Heat perception enables acute avoidance responses to prevent tissue damage and maintain body thermal homeostasis. Unlike other modalities, how heat signals are processed in the spinal cord remains ...unclear. By single-cell gene profiling, we identified ErbB4, a transmembrane tyrosine kinase, as a novel marker of heat-sensitive spinal neurons in mice. Ablating spinal ErbB4+ neurons attenuates heat sensation. These neurons receive monosynaptic inputs from TRPV1+ nociceptors and form excitatory synapses onto target neurons. Activation of ErbB4+ neurons enhances the heat response, while inhibition reduces the heat response. We showed that heat sensation is regulated by NRG1, an activator of ErbB4, and it involves dynamic activity of the tyrosine kinase that promotes glutamatergic transmission. Evidence indicates that the NRG1-ErbB4 signaling is also engaged in hypersensitivity of pathological pain. Together, these results identify a spinal neuron connection consisting of ErbB4+ neurons for heat sensation and reveal a regulatory mechanism by the NRG1-ErbB4 signaling.
The supporting technology of retaining small coal pillars in a double roadway layout can effectively relieve the tension of mining and excavation replacement and improve the coal recovery rate. The ...critical difficulty is that the supporting structure on both sides of the small coal pillar has not established an effective mechanical connection, and the improvement of the bearing capacity of the coal pillar is limited, so it is difficult to achieve long-term stability control of the small coal pillar. Taking the 301 and 302 working faces of Gaojiapu Coal Mine as the engineering background, this paper first constructs the overburden structure model of the whole process of mining with small coal pillars in a double roadway layout, obtains the load calculation and strength calculation methods of small coal pillars through the analysis of the mechanism of small coal pillars surrounding rock mechanics, and gives the selection design of support parameters of anchor cables and concrete filled steel tubular piers; Secondly, the influence rules of physical and mechanical parameters such as axial load, elastic modulus and residual strength of anchor solid under different reinforcement methods and the lateral reinforcement coefficient of anchor cable are obtained through experiments. Finally, the support parameters and the coal pillar width are reasonably designed. The field monitoring data show that the reinforcement technology of a small coal pillar with anchor cable as the main body can effectively control the deformation of the small coal pillar, which has specific guiding significance and application value for solving the long-term stability control problem of small coal pillar under the influence of mining.
Dopamine (DA) neurons in the ventral tegmental area (VTA) are critical to coping with stress. However, molecular mechanisms regulating their activity and stress-induced depression were not well ...understood. We found that the receptor tyrosine kinase ErbB4 in VTA was activated in stress-susceptible mice. Deleting ErbB4 in VTA or in DA neurons, or chemical genetic inhibition of ErbB4 kinase activity in VTA suppressed the development of chronic social defeat stress (CSDS)-induced depression-like behaviors. ErbB4 activation required the expression of NRG1 in the laterodorsal tegmentum (LDTg); LDTg-specific deletion of NRG1 inhibited depression-like behaviors. NRG1 and ErbB4 suppressed potassium currents of VTA DA neurons and increased their firing activity. Finally, we showed that acute inhibition of ErbB4 after stress attenuated DA neuron hyperactivity and expression of depression-like behaviors. Together, these observations demonstrate a critical role of NRG1-ErbB4 signaling in regulating depression-like behaviors and identify an unexpected mechanism by which the LDTg-VTA circuit regulates the activity of DA neurons.
Goal recognition (GR) is a method of inferring the goals of other agents, which enables humans or AI agents to proactively make response plans. Goal recognition design (GRD) has been proposed to ...deliberately redesign the underlying environment to accelerate goal recognition. Along with the GR and GRD problems, in this paper, we start by introducing the goal recognition control (GRC) problem under network interdiction, which focuses on controlling the goal recognition process. When the observer attempts to facilitate the explainability of the actor’s behavior and accelerate goal recognition by reducing the uncertainty, the actor wants to minimize the privacy information leakage by manipulating the asymmetric information and delay the goal recognition process. Then, the GRC under network interdiction is formulated as one static Stackelberg game, where the observer obtains asymmetric information about the actor’s intended goal and proactively interdicts the edges of the network with a bounded resource. The privacy leakage of the actor’s actions about the real goals is quantified by a min-entropy information metric and this privacy information metric is associated with the goal uncertainty. Next in importance, we define the privacy information metric based GRC under network interdiction (InfoGRC) and the information metric based GRC under threshold network interdiction (InfoGRCT). After dual reformulating, the InfoGRC and InfoGRCT as bi-level mixed-integer programming problems, one Benders decomposition-based approach is adopted to optimize the observer’s optimal interdiction resource allocation and the actor’s cost-optimal path-planning. Finally, some experimental evaluations are conducted to demonstrate the effectiveness of the InfoGRC and InfoGRCT models in the task of controlling the goal recognition process.
