ABSTRACT
Anaplastic lymphoma kinase (ALK) is a well-known oncogene involved in various malignancies such as anaplastic large cell lymphoma, lung cancer and neuroblastoma. Several substrates for fused ALK have been identified and their biological functions have been described. However, the lack of a comprehensive identification of ALK substrates limits our understanding of the biological roles of receptor ALK. Thus, this study aimed to identify novel ALK substrates and characterize their biological functions. We screened the interactors of the kinase domain of receptor ALK using proximity-dependent biotin identification and identified 43 interactors. We narrowed down the candidates by evaluating whether these interactors were downstream of ALK in a neuroblastoma cell line, NB-1. Among these, we identified amyloid beta precursor protein binding family B member 1 (APBB1) as an ALK downstream molecule involved in NB-1 cell viability. Finally, we assessed the kinase-substrate relationship between ALK and APBB1 and found that ALK phosphorylated multiple tyrosine residues in APBB1 both in-cell and in-tube assays, with tyrosine 269 as a major target. In conclusion, we successfully identified a new substrate for receptor ALK. Our results may help further elucidate the molecular mechanism of ALK downstream signaling in neuroblastoma.
ABSTRACT
The Human Glycome Atlas (HGA) Project was launched in April 2023, spearheaded by three Japanese institutes: the Tokai National Higher Education and Research System, the National Institutes of Natural Sciences, and Soka University. This was the first time that a field in the life sciences was adopted by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) for a Large-scale Academic Frontiers Promotion Project. This project aims to construct a knowledgebase of human glycans and glycoproteins as a standard for the human glycome. A high-throughput pipeline for comprehensively analyzing 20,000 blood samples in its first five years is planned, at which time an access-controlled version of a human glycomics knowledgebase, called TOHSA, will be released. By the end of the final tenth year, TOHSA will provide a central resource linking human glycan data with other omics data including disease-related information.
ABSTRACT
Glycosylation is increasingly recognized as a potential therapeutic target in Alzheimer's disease. In recent years, evidence of Alzheimer's disease-specific glycoproteins has been established. However, the mechanisms underlying their dysregulation, including tissue- and cell-type specificity, are not fully understood. We aimed to explore the upstream regulators of aberrant glycosylation by integrating multiple data sources using a glycogenomics approach. We identified dysregulation of the glycosyltransferase PLOD3 in oligodendrocytes as an upstream regulator of cerebral vessels and found that it is involved in COL4A5 synthesis, which is strongly correlated with amyloid fiber formation. Furthermore, COL4A5 has been suggested to interact with astrocytes via extracellular matrix receptors as a ligand. This study suggests directions for new therapeutic strategies for Alzheimer's disease targeting glycosyltransferases.
ABSTRACT
Axons of terminally differentiated neurons in the mammalian central nervous system (CNS) are unable to regenerate after dissection. One of the mechanisms underlying this is the inhibition of axonal regeneration by chondroitin sulfate (CS) and its neuronal receptor, PTPσ. Our previous results demonstrated that the CS-PTPσ axis disrupted autophagy flux by dephosphorylating cortactin, which led to the formation of dystrophic endballs and to the inhibition of axonal regeneration. In contrast, juvenile neurons vigorously extend axons toward their targets during development and maintain regenerative activity for axons even after injury. Although several intrinsic and extrinsic mechanisms have been reported to mediate the differences, the detailed mechanisms are still elusive. Here, we report that Glypican-2, a member of heparan sulfate proteoglycans (HSPG), which are able to antagonize CS-PTPσ by competing with the receptor, is specifically expressed in the axonal tips of embryonic neurons. Glypican-2 overexpression in adult neurons rescues the dystrophic endball back to a healthy growth cone on the CSPG gradient. Consistently, Glypican-2 restored cortactin phosphorylation in the axonal tips of adult neurons on CSPG. Taken together, our results clearly demonstrated Glypican-2's pivotal role in defining the axonal response to CS and provided a new therapeutic target for axonal injury.
