Search

Abstract Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.

Abstract Background In recent years, the prevalence and incidence of porcine epidemic diarrhea virus (PEDV) infection have been on the rise. The occurrence of multiviral infections and recombination mutations has led to accelerated viral evolution and reduced vaccine efficacy. In the present study, a PEDV strain was isolated from a pig farm (Chongqing Province, China) with an outbreak of porcine diarrhea, and its S gene was found to be recombinant. Results The optimal trypsin concentration for blind passage of PEDV in Vero cells was determined to be 7.5 µg/mL. Following two blind passages of the virus in Vero cells, the virus was unable to adapt to the cells. Therefore, PEDV was blindly passaged in IPEC-J2 cells using the optimal concentration of trypsin (5 µg/mL). Next, a series of characterization experiments were performed. Recombination analyses of the isolates using software revealed that the S gene of strain CHCQ-2023 was derived from the primary parent strain PEDV-1 C and secondary parent strain SQ2014, with recombination occurring at a 3152 bp breakpoint. Furthermore, a specific B-cell antigenic epitope was predicted on the S2 subunit of the S protein. Conclusion A PEDV strain was isolated and characterized, and its S gene was characterized. The findings provide a bioinformatic basis for the study of PEDV strain variation due to genetic recombination.

Abstract Gastric cancer (GC) remains a significant global health challenge due to its high morbidity and mortality rates. The development of GC is a multi-hit process and the exploration of precancerous lesions is crucial. To elucidate the molecular and cellular dynamics underlying gastric carcinogenesis, we conducted an integrative single-cell RNA sequencing analysis of 26,028 high-quality cells from gastric antral mucosa biopsies across various stages, including non-atrophic gastritis, chronic atrophic gastritis, intestinal metaplasia, and early gastric cancer. By constructing a detailed single-cell atlas, we identified distinct epithelial cell subpopulations and their corresponding molecular signatures. We focused on the biological link between gastric epithelial cells and cancer cells. Notably, we observed that gland mucous cells acquired an intestinal-like stem cell phenotype during metaplasia, with MUC6, MUC2 and OLFM4 emerging as the specific markers for unique endocrine cells in early malignant lesions. Additionally, our analysis highlighted UPP1 as a key oncogene, with its expression progressively increasing from normal epithelial cells to malignant cells. UPP1 upregulation was shown to promote GC cell proliferation and migration, implicating it in the oncogenic process. Further, we explored the impact of Helicobacter pylori infection on gene expression, revealing that Helicobacter pylori infection upregulates UPP1 via the NF-κB pathway. Our cell-cell communication analysis underscored the significant role of the Macrophage migration inhibitory factor pathway in the tumor microenvironment, contributing to GC progression. Various key molecules involved in intestinal metaplasia, along with UPP1 and the Macrophage migration inhibitory factor pathway, collectively illustrate the multifaceted nature and complexity of gastric cancer evolution, highlighting the cumulative impacts that drive tumorigenesis.

Abstract Lenvatinib, a multi-kinase inhibitor, has been approved as first-line treatment for advanced hepatocellular carcinoma (HCC), but its efficacy is limited. We have shown previously that lenvatinib and epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) combination therapy overcomes lenvatinib resistance in HCC with high level of EGFR expression (EGFRhigh). We present here the results of a single-arm, open-label, exploratory study of lenvatinib plus the EGFR-TKI gefitinib for patients with HCC resistance to lenvatinib (NCT04642547; n = 30). Only patients with EGFRhigh HCC and progressive disease after lenvatinib treatment were recruited in the study. The most frequent adverse events of all grades were fatigue (27 patients; 90%), followed by rash (25 patients; 83.3%), diarrhea (24 patients; 80%), and anorexia (12 patients; 40%). Among 30 patients, 9 (30%) achieved a confirmed partial response and 14 (46.7%) had stable disease according to mRECIST criteria. Based on RECIST1.1, 5 (16.7%) achieved a confirmed partial response and 18 (60%) had stable disease. The estimated median progression free survival (PFS) and overall survival (OS) time were 4.4 months (95% CI: 2.5 to 5.9) and13.7 months (95% CI: 9.0 to NA), respectively. The objective response rate (ORR) of the patients in the present study compares very favorable to that seen for the two approved second line treatments for HCC (cabozantinib ORR of 4%; regorafenib ORR of 11%). Given that this combination was well-tolerated, a further clinical study of this combination is warranted.

Abstract Background Prophylactic corticosteroids have been widely used to mitigate the inflammatory response induced by cardiopulmonary bypass (CPB). However, the impact of this treatment on clinically important outcomes in infants remains uncertain. Methods We systematically searched databases (Medline, Embase, and Cochrane Central Register of Controlled Trials), Clinical Trials Registry, and Google Scholar from inception to March 1, 2024. Randomized controlled trials (RCTs) in which infants undergoing on-pump cardiac surgery received prophylactic corticosteroids or placebo were selected. The risk of bias was assessed using the Cochrane Collaboration risk-of-bias tool. Considering clinical heterogeneity between studies, the random-effects model was used for analysis. Subgroup analyses on the neonatal studies and sensitivity analyses by the leave-one-out method were also conducted. Results Eight RCTs comprising 1,920 patients were included. Our analysis suggested no significant difference in postoperative mortality (2.1% vs. 3.3%, risk ratio (RR) = 0.71, 95% confidence interval (CI) [0.41, 1.21]). Significantly increased insulin treatment in infants (19.0% vs. 6.5%, RR = 2.78, 95% CI [2.05, 3.77]) and significantly reduced duration of mechanical ventilation in neonates (mean difference = -22.28 h, 95% CI [-42.58, -1.97]) were observed in the corticosteroids group. There were no differences between groups for postoperative acute kidney injury, cardiac arrest, extracorporeal membrane oxygenation support, low cardiac output syndrome, neurologic events, infection, or length of postoperative intensive care unit stay. Conclusions Current evidence does not support the routine prophylactic use of corticosteroids in infants undergoing cardiac surgery with CPB. Further large-scale research is needed to investigate the optimal agent, dosing regimen, and specific impact on various types of cardiac surgery. Trial registration This systematic review and meta-analysis was registered at the International Prospective Register of Systematic Reviews (CRD42023400176).

In light of the successful experience of ITQ-management in many countries’ fishery reforms, the Chinese government has also carried out corresponding reform pilot projects in some cities. But unfortunately, these reforms were not successful. Based on the author’s own participation in the pilot reform of the fishery industry in Zhoushan City, Zhejiang Province, this article analyzes the reasons for the failure of the reform through research methods such as interviews and investigations. This study finds out that on the surface, the reason for the failure is the inaction of local governments, which has led to inadequate definition, transfer, supervision, and protection of fishing rights. However, the underlying reason is the inadequacy of the existing legal system of China’s fishing industry, leading to a lack of corresponding responsibility of local governments, followed by the absence of motivation to reform. This article reveals the close connection between the willingness of local governments in implementing ITQ management and the existing legal design, and explores a neglected key issue— the responsibility of local governments that comply with the ITQ-management method. Although ITQ-management has achieved remarkable results in some developed countries, its failure in China reveals the importance of local government responsibility. Therefore, this article, targeted at the responsibilities of local governments, proposes suggestions like adding ITQ management legal responsibilities to fisheries law, and refining its structure, content and evaluation methods. This research can not only be used for reference by the Chinese legal system, but also by many other countries with inadequate local government responsibilities.

