Controlled interconversion of macrocyclic atropisomers via defined intermediates.

Macrocyclic conformations play a crucial role in regulating their properties. Our understanding of the determinants to control macrocyclic conformation interconversion is still in its infancy. Here we present a macrocycle, octamethyl cyclo[4](1,3-(4,6)-dimethylbenzene)[4]((4,6-benzene)(1,3-dicarboxylate) (OC-4), that can exist at 298 K as two stable atropisomers with C2v and C4v symmetry denoted as C2v-OC-4 and C4v-OC-4, respectively. Heating induces the efficient stepwise conversion of C2v- to C4v-OC-4 via a Cs-symmetric intermediate (Cs-OC-4). It differs from the typical transition state-mediated processes of simple C-C single bond rotations. Hydrolysis and further esterification with a countercation dependence promote the generation of C2v- and Cs-OC-4 from C4v-OC-4. In contrast to C2v-OC-4, C4v-OC-4 can bind linear guests to form pseudo-rotaxans, or bind C60 or C70 efficiently. The present study highlights the differences in recognition behavior that can result from conformational interconversion, as well as providing insights into the basic parameters that govern coupled molecular rotations.

Monocyte to High-density Lipoprotein Cholesterol Ratio as a Predictor of Nonalcoholic Fatty Liver Disease in Childhood Obesity.

OBJECTIVE: Inflammation is involved in the development and progression of nonalcoholic fatty liver disease (NAFLD). The monocyte to high-density lipoprotein cholesterol ratio (MHR) has emerged as a marker for various inflammation-related diseases. The aim of the present study was to investigate the association between the MHR and NAFLD in a population with childhood obesity. METHODS: Based on hepatic ultrasound, a total of 504 children with obesity (357 with NAFLD and 147 without NAFLD) were included in the study. The correlation between the MHR and NAFLD risk factors was assessed by Pearson's and Spearman's analyses. Multivariate stepwise logistic regression analyses were conducted to explore the association between the MHR and the risk of NAFLD. RESULTS: The MHR in patients with NAFLD was significantly greater than that in patients without NAFLD [0.52 (0.44-0.67) versus 0.44 (0.34-0.57), P<0.001]. Multivariate stepwise logistic regression analysis demonstrated that the MHR [odds ratio (OR): 1.033, 95% confidence interval (CI): 1.015-1.051; P<0.001] was an independent predictor of NAFLD in childhood obesity patients, as were age (OR: 1.205, 95% CI: 1.059-1.371; P=0.005], waist circumference [OR: 1.037, 95% CI: 1.008-1.067; P=0.012], and alanine transaminase [OR: 1.067, 95% CI: 1.045-1.089; P<0.001]. Additionally, MHR quartiles showed a significant positive association with the incidence of NAFLD after adjusting for potential confounding factors. CONCLUSION: The present study showed that the MHR may serve as an available and useful indicator of NAFLD in individuals with childhood obesity.

Retraction: Recent advances in total synthesis of protoberberine and chiral tetrahydroberberine alkaloids.

Retraction of 'Recent advances in total synthesis of protoberberine and chiral tetrahydroberberine alkaloids' by Zhen-Xi Niu et al., Nat. Prod. Rep., 2024, https://doi.org/10.1039/d4np00016a.

Unveiling an anoikis-related risk model and the role of RAD9A in colon cancer.

OBJECTIVE: Colorectal cancer (CRC), specifically colon adenocarcinoma, is the third most prevalent and the second most lethal form of cancer. Anoikis is found to be specialized form of programmed cell death (PCD), which plays a pivotal role in tumor progression. This study aimed to investigate the role of the anoikis related genes (ARGs) in colon cancer. METHODS: Consensus unsupervised clustering, differential expression analysis, tumor mutational burden analysis, and analysis of immune cell infiltration were utilized in the study. For the analysis of RNA sequences and clinical data of COAD patients, data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were obtained. A prognostic scoring system for overall survival (OS) prediction was developed using Cox regression and LASSO regression analysis. Furthermore, loss-of-function assay was utilized to explore the role of RAD9A played in the progression of colon cancer. RESULTS: The prognostic value of a risk score composed of NTRK2, EPHA2, RAD9A, CDC25C, and SNAI1 genes was significant. Furthermore, these findings suggested potential mechanisms that may influence prognosis, supporting the development of individualized treatment plans and management of patient outcomes. Further experiments confirmed that RAD9A could promote proliferation and metastasis of colon cancer cells. These effects may be achieved by affecting the phosphorylation of AKT. CONCLUSION: Differences in survival time and the tumor immune microenvironment (TIME) were observed between two gene clusters associated with ARGs. In addition, a prognostic risk model was established and confirmed as an independent risk factor. Furthermore, our data indicated that RAD9A promoted tumorigenicityby activating AKT in colon cancer.