Subject(s)
Chondroitin Sulfates , Glypicans , Animals , Chondroitin Sulfates/pharmacology , Cortactin , Receptor-Like Protein Tyrosine Phosphatases, Class 2/metabolism , Axons/physiology , Chondroitin Sulfate Proteoglycans/metabolism , Nerve Regeneration/physiology , MammalsABSTRACT
Protein-protein interactions (PPIs) play crucial roles in biological processes. The conventional methods based on affinity purification of a protein of interest (POI) have been widely used to identify unknown PPIs. Recently, proximity-dependent biotin identification (BioID) has been used increasingly to investigate PPIs. BioID utilizes the proximity-dependent biotinylation, in the presence of biotin, of endogenous proteins that are located within a certain distance of POI-fused biotin ligase, which enables us to reveal the more physiologically relevant PPIs in vivo compared to the conventional methods. However, there is little information on an appropriate way to administer biotin in vivo. Recent studies reported some biotin supplementations for in vivo BioID. In this commentary, we review the BioID technique as a tool to examine PPIs, and we introduce a potential method to achieve efficient proximity labelling for in vivo BioID.
Subject(s)
Biotin , Protein Interaction Mapping , Protein Interaction Mapping/methods , Proteins , Biotinylation , Chromatography, AffinityABSTRACT
OBJECTIVE: Sporadic inclusion body myositis (sIBM) is the most common acquired myopathy in patients older than 50 years of age. sIBM is hardly responds to any immunosuppressing theraphies, and its pathophysiology remains elusive. This study aims to explore pathogenic pathways underlying sIBM and identify novel therapeutic targets using metabolomic and transcriptomic analyses. METHODS: In this retrospective observational study, we analyzed biopsied muscle samples from 14 sIBM patients and six non-diseased subjects to identify metabolic profiles. Frozen muscle samples were used to measure metabolites with cation and anion modes of capillary electrophoresis time of flight mass spectrometry. We validated the metabolic pathway altered in muscles of sIBM patients through RNA sequencing and histopathological studies. RESULTS: A total of 198 metabolites were identified. Metabolomic and transcriptomic analyses identified specific metabolite changes in sIBM muscle samples. The pathways of histamine biosynthesis and certain glycosaminoglycan biosynthesis were upregulated in sIBM patients, whereas those of carnitine metabolism and creatine metabolism were downregulated. Histopathological examination showed infiltration of mast cells and deposition of chondroitin sulfate in skeletal muscle samples, supporting the results of metabolomic and transcriptomic analyses. INTERPRETATION: We identified alterations of several metabolic pathways in muscle samples of sIBM patients. These results suggest that mast cells, chondroitin sulfate biosynthesis, carnitine, and creatine play roles in sIBM pathophysiology.
Subject(s)
Myositis, Inclusion Body , Carnitine/metabolism , Chondroitin Sulfates/metabolism , Creatine/genetics , Creatine/metabolism , Gene Expression Profiling , Histamine/metabolism , Humans , Metabolome , Muscle, Skeletal , Myositis, Inclusion Body/geneticsABSTRACT
Solution-focused brief therapy is a psychotherapeutic model. The purpose of this study was to examine the effects of clarity of long-term solutions on positive attitude towards life. In order to examine the effects of the long-term solution image, the conditions for clarifying the long-term and short-term solution images, and not seeking clarification of the solution image were set and randomly assigned. A total of 94 participants who responded to all questions were included in the analysis. The results of this study indicate that clarity of the long-term solution enhances time-oriented attitude. In addition, the clarity of short-term solutions increases the reality of their goals. Furthermore, solution-building and, positive, and ideal levels of life were shown to increase after implementation, regardless of the condition. These results indicate that clarification of the long-term solution expands the positive attitude of valuing limited time.
Subject(s)
Attitude , Optimism , Humans , Time FactorsABSTRACT
The autophagy-lysosome pathway is a cellular clearance system for intracellular organelles, macromolecules and microorganisms. It is indispensable for cells not only to maintain their homeostasis but also to achieve more active cellular processes such as differentiation. Therefore, impairment or disruption of the autophagy-lysosome pathway leads to a wide spectrum of human diseases, ranging from several types of neurodegenerative diseases to malignancies. In elongating axons, autophagy preferentially occurs at growth cones, and disruption of autophagy is closely associated with incapacity for axonal regeneration after injury in the central nervous system. However, the roles of autophagy in developing neurons remain elusive. In particular, whether autophagy is involved in axon-dendrite determination is largely unclear. Using primary cultured mouse embryonic hippocampal neurons, we here showed the polarized distribution of autophagosomes among minor processes of neurons at stage 2. Time-lapse observation of neurons from GFP-LC3 transgenic mice demonstrated that an "LC3 surge"-i.e., a rapid accumulation of autophagic marker LC3 that continues for several hours in one minor process-proceeded the differentiation of neurons into axons. In addition, pharmacological activation and inhibition of autophagy by trehalose and bafilomycin, respectively, accelerated and delayed axonal determination. Taken together, our findings revealed the close association between LC3, a marker of autophagy, and axon determination in developing neurons.
