Identification of prognostic biomarkers for cholangiocarcinoma by combined analysis of molecular characteristics of clinical MVI subtypes and molecular subtypes.

Cholangiocarcinoma (CCA) is widely noted for its high degree of malignancy, rapid progression, and limited therapeutic options. This study was carried out on transcriptome data of 417 CCA samples from different anatomical locations. The effects of lipid metabolism related genes and immune related genes as CCA classifiers were compared. Key genes were derived from MVI subtypes and better molecular subtypes. Pathways such as epithelial mesenchymal transition (EMT) and cell cycle were significantly activated in MVI-positive group. CCA patients were classified into three (four) subtypes based on lipid metabolism (immune) related genes, with better prognosis observed in lipid metabolism-C1, immune-C2, and immune-C4. IPTW analysis found that the prognosis of lipid metabolism-C1 was significantly better than that of lipid metabolism-C2 + C3 before and after correction. KRT16 was finally selected as the key gene. And knockdown of KRT16 inhibited proliferation, migration and invasion of CCA cells.

Application of multi-planar reconstruction technique in endovascular repair of aortic dissection.

BACKGROUND: Endovascular repair of aortic dissection is an effective method commonly used in the treatment of Stanford type B aortic dissection. Stent placement during the operation was one-time and could not be repeatedly adjusted during the operation. Therefore, it is of great significance for cardiovascular physicians to fully understand the branch status, position, angle, and other information regarding aortic arch dissection before surgery. AIM: To provide more references for clinical cardiovascular physicians to develop treatment plans. METHODS: Data from 153 patients who underwent endovascular repair of aortic dissection at our hospital between January 2021 and December 2022 were retrospectively collected. All patients underwent multi-slice spiral computed tomography angiography. Based on distinct post-image processing techniques, the patients were categorized into three groups: Multiplanar reconstruction (MPR) (n = 55), volume reconstruction (VR) (n = 46), and maximum intensity projection (MIP) (n = 52). The detection rate of aortic rupture, accuracy of the DeBakey classification, rotation, and tilt angles of the C-arm during the procedure, dispersion after stent release, and the incidence of late complications were recorded and compared. RESULTS: The detection rates of interlayer rupture in the MPR and VR groups were significantly higher than that in the MIP group (P < 0.05). The detection rates of DeBakey subtypes I, II, and III in the MPR group were higher than those in the MIP group, and the detection rate of type III in the MPR group was significantly higher than that in the VR group (P < 0.05). There was no statistically significant difference in the detection rates of types I and II compared to the VR group (P > 0.05). The scatter rate of markers and the incidence of complications in the MPR group were significantly lower than those in the VR and MIP groups (P < 0.05). CONCLUSION: The application of MPR in the endovascular repair of aortic dissection has improved the detection rate of dissection rupture, the accuracy of anatomical classification, and safety.

Recent advances in C(sp3)-N bond formation via metallaphoto-redox catalysis.

The C(sp3)-N bond is ubiquitous in natural products, pharmaceuticals, biologically active molecules and functional materials. Consequently, the development of practical and efficient methods for C(sp3)-N bond formation has attracted more and more attention. Compared to the conventional ionic pathway-based thermal methods, photochemical processes that proceed through radical mechanisms by merging photoredox and transition-metal catalyses have emerged as powerful and alternative tools for C(sp3)-N bond formation. In this review, recent advances in the burgeoning field of C(sp3)-N bond formation via metallaphotoredox catalysis have been highlighted. The contents of this review are categorized according to the transition metals used (copper, nickel, cobalt, palladium, and iron) together with photocatalysis. Emphasis is placed on methodology achievements and mechanistic insight, aiming to inspire chemists to invent more efficient radical-involved C(sp3)-N bond-forming reactions.

Two Novel Diterpenoid Alkaloids from Aconitum pendulum.

