Exhaustion­like dysfunction of T and NKT cells in an X­linked severe combined immunodeficiency patient with maternal engraftment by single­cell analysis.

Maternal engraftment is frequently present in X­linked severe combined immunodeficiency (X­SCID) patients caused by pathogenic mutations in IL2GR. However, the functional status of the engrafted cells remains unclear because of the difficulty in separately evaluating the function of the maternal and autologous cells. The present study reported an X­SCID patient with a de novo c.677C>T (p.R226H) variant in exon 5 of IL2RG, exhibiting recurrent and persistent infections from 3­months­old. After the male patient suffering recurrent pneumonia and acute hematogenous disseminated tuberculosis when 13­months­old, single­cell RNA sequencing was applied to characterize the transcriptome landscape of his bone marrow mononuclear cells (BMMNCs). A novel bioinformatic analysis strategy was designed to discriminate maternal and autologous cells at single­cell resolution. The maternal engrafted cells consisted primarily of T, NKT and NK cells and the patient presented with the coexistence of autologous cells of these cell types. When compared respectively with normal counterparts, both maternal and autologous T and NKT cells increased the transcription of some important cytokines (GZMB, PRF1 and NKG7) against infections, but decreased the expression of a number of key transcription factors (FOS, JUN, TCF7 and LEF1) related to lymphocyte activation, proliferation and differentiation. Notably, the expression of multiple inhibitory factors (LAG3, CTLA4 and HAVCR2) were substantially enhanced in the T and NKT cells of both origins. In conclusion, both maternal and autologous T and NKT cells exhibited exhaustion­like dysfunction in this X­SCID patient suffering recurrent and persistent infections.

Circular RNA Plasmacytoma Variant Translocation 1 (CircPVT1) knockdown ameliorates hypoxia-induced bladder fibrosis by regulating the miR-203/Suppressor of Cytokine Signaling 3 (SOCS3) signaling axis.

The effects of circular RNAs (circRNAs) on bladder outlet obstruction (BOO)-induced hypertrophy and fibrogenesis in rats and hypoxia-induced bladder smooth muscle cell (BSMC) fibrosis remain unclear. This study aimed to determine the regulatory role of circRNAs in the phenotypic changes in BSMCs in BOO-induced rats.circRNAmicroarray and real-time PCR were used to explore differentiated expressed circRNAs. Bioinformatics analyses and dual-luciferase reporter were performed to identify the targets for circRNA PVT1 (circPVT1). BOO was performed to establish a bladder fibrosis animal model. The circPVT1 and suppressor of cytokine signaling 3 (SOCS3) expression levels were upregulated (p = 0.0061 and 0.0328, respectively), whereas the microRNA-203a (miR-203) level was downregulated in rats with bladder remodeling (p=0.0085). Bioinformatics analyses and dual-luciferase reporter assay results confirmed that circPVT1 sponges miR-203 and that the latter targets the 3'-untranslated region of SOCS3. Additionally, circPVT1 knockdown alleviated BOO-induced bladder hypertrophy and fibrogenesis. Furthermore, hypoxia was induced in BSMCs to establish a cell model of bladder fibrosis. Hypoxia induction in BSMCs resulted in upregulated circPVT1 and SOCS3 levels (p = 0.0052) and downregulated miR-203 levels. Transfection with circPVT1 and SOCS3 shRNA ameliorated hypoxia-induced transforming growth factor-ß (TGF-ß1), TGFßR1, α-smooth muscle actin, fibrotic growth factor, extracellular matrix subtypes, BSMC proliferation, and apoptosis-associated cell injury, whereas co-transfection with miR-203 inhibitor counteracted the effect of circPVT1 shRNA on these phenotypes.These findings revealed a novel circRNA regulator of BOO-associated bladder wall remodeling and hypoxia-induced phenotypic changes in BMSCs by targeting the miR-203-SOCS3 signaling axis.

LncRNA SNHG17 promotes tumor progression and predicts poor survival in human renal cell carcinoma via sponging miR-328-3p.