Subject(s)
Autophagy , Axons , Animals , Autophagy/physiology , Axons/pathology , Hippocampus , Mice , Mice, Transgenic , Neurons/metabolismABSTRACT
Reactive oxygen species (ROS) can both act as a poison causing cell death and important signaling molecules among various organisms. Photosynthetic organisms inevitably produce ROS, making the appropriate elimination of ROS an essential strategy for survival. Interestingly, the unicellular green alga Chlamydomonas reinhardtii expresses a mammalian form of thioredoxin reductase, TR1, which functions as a ROS scavenger in animal cells. To investigate the properties of TR1 in C. reinhardtii, we generated TR1 knockout strains using CRISPR/Cas9-based genome editing. We found a reduced tolerance to high-light and ROS stresses in the TR1 knockout strains compared to the parental strain. In addition, the regulation of phototactic orientation, known to be regulated by ROS, was affected in the knockout strains. These results suggest that TR1 contributes to a ROS-scavenging pathway in C. reinhardtii.
Subject(s)
Algal Proteins/genetics , Chlamydomonas reinhardtii/genetics , Light , Radiation Tolerance/genetics , Thioredoxin Reductase 1/genetics , Algal Proteins/metabolism , Animals , CRISPR-Cas Systems , Chlamydomonas reinhardtii/enzymology , Chlamydomonas reinhardtii/radiation effects , Gene Editing/methods , Gene Knockout Techniques , Hydrogen Peroxide/pharmacology , Mammals/genetics , Mammals/metabolism , Oxidants/pharmacology , Photosynthesis/genetics , Photosynthesis/radiation effects , Phototaxis/drug effects , Phototaxis/radiation effects , RNA-Seq/methods , Reactive Oxygen Species/metabolism , Thioredoxin Reductase 1/metabolismABSTRACT
Midkine (MK), a heparin-binding growth factor, is associated with the poor prognosis of the pediatric tumor, neuroblastoma. MK would be a druggable target as many studies showed inhibition of its function in various cancers suppressed tumor developments. To establish the therapy targeting MK, identification of its binding partners, and elucidation of its intracellular signaling are needed. It was reported that exogenous MK induced phosphorylation of ribosomal protein S6 (RPS6) downstream of mTOR signaling. Using RPS6 phosphorylation as a marker of MK response, we searched for MK reactive cell lines. We found that MK cell lines expressing less MK tended to respond better to MK. Next, using an MK reactive neuroblastoma cell line, MK-knocked down SH-SY5Y cells, we employed a proximity-dependent biotin identification method, which was invented to evaluate protein-protein interactions by biotinylation. We confirmed that secreted MK fused to the biotin ligase BioID2 (MK-BioID2) was able to biotinylate proteins from the cells. Biotinylated proteins were identified by liquid chromatography-mass spectrometry analyses. Twenty five proteins were found to be overlapped after three independent experiments, among which insulin-like growth binding protein 2 (IGFBP2) was further analyzed. IGFBP2 was indeed detected with immunoblotting after streptavidin pull down of MK-BioID2 labeled cell extract of MK-knocked down SH-SY5Y cells. Our study suggests that the BioID2 method is useful to identify binding partners of growth factors.
Subject(s)
Insulin-Like Growth Factor Binding Protein 2/analysis , Biotin/metabolism , Biotinylation , Carrier Proteins/metabolism , Humans , Midkine , NeuroblastomaABSTRACT
Caenorhabditis elegans (C. elegans) can produce various motion patterns despite having only 69 motor neurons and 95 muscle cells. Previous studies successfully elucidate the connectome and role of the respective motor neuron classes related to movement. However, these models have not analyzed the distribution of the synaptic and gap connection weights. In this study, we examined whether a motor neuron and muscle network can generate oscillations for both forward and backward movement and analyzed the distribution of the trained synaptic and gap connection weights through a machine learning approach. This paper presents a connectome-based neural network model consisting of motor neurons of classes A, B, D, AS, and muscle, considering both synaptic and gap connections. A supervised learning method called backpropagation through time was adapted to train the connection parameters by feeding teacher data composed of the command neuron input and muscle cell activation. Simulation results confirmed that the motor neuron circuit could generate oscillations with different phase patterns corresponding to forward and backward movement, and could be switched at arbitrary times according to the binary inputs simulating the output of command neurons. Subsequently, we confirmed that the trained synaptic and gap connection weights followed a Boltzmann-type distribution. It should be noted that the proposed model can be trained to reproduce the activity patterns measured for an animal (HRB4 strain). Therefore, the supervised learning approach adopted in this study may allow further analysis of complex activity patterns associated with movements.
