RESUMEN
Animals can adapt to dynamic environmental conditions by modulating their developmental programs. Understanding the genetic architecture and molecular mechanisms underlying developmental plasticity in response to changing environments is an important and emerging area of research. Here, we show a novel role of cAMP response element binding protein (CREB)-encoding crh-1 gene in developmental polyphenism of C. elegans. Under conditions that promote normal development in wild-type animals, crh-1 mutants inappropriately form transient pre-dauer (L2d) larvae and express the L2d marker gene. L2d formation in crh-1 mutants is specifically induced by the ascaroside pheromone ascr#5 (asc-ωC3; C3), and crh-1 functions autonomously in the ascr#5-sensing ASI neurons to inhibit L2d formation. Moreover, we find that CRH-1 directly binds upstream of the daf-7 TGF-ß locus and promotes its expression in the ASI neurons. Taken together, these results provide new insight into how animals alter their developmental programs in response to environmental changes.
Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Adaptación Fisiológica/genética , Animales , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Ciclo Celular , Procesos de Crecimiento Celular , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/fisiología , Expresión Génica/genética , Regulación de la Expresión Génica/genética , Regulación del Desarrollo de la Expresión Génica/genética , Larva/genética , Larva/crecimiento & desarrollo , Feromonas/metabolismo , Células Receptoras Sensoriales/metabolismo , Transducción de Señal/genética , Factores de Transcripción/genética , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/fisiologíaRESUMEN
Environmental fluctuations influence organismal aging by affecting various regulatory systems. One such system involves sensory neurons, which affect life span in many species. However, how sensory neurons coordinate organismal aging in response to changes in environmental signals remains elusive. Here, we found that a subset of sensory neurons shortens Caenorhabditis elegans' life span by differentially regulating the expression of a specific insulin-like peptide (ILP), INS-6. Notably, treatment with food-derived cues or optogenetic activation of sensory neurons significantly increases ins-6 expression and decreases life span. INS-6 in turn relays the longevity signals to nonneuronal tissues by decreasing the activity of the transcription factor DAF-16/FOXO. Together, our study delineates a mechanism through which environmental sensory cues regulate aging rates by modulating the activities of specific sensory neurons and ILPs.
Asunto(s)
Proteínas de Caenorhabditis elegans/genética , Alimentos , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica , Insulina/genética , Longevidad/genética , Hormonas Peptídicas/genética , Proteínas de Caenorhabditis elegans/metabolismo , Señales (Psicología) , Ambiente , Factores de Transcripción Forkhead/metabolismo , Insulina/metabolismo , Optogenética , Hormonas Peptídicas/metabolismo , Células Receptoras Sensoriales/fisiología , Transducción de SeñalRESUMEN
Animals change sensory responses and their eventual behaviors, depending on their internal metabolic status and external food availability. However, the mechanisms underlying feeding state-dependent behavioral changes remain undefined. Previous studies have shown that Caenorhabditis elegans hermaphrodite exhibits avoidance behaviors to acute exposure of a pheromone, ascr#3 (asc-ΔC9, C9). Here, we show that the ascr#3 avoidance behavior is modulated by feeding state via the insulin signaling pathway. Starvation increases ascr#3 avoidance behavior, and loss-of-function mutations in daf-2 insulin-like receptor gene dampen this starvation-induced ascr#3 avoidance behavior. DAF-2 and its downstream signaling molecules, including the DAF-16 FOXO transcription factor, act in the ascr#3-sensing ADL neurons to regulate synaptic transmission to downstream target neurons, including the AVA command interneurons. Moreover, we found that starvation decreases the secretion of INS-18 insulin-like peptides from the intestine, which antagonizes DAF-2 function in the ADL neurons. Altogether, this study provides insights about the molecular communication between intestine and sensory neurons delivering hunger message to sensory neurons, which regulates avoidance behavior from pheromones to facilitate survival chance.
