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Glaucoma is a progressive optic nerve degenerative disease that often leads to blindness. Local inflammatory responses are implicated in the pathology of glaucoma. Although inflammatory episodes outside the CNS, such as those due to acute systemic infections, have been linked to central neurodegeneration, they do not appear to be relevant to glaucoma. Based on clinical observations, we hypothesized that chronic subclinical peripheral inflammation contributes to neurodegeneration in glaucoma. Mouthwash specimens from patients with glaucoma and control subjects were analyzed for the amount of bacteria. To determine a possible pathogenic mechanism, low-dose subcutaneous lipopolysaccharide (LPS) was administered in two separate animal models of glaucoma. Glaucomatous neurodegeneration was assessed in the retina and optic nerve two months later. Changes in gene expression of toll-like receptor 4 (TLR4) signaling pathway and complement as well as changes in microglial numbers and morphology were analyzed in the retina and optic nerve. The effect of pharmacologic blockade of TLR4 with naloxone was determined. Patients with glaucoma had higher bacterial oral counts compared to control subjects (p<0.017). Low-dose LPS administration in glaucoma animal models resulted in enhancement of axonal degeneration and neuronal loss. Microglial activation in the optic nerve and retina as well as upregulation of TLR4 signaling and complement system were observed. Pharmacologic blockade of TLR4 partially ameliorated the enhanced damage. The above findings suggest that the oral microbiome contributes to glaucoma pathophysiology. A plausible mechanism by which increased bacterial loads can lead to neurodegeneration is provided by experiments in animal models of the disease and involves activation of microglia in the retina and optic nerve, mediated through TLR4 signaling and complement upregulation. The finding that commensal bacteria may play a role in the development and/or progression of glaucomatous pathology may also be relevant to other chronic neurodegenerative disorders.

Background Oral squamous cell carcinoma (OSCC) is the most common cancer in the head and neck region, accounting for nearly 90% of oral cavity tumors. OSCC cells often overexpress epidermal growth factor receptor (EGFR), which is linked to tumor formation, progression, and differentiation. Surgery and chemotherapy are the main treatments for OSCC, but they are ineffective compared to other oral cancers. Method To overcome these restrictions, anticancer-active Ir(III) complex-based photosensitizers are incorporated into a PANI-PEG-CS hydrogel and delivered to tumorous tissue, where they are activated by near-infrared (NIR) light to combat cancer. Results Hydrogels incorporating Ir(III) complex could be ingested by OSCC cells under NIR irradiation and have shown strong selectivity toward mitochondria. Further investigations confirmed that Ir increased ROS formation, decreased mitochondrial membrane potential, and depleted ATP levels, all of which led to OSCC cell apoptosis at 62.5 µg/ml. Western blot analysis showed that Ir(III)@PANI-PEG-CS hydrogel induces apoptosis in CAL-27 cells by activating the mitochondria-dependent apoptotic pathway and the PI3K/AKT pathway. Conclusion Nanocomposites selectively accumulate in malignant cells and effectively eliminate them using NIR irradiation. We conclude that complex Ir(III)@PANI-PEG-CS hydrogel may be a promising candidate for new anticancer therapies. Graphical Abstract

This study aimed to identify the heat-resistant bioactive components of Enterococcus faecium HDRsEf1 (HDRsEf1) and investigate their beneficial mechanism. Heat-treated culture supernatants of HDRsEf1 significantly suppressed CXCL-1 expression in LPS-stimulated MODE-K cells (p < 0.001), indicating the presence of heat-resistant anti-inflammatory components. Crude protein (P-Ef1) and crude expolysaccharide (EPS-Ef1) were isolated from an HDRsEf1 culture supernatant using ammonium sulfate and ethanal precipitation. Critically, only crude EPS-Ef1 retained an anti-inflammatory effect after heat treatment, while crude P-Ef1 lost this activity. Further investigation revealed that crude EPS-Ef1 (25 μg/mL) promoted MODE-K cell proliferation via EdU assays (p < 0.001), potentially through an upregulation of PCNA mRNA expression (p < 0.001). Animal studies demonstrated that an oral administration of crude EPS-Ef1 (4 mg/kg bw, 14 days) significantly increased body weight gain and jejunal crypt depth (p < 0.05) while reducing intestinal CXCL-1 mRNA levels (p < 0.001). These in vivo findings are consistent with in vitro observations. A structural analysis using HPAEC and SEC-MALLS-RI characterized crude EPS-Ef1 as a heteropolysaccharide (Mw 80.3 kDa) with a near-spherical conformation (slope 0.13) composed of mannose, glucose, glucuronic acid, and galactose (5.4:4.4:1.2:1). In summary, this study identifies crude EPS-Ef1 as the heat-resistant postbiotic component. Crude EPS-Ef1 possesses the dual effects of suppressing intestinal inflammation and promoting intestinal epithelial cell proliferation, which provides a theoretical foundation for a crude EPS-Ef1-based postbiotic.