Subject(s)
Connectome , Locomotion/physiology , Motor Neurons/physiology , Nerve Net/physiology , Animals , Caenorhabditis elegans/physiology , Computer Simulation , Models, Neurological , Muscle Cells/physiologyABSTRACT
Like other biomolecules including nucleic acid and protein, glycan plays pivotal roles in various cellular processes. For instance, it modulates protein folding and stability, organizes extracellular matrix and tissue elasticity, and regulates membrane trafficking. In addition, cell-surface glycans are often utilized as entry receptors for viruses, including SARS-CoV-2. Nevertheless, its roles as ligands to specific surface receptors have not been well understood with a few exceptions such as selectins and siglecs. Recent reports have demonstrated that chondroitin sulfate and heparan sulfate, both of which are glycosaminoglycans, work as physiological ligands on their shared receptor, protein tyrosine phosphatase sigma (PTPσ). These two glycans differentially determine the fates of neuronal axons after injury in our central nervous system. That is, heparan sulfate promotes axonal regeneration while chondroitin sulfate inhibits it, inducing dystrophic endbulbs at the axon tips. In our recent study, we demonstrated that the chondroitin sulfate (CS)-PTPσ axis disrupted autophagy flux at the axon tips by dephosphorylating cortactin. In this minireview, we introduce how glycans work as physiological ligands and regulate their intracellular signaling, especially focusing on chondroitin sulfate.
ABSTRACT
Midkine (MK) is a neurotrophic factor that participates in the embryonic central nervous system (CNS) development and neural stem cell regulation, interacting with sulfated glycosaminoglycans (GAGs). Chondroitin sulfate (CS) is the natural ligand in the CNS. In this work, we describe the interactions between a library of synthetic models of CS-types and mimics. We did a structural study of this library by NMR and MD (Molecular Dynamics), concluding that the basic shape is controlled by similar geometry of the glycosidic linkages. Their 3D structures are a helix with four residues per turn, almost linear. We have studied the tetrasaccharide-midkine complexes by ligand observed NMR techniques and concluded that the shape of the ligands does not change upon binding. The ligand orientation into the complex is very variable. It is placed inside the central cavity of MK formed by the two structured beta-sheets domains linked by an intrinsically disordered region (IDR). Docking analysis confirmed the participation of aromatics residues from MK completed with electrostatic interactions. Finally, we test the biological activity by increasing the MK expression using CS tetrasaccharides and their capacity in enhancing the growth stimulation effect of MK in NIH3T3 cells.
Subject(s)
Chondroitin Sulfates , Oligosaccharides , Animals , Glycosaminoglycans , Mice , Midkine , NIH 3T3 CellsABSTRACT
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that harbours a tyrosine kinase domain in its intracellular region and is expressed in both central and peripheral nervous systems. RTKs are activated upon ligand binding and receptor clustering; however, ALK remains an orphan receptor despite its pathological significance, especially in malignancy. Recent biochemical work showed that heparan sulphate (HS), an unbranched sulphated glycan, acts as a ligand for and activates ALK. Here, we show that dermatan sulphate (DS, chondroitin sulphate B) directly interacts with the extracellular N-terminal region of ALK as well as HS. The tetrasaccharide of DS was required and was sufficient for inducing autophosphorylation of ALK at tyrosine 1604, a marker for activated ALK. Interestingly, longer oligosaccharides caused enhanced activation of ALK, as was the case for HS. Our results provide a novel example of glycans as signalling molecules and shed light on the pathophysiological roles of ALK.
