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Abstract Objectives The relationship between hepatitis B virus (HBV) infection and gynecologic cancers is controversial. We aimed to evaluate the risk of gynecologic cancers associated with HBV infection using a meta-analysis. Methods Two independent reviewers identified publications in the PubMed, Embase and Cochrane Library databases that reported an association between HBV and the risk of gynecologic malignancy from inception to December 31, 2022. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the included articles. Pooled odds ratios (ORs) and 95% corresponding confidence intervals (CIs) were calculated using a fixed effects model or random effects model. Results We collected data from 7 studies that met the inclusion criteria, including 2 cohort studies and 5 case-control studies. HBV was significantly associated with the risk of cervical cancer in the general population (OR 1.22, 95% CI 1.09–1.38, P = 0.001), although the same trend was not found in endometrial cancer (OR 1.30, 95% CI 0.95–1.77, P = 0.105) and ovarian cancer (OR 1.03, 95% CI 0.79–1.35, P = 0.813). Subgroup analysis showed that HBV infection was positively associated with the risk of cervical cancer (OR 1.27, 95% CI 1.13–1.44, P = 0.000) in case-control studies. Asian women infected with HBV have a significantly increased risk of cervical cancer (OR 1.24, 95% CI 1.10–1.40, P = 0.001) and endometrial cancer (OR 1.46, 95% CI 1.07–1.99, P = 0.018). Hospital-based studies were found to be associated with an increased risk of cervical cancer (OR 1.30, 95% CI 1.14–1.47, P = 0.000) and endometrial cancer (OR 1.61, 95% CI 1.04–2.49, P = 0.032). The results of Begg’s and Egger’s tests showed no publication bias. Conclusions This meta-analysis shows a positive association between HBV infection and cervical cancer. HBV is positively correlated with the risk of cervical cancer and endometrial cancer in Asian women and hospital-based populations. More multicenter prospective studies are required to confirm the findings.

Abstract DARS, encoding for aspartyl-tRNA synthetase, is implicated in the pathogenesis of various cancers, including renal cell carcinoma, glioblastoma, colon cancer, and gastric cancer. Its role in BCR/ABL1-negative myeloproliferative neoplasms (MPNs), however, remains unexplored. This study aimed to elucidate the expression of DARS in patients with MPNs (PV 23, ET 19, PMF 16) through immunohistochemical analysis and to examine the profiles of circulating immune cells and cytokines using flow cytometry. Our findings indicate a significant overexpression of DARS in all MPNs subtypes at the protein level compared to controls (P

Abstract A low‐cost W‐band leaky‐wave antenna with two‐dimensional scanning capability is presented. By using the low‐loss transversal long‐slot array structure with a single‐layer parabolic reflector, the antenna realizes a passband from 85 to 102.8 GHz with Voltage Standing Wave Ratio

The exponential proliferation of renewable energy has resulted in a significant mismatch between power supply and demand, especially during extreme events. This incongruity presents challenges in efficiently harnessing renewable energy and enhancing the resilience of the power grid. To address this issue, this paper proposes shared energy storage (SES) planning based on the adaptive alternating direction method of multipliers (AADMM). The objective is to fully leverage SES, enhance the local consumption level of renewable energy, ensure power grid resilience, and reduce operational costs. First, to ensure the effective utilization of SES while minimizing initial investment and construction costs, a planning model for SES is formulated. Secondly, to maximize the benefits for multiple prosumers within the renewable energy and SES station, a profit maximization model for multiple prosumers is established. Lastly, to guarantee the privacy security of SES and multi-prosumers while optimizing computational efficiency, a distributed computing model for SES based on AADMM is developed. The results of the example show that the proposed model can not only reduce the cost of 47.96 CNY, but also increase the power self-sufficiency rate by 21.86%. In addition, compared with the traditional distributed optimization, the number of iterations of AADMM is increased by 47.05%, and the computational efficiency is increased by 54.67%. In addition, market prices have a great impact on energy trading, and the impact of market pricing on the operation of the park is not considered in our current research. In this case, our future research aims to consider how to price reasonably between prosumers and between prosumers and SES, so as to realize the stable participation of each subject in the energy market.

Background: Although associations between chronic obstructive pulmonary disease (COPD) or ischaemic heart disease (IHD) and lifestyle factors or air pollution factors (referred as LAFs below) are well-established, it is unclear the influences of LAFs on the trajectory of IHD and COPD multimorbidity (referred as ICM below). Therefore, this study investigated the influences of LAFs on the trajectory of ICM from healthy to IHD or COPD, to ICM, and to all-cause death. Methods: A cohort of 339,213 participants from the UK Biobank aged 37–73 who were free of IHD and COPD were included. A multi-state model was used to analyse the influences of high-risk factors including current smoking or quitting due to illness or physician's advice, current excessive alcohol drinking, physical inactivity, unhealthy body shape, and excessive air pollution with particulates matter with an aerodynamic diameter ≤2.5 μm (PM2.5) on ICM trajectory. Results: During a median follow-up of 13.74 years, 46,398 participants developed IHD or COPD (referred as IOC below), 3949 developed ICM, and 35,691 died from any cause. All five high-risk factors played crucial but different roles in these transitions. The hazard ratios (95 % confidence intervals) per one-factor increase were 1.29 (1.27–1.3), 1.38 (1.33–1.44), and 1.69 (1.56–1.84) for transitions from baseline to IOC, from IOC to ICM, and from baseline to ICM and 1.19 (1.17–1.21), 1.18 (1.15–1.21), and 1.12 (1.05–1.19) for mortality risk from baseline to all-cause death, from IOC to all-cause death, and from ICM to all-cause death, respectively. Conclusions: Our study revealed that LAFs have a stronger impact on morbidity outcomes than on morbidity outcomes. These findings provide evidence to develop strategies for managing the trajectory of ICM.

Abstract Pancreatic cancer is a malignant tumor of the digestive system. It is highly aggressive, easily metastasizes, and extremely difficult to treat. This study aimed to analyze the genes that might regulate pancreatic cancer migration to provide an essential basis for the prognostic assessment of pancreatic cancer and individualized treatment. A CRISPR knockout library directed against 915 murine genes was transfected into TB 32047 cell line to screen which gene loss promoted cell migration. Next-generation sequencing and PinAPL.py- analysis was performed to identify candidate genes. We then assessed the effect of serine/threonine kinase 11 (STK11) knockout on pancreatic cancer by wound-healing assay, chick agnosia (CAM) assay, and orthotopic mouse pancreatic cancer model. We performed RNA sequence and Western blotting for mechanistic studies to identify and verify the pathways. After accelerated Transwell migration screening, STK11 was identified as one of the top candidate genes. Further experiments showed that targeted knockout of STK11 promoted the cell migration and increased liver metastasis in mice. Mechanistic analyses revealed that STK11 knockout influences blood vessel morphogenesis and is closely associated with the enhanced expression of phosphodiesterases (PDEs), especially PDE4D, PDE4B, and PDE10A. PDE4 inhibitor Roflumilast inhibited STK11-KO cell migration and tumor size, further demonstrating that PDEs are essential for STK11-deficient cell migration. Our findings support the adoption of therapeutic strategies, including Roflumilast, for patients with STK11-mutated pancreatic cancer in order to improve treatment efficacy and ultimately prolong survival.

Due to the high heterogeneity of ovarian cancer (OC), it occupies the main cause of cancer-related death among women. As the most aggressive and frequent subtype of OC, high-grade serous cancer (HGSC) represents around 70 % of all patients. With the booming progress of single-cell RNA sequencing (scRNA-seq), unique and subtle changes among different cell states have been identified including novel risk genes and pathways. Here, our present study aims to identify differentially correlated core genes between normal and tumor status through HGSC scRNA-seq data analysis. R package high-dimension Weighted Gene Co-expression Network Analysis (hdWGCNA) was implemented for building gene interaction networks based on HGSC scRNA-seq data. DiffCorr was integrated for identifying differentially correlated genes between tumor and their adjacent normal counterparts. Software Cytoscape was implemented for constructing and visualizing biological networks. Real-time qPCR (RT-qPCR) was utilized to confirm expression pattern of new genes. We introduced ScHGSC-IGDC (Identifying Genes with Differential Correlations of HGSC based on scRNA-seq analysis), an in silico framework for identifying core genes in the development of HGSC. We detected thirty-four modules in the network. Scores of new genes with opposite correlations with others such as NDUFS5, TMSB4X, SERPINE2 and ITPR2 were identified. Further survival and literature validation emphasized their great values in the HGSC management. Meanwhile, RT-qPCR verified expression pattern of NDUFS5, TMSB4X, SERPINE2 and ITPR2 in human OC cell lines and tissues. Our research offered novel perspectives on the gene modulatory mechanisms from single cell resolution, guiding network based algorithms in cancer etiology field.

