Signal Transduction Mechanisms Research Articles

Dynamical nonequilibrium molecular dynamics simulations reveal allosteric networks, signal transduction mechanisms, and sites associated with drug resistance in biomolecular systems

Dynamical nonequilibrium molecular dynamics simulations reveal allosteric networks, signal transduction mechanisms, and sites associated with drug resistance in biomolecular systems

Exosome-mediated viral nucleic acid presentation in a crustacean expounds innate immunity from a novel perspective.

Our study revealed that the components of DNA virus could be packaged and transmitted through the exosomes of lower invertebrates, which strongly demonstrated the diversity of exosome-mediated viral immunity and its universality in animals. Furthermore, we elucidated the mechanism of apoptotic signal transduction between cells from the perspective of exosomes and revealed a novel strategy for the host to cope with viral infection.

Recent Advances in Artificial Sensory Neurons: Biological Fundamentals, Devices, Applications, and Challenges.

Spike-based neural networks, which use spikes or action potentials to represent information, have gained a lot of attention because of their high energy efficiency and low power consumption. To fully leverage its advantages, converting the external analog signals to spikes is an essential prerequisite. Conventional approaches including analog-to-digital converters or ring oscillators, and sensors suffer from high power and area costs. Recent efforts are devoted to constructing artificial sensory neurons based on emerging devices inspired by the biological sensory system. They can simultaneously perform sensing and spike conversion, overcoming the deficiencies of traditional sensory systems. This review summarizes and benchmarks the recent progress of artificial sensory neurons. It starts with the presentation of various mechanisms of biological signal transduction, followed by the systematic introduction of the emerging devices employed for artificial sensory neurons. Furthermore, the implementations with different perceptual capabilities are briefly outlined and the key metrics and potential applications are also provided. Finally, we highlight the challenges and perspectives for the future development of artificial sensory neurons.

Novel Ser74 of NF-κB/IκBα phosphorylated by MAPK/ERK regulates temperature adaptation in oysters.

Phosphorylation of Ser32 and Ser36 controls the degradation of IκBα is the conserved cascade mechanisms of immune core signaling pathway, NF-κB pathway in metazoans, but it's response to abiotic stress and the presence of novel phosphorylation mechanisms in other species remain unclear. Herein, we reported a novel heat-induced phosphorylation site (Ser74) at oysters' major IκBα, which independently regulated ubiquitination-proteasome degradation without the requirement of phosphorylation at S32 and S36. And this site was phosphorylated by ERK/MAPK pathway, which then promoted REL nuclear translocation to activate cell survival related genes to defend heat-stress. The MAPK-NF-κB cascade exhibited divergent thermal responses and adaptation patterns between two congeneric oyster species with differential habitat temperatures, indicating its involvement in shaping temperature adaptation. This study demonstrated that the existence of complex and unique phosphorylation-mediated signaling transduction mechanism in marine invertebrates, and expanded our understanding of the evolution and function of established classical pathway crosstalk mechanisms.

Transcriptome analysis of mammary epithelial cell between Sewa sheep and East FriEsian sheep from different localities.

Mammary epithelial cells, the only milk-producing cell type in the mammary gland, undergo dynamic proliferation and differentiation during pregnancy, culminating in lactation postpartum. The East FriEsian sheep ranks among the world's most prolific dairy breeds, while the Sewa sheep, a unique dual-purpose breed autochthonous to the Qinghai-Tibet Plateau, exhibits significantly lower milk production. Employing tissue culture methods, we successfully established mammary epithelial cell lines from both breeds. Morphological assessment of mammary epithelial cells and immunofluorescence identification of Cytokeratin 7 and Cytokeratin 8 confirmed the epithelial identity of the isolated cells. Subsequent RNA-seq analysis of these in vitro epithelial cell lines revealed 1813 differentially expressed genes (DEGs). Among these, 1108 were significantly up-regulated and 705 were down-regulated in Sewa epithelial sheep cells compared to East FriEsian epithelial cells. KEGG enrichment analysis identified cellular processes, environmental information processing, human diseases, metabolism, and organismal systems as the primary functional categories associated with DEGs. Gene ontology (GO) terms annotation, categorized into molecular function, biological processes, and cellular component, yielded "binding and catalytic activity," "molecular function regulator activity," and "cellular process," "biological regulation," and "regulation of biological process" as the top three terms within each domain, respectively. Clusters of Orthologous Groups of proteins (KOG) classification further revealed that "signal transduction mechanisms" accounted for the largest proportion of DEGs among all KOG categories. Finally, based on these analyses, ATF3 and MPP7 were identified as promising candidate genes for regulating lactation.

