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Jie He and colleagues report exome sequencing of 113 tumor-normal pairs of esophageal squamous cell carcinoma. They highlight mutations in genes involved in cell cycle and apoptosis regulation, histone modifier genes and genes encoding members of the Hippo and Notch pathways. Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers 1 . We performed exome sequencing on 113 tumor-normal pairs, yielding a mean of 82 non-silent mutations per tumor, and 8 cell lines. The mutational profile of ESCC closely resembles those of squamous cell carcinomas of other tissues but differs from that of esophageal adenocarcinoma. Genes involved in cell cycle and apoptosis regulation were mutated in 99% of cases by somatic alterations of TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%). Histone modifier genes were frequently mutated, including KMT2D (also called MLL2 ; 19%), KMT2C ( MLL3 ; 6%), KDM6A (7%), EP300 (10%) and CREBBP (6%). EP300 mutations were associated with poor survival. The Hippo and Notch pathways were dysregulated by mutations in FAT1 , FAT2 , FAT3 or FAT4 (27%) or AJUBA ( JUB ; 7%) and NOTCH1 , NOTCH2 or NOTCH3 (22%) or FBXW7 (5%), respectively. These results define the mutational landscape of ESCC and highlight mutations in epigenetic modulators with prognostic and potentially therapeutic implications.

Background Sugarcane is the most important sugar crop, contributing > 80% of global sugar production. High sucrose content is a key target of sugarcane breeding, yet sucrose improvement in sugarcane remains extremely slow for decades. Molecular breeding has the potential to break through the genetic bottleneck of sucrose improvement. Dissecting the molecular mechanism(s) and identifying the key genetic elements controlling sucrose accumulation will accelerate sucrose improvement by molecular breeding. In our previous work, a proteomics dataset based on 12 independent samples from high- and low-sugar genotypes treated with ethephon or water was established. However, in that study, employing conventional analysis, only 25 proteins involved in sugar metabolism were identified . Results In this work, the proteomics dataset used in our previous study was reanalyzed by three different statistical approaches, which include a logistic marginal regression, a penalized multiple logistic regression named Elastic net, as well as a Bayesian multiple logistic regression method named Stochastic search variable selection (SSVS) to identify more sugar metabolism-associated proteins. A total of 507 differentially abundant proteins (DAPs) were identified from this dataset, with 5 of them were validated by western blot. Among the DAPs, 49 proteins were found to participate in sugar metabolism-related processes including photosynthesis, carbon fixation as well as carbon, amino sugar, nucleotide sugar, starch and sucrose metabolism. Based on our studies, a putative network of key proteins regulating sucrose accumulation in sugarcane is proposed, with glucose-6-phosphate isomerase, 2-phospho-D-glycerate hydrolyase, malate dehydrogenase and phospho-glycerate kinase, as hub proteins. Conclusions The sugar metabolism-related proteins identified in this work are potential candidates for sucrose improvement by molecular breeding. Further, this work provides an alternative solution for omics data processing.

Abnormal migration of vascular smooth muscle cells (VSMCs) from the media to the interior is a critical process during the intimal restenosis caused by vascular injury. Here, we determined the role of platelet-derived microvesicles (PMVs) released by activated platelets in VSMC migration. A percutaneous transluminal angioplasty balloon dilatation catheter was used to establish vascular intimal injury. Collagen I was used to activate PMVs, mimicking collagen exposure during intimal injury. To determine the effects of PMVs on VSMC migration , scratch wound healing assays were performed. Fluorescence resonance energy transfer was used to detect variations of calcium dynamics in VSMCs. Morphological results showed that neointimal hyperplasia was markedly increased after balloon injury of the carotid artery in rats, and the main component was VSMCs. PMVs significantly promoted single cell migration and wound closure . Fluorescence resonance energy transfer revealed that PMVs induced temporal and dynamic calcium oscillations in the cytoplasms of VSMCs. The influx of extracellular calcium, but not calcium from intracellular stores, was involved in the process described above. The channel antagonist GSK219 and specific siRNA revealed that a membrane calcium channel, transient receptor potential vanilloid 4 (TRPV4), participated in the calcium oscillations and VSMC migration induced by PMVs. TRPV4 participated in the calcium oscillations and VSMC migration induced by PMVs. PMVs and the related molecules might be novel therapeutic targets for vascular remodeling during vascular injury.

