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Hao Duan,1,* Zhen-Qiang He,1,* Cheng-Cheng Guo,1 Jue-Hui Li,1 Jian Wang,1 Zhe Zhu,2 Ke Sai,1 Zhong-Ping Chen,1 Xiao-Bing Jiang,1 Yong-Gao Mou1 1Department of Neurosurgery/Neuro-Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; 2Department of Medicine, Division of Regenerative Medicine, University of California, San Diego, School of Medicine, La Jolla, CA, USA *These authors contributed equally to this work Purpose: The presence of brain metastasis (BM) in patients with colorectal cancer (CRC) is usually associated with terminal-stage illness; however, a subgroup of patients receiving aggressive treatment can have a satisfactory prognosis. This study was designed to investigate the profile of prognostic factors in CRC patients with BM treated aggressively. Patients and methods: CRC patients with BM were retrospectively reviewed. Survival analysis was performed to identify potential prognostic factors in the entire cohort of patients and a subgroup of patients treated aggressively. Aggressive treatments included surgical resection, radiotherapy, and/or chemotherapy. Overall survival was defined as the time between the diagnosis of BM and death or until the date of the last follow-up visit. Results: A total of 78 CRC patients were confirmed as having BM. Sixty-eight of them had extracranial metastases at the time of their BM diagnosis. The most common sites of extracranial metastases were lung (n=51, 65.4%), followed by liver (n=25, 32.1%) and bone (n=12, 15.4%). Fifty-one patients who were treated aggressively had significantly longer overall survival than those who accepted palliative care (14.1 months vs 2.0 months, P

Jun Chen,1,* Guo-jun Yan,1,* Rong-rong Hu,1 Qian-wen Gu,1 Ming-lei Chen,1 Wei Gu,1 Zhi-peng Chen,1 Bao-chang Cai1,2 1College of Pharmacy, 2Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China *These authors contributed equally to this projectObjective: Brucine was encapsulated into stealth liposomes using the ammonium sulfate gradient method to improve therapeutic index.Materials and methods: Four brucine stealth liposomal formulations were prepared, which were made from different phosphatidylcholines (PCs) with different phase transition temperatures (Tm). The PCs used were soy phosphatidylcholine (SPC), dipalmitoyl phosphatidylcholine (DPPC), hydrogenated soy phosphatidylcholine (HSPC), and distearoyl phosphatidylcholine (DSPC). The stabilities, pharmacokinetics, and toxicities of these liposomal formulations were evaluated and compared.Results: Size, zeta potential, and entrapment efficiency of brucine-loaded stealth liposomes (BSL) were not influenced by PC composition. In vitro release studies revealed that drug release rate increased with decreased Tm of PCs, especially with the presence of rat plasma. After intravenous administration, the area under the curve (AUC) values of BSL-SPC, BSL-DPPC, BSL-HSPC, and BSL-DSPC in plasma were 7.71, 9.24, 53.83, and 56.83-fold as large as that of free brucine, respectively. The LD50 values of brucine solution, BSL-SPC, BSL-DPPC, BSL-HSPC, and BSL-DSPC following intravenous injection were 13.17, 37.30, 37.69, 51.18, and 52.86 mg/kg, respectively. It was found in calcein retention experiments that the order of calcein retention in rat plasma was SPC < DPPC << HSPC < DSPC stealth liposomes.Conclusion: PC composition could exert significant influence on the stabilities, pharmacokinetics, and toxicities of brucine-loaded stealth liposomes. DSPC or HSPC with Tm above 50°C should be used to prepare the stealth liposomal formulation for the intravenous delivery of brucine. However, it was found in the present paper that the pharmacokinetics and toxicity of BSL were not influenced by the PC composition when the Tm of the PC was in the range of –20°C to 41°C.Keywords: brucine, stealth liposomes, phosphatidylcholine, pharmacokinetics, toxicity

Abstract Monodisperse magnetic nanoparticles (MNPs) were synthesized by thermal decomposition of iron-oleate and functionalized with silanes bearing various functional groups such as amino group (NH2), short-chain poly(ethylene glycol) (PEG), and carboxylic group (COOH). Then, silanes-functionalized magnetic nanoparticles (silanes-MNPs) were incubated in cell culture medium plus fetal calf serum to investigate the effects of proteins from culture medium on surface property of MNPs. Zeta potential measurements showed that although surface charges of silanes-MNPs were different, they exhibited negative charges at neutral pH and approximate isoelectric points after they were incubated in cell culture medium. The reason was that silanes-MNPs could easily adsorb proteins from culture medium via non-covalent binding, resulting in the formation of protein-silanes-MNPs conjugates. Moreover, silanes-MNPs with various functional groups had different adsorption capacity to proteins, as confirmed by Coomassie blue fast staining method. The in vitro cell experiments showed that protein-silanes-MNPs had higher cellular uptake by cancer cells than silanes-MNPs.

Abstract Collapse of the edge flow shear as the line-averaged density approaches the Greenwald density limit has been observed as a precursor to the enhanced edge particle flux characteristic of proximity to the density limit regime. Here, we report the use of a biased electrode to sustain the edge shear layer in high density discharges, in which the shear layer would otherwise collapse. A stable increase in line-averaged density is observed along with a strong increase in edge density. These experiments were carried out on the J-TEXT tokamak. The Reynolds stress at the edge is enhanced, and the zonal flow sustained, while density perturbation levels, the flux of turbulence internal energy (i.e., turbulence spreading), and particle and heat flux all decrease significantly. Electron adiabaticity increases, and bias voltage modulation experiments show that an increase in the edge shear leads the increase in adiabaticity. These results suggest that external edge E × B flow shear drive may be of interest for sustaining edge plasma states at high density, and support the hypothesis that collapse of the edge shear layer triggers the onset of the strong transport and turbulence characteristic of the density limit regime.

