues for breast cancer-targeted therapy.

Discovery of pyrrolo[2,3-d]pyrimidin-4-one derivative YCH3124 as a potent USP7 inhibitor for cancer therapy

USP7 is one of the most studied deubiquitinating enzymes, which is involved in the regulation of multiple cell signaling pathways and has been shown to be associated with the occurrence and progression of a variety of cancers. Inhibitors targeting USP7 have been studied by several teams, but most of them lack selectivity and have low activities. Herein, we reported a serious of pyrrole[2,3-d]pyrimidin-4-one derivatives through scaffold hopping of recently reported 4-hydroxypiperidine compounds. The representative compound Z33 (YCH3124) exhibited highly potent USP7 inhibition activity as well as anti-proliferative activity against four kinds of cancer cell lines. Further study revealed that YCH3124 effectively inhibited the downstream USP7 pathway and resulted in the accumulation of both p53 and p21 in a dose-dependent manner. Notably, YCH3124 disrupted cell cycle progression through restricting G1 phase and induced significant apoptosis in CHP-212 cells. In summary, our efforts provided a series of novel pyrrole[2,3-d]pyrimidin-4-one analogs as potent USP7 inhibitors with excellent anti-cancer activity.

Elucidating the Signaling Pathways Involved in Erectile Dysfunction

Background: Erectile Dysfunction (ED) is a common sexual disorder among men aged 20 years and over. It is predominantly characterized by alterations in the key physiological pathways regulating erectile function, such as nitric oxide and Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK). Beyond these pathways, multiple molecular signaling networks are involved in ED pathogenesis. Objective: This review aims todescribe the major signal transduction pathways that impact erectile function and contribute to the introduction of the pathogenesis of ED. Methods: A literature review of ED was performed from 2000 to 2023 using PubMed, Scopus, and Embase. “ED” and “related signaling pathway”, “molecular mechanisms” terms were used. Results: Further basic and clinical studies are required to define the underlying molecular mechanisms of ED. The signaling pathways that were not affected by phosphodiesterase type 5 inhibitors (PDE5i) may be the reason for the reduced efficacy of this first-line treatment option in a variety of conditions. Conclusion: There is still a need for a deeper description of the molecular mechanisms in terms of fibrosis, angiogenesis, apoptosis, inflammation, oxidative stress, autophagy, and hypoxia to identify new possible targets underlying the pathogenesis of ED. This comprehensive review expounds on the principal signaling pathways, offering valuable insights that may catalyze the development of innovative and enhanced therapies for managing ED.

Calcineurin inhibition enhances Caenorhabditis elegans lifespan by defecation defects-mediated calorie restriction and nuclear hormone signaling.

Calcineurin is a highly conserved calcium/calmodulin-dependent serine/threonine protein phosphatase with diverse functions. Inhibition of calcineurin is known to enhance the lifespan of Caenorhabditis elegans through multiple signaling pathways. Aiming to study the role of calcineurin in regulating innate immunity, we discover that calcineurin is required for the rhythmic defecation motor program (DMP) in C. elegans. Calcineurin inhibition leads to defects in the DMP, resulting in intestinal bloating, rapid colonization of the gut by bacteria, and increased susceptibility to bacterial infection. We demonstrate that intestinal bloating caused by calcineurin inhibition mimics the effects of calorie restriction, resulting in enhanced lifespan. The TFEB ortholog, HLH-30, is required for lifespan extension mediated by calcineurin inhibition. Finally, we show that the nuclear hormone receptor, NHR-8, is upregulated by calcineurin inhibition and is necessary for the increased lifespan. Our studies uncover a role for calcineurin in the C. elegans DMP and provide a new mechanism for calcineurin inhibition-mediated longevity extension.

Decoding the role of HIF-1α in immunoregulation in Litopenaeus vannamei under hypoxic stress

Hypoxia poses a significant challenge to aquatic organisms, especially Litopenaeus vannamei (L. vannamei), which play a vital role in the global aquaculture industry. Hypoxia-inducible factor 1α (HIF-1α) is a pivotal regulator of the organism's adaptation to hypoxic conditions. To understand of how HIF-1α affects the immunity of L. vannamei under hypoxic conditions, we conducted a thorough study involving various approaches. These included observing tissue morphology, analyzing the expression of immune-related genes, assessing the activities of immune-related enzymes, and exploring immune-related pathways. Our study revealed that RNA interference (RNAi)-mediated knockdown of HIF-1α markedly reduced HIF-1α expression in the gill (75 to 95%), whereas the reduction ranged from 2 to 43% in the hepatopancreas. Knockdown of HIF-1α resulted in increased damage to both gill and hepatopancreatic tissues in hypoxic conditions. Additionally, immune-related genes, including Astakine (AST), Hemocyanin (HC), and Ferritin (FT), as well as immune-related enzymes such as Acid Phosphatase (ACP), Alkaline Phosphatase (AKP), and Phenoloxidase (PO), exhibited intricate regulatory patterns in response to hypoxia stress following the knockdown of HIF-1α. Transcriptome analysis revealed that HIF-1α knockdown significantly impacts multiple signaling pathways, including the JAK-STAT signaling pathway, Th17 cell differentiation pathways, PI3K-Akt signaling pathway, ErbB signaling pathway, MAPK signaling pathway, chemokine signaling pathway, ribosomal pathways, apoptosis, lysosomes and arachidonic acid metabolism. These alterations disrupt the organism's immune balance and interfere with normal metabolic processes, potentially leading to various immune-related diseases. We speculate that the weakened immune response resulting from HIF-1 inhibition is due to the reduced metabolic capacity, and the existence of a direct regulatory relationship between them requires further exploration. This study greatly advances our understanding of the vital role that HIF-1α plays in regulating immune responses in shrimp under hypoxic conditions, thereby deepening our comprehension of this critical biological mechanism.

