Transgenic expression of Cre recombinase driven by a specific promoter is normally used to conditionally knockout a gene in a tissue- or cell-type-specific manner. In αMHC-Cre transgenic mouse model, expression of Cre recombinase is controlled by the myocardial-specific α-myosin heavy chain (αMHC) promoter, which is commonly used to edit myocardial-specific genes. Toxic effects of Cre expression have been reported, including intro-chromosome rearrangements, micronuclei formation and other forms of DNA damage, and cardiomyopathy was observed in cardiac-specific Cre transgenic mice. However, mechanisms associated with Cardiotoxicity of Cre remain poorly understood. In our study, our data unveiled that αMHC-Cre mice developed arrhythmias and died after six months progressively, and none of them survived more than one year. Histopathological examination showed that αMHC-Cre mice had aberrant proliferation of tumor-like tissue in the atrial chamber extended from and vacuolation of ventricular myocytes. Furthermore, the αMHC-Cre mice developed severe cardiac interstitial and perivascular fibrosis, accompanied by significant increase of expression levels of MMP-2 and MMP-9 in the cardiac atrium and ventricular. Moreover, cardiac-specific expression of Cre led to disintegration of the intercalated disc, along with altered proteins expression of the disc and calcium-handling abnormality. Comprehensively, we identified that the ferroptosis signaling pathway is involved in heart failure caused by cardiac-specific expression of Cre, on which oxidative stress results in cytoplasmic vacuole accumulation of lipid peroxidation on the myocardial cell membrane. Taken together, these results revealed that cardiac-specific expression of Cre recombinase can lead to atrial mesenchymal tumor-like growth in the mice, which causes cardiac dysfunction, including cardiac fibrosis, reduction of the intercalated disc and cardiomyocytes ferroptosis at the age older than six months in mice. Our study suggests that αMHC-Cre mouse models are effective in young mice, but not in old mice. Researchers need to be particularly careful when using αMHC-Cre mouse model to interpret those phenotypic impacts of gene responses. As the Cre-associated cardiac pathology matched mostly to that of the patients, the model could also be employed for investigating age-related cardiac dysfunction.
Liver hepatocellular carcinoma (LIHC) remains a global health challenge with poor prognosis and high mortality. FKBP1A was first discovered as a receptor for the immunosuppressant drug FK506 in immune cells and is critical for various tumors and cancers. However, the relationships between FKBP1A expression, cellular distribution, tumor immunity, and prognosis in LIHC remain unclear. Here, we investigated the expression level of FKBP1A and its prognostic value in LIHC via multiple datasets including ONCOMINE, TIMER, GEPIA, UALCAN, HCCDB, Kaplan–Meier plotter, LinkedOmics, and STRING. Human liver tissue microarray was employed to analyze the characteristics of FKBP1A protein including the expression level and pathological alteration in cellular distribution. FKBP1A expression was significantly higher in LIHC and correlated with tumor stage, grade and metastasis. The expression level of the FKBP1A protein was also increased in LIHC patients along with its accumulation in endoplasmic reticulum (ER). High FKBP1A expression was correlated with a poor survival rate in LIHC patients. The analysis of gene co-expression and the regulatory pathway network suggested that FKBP1A is mainly involved in protein synthesis, metabolism and the immune-related pathway. FKBP1A expression had a significantly positive association with the infiltration of hematopoietic immune cells including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Moreover, M2 macrophage infiltration was especially associated with a poor survival prognosis in LIHC. Furthermore, FKBP1A expression was significantly positively correlated with the expression of markers of M2 macrophages and immune checkpoint proteins such as PD-L1, CTLA-4, LAG3 and HAVCR2. Our study demonstrated that FKBP1A could be a potential prognostic target involved in tumor immune cell infiltration in LIHC.