The composites were synthesized by the reaction of Bi(NO3)3·5H2O, KI, and MoS2 and were prepared with different molar ratios of Bi/Mo (1:5, 1:2, 1:1, and 4:1) by altering the amount of bismuth nitrate pentahydrate. The phase composition and chemical bonds of the composites were characterized via X-ray diffraction and FT-IR, and the morphologies of the samples were characterized via scanning electron microscopy. With the increase of lanthanum source, the lamellar structure of the sample surface became more and more obvious. The results showed that the phase composition of the composites with different ratios of Bi/Mo was different. When the Bi/Mo reached 4:1, the composite material was Bi2MoO6/BiOI. The heterojunction structure formed between Bi2MoO6 and BiOI effectively promotes the separation of photogenerated electrons and holes and improved the photocatalytic activity. Therefore, the effect of the composites on the degradation of RhB was better than pure BiOI under the irradiation of a 350-W xenon lamp.

The composites were synthesized by the reaction of Bi(NO 3 ) 3 ·5H 2 O, KI, and MoS 2 and were prepared with different molar ratios of Bi/Mo (1:5, 1:2, 1:1, and 4:1) by altering the amount of bismuth nitrate pentahydrate. The phase composition and chemical bonds of the composites were characterized via X-ray diffraction and FT-IR, and the morphologies of the samples were characterized via scanning electron microscopy. With the increase of lanthanum source, the lamellar structure of the sample surface became more and more obvious. The results showed that the phase composition of the composites with different ratios of Bi/Mo was different. When the Bi/Mo reached 4:1, the composite material was Bi 2 MoO 6 /BiOI. The heterojunction structure formed between Bi 2 MoO 6 and BiOI effectively promotes the separation of photogenerated electrons and holes and improved the photocatalytic activity. Therefore, the effect of the composites on the degradation of RhB was better than pure BiOI under the irradiation of a 350-W xenon lamp.

Background Glaucoma is a progressive optic nerve degenerative disease that often leads to blindness. Local inflammatory responses are implicated in the pathology of glaucoma. Although inflammatory episodes outside the CNS, such as those due to acute systemic infections, have been linked to central neurodegeneration, they do not appear to be relevant to glaucoma. Based on clinical observations, we hypothesized that chronic subclinical peripheral inflammation contributes to neurodegeneration in glaucoma. Methods Mouthwash specimens from patients with glaucoma and control subjects were analyzed for the amount of bacteria. To determine a possible pathogenic mechanism, low-dose subcutaneous lipopolysaccharide (LPS) was administered in two separate animal models of glaucoma. Glaucomatous neurodegeneration was assessed in the retina and optic nerve two months later. Changes in gene expression of toll-like receptor 4 (TLR4) signaling pathway and complement as well as changes in microglial numbers and morphology were analyzed in the retina and optic nerve. The effect of pharmacologic blockade of TLR4 with naloxone was determined. Findings Patients with glaucoma had higher bacterial oral counts compared to control subjects (p<0.017). Low-dose LPS administration in glaucoma animal models resulted in enhancement of axonal degeneration and neuronal loss. Microglial activation in the optic nerve and retina as well as upregulation of TLR4 signaling and complement system were observed. Pharmacologic blockade of TLR4 partially ameliorated the enhanced damage. Conclusions The above findings suggest that the oral microbiome contributes to glaucoma pathophysiology. A plausible mechanism by which increased bacterial loads can lead to neurodegeneration is provided by experiments in animal models of the disease and involves activation of microglia in the retina and optic nerve, mediated through TLR4 signaling and complement upregulation. The finding that commensal bacteria may play a role in the development and/or progression of glaucomatous pathology may also be relevant to other chronic neurodegenerative disorders.