Enhanced particle transport events are discovered and analyzed as the density limit of the J-TEXT tokamak is approached. Edge shear layer collapse is observed and the ratio of Reynolds power to turbulence production decreases. Simultaneously, the divergence of turbulence internal energy flux (i.e. turbulence spreading) increases, indicating that shear layer collapse triggers an outward spreading event. Studies of correlations show that the enhanced particle transport events are quasi-coherent, and manifested primarily in density fluctuations which exhibit positive skewness. Electron adiabaticity emerges as the critical parameter which signals transport event onset. For α < 0.35 as density approaches the Greenwald density, both turbulence spreading and density fluctuations rise rapidly. Taken together, these results elucidate the connections between edge shear layer, density fluctuations, particle transport events, turbulence spreading and plasma edge cooling as the density limit is approached.

Enhancements of residual Reynolds stresses and symmetry breaking with resonant magnetic perturbations (RMPs) are presented. These experiments were performed using a Langmuir probe array in the edge plasmas of the J-TEXT tokamak. This study aims to explain the mechanisms for generating residual stresses and intrinsic rotations. It is observed that with RMPs, peaked residual stresses, steeper pressure gradients and stronger shear layers all appear around the resonant surface. The toroidal rotation is accelerated in the direction of the plasma current and shows a correlation with turbulence and the measured residual stresses near the resonant surfaces of RMPs. Symmetry breaking induced by magnetic islands is proposed as a new mechanism, which qualitatively explains the enhanced residual stresses and the acceleration of the toroidal rotation. The changes to the residual stresses and symmetry breaking with RMPs near the last closed surface are also discussed.

The temporal-spatial structures of plasma flows and turbulence around tearing mode islands are presented. The experiments were performed using Langmuir probe arrays in the edge plasmas of J-TEXT tokamak. The correlation analyses clearly show that the flows have similar structures of m/n = 3/1 as the magnetic island does (m and n are the poloidal and toroidal mode numbers, respectively). The sign of the potential fluctuations for the flows inverses and the powers significantly reduce at q = 3 surface. Approaching to the last closed flux surface for the magnetic islands, the radially elongated flow structure forms. The flows are concentrated near separatrix and show quadrupole structures. The turbulence is concentrated near X-point and partly trapped inside the magnetic islands.

The acceleration of the co-current toroidal rotations around resonant surfaces by resonant magnetic perturbations (RMPs) through turbulence is presented. These experiments were performed using a Langmuir probe array in the edge plasmas of the J-TEXT tokamak. This study aims at understanding the RMP effects on edge toroidal rotations and exploring its control method. With RMPs, the flat electron temperature T e profile, due to magnetic islands, appears around resonant surfaces (Zhao et al 2015 Nucl. Fusion 55 073022). When the resonant surface is closer to the last closed flux surface, the flat T e profile vanishes with RMPs. In both cases, the toroidal rotations significantly increase in the direction of the plasma current around the resonant surfaces with RMPs. The characteristics of turbulence are significantly affected by RMPs around the resonant surfaces. The turbulence intensity profile changes and the poloidal wave vector k θ increases with RMPs. The power fraction of the turbulence components in the ion diamagnetic drift direction increases with RMPs. The measurements of turbulent Reynolds stresses are consistent with the toroidal flows that can be driven by turbulence. The estimations of the energy transfer between the turbulence and toroidal flows suggest that turbulence energy transfers into toroidal flows. The result has the implication of the intrinsic rotation being driven by RMPs via turbulence.

The first comprehensive measurements of plasma flows and fluctuations nearby static magnetic islands driven by resonant magnetic perturbations are presented. These experiments were performed using multiple Langmuir probe arrays on the edge plasmas of the J-TEXT tokamak. Controlled variations of the island size and location are explored. This study aims to understand the interaction between turbulence and magnetic islands, and to elucidate magnetic island effects on edge turbulence and flow intensity profiles, edge electric fields, and thus confinement regime transitions. Turbulence and low frequency flows (LFFs) all drop inside the magnetic island, but increase at its boundary, as island width increases. The geodesic acoustic mode is damped in most of the edge area with magnetic islands. The sign of the radial electric field changes from negative to positive within the islands. The gradient of turbulent stresses vanishes at the island center, and becomes steeper at the boundaries of the islands. The particle transport induced by the turbulence is reduced inside the magnetic islands. The magnetic island effects on flows and turbulence can lead to an increase in LFFs and enhance Reynolds stresses near the last closed flux surface (LCFS). A stronger radial electric field layer can be formed near the LCFS when magnetic islands are present. The results suggest that magnetic islands can be used as a tool to enhance edge turbulence and flows, edge electric fields, and thus to trigger confinement regime transitions.

