Lonicerin alleviates intestinal myenteric neuron injury induced by hypoxia/reoxygenation treated macrophages by downregulating EZH2.

Intestinal ischemia-reperfusion (IR) injury is a common gastrointestinal disease that induces severe intestinal dysfunction. Intestinal myenteric neurons participate in maintaining the intestinal function, which will be severely injured by IR. Macrophages are widely reported to be involved in the pathogenesis of organ IR injury, including intestine, which is activated by NLRP3 signaling. Lonicerin (LCR) is a natural extracted monomer with inhibitory efficacy against the NLRP3 pathway in macrophages. The present study aims to explore the potential protective function of LCR in intestinal IR injury. Myenteric neurons were extracted from mice. RAW 264.7 cells were stimulated by H/R with or without 10 µM and 30 µM LCR. Remarkable increased release of IL-6, MCP-1, and TNF-α were observed in H/R treated RAW 264.7 cells, along with an upregulation of NLRP3, cleaved-caspase-1, IL-1ß, and EZH2, which were sharply repressed by LCR. Myenteric neurons were cultured with the supernatant collected from each group. Markedly decreased neuron number and shortened length of neuron axon were observed in the H/R group, which were signally reversed by LCR. RAW 264.7 cells were stimulated by H/R, followed by incubated with 30 µM LCR with or without pcDNA3.1-EZH2. The inhibition of LCR on NLRP3 signaling in H/R treated RAW 264.7 cells was abolished by EZH2 overexpression. Furthermore, the impact of LCR on neuron number and neuron axon length in myenteric neurons in the H/R group was abated by EZH2 overexpression. Collectively, LCR alleviated intestinal myenteric neuron injury induced by H/R treated macrophages via downregulating EZH2.

[Resveratrol enhances the local antioxidant ability of the ovary in rats with polycystic ovary syndrome].

OBJECTIVE: To investigate the effects of resveratrol (RSV) on ovarian morphology, plasma anti-Müllerian hormone (AMH) and insulin-like growth factor 1 levels (IGF-1), and oxidative stress parameters in rats with polycystic ovary syndrome (PCOS). METHODS: Forty-six rats were randomly divided into a normal control (n = 12), a PCOS model control (n = 12), a rosiglitazone (RSG, n = 11), and an RSV group (n = 11). The PCOS model was established in the latter three groups by rejection of epidehydroandrosterone. The rats in the normal control and PCOS model control groups were treated by gavage of normal saline and those in the RSG and RSV groups by intragastric administration of RSG at 10 mg/(kg·d) and RSV at 3.0 mg/(kg·d), respectively. After 4 weeks of treatment, the ovarian histology was observed under the light microscope, the levels of plasma AMH and IGF-1 measured by ELISA, and the activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT) in the ovarian tissue detected using the Ellman, Sun and AEBI methods, respectively. RESULTS: After a 4-week treatment, statistically significant differences were observed in the above indicators between the normal control and PCOS model control groups (P<0.05). The rats treated with RSG and RSV also showed significant differences in these parameters from the model controls (P<0.05). CONCLUSION: RSV can enhance the local antioxidant capacity of the ovary, reduce the levels of AMH and IGF-1, and improve the morphology of the ovarian tissue in rats with PCOS, indicating its potential value in the treatment of PCOS.

Digital biomarkers for precision diagnosis and monitoring in Parkinson's disease.

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder with high prevalence among the elderly, primarily manifested by progressive decline in motor function. The aging global demographic and increased life expectancy have led to a rapid surge in PD cases, imposing a significant societal burden. PD along with other neurodegenerative diseases has garnered increasing attention from the scientific community. In PD, motor symptoms are recognized when approximately 60% of dopaminergic neurons have been damaged. The irreversible feature of PD and benefits of early intervention underscore the importance of disease onset prediction and prompt diagnosis. The advent of digital health technology in recent years has elevated the role of digital biomarkers in precisely and sensitively detecting early PD clinical symptoms, evaluating treatment effectiveness, and guiding clinical medication, focusing especially on motor function, responsiveness and sleep quality assessments. This review examines prevalent digital biomarkers for PD and highlights the latest advancements.

Charge photogeneration and recombination dynamics in non-fullerene solar cells based on a polymer donor with a mono-fluorinated π-bridge.

