Passivating Defects and Constructing Catalytic Sites on CsPbBr3 with ZnBr2 for Photocatalytic CO2 Reduction.

In recent years, halide perovskites have attracted considerable attention for photocatalytic CO2 reduction. However, the presence of surface defects and the lack of specific catalytic sites for CO2 reduction lead to low photocatalytic performance. In this study, we demonstrate a facile method that post-treats CsPbBr3 with ZnBr2 for photocatalytic CO2 reduction. Our experimental and characterization results show that ZnBr2 has a dual role: the Br- ions in ZnBr2 passivate Br vacancies (VBr) on the CsPbBr3 surface, while Zn2+ cations act as catalytic sites for CO2 reduction. The ZnBr2-CsPbBr3 achieves a photocatalytic CO evolution rate of 57 µmol g-1 h-1, which is nearly three times higher than that of the pristine CsPbBr3. The enhanced performance over ZnBr2-CsPbBr3 is mainly due to the decreased VBr and lower reaction energy barrier for CO2 reduction. This work presents an effective method to simultaneously passivate surface defects and introduce catalytic sites, providing useful guidance for the regulation of perovskite photoelectric properties and the design of efficient photocatalysts.

Co contamination of Si: Plating & aging.

Cobalt has emerged as a vital material in 10 nm technology for localized interconnect layers, potentially offering a compelling alternative to Cu-based interconnects. In this study, we subjected the contamination arising from the presence of cobalt atoms in silicon to comprehensive investigation, employing electron transmission electron microscopy (TEM) observations in conjunction with first-principles calculations. The results show that a dense CoSi layer with a thickness of a few nanometers is formed at the interface of cobalt and Si. The CoSi layer blocks the diffusion of Co atoms into Si. This is due to the semiconducting nature of the covalent bond formed between Co and Si, leading to the emergence of a forbidden zone at the Co/CoSi interface. The diffusion of Co into CoSi is governed by the atomic exchange mechanism, however, the local distortion of the periodic atomic potential due to the presence of the forbidden zone at the Co/CoSi interface hinders the diffusion of Co into Si. Therefore, the deposition of a Co metal layer on a Si chip does not require an additional barrier layer.

Pickering emulsion gel of polyunsaturated fatty acid-rich oils stabilized by zein-tannic acid green nanoparticles for storage and oxidation stability enhancement.

HYPOTHESIS: Poor storage stability and oxidative deterioration are the common drawbacks of edible oils rich in polyunsaturated fatty acids (PUFAs). We hypothesized that the natural zein/tannic acid self-assembly nanoparticles (ZT NPs) could be employed as stabilizers to anchor at the oil-water interface, thus constructing Pickering emulsion gel (PKEG) system for three types of PUFA-rich oils, soybean oil (SO), fish oil (FO) and cod liver oil (CLO), to improve the storage and oxidation stability. EXPERIMENTS: ZT NPs were prepared by the anti-solvent coprecipitation method, and the three-phase contact angle, FT-IR, and XRD were mainly characterized. To observe the shell-core structure and oil-water interface details of SO/FO/CLO PKEGs by confocal laser scanning microscope and cryo-scanning electron microscope. Accelerated oxidation of FO was performed to assess the protective effect of PKEG on lipids. FINDINGS: The SO, FO, and CLO PKEGs stabilized by 2 % ZT NPs, with oil fraction (φ = 0.5-0.6), were obtained. PKEGs show high viscoelasticity, clear shell-core structure spatial network structure, and ideal storage stability. Under accelerated oxidation, the degree of oxidative rancidity of FO PKEG was obviously lower than that of free FO. Overall, this work opens up new possibilities for using natural PKEG to prevent oxidative deterioration and prolong the shelf-life of PUFA-rich oils.

[Nuclear factor E2-related factor 2 protein mediates sepsis-associated liver injury by regulating ferroptosis].