Abstract Background Learning to perform strabismus surgery is an essential aspect of ophthalmologists’ surgical training. Automated classification strategy for surgical steps can improve the effectiveness of training curricula and the efficient evaluation of residents’ performance. To this end, we aimed to develop and validate a deep learning (DL) model for automated detecting strabismus surgery steps in the videos. Methods In this study, we gathered 479 strabismus surgery videos from Shanghai Children’s Hospital, affiliated to Shanghai Jiao Tong University School of Medicine, spanning July 2017 to October 2021. The videos were manually cut into 3345 clips of the eight strabismus surgical steps based on the International Council of Ophthalmology’s Ophthalmology Surgical Competency Assessment Rubrics (ICO-OSCAR: strabismus). The videos dataset was randomly split by eye-level into a training (60%), validation (20%) and testing dataset (20%). We evaluated two hybrid DL algorithms: a Recurrent Neural Network (RNN) based and a Transformer-based model. The evaluation metrics included: accuracy, area under the receiver operating characteristic curve, precision, recall and F1-score. Results DL models identified the steps in video clips of strabismus surgery achieved macro-average AUC of 1.00 (95% CI 1.00–1.00) with Transformer-based model and 0.98 (95% CI 0.97-1.00) with RNN-based model, respectively. The Transformer-based model yielded a higher accuracy compared with RNN-based models (0.96 vs. 0.83, p

Identifying cable insulation defects is crucial for preventing system failures and ensuring the reliability of electrical infrastructure. This paper introduces a novel method leveraging the Markov transition field (MTF) and Transformer network to improve the precision of cable insulation defect identification and enhance the algorithm's noise resistance. Firstly, the algorithm performs modal transformation on the time series data acquired by the ultrasonic probe through MTF, generating corresponding images. Following this, the image data are input into a pre-trained Transformer network to achieve automated feature extraction. Subsequently, a multi-head attention mechanism is introduced, which assigns weights to the features extracted by the Transformer network, thereby emphasizing the most critical information for the identification task. Finally, more accurate defect identification is achieved based on the weighted features. The results demonstrate that this method achieves higher accuracy and stronger noise resistance compared to traditional image processing and recognition methods, making it a robust solution for cable insulation defect identification.

Ginger, as a rich herb resource in China, has played an important role in food and medicine since ancient times. It is also known as a medicinal and edible homologous plant that possesses unique medical and nutritional values. Ginger polysaccharide is considered one of the most important bio-active components in ginger, which have attracted many attentions for various of bioactivities. In this review, the methods of extraction and purification of polysaccharide, as well as structural characteristics are discussed, what’s more, functional properties including antioxidant, immunity regulatory, anti-tumor and their influencing factors are reviewed. It is expected to provide valuable reference for further research and industrial application of ginger polysaccharide.

The accurate estimation of grassland carrying capacity (GCC) in the alpine grasslands of the Changjiang River source region is crucial for managing livestock loads and ensuring ecological security on the Qinghai-Tibetan Plateau. Previous remote sensing methods have predominantly focused on yield indicators, often neglecting quality indicators, which hampers precise GCC estimation. Here, we collected 25 samples from the Dangqu basin, analyzing various grass parameters including yield, crude protein (CP), neutral detergent fiber (NDF), and acid detergent fiber (ADF). Then, we developed models to optimize GCC using quality indicators derived from GF5B images, assessing performance through Pearson correlation coefficient (R2), root mean square error (RMSE), and relative root mean square error (rRMSE). Results were found to show an average yield of 61.26 g/m2, with CP, ADF, and NDF ranging from 5.81% to 18.75%, 45.47% to 58.80%, and 27.50% to 31.81%, respectively. Spectra in the near-infrared range, such as 1918 nm, and spectral indices improved the accuracy of the hyperspectral inversion of grass parameters. The GCC increased from 0.51 SU·hm−2 to 0.63 SU·hm−2 post-optimization, showing an increasing trend from northwest to southeast. This study enhances GCC estimation accuracy, aiding in reasonable livestock management and effective ecological preservation.

In this study, a systematic taxonomic analysis was carried out on the lichen genus Peltula, collected from Helan Mountain in China; three new species (Peltula helanense, P. overlappine, and P. reticulata) and a new record (P. crispatula (Nyl.) Egea) for China were identified. Four species were identified by morph-anatomical, chemical, and phylogenetic analyses by combining two gene loci (ITS and LSU). Peltula helanense is with tiny individual thalli up to 1mm, attached by creamy-white cylindrical rhizoids and apothecia filling the whole squamule. Peltula overlappine is characterized by thallus squamulose forming rosette-shaped patches and squamules with distinctive thickened margins. Peltula reticulata is characterized by brownish brown thallus and squamules with densely reticulate upper surface. P. crispatula is characterized by irregular squamules attached to a tuft of hyphae. The four species are described in detail, compared, and discussed with similar species, and images of morpho-anatomical structures of the four species are also provided. Moreover, a key to the species of Peltula from Helan Mountain is provided. The results enrich the data of the genus Peltula and also indicate that the rich diversity of lichen species in Helan Mountain is worthy of in-depth study.

ObjectivesPerform a bibliometric analysis on the role of LAG-3 in the domain of cancer, elucidate the prevailing areas of research, and visually depict the evolutionary trajectory and prospective directions of LAG-3 research over the past twenty-three decades.Materials and methodsBetween 2000 and 2023, a comprehensive review of scholarly articles pertaining to LAG-3 research in the context of cancer was carried out using the Web of Science Core Collection (WoSCC) database. Bibliometric analysis can be conducted by taking advantage of VOSviewer (version 1.6.16) and CiteSpace (version 6.2.R4). Create a network diagram to visually represent various authors, countries, and organizations while assessing the publishing years, journals, references, and keywords.ResultsIn conclusion, 1841 records were identified and published in 587 publications. These records were authored by 12,849 individuals affiliated with 2491 institutes across 74 countries. There has been a substantial surge in publications subsequent to 2013. The USA, China, and Germany gave the majority of records, amounting to 69.69%. American institutions actively engage in collaboration with institutions located in other countries. Triebel, F., Vignali, Dario A. A., Workman, Creg J. Drake, Charles G., and Elkord, Eyad are highly regarded authors in their respective fields. However, it is worth noting that Triebel exhibits limited collaboration with other writers. The examination of the role of LAG-3 in cancer and its potential for use in clinical settings is a discernible trend, as seen by keyword analysis.ConclusionThe scientific interest in and attention towards LAG-3 has experienced a significant rise since 2013. The United States is leading the way, with China following closely behind. Promoting collaboration among writers, nations, and institutions with varied backgrounds is imperative. The discipline of immunotherapy is currently seeing ongoing progress. A thorough investigation of the distinctive cis ligand TCR-CD3 complex of LAG-3 and its signal transduction mechanism is necessary. Additionally, it is worthwhile to explore novel combinations of LAG-3 therapy.