Non-symmetric fluorine substitution is an important route for designing π-conjugated polymers for high-performance solar cells. However, excited state dynamics in a non-symmetric fluorinated polymer and solar cells are poorly understood. In this work, excited state dynamics in a neat mono-fluorinated polymer (PTzBI-dF) film and blend films (PTzBI-dF:Y6) were studied using time-resolved spectroscopy. For the neat donor film, we found the activation energy of the PTzBI-dF film transiting from radiative states to non-radiative states to be ∼58 meV. Besides, we found that both exciton diffusion coefficient and exciton diffusion length in the PTzBI-dF film are higher than those in the PTzBI-Cl film, which has no fluorinated π-bridge. The high exciton diffusion length of the PTzBI-dF film benefits from its long exciton lifetime (∼327.8 ps), which is much longer than that of the polymer donors such as P3HT and PM6. For PTzBI-dF:Y6 blend films, we found that the energy level offsets of the HOMO (0.13 eV) and LUMO (0.23 eV) are sufficient to dissociate the acceptor and donor excitons, respectively. Besides, we found that carrier recombination in PTzBI-dF:Y6 and PTzBI-Cl:Y6 blend films are dominated by bimolecular recombination processes, and thermal annealing treatment has a weak influence on the charge photogeneration and recombination process of the PTzBI-dF:Y6 film at an ultrafast time scale. Thus, this work is helpful for understanding photoelectrical conversion processes in non-symmetric fluorinated polymer-based solar cells.

Analysis of 12 kinds of cytokines in seminal plasma by flow cytometry and their correlations with routine semen parameters.

OBJECTIVE: To investigate the levels of 12 kinds of cytokines in seminal plasma and their correlations with routine semen parameters. METHODS: The remaining seminal plasma samples of 134 patients undergoing routine semen examination were collected for detecting cytokines. The parameters for sperm concentration, percentage of progressively motile sperm (PR), and motility were analyzed by a computer-assisted sperm analysis (CASA) system. According to the results of sperm concentration, PR and motility, 134 patients were divided into the normal routine semen parameters group, oligoasthenospermia group and azoospermia group. The levels of 12 kinds of cytokines in seminal plasma, including interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12P70, IL-17, interferin (IFN)-α, IFN-γ, and tumor necrosis factor (TNF)-α, were detected by flow cytometry. Two seminal plasma samples were detected for 10 times, respectively, to calculate the coefficients of variation (CV) of each cytokine. The linear range of each cytokine was measured using the standard, and the correlation coefficient (r) was calculated. RESULTS: The r2 of 12 kinds of cytokines detected by flow cytometry were all greater than 0.99. The reproducibility of 2 seminal plasma samples showed that the CVs of all cytokines were lower than 15 % except for TNF-α in sample 1 (15.15 %). Seminal plasma IL-6 levels were negatively correlated with semen volume (P < 0.01). Seminal plasma IL-5 levels were positively correlated with sperm concentration (P < 0.01). Seminal plasma IL-8 levels were negatively correlated with sperm motility (P < 0.01). Seminal plasma IL-8, IL-17 and IL-12P70 levels were negatively correlated with sperm PR (P < 0.05). In addition to the significant negative correlation between IL-5 and IL-17 (P < 0.05), there was a significant positive correlation between the majority of other cytokines. The levels of seminal plasma IL-17 and IL-12P70 in the oligoasthenospermia group and IL-1ß and IL-12P70 in the azoospermia group were significantly higher than those in the normal routine semen parameters group (P ≤ 0.05), while the levels of IL-10 in the azoospermia group were significantly lower than that in the normal routine semen parameters group (P < 0.05). CONCLUSION: There are certain correlations between seminal plasma cytokines and routine semen parameters and strong correlations between different seminal plasma cytokines, suggesting that the imbalance between seminal plasma cytokines may affect sperm quality. However, it still needs to be further confirmed by large samples and multi-center clinical studies and related basic researches.