Accumulated ß-catenin is associated with human atrial fibrosis and atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with increased risk of stroke and mortality. It has been reported that the process of atrial fibrosis was regulated by ß-catenin in rats with AF. However, pathophysiological mechanisms of this process in human with AF remain unclear. This study aims to investigate the possible mechanisms of ß-catenin in participating in the atrial fibrosis using human right atrial appendage (hRAA) tissues . METHODS: We compared the difference of ß-catenin expression in hRAA tissues between the patients with AF and sinus rhythm (SR). The possible function of ß-catenin in the development of AF was also explored in mice and primary cells. RESULTS: Firstly, the space between the membrane of the gap junctions of cardiomyocytes was wider in the AF group. Secondly, the expression of the gap junction function related proteins, Connexin40 and Connexin43, was decreased, while the expression of ß-catenin and its binding partner E-cadherin was increased in hRAA and cardiomyocytes of the AF group. Thirdly, ß-catenin colocalized with E-cadherin on the plasma membrane of cardiomyocytes in the SR group, while they were dissociated and accumulated intracellularly in the AF group. Furthermore, the expression of glycogen synthase kinase 3ß (GSK-3ß) and Adenomatous Polyposis Coli (APC), which participated in the degradation of ß-catenin, was decreased in hRAA tissues and cardiomyocytes of the AF group. Finally, the development of atrial fibrosis and AF were proved to be prevented after inhibiting ß-catenin expression in the AF model mice. CONCLUSIONS: Based on human atrial pathological and molecular analyses, our findings provided evidence that ß-catenin was associated with atrial fibrosis and AF progression.

A ghost moth olfactory prototype of the lepidopteran sex communication.

Sex role differentiation is a widespread phenomenon. Sex pheromones are often associated with sex roles and convey sex-specific information. In Lepidoptera, females release sex pheromones to attract males, which evolve sophisticated olfactory structures to relay pheromone signals. However, in some primitive moths, sex role differentiation becomes diverged. Here, we introduce the chromosome-level genome assembly from ancestral Himalaya ghost moths, revealing a unique olfactory evolution pattern and sex role parity among Lepidoptera. These olfactory structures of the ghost moths are characterized by a dense population of trichoid sensilla, both larger male and female antennal entry parts of brains, compared to the evolutionary later Lepidoptera. Furthermore, a unique tandem of 34 odorant receptor 19 homologs in Thitarodes xiaojinensis (TxiaOr19) has been identified, which presents overlapped motifs with pheromone receptors (PRs). Interestingly, the expanded TxiaOr19 was predicted to have unconventional tuning patterns compared to canonical PRs, with nonsexual dimorphic olfactory neuropils discovered, which contributes to the observed equal sex roles in Thitarodes adults. Additionally, transposable element activity bursts have provided traceable loci landscapes where parallel diversifications occurred between TxiaOr19 and PRs, indicating that the Or19 homolog expansions were diversified to PRs during evolution and thus established the classic sex roles in higher moths. This study elucidates an olfactory prototype of intermediate sex communication from Himalaya ghost moths.

Proximal Femoral Metastasis From Epidermal Growth Factor Receptor-Mutated Lung Adenocarcinoma Mimicking Osteosarcoma on Magnetic Resonance Imaging.

The aggressive nature of lung cancer is frequently accompanied by a high incidence of bone metastasis; however, proximal femoral metastasis from lung cancer is comparatively uncommon when compared to other malignancies. In this report, we present the case of a 53-year-old Asian male who presented with pain in the left thigh and back. Magnetic resonance imaging revealed severe bone destruction with involvement of adjacent soft tissue mass at the left thigh, exhibiting imaging findings that mimic osteosarcoma. Subsequent bone biopsy confirmed the diagnosis of epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma with bone metastasis. The patient achieved survival following administration of osimertinib and underwent surgery for femoral metastases without palliative surgery for lung cancer. Therefore, proximal femoral metastasis from EGFR-mutated lung adenocarcinoma should be considered as a differential diagnosis in patients suspected to have osteosarcoma. The imaging findings of proximal femoral metastasis from EGFR-mutated lung adenocarcinoma were presented, and their therapeutic management was discussed.

