Shikonin ameliorated LPS-induced acute lung injury in mice via modulating MCU-mediated mitochondrial Ca2+ and macrophage polarization.

BACKGROUND: Macrophages play a pivotal role in the development and recovery of acute lung injury (ALI), wherein their phenotypic differentiation and metabolic programming are orchestrated by mitochondria. Specifically, the mitochondrial calcium uniporter (MCU) regulates mitochondrial Ca2+ (mCa2+) uptake and may bridge the metabolic reprogramming and functional regulation of immune cells. However, the precise mechanism on macrophages remains elusive. Shikonin, a natural naphthoquinone, has demonstrated efficacy in mitigating ALI and suppressing glycolysis in macrophages, yet which mechanism remains to be fully elucidated. PURPOSE: This study explored whether Shikonin ameliorated ALI via modulating MCU-mediated mCa2+ and macrophage polarization. METHODS: This study firstly examined the protective effects of Shikonin on LPS-induced ALI mice, and investigated whether it is depends on macrophage by depleting macrophage using clodronate liposomes. The regulatory effect of Shikonin on macrophage polarization and mitochondrial MCU/Ca2+ signal was testified on RAW264.7 cells, and further validated by knocking-down MCU expression or by using RU360, an MCU inhibitor. Additionally, the crucial role of MCU in the therapeutic effect of Shikonin, along with its regulation on macrophage polarization was validated in mice with LPS-induced ALI under the intervention of RU360. RESULTS: Shikonin alleviated LPS-induced mice ALI, down-regulated inflammatory cytokines and inhibited the pro-inflammatory polarization of macrophages. Intravenous injection of clodronate liposomes on mice abolished the protective effects of Shikonin on ALI. On RAW264.7 cells, LPS&IFN decreased the protein expression of MCU, while induced pro-inflammatory polarization and glycolytic metabolism. In contrast, Shikonin increased MCU expression, activated MCU-mediated mCa2+ signal, promoted the polarization of macrophages to anti-inflammatory M2 phenotype, and driven a metabolic shift from glycolysis to oxidative phosphorylation. Either knocking-down MCU expression or pharmacological inhibiting MCU by using RU360 mitigated the effects of Shikonin on Raw 264.7 cells. Furthermore, RU360 counteracted the ameliorative effect of Shikonin on ALI mice. CONCLUSION: The current data showed that Shikonin alleviated LPS-induced mice ALI by activating mitochondrial MCU/mCa2+ signal and regulating macrophage metabolism.

Expression pattern and functional analysis of kinesin-14 KIFC1 in spermatogenesis of Macaca mulatta.

C-terminal kinesin motor KIFC1 is increasingly concerned with an essential role in germ cell development. During the spermatogenesis of mice, rats, and crustaceans, KIFC1 functions in regulating meiotic chromosome separation, acrosome vesicle transportation, and nuclear morphology maintenance. The expression pattern of KIFC1 is conservatively concentrated at the acrosome and nucleus of haploid sperm cells. However, whether KIFC1 has similar functions in non-human primates remains unknown. In this study, we constructed the testis-specific cDNA library and cloned different transcripts of KIFC1 based on the genomic sequence. New variants of KIFC1 were identified, and showed different functional domains from the predicted isoforms. The spatio-temporal expression of KIFC1 proteins in seminiferous tubules of rhesus monkeys showed an obvious nuclear localization, specifically expressed in the spermatocytes and early haploid spermatids. The transcripts of KIFC1 also exhibited considerable expression in the nucleus of rhesus LLC-MK2 cells. Besides, we demonstrated that KIFC1 located at the acrosome and microtubule flagella of the mature sperm, and KIFC1 inhibition resulted in sperm tail deformation as well as increased the instability of head-to-tail connection. In summary, this study filled a gap in the reproductive research of the KIFC1 gene in non-human primates.

Comparison of Moses laser and Raykeen laser in patients with impacted upper ureteral stone undergoing flexible ureteroscopic holmium laser lithotripsy.