POSTN+ cancer-associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) poses a significant clinical challenge because the long-term benefits of immune checkpoint blockade therapy are limited. A comprehensive understanding of the mechanisms underlying immunotherapy resistance in HCC is imperative for improving patient prognosis. DESIGN: In this study, to systematically investigate the characteristics of cancer-associated fibroblast (CAF) subsets and the dynamic communication among the tumor microenvironment (TME) components regulated by CAF subsets, we generated an HCC atlas by compiling single-cell RNA sequencing (scRNA-seq) datasets on 220 samples from six datasets. We combined spatial transcriptomics with scRNA-seq and multiplexed immunofluorescence to identify the specific CAF subsets in the TME that determine the efficacy of immunotherapy in HCC patients. RESULTS: Our findings highlight the pivotal role of POSTN+ CAFs as potent immune response barriers at specific tumor locations, as they hinder effective T-cell infiltration and decrease the efficacy of immunotherapy. Additionally, we elucidated the interplay between POSTN+ CAFs and SPP1+ macrophages, whereby the former recruits the latter and triggers increased SPP1 expression via the IL-6/STAT3 signaling pathway. Moreover, we demonstrated a spatial correlation between POSTN+ CAFs and SPP1+ macrophages, revealing an immunosuppressive microenvironment that limits the immunotherapy response. Notably, we found that patients with elevated expression levels of both POSTN+ CAFs and SPP1+ macrophages achieved less therapeutic benefit in an immunotherapy cohort. CONCLUSION: Our research elucidates light on the role of a particular subset of CAFs in immunotherapy resistance, emphasizing the potential benefits of targeting specific CAF subpopulations to improve clinical responses to immunotherapy.

Malignant glaucoma treated by low-dose laser cycloplasty: a 1-year multicenter prospective non-comparative study.

AIM: To report a one-year clinical outcomes of low-dose laser cycloplasty (LCP) among malignant glaucoma patients. METHODS: In this prospective, multicenter, non-comparative clinical study, participants with malignant glaucoma were recruited and underwent LCP at eight ophthalmic centers in China. Patients were followed up at 1wk, 1, 3, 6, and 12mo. Intraocular pressure (IOP), number of glaucoma medications, anterior chamber depth (ACD), and complications were recorded. Anatomical success was defined as the reformation of the anterior chamber based on slit-lamp biomicroscopy. Recurrence was defined by the presence of a shallow or flat anterior chamber after initial recovery from treatment. RESULTS: A total of 34 eyes received LCP. Mean IOP and medications decreased from 36.1±11.5 mm Hg with 3.3±1.5 glaucoma medications pre-treatment to 20.9±9.8 mm Hg (P<0.001) with 2.9±1.6 medications (P=0.046) at 1d, and 17.4±6.7 mm Hg (P<0.001) with 1.3±1.7 medications (P<0.001) at 12mo. The ACD increased from 1.1±0.8 mm at baseline to 1.7±1.0 mm and to 2.0±0.5 mm at 1d and 12mo, respectively. A total of 32 (94.1%) eyes achieved initial anatomical success. During follow-up, 2 (5.9%) eyes failed and 8 (23.5%) eyes relapsed, yielding a 12-month anatomical success rate of 64.3%. Complications including anterior synechia (8.82%), choroidal/ciliary detachment (5.88%) and hypopyon (2.94%) were observed within 1wk. CONCLUSION: LCP is simple, safe, and effective in reforming the anterior chamber in malignant glaucoma.

Dual-Functional Nanodroplet for Tumor Vasculature Ultrasound Imaging and Tumor Immunosuppressive Microenvironment Remodeling.

Accurately evaluating tumor neoangiogenesis and conducting precise interventions toward an immune-favorable microenvironment are of significant clinical importance. In this study, a novel nanodroplet termed as the nanodroplet-based ultrasound contrast agent and therapeutic (NDsUCA/Tx) is designed for ultrasound imaging and precise interventions of tumor neoangiogenesis. Briefly, the NDsUCA/Tx shell is constructed from an engineered CMs containing the tumor antigen, vascular endothelial growth factor receptor 1 (VEGFR1) extracellular domain 2-3, and CD93 ligand multimerin 2. The core is composed of perfluorohexane and the immune adjuvant R848. After injection, NDsUCA/Tx is found to be enriched in the tumor vasculature with high expression of CD93. When triggered by ultrasound, the perfluorohexane in NDsUCA/Tx underwent acoustic droplet vaporization and generated an enhanced ultrasound signal. Some microbubbles exploded and the resultant debris (with tumor antigen and R848) together with the adsorbed VEGF are taken up by nearby cells. This cleared the local VEGF for vascular normalization, and also served as a vaccine to activate the immune response. Using a syngeneic mouse model, the satisfactory performance of NDsUCA/Tx in tumor vasculature imaging and immune activation is confirmed. Thus, a multifunctional NDsUCA/Tx is successfully developed for molecular imaging of tumor neoangiogenesis and precise remodeling of the tumor microenvironment.

