Search

Targeted radionuclide therapy (TRT)，the use of radiopharmaceuticals to target and irradiate tumour cells，has become an important method for cancer treatment. The radiolanthanide Lutetium-177 (177Lu) is a medium-energy beta radionuclide with a suitable electron energy range for treatment of small tumors，and has been widely used in clinical targeted radionuclide therapy. The radiolanthanide terbium-161 (161Tb) isotope has similar decay properties，biochemical properties，and in vivo characteristics to 177Lu，and it releases more Auger electrons and internal conversion electrons than 177Lu. It has been proposed，and preclinically demonstrated，that 161Tb is a better alternative to 177Lu for the treatment of small prostate cancer lesions. According to the conferences and published articles on nuclear medicine in recent years，more and more attention has been paid to the preparation of 161Tb nuclides and the development of its labeled drugs in the field of radiopharmaceuticals. However，there is no mature production process for 161Tb internationally，which has seriously hindered the clinical research of 161Tb-labeled drugs. Currently，there are two main methods for the preparation research of 161Tb. One is to produce 161Tb through an accelerator，and the other is to produce carrier-free 161Tb using a high-throughput reactor or a fission neutron source via the reaction 160Gd(n，γ)161Gd→161Tb. Commercial production of 161Tb using an accelerator is very difficult. The most common method internationally is to irradiate enriched 160Gd2O3 target material with a reactor or a fission neutron source to produce carrier-free 161Tb. According to the investigation，there are several research institutes or companies at home and abroad are carrying out relevant research on the preparation of 161Tb. Chengdu Gaotong Isotope Co.，Ltd. (CNNC) used enriched 160Gd2O3 target material irradiated by a reactor with neutron flux of about 1-2×1014 n·cm−2·s−1 to separate a large amount of irradiated 160Gd by a two-column method to prepare no carrier-added 161TbCl3 nuclide solutions. Chengdu Gaotong Isotope Co.，Ltd. has carried out many experiments on the preparation of 161Tb from 160Gd target material enriched. After separation and purification，the radionuclide purity，radiochemical purity and activity of 161TbCl3 nuclide solution were detected by high purity germanium gamma spectrometer，activity meter and other instruments and equipment. The results showed that the radionuclide solution of 161TbCl3 with radionuclide purity greater than or equal to 99.9%，radiochemical purity greater than 99% and chemical purity was obtained after the separation and purification of 161Gd target material enriched by irradiation in the reactor.

Discontinuity is critical for strength, deformability, and permeability of rock mass. Set information is one of the essential discontinuity characteristics and is usually accessed by orientation grouping. Traditional methods of identifying optimal discontinuity set numbers are usually achieved by clustering validity indexes, which mainly relies on the aggregation and dispersion of clusters and leads to the inaccuracy and instability of evaluation. This paper proposes a new method of Fisher mixed evaluation (FME) to identify optimal group numbers of rock mass discontinuity orientation. In FME, orientation distribution is regarded as the superposition of Fisher mixed distributions. Optimal grouping results are identified by considering the fitting accuracy of Fisher mixed distributions, the probability monopoly and central location significance of independent Fisher centers. A Halley-Expectation-Maximization (EM) algorithm is derived to achieve an automatic fitting of Fisher mixed distribution. Three real rock discontinuity models combined with three orientation clustering algorithms are adopted for discontinuity grouping. Four clustering validity indexes are used to automatically identify optimal group numbers for comparison. The results show that FME is more accurate and robust than the other clustering validity indexes in optimal discontinuity group number identification for different rock models and orientation clustering algorithms.

Abstract Cleavage of carbon-carbon bonds remains a challenging task in organic synthesis. Traditional methods for splitting Csp2=Csp2 bonds into two halves typically involve non-redox (metathesis) or oxidative (ozonolysis) mechanisms, limiting their synthetic potential. Disproportionative deconstruction of alkenes, which yields one reduced and one oxidized fragment, remains an unexplored area. In this study, we introduce a redox-neutral approach for deleting a Csp2 carbon unit from substituted arylalkenes, resulting in the formation of an arene (reduction) and a carbonyl product (oxidation). This transformation is believed to proceed through a mechanistic sequence involving visible-light-promoted anti-Markovnikov hydration, followed by photoredox cleavage of Csp3-Csp3 bond in the alcohol intermediate. A crucial consideration in this design is addressing the compatibility between the highly reactive oxy radical species in the latter step and the required hydrogen-atom-transfer (HAT) reagent for both steps. We found that ethyl thioglycolate serves as the optimal hydrogen-atom shuttle, offering remarkable chemoselectivity among multiple potential HAT events in this transformation. By using D2O, we successfully prepared dideuteromethylated (-CD2H) arenes with good heavy atom enrichment. This work presents a redox-neutral alternative for alkene deconstruction, with considerable potential in late-stage modification of complex molecules.

Abstract Quadrotor technology has become increasingly important in the field of photovoltaic (PV) solar farm monitoring, but short battery life is one of the primary factors limiting its further application. To address above issue, this study proposes a linear temporal logic (LTL)-based path planning algorithm that considers the need for charging together with multiple visits to PV equipments, a single visit to communication equipment, and the avoidance of restricted regions, which enables the long-term monitoring of PV solar farms. Particularly, the location of a charging station can be determined optimally and efficiently by a heuristic algorithm based on the nonlinear programming and branch and bound (NLP-BB) algorithm. The simulation results indicate that the proposed method effectively solves the long-term monitoring path planning problem that is coupled with the optimal deployment of the charging station.

Abstract Observational studies have reported an association between inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), and hemorrhoids (HEM). However, the presence of a causal relationship within this observed association remains to be confirmed. Consequently, we utilized the Mendelian randomization (MR) method to assess the causal effects of IBD on hemorrhoids. We validated the association between IBD and hemorrhoids in humans based on genome-wide association studies (GWAS) data. To investigate the causal relationship between IBD and hemorrhoids, we performed a two-sample Mendelian randomization study using training and validation sets. The genetic variation data for IBD, CD, UC, and hemorrhoids were derived from published genome-wide association studies (GWAS) of individuals of European. Two-sample Mendelian randomization and Multivariable Mendelian randomization (MVMR) were employed to determine the causal relationship between IBD (CD or UC) and hemorrhoids. Genetically predicted overall IBD was positively associated with hemorrhoids risk, with ORs of 1.02 (95% CIs 1.01–1.03, P = 4.39 × 10−4) and 1.02 (95% CIs 1.01–1.03, P = 4.99 × 10−5) in the training and validation sets, respectively. Furthermore, we found that CD was positively associated with hemorrhoids risk, with ORs of 1.02 (95% CIs 1.01–1.03, P = 4.12 × 10−6) and 1.02 (95% CIs 1.01–1.02, P = 3.78 × 10−5) for CD in the training and validation sets, respectively. In addition, we found that UC in the training set was positively associated with hemorrhoids risk (ORs 1.02, 95% CIs 1.01–1.03, P = 4.65 × 10−3), while no significant causal relationship between UC and hemorrhoids was shown in the validation set (P > 0.05). However, after MVMR adjustment, UC in the training set was not associated with an increased risk of hemorrhoids. Our study showed that there is a causal relationship between CD and hemorrhoids, which may suggest that clinicians need to prevent the occurrence of hemorrhoids in CD patients.

Abstract Chemotherapy is currently one of the most effective methods in clinical cancer treatment. However, chemotherapy resistance is an important reason for poor chemotherapy efficacy and prognosis, which has become an urgent problem to be solved in the field of cancer chemotherapy. Therefore, it is very important to deeply study and analyze the mechanism of cancer chemotherapy resistance and its regulatory factors. Long non-coding RNA nuclear paraspeckle assembly transcript 1 (LncRNA NEAT1) has been shown to be closely associated with chemotherapy resistance in cancer. NEAT1 induces cancer cell resistance to chemotherapeutic drugs by regulating cell apoptosis, cell cycle, drug transport and metabolism, DNA damage repair, EMT, autophagy, cancer stem cell characteristics, and metabolic reprogramming. This indicates that NEAT1 may be an important target to overcome chemotherapy resistance and is expected to be a potential biomarker to predict the effect of chemotherapy. This article summarizes the expression characteristics and clinical characteristics of NEAT1 in different cancers, and deeply discusses the regulatory role of NEAT1 in cancer chemotherapy resistance and related molecular mechanisms, aiming to clarify NEAT1 as a new target to overcome cancer chemotherapy resistance and the feasibility of chemotherapy sensitizers, with a view to providing a potential therapeutic direction for overcoming the dilemma of cancer resistance in the future.

