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The clinical treatment of hepatocellular carcinoma (HCC) is still a heavy burden worldwide. Intracellular microRNAs (miRNAs) commonly express abnormally in cancers, thus they are potential therapeutic targets for cancer treatment. miR-21 is upregulated in HCC whereas miR-122 is enriched in normal hepatocyte but downregulated in HCC. In our study, we first generated a reporter genetic switch compromising of miR-21 and miR-122 sponges as sensor, green fluorescent protein (GFP) as reporter gene and L7Ae:K-turn as regulatory element. The reporter expression was turned up in miR-21 enriched environment while turned down in miR-122 enriched environment, indicating that the reporter switch is able to respond distinctly to different miRNA environment. Furthermore, an AAT promoter, which is hepatocyte-specific, is applied to increase the specificity to hepatocyte. A killing switch with AAT promoter and an apoptosis-inducing element, Bax, in addition to miR-21 and miR-122 significantly inhibited cell viability in Huh-7 by 70 % and in HepG2 by 60 %. By contrast, cell viability was not affected in five non-HCC cells. Thus, we provide a novel feasible strategy to improve the safety of miRNA-based therapeutic agent to cancer., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Age-related macular degeneration (AMD) is a common retinal neurodegenerative disease among the elderly. Neovascular AMD (nAMD), a leading cause of AMD-related blindness, involves choroidal neovascularization (CNV), which can be suppressed by anti-angiogenic treatments. However, current CNV treatments do not work in all nAMD patients. Here we investigate a novel target for AMD. Granzyme B (GzmB) is a serine protease that promotes aging, chronic inflammation and vascular permeability through the degradation of the extracellular matrix (ECM) and tight junctions. Extracellular GzmB is increased in retina pigment epithelium (RPE) and mast cells in the choroid of the healthy aging outer retina. It is further increased in donor eyes exhibiting features of nAMD and CNV. Here, we show in RPE-choroidal explant cultures that exogenous GzmB degrades the RPE-choroid ECM, promotes retinal/choroidal inflammation and angiogenesis while diminishing anti-angiogenic factor, thrombospondin-1 (TSP-1). The pharmacological inhibition of either GzmB or mast-cell degranulation significantly reduces choroidal angiogenesis. In line with our in vitro data, GzmB-deficiency reduces the extent of laser-induced CNV lesions and the age-related deterioration of electroretinogram (ERG) responses in mice. These findings suggest that targeting GzmB, a serine protease with no known endogenous inhibitors, may be a potential novel therapeutic approach to suppress CNV in nAMD., (© 2024. The Author(s).)

Zika virus (ZIKV) is an emerging flavivirus that causes congenital syndromes including microcephaly and fetal demise in pregnant women. No commercial vaccines against ZIKV are currently available. We previously generated a chimeric ZIKV (ChinZIKV) based on the Chaoyang virus (CYV) by replacing the prME protein of CYV with that of a contemporary ZIKV strain GZ01. Herein, we evaluated this vaccine candidate in a mouse model and showed that ChinZIKV was totally safe in both adult and suckling immunodeficient mice. No viral RNA was detected in the serum of mice inoculated with ChinZIKV. All of the mice inoculated with ChinZIKV survived, while mice inoculated with ZIKV succumbed to infection in 8 days. A single dose of ChinZIKV partially protected mice against lethal ZIKV challenge. In contrast, all the control PBS-immunized mice succumbed to infection after ZIKV challenge. Our results warrant further development of ChinZIKV as a vaccine candidate in clinical trials.