BACKGROUND: To compare the operative effect and clinical efficacy of the Moses laser mode and the Raykeen holmium laser energy platform powder mode under flexible ureteroscopic lithotripsy in patients with impacted upper ureteral stones. METHODS: From March 2022 to September 2022, 72 patients were divided into a Moses laser group and a Raykeen laser group according to surgical method, with 36 patients in each group. CT and ureteroscopy confirmed that all patients had isolated impacted upper ureteral stones. The stone volume (mm3), stone density (Hu) and severity of hydronephrosis were measured by CT. Postoperative complications were evaluated using the Clavien-Dindo score. RESULTS: There were no complications of ureteral stenosis related to the laser treatment. The operative time and lithotripsy time were lower in the Moses laser group than in the Raykeen laser group (P < 0.05). The stone-free survival rate did not differ significantly between the two groups (P = 0.722). Stone volume was found to be positively correlated with laser energy and lithotripsy time in both groups (P < 0.01). There was no significant correlation between laser energy and lithotripsy time or ureteral stone density (Hu) in the Moses laser group (P > 0.05) or the Raykeen laser group (P > 0.05). CONCLUSIONS: The contact mode of Moses technology and the powder mode of Raykeen laser lithotripsy can be used for the ablation of a single impacted upper ureteral stone. The ablation speed was related to the stone volume and the severity of polyp hyperplasia, not the stone density. We recommend the use of the powdered mode as a therapeutic measure for the treatment of impacted upper ureteral stones in flexible ureteroscopic lithotripsy.

Evaluation of tissue conditioner-assisted complete denture restoration: A randomized controlled clinical trial.

PURPOSE: To evaluate the clinical effect of three impression methods, conventional, closed-mouth, and tissue conditioner, on complete denture fabrication. METHODS: 60 subjects (edentulous with severely resorbed alveolar ridges - Atwood classification III or IV) who visited the Prosthodontic Department of Wuxi Stomatology Hospital, China, between January 2022 and June 2023, were selected for this study. The subjects were randomly divided into three groups of 20: a conventional impression group (CI group), a closed-mouth impression group (CM group), and a tissue conditioner group (TC group). Three months after denture restoration was completed, denture quality was assessed by clinicians in terms of marginal extension, retention, and stability. In addition, patients completed the oral health impact profile-edentulous (OHIP-EDENT) questionnaire to provide subjective satisfaction evaluations of the final denture restoration outcomes. RESULTS: The comprehensive denture quality evaluation results showed that the TC group had the lowest score, which was significantly lower than that of the CM (P= 0.014) and CI (P< 0.001) groups. The average score of the CM group was also significantly lower than that of the CI group (P= 0.004), indicating that tissue conditioner restoration was the most effective method. The OHIP-EDENT scores gradually decreased across the groups from CI to CM to TC (P= 0.001), indicating patients' oral health was significantly improved using tissue conditioner. CLINICAL SIGNIFICANCE: Tissue conditioner is a suitable dynamic functional impression method. It can significantly improve the effects for edentulous patients and increase their satisfaction.

The Role of Sole Lift in Treating Pediatric Idiopathic Scoliosis with Mild Thoracolumbar/Lumbar Curve.

