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Luteolin improves cardiac function and myocardial remodeling with down-regulation of JNK/c-Jun/miR-221 pathway-inhibited autophagy in the diabetic heart, suggesting that luteolin's inhibition of DCM is associated with reversing JNK-suppressed autophagy.

Contradictory characteristics of elevated mutational burden and a “cold” tumor microenvironment (TME) coexist in liver kinase B1 (LKB1)–mutant non–small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult to treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1-driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1-driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation–mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically “hot” TME. Accordingly, PARP1 inhibition restored the disrupted IFNγ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC.Significance:Targeting PARP exerts dual effects to overcome LKB1 loss–driven immunotherapy resistance through triggering DNA damage and adaptive immunity, providing a rationale for dual PARP and PD-1 inhibition in treating LKB1-mutant lung cancers.

Sequences for qPCR primers.

PARP1 inhibition restores phosphorylated STAT1 from poly(ADP-ribosyl)ation and triggers synthetic lethality in LKB1-deficient cells. (a) A549 lung cancer cells were transfected with lentivirus expressing the indicated genes (LV-Ctrl, LV-LKB1-WT, and LV-LKB1-Mut) followed by treatment with olaparib (5μM) for 24 hours. The expression of pSTAT1 and PARP1 was analyzed by western blotting. (b-d) LLC1-shLkb1 and LLC1-shCtrl cells were pre-treated with olaparib (5μmol/L) for 6 hours and then stimulated with IFNγ for another 24 hours. Total pSTAT1 and STAT1 were quantified using western blot (b) and cell-surface PD-L1 was measured by flow cytometry (c). Q-PCR analysis was used to detect the expression of CXCL9 and PD-L1 (d). (e, f) The three groups of A549 cells were treated with IFNγ or IFNγ/olaparib and then refreshed the culture medium. The ratio of CD8+ T (effector cells) to A549 cells (target cell) ratio was 5:1. After 6 hours of incubation, QT-PCR analysis was used to detect the expression of indicated molecules of CD8+ T cells. (g) CD8+ T cells were treated with PBS or olaparib (5μmol/L) for 24 hours, and then the cells were collected for quantification of GZMB, PRF1, TNF, and IFNγ. CD8a was selected as the reference gene. (h) LLC-LV-Ctrl cells were treated with IFNγ/anti-PD-1 antibodies (20 μg/mL) in the absence or presence of olaparib (5 µM) or BMDCs (Tumor cells: DCs= 1:1) for 24 hours. Flow cytometry assay was used for apoptosis analysis of tumor cells. The right graph showed the quantification of tumor cell apoptosis. The data are presented as the mean ± SD of triplicate experiments. Statistical significance was determined by Student's t-test; ns, not significant; ****, P < 0.0001; ***, P < 0.001; **, P < 0.01; *, P < 0.05.