Asunto(s)
Reacción de Prevención/fisiología , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Insulina/metabolismo , Receptor de Insulina/metabolismo , Inanición/metabolismo , Transmisión Sináptica/fisiología , Animales , Proteínas de Caenorhabditis elegans/genética , Factores de Transcripción Forkhead/genética , Neuronas/metabolismo , Hormonas Peptídicas/metabolismo , Feromonas/metabolismo , Receptor de Insulina/genética , Transducción de Señal , Transmisión Sináptica/genéticaRESUMEN
Fas-apoptotic inhibitory molecule 2 (FAIM2) is a member of the transmembrane BAX inhibitor motif-containing (TMBIM) family. TMBIM family is comprised of six anti-apoptotic proteins that suppress cell death by regulating endoplasmic reticulum Ca2+ homeostasis. Recent studies have implicated two TMBIM proteins, GRINA and BAX Inhibitor-1, in mediating cytoprotection via autophagy. However, whether FAIM2 plays a role in autophagy has been unknown. Here we show that FAIM2 localizes to the lysosomes at basal state and facilitates autophagy through interaction with microtubule-associated protein 1 light chain 3 proteins in human neuroblastoma SH-SY5Y cells. FAIM2 overexpression increased autophagy flux, while autophagy flux was impaired in shRNA-mediated knockdown (shFAIM2) cells, and the impairment was more evident in the presence of rapamycin. In shFAIM2 cells, autophagosome maturation through fusion with lysosomes was impaired, leading to accumulation of autophagosomes. A functional LC3-interacting region motif within FAIM2 was essential for the interaction with LC3 and rescue of autophagy flux in shFAIM2 cells while LC3-binding property of FAIM2 was dispensable for the anti-apoptotic function in response to Fas receptor-mediated apoptosis. Suppression of autophagosome maturation was also observed in a null mutant of Caenorhabditis elegans lacking xbx-6, the ortholog of FAIM2. Our study suggests that FAIM2 is a novel regulator of autophagy mediating autophagosome maturation through the interaction with LC3.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Autofagosomas/fisiología , Lisosomas/fisiología , Proteínas de la Membrana/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Secuencias de Aminoácidos , Animales , Apoptosis , Proteínas Reguladoras de la Apoptosis/genética , Autofagia/efectos de los fármacos , Caenorhabditis elegans/metabolismo , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Inmunosupresores/farmacología , Proteínas de Membrana de los Lisosomas/genética , Proteínas de Membrana de los Lisosomas/metabolismo , Proteínas de la Membrana/genética , Proteínas Asociadas a Microtúbulos/genética , Plásmidos , Transporte de Proteínas , Sirolimus/farmacologíaRESUMEN
Proneural genes are among the most early-acting genes in nervous system development, instructing blast cells to commit to a neuronal fate. Drosophila Atonal and Achaete-Scute complex (AS-C) genes, as well as their vertebrate orthologs, are basic helix-loop-helix (bHLH) transcription factors with such proneural activity. We show here that a C. elegans AS-C homolog, hlh-4, functions in a fundamentally different manner. In the embryonic, larval, and adult nervous systems, hlh-4 is expressed exclusively in a single nociceptive neuron class, ADL, and its expression in ADL is maintained via transcriptional autoregulation throughout the life of the animal. However, in hlh-4 null mutants, the ADL neuron is generated and still appears neuronal in overall morphology and expression of panneuronal and pansensory features. Rather than acting as a proneural gene, we find that hlh-4 is required for the ADL neuron to function properly, to adopt its correct morphology, to express its unusually large repertoire of olfactory receptor-encoding genes, and to express other known features of terminal ADL identity, including neurotransmitter phenotype, neuropeptides, ion channels, and electrical synapse proteins. hlh-4 is sufficient to induce ADL identity features upon ectopic expression in other neuron types. The expression of ADL terminal identity features is directly controlled by HLH-4 via a phylogenetically conserved E-box motif, which, through bioinformatic analysis, we find to constitute a predictive feature of ADL-expressed terminal identity markers. The lineage that produces the ADL neuron was previously shown to require the conventional, transient proneural activity of another AS-C homolog, hlh-14, demonstrating sequential activities of distinct AS-C-type bHLH genes in neuronal specification. Taken together, we have defined here an unconventional function of an AS-C-type bHLH gene as a terminal selector of neuronal identity and we speculate that such function could be reflective of an ancestral function of an "ur-" bHLH gene.