Abstract To compare and assess the choroidal and retinal microstructural vascularity in amblyopic eyes with the fellow eyes in anisometropic amblyopic children using angiography optical coherence tomography (Angio-OCT). Twenty-seven children (54 eyes; 5.59 ± 1.08 years old; 59.3% girls) were enrolled in this study. Choroidal thickness (CT) was measured with the use of the enhanced depth imaging mode in Angio-OCT. Parafoveal/peripapillary vascular density indices and the foveal avascular zone (FAZ) size were analyzed by MATLAB code programming on Angio-OCT images. The mean FAZ size of the amblyopic eyes were larger both in superficial and deep capillary plexus layer (SCPL/DCPL). Compared with the contralateral eyes (BCVA were normal), all the vascular density indices of SCPL and DCPL in the parafoveal and peripapillary zones were lower in the amblyopic eyes, however, the difference was insignificant (p > 0.05). No significant decrease was observed in four quadrants analyses of the amblyopic eyes (p > 0.05). Except for the measurement at 2000 µm and 1500 µm from the fovea in temple, CT in amblyopic eyes were significantly thicken than the fellow eyes (p

Winter jujube is susceptible to cold stress during cold storage, resulting in quality deterioration. Shelf life of winter jujube after cold storage has not been investigated. This study investigated the effects of 1.0 μL L−1 1-methylcyclopropene (1-MCP) fumigation treatment for 24 h on the quality characteristics of jujube fruits (Zizyphus jujuba Mill. cv. Dalidongzao) during cold storage. The jujubes from the early experimental stage (0 d) were stored at room temperature (20 ± 1 °C) to estimate the shelf life. The remaining jujubes were transferred to cold storage at 0 ± 1 °C and were removed during the middle (40 d) and the later (60 d) stages of the experiment. The decay rate, firmness, color, titratable acidity, total phenolics and flavonoids, antioxidant activity, and antioxidant enzyme activity of winter jujube were measured every 3 days until the end of shelf life. The results indicated that the application of 1-MCP treatment extended the time for jujube to exceed a decay rate of more than 10 % by three days after 40 and 60 days of cold storage. 1-MCP treatment effectively retard the decrease of total phenolic and flavonoid content in jujube, and maintain high free radical scavenging ability and antioxidant enzyme activity throughout shelf life storage.

ABSTRACTRecent studies have demonstrated that the antitumor immunity of immune cells can be modulated by gut microbiota and their metabolites. However, the underlying mechanisms remain unclear. Here, we showed that the serum butyric acid level is positively correlated with the expression of programmed cell death-1 (PD-1) on circulating CD8+ and Vγ9 Vδ2 (Vδ2+) T cells in patients with non-small cell lung cancer (NSCLC). Responder NSCLC patients exhibited higher levels of serum acetic acid, propionic acid, and butyric acid than non-responders. Depletion of the gut microbiota reduces butyrate levels in both feces and serum in tumor-bearing mice. Mechanistically, butyrate increased histone 3 lysine 27 acetylation (H3K27ac) at the promoter region of Pdcd1 and Cd28 in human CD8+ T cells, thereby promoting the expression of PD-1/CD28 and enhancing the efficacy of anti-PD-1 therapy. Butyrate supplementation promotes the expression of antitumor cytokines in cytotoxic CD8+ T cells by modulating the T-cell receptor (TCR) signaling pathway. Collectively, our findings reveal that the metabolite butyrate of the gut microbiota facilitates the efficacy of anti-PD-1 immunotherapy by modulating TCR signaling of cytotoxic CD8 T cells, and is a highly promising therapeutic biomarker for enhancing antitumor immunity.

ObjectiveTraditional Chinese medicine (TCM) has been used for the treatment of chronic liver diseases for a long time, with proven safety and efficacy in clinical settings. Previous studies suggest that the therapeutic mechanism of TCM for hepatitis B cirrhosis may involve the gut microbiota. Nevertheless, the causal relationship between the gut microbiota, which is closely linked to TCM, and cirrhosis remains unknown. This study aims to utilize two-sample Mendelian randomization (MR) to investigate the potential causal relationship between gut microbes and cirrhosis, as well as to elucidate the synergistic mechanisms between botanical drugs and microbiota in treating cirrhosis.MethodsEight databases were systematically searched through May 2022 to identify clinical studies on TCM for hepatitis B cirrhosis. We analyzed the frequency, properties, flavors, and meridians of Chinese medicinals based on TCM theories and utilized the Apriori algorithm to identify the core botanical drugs for cirrhosis treatment. Cross-database comparison elucidated gut microbes sharing therapeutic targets with these core botanical drugs. MR analysis assessed consistency between gut microbiota causally implicated in cirrhosis and microbiota sharing therapeutic targets with key botanicals.ResultsOur findings revealed differences between the Chinese medicinals used for compensated and decompensated cirrhosis, with distinct frequency, dosage, properties, flavors, and meridian based on TCM theory. Angelicae Sinensis Radix, Salviae Miltiorrhizae Radix Et Rhizoma, Poria, Paeoniae Radix Alba, Astragali Radix, Atrctylodis Macrocephalae Rhizoma were the main botanicals. Botanical drugs and gut microbiota target MAPK1, VEGFA, STAT3, AKT1, RELA, JUN, and ESR1 in the treatment of hepatitis B cirrhosis, and their combined use has shown promise for cirrhosis treatment. MR analysis demonstrated a positive correlation between increased ClostridialesvadinBB60 and Ruminococcustorques abundance and heightened cirrhosis risk. In contrast, Eubacteriumruminantium, Lachnospiraceae, Eubacteriumnodatum, RuminococcaceaeNK4A214, Veillonella, and RuminococcaceaeUCG002 associated with reduced cirrhosis risk. Notably, Lachnospiraceae shares key therapeutic targets with core botanicals, which can treat cirrhosis at a causal level.ConclusionWe identified 6 core botanical drugs for managing compensated and decompensated hepatitis B cirrhosis, despite slight prescription differences. The core botanical drugs affected cirrhosis through multiple targets and pathways. The shared biological effects between botanicals and protective gut microbiota offer a potential explanation for the therapeutic benefits of these key herbal components in treating cirrhosis. Elucidating these mechanisms provides crucial insights to inform new drug development and optimize clinical therapy for hepatitis B cirrhosis.

BackgroundThe evidence for the effectiveness of electroacupuncture (EA) for post-stroke urinary incontinence (PSUI) patients remains unclear. Therefore, the purpose of this systematic review and meta-analysis was to assess the efficacy of EA for PSUI.Methods and analysisEight English and Chinese databases were searched from their inception until 1 August 2023 to collect randomized controlled trials (RCTs) that investigated the effect of EA on PSUI. Two reviewers independently selected studies that met the eligibility criteria, extracted the necessary data, and assessed the risk of bias for included studies using Cochrane Handbook version 5.1.0. Meta-analysis was performed using Review Manager software (version 5.4.1). Publication bias detection was conducted using STATA (version 16.0). Sequential analysis was performed using TSA 0.9.5.10 Beta. The Grading of Recommendations Assessment, Development, and Evaluation System (GRADE) was used for assessing the certainty of evidence.ResultsWe included 15 RCTs involving a total of 1,414 patients. The narrative analysis revealed that compared with sham EA, genuine EA exhibited greater efficacy in reducing occurrences of 24-h urinary incontinence while also enhancing maximum cystometric capacity (MCC). Moreover, this effect remained significant even during the 3-month follow-up period. Fourteen studies were encompassed within the quantitative analysis. In contrast to active interventions, EA did not yield an improvement in the responder rate (RR 1.53, 95% CI 0.61 to 3.80, p = 0.36). When compared with basic treatments, the combination of EA with them led to a reduction in 24-h urinary incontinence occurrences (MD −0.56, 95% CI −0.60 to −0.52, p

Industrial structure markedly affects the level of carbon emissions generated in a region. It is imperative to study the industrial structure of the Chengdu-Chongqing region to obtain information to achieve regional high-quality development by promoting low-carbon development. We selected 16 cities in Chengdu-Chongqing area as the research object in this study. The total carbon emissions (CE), carbon intensity (CI) and per capita carbon emissions (PCE) were calculated for each city. The green industry development (GI) evaluation indexes were then extracted, and the comprehensive evaluation value was determined using the entropy weight-TOPSIS model (EWM-TOPSIS). The green industry development was used as the core explanatory variable to construct a system representing the dynamic relationship between green industry development and carbon intensity using the quantile regression (QR) model. The results of the study showed that: (1) the total carbon emissions of Chengdu-Chongqing region increased whereas the carbon intensity decreased from 2010 to 2020. (2) The green industry development evaluation results showed that Chengdu-Chongqing had unevenly distributed green industry development during the study period, and Chengdu and Chongqing cities had higher green industry development values than other cities. (3) The green industry development of the region had a significant negative effect on carbon intensity at low quantile and a significant positive effect on carbon intensity at high quantile. Energy supply (ES) was positively correlated with the carbon intensity of the region at 1 % level of significance, whereas urbanization rate (U) and power consumption (PEC) were negatively correlated with the carbon intensity at 1 % level of significance. We comprehensively evaluated the development of green industry and introduced it as a core explanatory variable into the quantile regression model to explore the relationship between regional carbon emission intensity and industrial development. The results provide a reference for designing strategies to promote high-quality development in the cities in the Chengdu-Chongqing region.

