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Abstract Germline mutations of the deubiquitinase BRCA1-associated protein 1 (BAP1) lead to the “BAP1 cancer syndrome” characterized by development of cancers. However, the role of BAP1 in hepatocellular carcinoma (HCC) is unclear. We found that BAP1 was upregulated at mRNA level in human HCCs and significantly correlated with a more aggressive tumour behaviour. Intriguingly, we observed cytoplasmic but no or minimal nuclear BAP1 in human HCC samples by immunohistochemistry. We observed that, while BAP1 protein was found mainly in the cytoplasm and less in the nuclei of HCC cell lines, BAP1 expression was predominantly nuclear in HepG2 cells, by cell fractionation and immunofluorescence analyses. Functionally, in the orthotopic liver injection mouse model, silencing the BAP1 predominant nuclear expression of HepG2 cells promoted intrahepatic tumor metastasis, with more frequent tumor microsatellite formation and venous invasion. With transcriptomic profiling, we identified RHOJ amongst the downregulated targets in HepG2 cells upon BAP1 knockdown. Subsequent overexpression of RHOJ suppressed cell migration in HCC cells, suggesting that BAP1 might upregulate RHOJ resulting in reduced cell migratory ability of HCC cells. Furthermore, we identified two transcription factors, CTCF and NRF1, which activated BAP1 transcription by binding to BAP1 promoter region. On the other hand, we uncovered that O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) physically bound to BAP1 in the nucleus, resulting in diminished stability of the nuclear BAP1. Intriguingly, OGT transcription was upregulated and was also under the control of CTCF and NRF1 in human HCC, acting as a negative regulator of BAP1. To summarize, this study uncovered the underlying mechanisms of the regulation of BAP1 and that loss of the nuclear localization of BAP1 protein contributed to enhanced cell migration in vitro and more aggressive tumor behavior in human HCCs.

Background Cardiovascular disease (CVD) is a major cause of human mortality worldwide, characterized by its insidious onset, intricate and variable course, and poor prognosis. Early identification and active intervention of potentially critically ill patients is essential to improve their prognosis. Objective To conduct a scoping review of the research on early warning assessment tools for cardiovascular disease risk at home and abroad, summarize and analyze their assessment content and application, ultimately providing reference for the selection of appropriate early warning tools for cardiovascular disease patients in China. Methods CNKI, Wanfang Data, VIP, CBM, PubMed, Web of Science, Cochrane Library, Embase, CINAHL, and Scopus were systematically searched from inception to May 2023. Two investigators independently screened literature and extracted data, analyzed in terms of assessment content, study subjects, validation method, reliability and validity, and predictive efficacy. Results A total of 16 papers were included, comprising 7 papers on the development and validation of assessment tools and 9 papers on the localized application of these tools, involving 20 early warning assessment tools for cardiovascular disease risk. The results of the analysis showed that each assessment tool contained 3 to 17 assessment items, with the most frequently mentioned items of age, systolic blood pressure, respiratory rate, oxygen saturation, heart rate, comorbidities, level of consciousness, and gender. The results of the reliability and validity tests for 2 papers indicated robust reliability and validity, while all other studies lacked reliability and validity evaluations. Ten papers reported the area under the curve (AUC), with values ranging from 0.550 to 0.926 9. Conclusion Diverse early warning assessment tools for cardiovascular disease risk are available, however, their overall quality remains to be improved and there is a lack of specific assessment tools. In the future, it is imperative to conduct further validations of the reliability and validity of the existing tools, and develop localized early warning assessment tools specialized for cardiovascular diseases considering the unique characteristics of the disease, which exhibit robust reliability and validity.

