Signal Transduction Functions Research Articles

C-terminal tagging enhances the detection sensitivity of interlekin receptor type 1.

Substances released outside of the cells during cell necrosis are collectively called danger-associated molecular patterns (DAMPS) or alarmins. A pro-inflammatory cytokine, interleukin-1α (IL-1α) is known as a typical alarmin. IL-1α transmits signals by binding to IL-1 receptor 1 (IL-1R1), type I protein, expressed on the cell membrane of target cells, but detection of IL-1R1 at the protein and mRNA levels is difficult. Although the reasons are not elucidated, we attempted to add the HiBiT-tag to the N-terminus (N'-R1) or C-terminus (C'-R1) of IL-1R1 to examine whether the detection sensitivity can be augmented. Increase in detection sensitivity will allow the investigation of its function and subcellular localization much further. Using uterine cervical cancer-derived HeLa cells and its derivative CR-R1-4 cells lacking IL-1R1, C'-R1 was demonstrated to significantly increase the detection sensitivity of IL-1R1. Furthermore, the signal transduction function of neither N'-R1 nor C'-R1 was affected. Immunofluorescence cell staining revealed that wild-type IL-1R1 is mainly localized in the nucleus, whereas C'-R1 is localized both in the nucleus and the cytoplasm. The above results showed that adding a tag to the C-terminus of IL-1R1 increases detection sensitivity while maintaining its function. In the future, we would like to further investigate the relationship between changes in the intracellular localization of C'-R1 and increases in detection sensitivity.

Comparative and Spatial Transcriptome Analysis of Rhododendron decorum Franch. During the Flowering Period and Revelation of the Plant Defense Mechanism.

Rhododendron is a globally distributed and extensive genus, comprising over 1000 species. In the southwestern mountains of China, there exists a remarkable diversity of Rhododendron, with Yunnan Province alone harboring more than 600 species. R. decorum Franch. has long been utilized by local communities for its medicinal and edible properties. However, the transcriptional regulation function, medicinal properties, and edibility characteristics of R. decorum Franch. currently lack a solid theoretical basis. Total RNA was extracted from leaves, corollas and androecium/gynoecium of R. decorum Franch. in Heqing county, followed by the construction of cDNA libraries and the de novo assembly of transcriptomes. A total of 63,050 unigenes were extracted from the flowers and leaf organs of R. decorum Franch. Among these unigenes, 43,517 were predicted to be coding sequences, with 32,690 being effectively annotated. Differential gene expression enrichment was observed among different organs within their respective transcriptomes; notably floral organs exhibited significant defense against plant diseases along with signal transduction functions. Furthermore, during the flower harvesting period, all floral organs exhibited gene enrichment pathways associated with carbohydrate metabolism. Additionally, the stamen and pistil displayed flavonoid metabolism pathways, suggesting their potential applications as functional food or medicine. Our results shed light on plant-pathogen defense mechanisms and the molecular bias of flavonoids biosynthesis on flower organs during the flowering period, which might help to understand the consumption of R. decorum Franch. corollas by the Bai nationality of Heqing county.

Exploring the Biomarkers and Potential Mechanisms of Botulinum Toxin Type A in the Treatment of Microglial Inflammatory Activation through P2X7 Receptors based on Transcriptome Sequencing.