OBJECTIVE: To investigate the effect of nuclear factor E2-related factor 2 (Nrf2) protein on ferroptosis in mice with sepsis-associated liver injury (SALI). METHODS: he male Sprague-Dawley (SD) mice were divided into 6 groups according to the random number table method, with 6 mice in each group. The SALI model of mice was established by cecal ligation and puncture (CLP), and the Sham group was only treated with laparotomy. CLP+Fer-1 group, CLP+Erastin group, CLP+ML385 group and CLP+Curcumin group were intraperitoneally injected with iron death inhibitor Ferrostatin-1 (Fer-1) 10 mg×kg-1×d-1, iron death activator Erastin 20 mg×kg-1×d-1, Nrf2 inhibitor ML385 30 mg×kg-1×d-1 and Nrf2 activator Curcumin 100 mg×kg-1×d-1 after CLP, respectively; Sham group and CLP group were given normal saline 10 mg×kg-1×d-1, each group was administered continuously for 10 days. Ten days after operation, the serum and liver tissues of mice were collected to detect the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, and the levels of malondialdehyde (MDA), glutathione (GSH) and Fe2+; in liver homogenate. The pathological changes of liver tissue were observed under light microscope after hematoxylin-eosin (HE) staining. The shape and length of mitochondria in liver cells were observed under transmission electron microscope. The protein expressions of Nrf2, glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) in liver tissue were detected by Western blotting. RESULTS: Compared with Sham group, the serum levels of ALT and AST in the CLP group were significantly increased; histologically, the hepatic cord was disordered, the cells were swollen and necrotic, and the length of mitochondria was significantly shortened; the levels of MDA and Fe2+ in liver tissue increased significantly, and the content of GSH decreased significantly; the protein expressions of Nrf2 and GPX4 in liver tissue decreased, and the protein expression of PTGS2 increased significantly. Compared with CLP group, the serum levels of ALT and AST in CLP+Fer-1 group and CLP+Curcumin group were significantly decreased [ALT (U/L): 80.65±19.44, 103.45±20.52 vs. 283.50±37.12, AST (U/L): 103.33±11.90, 127.33±15.79 vs. 288.67±36.82, all P < 0.05]; microscopically, the hepatic cord was irregular, the cells were slightly swollen, and the mitochondrial length was significantly increased (µm: 1.42±0.09, 1.43±0.21 vs. 1.07±0.25, both P < 0.05); the levels of MDA and Fe2+; in liver tissue decreased significantly, and the content of GSH increased significantly [MDA (mol/g): 0.87±0.23, 1.85±0.43 vs. 4.47±0.95, Fe2+ (µg/g): 63.80±7.15, 67.48±6.28 vs. 134.52±14.32, GSH (mol/g): 1.95±0.29, 1.95±0.45 vs. 0.55±0.29, all P < 0.05]; the protein expressions of Nrf2 and GPX4 in liver tissue were significantly increased, and the protein expression of PTGS2 was significantly decreased (Nrf2/GAPDH: 1.80±0.28, 2.10±0.43 vs. 0.70±0.24, GPX4/GAPDH: 0.80±0.06, 0.93±0.07 vs. 0.48±0.02, PTGS2/GAPDH: 0.76±0.05, 0.84±0.01 vs. 1.02±0.09, all P < 0.05). However, the results of the above indexes in the CLP+Erastin group and CLP+ML385 group were opposite, and the serum levels of ALT and AST were significantly increased [ALT (U/L): 344.52±40.79, 321.70±21.10 vs. 283.50±37.12, AST (U/L): 333.50±27.90, 333.00±16.67 vs. 288.67±36.82, all P < 0.05]; microscopically, the arrangement of hepatic cords was disordered, the cells were obviously swollen and necrotic, and the length of mitochondria was significantly shortened (µm: 0.78±0.13, 0.67±0.07 vs. 1.07±0.25, both P < 0.05); the levels of MDA and Fe2+ in liver tissue increased significantly, and the content of GSH decreased significantly [MDA (mol/g): 5.92±1.06, 5.62±0.56 vs. 4.47±0.95, Fe2+ (µg/g): 151.40±8.03, 151.88±8.68 vs. 134.52±14.32, GSH (mol/g): 0.25±0.08, 0.23±0.11 vs. 0.55±0.29, all P < 0.05]; the protein expressions of Nrf2 and GPX4 in liver tissue were significantly decreased, and the protein expression of PTGS2 was significantly increased (Nrf2/GAPDH: 0.46±0.09, 0.46±0.11 vs. 0.70±0.24, GPX4/GAPDH: 0.34±0.05, 0.40±0.01 vs. 0.48±0.02, PTGS2/GAPDH: 1.24±0.13, 1.16±0.11 vs. 1.02±0.09, all P < 0.05). CONCLUSIONS: CLP-induced SALI can lead to ferroptosis in mice hepatocytes, and Nrf2 protein in liver tissue can mediate SALI by regulating ferroptosis.

Prognostic models for mucinous and non-specific adeno cholangiocarcinoma: a population-based retrospective study.

