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Due to the influence of reservoir water level, rainfall and geological conditions, the Three Gorges Reservoir area is a landslide hazard-prone area, and the landslide genesis mechanism and evolution process are also extremely complex.By taking the Xinpu Xia'ertai landslide as an example, this paper summarizes and analyses the resurgence law of large palaeo-landslides based on multiple sources of data, such as GPS displacement monitoring data, fracture data, rainfall and reservoir water level, and through a geotechnical creep compression model. The paper also verifies the mechanism of fracture formation on the trailing edge of the displaced landslide.The results show the following: ①Rainfall is the dominant factor of landslide deformation. Landslide deformation causes the landslide body to produce cracks and form rainfall infiltration channels, which intensifies rock fragmentation and weak layer mudification and reduces landslide stability; besides, concentrated and continuous rainfall can destabilize landslides. ②By comparing the predicted value of the model with the surface monitoring data, it is feasible to take annual rainfall as the controlling factor in the medium- and long-term landslide prediction model and help to improve the prediction accuracy of landslides. ③Pushing landslide trailing edge cracks consist of landslide pushing displacement and geotechnical body compression. In this paper, the compression creep model is introduced to calculate the crack width and compare it with the monitoring data. This shows that the compression creep model is suitable for this type of slope, and the average deformation modulus of the geotechnical body is obtained by applying the backpropagation of the geotechnical body creep compression model. Thus, we judge the degree of rock fragmentation, which provides a reference for landslide stability analysis and subsequent engineering management.

Abstract Accurately determining the shear strength of structural planes is crucial for evaluating the stability of rock masses. The shear test using the sawtooth structural plane usually captures the main influencing factors of its shear characteristics. In this study, the two-dimensional particle flow code (PFC2D) numerical simulation method was used to conduct shear tests on the sawtooth structural planes of rock masses with undulant angles of 10°, 20°, and 30°, respectively. With the increase in normal stress and the undulant angle, the shear failure of the structural planes was found to no longer be pure slip failure or shear failure but accompanied by a compression-induced fracture phenomenon. Based on the analysis of the shear test results, a peak shear strength model considering different undulant angles and normal stresses was proposed, and the hyperbolic function post-peak shear strength model was improved. The peak shear strength obtained from the physical direct shear tests was compared with those calculated using the proposed model, Parton model, and Shen model. The calculation error under low and high normal stress of the proposed method was found to be within an acceptable range. Additionally, when calculating the peak shear strength of a structural plane under high normal stress, applying the calculation method proposed in this study is a better option than applying the other models. Furthermore, although the variation trend of the post-peak shear strength was similar to that of the experimental results, the values obtained using the hyperbolic variation model were too large. The variation trend of the post-peak shear strength obtained using the improved function was essentially consistent with the experimental results, and the calculated values were close to the experimental results. The systematic research on the shear strength calculation model of rock mass structural planes contributes to the theoretical research of rock mass mechanics, and this study can act as a guide for landslide prediction and control projects.

In view of the Tanjiawan landslide, which occurred in the northwest of Zigui County in May 2016, this paper preliminarily defined the affected area, characteristics and occurrence time sequence of the landslide based on multi-source data such as satellite remote sensing images, field survey data and historical data.By means of drilling, trough exploration and geophysical exploration, indoor and outdoor experiments were carried out to clarify the stratum characteristics and the physical and mechanical properties of the rock and soil mass in the landslide area.By analyzing the crack displacement and GPS data in the area, the deformation mechanism of the slope was discussed and the stability of the area was evaluated.The results show that: ①The Tanjiawan landslide belongs to reservoir descending landslide with irregular "chair-shaped" medium-sized loose layer; the surface morphology, geological structure and lithology of landslide area determine the formation and development of landslide, and the joint action of reservoir water level and precipitation stimulates the development of landslide; ②The landslide is divided into three levels of sliding body according to the time sequence, showing multiple, multi-layered and mutual shadows on the whole.The third-order sliding body has the characteristics of traction; ③The groundwater level in the landslide body decreases with the decrease of the reservoir level, but the rate of decline is slower than the reservoir level, and the hydraulic gradient and permeability in the slope body become significantly larger.Heavy rainfall at this time will lead to the occurrence of groundwater in the slope body, softening of rock and soil mass, and exacerbating landslide deformation, and necessary protective measures must be applied; ④Stability analysis shows that the landslide is in a critical stable state.Once rainfall and reservoir water level change, instability sliding may occur in some sections.

The soil parameters for large, complex landslides are typically derived from incomplete information based on a small sample set due to budgetary constraints. This informational incompleteness results in large statistical uncertainty in landslide reliability analyses. In this article, the bootstrap technique is proposed to quantify the statistical uncertainties associated with a small sample set, and a practice-oriented reliability analysis is performed. The results suggest that the obtained reliability indices are characterized by a long tail, in which the worst-case scenario has a local extreme value and a small population. The statistical uncertainties are quantified and characterized by a confidence interval at a specified confidence level. The confidence interval of the reliability index and identification of the worst-case scenario enable engineers to make more informed decisions.

