Metalloproteinase expression in venous aneurysms

IntroductionAlthough recognized with increasing frequency, the pathogenesis of venous aneurysms (VA) remains poorly understood. We evaluated 8 patients with 10 VA for the presence, localization and activity of metalloproteinases (MMPs).MethodsTissue specimens from VA (n=8), normal saphenous vein (NSV n=7) and varicose veins (VV n=7 were compared by histology and immunohistochemistry (IHC). Histologic sections were stained with H&E, Movats pentachrome and toluidine blue, and IHC specimens with antibodies to CD68, MMP2, MMP9, and MMP13. Protein expression and enzyme activity were determined by Western immunoblotting and zymography.ResultsThree of 4 patients with popliteal VA presented with edema and leg pain and the remaining patient with deep venous thrombosis (DVT) and pulmonary embolism (PE). The 5 popliteal VA were treated by; excision and reanastomosis (n=2) lateral venorrhaphy (n=2) and spiral saphenous vein graft (n=1). The 3 patients with 4 upper extremity VA had discomfort over a compressible mass. Two of the VA were excised and the remaining patients aneurysm ruptured spontaneously. The mesenteric VA, an incidental finding at laparotomy was excised. Thrombus was present in 2 popliteal, 1 upper extremity and in the mesenteric aneurysm. Histologically, VA and VV were characterized by fragmentation of the elastic lamellae, loss of smooth muscle cells (SMCs) and attenuation of the venous wall when compared to NSV. Varicose veins and VA also demonstrated increased expression of MMP-2, MMP-9 and MMP-13 in endothelial cells (ECs), SMCs and adventitial microvessels compared to NSV. Both pro-MMP-2 and pro-MMP-9 were detected by zymography in VA,VV and NSV but only MMP-2 activity was demonstrable.ConclusionsThe structural changes in the venous wall in addition to the increased expression of MMP-2, MMP-9 and MMP-13 in VA compared to NSV and VV suggests a possible causal role for these MMPs in their pathogenesis

RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome

韩家淮教授课题组的这项研究揭示了活性氧簇（ROS）通过直接特异地氧化受体相互作用丝氨酸/苏氨酸激酶1（RIP1）上的三个关键的半胱氨酸，进而特异地增强RIP1在S161上的自磷酸化，从而促进坏死小体的形成和程序性细胞坏死的发生。证实了RIP1的激酶活性在程序性细胞坏死中的主要功能是自磷酸化S161，且S161就是人们长期寻找的RIP1上与坏死相关的功能性磷酸化位点。坏死小体的形成是程序性细胞坏死发生的必要复合物，而S161的磷酸化是RIP1有效募集RIP3形成有功能的坏死小体所必需的。由于ROS的产生依赖于坏死小体里的RIP3的功能，因此ROS介导了程序性坏死通路里的正反馈调控。研究阐明了ROS促进程序性细胞坏死的分子机制，回答了领域内长期存在的两个科学问题，对全面解析程序性坏死机制并协助疾病治疗具有重要意义。 张荧荧和苏晟为该论文的共同第一作者。该项研究得到了973计划和国家自然科学基金委员会重点和重大研究计划项目的经费支持。【Abstract】Necroptosis is a type of programmed cell death with great significance in many pathological processes. Tumour necrosis factor-a(TNF), a proinflammatory cytokine, is a prototypic trigger of necroptosis. It is known that mitochondrial reactive oxygen species (ROS) promote necroptosis, and that kinase activity of receptor interacting protein 1 (RIP1) is required for TNF-induced necroptosis. However, how ROS function and what RIP1 phosphorylates to promote necroptosis are largely unknown. Here we show that three crucial cysteines in RIP1 are required for sensing ROS, and ROS subsequently activates RIP1 autophosphorylation on serine residue 161 (S161). The major function of RIP1 kinase activity in TNF-induced necroptosis is to autophosphorylate S161. This specific phosphorylation then enables RIP1 to recruit RIP3 and form a functional necrosome, a central controller of necroptosis. Since ROS induction is known to require necrosomal RIP3, ROS therefore function in a positive feedback circuit that ensures effective induction of necroptosis.This work was supported by the National Natural Science Foundation of China (91029304, 31420103910, 31330047 and 81630042), the National Basic Research Program of China (973 Program; 2015CB553800, 2013CB944903, 2014CB541804), the 111 Project (B12001), the National Science Foundation of China for Fostering Talents in Basic Research (J1310027)

Ferroptosis-related lncRNA signature predicts prognosis and immunotherapy efficacy in cutaneous melanoma