The AIM2 inflammasome represents a multifaceted oligomeric protein complex within the innate immune system, with the capacity to perceive double-stranded DNA (dsDNA) and engage in diverse physiological reactions and disease contexts, including cancer. While originally conceived as a discerning DNA sensor, AIM2 has demonstrated its capability to discern various nucleic acid variations, encompassing RNA and DNA-RNA hybrids. Through its interaction with nucleic acids, AIM2 orchestrates the assembly of a complex involving multiple proteins, aptly named the AIM2 inflammasome, which facilitates the enzymatic cleavage of proinflammatory cytokines, namely pro-IL-1β and pro-IL-18. This process, in turn, underpins its pivotal biological role. In this review, we provide a systematic summary and discussion of the latest advancements in AIM2 sensing various types of nucleic acids. Additionally, we discuss the modulation of AIM2 activation, which can cause cell death, including pyroptosis, apoptosis, and autophagic cell death. Finally, we fully illustrate the evidence for the dual role of AIM2 in different cancer types, including both anti-tumorigenic and pro-tumorigenic functions. Considering the above information, we uncover the therapeutic promise of modulating the AIM2 inflammasome in cancer treatment., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Vesicle-associated membrane protein 7 (VAMP7) plays oncogenic roles in cancers. However, its clinical significance in breast cancer (BC) tissues remains unknown., Objective: To elucidate the clinical implications of VAMP7, as well as its involvement in the tumor microenvironment and molecular pathways of breast cancer., Methods: BC (n=100) and non-cancerous breast tissues (n= 100) were collected for an immunohistochemical experiment (1:200). The protein expression level of VAMP7 was determined by using a semi-quantitative scoring method. High-throughput RNA-sequencing data of BC tissues were analyzed to confirm the mRNA expression trend of VAMP7. Additionally, the largest BC prognosis cohort data were collected to mine the potential impact VAMP7 has on BC progression. The association between VAMP7 and the microenvironment of BC was evaluated by using a CIBERSORT algorithm. Moreover, we explored the co-expressed molecular mechanisms of VAMP7 in BC by calculating Pearson correlation coefficients and overexpressed genes. Finally, the biological mechanism underlying the relationship between VAMP7 and the key pathways was also explored using gene set enrichment analysis (GSEA). Potential therapeutic strategies were predicted targeting VAMP7., Results: VAMP7 protein was significantly over-expressed in BC tissue than that in controls (p< 0.001). Compared with 459 normal breast tissues and 113 non-cancerous breast tissues, the expression level of VAMP7 mRNA was significantly increased in 1111 BC tissues. CD4+T cells, macrophages, and naïve B cells had a higher infiltration rate in BC tissues with high VAMP7 expression, while regulatory T cells and CD8+T cells had a lower infiltration rate. Over-expressed VAMP7 was associated with macrophages activation and transition from M1 to M2 polarization. Upregulated VAMP7 could predicted poorer OS, DMFS, PPS, and RFS outcomes. Upregulated VAMP7 co-expressed genes were significantly enriched in the cell cycle checkpoints. GSEA confirmed that over-expressed VAMP7 are markedly associated with functional enrichment in cell cycle related categories, including mitotic spindle, G2M checkpoint, and E2F targets. KU-55933 was predicted as a putative therapeutic drug for BC targeting VAMP7., Conclusions: VAMP7 was upregulated in BC tissue and correlated with poor prognosis of BC patients. VAMP7 may promote BC progression by targeting the cell cycle pathway.