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Regulación del Desarrollo de la Expresión Génica , Nociceptores/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Caenorhabditis elegans/citología , Caenorhabditis elegans/crecimiento & desarrollo , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Biología Computacional , Sinapsis Eléctricas/metabolismo , Sinapsis Eléctricas/ultraestructura , Embrión no Mamífero , Ontología de Genes , Canales Iónicos/genética , Canales Iónicos/metabolismo , Larva/citología , Larva/genética , Larva/crecimiento & desarrollo , Larva/metabolismo , Anotación de Secuencia Molecular , Neuropéptidos/genética , Neuropéptidos/metabolismo , Neurotransmisores/metabolismo , Nociceptores/citología , Fenotipo , Receptores Odorantes/genética , Receptores Odorantes/metabolismo , Transcripción GenéticaRESUMEN
Animal locomotion is mediated by a sensory system referred to as proprioception. Defects in the proprioceptive coordination of locomotion result in uncontrolled and inefficient movements. However, the molecular mechanisms underlying proprioception are not fully understood. Here, we identify two transient receptor potential cation (TRPC) channels, trp-1 and trp-2, as necessary and sufficient for proprioceptive responses in C. elegans head steering locomotion. Both channels are expressed in the SMDD neurons, which are required and sufficient for head bending, and mediate coordinated head steering by sensing mechanical stretches due to the contraction of head muscle and orchestrating dorsal head muscle contractions. Moreover, the SMDD neurons play dual roles to sense muscle stretch as well as to control muscle contractions. These results demonstrate that distinct locomotion patterns require dynamic and homeostatic modulation of feedback signals between neurons and muscles.
Asunto(s)
Caenorhabditis elegans/fisiología , Mecanorreceptores/fisiología , Neuronas Motoras/fisiología , Propiocepción/fisiología , Células Receptoras Sensoriales/fisiología , Canales Catiónicos TRPC/fisiología , Animales , Caenorhabditis elegans/genética , Locomoción/fisiología , Canales Catiónicos TRPC/genéticaRESUMEN
Despite the known importance of the transmembrane domain (TMD) of syndecan receptors in cell adhesion and signaling, the molecular basis for syndecan TMD function remains unknown. Using in vivo invertebrate models, we found that mammalian syndecan-2 rescued both the guidance defects in C. elegans hermaphrodite-specific neurons and the impaired development of the midline axons of Drosophila caused by the loss of endogenous syndecan. These compensatory effects, however, were reduced significantly when syndecan-2 dimerization-defective TMD mutants were introduced. To further investigate the role of the TMD, we generated a chimera, 2eTPC, comprising the TMD of syndecan-2 linked to the cytoplasmic domain of platelet-derived growth factor receptor (PDGFR). This chimera exhibited SDS-resistant dimer formation that was lost in the corresponding dimerization-defective syndecan-2 TMD mutant, 2eT(GL)PC. Moreover, 2eTPC specifically enhanced Tyr 579 and Tyr 857 phosphorylation in the PDGFR cytoplasmic domain, while the TMD mutant failed to support such phosphorylation. Finally, 2eTPC, but not 2eT(GL)PC, induced phosphorylation of Src and PI3 kinase (known downstream effectors of Tyr 579 phosphorylation) and promoted Src-mediated migration of NIH3T3 cells. Taken together, these data suggest that the TMD of a syndecan-2 specifically regulates receptor cytoplasmic domain function and subsequent downstream signaling events controlling cell behavior.