Background: Clinically, the diagnosis and treatment of cholangiocarcinoma are generally different according to the location of occurrence, and the studies rarely consider the differences between different pathological types. Cholangiocarcinomas in large- and middle-sized intrahepatic bile ducts are mostly mucinous, while in small sized bile duct are not; mucinous extrahepatic cholangiocarcinomas are also more common than mucinous intrahepatic cholangiocarcinoma. However, it is unclear whether these pathological type differences are related to the prognosis. Methods: Data of total 22509 patients was analyzed from Surveillance, Epidemiology, and End Results program database out of which 22299 patients were diagnosed with common adeno cholangiocarcinoma while 210 were diagnosed with mucinous cholangiocarcinoma. Based on the propensity score matching (PSM) analysis, between these two groups' clinical, demographic, and therapeutic features were contrasted. The data were analyzed using Cox and LASSO regression analysis and Kaplan-Meier survival curves. Ultimately, overall survival (OS) and cancer specific survival (CSS) related prognostic models were established and validated in test and external datasets and nomograms were created to forecast these patients' prognosis. Results: There was no difference in prognosis between mucinous cholangiocarcinoma and adeno cholangiocarcinoma. Therefore, we constructed prognostic model and nomogram that can be used for mucinous and adeno cholangiocarcinoma at the same time. By comparing the 9 independent key characteristics i.e. Age, tumor size, the number of primary tumors, AJCC stage, Grade, lymph node status, metastasis, surgery and chemotherapy, risk scores were calculated for each individual. By integrating these two pathological types in OS and CSS prognostic models, effective prognosis prediction results could be achieved in multiple datasets (OS: AUC 0.70-0.87; CSS: AUC 0.74-0.89). Conclusion: Age, tumor size, the number of primary tumors, AJCC stage, Grade, lymph node status, metastasis, surgery and chemotherapy are the independent prognostic factors in OS or CSS of the patients with mucinous and ordinary cholangiocarcinoma. Nomogram that can be used for mucinous and adeno cholangiocarcinoma at the same time is of significance in clinical practice and management of cholangiocarcinoma.

Changes to circulating tumor cells in the central vein during laparoscopic versus transanal endoscopic surgeries for rectal cancer: can surgical approach make a difference?

Background: The oncological safety of transanal total mesorectal excision (taTME) remains uncertain, and its special surgical approach may contribute to tumor cell dissemination. Thus, we conducted a study to investigate the impact of surgical approach on circulating tumor cell (CTC) counts and phenotypes in rectal cancer. Methods: This is a prospective randomized controlled study (ClinicalTrials: NCT05109130). The patients were randomized to either the taTME (n = 49) or laparoscopic TME (laTME) (n = 48) groups. Blood samples were collected from the central vein to measure CTC counts and phenotypes at three time points: preoperative (t1), immediately post-tumor removal (t2), and one week post-surgery (t3). The effect of surgical procedure on CTCs at each time point was analyzed, with the primary endpoint being the change in CTC counts from t1 to t3 for each surgical approach. This study adheres to Consolidated Standards of Reporting Trials Guidelines. Results: The baseline clinicopathologic characteristics of the laTME and taTME groups were balanced. The change in CTC count from t1 to t3 was 1.81 ± 5.66 in the laTME group and 2.18 ± 5.53 in the taTME group. The taTME surgery was non-inferior to laTME in terms of changing CTC counts (mean difference [MD]: -0.371; 95% confidence interval [CI]: -2.626 to 1.883, upper-sided 95% CI of 1.883 < 2, non-inferiority boundary value). Compared with that at t1, the CTC count at t2 did not change significantly. However, higher CTC counts were detected at t3 than at t2 in the taTME (P = 0.032) and laTME (P = 0.003) groups. From t1 to t3, CTC counts significantly increased in both the taTME (P = 0.008) and laTME (P = 0.031) groups. There were no significant differences in CTC phenotype changes between the two groups from t1 to t3. Conclusions: Compared with laTME, taTME did not affect CTC counts and phenotypes. Our findings indicate that taTME is not inferior to laTME in terms of CTC changes from an oncological perspective.

Topical administration of GLP-1 eyedrops improves retinal ganglion cell function by facilitating presynaptic GABA release in early experimental diabetes.

