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Reperfusion after acute myocardial infarction can cause ischemia/reperfusion (I/R) injury, which not only impedes restoration of the functions of tissues and organs but may also aggravate structural tissue and organ damage and dysfunction, worsening the patient’s condition. Thus, the mechanisms that underpin myocardial I/R injury need to be better understood. We aimed to examine the effect of dexmedetomidine on macrophage migration inhibitory factor (MIF) in cardiomyocytes from mice with myocardial I/R injury and to explore the mechanistic role of adenosine 5ʹ-monophosphate-activated protein kinase (AMPK) signaling in this process. Myocardial I/R injury was induced in mice. The expression of serum inflammatory factors, reactive oxygen species (ROS), adenosine triphosphate (ATP), and AMPK pathway-related proteins, as well as myocardial tissue structure and cell apoptosis rate, were compared between mice with I/R injury only; mice with I/R injury treated with dexmedetomidine, ISO-1 (MIF inhibitor), or both; and sham-operated mice. Dexmedetomidine reduced serum interleukin (IL)-6 and tumor necrosis factor-α concentrations and increased IL-10 concentration in mice with I/R injury. Moreover, dexmedetomidine reduced myocardial tissue ROS content and apoptosis rate and increased ATP content and MIF expression. MIF inhibition using ISO-1 reversed the protective effect of dexmedetomidine on myocardial I/R injury and reduced AMPK phosphorylation. Dexmedetomidine reduces the inflammatory response in mice with I/R injury and improves adverse symptoms, and its mechanism of action may be related to the MIF-AMPK pathway.

Lenvatinib is an inhibitor of multiple receptor tyrosine kinases that was recently authorized for first-line treatment of hepatocellular carcinoma (HCC). However, the clinical benefits derived from lenvatinib are limited, highlighting the urgent need to understand mechanisms of resistance. We report here that HCC cells develop resistance to lenvatinib by activating EGFR and stimulating the EGFR–STAT3–ABCB1 axis. Lenvatinib resistance was accompanied by aberrant cholesterol metabolism and lipid raft activation. ABCB1 was activated by EGFR in a lipid raft–dependent manner, which significantly enhanced the exocytosis of lenvatinib to mediate resistance. Furthermore, clinical specimens of HCC showed a correlation between the activation of the EGFR–STAT3–ABCB1 pathway and lenvatinib response. Erlotinib, an EGFR inhibitor that has also been shown to inhibit ABCB1, suppressed lenvatinib exocytosis, and combined treatment with lenvatinib and erlotinib demonstrated a significant synergistic effect on HCC both in vitro and in vivo. Taken together, these findings characterize a mechanism of resistance to a first-line treatment for HCC and offer a practical means to circumvent resistance and treat the disease. Significance: HCC cells acquire resistance to lenvatinib by activating the EGFR–STAT3–ABCB1 pathway, identifying combined treatment with erlotinib as a strategy to overcome acquired resistance and improve the clinical benefit of lenvatinib.

Lenvatinib is an inhibitor of multiple receptor tyrosine kinases that was recently authorized for first-line treatment of hepatocellular carcinoma (HCC). However, the clinical benefits derived from lenvatinib are limited, highlighting the urgent need to understand mechanisms of resistance. We report here that HCC cells develop resistance to lenvatinib by activating EGFR and stimulating the EGFR–STAT3–ABCB1 axis. Lenvatinib resistance was accompanied by aberrant cholesterol metabolism and lipid raft activation. ABCB1 was activated by EGFR in a lipid raft–dependent manner, which significantly enhanced the exocytosis of lenvatinib to mediate resistance. Furthermore, clinical specimens of HCC showed a correlation between the activation of the EGFR–STAT3–ABCB1 pathway and lenvatinib response. Erlotinib, an EGFR inhibitor that has also been shown to inhibit ABCB1, suppressed lenvatinib exocytosis, and combined treatment with lenvatinib and erlotinib demonstrated a significant synergistic effect on HCC both in vitro and in vivo. Taken together, these findings characterize a mechanism of resistance to a first-line treatment for HCC and offer a practical means to circumvent resistance and treat the disease.Significance:HCC cells acquire resistance to lenvatinib by activating the EGFR–STAT3–ABCB1 pathway, identifying combined treatment with erlotinib as a strategy to overcome acquired resistance and improve the clinical benefit of lenvatinib.

