An adaptive frequency-hopping detection for slowly-varying fading dispersive channels.

Frequency hopping (FH) signals have been widely used to improve performance against frequency selective fading phenomenon of underwater channels. However, the channel is slowly varying in regard to changes in weather conditions, and thus the conventional FH detection transmitting signals with fixed frequency cannot guarantee good detection performance in the dynamic underwater environment. To overcome the performance degradation in slowly-varying fading dispersive channels, this paper proposes an adaptive frequency-hopping (AFH) target detection method. Compared with conventional FH detection methods, the AFH can adaptively select the optimal detection frequency based on premeasured background noise and channel frequency response measured from previous experiments. Numerical simulations and lake trials are conducted to verify the effectiveness of the AFH. The simulation results show that the AFH has better detection performance than the conventional FH. The lake trial results have also verified the validity and feasibility of AFH. Importantly, AFH also achieves a better output signal-to-noise ratio under actual noise interference.

Tumor Microenvironment Specific Regulation Ca-Fe-Nanospheres for Ferroptosis-Promoted Domino Synergistic Therapy and Tumor Immune Response.

Reactive oxygen species (ROS)-mediated emerging treatments exhibit unique advantages in cancer therapy in recent years. While the efficacy of ROS-involved tumor therapy is greatly restricted by complex tumor microenvironment (TME). Herein, a dual-metal CaO2@CDs-Fe (CCF) nanosphere, with TME response and regulation capabilities, are proposed to improve ROS lethal power by a multiple cascade synergistic therapeutic strategy with domino effect. In response to weak acidic TME, CCF will decompose, accompanied with intracellular Ca2+ upregulated and abundant H2O2 and O2 produced to reverse antitherapeutic TME. Then the exposed CF cores can act as both Fenton agent and sonosensitizer to generate excessive ROS in the regulated TME for enhanced synergistic CDT/SDT. In combination with calcium overloading, the augmented ROS induced oxidative stress will cause more severe mitochondrial damage and cellular apoptosis. Furthermore, CCF can also reduce GPX4 expression and enlarge the lipid peroxidation, causing ferroptosis and apoptosis in parallel. These signals of damage will finally initiate damage-associated molecular patterns to activate immune response and to realize excellent antitumor effect. This outstanding domino ROS/calcium loading synergistic effect endows CCF with excellent anticancer effect to efficiently eliminate tumor by apoptosis/ferroptosis/ICD both in vitro and in vivo.

Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme OXCT1. We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in hepatocellular carcinoma in vivo, we conducted multiplex immunohistochemistry (mIHC) experiments on human HCC specimens. To explore the role of OXCT1 in mouse hepatocellular carcinoma tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4 trimethylation (H3K4me3) level in the Arg1 promoter. In addition, Pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreasing CD8+ T-cell exhaustion and deceleration of tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in HCC patients. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping HCC progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for HCC. Here, we found that ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. And the strategic pharmacological intervention or genetic downregulation of OXCT1 in TAMs enhances the antitumor immunity and decelerated tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer.

Chemotherapy-induced PTEN-L secretion promotes the selection of PTEN-deficient tumor cells.