Two previously uncharacterized compounds, an aconitine-type C19-diterpenoid alkaloid (1) and a napelline-type diterpenoid alkaloid C20-diterpenoid alkaloid (2), as well as ten known compounds (3-12), were isolated from Aconitum pendulum. Their structures were elucidated based on spectroscopic data, including 1D and 2D NMR, IR, HR-ESI-MS, and single-crystal X-ray diffraction analysis. The anti-insecticidal activities of these compounds were evaluated by contact toxicity tests against two-spotted spider mites, and compounds 1, 2, and 9 showed moderate contact toxicity, with LC50 values of 0.86±0.09, 0.95±0.23, and 0.89±0.19 mg/mL, respectively. This study highlights the potential use of diterpenoid alkaloids as natural plant-derived pesticides for the management of plant pests.

Myeloid cannabinoid CB1 receptor deletion confers atheroprotection in male mice by reducing macrophage proliferation in a sex-dependent manner.

AIMS: Although the cannabinoid CB1 receptor has been implicated in atherosclerosis, its cell-specific effects in this disease are not well understood. To address this, we generated a transgenic mouse model to study the role of myeloid CB1 signaling in atherosclerosis. METHODS AND RESULTS: Here, we report that male mice with myeloid-specific Cnr1 deficiency on atherogenic background developed smaller lesions and necrotic cores than controls, while only minor genotype differences were observed in females. Male Cnr1 deficient mice showed reduced arterial monocyte recruitment and macrophage proliferation with less inflammatory phenotype. The sex-specific differences in proliferation were dependent on estrogen receptor (ER)α-estradiol signaling. Kinase activity profiling identified a CB1-dependent regulation of p53 and cyclin-dependent kinases. Transcriptomic profiling further revealed chromatin modifications, mRNA processing and mitochondrial respiration among the key processes affected by CB1 signaling, which was supported by metabolic flux assays. Chronic administration of the peripherally-restricted CB1 antagonist JD5037 inhibited plaque progression and macrophage proliferation, but only in male mice. Finally, CNR1 expression was detectable in human carotid endarterectomy plaques and inversely correlated with proliferation, oxidative metabolism and inflammatory markers, suggesting a possible implication of CB1-dependent regulation in human pathophysiology. CONCLUSION: Impaired macrophage CB1 signaling is atheroprotective by limiting their arterial recruitment, proliferation and inflammatory reprogramming in male mice. The importance of macrophage CB1 signaling appears to be sex-dependent.

Realization of monolayer ZrTe5 topological insulators with wide band gaps.

Two-dimensional topological insulators hosting the quantum spin Hall effect have application potential in dissipationless electronics. To observe the quantum spin Hall effect at elevated temperatures, a wide band gap is indispensable to efficiently suppress bulk conduction. Yet, most candidate materials exhibit narrow or even negative band gaps. Here, via elegant control of van der Waals epitaxy, we have successfully grown monolayer ZrTe5 on a bilayer graphene/SiC substrate. The epitaxial ZrTe5 monolayer crystalizes in two allotrope isomers with different intralayer alignments of ZrTe3 prisms. Our scanning tunneling microscopy/spectroscopy characterization unveils an intrinsic full band gap as large as 254 meV and one-dimensional edge states localized along the periphery of the ZrTe5 monolayer. First-principles calculations further confirm that the large band gap originates from strong spin-orbit coupling, and the edge states are topologically nontrivial. These findings thus provide a highly desirable material platform for the exploration of the high-temperature quantum spin Hall effect.

Functional Group Induced Transformations in Stacking and Electron Structure in Mo2CTx/NiS Heterostructures.