OsPIPK-FAB, A Negative Regulator in Rice Immunity Unveiled by OsMBL1 Inhibition

Phosphatidylinositol signaling system plays a crucial role in plant physiology and development, phosphatidylinositol phosphate kinases (PIPKs) are one of the essential enzymes responsible for catalyzing the synthesis of phosphatidylinositol bisphosphate (PIP2) within this signaling pathway. However, its mechanism of signal transduction remains poorly exploited in plants. OsMBL1, a jacalin-related mannose-binding lectin in rice, plays a crucial role in plant defense mechanisms, acting as a key component of the pattern-triggered immunity (PTI) pathway. Here, a rice phosphatidylinositol-phosphate kinase FAB (OsPIPK-FAB), a member of the rice PIPKs family, as an interacting protein of OsMBL1 through yeast-two-hybrid (Y2H) screening assay. And this interaction was confirmed by using co-immunoprecipitation (Co-IP) and pull-down assay techniques. Furthermore, we demonstrated that the deletion of OsPIPK-FAB gene in plant enhanced resistance against rice blast while overexpression of OsPIPK-FAB increases sensitivity to the fungal infection. Additionally, through determination and measurement of the plant inositol 1,4,5-trisphosphate (IP3) contents and the plant phosphatidylinositol 4-phosphate 5-kinase (PIP5K) activity, we revealed that OsMBL1 inhibits the PIP5K kinase activity of OsPIPK-FAB as well as the plant IP3 contents in rice. Conclusively, these findings indicated that OsPIPK-FAB serves as a novel and critical component that is negatively involved in PTI activation and was inhibited by OsMBL1.

The role of IL-17 family cytokines in cardiac fibrosis.

Myocardial fibrosis is a common pathological feature in various cardiovascular diseases including myocardial infarction, heart failure, and myocarditis. Generally, persistent myocardial fibrosis correlates with poor prognosis and ranks among the leading causes of death globally. Currently, there is no effective treatment for myocardial fibrosis, partly due to its unclear pathogenic mechanism. Increasing studies have shown IL-17 family cytokines are strongly associated with the initiation and propagation of myocardial fibrosis. This review summarizes the expression, action, and signal transduction mechanisms of IL-17, focusing on its role in fibrosis associated with cardiovascular diseases such as myocardial infarction, heart failure, hypertension, diabetes, and myocarditis. It also discusses its potential as a therapeutic target, offering new insights for the clinical treatment of myocardial fibrosis.

Beneficial effects of AMP Scy-hepc on the gut microbiota contribute to the potential growth of Larimichthys crocea

BackgroundIn light of the global ban on antibiotics in animal feed, antimicrobial peptides (AMPs) have emerged as a compelling substitute, garnering considerable interest for their potential as feed additives. Our previous study revealed that the extended (one-year) daily administration of the AMP Scy-hepc substantially boosted the growth of Larimichthys crocea. However, the exact influence of dietary supplementation with AMPs on the gut microbiota and the potential beneficial mechanisms remain unclear. Inspired by this, the present study endeavors to examine the alterations in gut microbiota at various gut sites in L. crocea following a 60-day Scy-hepc feeding regimen, building upon our prior research efforts.ResultsUtilizing 16S rRNA sequencing, we found that dietary supplementation with Scy-hepc significantly promoted the growth of L. crocea, which may be caused by the remarkable changes in the microbial communities within the foregut and midgut. Notable changes were observed in Tenericutes, Firmicutes, Proteobacteria, Cyanobacteria and Spirochaetes. The bacterial load trends in both the foregut and midgut demonstrated a notable increase following a 60-day Scy-hepc feeding, as determined by absolute quantitative PCR analysis. Moreover, Scy-hepc supplementation increased the abundance of potential probiotics (Rhodobiaceae and Planococcaceae) and reduced the abundance of opportunistic pathogens (Flavobacteriia and Mollicutes). This led to a more intricate microbial network with enhanced metabolism-related functions, especially in lipid transport and metabolism, signal transduction mechanisms, and coenzyme transport and metabolism. And the microbial resistance (Rs) exhibits no significant change between the Scy-hepc and control groups, indicating a minimal level of toxicity to the gut microbiota of L. crocea.ConclusionsIn summary, this study provides compelling evidences supporting the beneficial alteration of gut microbiota in the foregut and midgut as an underlying mechanism by which Scy-hepc feeding promotes host growth. These findings offer a novel perspective for investigating the advantageous effects of AMPs on fish health and the advancement of aquaculture.

