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Abstract Panax notoginseng saponins (PNS) are the main active components of Panax notoginseng. But after oral administration, they need to be converted into rare ginsenosides by human gut microbiota and gastric juice before they can be readily absorbed into the bloodstream and exert their effects. The sources of rare ginsenosides are extremely limited in P. notoginseng and other medical plants, which hinders their application in functional foods and drugs. Therefore, the production of rare ginsenosides by the transformation of PNS using Aspergillus fumigatus was studied in this research. During 50 days at 25 ℃ and 150 rpm, A. fumigatus transformed PNS to 14 products (1–14). They were isolated by varied chromatographic methods, such as silica gel column chromatography, Rp-C18 reversed phase column chromatography, semi-preparative HPLC, Sephadex LH-20 gel column chromatography, and elucidated on the basis of their 1H-NMR, 13C-NMR and ESIMS spectroscopic data. Then, the transformed products (1–14) were isolated and identified as Rk3, Rh4, 20 (R)-Rh1, 20 (S)-Protopanaxatriol, C-K, 20 (R)-Rg3, 20 (S)-Rg3, 20 (S)-Rg2, 20 (R)-R2, Rk1, Rg5, 20 (S)-R2, 20 (R)-Rg2, and 20 (S)-I, respectively. In addition, all transformed products (1–14) were tested for their antimicrobial activity. Among them, compounds 5 (C-K) and 7 [20 (S)-Rg3] showed moderate antimicrobial activities against Staphylococcus aureus and Candida albicans with MIC values of 6.25, 1.25 μg/mL and 1.25, 25 μg/mL, respectively. This study lays the foundation for production of rare ginsenosides. Graphical abstract

Abstract Background Phylogeographic studies have gained prominence in linking past geological events to the distribution patterns of biodiversity, primarily in mountainous regions. However, such studies often focus on plant taxa, neglecting the intricate biogeographical patterns of microbes, particularly soil microbial communities. This article explores the spatial distribution of the nematode-trapping fungus Arthrobotrys oligospora, a widespread microorganism, in a tectonically active region at the southeastern edge of the Qinghai-Tibetan Plateau. By analysing the genetic variation of this fungus alongside the historical structure of major river watersheds, we sought to uncover potential connections between the two. Our study involved sampling 149 strains from 116 sites across six major watersheds in the region. Results The resulting haplotype network revealed five distinct clusters, each corresponding closely to a specific watershed. These clusters exhibited high haplotype diversity and low nucleotide diversity, supporting the notion of watershed-based segregation. Further analysis of haplotypes shared across watersheds provided evidence for three proposed past river connections. In particular, we found numerous shared haplotypes between the Yangtze and Mekong basins, as well as between the Yangtze and the Red basins. Evidence for a Irrawaddy-Salween-Red and a Yangtze-Pearl-Red river connections were also portrayed in our mapping exercise. Conclusions These findings emphasize the crucial role of historical geomorphological events in shaping the biogeography of microbial biodiversity, alongside contemporary biotic and abiotic factors. Watershed perimeters emerged as effective predictors of such patterns, suggesting their suitability as analytical units for regional-scale studies. Our study also demonstrates the potential of microorganisms and phylogeographic approaches to complement traditional geological analyses, providing a more comprehensive understanding of past landscape structure and its evolution.

Abstract Background The effectiveness of post-exposure prophylaxis (PEP) depends on participants adherence, making it crucial to assess and compare regimen options to enhance human immunodeficiency virus (HIV) prophylaxis strategies. However, no prospective study in China has shown that the completion rate and adherence of single-tablet regimens in HIV PEP are higher than those of multi-tablet preparations. Therefore, this study aimed to assess the completion rate and adherence of two HIV PEP regimens. Methods In this single-center, prospective, open-label cohort study, we included 179 participants from May 2022 to March 2023 and analyzed the differences in the 28-day medication completion rate, adherence, safety, tolerance, and effectiveness of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and tenofovir disoproxil fumarate, emtricitabine, and dolutegravir (TDF/FTC + DTG). Results The PEP completion rate and adherence were higher in the BIC/FTC/TAF group than in the TDF/FTC + DTG group (completion rate: 97.8% vs. 82.6%, P = 0.009; adherence: 99.6 ± 2.82% vs. 90.2 ± 25.29%, P = 0.003). The incidence of adverse reactions in the BIC/FTC/TAF and TDF/FTC + DTG groups was 15.2% and 10.3% (P = 0.33), respectively. In the TDF/FTC + DTG group, one participant stopped PEP owing to adverse reactions (1.1%). No other participants stopped PEP due to adverse events. Conclusions BIC/FTC/TAF and TDF/FTC + DTG have good safety and tolerance as PEP regimens. BIC/FTC/TAF has a higher completion rate and increased adherence, thus, is recommended as a PEP regimen. These findings emphasize the importance of regimen choice in optimizing PEP outcomes. Trial registration The study was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2200059994(2022-05-14), https://www.chictr.org.cn/bin/project/edit?pid=167391 ).

Abstract Cell migration, a hallmark of cancer malignancy, plays a critical role in cancers. Improperly initiated or misdirected cell migration can lead to invasive metastatic cancer. Migrasomes are newly discovered vesicular cellular organelles produced by migrating cells and depending on cell migration. Four marker proteins [NDST1 (bifunctionalheparan sulfate N-deacetylase/N-sulfotransferase 1), EOGT (Epidermal growth factor domains pecific O-linked N-acetylglucosaminetransferase), CPQ (carboxypeptidase Q), and PIGK (phosphatidylinositol glycan anchor biosynthesis, class K)] of migrasomes were successfully identified. There are three marker proteins (NDST1, PIGK, and EOGT) of migrasome expressed in cancer. In this review, we will discuss the process of migrasome discovery, the formation of migrasome, the possible functions of migrasome, and the differences between migrasomes and exosomes, especially, the biological functions of migrasome marker proteins in cancer, and discuss some possible roles of migrasomes in cancer. We speculate that migrasomes and migracytosis can play key roles in regulating the development of cancer.

Abstract Breast cancer (BC) ranks first among female malignant tumors and involves hormonal changes and genetic as well as environmental risk factors. In recent years, with the improvement of medical treatment, a variety of therapeutic approaches for breast cancer have emerged and have strengthened to accommodate molecular diversity. However, the primary way to improve the effective treatment of breast cancer patients is to overcome treatment resistance. Recent studies have provided insights into the mechanisms of resistance to exosome effects in BC. Exosomes are membrane-bound vesicles secreted by both healthy and malignant cells that facilitate intercellular communication. Specifically, exosomes released by tumor cells transport their contents to recipient cells, altering their properties and promoting oncogenic components, ultimately resulting in drug resistance. As important coordinators, non-coding RNAs (ncRNAs) are involved in this process and are aberrantly expressed in various human cancers. Exosome-derived ncRNAs, including microRNAs (miRNAs), long-noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as crucial components in understanding drug resistance in breast cancer. This review provides insights into the mechanism of exosome-derived ncRNAs in breast cancer drug resistance, thereby suggesting new strategies for the treatment of BC.

Abstract Soil fungi participate in various ecosystem processes and are important factors driving the restoration of degraded forests. However, little is known about the changes in fungal diversity and potential functions under the development of different vegetation types during natural (secondary forest succession) and anthropogenic (reforestation) forest restoration. In this study, we selected typical forest succession sequences (including Pinus densiflora Siebold & Zucc., pine‐broadleaf mixed forest of P. densiflora and Quercus acutissima Carruth., and Q. acutissima), as well as natural secondary deciduous broadleaved mixed forests and planted forests of Robinia pseudoacacia on Kunyu Mountain for analysis. We used ITS rRNA gene sequencing to characterize fungal communities and used the FUNGuild database to predict fungal functional groups. The results showed that forest succession affected fungal β‐diversity, but not the α‐diversity. There was a significant increase in Basidiomycota and a decrease in Ascomycota in the later successional stage, accompanied by an increase in the functional groups of ectomycorrhizal fungi (ECM). Conversely, planted forests exhibited decreased fungal α‐diversity and altered community compositions, characterized by fewer Basidiomycota and more Ascomycota and Mucoromycota. Planted forests led to a decrease in the relative abundances of ECM and an increase in animal pathogens. The TK content was the major factor explaining the distinction in fungal communities among the three successional stages, whereas pH, AP, and NH4+ were the major factors explaining community variations between natural and planted forests. Changes in vegetation types significantly affected the diversity and functional groups of soil fungal communities during forest succession and reforestation, providing key insights for forest ecosystem management in temperate forests.