Hepatocellular carcinoma (HCC) represents a substantial global health burden. Tumorinfiltrating B lymphocytes (TIL-Bs) contribute to tumor progression and significantly impact the efficacy of tumor therapy. However, the characteristics of TIL-Bs in HCC and their effect on HCC therapy remain elusive. Single-cell RNA sequencing (scRNAseq) was applied to investigate the heterogeneity, cellular differentiation and cell-cell communication of TIL-Bs in HCC. Further, the Cancer Genome Atlas-liver hepatocellular carcinoma (TCGA-LIHC) and liver cancer institutes (LCI) cohorts were applied to construct and validate the plasma cell marker-based prognostic risk model. The relationship between the prognostic risk model and the responsiveness of immunotherapy and chemotherapy in patients with HCC were estimated by OncoPredict and tumor immune dysfunction and exclusion (TIDE) algorithm. Finally, we established nomogram and calibration curves to evaluate the precision of the risk score in predicating survival probability. Our data identified five subtypes of TIL-Bs in HCC, each exhibiting varying levels of infiltration in tumor tissues. The interactions between TIL-Bs and other cell types contributed to shaping distinct tumor microenvironments (TME). Moreover, we found that TIL-Bs subtypes had disparate prognostic values in HCC patients. The prognostic risk model demonstrated exceptional predictive accuracy for overall survival and exhibited varying sensitivities to immunotherapy and chemotherapy among patients with HCC. Our data demonstrated that the risk score stood as an independent prognostic predictor and the nomogram results further affirmed its strong prognostic capability. This study reveals the heterogeneity of TIL-Bs and provides a prognostic risk model based on plasma cell markers in HCC, which could prove valuable in predicting prognosis and guiding the choice of suitable therapies for patients with HCC.

BackgroundThe European League of Rheumatology(EULAR)guidelines recommend Janus kinase (JAK) inhibitors for patients with moderate to severe rheumatoid arthritis (RA) who are insensitive or under-responsive to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). But there was no recommendation for which one was preferred in five currently approved JAK inhibitors. The objective of this network meta-analysis study was to evaluate the efficacy of five JAK inhibitors as monotherapy and combination therapy in patients with moderate-to-severe active rheumatoid arthritis.MethodsThe randomized controlled trials (RCTs) of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy or combined with csDMARD in the treatment of active RA were searched in database of PubMed, Embase, Web of Science and Cochrane Library, up to December 2023. The control group included placebo or csDMARD. Outcome indicators included American College of Rheumatology 20% response (ACR20), ACR50, ACR70 and the percentage of patients achieving 28-joint disease activity score using C-reactive protein (DAS28(CRP))

In the context of human activities and climate change, the gradual degradation of coastal water quality seriously threatens the balance of coastal and marine ecosystems. However, the spatiotemporal patterns of coastal water quality and its driving factors were still not well understood. Based on 31 water quality parameters from 2015 to 2020, a new approach of optimizing water quality index (WQI) model was proposed to quantitatively assess the spatial and temporal water quality along tropical Hainan Island, China. In addition, pollution sources were further identified by factor analysis and the effects of pollution source on water quality was finally quantitatively in our study. The results showed that the average water quality was moderate. Water quality at 86.36% of the monitoring stations was good while 13.53% of the monitoring stations has bad or very bad water quality. Besides, the coastal water quality had spatial and seasonal variation, along Hainan Island, China. The water quality at “bad” level was mainly appeared in the coastal waters along large cities (Haikou and Sanya) and some aquaculture regions. Seasonally, the average water quality in March, October and November was worse than in other months. Factor analysis revealed that water quality in this region was mostly affected by urbanization, planting and breeding factor, industrial factor, and they played the different role in different coastal zones. Waters at 10.23% of monitoring stations were at the greatest risk of deterioration due to severe pressure from environmental factors. Our study has significant important references for improving water quality and managing coastal water environment.

Abstract Background Astragalus grows mainly in drought areas. Cycloastragenol (CAG) is a tetracyclic triterpenoid allelochemical extracted from traditional Chinese medicine Astragalus root. Phospholipase C (PLC) and Gα-submit of the heterotrimeric G-protein (GPA1) are involved in many biotic or abiotic stresses. Nitric oxide (NO) is a crucial gas signal molecule in plants. Results In this study, using the seedlings of Arabidopsis thaliana (A. thaliana), the results showed that low concentrations of CAG induced stomatal closure, and high concentrations inhibited stomatal closure. 30 µmol·L−1 CAG significantly increased the relative expression levels of PLC1 and GPA1 and the activities of PLC and GTP hydrolysis. The stomatal aperture of plc1, gpa1, and plc1/gpa1 was higher than that of WT under CAG treatment. CAG increased the fluorescence intensity of NO in guard cells. Exogenous application of c-PTIO to WT significantly induced stomatal aperture under CAG treatment. CAG significantly increased the relative expression levels of NIA1 and NOA1. Mutants of noa1, nia1, and nia2 showed that NO production was mainly from NOA1 and NIA1 by CAG treatment. The fluorescence intensity of NO in guard cells of plc1, gpa1, and plc1/gpa1 was lower than WT, indicating that PLC1 and GPA1 were involved in the NO production in guard cells. There was no significant difference in the gene expression of PLC1 in WT, nia1, and noa1 under CAG treatment. The gene expression levels of NIA1 and NOA1 in plc1, gpa1, and plc1/gpa1 were significantly lower than WT, indicating that PLC1 and GPA1 were positively regulating NO production by regulating the expression of NIA1 and NOA1 under CAG treatment. Conclusions These results suggested that the NO accumulation was essential to induce stomatal closure under CAG treatment, and GPA1 and PLC1 acted upstream of NO.

Scientific and effective urban waterlogging risk prediction can help improve urban waterlogging disaster prevention capabilities. Combining the numerical simulation model with the data-driven model, the construction of the urban waterlogging risk predictive model can satisfy the prediction accuracy and improve the prediction timeliness. Thus, this paper established an urban waterlogging risk predictive model based on the coupling of the BP neural network and SWMM model, and set five input patterns, finally selected the accumulative precipitation process and precipitation characteristics as input to predict the regional waterlogging risks under different urban rainstorm scenarios. The results show that the overall performance of the pipe drainage system in the study area is lower, and it cannot resist the rainstorm with a higher return period. Moreover, the total waterlogging risk of the southern old city is higher than that of the northern new city in the study area. The calculation speed of the prediction model constructed in this paper is thousands of times higher than that of the numerical model, so the calculation speed is very fast, which meets the requirements of the forecast timeliness. HIGHLIGHTS Using fine data to build the SWMM model and various methods to verify the SWMM model.; Using web crawler technology to extract ponding points.; Using entropy weight method for risk quantization.; Using set pair analysis to evaluate the accuracy of the BP neural network.; Coupling SWMM model with BP neural network for risk prediction.;

In this paper a novel optical vector network analyzer (OVNA) utilizing a distributed feedback semiconductor optical amplifier (DFB-SOA) is introduced. The proposed OVNA is implemented by converting the transmission response of the optical device under test (ODUT) into the electrical domain. The main principle of the OVNA is predicated on the optical carrier restoration facilitated by the wavelength-selective amplification attribute of the DFB-SOA. The implemented OVNA effectively determined the transmission spectrum of an optical filter possessing a passband of 9-GHz bandwidth, achieving a commendable resolution of 25 MHz in the measurement process. The dynamic range of the OVNA can be broadened by adjust the driven current under the DFB-SOA. Additionally, the detection range of our system can be expanded through the utilization of broadband optoelectronic devices. Furthermore, the OVNA possesses considerable potential for integration onto a single chip.