Association between Deltoid Muscle Density and Proximal Humeral Fracture in Elderly Patients.

Background: The potential role of deltoid muscle density in the occurrence of proximal humeral fractures remains uncertain. Therefore, the primary objective of this study was to examine the correlation between deltoid muscle density, as measured by CT attenuation value in Hounsfield units (HU), and the incidence of proximal humeral fractures in elderly patients. By investigating this association, we aim to shed light on the possible influence of deltoid muscle density on fracture risk in this specific population. Methods: A total of 68 patients with computed tomography (CT) images were retrospectively reviewed. Among them, 34 patients presented with fractures following low-energy injuries, while the remaining 34 patients served as controls and underwent CT scans after low-energy injuries without any fractures. The muscle density of the deltoid muscles was assessed at the approximate tubercle of humerus. We compared these parameters between the two groups and conducted analyses considering factors such as age, sex, laterality, and deltoid muscle density of the shoulders. Results: The demographic factors related to the shoulder did not exhibit any significant association with proximal humeral fracture. However, we observed a noteworthy difference in deltoid muscle density between patients with fractures (40.85 ± 1.35) and the control group (47.08 ± 1.61) (p = 0.0042), indicating a lower muscle density in the fracture group. Conclusion: Based on the findings of this study, we can conclude that there exists a negative correlation between deltoid muscle density and the incidence of proximal humeral fractures. These results suggest that lower deltoid muscle density may be associated with an increased risk of proximal humeral fractures in the elderly population under investigation.

Peripartum outcomes and immune responses after SARS-CoV-2 infection in the third trimester of pregnancy.

BACKGROUND: SARS-CoV-2 infection in pregnant women during the third trimester resulted in overall adverse pregnancy outcomes compared to non-infected controls and a unique humoral and cellular response at delivery. In this study we aimed to assess the impact of SARS-CoV-2 infection on maternal/neonatal peripartum outcomes andimmunological profiles. METHOD: In this study, we recruited 304 SARS-CoV-2 infected pregnant women and 910 SARS-CoV-2 non-infected pregnant women who were admitted for delivery. Peripartum and neonates' outcomes response to SARS-CoV-2 infection were analyzed. Furthermore, we characterized the antibody and cytokines profile in SARS-CoV-2 infected maternal blood (MB) and cord blood (CB). We also assessed routine laboratory tests and liver function tests in MB before labor. Unpaired T test, Mann-Whitney test and Spearman test were used to analyze the data. RESULTS: SARS-CoV-2 infected pregnant women were significantly associated with increased risk of adverse pregnancy outcomes, including preterm labor (13.8% vs. 9.5%, p = 0.033) and meconium-stained amniotic fluid (8.9% vs. 5.5%, p = 0.039). The risk of low birth weight (< 2500 g) (10.5% vs. 6.5%, p = 0.021) and Apgar score < 8 at 1-minute (9.2% vs. 5.8%, p = 0.049) significantly increased in newborns from COVID-19 positive mothers than their counterparts. Our results showed that antibodies were increased in adverse-outcome SARS-CoV-2 infected mothers and their neonates, and abnormal proportion of immune cells were detected in SARS-CoV-2 infected mothers. While the immune response showed no difference between adverse-outcome infected pregnant women and normal-outcome infected pregnant women. Thus, SARS-CoV-2 infection during the third trimester of pregnancy induced a unique humoral and cellular response at delivery. CONCLUSION: SARS-CoV-2 infection closer to delivery could incline to adverse pregnancy outcomes. Therefore, the utmost care is required for SARS-CoV-2 infected pregnant women and their newborns. TRIAL REGISTRATION: The study protocol was approved by the Institutional Review Board of the First Hospital of Jilin University with the approval code number 23K170-001, and informed consent was obtained from all enrolled patients prior to sample collection.

Machine learning for accurate detection of small airway dysfunction-related respiratory changes: an observational study.