OBJECTIVE: Lower limb discrepancy (LLD) was frequently observed in patients with idiopathic scoliosis (IS), potentially associated with etiopathogenesis. Although sole lifts had been proposed as a conservative treatment for IS, evidence supporting their efficacy was limited. This study aimed to assess the effects of sole lift intervention on pediatric patients with mild IS, specifically focusing on thoracolumbar/lumbar (TL/L) curvature. METHODS: Twenty patients, with an average age of 12.3 ± 3.1 years and presenting mild TL/L curve (15.6° ± 6.2°), were selected from a pool of 267 pediatric IS patients in the outpatient of our spine center from February 2023 to August 2023. Inclusion criteria comprised a main TL/L curve ranging between 10° and 40°, the lower limb positioned at the convexity of the main curve, and LLD of less than 2 cm; individuals requiring bracing or surgical intervention were excluded. Custom sole lifts were used to address the shorter lower limb with the objective of leveling the pelvis. Radiographic evaluations were conducted both before and after intervention using standing full spine posteroanterior radiographs and full leg length radiographs. Statistical analysis was undertaken to evaluate curve correction and its associations with other influencing factors. RESULTS: The mean structural and functional LLD were 7.1 ± 4.5 mm and 7.1 ± 4.1 mm, respectively. Among the 20 patients, four exhibited structural LLD greater than 10 mm. The average follow-up duration was 6.4 ± 1.9 months (range: 3-8 months). Following sole lift intervention (7.0 ± 3.0 mm), a significant reduction was observed in the TL/L curve compared to the pre-sole lifting measurements (15.6° ± 6.2° vs. 12.1° ± 7.2°, p < 0.001), as well as a notable decrease in the thoracic curve (12.2° ± 4.0° vs. 8.6° ± 6.3°, p = 0.064). Nine patients experienced a significant curve reduction of ≥5°, while eight showed a reduction between 0° and 5°; however, two patients exhibited no change in curve magnitude. Furthermore, the correction rate of the TL/L curve correlated significantly with functional LLD (r = -0.484, p = 0.030) and pelvic obliquity (r = -0.556, p = 0.011), highlighting the active pelvic compensation in maintaining balance between the spine and lower limbs. Conversely, no significant correlation was observed between curve correction and structural LLD (p > 0.05). Additionally, even after adjusting for other influencing factors, the TL/L Cobb angle remained significantly different between pre- and post-sole lifting (p = 0.037). CONCLUSION: This study confirmed the effectiveness of sole lift intervention in correcting TL/L and thoracic curves among the mild IS children with a main TL/L curve, providing a supplementary conservative treatment option for patients with the lower limb at the convexity of the main curve. Moreover, our findings underscored the active compensation of the lower limbs and the pelvis in the etiopathogenesis of IS, highlighting the importance of considering their influence in treatment strategies.

Femtosecond laser writing of ant-inspired reconfigurable microbot collectives.

Microbot collectives can cooperate to accomplish complex tasks that are difficult for a single individual. However, various force-induced microbot collectives maintained by weak magnetic, light, and electric fields still face challenges such as unstable connections, the need for a continuous external stimuli source, and imprecise individual control. Here, we construct magnetic and light-driven ant microbot collectives capable of reconfiguring multiple assembled architectures with robustness. This methodology utilizes a flexible two-photon polymerization strategy to fabricate microbots consisting of magnetic photoresist, hydrogel, and metal nanoparticles. Under the cooperation of magnetic and light fields, the microbots can reversibly and selectively assemble (e.g., 90° assembly and 180° assembly) into various morphologies. Moreover, we demonstrate the ability of assembled microbots to cross a one-body-length gap and their adaptive capability to move through a constriction and transport microcargo. Our strategy will broaden the abilities of clustered microbots, including gap traversal, micro-object manipulation, and drug delivery.

Effect of an evidence-based early rehabilitation program on adult patients with venovenous extracorporeal membrane oxygenation: A cohort study.

OBJECTIVES: To assess the efficacy of early rehabilitation program for VV-ECMO patients and observe the influence on the respiratory and skeletal muscles. DESIGN: A cohort study. SETTING: The study was conducted with VVECMO patients in a comprehensive ICU with 32 beds. MAIN OUTCOME MEASURES: Ultrasound measurements were performed on each patients on day 1, 4, 7, 10, and 14, including diaphragmatic excursion (DE), diaphragmatic thickening fraction (DTF), intercostal muscle thickening fraction (ICMTF), thickness of the rectus femoris (RF), thickness of vastus intermedius (VI), and rectus femoris cross-sectional area (RF-CSA). Data on basic characteristics, results of ultrasound measurements, patients outcomes and adverse events were collected. RESULTS: 22 patients received usual rehabilitation measures were set as the control group and 23 patients underwent early rehabilitation program were set as the study group. There were no differences in diaphragmatic excursion, diaphragmatic thickening fraction, intercostal muscle thickening fraction, thickness of rectus femoris, thickness of vastus intermedius, rectus femoris cross-sectional area between two groups on day 1 after VV-ECMO treatment (P > 0.05). The variation of diaphragmatic thickening fraction and intercostal muscle thickening fraction decreased on the day 7 and 14 after treatment (P < 0.05). The variation of vastus intermedius thickness and rectus femoris cross-sectional area in the study group was less compared with those in the control group on day 4, 7, 10 and 14. The ECMO duration in the study group was shorter than that in the control group (12.00 [10.00-16.25] days vs. 8.00 [6.00-12.25] days, P = 0.002), but there was no difference in the duration of mechanical ventilation. CONCLUSION: Early rehabilitation program can ameliorate muscle atrophy. We recommend implementation of our rehabilitation program in VV-ECMO patients. This program can improve skeletal muscle atrophy and dysfunction in patients with VV-ECMO effectively and perhaps improve quality of life for patients in the future. IMPLICATIONS FOR CLINICAL PRACTICE: Early rehabilitation program put higher demands bedside nurses. It requires them to observe conditions of VVECMO patients closely, assess the feasibility of rehabilitation promptly, and monitor for any adverse reactions. Ultrasound measurement is a noninvasive and useful tool to assess muscle atrophy in ICU patients. Early rehabilitation program can improve skeletal muscle atrophy and dysfunction in patients with VV-ECMO effectively.

