Glycolysis is critical for cancer stem cell reprogramming; however, the underlying regulatory mechanisms remain elusive. Here, we show that pyruvate dehydrogenase kinase 1 (PDK1) is enriched in ...breast cancer stem cells (BCSCs), whereas depletion of PDK1 remarkably diminishes ALDH
subpopulations, decreases stemness-related transcriptional factor expression, and inhibits sphere-formation ability and tumor growth. Conversely, high levels of PDK1 enhance BCSC properties and are correlated with poor overall survival. In mouse xenograft tumor, PDK1 is accumulated in hypoxic regions and activates glycolysis to promote stem-like traits. Moreover, through screening hypoxia-related long non-coding RNAs (lncRNAs) in PDK1-positive tissue, we find that lncRNA H19 is responsible for glycolysis and BCSC maintenance. Furthermore, H19 knockdown decreases PDK1 expression in hypoxia, and ablation of PDK1 counteracts H19-mediated glycolysis and self-renewal ability in vitro and in vivo. Accordingly, H19 and PDK1 expression exhibits strong correlations in primary breast carcinomas. H19 acting as a competitive endogenous RNA sequesters miRNA let-7 to release Hypoxia-inducible factor 1α, leading to an increase in PDK1 expression. Lastly, aspirin markedly attenuates glycolysis and cancer stem-like characteristics by suppressing both H19 and PDK1. Thus, these novel findings demonstrate that the glycolysis gatekeeper PDK1 has a critical role in BCSC reprogramming and provides a potential therapeutic strategy for breast malignancy.
Targeting the immune checkpoint pathway has demonstrated antitumor cytotoxicity in treatment-refractory head and neck squamous cell carcinoma (HNSC). To understand the molecular mechanisms ...underpinning its antitumor response, we characterized the immune landscape of HNSC by their tumor and stromal compartments to identify novel immune molecular subgroups.
A training cohort of 522 HNSC samples from the Cancer Genome Atlas profiled by RNA sequencing was analyzed. We separated gene expression patterns from tumor, stromal, and immune cell gene using a non-negative matrix factorization algorithm. We correlated the expression patterns with a set of immune-related gene signatures, potential immune biomarkers, and clinicopathological features. Six independent datasets containing 838 HNSC samples were used for validation.
Approximately 40% of HNSCs in the cohort (211/522) were identified to show enriched inflammatory response, enhanced cytolytic activity, and active interferon-γ signaling (all, P < 0.001). We named this new molecular class of tumors the Immune Class. Then we found it contained two distinct microenvironment-based subtypes, characterized by markers of active or exhausted immune response. The Exhausted Immune Class was characterized by enrichment of activated stroma and anti-inflammatory M2 macrophage signatures, WNT/transforming growth factor-β signaling pathway activation and poor survival (all, P < 0.05). An enriched proinflammatory M1 macrophage signature, enhanced cytolytic activity, abundant tumor-infiltrating lymphocytes, high human papillomavirus (HPV) infection, and favorable prognosis were associated with Active Immune Class (all, P < 0.05). The robustness of these immune molecular subgroups was verified in the validation cohorts, and Active Immune Class showed potential response to programmed cell death-1 blockade (P = 0.01).
This study revealed a novel Immune Class in HNSC; two subclasses characterized by active or exhausted immune responses were also identified. These findings provide new insights into tailoring immunotherapeutic strategies for different HNSC subgroups.
•Sputtering-derived Hf1−xTixO2 gate dielectrics have been deposited on Si substrates.•Increase in crystallization temperature and reduction in Eg have been observed.•Formation of silicate layer for ...9% TiO2-doped HfO2/Si sample has been detected.
TiO2-doped HfO2 gate dielectric thin films have been deposited on Si(100) substrates by RF sputtering. The component, morphology, structure, optical and interfacial properties of Hf1−xTixO2 films related to TiO2 concentration are systematically investigated by atomic force microscope (AFM), X-ray diffraction (XRD), spectroscopic ellipsometry (SE), X-ray photoelectron spectroscopy (XPS), and Fourier transformation infrared (FTIR). By employing Cauchy–Urbach model, the optical constants, such as refractive index (n), extinction coefficient (k), absorption coefficient (α), and optical band gap (Eg) have been determined precisely. Measurements from XRD have confirmed that TiO2 incorporating into HfO2 films leads to the increase of the crystallization temperature of HfO2 films with increasing the TiO2 concentration. SE analyses have indicated that reduction in band gap and refractive index has been observed with increasing the TiO2 component in Hf1−xTixO2 films. The increase in Urbach parameter EU with the increase of TiO2 concentration also suggests the rise in disorder for Hf1−xTixO2 films. FTIR measurements for Hf1−xTixO2/Si gate stack indicate the existence of the interfacial layer regardless of the TiO2 concentration. For the 9% TiO2-doped HfO2 samples, the shift in FTIR characteristic peak suggests the formation of the silicate layer, which leads to the suppressed interfacial layer growth during deposition. As a result, it can be conclude that the TiO2 component in Hf1−xTixO2 films should be controlled precisely to guarantee interfacial properties of Hf1−xTixO2/Si gate stacks.