BACKGROUND: PTEN loss has been identified in various tumor types and is linked to unfavorable clinical outcomes. In addition to PTEN mutation, multiple mechanisms contribute to PTEN loss during tumor development. However, the natural selection process of PTEN-deficient tumor cells remains unclear. Here, we aimed at further elucidating the role of PTEN-L in tumor progression. METHODS: PTEN knockout cell lines were generated using CRISPR/Cas9 technology. Ni-NTA affinity column chromatography was employed for PTEN-L purification. Tumor cell metastasis was evaluated in murine models and observed using the IVIS Spectrum Imaging System. RNA-sequencing, western blotting, PCR, flow cytometry, and cell proliferation assays were employed to investigate tumor cell dormancy and related mechanisms. RESULTS: The chemotherapeutic drugs, cisplatin, paclitaxel, and doxorubicin, induced tumor cells to secrete PTEN-long (PTEN-L), which shields PTEN-deficient tumor cells from chemotherapy-induced apoptosis better than it shields PTEN-intact cells. Further investigation revealed that PTEN-L treatment induced dormancy in PTEN-null tumor cells, characterized by an increase in p16 and p27 levels, cell-cycle arrest, reduced cell proliferation, and enhanced DNA repair. Furthermore, PTEN-L treatment selectively promoted the accumulation and growth of PTEN-null tumor cells in the lungs of C57BL/6J mice, while evading immune surveillance. Mechanistically, PTEN-L induced dormancy in PTEN-null tumor cells by activating the p38 signaling pathway. Addition of a p38 inhibitor effectively reversed dormancy and growth of PTEN-deficient tumor cells in the lungs. We also demonstrated that PTEN expression played a pivotal role in determining the outcome of PTEN-L-mediated antitumor therapy. CONCLUSIONS: In summary, PTEN-L was identified as a potent inducer of dormancy in PTEN-deficient tumor cells, which increased their efficient selection within the tumor microenvironment.

Free Radicals Generated in Perfluorocarbon-Water (Liquid-Liquid) Interfacial Contact Electrification and Their Application in Cancer Therapy.

Electron transfer during solid-liquid contact electrification has been demonstrated to produce reactive oxygen species (ROS) such as hydroxyl radicals (•OH) and superoxide anion radicals (•O2-). Here, we show that such a process also occurs in liquid-liquid contact electrification. By preparing perfluorocarbon nanoemulsions to construct a perfluorocarbon-water "liquid-liquid" interface, we confirmed that electrons were transferred from water to perfluorocarbon in ultrasonication-induced high-frequency liquid-liquid contact to produce •OH and •O2-. The produced ROS could be applied to ablate tumors by triggering large-scale immunogenic cell death in tumor cells, promoting dendritic cell maturation and macrophage polarization, ultimately activating T cell-mediated antitumor immune response. Importantly, the raw material for producing •OH is water, so the tumor therapy is not limited by the endogenous substances (O2, H2O2, etc.) in the tumor microenvironment. This work provides new perspectives for elucidating the mechanism of generation of free radicals in liquid-liquid contact and provides an excellent tumor therapeutic modality.

Delivery of miR-29a improves the permeability of cisplatin by downregulating collagen I expression.

In the clinical setting, chemotherapy is the most widely used antitumor treatment, however, chemotherapy resistance significantly limits its efficacy. Reduced drug influx is a key mechanism of chemoresistance, and inhibition of the complexity of the tumor microenvironment (TME) may improve chemotherapy drug influx and therapeutic efficiency. In the current study, we identified that the major extracellular matrix protein collagen I is more highly expressed in lung cancer tissues than adjacent tissues in patients with lung cancer. Furthermore, Kaplan-Meier analysis suggested that COL1A1 expression was negatively correlated with the survival time of patients with lung cancer. Our previous study demonstrated that miR-29a inhibited collagen I expression in lung fibroblasts. Here, we investigated the effect of miR-29a on collagen I expression and the cellular behavior of lung cancer cells. Our results suggest that transfection with miR-29a could prevent Lewis lung carcinoma (LLC) migration by downregulating collagen I expression, but did not affect the proliferation, apoptosis, and cell cycle of LLC cells. In a 3D tumoroid model, we demonstrated that miR-29a transfection significantly increased cisplatin (CDDP) permeation and CDDP-induced cell death. Furthermore, neutral lipid emulsion-based miR-29a delivery improved the therapeutic effect of cisplatin in an LLC spontaneous tumor model in vivo. In summary, this study shows that targeting collagen I expression in the TME contributes to chemotherapy drug influx and improves therapeutic efficacy in lung cancer.

Interleukin-2/anti-interleukin-2 complex attenuates inflammation in a mouse COPD model by expanding CD4+ CD25+ Foxp3+ regulatory T cells.