Asunto(s)
Adhesión Celular , Dominios Proteicos , Transducción de Señal , Sindecano-2/metabolismo , Animales , Células HEK293 , Humanos , Ratones , Células 3T3 NIH , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Multimerización de Proteína , Procesamiento Proteico-Postraduccional , Sindecano-2/fisiología , Familia-src Quinasas/metabolismoRESUMEN
Caenorhabditis elegans secretes a complex cocktail of small chemicals collectively called ascaroside pheromones which serves as a chemical language for intra-species communication. Subsets of ascarosides have been shown to mediate a broad spectrum of C. elegans behavior and development, such as gender-specific attraction, repulsion, aggregation, olfactory plasticity, and dauer formation. Recent studies show that specific components of ascarosides elicit a rapid avoidance response that allows animals to avoid predators and escape from unfavorable conditions. Moreover, this avoidance behavior is modulated by external conditions, internal states, and previous experience, indicating that pheromone avoidance behavior is highly plastic. In this review, we describe molecular and circuit mechanisms underlying plasticity in pheromone avoidance behavior which pave a way to better understanding circuit mechanisms underlying behavioral plasticity in higher animals, including humans.
Asunto(s)
Adaptación Fisiológica/fisiología , Reacción de Prevención/fisiología , Caenorhabditis elegans/fisiología , Feromonas/fisiología , Animales , Conectoma , Conducta Alimentaria/fisiología , Predicción , Glucolípidos/química , Glucolípidos/fisiología , Lípidos/química , Lípidos/fisiología , Nematodos/fisiología , Vías Nerviosas/fisiología , Feromonas/química , Especificidad de la EspecieRESUMEN
The expression of specific transcription factors determines the differentiated features of postmitotic neurons. However, the mechanism by which specific molecules determine neuronal cell fate and the extent to which the functions of transcription factors are conserved in evolution are not fully understood. In C. elegans, the cholinergic and peptidergic SMB sensory/inter/motor neurons innervate muscle quadrants in the head and control the amplitude of sinusoidal movement. Here we show that the LIM homeobox protein LIM-4 determines neuronal characteristics of the SMB neurons. In lim-4 mutant animals, expression of terminal differentiation genes, such as the cholinergic gene battery and the flp-12 neuropeptide gene, is completely abolished and thus the function of the SMB neurons is compromised. LIM-4 activity promotes SMB identity by directly regulating the expression of the SMB marker genes via a distinct cis-regulatory motif. Two human LIM-4 orthologs, LHX6 and LHX8, functionally substitute for LIM-4 in C. elegans. Furthermore, C. elegans LIM-4 or human LHX6 can induce cholinergic and peptidergic characteristics in the human neuronal cell lines. Our results indicate that the evolutionarily conserved LIM-4/LHX6 homeodomain proteins function in generation of precise neuronal subtypes.
