miRNA-21-5p is an important contributor to the promotion of injured peripheral nerve regeneration using hypoxia-pretreated bone marrow-derived neural crest cells.

JOURNAL/nrgr/04.03/01300535-202501000-00035/figure1/v/2024-05-14T021156Z/r/image-tiff Our previous study found that rat bone marrow-derived neural crest cells (acting as Schwann cell progenitors) have the potential to promote long-distance nerve repair. Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication. Nevertheless, the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear. To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves, we collected conditioned culture medium from hypoxia-pretreated neural crest cells, and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation. The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells. We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells. Subsequently, to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons, we used a microfluidic axonal dissociation model of sensory neurons in vitro, and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons, which was greatly dependent on loaded miR-21-5p. Finally, we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb, as well as muscle tissue morphology of the hind limbs, were obviously restored. These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p. miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome. This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves, and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.

Chemokines and lymphocyte homing in Sjögren's syndrome.

Sjögren's syndrome (SS) is a chronic systemic autoimmune disease that typically presents with lymphocyte, dendritic cell, and macrophage infiltration of exocrine gland ducts and the formation of ectopic germinal centers. The interactions of lymphocyte homing receptors and addressins and chemokines and their receptors, such as α4ß7/MAdCAM-1, LFA-1/ICAM-1, CXCL13/CXCR5, CCL25/CCR9, CX3CL1/CX3CR1, play important roles in the migration of inflammatory cells to the focal glands and the promotion of ectopic germinal center formation in SS. A variety of molecules have been shown to be involved in lymphocyte homing, including tumor necrosis factor-α, interferon (IFN)-α, IFN-ß, and B cell activating factor. This process mainly involves the Janus kinase-signal transducer and activator of transcription signaling pathway, lymphotoxin-ß receptor pathway, and nuclear factor-κB signaling pathway. These findings have led to the development of antibodies to cell adhesion molecules, antagonists of chemokines and their receptors, compounds interfering with chemokine receptor signaling, and gene therapies targeting chemokines and their receptors, providing new targets for the treatment of SS in humans. The aim of this study was to explore the relationship between lymphocyte homing and the pathogenesis of SS, and to provide a review of recent studies addressing lymphocyte homing in targeted therapy for SS.

Effectiveness of the acute stroke care map program in reducing in-hospital delay for acute ischemic stroke in a Chinese urban area: an interrupted time series analysis.

Background: Timely intravenous thrombolysis (IVT) is crucial for improving outcomes in acute ischemic stroke (AIS) patients. This study evaluates the effectiveness of the Acute Stroke Care Map (ASCaM) initiative in Shenyang, aimed at reducing door-to-needle times (DNT) and thus improving the timeliness of care for AIS patients. Methods: An retrospective cohort study was conducted from April 2019 to December 2021 in 30 hospitals participating in the ASCaM initiative in Shenyang. The ASCaM bundle included strategies such as EMS prenotification, rapid stroke triage, on-call stroke neurologists, immediate neuroimaging interpretation, and the innovative Pre-hospital Emergency Call and Location Identification feature. An interrupted time series analysis (ITSA) was used to assess the impact of ASCaM on DNT, comparing 9 months pre-intervention with 24 months post-intervention. Results: Data from 9,680 IVT-treated ischemic stroke patients were analyzed, including 2,401 in the pre-intervention phase and 7,279 post-intervention. The ITSA revealed a significant reduction in monthly DNT by -1.12 min and a level change of -5.727 min post-ASCaM implementation. Conclusion: The ASCaM initiative significantly reduced in-hospital delays for AIS patients, demonstrating its effectiveness as a comprehensive stroke care improvement strategy in urban settings. These findings highlight the potential of coordinated care interventions to enhance timely access to reperfusion therapies and overall stroke prognosis.

Promotive effect of skin precursor-derived Schwann cells on brachial plexus neurotomy and motor neuron damage repair through milieu-regulating secretome.