Abstract Aims Surveys and research on the applications of the hepatic venous pressure gradient (HVPG) are important for understanding the current status and future development of this technology in China. This article aimed to investigate the status of hepatic venous pressure gradient measurement in China in 2022. Methods We investigated the overall status of HVPG technology in China—including hospital distribution, hospital level, annual number of cases, catheters used, average cost, indications, and current challenges by using online questionnaire. By counting the number and percentages of cases of these results, we hope to clarify the current status of HVPG measurements in China. Results According to the survey, 85 hospitals in China used HVPG technology in 2022 distributed across 29 provinces. A total of 4989 HVPG measurements were performed in all of the surveyed hospitals in 2022, of which 2813 cases (56.4%) were measured alone. The average cost of HVPG measurement was 5646.8 ± 2327.9 CNY. Of the clinical teams who performed the measurements (sometimes multiple per hospital), 94.3% (82/87) used the balloon method, and the majority of the teams (72.4%, 63/87) used embolectomy catheters. Conclusions This survey clarified the clinical application status of HVPG in China and confirmed that some medical institutions in China have established a foundation for this technology. It is still necessary to continue promoting and popularizing this technology in the future.

Abstract Hepatitis B virus (HBV) infection is highly prevalent in Guangzhou, China. This study aimed to examine the long-term trend of HB incidence from 2008 to 2022 and the independent impacts of age, period, and cohort on the trends. HBV data were collected from the China Information System for Disease Control and Prevention. Joinpoint regression was utilized to examine temporal trends, and an age-period-cohort model was employed to estimate the effects of age, period, and cohort. A total of 327,585 HBV cases were included in this study. The incidence of chronic and acute HB showed a decreasing trend in Guangzhou over the past 15 years, with an average annual percent change of − 4.31% and − 16.87%, respectively. Age, period, and cohort all exerted significant effects. The incidence of HB was higher in males than in females and non-central areas compared to central areas. Age groups of 0–4 years and 15–24 years were identified as high-risk groups. The period relative risks for chronic HB incidence decreased initially and then stabilized. Cohorts born later had lower risks. Chronic HB incidences remain high in Guangzhou, especially among males, younger individuals, and residents of non-central areas. More efforts are still needed to achieve hepatitis elimination targets.

Abstract Background Masquelet membrane induction technology is one of the treatment strategies for large bone defect (LBD). However, the angiogenesis ability of induced membrane decreases with time and autologous bone grafting is associated with donor site morbidity. This study investigates if the PRP-FG-nHA/PA66 scaffold can be used as a spacer instead of PMMA to improve the angiogenesis ability of induced membrane and reduce the amount of autologous bone graft. Methods Platelet rich plasma (PRP) was prepared and PRP-FG-nHA/PA66 scaffold was synthesized and observed. The sustained release of VEGFA and porosity of the scaffold were analyzed. We established a femur LBD model in male SD rats. 55 rats were randomly divided into four groups depending on the spacer filled in the defect area. “Defect only” group (n = 10), “PMMA” group (n = 15), “PRP-nHA/PA66” group (n = 15) and “PRP-FG-nHA/PA66” group (n = 15 ). At 6 weeks, the spacers were removed and the defects were grafted. The induced membrane and bone were collected and stained. The bone formation was detected by micro-CT and the callus union was scored on a three point system. Results The PRP-FG-nHA/PA66 scaffold was porosity and could maintain a high concentration of VEGFA after 30 days of preparation. The induced membrane in PRP-FG-nHA/PA66 group was thinner than PMMA, but the vessel density was higher.The weight of autogenous bone grafted in PRP-FG-nHA/PA66 group was significantly smaller than that of PMMA group. In PRP-FG-nHA/PA66 group, the bone defect was morphologically repaired. Conclusion The study showed that PRP-FG-nHA/PA66 scaffold can significantly reduce the amount of autologous bone graft, and can achieve similar bone defect repair effect as PMMA. Our findings provide some reference and theoretical support for the treatment of large segmental bone defects in humans.

Abstract Background Anthraquinone-fused enediynes (AFEs) are excellent payloads for antibody-drug conjugates (ADCs). The yields of AFEs in the original bacterial hosts are extremely low. Multiple traditional methods had been adopted to enhance the production of the AFEs. Despite these efforts, the production titers of these compounds are still low, presenting a practical challenge for their development. Tiancimycins (TNMs) are a class of AFEs produced by Streptomyces sp. CB03234. One of their salient features is that they exhibit rapid and complete cell killing ability against various cancer cell lines. Results In this study, a combinatorial metabolic engineering strategy guided by the CB03234-S genome and transcriptome was employed to improve the titers of TNMs. First, re-sequencing of CB03234-S (Ribosome engineered mutant strains) genome revealed the deletion of a 583-kb DNA fragment, accounting for about 7.5% of its genome. Second, by individual or combined inactivation of seven potential precursor competitive biosynthetic gene clusters (BGCs) in CB03234-S, a double-BGC inactivation mutant, S1009, was identified with an improved TNMs titer of 28.2 ± 0.8 mg/L. Third, overexpression of five essential biosynthetic genes, including two post-modification genes, and three self-resistance auxiliary genes, was also conducted, through which we discovered that mutants carrying the core genes, tnmE or tnmE10, exhibited enhanced TNMs production. The average TNMs yield reached 43.5 ± 2.4 mg/L in a 30-L fermenter, representing an approximately 360% increase over CB03234-S and the highest titer among all AFEs to date. Moreover, the resulting mutant produced TNM-W, a unique TNM derivative with a double bond instead of a common ethylene oxide moiety. Preliminary studies suggested that TNM-W was probably converted from TNM-A by both TnmE and TnmE10. Conclusions Based on the genome and transcriptome analyses, we adopted a combined metabolic engineering strategy for precursor enrichment and biosynthetic pathway reorganization to construct a high-yield strain of TNMs based on CB03234-S. Our study establishes a solid basis for the clinical development of AFE-based ADCs.

STFE(structural, transparent, fluorinated, envelope) membrane material is a new type of transparent architecture membrane material. Compared with general architecture membrane materials, which have the disadvantage of cannot balance strength and transparency, STFE has both high transparency and certain tensile strength. In this study, tensile strength tests were conducted on this new type of membrane material, and data obtained from different test methods, such as clamping test, winding test, and dumbbell-shaped test, were compared, and the mechanism for the differences was analyzed. The results showed that the winding-type test with smooth surface contact yielded the highest and most accurate strength data, clamping tests due to the tendency of the specimen to slip out of the clamping end, dumbbell tests due to the stress concentration effect, and winding tests with rough surface contact due to material damage caused by pressure, all reduce the measured tensile strength values. The measured tensile strength of STFE membrane material was 4241N/5 cm in the warp direction and 4335N/5 cm in the weft direction. This indicates that STFE membrane material has sufficient strength to be used in tensile membrane structures.