BACKGROUND: The use of machine learning(ML) methods would improve the diagnosis of small airway dysfunction(SAD) in subjects with chronic respiratory symptoms and preserved pulmonary function(PPF). This paper evaluated the performance of several ML algorithms associated with the impulse oscillometry(IOS) analysis to aid in the diagnostic of respiratory changes in SAD. We also find out the best configuration for this task. METHODS: IOS and spirometry were measured in 280 subjects, including a healthy control group (n = 78), a group with normal spirometry (n = 158) and a group with abnormal spirometry (n = 44). Various supervised machine learning (ML) algorithms and feature selection strategies were examined, such as Support Vector Machines (SVM), Random Forests (RF), Adaptive Boosting (ADABOOST), Navie Bayesian (BAYES), and K-Nearest Neighbors (KNN). RESULTS: The first experiment of this study demonstrated that the best oscillometric parameter (BOP) was R5, with an AUC value of 0.642, when comparing a healthy control group(CG) with patients in the group without lung volume-defined SAD(PPFN). The AUC value of BOP in the control group was 0.769 compared with patients with spirometry defined SAD(PPFA) in the PPF population. In the second experiment, the ML technique was used. In CGvsPPFN, RF and ADABOOST had the best diagnostic results (AUC = 0.914, 0.915), with significantly higher accuracy compared to BOP (p < 0.01). In CGvsPPFA, RF and ADABOOST had the best diagnostic results (AUC = 0.951, 0.971) and significantly higher diagnostic accuracy (p < 0.01). In the third, fourth and fifth experiments, different feature selection techniques allowed us to find the best IOS parameters (R5, (R5-R20)/R5 and Fres). The results demonstrate that the performance of ADABOOST remained essentially unaltered following the application of the feature selector, whereas the diagnostic accuracy of the remaining four classifiers (RF, SVM, BAYES, and KNN) is marginally enhanced. CONCLUSIONS: IOS combined with ML algorithms provide a new method for diagnosing SAD in subjects with chronic respiratory symptoms and PPF. The present study's findings provide evidence that this combination may help in the early diagnosis of respiratory changes in these patients.

Comparison of clinical research trends and hotspots in allergic rhinitis and asthma from 2013 to 2023 based on bibliometric analysis.

Purpose: To analyze and compare clinical research trends and hot topics in allergic rhinitis (AR) and asthma and provide valuable theoretical data and references for future research. Methods: Clinical studies focusing on AR or asthma published from 2013 to 2023 were retrieved from the Web of Science Core Collection. Eligible articles were screened and analyzed using bibliometrics from multiple indicators. Results: A total of 261 eligible articles on AR and 991 qualified articles on asthma were screened. The following bibliometric analyses identified the Journal of Allergy and Clinical Immunology as the most influential publication on AR and asthma and proved the significant contributions of Harvard University in clinical studies on AR and asthma. The analyses also revealed that the top ten prolific authors for AR were from China, the United Kingdom, Japan, and Germany, whereas the top ten productive authors for asthma were mainly from the USA. Collaborations among countries for AR were relatively concentrated in the Occident, whereas international cooperation on asthma was mainly achieved by the Occident and certain Eastern countries. Conclusions: This study compared and analyzed the current status and evolution of AR and asthma-related clinical research using bibliometric analysis. Additionally, the study comprehensively summarized the impactful authors, institutions, and countries, and revealed the replacement and evolution of hotspots.

Human peritoneal fluid exerts ovulation- and nonovulation-sourced oncogenic activities on transforming fallopian tube epithelial cells.

Secretory cells in the fallopian tube fimbria epithelium (FTE) are regarded as the main cells of origin of ovarian high-grade serous carcinoma (HGSC). Ovulation is the main cause of FTE oncogenesis, which proceeds through a sequence of TP53 mutations, chromosomal instability due to Rb/cyclin E aberration, in situ carcinoma (STIC), and metastasis to the ovary and peritoneum (metastatic HGSC). Previously, we have identified multiple oncogenic activities of the ovulatory follicular fluid (FF), which exerts the full spectrum of transforming activity on FTE cells at different stages of transformation. After ovulation, the FF is transfused into the peritoneal fluid (PF), in which the FTE constantly bathes. We wondered whether PF exerts the same spectrum of oncogenic activities as done by FF and whether these activities are derived from FF. By using a panel of FTE cell lines with p53 mutation (FT282-V), p53/CCNE1 aberrations (FT282-CCNE1), and p53/Rb aberrations plus spontaneous transformation, and peritoneal metastasis (FEXT2), we analyzed the changes of different transformation phenotypes after treating with FF and PF collected before or after ovulation. Similar to effects exhibited by FF, we found that, to a lesser extent, PF promoted anchorage-independent growth (AIG), migration, anoikis resistance, and peritoneal attachment in transforming FTE cells. The more transformed cells were typically more affected. Among the transforming activities exhibited by PF treatment, AIG, Matrigel invasion, and peritoneal attachment growth were higher with luteal-phase PF treatment than with the proliferative-phase PF treatment, suggesting an ovulation source. In contrast, changes in anoikis resistance and migration activities were similar in response to treatment with PF collected before and after ovulation, suggesting an ovulation-independent source. The overall transforming activity of luteal-phase PF was verified in an i.p. co-injection xenograft mouse model. Co-injection of Luc-FEXT2 cells with either FF or luteal-phase PF supported early peritoneal implantation, whereas co-injection with follicular-phase PF did not. This study, for the first time, demonstrates that PF from ovulating women can promote different oncogenic phenotypes in FTE cells at different stages of malignant transformation. Most of these activities, other than anoikis resistance and cell migration, are sourced from ovulation.