ABSTRACT: Diabetic retinopathy is a prominent cause of blindness in adults, with early retinal ganglion cell (RGC) loss contributing to visual dysfunction or blindness. In the brain, defects in y-aminobutyric acid (GABA) synaptic transmission are associated with pathophysiological and neurodegenerative disorders, whereas glucagon-like peptide-1 (GLP-1) has demonstrated neuroprotective effects. However, it is not yet clear whether diabetes causes alterations in inhibitory input to RGCs and whether and how GLP-1 protects against neurodegeneration in the diabetic retina through regulating inhibitory synaptic transmission to RGCs. In the present study, we used the patch-clamp technique to record GABA subtype A receptor-mediated miniature inhibitory postsynaptic currents (mIPSCs) in RGCs from streptozotocin-induced diabetes model rats. We found that early diabetes (4 weeks of hyperglycemia) decreased the frequency of GABAergic mIPSCs in RGCs without altering their amplitude, suggesting a reduction in the spontaneous release of GABA to RGCs. Topical administration of GLP-1 eyedrops over a period of 2 weeks effectively countered the hyperglycemia-induced downregulation of GABAergic mIPSC frequency, subsequently enhancing the survival of RGCs. Concurrently, the protective effects of GLP-1 on RGCs in diabetic rats were eliminated by topical administration of exendin-9-39, a specific GLP-1 receptor antagonist, or SR95531, a specific antagonist of the GABA subtype A receptor. Furthermore, extracellular perfusion of GLP-1 was found to elevate the frequencies of GABAergic mIPSCs in both ON- and OFF-type RGCs. This elevation was shown to be mediated by activation of the phosphatidylinositol-phospholipase C/inositol 1,4,5-trisphosphate receptor/Ca2+/protein kinase C signaling pathway downstream of GLP-1 receptor activation. Moreover, multielectrode array recordings revealed that GLP-1 functionally augmented the photoresponses of ON-type RGCs. Optomotor response tests demonstrated that diabetic rats exhibited reductions in visual acuity and contrast sensitivity that were significantly ameliorated by topical administration of GLP-1. These results suggest that GLP-1 facilitates the release of GABA onto RGCs through the activation of GLP-1 receptor, leading to the de-excitation of RGC circuits and the inhibition of excitotoxic processes associated with diabetic retinopathy. Collectively, our findings indicate that the GABA system has potential as a therapeutic target for mitigating early-stage diabetic retinopathy. Furthermore, the topical administration of GLP-1 eyedrops represents a non-invasive and effective treatment approach for managing early-stage diabetic retinopathy.

Norboldine improves cognitive impairment and pathological features in Alzheimer's disease by activating AMPK/GSK3ß/Nrf2 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Lindera aggregata (Sims) Kosterm is a common traditional herb that has multiple bioactivities. Radix Linderae (LR), the dry roots of Lindera aggregata (Sims) Kosterm, is a traditional Chinese herbal medicine with antioxidant, anti-inflammatory and immunomodulatory properties, first found in Kaibao Era. Norboldine (Nor) is an alkaloid extracted from LR and is one of the primary active ingredients of LR. However, the pharmacological functions and mechanism of Nor in Alzheimer's disease (AD) are still unknown. AIM OF THE STUDY: This study aims to investigate the effect and mechanism of Nor therapy in improving the cognitive impairment and pathological features of 3 × Tg mice. MATERIALS AND METHODS: 3 × Tg mice were treated with two concentrations of Nor for one month and then the memory and cognitive abilities of mice were assessed by novel object recognition experiment and Morris water maze. The impact of Nor on the pathology of ADwere examined in PC12 cells and animal tissues using western blotting and immunofluorescence. Finally, western blotting was used to verify the anti-apoptotic effect of Nor by activating AMPK/GSK3ß/Nrf2 signaling pathway at animal and cellular levels. RESULTS: In this study, we showed that Nor treatment improved the capacity of the learning and memory of 3 × Tg mice and alleviated AD pathology such as Aß deposition. In addition, Nor restored the abnormalities of mitochondrial membrane potential, significantly reduced the production of intracellular ROS and neuronal cell apoptosis. Mechanistically, we combined network pharmacology and experimental verification to show that Nor may exert antioxidant stress and anti-apoptotic through the AMPK/GSK3ß/Nrf2 signaling pathway. CONCLUSION: Our data provide some evidence that Nor exerts a neuroprotective effect through the AMPK/GSK3ß/Nrf2 pathway, thereby improving cognitive impairment in AD model mice. Natural products derived from traditional Chinese medicines are becoming increasingly popular in the process of new drug development and discovery, and our findings provide new perspectives for the discovery of improved treatment strategies for AD.

A Radiomics-Based Nomogram Using Ultrasound Carotid Plaque Evaluation For Predicting Cerebro-Cardiovascular Events In Asymptomatic Patients.