Interference of ATP-Adenosine Axis by Engineered Biohybrid for Amplifying Immunogenic Cell Death-Mediated Antitumor Immunotherapy.

Immunogenic cell death (ICD) often results in the production and accumulation of adenosine (ADO), a byproduct that negatively impacts the therapeutic effect as well as facilitates tumor development and metastasis. Here, an innovative strategy is elaborately developed to effectively activate ICD while avoiding the generation of immunosuppressive adenosine. Specifically, ZIF-90, an ATP-responsive consumer, is synthesized as the core carrier to encapsulate AB680 (CD73 inhibitor) and then coated with an iron-polyphenol layer to prepare the ICD inducer (AZTF), which is further grafted onto prebiotic bacteria via the esterification reaction to obtain the engineered biohybrid (Bc@AZTF). Particularly, the designed Bc@AZTF can actively enrich in tumor sites and respond to the acidic tumor microenvironment to offload AZTF nanoparticles, which can consume intracellular ATP (iATP) content and simultaneously inhibit the ATP-adenosine axis to reduce the accumulation of adenosine, thereby alleviating adenosine-mediated immunosuppression and strikingly amplifying ICD effect. Importantly, the synergy of anti-PD-1 (αPD-1) with Bc@AZTF not only establishes a collaborative antitumor immune network to potentiate effective tumoricidal immunity but also activates long-lasting immune memory effects to manage tumor recurrence and rechallenge, presenting a new paradigm for ICD treatment combined with adenosine metabolism.

Diffusion-tensor magnetic resonance imaging as a non-invasive assessment of extracellular matrix remodeling in lumbar paravertebral muscles of rats with sarcopenia.

BACKGROUND: Extracellular matrix (ECM) remodeling in skeletal muscle is a significant factor in the development of sarcopenia. This study aims to evaluate changes in ECM remodeling in the lumbar paravertebral muscles of sarcopenic rats using diffusion-tensor magnetic resonance imaging (DT-MRI) and compare them with histology. METHODS: Twenty 6-month-old female Sprague Dawley rats were randomly divided into the dexamethasone (DEX) group and the control (CON) group. Both groups underwent 3.0T MRI scanning, including Mensa, T2WI, and DT-MRI sequences. The changes in muscle fibers and extracellular matrix (ECM) of the erector spinal muscle were observed using hematoxylineosin and sirius red staining. The expressions of collagen I, III, and fibronectin in the erector spinae were detected by western blot. Pearson correlation analysis was employed to assess the correlation between MRI quantitative parameters and corresponding histopathology markers. RESULTS: The cross-sectional area and fractional anisotropy values of the erector spinae in the DEX group rats were significantly lower than those in the CON group (p < 0.05). Hematoxylin eosin staining revealed muscle fiber atrophy and disordered arrangement in the DEX group, while sirius red staining showed a significant increase in collagen volume fraction in the DEX group. The western blot results indicate a significant increase in the expression of collagen I, collagen III, and fibronectin in the DEX group (p < 0.001 for all). Correlation coefficients between fractional anisotropy values and collagen volume fraction, collagen I, collagen III, and fibronectin were - 0.71, -0.94, -0.85, and - 0.88, respectively (p < 0.05 for all). CONCLUSIONS: The fractional anisotropy value is strongly correlated with the pathological collagen volume fraction, collagen I, collagen III, and fibronectin. This indicates that DT-MRI can non-invasively evaluate the changes in extracellular matrix remodeling in the erector spinal muscle of sarcopenia. It provides a potential imaging biomarker for the diagnosis of sarcopenia.