LKB1 deficiency impairs IFNγ pathway by hindering STAT1 phosphorylation. (a) Western blotting for detection of LKB1 and pAMPK expression in K and KL lung tumors. (b) UMAP of sub-clustered CD45+ immune cells from lung tumor samples of K and KL, colored by cell types. (c) The proportion of each immune cell type in K vs KL. (d) UMAP of sub-clustered cells from lung tumor samples of KP and KPL mice, colored by their 10 major cell types. (e) Gene set enrichment analysis (GSEA) showing downregulated response to interferon-gamma in KPL compared with KP. (f) A549 lung cancer cells were transfected with lentivirus expressing the indicated genes (LV-Ctrl, LV-LKB1-WT, and LV-LKB1-Mut) followed by stimulation with IFNγ. The expression of LKB1 and pAMPK was analyzed by western blotting. (g) Expression of pSTAT1 was measured by immunofluorescent staining in the three groups of A549 cells treated with IFNγ for 24 hours. Nuclei were visualized with DAPI (blue). Scale bar = 100 μm. (h) Immunoblot of the indicated IFNγ-induced proteins in different lung cancer cells. (i) Decreased IFNγ signaling downstream molecules, PD-L1, and chemokines, in KPL vs KP malignant cells. (j) PD-L1 transcription and chemokine signature score in tumor cells of K vs KL. (k) Western blot illustrating LKB1 expression in LLC1 and CMT-167 cells respectively. (l, m) Lewis lung cancer cells (LLC1) were transfected with shRNA specific for Lkb1 (shLkb1) or noneffective scrambled shRNA (shCtrl) followed by treatment with IFNγ for 24 hours. Western blotting for the detection of pSTAT1, STAT1, LKB1, and pAMPK expression was performed. (n) Flow cytometry analysis of cell surface PD-L1 of tumor cells from mice bearing LLC1-shLkb1 and LLC1-shCtrl tumors. (o) Tumors from mice bearing LLC1-shLkb1 and LLC1-shCtrl derived tumors were analyzed by Q-PCR for detecting CXCL9, CXCL10, CXCL11 and CCL5. (p) Representative IHC staining of CD8+ T cells and quantification of infiltrated CD8+ T cells in LLC-LV-Lkb1 tumors treated with indicated treatment (n=3 mice each group). Scale bar: 100 µm. n = 5 fields from independent tumors. Error bars represent mean ± SD. Statistical analyses were performed using unpaired t-tests. (****, P < 0.0001; ***, P < 0.001; **, P < 0.01; *, P < 0.05). (q) LLC1/LV-Ctrl or LLC1/LV-Lkb1 tumors were administered with different treatments, anti-PD-1 monotherapy or combination treatment (n=7 mice/group). Tumor size was monitored. Results are presented as mean ± SEM; * P < 0.05; two-way ANOVA.

Olaparib-derived dual effects sensitize LKB1-deficient tumors to anti-PD-1 immunotherapy in preclinical models. (a) Mice-bearing orthotopic lung tumors were treated with different therapies. Bioluminescent images were shown. (b) Immunofluorescence staining of PD-L1 and CD8+T cells in resected lung tumors of mice bearing orthotopic tumors (n= 6 fields from independent tumors). Scale bar, 100 μm. (c). Quantification of tumor-infiltrating CD8+ T cells in immunofluorescence staining. (d, e) IHC statistical analysis of PAR and PD-L1 expression in resected lung tumors of mice bearing orthotopic tumors (n=5 fields from independent tumors). (f) Quantification of tumor-infiltrating CD8+ T cells in IHC staining in resected lung tumors of mice bearing orthotopic tumors (n= 5 fields from independent tumors). Data are represented as mean ± SD; Student's t-tests; * P < 0.05; ** P < 0.01; ***P

Olaparib promoted STING activation in LKB1-mutant/loss NSCLC cells and LLC-derived tumors. (a) Cells were pre-treated with olaparib (5 μM) for 6 hours and then stimulated with IFNγ for 24 hours. The cell lysates were then subjected to western blot analysis for key proteins in the STING signaling pathway. (b) Representative IHC staining of STING and pSTING in LLC-LV-Lkb1 tumors and LLC-LV-Ctrl tumors following different treatments. Scale bar: 200 μm. (c) IHC statistical analysis of STING and pSTING expression in LLC-LV-Ctrl/Lkb1 tumors following indicated treatment. n=5 fields from independent tumors. Data are represented as mean ± SD; Student's t-tests; ***P

LKB1-interacting proteins identified by LC-MS/MS analysis.