RATIONALE AND OBJECTIVES: This study aims to assess whether a radiomics-based nomogram correlates with a higher risk of future cerebro-cardiovascular events in patients with asymptomatic carotid plaques. Additionally, it investigates the nomogram's contribution to the revised Framingham Stroke Risk Profile (rFSRP) for predicting cerebro-cardiovascular risk. MATERIALS AND METHODS: Predictive models aimed at identifying an increased risk of future cerebro-cardiovascular events were developed and internally validated at one center, then externally validated at two other centers. Survival curves, constructed using the Kaplan-Meier method, were compared through the log-rank test. RESULTS: This study included a total of 2009 patients (3946 images). The final nomogram was generated using multivariate Cox regression variables, including dyslipidemia, lumen diameter, plaque echogenicity, and ultrasonography (US)-based radiomics risk. The Harrell's concordance index (C-index) for predicting events-free survival (EFS) was 0.708 in the training cohort, 0.574 in the external validation cohort 1, 0.632 in the internal validation cohort, and 0.639 in the external validation cohort 2. The final nomogram showed a significant increase in C-index compared to the clinical, conventional US, and US-based radiomics models (all P < 0.05). Furthermore, the final nomogram-assisted method significantly improved the sensitivity and accuracy of radiologists' visual qualitative score of plaque (both P < 0.001). Among 1058 patients with corresponding 1588 plaque US images classified as low-risk by the rFSRP, 75 (7.1%) patients with corresponding 93 (5.9%) carotid plaque images were appropriately reclassified to the high-risk category by the final nomogram. CONCLUSION: The radiomics-based nomogram demonstrated accurate prediction of cerebro-cardiovascular events in patients with asymptomatic carotid plaques. It also improved the sensitivity and accuracy of radiologists' visual qualitative score of carotid plaque and enhanced the risk stratification ability of rFSRP. SUMMARY: The radiomics-based nomogram allowed accurate prediction of cerebro-cardiovascular events, especially ipsilateral ischemic stroke in patients with asymptomatic carotid atherosclerotic plaques. KEY RESULTS: The radiomics-based nomogram allowed accurate prediction of cerebro-cardiovascular events, especially ipsilateral ischemic stroke in patients with asymptomatic carotid atherosclerotic plaques. The radiomics-based nomogram improved the sensitivity and accuracy of radiologists' visual qualitative score of carotid plaque. The radiomics-based nomogram improved the discrimination of high-risk populations from low-risk populations in asymptomatic patients with carotid atherosclerotic plaques and the risk stratification capability of the rFSRP.

Optimum Parameters in Ultrasound Coherent Plane Wave Compounding for High LPWV Estimation: Validation on Phantom and Feasibility in 10 Subjects.

OBJECTIVES: The aim of this study is to determine the optimum and fine values of the number and transmission angles of tilted plane waves for coherent plane-wave compounding (CPWC)-based high local pulse wave velocity (LPWV) estimation. METHODS: A Verasonics system incorporating a linear array probe L14-5/38 with 128 elements and a pulsatile pump, CompuFlow1000, were used to acquire radio frequency data of 3, 5, 7, and 9 tilted plane wave sequences with angle intervals from 0° to 12° with a coarse interval increment step of 1°, and the angle intervals from 0° to 2° with a fine interval increment step of 0.25° from a carotid vessel phantom with the LPWV of 13.42 ± 0.90 m/s. The mean value, standard deviation, and coefficients of variation (CV) of the estimated LPWVs were calculated to quantitatively assess the performance of different configurations for CPWC-based LPWV estimation. Ten healthy human subjects of two age groups were recruited to assess the in vivo feasibility of the optimum parameter values. RESULTS: The CPWC technique with three plane waves (PRF of 12 kHz corresponding to a frame rate of 4000 Hz) with an interval of 0.75° had LPWVs of 13.52 ± 0.08 m/s with the lowest CV of 1.84% on the phantom, and 5.49 ± 1.46 m/s with the lowest CV of 12.35% on 10 subjects. CONCLUSIONS: The optimum parameters determined in this study show the best repeatability of the LPWV measurements with a vessel phantom and 10 healthy subjects, which support further studies on larger datasets for potential applications.

The Polysaccharides from Pinellia ternata and Their Derivatives: Preparation, Structure Characteristics, and Activities in Vitro.

Three polysaccharides, PTC, PTH, and PTB, were extracted from Pinellia ternata using three different extraction conditions: room temperature water, hot water, and 2 % Na2CO3 solution. PTC and PTH were composed of rhamnose, glucose, galactose, mannose, glucuronic acid, galacturonic acid, and arabinose, which combine to form complex structures. PTB was composed solely of glucose and rhamnose. Further analysis indicated that PTC and PTB exhibited triple-helix structures. PTC showed the highest scavenging capacity against DPPH, superoxide anion, and hydroxyl radicals, with half maximal inhibitory concentrations (IC50) of 1004.1, 1584.1, and 1584.1 µg/mL, respectively. Additionally, PTC, PTH, and PTB were subjected to sulfation, phosphorylation, and selenization, resulting in the production of nine derivates. The distinctive absorptive bands of these derivates were determined through infrared spectroscopy. Selenized and sulfated derivates have shown significant antitumor and immunoenhancing properties. Our findings revealed that at 400 µg/mL, the inhibition rate of selenated PTB on HeLa cells was 54.2 % and that on HepG2 cells was 43.1 %. Additionally, selenized PTC displayed significant immunoenhancing activity, with a proliferation rate of 63.7 % at 400 µg/mL in RAW264.7 cells. These results provide valuable evidence supporting the consideration of polysaccharides from Pinellia ternata as a potential candidate for the development of antineoplastic drugs.

[Retracted] HCV­E2 inhibits hepatocellular carcinoma metastasis by stimulating mast cells to secrete exosomal shuttle microRNAs.

[This retracts the article DOI: 10.3892/ol.2017.6433.].

Structural Diversity in Ga/In-Hydroxamate Metal-Organic Materials.