An informed search strategy based on random statistical analysis was developed for synchronous recognition of groundwater pollution source information and aquifer parameters. An informed search iterative course (ISIC) was accordingly designed, and each iteration included the determination of attempt point and state transition. In this paper, two improvement techniques were first adopted for choosing attempt points and judging state transition in ISIC to improve search efficiency and precision. The first improvement was that the variable radius free search method was applied to choosing the attempt point, and the size of the search radius was constantly adjusted in ISIC, taking the search ergodicity and efficiency into account. The second improvement technique was a Tsallis formula used for state transition judgment, and the controlled factor in the Tsallis formula was regulated continuously so that the search could consider ergodicity and efficiency simultaneously. Furthermore, frequent calls to the groundwater pollution numerical simulator to calculate the likelihood have inflicted a huge computational burden during ISIC. An effective way is to construct a substitute for emulating the simulator with a low calculating load. However, the mapping relation between the import and export of the numerical simulator was complex and had many variables. The precision of the substitute based on shallow learning is low sometimes. Therefore, we adopted the deep learning method and built an improved deep confidence network (DCN) substitute to emulate the highly nonlinear simulator. Finally, the synchronous recognition results for groundwater pollution source information and aquifer parameters were gained when ISIC ceased. The above-mentioned methods were verified in a case involving groundwater pollution. The consequence indicated that the ISIC with an improved DCN substitute can synchronously recognize groundwater pollution source information and aquifer parameters with a high degree of precision and efficiency.

ObjectiveTo systematically evaluate the efficacy and safety of a new hypoglycemic drug, tirzepatide, for treating obesity based on indicators such as BMI, waist circumference, and body weight.MethodsA search formula was written using search terms such as “tirzepatide,” “overweight,” and “obesity.” A comprehensive search was conducted on databases such as PubMed, Cochrane Library, Embase, and Web of Science using a computer. Random controlled trial (RCT) literature was selected based on inclusion and exclusion criteria. After extracting the data, literature bias risk assessment and meta-analysis were conducted using RevMan 5.4 software. The search deadline is from the establishment of each database to May 2023.ResultsA total of 12 randomized controlled trials were included, with a total of 11,758 patients. Meta analysis results showed that compared with the glucagon like peptide-1 receptor agonist (GLP-1 RAs), placebo and insulin groups, tirzepatide could significantly reduce the BMI (body mass index) of patients [MD = −1.71, 95% CI (−2.46, −0.95), p 0.05).ConclusionTirzepatide, as a weight loss drug, significantly reduces BMI, waist circumference and body weight while gastrointestinal adverse reactions need to be vigilant. Overall, its efficacy is significant and its safety is high.

Abstract Ferroptosis, a newform of programmed cell death, driven by peroxidative damages of polyunsaturated-fatty-acid-containing phospholipids in cellular membranes and is extremely dependent on iron ions, which is differs characteristics from traditional cell death has attracted greater attention. Based on the curiosity of this new form of regulated cell death, there has a tremendous progress in the field of mechanistic understanding of ferroptosis recent years. Ferroptosis is closely associated with the development of many diseases and involved in many diseases related signaling pathways. Not only a variety of oncoproteins and tumor suppressors can regulate ferroptosis, but multiple oncogenic signaling pathways can also have a regulatory effect on ferroptosis. Ferroptosis results in the accumulation of large amounts of lipid peroxides thus involving the onset of oxidative stress and energy stress responses. The MAPK pathway plays a critical role in oxidative stress and AMPK acts as a sensor of cellular energy and is involved in the regulation of the energy stress response. Moreover, activation of AMPK can induce the occurrence of autophagy-dependent ferroptosis and p53-activated ferroptosis. In recent years, there have been new advances in the study of molecular mechanisms related to the regulation of ferroptosis by both pathways. In this review, we will summarize the molecular mechanisms by which the MAPK-AMPK signaling pathway regulates ferroptosis. Meanwhile, we sorted out the mysterious relationship between MAPK and AMPK, described the crosstalk among ferroptosis and MAPK-AMPK signaling pathways, and summarized the relevant ferroptosis inducers targeting this regulatory network. This will provide a new field for future research on ferroptosis mechanisms and provide a new vision for cancer treatment strategies. Video Abstract

Abstract Background Gastrointestinal (GI)‐neuroendocrine neoplasms (NENs) are subclassified in neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs), and mixed neuroendocrine–non‐neuroendocrine neoplasms (MiNENs). The genetic characteristics of GI‐NEN has been a hot issue in recent years, but more studies are needed to provide further details. This study aims to provide additional data about genomic characteristics of GI‐NENs and the genetic differences between NETs and NECs. Patients and Methods Thirteen samples were selected for next‐generation sequencing (NGS) analysis with a 425‐gene panel. Microsatellite instability (MSI) and tumor mutational burden (TMB) were calculated as well as immunohistochemistry (IHC) was used to test for protein expression. Results Genetic alterations were very common in NECs, but rare in NETs. The average TMB of NETs and NECs was 2.3 and 6.9, respectively. The TMB of NECs was significantly higher compared to NETs. The TP53 mutation rate was significantly higher in NECs than in NETs (100% vs. 20%), other mutations involved MTOR (n = 2, 15.4%), DDR2 (n = 3, 23.1%), ERBB4 (n = 1, 7.7%), BRCA1 (n = 1, 7.7%), BRCA2 (n = 1, 7.7%), ATM (n = 1, 7.7%), and SMAD4 (n = 1, 7.7%). Deep loss of SMAD4 (1/3, 33.3%), SDHB (1/3, 33.3%), RB1 (1/3, 33.3%), and BRCA2 (1/3, 33.3%), high‐level amplification of CRKL (1/3, 33.3%), CCNE1(1/3, 33.3%), and MCL1(1/3, 33.3%) were found in NECs. The integrated analysis found these genetic alterations frequently involve DNA repair and cell cycle, PI3K/AKT/mTOR and TGF‐β/SMAD4 signaling pathways. Conclusion Genetic alterations were very common in NECs and rare in NETs, and frequently involved three main signaling pathways. NEC patients harboring these genetic alterations may benefit from targeted therapy and PD‐1/PD‐L1 immunotherapy.

Aspergillus fumigatus is a common causative pathogen of aspergillosis. At present, triazole resistance of A. fumigatus poses an important challenge to human health globally. In this study, the biological characteristics and mechanisms of azole resistance of five A. fumigatus strains (AF1, AF2, AF4, AF5, and AF8) were explored. There were notable differences in the sporulation and biofilm formation abilities of the five test strains as compared to the standard strain AF293. The ability of strain AF1 to avoid phagocytosis by MH-S cells was significantly decreased as compared to strain AF293, while that of strains AF2, AF4, and AF5 were significantly increased. Fungal burden analysis with Galleria mellonella larvae revealed differences in pathogenicity among the five strains. Moreover, the broth microdilution and E-test assays confirmed that strains AF1 and AF2 were resistant to itraconazole and isaconazole, while strains AF4, AF5, and AF8 were resistant to voriconazole and isaconazole. Strains AF1 and AF2 carried the cyp51A mutations TR34/L98H/V242I/S297T/F495I combined with the hmg1 mutation S541G, whereas strains AF4 and AF8 carried the cyp51A mutation TR46/Y121F/V242I/T289A, while strain AF5 had no cyp51A mutation. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis revealed differences in the expression levels of genes associated with ergosterol synthesis and efflux pumps among the five strains. In addition, transcriptomics, RT-qPCR, and the NAD+/NADH ratio demonstrated that the mechanism of voriconazole resistance of strain AF5 was related to overexpression of genes associated with energy production and efflux pumps. These findings will help to further elucidate the triazole resistance mechanism in A. fumigatus.

