As a protective mechanism, the cornea is sensitive to noxious stimuli. Here, we show that in mice, a high proportion of corneal TRPM8
cold-sensing fibers express the heat-sensitive TRPV1 channel. ...Despite its insensitivity to cold, TRPV1 enhances membrane potential changes and electrical firing of TRPM8
neurons in response to cold stimulation. This elevated neuronal excitability leads to augmented ocular cold nociception in mice. In a model of dry eye disease, the expression of TRPV1 in TRPM8
cold-sensing fibers is increased, and results in severe cold allodynia. Overexpression of TRPV1 in TRPM8
sensory neurons leads to cold allodynia in both corneal and non-corneal tissues without affecting their thermal sensitivity. TRPV1-dependent neuronal sensitization facilitates the release of the neuropeptide substance P from TRPM8
cold-sensing neurons to signal nociception in response to cold. Our study identifies a mechanism underlying corneal cold nociception and suggests a potential target for the treatment of ocular pain.
Single-cell RNA sequencing methods focusing on the 5'-end of transcripts can reveal promoter and enhancer activity and efficiently profile immune receptor repertoire. However, ultra-high-throughput ...5'-end single-cell RNA sequencing methods have not been described. We introduce FIPRESCI, 5'-end single-cell combinatorial indexing RNA-Seq, enabling massive sample multiplexing and increasing the throughput of the droplet microfluidics system by over tenfold. We demonstrate FIPRESCI enables the generation of approximately 100,000 single-cell transcriptomes from E10.5 whole mouse embryos in a single-channel experiment, and simultaneous identification of subpopulation differences and T cell receptor signatures of peripheral blood T cells from 12 cancer patients.
As the largest barrier organ of the body, the skin is highly innervated by peripheral sensory neurons. The major function of these sensory neurons is to transmit sensations of temperature, pain, and ...itch to elicit protective responses. Inflammatory skin diseases are triggered by the aberrant activation of immune responses. Recently, increasing evidence has shown that the skin peripheral nervous system also acts as a regulator of immune responses, particularly innate immunity, in various skin inflammatory processes. Meanwhile, immune cells in the skin can express receptors that respond to neuropeptides/neurotransmitters, leading to crosstalk between the immune system and nervous system. Herein, we highlight recent advances of such bidirectional neuroimmune interactions in certain inflammatory skin conditions.
Itch and pain are refractory symptoms of many ocular conditions. Ocular itch is generated mainly in the conjunctiva and is absent from the cornea. In contrast, most ocular pain arises from the ...cornea. However, the underlying mechanisms remain unknown. Using genetic axonal tracing approaches, we discover distinct sensory innervation patterns between the conjunctiva and cornea. Further genetic and functional analyses in rodent models show that a subset of conjunctival-selective sensory fibers marked by MrgprA3 expression, rather than corneal sensory fibers, mediates ocular itch. Importantly, the actions of both histamine and nonhistamine pruritogens converge onto this unique subset of conjunctiva sensory fibers and enable them to play a key role in mediating itch associated with allergic conjunctivitis. This is distinct from skin itch, in which discrete populations of sensory neurons cooperate to carry itch. Finally, we provide proof of concept that selective silencing of conjunctiva itch-sensing fibers by pruritogen-mediated entry of sodium channel blocker QX-314 is a feasible therapeutic strategy to treat ocular itch in mice. Itch-sensing fibers also innervate the human conjunctiva and allow pharmacological silencing using QX-314. Our results cast new light on the neural mechanisms of ocular itch and open a new avenue for developing therapeutic strategies.
Autonomous learning capacity is a key competency that supports teachers’ professional development. In this study, a stratified sampling method was used to recruit 396 junior and senior high school ...mathematics teachers in T city, one of the provincial city in China. A questionnaire with high reliability and validity developed prior to the study by the researchers was employed to measure their autonomous learning capacity and differences across groups. Twelve teachers were then selected for interviews. The results showed satisfactory overall performance. By subdimension, teachers’ performance was the best in the development of study plans, followed by evaluation of learning outcomes, while they needed improvement in learning habit formation and proficiency in using learning methods. Furthermore, the analysis of differences across groups indicated that for autonomous learning capacity, female teachers were significantly better than their male peers; junior high school teachers were better compared to those in senior high school; teachers aged 41–50 underperformed those aged 51 and above; teachers who work in rural areas and townships did not perform worse than urban teachers; and those with doctoral degrees did not demonstrate considerable advantage over others. There were no significant differences in the overall autonomous learning capacity across years of teaching and job title groups. However, in the subdimensions, those with 21–30 years of teaching experience had lower proficiency in using learning methods and evaluation of learning outcomes, and teachers with senior titles did not demonstrate expected advantages in learning habit formation.