Supplementary Data from Inhibition of EGFR Overcomes Acquired Lenvatinib Resistance Driven by STAT3–ABCB1 Signaling in Hepatocellular Carcinoma

Intercellular cross-talk plays important roles in cancer progression and metastasis. Yet how these cancer cells interact with each other is still largely unknown. Exosomes released by tumor cells have been proved to be effective cell-to-cell signal mediators. We explored the functional roles of exosomes in metastasis and the potential prognostic values for hepatocellular carcinoma (HCC). Exosomes were extracted from HCC cells of different metastatic potentials. The metastatic effects of exosomes derived from highly metastatic HCC cells (HMH) were evaluated both in vitro and in vivo. Exosomal proteins were identified with iTRAQ mass spectrum and verified in cell lines, xenograft tumor samples, and functional analyses. Exosomes released by HMH significantly enhanced the in vitro invasion and in vivo metastasis of low metastatic HCC cells (LMH). S100 calcium-binding protein A4 (S100A4) was identified as a functional factor in exosomes derived from HMH. S100A4rich exosomes significantly promoted tumor metastasis both in vitro and in vivo compared with S100A4low exosomes or controls. Moreover, exosomal S100A4 could induce expression of osteopontin (OPN), along with other tumor metastasis/stemness-related genes. Exosomal S100A4 activated OPN transcription via STAT3 phosphorylation. HCC patients with high exosomal S100A4 in plasma also had a poorer prognosis. In conclusion, exosomes from HMH could promote the metastatic potential of LMH, and exosomal S100A4 is a key enhancer for HCC metastasis, activating STAT3 phosphorylation and up-regulating OPN expression. This suggested exosomal S100A4 to be a novel prognostic marker and therapeutic target for HCC metastasis.

Bears are fascinating mammals because of their complex pattern of speciation and rapid evolution of distinct phenotypes. Interspecific hybridization has been common and has shaped the complex evolutionary history of bears. In this study, based on the largest population-level genomic dataset to date involving all Ursinae species and recently developed methods for detecting hybrid speciation, we provide explicit evidence for the hybrid origin of Asiatic black bears, which arose through historical hybridization between the ancestor of polar bear/brown bear/American black bears and the ancestor of sun bear/sloth bears. This was inferred to have occurred soon after the divergence of the two parental lineages in Eurasia due to climate-driven population expansion and dispersal. In addition, we found that the intermediate body size of this hybrid species arose from its combination of relevant genes derived from two parental lineages of contrasting sizes. This and alternate fixation of numerous other loci that had diverged between parental lineages may have initiated the reproductive isolation of the Asiatic black bear from its two parents. Our study sheds further light on the evolutionary history of bears and documents the importance of hybridization in new species formation and phenotypic evolution in mammals.

Background Reperfusion of ischemic tissue has adverse impact on the myocardium. Dexmedetomidine (Dex) is a α2-adrenergic receptor (α2-AR) agonist with sedative and analgesic effects. Macrophage migration inhibition factor (MIF) is a pressure-regulating cytokine and is responsible for inflammatory and immune diseases. This study aims to reveal the consequences of Dex on myocardial ischemia-reperfusion injury (IRI) in young mice. Methods Fifty mice were raised and examined. At the end of the experiment, all mice were euthanized. The anterior descending department of the left coronary artery in mice was under ischemia for 60 min, then the ligation line was released and reperfused for 120 min to establish the IRI model. Mice were randomly divided into Sham, control, treatment using 4,5-dihydro-3-(4-hydroxyphenyl)-5-isoxazoleacetic acid (ISO-1), Dex treatment, and Dex combined ISO-1 treatment groups. Interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF-α) were determined by enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) and ATP levels were recorded. The expressions of MIF, P-adenosine monophosphate-activated kinase α (AMPKα), glucose transporter (GLUT)4, Bax and Bcl-2 were detected by Western Blot (WB). Hematoxylin and Eosin (H&E) staining was used to study cell morphology. Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. Echocardiography was carried out at the end of reperfusion, and the infarct size was calculated by Electron microscopy. Results I/R + Dex group showed significantly increased IL-6 and TNF-α levels and reduced myocardial cell necrosis and apoptosis. H&E staining showed alleviated myocardial disorder, myocardial cell swelling, myocardial fiber fracture, and inflammatory cell infiltration in I/R + Dex group. Myocardial cell necrosis and apoptosis were significantly reduced in I/R + Dex group. ATP level in myocardial tissue of mice in I/R group was substantially decreased, while that in Dex group was increased. WB results showed that MIF, P-AMPK α, GLUT4 and Bcl-2 levels were increased and Bax levels were decreased in I/R + Dex group. Conclusion Dex may exert myocardial protection in young mice through MIF/AMPK/GLUT4 axis.