Developing metal-organic materials (MOMs) with chemical robustness is a prerequisite to exploring their intriguing properties and applications. As part of a continuing effort to construct robust MOMs featuring chelated building units, here we introduce a "bent" thiophene-2,5-dihydroxamate ligand with multiple intrinsic conformations when it is used as a chelating linkage. This approach should further diversify the coordination chemistry in hydroxamate-based MOM structures without compromising the stability. In combination with Group 13 metals Ga/In to ensure homoleptic metal vertices, we report the successful crystallization of four MOMs with diverse structures and dimensionalities: SUM-81 as a 0D metal-organic polyhedron (MOP), SUM-82 as a 2D MOF with an fes topology, SUM-83 and SUM-84 as distinct 1D coordination polymers with shapes mimic stairs and mesh tubes, respectively. As these structures indeed contain the aforementioned different ligand conformations and combinations thereof, these results expand our understanding of the coordination chemistry of hydroxamates. To demonstrate the potential applicability of hydroxamate-chelated robust MOMs, the permanently porous SUM-81 MOP was successfully incorporated in a series of mixed matrix membranes for CO2/N2 separation, showing impressive performances.

Surufatinib combined with photodynamic therapy induces ferroptosis to inhibit cholangiocarcinoma in vitro and in tumor models.

The curative effect of single therapy for advanced cholangiocarcinoma (CCA) is poor, thus investigating combined treatment strategies holds promise for improving prognosis. Surufatinib (SUR) is a novel multikinase inhibitor that has been confirmed to prolong survival of patients with advanced CCA. Photodynamic therapy (PDT) can also ablate advanced CCA and relieve biliary obstruction. In this study, we explored the anti-CCA effect of SUR combined with PDT, and explored the underlying mechanism. We found that SUR could effectively inhibit the abilities of proliferation, migration and metastasis in CCA cells (HUCCT-1, RBE). The ability of SUR to inhibit CCA was also confirmed by the HUCCT-1 cell xenograft model in Balb/c nude mice and CCA patient-derived organoids. SUR combined with PDT can significantly enhance the inhibitory effect on CCA, and can be alleviated by two ferroptosis inhibitors (Ferrostatin-1, Deferoxamine). By detecting the level of reactive oxygen species, lipid peroxides, malondialdehyde and glutathione, we further confirmed that SUR combined with PDT can inhibit CCA cells by inducing ferroptosis. Glutathione peroxidase 4 (GPX4) belongs to the glutathione peroxidase family and is mainly responsible for the metabolism of intracellular hydrogen peroxide. GPX4 inhibits ferroptosis by reducing cytotoxic lipid peroxides (L-OOH) to the corresponding alcohols (L-OH). Acyl-CoA synthetase long-chain family member 4 (ACSL4) is a member of the long-chain fatty acid coenzyme a synthetase family and is mainly involved in the biosynthesis and catabolism of fatty acids. ACSL4 induces ferroptosis by promoting the accumulation of lipid peroxides. Both SUR and PDT can induce ferroptosis by promoting ACSL4 and inhibiting GPX4. The regulation effect is found to be more significant in combined treatment group. In conclusion, SUR combined with PDT exerted an anti-CCA effect by inducing ferroptosis. Combination therapy provides a new idea for the clinical treatment of CCA.

Clinical manifestations, antimicrobial resistance and genomic feature analysis of multidrug-resistant Elizabethkingia strains.

BACKGROUND: Elizabethkingia is emerging as an opportunistic pathogen in humans. The aim of this study was to investigate the clinical epidemiology, antimicrobial susceptibility, virulence factors, and genome features of Elizabethkingia spp. METHODS: Clinical data from 71 patients who were diagnosed with Elizabethkingia-induced pneumonia and bacteremia between August 2019 and September 2021 were analyzed. Whole-genome sequencing was performed on seven isolates, and the results were compared with a dataset of 83 available Elizabethkingia genomes. Genomic features, Kyoto Encyclopedia of Genes and Genomes (KEGG) results and clusters of orthologous groups (COGs) were analyzed. RESULTS: The mean age of the patients was 56.9 ± 20.7 years, and the in-hospital mortality rate was 29.6% (21/71). Elizabethkingia strains were obtained mainly from intensive care units (36.6%, 26/71) and emergency departments (32.4%, 23/71). The majority of the strains were isolated from respiratory tract specimens (85.9%, 61/71). All patients had a history of broad-spectrum antimicrobial exposure. Hospitalization for invasive mechanical ventilation or catheter insertion was found to be a risk factor for infection. The isolates displayed a high rate of resistance to cephalosporins and carbapenems, but all were susceptible to minocycline and colistin. Genomic analysis identified five ß-lactamase genes (blaGOB, blaBlaB, blaCME, blaOXA, and blaTEM) responsible for ß-lactam resistance and virulence genes involved in stress adaptation (ureB/G, katA/B, and clpP), adherence (groEL, tufA, and htpB) and immune modulation (gmd, tviB, cps4J, wbtIL, cap8E/D/G, and rfbC). Functional analysis of the COGs revealed that "metabolism" constituted the largest category within the core genome, while "information storage and processing" was predominant in both the accessory and unique genomes. The unique genes in our 7 strains were mostly enriched in KEGG pathways related to microRNAs in cancer, drug resistance (ß-lactam and vancomycin), ABC transporters, biological metabolism and biosynthesis, and nucleotide excision repair mechanisms. CONCLUSION: The Elizabethkingia genus exhibits multidrug resistance and carries carbapenemase genes. This study presents a comparative genomic analysis of Elizabethkingia, providing knowledge that facilitates a better understanding of this microorganism.