Asunto(s)
Proteínas de Caenorhabditis elegans/fisiología , Caenorhabditis elegans/genética , Interneuronas/fisiología , Proteínas con Homeodominio LIM/fisiología , Neuronas Motoras/fisiología , Células Receptoras Sensoriales/fisiología , Factores de Transcripción/fisiología , Animales , Secuencia de Bases , Caenorhabditis elegans/citología , Caenorhabditis elegans/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Neuronas Colinérgicas/metabolismo , Secuencia de Consenso , Regulación del Desarrollo de la Expresión Génica , Humanos , Proteínas del Tejido Nervioso/fisiología , Estrés Fisiológico , TranscriptomaRESUMEN
Feeding state and food availability can dramatically alter an animals' sensory response to chemicals in its environment. Dynamic changes in the expression of chemoreceptor genes may underlie some of these food and state-dependent changes in chemosensory behavior, but the mechanisms underlying these expression changes are unknown. Here, we identified a KIN-29 (SIK)-dependent chemoreceptor, srh-234, in C. elegans whose expression in the ADL sensory neuron type is regulated by integration of sensory and internal feeding state signals. We show that in addition to KIN-29, signaling is mediated by the DAF-2 insulin-like receptor, OCR-2 TRPV channel, and NPR-1 neuropeptide receptor. Cell-specific rescue experiments suggest that DAF-2 and OCR-2 act in ADL, while NPR-1 acts in the RMG interneurons. NPR-1-mediated regulation of srh-234 is dependent on gap-junctions, implying that circuit inputs regulate the expression of chemoreceptor genes in sensory neurons. Using physical and genetic manipulation of ADL neurons, we show that sensory inputs from food presence and ADL neural output regulate srh-234 expression. While KIN-29 and DAF-2 act primarily via the MEF-2 (MEF2) and DAF-16 (FOXO) transcription factors to regulate srh-234 expression in ADL neurons, OCR-2 and NPR-1 likely act via a calcium-dependent but MEF-2- and DAF-16-independent pathway. Together, our results suggest that sensory- and circuit-mediated regulation of chemoreceptor genes via multiple pathways may allow animals to precisely regulate and fine-tune their chemosensory responses as a function of internal and external conditions.
Asunto(s)
Proteínas de Caenorhabditis elegans/genética , Conducta Alimentaria , Insulina/genética , Proteínas Serina-Treonina Quinasas/genética , Receptor de Insulina/genética , Receptores de Neuropéptido Y/genética , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiología , Proteínas de Caenorhabditis elegans/biosíntesis , Regulación de la Expresión Génica , Insulina/biosíntesis , Mutación , Receptor de Insulina/biosíntesis , Receptores de Neuropéptido Y/biosíntesis , Células Receptoras Sensoriales/metabolismo , Transducción de Señal/genética , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Sore throat, hoarseness, dysphagia, and cough are common laryngopharyngeal discomforts after thyroidectomy. The incidence and severity of laryngopharyngeal symptoms after the use of a flexible reinforced laryngeal mask airway (LMA) were compared with those that occur after the use of a plain endotracheal tube in patients after thyroidectomy. METHODS: Seventy-six patients scheduled for total thyroidectomy were randomized into a plain endotracheal tube group (group E) or a flexible reinforced LMA group (group L). Total intravenous anesthesia (propofol and remifentanil) was used for maintenance of anesthesia. Hemodynamic variables were recorded during induction of anesthesia. The incidence and severity (100-point numerical rating scales) of laryngopharyngeal symptoms, including sore throat, hoarseness, dysphagia, and cough, were assessed at 1, 24, and 48 h after surgery. RESULTS: All patients were placed successfully with an endotracheal tube or a flexible reinforced LMA. The postoperative incidence and severity of sore throat (25 vs. 33 at 24 h, p = 0.035, 17 vs. 28 at 48 h, p = 0.017; 50 [0-100] vs. 80 [20-100] at 1 h, p = 0.002; 30 [0-80] vs. 50 [0-100] at 24 h, p < 0.001; 0 [0-40] vs. 30 [0-90] at 48 h, p < 0.001) and hoarseness were lower in group L than in group E. At 48 h postoperatively, dysphagia (p = 0.005) and cough (p = 0.028) occurred less frequently in group L than in group E patients. CONCLUSION: A flexible reinforced LMA placed during surgery decreases the incidence and severity of laryngopharyngeal symptoms and is a feasible anesthetic tool compared with a conventional endotracheal tube for thyroidectomy.