A series of seismic table tests about the large steel cylindrical liquid storage tank models with floating roof were taken in this study. Horizontal and vertical direction seismic excitations were input respectively to the experimental structure system under different working conditions to test and analyze the seismic response behavior. The effects of various factors, such as the liquid surface height, the floating roof, the different wave amplitudes and frequencies, as well as their combined effects on the seismic dynamic response were obtained. The absolute displacement and the uplift response behavior law of the test models were obtained under different conditions. It was concluded that not only uplift value but also the absolute displacement of the tank bottom should be considered. And it should be noticed that a critical input frequency exists during the model response changing with frequency. In addition, important factors in experiment were described systematically in this article, for example, the experimental equipment selection, the experimental method, the tank model design, the laser displacement sensors, the data acquisition, the measurement point layout method, seismic excitation input method and so on. A reliable basis could be provided for theoretical analysis, structural design and computer numerical simulation research through this investigation. [ABSTRACT FROM PUBLISHER]

Background: The zinc finger protein 36-like (ZFP36L) family is a CCCH-type group consisting of RNA-binding proteins, i.e., ZFP36L1 and ZFP36L2, which regulate cellular mRNA through the RNA decay pathway. ZFP36L1 combats flavivirus infections through the 5'-3' XRN1 and 3'-5' RNA exosome decay pathways. The present study clarified the role of human ZFP36L2 in the defense response of the host against flavivirus infection., Methods: Cell lines with overexpression or knockdown of ZFP36L2 were established using lentiviral vectors carrying genes for overexpression and short-hairpin RNA targeting specific genes, respectively. A plaque assay was employed to determine the viral titer. Immunofluorescence and real-time quantitative polymerase chain reaction were used to measure the viral RNA levels. The in vitro-transcribed RNA transcript derived from a replication-dead Japanese encephalitis virus (JEV) replicon containing the renilla luciferase reporter gene (J-R2A-NS5mt) was used to assess the stability of the flavivirus RNA. An RNA immunoprecipitation assay was used to detect the protein-RNA binding ability. Confocal microscopic images were captured to analyze protein colocalization., Results: ZFP36L2 served as an innate host defender against JEV and dengue virus. ZFP36L2 inhibited flavivirus infection solely through the 5'-3' XRN1 RNA decay pathway, whereas ZFP36L1 inhibited JEV infection via the 5'-3' XRN1 and 3'-5' RNA exosome RNA decay pathways. The direct binding between viral RNA and ZFP36L2 via its CCCH-type zinc finger motifs facilitated the degradation of flavivirus RNA mediated by 5'-3' XRN1. Furthermore, ZFP36L2 was localized in processing bodies (PBs), which participate in the 5'-3' XRN1-mediated RNA decay pathway. Nonetheless, the disruption of PBs did not affect the antiviral activity of ZFP36L2, suggesting that its localization is not essential for the function of the protein. Interestingly, the colocalization of ZFP36L2 and XRN1 with viral RNA and NS3 revealed that the antiviral activity of ZFP36L2 occurred within the replication complexes (RCs)., Conclusions: In summary, ZFP36L2 bound to and degraded viral RNA through the XRN1-mediated RNA decay pathway in the RCs, thereby inhibiting flavivirus replication. These findings provide valuable insights into the diverse antiviral mechanisms of the ZFP36-like family of proteins in the innate immune response against flavivirus infection., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: No potential conflicts of interest were disclosed., (© 2025. The Author(s).)

Blocking mitosis is a promising strategy to induce tumor cell death. However, AMPK- and PFKFB3-mediated glycolysis can maintain ATP supply and help tumor cells overcome antimitotic drugs. Inhibiting glycolysis provides an opportunity to decrease the resistance of tumor cells to antimitotic drugs. Meanwhile, increased glutathione (GSH) expression in cancer cells due to glycolysis becomes a target for developing microenvironment-responsive drugs. Herein, a novel cationic lipid with disulfide bonds in hydrophobic tails was synthesized and used to prepare a GSH-triggered lipid nanoparticle named 2-DG@SLNP(siR) encapsulating both Plk1 siRNA and 2-deoxyglucose (2-DG) for blocking mitosis and reducing drug resistance of nonsmall cell lung cancer (NSCLC) cells in vivo. Experimental results showed that the NSCLC cell cycle was arrested at the G2/M phase by Plk1 siRNA and glycolysis was effectively inhibited by 2-DG, demonstrating the potential of 2-DG@SLNP(siR) as an efficient platform for blocking mitosis and reducing drug resistance of cancer cells.

Herein, two new or overlooked features of ZIF-90 were identified and investigated. Imidazole-2-carboxaldehyde is fluorescent, but its fluorescence in ZIF-90 is quenched by an ACQ effect. ZIF-90 can enhance the fluorescence of Cy5, but quench that of 6-FAM. The applicability of the two newly identified features in biosensing was explored.