This study aims to explore the potential mechanism by which Botulinum toxin type A (BoNT/ A) inhibits microglial inflammatory activation through P2X7 receptors (P2X7R). BoNT/A is a promising analgesic drug, and previous studies have established that it alleviates Neuropathic Pain (NP) by inhibiting microglial inflammatory activation. This study examined the biomarkers and potential mechanisms by which BoNT/A relieves neuropathic pain by mediating microglial P2X7R and analyzing transcriptome sequencing data from mouse BV-2 microglial cells. The P2X7R agonist Bz-ATP was used to induce microglial inflammatory activation, whilst RNAseq technology was used to explore the biomarkers and potential mechanisms through which BoNT/A suppresses microglial inflammation. RNA sequencing was performed on three BV-2 cell samples treated with a P2X7R specific activator (Bz-ATP) and three BV-2 cell samples pre-treated with BoNT/A. Only data that successfully passed quality control measures were included in subsequent analysis. Initially, Differentially Expressed Genes (DEGs) were identified from BoNT/A and control samples, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Biomarkers were then identified by constructing a Protein- Protein Interaction (PPI) network and utilizing the CytoHubba plug-in in Cytoscape software. Lastly, enrichment analysis and regulatory network analysis were performed to elucidate the potential mechanism of BoNT/A in the treatment of NP. 93 DEGs related to the "cell component size regulation" GO term and enriched in the "axon guidance" KEGG pathway were identified. Subsequently, 6 biomarkers were identified, namely PTPRF, CHDH, CKM, Ky, Sema3b, and Sema3f, which were enriched in pathways related to biosynthesis and metabolism, disease progression, signal transduction, and organelle function, including the "ribosome" and "Wnt signaling pathway." Finally, a competing endogenous RNA (ceRNAs) network was constructed from 6 mRNAs, 66 miRNAs, and 31 lncRNAs, forming a complex relationship network. Six genes (PTPRF, Sema3b, Sema3f, CHDH, CKM, and Ky) were identified as biomarkers of microglial inflammatory activation following BoNT/A treatment. This finding may provide a valuable reference for the relief and treatment of neuropathic pain.

Integrated analysis of bulk and single-cell RNA sequencing reveals the impact of nicotinamide and tryptophan metabolism on glioma prognosis and immunotherapy sensitivity

BackgroundNicotinamide and tryptophan metabolism play important roles in regulating tumor synthesis metabolism and signal transduction functions. However, their comprehensive impact on the prognosis and the tumor immune microenvironment of glioma is still unclear. The purpose of this study was to investigate the association of nicotinamide and tryptophan metabolism with prognosis and immune status of gliomas and to develop relevant models for predicting prognosis and sensitivity to immunotherapy in gliomas.MethodsBulk and single-cell transcriptome data from TCGA, CGGA and GSE159416 were obtained for this study. Gliomas were classified based on nicotinamide and tryptophan metabolism, and PPI network associated with differentially expressed genes was established. The core genes were identified and the risk model was established by machine learning techniques, including univariate Cox regression and LASSO regression. Then the risk model was validated with data from the CGGA. Finally, the effects of genes in the risk model on the biological behavior of gliomas were verified by in vitro experiments.ResultsThe high nicotinamide and tryptophan metabolism is associated with poor prognosis and high levels of immune cell infiltration in glioma. Seven of the core genes related to nicotinamide and tryptophan metabolism were used to construct a risk model, and the model has good predictive ability for prognosis, immune microenvironment, and response to immune checkpoint therapy of glioma. We also confirmed that high expression of TGFBI can lead to an increased level of migration, invasion, and EMT of glioma cells, and the aforementioned effect of TGFBI can be reduced by FAK inhibitor PF-573,228.ConclusionsOur study evaluated the effects of nicotinamide and tryptophan metabolism on the prognosis and tumor immune microenvironment of glioma, which can help predict the prognosis and sensitivity to immunotherapy of glioma.

Potential cardiac-derived exosomal miRNAs involved in cardiac healing and remodeling after myocardial ischemia–reperfusion injury

