While testicular nuclear receptor 4 (TR4) may promote prostate cancer (PCa) metastasis, its role in the clear cell renal cell carcinoma (ccRCC) remains unclear. Here we found a higher expression of ...TR4 in ccRCC tumors from patients with distant metastases than those from metastasis‐free patients, suggesting TR4 may play positive roles in the ccRCC metastasis. Results from multiple in vitro ccRCC cell lines also confirmed TR4's positive roles in promoting ccRCC cell invasion/migration via altering the microRNA (miR‐32‐5p)/TR4/HGF/Met/MMP2‐MMP9 signaling. Mechanism dissection revealed that miR‐32‐5p could suppress TR4 protein expression levels via direct binding to the 3′UTR of TR4 mRNA, and TR4 might then alter the HGF/Met signaling at the transcriptional level via direct binding to the TR4‐response‐elements (TR4RE) on the HGF promoter. Then the in vitro data also demonstrated the efficacy of Sunitinib, a currently used drug to treat ccRCC, could be increased after targeting this newly identified miR‐32‐5p/TR4/HGF/Met signaling. The preclinical study using the in vivo mouse model with xenografted ccRCC cells confirmed the in vitro cell lines data. Together, these findings suggest that TR4 is a key player to promote ccRCC metastasis and targeting this miR‐32‐5p/TR4/HGF/Met signaling with small molecules including TR4‐shRNA or miR‐32‐5p may help to develop a new therapy to better suppress the ccRCC metastasis.
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About one‐third of patients with clear cell renal cell carcinoma (ccRCC) develop metastatic lesions, though the mechanisms behind this process are unclear. In this study, the transcriptional factor testicular nuclear receptor 4 (TR4) is identified as a potential promoter of ccRCC metastasis. Elevated TR4 expression was associated with metastasis in ccRCC cells and in clinical samples from ccRCC patients. In vitro, TR4 promoted RCC cell invasion and migration via altered hepatocyte growth factor (HGF)/Met/MMP2‐MMP9 signaling. Metastasis was suppressed in vitro and in vivo by the small molecules TR4‐shRNA and miR‐32‐5p, a microRNA typically downregulated in ccRCC metastatic patients.
This study aims to investigate the effects of glucose transport l (Glut1) gene on proliferation, differentiation, and apoptosis of colorectal cancer (CRC) cells by regulating the TGF‐β/PI3K‐AKT‐mTOR ...signaling pathway. Immunohistochemistry was conducted to detect the positive Glut1 expression. Normal human CRC epithelial cells (CCD‐18Co) and CRC cell line HCT116 were grouped into the control, blank, negative control (NC), and shGlut1‐1 groups. RT‐qPCR and Western blotting were performed to detect the expressions of Glut1, TGF‐β1, PI3K, AKT, PTEN, mTOR, Bcl‐2, and Bax. Protein expression of phosphorylated‐PI3K (p‐PI3K), p‐S473‐AKT, p‐S389‐S6K1, p‐T70‐4EBP1, Cleaved caspase‐3 and Cleaved‐PARP were detected. MTT assay, flow cytometry, and colony formation assay were performed in order to detect cell viability, cell cycle, and apoptosis, respectively. The positive expression rate of Glut1 in CRC tissues was 75% ± 8%, while in the adjacent normal tissues it was 0%. In comparison to adjacent normal tissues, CRC tissues had increased Glut1, TGF‐β1, PI3K, AKT, mTOR, and Bcl‐2 expressions, and p‐PI3K, p‐S473‐AKT, p‐S389‐S6K1, and p‐T70‐4EBP1 expressions; and decreased PTEN, Bax, Cleaved caspase‐3, and Cleaved‐PARP expressions. In comparison with the blank and NC groups, cells in the shGlut1‐1 group showed decreased Glut1, TGF‐β1, PI3K, AKT, mTOR, and Bcl‐2 expressions, and p‐PI3K, p‐S473‐AKT, p‐S389‐S6K1, and p‐T70‐4EBP1 expressions; and increased PTEN, Bax, Cleaved caspase‐3, and Cleaved‐PARP expressions, along with more arrested cells in C0/C1 phase than in S phase and slower cell growth. These results suggested that silencing the Glut1 gene inhibited proliferation and promoted apoptosis of CRC cells by inactivating TGF‐β/PI3K‐AKT‐mTOR signaling pathway.