Advanced-stage ovarian cancer is usually associated with peritoneal carcinomatosis. This study evaluates the prognostic role of the Peritoneal Cancer Index (PCI) in predicting the survival of patients with ovarian cancer. A literature search was conducted in electronic databases (Google Scholar, PubMed, Ovid, and Science Direct) and study selection was based on precise eligibility criteria. Random-effects meta-analyses were performed to estimate survival with low and high PCI scores and to pool hazard ratios (HR) of survival between lower and higher PCI scores. A total of 20 studies (2588 patients) were included. Median follow-up was 39 months [95%CI: 25, 54]. Complete cytoreduction rate was 80% [95% CI: 73, 87]. The median PCI score was 11.3 [95% CI: 9.9, 12.7]. Median survival was 56.7 months [95% CI: 45.2, 68.2] with below and 28.8 months [95% CI: 23.0, 34.6] with above any PCI cutoff. Most studies used PCI cutoffs between 10 and 20. The median progression-free survival was 23.7 months [95% CI: 16.5, 30.8] with below and 11.9 months [95% CI: 5.9, 17.9] with above any PCI cutoff. 5-year survival rates were 61.3% [95% CI: 49.9, 72.8] with PCI<10 cutoffs, 21.7% [95% CI: 11.6, 31.8] with PCI>10 cutoffs, 50.1% [95% CI: 39.0, 61.2] with PCI<20 cutoffs, and 21.7% [95% CI: 16.2, 27.1] with PCI>20 cutoffs. Pooled analysis of HRs showed that a higher PCI score was associated with worse survival in both univariate (HR 2.14 [95%CI: 1.63, 2.66]) and multivariate (HR 1.10 [95% CI: 1.02, 1.18]) analyses. In a set of studies that used varying PCI cutoffs, the PCI has been found to have a significant inverse association with the survival of patients with advanced ovarian cancer who underwent cytoreductive surgery., 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 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: The management of older aneurysmal subarachnoid haemorrhage (aSAH) cases is a clinical challenge. This study aimed to analyse the survival and functional outcomes in older aSAH patients (age ≥ 70 years) to provide evidence for making treatment decisions for such patients., Methods: We performed a 2-year follow-up analysis of the Chinese Multi-Centre Cerebral Aneurysm Database for older patients suffering from aSAH from 2017 to 2020. A survival analysis was used to investigate the mean survival and hazard ratios for death. Binary logarithmic regression was performed to investigate the odds ratio for independent survival and dependent survival., Results: A total of 1,136 consecutive older patients with aSAH were assessed in this study, and 944 patients (83.1%) were followed up. The overall mean survival was 37.79 ± 1.04 months. A total of 380 (40.25%) patients died within 2 years after aSAH. In survival analysis, the predictors of mortality were older age, intracerebral haemorrhage (ICH) history, Hunt-Hess (H-H) grade, World Federation of Neurosurgical Societies (WFNS) grade and operative treatment decreased the risk of mortality compared to conservative treatment. In binary logarithmic regression, the predictors of dependent survival were hypertension, diabetes, WFNS grade., Conclusions: The risk for 2-year mortality after aSAH increases markedly with older age, ICH history, H-H grade and WFNS grade. Risk factors for 2-year dependent survival were associated with hypertension, diabetes and WFNS grade in older patients with aSAH. Operative treatment markedly decreased mortality but did not significantly decrease the morbidity of dependent survival compared to conservative treatment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Semiconducting polymer chains constitute the building blocks for a wide range of electronic materials and devices. However, most of their electrical characteristics at the single-molecule level have received little attention. Elucidating these properties can help understanding performance limits and enable new applications. Here, coupled ionic-electronic charge transport is exploited to measure the quasi-1D electrical current through long single conjugated polymer chains as they form transient contacts with electrodes separated by ≈10 nm. Fluctuations between internal conformations of the individual polymers are resolved as abrupt, multilevel switches in the electrical current. This behavior is consistent with the theoretical simulations based on the worm-like-chain (WLC) model for semiflexible polymers. In addition to probing the intrinsic properties of single semiconducting polymer chains, the results provide an unprecedented window into the dynamics of random-coil polymers and enable the use of semiconducting polymers as electrical labels for single-molecule (bio)sensing assays., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

A series of bifunctional Ln(III)-based coordination polymers (CPs) {Ln(L)(DMA) 2 (NO 3 )} n [Ln(III) = Eu ( 1 ), Gd ( 2 ), and Dy ( 3 ); organic ligand H 2 L = 2,2'-(1,3,5,7-tetrahydroxyoctahydro-4,8-ethanopyrrolo[3,4- f ]isoindole-2,6(1 H ,3 H )-diyl)diacetic acid)] have been successfully synthesized. CPs 1 - 3 are isostructural and constructed from the dimeric Ln 2 unit in which two adjacent Ln III ions are bridged by two μ 3 -carboxyl oxygens, and the Ln 2 dimeric unit is connected by two NO 3 - ions, four DMA molecules, and four completely protonated L 2- ligands forming a 2D layer structure. The magnetic research reveals that CP 2 shows a significant cryogenic magnetocaloric effect (-Δ S m = 22.9 J kg -1 K -1 ; T = 2.0 K and Δ H = 7.0 T), whereas CP 3 exhibits slow magnetic relaxation property under H dc = 0 Oe field. Additionally, the luminescence explorations revealed that CP 1 can act as a recyclable luminescent probe for pollutant acetylacetone among various small organic solvent molecules, and the corresponding detection limit is 10 -7 mol/L. More importantly, CP 1 also exhibits good catalytic performance in the cycloaddition reaction of CO 2 and epoxides or cyanamides under mild conditions. As far as we know, CP 1 represents the first bifunctional lanthanide homogeneous catalyst that can efficiently catalyze the reaction of cyanamides/epoxides with CO 2 simultaneously.