BACKGROUND AND PURPOSE: Chronic, nonspecific inflammation of the alveoli and airways is an important pathological feature of chronic obstructive pulmonary disease (COPD), while sustained inflammatory reactions can cause alveolar damage. Regulatory T cells (Tregs) inhibit inflammation, whereas the interleukin-2/anti-interleukin-2 complex (IL-2C) increases the number of Tregs; however, whether the IL-2C has a therapeutic role in COPD remains unknown. Therefore, this study investigated whether IL-2C alleviates lung inflammation in COPD by increasing the number of Tregs. EXPERIMENTAL APPROACH: A mouse COPD model was created by exposing mice to lipopolysaccharides (LPS) and cigarette smoke (CS), and the effects of IL-2C treatment on COPD were evaluated. The number of Tregs in the spleen and lung, pulmonary pathological changes, and inflammatory damage were examined through flow cytometry, histopathology, and immunofluorescence, respectively. KEY RESULTS: IL-2C increased the number of Treg cells in the spleen and lungs after exposure to CS and LPS, reduced the number of T helper 17 (Th17) cells in lung tissue, and improved the Th17/Treg balance. IL-2C decreased the number of inflammatory cells and reduced the levels of pro-inflammatory cytokines IL-6, TNF-α, IL-1ß, CCL5, KC, and MCP-1 in bronchoalveolar lavage fluid and serum. IL-2C significantly reduced the pathological scores for lung inflammation, as well as decreased airway mucus secretion and infiltration of neutrophils and macrophages in the lungs. The depletion of Tregs using anti-CD25 antibodies eliminated the beneficial effects of IL-2C. CONCLUSIONS AND IMPLICATIONS: IL-2C is a potential therapeutic agent for alleviating excessive inflammation in the lungs of patients with COPD.

Serum exosomal miR-3662 down-regulates the expression of RBMS3 to promote malignant progression and gemcitabine resistance of breast cancer cells.

Breast cancer (BC) is a prevalent malignancy among women worldwide. As an anticancer drug of pyrimidine nucleoside analogs, gemcitabine can be used to treat BC, but its clinical application is restricted due to drug resistance. This study investigated the effect of serum exosomal microRNA-3662 (miR-3662) on gemcitabine resistance in BC cells by targeting RNA-Binding Motif Single-Stranded Interacting Protein 3 (RBMS3) and related molecular mechanisms. We performed the bioinformatics analyses on the differential miRNAs in BC and predicted the downstream regulators. Quantitative real-time polymerase chain reaction was conducted to determine miR-3662 and RBMS3 expression, while dual luciferase was conducted to confirme the regulatory relationship between them. Flow cytometry, cell counting kit-8, and transwell assays were applied to assess apoptosis, cell viability, invasion, and migration. The expression of marker proteins (TSG101, CD63, and CD81) in patients' serum exosomes was evaluated through western blot, and exosomes were observed using transmission electron microscopy. miR-3662 expression was significantly upregulated in BC, and miR-3662 knockdown significantly reduced BC cell viability and gemcitabine resistance. As the downstream gene of miR-3662, RBMS3 was significantly downregulated in BC, and dual luciferase assay verified the binding of RBMS3-3'UTR to miR-3662. Rescue experiments revealed that silencing RBMS3 reversed the inhibitory effect of miR-3662 knockdown on BC cells. Besides, we also found that miR-3662 expression was significantly low in serum exosome samples from BC patients and could be transmitted to tumor cells. miR-3662 was upregulated in serum exosomes and promoted BC cell progression and gemcitabine resistance by targeting RBMS3.

Structural and functional abnormalities in the medial prefrontal cortex were associated with pain and depressive symptoms in patients with adhesive capsulitis.