The high recurrence rate of cervical cancer is a leading cause of cancer deaths in women. 5-Fluorouracil (5-FU) is an antitumor drug used to treat many types of cancer, but its diminishing effectiveness and side effects limit its use. Norcantharidin (NCTD), a demethylated derivative of cantharidin, exhibits various biological activities. Here, we investigated whether NCTD could potentiate 5-FU to induce cervical cancer cell death. To assess the cell viability and synergistic effects of the drugs, cell counting kit-8 and colony formation assays were performed using HR-HPV-positive cervical cancer cell lines. Annexin V-FITC/PI staining and TUNEL assays were performed to confirm the induction of apoptosis. The synergistic effect of NCTD on the antitumor activity of 5-FU was analyzed using network pharmacology, molecular docking, and molecular dynamics simulations. Apoptosis-related proteins were examined using immunoblotting. The combination of NCTD and 5-FU was synergistic in cervical cancer cell lines. Network pharmacological analysis identified 10 common targets of NCTD and 5-FU for cervical cancer treatment. Molecular docking showed the strong binding affinity of both compounds with CA12, CASP9, and PTGS1. Molecular dynamics simulations showed that the complex system of both drugs with caspase-9 could be in a stable state. NCTD enhanced 5-FU-mediated cytotoxicity by activating apoptosis-related proteins. NCTD acts synergistically with 5-FU to inhibit cervical cancer cell proliferation. NCTD enhances 5-FU-induced apoptosis in cervical cancer cell lines via the caspase-dependent pathway.

Abstract Glutamine synthetase (GS) is vital in maintaining ammonia and glutamate (Glu) homeostasis in living organisms. However, the natural enzyme relies on adenosine triphosphate (ATP) to activate Glu, resulting in impaired GS function during ATP-deficient neurotoxic events. To date, no reports demonstrate using artificial nanostructures to mimic GS function. In this study, we synthesize aggregation-induced emission active polyP-Mn nanosheets (STPE-PMNSs) based on end-labeled polyphosphate (polyP), exhibiting remarkable GS-like activity independent of ATP presence. Further investigation reveals polyP in STPE-PMNSs serves as phosphate source to activate Glu at low ATP levels. This self-feeding mechanism offers a significant advantage in regulating Glu homeostasis at reduced ATP levels in nerve cells during excitotoxic conditions. STPE-PMNSs can effectively promote the conversion of Glu to glutamine (Gln) in excitatory neurotoxic human neuroblastoma cells (SH-SY5Y) and alleviate Glu-induced neurotoxicity. Additionally, the fluorescence signal of nanosheets enables precise monitoring of the subcellular distribution of STPE-PMNSs. More importantly, the intracellular fluorescence signal is enhanced in a conversion-responsive manner, allowing real-time tracking of reaction progression. This study presents a self-sustaining strategy to address GS functional impairment caused by ATP deficiency in nerve cells during neurotoxic events. Furthermore, it offers a fresh perspective on the potential biological applications of polyP-based nanostructures.

Abstract Versatile printing of polymers, metals, and composites always calls for simple, economic approaches. Here we present an approach to three-dimensional (3D) printing of polymeric, metallic, and composite materials at room conditions, based on the polymeric vapor-induced phase separation (VIPS) process. During VIPS 3D printing (VIPS-3DP), a dissolved polymer-based ink is deposited in an environment where nebulized non-solvent is present, inducing the low-volatility solvent to be extracted from the filament in a controllable manner due to its higher chemical affinity with the non-solvent used. The polymeric phase is hardened in situ as a result of the induced phase separation process. The low volatility of the solvent enables its reclamation after the printing process, significantly reducing its environmental footprint. We first demonstrate the use of VIPS-3DP for polymer printing, showcasing its potential in printing intricate structures. We further extend VIPS-3DP to the deposition of polymer-based metallic inks or composite powder-laden polymeric inks, which become metallic parts or composites after a thermal cycle is applied. Furthermore, spatially tunable porous structures and functionally graded parts are printed by using the printing path to set the inter-filament porosity as well as an inorganic space-holder as an intra-filament porogen.

Abstract Epidermal growth factor receptor (EGFR) exon 19 deletion is a major driver for the drug resistance of non-small cell lung cancer (NSCLC). Identification small inhibitor capable of selectively inhibiting EGFR-19del NSCLC is a desirable strategy to overcome drug resistance in NSCLC. This study aims to screen an inhibitor for EGFR exon 19 deletion cells and explore its underlying mechanism. High through-put screen was conducted to identify an inhibitor for EGFR-19del NSCLC cells. And tenovin-3 was identified as a selective inhibitor of PC9 cells, an EGFR-19del NSCLC cells. Tenovin-3 showed particular inhibition effect on PC9 cells proliferation through inducing apoptosis and ferroptosis. Mechanistically, tenovin-3 might induce the apoptosis and ferroptosis of PC9 cells through mitochondrial pathway, as indicated by the change of VDAC1 and cytochrome c (cyt c). And bioinformatics analyses showed that the expression levels of SLC7A11 and CPX4 were correlated with NSCLC patient’s survival. Our findings provide evidences for tenovin-3 to be developed into a novel candidate agent for NSCLC with EGFR exon 19 deletion. Our study also suggests that inducing ferroptosis may be a therapeutic strategy for NSCLC with EGFR exon 19 deletion.

Abstract Glioblastoma (GBM) is the most common primary malignant cancer of the central nervous system. Insufficient oxygenation (hypoxia) has been linked to GBM invasion and aggression, leading to poor patient outcomes. Hypoxia induces gene expression for cellular adaptations. However, GBM is characterized by high intertumoral (molecular subtypes) and intratumoral heterogeneity (cell states), and it is not well understood to what extent hypoxia triggers patient-specific gene responses and cellular diversity in GBM. Here, we surveyed eight patient-derived GBM stem cell lines for invasion phenotypes in 3D culture, which identified two GBM lines showing increased invasiveness in response to hypoxia. RNA-seq analysis of the two patient GBM lines revealed a set of shared hypoxia response genes concerning glucose metabolism, angiogenesis, and autophagy, but also a large set of patient-specific hypoxia-induced genes featuring cell migration and anti-inflammation, highlighting intertumoral diversity of hypoxia responses in GBM. We further applied the Shared GBM Hypoxia gene signature to single cell RNA-seq datasets of glioma patients, which showed that hypoxic cells displayed a shift towards mesenchymal-like (MES) and astrocyte-like (AC) states. Interestingly, in response to hypoxia, tumor cells in IDH-mutant gliomas displayed a strong shift to the AC state, whereas tumor cells in IDH-wildtype gliomas mainly shifted to the MES state. This distinct hypoxia response of IDH-mutant gliomas may contribute to its more favorable prognosis. Our transcriptomic studies provide a basis for future approaches to better understand the diversity of hypoxic niches in gliomas.

Abstract Optical imaging techniques provide low-cost, non-radiative images with high spatiotemporal resolution, making them advantageous for long-term dynamic observation of blood perfusion in stroke research and other brain studies compared to non-optical methods. However, high-resolution imaging in optical microscopy fundamentally requires a tight optical focus, and thus a limited depth of field (DOF). Consequently, large-scale, non-stitched, high-resolution images of curved surfaces, like brains, are difficult to acquire without z-axis scanning. To overcome this limitation, we developed a needle-shaped beam optical coherence tomography angiography (NB-OCTA) system, and for the first time, achieved a volumetric resolution of less than 8 μm in a non-stitched volume space of 6.4 mm × 4 mm × 620 μm in vivo. This system captures the distribution of blood vessels at 3.4-times larger depths than normal OCTA equipped with a Gaussian beam (GB-OCTA). We then employed NB-OCTA to perform long-term observation of cortical blood perfusion after stroke in vivo, and quantitatively analyzed the vessel area density (VAD) and the diameters of representative vessels in different regions over 10 days, revealing different spatiotemporal dynamics in the acute, sub-acute and chronic phase of post-ischemic revascularization. Benefiting from our NB-OCTA, we revealed that the recovery process is not only the result of spontaneous reperfusion, but also the formation of new vessels. This study provides visual and mechanistic insights into strokes and helps to deepen our understanding of the spontaneous response of brain after stroke.