Targeting New Functions and Applications of Bacterial Two-Component Systems.

Two-component signal transduction systems (TCSs) are regulatory systems widely distributed in eubacteria, archaea, and a few eukaryotic organisms, but not in mammalian cells. A typical TCS consists of a histidine kinase and a response regulator protein. Functional and mechanistic studies on different TCSs have greatly advanced the understanding of cellular phosphotransfer signal transduction mechanisms. In this concept paper, we focus on the His-Asp phosphotransfer mechanism, the ATP synthesis function, antimicrobial drug design, cellular biosensors design, and protein allostery mechanisms based on recent TCS investigations to inspire new applications and future research perspectives.

Oral supplementation with lactic acid bacteria improve the intestinal epithelial barrier and gut microbiota of broiler chicks to alleviate Salmonella Enteritidis infection

Lactic acid bacteria (LAB) play a key role in regulating the balance of gut microbiota and serve as a suitable alternative to antibiotics. This study aims to evaluate the characteristics of 2 LAB isolates Lactiplantibacillus plantarum Lp71 (L. plantarum Lp71) and Enterococcus faecium Ef72 (E. faecium Ef72), and their roles in alleviating Salmonella Enteritidis infection. Sixty 1-day-old chicks were randomly divided into 4 groups which treated with or without L. plantarum Lp71 and E. faecium Ef72 mixture for 21 d, and then intestinal samples were collected for gut microbiota analysis, pathological and immunohistochemical analysis at 24 h post infection with or without Salmonella Enteritidis on the 22nd d. The results showed that L. plantarum Lp71 and E. faecium Ef72 had the ability to anti-acid and anti-bile salt. Salmonella Enteritidis infection damaged the intestinal epithelial barrier and reduced the expression level of tight junction proteins (ZO-1, Claudin-1, Occludin). Oral supplementation with L. plantarum Lp71 and E. faecium Ef72 mixture could alleviated the damages to intestinal epithelial barrier by Salmonella Enteritidis infection. Salmonella Enteritidis could cause abnormal Akkermansia muciniphila proliferation and decrease the diversity of cecal microbiota in chicks. These conditions could have further led to reduce gut microbiota health index (GMHI), and improve microbial dysbiosis index (MDI). Moreover, oral supplementation with L. plantarum Lp71 and E. faecium Ef72 mixture could effectively prevent the aforementioned infection outcomes and increase the abundance proportions of the several key functions in metabolic pathways metabolic pathways such as transcription and signal transduction mechanisms. In summary, L. plantarum Lp71 and E. faecium Ef72 could be the probiotics candidates that used to prevent the damage from enteric pathogens such as Salmonella Enteritidis in broiler chicks.

Pharmacological inhibition reveals participation of the endocytic compartment in positive feedback IL-6 secretion in human skeletal myotubes