Objective: To explore the association between hypochloremia and mortality in critically ill patients with chronic heart failure (CHF). Methods: This is a retrospective cohort study from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database of patients with CHF diagnosed according to ICD-9 or ICD-10. Patients were divided into three groups according to serum chloride values. A multivariable logistic regression analysis was used to investigate the relationship between hypochloremia and short-term mortality. Results: A total of 2103 patients with CHF were enrolled in our study. The 30-day mortality was 6.7%. After adjusting for confounders, the 30-day mortality risks of the hypochloremia group were significantly higher than that of the group with normal serum chloride (OR 2.23, 95% CI 1.27–3.92, p = 0.005). Hypochloremia was consistently associated with increased mortality in patients that were older or had sepsis. Conclusion: Hypochloremia is associated with increased mortality in intensive care patients critically ill with CHF.

Abstract Background This study aimed to investigate the correlation between the high-risk characteristics of high-resolution MRI carotid vulnerable plaques and the clinical risk factors and concomitant acute cerebral infarction (ACI). Methods Forty-five patients diagnosed with a single vulnerable carotid plaque by MRI were divided into two groups based on whether they had ipsilateral ACI. The clinical risk factors and the observation values or frequency of occurrence of high-risk MRI phenotypes of plaque volume, LRNC, IPH and ulcer were statistically compared between the two groups. Results A total of 45 vulnerable carotid artery plaques were found in 45 patients, 23 patients with ACI and 22 patients without ACI. There were no significant differences in age, sex, smoking, serum TC, TG and LDL between the two groups (all P > 0.05), but the ACI group had significantly more patients with hypertension (P 0.05) with the exception of LRNC + IPH + Ulcer. The 14 cases of LRNC + IPH + LRNC + IPH + Ulcer (60.87%) in the group with ACI and was significantly greater than the 5 (22.73%) in patients without ACI (P

Acute kidney injury (AKI) can lead to loss of kidney function and a substantial increase in mortality. The burst of reactive oxygen species (ROS) plays a key role in the pathological progression of AKI. Mitochondrial-targeted antioxidant therapy is very promising because mitochondria are the main source of ROS in AKI. Antioxidant nanodrugs with actively targeted mitochondria have achieved encouraging success in many oxidative stress-induced diseases. However, most strategies to actively target mitochondria make the size of nanodrugs too large to pass through the glomerular system to reach the renal tubules, the main damage site of AKI. Here, an ultra-small Tungsten-based nanodots (TWNDs) with strong ROS scavenging can be very effective for treatment of AKI. TWNDs can reach the tubular site after crossing the glomerular barrier, and enter the mitochondria of the renal tubule without resorting to complex active targeting strategies. To our knowledge, this is the first time that ultra-small negatively charged nanodots can be used to passively target mitochondrial therapy for AKI. Through in-depth study of the therapeutic mechanism, such passive mitochondria-targeted TWNDs are highly effective in protecting mitochondria by reducing mitochondrial ROS and increasing mitophagy. In addition, TWNDs can also reduce the infiltration of inflammatory cells. This work provides a new way to passively target mitochondria for AKI, and give inspiration for the treatment of many major diseases closely related to mitochondria, such as myocardial infarction and cerebral infarction.

Candidate biological control agents of invasive insect pests are increasingly being found in new geographic regions as a result of unintentional introductions. However, testing the degree of genetic differentiation among adventive and native-range populations of these agents is rarely done. We used reduced-representation sequencing of genomic DNA to investigate the relationships among laboratory lines of Trissolcus japonicus (Ashmead) (Hymenoptera, Scelionidae), an egg parasitoid and biological control agent of the brown marmorated stink bug, Halyomorpha halys (Stål) (Hemiptera, Pentatomidae). We compared sequences from multiple adventive populations in North America (Canada, USA) and Europe (Switzerland) with populations sourced from part of its native range in China. We found considerably more genetic variation among lines sourced from adventive populations than among those within native populations. In the Pacific Northwest of North America (British Columbia, Canada and Washington State, USA), we found preliminary evidence of three distinct genetic clusters, two of which were highly dissimilar from all other lines we genotyped. In contrast, we found that other adventive lines with close geographic proximity (two from Ontario, Canada, three from Switzerland) had limited genetic variation. These findings provide a basis for testing biological differences among lines that will inform their use as biological control agents, and provide evidence to support a hypothesis of several independent introductions of T. japonicus in western North America from different source areas.

Abstract The design, fabrication, and measurement of a 7 × 7 mm‐wave array antenna have been presented for 5G communications. The substrate integrated waveguide (SIW)‐fed antenna element is formed of four parts: a rectangular radiating patch, a coupling slot cut onto the broadwall of the SIW, a transition layer, and a feeding layer at the bottom. The bandwidth and radiation efficiency has been improved by embedding an air cavity below the radiating patch, as the effective dielectric constant of the substrate is reduced. Moreover, a prototype has been fabricated and measured to verify the design principles. The finite array operating over 23–28 GHz has achieved active voltage standing wave ratios of less than 2 and 2.5 in the E‐ and H‐planes while scanning up to 45° respectively. Compared with the theoretical ideal gain, the average gain drop of the measured embedded element gain is 0.73dB.

UVB radiation can damage human skin, whereas Ginsenoside Rg3, the active ingredient in red ginseng that is processed from ginseng (Panax ginseng C.A. Meyer), could inhibit UVB induced cell damage through anti-oxidation. Meanwhile, P407/CS/HA hydrogel has significant biomedical applications as carriers of drugs. However, the beneficial effects of Rg3-loaded hydrogel (Rg3-Gel) on human HaCaT keratinocytes induced by UVB have rarely been reported. In our study, Rg3 was loaded into hydrogel and the effect of Rg3-Gel against UVB‑induced Hacat cells damages was determined by measuring its ability to alleviate UVB‑induced elevation of oxidative stress, pro-inflammatory and apoptotic response. We found that the treatment with Rg3-Gel inhibited the generation of intracellular ROS and MDA and upregulated the expression of antioxidant enzymes SOD and GSH-Px which were inhibited by UVB exposure. Increased levels of pro-inflammatory cytokines TNF‑α, COX‑2, iNOS and IL‑1β following UVB irradiation were suppressed by the introduction of Rg3-Gel. Additionally, the level of Bcl-2 was decreased and the expression of Bax and Caspase3 were enhanced by Rg3-Gel treatment. In conclusion, Rg3-Gel equipped with the synergistic effect of Rg3 and hydrogel has an effective inhibitory effect on UVB-induced oxidative stress, inflammatory and apoptosis.

Abstract The fast conversion of hydrogen peroxide (H2O2) into reactive oxygen species (ROS) at tumor sites is a promising anticancer strategy by manipulating nanomedicines with near‐infrared light in the second region (NIR‐II). However, this strategy is greatly compromised by the powerful antioxidant capacity of tumors and the limited ROS generation rate of nanomedicines. This dilemma mainly stems from the lack of an effective synthesis method to support high‐density copper‐based nanocatalysts on the surface of photothermal nanomaterials. Herein, a multifunctional nanoplatform (MCPQZ) with high–density cuprous (Cu2O) supported molybdenum disulfide (MoS2) nanoflowers (MC NFs) is developed for the efficient killing of tumors via a potent ROS storm by an innovative method. Under NIR‐II light irradiation, the ROS intensity and maximum reaction velocity (Vmax) produced by MC NFs are 21.6 and 33.8 times that of the non–irradiation group in vitro, which is much higher than most current nanomedicines. Moreover, the strong ROS storm in cancer cells is efficiently formed by MCPQZ (increased by 27.8 times compared to the control), thanks to the fact that MCPQZ effectively pre–weakens the multiple antioxidant systems of cancer cells. This work provides a novel insight to solve the bottleneck of ROS‐based cancer therapy.