BACKGROUND: Diminished mitochondrial autophagy in aged myocardium may be due to impaired HIF-1α protein expression. Previous studies confirmed that upregulation of HIF-1α expression protects myocardial tissue from ischemia/reperfusion (I/R) injury and found that sevoflurane post-conditioning (SpostC) mediated mitochondrial autophagy plays a significant role in myocardial protection. However, the protective mechanism of SpostC in aged myocardium is unclear. This study aimed to investigate whether SpostC regulates BNIP3 - mediated mitochondrial autophagy by upregulating HIF-1α expression, thus alleviating myocardial I/R injury in aged mice.Methods: An in vivo mouse model of myocardial I/R injury was established and treated with sevoflurane at the time of reperfusion, and at the end of reperfusion, echocardiographic changes, myocardial infarct size, mitochondrial ultrastructure, and autophagosomes were measured, mitochondrial respiratory function and enzyme activity were detected, serum LDH, CKM, CK-MB, TNNT2, IL-6 levels were determined, and Western blot was used to examine the expression levels of phosphorylated HIF-1α, LC3-II, BNIP3, Beclin1, TLR9, and IL-6 protein in myocardial tissue.RESULTS: In young, healthy myocardium, SpostC upregulated the expression of HIF-1α, activated the downstream target gene BNIP3 protein, and upregulated the expression levels of autophagy essential proteins LC3-II, Beclin-1, and TLR9, attenuated myocardial oxidative stress injury, stabilized mitochondrial ultrastructure, inhibited cardiomyocyte apoptosis, and ultimately reduced myocardial infarct size. In aged myocardium, SpostC also played an excellent myocardial protective role.CONCLUSION: SpostC was able to upregulate HIF-1α expression, promote BNIP3-mediated mitochondrial autophagy, reduce myocardial infarct size, and alleviate myocardial I/R injury in aged mice.

This study aims to decrease the dielectric constant of cellulose insulating paper by octa(aminophenyl)silsesquioxane (OAPS) grafting. OAPS was grafted onto the primary hydroxyl group of cellulose molecules via amino groups and epichlorohydrin. The dielectric constant and dielectric loss of insulating paper before and after modification were investigated. Relative to the unmodified paper, the dielectric constant of 15 wt% OAPS-grafted paper decreased from 5.27 to 4.28, and the dielectric loss decreased by 37.5% at 50 Hz. The movement and orientation polarization of the cellulose chains could be restricted due to the porous macromolecular structure and nano quantum interface effect produced by OAPS, thereby resulting in the reduction of cellulose polarizability. Moreover, the OAPS grafting modification does not degrade the other properties of cellulose insulation, i.e., its thermal stability, mechanical performance, fire-resistant properties, and electrical strength. OAPS grafting has promising potential application for preparing low dielectric constant insulating paper.

To evaluate the effects of HIF-1α overexpression on mitochondrial function in aged mice with myocardial ischemia-reperfusion (I/R). Mice were divided into 1) Blank (Sham) group; 2) Ischemia-reperfusion (I/R) group; 3) I/R+2ME2 group (I/R+HIF-1α blocker 2ME2. Compared with Sham group, in I/R group and I/R+2ME2 group, HR slowed down, LVDP and +dp/dtmax decreased, LVEDP, myocardial infarction area, and ROS generation rate was significantly increased; whereas the mitochondrial respiratory function (State3, RCR) and mitochondrial respiratory enzyme activity (NADH-OX, Cytc-OX and SUC-OX) were significantly reduced. Compared with the I/R group, the respiratory function of myocardial mtochondria (State3, RCR) and respiratory enzyme activity of myocardial (NADH-OX, Cytc-OX and SUC-OX) were significantly reduced in the I/R+2ME2 group; and the levels of p-HIF-1α and p-VEGF in the I/R+2ME2 group were significantly decreased. HIF-1α pathway upregulate the respiratory enzyme activity of myocardial and respiratory function of I/R myocardial mitochondria.

Wound healing and tumor progression share some common biological features; however, how variations in wound healing patterns affect hepatocellular carcinoma (HCC) prognosis remains unclear.We analyzed the wound healing patterns of 594 HCC samples from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) and correlated them with immune infiltration and the expression levels of immune checkpoint genes. A risk score, which we named the "heal.immune" score, was established via stepwise Cox estimation. We constructed a nomogram based on age, sex, TNM stage, and heal.immune score and explored its predictive value for HCC prognosis. Seventy-four clinical patients were enrolled in this study, and all were from Huashan Hospital of Fudan University between 2015 and 2017 to serve as an independent validation group.We identified two distinct wound healing patterns in HCC. The biological processes of healing cluster 1 (C1) are related to metabolism, while those of healing cluster 2 (C2) are related to the inflammatory response and immune cell accumulation. A total of 565 wound healing-related genes (based on Gene Ontology) and 25 immune checkpoint genes were considered. By analyzing differentially expressed genes and implementing a stepwise Cox estimation analysis, six genes withWe established a prognostic nomogram based on the heal.immune gene signature, which includes six wound healing- and immunity-related genes. This nomogram accurately predicts the OS of HCC patients.