Accumulating data shows that dysregulation of long non-coding RNAs (lncRNAs) are involved in human tumors' occurrence and progression. Small nucleolar RNA host genes (SNHGs) are recently revealed to play a carcinogenic role in various human neoplasms. However, the functions and underlying mechanisms of lncRNA SNHG17 in renal cell carcinoma (RCC) are still elusive. We analyzed the relationship between SNHG17 expression levels and clinicopathologic characteristics and prognosis in patients with RCC according to TCGA RNA-sequencing data and our cohort data. Loss-of-function and gain-of-function experiments were conducted to examine the biological behaviors of SNHG17 on RCC cell proliferation, migration, invasion, apoptosis, and tumor growth in vivo. The interaction between SNHG17, miR-328-3p, and Histone'sH2Avariant (H2AX) was verified by bioinformatics, dual-luciferase reporter gene, and RNA immunoprecipitation (RIP). Highly expressed SNHG17 was evident in RCC tissue samples and cell lines, and SNHG17 overexpression was related to advanced TNM stage and reduced relapse-free and overall survival of patients with RCC. Knockdown of SNHG17 prohibited malignant phenotypes, whereas ectopic SNHG17 expression showed the opposite effects. More importantly, SNHG17 could upregulate the expression of H2AX by acting as a miR-328-3p sponge. In vivo experiments confirmed that SNHG17 promoted the growth of RCC tumors. SNHG17/miR-328-3p/H2AXaxis might be involved in RCC progression, which provided a potential therapeutic target for RCC.

The safety of high-dose rocuronium bromide in general anesthesia for spinal surgery and its effects on muscle relaxation.

PURPOSE: This study aimed to investigate the effects of high-dose rocuronium bromide in general anesthesia for spinal surgery and analyze its safety. METHODS: A total of 90 patients with spine diseases who underwent elective spinal surgery in our hospital were enrolled as study subjects, and were divided into 2-fold group (intraoperative administration of 0.6 mg/kg rocuronium bromide, n=30), 3-fold group (0.9 mg/kg rocuronium bromide, n=30) and 4-fold group (1.2 mg/kg rocuronium bromide, n=30). The effects of rocuronium bromide on muscle relaxation, the operative time and the incidence of adverse reactions were compared among the three groups. RESULTS: The onset time of muscle relaxation in the 4-fold group was significantly lower than that in 2-fold and 3-fold groups. The duration of muscle relaxation and duration of action in the 4-fold group were significantly higher than those in the 2-fold and 3-fold groups (P<0.05). The satisfaction rate in the 4-fold group (100.00%) was significantly higher than that in the 2-fold group (66.67%) and the 3-fold group (86.67%) (P<0.05). The 4-fold group exhibited significantly higher intubating condition score at 1 min and significantly lower operative time than the 2-fold and 3-fold groups (P<0.05). The incidence of adverse reactions in the 4-fold group was 23.33%, slightly higher than those in the 2-fold (20.00%) and 3-fold groups (20.00%) (P>0.05). CONCLUSION: High-dose rocuronium bromide shortens the onset time of muscle relaxation in patients undergoing spinal surgery, creates better intubation conditions, has longer duration of action, and shortens the patient's operative time, without increasing adverse reactions such as skin flushing, rash, increased airway resistance and bronchospasm, laryngeal edema, etc. Meanwhile, high-dose rocuronium bromide can shorten intubation time, which is conducive to the smooth operation and reduces surgical stress injuries.

Effectiveness of supraglottic ventilation by transtracheal catheter for painless ERCP.

PURPOSE: This study aimed to investigate the effect of supraglottic ventilation via transtracheal catheter in painless endoscopic retrograde cholangiopancreatography (ERCP). METHODS: Sixty patients with painless ERCP who were treated in our hospital were enrolled as the study subjects and divided into a study group (n=30) and a control group (n=30) according to the method of ventilation during the operation. The control group received ventilation via modified laryngeal mask, while the study group received supraglottic ventilation through a transtracheal tube. The mean arterial pressure (MAP), heart rate (HR), oxygen saturation (SpO2), and End-tidal CO2 (EtCO2) at multiple time points after admission (T0), after induction of anesthesia (T1), immediately after catheter placement (T2), immediately after operation (T3), and at the time of resuscitation (T4) were compared between the two groups. The incidence of various adverse events in the perioperative period was also compared. RESULTS: The two groups showed significant fluctuations in intraoperative hemodynamic parameters. However, the changes in MAP, SpO2 and ETCO2 of the study group were more stable, and better than those of the control group at the T2 and T3 (P<0.05). The intubation time, operation time and recovery time of patients in the study group were significantly lower than those in the control group (P<0.05). The total incidence of adverse events in the study group was significantly lower than that in the control group (P<0.05). CONCLUSION: It is highly feasible to apply supraglottic ventilation with transvalvular catheter in painless ERCP, which can significantly stabilize the perioperative hemodynamic parameters, accelerate recovery and also help decrease the rate of postoperative complications.