BackgroundAutism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, repetitive behavior and language impairment, and its worldwide prevalence has been found to be increasing annually in recent years. Till now, ASD is uncurable as its pathogenesis remains unknown. However, studies on both animals and humans have demonstrated that fecal microbiota transplantation (FMT) may ameliorate the symptoms of ASD, as well as gastrointestinal symptoms. Nonetheless, there is still no agreement regarding the optimal dosage or duration of FMT treatment for individuals with ASD.MethodsThis clinical study is a double-blind, randomized, interventional trial conducted at a single center. The aim is to investigate the safety and efficacy of a pediatric formulation of FMT for ASD. A total of 42 children between the ages of 3–9 with ASD will be randomly assigned in a 2:1 ratio to either an FMT treatment group (n = 28) or a placebo group (n = 14), forming cohort 1. Additionally, 30 healthy children of similar age and gender will be recruited as the control group (cohort 2). Cohort 1 will be assessed using a variety of scales, including the Autism Behavior Checklist, Childhood Autism Rating Scale, Social Responsiveness Scale, Gastrointestinal Symptom Rating Scale, Children’s Sleep Habits Questionnaire, and Psychoeducational Profile (Third Edition). These assessments will evaluate the effectiveness of FMT in reducing core symptoms and comorbidities (such as gastrointestinal symptoms and sleep disturbances) in children with ASD. The study will use metagenomic and metabolomic sequencing to assess changes in the composition and structure of the intestinal flora and its metabolites in blood, urine, and feces following treatment. Furthermore, the study will evaluate the acceptability of the FMT formulation by participants’ legal guardians and investigate differences in the intestinal flora and metabolism in the FMT group before and after treatment compared to 30 healthy children.Clinical trial registrationhttps://www.chictr.org.cn/, identifier ChiCTR2200058459.

Abstract Preventing islet β‐cells death is crucial for treating type 2 diabetes mellitus (T2DM). Currently, clinical drugs are being developed to improve the quality of T2DM care and self‐care, but drugs focused on reducing islets β‐cell death are lacking. Given that β‐cell death in T2DM is dominated ultimately by excessive reactive oxygen species (ROS), eliminating excessive ROS in β‐cells is a highly promising therapeutic strategy. Nevertheless, no antioxidants have been approved for T2DM therapy because most of them cannot meet the long‐term and stable elimination of ROS in β‐cells without eliciting toxic side‐effects. Here, it is proposed to restore the endogenous antioxidant capacity of β‐cells to efficiently prevent β‐cell death using selenium nanodots (SENDs), a prodrug of the antioxidant enzyme glutathione peroxidase 1 (GPX1). SENDs not only scavenge ROS effectively, but also “send” selenium precisely to β‐cells with ROS response to greatly enhance the antioxidant capacity of β‐cells by increasing GPX1 expression. Therefore, SENDs greatly rescue β‐cells by restoring mitophagy and alleviating endoplasmic reticulum stress (ERS), and demonstrate much stronger efficacy than the first‐line drug metformin for T2DM treatment. Overall, this strategy highlights the great clinical application prospects of SENDs, offering a paradigm for an antioxidant enzyme prodrug for T2DM treatment.

The phased array antenna is one of the critical components of the space-borne SAR system and plays a key role in the quality of images. This paper focuses on the design of active phased array antenna for Gaofen-3 satellite, including its architecture, system design methods, key hardware, and the performance for the design implementation. The proposed phased array antenna have capabilities of beam broadening and scanning, left and right side look, polarization switching, in-orbit calibration, uploading beam-steering correction data, collecting self-checking information, and self-protection caused by over pulse width or duty cycle. The phased array antenna is mainly consisted of dual-polarized slotted waveguide antennas, TR modules, time-delay and amplifier modules and power distribution networks. Moreover, the solutions of the direct problem and inverse problem for accurately predicting the pattern and determining the states of TR modules for the required beam have been proposed. The obtained results can confirm that the cross-polarization level of both polarizations for the phased antenna array is below −35 dB. By employing the proposed antenna model, the beam steering error and dispersion error between the predicted and the measured beams in the range plane are less than 4% (100% probability) and less than 2% (95% probability). For beam steering in the azimuth plane, the beam steering error is less than 2% (90% probability), and less than 4% (100% probability). The ground and on-orbit test results have indicated that the functions and performance of the antenna meet the requirements of the SAR system.

Abstract Background The present study aimed to evaluate the effects of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection on the risk of cervical cancer. Methods We conducted a case–control study including 838 cervical cancer cases and 838 benign disease controls matched for age, ethnicity, and place of birth. Venous blood was tested for HBV and HCV serological markers. Multiple odds ratios (OR) and corresponding 95% confidence intervals (CI) for cervical cancer were estimated using logistic regression. HBV antigens were examined using immunohistochemical staining. Results Anti-HCV was positive in 10 cases (1.2%) and 0 controls (0%). Cases had higher percentage of chronic HBV infection (HBsAg-positive/anti-HBc-positive) and prior HBV infection (HBsAg-negative/anti-HBc-positive) than controls (6.3% vs 4.4%; 11.6% vs 7.3%). Both chronic HBV infection (OR 1.6; 95% CI 1.0–2.4) and prior HBV infection (OR 1.7; 95% CI 1.2–2.4) were associated with cervical cancer in univariate logistic regression analyses. In subgroup analysis among HPV-positive patients, the association between chronic HBV infection and cervical cancer disappeared (OR 1.2; 95% CI 0.4–3.4); while in subgroup among patients younger than 50 years, the association remained significant with adjustment for HPV infection and parity (adjusted OR 2.1; 95% CI 1.0–4.4). HBsAg and HBcAg were detected in 8% and 12% of cervical cancer cases who had seropositive HBsAg, respectively. Compared with the benign controls, individuals with both HBsAg and HPV positive had an increased risk of cervical cancer (adjusted OR 67.1; 95% CI 23.4–192.7). Conclusions HBV infection was associated with cervical cancer in patients with age younger than 50 years. Further prospective studies are needed to confirm this relationship.

Abstract Although aplastic anemia (AA) does not come under the category of blood malignant diseases, the infection that frequently occurs in this bone marrow failure can make it worse. Pulmonary infection is the most prevalent but limiting clinical diagnosis. To find biomarkers predicting bacterial or bacterial-combined fungal infections in the lungs, we reviewed 287 AA medical records including 151 without any infection, 87 with pure pulmonary bacterial infection, and 49 with bacterial and fungal infection were reviewed. There were substantial changes in IL-17F, IL-17A, IFN-γ, IL-6, IL-8, and IL-10 levels between the non-infected and lung bacterial infection groups (P

Objective To study the genotypes of ABO ambiguous blood group samples(n=20) and identify their molecular biological characteristics. Methods The serological phenotype of the samples was analyzed by serological techniques. Seven exons of ABO gene were amplified by polymerase chain reaction (PCR) and the PCR products were directly sequenced; the genotypes and sequences of ABO subtypes were analyzed. Results The serological phenotypes of 20 samples presenting ABO ambiguous blood group were as follows: weak A antigen (n=5), weak A antigen combined with anti-A1 antibody (n=5), normal A antigen combined with anti-A1 antibody (n=2), weak B antigen (n=8). The genotypes of them were as follows: Ax02/O01 (n=3), Ael07/O01 (n=2), B313/O01 (n=2), A204/O02 (n=1), A220/O01 (n=1), Ael07/O02 (n=1), Ael02/O01 (n=1), Ael02/O02 (n=1), Ax03/O01 (n=1), Ax03/O02 (n=1), B313/O02 (n=1), B302/O01 (n=1), B302/O02 (n=1), Bw19/O02 (n=1), A102/B313 (n=1) and A101/Bw37 (n=1). Conclusion ABO genotyping technology can accurately identify the ambiguous blood group of samples, provide definite genetic information of blood group and ensure the safety of clinical transfusion.

Forage quality is a key property of grassland ecosystems. In this study, grassland forage qualities were measured at 373 sampling sites throughout Guizhou Province in the karst mountain region of Southwest China, and the factors affecting it were explored. The forage quality level of most plant species was categorized into four levels: (1) preferred forage species; (2) desirable forage species; (3) consumed but undesirable forage species; and (4) non-consumable or toxic forage species. High temperature and precipitation appeared to facilitate the growth of preferred forage species, but limited the growth of other plants. Increasing soil pH had a positive impact on the number and biomass of preferred forage plants, but a negative influence on other plants, especially non-consumable or toxic plants. Both GDP and population density had a positive correlation with the number and biomass of preferred forage species, while such correlations for other levels of forage species tended to be negative. Grazing could lead to a decrease in the preferred forage species. Therefore, it is suggested that by focusing on soil improvement in grassland and maintaining an appropriate grazing intensity, global warming and rapid economic growth in Guizhou Province will likely contribute to increase the forage quality of karst grasslands in Southwest China.