TGF-ß1 mediates hypoxia-preconditioned olfactory mucosa mesenchymal stem cells improved neural functional recovery in Parkinson's disease models and patients.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN). Activation of the neuroinflammatory response has a pivotal role in PD. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for various nerve injuries, but there are limited reports on their use in PD and the underlying mechanisms remain unclear. METHODS: We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa (hOM)-MSCs on neural functional recovery in both PD models and patients, as well as the preventive effects on mouse models of PD. To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure, we employed single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) combined with full-length transcriptome isoform-sequencing (ISO-seq), and functional assay. Furthermore, we present the findings from an initial cohort of patients enrolled in a phase I first-in-human clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients. RESULTS: A functional assay identified that transforming growth factor-ß1 (TGF-ß1), secreted from hOM-MSCs, played a critical role in modulating mitochondrial function recovery in dopaminergic neurons. This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN, which are closely associated with neuroinflammatory responses. Mechanistically, exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-ß1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B (ALK/PI3K/Akt) signaling pathway in microglia located in the SN of PD patients. Furthermore, intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD. CONCLUSIONS: These findings provide compelling evidence for the involvement of TGF-ß1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD. Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD. Additionally, TGF-ß1 may be used alone or combined with hOM-MSCs therapy for treating PD.

Differential lncRNA profiles of blood plasma-derived exosomes from systemic lupus erythematosus.

INTRODUCTION: Long non-coding RNAs (lncRNAs) dysregulation is key in the pathogenesis of systemic lupus erythematosus (SLE), but the role of exosomal lncRNAs in SLE has not been well studied. We elucidated the profiles of plasma exosomal lncRNAs expression in patients with SLE and predictd their potential clinical significance in SLE. METHODS: In the screening stage, six newly diagnosed and untreated patients with SLE and six healthy controls were examined by high-throughput sequencing technology, and differential exosomal lncRNA profiles were constructed. In the validation phase, two differentially selected exosomal lncRNAs from 20 patients each with active and stable SLE and 20 healthy controls were verified with RT-qPCR. The correlation between the selected exosomal lncRNAs and SLE clinical indicators was examined. The diagnostic value of the selected exosomal lncRNAs in SLE was analyzed by the receiver operator characteristic (ROC) curve. RESULTS: Exosomes were successfully extracted from the patients and controls. Sequencing-phase sequencing demonstrated 528 upregulated lncRNAs and 7491 downregulated lncRNAs. In the validation stage, exosomal LINC00667 and DANCR were significantly upregulated in the patients, and positively correlated with Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K). Exosomal DANCR expression between the active and stable SLE patients was different. The area under the curve(AUC) of exosomal LINC00667 and DANCR for SLE diagnosis was 0.815 and 0.759, respectively. CONCLUSIONS: Exosomal LINC00667 and DANCR were upregulated in SLE, and might be new biomarkers thereof. Exosomal DANCR was associated with SLE activity.

Focused ultrasound enables selective actuation and Newton-level force output of untethered soft robots.

Untethered miniature soft robots have significant application potentials in biomedical and industrial fields due to their space accessibility and safe human interaction. However, the lack of selective and forceful actuation is still challenging in revolutionizing and unleashing their versatility. Here, we propose a focused ultrasound-controlled phase transition strategy for achieving millimeter-level spatially selective actuation and Newton-level force of soft robots, which harnesses ultrasound-induced heating to trigger the phase transition inside the robot, enabling powerful actuation through inflation. The millimeter-level spatial resolution empowers single robot to perform multiple tasks according to specific requirements. As a concept-of-demonstration, we designed soft robot for liquid cargo delivery and biopsy robot for tissue acquisition and patching. Additionally, an autonomous control system is integrated with ultrasound imaging to enable automatic acoustic field alignment and control. The proposed method advances the spatiotemporal response capability of untethered miniature soft robots, holding promise for broadening their versatility and adaptability.