Brachial plexus injury (BPI) with motor neurons (MNs) damage still remain poor recovery in preclinical research and clinical therapy, while cell-based therapy approaches emerged as novel strategies. Previous work of rat skin precursor-derived Schwann cells (SKP-SCs) provided substantial foundation for repairing peripheral nerve injury (PNI). Given that, our present work focused on exploring the repair efficacy and possible mechanisms of SKP-SCs implantation on rat BPI combined with neurorrhaphy post-neurotomy. Results indicated the significant locomotive and sensory function recovery, with improved morphological remodeling of regenerated nerves and angiogenesis, as well as amelioration of target muscles atrophy and motor endplate degeneration. Besides, MNs could restore from oxygen-glucose-deprivation (OGD) injury upon SKP-SCs-sourced secretome treatment, implying the underlying paracrine mechanisms. Moreover, rat cytokine array assay detected 67 cytokines from SKP-SC-secretome, and bioinformatic analyses of screened 32 cytokines presented multiple functional clusters covering diverse cell types, including inflammatory cells, Schwann cells, vascular endothelial cells (VECs), neurons, and SKP-SCs themselves, relating distinct biological processes to nerve regeneration. Especially, a panel of hypoxia-responsive cytokines (HRCK), can participate into multicellular biological process regulation for permissive regeneration milieu, which underscored the benefits of SKP-SCs and sourced secretome, facilitating the chorus of nerve regenerative microenvironment. Furthermore, platelet-derived growth factor-AA (PDGF-AA) and vascular endothelial growth factor-A (VEGF-A) were outstanding cytokines involved with nerve regenerative microenvironment regulating, with significantly elevated mRNA expression level in hypoxia-responsive SKP-SCs. Altogether, through recapitulating the implanted SKP-SCs and derived secretome as niche sensor and paracrine transmitters respectively, HRCK would be further excavated as molecular underpinning of the neural recuperative mechanizations for efficient cell therapy; meanwhile, the analysis paradigm in this study validated and anticipated the actions and mechanisms of SKP-SCs on traumatic BPI repair, and was beneficial to identify promising bioactive molecule cocktail and signaling targets for cell-free therapy strategy on neural repair and regeneration.

Mechanisms of ligand recognition and activation of melanin-concentrating hormone receptors.

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide that regulates food intake, energy balance, and other physiological functions by stimulating MCHR1 and MCHR2 receptors, both of which are class A G protein-coupled receptors. MCHR1 predominately couples to inhibitory G protein, Gi/o, and MCHR2 can only couple to Gq/11. Here we present cryo-electron microscopy structures of MCH-activated MCHR1 with Gi and MCH-activated MCHR2 with Gq at the global resolutions of 3.01 Å and 2.40 Å, respectively. These structures reveal that MCH adopts a consistent cysteine-mediated hairpin loop configuration when bound to both receptors. A central arginine from the LGRVY core motif between the two cysteines of MCH penetrates deeply into the transmembrane pocket, triggering receptor activation. Integrated with mutational and functional insights, our findings elucidate the molecular underpinnings of ligand recognition and MCH receptor activation and offer a structural foundation for targeted drug design.

The predictive accuracy of machine learning for the risk of death in HIV patients: a systematic review and meta-analysis.

BACKGROUND: Early prediction of mortality in individuals with HIV (PWH) has perpetually posed a formidable challenge. With the widespread integration of machine learning into clinical practice, some researchers endeavor to formulate models predicting the mortality risk for PWH. Nevertheless, the diverse timeframes of mortality among PWH and the potential multitude of modeling variables have cast doubt on the efficacy of the current predictive model for HIV-related deaths. To address this, we undertook a systematic review and meta-analysis, aiming to comprehensively assess the utilization of machine learning in the early prediction of HIV-related deaths and furnish evidence-based support for the advancement of artificial intelligence in this domain. METHODS: We systematically combed through the PubMed, Cochrane, Embase, and Web of Science databases on November 25, 2023. To evaluate the bias risk in the original studies included, we employed the Predictive Model Bias Risk Assessment Tool (PROBAST). During the meta-analysis, we conducted subgroup analysis based on survival and non-survival models. Additionally, we utilized meta-regression to explore the influence of death time on the predictive value of the model for HIV-related deaths. RESULTS: After our comprehensive review, we analyzed a total of 24 pieces of literature, encompassing data from 401,389 individuals diagnosed with HIV. Within this dataset, 23 articles specifically delved into deaths during long-term follow-ups outside hospital settings. The machine learning models applied for predicting these deaths comprised survival models (COX regression) and other non-survival models. The outcomes of the meta-analysis unveiled that within the training set, the c-index for predicting deaths among people with HIV (PWH) using predictive models stands at 0.83 (95% CI: 0.75-0.91). In the validation set, the c-index is slightly lower at 0.81 (95% CI: 0.78-0.85). Notably, the meta-regression analysis demonstrated that neither follow-up time nor the occurrence of death events significantly impacted the performance of the machine learning models. CONCLUSIONS: The study suggests that machine learning is a viable approach for developing non-time-based predictions regarding HIV deaths. Nevertheless, the limited inclusion of original studies necessitates additional multicenter studies for thorough validation.