Anti-PD-1/olaparib treatment promotes IFNγ secretion by CD8+ T cells in the tumor microenvironment. Mice-bearing orthotopic lung tumors were treated with different therapies. Representative IHC stainings of IFNγ expression in tumor tissues were shown. Scale bar, 50 μm.The right graph showed the IHC statistical analysis of IFNγ expression in tumor tissues. n = 5 fields from independent tumors. Data are represented as mean ± SD; Student's t-tests; **P

Mechanistic link between LKB1 and PARP1. (a) A bioinformatics tool (Pepsite) was utilized to predict the possibility of PARP1 docking on the di-Arg ER retention motif of LKB1 (PRR). (b) Localization of PARP1 (green) relative to LKB1 (red) in LKB1-WT A549 cells and H1299 cells. Scale bar = 20 μm. (c) Lysates from H1299 cells were subjected to IP with anti-PARP1 and anti-LKB1 antibodies and western blot analysis with the indicated antibodies. (d) IHC statistical analysis of PAR expression in LLC-shCtrl and LLC-shLkb1 tumors. n=5 fields from independent tumors. Data are represented as mean ± SD; Student's t-tests; **, P < 0.01.

Overexpression of mutant PARP1 promotes activation of the IFNγ signaling pathway. (a, b) A549 lung cancer cells and LLC1 lung cancer cells were transfected with the catalytic mutant Flag-PARP1 (E988) followed by stimulation with IFNγ. The lysates were then subjected to western blot analysis for indicated proteins.

Liver kinase B1 (LKB1) mutation is prevalent and a driver of resistance to immune checkpoint blockade (ICB) therapy for lung adenocarcinoma. Here leveraging single cell RNA sequencing data, we demonstrate that trafficking and adhesion process of activated T cells are defected in genetically engineered Kras-driven mouse model with Lkb1 conditional knockout. LKB1 mutant cancer cells result in marked suppression of intercellular adhesion molecule-1 (ICAM1). Ectopic expression of Icam1 in Lkb1-deficient tumor increases homing and activation of adoptively transferred SIINFEKL-specific CD8+ T cells, reactivates tumor-effector cell interactions and re-sensitises tumors to ICB. Further discovery proves that CDK4/6 inhibitors upregulate ICAM1 transcription by inhibiting phosphorylation of retinoblastoma protein RB in LKB1 deficient cancer cells. Finally, a tailored combination strategy using CDK4/6 inhibitors and anti-PD-1 antibodies promotes ICAM1-triggered immune response in multiple Lkb1-deficient murine models. Our findings renovate that ICAM1 on tumor cells orchestrates anti-tumor immune response, especially for adaptive immunity.

BackgroundThe increased risk of cardiovascular events in patients prescribed macrolides has been subject to debate for decades.MethodsMedline, EMBASE databases and ClinicalTrials.gov were searched from inception until August 31, 2022 for studies investigating the link between macrolides and cardiovascular risk. A meta-analysis was performed using a random-effects model.ResultsA total of 80 studies involving 39,374,874 patients were included. No association was found between macrolides and all-cause death. However, compared with the non-macrolide group, macrolides were associated with a significantly increased risk of ventricular arrhythmia or sudden cardiac death (VA or SCD) (azithromycin, relative ratio [RR]: 1.53; 95% confidence interval [CI]: 1.19 to 1.97; clarithromycin, RR: 1.52; 95% CI: 1.07 to 2.16). Besides, administration of macrolides was associated with a higher risk of cardiovascular disease (CVD) death (azithromycin, RR: 1.63; 95% CI: 1.17 to 2.27) and a slightly increased risk of myocardial infarction (MI) (azithromycin, RR: 1.08; 95% CI: 1.02 to 1.15). Interestingly, no association was observed between roxithromycin and adverse cardiac outcomes. Increased risk of VA or SCD was observed for recent or current use of macrolides, MI for former use, and CVD death for current use.ConclusionAdministration of macrolide antibiotics and timing of macrolide use are associated with increased risk for SCD or VTA and cardiovascular death, but not all-cause death.