The impact of gut microbial dysbiosis on the atrophy of the hippocampus and abnormal metabolism of N-acetyl aspartate in type 2 diabetic rats.

Rationale and objectives: This study aimed to investigate the effect of intestinal dysbiosis on the hippocampal volume using proton magnetic resonance spectroscopy (1H-MRS) in a type 2 diabetes mellitus (T2DM) rat model. Materials and methods: We established a T2DM animal model with high-fat diet and streptozotocin (HFD/STZ) administration to Sprague-Dawley rats. Short-term ceftriaxone sodium administration was used to establish a T2DM intestinal dysbiosis (T2DM-ID) model. After establishing the model, fecal microbiota were detected using 16S rRNA sequencing. The models were then subjected to magnetic resonance imaging (MRI). Associations between MRI findings and fecal microbiota were evaluated. Results: Magnetic resonance imaging (MRI) showed that the bilateral hippocampal voxel value and N-acetylaspartate (NAA) level were lower in the experimental group than in the normal control (NC) group (p < 0.05) and that NAA/creatine in the left hippocampus was lower in the T2DM-ID group than in the NC group (p < 0.05). α and ß diversities differed significantly among the three groups (p < 0.05). In the T2DM and T2DM-ID groups, the abundance of bacteria in the phylum Proteobacteria increased significantly, whereas that of bacteria in the phylum Firmicutes decreased. The relative abundance of Actinobacteria was significantly increased in the T2DM-ID group. The Chao1 index (r = 0.33, p < 0.05) and relative abundance of Firmicutes (r = 0.48, p < 0.05) were positively correlated with the left hippocampal voxel, while the relative abundance of Proteobacteria was negatively correlated with the left hippocampal voxel (r = -0.44, p < 0.05). NAA levels, bilateral hippocampal voxels, and the relative abundance of Lactobacillus, Clostridia_UCG_014, and other genera were correlated positively (r = 0.34-0.70, p < 0.05). NAA levels and the relative abundances of Blautia and Enterococcus were correlated negatively (r = -0.32-0.44, p < 0.05). Conclusion: The T2DM-ID rat model showed hippocampal volume atrophy and decreased levels of neuronal markers (such as NAA). The abnormal content of specific gut microorganisms may be a key biomarker of T2DM-associated brain damage.

Single-cell analysis reveals hypoxia-induced immunosuppressive microenvironment in intrahepatic cholangiocarcinoma.

The role of hypoxia in the tumor microenvironment of intrahepatic cholangiocarcinoma (iCCA) remains unclear. Here, we generated a comprehensive atlas of the entire tumor microenvironment and delineated the multifaceted cell-cell interactions to decipher hypoxia-induced pro-tumor immune suppression. We discovered hypoxia is significantly associated with iCCA progression via the activation of HIF1A expression. Moreover, hypoxia-dependent PPARγ-mediated fatty acid oxidation in APOE+ TAMs promoted M2 macrophage polarization by activating the HIF1A-PPARG-CD36 axis. These polarized APOE+ TAMs recruited Treg cell infiltration via the CCL3-CCR5 pair to form an immunosuppressive microenvironment. APOE+ TAMs tended to co-localize spatially with Treg cells in the malignant tissue based on spatial transcriptome data and immunofluorescence analysis results. We identified tumor-reactive CXCL13+ CD8-PreTex with specific high expression of ENTPD1 and ITGAE, which acted as precursors of CD8-Tex and had higher cytotoxicity, lower exhaustion, and more vigorous proliferation. Consequently, CXCL13+ CD8-PreTex functioned as a positive regulator of antitumor immunity by expressing the pro-inflammatory cytokines IFNG and TNF, associated with a better survival outcome. Our study reveals the mechanisms involved in hypoxia-induced immunosuppression and suggests that targeting precursor-exhausted CXCL13+CD8+ T cells might provide a pratical immunotherapeutic approach.

