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Abstract Background Cholangiocarcinoma (CCA) is one of the deadliest cancers of the digestive tract. The prognosis of CCA is poor and the 5-year survival rate is low. Bioinformatic analysis showed that early mitotic inhibitor 2 (EMI2) was overexpressed in CCA but the underlying mechanism is not known. Methods The data on bile duct carcinoma from TCGA and GEO databases were used to detect the expression of EMI2. The transcription factors of EMI2 were predicted using JASPAR and PROMO databases. Among the predicted transcription factors, YY1 has been rarely reported in cholangiocarcinoma, and was verified using the luciferase reporter gene assay. RT-PCR was performed to predict the downstream pathway of EMI2, and PI3K/Akt was suspected to be associated with it. Subsequently, in vivo and in vitro experiments were conducted to verify the effects of silencing and overexpressing EMI2 and YY1 on the proliferation, invasion, and metastasis of the bile duct cancer cells. Results EMI2 was highly expressed in CCA. Silencing EMI2 inhibited the proliferation, invasion, and migration of CCA cells, arrested cell cycle in the G1 phase, and promoted of apoptosis. The luciferase reporter gene assay showed that YY1 bound to the promoter region of EMI2, and after silencing YY1, the expression of EMI2 decreased and the progression of CCA was inhibited. Moreover, key proteins in the PI3K/Akt signaling pathway decreased after silencing EMI2. Conclusion EMI2 may be one of the direct targets of YY1 and promotes the progression of CCA through the PI3K/Akt signaling pathway.

Background Currently, research on the factors influencing the health status of older adults with multimorbidity in China is scattered, and it is difficult to give a comprehensive consideration from a holistic perspective, and the contribution of factors leading to health disparities is not explored, resulting in the ineffectiveness of current health management often programs in older adults with multimorbidity. Objective By introducing a health bifactor model, this study aims to understand the endogenous and exogenous influencing factors and their contributions to the health of older adults with multimorbidity and provide a practical basis for developing precise health management plans for older adults with multimorbidity. Methods In this study, using the China Health and Retirement Longitudinal Survey (CHARLS) 2018 data and introducing the two-factor model of health developed from the Grossman health production function (including both endogenous and exogenous aspects of health determinants). First, the Wilcoxon rank sum test was used to analyze whether there were differences in the health status of older adults with multimorbidity by gender. Secondly, the OLS regression model was used to analyze the mechanism of the two-factor model of health on the health of older adults with multimorbidity. Finally, the Shapley value method was further used to decompose the contribution of health endogenous factors to their health. Results The study found that factors such as still drinking alcohol, having no disease control methods, being satisfied with medical services, having a high level of education, having a pension, not using health services, attending free health checks, caring for grandchildren and being satisfied with their children's relationship were more likely to improve the health of older people with multiple chronic conditions. The results of the Shapley decomposition showed that socioeconomic status was the most important factor in the full sample, while family health support, health-related behaviors, and health-related behaviors were the most important factors. Coping strategies was the next most important, and social health resources was the least influential. In the gender subgroup analysis, socioeconomic status remained the most important factor; for older men with multiple chronic illnesses, health-related behaviors were the next most important factor; for older women with multiple chronic illnesses, coping strategies were the next most important. Conclusion The health status of older men with multimorbidity is better than that of women, socioeconomic status is the most important factor affecting the health of older adults with multimorbidity, and the remaining four dimensions have different contributions to the health differences between men and women. It is recommended that precise health management should be implemented according to the size of the contribution of each dimension of different health endogenous factors to improve the health status of older adults with multimorbidity with maximum benefit.

Abstract Background The essential roles of platelets in thrombosis have been well recognized. Unexpectedly, thrombosis is prevalent during thrombocytopenia induced by cytotoxicity of biological, physical and chemical origins, which could be suffered by military personnel and civilians during chemical, biological, radioactive, and nuclear events. Especially, thrombosis is considered a major cause of mortality from radiation injury-induced thrombocytopenia, while the underlying pathogenic mechanism remains elusive. Methods A mouse model of radiation injury-induced thrombocytopenia was built by exposing mice to a sublethal dose of ionizing radiation (IR). The phenotypic and functional changes of platelets and megakaryocytes (MKs) were determined by a comprehensive set of in vitro and in vivo assays, including flow cytometry, flow chamber, histopathology, Western blotting, and chromatin immunoprecipitation, in combination with transcriptomic analysis. The molecular mechanism was investigated both in vitro and in vivo, and was consolidated using MK-specific knockout mice. The translational potential was evaluated using a human MK cell line and several pharmacological inhibitors. Results In contrast to primitive MKs, mature MKs (mMKs) are intrinsically programmed to be apoptosis-resistant through reprogramming the Bcl-xL-BAX/BAK axis. Interestingly, mMKs undergo minority mitochondrial outer membrane permeabilization (MOMP) post IR, resulting in the activation of the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway via the release of mitochondrial DNA. The subsequent interferon-β (IFN-β) response in mMKs upregulates a GTPase guanylate-binding protein 2 (GBP2) to produce large and hyperreactive platelets that favor thrombosis. Further, we unmask that autophagy restrains minority MOMP in mMKs post IR. Conclusions Our study identifies that megakaryocytic mitochondria-cGAS/STING-IFN-β-GBP2 axis serves as a fundamental checkpoint that instructs the size and function of platelets upon radiation injury and can be harnessed to treat platelet pathologies.