Effect of osmanthus hydrolat on the aroma quality and volatile components of osmanthus black tea.

Osmanthus fragrans is an evergreen shrub with a pleasant fragrance and a wide range of applications in many fields. The condensed hydrolat obtained during the drying process of its fresh flowers was collected in a low-temperature vacuum environment and its sensory evaluation and volatile components were studied. The main aroma compounds in Osmanthus fragrans were dihydro-ß-ionone, nonanal, ß-cyclocitral, ß-ionone, benzaldehyde, α-ionone, and 6-methyl-5-hepten-2-one, whose contents were used as the main evaluation criteria, and the hydrolats obtained under different scenting and drying times were compared. This process can effectively collect the aroma components in Osmanthus fragrans and the optimal drying conditions were 50 °C for 5 h. The hydrolat was used to provide the scent of osmanthus black tea, which had a fresher and mellower taste, while the fragrance of osmanthus was abundant. These results show that osmanthus hydrolat can be used to provide the scent of floral black tea. Chemical compounds studied in this article: (-)-Catechin (PubChem CID: 1203); (-)-epigallocatechin gallate (PubChem CID: 65064); (-)-epicatechin gallate (PubChem CID: 367141); (-)-epigallocatechin (PubChem CID: 72277); (-)-epicatechin (PubChem CID: 72276); (-)-gallocatechin gallate (PubChem CID: 199472); (-)-catechin gallate (PubChem CID: 6419835); (-)-gallocatechin (PubChem CID: 9882981).

Changes in the recent three decades and survey on the current status of surgical treatment for esophageal cancer in China.

BACKGROUND: To review the changes and survey on status quo of the surgical treatment for esophageal cancer in China. The differences in diagnosis and treatment for esophageal cancer among hospitals in different regions across China were also investigated. METHODS: We sent questionnaires to 46 hospitals across China, investigating the volume of esophageal cancer surgeries, surgical procedures, and perioperative management under the guidance of esophageal surgery chiefs. RESULTS: A total of 46 questionnaires were sent out and collected. The survey results showed that in the past 5 years, the volume of surgeries for esophageal cancer remained stable by 23.9% of those hospitals, increased by 30.4%, and decreased by 45.7%. Of those patients treated by surgery, 19.1% were in the early stages, and 80.9% were in locally advanced stages. In terms of surgical procedures, 73.4% of the patients were treated by minimally invasive surgery and 85.7% of esophageal substitutes were a gastric conduit, 93.1% of the substitutes were pulled to the neck through the esophageal bed. For the lymph node dissection, 78.5% of the patients had a complete two-field lymph node dissection including the para-recurrent laryngeal nerve lymph nodes. Of the patients with neoadjuvant therapy, 53.5% received chemotherapy or chemotherapy plus immunotherapy (47.0%), and 43.5% had chemoradiation. CONCLUSIONS: Currently, in China, minimally invasive surgery-oriented multimodality treatment, including complete two-field lymph node dissection, has become the standard approach for esophageal cancer management. Over the past decade, this standardized approach has significantly improved prognosis compared to previous decades.

Pruned tea biomass plays a significant role in functional food production: A review on characterization and comprehensive utilization of abandon-plucked fresh tea leaves.

Tea is the second largest nonalcoholic beverage in the world due to its characteristic flavor and well-known functional properties in vitro and in vivo. Global tea production reaches 6.397 million tons in 2022 and continues to rise. Fresh tea leaves are mainly harvested in spring, whereas thousands of tons are discarded in summer and autumn. Herein, pruned tea biomass refers to abandon-plucked leaves being pruned in the non-plucking period, especially in summer and autumn. At present, no relevant concluding remarks have been made on this undervalued biomass. This review summarizes the seasonal differences of intrinsic metabolites and pays special attention to the most critical bioactive and flavor compounds, including polyphenols, theanine, and caffeine. Additionally, meaningful and profound methods to transform abandon-plucked fresh tea leaves into high-value products are reviewed. In summer and autumn, tea plants accumulate much more phenols than in spring, especially epigallocatechin gallate (galloyl catechin), anthocyanins (catechin derivatives), and proanthocyanidins (polymerized catechins). Vigorous carbon metabolism induced by high light intensity and temperature in summer and autumn also accumulates carbohydrates, such as soluble sugars and cellulose. The characteristics of abandon-plucked tea leaves make them not ideal raw materials for tea, but suitable for novel tea products like beverages and food ingredients using traditional or hybrid technologies such as enzymatic transformation, microbial fermentation, formula screening, and extraction, with the abundant polyphenols in summer and autumn tea serving as prominent flavor and bioactive contributors.