Severe left ventricular outflow tract obstruction (LVOTO) of hypertrophic cardiomyopathy is an acutely life-threatening, must-not miss, cardiology emergency that infrequently presents to the emergency department (ED). Patients with this condition usually manifest chest pain, syncope, cardiogenic shock, and severe ischemia. LVOTO is easy misdiagnosed as acute coronary syndrome. In our patient, the ECG showed a significant ST-segment depression and a 0/0 mmHg blood pressure when the peak left ventricular outflow tract gradient was abruptly increased by provocable activities. However, the patient had normal coronaries on cardiac catheterization, and, upon being immediately treated with intravenous esmolol, his symptoms were relieved and blood pressure was normal after 30 minutes. This case highlights, not only that early and exact diagnosis of LVOTO is crucial, but also the importance of the therapeutic strategies used.

Abstract Background Malaria-associated acute lung injury (MA-ALI) is a well-recognized clinical complication of severe, complicated malaria that is partly driven by sequestrations of infected red blood cells (iRBCs) on lung postcapillary induced impaired blood flow. In earlier studies the mechanosensitive Piezo1 channel emerged as a regulator of mechanical stimuli, but the function and underlying mechanism of Piezo1 impacting MA-ALI severity via sensing the impaired pulmonary blood flow are still not fully elucidated. Thus, the present study aimed to explore the role of Piezo1 in the severity of murine MA-ALI. Methods Here, we utilized a widely accepted murine model of MA-ALI using C57BL/6 mice with Plasmodium berghei ANKA infection and then added a Piezo1 inhibitor (GsMTx4) to the model. The iRBC-stimulated Raw264.7 macrophages in vitro were also targeted with GsMTx4 to further explore the potential mechanism. Results Our data showed an elevation in the expression of Piezo1 and number of Piezo1+-CD68+ macrophages in lung tissues of the experimental MA-ALI mice. Compared to the infected control mice, the blockage of Piezo1 with GsMTx4 dramatically improved the survival rate but decreased body weight loss, peripheral blood parasitemia/lung parasite burden, experimental cerebral malaria incidence, total protein concentrations in bronchoalveolar lavage fluid, lung wet/dry weight ratio, vascular leakage, pathological damage, apoptosis and number of CD68+ and CD86+ macrophages in lung tissues. This was accompanied by a dramatic increase in the number of CD206+ macrophages (M2-like subtype), upregulation of anti-inflammatory cytokines (e.g. IL-4 and IL-10) and downregulation of pro-inflammatory cytokines (e.g. TNF-α and IL-1β). In addition, GsMTx4 treatment remarkably decreased pulmonary intracellular iron accumulation, protein level of 4-HNE (an activator of ferroptosis) and the number of CD68+-Piezo1+ and CD68+-4-HNE+ macrophages but significantly increased protein levels of GPX4 (an inhibitor of ferroptosis) in experimental MA-ALI mice. Similarly, in vitro study showed that the administration of GsMTx4 led to a remarkable elevation in the mRNA levels of CD206, IL-4, IL-10 and GPX-4 but to a substantial decline in CD86, TNF-α, IL-1β and 4-HNE in the iRBC-stimulated Raw264.7 cells. Conclusions Our findings indicated that blockage of Piezo1 with GsMTx4 alleviated the severity of experimental MA-ALI in mice partly by triggering pulmonary macrophage M2 polarization and subsequent anti-inflammatory responses but inhibited apoptosis and ferroptosis in lung tissue. Our data suggested that targeting Piezo1 in macrophages could be a promising therapeutic strategy for treating MA-ALI. Graphical Abstract

Abstract Background Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphologic features, and PCOS is associated with infertility. PH domain Leucine-rich repeat Protein Phosphatase 1 (PHLPP1) has been shown to regulate AKT. The aim of present study is to investigate the role of PHLPP1 in PCOS. Methods The expression levels of PHLPP1 in dihydrotestosterone (DHT)-treated human ovarian granular KGN cells were determined by qRT-PCR and Western blot. PHLPP1 was silenced or overexpressed using lentivirus. Cell proliferation was detected by CCK-8. Apoptosis and ROS generation were analyzed by flow cytometry. Glycolysis was analyzed by measuring extracellular acidification rate (ECAR). Results DHT treatment suppressed proliferation, promoted apoptosis, enhanced ROS, and inhibited glycolysis in KGN cells. PHLPP1 silencing alleviated the DHT-induced suppression of proliferation and glycolysis, and promotion of apoptosis and ROS in KGN cells. PHLPP1 regulated cell proliferation and glycolysis in human KGN cells via the AKT signaling pathway. Conclusions Our results showed that PHLPP1 mediates the proliferation and aerobic glycolysis activity of human ovarian granular cells through regulating AKT signaling.

Accurate identification of fungal species is crucial for mycological research, relying significantly on experienced taxonomists’ ability to recognize fungal morphology. With the dwindling number of taxonomists, developing a rapid, accurate, and automated fungal identification method is essential, promising to markedly decrease the time and resources needed for such tasks. To address the challenges in the automatic identification of nematode-trapping fungi (NTF, belong to Orbiliaceae, Orbiliomycetes, a group of filamentous fungi that catch nematodes in soil), specifically focusing on their conidia which are often aggregated and morphologically similar, we developed an enhanced method. Our approach integrates an efficient channel attention (ECA) mechanism within the backbone layer of YOLOv8l, improving the algorithm’s capability to detect global information effectively. This adjustment significantly optimizes the detection and differentiation of limited features and small-sized conidia among aggregated samples. The experimental outcomes demonstrated that our method increases precision by 0.3%, recall by 1.8%, and mean average precision (mAP) by 0.4%, surpassing the performance of existing target detection algorithms. In addition, this method accurately identified the aggregated fungal conidia and distinguished morphologically similar spores. In conclusion, the system accurately detects and recognizes the conidia of NTF in mixed spore environments, thus providing crucial technical support for the automatic detection and early prediction of NTF.

Abstract Objective To assess lung deformation in patients with idiopathic pulmonary fibrosis (IPF) using with elastic registration algorithm applied to three-dimensional ultrashort echo time (3D-UTE) MRI and analyze relationship of lung deformation with the severity of IPF. Methods Seventy-six patients with IPF (mean age: 62 ± 6 years) and 62 age- and gender-matched healthy controls (mean age: 58 ± 4 years) were prospectively enrolled. End-inspiration and end-expiration images acquired with a single breath-hold 3D-UTE sequence were registered using elastic registration algorithm. Jacobian determinants were calculated from deformation fields and represented on color maps. Jac-mean (absolute value of the log means of Jacobian determinants) and the Dice similarity coefficient (Dice) were compared between different groups. Results Compared with healthy controls, the Jac-mean of IPF patients significantly decreased (0.21 ± 0.08 vs. 0.27 ± 0. 07, p < 0.001). Furthermore, the Jac-mean and Dice correlated with the metrics of pulmonary function tests and the composite physiological index. The lung deformation in IPF patients with dyspnea Medical Research Council (MRC) ≥ 3 (Jac-mean: 0.16 ± 0.03; Dice: 0.06 ± 0.02) was significantly lower than MRC1 (Jac-mean: 0. 25 ± 0.03, p < 0.001; Dice: 0.10 ± 0.01, p < 0.001) and MRC 2 (Jac-mean: 0.22 ± 0.11, p = 0.001; Dice: 0.08 ± 0.03, p = 0.006). Meanwhile, Jac-mean and Dice correlated with health-related quality of life, 6 min-walk distance, and the extent of pulmonary fibrosis. Jac-mean correlated with pulmonary vascular-related indexes on high-resolution CT. Conclusion The decreased lung deformation in IPF patients correlated with the clinical severity of IPF patients. Elastic registration of inspiratory-to-expiratory 3D UTE MRI may be a new morphological and functional marker for non-radiation and noninvasive evaluation of IPF. Critical relevance statement This prospective study demonstrated that lung deformation decreased in idiopathic pulmonary fibrosis (IPF) patients and correlated with the severity of IPF. Elastic registration of inspiratory-to-expiratory three-dimensional ultrashort echo time (3D UTE) MRI may be a new morphological and functional marker for non-radiation and noninvasive evaluation of IPF. Key points • Elastic registration of inspiratory-to-expiratory three-dimensional ultrashort echo time (3D UTE) MRI could evaluate lung deformation. • Lung deformation significantly decreased in idiopathic pulmonary fibrosis (IPF) patients, compared with the healthy controls. • Reduced lung deformation of IPF patients correlated with worsened pulmonary function and the composite physiological index (CPI). Graphical Abstract