Abstract Background Tumor angiogenesis inhibitors have been applied for non-small cell lung cancer (NSCLC) therapy. However, the drug resistance hinders their further development. Intercellular crosstalk between lung cancer cells and vascular cells was crucial for anti-angiogenenic resistance (AAD). However, the understanding of this crosstalk is still rudimentary. Our previous study showed that Glioma-associated oncogene 1 (Gli1) is a driver of NSCLC metastasis, but its role in lung cancer cell-vascular cell crosstalk remains unclear. Methods Conditioned medium (CM) from Gli1-overexpressing or Gli1-knockdown NSCLC cells was used to educate endothelia cells and pericytes, and the effects of these media on angiogenesis and the maturation of new blood vessels were evaluated via wound healing assays, Transwell migration and invasion assays, tube formation assays and 3D coculture assays. The xenograft model was conducted to establish the effect of Gli1 on tumor angiogenesis and growth. Angiogenic antibody microarray analysis, ELISA, luciferase reporte, chromatin immunoprecipitation (ChIP), bFGF protein stability and ubiquitination assay were performed to explore how Gli1 regulate bFGF expression. Results Gli1 overexpression in NSCLC cells enhanced the endothelial cell and pericyte motility required for angiogenesis required for angiogenesis. However, Gli1 knockout in NSCLC cells had opposite effect on this process. bFGF was critical for the enhancement effect on tumor angiogenesis. bFGF treatment reversed the Gli1 knockdown-mediated inhibition of angiogenesis. Mechanistically, Gli1 increased the bFGF protein level by promoting bFGF transcriptional activity and protein stability. Importantly, suppressing Gli1 with GANT-61 obviously inhibited angiogenesis. Conclusion The Gli1-bFGF axis is crucial for the crosstalk between lung cancer cells and vascular cells. Targeting Gli1 is a potential therapeutic approach for NSCLC angiogenesis.

Abstract The complexity of emotions has thus far limited our understanding of them. To obtain a clear understanding of the nature of emotion, this paper proposes a novel emotion theory and establishes a universal model of the conscious world in the human brain, the substanguage and interaction model (SIM). Based on an analysis of the possibilities of the interaction process in the SIM, two basic emotions that are indecomposable factors within all emotions—hope and fear—are identified. A questionnaire survey reveals that this basic emotion exhibits high acceptability. Based on emotion theory, this paper reasonably explains the phenomena of facial attraction and infantile facial preference and discusses the psychological reasons for phonocentrism, the phenomenon of preferring the spoken word over the written word. In addition, this paper explores the possibility of artificial intelligence possessing self-emotions. Emotions are relevant to many areas of human knowledge, as well as to everyone’s daily lives, and the simple, clear way to understand emotions provided in this paper may be instructive for everyone.

Ga and Ag elements with good biocompatibility are introduced into a Mg–2Zn alloy to design an antibacterial alloy able to inhibit the bacterial infection of bone implants. The effects of Ga/Ag element on the corrosion behavior, cytotoxicity, and antibacterial activity of the as-extruded Mg–2Zn alloy are investigated in vitro. The immersion measurement results show that the mass loss rate of the Mg–2Zn alloy increases from 0.09 ± 0.006 mm/y to 0.24 ± 0.03 mm/y after the addition of 0.5 wt% Ga and 0.5 wt% Ag. This is due to that Ga and Ag elements can increase the cathodic current density and reduce the charge transfer resistance (Rct). Furthermore, Ag is enriched in the Mg7(ZnAg)3 phase, resulting in an increase in the micro-galvanic corrosion and the maximum local corrosion depth. The cytotoxicity tests reveal that Ag and Ga do not induce toxicity to osteoblastic cells (MC3T3-E1) after incubation for 72 h. Moreover, the addition of Ag and Ga increases prominently the antibacterial activity of Mg–2Zn alloys, which is principally associated with the release of Ga and Ag ions and the alkaline antibacterial environment.

Surface modification of magnesium alloys was performed using a coating process to optimize their performance. Friction stir processing for preparing magnesium-based high-entropy alloy coatings effectively addressed issues such as oxidation, pores, cracks, and poor coating quality found in existing processes. In addition, it substantially enhanced the hardness and wear resistance of magnesium alloys. The micro-structure and elemental distribution for the cross-section and surface for the magnesium-based high-entropy alloy coating had been studied. The impact of magnesium-based high-entropy alloy upon hardness and wear resistance of the magnesium alloy had been analyzed, focusing on its favorable forming and binding characteristics. Finally, the heat conduction process during friction stir processing were discussed in detail. The theoretical basis for the preparation of magnesium-based high entropy coatings was improved.

BackgroundMetabolically associated fatty liver disease (MAFLD) insidiously affects people's health, and many models have been proposed for the evaluation of liver fibrosis. However, there is still a lack of noninvasive and sensitive models to screen MAFLD in high-risk populations. ObjectiveThe purpose of this study was to explore a new method for early screening of the public and establish a home-based tool for regular self-assessment and monitoring of MAFLD. MethodsIn this cross-sectional study, there were 1758 eligible participants in the training set and 200 eligible participants in the testing set. Routine blood, blood biochemistry, and FibroScan tests were performed, and body composition was analyzed using a body composition instrument. Additionally, we recorded multiple factors including disease-related risk factors, the Forns index score, the hepatic steatosis index (HSI), the triglyceride glucose index, total body water (TBW), body fat mass (BFM), visceral fat area, waist-height ratio (WHtR), and basal metabolic rate. Binary logistic regression analysis was performed to explore the potential anthropometric indicators that have a predictive ability to screen for MAFLD. A new model, named the MAFLD Screening Index (MFSI), was established using binary logistic regression analysis, and BFM, WHtR, and TBW were included. A simple rating table, named the MAFLD Rating Table (MRT), was also established using these indicators. ResultsThe performance of the HSI (area under the curve [AUC]=0.873, specificity=76.8%, sensitivity=81.4%), WHtR (AUC=0.866, specificity=79.8%, sensitivity=80.8%), and BFM (AUC=0.842, specificity=76.9%, sensitivity=76.2%) in discriminating between the MAFLD group and non-fatty liver group was evaluated (P

Objective: This study aimed to assess the chemopreventive effect of ursodeoxycholic acid (UDCA) against COVID-19 and to analyze infection risk factors, symptoms, and recovery in outpatients with UDCA exposure.Methods: The study enrolled outpatients prescribed UDCA from the Second Affiliated Hospital of Chongqing Medical University, China, between 01 July 2022, and 31 December 2022. Data on demographics, comorbidities, and drug combinations were collected using electronic medical records. COVID-19 infection, symptoms, severity, prognosis, vaccinations, and UDCA administration were surveyed by telephone interviews. UDCA non-users served as controls and were matched in a 1:2 ratio with UDCA users using propensity score matching with the nearest neighbor algorithm. Infection rates, symptomatology, severity, and prognosis were compared between matched and control cohorts, and risk factors and infection and recovery symptoms were analyzed in UDCA-exposed outpatients.Results: UDCA-exposed outpatients (n = 778, 74.8%) and matched UDCA users (n = 95, 74.2%) showed significantly lower SARS-CoV-2 infection rates than control patients (n = 59, 92.2%) (p < 0.05). The matched UDCA group exhibited substantially lower fever, cough, sore throat, and fatigue rates than controls (p < 0.05). Participants with UDCA exposure generally experienced mild symptoms, while those without UDCA had moderate symptoms. The matched UDCA group also had significantly shorter durations of fever and cough (p < 0.05). Risk factors such as age over 60, less than 1 month of UDCA administration, diabetes mellitus, and coronary artery disease significantly increased SARS-CoV-2 infection rates (p < 0.05), while smoking led to a decrease (p < 0.05). Hypertension was associated with a prolonged COVID-19 recovery (p < 0.05), while smoking, vaccination, and fatty liver disease were associated with shorter recovery periods (p < 0.05). The main symptoms in the full UDCA cohort were fever, cough, and sore throat, with fatigue, cough, and hyposthenia being the most persistent.Conclusion: UDCA demonstrated chemopreventive effect against SARS-CoV-2 in outpatients by significantly reducing infection incidence and mitigating COVID-19 symptoms, severity, and recovery duration. Old age, short UDCA course, and comorbidities such as diabetes mellitus and CAD increased infection rates, while hypertension prolonged recovery. Smoking, vaccination, and fatty liver disease reduced infection rates and shortened recovery. UDCA had minimal impact on symptom types. Larger and longer-term clinical studies are needed further to assess UDCA’s effectiveness in COVID-19 prevention or treatment.