Dry eye disease (DED) is a multifactorial disease with a high prevalence worldwide. Uncomfortable corneal sensations severely affect daily life in DED patients. Hence, corneal neuron injury is a ...vital pathogenesis in DED. Notably, endoplasmic reticulum stress (ERS) plays a role in peripheral neuron injury. However, the role of ERS in DED corneal neuron injury is still far from being clear. In this study, we established an environmental DED (eDED) model
and a hyperosmotic DED model
. Subsequently, trigeminal ganglion (TG) corneal neurons were retrograde labeled by WGA-Alexa Fluor 555, and fluorescence-activated cell sorting was used to collect targeted corneal neurons for RNA sequencing in mice. Our results revealed that TG corneal neuron injury but not apoptosis in DED. ERS-related genes and proteins were upregulated in TG corneal neurons of the eDED mice. ERS inhibition alleviated TG corneal neuron's ERS-related injury. Therefore, ERS-induced TG corneal neuron injury may be an important pathomechanism and provide a promising therapeutic approach to DED.
Pain and itch coding mechanisms in polymodal sensory neurons remain elusive. MrgprD+ neurons represent a major polymodal population and mediate both mechanical pain and nonhistaminergic itch. Here, ...we show that chemogenetic activation of MrgprD+ neurons elicited both pain- and itch-related behavior in a dose-dependent manner, revealing an unanticipated compatibility between pain and itch in polymodal neurons. While VGlut2-dependent glutamate release is required for both pain and itch transmission from MrgprD+ neurons, the neuropeptide neuromedin B (NMB) is selectively required for itch signaling. Electrophysiological recordings further demonstrated that glutamate synergizes with NMB to excite NMB-sensitive postsynaptic neurons. Ablation of these spinal neurons selectively abolished itch signals from MrgprD+ neurons, without affecting pain signals, suggesting a dedicated itch-processing central circuit. These findings reveal distinct neurotransmitters and neural circuit requirements for pain and itch signaling from MrgprD+ polymodal sensory neurons, providing new insights on coding and processing of pain and itch.
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•Polymodal MrgprD+ primary afferent neurons express Vglut2 and Nmb•Glutamate is required for both pain and itch signaling from MrgprD+ neurons•NMB is selectively required for itch signaling•NMBR+ central neurons are required for MrgprD+-neuron-mediated itch signals
Guo et al. identify the pain and itch coding mechanisms of MrgprD+ primary afferent neurons. While only glutamate is required for mechanical pain signals mediated by this population, the neuropeptide neuromedin B (NMB) and a subthreshold quantity of glutamate are released together to excite NMB-sensitive postsynaptic circuits for itch signals.
The laser drilling of carbon steel is always suffered from the formation of slag, the presence of cutting burrs, the generation of a significant quantity of spatter, and the incomplete penetration of ...the substrate. In order to avoid these defects formed during the laser drilling of carbon steel, the COMSOL multi-physics simulation method was used to model and optimize the laser drilling process. Considering the splash evolution of the material during the complex drilling process, the transient evolution of the temperature field, the flow of the molten fluid, the geometrical changes, and the absorption of the laser energy during the laser drilling process were investigated. The simulated borehole dimensions are consistent with the experimental results. The process parameters have a great influence on the fluid flow pattern and material slag splashing. The laser power has a significant effect on the laser processing compared with the process parameters. With the increase in laser power and the decrease in laser heat source radius, the time required for perforation is reduced, the flow of melt is accelerated, the perforation efficiency is increased, and the hole wall is smoother, but the degree of spattering is greater. The optimized process parameters were obtained: laser heat source radius of 0.3 mm, laser power of 3000 W. These findings can help reduce the machining defects in carbon steel with excellent mechanical properties by optimizing the laser drilling processing parameters.
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