Abstract Background and Objective High‐grade glioma (HGG) is known to be characterized by a high degree of malignancy and a worse prognosis. The classical treatment is safe resection supplemented by radiotherapy and chemotherapy. Tumor treating fields (TTFields), an emerging physiotherapeutic modality that targets malignant solid tumors using medium‐frequency, low‐intensity, alternating electric fields to interfere with cell division, have been used for the treatment of new diagnosis of glioblastoma, however, their administration in HGG requires further clinical evidence. The efficacy and safety of TTFields in Chinese patients with HGG were retrospectively evaluated by us in a single center. Methods We enrolled and analyzed 52 patients with newly diagnosed HGG undergoing surgery and standard chemoradiotherapy regimens from December 2019 to June 2022, and followed them until June 2023. Based on whether they used TTFields, they were divided into a TTFields group and a non‐TTFields group. Progression‐free survival (PFS) and overall survival (OS) were compared between the two groups. Results There were 26 cases in the TTFields group and 26 cases in the non‐TTFields group. In the TTFields group, the median PFS was 14.2 months (95% CI: 9.50–18.90), the median OS was 19.7 months (95% CI: 14.95–24.25) , the median interval from surgery to the start of treatment with TTFields was 2.47 months (95% CI: 1.47–4.13), and the median duration of treatment with TTFields was 10.6 months (95% CI: 9.57–11.63). 15 (57.69%) patients experienced an adverse event and no serious adverse event was reported. In the non‐TTFields group, the median PFS was 9.57 months (95% CI: 6.23–12.91) and the median OS was 16.07 months (95% CI: 12.90–19.24). There was a statistically significant difference in PFS (p = 0.005) and OS (p = 0.007) between the two groups. Conclusions In this retrospective analysis, TTFields were observed to improve newly diagnosed HGG patients' median PFS and OS. Compliance was much higher than reported in clinical trials and safety remained good.

Abstract Introduction The efficacy and safety of ainuovirine+lamivudine+tenofovir (ANV+3TC+TDF) and efavirenz+lamivudine+tenofovir (EFV+3TC+TDF) have been confirmed in previous clinical trials; however, there are no related studies on patient‐reported outcomes. This study aimed to evaluate the effectiveness and safety of these 2 antiretroviral therapy regimens and to understand the patient's symptom experience and subjective experience of sleep quality through patient‐reported outcomes. Methods This is a single‐center prospective cohort study with 243 patients evaluated from October 1, 2021 to June 30, 2022. Virological effectiveness and patient‐reported outcomes results were analyzed. The primary endpoint was the proportion of HIV viral load

Abstract. Background:. The presence of fibrosis is a criterion for subtype classification in the newly updated hypersensitivity pneumonitis (HP) guidelines. The present study aimed to summarize differences in clinical characteristics and prognosis of non-fibrotic hypersensitivity pneumonitis (NFHP) and fibrotic hypersensitivity pneumonitis (FHP) and explore factors associated with the presence of fibrosis. Methods:. In this prospective cohort study, patients diagnosed with HP through a multidisciplinary discussion were enrolled. Collected data included demographic and clinical characteristics, laboratory findings, and radiologic and histopathological features. Logistic regression analyses were performed to explore factors related to the presence of fibrosis. Results:. A total of 202 patients with HP were enrolled, including 87 (43.1%) NFHP patients and 115 (56.9%) FHP patients. Patients with FHP were older and more frequently presented with dyspnea, crackles, and digital clubbing than patients with NFHP. Serum levels of carcinoembryonic antigen, carbohydrate antigen 125, carbohydrate antigen 153, gastrin-releasing peptide precursor, squamous cell carcinoma antigen, and antigen cytokeratin 21-1, and count of bronchoalveolar lavage (BAL) eosinophils were higher in the FHP group than in the NFHP group. BAL lymphocytosis was present in both groups, but less pronounced in the FHP group. Multivariable regression analyses revealed that older age,

Abstract Carotenoids, as natural tetraterpenes, play a pivotal role in the yellow coloration of peaches and contribute to human dietary health. Despite a relatively clear understanding of the carotenoid biosynthesis pathway, the regulatory mechanism of miRNAs involved in carotenoid synthesis in yellow peaches remain poorly elucidated. This study investigated a total of 14 carotenoids and 40 xanthophyll lipids, including six differentially accumulated carotenoids: violaxanthin, neoxanthin, lutein, zeaxanthin, cryptoxanthin, and (E/Z)-phytoene. An integrated analysis of RNA-seq, miRNA-seq and degradome sequencing revealed that miRNAs could modulate structural genes such as PSY2, CRTISO, ZDS1, CHYB, VDE, ZEP, NCED1, NCED3 and the transcription factors NAC, ARF, WRKY, MYB, and bZIP, thereby participating in carotenoid biosynthesis and metabolism. The authenticity of miRNAs and target gene was corroborated through quantitative real-time PCR. Moreover, through weighted gene coexpression network analysis and a phylogenetic evolutionary study, coexpressed genes and MYB transcription factors potentially implicated in carotenoid synthesis were identified. The results of transient expression experiments indicated that mdm-miR858 inhibited the expression of PpMYB9 through targeted cleavage. Building upon these findings, a regulatory network governing miRNA-mediated carotenoid synthesis was proposed. In summary, this study comprehensively identified miRNAs engaged in carotenoid biosynthesis and their putative target genes, thus enhancing the understanding of carotenoid accumulation and regulatory mechanism in yellow peach peel and expanding the gene regulatory network of carotenoid synthesis. Graphical Abstract

Abstract Introduction Bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and dolutegravir plus lamivudine (DTG + 3TC) are well tolerated and effective in clinical trials. This study aimed to evaluate the safety and efficacy of these two schemes in a real-world setting and to obtain the first dataset for switching to BIC/FTC/TAF and DTG + 3TC in a Chinese population. Methods This retrospective single-center cohort study in China included participants who switched to DTG + 3TC or BIC/FTC/TAF between January 2020 and February 2023. The main endpoint was the proportion of participants with HIV-1 RNA levels of ≥ 50 copies/mL. Safety, tolerance, and the incidence of low-level viremia (LLV) were evaluated. Results A total of 525 participants were included, 454 of whom were included in the PP analysis. At week 48, the proportions of participants with HIV-1 RNA ≥ 50 copies/mL were 4.4% (10/225) for DTG + 3TC and 6.1% (14/229) for BIC/FTC/TAF; virological efficacy did not differ significantly between the two groups. Consistent results were obtained in an intent-to-treat (ITT) analysis. The incidences of LLV were 3.6% (7/193) and 4.9% (10/206), respectively. During the study, none of the participants stopped taking drugs because of a lack of efficacy or adverse reactions. Conclusions Both regimens are well tolerated and effective for switching HIV-1 infection therapy. However, the detection of genotypic drug resistance should be considered when baseline virological non-suppression is observed.