Quantifying emesis in Suncus murinus ( S. murinus ) has traditionally relied on direct observation or reviewing recorded behaviour, which are laborious, time-consuming processes that are susceptible to operator error. With rapid advancements in deep learning, automated animal behaviour quantification tools with high accuracy have emerged. In this study, we pioneere the use of both three-dimensional convolutional neural networks and self-attention mechanisms to develop the Automatic Emesis Detection (AED) tool for the quantification of emesis in S. murinus , achieving an overall accuracy of 98.92%. Specifically, we use motion-induced emesis videos as training datasets, with validation results demonstrating an accuracy of 99.42% for motion-induced emesis. In our model generalisation and application studies, we assess the AED tool using various emetics, including resiniferatoxin, nicotine, copper sulphate, naloxone, U46619, cyclophosphamide, exendin-4, and cisplatin. The prediction accuracies for these emetics are 97.10%, 100%, 100%, 97.10%, 98.97%, 96.93%, 98.91%, and 98.41%, respectively. In conclusion, employing deep learning-based automatic analysis improves efficiency and accuracy and mitigates human bias and errors. Our study provides valuable insights into the development of deep learning neural network models aimed at automating the analysis of various behaviours in S. murinus , with potential applications in preclinical research and drug development. The Automatic Emesis Detection (AED) tool uses deep learning to quantify emesis in Suncus murinus with high accuracy, reducing human error and enhancing efficiency, offering potential for preclinical research and drug development.

The arterial mechanical microenvironment, including stiffness, is a crucial pathophysiological feature of vascular remodeling, such as neointimal hyperplasia after carotid endarterectomy and balloon dilatation surgeries. In this study, we examined changes in neointimal stiffness in a Sprague-Dawley rat carotid artery intimal injury model and revealed that extracellular matrix (ECM) secretion and vascular stiffness were increased. Once the endothelial layer is damaged in vivo , activated platelets adhere to the intima and may secrete platelet-derived extracellular vesicles (pEVs) and communicate with vascular smooth muscle cells (VSMCs). In vitro , pEVs stimulated VSMCs to promote collagen secretion and cell adhesion. MRNA sequencing analysis of a carotid artery intimal injury model showed that ECM factors, including col8a1, col8a2, col12a1, and elastin, were upregulated. Subsequently, ingenuity pathway analysis (IPA) was used to examine the possible signaling pathways involved in the formation of ECM, of which the Akt pathway played a central role. In vitro , pEVs activated Akt signaling through the PIP 3 pathway and induced the production of Col8a1. MicroRNA (miR) sequencing of pEVs released from activated platelets revealed that 14 of the top 30 miRs in pEVs targeted PTEN, which could promote the activation of the Akt pathway. Further research showed that the most abundant miR targeting PTEN was miR-92a-3p, which promoted Col8a1 expression. Interestingly, knockdown of Col8a1 expression in vivo abrogated the increase in carotid artery stiffness and simultaneously increased the degree of neointimal hyperplasia. Our results revealed that pEVs may deliver miR-92a-3p to VSMCs to induce the production and secretion of Col8a1 via the PTEN/PIP3/Akt pathway, subsequently increasing vascular stiffness. Therefore, pEVs and key molecules may be potential therapeutic targets for treating neointimal hyperplasia.

Phenotypic switch of vascular smooth muscle cells (VSMCs) is important in vascular remodeling which causes hyperplasia and restenosis after intimal injury. Platelets are activated at injured intima and secrete platelet-derived microvesicles (PMVs). Herein, we demonstrated the role of PMVs in VSMC phenotypic switch and the potential underlying mechanisms. In vivo , platelets were locally adhered and activated at intimal injury site, while Lamtor1 was promoted and VSMCs were dedifferentiated. PMVs, collected from collagen-activated platelets in vitro which mimicked collagen exposure during intimal injury, promoted VSMC dedifferentiation, induced Lamtor1 expression, and activated mTORC1 signaling, reflected by the phosphorylation of two downstream targets, i.e., S6K and 4E-BP1. Knockdown of Lamtor1 with small interfering RNA attenuated these processes induced by PMVs. Based on the previously published proteomic data, Ingenuity Pathway Analysis revealed that Src may participate in regulating effects of PMVs. Src inhibitor significantly reversed the effects of PMVs on VSMC dedifferentiation, Lamtor1 expression and mTORC1 activation. Furthermore, in SMC-specific Lamtor1 knockout mice, intimal hyperplasia was markedly attenuated after intimal injury compared with the wild type. Our data suggested that PMVs secreted by activated platelets promoted VSMC dedifferentiation via Src/Lamtor1/mTORC1 signaling pathway. Lamtor1 may be a potential therapeutic target for intimal hyperplasia after injury.