Abstract Lymphocyte decline, particularly the depletion of NK cells, is a prominent feature of immunosuppression following severe tissue injury, heightening the susceptibility of severe trauma patients to life-threatening infections. Previous research indicates that the reduction in the number of NK cells is closely associated with the process of cell death. Nonetheless, the precise mechanism of NK cell death remains unknown. Here, we discovered that following severe traumatic injury, NK cells undergo several cell death pathways, dominated by apoptosis and pyroptosis with coexistence of necrotic cell death, immunogenic cell death, ferroptosis, and autophagy. These NK cells with different paradigms of death have diverse cytokine expression profiles and diverse interactions with other immune cells. Further exploration revealed that hypoxia was strongly associated with this diverse paradigm of NK cell death. Detailed investigation of paradigms of cell death may help to enhance comprehension of lymphopenia post-severe trauma, to develop new strategy in preventing immunosuppression, and then to improve outcome for severe trauma population.

Background and ObjectiveChronic atrophic gastritis (CAG) is a complex chronic disease caused by multiple factors that frequently occurs disease in the clinic. The worldwide prevalence of CAG is high. Interestingly, clinical CAG patients often present with a variety of symptom phenotypes, which makes it more difficult for clinicians to treat. Therefore, there is an urgent need to improve our understanding of the complexity of the clinical CAG population, obtain more accurate disease subtypes, and explore the relationship between clinical symptoms and medication. Therefore, based on the integrated platform of complex networks and clinical research, we classified the collected patients with CAG according to their different clinical characteristics and conducted correlation analysis on the classification results to identify more accurate disease subtypes to aid in personalized clinical treatment.MethodTraditional Chinese medicine (TCM) offers an empirical understanding of the clinical subtypes of complicated disorders since TCM therapy is tailored to the patient’s symptom profile. We gathered 6,253 TCM clinical electronic medical records (EMRs) from CAG patients and manually annotated, extracted, and preprocessed the data. A shared symptom-patient similarity network (PSN) was created. CAG patient subgroups were established, and their clinical features were determined through enrichment analysis employing community identification methods. Different clinical features of relevant subgroups were correlated based on effectiveness to identify symptom–botanical botanical drugs correspondence. Moreover, network pharmacology was employed to identify possible biological relationships between screened symptoms and medications and to identify various clinical and molecular aspects of the key subtypes using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis.Results5,132 patients were included in the study: 2,699 males (52.60%) and 2,433 females (47.41%). The population was divided into 176 modules. We selected the first 3 modules (M29, M3, and M0) to illustrate the characteristic phenotypes and genotypes of CAG disease subtypes. The M29 subgroup was characterized by gastric fullness disease and internal syndrome of turbidity and poison. The M3 subgroup was characterized by epigastric pain and disharmony between the liver and stomach. The M0 subgroup was characterized by epigastric pain and dampness-heat syndrome. In symptom analysis, The top symptoms for symptom improvement in all three subgroups were stomach pain, bloating, insomnia, poor appetite, and heartburn. However, the three groups were different. The M29 subgroup was more likely to have stomach distention, anorexia, and palpitations. Citrus medica, Solanum nigrum, Jiangcan, Shan ci mushrooms, and Dillon were the most popular botanical drugs. The M3 subgroup has a higher incidence of yellow urine, a bitter tongue, and stomachaches. Smilax glabra, Cyperus rotundus, Angelica sinensis, Conioselinum anthriscoides, and Paeonia lactiflora were the botanical drugs used. Vomiting, nausea, stomach pain, and appetite loss are common in the M0 subgroup. The primary medications are Scutellaria baicalensis, Smilax glabra, Picrorhiza kurroa, Lilium lancifolium, and Artemisia scoparia. Through GO and KEGG pathway analysis, We found that in the M29 subgroup, Citrus medica, Solanum nigrum, Jiangcan, Shan ci mushrooms, and Dillon may exert their therapeutic effects on the symptoms of gastric distension, anorexia, and palpitations by modulating apoptosis and NF-κB signaling pathways. In the M3 subgroup, Smilax glabra, Cyperus rotundus, Angelica sinensis, Conioselinum anthriscoides, and Paeonia lactiflora may be treated by NF-κB and JAK-STAT signaling pathway for the treatment of stomach pain, bitter mouth, and yellow urine. In the M0 subgroup, Scutellaria baicalensis, Smilax glabra, Picrorhiza kurroa, Lilium lancifolium, and Artemisia scoparia may exert their therapeutic effects on poor appetite, stomach pain, vomiting, and nausea through the PI3K-Akt signaling pathway.ConclusionBased on PSN identification and community detection analysis, CAG population division can provide useful recommendations for clinical CAG treatment. This method is useful for CAG illness classification and genotyping investigations and can be used for other complicated chronic diseases.