Migratory cells exist in the heart, such as immune cells, fibroblasts, endothelial cells, etc. During myocardium injury, such as ischemia–reperfusion (MIRI), cells migrate to the site of injury to perform repair functions. However, excessive aggregation of these cells may exacerbate damage to the structure and function of the heart, such as acute myocarditis and myocardial fibrosis. Myocardial injury releases exosomes, which are a type of vesicle with signal transduction function and the miRNA carried by exosomes can control cell migration function. Therefore, regulating this migratory cell population through cardiac-derived exosomal miRNA is crucial for protecting and maintaining cardiac function. Through whole transcriptome RNA sequencing, exosomal miRNA sequencing and single-cell dataset analysis, we (1) determined the potential molecular regulatory role of the lncRNA‒miRNA‒mRNA axis in MIRI, (2) screened four important exosomal miRNAs that could be released by cardiac tissue, and (3) screened seven genes related to cell locomotion that are regulated by four miRNAs, among which Tradd and Ephb6 may be specific for promoting migration of different cells of myocardial tissue in myocardial infarct. We generated a core miRNA‒mRNA network based on the functions of the target genes, which may be not only a target for cardiac repair but also a potential diagnostic marker for interactions between the heart and other tissues or organs. In conclusion, we elucidated the potential mechanism of MIRI in cardiac remodeling from the perspective of cell migration, and inhibition of cellular overmigration based on this network may provide new therapeutic targets for MIRI and to prevent MIRI from developing into other diseases.

Dysregulation of muscle cholesterol transport in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons, with a typical lifespan of 3-5 years. Altered metabolism is a key feature of ALS that strongly influences prognosis, with an increase in whole-body energy expenditure and changes in skeletal muscle metabolism, including greater reliance on fat oxidation. Dyslipidemia has been described in ALS as part of the metabolic dysregulation, but its role in the pathophysiology of the disease remains controversial. Among the lipids, cholesterol is of particular interest as a vital component of cell membranes, playing a key role in signal transduction and mitochondrial function in muscle. The aim of this study was to investigate whether motor dysfunction in ALS might be associated with dysregulation of muscle cholesterol metabolism. We determined cholesterol content and analyzed the expression of key determinants of the cholesterol metabolism pathway in muscle biopsies from thirteen ALS patients and ten asymptomatic ALS-mutation gene carriers compared to sixteen controls. Using human control primary myotubes, we further investigated the potential contribution of cholesterol dyshomeostasis to reliance on mitochondrial fatty acid. We found that cholesterol accumulates in the skeletal muscle of ALS patients and that cholesterol overload significantly correlates with disease severity evaluated by the Revised ALS Functional Rating Scale. These defects are associated with overexpression of the genes of the lysosomal cholesterol transporters Niemann-Pick type C1 (NPC1) and 2 (NPC2), which are required for cholesterol transfer from late endosomes/lysosomes to cellular membranes. Most notably, a significant increase in NPC2 mRNA levels could be detected in muscle samples from asymptomatic ALS-mutation carriers, long before disease onset. We found that filipin-stained unesterified cholesterol accumulated in the lysosomal compartment in ALS muscle samples, suggesting dysfunction of the NPC1/2 system. Accordingly, we report here that experimental NPC1 inhibition or lysosomal pH alteration in human primary myotubes was sufficient to induce the overexpression of NPC1 and NPC2 mRNA. Finally, acute NPC1 inhibition in human control myotubes induced a shift towards a preferential use of fatty acids, thus reproducing the metabolic defect characteristic of ALS muscle. We conclude that cholesterol homeostasis is dysregulated in ALS muscle from the presymptomatic stage. Targeting NPC1/2 dysfunction may be a new therapeutic strategy for ALS to restore muscle energy metabolism and slow motor symptom progression.

Exploration of Synergistic Regulation Mechanisms of Cerebral Ganglion and Muscle in Eriocheir sinensis Activated in Response to Alkalinity Stress.

The cerebral ganglion and muscle are important regulatory tissues in Eriocheir sinensis. Therefore, it is of great significance to explore their synergistic roles in this organism's anti-stress response. In this study, proteomics, metabolomics, and combination analyses of the cerebral ganglion and muscle of E. sinensis under alkalinity stress were performed. The cerebral ganglion and muscle played a significant synergistic regulatory role in alkalinity adaptation. The key regulatory pathways involved were amino acid metabolism, energy metabolism, signal transduction, and the organismal system. They also played a modulatory role in the TCA cycle, nerve signal transduction, immune response, homeostasis maintenance, and ion channel function. In conclusion, the present study provides a theoretical reference for further research on the mechanisms regulating the growth and development of E. sinensis in saline-alkaline environments. In addition, it provides theoretical guidelines for promoting the vigorous development of the E. sinensis breeding industry in saline-alkaline environments in the future.