Background & Aims: Exploiting key regulators responsible for hepatocarcinogenesis is of great importance for the prevention and treatment of hepatocellular carcinoma (HCC). However, the key players contributing to hepatocarcinogenesis remain poorly understood. We explored the molecular mechanisms underlying the carcinogenesis and progression of HCC for the development of potential new therapeutic targets. Methods: The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) and Genotype-Tissue Expression (GTEx) databases were used to identify genes with enhanced expression in the liver associated with HCC progression. A murine liver-specific Ftcd knockout (Ftcd-LKO) model was generated to investigate the role of formimidoyltransferase cyclodeaminase (FTCD) in HCC. Multi-omics analysis of transcriptomics, metabolomics, and proteomics data were applied to further analyse the molecular effects of FTCD expression on hepatocarcinogenesis. Functional and biochemical studies were performed to determine the significance of loss of FTCD expression and the therapeutic potential of Akt inhibitors in FTCD-deficient cancer cells. Results: FTCD is highly expressed in the liver but significantly downregulated in HCC. Patients with HCC and low levels of FTCD exhibited worse prognosis, and patients with liver cirrhosis and low FTCD levels exhibited a notable higher probability of developing HCC. Hepatocyte-specific knockout of FTCD promoted both chronic diethylnitrosamine-induced and spontaneous hepatocarcinogenesis in mice. Multi-omics analysis showed that loss of FTCD affected fatty acid and cholesterol metabolism in hepatocarcinogenesis. Mechanistically, loss of FTCD upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element–binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis. Conclusions: Taken together, we identified a FTCD-regulated lipid metabolic mechanism involving PPARγ and SREBP2 signaling in hepatocarcinogenesis and provide a rationale for therapeutically targeting of HCC driven by downregulation of FTCD. Impact and implications: Exploiting key molecules responsible for hepatocarcinogenesis is significant for the prevention and treatment of HCC. Herein, we identified formimidoyltransferase cyclodeaminase (FTCD) as the top enhanced gene, which could serve as a predictive and prognostic marker for patients with HCC. We generated and characterised the first Ftcd liver-specific knockout murine model. We found loss of FTCD expression upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element–binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis, and provided a rationale for therapeutic targeting of HCC driven by downregulation of FTCD.

The natural color of biological specimens plays a crucial role in body protection, signaling, physiological adaptations, etc. Full-color optical sectioning structured illumination microscopy (OS-SIM) color is a promising approach that can reconstruct biological specimens in three-dimension meanwhile maintaining their natural color. Full-color OS-SIM takes the advantages of rapid imaging speed, compatibility with fluorescence and non-fluorescence samples, compact configuration, and low cost. However, the commonly used HSV-RMS reconstruction algorithm for full-color OS-SIM faces two issues to be improved. One is the RMS (root-mean-square) OS reconstruction algorithm is prone to background noise, and the other is the reconstruction is bound in RGB and HSV color spaces, consuming more reconstructing time. In this paper, we propose a full-color Fourier-OS-SIM method that allows for the OS reconstruction using the high-frequency spectrum of the sample and thus is immune to the low-frequency background noise. The full-color Fourier-OS-SIM directly runs in the RGB color space, providing an easy way to restore the color information. Simulation and experiments with various samples (pollen grains and tiny animals) demonstrate that the full-color Fourier-OS-SIM method is superior to the HSV-RMS method regarding background noise suppression. Moreover, benefiting from the background noise suppression merit, the quantitative morphological height map analysis with the full-color Fourier-OS-SIM method is more accurate. The proposed full-color Fourier-OS-SIM method is expected to find broad applications in biological and industrial fields where the 3D morphology and the color information of objects both need to be recovered.

Abstract Heterotopic ossification (HO) is the abnormal formation of bone in extraskeletal sites. However, the mechanisms linking HO pathogenesis with bone mass dysfunction remain unclear. Here, we showed that mice harboring injury-induced and BMP4-dependent HO exhibit bone mass loss similar to that presented by patients with HO. Moreover, we found that injury-induced hyperinflammatory responses at the injury site triggered HO initiation but did not result in bone mass loss at 1 day post-injury (dpi). In contrast, a suppressive immune response promoted HO propagation and bone mass loss by 7 dpi. Correcting immune dysregulation by PD1/PDL1 blockade dramatically alleviated HO propagation and bone mass loss. We further demonstrated that fetuin-A (FetA), which has been frequently detected in HO lesions but rarely observed in HO-adjacent normal bone, acts as an immunomodulator to promote PD1 expression and M2 macrophage polarization, leading to immunosuppression. Intervention with recombinant FetA inhibited hyperinflammation and prevented HO and associated bone mass loss. Collectively, our findings provide new insights into the osteoimmunological interactions that occur during HO formation and suggest that FetA is an immunosuppressor and a potential therapeutic option for the treatment of HO.

Oxidative stress, inflammatory response, and gut-liver axis dysbiosis have been suggested as the primarily involved in the pathogenesis of alcoholic liver injury. Previous research established that yeast extract (YE) has antioxidant, immune-boosting or microbiota-regulating properties. However, there is currently lack of information regarding the efficacy of YE on alcoholic liver injury. This study seeks to obtain data that will help to address this research gap using a Wistar male rat experimental model. Histologic and biochemical analysis results showed that the groups treated with both low-dose yeast extract (YEL) and high-dose yeast extract (YEH) had lower degrees of alcohol-induced liver injury. The abundance of Peptococcus and Ruminococcus reduced in the low-dose yeast extract (YEL) group, while that of Peptococcus, Romboutsia, Parasutterella, and Faecalibaculum reduced in the high-dose (YEH) group. Furthermore, Spearman analysis showed that the gut microbes were significantly associated with several liver-related indicators. For the analysis of differential metabolites and enriched pathways in the YEL group, the abundance of lysophosphatidylcholine (16:0/0:0) significantly increased, and then the levels of histamine, adenosine and 5′ -adenine nucleotide were remarkedly elevated in the YEH group. These findings suggest that both high and low doses of YE can have different protective effects on liver injury in alcoholic liver disease (ALD) rats, in addition to improving gut microbiota disorder. Besides, high-dose YE has been found to be more effective than low-dose YE in metabolic regulation, as well as in dealing with oxidative stress and inflammatory responses.

Abstract Hydrogel is frequently used as a solid electrolyte for all solid‐state supercapacitors (SCs) because of its liquid‐like ion‐transport property and high conformability. However, due to the higher water content, the hydrogel electrolyte undergoes inevitable freezing and/or dehydration with climate change. Herein, polypyrrole/carbon all‐solid‐state SCs (PCSCs) were developed based on a hierarchical polypyrrole/carbon nanotube electrode and a highly stretchable double‐network polymer hydrogel electrolyte with LiCl/ethylene glycol as a mixed solvent. The PCSCs showed excellent electrochemical performance and cycle stability with a wide operating temperature. The specific capacitances could reach 202.2 and 112.3 mF cm−2 at current densities of 0.5 and 3.0 mA cm−2, respectively. Meanwhile, the PCSCs showed outstanding mechanical properties in maintaining a high areal capacitance under deformations of bending and tension. The excellent water retention of the device also ensured the stable electrochemical performance of PCSCs in a wide temperature range (30–80°C), which could potentially represent a reliable application in various harsh environments.