These results suggested that Glut1 gene silencing inhibits proliferation and promotes apoptosis of CRC cells by inactivating TGF‐β/PI3K‐AKT‐mTOR signaling pathway.
Summary
In acidic soils, aluminum (Al) toxicity is the main factor inhibiting plant root development and reducing crops yield. STOP1 (SENSITIVE TO PROTON RHIZOTOXICITY 1) was a critical factor in ...detoxifying Al stress. Under Al stress, STOP1 expression was not induced, although STOP1 protein accumulated, even in the presence of RAE1 (STOP1 DEGRADATION E3‐LIGASE). How the Al stress triggers and stabilises the accumulation of STOP1 is still unknown.
Here, we characterised SlSTOP1‐interacting zinc finger protein (SlSZP1) using a yeast‐two‐hybrid screening, and generated slstop1, slszp1 and slstop1/slszp1 knockout mutants using clustered regularly interspaced short palindromic repeats (CRISPR) in tomato.
SlSZP1 is induced by Al stress but it is not regulated by SlSTOP1. The slstop1, slszp1 and slstop1/slszp1 knockout mutants exhibited hypersensitivity to Al stress. The expression of SlSTOP1‐targeted genes, such as SlRAE1 and SlASR2 (ALUMINUM SENSITIVE), was inhibited in both slstop1 and slszp1 mutants, but not directly regulated by SlSZP1. Furthermore, the degradation of SlSTOP1 by SlRAE1 was prevented by SlSZP1. Al stress increased the accumulation of SlSTOP1 in wild‐type (WT) but not in slszp1 mutants. The overexpression of either SlSTOP1 or SlSZP1 did not enhance plant Al resistance.
Altogether, our results show that SlSZP1 is an important factor for protecting SlSTOP1 from SlRAE1‐mediated degradation.
Multijunction/tandem solar cells have naturally attracted great attention because they are not subject to the Shockley–Queisser limit. Perovskite solar cells are ideal candidates for the top cell in ...multijunction/tandem devices due to the high power conversion efficiency (PCE) and relatively low voltage loss. Herein, sandwiched gold nanomesh between MoO3 layers is designed as a transparent electrode. The large surface tension of MoO3 effectively improves wettability for gold, resulting in Frank–van der Merwe growth to produce an ultrathin gold nanomesh layer, which guarantees not only excellent conductivity but also great optical transparency, which is particularly important for a multijunction/tandem solar cell. The top MoO3 layer reduces the reflection at the gold layer to further increase light transmission. As a result, the semitransparent perovskite cell shows an 18.3% efficiency, the highest reported for this type of device. When the semitransparent perovskite device is mechanically stacked with a heterojunction silicon solar cell of 23.3% PCE, it yields a combined efficiency of 27.0%, higher than those of both the sub‐cells. This breakthrough in elevating the efficiency of semitransparent and multijunction/tandem devices can help to break the Shockley–Queisser limit.
The efficiencies of semitransparent perovskite device and four‐terminal perovskite/silicon multijunction/tandem solar cells rise to 18.3% and 27.0%, respectively. This is the highest recorded efficiency for semitransparent perovskite solar cells thus far. The high efficiencies originate from good transparency and high conductivity of the nanomesh‐structured gold top electrode.