The evolution of cloud computing towards X-as-a-Service models and the adoption of microservices architecture have significantly matured the field. As these technologies advance, they bring challenges such as data consistency, transaction traceability, and efficient information processing, particularly in edge computing environments. This paper explores the integration of microservices architecture, edge computing, and blockchain technology to address these challenges, with a focus on secure file sharing. We present a framework that uses identity authentication and leverages Ethereum blockchain, IPFS, and HDFS for decentralized, tamper-resistant file sharing. Our implementation in the FsMbe system fetches data using the DHT of the distributed network after authentication by Ethereum and employs multi-round AES encryption for data sharing. Extensive experiments were conducted to evaluate our framework’s performance in various scenarios, including small data communication between microservices in edge groups and large file transfers between edge nodes in larger groups. The framework demonstrated stable data transfer performance, particularly for small payloads, even as the number of clients increased. This research contributes to secure and efficient data management in edge computing and microservice environments, providing a robust solution for decentralized file sharing with enhanced performance and security.

In this study, we examined the cyclic stability of Prussian blue (PB) films in electrolytes with acid. The cyclic stabilities of the PB films were investigated in K+ based electrolytes with different values of solution pH. The acidified KCl solution can significantly improve the durability of the film. Among the three pH values tested, the KCl solutions (pH = 2.15 and pH = 3.03) showed better performance. Furthermore, we investigated the cyclic stabilities of the PB films in LiClO4/PC electrolyte containing different acids. We found that the cyclic stability of PB film was significantly improved when a small amount of acetic acid was dissolved in LiClO4/PC electrolyte. The PB film exhibited stable optical modulation after up to 20,000 cycles in LiClO4/PC electrolyte containing acetic acid—a much higher result than those of some literatures. This suggests that the addition of acetic acid to LiClO4/PC electrolyte can promote the development of PB-based devices with improved stability.

BACKGROUND: Partial pressure of end-tidal carbon dioxide(PETCO2) has been used to monitor the effectiveness of precordial compression(PC) and regarded as a prognostic value of outcomes in cardiopulmonary resuscitation(CPR). This study was to investigate changes of PETCO2 during CPR in rats with ventricular fi brillation(VF) versus asphyxial cardiac arrest.METHODS: Sixty-two male Sprague-Dawley(SD) rats were randomly divided into an asphyxial group(n=32) and a VF group(n=30). PETCO2 was measured during CPR from a 6-minute period of VF or asphyxial cardiac arrest.RESULTS: The initial values of PETCO2 immediately after PC in the VF group were signifi cantly lower than those in the asphyxial group(12.8±4.87 mmHg vs. 49.2±8.13 mmHg, P=0.000). In the VF group, the values of PETCO2 after 6 minutes of PC were significantly higher in rats with return of spontaneous circulation(ROSC), compared with those in rats without ROSC(16.5±3.07 mmHg vs. 13.2±2.62 mmHg, P=0.004). In the asphyxial group, the values of PETCO2 after 2 minutes of PC in rats with ROSC were signifi cantly higher than those in rats without ROSC(20.8±3.24 mmHg vs. 13.9±1.50 mmHg, P=0.000). Receiver operator characteristic(ROC) curves of PETCO2 showed signifi cant sensitivity and specifi city for predicting ROSC in VF versus asphyxial cardiac arrest.CONCLUSIONS: The initial values of PETCO2 immediately after CPR may be helpful in differentiating the causes of cardiac arrest. Changes of PETCO2 during CPR can predict outcomes of CPR.

Aim： To investigate the effects of mesenchymal stem cells （MSCs） transplantation on rat global cerebral ischemia and the underlying mechanisms. Methods： Adult male SD rats underwent asphxial cardiac arrest to induce global cerebral ischemia, then received intravenous injection of 5×10^6 cultured MSCs of SD rats at 2 h after resuscitation. In another group of cardiac arrest rats, tumor necrosis factor-α-induced protein 6 （TSG-6, 6 pg） was injected into the right lateral ventricle. Functional outcome was assessed at 1, 3, and 7 d after resuscitation. Donor MSCs in the brains were detected at 3 d after resuscitation. The level of serum S-IOOB and proinflammatory cytokines in cerebral cortex were assayed using ELISA. The expression of TSG-6 and proinflammatory cytokines in cerebral cortex was assayed using RT-PCR. Western blot was performed to determine the levels of TSG-6 and neutrophil elastase in cerebral cortex. Results： MSCs transplantation significantly reduced serum S-100B level, and improved neurological function after global cerebral ischemia compared to the PBS-treated group. The MSCs injected migrated into the ischemic brains, and were observed mainly in the cerebral cortex. Furthermore, MSCs transplantation significantly increased the expression of TSG-6, and reduced the expression of neutrophil elastase and proinflammatory cytokines in the cerebral cortex. Intracerebroventricular injection of TSG-6 reproduced the beneficial effects of MSCs transplantation in rats with global cerebral ischemia. Conclusion： MSCs transplantation improves functional recovery and reduces inflammatory responses in rats with global cerebral ischemia, maybe via upregulation of TSG-6 expression.