Abstract The purpose of this study was to compare the differences of V-pattern exotropia in craniosynostosis and normal children. 39 children were included in this study, 19 craniosynostosis and 20 children in control group. They underwent comprehensive ocular examinations and received strabismus surgery. The extraocular muscle samples were analysed. Compared with the control group, craniosynostosis group had larger deviation in primary and up gaze, larger V pattern, and more severe inferior oblique overaction. For 20–40, and 50–60 prism diopter exotropia, the lateral recession in the craniosynostosis group was larger than that in the control group, 7.13 ± 0.44 mm vs 6.71 ± 0.47 mm, 8.90 ± 0.21 mm vs 7.75 ± 0.46 mm (p = 0.025, 0.000). The anterior transposition of craniosynostosis group was more anterior than that of control group, posterior 1.03 ± 1.24 vs 2.68 ± 0.94 mm (p = 0.000). Compared with the control group, the extraocular muscle abnormality in craniosynostosis was significant, 32% vs 5% (p = 0.031). There were 40 proteins in craniosynostosis group, which were different from those in control group. A larger V pattern and larger deviation is common in craniosynostosis children. For the same PD of deviation, it usually needs more recession in craniosynostosis because of the thinner and weaker extraocular muscles. Collagen related proteins were increased in craniosynostosis, and decreased contraction related protein tropomodulin might play key role for the weakness of EOMs.

Based on 601 articles on feminist translation theory published in China National Knowledge Infrastructure (CNKI) in the last 20 years from 2002 to 2021, this article draws a scientific knowledge map and makes a visual analysis of the research articles on feminist translation theory in China using CiteSpace as a visual tool. It was found that (1) both the cooperation between researchers and between research institutions in the domain of feminist translation research in China was not strong; (2) the focus of feminist translation research in China is mainly on feminism, feminist translation theory, feminist translation, and translation; (3) according to the map of the time zone and keywords mutation, feminist translation research in China is constantly moving toward a decline after fast development.

Summary: Background: Identification of tumor dependencies is important for developing therapeutic strategies for liver cancer. Methods: A genome-wide CRISPR screen was performed for finding critical vulnerabilities in liver cancer cells. Compounds screen, RNA sequencing, and human phospho-receptor tyrosine kinase arrays were applied to explore mechanisms and search for synergistic drugs. Findings: We identified mitochondrial translation-related genes associated with proliferation for liver cancer cells. Tigecycline induced deficiency of respiratory chain by disturbing mitochondrial translation process and showed therapeutic potential in liver cancer. For liver cancer cells extremely insensitive to tigecycline, a compounds screen was applied to identify MEK inhibitors as synergistic drugs to tigecycline-insensitive liver cancer cells. Mechanistically, sustained activation of EGFR-ERK1/2-MYC cascade conferred the insensitivity to tigecycline, which was mediated by enhanced secretion of EREG and AREG. Moreover, glycolytic enzymes, such as HK2 and PKM2 were upregulated to stimulate glycolysisin a MYC-dependent manner. Tigecycline induced respiratory chain deficiency in combination with cutting off EGFR-ERK1/2-MYC cascade by MEK inhibitors or EGFR inhibitors, resulting in decrease of both oxidative phosphorylation and glycolysis in liver cancer cells. Interpretation: Our study proved that blocking EGFR-ERK1/2-MYC cascade combined with tigecycline could be a potential therapeutic strategy for liver cancer. Funding: This work was funded by grants from the National Natural Science Foundation of China (82073039, 82222047, 81920108025), Program of Shanghai Academic/Technology Research Leader (22XD1423100), Shanghai Municipal Science and Technology Project (20JC1411100), 111 Project (B21024), Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20212700, SHSMU-ZDCX20210802) and Shanghai Jiao Tong University School of Medicine (YG2019GD01).

Abstract Background Additional epidermal growth factor receptor (EGFR) mutations confer the drug resistance to generations of EGFR targeted tyrosine kinase inhibitor (EGFR-TKI), posing a major challenge to developing effective treatment of lung adenocarcinoma (LUAD). The strategy of combining EGFR-TKI with other synergistic or sensitizing therapeutic agents are considered a promising approach in the era of precision medicine. Moreover, the role and mechanism of SHP2, which is involved in cell proliferation, cytokine production, stemness maintenance and drug resistance, has not been carefully explored in lung adenocarcinoma (LUAD). Methods To evaluate the impact of SHP2 on the efficacy of EGFR T790M mutant LUAD cells to Osimertinib, SHP2 inhibition was tested in Osimertinib treated LUAD cells. Cell proliferation and stemness were tested in SHP2 modified LUAD cells. RNA sequencing was performed to explore the mechanism of SHP2 promoted stemness. Results This study demonstrated that high SHP2 expression level correlates with poor outcome of LUAD patients, and SHP2 expression is enriched in Osimertinib resistant LUAD cells. SHP2 inhibition suppressed the cell proliferation and damaged the stemness of EGFR T790M mutant LUAD. SHP2 facilitates the secretion of CXCL8 cytokine from the EGFR T790M mutant LUAD cells, through a CXCL8-CXCR1/2 positive feedback loop that promotes stemness and tumorigenesis. Our results further show that SHP2 mediates CXCL8-CXCR1/2 feedback loop through ERK-AKT-NFκB and GSK3β-β-Catenin signaling in EGFR T790M mutant LUAD cells. Conclusions Our data revealed that SHP2 inhibition enhances the anti-cancer effect of Osimertinib in EGFR T790M mutant LUAD by blocking CXCL8-CXCR1/2 loop mediated stemness, which may help provide an alternative therapeutic option to enhance the clinical efficacy of osimertinib in EGFR T790M mutant LUAD patients.

Abstract Background Nationwide studies that examine climatic modification effects on the association between air pollution and health outcome are limited in developing countries. Moreover, few studies focus on PM1 pollution despite its greater health effect. Objectives This study aims to determine the modification effects of climatic factors on the associations between PM1 and the incidence rates of lung cancer for males and females in China. Methods We conducted a nationwide analysis in 345 Chinese counties (districts) from 2014 to 2015. Mean air temperature and relative humidity over the study period were used as the proxies of climatic conditions. In terms of the multivariable linear regression model, we examined climatic modification effects in the stratified and combined datasets according to the three-category and binary divisions of climatic factors. Moreover, we performed three sensitivity analyses to test the robustness of climatic modification effects. Results We found a stronger association between PM1 and the incidence rate of male lung cancer in counties with high levels of air temperature or relative humidity. If there is a 10 μg/m3 shift in PM1, then the change in male incidence rate relative to its mean was higher by 4.39% (95% CI: 2.19, 6.58%) and 8.37% (95% CI: 5.18, 11.56%) in the middle and high temperature groups than in the low temperature group, respectively. The findings of climatic modification effects were robust in the three sensitivity analyses. No significant modification effect was discovered for female incidence rate. Conclusions Male residents in high temperature or humidity counties suffer from a larger effect of PM1 on the incidence rate of lung cancer in China. Future research on air pollution-related health impact assessment should consider the differential air pollution effects across different climatic conditions.