Background Culex pipiens pallens (Diptera: Culicidae) can survive at low temperature for long periods. Understanding the effects of low-temperature stress on the gut microflora and gene expression levels in Cx. pipiens pallens, as well as their correlation, will contribute to the study of the overwintering mechanism of Cx. pipiens pallens. Methods The gut bacteria were removed by antibiotic treatment, and the survival of Cx. pipiens pallens under low-temperature stress was observed and compared with the control group. Then, full-length 16S rRNA sequencing and the Illumina HiSeq X Ten sequencing platform were used to evaluate the gut microflora and gene expression levels in Cx. pipiens pallens under low-temperature stress. Results Under the low-temperature stress of 7 °C, the median survival time of Cx. pipiens pallens in the antibiotic treatment group was significantly shortened by approximately 70% compared to that in the control group. The species diversity index (Shannon, Simpson, Ace, Chao1) of Cx. pipiens pallens decreased under low-temperature stress (7 °C). Non-metric multidimensional scaling (NMDS) analysis divided all the gut samples into two groups: control group and treatment group. Pseudomonas was the dominant taxon identified in the control group, followed by Elizabethkingia and Dyadobacter; in the treatment group, Pseudomonas was the dominant taxon, followed by Aeromonas and Comamonas. Of the 2417 differentially expressed genes (DEGs), 1316 were upregulated, and 1101 were downregulated. Functional GO terms were enriched in 23 biological processes, 20 cellular components and 21 molecular functions. KEGG annotation results showed that most of these genes were related to energy metabolism-related pathways. The results of Pearson’s correlation analysis showed a significant correlation between the gut microcommunity at the genus level and several DEGs. Conclusions These results suggest that the mechanism of adaptation of Cx. pipiens pallens to low-temperature stress may be the result of interactions between the gut bacterial community and transcriptome. Graphical Abstract

This paper focuses on mean exponential stability and L1-gain analysis for nonlinear positive Markov jump systems (NPMJSs) based on a switching transition probability (STP), where sector nonlinear functions and delays are adopted. By developing a nonlinear stochastic copositive Lyapunov-Krasovskii functional (NSCLKF) approach, a sufficient condition for mean exponential stability of nonlinear positive time-delay Markov jump system is first presented under mode-dependent average dwell time (MDADT) switching by using linear programming (LP) approach. Further, L1-gain performance analysis is obtained. Moreover, the corresponding results for NPMJSs are given under average dwell time (ADT) switching. Illustrative results are provided to verify the validity of the theoretical results.

BACKGROUND Liver cancer is the fourth most significant cause of cancer-related death. Lack of early diagnosis strategy and a scarcity of efficient therapy constitute the main reasons for its lethality. Exosomes, which contain various bioactive molecules, are characterized by high biocompatibility, low immunogenicity, and high transport efficiency. As a result, exosomes have become a research hotspot and present significant potential for cancer diagnosis biomarkers, biotherapeutics, therapy targets, drug carriers and therapeutic agents. AIM To explore the potential of exosomes in the diagnosis and treatment of liver cancer. METHODS We conducted a systematic literature search via PubMed and Web of Science. The following keywords were used: "exosomal biomarkers", "exosomal therapy", "exosomal therapy", and "liver cancer" or "HCC". The duplicate data were deleted by EndNote software. Literature search focused on full-texts and references of each article were carefully checked. One author (Xiao-Cui Wei) screened the literature that met the following inclusion criteria: (1) Detection of exosomes or their contents in clinical samples (body fluid or tissue); or (2) Exosomes served as drug carriers or therapeutic factors. Two authors (Xiao-Cui Wei and Li-Juan Liu) independently reviewed all retained literature and analyzed the information. RESULTS A total of 1295 studies were identified using the systematic literature search. Of these, 835 duplicate studies were removed. A further 402 irrelevant studies were excluded due to being irrelevant, including other diseases, review articles, the literature containing neither clinical samples nor animal experiments, exosome-independent studies, methods for detecting exosomes, or articles in Chinese. Finally, 58 published papers were retained and analyzed in the study. It showed a list of potential exosomal biomarkers that were upregulated in the blood samples of patients with liver cancer. Those downregulated in exosomes might serve as possible biotherapeutics. Some exosomes derived from cells in vitro were used for cytology or animal experiments to explore the mechanism of these exosome contents in disease. These contents might serve as potential targets for liver cancer. Additionally, we also discussed that exosomes serve as drug carriers or therapeutic factors. CONCLUSION Exosomes might serve as potential biomarkers or therapeutic biotargets in liver cancer and have the potential to act as drug carriers and self-treatment factors for liver cancer patients.