Asunto(s)
Máscaras Laríngeas , Tiroidectomía , Adulto , Anciano , Femenino , Humanos , Intubación Intratraqueal , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Estudios Prospectivos , Adulto JovenRESUMEN
The differentiated features of postmitotic neurons are dictated by the expression of specific transcription factors. The mechanisms by which the precise spatiotemporal expression patterns of these factors are regulated are poorly understood. In C. elegans, the ceh-36 Otx homeobox gene is expressed in the AWC sensory neurons throughout postembryonic development, and regulates terminal differentiation of this neuronal subtype. Here, we show that the HMX/NKX homeodomain protein MLS-2 regulates ceh-36 expression specifically in the AWC neurons. Consequently, the AWC neurons fail to express neuron type-specific characteristics in mls-2 mutants. mls-2 is expressed transiently in postmitotic AWC neurons, and directly initiates ceh-36 expression. CEH-36 subsequently interacts with a distinct site in its cis-regulatory sequences to maintain its own expression, and also directly regulates the expression of AWC-specific terminal differentiation genes. We also show that MLS-2 acts in additional neuron types to regulate their development and differentiation. Our analysis describes a transcription factor cascade that defines the unique postmitotic characteristics of a sensory neuron subtype, and provides insights into the spatiotemporal regulatory mechanisms that generate functional diversity in the sensory nervous system.
Asunto(s)
Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/fisiología , Caenorhabditis elegans/genética , Diferenciación Celular/genética , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/fisiología , Células Receptoras Sensoriales/fisiología , Factores de Transcripción/genética , Alelos , Secuencia de Aminoácidos , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans/embriología , Proteínas de Caenorhabditis elegans/metabolismo , Embrión no Mamífero , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Datos de Secuencia Molecular , Mutación/fisiología , Factores de Transcripción Otx/genética , Polimorfismo de Nucleótido Simple , Células Receptoras Sensoriales/clasificación , Células Receptoras Sensoriales/metabolismoRESUMEN
Neuronal differentiation is highly coordinated through a cascade of gene expression, mediated via interactions between transacting transcription factors and cis-regulatory elements of their target genes. However, the mechanisms of transcriptional regulation that determine neuronal cell-fate are not fully understood. Here, we show that the nuclear transcription factor Y (NF-Y) subunit, NFYA-1, is necessary and sufficient to express the flp-3 neuropeptide gene in the IL1 neurons of C. elegans. flp-3 expression is decreased in dorsal and lateral, but not ventral IL1s of nfya-1 mutants. The expression of another terminally differentiated gene, eat-4 vesicular glutamate transporter, is abolished, whereas the unc-8 DEG/ENaC gene and pan-neuronal genes are expressed normally in IL1s of nfya-1 mutants. nfya-1 is expressed in and acts in IL1s to regulate flp-3 and eat-4 expression. Ectopic expression of NFYA-1 drives the expression of flp-3 gene in other cell-types. Promoter analysis of IL1-expressed genes results in the identification of several cisregulatory motifs which are necessary for IL1 expression, including a putative CCAAT-box located in the flp-3 promoter that NFYA-1 directly interacts with. NFYA-1 and NFYA-2, together with NFYB-1 and NFYC-1, exhibit partly or fully redundant roles in the regulation of flp-3 or unc-8 expression, respectively. Taken together, our data indicate that the NF-Y complex regulates neuronal subtype-specification via regulating a set of terminal-differentiation genes. [BMB Reports 2023; 56(3): 153-159].
Asunto(s)
Proteínas de Caenorhabditis elegans , Factores de Transcripción , Animales , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Regulación de la Expresión Génica , Regiones Promotoras Genéticas/genética , Neuronas/metabolismo , Canales Iónicos/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismoRESUMEN
Animals detect and discriminate countless environmental chemicals for their well-being and survival. Although a single chemical can trigger opposing behavioral responses depending on its concentration, the mechanisms underlying such a concentration-dependent switching remain poorly understood. Here, we show that C. elegans exhibits either attraction or avoidance of the bacteria-derived volatile chemical dimethyl trisulfide (DMTS) depending on its concentration. This behavioral switching is mediated by two different types of chemosensory neurons, both of which express the DMTS-sensitive seven-transmembrane G protein-coupled receptor (GPCR) SRI-14. These two sensory neurons share downstream interneurons that process and translate DMTS signals via distinct glutamate receptors to generate the appropriate behavioral outcome. Thus, our results present one mechanism by which an animal connects two distinct types of chemosensory neurons detecting a common ligand to alternate downstream circuitry, thus efficiently switching between specific behavioral programs based on ligand concentration.
