Early Sacral Neuromodulation Prevented Detrusor Overactivity in Rats With Spinal Cord Injury.

OBJECTIVES: Sacral neuromodulation (SNM) has been shown to alleviate bladder dysfunction in patients with overactive bladder and nonobstructive urinary retention. However, the therapeutic effect and mechanism of SNM in neurogenic bladder dysfunction are still not fully understood. Using a rat model of spinal cord injury (SCI), this study aims to investigate the therapeutic effect of early SNM in the bladder-areflexia phase on neurogenic bladder dysfunction and evaluate its possible mechanism. MATERIALS AND METHODS: Basic physiological parameters such as body/bladder weight, blood pressure, and electrocardiogram results were measured to evaluate the safety of SNM. Enzyme-linked immunosorbent assays and quantitative real-time polymerase chain reaction were used to examine the expression of proinflammatory factors. Hematoxylin and eosin and Masson's trichrome staining were used to observe morphological changes, and cystometry was used to evaluate urodynamic changes after SNM treatment. Western blotting and immunofluorescence staining were used to measure the levels of transient receptor potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) in the L6-S1 dorsal root ganglia (DRGs) and bladder. Capsaicin desensitization was used to investigate whether inhibiting TRPV1 could prevent detrusor overactivity in SCI rats. RESULTS: Early SNM did not affect the body/bladder weight, heart rate, blood pressure, or the expression of proinflammatory cytokines (PGE2, IL-1, IL-2, IL-6, TGF-ß, or TNF-α) in the bladders of SCI rats. Morphologically, early SNM prevented urothelial edema (p = 0.0248) but did not influence collagen/smooth muscle in the bladder. Compared with untreated rats with SCI, the rats treated with SNM exhibited increased bladder capacity (p = 0.0132) and voiding efficiency (p = 0.0179), and decreased nonvoiding contraction (NVC) frequency (p = 0.0240). The maximum pressure, basal pressure, postvoid residual, and NVC amplitude did not change significantly. After the SNM treatment, the expression of TRPV1 in the bladder and CGRP in L6-S1 DRGs weredecreased (L6, p = 0.0160; S1, p = 0.0024) in SCI rats. In capsaicin-desensitized SCI rats, urodynamic results showed an increase in bladder capacity (p = 0.0116) and voiding efficiency (p = 0.0048), and diminished NVC frequency (p = 0.0116), while other parameters did not change significantly. CONCLUSIONS: Early SNM prevented urothelial edema morphologically and detrusor overactivity in SCI rats. Inhibition of TRPV1 in the bladder and DRGs may be one of the potential mechanisms for preventing detrusor overactivity by SNM.

Unlocking Efficiency: Minimizing Energy Loss in Electrocatalysts for Water Splitting.

Catalysts play a crucial role in water electrolysis by reducing the energy barriers for hydrogen and oxygen evolution reactions (HER and OER). Research aims to enhance the intrinsic activities of potential catalysts through material selection, microstructure design, and various engineering techniques. However, the energy consumption of catalysts has often been overlooked due to the intricate interplay among catalyst microstructure, dimensionality, catalyst-electrolyte-gas dynamics, surface chemistry, electron transport within electrodes, and electron transfer among electrode components. Efficient catalyst development for high-current-density applications is essential to meet the increasing demand for green hydrogen. This involves transforming catalysts with high intrinsic activities into electrodes capable of sustaining high current densities. This review focuses on current improvement strategies of mass exchange, charge transfer, and reducing electrode resistance to decrease energy consumption. It aims to bridge the gap between laboratory-developed, highly efficient catalysts and industrial applications regarding catalyst structural design, surface chemistry, and catalyst-electrode interplay, outlining the development roadmap of hierarchically structured electrode-based water electrolysis for minimizing energy loss in electrocatalysts for water splitting.

Knowledge, Attitudes, and Practices of Physicians Regarding Targeted Drug Therapy for Lung Cancer.