Global One Health index for zoonoses: A performance assessment in 160 countries and territories.

The One Health (OH) approach is used to control/prevent zoonotic events. However, there is a lack of tools for systematically assessing OH practices. Here, we applied the Global OH Index (GOHI) to evaluate the global OH performance for zoonoses (GOHI-Zoonoses). The fuzzy analytic hierarchy process algorithm and fuzzy comparison matrix were used to calculate the weights and scores of five key indicators, 16 subindicators, and 31 datasets for 160 countries and territories worldwide. The distribution of GOHI-Zoonoses scores varies significantly across countries and regions, reflecting the strengths and weaknesses in controlling or responding to zoonotic threats. Correlation analyses revealed that the GOHI-Zoonoses score was associated with economic, sociodemographic, environmental, climatic, and zoological factors. Additionally, the Human Development Index had a positive effect on the score. This study provides an evidence-based reference and guidance for global, regional, and country-level efforts to optimize the health of people, animals, and the environment.

Electroencephalography-based biological and functional characteristics of spinal cord injury patients with neuropathic pain and numbness.

Objectives: To identify potential treatment targets for spinal cord injury (SCI)-related neuropathic pain (NP) by analysing the differences in electroencephalogram (EEG) and brain network connections among SCI patients with NP or numbness. Participants and methods: The EEG signals during rest, as well as left- and right-hand and feet motor imagination (MI), were recorded. The power spectral density (PSD) of the θ (4-8 Hz), α (8-12 Hz), and ß (13-30 Hz) bands was calculated by applying Continuous Wavelet Transform (CWT) and Modified S-transform (MST) to the data. We used 21 electrodes as network nodes and performed statistical measurements of the phase synchronisation between two brain regions using a phase-locking value, which captures nonlinear phase synchronisation. Results: The specificity of the MST algorithm was higher than that of the CWT. Widespread non-lateralised event-related synchronization was observed in both groups during the left- and right-hand MI. The PWP (patients with pain) group had lower θ and α bands PSD values in multiple channels of regions including the frontal, premotor, motor, and temporal regions compared with the PWN (patients with numbness) group (all p < 0.05), but higher ß band PSD values in multiple channels of regions including the frontal, premotor, motor, and parietal region compared with the PWN group (all p < 0.05). During left-hand and feet MI, in the lower frequency bands (θ and α bands), the brain network connections of the PWP group were significantly weaker than the PWN group except for the frontal region. Conversely, in the higher frequency bands (ß band), the brain network connections of the PWP group were significantly stronger in all regions than the PWN group. Conclusion: The differences in the power of EEG and network connectivity in the frontal, premotor, motor, and temporal regions are potential biological and functional characteristics that can be used to distinguish NP from numbness. The differences in brain network connections between the two groups suggest that the distinct mechanisms for pain and numbness.

Transcutaneous auricular vagus nerve stimulation as a novel therapy connecting the central and peripheral systems: a review.

Currently, clinical practice and scientific research mostly revolve around a single disease or system, but the single disease-oriented diagnostic and therapeutic paradigm needs to be revised. This review describes how transcutaneous auricular vagus nerve stimulation (taVNS), a novel non-invasive neuromodulation approach, connects the central and peripheral systems of the body. Through stimulation of the widely distributed vagus nerve from the head to the abdominal cavity, this therapy can improve and treat central system disorders, peripheral system disorders, and central-peripheral comorbidities caused by autonomic dysfunction. In the past, research on taVNS has focused on the treatment of central system disorders by modulating this brain nerve. As the vagus nerve innervates the heart, lungs, liver, pancreas, gastrointestinal tract, spleen and other peripheral organs, taVNS could have an overall modulatory effect on the region of the body where the vagus nerve is widespread. Based on this physiological basis, the authors summarize the existing evidence of the taVNS ability to regulate cardiac function, adiposity, glucose levels, gastrointestinal function, and immune function, among others, to treat peripheral system diseases, and complex diseases with central and peripheral comorbidities. This review shows the successful examples and research progress of taVNS using peripheral neuromodulation mechanisms from more perspectives, demonstrating the expanded scope and value of taVNS to provide new ideas and approaches for holistic therapy from both central and peripheral perspectives.