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Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans , Receptores Odorantes/metabolismo , Animales , Caenorhabditis elegans/fisiología , Proteínas de Caenorhabditis elegans/genética , Ligandos , Receptores Acoplados a Proteínas G/genética , Células Receptoras SensorialesRESUMEN
The clinical research faces numerous challenges, from patient enrollment to data privacy concerns and regulatory requirements to spiraling costs. Blockchain technology has the potential to overcome these challenges, thus making clinical trials transparent and enhancing public trust in a fair and open process with all stakeholders because of its distinct features such as data immutability and transparency. This paper proposes a permissioned blockchain platform to ensure clinical data transparency and provides secure clinical trial-related solutions. We explore the core functionalities of blockchain applied to clinical trials and illustrate its general principle concretely. These clinical trial operations are automated using the smart contract, which ensures traceability, prevents a posteriori reconstruction, and securely automates the clinical trial. A web-based user interface is also implemented to visualize the data from the blockchain and ease the interaction with the blockchain network. A proof of concept is implemented on Hyperledger Fabric in the case study of clinical management for multiple clinical trials to demonstrate the designed approach's feasibility. Lastly, the experiment results demonstrate the efficiency and usability of the proposed platform.
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Cadena de Bloques , Ensayos Clínicos como Asunto , Seguridad Computacional , Humanos , Reproducibilidad de los ResultadosRESUMEN
The characteristics or aspects of important fiducial points (FPs) in the electrocardiogram (ECG) signal are complicated because of various factors, such as non-stationary effects and low signal-to-noise ratio. Due to the various noises caused by the ECG signal measurement environment and by typical ECG signal deformation due to heart diseases, detecting such FPs becomes a challenging task. In this study, we introduce a novel PQRST complex detector using a one-dimensional bilateral filter (1DBF) and the temporal characteristics of FPs. The 1DBF with noise suppression and edge preservation preserves the P- or T-wave whereas it suppresses the QRS-interval. The 1DBF acts as a background predictor for predicting the background corresponding to the P- and T-waves and the remaining flat interval excluding the QRS-interval. The R-peak and QRS-interval are founded by the difference of the original ECG signal and the predicted background signal. Then, the Q- and S-points and the FPs related to the P- and T-wave are sequentially detected using the determined searching range and detection order based on the detected R-peak. The detection performance of the proposed method is analyzed through the MIT-BIH database (MIT-DB) and the QT database (QT-DB).
Asunto(s)
Algoritmos , Procesamiento de Señales Asistido por Computador , Arritmias Cardíacas , Bases de Datos Factuales , Electrocardiografía , HumanosRESUMEN
In animals, proper locomotion is crucial to find mates and foods and avoid predators or dangers. Multiple sensory systems detect external and internal cues and integrate them to modulate motor outputs. Proprioception is the internal sense of body position, and proprioceptive control of locomotion is essential to generate and maintain precise patterns of movement or gaits. This proprioceptive feedback system is conserved in many animal species and is mediated by stretch-sensitive receptors called proprioceptors. Recent studies have identified multiple proprioceptive neurons and proprioceptors and their roles in the locomotion of various model organisms. In this review we describe molecular and neuronal mechanisms underlying proprioceptive feedback systems in C. elegans, Drosophila, and mice. [BMB Reports 2021; 54(8): 393-402].