Purpose: This study aimed to examine the KAP of physicians regarding targeted drug therapy for lung cancer in China. Methods: This cross-sectional study enrolled physicians working in hospitals in Nanyang. A self-administered questionnaire was developed (Cronbach's α=0.912) to collect the demographic information and KAP. Results: This study included 191 valid questionnaires. Most participants were male (70.2%) and aged 36-50 (55.5%). The median knowledge score was 29 (24-31) (/36, 80.6%), the mean attitude score was 42 (39-44) (/50, 84.0%), and the mean practice score was 28 (26-29) (/30, 93.3%), indicating sufficient knowledge, positive attitudes, and proactive practice. The female gender (OR=5.291, 95% CI: 1.426-19.634, P=0.013), working in non-public tertiary hospitals (OR=0.053, 95% CI: 0.008-0.360, P=0.003), and working in medical oncology (OR=10.764, 95% CI: 2.638-43.922, P=0.001) were independently associated with adequate knowledge. Only the knowledge scores (OR=1.121, 95% CI: 1.036-1.212, P=0.004) were independently associated with a positive attitude. Only the attitude scores (OR=1.895, 95% CI: 1.333-2.694, P<0.001) were independently associated with proactive practice. Conclusion: Physicians working in thoracic surgery, respiratory medicine, or medical oncology displayed sufficient knowledge, positive attitude, and proactive practice toward targeted therapy for lung cancer.

Enantioselective Hydroaminoalkylation of Azaaryl Ketones through Asymmetric Photoredox Catalysis.

An enantioselective hydroaminoalkylation of azaaryl ketones under a transition-metal-free asymmetric photoredox catalysis platform is reported. A series of valuable azaarene-functionalized 1,2-amino alcohols featuring attractive quaternary carbon stereocenters have been synthesized in high yields with good to excellent enantioselectivities. The viability of readily accessible N-aryl glycines as reaction partners facilitates the conjugate modification of these products into important derivatives, thereby enhancing the synthetic utility of the current approach.

Design of Coatings for Sulfur-Based Cathode Materials in Lithium-Sulfur Batteries: A review.

Lithium-sulfur batteries (LSBs) are considered next-generation energy storage and conversion solutions owing to their high theoretical specific capacity and the high abundance/low-cost of sulfur-based cathode materials. However, LSBs still encounter significant challenges, including the low conductivities of sulfur-based materials, severe volumetric expansion of sulfur during the discharge process, and the persistent "shuttle effect" of polysulfides. In recent years, a tremendous amount of research has been conducted to address the above challenges by developing coating and compositing materials and corresponding fabrication strategies for sulfur-based cathode materials. In this study, the surface coating, compositing materials, and fabrication methodologies of LSB cathodes are comprehensively reviewed in terms of advanced materials, structure/component characterization, functional mechanisms, and performance validation. Some technical challenges are analyzed in detail, and possible future research directions are proposed to overcome the challenges toward practical applications of lithium-sulfur batteries.

Elastic Properties of Low-Dimensional Single-Crystalline Dielectric Oxides through Controlled Large-Area Wrinkle Generation.

Freestanding single-crystalline SrTiO3 membranes, as high-κ dielectrics, hold significant promise as the gate dielectric in two-dimensional (2D) flexible electronics. Nevertheless, the mechanical properties of the SrTiO3 membranes, such as elasticity, remain a critical piece of the puzzle to adequately address the viability of their applications in flexible devices. Here, we report statistical analysis on plane-strain effective Young's modulus of large-area SrTiO3 membranes (5 × 5 mm2) over a series of thicknesses (from 6.5 to 32.2 nm), taking advantage of a highly efficient buckling-based method, which reveals its evident thickness-dependent behavior ranging from 46.01 to 227.17 GPa. Based on microscopic and theoretical results, we elucidate these thickness-dependent behaviors and statistical data deviation with a bilayer model, which consists of a surface layer and a bulk-like layer. The analytical results show that the ∼3.1 nm surface layer has a significant elastic softening compared to the bulk-like layer, while the extracted modulus of the bulk-like layer shows a variation of ∼40 GPa. This variation is considered as a combined contribution from oxygen deficiency presenting in SrTiO3 membranes, and the alignment between applied strain and the crystal orientation. Upon comparison of the extracted elastic properties and electrostatic control capability to those of other typical gate dielectrics, the superior performance of single-crystalline SrTiO3 membranes has been revealed in the context of flexible gate dielectrics, indicating the significant potential of their application in high-performance flexible 2D electronics.