Theta burst stimulation for enhancing upper extremity motor functions after stroke: a systematic review of clinical and mechanistic evidence.

This systematic review aimed to evaluate the effects of different theta burst stimulation (TBS) protocols on improving upper extremity motor functions in patients with stroke, their associated modulators of efficacy, and the underlying neural mechanisms. We conducted a meta-analytic review of 29 controlled trials published from January 1, 2000, to August 29, 2023, which investigated the effects of TBS on upper extremity motor, neurophysiological, and neuroimaging outcomes in poststroke patients. TBS significantly improved upper extremity motor impairment (Hedge's g = 0.646, p = 0.003) and functional activity (Hedge's g = 0.500, p < 0.001) compared to controls. Meta-regression revealed a significant relationship between the percentage of patients with subcortical stroke and the effect sizes of motor impairment (p = 0.015) and functional activity (p = 0.018). Subgroup analysis revealed a significant difference in the improvement of upper extremity motor impairment between studies using 600-pulse and 1200-pulse TBS (p = 0.002). Neurophysiological studies have consistently found that intermittent TBS increases ipsilesional corticomotor excitability. However, evidence to support the regional effects of continuous TBS, as well as the remote and network effects of TBS, is still mixed and relatively insufficient. In conclusion, TBS is effective in enhancing poststroke upper extremity motor function. Patients with preserved cortices may respond better to TBS. Novel TBS protocols with a higher dose may lead to superior efficacy compared with the conventional 600-pulse protocol. The mechanisms of poststroke recovery facilitated by TBS can be primarily attributed to the modulation of corticomotor excitability and is possibly caused by the recruitment of corticomotor networks connected to the ipsilesional motor cortex.

Effectiveness and safety of Lacosamide in pediatric patients with epilepsy under four years: Results from a prospective cohort study in China.

BACKGROUND: Lacosamide (LCM) has shown promising efficacy and safety outcomes in clinical trials. However, the evidence is limited among pediatric patients especially under four years in real-world. The study investigated the treatment outcomes and safety of LCM in patients under four years based on the data of the epilepsy registry of Children in China. METHODS: A prospective cohort study was conducted among patients under 4 years who newly received LCM as monotherapy or adjunctive therapy. The treatment outcomes were measured by retention rate of LCM, 50 % response rates and seizure-free rates during follow-up. The retention rate of LCM was assessed using the Kaplan-Meier survival model. Adverse events were reported as a percentage of all participants. RESULTS: Of 109 participants (mean follow-up: 18.6 months), 59 received LCM as monotherapy and 50 as adjunctive therapy. Sixty patients had focal epilepsy, 44 had generalized epilepsy and 5 had combined generalized and focal epilepsy. 70 % of patients in the monotherapy group and 41 % in the adjunctive therapy group remained on LCM treatment without additional treatments for at least one year. In patients with monotherapy, 50 % response rate and seizure-free rate were 75 % and 56 % at 12 months, respectively. In adjunctive therapy group, these rates were 51 % and 36 %, respectively. Lower baseline seizure frequency in both treatment groups (monotherapy: p < 0.001; adjunctive therapy: p = 0.02) and younger age groups within the monotherapy group (P = 0.04) correlated with a higher LCM retention rate. Adverse events were reported by 15 patients (13.8 %), with somnolence being the most common (7 of 15 patients). CONCLUSION: With a comprehensive information and high-quality of data, the study demonstrates the effective treatment outcome and safety of LCM. The study adds reliable evidence to exiting real-word evidence of LCM in the specific age group of patients with epilepsy to fill the evidence gap.

Rapamycin improves the survival of epilepsy model cells by blocking phosphorylation of mTOR base on computer simulations and cellular experiments.