Introduction: Chronic pain and depression have been shown to coexist in patients with adhesive capsulitis (AC). Recent studies identified the shared brain plasticity between pain and depression; however, how such neuroplasticity contributes to AC remains unclear. Here, we employed a combination of psychophysics, structural MRI, and functional MRI techniques to examine the brain's structural and functional changes in AC. Methods: Fifty-two patients with AC and 52 healthy controls (HCs) were included in our study. Voxelwise comparisons were performed to reveal the differences in grey matter volume (GMV) and regional homogeneity (ReHo) between AC and HCs. Furthermore, region of interest to whole brain functional connectivity (FC) was calculated and compared between the groups. Finally, Pearson correlation coefficients were computed to reveal the association between clinical data and brain alterations. Mediation analyses were performed to investigate the path association among brain alterations and clinical measures. Results: Three main findings were observed: (1) patients with AC exhibited a higher depression subscale of hospital anxiety and depression scale (HADS-D) score correlating with the GMV within the right medial prefrontal cortices (mPFC) compared with HCs; (2) relative to HCs, patients with AC exhibited lower ReHo within the right mPFC, which largely overlapped with the structural abnormalities; (3) the impact of pain duration on HADS-D score was mediated by ventral part of medial prefrontal cortices (vmPFC) GMV in patients with AC. Conclusion: In summary, our current findings suggest that vmPFC alterations correlate with both the pain duration and the emotional comorbidities experienced by patients with AC. Our research provides an enhanced comprehension of the underlying mechanisms of AC, thereby facilitating the development of more effective treatment approaches for AC.

Nanomaterials-Involved Tumor-Associated Macrophages' Reprogramming for Antitumor Therapy.

Tumor-associated macrophages (TAMs) play pivotal roles in tumor development. As primary contents of tumor environment (TME), TAMs secrete inflammation-related substances to regulate tumoral occurrence and development. There are two kinds of TAMs: the tumoricidal M1-like TAMs and protumoral M2-like TAMs. Reprogramming TAMs from immunosuppressive M2 to immunocompetent M1 phenotype is considered a feasible way to improve immunotherapeutic efficiency. Notably, nanomaterials show great potential for biomedical fields due to their controllable structures and properties. There are many types of nanomaterials that exhibit great regulatory activities for TAMs' reprogramming. In this review, the recent progress of nanomaterials-involved TAMs' reprogramming is comprehensively discussed. The various nanomaterials for TAMs' reprogramming and the reprogramming strategies are summarized and introduced. Additionally, the challenges and perspectives of TAMs' reprogramming for efficient therapy are discussed, aiming to provide inspiration for TAMs' regulator design and promote the development of TAMs-mediated immunotherapy.

MiR-23a-5p alleviates chronic obstructive pulmonary disease through targeted regulation of RAGE-ROS pathway.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common respiratory disease and represents the third leading cause of death worldwide. This study aimed to investigate miRNA regulation of Receptor for Advanced Glycation End-products (RAGE), a causal receptor in the pathogenesis of cigarette smoke (CS)-related COPD, to guide development of therapeutic strategies. METHODS: RAGE expression was quantified in lung tissue of COPD patients and healthy controls, and in mice with CS-induced COPD. RNA-sequencing of peripheral blood from COPD patients with binding site prediction was used to screen differentially expressed miRNAs that may interact with RAGE. Investigation of miR-23a-5p as a potential regulator of COPD progression was conducted with miR-23a-5p agomir in COPD mice in vivo using histology and SCIREQ functional assays, while miR-23a-5p mimics or RAGE inhibitor were applied in 16-HBE human bronchial epithelial cells in vitro. RNA-sequencing, ELISA, and standard molecular techniques were used to characterize downstream signaling pathways in COPD mice and 16-HBE cells treated with cigarette smoke extract (CSE). RESULTS: RAGE expression is significantly increased in lung tissue of COPD patients, COPD model mice, and CSE-treated 16-HBE cells, while inhibiting RAGE expression significantly reduces COPD severity in mice. RNA-seq analysis of peripheral blood from COPD patients identified miR-23a-5p as the most significant candidate miRNA interaction partner of RAGE, and miR-23a-5p is significantly downregulated in mice and cells treated with CS or CSE, respectively. Injection of miR-23a-5p agomir leads to significantly reduced airway inflammation and alleviation of symptoms in COPD mice, while overexpressing miR-23a-5p leads to improved lung function. RNA-seq with validation confirmed that reactive oxygen species (ROS) signaling is increased under CSE-induced aberrant upregulation of RAGE, and suppressed in CSE-stimulated cells treated with miR-23a-5p mimics or overexpression. ERK phosphorylation and subsequent cytokine production was also increased under RAGE activation, but inhibited by increasing miR-23a-5p levels, implying that the miR-23a-5p/RAGE/ROS axis mediates COPD pathogenesis via ERK activation. CONCLUSIONS: This study identifies a miR-23a-5p/RAGE/ROS signaling axis required for pathogenesis of COPD. MiR-23a-5p functions as a negative regulator of RAGE and downstream activation of ROS signaling, and can inhibit COPD progression in vitro and in vivo, suggesting therapeutic targets to improve COPD treatment.