The two-dimensional transition metal carbide/nitride family (MXenes) has garnered significant attention due to their highly customizable surface functional groups. Leveraging modern material science techniques, the customizability of MXenes can be enhanced further through the construction of associated heterostructures. As indicated by recent research, the Mo2CTx/NiS heterostructure has emerged as a promising candidate exhibiting superior physical and chemical application potential. The geometrical structure of Mo2CTx/NiS heterostructure is modeled and 6 possible configurations are validated by Density Functional Theory simulations. The variation in functional groups leads to structural changes in Mo2CTx/NiS interfaces, primarily attributed to the competition between van der Waals and covalent interactions. The presence of different functional groups results in significant band fluctuations near the Fermi level for Ni and Mo atoms, influencing the role of atoms and electron's ability to escape near the interface. This, in turn, modulates the strength of covalent interactions at the MXenes/NiS interface and alters the ease of dissociation of the MXenes/NiS complex. Notably, the Mo2CO2/NiS(P63/mmc) heterostructure exhibits polymorphism, signifying that two atomic arrangements can stabilize the structure. The transition process between these polymorphs is also simulated, further indicating the modulation of the electronic level of properties by a sliding operation.

Antibody-activation of connexin hemichannels in bone osteocytes with ATP release suppresses breast cancer and osteosarcoma malignancy.

Bone tissue represents the most frequent site of cancer metastasis. We developed a hemichannel-activating antibody, Cx43-M2. Cx43-M2, directly targeting osteocytes in situ, activates osteocytic hemichannels and elevates extracellular ATP, thereby inhibiting the growth and migration of cultured breast and osteosarcoma cancer cells. Cx43-M2 significantly decreases breast cancer metastasis, osteosarcoma growth, and osteolytic activity, while improving survival rates in mice. The antibody's inhibition of breast cancer and osteosarcoma is dose dependent in both mouse and human cancer metastatic models. Furthermore, Cx43-M2 enhances anti-tumor immunity by increasing the population and activation of tumor-infiltrating immune-promoting effector T lymphocytes, while reducing immune-suppressive regulatory T cells. Our results suggest that the Cx43-M2 antibody, by activating Cx43 hemichannels and facilitating ATP release and purinergic signaling, transforms the cancer microenvironment from a supportive to a suppressive state. Collectively, our study underscores the potential of Cx43-M2 as a therapeutic for treating breast cancer bone metastasis and osteosarcoma.

CircRNA SEC24A promotes osteoarthritis through miR-107-5p/CASP3 axis.

Background: Osteoarthritis (OA) is the most frequently diagnosed chronic joint disease. CircSEC24A is significantly elevated in OA chondrocytes upon IL-1ß stimulation. However, its biological function in OA is still not fully understood. Methods: The circRNAs-miRNA-mRNA network was predicted by bioinformatics analysis. An in vitro OA chondrocytes model was established by IL-1ß stimulation. The expression of circSEC24A, miR-107-5p, CASP3, apoptosis-related molecules and extracellular matrix (ECM) components were detected by Western blot and qRT-PCR. MTT assay and Annexin V/PI staining were employed to monitor cell viability and apoptosis, respectively. The interaction between circSEC24A and miR-107-5p, as well as the binding between miR-107-5p and CASP3 3' UTR were detected by luciferase reporter and RIP assays. Cytokine secretion was monitored by ELISA assay. The role of circSEC24A was also explored in anterior cruciate ligament transection (ACLT) rat models. Results: CircSEC24A and CASP3 were increased, but miR-107-5p was decreased in rat OA cartilage tissues and OA chondrocytes. CircSEC24A acted as a sponge of miR-107-5p. Knockdown of circSEC24A promoted chondrocyte proliferation, but suppressed chondrocyte apoptosis, ECM degradation and inflammation via sponging miR-107-5p. CASP3 was identified as a miR-107-5p target gene. MiR-107-5p mimics protected against OA progression via targeting CASP3. Silencing of circSEC24A alleviated OA progression in ACLT model. Conclusion: CircSEC24A promotes OA progression through miR-107-5p/CASP3 axis.

The role of Pleistocene dispersal in shaping species richness of sky island wintergreens from the Himalaya-Hengduan Mountains.