Platelet FcγRIIA: An emerging regulator and biomarker in cardiovascular disease and cancer.

Platelets, anucleate blood cells derive from megakaryocytes, are involved in cardiovascular diseases and tumors. FcγRIIA, the only FcγR expressed on human platelets, is known for its role in immune-related diseases. A growing body of evidence reveals that platelet FcγRIIA is a potential target for the prevention and control of cardiovascular disease and cancer, and is an advantageous biomarker. In this review, we describe the structure and physiological function of platelet FcγRIIA, its regulatory role in cardiovascular disease and cancer, and its potential clinical application.

A carbon quantum dot-decorated g-C3N4 composite as a sulfur hosting material for lithium-sulfur batteries.

Although lithium-sulfur (Li-S) batteries have attracted strong consideration regarding their fundamental mechanism and energy applications, the inferior cycling performance and low reaction rate caused by the "shuttling effect" and the sluggish reaction kinetics of lithium polysulfides (LiPSs) impede their practical application. In this work, graphitic C3N4 (g-C3N4) assembled with highly-dispersed nitrogen-containing carbon quantum dots (CQDs) is designed as a cooperative catalyst to accelerate the reaction kinetics of LiPS conversion, the precipitation of Li2S during discharging, and insoluble Li2S decomposition during the charging process. Meanwhile, the introduction of CQDs improves the conductivity of the g-C3N4 substrate, showing great significance for the construction of high-performance electrocatalysts. As a result, the as-obtained composite shows efficient adsorption and electrochemical conversion of LiPSs, and the Li-S batteries assembled with CQDs/g-C3N4 exhibit an initial specific capacity of 1300.0 mA h g-1 at the current density of 0.1C and retain 582.3 mA h g-1 after 200 cycles. The electrode with the modified composite displays a greater capacity contribution of Li2S precipitation (175.7 mA h g-1), indicating an enhanced catalytic activity of g-C3N4 decorated by CQDs. The rational design of CQDs/g-C3N4 as a sulfur host could be an effective strategy for developing high performance Li-S batteries.

The neighborhood effects on the online financial investment of rural households: Evidence from China.

Neighborhood effects are a common strategy for rural households to deal with irrational situations such as deficient information and ability. Based on the 2019 CHFS survey data, we designed a Probit model to verify whether neighborhood effects exist in the online financial investment of rural households. Our paper constructs a multiple mediation model to explore its mechanism. Otherwise, we execute the heterogeneity analysis by dividing the total sample into groups. Our paper proved that (1) Rural households have significant neighborhood effects on online financial investment. (2) Heterogeneity analysis shows that neighborhood effects are stronger among women, the younger, low-education, and low-income rural households. (3) Through the multiple mediation model, we proved that the neighborhood effects on online financial investment of the peasant household work by the financial knowledge spillover and risk-taking enhancement. Our study conduces to a better understanding of the financial decision-making of rural households, which may provide a practical implication for the popularization of new financial products and the optimal design of policy interventions.

Long noncoding RNA protein-disulfide isomerase-associated 3 regulated high glucose-induced podocyte apoptosis in diabetic nephropathy through targeting miR-139-3p.