Fe3+doped lanthanum nickelate perovskite ceramics were prepared by sol-gel method. Scanning electron microscope（SEM），energy dispersive spectrometer（EDS）and diffractometer（XRD）were used to characterize the micro morphology，element distribution and phase of Fe3+doped lanthanum nickelate. The electromagnetic parameters of Fe3+ doped lanthanum nickel oxide ceramics were measured by using vector network analyzer， the absorption performance was simulated，and the influence of Fe3+ doping amount on the absorption mechanism of lanthanum nickel oxide perovskite ceramics was studied. The XRD results indicate that Fe3+ ions successfully occupy the lattice position of Ni3+ ions，forming perovskite structured ceramics. The SEM results indicate that Fe3+ doping has little effect on the particle morphology of LaNiO3 ceramic material，while the EDS results confirm that the distribution of Fe element in LaNiO3 ceramic material is uniform and non-agglomerated. In terms of absorption performance，the optimal doping amount of Fe3+ doped LaNiO3 ceramic material is 0.05，with a matching thickness of 1.40 mm and a maximum peak value of –18.145 dB. The frequency bandwidth below –10 dB is 1.42 GHz（9.38-10.8 GHz）.

Methylobacterium species, the representative bacteria distributed in phyllosphere region of plants, often synthesize carotenoids to resist harmful UV radiations. Methylobacterium extorquens is known to produce a carotenoid pigment and recent research revealed that this carotenoid has a C30 backbone. However, its exact structure remains unknown. In the present study, the carotenoid produced by M. extorquens AM1 was isolated and its structure was determined as 4-[2-O-11Z-octadecenoyl-β-glucopyranosyl]-4,4′-diapolycopenedioc acid (1), a glycosylated C30 carotenoid. Furthermore, the genes related to the C30 carotenoid synthesis were investigated. Squalene, the precursor of the C30 carotenoid, is synthesized by the co-occurrence of META1p1815, META1p1816 and META1p1817. Further overexpression of the genes related to squalene synthesis improved the titer of carotenoid 1. By using gene deletion and gene complementation experiments, the glycosyltransferase META1p3663 and acyltransferase META1p3664 were firstly confirmed to catalyze the tailoring steps from 4,4′-diapolycopene-4,4′-dioic acid to carotenoid 1. In conclusion, the structure and biosynthetic genes of carotenoid 1 produced by M. extorquens AM1 were firstly characterized in this work, which shed lights on engineering M. extorquens AM1 for producing carotenoid 1 in high yield.

Abstract Urbanization is commonly associated with biodiversity loss and habitat fragmentation. However, urban environments often have greenspaces that can support wildlife populations, including rare species. The challenge for conservation planners working in these systems is identifying priority habitats and corridors for protection before they are lost. In a rapidly changing urban environment, this requires prompt decisions informed by accurate spatial information. Here, we combine several approaches to map habitat and assess connectivity for a diverse set of rare species in seven urban study areas across southern Michigan, USA. We incorporated multiple connectivity tools for a comprehensive appraisal of species‐habitat patterns across these urban landscapes. We observed distinct differences in connectivity by taxonomic group and site. The three turtle species (Blanding's, Eastern Box, and Spotted) consistently had more habitat predicted to be suitable per site than other evaluated species. This is promising for this at‐risk taxonomic group and allows conservation efforts to focus on mitigating threats such as road mortality. Grassland and prairie‐associated species (American Bumble Bee, Black and Gold Bumble Bee, and Henslow's Sparrow) had the least amount of habitat on a site‐by‐site basis. Kalamazoo and the northern Detroit sites had the highest levels of multi‐species connectivity across the entire study area based on the least cost paths. These connectivity results have direct applications in urban planning. Kalamazoo, one of the focal urban regions, has implemented a Natural Features Protection (NFP) plan to bolster natural area protections within the city. We compared our connectivity results to the NFP area and show where this plan will have an immediate positive impact and additional areas for potential consideration in future expansions of the protection network. Our results show that conservation opportunities exist within each of the assessed urban areas for maintaining rare species, a key benefit of this multi‐species and multi‐site approach.