IL-6 is an important cytokine involved in metabolic, immunological, and cell-fate responses. It is released upon stimulation by skeletal muscle cells through partially characterized mechanisms. In some cell types, IL-6 has been reported to activate a positive feedback loop involving endocytic vesicles, but evidence is mostly based on transcription and signal transduction mechanisms and is very scarce in muscle cells. Our aim was to directly demonstrate the presence of positive feedback in the ATP-induced release of IL-6 into the supernatant of human skeletal muscle cultures. The total release (production) of IL-6 was reduced for higher volumes of supernatant, when the secreted IL-6 molecules are more diluted, and enhanced when the supernatant volume was lower. In addition, secretion was impaired both by tocilizumab, a blocker of human IL-6 receptors, and by the soluble form of the receptor. The secretion in response to ATP was also inhibited by treatment with the endocytosis inhibitor dynasore, and by disruption of the acidic gradient of the endocytic compartment using different methods (chloroquine, NH4Cl or monensin). IL-6 secretion was also impaired by NED-19, a specific inhibitor of the two pore channels receptor mediating Ca2+ release from the endolysosomal compartment. IL-6 and ATP increased IL-6 mRNA levels, an effect blocked by tocilizumab. Altogether, our results demonstrate that ATP-secreted IL-6 activates a positive loop based on IL-6 receptors, endocytosis, two pore channels and IL-6 transcription. Given the importance of muscle IL-6 as a systemic regulator and as an inflammatory mediator, our study can help to understand muscle pathophysiology.

Mechanisms of RET mediated signal transduction.

The RET receptor tyrosine kinase is physiologically stimulated by growth factors belonging to the glial cell line-derived neurotrophic factor (GDNF) family (GFLs) and by the growth differentiation factor-15 (GDF15) cytokine. RET plays a critical role in normal development as well as in various human tumors and developmental disorders. This review focuses on mechanisms of RET signaling and their alterations in human diseases.

Olfactory cilia, regulation and control of olfaction.

The sense of smell is still considered a fuzzy sensation. Softly wafting aromas can stimulate the appetite and trigger memories; however, there are many unexplored aspects of its underlying mechanisms, and not all of these have been elucidated. Although the final sense of smell takes place in the brain, it is greatly affected during the preliminary stage, when odorants are converted into electrical signals. After signal conversion through ion channels in olfactory cilia, action potentials are generated through other types of ion channels located in the cell body. Spike trains through axons transmit this information as digital signals to the brain, however, before odorants are converted into digital electric signals, such as an action potential, modification of the transduction signal has already occurred. This review focuses on the early stages of olfactory signaling. Modification of signal transduction mechanisms and their effect on the human sense of smell through three characteristics (signal amplification, olfactory adaptation, and olfactory masking) produced by olfactory cilia, which is the site of signal transduction are being addressed in this review.

Interactions between Brassinosteroids and Strigolactones in Alleviating Salt Stress in Maize.

Exogenous brassinolide (BR) and strigolactones (SLs) play an important role in alleviating salt stress in maize. We studied the morphological and physiological responses of the salt-sensitive genotype PH4CV and salt-tolerant genotype Zheng58 to BR (1.65 nM), SL (1 µM), and BS (1.65 nM BR + 1 µM SL) under salt stress. Phenotypic analysis showed that salt stress significantly inhibited the growth of maize seedlings and significantly increased the content of Na+ in the roots. Exogenous hormones increased oxidase activity and decreased Na+ content in the roots and mitigated salt stress. Transcriptome analysis showed that the interaction of BR and SL is involved in photosynthesis-antenna proteins, the TCA cycle, and plant hormone signal transduction pathways. This interaction influences the expression of chlorophyll a/b-binding protein and glucose-6-phosphate isomerase 1 chloroplastic, and aconitase genes are affected. Furthermore, the application of exogenous hormones regulates the expression of genes associated with the signaling pathways of cytokinin (CK), gibberellins (GA), auxin (IAA), brassinosteroid (BR), abscisic acid (ABA), and jasmonic acid (JA). Additionally, exogenous hormones inhibit the expression of the AKT2/3 genes, which are responsible for regulating ion transduction and potassium ion influx. Four candidate genes that may regulate the seedling length of maize were screened out through WGCNA. Respective KOG notes concerned inorganic ion transport and metabolism, signal transduction mechanisms, energy production and conversion, and amino acid transport and metabolism. The findings of this study provide a foundation for the proposition that BR and SL can be employed to regulate salt stress alleviation in maize.

Multifunctional Ethyl Violet@NH2-MIL-88B(Fe) Hybrids: CRISPR-Cas12a-Assisted PEC-FL-CL Triple-Mode Sensitive Detection of HPV-16.