Total thrust and torque are two key indicators of shield movement performance. Most existing data-driven machine learning studies focus on developing more accurate models for predicting total thrust and torque but overlook the interpretability of the models. To address this black-box issue, this study proposes an interpretable probabilistic prediction algorithm for the shield movement performance. The algorithm uses the natural gradient boosting (NGBoost) model to iteratively update the parametric probability distributions (e.g., mean and variance) and achieve probabilistic predictions of the total thrust and torque. The impact of each feature on the prediction values and uncertainty is quantified by extending the importance analysis of a single deterministic predictive value to both the mean and variance. The feature interactions are analyzed and their predictive contributions are quantified by the shapley additive explanations (SHAP) method. The transparency of the NGBoost model is improved through the visualization of the decision-making process. A shield tunneling project in Hangzhou is used to validate the effectiveness of the proposed algorithm. The results indicate that the NGboost model outperforms other five models in terms of accuracy. The prediction results are interpretable, and the interpretable probabilistic model provides decision-makers with a more intuitive and reliable reference.

In this study, we investigate the enhancement of effective transconductance and gain linearity in submicrometer gate AlGaN-barrier-based transistors utilizing ScAlN/GaN coupling-channel structures. A novel asymmetric gate design, incorporating an AlGaN cap on ScAlN/GaN HEMT, is proposed. This configuration demonstrates a flat transconductance profile and significantly reduced transconductance derivative, thereby improving the linearity of GaN-based transistors. For transistors with a gate length of 0.5 μm, both the current gain cut-off frequency and power gain cut-off frequency are measured at 53.52 GHz and 72.98 GHz, respectively. These values represent a more than threefold increase from the corresponding frequencies of conventional devices. Moreover, the theoretical Output Third-Order Intercept value of the proposed structure has increased by 7.5 dBm compared to conventional HEMTs. This superior linear performance can be attributed to the combined effect of AlGaN cap layer and air cavity. Furthermore, the introduction of the ScAlN layer results in a substantial impact, including a decrease in electron concentration from 4.96 × 1019/cm3 to 1.98 × 1019/cm3 and an increase in electron velocity from 4.5 × 107 to 7.6 × 108 cm/s. These findings underscore the potential of the proposed device for high-frequency applications requiring superior linearity.

PoRVA and PEDV coinfections are extremely common in clinical practice. Although coinfections of PoRVA and PEDV are known to result in increased mortality, the underlying mechanism remains unknown. Here, we found that PoRVA infection promoted PEDV infection in vivo and in vitro and that PoRVA G9P[23] (RVA-HNNY strain) enhanced PEDV replication more significantly than did PoRVA G5P[7] (RVA-SXXA strain). Metabolomic analysis revealed that RVA-HNNY more efficiently induced an increase in the intracellular glutamine content in porcine small intestinal epithelial cells than did RVA-SXXA, which more markedly promoted ATP production to facilitate PEDV replication, whereas glutamine deprivation abrogated the effect of PoRVA infection on promoting PEDV replication. Further studies showed that PoRVA infection promoted glutamine uptake by upregulating the expression of the glutamine transporter protein SLC1A5. In SLC1A5 knockout cells, PoRVA infection neither elevated intracellular glutamine nor promoted PEDV replication. During PoRVA infection, the activity and protein expression levels of glutamine catabolism-related enzymes (GLS1 and GLUD1) were also significantly increased promoting ATP production through glutamine anaplerosis into the TCA cycle. Consistent with that, siRNAs or inhibitors of GLS1 and GLUD1 significantly inhibited the promotion of PEDV replication by PoRVA. Notably, RVA-HNNY infection more markedly promoted SLC1A5, GLS1 and GLUD1 expression to more significantly increase the uptake and catabolism of glutamine than RVA-SXXA infection. Collectively, our findings illuminate a novel mechanism by which PoRVA infection promotes PEDV infection and reveal that the modulation of glutamine uptake is key for the different efficiencies of PoRVA G9P[23] and PoRVA G5P[7] in promoting PEDV replication.

Background: A new minimally invasive technique, ultrasound-guided thermal ablation has become one of the treatment methods for benign thyroid nodules. This study aims to evaluate the efficacy and safety of laser ablation (LA), radiofrequency ablation (RFA), and microwave ablation (MWA) in the treatment of elderly patients with benign thyroid nodules. Methods: PubMed, Web of Science, and Cochrane Library were searched for qualified randomized controlled studies (RCTs) issued from establishing databases to March 2022. After screening and evaluating the article quality, the data on nodular volume reduction rate (VRR) and the incidence of complications after thermal ablation were extracted and analyzed by RevMan 5.3 and Stata l4.0. Results: The meta-analysis included seven articles with 3055 participants. We found that LA, RFA, and MWA could markedly reduce the volume of benign thyroid nodules. LA was superior to RFA and MWA in reducing the volume of benign thyroid nodules in 6 months of follow-up (all P

Abstract Whole-exome sequencing (WES) is widely used to diagnose complex genetic diseases and rare conditions. The implementation of a robust and effective quality control system for sample identification and tracking throughout the WES process is essential. We established a multiplex panel that included 22 coding single-nucleotide polymorphism (cSNP) loci. The personal identification and paternity identification abilities of the panel were evaluated, and a preliminary validation of the practical feasibility of the panel was conducted in a clinical WES case. These results indicate that the cSNP panel could be a useful tool for sample tracking in WES.

Abstract Heritage holds significant historical, cultural, or natural value. GIS technology integrates spatial and attribute data of heritage sites, providing a powerful modern tool for better understanding, preservation, and management of heritage resources. To reveal the progress and trends in GIS applications in heritage studies (GIS-Heritage), this study collected and analyzed 1026 relevant research articles published between 1994 and 2023 from the Web of Science database. The analysis was conducted using the VOSviewer software for bibliometric and visualization analysis. The results demonstrated that Italy has made the largest contributions in the field of GIS-Heritage. There exists a close collaboration among research institutions. Journals like the Journal of Cultural Heritage played crucial roles. The most influential authors include Brown, Agapiou, and Nicu. The key research themes identified encompass cultural heritage, GIS, sustainable development, spatial analysis, archaeology, conservation, and photogrammetry. Based on the findings of the bibliometric analysis, this paper puts forward future research recommendations in the field of GIS-Heritage, focusing on data integration, technological innovation, as well as interdisciplinary and international collaboration.

Two new marine nematode species belonging to the order Monhysterida are described from the sea of China. Halomonhystera zhangi sp. nov. is characterized by its relatively small body size; short anterior sensory setae; small, circular amphidial fovea located at the level of buccal cavity base; funnel-shaped buccal cavity; an excretory-secretory system with a large ventral gland and opening as a very narrow canal just posterior to the level of cephalic setae; slightly curved slender spicules with cephalated proximal end and tapered distal end; rod-like gubernaculum without apophysis; two papilliform precloacal supplements just in front of the cloaca; conico-cylindrical tail with two ventral papillae, each with a seta; and distance between the vulva and anus slightly longer than the tail length. This is the first new species of epiphytic nematode reported in China. The second new species, Stylotheristus flagellicaudatus sp. nov., has a relatively shorter body and longer tail; striated cuticle; The anterior sensilla arranged in two circles, the first circle consisting of six inner labial setiform papillae (3–4 µm) and the second circle consisting of 16 long setae (12–19 µm); a transversely oval amphideal fovea; a well-developed muscle around the funnel-shaped buccal cavity; short spicules and a gubernaculum composed of a single piece; and precloacal supplements absent. An updated key to all species of Halomonhystera and pictorial key to all species of Stylotheristus are also given.