There hides a certain relationship among various monitoring data in a landslide, and the mining of this relationship is of significance to landslide research. In this paper, we first collect multiple monitoring data of riverside 1# slump-mass of Huangtupo landslide, the Three Gorges Reservoir Region, China, including Global Positioning System (GPS) monitoring data, inclinometer data, reservoir water level, rainfall, water content, crack width, groundwater level and temperature data, etc. By adopting the combination of quantitative statistics and qualitative simulation method for multi-sensor fusion monitoring data analysis, we overcome the one-sidedness of using a single method or single data type. The result of fusion analysis has indicated that in time periods with low rainfall or when the rainfall is not the major factor, main factors affecting landslide movement are crack development, water content of the landslide and water level of the Three Gorges Reservoir. Compared with the actual monitoring data, the fusion analysis results has a maximum error of 1.9%, which shows a good effect.

In recent years, hundreds of Earth observation satellites have been launched to collect massive amounts of remote sensing images. However, the considerable cost and time to process the significant amount of data have become the greatest obstacle between data and knowledge. In order to accelerate the transformation from remote sensing images to urban thematic maps, a strategy to map the bare land automatically from Landsat imagery was developed and assessed in this study. First, a normalized difference bare land index (NBLI) was presented to maximally differentiate bare land from other land types in Wuhan City, China. Then, an unsupervised classifier was employed to extract the bare land from the NBLI image without training samples or self-assigned thresholds. Experimental results showed good performance on overall accuracy (92%), kappa coefficient (0.84), area ratio (1.1321), and match rate (83.96%), respectively. Results in multiple years disclosed that bare lands in the study site gradually moved from inner loops to the outer loops since 2007, in two main directions. This study demonstrated that the proposed method was an accurate and reliable option to extract the bare land, which led to a promising approach to mapping urban land use/land cover (LULC) automatically with simple indices.

Abstract Aims The benefits of lowering heart rate (HR) in heart failure (HF) with preserved ejection fraction (HFpEF) patients are still a matter of debate. This study aimed to investigate the relationship between changes in HR during hospitalization and cardiovascular (CV) events and all‐cause death in hospitalized HFpEF patients. Methods and results Hospitalized HF patients between January 2017 and December 2021 were consecutively enrolled in a national, multicentred, and prospective registry database, the China Cardiovascular Association Database‐HF Center Registry. HF patients with a left ventricular ejection fraction of ≥50% were defined as HFpEF patients. The study analysed admission/discharge HR, change in HR during hospitalization (∆HR), and ∆HR ratio (∆HR/admission HR). The patients were categorized into three groups: no HR dropping group (ΔHR ratio > 0.0%), moderate HR dropping group (−15%

Introduction: N6-methyladenosine (m6A) methylation produces a marked effect on cardiovascular diseases. The m6A demethylase AlkB homolog 5 (ALKBH5), as an m6A “eraser”, is responsible for decreased m6A modification. However, its role in cardiac fibroblasts during the post-myocardial infarction (MI) healing process remains elusive. Objectives: To investigate the effect of ALKBH5 in cardiac fibroblasts during infarct repair. Methods: MI was mimicked by permanent left anterior descending artery ligation in global ALKBH5-knockout, ALKBH5-knockin, and fibroblast-specific ALKBH5-knockout mice to study the function of ALKBH5 during post-MI collagen repair. Methylated RNA immunoprecipitation sequencing was performed to explore potential ALKBH5 targets. Results: Dramatic alterations in ALKBH5 expression were observed during the early stages post-MI and in hypoxic fibroblasts. Global ALKBH5 knockin reduced infarct size and ameliorated cardiac function after MI. The global and fibroblast-specific ALKBH5-knockout mice both exhibited low survival rates along with poor collagen repair, impaired cardiac function, and cardiac rupture. Both in vivo and in vitro ALKBH5 loss resulted in impaired fibroblast activation and decreased collagen deposition. Additionally, hypoxia, but not TGF-β1 or Ang II, upregulated ALKBH5 expression in myofibroblasts by HIF-1α-dependent transcriptional regulation. Mechanistically, ALKBH5 promoted the stability of ErbB4 mRNA and the degradation of ST14 mRNA via m6A demethylation. Fibroblast-specific ErbB4 overexpression ameliorated the impaired fibroblast-to-myofibroblast transformation and poor post-MI repair due to ALKBH5 knockout. Conclusion: Fibroblast ALKBH5 positively regulates post-MI healing by stabilization of ErbB4 mRNA in an m6A-dependent manner. ALKBH5/ErbB4 might be potential therapeutic targets for post-MI cardiac rupture.