The influx of seasonal migrants has a significant impact on public services in destination places and may reshape the spatial accessibility and equity patterns of park green space (PGS). However, the two-step floating catchment area (2SFCA) method and its extended forms neglect discrepancies between the travel behaviors of seasonal migrants and native residents and thus fail to delineate variations in PGS accessibility and equity in areas with seasonal migrants. To avoid this issue, this study drew on the case of Sanya, a city with large numbers of Houniao, who are primarily retirees leading seasonal migration between the north and the south of China. A multi-group, multi-mode Gaussian-based 2SFCA method was also proposed to evaluate the PGS accessibility and equity before and after the Houniao influx. The method considered the changes in the COVID-19 restrictions from a refined perspective, with fine-scale residential areas being the research units and travel time requested from the web map application programming interface. The results showed that most residential areas were found to have relatively low PGS accessibility and equity levels, except for those in the south-central and southwestern urban areas of Sanya. Both the Houniao influx and lifted COVID-19 restrictions affected the spatial patterns of PGS accessibility and equity. PGS accessibility and equity were decreased by the Houniao influx, whereas walking and public transport within a few residential areas outside Houniao gathering spots improved. This study can serve as a basis for the reasonable planning of PGS and other public services in cities receiving seasonal migrants, such as Sanya.

Pancreatic cancer is among the cancers with the highest mortality rates. Most of the patients are found to have advanced cancer, losing the chance of surgical treatment, and there is an urgent need to find new treatment methods. Targeted therapy for specific genes that play a key role in cancer is now an important means to improve the survival rate of patients. We determined that CD73 is highly expressed in pancreatic cancer by flow cytometry and qRT-PCR assays combined with bioinformatics techniques. Application of CRISPR/Cas9 technology to knockout CD73 in human and murine cell lines, respectively, revealed that CD73 inactivation inhibited cell growth and migration and induced G1 cell cycle arrest. We also found that CD73 deletion inhibited the ERK/STAT3 pathway and activated the E-cadherin pathway. In addition, a CRISPR/Cas9 protein kinase library screen was performed and identified Pbk, Fastk, Cdk19, Adck5, Trim28, and Pfkp as possible genes regulating CD73.

Abstract Cancer cell-derived extracellular vesicles (EVs) have extensive application in the formation of their environment, including metastasis. This study explored the ability of gastric cancer (GC) cell-derived EVs-mediated microRNA-129-5p/E2F transcription factor 7/mitogen-activated protein kinase/extracellular regulated protein kinase (miR-129-5p/E2F7/MAPK/ERK) axis to affect the peritoneal metastasis of GC by delivering lncRNA small nucleolar RNA host gene 12 (SNHG12). EV-derived lncRNA and SNHG12/miR-129-5p/E2F7 network were determined by bioinformatics analysis. The regulatory relationship among SNHG12, miR-129-5p, and E2F7 was verified using a combination of dual-luciferase reporter gene, RNA immunoprecipitation, and RNA pull-down assays. The SNHG12, miR-129-5p, and E2F7 expression was measured by RT-qPCR. After GC cell-derived EVs were isolated and co-cultured with human peritoneal mesothelial cells (HPMCs), the uptake of EVs by HPMCs was observed under laser scanning confocal microscopy. Cell viability and apoptosis were examined using cell counting kit-8 and flow cytometry, respectively. Western blot analysis was performed to measure the mesothelial–mesenchymal transition (MMT)-related protein expression. The pathological and morphological characteristics of metastatic tumors in nude mice were observed by hematoxylin–eosin staining. A high SNHG12 expression was correlated with the poor prognosis of patients with GC. GC-derived EVs led to increased HPMC apoptosis and MMT by transferring SNHG12, whereas the knockdown of SNHG12 annulled the aforementioned results. SNHG12 sponged miR-129-5p to boost E2F7 expression and activate the MAPK/ERK signaling, thus inducing HPMC apoptosis and MMT. In vivo experiments further verified that EVs derived from GC cells promoted peritoneal metastasis in nude mice. GC cell-derived EVs elevated the E2F7 expression and activated the MAPK/ERK signaling to promote peritoneal metastasis through the delivery of SNHG12.

BackgroundStress hyperglycemia frequently occurs in patients with acute ischemic stroke (AIS). The influence of stress hyperglycemia on the outcomes of patients with AIS remains ambiguous.MethodsData from our institution on patients with AIS between June 2020 and June 2021 were retrospectively analyzed. The severity of the stroke was assessed using the National Institutes of Health Stroke Scale (NIHSS) at admission, and the primary endpoint was functional outcomes. Stress hyperglycemia was measured by the glucose-to-HbA1c ratio. In the multivariable analysis, two models that retained or excluded the NIHSS were adopted to explore the relationship between stress hyperglycemia and outcomes. The receiver operating characteristic curve (ROC) was calculated to determine an optimized cutoff value.ResultsThe optimal cutoff value was 1.135. When all patients were included, model 1 did not find an association between the glucose-to-HbA1c ratio and functional outcomes. In model 2, the glucose-to-HbA1c ratio×10 (Glucose-to-HbA1c ratio ×10) was the independent predictor of functional outcomes (OR 1.19, 95% CI 1.07–1.33, p < 0.01). Separately, in patients without diabetes, the glucose-to-HbA1c ratio×10 was the independent predictor of functional outcomes in both model 1 (OR 1.37, 95% CI 1.08–1.73, p = 0.01) and model 2 (OR 1.48, 95% CI 1.22–1.79, p < 0.01), but not in patients with diabetes. In addition, the glucose-to-HbA1c ratio×10 was the independent predictor of stroke severity (OR 1.16, 95% CI 1.05–1.28, p < 0.01).ConclusionThe glucose-to-HbA1c ratio was associated with more severe AIS. Specifically, the glucose-to-HbA1c ratio was associated with the functional outcomes in patients without diabetes but not in patients with diabetes.

ABSTRACT Oropharyngeal candidiasis (OPC), which has a high incidence in immunocompromised and denture stomatitis patients, is commonly caused by Candida albicans infection and in some cases develops into disseminated candidiasis throughout the throat and esophagus, resulting in high mortality. New drugs are needed to combat OPC because of the limited treatment options currently available and increasing resistance to existing drugs. Here, we confirmed that riboflavin (RF), a cofactor of flavin adenine mononucleotide and flavin adenine dinucleotide, has broad-spectrum anti-Candida activity. The formation of C. albicans hyphae and biofilm was inhibited by RF. Mechanistically, RF disrupted membrane and cell wall integrity, as well as promoting reactive oxygen species and pyruvate accumulation. Furthermore, RF targeted multiple essential pathways via functional disruption of thiamine and RF metabolic pathways, central carbon metabolism, and ribosome metabolism. Similar to the results in vitro, the inhibitory effect of RF on C. albicans hyphae was confirmed in a mouse model of OPC. Moreover, after 5 consecutive days of intraperitoneal injection, RF exhibited therapeutic efficacy, as demonstrated by phenotype investigation, the fungal burden, and histopathological analysis. These findings revealed that RF exerts a multifaceted anti-Candida effect and has potential benefits in the treatment of OPC. IMPORTANCE Candida species are common pathogens in fungal infections, causing mucosal infection and invasive infection in immunodeficient patients. Given the limited classes of drugs and resistance to these drugs, new antifungal agents need to be developed. Drug repurposing is a potential method for antifungal drug development. This study demonstrated that riboflavin (RF) exhibited broad-spectrum anti-Candida activity. RF affected multiple targets involving the membrane and cell wall integrity, the accumulation of reactive oxygen species and pyruvate, and the altered metabolic pathways in C. albicans. Moreover, RF exhibited efficacy in the treatment of C. albicans in an oropharyngeal candidiasis mouse model. Taken together, the antifungal activity and the promising clinical application of RF were highlighted.