In this paper, the problems of stochastic finite-time stability and stabilization of discrete-time positive Markov jump systems are investigated. To deal with time-varying delays and switching transition probability (STP), stochastic finite-time stability conditions are established under mode-dependent average dwell time (MDADT) switching signal by developing a stochastic copositive Lyapunov-Krasovskii functional approach. Then a dual-mode dependent output feedback controller is designed, thus stochastic finite-time stabilization is achieved based on linear programming technique. Finally, two examples are given to show the effectiveness of our results.

BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. The association of hepatitis B virus (HBV) infection with HCC is hitherto documented. Exosomal miRNAs contribute to cancer progression and chemoresistance. HBV X protein has been known to modulate miRNAs that facilitate cell proliferation and the process of hepatocarcinogenesis. However, there has been no report on hepatitis B core antigen (HBc) regulating exosomal miRNAs to induce drug resistance of HCC cells. AIM To elucidate the mechanism by which HBc promotes Doxorubicin hydrochloride (Dox) resistance in HCC. METHODS Exosomes were isolated by ultracentrifugation. The morphology and size of exosomes were evaluated by Dynamic Light Scattering (DLS) and transmission electron microscopy (TEM). The miRNAs differentially expressed in HCC were identified using The Cancer Genome Atlas (TCGA) database. The level of miR-135a-5p in patient tissue samples was detected by quantitative polymerase chain reaction. TargetScan and luciferase assay were used to predict and prove the target gene of miR-135a-5p. Finally, we identified the effects of miR-135a-5p on anti-apoptosis and the proliferation of HCC in the presence or absence of Dox using flow cytometry, Cell counting kit 8 (CCK-8) assay and western blot. RESULTS We found that HBc increased the expression of exosomal miR-135a-5p. Integrated analysis of bioinformatics and patient samples found that miR-135a-5p was increased in HCC tissues in comparison with paracancerous tissues. Bioinformatic analysis and in vitro validation identified vesicle-associated membrane protein 2 (VAMP2) as a novel target gene of miR-135a-5p. Functional assays showed that exosomal miR-135a-5p induced apoptosis protection, cell proliferation, and chemotherapy resistance in HCC. In addition, the rescue experiment demonstrated that VAMP2 reversed apoptosis protection, cell growth, and drug resistance by miR-135a-5p. Finally, HBc promoted HCC anti-apoptosis, proliferation, and drug resistance and prevented Dox-induced apoptosis via the miR-135a-5p/VAMP2 axis. CONCLUSION These data suggested that HBc upregulated the expression of exosomal miR-135a-5p and promoted anti-apoptosis, cell proliferation, and chemical resistance through miR-135a-5p/VAMP2. Thus, our work indicated an essential role of the miR-135a-5p/VAMP2 regulatory axis in chemotherapy resistance of HCC and a potential molecular therapeutic target for HCC.