A new species of the genus Leptobrachella, L. guinanensis sp. nov., is described in this study based on morphological, molecular, and bioacoustic data. The species was discovered in the Shiwandashan National Nature Reserve in Shangsi County, Guangxi, China. Phylogenetically, L. guinanensis sp. nov. is closely related to L. ventripunctata. However, there are distinct morphological differences between L. guinanensis sp. nov. and L. ventripunctata, as well as three other sympatric species (L. shangsiensis, L. shiwandashanensis, and L. sungi). These differences include body size (SVL 30.5–32.5 mm in males; 38.7–41.8 mm in females in the new species vs 25.5–28.0 mm in males, 31.5–35.0 mm in females in L. ventripunctata), the absence of brown spots on the ventral surface (vs chest and belly creamy white with many scattered brown spots in L. ventripunctata), 1/3 toe webbing and wide toe lateral fringes (vs no toe webbing and no lateral fringes in L. ventripunctata), and distinct dermal ridges under toes (vs absent in L. ventripunctata). Furthermore, the dominant vocal frequencies of the new species range from 7.3 to 8.3 kHz, which is unique compared to other Leptobrachella species and represents the highest dominant frequencies ever recorded. The Shiwandashan National Nature Reserve is now home to four known sympatric species of Leptobrachella.

Background: To compare the efficacy of Three-scope combined (laparoscopic, rigid choledochoscopy and electronic choledochoscopy, TS) with laparoscopic hepatectomy (LH) for patients with hepatolithiasis (HL). Methods: Between January 2019 and January 2020, 118 consecutive patients with HL treated with TS (TS group, n = 57) or LH (LH group, n = 61) were analyzed in this study. Perioperative and long-term outcomes, including operative time, intraoperative blood loss, blood transfusion, postoperative bowel function recovery time, postoperative hospital stay, complication rate, stone removal rate, and stone recurrence rate, were compared and analyzed between the two groups. Results: Compared with the LH group, the TS group had significantly lower intraoperative blood loss and transfusions, significantly shorter operative time and hospital stay, and fewer complications (P 0.05 for all). Conclusion: TS is a safe and effective treatment for HL and is superior to LH in terms of overall treatment outcome and complications.

Abstract Background The first local outbreak of Delta Variant B.1.617.2 COVID-19 of China occurred in Guangzhou city, south China, in May 2021. This study analyzed the transmission chains and local cluster characteristics of this outbreak, intended to provide information support for the development and adjustment of local prevention and control strategies. Methods The transmission chains and local cluster characteristics of 161 local cases in the outbreak were described and analyzed. Incubation period, serial interval and generation time were calculated using the exact time of exposure and symptom onset date of the cases. The daily number of reported cases and the estimated generation time were used to estimate the effective reproduction number (Rt). Results We identified 7 superspreading events who had more than 5 next generation cases and their infected cases infected 70.81%(114/161) of all the cases transmission. Dining and family exposure were the main transmission routes in the outbreak, with 29.19% exposed through dining and 32.30% exposed through family places. Through further analysis of the outbreak, the estimated mean incubation period was 4.22 (95%CI: 3.66–4.94) days, the estimated mean generation time was 2.60 (95%CI: 1.96–3.11) days, and the estimated Rt was 3.29 (95%CI: 2.25–5.07). Conclusions Classification and dynamically adjusted prevention and control measures had been carried out according to analysis of transmission chains and epidemical risk levels, including promoting nucleic acid screening at different regions and different risk levels, dividing closed-off area, controlled area according to the risk of infection, raising the requirements of leaving Guangzhou. By the above control measures, Guangzhou effectively control the outbreak within 28 days without implementing a large-scale lockdown policy.

Abstract We report an organocatalyst that combines a triazolium N-heterocyclic carbene (NHC) with a squaramide as a hydrogen-bonding donor (HBD), which can effectively catalyze the atroposelective ring-opening of biaryl lactams via a unique amide C–N bond cleavage mode. The free carbene species attacks the amide carbonyl, forming an axially chiral acyl-azolium intermediate. Various axially chiral biaryl amines can be accessed by this methodology with up to 99% ee and 99% yield. By using mercaptan as a catalyst turnover agent, the resulting thioester synthon can be transformed into several interesting atropisomers. Both control experiments and theoretical calculations reveal the crucial role of the hybrid NHC-HBD skeleton, which activates the amide via H-bonding and brings it spatially close to the carbene centre. This discovery illustrates the potential of the NHC-HBD chimera and demonstrates a complementary strategy for amide bond activation and manipulation.

Abstract Background High-performance total hip arthroplasty (THA) depends on the accurate position of components. However, femoral anteversion is variable, and current studies only used traditional instruments to evaluate it, such as protractor and spirit level with limited cases. This study aimed to identify the variability in the measured femoral native anteversion and intraoperative stem anteversion under different measurement methods, including intraoperative robotic method. We hypothesized that robotic technology was more accurate than traditional instruments for femoral anteversion evaluation. Methods This study included 117 hips of patients who underwent robotic-assisted THA between November 2019 and March 2021. Preoperative native femoral anteversion was measured using a robotic system. Intraoperative femoral stem anteversion was evaluated visually, and then measured with a goniometer and a robotic system, respectively. Variability in the measured femoral native anteversion and intraoperative femoral stem anteversion was calculated and compared. Intraclass correlation coefficient (ICC) and Pearson correlation analysis were used to assess the consistency and correlation of anteversion of different measurements and postoperative CT-measured stem anteversion, respectively. Results The result of measurement for preoperative native femoral anteversion was more variable than the intraoperative robotic-measured stem anteversion. Intraoperative robotic-measured stem version showed the highest correlation with postoperative CT measurement of stem version (r = 0.806, P

Calotes wangi sp. nov., a new species of the agamid genus Calotes Cuvier, 1817, from southern China and northern Vietnam, is described. This species can be distinguished from all known congeners by a combination of morphological characteristics and genetic divergence in the mitochondrial tRNA, ND2, and CO1 genes. Molecular phylogenetic analysis revealed that the new species was formed as a monophyletic group and that considerable genetic divergence existed between its congeners (minimum p-distance, 4.6%). Calotes wangi sp. nov. is distinguished by a combination of the following characteristics: average SVL < 90 mm for adult males; 10–14 dorsal eyelid scales; scales on side of neck and adjacent shoulder area pointing obliquely upward; keels on neck scales weakly to strongly developed; fold in front of the shoulder absent; pair of dark triangular patches extending from the front of the shoulder to the jaw angles; and orange coloration of the tongue. Calotes wangi sp. nov. is similar to C. irawadi but differs in having scales between the nasal shield and the orbit and a fourth toe with a claw that can reach between the eyes and tympanum (even to the snout when hind the limbs are adpressed forward). Phylogenetic analyses revealed two well-supported subspecies, Lineages A and B in C. wangi sp. nov., with mean uncorrected p-distances between them of 2%. We propose that Lineage A, which is mainly from the central and southern Wuzhi Mountains on Hainan Island, is a subspecies, C. w. hainanensis ssp. nov. Lineage B mainly comprises individuals from other sites on the island plus the adjacent mainland, and is described as subspecies, C. w. wangi ssp. nov. A diagnostic key to all Calotes species of China is also provided.

Abstract Tailoring vacancies is a feasible way to improve the mechanical properties of ceramics. However, high concentrations of vacancies usually compromise the strength (or hardness). We show that a high elasticity and flexural strength could be achieved simultaneously using a nitride superlattice architecture with disordered anion vacancies up to 50%. Enhanced mechanical properties primarily result from a distinctive deformation mechanism in superlattice ceramics, i.e., unit-cell disturbances. Such a disturbance substantially relieves local high-stress concentration, thus enhancing deformability. No dislocation activity involved also rationalizes its high strength. The work renders a unique understanding of the deformation and strengthening/toughening mechanism in nitride ceramics.