Metal-amplified sonodynamic therapy of Ti-based chitosan-polyvinyl alcohol hybrid hydrogel dressing against subcutaneous Staphylococcus aureus infection.

Ultrasound (US)-mediated sonodynamic therapy (SDT) has received extensive attention in pathogen elimination for non-invasiveness and high spatial and temporal accuracy. Considering that hydrogel can provide a healing-friendly environment for wounds, in this work, hybrid hydrogels are constructed by embedding Ag doped TiO2 nanoparticles in chitosan-polyvinyl alcohol hydrogels for enhanced sonodynamic antibacterial therapy. With metal silver doped, TiO2 nanoparticles sonosensitivity is improved to generate more reactive oxygen species (ROS), which endows hybrid hydrogels with high-efficient antibacterial properties. In vivo results show that hybrid hydrogel dressing can prevent infection and promote wound closure within 2 days. The healing ratio excess 95 % with no pus produced at the end of treatment. The therapeutic mechanism was identified that heterojunction formed in Ag doped TiO2 facilitates the separation of charge carriers under US irradiation, leading to elevating ROS generation. The generated ROS promote hybrid hydrogels sonodynamic antibacterial therapeutic efficacy to thoroughly eliminate pathogen via disrupting bacterial cell membrane integrity, decreasing membrane fluidity and increasing membrane permeability. Besides, biofilm formation could be effectively inhibited. This work developed a hybrid hydrogel with amplified SDT effect for wound healing, which is expected to provide inspiration of hybrid hydrogels design and Ti-based nanomaterials sonosensitivity enhancement.

Developing predictive models for surgical outcomes in patients with degenerative cervical myelopathy: a comparison of statistical and machine learning approaches.

BACKGROUND CONTEXT: Machine learning (ML) is widely used to predict the prognosis of numerous diseases. PURPOSE: This retrospective analysis aimed to develop a prognostic prediction model using ML algorithms and identify predictors associated with poor surgical outcomes in patients with degenerative cervical myelopathy (DCM). STUDY DESIGN: A retrospective study. PATIENT SAMPLE: A total of 406 symptomatic DCM patients who underwent surgical decompression were enrolled and analyzed from three independent medical centers. OUTCOME MEASURES: We calculated the area under the curve (AUC), classification accuracy, sensitivity, and specificity of each model. METHODS: The Japanese Orthopedic Association (JOA) score was obtained before and 1 year following decompression surgery, and patients were grouped into good and poor outcome groups based on a cut-off value of 60% based on a previous study. Two datasets were fused for training, 1 dataset was held out as an external validation set. Optimal feature-subset and hyperparameters for each model were adjusted based on a 2,000-resample bootstrap-based internal validation via exhaustive search and grid search. The performance of each model was then tested on the external validation set. RESULTS: The Support Vector Machine (SVM) model showed the highest predictive accuracy compared to other methods, with an AUC of 0.82 and an accuracy of 75.7%. Age, sex, disease duration, and preoperative JOA score were identified as the most commonly selected features by both the ML and statistical models. Grid search optimization for hyperparameters successfully enhanced the predictive performance of each ML model, and the SVM model still had the best performance with an AUC of 0.93 and an accuracy of 86.4%. CONCLUSIONS: Overall, the study demonstrated that ML classifiers such as SVM can effectively predict surgical outcomes for patients with DCM while identifying associated predictors in a multivariate manner.