The fiber length has a significant impact on the fiber bridging capacity and the mechanical properties of high ductility cementitious composites (HDCCs), which is related to fiber/matrix interfacial ...bonding. However, this fundamental knowledge of HDCCs design has rarely been investigated systematically. To this end, this study deeply investigates the effect of the fiber length on the bridging stress and the complementary energy with various fiber/matrix interfacial bonds in theory. Then, the mechanical performances of HDCCs with various fiber lengths and compressive strengths were evaluated experimentally. In micromechanical design, longer fibers can achieve stronger bridging stress and more sufficient complementary energy regardless of the fiber/matrix interfacial bonding properties. However, it should be noted that the increase in bridging capacity was quite slow for the overlong fibers and excessive interfacial bonding. The experiments indicated that overlong fibers (18 mm and 24 mm) easily twined on the mixer blade and were hard to disperse evenly. The HDCCs with shorter fibers displayed better workability. The compressive strength was less affected by the fiber length, and most striking differences were less than 5.0%, while the flexural properties and the tensile properties first increased and then decreased when the fiber length ranged from 6 mm to 24 mm. Consequently, the fibers with lengths of 9 mm and the fibers with lengths of 12 mm were better candidates for the HDCCs with compressive strengths of 30 MPa to 80 MPa, and fibers with lengths of 9 mm caused the HDCCs to exhibit higher ductility properties in general.
Germplasm screening is essential to effectively understand the mechanisms underlying aluminum (Al) toxicity, hence guide breeding strategies for alleviating the decline in crop productivity. This ...study screened a large population of 481 maize acessions by measuring eight net root traits, two biomass traits, and three Al concentration traits of seedlings in hydroponic cultures under Al stress. Aluminum stress significantly restrained the plant biomass and root growth. Meanwhile, genetic correlation analysis indicated that biomass traits were significantly correlated with net root traits in the presence or absence of Al treatment. The relative traits exhibited similar results; Al tolerance coefficient (ATC) of biomass traits and ATC of net root traits. Using principal component analysis (PCA), all maize acessions were classified as tolerant, meso-tolerant, or sensitive to Al stress according to Al tolerance index (ATI). The acessions were further categorized under high-performance, low-performance, or moderate-performance groups according to Al tolerance performance index (API). Subsequently, ATI and API defined seven Al-tolerant acessions with high performance and four Al-sensitive acessions with low performance. This large-scale evaluation of Al tolerance identified high-quality Al-tolerance maize acessions, hence providing vital information for further genetic analyses and breeding of maize for Al tolerance.
Dopamine (DA) transmission is critical to motivation, movement, and emotion. Unlike glutamatergic and GABAergic synapses, the development of DA synapses is less understood. We show that bassoon (BSN) ...clusters along DA axons in the core of nucleus accumbens (NAcc) were increased in neonatal stages and reduced afterward, suggesting DA synapse elimination. Remarkably, DA neuron-specific ablating neuregulin 3 (NRG3), a protein whose levels correlate with BSN clusters, increased the clusters and impaired DA release and behaviors related to DA transmission. An unbiased screen of transmembrane proteins with the extracellular domain (ECD) of NRG3 identified Caspr3 (contactin associate-like protein 3) as a binding partner. Caspr3 was enriched in striatal medium spiny neurons (MSNs). NRG3 and Caspr3 interact in trans, which was blocked by Caspr3-ECD. Caspr3 null mice displayed phenotypes similar to those in DAT-Nrg3f/f mice in DA axonal BSN clusters and DA transmission. Finally, in vivo disruption of the NRG3-Caspr3 interaction increased BSN clusters. Together, these results demonstrate that DA synapse development is controlled by trans interaction between NRG3 in DA neurons and Caspr3 in MSNs, identifying a novel pair of cell adhesion molecules for brain circuit wiring.
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•Correlation of NRG3 with DA axonal bassoon clusters during development•Ablation of NRG3 increased DA axonal bassoon clusters and DA transmission•Caspr3 interacts in trans with NRG3 in the striatum•Disruption of the NRG3-Caspr3 interaction increased DA bassoon clusters on MSNs
Cui et al. show that Neuregulin3 in dopaminergic neurons interacts with Caspr3 from medium spiny neurons in trans and controls the development of dopaminergic axonal bassoon clusters. Disruption of this NRG3-Caspr3 interaction increases dopamine release and impairs the behaviors related to dopaminergic transmission.