Transcriptome-wide m6A methylation and metabolomic analysis reveal regulatory networks in rice roots under manganese stress

Rice (Oryza sativa) has a higher tolerance to manganese (Mn) stress than other cereals. However, the regulatory mechanisms governing Mn tolerance in rice remain poorly understood. In this work, seedlings of the rice cultivar Nipponbare were treated with 1.0 mM MnCl2 for 10 days before root samples were collected for transcriptome-wide N6-methyladenosine (m6A) methylation and metabolome profiling. In the presence of extra Mn, we identified 2050 significantly modified m6A peaks and 2549 differentially expressed genes (DEGs). These DEGs were linked to key signaling pathways such as MAPK signaling, calcium signaling, and peroxides. Among these, 282 DEGs showed differential m6A methylation peaks, including 29 transcription factors, indicating they might be key upstream regulators of the Mn toxicity response. Furthermore, metabolomic research indicated considerable metabolic alterations in rice roots under Mn stress, notably in purine metabolism, amino acid biosynthesis, and glycerophospholipid metabolic pathways. Almost half of the metabolites were lipids or lipid-like compounds, indicating a potential function in signal transduction and membrane biogenesis. The findings lead to a better understanding of regulatory networks in rice roots that aid in Mn stress tolerance.

Regulation of Mitochondria-Derived Immune Activation by 'Antiviral' TRIM Proteins.

Mitochondria are key orchestrators of antiviral responses that serve as platforms for the assembly and activation of innate immune-signaling complexes. In response to viral infection, mitochondria can be triggered to release immune-stimulatory molecules that can boost interferon production. These same molecules can be released by damaged mitochondria to induce pathogenic, antiviral-like immune responses in the absence of infection. This review explores how members of the tripartite motif-containing (TRIM) protein family, which are recognized for their roles in antiviral defense, regulate mitochondria-based innate immune activation. In antiviral defense, TRIMs are essential components of immune signal transduction pathways and function as directly acting viral restriction factors. TRIMs carry out conceptually similar activities when controlling immune activation related to mitochondria. First, they modulate immune-signaling pathways that can be activated by mitochondrial molecules. Second, they co-ordinate the direct removal of mitochondria and associated immune-activating factors through mitophagy. These insights broaden the scope of TRIM actions in innate immunity and may implicate TRIMs in diseases associated with mitochondria-derived inflammation.

Essential role of glycoprotein Ibα in platelet activation

AbstractGlycoprotein Ibα (GPIbα), the ligand-binding subunit of platelet GPIb-IX complex, interacts with von Willebrand factor (VWF) exposed at the injured vessel wall, initiating platelet adhesion, activation, hemostasis, and thrombus formation. The cytoplasmic tail of GPIbα interacts with 14-3-3ζ, regulating the VWF-GPIbα–elicited signal transduction and VWF binding function of GPIbα. However, we unexpectedly found that the GPIbα–14-3-3ζ association, beyond VWF-dependent function, is essential for general platelet activation. We found that the myristoylated peptide of GPIbα C-terminus MPαC, a potential GPIbα inhibitor, by itself induced platelet aggregation, integrin αIIbβ3 activation, granule secretion, and phosphatidylserine (PS) exposure. Conversely, the deletion of the cytoplasmic tail of GPIbα in mouse platelets (10aa−/−) decreased platelet aggregation, integrin αIIbβ3 activation, granule secretion, and PS exposure induced by various physiological agonists. Phosphoproteome-based kinase activity profiling revealed significantly upregulated protein kinase C (PKC) activity in MPαC-treated platelets. MPαC-induced platelet activation was abolished by the pan-PKC inhibitor and PKCα deletion. Decreased PKC activity was observed in both resting and agonist-stimulated 10aa−/− platelets. GPIbα regulates PKCα activity by sequestering 14-3-3ζ from PKCα. In vivo, the deletion of the GPIbα cytoplasmic tail impaired mouse hemostasis and thrombus formation and protected against platelet-dependent pulmonary thromboembolism. Therefore, our findings demonstrate an essential role for the GPIbα cytoplasmic tail in regulating platelet general activation and thrombus formation beyond the VWF–GPIbα axis.