Abnormal preoperative fMRI signal variability in the pain ascending pathway is associated with the postoperative axial pain intensity in degenerative cervical myelopathy patients.

BACKGROUND CONTEXT: The moment-to-moment variability of resting-state brain activity has been suggested to play an active role in chronic pain. PURPOSE: To investigate preoperative alterations in regional blood-oxygen-level-dependent signal variability (BOLDsv) and inter-regional dynamic functional connectivity (dFC) in individuals with degenerative cervical myelopathy (DCM), and their potential association with postoperative axial pain severity. STUDY DESIGN: Cross-sectional study. PATIENT SAMPLE: Resting-state functional magnetic resonance imaging was obtained in 42 migraine individuals and 40 healthy controls (HCs). OUTCOME MEASURES: We calculated the standard deviation (SD) of the BOLD time-series at each voxel and the SD and mean of the dynamic conditional correlation between the brain regions which showed significant group differences in BOLDsv. METHODS: A group comparison was conducted using whole-brain voxel-wise analysis of the standard deviation (SD) of the BOLD time-series which was a measure of the BOLDsv. The brain areas displaying notable group discrepancies in BOLDsv were utilized to outline regions of interest (ROIs). To determine the strength/variability of the dFC, the mean and SD of the dynamic conditional correlation were calculated within these ROIs. Moreover, the postoperative axial pain (PAP) severity of patients was evaluated. RESULTS: Our results revealed that DCM patients with postoperative axial pain (PAP) demonstrated considerably increased BOLDsv in the bilateral thalamus and right insular, but significantly lower BOLDsv in the right S1. By applying dynamic functional connectivity (dFC) analysis, we found that DCM patients with PAP exhibited greater fluctuation of dFC in the thalamo-cortical pathway (specifically, thalamus-S1), when compared to HCs and patients without PAP (nPAP). Lastly, we established that dysfunctional BOLDsv and dFC in the ascending pain pathway were positively associated with the severity of PAP in DCM patients. CONCLUSION: Our results indicate a potential correlation between impaired pain ascending pathway and postoperative axial pain in DCM patients. These findings could potentially spark novel treatment approaches for individuals experiencing preoperative axial pain.

Development of in situ Li isotope analysis using laser ablation quadrupole inductively coupled plasma mass spectrometry.

RATIONALE: Lithium isotope geochemistry is an important tool in the studies of Earth and planetary materials. In situ Li isotope analyses are typically performed using secondary ion mass spectrometry (SIMS) or laser ablation multicollector inductively coupled plasma mass spectrometry (LA-MC-ICPMS), but these instruments are not widely accessible. Here, the capability of laser ablation quadrupole ICPMS for conducting Li isotopic analyses is evaluated. METHODS: An array of MPI-DING and USGS silicate glass reference materials was analyzed repeatedly over the course of 6 months. These materials range from komatiite to rhyolite in terms of silica content (45.5-75.6 wt%) with 9-45 ppm Li. Their Li isotope compositions have been previously characterized so that matrix effects could be tested with these reference materials. Analyses were conducted using an NWR193 laser ablation system coupled to an Agilent 7900 ICPMS system. RESULTS: Analytical precision is primarily limited by Li concentration in the samples. For samples with ~9 ppm Li, the internal precision is 6‰ (2 SD, 150 µm spot diameter), whereas that for a sample with ~45 ppm Li is 4‰ (2 SD, 120 µm spot diameter). The technique is somewhat sensitive to sample matrix: samples with SiO2 content that deviates from the bracketing standard display fractionated δ7 Li, necessitating correction using a session-specific matrix correction curve. CONCLUSION: Lithium isotope analysis by ns-LA-QICPMS is worthwhile for samples with high Li concentrations and when a matrix-matched standard can be obtained. Although the precision of this method is not as high as those achievable with SIMS and LA-MC-ICPMS, it remains adequate for resolving large isotope fractionations found in natural and laboratory settings.