Influence of anesthetic induction of propofol combined with esketamine on perioperative stress and inflammatory responses and postoperative cognition of elderly surgical patients.

OBJECTIVE: To analyze the influence of anesthetic induction of propofol combined with esketamine on perioperative stress and inflammatory responses and postoperative cognition in elderly surgical patients. METHODS: A total of 80 elderly surgical patients were randomly divided into a control group (n=40) and a study group (n=40). The control group received anesthetic induction with propofol combined with sufentanil, while the study group received anesthetic induction with propofol combined with esketamine. Hemodynamics, stress and inflammatory responses and changes in cognitive function, perioperative related indexes and adverse responses were compared between the two groups. RESULTS: At T1, the levels of adrenaline, norepinephrine, endothelin, C-reactive protein, white blood cell and procalcitonin in the two groups were not markedly changed compared with those at T0. The levels of the indices at T2 and T3 were elevated compared with those at T1. However, the levels of the indices at T4 were almost close to those at T0, and the levels in the study group were higher than those in the control group. There were statistically significant differences in the comparison of the interaction of the levels of the aforementioned indices between groups, between time points, and between groups and time points (P < 0.05). At 24 h after surgery, the Montreal Cognitive Assessment (MoCA) scores were decreased in both groups, and the MoCA scores in the study group were higher than those in the control group (P < 0.05). The anesthesia time and consciousness recovery time in the study group were shorter than those in the control group (P < 0.05). CONCLUSION: The anesthetic induction of propofol combined with esketamine, exhibits a good safety profile and reliability, it can improve hemodynamics and surgical stress and inflammatory responses, shorten anesthesia time, promote the recovery of postoperative cognitive function, and cause relatively mild adverse responses.

Altered Dynamic Amplitude of Low-Frequency Fluctuations in Patients With Migraine Without Aura.

Migraine is a chronic and idiopathic disorder leading to cognitive and affective problems. However, the neural basis of migraine without aura is still unclear. In this study, dynamic amplitude of low-frequency fluctuations (dALFF) analyses were performed in 21 patients with migraine without aura and 21 gender- and age-matched healthy controls to identify the voxel-level abnormal functional dynamics. Significantly decreased dALFF in the bilateral anterior insula, bilateral lateral orbitofrontal cortex, bilateral medial prefrontal cortex, bilateral anterior cingulate cortex, and left middle frontal cortex were found in patients with migraine without aura. The dALFF values in the anterior cingulate cortex were negatively correlated with pain intensity, i.e., visual analog scale. Finally, support vector machine was used to classify patients with migraine without aura from healthy controls and achieved an accuracy of 83.33%, sensitivity of 90.48%, and specificity of 76.19%. Our findings provide the evidence that migraine influences the brain functional activity dynamics and reveal the neural basis for migraine, which could facilitate understanding the neuropathology of migraine and future treatment.

Pulmonary lymphoepithelioma-like carcinoma: A case report with emphasis on computed tomography findings.

RATIONALE: Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare type of primary malignant lung tumor characterized by Epstein-Barr virus infection, with, to the authors' knowledge, a total of only 500 reported cases during the past 30 years worldwide. Histologically, PLELC is similar to undifferentiated nasopharyngeal carcinoma and poorly differentiated squamous cell carcinoma. However, although PLELC accounts for <1% of all lung cancers, it has a better prognosis and is usually detected in non-smokers and individuals of Asian ancestry. PATIENT CONCERNS: The patient presented with chest distress of no apparent cause, dizziness, headaches, and a feeling of disequilibrium without remission, as well as a pulmonary nodule incidentally detected on contrast-enhanced computed tomography (CT). DIAGNOSIS: PLELC was confirmed histopathologically rather than on preoperative CT; nevertheless, CT findings still contributed to the diagnosis. INTERVENTIONS: The patient underwent thoracoscopic wedge resection of the affected lung. OUTCOMES: The patient recovered after the lung nodule was completely removed, and was discharged. No evidence of recurrence or metastasis was found at the latest follow-up appointment 2 months after the operation. LESSONS: PLELC is a rare bronchogenic carcinoma associated with lymphatic tissue with a favorable prognosis in most cases. With nonspecific clinical symptoms, specific radiological findings may facilitate an early diagnosis in some cases, followed by timely surgical intervention.