The phytochemical plumbagin: mechanism behind its "pleiotropic" nature and potential as an anticancer treatment.

Chemotherapeutics are most often used to treat cancer, but side effects, drug resistance, and toxicity often compromise their effectiveness. In contrast, phytocompound plumbagin possesses a distinct pleiotropic nature, targeting multiple signaling pathways, such as ROS generation, cell death, cellular proliferation, metastasis, and drug resistance, and is shown to enhance the efficacy of chemotherapeutic drugs. Plumbagin has been shown to act synergistically with various chemotherapeutic drugs and enhance their efficacy in drug-resistant cancers. The pleiotropic nature is believed to be due to plumbagin's unique structure, which contains a naphthoquinone ring and a hydroxyl group responsible for plumbagin's various biological responses. Despite limitations such as restricted bioavailability and delivery, recent developments aim to address these challenges and harness the potential of plumbagin as an anticancer therapeutics. This review delves into the structural aspect of the plumbagin molecule contributing to its pleiotropic nature, explores the diverse mechanism that it targets, and discusses emerging strategies to overcome its limitations.

The Arabidopsis splicing factor PORCUPINE/SmE1 orchestrates temperature-dependent root development via auxin homeostasis maintenance.

Appropriate abiotic stress response is pivotal for plant survival and makes use of multiple signaling molecules and phytohormones to achieve specific and fast molecular adjustments. A multitude of studies has highlighted the role of alternative splicing in response to abiotic stress, including temperature, emphasizing the role of transcriptional regulation for stress response. Here we investigated the role of the core-splicing factor PORCUPINE (PCP) on temperature-dependent root development. We used marker lines and transcriptomic analyses to study the expression profiles of meristematic regulators and mitotic markers, and chemical treatments, as well as root hormone profiling to assess the effect of auxin signaling. The loss of PCP significantly alters RAM architecture in a temperature-dependent manner. Our results indicate that PCP modulates the expression of central meristematic regulators and is required to maintain appropriate levels of auxin in the RAM. We conclude that alternative pre-mRNA splicing is sensitive to moderate temperature fluctuations and contributes to root meristem maintenance, possibly through the regulation of phytohormone homeostasis and meristematic activity.

Self-assembled Human Serum Protein-based Core-shell Nanoparticles to inhibit key oncogenic signalling in Drug-Resistant Leukemia

Simultaneous inhibition of multiple oncogenic signaling pathways is crucial for managing refractory cancers. This study introduces two unique core-shell nanoparticle (CS-NP) systems crafted from natural proteins that simultaneously target two crucial oncogenic pathways in refractory chronic myeloid leukemia (CML). Molecular analysis of approximately 14 refractory CML patients identified resistance to the standard treatment drug, imatinib, attributed to the overex-pression of the STAT5-transferrin pathway alongside the classic BCR-ABL fusion gene. To address this, we developed two dual-drug-loaded core-shell nanoparticles: (a) CS-NP1: Protamine sulfate nanocores carrying BCR-ABL siRNA and an albumin shell loaded with the STAT5 in-hibitor sorafenib, denoted as (PS-siRNA)-(Tf-Soraf) CS-NP; (b) CS-NP2: features a second-generation BCR-ABL inhibitor, dasatinib, in the albumin nanocore, and sorafenib in the transferrin nanoshell, labeled as (nAlb-Dasa)-(Tf-Soraf). We hypothesized that these dual-drug-loaded CS-NPs would effectively target both BCR-ABL and STAT5 pathways, with the transferrin nanoshell aiding in precise delivery to refractory CML cells overexpressing TfR1 due to STAT5 activity. Initial evaluations in drug resistant CML cell lines and patient-derived cells demonstrated significant cytotoxicity. Remarkably, even patients with BCR-ABL oncogene mutations displayed over 95% cytotoxicity with the CS-NPs. Furthermore, in vivo testing on a human xeno-graft model with a BCR-ABL+/+/STAT5+/+/TfR+/+ phenotype showcased a strong anti-tumor response. These results underscore the potential of a molecular-diagnosis-based rational design approach for protein-protein core-shell nanoparticles to simultaneously inhibit multiple oncogenic pathways, thereby overcoming resistance to targeted molecular therapies.