BACKGROUND: Podocyte apoptosis plays a vital role in proteinuria pathogenesis in diabetic nephropathy (DN). The regulatory relationship between long noncoding RNAs (lncRNAs) and podocyte apoptosis has recently become another research hot spot in the DN field. AIM: To investigate whether lncRNA protein-disulfide isomerase-associated 3 (Pdia3) could regulate podocyte apoptosis through miR-139-3p and revealed the underlying mechanism. METHODS: Using normal glucose or high glucose (HG)-cultured podocytes, the cellular functions and exact mechanisms underlying the regulatory effects of lncRNA Pdia3 on podocyte apoptosis and endoplasmic reticulum stress (ERS) were explored. LncRNA Pdia3 and miR-139-3p expression were measured through quantitative real-time polymerase chain reaction. Relative cell viability was detected through the cell counting kit-8 colorimetric assay. The podocyte apoptosis rate in each group was measured through flow cytometry. The interaction between lncRNA Pdia3 and miR-139-3p was examined through the dual luciferase reporter assay. Finally, western blotting was performed to detect the effect of lncRNA Pdia3 on podocyte apoptosis and ERS via miR-139-3p. RESULTS: The expression of lncRNA Pdia3 was significantly downregulated in HG-cultured podocytes. Next, lncRNA Pdia3 was involved in HG-induced podocyte apoptosis. Furthermore, the dual luciferase reporter assay confirmed the direct interaction between lncRNA Pdia3 and miR-139-3p. LncRNA Pdia3 overexpression attenuated podocyte apoptosis and ERS through miR-139-3p in HG-cultured podocytes. CONCLUSION: Taken together, this study demonstrated that lncRNA Pdia3 overexpression could attenuate HG-induced podocyte apoptosis and ERS by acting as a competing endogenous RNA of miR-139-3p, which might provide a potential therapeutic target for DN.

An experimental model for primary neuropathic corneal pain induced by long ciliary nerve ligation in rats.

ABSTRACT: Neuropathic corneal pain (NCP) is a new and ill-defined disease characterized by pain, discomfort, aching, burning sensation, irritation, dryness, and grittiness. However, the mechanism underlying NCP remain unclear. Here, we reported a novel rat model of primary NCP induced by long ciliary nerve (LCN) ligation. After sustained LCN ligation, the rats developed increased corneal mechanical and chemical sensitivity, spontaneous blinking, and photophobia, which were ameliorated by intraperitoneal injection of morphine or gabapentin. However, neither tear reduction nor corneal injury was observed in LCN-ligated rats. Furthermore, after LCN ligation, the rats displayed a significant reduction in corneal nerve density, as well as increased tortuosity and beading nerve ending. Long ciliary nerve ligation also notably elevated corneal responsiveness under resting or menthol-stimulated conditions. At a cellular level, we observed that LCN ligation increased calcitonin gene-related peptide (neuropeptide)-positive cells in the trigeminal ganglion (TG). At a molecular level, upregulated mRNA levels of ion channels Piezo2, TRPM8, and TRPV1, as well as inflammatory factors TNF-α, IL-1ß, and IL-6, were also detected in the TG after LCN ligation. Meanwhile, consecutive oral gabapentin attenuated LCN ligation-induced corneal hyperalgesia and increased levels of ion channels and inflammation factors in TG. This study provides a reliable primary NCP model induced by LCN ligation in rats using a simple, minimally invasive surgery technique, which may help shed light on the underlying cellular and molecular bases of NCP and aid in developing a new treatment for the disease.

Medial Septal Glutamatergic Neurons Modulate States of Consciousness during Sevoflurane Anesthesia in Mice.

BACKGROUND: Multiple neural structures involved in maintaining wakefulness have been found to promote arousal from general anesthesia. The medial septum is a critical region that modulates arousal behavior. This study hypothesized that glutamatergic neurons in the medial septum play a crucial role in regulating states of consciousness during sevoflurane general anesthesia. METHODS: Adult male mice were used in this study. The effects of sevoflurane anesthesia on neuronal activity were determined by fiber photometry. Lesions and chemogenetic manipulations were used to study the effects of the altered activity of medial septal glutamatergic neurons on anesthesia induction, emergence, and sensitivity to sevoflurane. Optogenetic stimulation was used to observe the role of acute activation of medial septal glutamatergic neurons on cortical activity and behavioral changes during sevoflurane-induced continuous steady state of general anesthesia and burst suppression state. RESULTS: The authors found that medial septal glutamatergic neuronal activity decreased during sevoflurane anesthesia induction and recovered in the early period of emergence. Chemogenetic activation of medial septal glutamatergic neurons prolonged the induction time (mean ± SD, hM3Dq-clozapine N-oxide vs. hM3Dq-saline, 297.5 ± 60.1 s vs. 229.4 ± 29.9 s, P < 0.001, n = 11) and decreased the emergence time (53.2 ± 11.8 s vs. 77.5 ± 33.5 s, P = 0.025, n = 11). Lesions or chemogenetic inhibition of these neurons produced the opposite effects. During steady state of general anesthesia and deep anesthesia-induced burst suppression state, acute optogenetic activation of medial septal glutamatergic neurons induced cortical activation and behavioral emergence. CONCLUSIONS: The study findings reveal that activation of medial septal glutamatergic neurons has arousal-promoting effects during sevoflurane anesthesia in male mice. The activation of these neurons prolongs the induction and accelerates the emergence of anesthesia.