Abstract Background The safety of perioperative intravenous hydroxyethyl starch (HES) products, specifically HES 130/0.4, continues to be the source of much debate. The aim of this meta-analysis was to update the existing evidence and gain further insight into the clinical effects of HES 130/0.4 on postoperative outcomes for volume replacement therapy in surgical patients. Methods MEDLINE, EMBASE, and Cochrane Library databases were searched from inception to March 2020 for relevant randomized controlled trials (RCTs) on perioperative use of HES 130/0.4 in adult surgical patients. The primary outcome was postoperative mortality and secondary outcomes were the incidence of acute kidney injury (AKI) and requirement for renal replacement therapy (RRT). The analysis was performed using the random-effects method and the risk ratio (RR) with a 95% confidence interval (CI). We performed the risk-of-bias assessment of eligible studies and assessed the overall quality of evidence for each outcome. Results Twenty-five RCTs with 4111 participants were finally included. There were no statistical differences between HES 130/0.4 and other fluids in mortality at 30 days (RR 1.28, 95% CI 0.88 to 1.86, p = 0.20), the incidence of AKI (RR 1.23, 95% CI 0.99 to 1.53, p = 0.07), or requirement for RRT (RR 0.75, 95% CI 0.37 to 1.53, p = 0.43). Overall, there was a moderate certainty of evidence for all the outcomes. There was no subgroup difference related to the type of surgery (p = 0.17) in the incidence of AKI. As for the type of comparator fluids, however, there was a trend that was not statistically significant (p = 0.06) towards the increased incidence of AKI in the HES 130/0.4 group (RR 1.22, 95% CI 0.97 to 1.54) compared with the crystalloid group (RR 1.21, 95% CI 0.27 to 3.91). Subgroup analyses according to the type of surgery demonstrated consistent findings. Conclusions This systematic review and meta-analysis suggests that the use of HES 130/0.4 for volume replacement therapy compared with other fluids resulted in no significant difference in postoperative mortality or kidney dysfunction among surgical patients. Given the absent evidence of confirmed benefit and the potential trend of increased kidney injury, we cannot recommend the routine clinical use of HES 130/0.4 for volume replacement therapy in surgical patients from the perspective of benefit/risk profile. However, the results need to be interpreted with caution due to the limited sample size, and further well-powered RCTs are warranted. Trial registration PROSPERO registry reference: CRD42020173058

In recent years, the major geological hazard of landslides has greatly impact normal human life. Deep belief networks (DBN) is a commonly used deep learning model, and the DBN hyperparameter determination problem is the key to its application. To improve the accuracy of regional landslide susceptibility prediction, this paper introduces the particle swarm algorithm (PSO) to determine the hyperparameters of the DBN; this is applied to regional landslide susceptibility prediction. Firstly, PSO is used to optimize the hyperparameters of the DBN and obtain a set of hyperparameters with the optimal fitness function. A landslide susceptibility prediction model based on PSO-DBN is then constructed and the K-fold cross-validation method is used to determine its accuracy. The model is applied to landslide susceptibility prediction in the most impacted area of the Wenchuan earthquake to analyze the model’s accuracy. Finally, model susceptibility analysis is performed. The research results show that the final optimal model accuracy of the PSO-DBN model is 95.52%, which is approximately 28.31% and 15.35% higher than that of the logistic regression (LR) model and the common DBN model, respectively. The Kappa coefficient is 0.883, which is higher than that of the LR model. Compared with the LR model and the common DBN model, Kappa coefficient is improved by approximately 0.542 and 0.269 respectively; the area under the curve (AUC) is 0.951, which is improved by approximately 0.201 and 0.080 compared to the LR model and the common DBN model. The susceptibility of the model to the inertia factor is low, the average change in model accuracy (when the inertia factor changes by 0.1) is approximately 0.1%, and the overall stability of the model is high. The landslide susceptibility level is very high. The area includes 219 landslide points, which account for 39.2% of total landslide points. In the area with a high level of landslide susceptibility are 191 landslide points, accounting for 34.2% of total landslide points. Together, the two contain approximately 73.4% of the landslide points. This indicates that the model prediction results agree well with the spatial distribution characteristics of the landslide.

Circular RNAs (circRNA) is a class of non-coding RNAs that can regulate gene translation and function. Here the authors show that a circRNA, circNDUFB2, is downregulated in non-small cell lung cancer tissues, and likely contributes to anti-tumor immunity by regulating both degradation of oncoproteins and induction of innate immunity.

Abstract Krüppel‐like factor 4 (KLF4) has a tumor suppressor role in the progression of gastric cancer (GC), and inhibition or loss of KLF4 expression was identified in GC. The aim of this study was to explore the new molecular mechanism of KLF4 inactivation in gastric cancer. Herein, we report that Helicobacter pylori infection or Cag pathogenicity island protein A (CagA) gene transduction resulted in KLF4 expression downregulation and promoted gastric epithelial cell and gastric cancel cell proliferation, migration, and colony formation. Mechanistically, we found that CagA gene transduction led to DNA methylation of the KLF4 promoter, an effect that was relevant to the significant downregulation of TET1 expression. Causally, knockdown of TET1 expression decreased KLF4 expression, whereas overexpression of TET1 had the opposite effect. Clinically, we found that KLF4 expression and the 5‐hmC levels were lower in GC cells with H pylori infection than in GC cells without H pylori infection. Thus, our study not only sheds new light on how H pylori infection promotes the progression of GC but also elucidates a novel mechanism of KLF4 inactivation in GC pathogenesis. During pathogenesis, an alteration in the H pylori/CagA‐TET1‐KLF4 signaling pathway plays a critical role, suggesting that this pathway may be a prospective target for gastric carcinoma intervention and therapy.

Square cylinders are widely used in various fields. For example, they are common structures in fishways. The flow around square cylinders has been a common problem in various fields. However, reducing the flow drag of the square cylinder is a problem that remains unexplored. Many previous studies have reported the drag reduction of 2D square cylinders, which failed to reflect the drag of real structures. Also, some studies focus on the drag force of the inner wall of the square cylinder modified by the microstructure. Achieving drag reduction by microstructuring the surface of the 3D square cylinder is a challenging problem. This study applied a 3D numerical simulation and deep neural network to study the drag reduction performance of the square cylinder under different patch sizes. We studied the drag reduction performance of protrusion and pit-patched square cylinders and tried to find the rule between drag reduction performance and patch configuration. The results show that the square cylinder has better drag reduction performance in some cases. However, its drag reduction performance is greatly affected by the protrusion structure. Also, too large protrusions will increase the drag force of the structure. When the surface protrusion accounts for 10% of the total area of the square cylinder, the drag reduction performance is the best (22.1%). The pit patch structure demonstrated an insignificant drag reduction performance and even increased the drag in most cases. The DNN prediction model demonstrated the robustness of the numerical simulation data.

Bone marrow microenvironment (BMM) has been proven to have benefits for both normal hematopoietic stem cell niche and pathological leukemic stem cell niche. In fact, the pathological leukemia microenvironment reprograms bone marrow niche cells, especially mesenchymal stem cells for leukemia progression, chemoresistance and relapse. The growth and differentiation of MSCs are modulated by leukemia stem cells. Moreover, chromatin abnormality of mesenchymal stem cells is sufficient for leukemia initiation. Here, we summarize the detailed relationship between MSC and leukemia. MSCs can actively and passively regulate the progression of myelogenous leukemia through cell-to-cell contact, cytokine-receptor interaction, and exosome communication. These behaviors benefit LSCs proliferation and survival and inhibit physiological hematopoiesis. Finally, we describe the recent advances in therapy targeting MSC hoping to provide new perspectives and therapeutic strategies for leukemia.