Asunto(s)
Actividad Motora/fisiología , Propiocepción/genética , Propiocepción/fisiología , Animales , Caenorhabditis elegans , Drosophila , Retroalimentación Sensorial/fisiología , Humanos , Cinestesia/fisiología , Locomoción/fisiología , Ratones , Neuronas Motoras/fisiología , Equilibrio Postural/fisiología , Células Receptoras Sensoriales/fisiologíaRESUMEN
Dietary restriction extends lifespan in various organisms by reducing the levels of both nutrients and non-nutritional food-derived cues. However, the identity of specific food-derived chemical cues that alter lifespan remains unclear. Here, we identified several volatile attractants that decreased the longevity on food deprivation, a dietary restriction regimen in Caenorhabditis elegans. In particular, we found that the odor of diacetyl decreased the activity of DAF-16/FOXO, a life-extending transcription factor acting downstream of insulin/IGF-1 signaling. We then demonstrated that the odor of lactic acid bacteria, which produce diacetyl, reduced the nuclear accumulation of DAF-16/FOXO. Unexpectedly, we showed that the odor of diacetyl decreased longevity independently of two established diacetyl receptors, ODR-10 and SRI-14, in sensory neurons. Thus, diacetyl, a food-derived odorant, may shorten food deprivation-induced longevity via decreasing the activity of DAF-16/FOXO through binding to unidentified receptors.
Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Diacetil/efectos adversos , Factores de Transcripción Forkhead/metabolismo , Odorantes/análisis , Animales , Dietoterapia , Regulación hacia Abajo , LongevidadRESUMEN
Neuropeptides are short sequences ofamino acids that function in all multicellular organisms to communicate information between cells. The first sequence ofa neuropeptide was reported in 1970' and the number of identified neuropeptides remained relatively small until the 1990s when the DNA sequence of multiple genomes revealed treasure troves ofinformation. Byblasting away at the genome, gene families, the sizes ofwhich were previously unknown, could now be determined. This information has led to an exponential increase in the number of putative neuropeptides and their respective gene families. The molecular biology age greatly benefited the neuropeptide field in the nematode Caenorhabditis elegans. Its genome was among the first to be sequenced and this allowed us the opportunity to screen the genome for neuropeptide genes. Initially, the screeningwas slow, as the Genefinder and BLAST programs had difficulty identifying small genes and peptides. However, as the bioinformatics programs improved, the extent of the neuropeptide gene families in C. elegans gradually emerged.
Asunto(s)
Caenorhabditis elegans/genética , Neuropéptidos/genética , Secuencia de Aminoácidos , Animales , Caenorhabditis elegans/fisiología , Regulación de la Expresión Génica , Datos de Secuencia Molecular , Familia de Multigenes , Neuropéptidos/química , Neuropéptidos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The regulation of chemoreceptor (CR) gene expression by environmental signals and internal cues may contribute to the modulation of multiple physiological processes and behavior in Caenorhabditis elegans. We previously showed that KIN-29, a homolog of salt-inducible kinase, acts in sensory neurons to regulate the expression of a subset of CR genes, as well as sensory behaviors. Here we show that the cGMP-dependent protein kinase EGL-4 acts partly in parallel with KIN-29 to regulate CR gene expression. Sensory inputs inhibit both EGL-4 and KIN-29 functions, and KIN-29 function is inhibited in turn by cAMP-dependent protein kinase (PKA) activation. EGL-4 and KIN-29 regulate CR gene expression by antagonizing the gene repression functions of the class II HDAC HDA-4 and the MEF-2 transcription factor, and KIN-29, EGL-4, and PKA target distinct residues in HDA-4 to regulate its function and subcellular localization. While KIN-29 acts primarily via MEF-2/HDA-4 to regulate additional sensory signal-regulated physiological processes and behaviors, EGL-4 acts via both MEF-2-dependent and -independent pathways. Our results suggest that integration of complex sensory inputs via multiple signaling pathways allows animals to precisely regulate sensory gene expression, thereby appropriately modulating physiology and behavior.