Disrupting microtubule dynamics has emerged as a promising strategy for cancer therapy. Novel trimethoxyanilino-substituted pyrimidine and quinazoline derivatives were designed and synthesized to serve as potent microtubule-inhibiting agents with anti-proliferative activity. Compound 2k demonstrates high efficacy against B16-F10 cancer cells at low nanomolar concentrations, with an IC 50 of 0.098 ± 0.006 μM, which is comparable to colchicine. Mechanistic studies have revealed that 2k has the ability to inhibit microtubule protein polymerization in vitro, resulting in cell cycle arrest and apoptosis. Furthermore, 2k inhibits tumor cell migration and exhibits significant anti-tumor efficacy in a melanoma tumor model without causing obvious toxicity. In summary, the pyrimidine derivative 2k exhibits excellent anticancer activity and provides a new scaffold for the development of novel microtubule inhibitors, which deserves further in-depth research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The human ATP-binding cassette (ABC) transporter ABCA7 participates in the lipidation of apolipoprotein ApoE, a commonly recognized risk factor for Alzheimer's disease (AD). How ABCA7 is involved in the molecular pathogenesis of AD remains poorly understood. Using cryoelectron microscopy (cryo-EM), we determined ABCA7 structures in the apo and substrate-bound forms, respectively. Combined with activity assays, we assigned the residues that specifically bind two molecules of phosphatidylserine (PS) that are arranged in a "tail-to-tail" manner. Pull-down assays confirmed that ApoE directly interacts with ABCA7; and moreover, both ATPase and lipid transport activities of ABCA7 were significantly enhanced in the presence of ApoE. We also measured the activities of a familial AD variant and a protective clinically reported variant in the ABCA7 gene. Our findings not only give structural insights into ABCA7-mediated PS translocation, but we also provide first biochemical evidence for its link to AD by forwarding lipids to ApoE., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: We report the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of a multi-kinase inhibitor (TG02 capsule) as a new therapy for patients with recurrent high-grade gliomas in China., Methods: This is a single-center, dose-escalation, open-label phase I study, which enrolled patients with recurrent high-grade gliomas who failed to temozolomide. Patients were assigned sequentially into different dose groups and received TG02 every 4 weeks. The dose was increased in a traditional 3 + 3 design. Primary endpoints were the dose-limited toxicity (DLT) and the maximum tolerated dose (MTD)., Results: Twelve patients (8 glioblastomas, 4 diffuse astrocytoma) were enrolled between May 2019 and November 2021. Three patients received 100 mg and 9 received 150 mg TG02 twice a week. The plasma concentration of TG02 reached the maximum at 2 h after administration, and the elimination half-life was about 7 h. No DLT occurred and MTD was not defined in this study. Eleven patients had one or more investigator-assessed treatment-related adverse events (TRAEs). The most frequent TRAEs were vomiting (91.7%) and diarrhea (75.0%), and 50% of the patients had grade 3 or 4 adverse events. There were no treatment-related deaths. The median progression-free survival and overall survival were 1.77 (95% confidence interval [CI]: 0.82-4.24) and 9.63 (95% CI: 2.66-not estimated) months, respectively., Conclusions: TG02 capsule 150 mg twice a week is safe and tolerable in Chinese patients with recurrent high-grade gliomas. Patients who failed to temozolomide showed obvious tumor reduction when switching to TG02 capsule. The efficacy of recurrent gliomas warrants further investigation., (© 2024 S. Karger AG, Basel.)

Competing Interests: Conflicts of Interest: Zhang WY, None; Chen J, None; Liu HM, None; Jiang XH, None; Chen ZP, None; You ZP, None; Zou YL, None.

The transition metal catalyzed coupling reaction has revolutionized the strategies for forging the carbon-carbon bonds. In contrast to traditional cross-coupling methods using pre-prepared nucleophilic organometallic reagents, reductive coupling reactions for the C-C bonds formation provide some advantages. Because both coupling partners are reduced in the final products using a stoichiometric amount of a reductant, this approach not only avoids the need to use sensitive organometallic species, but also provides an orthogonal and complementary access to classical coupling reaction. Notably, the reductive coupling reactions feature readily available fragments, promote good step economy, exhibit high functional group tolerance and unique chemoselectivity, which have propelled their increasingly popular in the organic synthesis. In recent years, due to the low price, minimal toxicity, and environmentally benign character, iron-catalyzed carbon-carbon coupling reactions have garnered significant attention from the organic synthetic chemists and pharmacologists, especially the iron-catalyzed reductive coupling. This review aims to provide an insightful overview of recent advances in iron-catalyzed reductive coupling reactions, and to illustrate their possible reaction mechanisms., (© 2024 The Chemical Society of Japan and Wiley-VCH GmbH.)