Secondary lymphedema is caused by damage to the lymphatic system from surgery, cancer treatment, infection, trauma, or obesity. This damage induces stresses such as oxidative stress and hypoxia in lymphatic tissue, impairing the lymphatic system. In response to damage, vascular endothelial growth factor C (VEGF-C) levels increase to induce lymphangiogenesis. Unfortunately, VEGF-C often fails to repair the lymphatic damage in lymphedema. The underlying mechanism contributing to lymphedema is not well understood. In this study, we found that surgery-induced tail lymphedema in a mouse model increased oxidative damage and cell death over 16 days. This corresponded with increased VEGF-C levels in mouse tail lymphedema tissue associated with macrophage infiltration. Similarly, in the plasma of patients with secondary lymphedema, we found a positive correlation between VEGF-C levels and redox imbalance. To determine the effect of oxidative stress in the presence or absence of VEGF-C, we found that hydrogen peroxide (H2O2) induced cell death in human dermal lymphatic endothelial cells (HDLECs), which was potentiated by VEGF-C. The cell death induced by VEGF-C and H2O2 in HDLECs was accompanied by increased reactive oxygen species (ROS) levels and a loss of mitochondrial membrane potential. Antioxidant pre-treatment rescued HDLECs from VEGF-C-induced cell death and decreased ROS under oxidative stress. As expected, VEGF-C increased the number of viable and proliferating HDLECs. However, upon H2O2 treatment, VEGF-C failed to increase either viable or proliferating cells. Since oxidative stress leads to DNA damage, we also determined whether VEGF-C treatment induces DNA damage in HDLECs undergoing oxidative stress. Indeed, DNA damage, detected in the form of gamma H2AX (γH2AX), was increased by VEGF-C under oxidative stress. The potentiation of oxidative stress damage induced by VEFG-C in HDLECs was associated with p53 activation. Finally, the inhibition of vascular endothelial growth factor receptor-3 (VEGFR-3) activation blocked VEGF-C-induced cell death following H2O2 treatment. These results indicate that VEGF-C further sensitizes lymphatic endothelial cells to oxidative stress by increasing ROS and DNA damage, potentially compromising lymphangiogenesis.

ObjectiveTo evaluate the causal relationship between childhood body-mass index (BMI) at different ages and adult cardiometabolic traits.MethodsWe retrieved genetic instrument variables (IVs) for exposures (standardized BMI at newborn, infant, toddler and late childhood), cardiometabolic traits and potential confounders or mediators (adult BMI, SHBG, testosterone and age at menarche) from the corresponding genome-wide association analysis. We performed univariate and multivariable Mendelian randomization (MR) to dissect associations between age-specific childhood BMI and adult cardiometabolic outcomes. Odds ratio was used to present the direction of the causal association.ResultsIn univariate MR, higher newborn BMI was causally associated with reduced risk for type 2 diabetes in women. Late childhood BMI was associated with increased risk for female diabetes and coronary artery disease (CAD), myocardial infarction (MI), and chronic kidney disease (CKD) in general population. Among these associations, only association between late childhood BMI with MI remained significant after adjusting for adult male BMI and sex hormones, (OR = 1.120, 95% CI 1.023-1.226, p = 0.014). Besides, in multivariable MR, we found evidence for causal association between newborn BMI with reduced risk for CAD (OR = 0.862, 95% CI 0.751-0.989, p = 0.034) and MI (OR = 0.864, 95% CI 0.752-0.991, p = 0.037) in men. No obvious impact of infant or toddler BMI was identified on the above-mentioned diseases. For continuous cardiometabolic traits, in all age epochs except infant, higher BMI was associated with increased level of fasting glucose in women.ConclusionBMI at birth and late childhood exerts different impact on adult cardiometabolic diseases, while BMI at infant and toddler ages is not causally associated with these outcomes. The effect of childhood BMI may be influenced by sex disparities.

PurposeThe current study designed a unique type of corneal topography evaluation method based on deep learning and traditional image processing algorithms. The type of corneal topography of patients was evaluated through the segmentation of important medical zones and the calculation of relevant medical indicators of orthokeratology (OK) lenses.MethodsThe clinical data of 1,302 myopic subjects was collected retrospectively. A series of neural network-based U-Net was used to segment the pupil and the treatment zone in the corneal topography, and the decentration, effective defocusing contact range, and other indicators were calculated according to the image processing algorithm. The type of corneal topography was evaluated according to the evaluation criteria given by the optometrist. Finally, the method described in this article was used to evaluate the type of corneal topography and compare it with the type classified by the optometrist.ResultsWhen the important medical zones in the corneal topography were segmented, the precision and recall of the treatment zone reached 0.9587 and 0.9459, respectively, and the precision and recall of the pupil reached 0.9771 and 0.9712. Finally, the method described in this article was used to evaluate the type of corneal topography. When the reviewed findings based on deep learning and image processing algorithms were compared to the type of corneal topography marked by the professional optometrist, they demonstrated high accuracy with more than 98%.ConclusionThe current study provided an effective and accurate deep learning algorithm to evaluate the type of corneal topography. The deep learning algorithm played an auxiliary role in the OK lens fitting, which could help optometrists select the parameters of OK lenses effectively.

Evapotranspiration (ET) is an important process of the regional hydrothermal cycle. However, it is unclear how the mitigation of urban ET in urban thermal environments occurs in a spatial context. Landsat 8 satellite images from 2014 to 2018 of Xuzhou and corresponding meteorological observations were selected, and the improved mono-window algorithm (IMW) and urban RS-PM model were applied to invert land surface temperature (LST) and ET, respectively. In addition, spatial analysis methods (a profile analysis, standard deviation ellipse (SDE) analysis, and bivariate Moran's I) were employed to quantify and simulate the spatial characteristics of the ET effect on LST. The results indicated the following: (1) There was a significant linear negative correlation between ET and LST, which confirms that ET has a negative effect on LST; (2) the SDE overlap ratios between patches with higher ET and lower LST imply that higher ET patches have a significant impact on the spatial distribution of LST; and (3) bivariate Moran's I between ET and LST and their linear mixture spectral analysis (LISA) maps reveal a significant negative spatial correlation between ET and LST. In addition, the landscape pattern of higher ET parches is also an important factor affecting the environmental temperature. HIGHLIGHTS A significant negative spatial correlation between ET and LST was found.; Areas with various ET intensities have different regulatory effects on LST.; Higher ET intensity is not an absolute factor in mitigating the urban thermal environment.; Landscape pattern of the patches with higher ET also has a significant impact on LST regulation.;

Abstract Studies have found that RNA encoding proteins only account for a small part of the total number, most RNA is non-coding RNA, and non-coding RNA may affect the occurrence and development of human cancers by affecting gene expression, therefore play an important role in human pathology. At present, ncRNAs studied include miRNA, circRNA, lncRNA, piRNA, and snoRNA, etc. After decades of research, the basic role of these ncRNAs in many cancers has been clear. As far as we know, the role of miRNAs in cancer is one of the hottest research directions, however, it is also found that the imbalance of ncRNAs will affect the occurrence of gastric cancer, breast cancer, lung cancer, meanwhile, it may also affect the prognosis of these cancers. Therefore, the study of ncRNAs in cancers may help to find new cancer diagnostic and treatment methods. Here, we reviewed the biosynthesis and characteristics of miRNA, cricRNA, and lncRNA etc., their roles in human cancers, as well as the mechanism through which these ncRNAs affect human cancers.

Highlights The gelation of hole transport layer generates a dense and uniform hole transport layer film and significantly inhibits the aggregation of lithium bis(trifluoromethane sulfonyl)imide in spiro-OMeTAD. The gelated hole transport layer confers enhanced charge carrier transport and better humidity and operational stability of perovskite solar cells.