Glycosphingolipids in Osteoarthritis and Cartilage-Regeneration Therapy: Mechanisms and Therapeutic Prospects Based on a Narrative Review of the Literature.

Glycosphingolipids (GSLs), a subtype of glycolipids containing sphingosine, are critical components of vertebrate plasma membranes, playing a pivotal role in cellular signaling and interactions. In human articular cartilage in osteoarthritis (OA), GSL expression is known notably to decrease. This review focuses on the roles of gangliosides, a specific type of GSL, in cartilage degeneration and regeneration, emphasizing their regulatory function in signal transduction. The expression of gangliosides, whether endogenous or augmented exogenously, is regulated at the enzymatic level, targeting specific glycosyltransferases. This regulation has significant implications for the composition of cell-surface gangliosides and their impact on signal transduction in chondrocytes and progenitor cells. Different levels of ganglioside expression can influence signaling pathways in various ways, potentially affecting cell properties, including malignancy. Moreover, gene manipulations against gangliosides have been shown to regulate cartilage metabolisms and chondrocyte differentiation in vivo and in vitro. This review highlights the potential of targeting gangliosides in the development of therapeutic strategies for osteoarthritis and cartilage injury and addresses promising directions for future research and treatment.

β-Sitosterol Reduces the Content of Triglyceride and Cholesterol in a High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease Zebrafish (Danio rerio) Model.

Non-alcoholic fatty liver disease (NAFLD) is strongly associated with hyperlipidemia, which is closely related to high levels of sugar and fat. β-sitosterol is a natural product with significant hypolipidemic and cholesterol-lowering effects. However, the underlying mechanism of its action on aquatic products is not completely understood. A high-fat diet (HFD)-induced NAFLD zebrafish model was successfully established, and the anti-hyperlipidemic effect and potential mechanism of β-sitosterol were studied using oil red O staining, filipin staining, and lipid metabolomics. β-sitosterol significantly reduced the accumulation of triglyceride, glucose, and cholesterol in the zebrafish model. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that differential lipid molecules in β-sitosterol mainly regulated the lipid metabolism and signal transduction function of the zebrafish model. β-sitosterol mainly affected steroid biosynthesis and steroid hormone biosynthesis in the zebrafish model. Compared with the HFD group, the addition of 500 mg/100 g of β-sitosterol significantly inhibited the expression of Ppar-γ and Rxr-α in the zebrafish model by at least 50% and 25%, respectively. β-sitosterol can reduce lipid accumulation in the zebrafish model of NAFLD by regulating lipid metabolism and signal transduction and inhibiting adipogenesis and lipid storage.

Genome-Wide Identification and Expression Analysis of Kiwifruit Leucine-Rich Repeat Receptor-Like Proteins Reveal Their Roles in Biotic and Abiotic Stress Responses.

Leucine-rich repeat receptor-like proteins (LRR-RLPs), a major group of receptor-like proteins in plants, have diverse functions in plant physiology, including growth, development, signal transduction, and stress responses. Despite their importance, the specific roles of kiwifruit LRR-RLPs in response to biotic and abiotic stresses remain poorly understood. In this study, we performed family identification, characterization, transcriptome data analysis, and differential gene expression analysis of kiwifruit LRR-RLPs. We identified totals of 101, 164, and 105 LRR-RLPs in Actinidia chinensis 'Hongyang', Actinidia eriantha 'Huate', and Actinidia chinensis 'Red5', respectively. Synteny analysis revealed that the expansion of kiwifruit LRR-RLPs was primarily attributed to segmental duplication events. Based on RNA-seq data from pathogen-infected kiwifruits, we identified specific LRR-RLP genes potentially involved in different stages of pathogen infection. Additionally, we observed the potential involvement of kiwifruit LRR-RLPs in abiotic stress responses, with upstream transcription factors possibly regulating their expression. Furthermore, protein interaction network analysis unveiled the participation of kiwifruit LRR-RLP in the regulatory network of abiotic stress responses. These findings highlight the crucial roles of LRR-RLPs in mediating both biotic and abiotic stress responses in kiwifruit, offering valuable insights for the breeding of stress-resistant kiwifruit varieties.