The cast-grown monocrystalline-like silicon (mono-like Si) technology has been reactivated recently for the manufacture of high-efficiency solar cells at low cost. In this paper, we have provided a ...progressive research, both experimentally and theoretically, to improve the efficiency of mono-like Si passivated emitter and rear cells (PERCs) through production lines. By employing rear surface passivation of AlOx/triple-SiNx:H layers, the average efficiency has increased to 21.87% with a champion efficiency of 22.32% from the standard mono-like Si PERCs of 21.72% efficiency with AlOx capped with double-SiNx:H layers. We have further optimized the rear electrode contact patterns and introduced the selective emitter (SE) technology, yielding an absolute efficiency improvement of 0.19% and 0.26%, respectively. Integrating all approaches of the triple-SiNx:H, rear contact pattern optimization and SE technology, we have demonstrated that the mono-like Si PERCs can reach the average efficiency of 22.2% with a maximum efficiency of 22.5%, similar to the current Czochralski monocrystalline Si counterparts.
Abstract
Einstein–Podolsky–Rosen (EPR) steering is a quantum effect based on quantum entanglement and it is the key resource for building quantum networks because of its useful properties. Based on ...the criterion for genuine multipartite EPR steering, the genuine quadripartite EPR steering is confirmed and it can be generated by a spontaneous parametric down-conversion cascaded process with two sum-frequency generations in an optical superlattice. This occurs either below the oscillation threshold and without oscillation threshold. The influence of the parameters of cascaded nonlinear process on the quadripartite EPR steering among signal, idler, and two sum-frequency beams are also discussed. Choosing appropriate nonlinear parameters can achieve good quadripartite quantum steering. This scheme of the generation of genuine quadripartite EPR steering has potential applications in quantum communication and computing.
β‐hydroxybutyric acid (BHBA) has recently been shown to regulate hormone synthesis and secretion in the hypothalamus. However, little is known about the effects of BHBA‐mediated hormone regulation or ...the detailed mechanisms by which BHBA regulates growth hormone‐releasing hormone (GHRH) synthesis and secretion. In the present study, we examined the expression of the BHBA receptor GPR109A in primary hypothalamic cell cultures. We hypothesised that BHBA regulates GHRH via GPR109A and its downstream signals. Initial in vivo studies conducted in rats demonstrated that GHRH mRNA expression in the hypothalamus was strongly inversely correlated with BHBA levels in the cerebrospinal fluid during postnatal development (r = −0.89, P < 0.01). Furthermore, i.c.v. administration of BHBA acutely decreased GHRH mRNA expression in rats. Further in vitro studies revealed a decrease in GHRH synthesis and secretion in primary hypothalamic cells after treatment with BHBA; this effect was inhibited when hypothalamic cells were pretreated with pertussis toxin (PTX). BHBA had no effect on GHRH synthesis and secretion in GT1‐7 cells, which do not exhibit cell surface expression of GPR109A. Furthermore, BHBA acutely decreased the transcription of the homeobox gene for Gsh‐1 in the hypothalamus in both in vivo and in vitro, and this effect was also inhibited by PTX in vitro. In primary hypothalamic cells, BHBA activated the extracellular signal‐regulated kinase (ERK)1/2, p38 and c‐Jun N‐terminal kinase mitogen‐activated protein kinase (MAPK) kinases, as shown by western blot analysis. Moreover, inhibition of ERK1/2 with U0126 attenuated the BHBA‐mediated reduction in Gsh‐1 expression and GHRH synthesis and secretion. These results strongly suggest that BHBA directly regulates GHRH synthesis and secretion via the GPR109A/ERK1/2 MAPK pathway, and also that Gsh‐1 is essential for this function.
This paper proposes a nautilus-inspired bionic volute for a multiblade centrifugal fan. Analysis of the noises generated by the fan is presented. This is made possible by a model that integrates a ...steady-state equation using the Reynolds-averaged Navier-Stokes (RANS) model and an unsteady-state estimation using the large-eddy simulation (LES) model and the Ffowcs Williams-Hawkings aerodynamic noise model, and by numerical solution to the model. Our computational model is validated on the sound pressure level with the help of the measurements on a physical system. The validation suggests that the proposed bionic volute significantly increases the aerodynamic performance particularly in terms of transformation between the pressure and flow rate under the rated power. The noise associated to the bionic volute is found to be predominantly tonal noise, and this is the primary source of the noise of the fan. Another finding is that the large expansion profile of the proposed volute contributes to the attenuation of the tonal noise associated to the periodic jet impingement at the impeller outlet.
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