Research progress on the quality control of mRNA vaccines.

INTRODUCTION: The mRNA vaccine technologies have progressed rapidly in recent years. The COVID-19 pandemic has accelerated the application of mRNA vaccines, with research and development and clinical trials underway for many vaccines. Application of the quality by design (QbD) framework to mRNA vaccine development and establishing standardized quality control protocols for mRNA vaccines are essential for the continued development of high-quality mRNA vaccines. AREAS COVERED: mRNA vaccines include linear mRNA, self-amplifying mRNA, and circular RNA vaccines. This article summarizes the progress of research on quality control of these three types of vaccines and presents associated challenges and considerations. EXPERT OPINION: Although there has been rapid progress in research on linear mRNA vaccines, their degradation patterns remain unclear. In addition, standardized assays for key impurities, such as residual dsRNA and T7 RNA polymerase, are still lacking. For self-amplifying mRNA vaccines, a key focus should be control of stability in vivo and in vitro. For circular RNA vaccines, standardized assays, and reference standards for determining degree of circularization should be established and optimized.

Cultivating High-Performance Flexible All-in-One Supercapacitors With 3D Network Through Continuous Biosynthesis.

Flexible supercapacitors can potentially power next-generation flexible electronics. However, the mechanical and electrochemical stability of flexible supercapacitors under different flexible conditions is limited by the weak bonding between adjacent layers, posing a significant hindrance to their practical applicability. Herein, based on the uninterrupted 3D network during the growth of bacterial cellulose (BC), a flexible all-in-one supercapacitor is cultivated through a continuous biosynthesis process. This strategy ensures the continuity of the 3D network of BC throughout the material, thereby forming a continuous electrode-separator-electrode structure. Benefitting from this bioinspired structure, the all-in-one supercapacitor not only achieves a high areal capacitance (3.79 F cm-2) of electrodes but also demonstrates the integration of high tensile strength (2.15 MPa), high shear strength (more than 54.6 kPa), and high bending resistance, indicating a novel pathway toward high-performance flexible power sources.

Leisure-time physical activity is associated with depressive symptoms in cancer patients: Data from the NHANES 2007-2018.

BACKGROUND: Cancer patients have a higher risk of depression and are associated with severe adverse prognosis. The relationship between leisure-time physical activity (LTPA) and depressive symptoms in cancer patients is currently unclear. Therefore, our study mainly explores the potential association between LTPA and the weekly cumulative time of LTPA with depressive symptoms in cancer patients. METHODS: We included and analyzed 3368 cancer patients (aged >20 years) from the National Health and Nutrition Examination Survey (NHANES) of the United States from 1999 to 2018. The LTPA score was evaluated through a self-report questionnaire, while depressive symptoms were evaluated through the Health Questionnaire-9 (PHQ-9). Multiple logistic regression analysis was used to explore the relationship between LTPA duration and the occurrence of cancer-related depressiive symptoms. Linear correlation was studied using the restricted cubic spline method. RESULTS: According to a fully adjusted multivariate logistic regression model with confounding variables, the odds ratio (OR) between LTPA and depressive symptoms in cancer patients in this study was 0.59 (95 % confidence interval = 0.39, 0.92; P = 0.02). When the LTPA level was ≥300 min/week, the incidence of depressive symptoms was reduced by 59 % (OR = 0.41, 95 % CI = 0.21, 0.83). In addition, the cubic spline method was used to obtain a linear negative correlation between LTPA duration and tumor depressive symptoms. CONCLUSION: LTPA was negatively correlated with cancer-related depressive symptoms, and the cumulative time of LTPA/week was linearly correlated with depressive symptoms. The slope of the benefit curve changed significantly when the cumulative time of LTPA reached 600 min per week, suggesting that appropriately increasing LTPA had significant benefits on mental health of cancer patients.