Generalized fear is a maladaptive behavior in which non-threatening stimuli elicit a fearful response. The ventral tegmental area (VTA) has been demonstrated to play important roles in fear response and fear memory generalization, but the precious neural circuit mechanism is still unclear. Here, we demonstrated that VTA-zona incerta (ZI) glutamatergic projection is involved in regulating high-intensity threatening training induced generalization and anxiety. Combining calcium signal recording and chemogentics, our work reveals that VTA glutamatergic neurons respond to closed arm entering in the model of PTSD. Inhibition of VTA glutamatergic neurons or the glutamatergic projection to ZI could both relieve fear generalization and anxiety. Together, our study proves the VTA - ZI glutamatergic circuit is involved in mediating fear generalization and anxiety, and provides a potential target for treating post-traumatic stress disorder., Competing Interests: Declaration of Competing Interest The authors have declared that there are no conflicts of interest in relation to the subject of this study., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hepatobiliary and pancreatic (HBP) cancers impose a considerable burden on young populations (aged 15 to 49 years), resulting in a substantial number of new cases and fatalities each year. In young populations, the HBP cancers shows extensive variance worldwide and the updated data in China is lacking., Aim: To investigate the current status, trends, projections, and underlying risk factors of HBP cancers among young populations in China., Methods: The Global Burden of Disease Study 2019 provided data on the annual incidence, mortality, disability-adjusted life years (DALYs), age-standardized incidence rate (ASIR), mortality rate (ASMR), and DALYs rate (ASDR) of HBP cancers in young Chinese adults between 1990 and 2019. Temporal trends were assessed using estimated annual percentage change and hierarchical clustering. Sex-specific mortality and DALYs caused by various risks were analyzed across China and other regions, with future trends until 2035 projected using the Bayesian age-period-cohort model., Results: From 1990 to 2019, incident cases, deaths, DALYs, ASIR, ASMR, and ASDR for liver cancer (LC) in young Chinese individuals decreased, classified into 'significant decrease' group. Conversely, cases of gallbladder and biliary tract cancer and pancreatic cancer rose, categorized as either 'significant increase' or 'minor increase' groups. The contribution of risk factors to mortality and DALYs for HBP tumors increased to varying degrees. Healthy lifestyle behaviors, such as tobacco control, weight management, alcohol moderation, and drug avoidance, could lower HBP cancers incidence. Moreover, except for LC in females, which is likely to initially decline slightly and then rise, the forecasting model predicted that the ASIR and ASMR for all HPB cancers subtypes by gender will increase among young adults., Conclusion: HBP cancers burden among young adults in China is expected to increase until 2035, necessitating lifestyle interventions and targeted treatment strategies to mitigate the public health impact of these cancers., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Accurate monitoring of base excision repair (BER) activity in cancer cells is critical for advancing the comprehension of DNA repair processes, gaining insights into cancer development, and guiding treatment strategies. However, current assay techniques for assessing BER activity in cancer cells face challenges due to the heterogeneous origins and diversity of BER enzymes. In this work, we present a hi g hly reli a ble t riple loop-int e rlocked DNA co d ec (GATED) that enables precise assessment of BER activity in cancer cells through signal amplification mediated by multienzyme orthogonal activation. The GATED device features a dumbbell-shaped DNA probe to encode two BER enzymes for BER-related signal conversion as well as two bound circular DNA to decode the apurinic/apyrimidinic sites for apurinic/apyrimidinic endonuclease 1 (APE1)-mediated signal amplification. Importantly, GATED is orthogonally activated by multiple target BER enzymes (i.e., uracil DNA glycosylase, thymine DNA glycosylase, and APE1), resulting in a unified fluorescent signal that significantly improves the detection specificity and sensitivity to BER enzymes. Additionally, we demonstrate that the GATED has exceptional biostability within complex biological systems, where it was successfully employed to monitor BER activity in cancer cells with high specificity and enabled cell-based high-throughput screening for BER inhibitors. The GATED provides a much-needed tool for the real-time monitoring of BER activity and the screening of BER inhibitors in cancer cells, potentially advancing both the investigation and clinical application of BER biology.

Granzyme A (GzmA) secreted by natural killer (NK) cells has garnered considerable interest as a biomarker to evaluate the efficacy of cancer immunotherapy. However, current methodologies to selectively monitor the spatial distribution of GzmA in cancer cells during NK cell-targeted therapy are extremely challenging, primarily due to the existence of diverse cell populations, the low levels of GzmA expression, and the limited availability of GzmA probes. Herein we develop a multi-modular, structurally-ordered DNA nanodevice for evaluating NK cell-mediated cancer immunotherapy (MODERN), that permits spatioselective imaging of GzmA in cancer cells through GzmA-induced apurinic/apyrimidinic endonuclease 1 (APE1) inactivation. The MODERN incorporates multiple functional modules, including an APE1-gated recognition module, a photo-activated amplification module, an aptamer-mediated tumor-target module, and a polycatenane DNA module, enabling improved sensitivity and specificity towards intracellular GzmA. The MODERN was activated (on) in cancer cells due to the overexpression of APE1, whereas it remained silent (off) in the NK-treated cancer cells owing to the GzmA-induced APE1 inactivation. Furthermore, we demonstrated that GzmA-induced APE1 inactivation blocks the cellular repair of target cells, resulting in efficient cell death. This MODERN that relies on the specific inactivation of APE1 by GzmA should be beneficial for evaluating the efficacy of cancer immunotherapy., (© 2024 Wiley-VCH GmbH.)

Purpose: To explore the value of tissue quantitative diffusion analysis of ultrasound elastography in the diagnosis of early-stage chronic kidney disease (CKD)., Methods: The observation group comprised 54 patients with early-stage CKD treated at Fuzhou No 7 Hospital, and the control group consisted of 40 healthy individuals who underwent physical examinations at the same hospital. The renal parenchyma of the participants were examined using ultrasonography, color Doppler ultrasonography, and tissue quantitative diffusion analysis of ultrasound elastography. Renal dimensions (diameter, thickness, and renal parenchyma thickness), interlobar artery blood flow parameters, and 11 elastic characteristic values were analyzed and compared between the two groups. The area under the receiver-operating characteristic (ROC) curve, cut-off values, sensitivity, and specificity were calculated using the ROC curve analysis., Results: There were no significant differences in the blood flow parameters of the interlobar artery and the dimensions of renal meridians between the two groups. In the observation group, the mean (MEAN) decreased, while the blue area ratio and skewness, increased, compared to the control group (p < 0.05). In addition, the ROC curve revealed that the blue area ratio, MEAN, and skewness had significant diagnostic value (the area under the curve > 0.7). Notably, the best cut-off value of the MEAN was found to be 106, indicating that a MEAN value less than 106 represented early-stage CKD. Also, this cutoff value had a sensitivity of 80% and a specificity of 81%., Conclusion: Tissue quantitative diffusion analysis of ultrasound elastography can quantitatively evaluate renal parenchymal damage in early-stage CKD using quantitative diffusion parameters, with the MEAN parameter, having a cutoff of 106, being particularly effective. This parameter and cutoff value offer a valuable tool for the early detection and diagnosis of CKD, potentially improving patient outcomes through earlier intervention., Clinical Trial Number: Not applicable., (© 2024. The Author(s).)