SIPL1, Regulated by MAZ, Promotes Tumor Progression and Predicts Poor Survival in Human Triple-Negative Breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer owing to a lack of effective targeted therapy and acquired chemoresistance. Here, we explored the function and mechanism of shank-interacting protein-like 1 (SIPL1) in TNBC progression. METHODS: SIPL1 expression was examined in human TNBC tissues and cell lines by quantitative reverse transcription PCR, western blot, and immunohistochemistry. SIPL1 overexpression and silenced cell lines were established in BT-549 and MDA-MB-231 cells. The biological functions of SIPL1 in TNBC were studied in vitro using the CCK-8 assay, CellTiter-Glo Luminescent Cell Viability assay, caspase-3/8/9 assay, wound healing assay, and transwell assay and in vivo using a nude mouse model. The potential mechanisms underlying the effects of SIPL1 on TNBC progression were explored using bioinformatics analysis, luciferase reporter assays, and chromatin immunoprecipitation followed by qPCR. RESULTS: SIPL1 expression was higher in human TNBC tissues and cell lines than in adjacent normal tissues and a breast epithelial cell line (MCF10A). High expression of SIPL1 was positively correlated with poor overall and disease-free survival in patients with TNBC. SIPL1 overexpression elevated and SIPL1 silencing repressed the malignant phenotypes of TNBC cells in vitro. SIPL1 overexpression promoted xenograft tumor growth in vivo. Myc-associated zinc-finger protein (MAZ) transcriptionally activated SIPL1. Finally, we found that SIPL1 promoted TNBC malignant phenotypes via activation of the AKT/NF-κB signaling pathways. CONCLUSIONS: These results indicate that the MAZ/SIPL1/AKT/NF-κB axis plays a crucial role in promoting the malignant phenotypes of TNBC cells.

COPII mitigates ER stress by promoting formation of ER whorls.

Cells mitigate ER stress through the unfolded protein response (UPR). Here, we report formation of ER whorls as an effector mechanism of the ER stress response. We found that strong ER stress induces formation of ER whorls, which contain ER-resident proteins such as the Sec61 complex and PKR-like ER kinase (PERK). ER whorl formation is dependent on PERK kinase activity and is mediated by COPII machinery, which facilitates ER membrane budding to form tubular-vesicular ER whorl precursors. ER whorl precursors then go through Sec22b-mediated fusion to form ER whorls. We further show that ER whorls contribute to ER stress-induced translational inhibition by possibly modulating PERK activity and by sequestering translocons in a ribosome-free environment. We propose that formation of ER whorls reflects a new type of ER stress response that controls inhibition of protein translation.

Concurrent alterations of white matter microstructure and functional activities in medication-free major depressive disorder.

Although numerous studies have revealed the structural and functional alterations in major depressive disorder (MDD) using unimodal diffusion magnetic resonance imaging (MRI) or functional MRI, however, the potential associations between changed microstructure and corresponding functional activities in the MDD has been largely uninvestigated. Herein, 27 medication-free MDD patients and 54 gender-, age-, and educational level-matched healthy controls (HC) were used to investigate the concurrent alterations of white matter microstructure and functional activities using tract-based spatial statistics (TBSS) analyses, fractional amplitude of low-frequency fluctuation (fALFF), and degree centrality (DC). The TBSS analyses revealed significantly decreased fractional anisotropy (FA) in the superior longitudinal fasciculus (SLF I) in the MDD patients compared to HC. Correlation analyses showed that decreased FA in the SLF I was significantly correlated with fALFF in left pre/postcentral gyrus and binary, weighted DC in right posterior cerebellum. Moreover, the fALFF in left pre/postcentral gyrus significantly reduced in MDD patients while binary and weighted DC in right posterior cerebellum significantly increased in MDD patients. Our results revealed concurrent structural and functional changes in MDD patients suggesting that the underlying structural disruptions are an important indicator of functional abnormalities.

Abnormal Whole Brain Functional Connectivity Pattern Homogeneity and Couplings in Migraine Without Aura.

Previous studies have reported abnormal amplitude of low-frequency fluctuation and regional homogeneity in patients with migraine without aura using resting-state functional magnetic resonance imaging. However, how whole brain functional connectivity pattern homogeneity and its corresponding functional connectivity changes in patients with migraine without aura is unknown. In the current study, we employed a recently developed whole brain functional connectivity homogeneity (FcHo) method to identify the voxel-wise changes of functional connectivity patterns in 21 patients with migraine without aura and 21 gender and age matched healthy controls. Moreover, resting-state functional connectivity analysis was used to reveal the changes of corresponding functional connectivities. FcHo analyses identified significantly decreased FcHo values in the posterior cingulate cortex (PCC), thalamus (THA), and left anterior insula (AI) in patients with migraine without aura compared to healthy controls. Functional connectivity analyses further found decreased functional connectivities between PCC and medial prefrontal cortex (MPFC), between AI and anterior cingulate cortex, and between THA and left precentral gyrus (PCG). The functional connectivities between THA and PCG were negatively correlated with pain intensity. Our findings indicated that whole brain FcHo and connectivity abnormalities of these regions may be associated with functional impairments in pain processing in patients with migraine without aura.