An emerging quaternary semiconductor nanoribbon with gate-tunable anisotropic conductance.

Two-dimensional noble transition metal chalcogenide (NTMC) semiconductors represent compelling building blocks for fabricating flexible electronic and optoelectronic devices. While binary and ternary compounds have been reported, the existence of quaternary NTMCs with a greater elemental degree of freedom remains largely unexplored. This study presents the pioneering experimental realization of a novel semiconducting quaternary NTMC material, AuPdNaS2, synthesized directly on Au foils through chemical vapor deposition. The ribbon-shaped morphology of the AuPdNaS2 crystal can be finely tuned to a thickness as low as 9.2 nm. Scanning transmission electron microscopy reveals the atomic arrangement, showcasing robust anisotropic features; thus, AuPdNaS2 exhibits distinct anisotropic phonon vibrations and electrical properties. The field-effect transistor constructed from AuPdNaS2 crystal demonstrates a pronounced anisotropic conductance (σmax/σmin = 3.20) under gate voltage control. This investigation significantly expands the repertoire of NTMC materials and underscores the potential applications of AuPdNaS2 in nano-electronic devices.

Mechanism of Lian Hua Qing Wen capsules regulates the inflammatory response caused by M1 macrophage based on cellular experiments and computer simulations.

PURPOSE: The polarization of macrophages with the resulting inflammatory response play a crucial part in tissue and organ damage due to inflammatory. Study has proved Lian Hua Qing Wen capsules (LHQW) can reduce activation of inflammatory response and damage of tissue derived from the inflammatory reactions. However, the mechanism of LHQW regulates the macrophage-induced inflammatory response is unclear. Therefore, we investigated the mechanism of LHQW regulated the inflammatory response of M1 macrophages by cellular experiments and computer simulations. METHODS: This study has analysed the targets and mechanisms of macrophage regulating inflammatory response at gene and protein levels through bioinformatics. The monomeric components of LHQW were analyzed by High Performance Liquid Chromatography (HPLC). We established the in vitro cell model by M1 macrophages (Induction of THP-1 cells into M1 macrophages). RT-qPCR and immunofluorescence were used to detect changes in gene and protein levels of key targets after LHQW treatment. Computer simulations were utilized to verify the binding stability of monomeric components and protein targets. RESULTS: Macrophages had 140,690 gene targets, inflammatory response had 12,192 gene targets, intersection gene targets were 11,772. Key monomeric components (including: Pinocembrin, Fargesone-A, Nodakenin and Bowdichione) of LHQW were screened by HPLC. The results of cellular experiments indicated that LHQW could significantly reduce the mRNA expression of CCR5, CSF2, IFNG and TNF, thereby alleviating the inflammatory response caused by M1 macrophage. The computer simulations further validated the binding stability and conformation of key monomeric components and key protein targets, and IFNG/Nodakenin was able to form the most stable binding conformation for its action. CONCLUSION: In this study, the mechanism of LHQW inhibits the polarization of macrophages and the resulting inflammatory response was investigated by computer simulations and cellular experiments. We found that LHQW may not only reduce cell damage and death by acting on TNF and CCR5, but also inhibit the immune recognition process and inflammatory response by regulating CSF2 and IFNG to prevent polarization of macrophages. Therefore, these results suggested that LHQW may act through multiple targets to inhibit the polarization of macrophages and the resulting inflammatory response.

The lncRNA LINC01605 promotes the progression of pancreatic ductal adenocarcinoma by activating the mTOR signaling pathway.