Structural Design and DLP 3D Printing Preparation of High Strain Stable Flexible Pressure Sensors.

Flexible pressure sensors are crucial force-sensitive devices in wearable electronics, robotics, and other fields due to their stretchability, high sensitivity, and easy integration. However, a limitation of existing pressure sensors is their reduced sensing accuracy when subjected to stretching. This study addresses this issue by adopting finite element simulation optimization, using digital light processing (DLP) 3D printing technology to design and fabricate the force-sensitive structure of flexible pressure sensors. This is the first systematic study of how force-sensitive structures enhance tensile strain stability of flexible resistive pressure sensors. 18 types of force-sensitive structures have been investigated by finite element design, simultaneously, the modulus of the force-sensitive structure is also a critical consideration as it exerts a significant influence on the overall tensile stability of the sensor. Based on simulation results, a well-designed and highly stretch-stable flexible resistive pressure sensor has been fabricated which exhibits a resistance change rate of 0.76% and pressure sensitivity change rate of 0.22% when subjected to strains ranging from no tensile strain to 20% tensile strain, demonstrating extremely low stretching response characteristics. This study presents innovative solutions for designing and fabricating flexible resistive pressure sensors that maintain stable sensing performance even under stretch conditions.

Comparison of different weight-based scalars of remimazolam tosylate for anesthesia induction in obese patients: study protocol for a prospective, controlled trial.

BACKGROUND: The physiologic and anthropometric characteristics changes associated with obesity may result in the alternation of pharmacologic management. Remimazolam tosylate is a new type of ultra-short-acting benzodiazepine with stable context-sensitive half-time (CSHT) and no lipid accumulation after long-time infusion. Although remimazolam tosylate has potential advantages for the induction and maintenance of anesthesia in obese patients, the appropriate induction dosing scalars among obese patients are unknown. Therefore, we aim to compare the different weight-based scalars for dosing remimazolam tosylate of anesthesia induction among obese patients. METHODS/DESIGN: The study will be performed as a prospective, single-center, double-blind, controlled clinical trial. The study design is a comparison of remimazolam tosylate requirements based on total body weight (TBW) or lean body weight (LBW) to reach a Modified Observer's Assessment of Alertness and Sedation (MOAA/S) score of 0 among obese subjects (BMI ≥ 35 kg/m2). Another twenty normal-weight subjects (18.5 kg/m2 ≤ BMI < 25 kg/m2) will be enrolled as a control group, whose induction dose is scaled based on TBW. The infusion rate of remimazolam tosylate during induction is 12 mg/kg/h in all groups. DISCUSSION: Results of the present study will provide evidence of dose scalar of remimazolam tosylate to guide the clinical practice of anesthesia induction in obese patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR220005664. Registered on 9 February 2022, https://www.chictr.org.cn/showproj.aspx?proj=151150 .

TRIM21 of Micropterus salmoides exerts antiviral roles against largemouth bass ulcer syndrome virus.