Prognostic factors and predictive models for patients with lung large cell neuroendocrine carcinoma: Based on SEER database.

BACKGROUND: Lung Large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive, high-grade neuroendocrine carcinoma with a poor prognosis, mainly seen in elderly men. To date, we have found no studies on predictive models for LCNEC. METHODS: We extracted data from the Surveillance, Epidemiology, and End Results (SEER) database of confirmed LCNEC from 2010 to 2018. Univariate and multivariate Cox proportional risk regression analyses were used to identify independent risk factors, and then we constructed a novel nomogram and assessed the predictive effectiveness by receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS: A total of 2546 patients with LCNEC were included, excluding those diagnosed with autopsy or death certificate, tumor, lymph node, metastasis (TNM) stage, tumor grade deficiency, etc., and finally, a total of 743 cases were included in the study. After univariate and multivariate analyses, we concluded that the independent risk factors were N stage, intrapulmonary metastasis, bone metastasis, brain metastasis, and surgical intervention. The results of ROC curves, calibration curves, and DCA in the training and validation groups confirmed that the nomogram could accurately predict the prognosis. CONCLUSIONS: The nomogram obtained from our study is expected to be a useful tool for personalized prognostic prediction of LCNEC patients, which may help in clinical decision-making.

Relationship between lactate-to-albumin ratio and 28-day mortality in patients with exacerbation of chronic obstructive pulmonary disease admitted to the Intensive Care Unit.

AIM: To explore the predictive value of lactate-to-albumin ratio (LAR) on 28-day mortality in patients with exacerbation of chronic obstructive pulmonary disease (AECOPD) admitted to the Intensive Care Unit (ICU). METHODS: According to ICD-9 and ICD-10 diagnosis codes, patients diagnosed with AECOPD in the Medical Information Mart for Intensive Care IV (v.2.2) database were selected. The primary endpoint was 28-day mortality after ICU admission. We used receiver operating characteristic (ROC) curve, Kaplan-Meier (K-M) survival curve, logistic regression analyses and subgroup analysis to assess predictive power of LAR. RESULTS: 606 patients were included in this study. The 28-day mortality was 29.7%. The area under the ROC curves (AUC) for LAR were 0.641 [95% confidence interval (CI) 0.592-0.689], which was comparable with OASIS (AUC: 0.662; 95% CI 0.616-0.709; p = 0.471) and SOFA (AUC: 0.660; 95% CI 0.612-0.708; p = 0.500). The cutoff value of LAR was 0.645 by ROC curve. The high-LAR group showed a bad prognosis in K-M analysis (p < 0.001). Multivariate logistic regression shown that LAR was significantly associated with a poor outcome (odds ratio: 1.77; 95% CI 1.16-2.71; p = 0.008). Subgroup analysis showed no significant interaction of LAR with each subgroup (p for interaction: 0.175-0.775). CONCLUSION: LAR is a rational and easily accessible marker, which is remarkably associated with 28-day mortality in ICU patients with AECOPD.

Successful Recovery of a Catatonic Patient with Severe Pneumonia and Respiratory Failure: Modified Electroconvulsive Therapy Following Tracheotomy.

BACKGROUD: Catatonia encompasses a group of severe psychomotor syndromes affecting patients' motor, speech, and complex behaviors. Common features include rigidity, reduced mobility, speech, sputum production, defecation, and eating. Risks associated with catatonia, such as increased muscle tension and reduced swallowing and coughing reflexes, along with risks from therapeutic approaches like prolonged bed rest and sedative drugs, can elevate the risk of aspiration pneumonia, severe pneumonia, and acute respiratory failure. These complications significantly impede catatonia treatment, leading to poor prognosis and jeopardizing patient safety. CASE DESCRIPTION: In this report, we present a case of catatonia complicated by severe pneumonia and respiratory failure, successfully managed with modified electroconvulsive therapy alongside tracheotomy. We hope this case provides valuable insights for psychiatrists encountering similar scenarios, facilitating the development of rational therapeutic strategies for prompt improvement of patient condition.