The multimode assay based on multiple response mechanisms has received great attention to effectively improve the accuracy of a sensing platform. However, multifunctional sensing materials for simultaneously satisfying the multiple-mode detections are still in shortage due to the incompatibility of the signal transduction mechanisms in different modes. Here, taking human papillomavirus 16 (HPV-16) DNA (TDNA) as the model due to its important role in cervical cancer, a novel multifunctional material, ethyl violet (EV)@NH2-MIL-88B(Fe) (ENM) hybrids, have been successfully prepared, which could simultaneously satisfy CRISPR-Cas12a-assisted photoelectrochemical (PEC)-fluorescent (FL)-colorimetric (CL) triple-mode detection of TDNA. Based on the TDNA-induced trans-cleavage ability of CRISPR-Cas12a and efficient separation of magnetic beads, ENM was obtained from the single-stranded DNA-surrounded streptavidin-modified magnetic beads-ENM (SMB-ssDNA-ENM) and decomposed by pyrophosphate to get free EV, 2-aminoterephthalic acid (NH2-BDC), and Fe3+. Thus, TDNA was sensitively detected based on the EV-enhanced PEC signal of SnS2 nanosheets (PEC mode), fluorescent signal of NH2-BDC (FL mode), and characteristic absorption peak at about 720 nm of Fe3+-induced Prussian blue (PB) (CL mode). The designed PEC-FL-CL triple-mode biosensing platform had good performance for the detection of TDNA with a wide linear range (0.1 fM-100 nM) and ultralow detection limits (0.07 fM for PEC, 0.03 fM for FL and 0.09 fM for CL). Additionally, the developed PEC-FL-CL triple-mode biosensing platform has great potential for applications in early disease diagnosis and bioanalysis, as it can be easily extended to other DNA assays through modification of the crRNA sequence within the CRISPR-Cas12a system.

Exogenous methyl jasmonate induces CHS and promotes flavonoid accumulation in Zanthoxylum bungeanum

Methyl jasmonate (MeJA) is widely involved in the life processes of plants, especially playing an active role in regulating the synthesis and accumulation of metabolites. Prickly ash (Zanthoxylum bungeanum), as a species of spice tree, is rich in flavonoids throughout its entire plant, showing enormous potential for development into functional foods. Flavonoids play crucial roles in signal transduction and defense mechanisms between plants and their environment, influencing the ecological adaptability of plants. Analyzing the regulatory relationship between methyl jasmonate and flavonoid metabolites will help understand the self-protection mechanism of Zanthoxylum bungeanum under adverse stress. Research results show that the upstream promoter of CHSs (Chalcone synthase), a key gene for flavonoid synthesis, contains multiple methyl jasmonate response elements. Exogenous MeJA induction experiments proved that MeJA can significantly increase the expression levels of ZbCHS71, ZbCHS43 and ZbCHS26 in different tissues of Zanthoxylum bungeanum and directly promote the synthesis and accumulation of flavonoid metabolites. The research results help analyze the regulatory relationship between methyl jasmonate and flavonoids, and provide a reference for research on the accumulation of protective substances under stress conditions in Zanthoxylum bungeanum.

The signal that stimulates mammalian embryo development.

Embryo development is stimulated by calcium (Ca2+) signals that are generated in the egg cytoplasm by the fertilizing sperm. Eggs are formed via oogenesis. They go through a cell division known as meiosis, during which their diploid chromosome number is halved and new genetic combinations are created by crossing over. During formation the eggs also acquire cellular components that are necessary to produce the Ca2+ signal and also, to support development of the newly formed embryo. Ionized calcium is a universal second messenger used by cells in a plethora of biological processes and the eggs develop a "toolkit", a set of molecules needed for signaling. Meiosis stops twice and these arrests are controlled by a complex interaction of regulatory proteins. The first meiotic arrest lasts until after puberty, when a luteinizing hormone surge stimulates meiotic resumption. The cell cycle proceeds to stop again in the middle of the second meiotic division, right before ovulation. The union of the female and male gametes takes place in the oviduct. Following gamete fusion, the sperm triggers the release of Ca2+ from the egg's intracellular stores which in mammals is followed by repetitive Ca2+ spikes known as Ca2+ oscillations in the cytosol that last for several hours. Downstream sensor proteins help decoding the signal and stimulate other molecules whose actions are required for proper development including those that help to prevent the fusion of additional sperm cells to the egg and those that assist in the release from the second meiotic arrest, completion of meiosis and entering the first mitotic cell division. Here I review the major steps of egg formation, discuss the signaling toolkit that is essential to generate the Ca2+ signal and describe the steps of the signal transduction mechanism that activates the egg's developmental program and turns it into an embryo.