The Role of Sulfhydryl (Thiols) Groups in Oral and Periodontal Diseases.

The sulfhydryl (thiols) group of glutathione plays an important role in the neutralization of foreign organic compounds and the reduction in peroxides. The purpose of the study is to evaluate the concentration of sulfhydryl groups in the gingival tissue of healthy individuals and those with gingivitis or periodontitis, and to examine the differences between these groups. To assess the concentration of sulfhydryl groups (thiols) in the gingival tissue of healthy individuals and those with gingivitis or periodontitis, we used spectrophotometric analysis using dithionitrobenzoate (DTNB) as a reagent to measure the accessible sulfhydryl groups present in gingival tissue proteins. The sample was divided into three distinct groups: individuals with periodontal health, gingivitis, and periodontitis, and different indices were used to assess the periodontal status of the participants. Next, a statistical analysis was conducted to compare the concentrations of sulfhydryl groups among the different groups of patients. The results of this study showed significantly decreased levels of sulfhydryl (thiols) groups in gingival tissue from patients with gingivitis and periodontitis, compared with healthy people (control group). These results confirm the role of sulfhydryl (thiols) groups in defense against free radicals. They share a significant role in detoxification, signal transduction, apoptosis, and various other functions at the molecular level.

Abstract LB225: Regulation of breast cancer stem cell identity by PLK1 and FOXC2

Abstract One of the main drivers for the drastic reduction in survival rates caused by metastatic breast cancer is attributed to Epithelial-to-Mesenchymal Transition (EMT). During embryonic development and wound healing, EMT plays a vital role and during cancer pathogenesis, cancer cells reactivate this program to gain plasticity, migration, and invasion promoting metastasis. In addition, EMT also plays a crucial role in generating a subpopulation of highly resilient tumor cells known as cancer stem cells (CSCs). Moreover, following conventional treatment, residual tumor cells that remain after treatment tend to exhibit CSC properties. EMT-induced cancer stem cells exhibit heightened plasticity and stemness, significantly fueling the metastatic spread of cancer and enhancing the endurance and adaptability throughout the process of metastasis. Thus, understanding the molecular intricacies governing stem cell properties holds immense potential for developing targeted therapies to target metastasis and the development of resistance to treatments. To further elucidate EMT-induced cancer stem cell generation, our lab has demonstrated that the Polo-like kinase 1 (PLK1), an important G2/M regulator, plays an important role in the generation of CSCs through Forkhead box protein C2 (FOXC2). Most importantly, we have shown that the FOXC2 transcription factor, known to be crucial in embryonic development, now has emerging roles in metastatic cancer progression. FOXC2 is positioned at the center of the complex network of signal transduction pathways and functions downstream of most EMT-inducing transcription factors. FOXC2 is necessary for the acquisition and maintenance of stem cell property. In addition, we found that phosphorylation of FOXC2 by PLK1 stabilizes, and inhibition of PLK1 causes a decrease in FOXC2 and stemness in cancer cells. This led us to hypothesize that EMT-induced CSC generation is driven by the PLK1-FOXC2 axis. By expressing phosphomimetic and non-phosphorylatable FOXC2 mutants in breast cancer cell lines, we show that PLK1 phosphorylation is necessary for gaining stemness and an increase in symmetric self-renewal type of stem cell division. Evidence will be presented as to how we are targeting the PLK1-FOXC2 axis to make tumors sensitive to standard-of-care treatments. Citation Format: Joanna Joyce Maddela, Maria Castaneda, Petra den Hollander, Nick Kuburich, Sendurai Mani. Regulation of breast cancer stem cell identity by PLK1 and FOXC2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB225.