In addition to topography and climate, biogeographic dispersal has been considered to influence plant diversity in the Himalaya-Hengduan Mountains (HHM), yet, the mode and tempo of sky island dispersal and its influence on species richness has been little explored. Through phylogenetic analysis of Gaultheria ser. Trichophyllae, a sky island alpine clade within the HHM, we test the hypothesis that dispersal has affected current local species richness. We inferred the dynamics of biogeographic dispersal with correlation tests on direction, distance, occurrence time, and regional species richness. We found that G. ser. Trichophyllae originated at the end of the Miocene and mostly dispersed toward higher longitudes (eastward). In particular, shorter intra-regional eastward dispersals and longer inter-regional westward dispersals were most frequently observed. We detected a prevalence of eastward intra-region dispersals in both glacial periods and interglacials. These dispersals may have been facilitated by the reorganization of paleo-drainages and monsoon intensification through time. We suggest that the timing of dispersal corresponding to glacial periods and the prevalence of intra-region dispersal, rather than dispersal frequency, most influenced the pattern of species richness of G. ser. Trichophyllae. This study facilitates a more comprehensive understanding of biodiversity in the sky islands within the HHM.

X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson's Disease Mouse Model.

The secretory glutaminyl cyclase (sQC) and Golgi-resident glutaminyl cyclase (gQC) are responsible for N-terminal protein pyroglutamation and associated with various human diseases. Although several sQC/gQC inhibitors have been reported, only one inhibitor, PQ912, is currently undergoing clinic trials for the treatment of Alzheimer's disease. We report an X-ray crystal structure of sQC complexed with PQ912, revealing that the benzimidazole makes "anchor" interactions with the active site zinc ion and catalytic triad. Structure-guided design and optimization led to a series of new benzimidazole derivatives exhibiting nanomolar inhibition for both sQC and gQC. In a MPTP-induced Parkinson's disease (PD) mouse model, BI-43 manifested efficacy in mitigating locomotor deficits through reversing dopaminergic neuronal loss, reducing microglia, and decreasing levels of the sQC/gQC substrates, α-synuclein, and CCL2. This study not only offers structural basis and new leads for drug discovery targeting sQC/gQC but also provides evidence supporting sQC/gQC as potential targets for PD treatment.

[A new cucurbitane glycoside from Picrorhiza scrophulariiflora].

Chemical constituents from the ethanol extract of Picrorhiza scrophulariiflora were isolated and purified by column chromatography. Their structures were identified by HR-MS, 1D and 2D-NMR, and their cytotoxicity was assessed by CCK-8 assay. Four compounds were isolated and identified as follows: 2ß-D-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosterol-5,25-diene-22-one(1), 2ß-D-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5,24-diene-22-one(2), 25-acetoxy-2ß-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5-ene-22-one(3) and 25-acetoxy-2ß-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5,23-(E)-diene-22-one(4). Compound 1 represents a new cucurbitane glycoside. The half inhibitory concentrations of the 4 compounds exceeded 100 µmol·L~(-1) against four tumor cell lines, indicating no significant cytotoxicity.

The efficacy of using a multiparametric magnetic resonance imaging-based radiomics model to distinguish glioma recurrence from pseudoprogression.

OBJECTIVE: The early differential diagnosis of the postoperative recurrence or pseudoprogression (psPD) of a glioma is of great guiding significance for individualized clinical treatment. This study aimed to evaluate the ability of a multiparametric magnetic resonance imaging (MRI)-based radiomics model to distinguish between the postoperative recurrence and psPD of a glioma early on and in a noninvasive manner. METHODS: A total of 52 patients with gliomas who attended the Hainan Provincial People's Hospital between 2000 and 2021 and met the inclusion criteria were selected for this study. 1137 and 1137 radiomic features were extracted from T1 enhanced and T2WI/FLAIR sequence images, respectively.After clearing some invalid information and LASSO screening, a total of 9 and 10 characteristic radiological features were extracted and randomly divided into the training set and the test set according to 7:3 ratio. Select-Kbest and minimum Absolute contraction and selection operator (LASSO) were used for feature selection. Support vector machine and logistic regression were used to form a multi-parameter model for training and prediction. The optimal sequence and classifier were selected according to the area under the curve (AUC) and accuracy. RESULTS: Radiomic models 1, 2 and 3 based on T1WI, T2FLAIR and T1WI + T2T2FLAIR sequences have better performance in the identification of postoperative recurrence and false progression of T1 glioma. The performance of model 2 is more stable, and the performance of support vector machine classifier is more stable. The multiparameter model based on CE-T1 + T2WI/FLAIR sequence showed the best performance (AUC:0.96, sensitivity: 0.87, specificity: 0.94, accuracy: 0.89,95% CI:0.93-1). CONCLUSION: The use of multiparametric MRI-based radiomics provides a noninvasive, stable, and accurate method for differentiating between the postoperative recurrence and psPD of a glioma, which allows for timely individualized clinical treatment.