BACKGROUND: This study investigated the molecular mechanism of long intergenic non-protein coding RNA 1605 (LINC01605) in the process of tumor growth and liver metastasis of pancreatic ductal adenocarcinoma (PDAC). METHODS: LINC01605 was filtered out with specificity through TCGA datasets (related to DFS) and our RNA-sequencing data of PDAC tissue samples from Renji Hospital. The expression level and clinical relevance of LINC01605 were then verified in clinical cohorts and samples by immunohistochemical staining assay and survival analysis. Loss- and gain-of-function experiments were performed to estimate the regulatory effects of LINC01605 in vitro. RNA-seq of LINC01605-knockdown PDAC cells and subsequent inhibitor-based cellular function, western blotting, immunofluorescence and rescue experiments were conducted to explore the mechanisms by which LINC01605 regulates the behaviors of PDAC tumor cells. Subcutaneous xenograft models and intrasplenic liver metastasis models were employed to study its role in PDAC tumor growth and liver metastasis in vivo. RESULTS: LINC01605 expression is upregulated in both PDAC primary tumor and liver metastasis tissues and correlates with poor clinical prognosis. Loss and gain of function experiments in cells demonstrated that LINC01605 promotes the proliferation and migration of PDAC cells in vitro. In subsequent verification experiments, we found that LINC01605 contributes to PDAC progression through cholesterol metabolism regulation in a LIN28B-interacting manner by activating the mTOR signaling pathway. Furthermore, the animal models showed that LINC01605 facilitates the proliferation and metastatic invasion of PDAC cells in vivo. CONCLUSIONS: Our results indicate that the upregulated lncRNA LINC01605 promotes PDAC tumor cell proliferation and migration by regulating cholesterol metabolism via activation of the mTOR signaling pathway in a LIN28B-interacting manner. These findings provide new insight into the role of LINC01605 in PDAC tumor growth and liver metastasis as well as its value for clinical approaches as a metabolic therapeutic target in PDAC.

Minisci-Type Dehydrogenative Coupling of C(sp3)-H and N-Heteroaromatics Enabled by Photoelectrochemical Hydrogen Atom Transfer.

Minisci-type dehydrogenative coupling of C(sp3)-H and N-heteroaromatics was performed with N-hydroxysuccinimide as a hydrogen atom transfer catalyst in a photoelectrochemical cell composed of a mesoporous BiVO4 photoanode and a Pt electrode. In the absence of metal catalysts and chemical oxidants, a range of N-heteroarenes (e.g., quinolines, isoquinolines, and quinoxaline) can undergo coupling with various C(sp3)-H partners to form the corresponding products in excellent yields.

[Spatio-temporal Differentiation of County Carbon Budget and Territorial Space Optimization Zoning Strategy in Gansu Province from the Perspective of Carbon Neutrality].

Under the background of comprehensively practicing the overall system concept of the "living community" in the new era, incorporating the carbon neutral development goal into the territorial spatial planning and construction and establishing the territorial spatial pattern and optimization strategy in line with the actual development of Gansu Province are of great significance for promoting the comprehensive green low-carbon transformation and high-quality development of regional economy and society. Taking counties in Gansu Province as an example, based on the perspective of carbon neutrality research, the land use carbon budget of 87 counties in Gansu Province in 2010, 2015, and 2021 was calculated and analyzed. GIS spatial analysis and social network analysis were used to further explore their spatial differentiation characteristics and the overall characteristics of the carbon emission spatial correlation network. At last, combined with the main function zoning, the low-carbon oriented land space optimization zoning was carried out, and differentiated low-carbon development strategies were proposed. The results were as follows： ① Carbon emissions in Gansu Province showed an upward trend, but the increase rate decreased, showing a spatial distribution of "high in the central and eastern part of the country, low in the southwest." Construction land was the main carbon source. The carbon uptake showed a spatial distribution of "high in the south and low in the north, high in the west and low in the east." Woodlands were the main carbon sinks. The net carbon emissions showed an increasing trend, and approximately 58.62% of the counties in the province were in a carbon imbalance situation. ② In 2021, the spatial network of county carbon emissions was closely related, showing a "core-edge" pattern. The Chenguan District and Qilihe District were in the core position of the network and received more correlation relationships in the network. The network contacts in Longzhong area were frequent, followed by the contacts in Longdongnan area. ③ Based on carbon emissions, carbon sequestration, and ecological carrying capacity coefficients and using the results of spatial correlation of social networks as role positions, the province was divided into four carbon-neutral sub-districts. At the same time, superimposed analysis of the main function zoning, the county area of the province was reconstructed into seven territorial space zones, and the differentiated regional low-carbon optimization development strategy was proposed for each zone.

Prevalence and Molecular Characterization of Cryptosporidium spp., Giardia duodenalis, and Enterocytozoon bieneusi in Cattle in Heilongjiang Province, Northeast China.