Liver cancer (hepatocellular carcinoma) is a common cancer worldwide. It is an aggressive cancer, with high rates of tumor relapse and metastasis, high chemoresistance, and poor prognosis. Liver tumor-initiating cells (LTICs) are a distinctive subset of liver cancer cells with self-renewal and differentiation capacities that contribute to intratumoral heterogeneity, tumor recurrence, metastasis, and chemo-drug resistance. LTICs, marked by different TIC markers, have high plasticity and use diverse signaling pathways to promote tumorigenesis and tumor progression. LTICs are nurtured in the tumor microenvironment (TME), where noncellular and cellular components participate to build an immunosuppressive and tumor-promoting niche. As a result, the TME has emerged as a promising anticancer therapeutic target, as exemplified by some successful applications of tumor immunotherapy. In this review, we discuss the plasticity of LTICs in terms of cellular differentiation, epithelial–mesenchymal transition, and cellular metabolism. We also discuss the various components of the TME, including its noncellular and cellular components. Thereafter, we discuss the mutual interactions between TME and LTICs, including recently reported molecular mechanisms. Lastly, we summarize and describe new ideas concerning novel approaches and strategies for liver cancer therapy.

Background & Aims: Metabolic reprogramming is recognized as a cancer hallmark intimately linked to tumor hypoxia, which supports rapid tumor growth and mitigates the consequential oxidative stress. Phosphofructokinase-fructose bisphosphatase (PFKFB) is a family of bidirectional glycolytic enzymes possessing both kinase and phosphatase functions and has emerged as important oncogene in multiple types of cancer. However, its clinical relevance, functional significance, and underlying mechanistic insights in hepatocellular carcinoma (HCC), the primary malignancy that develops in the most important metabolic organ, has never been addressed. Methods: PFKFB4 expression was examined by RNA sequencing in The Cancer Genome Atlas and our in-house HCC cohort. The up-regulation of PFKFB4 expression was confirmed further by quantitative polymerase chain reaction in an expanded hepatitis B virus–associated HCC cohort followed by clinicopathologic correlation analysis. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated PFKFB4 knockout cells were generated for functional characterization in vivo, targeted metabolomic profiling, as well as RNA sequencing analysis to comprehensively examine the impact of PFKFB4 loss in HCC. Results: PFKFB4 expression was up-regulated significantly in HCC and correlated positively with TP53 and TSC2 loss-of-function mutations. In silico transcriptome-based analysis further revealed PFKFB4 functions as a critical hypoxia-inducible gene. Clinically, PFKFB4 up-regulation was associated with more aggressive tumor behavior. Functionally, CRISPR/Cas9-mediated PFKFB4 knockout significantly impaired in vivo HCC development. Targeted metabolomic profiling revealed that PFKFB4 functions as a phosphatase in HCC and its ablation caused an accumulation of metabolites in downstream glycolysis and the pentose phosphate pathway. In addition, PFKFB4 loss induced hypoxia-responsive genes in glycolysis and reactive oxygen species detoxification. Conversely, ectopic PFKFB4 expression conferred sorafenib resistance. Conclusions: PFKFB4 up-regulation supports HCC development and shows therapeutic implications.