Three new phenols and one new lignan from Clematis terniflora var. manshurica (Rupr.) Ohwi with their anti-inflammatory activity.

Three undescribed phenols, mandshusica C-E (1-3) and a new lignan, mandshusica F (5), along with six known compounds (4, 6-10) were isolated from the roots and rhizomes of Clematis terniflora var. manshurica (Rupr.) Ohwi. Their structures were elucidated by extensive spectroscopic analysis as well as NMR and ECD calculations. Moreover, the possible biosynthetic pathways of compounds 1-3 were also discussed. All compounds were evaluated for their anti-inflammatory activities in LPS-induced RAW 264.7 cells. Compounds 1, 3, 4 significantly reduced the levels of NO and TNF-α, while compounds 2 and 8 significantly inhibited NO production in LPS-induced RAW264.7 cells.

Enhanced quantum secret sharing protocol for anonymous secure communication utilizing W states.

Quantum secret sharing (QSS) represents the fusion of quantum mechanics principles with secret information sharing, allowing a sender to distribute a secret among receivers for collective recovery. This paper introduces the concept of quantum anonymous secret sharing (QASS) to enhance the practicality of such protocols. We propose a QASS protocol leveraging W states, ensuring both recover-security and anonymity of shared secrets. Our protocol undergoes rigorous evaluation verifying their accuracy and fortifying their security against scenarios involving the active adversary. Additionally, acknowledging the imperfections inherent in real-world communication channels, we conduct a comprehensive analysis of protocol security and efficacy in noisy quantum networks. Our investigations reveal that W states exhibit good performance in mitigating noise interference, making them apt for practical applications.

Depletion of squalene epoxidase in synergy with glutathione peroxidase 4 inhibitor RSL3 overcomes oxidative stress resistance in lung squamous cell carcinoma.

Background: Lung squamous cell carcinoma (LUSC) lacks effective targeted therapies and has a poor prognosis. Disruption of squalene epoxidase (SQLE) has been implicated in metabolic disorders and cancer. However, the role of SQLE as a monooxygenase involved in oxidative stress remains unclear. Methods: We analyzed the expression and prognosis of lung adenocarcinoma (LUAD) and LUSC samples from GEO and TCGA databases. The proliferative activity of the tumors after intervention of SQLE was verified by cell and animal experiments. JC-1 assay, flow cytometry, and Western blot were used to show changes in apoptosis after intervention of SQLE. Flow cytometry and fluorescence assay of ROS levels were used to indicate oxidative stress status. Results: We investigated the unique role of SQLE expression in the diagnosis and prognosis prediction of LUSC. Knockdown of SQLE or treatment with the SQLE inhibitor terbinafine can suppress the proliferation of LUSC cells by inducing apoptosis and reactive oxygen species accumulation. However, depletion of SQLE also results in the impairment of lipid peroxidation and ferroptosis resistance such as upregulation of glutathione peroxidase 4. Therefore, prevention of SQLE in synergy with glutathione peroxidase 4 inhibitor RSL3 effectively mitigates the proliferation and growth of LUSC. Conclusion: Our study indicates that the low expression of SQLE employs adaptive survival through regulating the balance of apoptosis and ferroptosis resistance. In future, the combinational therapy of targeting SQLE and ferroptosis could be a promising approach in treating LUSC.