Phylogeny and Expansion of Serine/Threonine Kinases in Phagocytotic Bacteria in the Phylum Planctomycetota.

The recently isolated bacterium "Candidatus Uabimicrobium amorphum" is the only known prokaryote that can engulf other bacterial cells. Its proteome contains a high fraction of proteins involved in signal transduction systems, which is a feature normally associated with multicellularity in eukaryotes. Here, we present a protein-based phylogeny which shows that "Ca. Uabimicrobium amorphum" represents an early diverging lineage that clusters with the Saltatorellus clade within the phylum Planctomycetota. A gene flux analysis indicated a gain of 126 protein families for signal transduction functions in "Ca. Uabimicrobium amorphum", of which 66 families contained eukaryotic-like Serine/Threonine kinases with Pkinase domains. In total, we predicted 525 functional Serine/Threonine kinases in "Ca. Uabimicrobium amorphum", which represent 8% of the proteome and is the highest fraction of Serine/Threonine kinases in a bacterial proteome. The majority of Serine/Threonine kinases in this species are membrane proteins and 30% contain long, tandem arrays of WD40 or TPR domains. The pKinase domain was predicted to be located in the cytoplasm, while the WD40 and TPR domains were predicted to be located in the periplasm. Such domain combinations were also identified in the Serine/Threonine kinases of other species in the Planctomycetota, although in much lower abundances. A phylogenetic analysis of the Serine/Threonine kinases in the Planctomycetota inferred from the Pkinase domain alone provided support for lineage-specific expansions of the Serine/Threonine kinases in "Ca. Uabimicrobium amorphum". The results imply that expansions of eukaryotic-like signal transduction systems are not restricted to multicellular organisms, but have occurred in parallel in prokaryotes with predatory lifestyles and phagocytotic-like behaviors.

An ensemble computational model for prediction of clathrin protein by coupling machine learning with discrete cosine transform

Clathrin protein (CP) plays a pivotal role in numerous cellular processes, including endocytosis, signal transduction, and neuronal function. Dysregulation of CP has been associated with a spectrum of diseases. Given its involvement in various cellular functions, CP has garnered significant attention for its potential applications in drug design and medicine, ranging from targeted drug delivery to addressing viral infections, neurological disorders, and cancer. The accurate identification of CP is crucial for unraveling its function and devising novel therapeutic strategies. Computational methods offer a rapid, cost-effective, and less labor-intensive alternative to traditional identification methods, making them especially appealing for high-throughput screening. This paper introduces CL-Pred, a novel computational method for CP identification. CL-Pred leverages three feature descriptors: Dipeptide Deviation from Expected Mean (DDE), Bigram Position Specific Scoring Matrix (BiPSSM), and Position Specific Scoring Matrix-Tetra Slice-Discrete Cosine Transform (PSSM-TS-DCT). The model is trained using three classifiers: Support Vector Machine (SVM), Extremely Randomized Tree (ERT), and Light eXtreme Gradient Boosting (LiXGB). Notably, the LiXGB-based model achieves outstanding performance, demonstrating accuracies of 94.63% and 93.65% on the training and testing datasets, respectively. The proposed CL-Pred method is poised to significantly advance our comprehension of clathrin-mediated endocytosis, cellular physiology, and disease pathogenesis. Furthermore, it holds promise for identifying potential drug targets across a spectrum of diseases. Communicated by Ramaswamy H. Sarma

Dysregulation of sphingolipid metabolism in pain.

