BackgroundHeat shock protein 90 (HSP90) functions as a well-known onco-protein to regulate protein conformation, stability and degradation. Pyruvate kinase M2 (PKM2), a critical regulator of the metabolism, growth and metastasis of cancer cells, has been confirmed to be overexpressed in various human cancer including hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying the oncogenic functions of HSP90 and PKM2 overexpression in HCC remain unknown.MethodsThe expression of HSP90 and PKM2 in HCC specimens and cells were detected by immunoblotting and immunostaining. The interaction between HSP90 and PKM2 was confirmed by tandem affinity purification, co-immunoprecipitation and Glutathione S transferase (GST)-pulldown assay.ResultsIn this study, we found that HSP90 could bind to PKM2 and subsequently increased PKM2 abundance in HCC cells. Immunohistochemistry (IHC) staining showed that HSP90 level was positively correlated with PKM2 level in HCC tissues. Mechanistically, HSP90 was found to increase the phosphorylation of PKM2 at Thr-328. Protein kinase glycogen synthase kinase-3β (GSK-3β) formed a protein complex with HSP90 and PKM2, and directly mediated Thr-328 phosphorylation of PKM2 induced by HSP90. Thr-328 phosphorylation was critical for maintaining PKM2 stability and its biological functions in regulating glycolysis, mitochondria respiration, proliferation and apoptosis. Functionally, we found that HSP90 promoted the glycolysis and proliferation and inhibited apoptosis of HCC cells in a PKM2 dependent manner. In vivo experiments disclosed that PKM2 was required for the promoting effects of HSP90 on the growth of HCC cells in mice. Furthermore, we demonstrated that positive expression of HSP90 and PKM2 was correlated with poor clinicopathological features including high alpha fetoprotein (AFP) level, large tumor size, portal vein tumor thrombus (PVTT) and advanced tumor-node-metastasis (TNM) stage. Furthermore, we demonstrated that positive expression of HSP90 and PKM2, and a combination of these proteins could strongly predict the poor prognosis of HCC patients.ConclusionsWe suggest that HSP90 potentiates the glycolysis and proliferation, reduces the apoptosis and thus enhances the growth of HCC cells through PKM2.Electronic supplementary materialThe online version of this article (10.1186/s12943-017-0748-y) contains supplementary material, which is available to authorized users.

BackgroundIncreasing evidences demonstrate that miRNAs contribute to development and progression of hepatocellular carcinoma (HCC). Underexpression of miR-1296 is recently reported to promote growth and metastasis of human cancers. However, the expression and role of miR-1296 in HCC remain unknown.MethodsThe levels of miR-1296 in HCC tissues and cells were detected by qRT-PCR. Immunoblotting and immunofluorescence were used for detection of epithelial-to-mesenchymal transition (EMT) progression in HCC cells. Transwell assays were performed to determine migration and invasion of HCC cells. A lung metastasis mouse model was used to evaluated metastasis of HCC in vivo. The putative targets of miR-1296 were disclosed by public databases and a dual-luciferase reporter assay.ResultsWe found that the expression of miR-1296 was reduced in HCC tissues and cell lines, and it was associated with metastasis and recurrence of HCC. Notably, miR-1296 overexpression inhibited migration, invasion and EMT progress of HCCLM3 cells, while miR-1296 loss facilitated these biological behaviors of Hep3B cells in vitro and in vivo. In addition, miR-1296 inversely regulated SRPK1 abundance by directly binding to its 3′-UTR, which subsequently resulted in suppression of p-AKT. Either SRPK1 re-expression or PI3K/AKT pathway activation, at least partially, abolished the effects of miR-1296 on migration, invasion and EMT progress of HCC cells. Furthermore, miR-1296 and SRPK1 expression were markedly correlated with adverse clinical features and poor prognosis of HCC patients. We showed that hypoxia was responsible for the underexpression of miR-1296 in HCC. And the promoting effects of hypoxia on metastasis and EMT of HCC cells were reversed by miR-1296.ConclusionsUnderexpression of miR-1296 potentially serves as a prognostic biomarker in HCC. Hypoxia-induced miR-1296 loss promotes metastasis and EMT of HCC cells probably by targeting SRPK1/AKT pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0675-y) contains supplementary material, which is available to authorized users.

To meet the growing demands in flexible and wearable electronics, various sensors have been designed for detecting and monitoring the physical quantity changes. However, most of these sensors can only detect one certain kind of physical quantity based on a single mechanism. In this paper, we have fabricated a multifunctional sensor made from carbonized electrospun polyacrylonitrile/barium titanate (PAN-C/BTO) nanofiber film. It can detect two physical quantities (pressure and curvature), independently and simultaneously, by integrating piezoresistive, piezoelectric, and triboelectric effects. For flex sensing with the impedance change of PAN-C/BTO nanofiber films during bending, it had a sensitivity of 1.12 deg from 58.9° to 120.2° and a working range of 28°-150°. For self-powered force sensing, it had a gauge factor of 1.44 V·N within the range of 0.15-25 N. The sensor had a long stability over 60 000 cycles at both sensing modes. The inclusion of barium titanate nanoparticles (BTO NPs) into the nanofiber film had an over 2.4 times enhancement of sensitivity for pressure sensing because of the synergy of piezoelectric and triboelectric effects. On the basis of multifunction and modularity, a series of potential applications of the sensor were demonstrated, including sensing human's swallowing, walking gaits, finger flexure, and finger-tapping. The self-powered flexible dual-mode sensor has great application potential in human-computer interactive and smart wearable sensing systems.