Abstract Background Bone mineral density (BMD) is important for the outcome of cervical spine surgery. As the gold standard of assessing BMD, dual-energy X-ray absorptiometry scans are often not ordered or go unreviewed in patients’ charts. As the supplement, MRI-based vertebral bone quality (VBQ) was found to accurately predict osteopenia/osteoporosis and postoperative complications in lumbar spine. However, discussion of the efficiency of VBQ in cervical spine is lacking. And measurement methods of VBQ in cervical spine are diverse and not universally acknowledged like lumbar spine. We aimed to compare the predictive performance of three kinds of different Cervical-VBQ (C-VBQ) scores for bone mineral density assessment in patients undergoing cervical spine surgery. HU value of cervical spine was set as a reference. Methods Adult patients receiving cervical spine surgery for degenerative diseases were retrospectively included between Jan 2015 and Dec 2022 in our hospital. The VBQ scores and HU value were measured from preoperative MRI and CT. The correlation between HU value/C-VBQs (named C-VBQ1/2/3 according to different calculating methods) and DEXA T-score was analyzed using univariate linear correlation and Pearson’s correlation. We evaluated the predictive performance of those two parameters and achieved the most appropriate cutoff value by comparing the receiver operating characteristic (ROC) curves. Results 106 patients (34 patients with T ≥ − 1.0 vs 72 patients with T

Abstract Objective: Inflammation plays a critical role in the progression of chronic liver diseases, and diet can modulate inflammation. Whether an inflammatory dietary pattern is associated with higher risk of hepatic steatosis or fibrosis remains unclear. We aimed to investigate the associations between inflammatory dietary pattern and the odds of hepatic steatosis and fibrosis. Design: In this nationwide cross-sectional study, diet was measured using two 24-h dietary recalls. Empirical dietary inflammatory pattern (EDIP) score was derived to assess the inflammatory potential of usual diet, which has been validated to highly predict inflammation markers in the study population. Controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) were derived from FibroScan to define steatosis and fibrosis, respectively. Setting: US National Health and Nutrition Examination Survey. Participants: 4171 participants aged ≥18 years. Results: A total of 1436 participants were diagnosed with S1 steatosis (CAP ≥ 274 dB/m), 255 with advanced fibrosis (LSM ≥ 9·7 kPa). Compared with those in the lowest tertile of EDIP-adherence scores, participants in the highest tertile had 74 % higher odds of steatosis (OR: 1·74, 95 % CI (1·26, 2·41)). Such positive association persisted among never drinkers, or participants who were free of hepatitis B and/or C. Similarly, EDIP was positively associated with CAP in multivariate linear model (P < 0·001). We found a non-significant association of EDIP score with advanced fibrosis or LSM (P = 0·837). Conclusions: Our findings suggest that a diet score that is associated with inflammatory markers is associated with hepatic steatosis. Reducing or avoiding pro-inflammatory diets intake might be an attractive strategy for fatty liver disease prevention.

Background: Osteoarthritis (OA) is a chronic joint disease characterized by degeneration of the articular cartilage or inflamed joints. Britanin is a guaiacyl-type sesquiterpene lactone possessing anti-inflammatory and antioxidant activities. Methods: In this study, western blotting, Reverse-transcription PCR (RT-PCR), and immunofluorescent staining method were used to clarifying the molecular mechanisms of britanin in alleviating chondrocyte ferroptosis. The effect of britanin on reactive oxygen species (ROS) and lipid peroxidation levels in chondrocytes was examined by Dihydroethidium (DHE) stain and fluorescent dye BODIPY581 / 591 C11. The destabilized medial meniscus (DMM) model was used to mimic OA, then britanin was injected into the knee articular cavity. The morphological analysis was performed by hematoxylin and eosin (H&E) staining, Safranin O-Fast green staining and Micro-computed tomography (Micro-CT) analysis. Immunohistochemical analysis and Immunofluorescence assay was conducted to verify the effect of britanin in vivo. Results: The results revealed that britanin treatment regulates the expression of chondrocyte extracellular matrix–related factors, such as ADAMTS5, MMP13, SOX9, aggrecan, and COL2A1. Britanin also significantly reversed the influence of interleukin (IL)-1β on the levels of reactive oxygen species and lipid peroxidation and upregulated glutathione peroxidase 4 (GPX4) expression in IL-1β-induced chondrocytes. Erastin could alleviate the effects of britanin on chondrocytes. Moreover, britanin could prevent IL-1β-induced oxidative stress and ferroptosis in chondrocytes. Britanin also upregulated the expression of nuclear factor E2–related factor 2 (Nrf2) in IL-1β-induced chondrocytes, and Nrf2 activator played a similar role as that of britanin in IL-1β-induced chondrocytes. Furthermore, injecting britanin into the knee joints of OA rats alleviated cartilage destruction caused by surgical resection. Conclusions: These findings confirmed that britanin can inhibit ferroptosis in OA chondrocytes through the Nrf2-GPX4 pathway. Thus, britanin has the potential to be developed as a drug for OA therapy.

ABSTRACT: The S2 subunit of infectious bronchitis virus (IBV) is a heavily glycosylated protein that can impact various characteristics of the virus. It is currently known that N-glycosylation modifications are predominantly located on the S2 subunit. However, the exact role of their N-glycosylation modification remains undisclosed. To elucidate the function of these N-glycosylation sites, we identified 14 common sites distributed on the S2 subunit of the 5 genotypes of IBV in present study. Subsequently, we selected 7 sites to generate mutants and assessed their impact on viral virulence, replication ability, and antigenicity. Our finding revealed that only 2 substitutions, N545S and K717N, increased the viral replication titer and antigenicity, and ultimately the pathogenicity in chicks. To delve into the mechanisms underlying this increased pathogenicity, we discovered that K717N can change the structure of antigenic epitopes. The N545S substitution not only influenced antigenic epitope structure, but also enhanced the ability of the virus to enter CEKs during the early stages of viral replication. These results suggest that the enhanced viral pathogenicity associated with N545S and K717N substitutions is multifaceted, with acceleration of the viral membrane fusion process and alterations in epitope structure representing crucial factors in the capability of N-glycosylation modifications to boost viral virulence. These insights provide valuable guidance for the efficient development of live attenuated vaccines.

Background: The application of sentinel lymph node biopsy (SLNB) has expanded from early breast cancer to locally advanced breast cancer with neoadjuvant chemotherapy (NAC). For patients with negative axillary lymph nodes, performing SLNB before or after NAC remains controversial. Objectives: To evaluate the diagnostic feasibility and reliability of SLNB after NAC in breast cancer patients with negative axillary nodes at initial diagnosis. Design: To calculate pooled identification rate (IR) and false negative rate (FNR) of SLNB after NAC on breast cancer patients with initially negative axillary nodes by enrolling relevant studies and perform subgroup analysis by the type of tracer and the number of biopsied sentinel lymph nodes in average. Data sources and methods: The PubMed, Embase, Cochrane, Web of Science, and Scopus databases from January 1, 2002, to March 1, 2022, were searched for studies. The QUADAS-2 tool and MINORS item were employed to evaluate the quality of the included studies. I 2 and Q tests were used to evaluate the heterogeneity among the studies. Random-effects model and fixed-effects model were employed to calculate the pooled IR, FNR, and 95% confidence interval (CI). Publication bias was evaluated, and sensitivity analysis was performed. Subgroup analysis was performed according to the type of tracer (single/double) and the number of biopsied sentinel lymph nodes in average (⩽2/>2). Results: A total of 21 studies covering 1716 patients were enrolled in this study (IR = 93%, 95% CI = 90-96; FNR = 8%, 95% CI = 6-11). Conclusion: The SLNB after NAC can serve as a feasible and reliable approach in breast cancer patients with negative axillary lymph node. In our study, no significant impact of tracer was found on the IR and FNR of SLNB, and the number of biopsy nodes >2 leads to the decreased FNR of SLNB.