The link between gut microbiome and Alzheimer's disease: From the perspective of new revised criteria for diagnosis and staging of Alzheimer's disease.

Over the past decades, accumulating evidence suggests that the gut microbiome exerts a key role in Alzheimer's disease (AD). The Alzheimer's Association Workgroup is updating the diagnostic criteria for AD, which changed the profiles and categorization of biomarkers from "AT(N)" to "ATNIVS." Previously, most of studies focus on the correlation between the gut microbiome and amyloid beta deposition ("A"), the initial AD pathological feature triggering the "downstream" tauopathy and neurodegeneration. However, limited research investigated the interactions between the gut microbiome and other AD pathogenesis ("TNIVS"). In this review, we summarize current findings of the gut microbial characteristics in the whole spectrum of AD. Then, we describe the association of the gut microbiome with updated biomarker categories of AD pathogenesis. In addition, we outline the gut microbiome-related therapeutic strategies for AD. Finally, we discuss current key issues of the gut microbiome research in the AD field and future research directions. HIGHLIGHTS: The new revised criteria for Alzheimer's disease (AD) proposed by the Alzheimer's Association Workgroup have updated the profiles and categorization of biomarkers from "AT(N)" to "ATNIVS." The associations of the gut microbiome with updated biomarker categories of AD pathogenesis are described. Current findings of the gut microbial characteristics in the whole spectrum of AD are summarized. Therapeutic strategies for AD based on the gut microbiome are proposed.

Circulating Small Extracellular Vesicles Involved in Systemic Regulation Respond to RGC Degeneration in Glaucoma.

Glaucoma is a leading cause of irreversible blindness worldwide and is characterized by progressive retinal ganglion cell (RGC) degeneration and vision loss. Since irreversible neurodegeneration occurs before diagnosable, early diagnosis and effective neuroprotection are critical for glaucoma management. Small extracellular vesicles (sEVs) are demonstrated to be potential novel biomarkers and therapeutics for a variety of diseases. In this study, it is found that intravitreal injection of circulating plasma-derived sEVs (PDEV) from glaucoma patients ameliorated retinal degeneration in chronic ocular hypertension (COH) mice. Moreover, it is found that PDEV-miR-29s are significantly upregulated in glaucoma patients and are associated with visual field defects in progressed glaucoma. Subsequently, in vivo and in vitro experiments are conducted to investigate the possible function of miR-29s in RGC pathophysiology. It is showed that the overexpression of miR-29b-3p effectively prevents RGC degeneration in COH mice and promotes the neuronal differentiation of human induced pluripotent stem cells (hiPSCs). Interestingly, engineered sEVs with sufficient miR-29b-3p delivery exhibit more effective RGC protection and neuronal differentiation efficiency. Thus, elevated PDEV-miR-29s may imply systemic regulation to prevent RGC degeneration in glaucoma patients. This study provides new insights into PDEV-based glaucoma diagnosis and therapeutic strategies for neurodegenerative diseases.

Oxygen vacancy formation strengthened microwave catalysis of Zn-Zr solid solution for antibiotic-free therapy strategies of bacteria-infected osteomyelitis.

Osteomyelitis, a grave deep tissue infection primarily caused by Staphylococcus aureus, results in serious complications such as abscesses and sepsis. With the incidence from open fractures exceeding 30 % and prevalent antibiotic resistance due to extensive treatment regimens, there's an urgent need for innovative, antibiotic-free strategies. Photothermal therapy (PTT) and photodynamic therapy (PDT) renowned for generating localized reactive oxygen species (ROS), face limitations in penetration depth. To overcome this, our method combines the deep penetration attributes of medical microwaves (MW) with the synergistic effects of the ZnO/ZrO2 solid solution. Comprehensive in vitro and in vivo evaluations showcased the solid-solution's potent antibacterial efficacy and biocompatibility. The ZnO/ZrO2 solid solution, especially in a 7:3 M ratio, manifests superior microstructural characteristics, optimizing MW-assisted therapy. Our findings highlight the potential of this integrated strategy as a promising avenue in osteomyelitis management.