We study the electronic, mechanical and optical properties of the monolayer PdS 2 , PdSe 2 and PtSe 2 under mechanical strains of various magnitudes and directions. It is found that the band structures of these materials are more sensitive to biaxial strains. Moreover, the Young's modulus of all three materials are calculated in the a and b directions. Simulation results show the Young's modulus of monolayer PdS 2 , PdSe 2 and PtSe 2 are 116.4 GPa, 58.5 GPa and 115.9 GPa in the a direction and 166.5 GPa, 123.6 GPa and 117.7 GPa in the b direction. We analyze the peak shift of the real (߳ ଵ ) and imaginary (߳ ଶ ) parts of the complex dielectric constants for these three materials. We found that the peak of the complex dielectric constant red-shifts towards lower energy and ߳ ଵ (0) monotonously increase with the compressive and tensile strains increase. Among these three materials, PdS 2 exhibits excellent electronic and optical tunability under tensile strains, for example the peak wavelength of the imaginary dielectric constant can be adjusted from 2 eV to 1 eV when the strain varies from 0% to 10%, leading to approximately 5% red-shift in wavelength per 1% mechanical tensile strain. The results indicate that these monolayer materials will have potential applications in tunable nanoelectromechanical devices.

Background and Purpose— Early presentation is critical for receiving effective reperfusion therapy for acute ischemic stroke, therefore, we undertook a national survey of awareness and responses to acute stroke symptoms in China. Methods— We undertook a cross-sectional community-based study of 187 723 adults (age ≥40 years) presenting to 69 administrative areas across China between January 2017 and May 2017 to determine the national stroke recognition rate and the correct action rate. Multivariable logistic regression models were used to identify factors associated with stroke recognition and intention-to-avail emergency medical services. Results— Estimates of stroke recognition rate and correct action rate were 81.9% (153 675/187 723) and 60.9% (114 380/187 723), respectively, but these rates varied widely by sociodemographic status, region, and stroke risk. Approximately one-third of participants who recognized a stroke failed to call emergency medical service. Low likelihood of emergency medical service use was associated with younger age (40–59 years), being male, rural location, (regions of east, south, and northwest China), high body mass index (≥24), low education (primary school or below), low personal income (<US $731 per annum), living with immediate family, having multiple children (≥2), having a friend with stroke, exposure to less avenues to learn about stroke, nonsmoking, regular exercise, unknown family history, and no history of cardiovascular disease. Intention of calling emergency medical service was strongly related to awareness of stroke (odds ratio 2.05; 95% CI, 2.00–2.10; P <0.001). Conclusions— Substantial discrepancies exist between stroke recognition and correct action and not all stroke patients know the appropriate responses. Further, national stroke educational programs with specific plans targeting different groups are needed, which do not solely focus on stroke recognition, but also on the appropriate responses at the time of a stroke.

HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Background and Aims Nuclear‐located covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is a determining factor for HBV persistence and the key obstacle for a cure of chronic hepatitis B. However, it remains unclear whether and how the host immune system senses HBV cccDNA and its biological consequences. Approach and Results Here, we demonstrated that interferon‐inducible protein 16 (IFI16) could serve as a unique innate sensor to recognize and bind to HBV cccDNA in hepatic nuclei, leading to the inhibition of cccDNA transcription and HBV replication. Mechanistically, our data showed that IFI16 promoted the epigenetic suppression of HBV cccDNA by targeting an interferon‐stimulated response element (ISRE) present in cccDNA. It is of interest that this ISRE was also revealed to play an important role in IFI16–activated type I interferon responses. Furthermore, our data revealed that HBV could down‐regulate the expression level of IFI16 in hepatocytes, and there was a negative correlation between IFI16 and HBV transcripts in liver biopsies, suggesting the possible role of IFI16 in suppressing cccDNA function under physiological conditions. Conclusions The nuclear sensor IFI16 suppresses cccDNA function by integrating innate immune activation and epigenetic regulation by targeting the ISRE of cccDNA, and IFI16 may present as a therapeutic target against HBV infection.

Over the past few decades, flexible sensors have been developed from the "electronic" level to the "iontronic" level, and gradually to the "ionic" level. Ionic flexible sensors (IFS) are one kind of advanced sensors that are based on the concept of ion migration. Compared to conventional electronic sensors, IFS can not only replicate the topological structures of human skin, but also are capable of achieving tactile perception functions similar to that of human skin, which provide effective tools and methods for narrowing the gap between conventional electronics and biological interfaces. In this review, the latest research and developments on several typical sensing mechanisms, compositions, structural design, and applications of IFS are comprehensively reviewed. Particularly, the development of novel ionic materials, structural designs, and biomimetic approaches has resulted in the development of a wide range of novel and exciting IFS, which can effectively sense pressure, strain, and humidity with high sensitivity and reliability, and exhibit self-powered, self-healing, biodegradability, and other properties of the human skin. Furthermore, the typical applications of IFS in artificial skin, human-interactive technologies, wearable health monitors, and other related fields are reviewed. Finally, the perspectives on the current challenges and future directions of IFS are presented.