Pain is a clinical condition that is currently of great concern and is often caused by tissue or nerve damage or occurs as a concomitant symptom of a variety of diseases such as cancer. Severe pain seriously affects the functional status of the body. However, existing pain management programs are not fully satisfactory. Therefore, there is a need to delve deeper into the pathological mechanisms underlying pain generation and to find new targets for drug therapy. Sphingolipids (SLs), as a major component of the bilayer structure of eukaryotic cell membranes, also have powerful signal transduction functions. Sphingolipids are abundant, and their intracellular metabolism constitutes a huge network. Sphingolipids and their various metabolites play significant roles in cell proliferation, differentiation, apoptosis, etc., and have powerful biological activities. The molecules related to sphingolipid metabolism, mainly the core molecule ceramide and the downstream metabolism molecule sphingosine-1-phosphate (S1P), are involved in the specific mechanisms of neurological disorders as well as the onset and progression of various types of pain, and are closely related to a variety of pain-related diseases. Therefore, sphingolipid metabolism can be the focus of research on pain regulation and provide new drug targets and ideas for pain.

The growth factor multimodality on treating human dental mesenchymal stem cells: a systematic review

BackgroundEnsuring the quantity, quality, and efficacy of human dental mesenchymal stem cells (MSCs) has become an urgent problem as their applications increase. Growth factors (GFs) have low toxicity, good biocompatibility, and regulate stem cell survival and differentiation. They bind to specific receptors on target cells, initiating signal transduction and triggering biological functions. So far, relatively few studies have been conducted to summarize the effect of different GFs on the application of dental MSCs. We have reviewed the literature from the past decade to examine the effectiveness and mechanism of applying one or multiple GFs to human dental MSCs. Our review is based on the premise that a single dental MSC cannot fulfill all applications and that different dental MSCs react differently to GFs.MethodsA search for published articles was carried out using the Web of Science core collection and PubMed. The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines. This review considered studies from 2014 to 2023 that examined the effects of GFs on human dental MSCs. The final selection of articles was made on the 15th of July 2023.ResultsThree thousand eight hundred sixty-seven pieces of literature were gathered for this systematic review initially, only 56 of them were selected based on their focus on the effects of GFs during the application of human dental MSCs. Out of the 56, 32 literature pieces were focused on a single growth factor while 24 were focused on multiple growth factors. This study shows that GFs can regulate human dental MSCs through a multi-way processing manner.ConclusionMultimodal treatment of GFs can effectively regulate human dental MSCs, ensuring stem cell quality, quantity, and curative effects.

Impact of wine-grape continuous cropping on soil enzyme activity and the composition and function of the soil microbial community in arid areas.

Continuous cropping affected the stability of soil enzyme activity and the structural characteristics of microbial community. Owing to challenges in the study of complex rhizosphere microbial communities, the composition and function of these microbial communities in farmland ecosystems remain elusive. Here, we studied the microbial communities of the rhizosphere of wine grapes with different years of continuous cropping and investigated their relationships with soil enzyme activity. Metagenomic sequencing was conducted on the rhizosphere soils from one uncultivated wasteland and four vineyards with varying durations of continuous cropping. The predominant microbial were bacteria (98.39%), followed by archaea (1.15%) and eukaryotes (0.45%). Continuous cropping caused a significant increase in the relative abundance of Rhizobiales and Micrococcales but a marked decrease in Solirubrobacterales. At the genus level, 75, 88, 65, 132, and 128 microbial genera were unique to uncultivated wasteland, 5, 10, 15, and 20 years of continuous cropping, respectively. The relative abundance of genes with signal transduction function was the highest. The activity of all enzymes measured in this study peaked at 5 years of continuous cropping, and then decreased with 10 to 15 year of continuous cropping, but increased at 20 years again. In addition, soil enzyme activity, especially of alkaline phosphatase was significantly correlated with the diversity of the dominant microorganisms at the genus level. Moreover, the coupled enzyme activities had a greater impact on the diversity of the microbial community than that of individual enzymes. Our findings reveal the composition and function of the soil microbial communities and enzymes activity in response to changes in cropping years, which has important implications for overcoming continuous cropping obstacles and optimizing land use.