Carotenoids are naturally occurring tetraterpenoids that play a key role in fruit coloration, and yellow peaches are one of the best sources of carotenoid intake. MYB transcription factors are one of the largest families in plants and play an important role in the regulation of plant secondary metabolite biosynthesis. However, peach MYB family genes have not been fully analyzed, and in particular, MYBs that regulate carotenoid biosynthesis have not been fully characterized. In this study, 190 peach MYB genes, containing 68 1R-MYBs, 118 2R-MYBs, 3 3R-MYBs, and 1 4R-MYB, were identified at the genome level using bioinformatics methods. These 190 MYBs were classified into 27 subfamilies based on their phylogenetic relationships with Arabidopsis thaliana MYB family members, and they were unevenly distributed across eight chromosomes. MYB genes of the same subfamily exhibit similar but not identical gene structures and conserved motifs. The promoter regions contain cis-acting elements associated with stress response, hormone response, and plant growth and development. There were 54 collinear pairs of MYB genes in the peach genome, compared with 233 and 221 collinear pairs with Rosa chinensis and Arabidopsis, respectively. Thirteen differentially expressed genes in the carotenoid biosynthesis pathway in yellow peach were identified by transcriptome sequencing and contained MYB binding sites on their promoters. Based on a phylogenetic analysis, we identified 13 PpMYBs that may be involved in carotenoid biosynthesis, and a correlation analysis revealed that they regulate carotenoid accumulation by positively or negatively regulating the expression of carotenoid biosynthetic genes. Further degradome sequencing screened that mdm-miR858 was able to target PpMYB17 and PpMYB126 involved in the regulation of carotenoid biosynthesis. Our findings provide new insights into the potential role of MYB transcription factors in carotenoid biosynthesis and provide a theoretical basis for their molecular mechanisms.

Venetoclax and obinutuzumab are becoming frontline therapies for chronic lymphocytic leukemia (CLL) patients. Unfortunately, drug resistance still occurs, and the combination could be immunosuppressive. Lysosomes have previously been identified as a target for obinutuzumab cytotoxicity in CLL cells, but the mechanism remains unclear. In addition, studies have shown that lysosomotropic agents can cause synergistic cell death in vitro when combined with the BTK inhibitor, ibrutinib, in primary CLL cells. This indicates that targeting lysosomes could be a treatment strategy for CLL. In this study, we have shown that obinutuzumab induces lysosome membrane permeabilization (LMP) and cathepsin D release in CLL cells. Inhibition of cathepsins reduced obinutuzumab-induced cell death in CLL cells. We further determined that the lysosomotropic agent siramesine in combination with venetoclax increased cell death in primary CLL cells through an increase in reactive oxygen species (ROS) and cathepsin release. Siramesine treatment also induced synergistic cytotoxicity when combined with venetoclax. Microenvironmental factors IL4 and CD40L or incubation with HS-5 stromal cells failed to significantly protect CLL cells from siramesine- and venetoclax-induced apoptosis. We also found that siramesine treatment inhibited autophagy through reduced autolysosomes. Finally, the autophagy inhibitor chloroquine failed to further increase siramesine-induced cell death. Taken together, lysosome-targeting drugs could be an effective strategy in combination with venetoclax to overcome drug resistance in CLL.

The interaction between fig wasps and their host fig trees (Ficus spp.) is a striking example of an obligate pollination mutualism. Male and female fig wasps are confined within their natal patch instead of panmictic; under this circumstance, mating only occurs between individuals of the same patch. This is known as a local mate competition (LMC). It pays foundresses to invest mainly in daughters and to only produce enough sons to ensure that all female offspring can be fertilized, but in nature, pollinating fig wasps may face many problems with host quality, such as limitation of oviposition sites and the nutrition deficiency of the host fig. The sex ratio of wasps can determine the stability of fig–fig wasp mutualistic system and, thus, the stability of other species associated with it. In this study, we controlled the quality of host figs in three ways. The results showed that the host fig age can influence the sex ratio of pollinator offspring, while the foundress numbers and the presence of pollen have no significant effect on it. A compelling explanation for this result is that the sex-dependent mortality occurs. This is a novel finding of how host quality influences the interaction of fig and fig wasps, which can also help us understand the evolution and stability mechanism of this symbiotic system.

Abstract Breast cancer and diabetes are significant health challenges, and effective treatments for both diseases are lacking. Proton pump inhibitors (PPIs) have demonstrated anticancer and hypoglycemic effects, but their mechanisms of action are not yet fully understood. We used the GeneCards and PharmMapper databases to identify therapeutic targets for diabetes, breast cancer and PPIs. We identified common targets and constructed a regulatory network of diseases and drugs using the STRING database and Cytoscape software. We also explored the binding between small molecule ligands and protein receptors using Discovery Studio software. We identified 33 shared targets for breast cancer, diabetes, and PPIs including lansoprazole, omeprazole, and pantoprazole, which play a critical role in fatty acid transport, insulin resistance, apoptosis, and cancer-related signaling pathways. Our findings demonstrated that PPIs had a strong affinity for AKT1 and MMP9. This study provides insights into the mechanisms of action of PPIs in breast cancer and diabetes and identifies AKT1 and MMP9 as critical targets for future drug development. Our findings highlight the potential of PPIs as a novel therapeutic approach for these challenging diseases.

Venetoclax (VCX) is a BCL2 inhibitor approved for treating B cell-derived leukemia, including chronic lymphocytic leukemia (CLL). VCX’s role in apoptosis induction is well-defined, whereas its other mechanistic roles need to be clarified. Autophagy is an intracellular degradation process involving the lysosome, playing a fundamental role in cancer cell survival and death. In this study, we aim to investigate VCX’s function in autophagy. Following the measurement of autophagic flux by western blot and fluorescent microscopy, we demonstrate that VCX is a novel autophagy inhibitor and reduces the level of the essential autophagy pathway protein ATG12 (autophagy-related 12). VCX sensitizes B cell lines and primary CLL cells to cell death induced by amino acid starvation or ibrutinib. These findings provide a rationale for VCX treatment in combination therapies that inhibit the pro-cell survival function of autophagy in B cell-derived malignancies. Abbreviations: ATG12, autophagy-related 12; BCL2, BCL2 apoptosis regulator; CLL, chronic lymphocytic leukemia; CQ, chloroquine; IBR, ibrutinib; BTK, Bruton’s tyrosine kinase; LC3B, MAP1LC3B (microtubule-associated protein 1 light chain 3 beta); VCX, venetoclax; BECN1, beclin 1

ABSTRACT Importance Infantile spasm (IS) is a kind of refractory epilepsy. The first‐line treatments for IS are adrenocorticotropic hormone (ACTH), oral corticosteroids, and vigabatrin. Objective This study aimed to evaluate the efficacy of magnesium sulfate and ACTH (MgSO4+ACTH) combination therapy in patients with IS who failed first‐line treatments. Methods In this retrospective study, the clinical data of patients with IS who failed first‐line treatments were collected in the Chinese PLA General Hospital. Patients received MgSO4+ACTH combination therapy after first‐line treatments failed. The course of treatments was 2 weeks. The therapeutic dose of ACTH and MgSO4 was 2.5 U·kg−1·d−1 and 0.25 g·kg−1·d−1, respectively. Results A total of 229 patients with IS who failed the first‐line treatments were collected. At the end of the MgSO4+ACTH combination treatment, the seizure‐free rate was 48.5% (111/229), and the resolution of hypsarrhythmia on electroencephalogram (EEG) was 72.1% (165/229). About 21.4% (49/229) of patients showed side effects, including infectious diseases, hypokalemia, and diarrhea. Interpretation For patients with IS who failed first‐line treatments, in terms of the seizure‐free rate and resolution of hypsarrhythmia on EEG, MgSO4+ACTH combination therapy can be considered.