Objective: To investigate the effect of long-term oral aspirin on the changes in the aneurysm sac and persistent type Ⅱ endoleak after endovascular aortic repair (EVAR) of infrarenal abdominal aortic aneurysms based on propensity score-matched analysis. Methods: A retrospective cohort study was used to analyze the clinical data of 133 patients with infrarenal abdominal aortic aneurysms treated with EVAR from January 2019 to December 2021 in the Department of Vascular Surgery, Nanjing Drum Tower Hospital. There were 113 males and 20 females, aged (74.8±7.2) years (range: 59 to 95 years). Patients were divided into the group receiving aspirin ( n =80) and the group not taking aspirin ( n =53) based on whether they took aspirin regularly for a long time after surgery. The two groups were matched in a 1∶1 ratio using propensity score matching and the caliper value was 0.05. Cumulative probability curve was plotted using the Kaplan-Meier method and the Log-rank test was used to compare the differences in primary endpoint events (enlargement of the aneurysm sac, occurrence of persistent type Ⅱ endoleak) and secondary endpoint events (adverse cardiovascular events and clinically relevant bleeding events) between the two groups. Results: The follow-up time was (38.4±11.8) months (range: 30 to 58 months). Among the 133 patients, a total of 25 cases (18.8%) suffered enlargement of the aneurysm sac, including 20 cases in the group receiving aspirin and 5 cases in the group not taking aspirin; 35 cases (26.3%) suffered persistent type Ⅱ endoleak, including 26 cases in the group receiving aspirin and 9 cases in the group not taking aspirin. Adverse cardiovascular events occurred in 11 cases (8.3%) and clinically relevant bleeding events were reported in 5 cases (3.8%). A matched cohort was established after propensity score matching, resulting in 32 cases per group. The survival analysis found that the rate of aneurysm sac enlargement was significantly higher in the group receiving aspirin than that in the group not taking aspirin (Log-rank test: P =0.010), and the incidence of persistent type Ⅱ endoleak was significantly higher than that in the group not taking aspirin (Log-rank test: P =0.019). The incidence of adverse cardiovascular events and clinically relevant bleeding events were not significantly different in two groups (Log-rank test: P =0.061, P =0.286). Conclusions: The risk of aneurysm sac expansion and persistent type Ⅱ endoleak were significantly higher in patients taking long-term aspirin after EVAR than in the group not taking asprin. Therefore, high-risk abdominal aortic aneurysm patients who are prone to aneurysm sac expansion should be evaluated in advance so that the risks and benefits of surgery can be comprehensively evaluated and treatment strategies can be optimized.

Cognitive impairment is a common issue among human patients undergoing surgery, yet the neural mechanism causing this impairment remains unidentified. Surgical procedures often lead to glial cell activation and neuronal hypoexcitability, both of which are known to contribute to postoperative cognitive dysfunction (POCD). However, the role of neuron-glia crosstalk in the pathology of POCD is still unclear. Through integrated transcriptomics and proteomics analyses, we found that the complement cascades and microglial phagocytotic signaling pathways are activated in a mouse model of POCD. Following surgery, there is a significant increase in the presence of complement C3, but not C1q, in conjunction with presynaptic elements. This triggers a reduction in excitatory synapses, a decline in excitatory synaptic transmission, and subsequent memory deficits in the mouse model. By genetically knockout out C3ar1 or inhibiting p-STAT3 signaling, we successfully prevented neuronal hypoexcitability and alleviated cognitive impairment in the mouse model. Therefore, targeting the C3aR and downstream p-STAT3 signaling pathways could serve as potential therapeutic approaches for mitigating POCD., (© 2024. The Author(s).)

Human ABC transporters ABCD1-3 are all localized on the peroxisomal membrane and participate in the β-oxidation of fatty acyl-CoAs, but they differ from each other in substrate specificity. The transport of branched-chain fatty acids from cytosol to peroxisome is specifically driven by ABCD3, dysfunction of which causes severe liver diseases such as hepatosplenomegaly. Here we report two cryogenic electron microscopy (cryo-EM) structures of ABCD3 bound to phytanoyl-CoA and ATP at resolutions of 2.9 Å and 3.2 Å, respectively. A pair of phytanoyl-CoA molecules were observed in ABCD3, each binding to one transmembrane domain (TMD), which is distinct from our previously reported structure of ABCD1, where each fatty acyl-CoA molecule strongly crosslinks two TMDs. Upon ATP binding, ABCD3 exhibits a conformation that is open towards the peroxisomal matrix, leaving two extra densities corresponding to two CoA molecules deeply embedded in the translocation cavity. Structural analysis combined with substrate-stimulated ATPase activity assays indicated that the present structures might represent two states of ABCD3 in the transport cycle. These findings advance our understanding of fatty acid oxidation and the molecular pathology of related diseases., (© 2024. The Author(s).)