Abstract Breast cancer is the most common diagnosed cancer, the HER2-positive subtype account for 15% of all breast cancer. HER2-targeted therapy is the mainstay treatment for HER2-positive breast cancer. Cuproptosis is a novel form of programmed cell death, and is caused by mitochondrial lipoylation and destabilization of iron-sulfur proteins triggered by copper, which was considered as a key player in various biological processes. However, the roles of cuproptosis-related genes in HER2-positive breast cancer remain largely unknown. In the present study, we constructed a prognostic prediction model of HER2-positive breast cancer patients using TCGA database. Dysregulated genes for cells resistant to HER2-targeted therapy were analyzed in the GEO dataset. KEGG pathway, GO enrichment and GSEA was performed respectively. The immune landscape of DLAT was analyzed by CIBERSORT algorithm and TIDE algorithm. HER2-positive breast cancer patients with high CRGs risk score showed shorter OS. DLAT was downregulated and correlated with better survival of HER2-positive breast cancer patients (HR = 3.30, p = 0.022). High expressed DLAT was associated with resistant to HER2-targeted therapy. Knocking down DLAT with siRNA increased sensitivity of breast cancer to trastuzumab. KEGG pathway and GO enrichment of DEGs indicated that DLAT participates in various pathways correlated with organelle fission, chromosome segregation, nuclear division, hormone-mediated signaling pathway, regulation of intracellular estrogen receptor signaling pathway, condensed chromosome and PPAR signaling pathway. There was a negative correlation between TIDE and DLAT expression (r = − 0.292, p

Abstract Cardiac fibroblasts (CFs) are the primary cells tasked with depositing and remodeling collagen and significantly associated with heart failure (HF). TEAD1 has been shown to be essential for heart development and homeostasis. However, fibroblast endogenous TEAD1 in cardiac remodeling remains incompletely understood. Transcriptomic analyses revealed consistently upregulated cardiac TEAD1 expression in mice 4 weeks after transverse aortic constriction (TAC) and Ang-II infusion. Further investigation revealed that CFs were the primary cell type expressing elevated TEAD1 levels in response to pressure overload. Conditional TEAD1 knockout was achieved by crossing TEAD1-floxed mice with CFs- and myofibroblasts-specific Cre mice. Echocardiographic and histological analyses demonstrated that CFs- and myofibroblasts-specific TEAD1 deficiency and treatment with TEAD1 inhibitor, VT103, ameliorated TAC-induced cardiac remodeling. Mechanistically, RNA-seq and ChIP-seq analysis identified Wnt4 as a novel TEAD1 target. TEAD1 has been shown to promote the fibroblast-to-myofibroblast transition through the Wnt signalling pathway, and genetic Wnt4 knockdown inhibited the pro-transformation phenotype in CFs with TEAD1 overexpression. Furthermore, co-immunoprecipitation combined with mass spectrometry, chromatin immunoprecipitation, and luciferase assays demonstrated interaction between TEAD1 and BET protein BRD4, leading to the binding and activation of the Wnt4 promoter. In conclusion, TEAD1 is an essential regulator of the pro-fibrotic CFs phenotype associated with pathological cardiac remodeling via the BRD4/Wnt4 signalling pathway.

BackgroundThe cGAS-STING axis-mediated type I interferon pathway is a crucial strategy for host defense against DNA virus infection. Numerous evasion strategies developed by the pseudorabies virus (PRV) counteract host antiviral immunity. To what extent PRV-encoded proteins evade the cGAS-STING signaling pathway is unknown.MethodsUsing US2 stably expressing cell lines and US2-deficient PRV model, we revealed that the PRV tegument protein US2 reduces STING protein stability and downregulates STING-mediated antiviral signaling.ResultsTo promote K48-linked ubiquitination and STING degradation, US2 interacts with the LBD structural domain of STING and recruits the E3 ligase TRIM21. TRIM21 deficiency consistently strengthens the host antiviral immune response brought on by PRV infection. Additionally, US2-deficient PRV is less harmful in mice.ConclusionsOur study implies that PRV US2 inhibits IFN signaling by a new mechanism that selectively targets STING while successfully evading the host antiviral response. As a result, the present study reveals a novel strategy by which PRV evades host defense and offers explanations for why the Bartha-K61 classical vaccine strain failed to offer effective defense against PRV variant strains in China, indicating that US2 may be a key target for developing gene-deficient PRV vaccines.