Breast cancer development and progression rely not only on the proliferation of neoplastic cells but also on the significant heterogeneity in the surrounding tumor microenvironment. Its unique microenvironment, including tumor-infiltrating lymphocytes, complex myeloid cells, lipid-associated macrophages, cancer-associated fibroblasts (CAFs), and other molecules that promote the growth and migration of tumor cells, has been shown to play a crucial role in the occurrence, growth, and metastasis of breast cancer. However, a detailed understanding of the complex microenvironment in breast cancer remains largely unknown. The unique pattern of breast cancer microenvironment cells has been poorly studied, and neither has the supportive role of these cells in pathogenesis been assessed. Single-cell multiomics biotechnology, especially single-cell RNA sequencing (scRNA-seq) reveals single-cell expression levels at much higher resolution, finely dissecting the molecular characteristics of tumor microenvironment. Here, we review the recent literature on breast cancer microenvironment, focusing on scRNA-seq studies and analyzing heterogeneity and spatial location of different cells, including T and B cells, macrophages/monocytes, neutrophils, and stromal cells. This review aims to provide a more comprehensive perception of breast cancer microenvironment and annotation for their clinical classification, diagnosis, and treatment. Furthermore, we discuss the impact of novel single-cell omics technologies, such as abundant omics exploration strategies, multiomics conjoint analysis mode, and deep learning network architecture, on the future research of breast cancer immune microenvironment.

Various coronaviruses have emerged as a result of cross-species transmission among humans and domestic animals. Porcine epidemic diarrhea virus (PEDV; family Coronaviridae, genus Alphacoronavirus) causes acute diarrhea, vomiting, dehydration, and high mortality in neonatal piglets. Porcine small intestinal epithelial cells (IPEC-J2 cells) can be used as target cells for PEDV infection. However, the origin of PEDV in pigs, the host range, and cross-species infection of PEDV remain unclear. To determine whether PEDV has the ability to infect human cells in vitro, human small intestinal epithelial cells (FHs 74 Int cells) were inoculated with PEDV LJX and PEDV CV777 strains. The results indicated that PEDV LJX, but not PEDV CV777, could infect FHs 74 Int cells. Furthermore, we observed M gene mRNA transcripts and N protein expression in infected FHs 74 Int cells. A one-step growth curve showed that the highest viral titer of PEDV occurred at 12 h post infection. Viral particles in vacuoles were observed in FHs 74 Int cells at 24 h post infection. The results proved that human small intestinal epithelial cells are susceptible to PEDV infection, suggesting the possibility of cross-species transmission of PEDV.

AimsVascular calcification is a common clinical complication of chronic kidney disease (CKD), atherosclerosis (AS), and diabetes, which is associated with increased cardiovascular morbidity and mortality in patients. The transdifferentiation of vascular smooth muscle cells (VSMCs) to an osteochondrogenic phenotype is a crucial step during vascular calcification. The transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) plays an important role in regulating cell proliferation and differentiation, but whether it regulates the calcification of arteries and VSMCs remains unclear. Therefore, this study aims to understand the role of C/EBPα in the regulation of vascular calcification.Methods and ResultsBoth mRNA and protein expression levels of C/EBPα were significantly increased in calcified arteries from mice treated with a high dose of vitamin D3 (vD3). Upregulation of C/EBPα was also observed in the high phosphate- and calcium-induced VSMC calcification process. The siRNA-mediated knockdown of C/EBPα significantly attenuated VSMC calcification in vitro. Moreover, C/EBPα depletion in VSMCs significantly reduced the mRNA expression of the osteochondrogenic genes, e.g., sex-determining region Y-box 9 (Sox9). C/EBPα overexpression can induce SOX9 overexpression. Similar changes in the protein expression of SOX9 were also observed in VSMCs after C/EBPα depletion or overexpression. In addition, silencing of Sox9 expression significantly inhibited the phosphate- and calcium-induced VSMC calcification in vitro.ConclusionFindings in this study indicate that C/EBPα is a key regulator of the osteochondrogenic transdifferentiation of VSMCs and vascular calcification, which may represent a novel therapeutic target for vascular calcification.

While IgM and IgG response to SARS-CoV-2 has been extensively studied, relatively little is known about secretory IgA (sIgA) response in respiratory mucosa. Here we report IgA response to the SARS-CoV-2 in sputum, throat swabs, and serum with nucleocapsid protein (NP) enzyme-linked immunosorbent assays (ELISA) in a cohort of 28 COVID-19 patients and 55 vaccine recipients. The assays showed sIgA in respiratory mucosa could be detected on the first day after illness onset (AIO), and the median conversion time for sIgA in sputum, throat swabs, and serum was 3, 4, and 10 days, respectively. The positive rates of sIgA first week AIO were 100% (24/28) and 85.7% (24/28) in sputum and throat swabs, respectively, and were both 100% during the mid-onset (2–3 weeks AIO). During the recovery period, sIgA positive rates in sputum and throat swabs gradually decreased from 60.7% (17/28) and 57.1% (16/28) 1 month AIO and the sIgA antibodies were all undetectable 6 months AIO. However, serum IgA positive rate was still 100% at 4 months and 53.6% (15/28) at 6 months. Throat swabs obtained from volunteers who received inactivated SARS-CoV-2 vaccines by intramuscular delivery all showed negative results in IgA ELISA. These findings will likely improve our understanding of respiratory mucosal immunity of this emerging disease and help in containing the pandemic and developing vaccines.

Pharmacologic perturbation projects, such as Connectivity Map (CMap) and Library of Integrated Network-based Cellular Signatures (LINCS), have produced many perturbed expression data, providing enormous opportunities for computational therapeutic discovery. However, there is no consensus on which methodologies and parameters are the most optimal to conduct such analysis. Aiming to fill this gap, new benchmarking standards were developed to quantitatively evaluate drug retrieval performance. Investigations of potential factors influencing drug retrieval were conducted based on these standards. As a result, we determined an optimal approach for LINCS data-based therapeutic discovery. With this approach, homoharringtonine (HHT) was identified to be a candidate agent with potential therapeutic and preventive effects on liver cancer. The antitumor and antifibrotic activity of HHT was validated experimentally using subcutaneous xenograft tumor model and carbon tetrachloride (CCL4)-induced liver fibrosis model, demonstrating the reliability of the prediction results. In summary, our findings will not only impact the future applications of LINCS data but also offer new opportunities for therapeutic intervention of liver cancer.

The Vortex-Induced Vibration (VIV) of a circular cylinder with different surface roughness is numerically simulated at a subcritical Reynolds number of 3900. The effects of surface roughness on the vibration response amplitude, hydrodynamic coefficients and wake vortex are analyzed. The results show that as surface roughness increases, four branches (initial, upper, super-upper and lower branches) appear in the VIV response for a smooth cylinder, and for a cylinder with a small surface roughness of KS/D=2.5×10−3 , this response changes to three branches (initial, upper and lower branches). The vortex shedding for the initial and lower branches is 2S mode, and that for the upper and super-upper branches (lock-in range) is P + S−, P+S+ and 2P modes. With increasing surface roughness, the maximum amplitude has little difference, and the width of the lock-in range increases. A large jump in the vortex phase at the transition of the initial and upper branches and a large jump in the total lift phase at the transition of the upper and lower branches are found, and these jumps are associated with a switch in the timing of vortex shedding (jump of the vortex phase: 2S mode to P + S− mode; jump of the lift phase: other modes to 2S mode). The results are significant for the development of flow and vibration control technology.