Tripartite motif 21 (TRIM21), a member of the TRIM family, plays an important role in apoptosis, autophagy and ubiquitination in human, and has been proven to play antiviral roles in different organisms. In this study, the TRIM21 gene of Micropterus salmoides (MsTRIM21) was cloned, and it encoded 376 amino acids, which showed 89.3% similarity with Micropterus dolomieu and 38.3% with homo sapiens. Bioinformatics analysis revealed MsTRIM21 contained four domains: C4HC3-type RING-variant (RINGv), coiled coil, PRY and SPRY. The high expression level of MsTRIM21 could be detected in liver, stomach and muscle of healthy Micropterus salmoides, and it was significantly upregulated in head kidney, muscle, gill and brain and significantly down-regulated in the stomach of Micropterus salmoides infected with largemouth bass ulcer syndrome virus (LBUSV). The overexpression of MsTRIM21 could significantly inhibit the viral replication in vitro, evidenced by the reduction of CPE severity and the downregulation of the viral gene transcription. In addition, the overexpression of MsTRIM21 could significantly increase the expression level of interferon regulatory factor (IRF) 3, IRF7, myxovirus resistance 1 (Mx1), interferon stimulated gene 15 (ISG15), double-stranded RNA-activated protein kinase (PKR) and tumor necrosis factor α (TNF-α) in vitro, indicating the enhancement of innate immune response and inflammatory response, which may directly affect the replication of LBUSV. Thus, these results provide new lights on the roles of fish TRIM21 in innate immune response against iridovirus.

A Predictive Model of Major Postoperative Respiratory Adverse Events in Pediatric Patients Undergoing Rigid Bronchoscopy for Exploration and Foreign Body Removal.

Background: No nomogram has been established to predict the incidence of major postoperative respiratory adverse events (mPRAEs) in children undergoing rigid bronchoscopy for airway foreign bodies (AFB) removal and exploration of the airway, though some studies have confirmed the risk factors. Methods: 1214 pediatric patients (≤3 years old) undergoing rigid bronchoscopy for AFB from June 2014 to December 2020 were enrolled in this study. The primary outcome was the occurrence of mPRAEs, including laryngospasm and bronchospasm. Following that, a nomogram prediction model for the mPRAEs was developed. Results: The incidence of mPRAEs was 84 (6.9%) among 1214 subjects. American Society of Anesthesiologists physical status (ASA-PS), intraoperative desaturation (SpO2 < 90%), procedural duration and ventilatory approach were all independent risk factors of mPRAEs. The area under the receiver operating characteristic curve (AUC) value of the nomogram for predicting mPRAEs was 0.815 (95% CI: 0.770-0.861), and the average AUC for ten-fold cross-validation was 0.799. These nomograms were well calibrated by Hosmer-Lemshow (p = 0.607). Decision curve analysis showed that the nomogram prediction model is effective in clinical settings. Conclusions: Combining ASA-PS, intraoperative desaturation, procedural duration, and ventilatory approach, the nomogram model is adequate for predicting the risk of developing mPRAEs, followed by rigid bronchoscopy for AFB removal and exploration.

The effect of intraoperative transnasal humidified rapid-insufflation ventilatory exchange on emergence from general anesthesia in patients undergoing microlaryngeal surgery: a randomized controlled trial.

BACKGROUND: Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) has received extensive attention for its utility in tubeless anesthesia. Still, the effects of its carbon dioxide accumulation on emergence from anesthesia have not been reported. This randomized controlled trial aimed at exploring the impact of THRIVE combined with laryngeal mask (LM) on the quality of emergence in patients undergoing microlaryngeal surgery. METHODS: After research ethics board approval, 40 eligible patients receiving elective microlaryngeal vocal cord polypectomy were randomly allocated 1:1 to two groups, THRIVE + LM group: intraoperative apneic oxygenation using THRIVE followed by mechanical ventilation through a laryngeal mask in the post-anesthesia care unit (PACU), or MV + ETT group: mechanically ventilated through an endotracheal tube for both intraoperative and post-anesthesia periods. The primary outcome was duration of PACU stay. Other parameters reflecting quality of emergence and carbon dioxide accumulation were also recorded. RESULTS: Duration of PACU stay (22.4 ± 6.4 vs. 28.9 ± 8.8 min, p = 0.011) was shorter in the THRIVE + LM group. The incidence of cough (2/20, 10% vs. 19/20, 95%, P < 0.001) was significantly lower in the THRIVE + LM group. Peripheral arterial oxygen saturation and mean arterial pressure during intraoperative and PACU stay, Quality of Recovery Item 40 total score at one day after surgery and Voice Handicap Index-10 score at seven days after surgery were of no difference between two groups. CONCLUSIONS: The THRIVE + LM strategy could accelerate emergence from anesthesia and reduce the incidence of cough without compromising oxygenation. However, these benefits did not convert to the QoR-40 and VHI-10 scores improvement. TRIAL REGISTRATION: ChiCTR2000038652.