Objective: To investigate the effects of cell passage number on the establishment of an oxidative stress model in human colon adenocarcinoma cells (Caco-2) caused by tert-butyl hydroperoxide (t-BHP). Methods: First, by applying various t-BHP concentrations (1, 2 and 3 mmol/L) to the F15 generation of Caco-2 cells for 1, 2, 3, 4, 5 and 6 hours, the content of malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG) in different treatment groups were measured to determine the basic conditions for constructing the oxidative stress model of Caco-2 cells. Then, based on the fundamental parameters, the effect of cell passage number (F14, F15, F18, F19 and F20) on the development of oxidative stress model was investigated using the content of 8-OHdG as an index. Results: When exposed to 1, 2 and 3 mmol/L of t-BHP for 3 to 6 hours, the oxidative stress model of Caco-2 cells from the F15 generation could be established steadily. The content of 8-OHdG in Caco-2 cells of the F14, F15 and F18 generations was significantly higher than that in control group (which had not been treated with t-BHP) after being exposed to 2.0 mmol/L t-BHP for 5 hours (P

Abstract Background Studies on the incidence of venous thromboembolism (VTE) events in patients with interstitial lung disease (ILD) are limited and the results are inconsistent. The aim of this research was to investigate the incidence and risk factors of VTE in ILD during hospitalization. Materials and methods In this retrospective, cross-sectional, observational study, a total of 5009 patients diagnosed with ILD from January 2016 to March 2022 in our hospital were retrospectively included. In ILD patients, VTE including pulmonary thromboembolism (PTE) and deep vein thrombosis (DVT) were screened from the electronic medical record system. Diagnosis of PTE and DVT were performed by CT pulmonary angiography (CTPA), CTV or ultrasound. And then the incidence and risk factors of VTE in different types of ILD were assessed. Results Among 5009 patients with ILD, VTE was detected in 129 (2.6%) patients, including 15(0.3%) patients with both PTE and DVT, 34 (0.7%) patients with PTE and 80 (1.6%) patients with DVT. 85.1% of patients with APE were in the intermediate-low risk group. The incidence of VTE in Anti-Neutrophil Cytoplasmic Antibodies -associated vasculitis related ILD (ANCA-AV-ILD), hypersensitivity pneumonitis and idiopathic pulmonary fibrosis (IPF) respectively was 7.9% and 3.6% and 3.5%. In patients with connective tissue disease-associated ILD (CTD-ILD), the incidence of VTE, DVT, PTE, combined PTE and DVT respectively was 3.0%, 2.3%, 0.4% and 0.3%. Among the various risk factors, different ILD categories, age ≥ 80 years (OR 4.178, 95% CI 2.097–8.321, P 21 days). Conclusion The incidence of VTE during hospitalization in ILD patients was 2.6%, with a 1.6% incidence of DVT, higher than the 0.7% incidence of PTE. Advanced age, ILD categories, respiratory failure and varicose veins as independent risk factors for the development of VTE should be closely monitored.

Abstract Background SHR2554, a novel oral Enhancer of Zeste Homolog 2 inhibitor, shows broad‐spectrum anti‐tumor efficacy in preclinical studies. As SHR2554 is mainly metabolized by CYP3A4, it is helpful to conduct research on the effects of itraconazole, a strong inhibitor of CYP3A4‐metabolizing enzymes, on the pharmacokinetic characteristics and safety of SHR2554. Methods We conducted a single‐center, open‐label pharmacokinetic study of itraconazole on SHR2554 in 18 healthy Chinese subjects. Subjects were orally administrated SHR2554 50 mg on Day 1, itraconazole 200 mg Quaque Die (QD) from Days 4 to 7, SHR2554 50 mg co‐administrated with itraconazole 200 mg on Day 8, and itraconazole 200 mg QD from Days 9 to 12. Then, 4 ml of venous blood was collected at predetermined time points. Plasma SHR2554 concentrations were analyzed using a validated high‐performance liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters were calculated using Phoenix WinNonlin v8.1. Results The Cmax of SHR2554 alone and in combination was 10.197 ± 7.0262 ng·ml−1 versus 70.538 ± 25.0219 ng·ml−1, AUC0–∞ was 50.99 ± 19.358 h·ng·ml−1 versus 641.53 ± 319.538 h·ng·ml−1, and AUC0–t was 28.70 ± 18.913 h·ng·ml−1 versus 612.13 ± 315.720 h·ng·ml−1. Co‐administration of SHR2554 and itraconazole caused 7.73‐, 12.47‐, and 23.75‐fold adjusted geometric mean ratios increases in SHR2554 Cmax, AUC0−∞ and AUC0−t respectively. The co‐administration regimen was well tolerated and had a good safety profile. Conclusions Compared with a single dose of SHR2554 50 mg, the exposure of SHR2554 in vivo was significantly affected by the combined administration of itraconazole.

Abstract Background Many data suggest that the sucrose non-fermenting 1-related kinases 2 (SnRK2s) are very important to abiotic stress for plants. In rice, these kinases are known as osmotic stress/ABA–activated protein kinases (SAPKs). Osmotic stress/ABA–activated protein kinase 3 (OsSAPK3) is a member of SnRK2II in rice, but its function is still unclear. Results The expression of OsSAPK3 was up regulated by drought, NaCl, PEG and ABA. OsSAPK3 mutated seedings (sapk3-1 and sapk3-2) showed reduced hypersensitivity to exogenous ABA. In addition, under drought conditions, sapk3-1 and sapk3-2 showed more intolerance to drought, including decreased survival rate, increased water loss rate, increased stomatal conductance and significantly decreased expression levels of SLAC1 and SLAC7. Physiological and metabolic analyses showed that OsSAPK3 might play an important role in drought stress signaling pathway by affecting osmotic adjustment and osmolytes, ROS detoxification and expression of ABA dependent and independent dehydration-responsive genes. All gronomic traits analyses demonstrated that OsSAPK3 could improve rice yield by affecting the regulation of tiller numbers and grain size. Conclusion OsSAPK3 plays an important role in both ABA-dependent and ABA-independent drought stress responses. More interestingly, OsSAPK3 could improve rice yield by indirectly regulating tiller number and grain size. These findings provide new insight for the development of drought-resistant rice.

Abstract Background Microfibrillar-associated protein (MFAP4), initially identified as an extracellular matrix protein, has been demonstrated in multiple human disorders, but it is yet to be discovered following acute coronary syndrome (ACS) in clinical practice. Therefore, this study aimed to investigate the relationship between circulating MFAP4 levels and coronary stenosis in ACS. Methods We performed the study in 148 ACS subjects, including 75 ST-segment elevation myocardial infarction (STEMI), 27 non-ST-segment elevation myocardial infarction (non-STEMI) and 46 unstable angina (UA). Clinical variables were collected and Gensini and Syntax stenosis scoring systems were applied to assess the severity of coronary stenosis. Kaplan–Meier and logistic regression analysis were used to analyze the relationship between MFAP4 and the severity of coronary stenosis or ACS outcomes. Spearman analysis was used to describe the correlation between MFAP4 and clinical parameters. Results Circulating MFAP4 levels were significantly decreased in the STEMI group (0.008 ng/ml) compared with the non-STEMI group (0.014 ng/ml) and UA group (0.019 ng/ml) (p

Abstract Background An increasing prevalence of mental disorders (MDs) has been reported among children and adolescents. However, only few studies have conducted ocular examinations, including those on refractive status, in these groups of patients. Thus, the purpose of this study was to evaluate the refractive status and ocular findings in children and adolescents with MDs compared with matched controls with similar socioeconomic backgrounds. Methods A total of 178 participants with MDs and 200 controls were recruited between April 2021 and May 2022. All the children and adolescents underwent cycloplegic or noncycloplegic autorefraction and retinoscopy, slit-lamp biomicroscopy, and dilated fundus examinations. Ocular alignment was assessed using Hirschberg, Krimsky, or prism cover tests. The prevalence of refractive errors and ocular findings was the main outcome. Results Twenty-seven percent of patients with MDs and 8% of controls had ocular findings, the most common of which were conjunctivitis, keratitis, and trichiasis. For refractive status, 70% (124/178) of patients with MDs had myopia ≤-1.00 DS, and 2% (4/178) had hyperopia ≥+2.00 DS. In the control group, 70% (140/200) of patients had myopia ≤-1.00 DS, and 1% (2/200) had hyperopia ≥+2.00 DS. No differences were observed between the MD and control groups. However, the patients in the MD group (14.25±2.69 years) were significantly more susceptible to strabismus (P

Sirtuins (SIRT) exhibit deacetylation or ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria, and cytoplasm. The role of the only sirtuin that resides in the cytoplasm, SIRT2, in the development of ischemic injury and cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion of Sirt2 (Sirt2-/-) display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that SIRT2 exerts maladaptive effects in the heart in response to stress. Similar results were obtained in mice with cardiomyocyte-specific Sirt2 deletion. Mechanistic studies suggest that SIRT2 modulates cellular levels and activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2), which results in reduced expression of antioxidant proteins. Deletion of Nrf2 in the hearts of Sirt2-/- mice reversed protection after PO. Finally, treatment of mouse hearts with a specific SIRT2 inhibitor reduced cardiac size and attenuates cardiac hypertrophy in response to PO. These data indicate that SIRT2 has detrimental effects in the heart and plays a role in cardiac response to injury and the progression of cardiac hypertrophy, which makes this protein a unique member of the SIRT family. Additionally, our studies provide a novel approach for treatment of cardiac hypertrophy and injury by targeting SIRT2 pharmacologically, providing a novel avenue for the treatment of these disorders.