Radiographic characteristics-based classification system for percutaneous endoscopic lumbar discectomy surgical approach selection in patients with L5-S1 disc herniation: a hierarchical clustering analysis.

Background: No classification system exists for aiding the selection of surgical approaches in L5-S1 disc herniation when undergoing percutaneous endoscopic lumbar discectomy (PELD). We aimed to identify radiographic subtypes to aid the selection of percutaneous endoscopic transforaminal discectomy (PETD) and percutaneous endoscopic interlaminar discectomy (PEID) in patients with L5-S1 disc herniation via unsupervised hierarchical clustering analysis. Methods: In this retrospective case-control study, we gathered 296 anteroposterior and lateral lumbar spine radiographs (dataset 1) from Tianjin Hospital between January 2016 and October 2021 for clustering analyses. Additionally, we analyzed 111 patients who underwent PEID or PETD for L5-S1 disc herniation at Tianjin Hospital from January 2016 to August 2022. We included patients with radicular leg pain or back pain associated with intra-canal disc herniation who failed in conservative treatments over 6 weeks. First, pair-wise Spearman correlation coefficients were calculated among plain radiographic metrics in dataset 1 to reveal the association among these radiographic metrics. Second, hierarchical clustering analysis was conducted to unsupervised cluster the plain films into several subtypes. Last, for each radiographic subtype, the intraoperative blood loss (IBL), operation time (OT), total operating room time (TORT) along with visual analogue scale (VAS) and Oswestry Disability Index (ODI) were compared between patients underwent PETD or PEID with age as covariates. Results: This study yielded 3 main findings: (I) iliac height (IH) was negatively correlated with intervertebral foramen width (IFW), intervertebral foramen height (IFH), and intertransverse height (ITH) (R=-0.50, -0.42, and -0.46, all P<0.001), ITH was positively correlated with IFW and IFH (R=0.40 and 0.53, all P<0.001); (II) 2 lumbosacral radiographic subtypes were identified via hierarchical clustering analysis; (III) relative to subtype 1, the patients identified as subtype 2 exhibited lesser IBL, shorter OT, and shorter TORT following PETD (t=2.92, P=0.006; t=2.65, P=0.012; t=3.17, P=0.003). Conclusions: The morphology pattern of the lumbosacral region affect the ease of different PELD procedures when performing percutaneous discectomy at the segment of L5-S1. Without considering the type of disc herniation, this classification system might aid spine surgeons in the selection of an appropriate surgical approach.

Transcriptional correlates of frequency-dependent brain functional activity associated with symptom severity in degenerative cervical myelopathy.

BACKGROUND: Neuroimaging techniques provide insights into the brain abnormalities secondary to degenerative cervical myelopathy (DCM) and their association with neurological deficits. However, the neural correlates underlying the discrepancy between symptom severity and the degree of spinal cord compression, as well as the transcriptional correlates of these cortical abnormalities, remain unknown in DCM patients. METHODS: In this cross-sectional study, which collected resting-state functional MRI (rs-fMRI) images and the Japanese Orthopedic Association (JOA) score, enrolled 104 participants (54 patients and 50 healthy controls). The frequency-dependent amplitude of low-frequency fluctuation (ALFF) was obtained for all participants. We investigated the ALFF differences between mild-symptom DCM patients and severe-symptom DCM patients while carefully matching the degree of compression between these two groups via both univariate comparison and searchlight classification for three frequency bands (e.g., Slow-4, Slow-5, and Full-band). Additionally, we identified genes associated with symptom severity in DCM patients by linking the spatial patterns of gene expression of Allen Human Brain Atlas and brain functional differences between mild symptom and severe symptom groups. RESULTS: (1) We found that the frequency-specific brain activities within the sensorimotor network (SMN), visual network (VN), and default mode network (DMN) were associated with the varying degrees of functional impairment in DCM patients; (2) the frequency-specific brain activity within the SMN correlated with the functional recovery in patients with DCM; (3) a spatial correlation between the brain-wide expression of genes involved in neuronal migration and the brain functional activities associated with symptom severity was identified in DCM patients. CONCLUSION: In conclusion, our study bridges gaps between genes, cell classes, biological processes, and brain functional correlates of DCM. While our findings are correlational in nature, they suggest that the neural activities of sensorimotor cortices in DCM are associated with the severity of symptoms and might be associated with neuronal migration within the brain.