The excitability of interneurons requires Na.sub.v1.1, the a subunit of the voltage-gated sodium channel. Na.sub.v1.1 deficiency and mutations reduce interneuron excitability, a major pathological ...mechanism for epilepsy syndromes. However, the regulatory mechanisms of Na.sub.v1.1 expression remain unclear. Here, we provide evidence that neddylation is critical to Na.sub.v1.1 stability. Mutant mice lacking Nae1, an obligatory component of the E1 ligase for neddylation, in parvalbumin-positive interneurons (PVINs) exhibited spontaneous epileptic seizures and premature death. Electrophysiological studies indicate that Nae1 deletion reduced PVIN excitability and GABA release and consequently increased the network excitability of pyramidal neurons (PyNs). Further analysis revealed a reduction in sodium-current density, not a change in channel property, in mutant PVINs and decreased Na.sub.v1.1 protein levels. These results suggest that insufficient neddylation in PVINs reduces Na.sub.v1.1 stability and thus the excitability of PVINs; the ensuing increased PyN activity causes seizures in mice. Consistently, Na.sub.v1.1 was found reduced by proteomic analysis that revealed abnormality in synapses and metabolic pathways. Our findings describe a role of neddylation in maintaining Na.sub.v1.1 stability for PVIN excitability and reveal what we believe is a new mechanism in the pathogenesis of epilepsy.
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders with symptoms including social deficits, anxiety, and communication difficulties. However, ASD pathogenic mechanisms are ...poorly understood. Mutations of
CUL3
, which encodes Cullin 3 (CUL3), a component of an E3 ligase complex, are thought of as risk factors for ASD and schizophrenia (SCZ). CUL3 is abundant in the brain, yet little is known of its function. Here we showed that CUL3 is critical for neurodevelopment. CUL3 deficient mice exhibited social deficits and anxiety-like behaviors with enhanced glutamatergic transmission and neuronal excitability. Proteomic analysis revealed eIF4G1, a protein for Cap-dependent translation, as a potential target of CUL3. ASD-associated cellular and behavioral deficits could be rescued by pharmacological inhibition of the eIF4G1 function and chemogenetic inhibition of neuronal activity. Thus, CUL3 is critical to neural development, neurotransmission, and excitation-inhibition (E-I) balance. Our study reveals novel insight into pathophysiological mechanisms of ASD and SCZ.
Mutations of
CUL3
, a component of an E3 ligase complex, are thought of as risk factors for Autism spectrum disorders (ASD) and schizophrenia. Here Dong and colleagues showed CUL3 deficiency in mice caused social deficits and anxiety-like behaviors and enhanced glutamatergic transmission and neuronal excitability. Proteomic analysis revealed eIF4G1, a protein for Cap-dependent translation, as a potential target of CUL3 deficiency. Pharmacological inhibition of eIF4G1 and chemogenetic inhibition of neuronal activity attenuated ASD-associated cellular and behavioral deficits.
The excitability of interneurons requires Nav1.1, the a subunit of the voltage-gated sodium channel. Nav1.1 deficiency and mutations reduce interneuron excitability, a major pathological mechanism ...for epilepsy syndromes. However, the regulatory mechanisms of Nav1.1 expression remain unclear. Here, we provide evidence that neddylation is critical to Nav1.1 stability. Mutant mice lacking Nae1, an obligatory component of the E1 ligase for neddylation, in parvalbumin-positive interneurons (PVINs) exhibited spontaneous epileptic seizures and premature death. Electrophysiological studies indicate that Nae1 deletion reduced PVIN excitability and GABA release and consequently increased the network excitability of pyramidal neurons (PyNs). Further analysis revealed a reduction in sodium-current density, not a change in channel property, in mutant PVINs and decreased Nav1.1 protein levels. These results suggest that insufficient neddylation in PVINs reduces Nav1.1 stability and thus the excitability of PVINs; the ensuing increased PyN activity causes seizures in mice. Consistently, Nav1.1 was found reduced by proteomic analysis that revealed abnormality in synapses and metabolic pathways. Our findings describe a role of neddylation in maintaining Nav1.1 stability for PVIN excitability and reveal what we believe is a new mechanism in the pathogenesis of epilepsy.
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