Objective: To investigate the correlation between perivascular fat density (PFD) and plaque stability in patients with carotid artery stenosis. Methods: Clinical data of 110 patients with carotid artery stenosis treated at Drum Tower Hospital, Nanjing University Medical School from January 2018 to December 2022 were retrospectively collected. Based on pathological results of carotid plaque specimens obtained from carotid endarterectomy (CEA), patients were categorized into stable plaque group ( n =51) and vulnerable plaque group ( n =59). All patients underwent preoperative carotid CT angiography (CTA) to measure PFD at the narrowest carotid artery. Preoperative levels of interleukin-6 (IL-6) and other hematological parameters were collected. Multivariable logistic regression analysis was used to identify factors associated with plaque stability in carotid artery stenosis patients. Area under the curve (AUC) of receiver operating characteristic (ROC) was performed to evaluate the predictive value of PFD for plaque stability. Results: The stable plaque group consisted of 43 males and 8 females with a mean age of (67.6±9.0) years, while the vulnerable plaque group comprised 48 males and 11 females with a mean age of (69.3±9.0) years. The proportions of smokers were 31.4% (16/51) and 50.8% (30/59) in the stable and vulnerable plaque groups, respectively. The proportions of patients with diabetes were 33.3% (17/51) and 52.5% (31/59), respectively. IL-6 levels were 3.46(2.67, 5.34) and 4.51(3.62, 5.51) ng/L in the stable and vulnerable groups, respectively. Mean PFD values were (-69.04±5.35) and (-63.24±6.08) HU, respectively, with maximum PFD values of (-62.90±6.98) and (-56.93±5.90) HU, respectively. The differences were statistically significant (all P <0.05). Multivariable logistic regression analysis showed that increased mean PFD ( OR =1.167, 95% CI : 1.029-1.324, P =0.016) and elevated IL-6 levels ( OR =1.489, 95% CI : 1.151-1.926, P =0.002) were associated with vulnerability of carotid artery plaques. ROC curve analysis results showed that a cut-off value of -65.5 HU, the AUC for predicting plaque stability based on the mean PFD was 0.756 (95% CI : 0.667-0.844, P <0.001), with sensitivity of 64.4% and specificity of 74.5%. Conclusion: Increased mean PFD at the narrowest carotid artery is associated with vulnerability of plaques in patients with carotid artery stenosis.

Glioma, a malignant and infiltrative neoplasm of the central nervous system, poses a significant threat due to its high mortality rates. Branched-chain amino acid transaminase 1 (BCAT1), a key enzyme in branched-chain amino acid (BCAA) catabolism, exhibits elevated expression in gliomas and correlates strongly with poor prognosis. Nonetheless, the regulatory mechanisms underlying this increased BCAT1 expression remains incompletely understood. In this study, we reveal that ubiquitination at Lys360 facilitates BCAT1 degradation, with low ubiquitination levels contributing to high BCAT1 expression in glioma cells. The Carboxyl terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase, interacts with BCAT1 via its coiled-coil (CC) domain, promoting its K48-linkage ubiquitin degradation through proteasomal pathway. Moreover, CHIP-mediated BCAT1 degradation induces metabolic reprogramming, and impedes glioma cell proliferation and tumor growth both in vitro and in vivo. Furthermore, a positive correlation is observed between low CHIP expression, elevated BCAT1 levels, and unfavorable prognosis among glioma patients. Additionally, we show that the CHIP/BCAT1 axis enhances glioma sensitivity to temozolomide by reducing glutathione (GSH) synthesis and increasing oxidative stress. These findings underscore the critical role of CHIP/BCAT1 axis in glioma cell proliferation and temozolomide sensitivity, highlighting its potential as a diagnostic marker and therapeutic target in glioma treatment., (© 2024. The Author(s).)

Exoristobia philippinensis (Hymenoptera: Encyrtidae) is a worldwide parasitic wasp. This work presents the mitochondrial genome (mitogenome) of E. philippinensis for the first time. The complete mitochondrial genome of E. philippinensis was sequenced and annotated, which was 15,751 bp in length, and encoded 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), and two ribosomal RNA genes (rRNAs). All 13 PCGs were initiated by the ATN (ATG, ATT, and ATA) codon, terminated with the stop codon TAA except for ND1 which ends with TAG. Phylogenetic analysis showed that E. philippinensis has a sister relationship with the genus Lamennaisia ., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly, which is primarily attributed to oxidative stress-induced damage to the retinal pigment epithelium (RPE). Human amniotic mesenchymal stem cells (hAMSC) were considered to be one of the most promising stem cells for clinical application due to their low immunogenicity, tissue repair ability, pluripotent potential and potent paracrine effects. The conditional medium (hAMSC-CM) and exosomes (hAMSC-exo) derived from hAMSC, as mediators of intercellular communication, play an important role in the treatment of retinal diseases, but their effect and mechanism on oxidative stress-induced retinal degeneration are not explored. Here, we reported that hAMSC-CM alleviated H 2 O 2 -induced ARPE-19 cell death through inhibiting mitochondrial-mediated apoptosis pathway in vitro. The overproduction of reactive oxygen species (ROS), alteration in mitochondrial morphology, loss of mitochondrial membrane potential and elevation of Bax/Bcl2 ratio in ARPE-19 cells under oxidative stress were efficiently reversed by hAMSC-CM. Moreover, it was found that hAMSC-CM protected cells against oxidative injury via PI3K/Akt/FoxO3 signaling. Intriguingly, exosome inhibitor GW4869 alleviated the inhibitory effect of hAMSC-CM on H 2 O 2 -induced decrease in cell viability of ARPE-19 cells. We further demonstrated that hAMSC-exo exerted the similar protective effect on ARPE-19 cells against oxidative damage as hAMSC-CM. Additionally, both hAMSC-CM and hAMSC-exo ameliorated sodium iodate-induced deterioration of RPE and retinal damage in vivo. These results first indicate that hAMSC-CM and hAMSC-exo protect RPE cells from oxidative damage by regulating PI3K/Akt/FoxO3 pathway, suggesting hAMSC-CM and hAMSC-exo will be a promising cell-free therapy for the treatment of AMD in the future., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Vessel transplantation is currently considered the "gold standard" treatment for cardiovascular disease. However, ideal artificial vascular grafts should possess good biocompatibility and mechanical strength that match those of native autologous vascular tissue to promote in vivo tissue regeneration. In this study, a series of dynamic cross-linking double-network hydrogels and the resultant hydrogel tubes were prepared. The hydrogels (named PCO), composed of rigid poly(vinyl alcohol) (PVA), flexible carboxymethyl chitosan (CMCS), and a cross-linker of aldehyde-based β-cyclodextrin (OCD), were formed in a double-network structure with multiple dynamical cross-linking including dynamic imine bonds, hydrogen bonds, and microcrystalline regions. The PCO hydrogels exhibited superior mechanical strength, good network stability, and fatigue resistance. Additionally, it demonstrated excellent cell and blood compatibility. The results showed that the introduction of CMCS/OCD led to a significant increase in the proliferation rate of endothelial cells seeded on the surface of the hydrogel. The hemolysis rate in the test was lower than 0.3%, and both protein adsorption and platelet adhesion were reduced, indicating an excellent anticoagulant function. The plasma recalcification time test results showed that endogenous coagulation was alleviated to some extent. When formed into blood vessels and incubated with blood, no thrombus formation was observed, and there was minimal red blood cell aggregation. Therefore, this novel hydrogel tube, with excellent mechanical properties, exhibits antiadhesive characteristics toward blood cells and proteins, as well as antithrombotic properties, making it hold tremendous potential for applications in the biomedical and engineering fields.