PURPOSE: Epilepsy is a chronic brain dysfunction characterized by recurrent epileptic seizures. Rapamycin is a naturally occurring macrolide from Streptomyces hygroscopicus, and rapamycin may provide a protective effect on the nervous system by affecting mTOR. Therefore, we investigated the pharmacologic mechanism of rapamycin treating epilepsy through bioinformatics analysis, cellular experiments and supercomputer simulation. METHODS: Bioinformatics analysis was used to analyze targets of rapamycin treating epilepsy. We established epilepsy cell model by HT22 cells. RT-qPCR, WB and IF were used to verify the effects of rapamycin on mTOR at gene level and protein level. Computer simulations were used to model and evaluate the stability of rapamycin binding to mTOR protein. RESULTS: Bioinformatics indicated mTOR played an essential role in signaling pathways of cell growth and cell metabolism. Cellular experiments showed that rapamycin could promote cell survival, and rapamycin did not have an effect on mRNA expression of mTOR. However, rapamycin was able to significantly inhibit the phosphorylation of mTOR at protein level. Computer simulations indicated that rapamycin was involved in the treatment of epilepsy through regulating phosphorylation of mTOR at protein level. CONCLUSION: We found that rapamycin was capable of promoting the survival of epilepsy cells by inhibiting the phosphorylation of mTOR at protein level, and rapamycin did not have an effect on mRNA expression of mTOR. In addition to the traditional study that rapamycin affects mTORC1 complex by acting on FKBP12, this study found rapamycin could also directly block the phosphorylation of mTOR, therefore affecting the assembly of mTORC1 complex and mTOR signaling pathway.

Characteristics of pine wood nematode disease in Nankang District, Ganzhou, Jiangxi Province, China.

Pine wood nematode (PWN) disease is one of the major disasters in forests of southern China, causing substantial forest resources and ecological and economic losses. Based on field surveys and WFV image data from the GF-1 satellite, we constructed a spatial identification model of PWN disease with the random forest model to explore the relative influences of topography, human activities and stand factors on the occurrence of diseases and predict their spatial distribution. We then used the spatial autocorrelation analysis to assess the distribution characteristics of PWN disease at the regional scale. The results showed that the random forest model constructed in this study was effective in identifying pine nematode diseases (AUC value=0.99, overall accuracy=0.96). The norma-lized difference greenness index (NDGI), the distance to the highway, and normalized vegetation index (NDVI) were important factors in explaining the spatial variations of PWN disease occurrence. There was a positive spatial correlation in the occurrence of PWN disease (not randomly distributed but with obvious spatial aggregation characteristics). The high occurrence areas of pine wood nematode disease concentrated in Chitu Township, Zhufang Township and Shibatang Township, low occurrence areas concentrated in the vicinity of Rongjiang Street. The areas far away from the highway, low in elevation, and close to county roads were suffered to PWN disease. The results could serve the regional monitoring of pine nematode disease occurrence and provide practical guidance for PWN disease management.

[Effects of Land Use Structure and Spatial Pattern at Different Temporal and Spatial Scales on Water Quality in Suzhou Creek].

Relationships between land use and water quality of rivers and lakes vary spatially and temporally. These variations were analyzed using spatial analysis and mathematical statistical methods for the Suzhou Creek in Shanghai. Based on the data of water quality and land use in 2001， 2005， 2010， 2015， and 2020， five spatial scales （200， 500， 1 000， 2 000， and 5 000 m reach buffer） of the landscape pattern were extracted using correlation and redundancy analysis to explore the impact of land use composition and spatial pattern on water quality at different spatial and temporal scales. The results showed that： ① the water quality of Suzhou Creek has gradually improved in the past 20 years； other indicators were between Class II to Class IV in 2020 except TN， and TN was the main pollutant. ② The main land use type of the buffer zone was construction land， and the proportion of greenland and woodland showed a small growth trend. ③ The water quality was closely related to landscape pattern， showing temporal and spatial scale effects. On the time scale， indicators such as construction land， agricultural land， landscape dominance， aggregation， and diversity had significant correlations with various water quality parameters， and there was an inverse correlation in 2010 compared with that in other years for NH4+-N， TP， and TN. The landscape pattern in 2001 had the greatest explanation for water quality， with an explanation rate of 93.65%. The impact of greenland and woodland on water quality has begun to emerge in the past 10 years. ④ On the spatial scale， there were significant correlations between greenland and woodland， patch number， landscape shape index， diversity index， and water quality. There was a strong positive regulatory effect of greenland and woodland on NH4+-N， TP， and TN at the scale of 2 000 m. The patch number and landscape shape index had relatively strong regulatory effects on water quality on a larger spatial scale， whereas the Shannon diversity index had a better positive regulatory effect on water quality on a small scale. The landscape pattern within a buffer of 2 000 m had the highest interpretation degree for all factors， with an explanation rate of 68.47%. The study showed that rationally planning the proportion of greenland and woodland within the 2 000 m buffer zone and optimizing its landscape configuration is an important measure to purify the surface water quality of Suzhou Creek.