BackgroundPrimary dysmenorrhea (PD) is one of the most common reasons that affect the life quality of women during childbearing age. This research aims to explore the efficacy and curative effect characteristics of oral contraceptives and low-power visible-light-activated photodynamic therapy (PDT). Besides investigating the possible mechanism of PDT, we expected to find a treatment model with better efficacy and fewer side effects.MethodIt was a multicenter, randomized, parallel-controlled study. Eligible participants were randomly assigned to three groups: placebo group, oral contraceptive (Marvelon) group, and the PDT group. They were treated continuously for three menstrual cycles and followed up for two cycles after treatment. The scores of the visual analog scale (VAS) and the concentration of pain-related small molecules in blood before and after treatment were recorded in each group, which can evaluate the therapeutic characteristics of different treatments.ResultBoth Marvelon and PDT were effective. The effect of Marvelon appears quickly which can significantly relieve symptoms at the beginning, while PDT shows a relatively slow role. There was no significant difference in the final efficacy two cycles after treatment. The therapeutic effect was achieved by reducing the concentrations of prostaglandin 2 (PGE2) and endothelin (ET) in the blood.ConclusionMarvelon and PDT are effective methods for the treatment of PD. The long-term efficacy of the two is similar, while the therapeutic characteristics and the side effects are different. Patients can choose the suitable way according to their individual needs.

Ferroptosis is a novel form of regulated cell death characterized by iron-dependent excessive lipid peroxidation. The core organelle involved in ferroptosis is mitochondria. Mitochondria undergoing ferroptosis are distinct from normal mitochondria in terms of morphology, biochemistry, gene expression, and energy metabolism. An increasing number of studies have shown that mitochondria and their associated metabolic pathways mediate ferroptosis in the development and progression of breast cancer. In this review, we discuss the relevant research about ferroptosis in breast cancer and provide a comprehensive summary of mitochondrial regulation in ferroptosis from the perspective of lipid metabolism, oxidative phosphorylation, ion metabolism, glycometabolism, and nucleotide metabolism. We also summarize the application of mitochondrial metabolism-related pathways as ferroptosis treatment targets. Here we provide new insights into the relationship between mitochondria, ferroptosis, and breast cancer treatment.

Myocardial ischemia-reperfusion (MI/R) injury is common in patients who undergo revascularization therapy for myocardial infarction, often leading to cardiac dysfunction. Carbon monoxide (CO) has emerged as a therapeutic molecule due to its beneficial properties such as anti-inflammatory, anti-apoptotic, and mitochondrial biogenesis-promoting properties. However, its clinical application is limited due to uncontrolled release, potential toxicity, and poor targeting efficiency. To address these limitations, a peroxynitrite (ONOO−)-triggered CO donor (PCOD585) is utilized to generate a poly (lactic-co-glycolic acid) (PLGA)-based, biomimetic CO nanogenerator (M/PCOD@PLGA) that is coated with the macrophage membrane, which could target to the ischemic area and neutralize proinflammatory cytokines. In the ischemic area, local produced ONOO− triggers the continuous release of CO from M/PCOD@PLGA, which efficiently ameliorates MI/R injury by clearing harmful ONOO−, attenuating the inflammatory response, inhibiting cardiomyocyte apoptosis, and promoting mitochondrial biogenesis. This study provides a novel insight into the safe therapeutic use of CO for MI/R injury by utilizing a novel CO donor combined with biomimetic technology. The M/PCOD@PLGA nanogenerator offers targeted delivery of CO to the ischemic area, minimizing potential toxicity and enhancing therapeutic efficacy.

Abstract Background Traditional Chinese medicine has been used for a long time to treat a variety of gynecological diseases. Among various traditional Chinese medicine, Dingkun Pill (DK) has been used for the treatment of female gynecological diseases. However, DK therapeutic effect on PCOS and the target tissue for its potential effect need to be explored. This study aims to explore the therapeutic effect of DK for PCOS in mice from three aspects: metabolism, endocrine and fertility, and determine whether the brown adipose tissue is the target organ to alleviate the PCOS phenotype. Methods PCOS mouse model was constructed by subcutaneous injection of DHEA. The estrous cycle, ovulation, and pregnancy outcome was examined in mice. The level of hormone including the LH, FSH, estrogen and testosterone in the serum were measured by ELISA. Both the glucose sensitivity and insulin sensitivity were determined in mice with different treatment. The histomorphology and lipid contents in the brown adipose tissue were analyzed. RNA-Seq was conducted for the brown adipose tissue and different expression of critical metabolism marker genes was confirmed by real-time PCR. Results The data showed that the fertility in PCOS mice with DK treatment was significantly increased, and the metabolic disorder was partially restored. Both the whiten of brown adipose tissue and reduced UCP1 expression induced by DHEA was rescued by the DK. The RNA-Seq data further demonstrated both the DHEA induced downregulation of lipolysis genes and oxidative phosphorylation genes were at least partially rescued by DK in the brown adipose tissue. Conclusions DK has therapeutic effect on PCOS in DHEA treated mice and the brown adipose tissue is at least one critical target organ to alleviate the PCOS. This is achieved by not only regulating the lipid mobilization of brown adipose, but also restoring its thermogenic function.