Gastrointestinal (GI) cancers, including malignancies in the gastrointestinal tract and accessory organs of digestion, represent the leading cause of death worldwide due to the poor prognosis of most GI cancers. An investigation into the potential molecular targets of prediction, diagnosis, prognosis, and therapy in GI cancers is urgently required. Proliferating cell nuclear antigen (PCNA) clamp associated factor (PCLAF), which plays an essential role in cell proliferation, apoptosis, and cell cycle regulation by binding to PCNA, is a potential molecular target of GI cancers as it contributes to a series of malignant properties, including tumorigenesis, epithelial-mesenchymal transition, migration, and invasion. Furthermore, PCLAF is an underlying plasma prediction target in colorectal cancer and liver cancer. In addition to GI cancers, PCLAF is also involved in other types of cancers and autoimmune diseases. Several pivotal pathways, including the Rb/E2F pathway, NF-κB pathway, and p53-p21 cascade, are implicated in PCLAF-mediated diseases. PCLAF also contributes to some diseases through dysregulation of the p53 pathway, WNT signal pathway, MEK/ERK pathway, and PI3K/AKT/mTOR signal cascade. This review mainly describes in detail the role of PCLAF in physiological status and GI cancers. The signaling pathways involved in PCLAF are also summarized. Suppression of the interaction of PCLAF/PCNA or the expression of PCLAF might be potential biological therapeutic strategies for GI cancers.

A photo-switchable hetero-complementary quadruple H-bonding array, which consists of an azobenzene-derived ureidopyrimidinone (UPy) module (Azo-UPy) and a nonphotoactive diamidonaphthyridine (DAN) derivative (Napy-1), is constructed based on a reversible photo-locking approach. Upon UV (390 nm)/Vis (460 nm) light irradiations, photo-switchable quadruple H-bonded dimerization between Azo-UPy and Napy-1 can be achieved with exhibiting 4.8×104 -fold differences in binding strength (ON/OFF ratios). Furthermore, smart polymeric gels with unique photo-controlled macroscopic self-assembly behavior can be fabricated by introducing such quadruple H-bonding array as photo-regulable noncovalent interfacial connections.

Exploring new noncovalent bonding motifs with reversibly tunable binding affinity is of fundamental importance in manipulating the properties and functions of supramolecular self-assembly systems and materials. Herein, for the first time, we demonstrate a unique visible-light-switchable telluro-triazole/triazolium-based chalcogen bonding (ChB) system in which the Te moieties are connected by azobenzene cores. The binding strengths between these azo-derived ChB receptors and the halide anions (Cl

Contradictory characteristics of elevated mutational burden and a “cold” tumor microenvironment (TME) coexist in liver kinase B1 (LKB1)–mutant non–small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult to treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1-driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1-driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation–mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically “hot” TME. Accordingly, PARP1 inhibition restored the disrupted IFNγ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC.Significance:Targeting PARP exerts dual effects to overcome LKB1 loss–driven immunotherapy resistance through triggering DNA damage and adaptive immunity, providing a rationale for dual PARP and PD-1 inhibition in treating LKB1-mutant lung cancers.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally, with hepatitis B virus (HBV) infection accounting for over half of all cases. HBV leads to the development of HCC according to a body of literature. Our previous research and other studies also suggest that HBV causes chemotherapeutic treatment resistance, however, the mechanism is uncertain. The WNT family, which encodes secreted signaling molecules, has been linked to carcinogenesis in a variety of malignancies, including HCC. However, little is known regarding WNT7B, a WNT ligand, in the development of HCC and HBV-induced chemoresistance. In this study, the bioinformatics analysis and immunohistochemistry (IHC) staining of clinical samples revealed that WNT7B was overexpressed in HBV-associated HCC tissues versus nontumor liver tissues, which was related to HCC patient survival. Further study in vitro showed that WNT7B and its receptor frizzled-4 (FZD4) were upregulated in response to large hepatitis B surface antigens (L-HBs). L-HBs increased canonical WNT signaling in HCC cells through WNT7B/FZD4. According to functional experiments, WNT7B enhanced the cell proliferation and metastasis in HCC. In vivo and in vitro studies investigated whether L-HBs induced sorafenib resistance by WNT7B in HCC. Interestingly, L-HBs suppressed sorafenib-induced mitophagy by increasing WNT7B/CTNNB1 signaling, resulting in chemoresistance. The findings revealed that WNT7B could be a promising molecular therapeutic target as well as a predictor of sorafenib resistance in HBV-related HCC. The suppression of HBV structural proteins such as L-HBs may play a crucial role in systemic chemotherapy resistance in HBV-associated HCC.