To adapt to habitat temperature, vertebrates have developed sophisticated physiological and ecological mechanisms through evolution. Transient receptor potential melastatin 8 (TRPM8) serves as the primary sensor for cold. However, how cold activates TRPM8 and how this sensor is tuned for thermal adaptation remain largely unknown. Here we established a molecular framework of how cold is sensed in TRPM8 with a combination of patch-clamp recording, unnatural amino acid imaging, and structural modeling. We first observed that the maximum cold activation of TRPM8 in eight different vertebrates (i.e., African elephant and emperor penguin) with distinct side-chain hydrophobicity (SCH) in the pore domain (PD) is tuned to match their habitat temperature. We further showed that altering SCH for residues in the PD with solventaccessibility changes leads to specific tuning of the cold response in TRPM8. We also observed that knockin mice expressing the penguin’s TRPM8 exhibited remarkable tolerance to cold. Together, our findings suggest a paradigm of thermal adaptation in vertebrates, where the evolutionary tuning of the cold activation in the TRPM8 ion channel through altering SCH and solvent accessibility in its PD largely contributes to the setting of the cold-sensitive/ tolerant phenotype.

Background/Aims: Elevated serum cholesterol levels were linked to a higher risk of colorectal adenoma and colorectal cancer (CRC), while the effect of cholesterol on CRC metastasis has not been widely studied. Methods: CRC patients were enrolled to evaluate the association between low-density lipoprotein cholesterol (LDL) and CRC metastases, and LDL receptor (LDLR) level of the CRC tissue was assessed by immunohistochemistry. The effects of LDL on cell proliferation, migration and stemness were assessed in CRC cells in vitro, and the effects of high fat diet (HFD) on tumor growth and intestinal tumorigenicity were investigated in vivo. ROS assays, gene expression array analysis and western blot were used to explore the mechanisms of LDL in CRC progression. Results: The level of LDL was positively correlated with liver metastases, and a higher level of LDL receptor (LDLR) expression was associated with advanced N and M stages of CRC. In vitro, LDL promoted the migration and sphere formation of CRC cells and induced upregulated expression of “stemness” genes including Sox2, Oct4, Nanog and Bmi 1. High-fat diet (HFD) significantly enhanced tumor growth in vivo, and was associated with a shorter intestinal length in azoxymethane/dextran sodium sulfate (AOM/DSS)-treated mice. Furthermore, LDL significantly elevated reactive oxygen species (ROS) levels and Whole Human Genome Microarray found 87 differentially expressed genes between LDL-treated CRC cells and controls, which were largely clustered in the MAP kinase (MAPK) signaling pathway. Conclusions: LDL enhances intestinal inflammation and CRC progression via activation of ROS and signaling pathways including the MAPK pathway. Inflammation is strongly associated with cancer initiation, and the role of LDL in intestinal tumorigenicity should be further explored.