Background Consumer wearable devices such as wristbands and smartwatches have potential application value in communicable disease surveillance. Objective We investigated the ability of wearable devices to monitor COVID-19 patients of varying severity. Methods COVID-19 patients with mobile phones supporting wearable device applications were selected from Dalian Sixth People Hospital. Physiological parameters from the wearable devices and electronic questionnaires were collected from the device wearing until 14 days post-discharge. Clinical information during hospitalization was also recorded. Based on imaging data, the patients were categorized into the milder group without pneumonia and the more severe group with pneumonia. We plotted the curves of the physiological parameters of the two groups to compare the differences and changes. Results Ninety-eight patients were included in the analysis. The mean age was 39.6 ± 10.5 years, including 45 males (45.9%). There were 24 asymptomatic patients, 10 mild patients, 60 moderate patients, and 4 severe patients. Compared with the milder group, the more severe group had higher heart rate-related parameters, while the heart rate variability (HRV) was the opposite. In the more severe group, the heart rate-related parameters showed a downward trend from 0 to 7 days after the fever resolution. Among them, the resting heart rate and sleep heart rate decreased on the 25th day after the onset and were close to the milder group 1 week after discharge. Conclusions Consumer wearable devices have the potential to monitor respiratory infections. Heart rate-related parameters obtained from these devices can be sensitive indicators of COVID-19 severity and correlate with disease evolution. Trial registration ClinicalTrials.gov NCT04459637.

Lead (Pb) is a heavy metal that can have harmful effects on the environment, which has severe cytotoxicity in many animal tissues. N-acetylcysteine (NAC) has antioxidant activity, reducing lead-induced oxidative stress and apoptosis, but its role in chicken cells is unknown. The current study explored the antagonistic effect of NAC on lead-induced apoptosis and oxidative stress in chicken embryo fibroblast (CEF). In this study, CEF was used as a model to measure the cytotoxic effects of lead nitrate at different concentrations, demonstrating a dose-dependent effect on CEF activity. Employing inverted microscopy, the investigation of morphological alterations in CEF cells was conducted. Fluorescence staining methodology enabled the assessment of reactive oxygen species (ROS) levels within CEF cells. Moreover, an enzyme-linked immunosorbent assay was utilized to detect the presence of oxidative damage indicators encompassing superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) activity, malondialdehyde (MDA) content, and total antioxidant capacity (T-AOC) within CEF cells. Furthermore, the determination of the apoptosis rate of CEF cells was accomplished through the utilization of the Hoechst 33258 staining method in combination with the Annexin V-FITC dual staining method. By using RT-qPCR for detection, lead treatment increased expression of pro-apoptotic genes, caspase-3, and caspase-9, and reduced expression of anti-apoptotic genes, Bcl-2, and BI-1. Reduced antioxidant capacity was shown by increased ROS and MDA levels in CEF cells after lead treatment. The results showed that NAC inhibited the expression of caspase-3 and caspase-9 in lead-treated CEF cells, while NAC had a certain inhibitory effect on the relative expression of Bcl-2 and BI-1 mRNA in lead-induced CEF cells. NAC significantly reduced lead-induced oxidative damage and apoptosis. Overall, our results demonstrate a novel protective effect of NAC against lead-induced injury in chicken cells, providing a theoretical basis for future investigations of drugs that are effective in preventing lead poisoning in animals.

Adenosine kinase (ADK) plays the major role in cardiac adenosine metabolism, so that inhibition of ADK increases myocardial adenosine levels. While the cardioprotective actions of extracellular adenosine against ischemia/reperfusion (I/R) are well-established, the role of cellular adenosine in protection against I/R remains unknown. Here we investigated the role of cellular adenosine in epigenetic regulation on cardiomyocyte gene expression, glucose metabolism and tolerance to I/R. Evans blue/TTC staining and echocardiography were used to assess the extent of I/R injury in mice. Glucose metabolism was evaluated by positron emission tomography and computed tomography (PET/CT). Methylated DNA immunoprecipitation (MeDIP) and bisulfite sequencing PCR (BSP) were used to evaluate DNA methylation. Lentiviral/adenovirus transduction was used to overexpress DNMT1, and the OSI-906 was administered to inhibit IGF-1. Cardiomyocyte-specific ADK/IGF-1-knockout mice were used for mechanistic experiments.Cardiomyocyte-specific ADK knockout enhanced glucose metabolism and ameliorated myocardial I/R injury in vivo. Mechanistically, ADK deletion caused cellular adenosine accumulation, decreased DNA methyltransferase 1 (DNMT1) expression and caused hypomethylation of multiple metabolic genes, including insulin growth factor 1 (IGF-1). DNMT1 overexpression abrogated these beneficial effects by enhancing apoptosis and decreasing IGF-1 expression. Inhibition of IGF-1 signaling with OSI-906 or genetic knocking down of IGF-1 also abrogated the cardioprotective effects of ADK knockout, revealing the therapeutic potential of increasing IGF-1 expression in attenuating myocardial I/R injury. In conclusion, the present study demonstrated that cardiomyocyte ADK deletion ameliorates myocardial I/R injury via epigenetic upregulation of IGF-1 expression via the cardiomyocyte adenosine/DNMT1/IGF-1 axis.