Abstract Background Prospective studies examining long‐term therapeutic outcomes of the Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF) regimen in human immunodeficiency virus (HIV) infection remain limited. This study assessed the actual efficacy and safety of BIC/FTC/TAF in HIV‐infected individuals in southwest China. Methods This was a single‐center, prospective study enrolling ART‐naïve (n = 32) and ART‐experienced (n = 177) HIV‐infected patients administered BIC/FTC/TAF treatment between March 2022 and August 2022. The data were collected until February 28, 2023. Virological reactions and adverse events to the treatment were recorded, and patient subjective feelings in the form of Electronic Patient Reporting Outcome (ePRO) were collected. The primary endpoint was the rate of patients with HIV viral load

ABSTRACT Yersinia pestis is the etiological agent of plague. Marmota himalayana of the Qinghai-Tibetan plateau is the primary host of flea-borne Y. pestis. This study is the report of isolation of Mu-like bacteriophages of Y. pestis from M. himalayana. The isolation and characterization of four Mu-like phages of Y. pestis were reported, which were named as vB_YpM_3, vB_YpM_5, vB_YpM_6, and vB_YpM_23 according to their morphology. Comparative genome analysis revealed that vB_YpM_3, vB_YpM_5, vB_YpM_6, and vB_YpM_23 are phylogenetically closest to Escherichia coli phages Mu, D108 and Shigella flexneri phage SfMu. The role of LPS core structure of Y. pestis in the phages’ receptor was pinpointed. All the phages exhibit “temperature dependent infection,” which is independent of the growth temperature of the host bacteria and dependent of the temperature of phage infection. The phages lyse the host bacteria at 37°C, but enter the lysogenic cycle and become prophages in the chromosome of the host bacteria at 26°C. IMPORTANCE Mu-like bacteriophages of Y. pestis were isolated from M. himalayana of the Qinghai-Tibetan plateau in China. These bacteriophages have a unique temperature dependent life cycle, follow a lytic cycle at the temperature of warm-blooded mammals (37°С), and enter the lysogenic cycle at the temperature of its flea-vector (26°С). A switch from the lysogenic to the lytic cycle occurred when lysogenic bacteria were incubated from lower temperature to higher temperature (initially incubating at 26°C and shifting to 37°C). It is speculated that the temperature dependent lifestyle of bacteriophages may affect the population dynamics and pathogenicity of Y. pestis.

Abstract Background The deficiency of serine/threonine protein kinase 11 (STK11), one of the most common tumor suppressor genes in non‐small‐cell lung cancer, is a crucial player in tumor immune microenvironment regulation. This study attempted to unveil how mutated STK11 impact the differentiation of macrophages in lung adenocarcinoma (LUAD). Methods STK11 and CD1E expression levels in different cell models were assessed by quantitative reverse transcription polymerase chain reaction. Western blot was utilized to detect the protein expression levels of STK11, CD1E, apoptosis markers, and AMPK signaling pathway markers after transfection treatment. Cell viability and macrophage differentiation were detected by CCK‐8 and flow cytometry. Immunohistochemistry and immunofluorescence were employed to detect the expression of related genes and macrophage markers, respectively. Results This study found that STK11 mutations promoted the proliferation of LUAD cells and inhibited the differentiation of M1 macrophages, apoptosis, and the AMPK signaling pathway. Mutated STK11 led to CD1E downregulation, which curbed the differentiation of M1 macrophages and hence promoted LUAD progression. It was further validated by the in vivo experimental results that STK11 mutation significantly decreased the immune infiltration of M1 macrophages and promoted LUAD progression. Conclusion It was revealed that STK11 mutation affected CD1E expression to regulate macrophage differentiation in LUAD and then promote tumor progression. In this way, CD1E could be a potential biological target for the therapeutic interventions of STK11‐mutant LUAD patients. These findings also threw new light on a new therapeutic strategy for STK11‐mutant tumor patients that assisted the macrophage polarization pathway.

Abstract Background The evaluation of refraction is indispensable in ophthalmic clinics, generally requiring a refractor or retinoscopy under cycloplegia. Retinal fundus photographs (RFPs) supply a wealth of information related to the human eye and might provide a promising approach that is more convenient and objective. Here, we aimed to develop and validate a fusion model-based deep learning system (FMDLS) to identify ocular refraction via RFPs and compare with the cycloplegic refraction. In this population-based comparative study, we retrospectively collected 11,973 RFPs from May 1, 2020 to November 20, 2021. The performance of the regression models for sphere and cylinder was evaluated using mean absolute error (MAE). The accuracy, sensitivity, specificity, area under the receiver operating characteristic curve, and F1-score were used to evaluate the classification model of the cylinder axis. Results Overall, 7873 RFPs were retained for analysis. For sphere and cylinder, the MAE values between the FMDLS and cycloplegic refraction were 0.50 D and 0.31 D, representing an increase of 29.41% and 26.67%, respectively, when compared with the single models. The correlation coefficients (r) were 0.949 and 0.807, respectively. For axis analysis, the accuracy, specificity, sensitivity, and area under the curve value of the classification model were 0.89, 0.941, 0.882, and 0.814, respectively, and the F1-score was 0.88. Conclusions The FMDLS successfully identified the ocular refraction in sphere, cylinder, and axis, and showed good agreement with the cycloplegic refraction. The RFPs can provide not only comprehensive fundus information but also the refractive state of the eye, highlighting their potential clinical value.

Objectives To evaluate the safety and efficacy of high-dose amoxicillin-proton pump inhibitor dual therapy, and to provide a new eradication regimen as a first-line option for patients with H. pylori infection. Methods A total of 971 H. pylori positive patients who received initial treatment were recruited from March to August 2020, and randomly divided into treatment group and control group. The treatment group received of 20 mg esomeprazole four times daily and 750 mg amoxicillin four times daily for 14 days. Control group received of 220 mg bismuth potassium citrate twice daily, 20 mg esomeprazole twice daily, 1000 mg amoxicillin twice daily and 250 mg clarithromycin capsule twice daily for 14 days. Four weeks after the end of treatment, the urea breath test was reviewed to detect whether H. pylori was eradicated. Results There were no statistical differences in age, gender, the total clinical symptom scores before and after initial treatment, the compliance, and the degree of remission of symptoms before and after initial treatment between the two groups. The eradication rates of H. pylori between dual therapy and quadruple therapy were 88.31% and 85.26% (p=.158) by intention-to-treat (ITT) analysis, 88.66% and 85.44% (p=.186) by modified intention-to-treat (mITT) analysis, and 91.63% and 90.60% (p=.116) by PP analysis, respectively. Adverse events in dual therapy group were significantly lower than quadruple therapy group (13.3% vs. 28.2% (p

Bacteria are the key group of micro-organisms during the fermentation of Paocai. This study applied the high-throughput sequencing technology to trace the dynamics of Paocai brine bacterial community structures at constant temperature (25 ℃) under airtight microcosm condition. The results showed that there were 10 phyla and 205 genera had been detected within 30 days after the experiment setup. Among them, there were 12 dominant genera which accounted for 94.7%~97.8% of the total OTUs. The sub-dominant were 13 genera and accounted for 2.1%~3.3%. The rare genera were 180 genera and accounted for 0.08%~2.7%. During the 1~7 days after the experiment setup, the community was relatively stable (phase A). From the 8~20 days, the sub-dominant and rare genera were continuously changing (phase B), and on the 8th day, the communities of sub-dominant and rare genera were acutely fluctuated. From 22~30 days, all of the genera changed obviously (phase C). Meanwhile, the Chao1, Ace indices were increasing during 1~30 days, in addition, the Shannon and Simpson indices reached the thresholds during phase C. Therefore, phase A and B, phase B and C had the similar communities, but not the phase A and C, while the pH during the three phases changed correspondingly. The results also showed that at 25 ℃, the dynamics of sub-dominant and rare genera were the key factor which caused the dynamic of the bacterial communities in Paocai brine during the 30 days experiment. In addition, the accumulated effect had been detected, the pH and the bacterial communities havd mutual influences. The optimal preservation time for the Paocai brine was one week under airtight condition at 25 ℃. The functional effects of rare genera from Paocai brine need pay more attentions on.