Evaluating the genetic status of threatened species is an essential task in conservation genetics. However, the genetic status of threatened species has been mostly evaluated through techniques that fail to estimate genetic diversity at the whole genomic level. Next generation sequencing can meet this demand, but high quality samples such as blood or muscle tissues are required. However, it is difficult to collect such samples from threatened species because sampling work may impact their health. Therefore, it is essential to design a workflow to evaluate the whole genomic status of threatened species using non-destructive sampling. Even though non-destructive sampling has been used in traditional barcoding technique, the barcoding technique cannot evaluate the whole genomic status. Brown Eared Pheasant (Crossoptilon mantchuricum) is an endangered species, with captive populations maintained in Taiyuan Zoo, China, and Europe. However, the genetic diversity, inbreeding pattern, and mutation load of these two populations are unclear. To uncover the genetic status of these two captive populations, we applied 2b-RAD technology to evaluate the genomic status of these populations using feathers as samples. The feathers could be collected by non-destructive sampling. The results indicate that the Taiyuan Zoo population has a lower genetic diversity and higher inbreeding coefficient than the European population. The Taiyuan Zoo population has lethal mutations when homozygous. The current project uses a non-destructive sampling technique to evaluate the whole genomic status of the two captive populations, providing a paradigm for conservation genetics, which will facilitate the development of conservation biology.

Abstract The Casitas B-lineage lymphoma (Cbl) family proteins are E3 ubiquitin ligases implicated in the regulation of various immune cells. However, their function in dendritic cells (DCs) remains unclear. To investigate the role of Cbl family members in DCs, we created dendritic cell double-deficient Casitas B lymphoma-b (Cbl-b) and Casitas B lineage lymphoma (c-Cbl) mice by crossing Cbl-b−/− mice with c-Cblflox/flox CD11c-Cre+ mice. We found that specific deletion of Cbl-b and c-Cbl in CD11c+ cells, predominantly in DCs, led to liver fibrosis, cirrhosis, and accumulation of systemic conventional Type I DCs (cDC1s) due to enhanced cell proliferation and decreased cell apoptosis. In addition to a change in DC number, double knockout (dKO) cDC1s exhibited a partially activated status as indicated by high basal expression levels of certain cytokines and possessed an enhanced capacity to prime T cells. After adoptive transfer, dKO cDC1s could drive liver fibrosis too. In further experiments, we demonstrated that Cbl-b and c-Cbl could target signal transducer and activator of transcription 5 (STAT5), a transcriptional repressor for the pro-apoptotic protein Bim, to promote ubiquitination-mediated degradation and cell apoptosis in cDC1s. Further extensive experiments revealed that Cbl-b mediated K27-linked ubiquitination of lysine 164 of STAT5a while c-Cbl induced K29-linked ubiquitination of lysine 696 of STAT5a and K27-linked ubiquitination of lysine 140 and 694 of STAT5b. Thus, our findings indicate a functional redundancy of Cbl-b and c-Cbl in cDC homeostasis and maturation.

Cryptococcus neoformans is an invasive fungus that causes both acute and chronic infections, especially in immunocompromised patients. Owing to the increase in the prevalence of drug-resistant pathogenic fungi and the limitations of current treatment strategies, drug repositioning has become a feasible strategy to accelerate the development of new drugs. In this study, the minimum inhibitory concentration of vitamin D3 (VD3) against C. neoformans was found to be 0.4 mg/mL by broth microdilution assay. The antifungal activities of VD3 were further verified by solid dilution assays and “time-kill” curves. The results showed that VD3 reduced fungal cell adhesion and hydrophobicity and inhibited biofilm formation at various developmental stages, as confirmed by crystal violet staining and the 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay. Fluorescence staining of cellular components and a stress susceptibility assay indicated that VD3 compromised cell integrity. Reverse transcription quantitative PCR demonstrated that VD3 treatment upregulated the expression of fungal genes related to cell wall synthesis (i.e., CDA3, CHS3, FKS1, and AGS1). Moreover, VD3 enhanced cell membrane permeability and caused the accumulation of intracellular reactive oxygen species. Finally, VD3 significantly reduced the tissue fungal burden and prolonged the survival of Galleria mellonella larvae infected with C. neoformans. These results showed that VD3 could exert significant antifungal activities both in vitro and in vivo, demonstrating its potential application in the treatment of cryptococcal infections.

As a consumer product, black chokeberry (Aronia melanocarpa) is difficult to consume due to its pungent taste. It is mainly used in various food industries to produce a variety of juices, preserves, extracts, fruit teas and nutritional supplements. Traditionally, Potawatomi Native Americans used black chokeberry to treat colds, coughs and fever. It has been found to contain numerous active ingredients. Currently, there are many health and medical products that contain black chokeberry. The purpose of this review is to understand the nutritional benefits of black chokeberry and to explore its beneficial effects on biological systems in vitro, thereby emphasizing its therapeutic prospects.

Abstract Long non-coding RNAs (lncRNAs) play a crucial role in macrophage development but little is known about their role in asthma. Here, we investigated the role of lncRNA lncTRPM2-AS in asthma and found that lncTRPM2-AS participates in the promotion of macrophage inflammation. Downregulation of lncTRPM2-AS promoted apoptosis and inhibited proliferation and production of cytokines including IL-1β, IL-4, IL-6, IL-10, TNF-α, and TGF-β. RNA-immunoprecipitation and mass spectrometry indicated that the protein TRPM2 interacted with both lncTRPM2-AS and the E3 ubiquitin ligase TRIM21. LncTRPM2-AS silencing enhanced the interaction between TRIM21 and TRPM2, resulting in elevated levels of ubiquitin-related degradation of TRPM2. Mutation analysis indicated that TRPM2 K1218 is a key site for TRIM21-dependent ubiquitination. Downregulation of lncTRPM2-AS significantly decreased intracellular calcium levels by restraining TRPM2 protein expression, which in turn decreased ROS levels and increased autophagy to promote macrophage apoptosis and reduce cytokine production, together inhibiting macrophage inflammation. Taken together, our findings demonstrate that lncTRPM2-AS blocks the ubiquitination of TRPM2 via TRIM21 and inhibits autophagy-induced apoptosis which may contribute to macrophage inflammation in asthma.

Abstract Understanding competition between scelionid parasitoids that exploit the same host may provide insight into strategies that allow coexistence on a shared resource. Competition studies typically focus on interactions between native and exotic parasitoids that do not share an evolutionary history; however, coevolved parasitoids may be more likely to demonstrate strategies to avoid or exploit a shared resource. We examined intrinsic and extrinsic competition between Asian Trissolcus japonicus (Ashmead) and T. cultratus (Mayr) (Hymenoptera: Scelionidae) associated with Halyomorpha halys (Stål) (Hemiptera: Pentatomidae) that share an evolutionary history. Interspecific interactions were assessed by providing parasitized egg masses to each species at various intervals post‐parasitism, and measuring host acceptance, developmental suitability, and guarding behaviour. Trissolcus japonicus showed high acceptance of parasitized hosts up to 72 h following oviposition by T. cultratus, despite a very poor developmental outcome. In contrast, T. cultratus generally avoided ovipositing in H. halys eggs containing T. japonicus early‐instar larvae but did not avoid parasitizing H. halys that contained eggs and third instar larvae. The adaptive value of this behaviour was supported by developmental outcome: T. cultratus outcompeted T. japonicus eggs but not early‐instar larvae, and a trophic shift occurred wherein T. cultratus developed as a facultative hyperparasitoid on third instar T. japonicus larvae. Trissolcus japonicus guarded egg masses 8–12× longer and displayed more aggressive interactions than T. cultratus, suggesting T. japonicus is the superior extrinsic competitor. Development as a facultative hyperparasitoid provided a competitive niche for Asian T. cultratus and confirms its instrinsic competitive superiority. This also occurs in a biologically distinct European population of T. cultratus, suggesting that facultative hyperparasitism as a competitive strategy is retained in geographically separated populations that have not coevolved with H. halys or T. japonicus.