Objective: Although blood urea nitrogen (BUN) has a crucial impact on many diseases, its effect on outcomes in patients with hyperlipidemia remains unknown. The study aimed to investigate the relationships between BUN levels and all-cause and cardiovascular disease (CVD) mortality in individuals with hyperlipidemia., Methods: This analysis comprised 28,122 subjects with hyperlipidemia from the National Health and Nutrition Examination Survey (NHANES) spanning 1999 to 2018. The risk of BUN on mortality was evaluated using weighted Cox regression models. Additionally, to illustrate the dose-response association, the restricted cubic spline (RCS) was used., Results: During the observation period, 4276 participant deaths were recorded, of which 1206 were due to CVD. Compared to patients with hyperlipidemia in the third BUN quintile, the hazard ratios (HRs) for all-cause mortality were 1.26 (95% CIs: 1.09, 1.45) and 1.22 (95% CIs: 1.09, 1.37) for patients in the first and fifth quintiles of BUN, respectively. The HRs for CVD mortality among patients in the fifth quintile of BUN were 1.48 (95% CIs: 1.14, 1.93). BUN levels were found to have a U-shaped association with all-cause mortality and a linear association with CVD mortality using restricted triple spline analysis., Conclusions: This study revealed that both low and high BUN levels in patients with hyperlipidemia are associated with heightened all-cause mortality. Furthermore, elevated BUN levels are also associated with increased CVD mortality. The findings indicate that patients with hyperlipidemia may face an elevated risk of death if they have abnormal BUN levels., (© 2024. The Author(s).)

Background: Constipation, a highly prevalent functional gastrointestinal disorder, induces a significant burden on the quality of patients' life and is associated with substantial healthcare expenditures. Therefore, identifying efficient therapeutic modalities for constipation is of paramount importance. Oxidative stress is a pivotal contributor to colonic dysmotility and is the underlying pathology responsible for constipation symptoms. Consequently, we postulate that hydrogen therapy, an emerging and promising intervention, can serve as a safe and efficacious treatment for constipation., Aim: To determine whether hydrogen-rich water (HRW) alleviates constipation and its potential mechanism., Methods: Constipation models were established by orally loperamide to Sprague-Dawley rats. Rats freely consumed HRW, and were recorded their 24 h total stool weight, fecal water content, and charcoal propulsion rate. Fecal samples were subjected to 16S rDNA gene sequencing. Serum non-targeted metabolomic analysis, malondialdehyde, and superoxide dismutase levels were determined. Colonic tissues were stained with hematoxylin and eosin, Alcian blue-periodic acid-Schiff, reactive oxygen species (ROS) immunofluorescence, and immunohistochemistry for cell growth factor receptor kit (c-kit), PGP 9.5, sirtuin1 (SIRT1), nuclear factor-erythroid-2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). Quantitative real-time PCR and western blot analysis were conducted to determine the expression level of SIRT1, Nrf2 and HO-1. A rescue experiment was conducted by intraperitoneally injecting the SIRT1 inhibitor, EX527, into constipated rats. NCM460 cells were induced with H 2 O 2 and treated with the metabolites to evaluate ROS and SIRT1 expression., Results: HRW alleviated constipation symptoms by improving the total amount of stool over 24 h, fecal water content, charcoal propulsion rate, thickness of the intestinal mucus layer, c-kit expression, and the number of intestinal neurons. HRW modulated intestinal microbiota imbalance and abnormalities in serum metabolism. HRW could also reduce intestinal oxidative stress through the SIRT1/Nrf2/HO-1 signaling pathway. This regulatory effect on oxidative stress was confirmed via an intraperitoneal injection of a SIRT1 inhibitor to constipated rats. The serum metabolites, β-leucine (β-Leu) and traumatic acid, were also found to attenuate H 2 O 2 -induced oxidative stress in NCM460 cells by up-regulating SIRT1., Conclusion: HRW attenuates constipation-associated intestinal oxidative stress via SIRT1/Nrf2/HO-1 signaling pathway, modulating gut microbiota and serum metabolites. β-Leu and traumatic acid are potential metabolites that upregulate SIRT1 expression and reduce oxidative stress., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)