Abstract Myelination is considered to be an important developmental process during human brain maturation and closely correlated with gestational age. Quantitative assessment of the myelination status requires dedicated imaging, but the conventional T2-weighted scans routinely acquired during clinical imaging of neonates carry signatures that are thought to be associated with myelination. In this work, we develop a quatitative marker of progressing myelination for assessment preterm neonatal brain maturation based on novel automatic segmentation method for myelin-like signals on T2-weighted magnetic resonance images. Firstly we define a segmentation protocol for myelin-like signals. We then develop an expectation-maximization framework to obtain the automatic segmentations of myelin-like signals with explicit class for partial volume voxels whose locations are configured in relation to the composing pure tissues via second-order Markov random fields. The proposed segmentation achieves high Dice overlaps of 0.83 with manual annotations. The automatic segmentations are then used to track volumes of myelinated tissues in the regions of the central brain structures and brainstem. Finally, we construct a spatio-temporal growth models for myelin-like signals, which allows us to predict gestational age at scan in preterm infants with root mean squared error 1.41 weeks.

Circular RNAs are known to regulate cancer. Here, the authors show that the circular RNA circTP63 promotes lung squamous cell carcinoma by competing with endogenous RNA to upregulate FOXM1.

Abstract Richter syndrome (RS) indicates the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma (mostly DLBCL). Richter syndrome is a rare complication with an aggressive clinical course, bearing an unfavorable prognosis. Currently, there is no effective treatment for it. As a novel cellular‐based immune therapy, chimeric antigen receptor‐modified T (CART) cells treatment is gradually used in treating hematological malignancies, especially in CD19+ B‐cell malignancy. Therefore, CD19‐directed chimeric antigen receptor‐modified T cells (CART‐19) treatment is promising to be used as a new method for RS patients. In our study, one RS patient expressing high level of CD19 molecule was enrolled in clinical trial; he has received a series of treatments but did not achieve a satisfactory therapeutic effect. The patient totally received 3.55 × 108 autologous CART‐19 cells infusion. After CART‐19 infusion, the mainly clinical side effect was repeated fever. The maximal duration period was 24 days and the highest temperature was 40.1°C. Pancytopenia and significantly serum cytokines level rise were observed, including IFN‐γ, IL‐6, and IL‐10. Before discharge, the level of cytokines reduced to normal levels. In addition, we detected the serum biochemical indices as like K+, Ca2+, creatinine, and glutamic‐pyruvic transaminase, all of these indices were normal. This showed that there was no tumor necrosis syndrome after treatment. The proportion of B cells in patient's peripheral blood decreased from 72% to 40.2% after infusion, co‐occurring with reduction in lymph nodes and hematopoietic reconstitution. Based on the recent revolution in the therapeutic landscape for hematological malignancies including B‐cell lymphomas, CART‐CD19 cell therapy as a new therapeutic option for RS might be available in the coming years. It aims to reduce patient's tumor burden, prolong their survival time, and provide opportunities for other sequential therapy such as chemotherapy and bone marrow transplantation.

Long non-coding RNA (lncRNA) PCAT6 is a member of the Prostate Cancer Associated Transcripts family of molecules. In this review, we focus on the latest studies involving PCAT6 in the diagnosis, treatment, and prognosis of malignant tumors of the digestive, respiratory, urinary, reproductive, motion, and nervous systems. PCAT6 was found to be highly expressed in gastric cancer, colon cancer, hepatocellular carcinoma, lung cancer, bladder cancer, ovarian cancer, breast cancer, cervical cancer, osteosarcoma, glioblastoma, and other tumors. PCAT6 can promote the development and progression of different types of malignant tumors through various mechanisms. Overall, these findings suggest that PCAT6 may play an increasingly vital role in the clinical assessment of these malignant tumors. It can function as an oncogene and may be used as a potential new prognostic biomarker of these tumors.

Linear ubiquitination is a reversible posttranslational modification, which plays key roles in multiple biological processes. Linear ubiquitin chain assembly complex (LUBAC) catalyzes linear ubiquitination, while the deubiquitinase OTULIN (OTU deubiquitinase with linear linkage specificity, FAM105B) exclusively cleaves the linear ubiquitin chains. However, our understanding of linear ubiquitination is restricted to a few substrates and pathways. Here we used a human proteome microarray to detect the interacting proteins of LUBAC and OTULIN by systematically screening up to 20,000 proteins. We identified many potential interacting proteins of LUBAC and OTULIN, which may function as regulators or substrates of linear ubiquitination. Interestingly, our results also hint that linear ubiquitination may have broad functions in diverse pathways. In addition, we recognized lymphocyte activation gene-3 (LAG3, CD223), a transmembrane receptor that negatively regulates lymphocyte functions as a novel substrate of linear ubiquitination in the adaptive immunity pathway. In conclusion, our results provide searchable, accessible data for the interacting proteins of LUBAC and OTULIN, which broaden our understanding of linear ubiquitination.

Leveraging global state information to enhance policy optimization is a common approach in multi-agent reinforcement learning (MARL). Even with the supplement of state information, the agents still suffer from insufficient exploration in the training stage. Moreover, training with batch-sampled examples from the replay buffer will induce the policy overfitting problem, i.e., multi-agent proximal policy optimization (MAPPO) may not perform as good as independent PPO (IPPO) even with additional information in the centralized critic. In this paper, we propose a novel noise-injection method to regularize the policies of agents and mitigate the overfitting issue. We analyze the cause of policy overfitting in actor–critic MARL, and design two specific patterns of noise injection applied to the advantage function with random Gaussian noise to stabilize the training and enhance the performance. The experimental results on the Matrix Game and StarCraft II show the higher training efficiency and superior performance of our method, and the ablation studies indicate our method will keep higher entropy of agents’ policies during training, which leads to more exploration.

To meet critical requirements on flexible electronic devices, multifunctionalized flexible sensors with excellent electromechanical performance and temperature perception are required. Herein, lignin-reinforced thermoresponsive poly(ionic liquid) hydrogel is prepared through an ultrasound-assisted synthesized method. Benefitting from the electrostatic interaction between lignin and ionic liquid, the hydrogel displays high stretchability (over 1425%), excellent toughness (over 132 kPa), and impressive stress loading-unloading cyclic stability. The hydrogel strain sensor presents excellent electromechanical performance with a high gauge factor (1.37) and rapid response rate (198 ms), which lays the foundation for human body movement detection and smart input. Moreover, owing to the thermal-sensitive feature of poly(ionic liquid), the as-prepared hydrogel displays remarkable thermal response sensitivity (0.217°C-1) in body temperature range and low limit of detection, which can be applied as a body shell temperature indicator. Particularly, the hydrogel can detect dual stimuli of strain and temperature and identify each signal individually, showing the specific application in human-machine interaction and artificial intelligence. By integrating the hydrogel strain sensor into a wireless sensation system, remote motion capture and gesture identification is realized in real-time.

The dependency of cancer cells on glutamine may be exploited therapeutically as a new strategy for treating cancers that lack druggable driver genes. Here we found that human liver cancer was dependent on extracellular glutamine. However, targeting glutamine addiction using the glutaminase inhibitor CB-839 as monotherapy had a very limited anticancer effect, even against the most glutamine addicted human liver cancer cells. Using a chemical library, we identified V-9302, a novel inhibitor of glutamine transporter ASCT2, as sensitizing glutamine dependent (GD) cells to CB-839 treatment. Mechanically, a combination of CB-839 and V-9302 depleted glutathione and induced reactive oxygen species (ROS), resulting in apoptosis of GD cells. Moreover, this combination also showed tumor inhibition in HCC xenograft mouse models in vivo. Our findings indicate that dual inhibition of glutamine metabolism by targeting both glutaminase and glutamine transporter ASCT2 represents a potential novel treatment strategy for glutamine addicted liver cancers.