Posterior scleral reinforcement surgery effectively slows the rate of high myopic progression in children.

PURPOSE: To investigate the rate of axial length elongation and high myopia progression in operated eyes before and after posterior scleral reinforcement (PSR) surgery. METHODS: This was a retrospective study. Children with pathological myopia treated with PSR at Beijing Tongren Hospital between May 2013 and May 2020 were recruited into the PSR surgery group. Children matched for age and myopia were recruited into the control group. All children underwent comprehensive ophthalmologic examinations. The presurgical and postsurgical rates of axial length elongation and myopic (spherical equivalent) progression were calculated. RESULTS: A total of 35 PSR patients were included in the study. The mean age was 6.5±3.0 years (range 2 to 14 years). Mean follow-up was 544 days (range 216 to 1657 days). The rate of axial length elongation was significantly less after posterior scleral reinforcement surgery (0.505±0.048mm per year prior to surgery; 0.382±0.045mm per year after surgery, P<0.001). The rate of myopic progression decreased after posterior scleral reinforcement surgery (1.162±0.118 D per year prior to surgery; 0.153±0.437 D per year after surgery, P=0.0239). There was no statistically significant difference in axial length elongation or myopic progression between pre-inclusion and post-inclusion in the control group. Moreover, the children's best-corrected visual acuity was significantly improved after posterior scleral reinforcement surgery (P<0.001). CONCLUSION: Posterior scleral reinforcement surgery effectively decreased the rate of high myopic progression and axial length elongation in children.

Transcutaneous vagus nerve stimulation modulates depression-like phenotype induced by high-fat diet via P2X7R/NLRP3/IL-1ß in the prefrontal cortex.

BACKGROUND: Depression is a common psychiatric disorder in diabetic patients. Depressive mood associated with obesity/metabolic disorders is related to the inflammatory response caused by long-term consumption of high-fat diets, but its molecular mechanism is unclear. In this study, we investigated whether the antidepressant effect of transcutaneous auricular vagus nerve stimulation (taVNS) in high-fat diet rats works through the P2X7R/NLRP3/IL-1ß pathway. METHODS: We first used 16S rRNA gene sequencing analysis and LC-MS metabolomics assays in Zucker diabetic fatty (ZDF) rats with long-term high-fat diet (Purina #5008) induced significant depression-like behaviors. Next, the forced swimming test (FST) and open field test (OFT) were measured to evaluate the antidepressive effect of taVNS. Immunofluorescence and western blotting (WB) were used to measure the microglia state and the expression of P2X7R, NLRP3, and IL-1ß in PFC. RESULTS: Purina#5008 diet induced significant depression-like behaviors in ZDF rats and was closely related to purine and inflammatory metabolites. Consecutive taVNS increased plasma insulin concentration, reduced glycated hemoglobin and glucagon content in ZDF rats, significantly improved the depressive-like phenotype in ZDF rats through reducing the microglia activity, and increased the expression of P2X7R, NLRP3, and IL-1ß in the prefrontal cortex (PFC). CONCLUSION: The P2X7R/NLRP3/IL-1ß signaling pathway may play an important role in the antidepressant-like behavior of taVNS, which provides a promising mechanism for taVNS clinical treatment of diabetes combined with depression.

Optimal decision-making in relieving global high temperature-related disease burden by data-driven simulation.