Recent strategies of carbon dot-based nanodrugs for enhanced emerging antitumor modalities.

Nanomaterial-based cancer therapy has recently emerged as a new therapeutic modality with the advantages of minimal invasiveness and negligible normal tissue toxicity over traditional cancer treatments. However, the complex microenvironment and self-protective mechanisms of tumors have suppressed the therapeutic effect of emerging antitumor modalities, which seriously hindered the transformation of these modalities to clinical settings. Due to the excellent biocompatibility, unique physicochemical properties and easy surface modification, carbon dots, as promising nanomaterials in the biomedical field, can effectively improve the therapeutic effect of emerging antitumor modalities as multifunctional nanoplatforms. In this review, the mechanism and limitations of emerging therapeutic modalities are described. Further, the recent advances related to carbon dot-based nanoplatforms in overcoming the therapeutic barriers of various emerging therapies are systematically summarized. Finally, the prospects and potential obstacles for the clinical translation of carbon dot-based nanoplatforms in tumor therapy are also discussed. This review is expected to provide a reference for nanomaterial design and its development for the efficacy enhancement of emerging therapeutic modalities.

Alterations in Peripheral Metabolites as Key Actors in Alzheimer's Disease.

Growing evidence supports that Alzheimer's disease (AD) could be regarded as a metabolic disease, accompanying central and peripheral metabolic disturbance. Nowadays, exploring novel and potentially alternative hallmarks for AD is needed. Peripheral metabolites based on blood and gut may provide new biochemical insights about disease mechanisms. These metabolites can influence brain energy homeostasis, maintain gut mucosal integrity, and regulate the host immune system, which may further play a key role in modulating the cognitive function and behavior of AD. Recently, metabolomics has been used to identify key AD-related metabolic changes and define metabolic changes during AD disease trajectory. This review aims to summarize the key blood- and microbial-derived metabolites that are altered in AD and identify the potential metabolic biomarkers of AD, which will provide future targets for precision therapeutic modulation.

Antibacterial peptides from Monochamus alternatus induced oxidative stress and reproductive defects in pine wood nematode through the ERK/MAPK signaling pathway.

Pine wilt disease is a devastating disease of pine caused by the pine wood nematode (PWN) Bursaphelenchus xylophilus. Long-term use of chemical nematicides leads to the development of resistance in nematodes and harms the environment. Evaluations for green environmental protection agents, identified the antibacterial peptide, MaltDef1, from Monochamus alternatus which had nematicidal effect. We studied its nematicidal activity and action against PWN. In this study, the antibacterial peptide S-defensin was synthesized from M. alternatus. The results showed that S-defensin caused mortality to the PWN, causing shrinkage, pore, cell membrane dissolution and muscle atrophy. In addition, PWN reproduction was also affected by S-defensin; it decreased in a concentration dependent manner with increasing treatment concentration. By contrast, reactive oxygen species (ROS) in vivo increased in a concentration-dependent manner. We applied transcriptome to analyze the changes in gene expressions in S-defensin treated PWN, and found that the most significantly enriched pathway was the ERK/MAPK signaling pathway. RNAi was used to validate the functions of four differential genes (Let-23, Let-60, Mek-2 and Lin-1) in this pathway. The results showed that knockdown of these genes significantly decreased the survival rate and reproductive yield of, and also increased ROS in PWN. The antibacterial peptide S-defensin had a significant inhibitory effect on the survival and reproduction of PWN, shown by cell membrane damage and intracellular biological oxidative stress via regulating the ERK/MAPK signaling pathway. This indicates that S-defensin has a target in B. xylophilus, against which new green target pesticides can be developed.