Background Age-related macular degeneration (AMD) is the leading cause of severe vision loss in patients over 55 years old in the industrialized world. In the past 20 years, approximately 288 million patents have been affected by this disease. Despite this high prevalence, the molecular mechanism for AMD remains unclear, and there remains no effective treatment for this disease. The mosaic loss of Y chromosome (mLOY) has been identified as a common phenomenon in multiple age-related disease (i.e., oncogenesis and cardiovascular disease) has recently been identified by genome-wide analysis to be linked to AMD as well. As the Y chromosome mainly possesses three genomic functions, sister chromatin cohesion, cell cycle mitosis, and apoptotic signaling, here we characterize the Y chromosome euchromatic genes and non-chromosome AMD genes in relevance to cellular proliferation and apoptotic signaling of leukocytes. Results Using STRING, a publically available database of all protein–protein interaction, Grassmann et al. found the genes on the Y chromosome is mainly believed to take part in three major cellular genomic functions- sister chromatin cohesion, cell cycle mitosis, and apoptotic signaling. Based on data from the Ensembl Genome database, we focus on our discussion on coding genes found in the euchromatins but not the PAR1 and PAR2 regions of the Y chromosomes. All 14 known euchromatic genes on the Y chromosome short arm and all 31 known euchromatic genes on the Y chromosome long arm (Yq) are directly or indirectly involved in the cell cycle (meiosis and mitosis) and proliferation. We sorted non-Y chromosome AMD associated genes into these three categories to identify signaling pathways that may compound with cellular dysregulation due to mLOY. Of the genes associated with AMD, complement pathway genes such as C2, C9 and CFH/ARMD4 are associated with proliferation, receptor-mediated endocytosis genes such as APOE, DAB2 and others associated with apoptotic signaling. Because nucleated cells found in peripheral circulation are mainly composed of leukocytes with reduced expression of CD99, a protein essential for leukocytes adhesion, translocation, and function, mLOY in these cells likely affect retinal degeneration through altered immunological surveillance. In fact, there is precedence that circulating macrophage can stabilize and modify the cardiac rhythm and contractility post ischemic damage. Therefore, the most likely mechanism through which peripheral mLOY affects AMD development in men is through the role affected leukocytes play in retinal proliferation and apoptosis. Conclusions mLOY in peripheral blood is newly discovered in AMD by Grassmann et al. as it is a common phenomenon in oncogenesis and cardiac dysfunction. Here the recent data conclude the possible mechanism for the newly identified link between mLOY and AMD, and provide support that mLOY in circulating macrophage-monocyte of affected male patients promotes AMD by targeting the retina and causing macular degeneration.
Artificial vegetation restoration is an effective method for improving soil quality. In areas experiencing coal mine subsidence, the microbial community is essential for reconstructing the ecological balance of the soil. Studies are needed to examine how soil microbial community structure respond to different artificial forest restoration types and ages, especially over long-term periods. Therefore, in this study, 10, 20, and 30-year trials were chosen with two restoration types: Pinus tabuliformis (PT) and Ulmus pumila (UP). The objective was to determine how various types and ages of forest restoration affect the structure of soil bacterial communities, as well as the soil environmental factors driving these changes. The results showed that artificial 30-year restoration for both PT and UP can improve soil physical and chemical properties more than restoration after 10 and 20 years. The soil bacterial community structure remarkably differed among the different forest types and restoration ages. The bacterial diversity was higher in UP than in PT; the alpha diversity at longer restoration years (30 and 20) was significantly higher than at 10 years for both PT and UP. Moreover, soil nutrients and pH were the primary soil environmental factors driving bacterial community structure in the PT and UP. Finally, the integrated fertility index (IFI) at 30 years of restoration was considerably higher for PT and UP, and thus, is more beneficial to the restoration of soil after coal mining. Our findings are useful for studying improvement in soil quality and the restoration of the ecological environment in mining areas.
Cropping system models can be useful tools for assessing tillage systems, which are both economically and environmentally viable. The objectives of this study were to evaluate the decision support system for agrotechnology transfer (DSSAT) CERES-Maize model’s ability to predict maize growth and yield, as well as soil water dynamics, and to apply the evaluated model to predict evapotranspiration processes under conventional tillage (CT) and no-tillage (NT) systems in a semi-arid loess plateau area of China from 2014 to 2016. The field experiment results showed that NT increased the surface soil bulk density and water-holding capacity but decreased the total porosity for the surface soil and the maize grain yield. Model calibration for maize cultivar was achieved using grain yield measurements from 2014 to 2016 for CT, and model evaluation was achieved using soil and crop measurements from both CT and NT for the same 3 yr period. Good agreement was reached for CT grain yields for model calibration (nRMSE = 4.02%; d = 0.87), indicating that the model was successfully calibrated. Overall, the results of model evaluation were acceptable, with good agreement for NT grain yields (nRMSE = 4.26%; d = 0.86); the agreement for LAI ranged from good to moderate (RMSE = 0.30‒0.31; d = 0.84‒0.85); the agreement for soil water content was good for NT (RMSE = 0.03‒0.08; d = 0.81‒0.95), but ranged from good to poor for CT (RMSE = 0.06‒0.09; d = 0.42‒0.88); the overall agreement between measured and simulated soil water varied from poor to good depending on soil depth and tillage. It was concluded that the DSSAT CERES-Maize model provided generally good-to-moderate simulations of continuous maize production (yield and LAI) for a short-term tillage experiment in the loess plateau, China, but generally good-to-poor simulations of soil water content.
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