It is difficult and challenging to design and construct high-nuclearity Ln(III)-based clusters due to the high coordination numbers and versatile coordination geometries of Ln(III) ions. Herein, two novel octanuclear Ln(III)-based clusters [Ln 8 (H 2 L - ) 4 (HL 2- ) 4 (NO 3 ) 6 (CO 3 ) 2 ](NO 3 ) 2 ·2CH 3 CN (Ln = Nd (1) and Sm (2)) have been synthesized under solvothermal conditions. The X-ray single analysis reveals that both 1 and 2 are octanuclear structures and the eight central Ln(III) ions are bridged by two CO 3 2- anions. Catalytic study revealed that 1 and 2 can effectively catalyze the cycloaddition reaction of CO 2 and aziridines or epoxides simultaneously under mild conditions. What is more, cluster 1, as a heterogeneous catalyst, can be reused at least three times without obvious loss in catalytic activity for coupling of CO 2 and epoxides. To our knowledge, cluster 1 is the first Ln(III)-based cluster catalyst used for the conversion of CO 2 with aziridines or epoxides simultaneously. This work provides a successful strategy to integrate high-nuclear Ln(III)-based clusters for CO 2 conversion, which may open a new space for the construction of multifunctional high-nuclear Ln(III)-based clusters as efficient catalysts for CO 2 conversion.

The genus Flavivirus is a group of arthropod-borne single-stranded RNA viruses, which includes important human and animal pathogens such as Japanese encephalitis virus (JEV), Zika virus (ZIKV), Dengue virus (DENV), yellow fever virus (YFV), West Nile virus (WNV), and Tick-borne encephalitis virus (TBEV). Reverse genetics has been a useful tool for understanding biological properties and the pathogenesis of flaviviruses. However, the conventional construction of full-length infectious clones for flavivirus is time-consuming and difficult due to the toxicity of the flavivirus genome to E. coli . Herein, we applied a simple, rapid, and bacterium-free circular polymerase extension reaction (CPER) method to synthesize recombinant flaviviruses in vertebrate cells as well as insect cells. We started with the de novo synthesis of the JEV vaccine strain SA-14-14-2 in Vero cells using CPER, and then modified the CPER method to recover insect-specific flaviviruses (ISFs) in mosquito C6/36 cells. Chimeric Zika virus (ChinZIKV) based on the Chaoyang virus (CYV) backbone and the Culex flavivirus reporter virus expressing green fluorescent protein (CxFV-GFP) were subsequently rescued in C6/36 cells. CPER is a simple method for the rapid generation of flaviviruses and other potential RNA viruses. A CPER-based recovery system for flaviviruses of different host ranges was established, which would facilitate the development of countermeasures against flavivirus outbreaks in the future.