Gpr174 is a regulator of regulatory T cells, which play an important role in angiogenesis after hindlimb ischemia. Here, the authors show GPR174-deficient Tregs promote AREG expression by inhibiting Gαs/cAMP/PKA signal pathway and increasing EGR1 nuclear accumulation to improve angiogenesis and vascular remodeling in response to ischemic injury.

Background: Abelson interactor Family Member 3 (ABI3) encodes protein that not only suppresses the ectopic metastasis of tumor cells but also hinders their migration. Although ABI3 had been found to modulate the advancement of diverse neoplasms, there is no comprehensive pan-cancer analysis of its effects.Methods: The transcriptomics data of neoplasm and normal tissues were retrieved from the Genomic Data Commons (GDC) data portal, and UCSC XENA database. To gather protein information for ABI3, Human Protein Atlas (HPA) and GeneMANIA websites were utilized. Additionally, Tumor Immune Single-cell Hub (TISCH) database was consulted to determine the primary cell types expressing ABI3 in cancer microenvironments. Univariate Cox regression approach was leveraged to evaluate ABI3’s prognostic role across cancers. The Cbioportal and Gene Set Cancer Analysis (GSCA) website were leveraged to scrutinize the genomic landscape information across cancers. TIMER2.0 was leveraged to probe the immune cell infiltrations associated with ABI3 across cancers. The associations of ABI3 with immune-related genes were analyzed through Spearman correlation method. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were utilized to search associated biological pathways. The CellMiner database and molecular docking were implemented to identify potential interactions between the ABI3 protein and specific anticarcinogen.Findings: ABI3 expression and its ability to predict prognosis varied distinct tumor, with particularly high expression observed in Tprolif cells and monocytes/macrophages. Copy number variation (CNV) and methylation negatively correlated with ABI3 expression in the majority of malignancies. Corresponding mutation survival analysis indicated that the mutation status of ABI3 was strongly connected to the prognosis of LGG patients. ABI3 expression was linked to immunotherapeutic biomarkers and response in cancers. ESTIMATE and immune infiltrations analyses presented ABI3 association with immunosuppression. ABI3 was significantly correlated with immunoregulators and immune-related pathways. Lastly, prospective ABI3-targeted drugs were filtered and docked to ABI3 protein.Interpretation: Our study reveals that ABI3 acts as a robust tumor biomarker. Its functions are vital that could inhibit ectopic metastasis of tumor cells and modulate cellular adhesion and migration. The discoveries presented here may have noteworthy consequences for the creation of fresh anticancer suppressors, especially those targeting BRCA.

Summary: Doxorubicin is a wildly used effective anticancer agent. However, doxorubicin use is also related to cardiotoxic side effect in some patients. Mitochondrial damage has been shown to be one of the pathogeneses of doxorubicin-induced myocardial injury. In this study, we demonstrated that mitochondrial transplantation could inhibit doxorubicin-induced cardiotoxicity by directly supplying functional mitochondria. Mitochondrial transplantation improved contractile function and respiratory capacity, reduced cellular apoptosis and oxidative stress in cardiomyocytes. Mitochondria isolated from various sources, including mouse hearts, mouse and human arterial blood, and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), all exerted similar cardioprotective effects. Mechanically, mitochondrial transplantation activates glutamine metabolism in doxorubicin-treated mice heart and blocking glutamine metabolism attenuated the cardioprotective effects of mitochondrial transplantation. Overall, our study demonstrates that mitochondria isolated from arterial blood could be used for mitochondrial transplantation, which might serve as a feasible promising therapeutic option for patients with doxorubicin-induced cardiotoxicity.

Background: To explore the needs of obstetricians and gynecologists (OB-GYNs) for training methods and contents, under China’s three-level diagnosis and treatment system. Methods: Epidemiological investigation was adopted, and network questionnaires were distributed in the largest academic training platform of obstetrics and gynecology in China, from April 2020 to May 2020. The investigation contents mainly included training methods and contents of continuing medical education (CME), as well as the mastery of diseases by doctors from hospitals at different levels of training. Results: The questionnaire received a total of 16,400 cumulative page views. 4458 questionnaires were collected in total, and 3954 questionnaires were included in the research. Doctors from hospitals at different levels chose the professional direction of gynecological endocrine diseases as the subject requiring the most strengthening of training, with ratios of 80.47%, 81.60% and 82.10%, respectively. Abnormal uterine bleeding (AUB) was the most desirable training content for doctors from primary, secondary, and other hospitals, while training of polycystic ovary syndrome (PCOS) was mostly needed by doctors from tertiary hospitals. According to the investigation, network education was the major training form favored by doctors, as well as a preferential way to acquire professional resources. The number of doctors selecting site meeting report only took up 4.70%. Based on the single-factor chi-square (χ2) analysis of the degree of mastery of 19 diseases, significant statistical differences were found among doctors from hospitals at each level, except for birth control (p < 0.001). After related factors were corrected, the multivariate regression analysis indicated that the degree of mastery of diseases was positively correlated to hospital levels. Conclusions: Doctors from hospitals at each level failed to effectively master gynecological endocrine diseases, and AUB, menopausal syndrome, and PCOS were confirmed as diseases for which the doctors had the greatest need of continuing education.