The rapid acceleration of global warming has led to an increased burden of high temperature-related diseases (HTDs), highlighting the need for advanced evidence-based management strategies. We have developed a conceptual framework aimed at alleviating the global burden of HTDs, grounded in the One Health concept. This framework refines the impact pathway and establishes systematic data-driven models to inform the adoption of evidence-based decision-making, tailored to distinct contexts. We collected extensive national-level data from authoritative public databases for the years 2010-2019. The burdens of five categories of disease causes - cardiovascular diseases, infectious respiratory diseases, injuries, metabolic diseases, and non-infectious respiratory diseases - were designated as intermediate outcome variables. The cumulative burden of these five categories, referred to as the total HTD burden, was the final outcome variable. We evaluated the predictive performance of eight models and subsequently introduced twelve intervention measures, allowing us to explore optimal decision-making strategies and assess their corresponding contributions. Our model selection results demonstrated the superior performance of the Graph Neural Network (GNN) model across various metrics. Utilizing simulations driven by the GNN model, we identified a set of optimal intervention strategies for reducing disease burden, specifically tailored to the seven major regions: East Asia and Pacific, Europe and Central Asia, Latin America and the Caribbean, Middle East and North Africa, North America, South Asia, and Sub-Saharan Africa. Sectoral mitigation and adaptation measures, acting upon our categories of Infrastructure & Community, Ecosystem Resilience, and Health System Capacity, exhibited particularly strong performance for various regions and diseases. Seven out of twelve interventions were included in the optimal intervention package for each region, including raising low-carbon energy use, increasing energy intensity, improving livestock feed, expanding basic health care delivery coverage, enhancing health financing, addressing air pollution, and improving road infrastructure. The outcome of this study is a global decision-making tool, offering a systematic methodology for policymakers to develop targeted intervention strategies to address the increasingly severe challenge of HTDs in the context of global warming.

Metabolic Regulation-Mediated Reversion of the Tumor Immunosuppressive Microenvironment for Potentiating Cooperative Metabolic Therapy and Immunotherapy.

Tumor cells exhibit heightened glucose (Glu) consumption and increased lactic acid (LA) production, resulting in the formation of an immunosuppressive tumor microenvironment (TME) that facilitates malignant proliferation and metastasis. In this study, we meticulously engineer an antitumor nanoplatform, denoted as ZLGCR, by incorporating glucose oxidase, LA oxidase, and CpG oligodeoxynucleotide into zeolitic imidazolate framework-8 that is camouflaged with a red blood cell membrane. Significantly, ZLGCR-mediated consumption of Glu and LA not only amplifies the effectiveness of metabolic therapy but also reverses the immunosuppressive TME, thereby enhancing the therapeutic outcomes of CpG-mediated antitumor immunotherapy. It is particularly important that the synergistic effect of metabolic therapy and immunotherapy is further augmented when combined with immune checkpoint blockade therapy. Consequently, this engineered antitumor nanoplatform will achieve a cooperative tumor-suppressive outcome through the modulation of metabolism and immune responses within the TME.

The effect of age, sex, and eastern cooperative oncology group performance status on the efficacy and safety of immune checkpoint inhibitors in patients with hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: The effect of age, sex, and eastern cooperative oncology group performance status (ECOG PS) on the efficacy and safety of immune checkpoint inhibitor (ICI) therapy among hepatocellular carcinoma (HCC) patients remains elusive. Thus, a meta-analysis was conducted to evaluate whether such effects exist. RESEARCH DESIGN AND METHODS: Eligible studies in PubMed, Embase, and Cochrane Library databases were retrieved. RESULTS: One-hundred-and-eleven studies involving 14,768 HCC patients were included. The findings indicated that the ECOG PS didn't have a significant effect on the ORR and PFS in ICI-treated HCC patients (higher ECOG PS vs. lower ECOG PS: ORR: OR = 0.78, 95%CI = 0.55-1.10; PFS: HR = 1.15, 95%CI = 0.97-1.35), while those patients with a higher ECOG PS may have a worse OS (HR = 1.52, 95% CI = 1.26-1.84). There is no significant evidence of the effect of age (older vs. younger) or sex (males vs. females) on the efficacy of ICI therapy in HCC. CONCLUSION: ICI therapy in HCC should not be restricted strictly to certain patients in age or sex categories, while HCC patients with higher ECOG PS may require closer medication or follow-up strategy during ICI therapy. PROSPERO REGISTRATION: CRD42024518407.