Age-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in the elderly. The pathology of neovascular age-related macular degeneration (nAMD), also known as wet AMD, is associated with an abnormal blood vessel growth in the eye and involves an imbalance of proangiogenic and antiangiogenic factors. Thrombospondin (TSP)-1 and TSP-2 are endogenous matricellular proteins that inhibit angiogenesis. TSP-1 is significantly diminished in eyes with AMD, although the mechanisms involved in its reduction are unknown. Granzyme B (GzmB) is a serine protease with an increased extracellular activity in the outer retina and choroid of human eyes with nAMD-related choroidal neovascularization (CNV). This study investigated whether TSP-1 and TSP-2 are GzmB substrates using in silico and cell-free cleavage assays and explored the relationship between GzmB and TSP-1 in human eyes with nAMD-related CNV and the effect of GzmB on TSP-1 in retinal pigment epithelial culture and an explant choroid sprouting assay (CSA). In this study, TSP-1 and TSP-2 were identified as GzmB substrates. Cell-free cleavage assays substantiated the GzmB proteolysis of TSP-1 and TSP-2 by showing dose-dependent and time-dependent cleavage products. TSP-1 and TSP-2 proteolysis were hindered by the inhibition of GzmB. In the retinal pigment epithelium and choroid of human eyes with CNV, we observed a significant inverse correlation between TSP-1 and GzmB, as indicated by lower TSP-1 and higher GzmB immunoreactivity. In CSA, the vascular sprouting area increased significantly with GzmB treatment and reduced significantly with TSP-1 treatment. Western blot showed significantly reduced expression of TSP-1 in GzmB-treated retinal pigment epithelial cell culture and CSA supernatant compared with that in controls. Together, our findings suggest that the proteolysis of antiangiogenic factors such as TSP-1 by extracellular GzmB might represent a mechanism through which GzmB may contribute to nAMD-related CNV. Future studies are needed to investigate whether pharmacologic inhibition of extracellular GzmB can mitigate nAMD-related CNV by preserving intact TSP-1., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The clinical work of ICU doctors is characterized by high intensity and medical risks, which lead to a highly stressful state for a long time and the occurrence of resignation due to long-term burnout. This study analyzes the correlation between the personal life, hospital work, social opinion, and psychological assessment of ICU physicians and their resignation intention., Subjects and Methods: This study is a multicenter questionnaire on the factors influencing resignation intention among ICU physicians. The study was completed through Critical Care E Institute (CCEI) and China Calm Therapy Research Group Academic Organization (CNCSG) by contacting critical care physicians in 3-A hospitals in 34 provinces in China. The questionnaire was in electronic format, and the results were filled in using the WeChat scan code. The survey included 22 indicators which included basic information about physicians (including gender, marriage, children, and income, etc.), hospital work (weekly working hours, on night duty, hospital environment, the evaluation of hospital's emphasis on medical staff, etc.), and SCL-90 psychological assessment., Results: A total of 1,749 ICU physicians completed the questionnaire. The results showed that 1,208 physicians (69.1%) intended to resign. There were statistical differences between the group's resignation intention and without resignation intention on 13 indicators. These indicators include professional title, night shift every few days, hospital hours/week, income satisfaction, work environment satisfaction, career prospect, and SCL-90 score, etc. (all p<0.05, respectively). The remaining nine indicators were not statistically different between the two groups (all p>0.05, respectively). Logistics analysis showed that working years, hospital hours (h/week), income satisfaction, work environment satisfaction, pride in hospital work, career prospects, and total SCL-90 score were all independent influences on physicians' choice of resignation intention (all p<0.05, respectively). The ROC curves' results showed that all seven indicators' predictive diagnostic value was low, with AUC areas ranging from 0.567 to 0.660. However, the combined diagnostic model of seven indicators has moderate diagnostic value. The AUC area of the model was 0.740 (95% CI: 0.718-0.760), with a sensitivity of 75.99% and specificity of 60.07%., Conclusions: Physicians' income, working years, work environment satisfaction, career prospects, and psychological well-being can influence the choice of physicians' resignation intention in Chinese intensive care units. Government administration and hospitals can develop appropriate policies to enhance doctors working in hospital, thus reducing physicians' resignation choices.