Abstract Cardiomyocyte pyroptosis and apoptosis play a vital role in the pathophysiology of several cardiovascular diseases. Our recent study revealed that gasdermin D (GSDMD) can promote myocardial I/R injury via the caspase-11/GSDMD pathway. We also found that GSDMD deletion attenuated myocardial I/R and MI injury by reducing cardiomyocyte apoptosis and pyroptosis. However, how GSDMD mediates cardiomyocyte apoptosis and protects myocardial function remains unclear. Here, we found that doxorubicin (DOX) treatment resulted in increased apoptosis and pyroptosis in cardiomyocytes and that caspase-11/GSDMD could mediate DOX-induced cardiotoxicity (DIC) injury. Interestingly, GSDMD overexpression promoted cardiomyocyte apoptosis, which was attenuated by GSDMD knockdown. Notably, GSDMD overexpression exacerbated DIC injury, impaired cardiac function in vitro and in vivo, and enhanced DOX-induced cardiomyocyte autophagy. Mechanistically, GSDMD regulated the activity of FAM134B, an endoplasmic reticulum autophagy receptor, by pore formation on the endoplasmic reticulum membrane via its N-terminus, thus activating endoplasmic reticulum stress. In turn, FAM134B interacted with autophagic protein LC3, thus inducing cardiac autophagy, promoting cardiomyocyte apoptosis, and aggravating DIC. These results suggest that GSDMD promotes autophagy and induces cardiomyocyte apoptosis by modulating the reaction of FAM134B and LC3, thereby promoting DIC injury. Targeted regulation of GSDMD may be a new target for the prevention and treatment of DIC.

Abstract Background The ketogenic diet (KD) has anti-tumor and anti-diabetic effects in addition to its anti-epileptic role. It could also improve cardiac function and attenuate neurological insult. However, the effect of KD on blood perfusion or tissue recovery after ischemia remains largely unknown. Thus, we observed blood flow and ischemic tissue recovery following hind limb ischemia (HLI) in mice. Methods C57 mice were fed with either a KD or normal diet (ND) for 2 weeks, before inducing hind limb ischemia, blood perfusion of ischemic limb tissue was observed at 0, 7, and 21 days post operation. Results KD not only decreased blood perfusion of ischemic limb tissue but also delayed muscle recovery after ischemia, induced muscle atrophy of non-ischemic tissue compared to mice fed with ND. Furthermore, KD delayed wound healing at the surgical site and aggravated inflammation of the ischemic tissue. At the cellular level, KD altered the metabolic status of limb tissue by decreasing glucose and ketone body utilization while increasing fatty acid oxidation. Following ischemia, glycolysis, ketolysis, and fatty acid utilization in limb tissue were all further reduced by KD, while ketogenesis was mildly increased post KD in this mice model. Conclusion The KD may cause impaired tissue recovery after ischemia and possible muscle atrophy under a prolonged diet. Our results hint that patients with limb ischemia should avoid ketogenic diet.

Recently, cardiovascular diseases (CVDs) were identified as the leading cause of mortality, imposing a heavy burden on health care systems and the social economy. Nicotinamide adenine dinucleotide (NAD+), as a pivotal co-substrate for a range of different enzymes, is involved in many signal transduction pathways activated in CVDs. Emerging evidence has shown that NAD+ can exert remediating effects on CVDs by regulating metabolism, maintaining redox homeostasis and modulating the immune response. In fact, NAD+ might delay ageing through sirtuin and non-sirtuin pathways and thus contribute to interventions for age-related diseases such as CVDs. Considering that robust clinical studies of NAD+ are ongoing, we discuss current challenges and the future translational potential of NAD+ based on existing studies and our understanding. Despite some remaining gaps in its clinical application, NAD+ has been shown to have broad prospects and pan-effects, making it a suitable prophylactic drug for CVDs.