Exosomes are a subset of extracellular vesicles that carry specific combinations of proteins, nucleic acids, metabolites, and lipids. Mounting evidence suggests that exosomes participate in intercellular communication and act as important molecular vehicles in the regulation of numerous physiological and pathological processes, including cancer development. Exosomes are released by various cell types under both normal and pathological conditions, and they can be found in multiple bodily fluids. Moreover, exosomes carrying a wide variety of important macromolecules provide a window into altered cellular or tissue states. Their presence in biological fluids renders them an attractive, minimally invasive approach for liquid biopsies with potential biomarkers for cancer diagnosis, prediction, and surveillance. Due to their biocompatibility and low immunogenicity and cytotoxicity, exosomes have potential clinical applications in the development of innovative therapeutic approaches. Here, we summarize recent advances in various technologies for exosome isolation for cancer research. We outline the functions of exosomes in regulating tumor metastasis, drug resistance, and immune modulation in the context of cancer development. Finally, we discuss prospects and challenges for the clinical development of exosome-based liquid biopsies and therapeutics.

Kevlar pulp treated with low-temperature plasma and nano cellulose fibrils (NCFs) have been introduced as reinforcements in the preparation for composite insulating paper with low relative permittivity, dielectric loss, good mechanical properties, and thermal stability. More polar groups of Kevlar fibers could be exposed after plasma treatment. Results showed that the relative permittivity of the composite paper containing 20% Kevlar pulp, 10% NCF, and 70% softwood pulp is decreased by 29.6% and the dielectric loss is decreased by 43.2% at 50 Hz, 25°, compared with the conventional paper formed by pure softwood pulp. The change was due to the introduction of Kevlar pulp with intrinsic low dielectric constant and loss, which decreases the whole polarizability of the paper. The mechanical properties of the composite paper became worse after introducing 20% Kevlar pulp. About 10% NCF can work as a mechanical reinforcement to compensate for the tensile and Yang's modulus loss. Scanning electron microscopy results showed that NCF could fill the void defects and improve the interface bonding of the fibers to enhance the paper mechanical properties. The composite paper also had better insulating and thermal properties than the conventional paper. It has been concluded that the Kevlar pulp/NCF/softwood pulp composite paper has the potential to replace the pure softwood paper for the application of high-voltage ac transformer insulation.

Learning words through contextual inference is a key way to enlarge one's vocabulary especially for adults. However, few studies focused on the effects of different information contained in contexts on novel word learning. The present study used behavioral and fNIRS techniques to investigate the influences of positive, neutral and negative emotions inherent in self-related or other-related referential contexts. Participants were asked to perform a semantic consistency and a source judgment task after learning the relations between novel words and concepts in different contexts. The results showed that self-reference during lexical encoding could promote word learning generally. More importantly, there existed a self-positivity bias which is manifested in the significant interactions between contextual emotions and referential value. These interactions are related to the neural activities of the DLPFC and IFG. These results revealed the contextual information's integrative contributions to semantic meaning acquisition and episodic source memory related with novel word learning.

Oil-impregnated cellulose paper is the main insulation material used in power transformers. The thermal stability of cellulose insulation is important for the steady and safe operation of a transformer. The reinforcement of the thermal stability of cellulose via physical and chemical modification has attracted much research attention. Considering that traditional experiments are costly and time-consuming, molecular dynamics simulation is introduced to predict or estimate the performance of modified cellulose by calculating several key parameters. However, linking the model performance parameters with macroscopic properties of materials at the molecular simulation scale is difficult. In this study, two parameters, namely, mean square displacement (MSD) and glass transition temperature (Tg), are proposed to evaluate the thermal stability of cellulose. The validity of these two parameters to characterize the thermal stability of cellulose is verified by the simulation results from natural cellulose and acetylation-grafted cellulose models. In engineering application, acetylation-grafted cellulose performs better than natural cellulose in terms of thermal stability. According to the simulation results, the Tg of acetylation-grafted cellulose is approximately 111 K higher than that of natural cellulose. Compared with the natural cellulose, the MSD of acetylation-grafted cellulose considerably decreased, indicating that the intensity of movement for the acetylation-grafted cellulose chain is prominently smaller than the natural cellulose chain at every time step. These results also show that acetylation-grafted cellulose can improve the thermal stability of cellulose, which is consistent with previous studies.

To study the influence of fenhexamid in pesticide residue to the human ovarian cancer BG-1 cell proliferation. Detecting the effectiveness of 17β-estradiol, fenhexamid and Fulvestrant to BG-1 cell proliferation by MTT, and detecting the expression levels of cyclin D1 and cyclin E by Western blot. Fenhexamid can promote BG-1 cell proliferation for its estrogen-like effect. On the other hand, it can help to improve the expression levels of cyclin D1 and cyclin E in BG-1 cells which is regulated by ER-dependent pathway. And 17β-estradiol is also regulated by the same way. The existence of fenhexamid can promote ovarian cancer cell proliferation, so for patients with ovarian cancer, fenhexamid in pesticide residue may make medical conditions worse.