Vitamin D supplementation may be beneficial in improving the prognosis of patients with chronic obstructive pulmonary disease in the intensive care unit: a retrospective study.

Background: Vitamin D is a crucial fat-soluble vitamin that has garnered significant attention due to its potential impact on respiratory health. It is noteworthy that many patients with chronic obstructive pulmonary disease (COPD) often experience deficiencies or insufficiencies of vitamin D. To address this issue, our retrospective study aimed to explore the potential association between serum 25-hydroxyvitamin D concentration and the prognoses of COPD patients in the Intensive Care Unit (ICU). Methods: This study utilised data from the Medical Information Marketplace in Intensive Care IV (MIMIC-IV), a database of patients admitted to the Intensive Care Unit at Beth Israel Deaconess Medical Center (BIDMC) in the United States of America, with a focus on patients with a diagnosis of COPD. These patients were categorized into two groups: those who received vitamin D supplementation during their ICU stay and those who did not. We assessed in-hospital mortality and ICU mortality outcomes. Our analysis involved various analytical tools, including Kaplan-Meier survival curves, Cox proportional risk regression models, and subgroup analyses, to investigate the relationship between vitamin D supplementation and these outcomes. Additionally, we employed propensity-score matching (PSM) to enhance the reliability of our findings. Results: The study included a total of 3,203 COPD patients, with 587 in the vitamin D group and 2,616 in the no-vitamin D group. The Kaplan-Meier survival curve demonstrated a significant difference in survival probability between the two groups. After adjusting for potential confounders using Cox regression models, the vitamin D group exhibited a substantially lower risk of in-hospital and ICU mortalities compared to the no-vitamin D group. The hazard ratios for in-hospital and ICU mortalities in the vitamin D group were 1.7 (95% CI: 1.3, 2.3) and 1.8 (95% CI: 1.2, 2.6), respectively. Propensity-score matching (PSM) estimation yielded consistent results. Furthermore, in the subgroup analysis, female patients who received vitamin D supplementation showed a reduced risk of in-hospital mortality. Conclusion: The study suggests that vitamin D supplementation may be linked to a reduction in in-hospital and ICU mortalities among COPD patients in the ICU. Of particular note is the potential benefit observed in terms of in-hospital mortality, especially for female patients.

A study of high dose furmonertinib in EGFR exon 20 insertion mutation-positive advanced non-small cell lung cancer.

Background: The epidermal growth factor receptor (EGFR) ex20ins mutation, as a rare subtype of mutation, has gradually attracted attention. Its heterogeneity is high, its prognosis is extremely poor, and the efficacy of existing traditional treatment plans is limited. In this study, we aimed to evaluate efficacy of high dose furmonertinib as a first-line treatment for EGFR ex20ins-positive NSCLC. Methods: This is a retrospective, multi-center, non-interventional study. From May 2021 to March 2023, 9 NSCLC patients with EGFR ex20ins were enrolled. Efficacy and safety of 160 mg furmonertinib were evaluated. Objective response rate (ORR), disease control rate (DCR), median progression-free survival (PFS) and treatment related adverse events (TRAEs) were assessed. Results: Of the evaluated patients, six patients experienced partial remission (PR), two patients experienced stable disease (SD) and one patient experienced progress disease (PD). Data indicated 66.7% ORR and 88.9% DCR. The median progression free survival (PFS) was 7.2 months (95% CI: 6.616 - 7.784). Besides, a longgest PFS with 18 months was found in one patient with p.H773_V774insGTNPH mutation. No ≥ level 3 adverse events have been found. Conclusions: The study proved the potential efficacy of 160mg furmonertinib in patients with advanced NSCLC with EGFR ex20ins. Meanwhile, 160mg furmonertinib had a good safety profile.