BackgroundLaparoscopic left hemihepatectomy (LLH) is commonly used for benign and malignant left liver lesions. We compared the benefits and drawbacks of LLH from the head side approach (LLHH) with those of conventional laparoscopic left hemihepatectomy (CLLH). This study was conducted to investigate the safety and feasibility of LLHH by comparing it with CLLH.MethodsIn this study, 94 patients with tumor or hepatolithiasis who underwent LLHH (n = 39) and CLLH (n = 55) between January 2016 and January 2023 were included. The preoperative features, intraoperative details, and postoperative outcomes were compared between the two groups.ResultsFor hepatolithiasis, patients who underwent LLHH exhibited shorter operative time (p = 0.035) and less blood loss (p = 0.023) than those who underwent CLLH. However, for tumors, patients undergoing LLHH only showed shorter operative time (p = 0.046) than those undergoing CLLH. Moreover, no statistically significant differences in hospital stay, transfusion, hospital expenses, postoperative white blood cell (WBC) count, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were observed between the two groups (p > 0.05) for tumor or hepatolithiasis. For hepatocellular carcinoma (HCC), no differences in both overall survival (p = 0.532) and disease-free survival (p = 0.274) were observed between the two groups.ConclusionLLHH is a safe and feasible surgical procedure for tumors or hepatolithiasis of the left liver.

Existing studies on soil-pipe interaction due to tunneling mainly focus on short-term responses. However, in areas with high water tables and low permeability soil, long-term ground movement and associated pipe responses may occur due to dissipation of excess pore pressure generated during tunnel construction. In this paper, a Winkler solution with time-varying subgrade modulus and the corresponding greenfield soil displacement formula are developed to investigate the tunneling effects on existing pipelines. The pipe is considered as an infinite Euler beam of finite width resting on a poroelastic half-space, and adhesion and drainage effects between the pipe and soil are considered using bounding techniques. The greenfield consolidation settlement is evaluated using a modified Gaussian curve. The findings indicate that the subgrade modulus decreases while greenfield soil displacement increases during the consolidation process. The time-dependent behavior of the subgrade modulus is governed by the drainage condition at the pipe-soil interface, whereas the greenfield soil displacement is primarily influenced by the drainage condition at the tunnel-soil interface. The study reveals that the bonded contact condition, hydraulic boundary condition, and displacement constraint conditions all influence the bending moment of the pipe.

Exosomes are extracellular vesicles comprising bilayer phospholipid membranes and are secreted by eukaryotic cells. They are released via cellular exocytosis, contain DNA, RNA, proteins, and other substances, and participate in various cellular communications between tissues and organs. Since the discovery of exosomes in 1983, animal-derived exosomes have become a research focus for small-molecule drug delivery in biology, medicine, and other fields owing to their good biocompatibility and homing effects. Recent studies have found that plant-derived exosome-like nanovesicles (PELNVs) exhibit certain biological effects, such as anti-inflammatory and anti-tumor abilities, and have minimal toxic side effects. Because they are rich in active lipid molecules with certain pharmacological effects, PELNVs could be novel carriers for drug delivery. In this review, the biological formation and effects, isolation, and extraction of PELNVs, as well as characteristics of transporting drugs as carriers are summarized to provide new ideas and methods for future research on plant-derived exosome-like nanovesicles.

Among the Acinetobacter genus, Acinetobacter pittii stands out as an important opportunistic infection causative agent commonly found in hospital settings, which poses a serious threat to human health. Recently, the high prevalence of carbapenem-resistant A. pittii isolates has created significant therapeutic challenges for clinicians. Bacteriophages and their derived enzymes are promising therapeutic alternatives or adjuncts to antibiotics effective against multidrug-resistant bacterial infections. However, studies investigating the depolymerases specific to A. pittii strains are scarce. In this study, we identified and characterized a capsule depolymerase, Dpo27, encoded by the bacteriophage IME-Ap7, which targets A. pittii. A total of 23 clinical isolates of Acinetobacter spp. were identified as A. pittii (21.91%, 23/105), and seven A. pittii strains with various K locus (KL) types (KL14, KL32, KL38, KL111, KL163, KL207, and KL220) were used as host bacteria for phage screening. The lytic phage IME-Ap7 was isolated using A. pittii 7 (KL220) as an indicator bacterium and was observed for depolymerase activity. A putative tail fiber gene encoding a polysaccharide-degrading enzyme (Dpo27) was identified and expressed. The results of the modified single-spot assay showed that both A. pittii 7 and 1492 were sensitive to Dpo27, which was assigned the KL220 type. After incubation with Dpo27, A. pittii strain was susceptible to killing by human serum; moreover, the protein displayed no hemolytic activity against erythrocytes. Furthermore, the protein exhibited sustained activity across a wide pH range (5.0–10.0) and at temperatures between 20 and 50°C. In summary, the identified capsule depolymerase Dpo27 holds promise as an alternative treatment for combating KL220-type A. pittii infections.

Aim: Disturbed intestinal microbiota has been implicated in the inflammatory microenvironment of the colon, which usually results in ulcerative colitis (UC). Given the limitations of these drugs, it is important to explore alternative means of protecting the gut health from UC. This study aimed to investigate the potential of polysaccharides as beneficial nutrients in the regulation of the gut microbiota, which determines the inflammatory microenvironment of the colon. Materials and methods: Mice were treated with dextran sulfate sodium (DSS) to evaluate the effects and mechanisms of Lycium barbarum polysaccharide (LBP) in remodeling the inflammatory microenvironment and improving gut health. Body weight and disease activity indices were monitored daily. Hematoxylin and eosin staining was used to analyze colon dynamics. The levels of inflammatory indicators and expression of MUC-2, claudin-1, ZO-1, and G-protein-coupled receptor 5 (TGR5) were determined using assay kits and immunohistochemistry, respectively. 16S rRNA high-throughput sequencing of the intestinal microbiota and liquid chromatography-tandem mass spectrometry for related bile acids were used. Results: LBP significantly improved the colonic tissue structure by upregulating MUC-2, claudin-1, and ZO-1 protein expression. The bacterial genus Dubosiella was dominant in healthy mice, but significantly decreased in mice treated with DSS. LBP rehabilitated Dubosiella in the sick guts of DSS mice to a level close to that of healthy mice. The levels of other beneficial bacterial genera Akkermansia and Bifidobacterium were also increased, whereas those of the harmful bacterial genera Turicibacter, Clostridium_sensu_stricto_1, Escherichia-Shigella, and Faecalibaculum decreased. The activity of beneficial bacteria promoted the bile acids lithocholic and deoxycholic acids in mice with UC, which improved the gut barrier function through the upregulation of TGR5. Conclusion: The inflammatory microenvironment in the gut is determined by the balance of the gut microbiota. LBP showed great potential as a beneficial nutrient for rehabilitating Dubosiella which is dominant in the gut of healthy mice. Nutrient-related LBP may play an important role in gut health management.

Abstract Although natural products are essential sources of small‐molecule antitumor drugs, some can exert substantial toxicities, limiting their clinical utility. Anthraquinone‐fused enediyne natural products are remarkably potent antitumor drug candidates, and uncialamycin and tiancimycin (TNM) A are under development as antibody‐drug conjugates. Herein, a novel drug delivery system is introduced for TNM A using anti‐human epidermal growth factor receptor 2 (HER2) immunoliposomes (ILs). Trastuzumab‐coated TNM A‐loaded ILs (HER2‐TNM A‐ILs) is engineered with an average particle size of 182.8 ± 2.1 nm and a zeta potential of 1.75 ± 0.12 mV. Compared with liposomes lacking trastuzumab, HER2‐TNM A‐ILs exhibited selective toxicity against HER2‐positive KPL‐4 and SKBR3 cells. Coumarin‐6, a fluorescent TNM A surrogate, is encapsulated within anti‐HER2 ILs; the resultant ILs have enhanced cellular uptake in KPL‐4 and SKBR3 cells when compared with control liposomes. Furthermore, ILs loaded with more Cy5.5 accumulated in KPL‐4 mouse tumors. A single HER2‐TNM A‐IL dose (0.02 mg kg−1) suppressed the growth of HER2‐positive KPL‐4 mouse tumors without apparent toxicity. This study not only provides a straightforward method for the effective delivery of TNM A against HER2‐positive breast tumors but also underscores the potential of IL‐based drug delivery systems when employing highly potent cytotoxins as payloads.