Background: Uterine malformations can be divided into the dysmorphic uterus (U1); septate uterus (U2); bicorporeal uterus (U3); hemi-uterus (U4) and hypoplastic uterus (U5) with clinical significance ranging from mild to severe. This study aims to investigate whether different types of uterine malformations in infertile patients who have undergone hysteroscopic and laparoscopic surgery are associated with different pregnancy outcomes. Methods: This is a retrospective study of patients with uterine malformations and infertility admitted to the Department of Gynecology of Peking Union Medical College Hospital between January 2003 and December 2020. Patients were followed through 31 October 2021. Those lost to follow-up or who had not tried to become pregnant were excluded. Fertility outcomes included pregnancy rate, live birth rate and miscarriage rate. Fertility outcomes among patients experiencing different uterine anomalies were compared using one-way analysis of variance (ANOVA). Results: A total of 161 patients were included, of whom 62 (38.5%) had no other infertility-related factors except a uterine malformation. The rate of concomitant endometriosis (36.0%) was significantly higher than among the non-specific infertile population (p < 0.05). One hundred seventeen patients achieved a total of 151 pregnancies postoperatively. The total pregnancy rate was 77.5%, and the live birth rate was 73.4%. The pregnancy and miscarriage rates in patients with uterine septum with a single cervix were 76.0% and 15.5%, respectively; 75.0% and 37.5% among patients with unicornuate uterus with a single cervix; 88.9% and 9.5% among patients with uterine septum with a double cervix; 100% and 25% among patients with uterus duplex with double cervix; and 50% and 25% among patients with bicornuate uterus with a single cervix. Patients were grouped into either the septum group or the unicornuate uterus group dependent on the ability to enlarge the uterine cavity by surgery. The pregnancy rates for the two groups were 78.1% and 80.6%, respectively, with no significant difference noted (p = 0.599), although there was a significant difference in the miscarriage rate (14.4% vs. 33.3%) (p = 0.002). Conclusion: This retrospective analysis can help to illustrate differences in pregnancy outcomes of different types of uterine malformations although it lacked a proper control group. The non-obstructive uterine malformation may not be a dominant cause of infertility, and the volume of the uterine cavity may be a key factor leading to first-trimester miscarriage, rather than an important causative factor for infertility.

Objective: To compare the changes of metabolites between Low-level light therapy (LLLT) and combined oral contraceptive (COC) after treatment of primary dysmenorrhea (PD), and to compare and analyze the biological and biochemical effects of the two treatments by analyzing the differences in metabolite profiles. Methods: A multicenter, double-blind, prospective, parallel, randomized controlled study was conducted on 69 women aged 16–35 years old with PD who were randomly divided into COC treatment group or LLLT treatment group. Low-level light therapy with light-emitting diodes (LED) was applied on two acupoints named “Guanyuan” (CV4) and “Qihai” (CV6). After 12 weeks of treatment intervention, blood samples were collected before and after treatment for metabolomic analysis. We used UPLC-MS/MS analysis to compare the differences in metabolite changes between LLLT and COC before and after treatment. Results: 76 differential metabolites were detected in the LLLT group, and 92 differential metabolites were detected in the COC group, which were up-regulated or down-regulated (p

Abstract. Background:. As one of the most common endocrinal disorders for women at childbearing age, the diagnostic criteria of polycystic ovary syndrome (PCOS) have been defined differently among different international health organizations. Phenotypic heterogeneity of PCOS also brings about difficulties for its diagnosis and management assessment. Therefore, more efficient biomarkers representing the progression of PCOS are expected to be integrated into the monitoring of management process using metabolomic approaches. Methods:. In this prospective randomized controlled trial, 117 PCOS patients were enrolled from December 2016 to September 2017. Classical diagnostic parameters, blood glucose, and metabolome were measured in these patients before and at 2 months and 3 months of different medical interventions. The receiver operating characteristic (ROC) curves were built based on multivariate statistical analysis using data at baseline and 3 months’ management, and combinational biomarkers with appreciable sensitivity and specificity were selected, which then validated with data collected at 2 months. Results:. A set of metabolites including glutamic acid, aspartic acid, 1-methylnicotinamide, acetylcarnitine, glycerophosphocholine, and oleamide were filtered out with high performance in representing the improvement through 3-month management of PCOS with high sensitivity and specificity in ROC analysis and validation with other two groups showed an appreciable area under the curve over 0.96. Conclusions:. The six metabolites were representative of the remission of PCOS through medical intervention, making them a set of potential biomarkers for assessing the outcome of PCOS management. Trial Registration:. ClinicalTrials.gov, NCT03264638.

N6-methyladenosine (m6A) RNA methylation is an emerging area of epigenetics, which is a reversible and dynamic modification mediating by ‘writers’ (methylase, adding methyl groups, METTL3, METTL14, and WTAP), ‘erasers’ (demethylase, deleting methyl groups, FTO and ALKBH5), and ‘readers’ (YTHDF1-3, YTHDC1 and YTHDC2). Recent studies in human, animal models and cell levels have disclosed a critical role of m6A modification in regulating the homeostasis of metabolic processes and cardiovascular function. Evidence from these studies identify m6A as a candidate of biomarker and therapeutic target for metabolic abnormality and cardiovascular diseases (CVD). Comprehensive understanding of the complexity of m6A regulation in metabolic diseases and CVD will be helpful for us to understand the pathogenesis of CVD. In this review, we discuss the regulatory role of m6A in metabolic abnormality and CVD. We will emphasize the clinical relevance of m6A dysregulation in CVD.