Abstract Background Cell division cycle 6 (CDC6) has been proven to be associated with the initiation and progression of human multiple tumors. However, it’s role in glioma, which is ranked as one of the common primary malignant tumor in the central nervous system and is associated with high morbidity and mortality, is unclear. Methods In this study, we explored CDC6 gene expression level in pan-cancer. Furthermore, we focused on the relationships between CDC6 expression, its prognostic value, potential biological functions, and immune infiltrates in glioma patients. We also performed vitro experiments to assess the effect of CDC6 expression on proliferative, apoptotic, migrant and invasive abilities of glioma cells. Results As a result, CDC6 expression was upregulated in multiple types of cancer, including glioma. Moreover, high expression of CDC6 was significantly associated with age, IDH status, 1p/19q codeletion status, WHO grade and histological type in glioma (all p

Helical piles are a new type of pile that has good application prospects, and researchers have carried out an in-depth investigation into their vertical uplift and compressive bearing capacity. However, there is relatively little research on the dynamic bearing characteristics of helical piles. Therefore, the lateral vibration of a helical pile embedded in the viscoelastic foundation is systematically studied in this article. Utilizing the equivalent stiffness method to transform a helical pile into a cylindrical pile of special diameter, the lateral vibration model of the helical pile considering shear deformation is established based on the Winkler foundation model and the Timoshenko beam theory. The analytical solutions for the lateral dynamic displacement, bending moment, and shear force of the helical pile are strictly derived, and the rationality of the present solutions is also verified by comparing them with existing solutions. Based on the present solutions, a parametric study is carried out to investigate the influence of the pile and soil properties on the lateral dynamic response of the helical pile. It is found that the load excitation frequency and pile–soil stiffness ratio have a significant influence on the lateral dynamic displacement, bending moment, and shear force of the helical pile with space and time response.

【Objective】The study was conducted to explore the phyllosphere bacterial community structure and diversity of landscaping plants in the niche, and to understand the effects of similar environmental conditions and plant characteristics on microbial community in the niche, with a view to provide references for the health management of garden plants and the exploitation of phyllosphere bacterial resources.【Method】High-throughput sequencing technology was applied to explore the bacterial community structure and diversity of Eriobotyra japonica, Magnolia grandiflora and Ficus altissima leaves facing east within 50 m radius circle of Dali University campus.【Result】Among the three garden plants, E. japonica had the highest phyllosphere bacterial diversity, followed by M. grandiflora and F. altissima. The dominant bacterial phylum of phyllosphere bacteria in different plants was Proteobacteria, and the first dominant bacterial genus was different. However, the top five dominant genera were Sphingopyxis, Methylobacterium, Spirosoma, Hymenobacter and Achromobacter. There were significant differences in phyllosphere bacterial community structure among the three plants, but the bacterial communities were similar among the leaves with different sizes of the same plant. Only E. japonica and M. grandiflora leaves had the largest phylum and genus distribution, indicating that the phyllosphere bacterial communities of evergreen broad-leaved plants was more diverse and complex than those of deciduous broad-leaved plants.【Conclusion】There were differences in the composition and diversity of phyllosphere bacterial communities among different plants, and the primary reasons for these differences were the characteristics of the plants themselves. Therefore, it is urgent to strengthen the researches on the utilization of phyllosphere bacterial resources of plants.

Abstract Background Metastatic non‐small cell lung cancer (NSCLC) is mostly seen in older patients and is associated with poor prognosis. There is no reliable method to predict the prognosis of elderly patients (≥60 years old) with metastatic NSCLC. The aim of our study was to develop and validate nomograms which accurately predict survival in this group of patients. Methods NSCLC patients diagnosed between 2010 and 2015 were all identified from the Surveillance, Epidemiology, and End Results (SEER) database. Nomograms were constructed by significant clinicopathological variables (p

A T/C variant in miR-27a is associated with bipolar disorder, potentially by reducing the ability of this microRNA to target important neurodevelopmental genes like NCAM1.

Indole compounds with their unique properties of mimicking peptide structures and reversible binding to enzymes are of great exploitative value in the regulation of plant growth. They stimulate root and fruit formation and activate the plant’s immune system against biotic and abiotic factors harmful to the plant. Analysis of target recognition, receptor recognition, key activation sites and activation mechanisms of indoles in plant to enhance crop growth or disease resistance is a crucial step for further developing compounds as plant growth regulators and immune inducers. Therefore, this review focused on the mechanism of action of indoles in regulating plant growth and enhancing plant resistance to biotic and abiotic stresses.

BackgroundThe prognosis of colorectal cancer with atypical metastasis is poor. However, atypical metastasis was less common and under-appreciated.MethodsIn this study we attempted to present the first machine learning models to predict the risk of atypical metastasis in colorectal cancer patients. We evaluated the differences between metastasis and non-metastasis groups, assessed factors associated with atypical metastasis using univariate and multivariate logistic regression analyses, and preliminarily developed the multiple machine learning models to predict atypical metastasis.Results168 patients were included. Prognostic Nutritional Index (PNI) [OR = 0.998; P = 0.030], Cancer antigen 19–9 (CA19-9) [OR = 1.011; P = 0.043] and MR-Distance [-mid OR = 0.289; P = 0.009] [-high OR = 0.248; P = 0.021] were shown to be independent risk factors for the atypical metastasis via multivariate analysis. Furthermore, the machine learning model based on AdaBoost algorithm (AUC: 0736) has better predictive performance comparing to Logistic Regression (AUC: 0.671) and KNeighbors Classifier (AUC: 0.618) by area under the curve (AUC) in the validation cohorts. The accuracy, sensitivity, and specificity of the model trained using the Adaboost method in the validation set are 0.786, 0.776 and 0.700, while 0.601, 0.933, 0.508 using Logistic Regression and 0.743, 0.390, 0.831 using KNeighbors Classifier.ConclusionMachine-learning approaches containing PNI, CA19-9 and MR-Distance show great potentials in atypical metastasis prediction.

The development of digital economy affects environmental pollution emission and green sustainable development. However, the relationship between digital economy and industrial wastewater discharge has rarely been examined. This study establishes the urban digital economy evaluation index system, measures the digital economy indexes of 281 prefecture-level cities in China from 2011 to 2016, and examines the impact effect of digital economy development on industrial wastewater discharge using the system generalized method of moment method and the intermediary effects model. The empirical results indicate that the digital economy reduces the industrial wastewater discharge. As evidence shows, the digital economy significantly promotes the upgrading of industrial structure, which is an important factor affecting the industrial wastewater discharge. Additionally, the inhibiting effect of digital economy on industrial wastewater discharge is more significant in big cities. This study provides a scientific base and guidance for reducing environmental pollution emissions and promoting the development of digital economy. HIGHLIGHTS The effect of digital economy on industrial wastewater discharge is explored.; The digital economy reduces the discharge of industrial wastewater.; The mediating role of upgrading the industrial structure is established.; The inhibitory effect of digital economy on the discharge of industrial wastewater is significant in big cities.;