Abstract Periprocedural antithrombotic management with glycoprotein IIb/IIIa inhibitors (GPI) for intracranial artery stenting is still controversial. We sought to assess the safety and efficacy of prophylactic tirofiban infusion for acute intracranial intraprocedural stent thrombosis in routine clinical practice. From January 2013 to December 2019, consecutive patients treated with endovascular stenting for symptomatic intracranial atherosclerotic stenosis (ICAS) were identified and dichotomized by whether tirofiban was used. The efficacy and safety outcomes were compared by propensity score matching. A total of 160 consecutive patients in the tirofiban group and 177 patients in the non-tirofiban group were enrolled. Propensity score matching analysis selected 236 matched patients. One acute intraprocedural stent thrombosis (AIST) occurred in patients receiving prophylactic tirofiban, while 8 in the non-tirofiban group. The incidence of AIST in the tirofiban group was significantly lower than that in the non-tirofiban group (0.8% vs 6.8%, P = 0.039). The periprocedural ischemic events (8.5% vs 5.1%, P = 0.424), periprocedural intracranial hemorrhage (4.2% vs 0.8%, P = 0.219) and 30-day total mortality (3.4% vs 0%, P = 0.125) were not statistically different between the two groups. Compared with conventional stenting angioplasty without tirofiban, tirofiban prophylactic infusion can lower the incidence of AIST, without increasing the risk of periprocedural intracranial hemorrhage and 30-day total mortality. However, there is no superiority in reducing periprocedural ischemic events. The current study adds more important insights to the available clinical evidence on the use of tirofiban during stenting of ICAS.

Aims: To analyze the clinical characteristics, treatment outcomes and sleep psychological problems of children and parents infected with familial aggregation Omicron variants under a parent-child ward treatment mode to provide a theoretical reference for the diagnosis and comprehensive treatment of Omicron variant strains. Methods: The clinical data of 225 children and 230 adult family members admitted were retrospectively collected and analyzed to investigate their clinical characteristics and response to treatments. Results: The proportion of infected adults and children was the same, and the proportion of children with mild disease was higher than that of adults, but the clinical symptoms were milder. The clinical symptoms of fever, nausea, vomiting and wheezing in children were significantly higher than in adults (P < 0.05). In addition, dry pharynx, pharynx itching and pharyngeal pain were lower than in adults (P < 0.05). The time of turning negative in the moderate group was longer than in the mild group, and the time of turning negative in the unvaccinated group was higher than in the vaccinated group (P < 0.05). The Cycle Threshold Value (Ct value) of Open Reading Frame 1ab (ORF1ab) and Nucleocapsid protein (N) gene of children were higher adults. The increase in the rate of Ct value of ORF1ab and N gene in adults treated with Traditional Chinese Medicine (TCM) was significantly higher than in those who underwent symptomatic treatment (P < 0.01). Based on the Children's Sleep Habits Questionnaire (CSHQ)score, we found varying levels of sleep problems in sleeping habits, latency and anxiety, night awakenings and abnormal sleep at all ages (P < 0.05). In the adult group, those with Self-Rating Scale of Sleep (SRSS) scores ≥3 accounted for more than 50% of adults with insomnia, sleep deprivation, sleep instability and early awakening. The proportion of adults with anxiety and depression was 21.3% and 16.4%. Conclusion: Infections in children and adults during this pandemic were mainly associated with familial aggregation infections, and their clinical symptoms were mainly located in the upper respiratory tract. With comprehensive treatment, children became negative faster, vaccination led to faster recovery, and although some patients experienced sleeping and psychological issues, all patients had good prognoses following comprehensive diagnosis under a parent-child ward treatment mode.

BackgroundStudies show that lung ultrasound (LUS) can accurately diagnose community-acquired pneumonia (CAP) and keep children away from radiation, however, it takes a long time and requires experienced doctors. Therefore, a robust, automatic and computer-based diagnosis of LUS is essential.ObjectiveTo construct and analyze convolutional neural networks (CNNs) based on transfer learning (TL) to explore the feasibility of ultrasound image diagnosis and grading in CAP of children.Methods89 children expected to receive a diagnosis of CAP were prospectively enrolled. Clinical data were collected, a LUS images database was established comprising 916 LUS images, and the diagnostic values of LUS in CAP were analyzed. We employed pre-trained models (AlexNet, VGG 16, VGG 19, Inception v3, ResNet 18, ResNet 50, DenseNet 121 and DenseNet 201) to perform CAP diagnosis and grading on the LUS database and evaluated the performance of each model.ResultsAmong the 89 children, 24 were in the non-CAP group, and 65 were finally diagnosed with CAP, including 44 in the mild group and 21 in the severe group. LUS was highly consistent with clinical diagnosis, CXR and chest CT (kappa values = 0.943, 0.837, 0.835). Experimental results revealed that, after k-fold cross-validation, Inception v3 obtained the best diagnosis accuracy, PPV, sensitivity and AUC of 0.87 ± 0.02, 0.90 ± 0.03, 0.92 ± 0.04 and 0.82 ± 0.04, respectively, for our dataset out of all pre-trained models. As a result, best accuracy, PPV and specificity of 0.75 ± 0.03, 0.89 ± 0.05 and 0.80 ± 0.10 were achieved for severity classification in Inception v3.ConclusionsLUS is a reliable method for diagnosing CAP in children. Experiments showed that, after transfer learning, the CNN models successfully diagnosed and classified LUS of CAP in children; of these, the Inception v3 achieves the best performance and may serve as a tool for the further research and development of AI automatic diagnosis LUS system in clinical applications.Registrationwww.chictr.org.cn ChiCTR2200057328.

Exposure to ultraviolet (UV) radiation is a key cause of skin inflammation and photodamage in the environment. Dihydroquercetin composite nanofiber membrane (CPD) is a nano-scale membrane cloth prepared by electrospinning technology. The results in this study showed that CPD could enhance the activities of endogenous antioxidant enzymes such as SOD and GSH-Px induced by UVA radiation, and reduce the overexpression of ROS. MAPKs/Nrf2 signaling is associated with inflammation, apoptosis and oxidative stress. Compared with control HaCaT cells, we found that CPD pretreatment prevents MAPK (p-ERK, p-JNK, and p-P38)/Nrf2-induced inflammation, apoptosis, and oxidative stress signaling during UVA exposure pathway overexpression. Immunofluorescence experiments also showed that CPD could reduce the fluorescence intensity of Caspase-3 and TNF-α. These results suggest that CPD may be a successful healing agent that provides reinforcement against UVA-induced oxidative and irritating skin compensation.

Periodontal disease (PD) is a local inflammatory disease with high morbidity, manifesting tissue destruction results from inflammation of the host immune response to bacterial antigens and irritants. The supportive function of connective tissue and skeletal tissue can be jeopardized without prompt and effective intervention, representing the major cause of tooth loss. However, traditional treatments exhibited great limitations, such as low efficacies, causing serious side effects and recurrent inflammatory episodes. As a major defense mechanism, reactive oxygen species (ROS) play important roles in the pathological progression of PD. Antioxidant therapy is widely believed to be an effective strategy for ROS-triggered diseases, including oxidative stress-induced PD. Most antioxidants can only scavenge one or a few limited kinds of ROS and cannot handle all kinds. In addition, current antioxidant nanomaterials present limitations associated with toxicity, low stability, and poor biocompatibility. To this end, we develop ultra-small molybdenum-based nanodots (MoNDs) with strong ROS in oxidative stress-induced PD. To the best of our knowledge, this is the first time that MoNDs have been used for PD. In the present study, MoNDs have shown extremely good therapeutic effects as ROS scavengers. Spectroscopic and in vitro experiments provided strong evidence for the roles of MoNDs in eliminating multiple ROS and inhibiting ROS-induced inflammatory responses. In addition, the mouse model of PD was established and demonstrated the feasibility of MoNDs as powerful antioxidants. It can alleviate periodontal inflammation by scavenging multiple ROS without obvious side effects and exhibit good biocompatibility. Thus, this newly developed nanomedicine is effective in scavenging ROS and inhibiting M1 phenotypic polarization, which provides promising candidates for the treatment of PD.