Recent advances in deep learning for medical image segmentation demonstrate expert-level accuracy. However, application of these models in clinically realistic environments can result in poor ...generalization and decreased accuracy, mainly due to the domain shift across different hospitals, scanner vendors, imaging protocols, and patient populations etc. Common transfer learning and domain adaptation techniques are proposed to address this bottleneck. However, these solutions require data (and annotations) from the target domain to retrain the model, and is therefore restrictive in practice for widespread model deployment. Ideally, we wish to have a trained (locked) model that can work uniformly well across unseen domains without further training. In this paper, we propose a deep stacked transformation approach for domain generalization. Specifically, a series of {n} stacked transformations are applied to each image during network training. The underlying assumption is that the "expected" domain shift for a specific medical imaging modality could be simulated by applying extensive data augmentation on a single source domain, and consequently, a deep model trained on the augmented "big" data (BigAug) could generalize well on unseen domains. We exploit four surprisingly effective, but previously understudied, image-based characteristics for data augmentation to overcome the domain generalization problem. We train and evaluate the BigAug model (with {n}={9} transformations) on three different 3D segmentation tasks (prostate gland, left atrial, left ventricle) covering two medical imaging modalities (MRI and ultrasound) involving eight publicly available challenge datasets. The results show that when training on relatively small dataset (n = 10~32 volumes, depending on the size of the available datasets) from a single source domain: (i) BigAug models degrade an average of 11%(Dice score change) from source to unseen domain, substantially better than conventional augmentation (degrading 39%) and CycleGAN-based domain adaptation method (degrading 25%), (ii) BigAug is better than "shallower" stacked transforms (i.e. those with fewer transforms) on unseen domains and demonstrates modest improvement to conventional augmentation on the source domain, (iii) after training with BigAug on one source domain, performance on an unseen domain is similar to training a model from scratch on that domain when using the same number of training samples. When training on large datasets (n = 465 volumes) with BigAug, (iv) application to unseen domains reaches the performance of state-of-the-art fully supervised models that are trained and tested on their source domains. These findings establish a strong benchmark for the study of domain generalization in medical imaging, and can be generalized to the design of highly robust deep segmentation models for clinical deployment.
Microgrids can effectively integrate distributed generation (DG) to supply power to local loads. However, uncertainties from renewable DG and loads may lead to increased operating costs or operating ...constraint violations. To solve these issues, this paper proposes a two-stage coordination approach of price-based demand response (PBDR) and battery energy storage systems (BESSs) to minimize the total operating cost and enhance operational reliability. In the first stage, day-ahead PBDR is scheduled, aiming to shift loads to improve renewable energy utilization efficiency. Considering limited prediction horizon of uncertainties when dispatching BESSs, hourly state of charge (SoC) limits are also optimized over the whole-day horizon with consideration of BESS degradation cost in the day-ahead stage. Then in the second stage, the BESSs are dispatched hourly within the optimized SoC limits to track uncertainty realization and compensate the first-stage PBDR decisions. Furthermore, a two-stage interval optimization (TSIO) method is proposed to formulate the problem. Accordingly, a solution algorithm is developed to coordinately solve the two operation stages under the uncertainties. The proposed coordination approach is verified with uncertainty realization scenarios. The results indicate the high energy utilization efficiency and strong operational reliability of the proposed coordination approach.
The MYC oncogene is overexpressed in hepatocellular carcinoma (HCC) and has been associated with widespread microRNA (miRNA) repression; however, the underlying mechanisms are largely unknown. Here, ...we report that the c‐Myc oncogenic transcription factor physically interacts with enhancer of zeste homolog 2 (EZH2), a core enzymatic unit of polycomb repressive complex 2 (PRC2). Furthermore, miR‐101, an important tumor‐suppressive miRNA in human hepatocarcinomas, is epigenetically repressed by PRC2 complex in a c‐Myc‐mediated manner. miR‐101, in turn, inhibits the expression of two subunits of PRC2 (EZH2 and EED), thus creating a double‐negative feedback loop that regulates the process of hepatocarcinogenesis. Restoration of miR‐101 expression suppresses multiple malignant phenotypes of HCC cells by coordinate repression of a cohort of oncogenes, including STMN1, JUNB, and CXCR7, and further increases expression of endogenous miR‐101 by inhibition of PRC2 activation. In addition, co‐overexpression of c‐Myc and EZH2 in HCC samples was closely associated with lower expression of miR‐101 (P < 0.0001) and poorer prognosis of HCC patients (P < 0.01). Conclusions: c‐Myc collaborates with EZH2‐containing PRC2 complex in silencing tumor‐suppressive miRNAs during hepatocarcinogenesis and provides promising therapeutic candidates for human HCC. (Hepatology 2014;59:1850–1863)
The ruminants are one of the most successful mammalian lineages, exhibiting morphological and habitat diversity and containing several key livestock species. To better understand their evolution, we ...generated and analyzed de novo assembled genomes of 44 ruminant species, representing all six Ruminantia families. We used these genomes to create a time-calibrated phylogeny to resolve topological controversies, overcoming the challenges of incomplete lineage sorting. Population dynamic analyses show that population declines commenced between 100,000 and 50,000 years ago, which is concomitant with expansion in human populations. We also reveal genes and regulatory elements that possibly contribute to the evolution of the digestive system, cranial appendages, immune system, metabolism, body size, cursorial locomotion, and dentition of the ruminants.