While the formation of superatomic nanoclusters by the three-dimensional assembly of icosahedral units was predicted in 1987, the synthesis and structural determination of such clusters have proven to be incredibly challenging. Herein, we employ a mixed-ligand strategy to prepare phosphinous acid-phosphinito gold nanocluster Au

In situ growth of nanostructures on substrates is a strategy for designing highly efficient catalytic materials. Herein, multimetallic CuCoNi oxide nanowires are synthesized in situ on a three-dimensional nickel foam (NF) substrate (CuCoNi-NF) by a hydrothermal method and applied to peroxydisulfate (PDS) activation as immobilized catalysts. The catalytic performance of CuCoNi-NF is evaluated through the degradation of organic pollutants such as bisphenol A (BPA) and practical wastewater. The results indicate that the NF not only plays an important role as the substrate support but also serves as an internal Ni source for material fabrication. CuCoNi-NF exhibits high activity and stability during PDS activation as it mediates electron transfer from BPA to PDS. CuCoNi-NF first donates electrons to PDS to arrive at an oxidized state and subsequently deprives electrons from BPA to return to the initial state. CuCoNi-NF maintains high catalytic activity in the pH range of 5.2-9.2, adapts to a high ionic strength up to 100 mM, and resists background HCO

Although the phytotoxicity of graphene-based materials has been investigated extensively, the effects of different graphene-based materials on nutrient uptake in plants remain unclear. Here, we analyzed the differences in phytotoxicity between single-layer graphene oxide (sGO) and multi-layer graphene oxide (mGO) by analyzing the growth status and nitrate (NO

In the present study, we surveyed the ascomycetes from bamboo of

Atomically precise copper clusters are highly desirable catalysts for electrocatalytic CO

Background: Dyskeratosis congenita is a rare hereditary disease. A correct diagnosis of this disease might be delayed due to its rarity. Therefore, a deep understanding of the characteristics of this condition is necessary to assist in early diagnosis.Case presentation: A 16-year-old male was admitted to the hospital with the complaint of abdominal pain. The patient was examined to consider the diagnosis of acute portal vein thrombosis. In the previously-consulted hospital, the patient was diagnosed with "splenomegaly, portal hypertension, and hypoxemia" and treated with splenic resection. After surgery, he began developing portal vein thrombosis. Since the patient had the classic triad of reticulate hyperpigmentation, nail dystrophy, and leukoplakia, these observations in combination with the patient's genetic testing report for hereditary diseases prepared outside our hospital led to the diagnosis of congenital dyskeratosis in our hospital. Conclusion: In the absence of any other evident reasons, when the patient presents with changes in the skin, nails, leukoplakia, etc., and multiple organ functions are affected at the same time, a diagnosis of dyskeratosis congenita should be suspected. A better understanding of the genetics underlying this rare disease condition would assist in improving its diagnosis and better monitoring disease progression and treatment.

Purpose: To investigate the prevalence and clinical characteristics of myelinated retinal nerve fibre (MRNF) in a large teleophthalmology system.Methods: All records between January 2015 and Decemb...