Objective: Ciprofol is a novel 2,6-disubstituted phenol derivative that has improved pharmacokinetic and pharmacodynamic properties compared with propofol. This study was conducted to compare the efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil for patients undergoing fiberoptic bronchoscopy. Methods: Overall, 92 patients undergoing fiberoptic bronchoscopy were included in this prospective, randomized, double-blind, non-inferiority trial and were equally divided into two groups (n = 46 each). Fentanyl (50 μg) was given 2 min before the intravenous infusion of 0.3 mg/kg of ciprofol or 1.2 mg/kg of propofol over a time period of 30 s. During anesthesia maintenance, 0.05–0.2 μg/kg/min of remifentanil combined with one-third to one-fourth of the initial dose of ciprofol or propofol was repeated at 2-min intervals, as required, to maintain a Modified Observer’s Assessment of Alertness and Sedation (MOAA/S) scale score <3. The primary outcome was the successful rate of fiberoptic bronchoscopy. Secondary outcomes included demographic characteristics, time metrics, hemodynamics, coughing severity, intubating conditions, lowest oxygen saturation, utilization of study drug doses, number of remedies (lidocaine and vasoactive drugs) used, satisfaction scores of both patients and the endoscopist, occurrence of intraoperative awareness, patients’ willing to repeat fiberoptic bronchoscopy, and occurrence and severity of adverse events. Results: The successful completion rate of fiberoptic bronchoscopy was 91.30% (42 of 46; 95% confidence interval [CI]: 82.80%–99.80%) in the ciprofol-remifentanil group and 89.13% (41 of 46; 95% CI: 79.80%–98.50%) in the propofol-remifentanil group. Though the clinically acceptable intubating condition was improved in the ciprofol-remifentanil group, this difference has no clinical statistical difference ( p > 0.05). No significant differences were noted between the two groups with respect to time metrics, consumption of fentanyl and remifentanil, or number of remedies (lidocaine and vasoactive drugs). Patients’ willingness to repeat fiberoptic bronchoscopy and the satisfaction of both patients and endoscopist were significantly higher in the ciprofol-remifentanil than in the propofol-remifentanil group ( p < 0.05). Compared with patients in the propofol-remifentanil group, patients in the ciprofol-remifentanil group had more stable hemodynamics. The lowest oxygen saturation was significantly higher in the ciprofol-remifentanil than in the propofol-remifentanil group ( p < 0.05). The numbers of patients who experienced pain on injection in the ciprofol-remifentanil group was significantly lower than the number in the propofol-remifentanil group ( p < 0.01). Severity of coughing, clinically acceptable severity of coughing, incidence of intraoperative awareness, and other adverse events were all similar between the two groups ( p > 0.05). Only four patients experienced grade 2 adverse events (severe hypotension in one patient in the ciprofol-remifentanil group and three patients in the propofol-remifentanil group; p > 0.05); they were treated with noradrenaline. Conclusion: Ciprofol-remifentanil was non-inferior to propofol-remifentanil with regard to successful sedation for flexible bronchoscopy, when used with pre-intravenous administration of 50 μg of fentanyl. At the same time, patients’ willingness to repeat flexible bronchoscopy and the satisfactions were all significantly improved.

With the rapid development of Global Navigation Satellite System (GNSS) technology, the long-term accumulated GNSS observations of global reference stations have provided valuable data for geodesy and geodynamics studies since the 1990s. Acquiring the precise velocity of GNSS stations is very important for the study of global plate movement, crustal deformation, etc. However, the seismic activities nearby some GNSS observation stations may seriously change the station’s motion trajectory. Therefore, our research was motivated to propose a method allowing for station seismic deformation, and apply it to construct an updated global GNSS velocity field. The main contributions of this work included the following. Firstly, we improved the GNSS data processing procedures and seismic data selection strategies to obtain GNSS coordinate time series with mm-level precision (3–5 and 6–8 mm in the horizontal and vertical, respectively) and information of each site impacted by seismic events, which provides necessary input data for further analysis. Secondly, an Integrated Time Series Method (ITSM) concerning the effect of seismic deformation was proposed to model the station’s nonlinear motion accurately. Distinguished with existing studies, all parameters including seismic relaxation time can be simultaneously estimated by ITSM, which improves the accuracy and reliability of GNSS station velocity significantly. Thirdly, to optimize the ITSM-based model, the influences of seismic relaxation time (a. 0.1 × true, b. 10 × true, c. true), parameterization mode (a. Offset + Velocity, b. Offset + Velocity + PSD, c. Offset + Velocity + PSD + Period), and the Post-Seismic Deformation (PSD) model (a. None, b. Exp, c. Log, d. Exp + Log) on results of GNSS time series analyzing were discussed. The results showed that the fitting accuracy of GNSS displacements was better than 5 mm and 10 mm in the horizontal and vertical, respectively. Finally, the global GNSS station velocity field (referred to as GGV2020 hereafter) was refined by ITSM using global GNSS observations and seismic data during 1990–2020. This not only helps interpret plate tectonic motion, establish and maintain a Dynamic Terrestrial Reference Frame (DTRF) but also contributes to better investigating geodynamic processes. GGV2020 results showed that the accuracy of global velocity was better than 1 mm/a, and the averages of Root Mean Square Error (RMSE) were 0.19 mm/a, 0.19 mm/a, and 0.33 mm/a in the north, east, and up direction, respectively. Besides, the RMSE obeys normal distribution. Compared with ITRF2014, there was a difference of about 1–2 mm/a between them due to differences in terms of observation span, processing model, and geodetic technology. Moreover, GGV2020 is expected to enrich and update the existing velocity field products to describe the characteristics of regional crustal movement in more detail, especially in Antarctica.