Establishment of the First National Standard for Neutralizing Antibodies against SARS-CoV-2 XBB Variants.

Neutralizing antibodies (NtAbs) against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are indicators of vaccine efficacy that enable immunity surveillance. However, the rapid mutation of SARS-CoV-2 variants prevents the timely establishment of standards required for effective XBB vaccine evaluation. Therefore, we prepared four candidate standards (No. 11, No. 44, No. 22, and No. 33) using plasma, purified immunoglobulin, and a broad-spectrum neutralizing monoclonal antibody. Collaborative calibration was conducted across nine Chinese laboratories using neutralization methods against 11 strains containing the XBB and BA.2.86 sublineages. This study demonstrated the reduced neutralization potency of the first International Standard antibodies to SARS-CoV-2 variants of concern against XBB variants. No. 44 displayed broad-spectrum neutralizing activity against XBB sublineages, effectively reduced interlaboratory variability for nearly all XBB variants, and effectively minimized the geometric mean titer (GMT) difference between the live and pseudotyped virus. No. 22 showed a broader spectrum and higher neutralizing activity against all strains but failed to reduce interlaboratory variability. Thus, No. 44 was approved as a National Standard for NtAbs against XBB variants, providing a unified NtAb measurement standard for XBB variants for the first time. Moreover, No. 22 was approved as a national reference reagent for NtAbs against SARS-CoV-2, offering a broad-spectrum activity reference for current and potentially emerging variants.

Rosiglitazone Promotes Microglial Distribution via Activation of PPARγ and CD36 in the ICH Rat Model.

OBJECTIVES: Intracerebral hemorrhage (ICH) is a serious public health problem with high mortality and morbidity. The current study aims to investigate the effects of rosiglitazone on the microglial distribution and the expression of PPARγ and CD36 in the ICH rat model. METHODS NEW: Sprague-Dawley male rats (n=116) were randomly divided into four groups: control, ICH, rosiglitazone, and PPARγ antagonist (GW9662). Hematoxylin-eosin staining was used to observe the brain edema in the ICH rat model. The effect of rosiglitazone on the expression of OX-42, a microglial marker, was evaluated by immunohistochemistry. Immunohistochemistry, quantitative real-time PCR, and western blot were utilized to assess the role of rosiglitazone in the expression of PPARγ and CD36. RESULTS: ICH rats exhibited a remarkable brain edema at 72 h. OX-42 expression was significantly increased in brain tissues of ICH rats. Rosiglitazone remarkably promoted the OX-42 expression in ICH rats, whereas GW9662 suppressed OX-42 expression. In addition, immunohistochemistry analysis showed that rosiglitazone markedly enhanced the expression of PPARγ and CD36 in brain tissues around the hematoma in ICH rats, while GW9662 inhibited their expression in ICH rats. Moreover, rosiglitazone significantly promoted the mRNA and protein expression of PPARγ and CD36 in the brain tissues of ICH rats, while GW9662 showed the opposite trend. CONCLUSION: Rosiglitazone may improve microglial distribution via promoting the expression of PPARγ and CD36 around the hematoma in the ICH rat model, which may provide effective therapeutic targets for the treatment of ICH.

Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect.

Research into kappa opioid receptor (KOR) agonists with attenuated central-nervous-system side effects is a critical focus for developing productive and safe analgesics. Herein, a series of ortho-substituted N-cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaines were designed, synthesized, and subjected to bioassays. Compound 7a exhibited high subtype selectivity and potent agonistic activity toward KOR (KOR, Ki = 3.9 nM, MOR/KOR = 270, DOR/KOR = 1075; [35S]GTPγS binding, EC50 = 3.4 nM). Additionally, this compound exhibited robust and persistent antinociceptive effects in rodent models with different animal strains (hot plate test, ED50 = 0.20-0.30 mg/kg, i.p.; abdominal constriction test, ED50 = 0.20-0.60 mg/kg, i.p.), with its KOR-mediated mechanism for antinociception firmly established. Notably, compound 7a, unlike conventional KOR agonists, displayed minimal sedation and aversion at the antinociceptive ED50 dose. This feature addresses a crucial limitation in existing KOR agonists, positioning compound 7a as a promising novel therapeutic agent.