This retrospective study aimed to compare the effects of acupotomy combined with intra-articular injection of sodium hyaluronate (IA-SH) for the treatment of knee osteoarthritis (KOA). Eighty electronic medical records of patients with KOA were retrospectively analyzed. The patients were divided into an intervention group (n = 40, acupotomy plus IA-SH) and a control group (n = 40, IA-SH). Outcome measures included the visual analog scale, the Western Ontario and McMaster Universities Arthritis Index (WOMAC), and adverse events. Outcome data were collected and analyzed before and after treatment. The results of this study showed that there was a greater reduction in the visual analog scale (P < .01) and WOMAC scores (pain, P < .01; stiffness, P < .01; function, P < .01; total, P < .01) in the intervention group than in the control group. In addition, there were no significant differences in adverse events between the 2 groups. In this study, the effects of acupotomy plus IA-SH were superior to those of IA-SH alone for the treatment of patients with KOA. Further prospective studies are required to confirm these findings., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

The efficient capture of multi-pollutant residues in food is vital for food safety monitoring. In this study, in-situ-fabricated magnetic MIL-53(Al) metal organic frameworks (MOFs), with good magnetic responsiveness, were synthesized and applied for the magnetic solid-phase extraction (MSPE) of chloramphenicol, bisphenol A, estradiol, and diethylstilbestrol. Terephthalic acid (H 2 BDC) organic ligands were pre-coupled on the surface of amino-Fe 3 O 4 composites (H 2 BDC@Fe 3 O 4 ). Fe 3 O 4 @MIL-53(Al) MOF was fabricated by in-situ hydrothermal polymerization of H 2 BDC, Al (NO 3 ) 3 , and H 2 BDC@Fe 3 O 4 . This approach highly increased the stability of the material. The magnetic Fe 3 O 4 @MIL-53(Al) MOF-based MSPE was combined with high-performance liquid chromatography-photo diode array detection, to establish a novel sensitive method for analyzing multi-pollutant residues in milk. This method showed good linear correlations, in the range of 0.05-5.00 μg/mL, with good reproducibility. The limit of detection was 0.004-0.108 μg/mL. The presented method was verified using a milk sample, spiked with four pollutants, which enabled high-throughput detection and the accuracies of 88.17-107.58% confirmed its applicability, in real sample analysis.

To explore the differences between growth and population dynamics of natural Lycorma delicatula in the plantations and semi-natural forests, the susceptible stages and major suppression factors were determined to provide basis for the prediction and controlling the pest. The development duration and life table of L. delicatula in different habitats were established by using tracking method. The index of exclusion effect for lethal factors and the K -value in each development stage were calculated. The population trends were analyzed through the survival curve and key drivers of population change. The results showed that the development duration of L. delicatula in the plantation habitat and semi-natural habitat was significantly different, with thelatter being 25.7 d longer than the former. There were significant differences in the development duration of 1st-3rd-instars nymphs and pre-oviposition period of adults between these two habitats, but no significant difference in the 4th-instar nymphs. The total mortality rate in the plantation habitat and semi-natural habitat was 83.6% and 98.6%, respectively. The index of population trend in the plantation habitat was significantly higher than that in the semi-natural habitat. The population of L. delicatula increased sharply in the plantation habitat, but showed a decline trend in the semi-natural habitat. All of the survival curves of L. delicatula were Deevey-Ⅲ type, and the EIPCs of the "parasitic natural enemies" in egg stage were the highest in both habitats as 1.3 and 1.6, and the total K values were 0.2 and 0.3, respectively. The regression slopes of K -value of natural enemies were the highest (both 0.6). These findings revealed that the semi-natural habitat played an important role in the natural regulation of L. delicatula .