For the deoxygenation of fatty acids to hydrocarbon biofuels, the catalytic mechanism is still unclear at the molecular level. Here, the deoxygenation mechanism of butyric acid catalyzed by a Ni12P6 cluster has been theoretically studied at the GGA–PBE/DNP, DSPP level in dodecane solution, in which butyric acid and the Ni12P6 cluster are preferred as the reactant model of palmitic acid and the catalyst model of Ni2P, respectively. For the deoxygenation of butyric acid, there are three main reactions i.e., (reaction (I)) through direct decarboxylation to propane, (reaction (II)) through decarbonylation and hydrodehydration/hydroreduction to propane, and (reaction (III)) through hydroreduction and/or hydrodehydration to n-butane. Propane stems from the decarbonylation (reaction (II)) rather than direct decarboxylation (reaction (I)). For reaction (II), the optimal pathway should be through butyraldehyde or direct decarbonylation and not through propyl alcohol. Furthermore, CO mainly originates from butyraldehyde at low temperature and from direct decarbonylation at high temperature. From butyraldehyde, decreasing temperature is beneficial to the n-butyl alcohol formation through hydroreduction, and increasing temperature is preferable to the propane formation through decarbonylation. For reaction (III), from n-butyl alcohol, n-butane comes from direct hydrodehydration at low temperature, and from successive dehydration and hydroreduction through n-butylene at high temperature. The present reaction mechanism network may promote the novel design of a highly selective catalyst toward the deoxygenation of fatty acids.

Al-Containing MCM-41 catalysts exhibit good catalytic activity toward glucose-to-fructose isomerization. However, the catalytic contribution of typical functional groups over Al active sites is a little unclear. Here, on the pore surface of Al-doped MCM-41, there are two different active sites, i.e., –[SiO]2[SiO(H)]Al[OH] ([Al-1]) with one hydroxyl and –[SiO][SiO(H)]Al[OH]2 ([Al-2]) with two hydroxyls. Over these two active sites, the catalytic mechanisms for the isomerization of glucose to fructose have been theoretically studied, combining molecular mechanics and hybrid quantum mechanics calculations. The glucose-to-fructose isomerization usually involves three successive reaction stages, i.e., ring-opening, tautomerization, and ring-closure. Among them, aldose–ketose tautomerization is the rate-determining step, which is related to the intramolecular C2 → C1 H-shift. The catalytic activity of the Al-containing active sites originates from three factors, i.e., the Lewis acidity of the Al site, a proton donor in the form of an Al–O(H)–Si group and a proton acceptor in the form of an Al–OH group. The [Al-2] active site with two hydroxyls displays higher catalytic activity than the [Al-1] active site with one hydroxyl, which mainly depends on the Lewis acidity of the aluminium atom in the active site.

Herein, we report a 54-nuclei copper nanocluster, [Cu54S13O6(tBuS)20(tBuSO3)12] (Cu54), which is the largest atom-precise CuI/CuII mix-valent cluster reported. The Cu54 nanoclusters supported by TiO2 exhibit decent photocatalytic activity for phenol degradation under visible light. This work provides a platform to explore the catalytic behaviors of CuI/CuII nanosystems.

In this paper, a unique orthogonal photoresponsive tristable [3]rotaxane molecular shuttle (R1) is constructed, which consists of two CBPQT4+ macrocycles interlocked via a dumbbell component containing three recognition sites, including photoswitchable azobenzene (AB) and naphthalene-derived azobenzene (NP-AB) units separated by a 1,5-dioxynaphthalene (DNP) unit. The two azo units that are encapsulated by the CBPQT4+ macrocycles in the pristine state can be E/Z photoisomerized separately upon irradiation using UV (365 nm) and yellow (>550 nm) light (for the AB unit) and using blue (420–430 nm) and yellow (>550 nm) light (for the NP-AB unit), thus achieving the distinctive orthogonal phototriggered shuttling of the CBPQT4+ macrocycles between the azo and DNP units. This means that charge transfer (CT) absorption (at 620 nm, generated from the NP⊂CBPQT4+ encapsulation complex) related to R1 can be fully photoregulated between three spectral states with good reversibility. Moreover, UV-light-irradiated [2]rotaxane analogues that are embedded with NP-AB or AB units are found to be insensitive to red light (620 nm) irradiation. These features, together with the peculiarity of the orthogonal photo-responsiveness, enable this novel photochromic [3]rotaxane to be potentially applied as a multistate molecular switch or as an optical information storage medium with non-destructive readout.