Subject(s)
Anaplastic Lymphoma Kinase/agonists , Anticoagulants/pharmacology , Dermatan Sulfate/pharmacology , Neoplasms/pathology , Anaplastic Lymphoma Kinase/metabolism , Anticoagulants/chemistry , Cell Line , Dermatan Sulfate/chemistry , Enzyme Activation , Humans , Ligands , Neoplasms/drug therapy , Neoplasms/metabolism , Phosphorylation , Protein Binding , Signal TransductionABSTRACT
Type IIa receptor tyrosine phosphatases (RPTPs) play pivotal roles in neuronal network formation. It is emerging that the interactions of RPTPs with glycans, i.e., chondroitin sulfate (CS) and heparan sulfate (HS), are critical for their functions. We highlight here the significance of these interactions in axon regeneration and synaptogenesis. For example, PTPσ, a member of type IIa RPTPs, on axon terminals is monomerized and activated by the extracellular CS deposited in neural injuries, dephosphorylates cortactin, disrupts autophagy flux, and consequently inhibits axon regeneration. In contrast, HS induces PTPσ oligomerization, suppresses PTPσ phosphatase activity, and promotes axon regeneration. PTPσ also serves as an organizer of excitatory synapses. PTPσ and neurexin bind one another on presynapses and further bind to postsynaptic leucine-rich repeat transmembrane protein 4 (LRRTM4). Neurexin is now known as a heparan sulfate proteoglycan (HSPG), and its HS is essential for the binding between these three molecules. Another HSPG, glypican 4, binds to presynaptic PTPσ and postsynaptic LRRTM4 in an HS-dependent manner. Type IIa RPTPs are also involved in the formation of excitatory and inhibitory synapses by heterophilic binding to a variety of postsynaptic partners. We also discuss the important issue of possible mechanisms coordinating axon extension and synapse formation.
Subject(s)
Axons/metabolism , Nerve Regeneration , Polysaccharides/physiology , Receptor-Like Protein Tyrosine Phosphatases/physiology , Synapses/metabolism , Animals , Axons/physiology , Humans , Polysaccharides/metabolism , Receptor-Like Protein Tyrosine Phosphatases/metabolism , Synapses/physiologyABSTRACT
The receptor-type protein tyrosine phosphatase sigma (PTPRσ) regulates axonal regeneration/sprouting as a molecular switch in response to glycan ligands. Cell surface heparan sulfate oligomerizes PTPRσ and inactivates its enzymatic activity, which in turn promotes axonal growth. In contrast, matrix-associated chondroitin sulfate monomerizes PTPRσ and activates it. This leads to dephosphorylation of its specific substrates, such as cortactin, resulting in a failure of axonal regeneration after injury. However, this molecular switch model has never been challenged in a clinical situation. In this study, we demonstrated that enoxaparin, a globally approved anticoagulant consisting of heparin oligosaccharides with an average molecular weight of 45 kDa, induced clustering and inactivated PTPRσ in vitro. Enoxaparin induced PTPRσ clustering, and counteracted PTPRσ-mediated dephosphorylation of cortactin, which was shown to be important for inhibition of axonal regeneration. Systemic administration of enoxaparin promoted anatomical recovery after both optic nerve and spinal cord injuries in rats at clinically tolerated doses. Moreover, enoxaparin promoted recovery of motor function without obvious hemorrhage. Collectively, our data provide a new strategy for the treatment of traumatic axonal injury.
Subject(s)
Anticoagulants/therapeutic use , Enoxaparin/therapeutic use , Receptor-Like Protein Tyrosine Phosphatases, Class 2/antagonists & inhibitors , Recovery of Function/drug effects , Spinal Cord Injuries/drug therapy , Animals , Anticoagulants/pharmacology , Enoxaparin/pharmacology , Evoked Potentials, Motor/drug effects , Evoked Potentials, Motor/physiology , Female , HEK293 Cells , Humans , Rats , Rats, Sprague-Dawley , Receptor-Like Protein Tyrosine Phosphatases, Class 2/metabolism , Recovery of Function/physiology , Spinal Cord Injuries/metabolism , Thoracic Vertebrae/injuriesABSTRACT
Receptor protein tyrosine phosphatases (RPTPs) are type-I transmembrane proteins and involved in various biological and pathological processes. Their functions are supposed to be exerted through tyrosine dephosphorylation of their specific substrates. However, our comprehensive understanding of specific substrates or interacting proteins for RPTPs is poor. PTPRσ belongs to class 2a RPTP family, dephosphorylates cortactin, and leads to autophagy flux disruption and axonal regeneration inhibition in response to its ligand chondroitin sulphate. Here, we applied proximity-dependent biotin identification (BioID) assay, a proximity-labelling assay, to PTPRσ and reproducibly identified the 99 candidates as interactors for PTPRσ including already-known interactors such as Liprin-α and Trio. Of note, cortactin was also listed up in our assay. Our results suggest that the BioID assay is a powerful and reliable tool to identify RPTP-interacting proteins including its specific substrate.