Progress and challenges in the clinical evaluation of immune responses to respiratory mucosal vaccines.

INTRODUCTION: Following the coronavirus disease pandemic, respiratory mucosal vaccines that elicit both mucosal and systemic immune responses have garnered increasing attention. However, human physiological characteristics pose significant challenges in the evaluation of mucosal immunity, which directly impedes the development and application of respiratory mucosal vaccines. AREAS COVERED: This study summarizes the characteristics of immune responses in the respiratory mucosa and reviews the current status and challenges in evaluating immune response to respiratory mucosal vaccines. EXPERT OPINION: Secretory Immunoglobulin A (S-IgA) is a major effector molecule at mucosal sites and a commonly used indicator for evaluating respiratory mucosal vaccines. However, the unique physiological structure of the respiratory tract pose significant challenges for the clinical collection and detection of S-IgA. Therefore, it is imperative to develop a sampling method with high collection efficiency and acceptance, a sensitive detection method, reference materials for mucosal antibodies, and to establish a threshold for S-IgA that correlates with clinical protection. Sample collection is even more challenging when evaluating mucosal cell immunity. Therefore, a mucosal cell sampling method with high operability and high tolerance should be established. Targets of the circulatory system capable of reflecting mucosal cellular immunity should also be explored.

Speciation and distribution of arsenic in cold seep sediments of the South China Sea.

Arsenic (As) is an abundant metalloid in marine environments, while the biogeochemical cycling of As in cold seeps remains poorly understood. We characterized the speciation of As and investigated controls of As distribution in cold seeps of South China Sea. High methane concentrations (0.2-5.5 mmol/L) and rapid sulfate depletion were observed in the seepage. Dissolved inorganic arsenic (DIAs) was enriched in the porewater ranging from 7.5 to 23.5 µg/L. As in the solid phase ranged from 2.9 to 22.6 µg/g, and sulfide mineral-bound As dominated the total arsenic (TAs) pool, followed by iron (manganese, aluminum) oxide-bound As. The significant correlations between porewater Fe2+ and DIAs reflect the controls of iron on DIAs release. Incubation experiments showed that adsorption to the solid phase and sulfate reduction activity affected the bioavailability and removal of DIAs, suggesting that multiple processes regulate the speciation and transformation of As in seep sediments.

Value of rapid on-site evaluation combined with interventional pulmonology techniques in the diagnosis of pulmonary cryptococcosis.

OBJECTIVES: The aim of this study is to evaluate the diagnostic value of rapid on-site evaluation (ROSE) combined with computed tomography-guided percutaneous needle biopsy (CT-PNB) or radial endobronchial ultrasound-guided transbronchial lung biopsy (EBUS-TBLB) for pulmonary cryptococcosis (PC). METHODS: Clinical data of 33 patients diagnosed with PC at the Third Affiliated Hospital of Soochow University between February 2018 and June 2023 were retrospectively analysed. Patients were divided into the CT-PNB and EBUS-TBLB groups based on the intervention method, and the diagnostic positivity rate and incidence of complications were compared between the two groups. RESULTS: Compared with the final diagnosis, the positive diagnostic rates of ROSE, histopathology and serum CrAg of all patients were 81.8% (27/33), 72.7% (24/33) and 63.6% (21/33), respectively. The average turnaround times of the three methods were 0.1 (0.1-0.2) h, 96.0 (48.0-120.0) h and 7.8 (4.5-13.6) h, respectively (P < 0.001). The coincidence rate between histopathology and ROSE was 84.8% with a kappa value of 0.574. The positive diagnostic rate for PC was significantly higher in the CT-PNB group than in the EBUS-TBLB group (92.9% vs. 57.9%), and the difference was statistically significant (P < 0.05). Combined with the ROSE results, the positive diagnostic rate in the EBUS-TBLB group increased to 84.2% (16/19). CONCLUSION: ROSE has commendable accuracy and timeliness, and CT-PNB offers further advantages in this regard. ROSE enhances the diagnostic efficiency of EBUS-TBLB for PC and is safe and effective.