Resistant starch confers protection of dietary against diabetic cardiomyopathy

Long-term dysfunction of glucose metabolism causes cardiac dysfunction called diabetic cardiomyopathy (DCM). To investigate the effect and underlying mechanism of RS on the process of DCM, mouse models induced by a high-fat diet (HFD) and streptozotocin (STZ) were fed RS (2 g/kg/day) and vehicle treatment (by oral gavage) for 14 weeks. Various analyses, including qRT-PCR, western blot, immunofluorescence staining, histology staining, cardiac function, and diversity detection of intestinal microbiota were performed. RS intervention could directly improve myocardial fibrosis, hypertrophy, apoptosis, and cardiac insufficiency in DCM. These beneficial effects may be achieved by elevating the expression of IGF-1, activating the ERK phosphorylation. Furthermore, by carrying out nano LC-MS/MS analyses and 16S rDNA sequencing, we found RS might primarily affect proteins in the cytoplasm involved in post-translational modification, protein conversion, and signal transduction mechanisms. RS altered intestinal microbiota and improved intestinal mucosal permeability towards a favorable direction in DCM. This multidimensional assessment of RS suggests that might be a promising approach towards the treatment of DCM.

Artificial basilar membrane/hair cell integrated acoustic system for keyword spotting in noisy environments inspired by human cochlea

We report a novel speech recognition method using a noise-robust acoustic sensor system that integrates a spatially frequency-separating sensor with a nonlinear amplification algorithm, mimicking the cochlea’s basilar membrane and hair cells. The multichannel piezoelectric artificial basilar membrane (ABM) sensor detects specific sound frequencies with high sensitivity over 0.2–6 kHz. The signal processing model of the Artificial Hair Cell inspired by the signal transduction mechanism of inner hair cells, simultaneously enhances the frequency selectivity of ABM sensors and improves noise robustness. In a 0 dB SNR noisy environment, it effectively detected the voice signal with a maximum SNR of 57 dB. Furthermore, we converted the frequency-separated signals for speech sounds in various noisy environments into heatmap images and utilized them as input for a CNN-based speech recognition algorithm. Consequently, our system demonstrated noise-robust recognition performance with 94 % accuracy, even in noisy environments.

Screening of herbal extracts binding with vascular endothelial growth factor by applying HerboChip platform

BackgroundTraditional Chinese medicine (TCM) has been hailed as a rich source of medicine, but many types of herbs and their functions still need to be rapidly discovered and elucidated. HerboChip, a target-based drug screening platform, is an array of different fractions deriving from herbal extracts. This study was designed to identify effective components from TCM that interact with vascular endothelial growth factor (VEGF) as a target using HerboChip.MethodsSelected TCMs that are traditionally used as remedies for cancer prevention and wound healing were determined and extracted with 50% ethanol. Biotinylated-VEGF was hybridized with over 500 chips coated with different HPLC-separated fractions from TCM extracts and straptavidin-Cy5 was applied to identify plant extracts containing VEGF-binding fractions. Cytotoxicity of selected herbal extracts and their activities on VEGF-mediated angiogenic functions were evaluated.ResultsOver 500 chips were screened within a week, and ten positive hits were identified. The interaction of the identified herbal extracts with VEGF was confirmed in cultured endothelial cells. The identified herbs promoted or inhibited VEGF-mediated cell proliferation, migration and tube formation. Results from western blotting analysis demonstrated the identified herbal extracts significantly affected VEGF-triggered phosphorylations of eNOS, Akt and Erk. Five TCMs demonstrated potentiating activities on the VEGF response and five TCMs revealed suppressive activities.ConclusionsThe current results demonstrated the applicability of the HerboChip platform and systematically elucidated the activity of selected TCMs on angiogenesis and its related signal transduction mechanisms.