Long noncoding RNA SNHG4 promotes renal cell carcinoma tumorigenesis and invasion by acting as ceRNA to sponge miR-204-5p and upregulate RUNX2.

BACKGROUND: Long noncoding RNAs (lncRNAs) are involved in the tumorigenesis and progression of human cancers, including renal cell carcinoma (RCC). Small nucleolar RNA host gene 4 (SNHG4) is reported to play an essential role in tumor growth and progression. However, the molecular mechanisms and function of SNHG4 in RCC remain undocumented. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to examine expression levels of SNHG4 in RCC tissue samples and cell lines. Cell counting kit-8, western blotting, activities of caspase-3, -8, and -9, wound-healing, and transwell invasion assays were performed to explore cell proliferation, apoptosis, migration, and invasion. The interaction among SNHG4, miR-204-5p, and RUNX2 was verified by bioinformatic analysis, a luciferase gene report, qRT-PCR, western blot analysis, and RNA immunoprecipitation assays. Xenograft mouse models were carried out to examine the role of SNHG4 in RCC in vivo. RESULTS: SNHG4 was highly expressed in RCC tissue samples and cell lines, and its upregulation was significantly involved in node involvement, distant metastasis, and reduced overall and relapse-free survival of patients with RCC. SNHG4 acted as an oncogenic lncRNA with promoted RCC cell proliferation, migration, invasion, and inhibited apoptosis. SNHG4 boosted tumor growth in xenograft mouse models. Mechanistically, SNHG4 functioned as a competing endogenous RNA (ceRNA) for sponging miR-204-5p, leading to the upregulation of its target RUNX2 to promote RCC cell proliferation and invasion. CONCLUSION: SNHG4 and miR-204-5p might be indicated in RCC progression via RUNX2, suggesting the potential use of SNHG4/miR-204-5p/RUNX2 axis in RCC treatment.

Hypoxia-inhibited miR-338-3p suppresses breast cancer progression by directly targeting ZEB2.

Hypoxia plays an essential role in the development of various cancers. The biological function and underlying mechanism of microRNA-338-3p (miR-338-3p) under hypoxia remain unclarified in breast cancer (BC). Herein, we performed bioinformatics, gain and loss of function of miR-338-3p, a luciferase reporter assay, and chromatin immunoprecipitation (ChIP) in vitro and in a tumor xenograft model. We also explored the potential signaling pathways of miR-338-3p in BC. We detected the expression levels and prognostic significance of miR-338-3p in BC by qRT-PCR and in situ hybridization. MiR-338-3p was lowly expressed in BC tissues and cell lines, and BC patients with underexpression of miR-338-3p tend to have a dismal overall survival. Functional experiments showed that miR-338-3p overexpression inhibited BC cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) process, whereas miR-338-3p silencing abolished these biological behaviors. Zinc finger E-box-binding homeobox 2 (ZEB2) was validated as a direct target of miR-338-3p. ZEB2 overexpression promoted while ZEB2 knockdown abolished the promoted effects of miR-338-3p knockdown on cell biological behaviors through the NF-ĸB and PI3K/Akt signal pathways. HIF1A can transcriptionally downregulate miR-338-3p under hypoxia. In total, miR-338-3p counteracts hypoxia-induced BC cells growth, migration, invasion, and EMT via the ZEB2 and NF-ĸB/PI3K signal pathways, implicating miR-338-3p may be a promising target to treat patients with BC.

LncRNA SNHG3 sponges miR-577 to up-regulate SMURF1 expression in prostate cancer.