In this paper, the passivity for multiple state or spatial diffusion coupled parabolic complex networks (PCNs) with and without control input constraint are considered. Firstly, we investigate the ...passivity of multiple state coupled PCNs without control input constraint, and some relevant criteria are derived by devising suitable boundary controller and making use of Lyapunov function method. What is more, the control input constraint for multiple state coupled PCNs is also taken into account, and several sufficient conditions are also derived so as to assure the existence of the boundary controller. In addition, the passivity of multiple spatial diffusion coupled PCNs with and without control input constraint is also investigated. Finally, two simulation examples are presented to verify the validity of the obtained criteria.
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with an increasing case number and extensive geographical expansion, raising concerns locally and globally; ...however, the description of its clinical features needs to be addressed by large studies. We aimed to determine all the clinical features of SFTS in a large population of patients in an endemic area.
In this prospective observational study, data were collected on patients admitted to the People's Liberation Army Hospital in Xinyang, Henan Province, China, with laboratory-diagnosed SFTS. Demographic, clinical, laboratory, and treatment data were collected for each patient, and patients were followed up within 2 weeks after discharge or discontinuation of treatment. The association between each demographic, clinical, and laboratory variable with a fatal outcome was assessed. A clinical scoring model was designed for the early prediction of a fatal outcome, and the effect of treatment on outcome was analysed.
Between April 1, 2011, and Oct 31, 2017, 2096 patients with laboratory-confirmed SFTS were admitted. Mean age at admission was 61·4 years (SD 12·2) and 1239 (59%) patients were female. The case fatality rate (CFR) was 16·2% (95% CI 14·6–17·8). A higher risk was associated with being male (unadjusted odds ratio OR 1·45, 95% CI 1·15–1·83; p=0·002), older age (for a 10-year increase, unadjusted OR 1·82, 95% CI 1·62–2·04; p<0·0001), longer delay in admission (for every extra day taken before admission to hospital, unadjusted OR 1·18, 1·12–1·24; p<0·0001), presence of diarrhoea (adjusted OR 1·44, 1·12–1·87; p=0·005) or dyspnoea (adjusted OR 8·35, 5·97–11·69; p<0·0001), and development of haemorrhagic signs (adjusted OR 2·79, 95% CI 2·18–3·57; p<0·0001) or neurological symptoms (adjusted OR 30·26, 21·39–42·81; p<0·0001). Laboratory variables that were associated with death included abnormal concentrations of lactate dehydrogenase, aspartate aminotransferase, and blood urea nitrogen, and abnormal neutrophil percentage, which together with age and neurological symptoms were combined in the clinical scoring system. A total score of more than 8 was the optimal threshold to predict risk of death for patients who were evaluated within 6 days after symptom onset (area under the curve 0·879, 95% CI 0·855–0·902). For all participants, viraemia was a strong predictor of fatal outcome (all p<0·0001). Ribavirin therapy was effective in reducing CFR from 6·25% (15 of 240 participants) to 1·16% (two of 173 participants), but only in patients with a viral load below 1×106 copies per mL (hazard ratio 9·72, 95% CI 1·30–72·87; p=0·027).
The changing epidemiological features and high CFR of SFTS underscore the necessity of continued surveillance. Early prediction of fatal outcome can be attained by monitoring of clinical and laboratory data. Ribavirin should be applied early, with best results achieved before the viral load reaches 1 × 106 copies per mL.
National Natural Science Foundation of China.
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