Crytosporidium spp., Giardia duodenalis, and Enterocytozoon bieneusi are important diarrheal pathogens with a global distribution that threatens the health of humans and animals. Despite cattle being potential transmission hosts of these protozoans, the associated risks to public health have been neglected. In the present study, a total of 1155 cattle fecal samples were collected from 13 administrative regions of Heilongjiang Province. The prevalence of Cryptosporidium spp., G. duodenalis, and E. bieneusi were 5.5% (64/1155; 95% CI: 4.2-6.9), 3.8% (44/1155; 95% CI: 2.7-4.9), and 6.5% (75/1155; 95% CI: 5.1-7.9), respectively. Among these positive fecal samples, five Cryptosporidium species (C. andersoni, C. bovis, C. ryanae, C. parvum, and C. occultus), two G. duodenalis assemblages (E and A), and eight E. bieneusi genotypes (BEB4, BEB6, BEB8, J, I, CHS7, CHS8, and COS-I) were identified. Phylogenetic analysis showed that all eight genotypes of E. bieneusi identified in the present study belonged to group 2. It is worth noting that some species/genotypes of these intestinal protozoans are zoonotic, suggesting a risk of zoonotic disease transmission in endemic areas. The findings expanded our understanding of the genetic composition and zoonotic potential of Cryptosporidium spp., G. duodenalis, and E. bieneusi in cattle in Heilongjiang Province.

HHO optimized support vector machine classifier for traditional Chinese medicine syndrome differentiation of diabetic retinopathy.

AIM: To develop a classifier for traditional Chinese medicine (TCM) syndrome differentiation of diabetic retinopathy (DR), using optimized machine learning algorithms, which can provide the basis for TCM objective and intelligent syndrome differentiation. METHODS: Collated data on real-world DR cases were collected. A variety of machine learning methods were used to construct TCM syndrome classification model, and the best performance was selected as the basic model. Genetic Algorithm (GA) was used for feature selection to obtain the optimal feature combination. Harris Hawk Optimization (HHO) was used for parameter optimization, and a classification model based on feature selection and parameter optimization was constructed. The performance of the model was compared with other optimization algorithms. The models were evaluated with accuracy, precision, recall, and F1 score as indicators. RESULTS: Data on 970 cases that met screening requirements were collected. Support Vector Machine (SVM) was the best basic classification model. The accuracy rate of the model was 82.05%, the precision rate was 82.34%, the recall rate was 81.81%, and the F1 value was 81.76%. After GA screening, the optimal feature combination contained 37 feature values, which was consistent with TCM clinical practice. The model based on optimal combination and SVM (GA_SVM) had an accuracy improvement of 1.92% compared to the basic classifier. SVM model based on HHO and GA optimization (HHO_GA_SVM) had the best performance and convergence speed compared with other optimization algorithms. Compared with the basic classification model, the accuracy was improved by 3.51%. CONCLUSION: HHO and GA optimization can improve the model performance of SVM in TCM syndrome differentiation of DR. It provides a new method and research idea for TCM intelligent assisted syndrome differentiation.

[Research progress on nitrate isotope coupled multi-tracer tracing groundwater nitrate pollution]. / ç¡é ¸ç›åŒä½ç´ è€¦åˆå¤šç¤ºè¸ªå‰‚æº¯æºåœ°ä¸‹æ°´ç¡é ¸ç›æ±¡æŸ“ç ”ç©¶è¿›å±•.

Nitrate pollution in groundwater has become a global concern. One of the most important issues in controlling the nitrate pollution of groundwater is to identify the pollution source quickly and accurately. In this review, we firstly summarized the isotopic background values of potential sources of nitrate pollution in groundwater in 17 provinces (cities, autonomous regions) and 29 study areas in China, which could provide the fundamental database for subsequent research. Secondly, we reviewed the research progress of nitrate isotopes combined with multiple tracers for tracing nitrate in groundwater, and discussed their applicable conditions, advantages, and disadvantages. We found that halides and microorganisms combined with nitrate isotopes could accurately trace the pollution sources of domestic sewage, excrement and agricultural activities. The combination of Δ17O and nitrate isotopes could effectively distinguish the source of atmospheric deposition of nitrate in groundwater. The combination of groundwater age and nitrate isotopes could further determine the time scale of nitrate pollution. In addition, we summarized the application cases and compared the characteristics of mass balance mixing model, IsoSource model, Bayesian isotope mixing model, and EMMTE model for quantitative identification of nitrate pollution in groundwater. For the complexity and concealment of groundwater pollution sources, the coupling of nitrate isotopes with other chemical and biological tracing methods, as well as the application of nitrate isotope quantitative models, are effective tools for reliably identifying groundwater nitrate sources and transformation processes.

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.