Prostate cancer remains one of the most prevalent cancers and the main causes of cancer-related deaths in males. Various articles introduced that long noncoding RNAs (lncRNAs) are found in vital functions in the development and progression of cancers. Although SNHG3 (small nucleolar RNA host gene 3) has been investigated in many cancers, now researches on the role and mechanism of SNHG3 in prostate cancer are lacked. In this work, SNHG3 exerted high expression in prostate cancer cell lines. Suppression of SNHG3 inhibited cell proliferation, migration, EMT (epithelial-mesenchymal transition) process and promoted cell apoptosis. Additionally, it was found that SNHG3 could bind with miR-577. Subsequently, SMURF1 (Smad ubiquitination regulatory factor 1) was identified as a downstream target of miR-577 and had a negative correlation with miR-577. SNHG3 was found to positively regulate SMURF1 expression. Furthermore, rescue assays demonstrated that co-transfection of pcDNA3.1/SMURF1 reversed the effects of SNHG3 knockdown in cell proliferation, migration, EMT process and cell apoptosis. SNHG3 also promoted tumorigenesis in vivo. All the results above explained that SNHG3 accelerated prostate cancer progression by sponging miR-577 to up-regulate SMURF1 expression, suggesting that SNHG3 may act as a biomarker for prostate cancer patients.

Oxymatrine inhibits the migration and invasion of hepatocellular carcinoma cells by reducing the activity of MMP-2/-9 via regulating p38 signaling pathway.

As one of the major alkaloid components in Sophoraflavescensait (kushen), oxymatrine has been used widely across the world in anti-inflammatory and anti-cancer therapies. However, the effect in the metastasis of hepatocellular carcinoma (HCC) and related mechanism(s) are still unclear. The present study aimed to investigate the anti-metastatic effect of oxymatrine on HCC cells. Oxymatrine could also inhibit the protein levels of MMP-2/-9 in a dose-dependent relationship. Moreover, oxymatrine reduces the activity of p38 signaling pathway via inhibiting the phosphorylation of p38. The inhibition effect of oxymatrine on the expression of MMP-2/-9 and the phosphorylated of p38 was also detected in vivo. Combined treatment with p38 signaling pathway inhibitor and oxymatrine may have a synergistic effect on MMP-2/-9 and invasion of HCC cells. Therefore, oxymatrine may have inhibited GBC invasiveness by reducing the expression of MMP-2/-9 via inhibiting the activity of p38 signaling pathway. As a potentially novel therapeutic drug, oxymatrine may play an important role in the treatment of HCC.

Publisher Correction: Migrasome formation is mediated by assembly of micron-scale tetraspanin macrodomains.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Migrasome formation is mediated by assembly of micron-scale tetraspanin macrodomains.

Migrasomes are recently discovered cellular organelles that form as large vesicle-like structures on retraction fibres of migrating cells. While the process of migrasome formation has been described before, the molecular mechanism underlying migrasome biogenesis remains unclear. Here, we propose that the mechanism of migrasome formation consists of the assembly of tetraspanin- and cholesterol-enriched membrane microdomains into micron-scale macrodomains, which swell into migrasomes. The major finding underlying the mechanism is that tetraspanins and cholesterol are necessary and sufficient for migrasome formation. We demonstrate the necessity of tetraspanins and cholesterol via live-cell experiments, and their sufficiency by generating migrasome-like structures in reconstituted membrane systems. We substantiate the mechanism by a theoretical model proposing that the key factor driving migrasome formation is the elevated membrane stiffness of the tetraspanin- and cholesterol-enriched macrodomains. Finally, the theoretical model was quantitatively validated by experimental demonstration of the membrane-stiffening effect of tetraspanin 4 and cholesterol.

Voltage-gated sodium channel 1.7 expression decreases in dorsal root ganglia in a spinal nerve ligation neuropathic pain model.

The role of the voltage-gated sodium channel 1.7 (Nav1.7) is unclear in models of neuropathic pain induced by nerve injury. In the present study, we measured expression levels of Nav1.7 in two distinct neuropathic pain models: spinal nerve ligation (SNL) and chronic constriction injury (CCI). In the SNL model, both mRNA and protein levels of Nav1.7 were markedly lower in the L5 dorsal root ganglia (DRG) but were significantly higher in the L4 DRG. Nav1.7 protein levels were notably higher in both L4 and L5 DRGs under CCI conditions. We found that excessive damage of L5 nerves such as SNL reduced expression levels of Nav1.7 in the injured L5 DRG and activated the adjacent uninjured DRG, resulting in Nav1.7 level increases in the adjacent L4 DRG. We confirmed again that Nav1.7 was closely related to neuropathic pain induced by nerve injury. More importantly, our results suggest that tracing the molecular changes exclusively in the L5 DRG in SNL model may not completely explain the pain mechanism; it is necessary to study the adjacent uninjured L4 DRG.