Subject(s)
Chondroitin Sulfates/metabolism , Receptor-Like Protein Tyrosine Phosphatases, Class 4/metabolism , Recombinant Fusion Proteins/metabolism , Autophagy/physiology , Biotinylation/methods , Cell Line , HEK293 Cells , Humans , Phosphorylation , Protein Binding , Protein Interaction Domains and Motifs , Proteomics/methods , Receptor-Like Protein Tyrosine Phosphatases, Class 4/genetics , Recombinant Fusion Proteins/geneticsABSTRACT
Chondroitin sulfate (CS) and heparan sulfate (HS) are glycosaminoglycans that both bind the receptor-type protein tyrosine phosphatase PTPRσ, affecting axonal regeneration. CS inhibits axonal growth, while HS promotes it. Here, we have prepared a library of HS octasaccharides and, together with synthetic CS oligomers, we found that PTPRσ preferentially interacts with CS-E-a rare sulfation pattern in natural CS-and most HS oligomers bearing sulfate and sulfamate groups. Consequently, short and long stretches of natural CS and HS, respectively, bind to PTPRσ. CS activates PTPRσ, which dephosphorylates cortactin-herein identified as a new PTPRσ substrate-and disrupts autophagy flux at the autophagosome-lysosome fusion step. Such disruption is required and sufficient for dystrophic endball formation and inhibition of axonal regeneration. Therefore, sulfation patterns determine the length of the glycosaminoglycan segment that bind to PTPRσ and define the fate of axonal regeneration through a mechanism involving PTPRσ, cortactin and autophagy.
Subject(s)
Autophagy/drug effects , Chondroitin Sulfates/pharmacology , Cortactin/metabolism , Heparitin Sulfate/pharmacology , Nerve Regeneration/drug effects , Receptor-Like Protein Tyrosine Phosphatases, Class 5/metabolism , Animals , Chondroitin Sulfates/chemistry , Heparitin Sulfate/chemistry , Humans , MiceABSTRACT
Interleukin-18 (IL-18) is a pro-inflammatory cytokine that evokes both innate and acquired immune responses. IL-18 is initially synthesized as an inactive precursor and the cleavage for processing into a mature, active molecule is mediated by pro-inflammatory caspases following the activation of inflammasomes. Two types of monoclonal antibodies were raised: anti-IL-1863-68 antibodies which recognize full-length1-193 and cleaved IL-18; and anti-IL-18 neoepitope antibodies which specifically recognize the new N-terminal 37YFGKLESK44 of IL-18 cleaved by pro-inflammatory caspase-1/4. These mAbs were suitable for Western blotting, capillary Western immunoassay (WES), immunofluorescence, immunoprecipitation, and function-blocking assays. WES analysis of these mAbs allowed visualization of the IL-18 bands and provided a molecular weight corresponding to the pro-inflammatory caspase-1/4 cleaved, active form IL-1837-193, and not to the inactive precursor IL-18, in the serum of patients with adult-onset Still's disease (6/14, 42%) and hemophagocytic activation syndrome (2/6, 33%). These monoclonal antibodies will be very useful in IL-18 and inflammasome biology and for diagnostic and therapeutic strategies for inflammatory diseases.
Subject(s)
Antibodies, Monoclonal/biosynthesis , Antibodies, Monoclonal/immunology , Caspases/metabolism , Inflammation Mediators/immunology , Interleukin-18/immunology , Antibody Affinity , Cell Line, Tumor , HEK293 Cells , Humans , Inflammation Mediators/metabolism , Interferon-gamma/metabolism , Interleukin-18/metabolism , ProteolysisABSTRACT
The small roundworm Caenorhabditis elegans employs two strategies, termed pirouette and weathervane, which are closely related to the internal representation of chemical gradients parallel and perpendicular to the travelling direction, respectively, to perform chemotaxis. These gradients must be calculated from the chemical information obtained at a single point, because the sensory neurons are located close to each other at the nose tip. To formulate the relationship between this sensory input and internal representations of the chemical gradient, this study proposes a simple computational model derived from the directional decomposition of the chemical concentration at the nose tip that can generate internal representations of the chemical gradient. The ability of the computational model was verified by using a chemotaxis simulator that can simulate the body motions of pirouette and weathervane, which confirmed that the computational model enables the conversion of the sensory input and head-bending angles into both types of gradients with high correlations of approximately r > 0.90 (p < 0.01) with the true gradients. In addition, the chemotaxis index of the model was 0.64, which is slightly higher than that in the actual animal (0.57). In addition, simulation using a connectome-based neural network model confirmed that the proposed computational model is implementable in the actual network structure.