Medial septum glutamatergic neurons modulate nociception in chronic neuropathic pain via projections to lateral hypothalamus.

The medial septum (MS) contributes in pain processing and regulation, especially concerning persistent nociception. However, the role of MS glutamatergic neurons in pain and the underlying neural circuit mechanisms in pain remain poorly understood. In this study, chronic constrictive injury of the sciatic nerve (CCI) surgery was performed to induce thermal and mechanical hyperalgesia in mice. The chemogenetic activation of MS glutamatergic neurons decreased pain thresholds in naïve mice. In contrast, inhibition or ablation of these neurons has improved nociception thresholds in naïve mice and relieved thermal and mechanical hyperalgesia in CCI mice. Anterograde viral tracing revealed that MS glutamatergic neurons had projections to the lateral hypothalamus (LH) and supramammillary nucleus (SuM). We further demonstrated that MS glutamatergic neurons regulate pain thresholds by projecting to LH but not SuM, because the inhibition of MS-LH glutamatergic projections suppressed pain thresholds in CCI and naïve mice, yet, optogenetic activation or inhibition of MS-SuM glutamatergic projections had no effect on pain thresholds in naïve mice. In conclusion, our results reveal that MS glutamatergic neurons play a significant role in regulating pain perception and decipher that MS glutamatergic neurons modulate nociception via projections to LH.

Corticosterone mediates FKBP51 signaling and inflammation response in the trigeminal ganglion in chronic stress-induced corneal hyperalgesia mice.

Stress-induced hyperalgesia is a health-threatening condition that lacks effective therapeutic intervention, impairing the quality of life. Interestingly, a high prevalence of corneal pain symptoms was also found in patients experienced severe stressors. Excessive secretion corticosterone in rodents has been shown to contribute to the development of visceral and mechanical hyperalgesia under stressful conditions. The co-chaperone protein FK506-binding protein 5 (FKBP5) was reported to modulate steroid sensitivity and inhibition of FKBP51 possessed anxiolytic and anti-hyperalgesic in the stressed-mice model. However, whether corticosterone and FKBP5 play a role in chronic stress-induced corneal hyperalgesia remains unknown. The aim of this study was to evaluate the corneal sensitivity after exposure to chronic restraint stress (CRS) and investigate the potential role of corticosterone and FKBP5 mediated proinflammatory cytokines release in trigeminal ganglion (TG) in corneal hyperalgesia under chronic stressful situations. Firstly, mice displayed increased corneal sensitivity without changes in tear production and corneal injury after CRS for 4 hours/day for 14 days. Meanwhile, corticosterone deficiency via adrenalectomy could prevent CRS-induced corneal hyperalgesia, whereas chronic corticosterone feeding increased the corneal sensitivity accompanied by increasing proinflammatory cytokines levels of phospho-NF-κB (p-NF-κB), tumor necrosis factor (TNF)-α and interleukin (IL)-1ß in the TG on d14. Notably, we found that FKBP51 was significantly upregulated in the TG in the stressed-mice. Intraperitoneal injection of FKBP51 inhibitor significantly alleviated CRS-induced corneal hyperalgesia, and reversed calcitonin gene related peptide (CGRP) increase and proinflammatory cytokines production in the TG. Moreover, FKBP51 inhibitor could also exert its anti-hyperalgesic effect on corneal pain through intra-TG injection. Our study proves that CRS can induce corneal hyperalgesia in mice and uncovers the role of corticosterone and FKBP51 in modulating corneal sensitivity, providing a novel treatment strategy for stress-induced corneal hyperalgesia. AVAILABILITY OF DATA AND MATERIALS: All data and additional file are available upon request from the corresponding author.