PurposeFerroptosis-related lncRNAs are promising biomarkers for predicting the prognosis of many cancers. However, a ferroptosis-related signature to predict the prognosis of cutaneous melanoma (CM) has not been identified. The purpose of this study was to construct a ferroptosis-related lncRNA signature to predict prognosis and immunotherapy efficacy in CM.MethodsFerroptosis-related differentially expressed genes (FDEGs) and lncRNAs (FDELs) were identified using TCGA, GTEx, and FerrDb datasets. We performed Cox and LASSO regressions to identify key FDELs, and constructed a risk score to stratify patients into high- and low-risk groups. The lncRNA signature was evaluated using the areas under the receiver operating characteristic curves (AUCs) and Kaplan-Meier analyses in the training, testing, and entire cohorts. Multivariate Cox regression analyses including the lncRNA signature and common clinicopathological characteristics were performed to identify independent predictors of overall survival (OS). A nomogram was developed for clinical use. We performed gene set enrichment analyses (GSEA) to identify significantly enriched pathways. Differences in the tumor microenvironment (TME) between the 2 groups were assessed using 7 algorithms. To predict the efficacy of immune checkpoint inhibitors (ICI), we analyzed the association between PD1 and CTLA4 expression and the risk score. Finally, differences in Tumor Mutational Burden (TMB) and molecular drugs Sensitivity between the 2 groups were performed.ResultsWe identified 5 lncRNAs (AATBC, AC145423.2, LINC01871, AC125807.2, and AC245041.1) to construct the risk score. The AUC of the lncRNA signature was 0.743 in the training cohort and was validated in the testing and entire cohorts. Kaplan-Meier analyses revealed that the high-risk group had poorer prognosis. Multivariate Cox regression showed that the lncRNA signature was an independent predictor of OS with higher accuracy than traditional clinicopathological features. The 1-, 3-, and 5-year survival probabilities for CM patients were 92.7%, 57.2%, and 40.2% with an AUC of 0.804, indicating a good accuracy and reliability of the nomogram. GSEA showed that the high-risk group had lower ferroptosis and immune response. TME analyses confirmed that the high-risk group had lower immune cell infiltration (e.g., CD8+ T cells, CD4+ memory-activated T cells, and M1 macrophages) and lower immune functions (e.g., immune checkpoint activation). Low-risk patients whose disease expressed PD1 or CTLA4 were likely to respond better to ICIs. The analysis demonstrated that the TMB had significantly difference between low- and high- risk groups. Chemotherapy drugs, such as sorafenib, Imatinib, ABT.888 (Veliparib), Docetaxel, and Paclitaxel showed Significant differences in the estimated IC50 between the two risk groups.ConclusionOur novel ferroptosis-related lncRNA signature was able to accurately predict the prognosis and ICI outcomes of CM patients. These ferroptosis-related lncRNAs might be potential biomarkers and therapeutic targets for CM

Repair and Reconstruction of a Resected Tumor Defect Using a Composite of Tissue Flap–Nanotherapeutic–Silk Fibroin and Chitosan Scaffold

A multifaceted strategy using a composite of anti-cancer nanotherapeutic and natural biomaterials silk fibroin (SF) and chitosan (CS) blend scaffolds was investigated for the treatment of a tissue defect post-tumor resection by providing local release of the therapeutic and filling of the defect site with the regenerative bioscaffolds. The scaffold-emodin nanoparticle composites were fabricated and characterized for drug entrapment and release, mechanical strength, and efficacy against GILM2 breast cancer cells in vitro and in vivo in a rat tumor model. Emodin nanoparticles were embedded in SF and SFCS scaffolds and the amount of emodin entrapment was a function of the scaffold composition and emodin loading concentration. In vitro, there was a burst release of emodin from all scaffolds during the first 2 days though it was detected even after 24 days. Increase in emodin concentration in the scaffolds decreased the overall elastic modulus and ultimate tensile strength of the scaffolds. After 6 weeks of in vivo implantation, the cell density (p < 0.05) and percent degradation (p < 0.01) within the remodeled no emodin SFCS scaffold was significantly higher than the emodin loaded SFCS scaffolds, although there was no significant difference in the amount of collagen deposition in the regenerated SFCS scaffold. The presence and release of emodin from the SFCS scaffolds inhibited the integration of SFCS into the adjacent tumor due to the formation of an interfacial barrier of connective tissue that was lacking in emodin-free SFCS scaffolds. While no significant difference in tumor size was observed between the in vivo tested groups, tumors treated with emodin loaded SFCS scaffolds had decreased presence and size and similar regeneration of new tissue as compared to no emodin SFCS scaffolds

Enhancing cloud-based IoT security through trustworthy cloud service: An integration of security and reputation approach

The Internet of Things (IoT) provides a new paradigm for the development of heterogeneous and distributed systems, and it has increasingly become a ubiquitous computing service platform. However, due to the lack of sufficient computing and storage resources dedicated to the processing and storage of huge volumes of the IoT data, it tends to adopt a cloud-based architecture to address the issues of resource constraints. Hence, a series of challenging security and trust concerns have arisen in the cloud-based IoT context. To this end, a novel trust assessment framework for the security and reputation of cloud services is proposed. This framework enables the trust evaluation of cloud services in order to ensure the security of the cloud-based IoT context via integrating security- and reputation-based trust assessment methods. The security-based trust assessment method employs the cloud-specific security metrics to evaluate the security of a cloud service. Furthermore, the feedback ratings on the quality of cloud service are exploited in the reputation-based trust assessment method in order to evaluate the reputation of a cloud service. The experiments conducted using a synthesized dataset of security metrics and a real-world web service dataset show that our proposed trust assessment framework can efficiently and effectively assess the trustworthiness of a cloud service while outperforming other trust assessment methods.The Internet of Things (IoT) provides a new paradigm for the development of heterogeneous and distributed systems, and it has increasingly become a ubiquitous computing service platform. However, due to the lack of sufficient computing and storage resources dedicated to the processing and storage of huge volumes of the IoT data, it tends to adopt a cloud-based architecture to address the issues of resource constraints. Hence, a series of challenging security and trust concerns have arisen in the cloud-based IoT context. To this end, a novel trust assessment framework for the security and reputation of cloud services is proposed. This framework enables the trust evaluation of cloud services in order to ensure the security of the cloud-based IoT context via integrating security- and reputation-based trust assessment methods. The security-based trust assessment method employs the cloud-specific security metrics to evaluate the security of a cloud service. Furthermore, the feedback ratings on the quality of cloud service are exploited in the reputation-based trust assessment method in order to evaluate the reputation of a cloud service. The experiments conducted using a synthesized dataset of security metrics and a real-world web service dataset show that our proposed trust assessment framework can efficiently and effectively assess the trustworthiness of a cloud service while outperforming other trust assessment methods

Analysis and research on the fault-tolerant performance of the high-frequency isolated energy conversion link for an integrated distribution transformer system

In order to enhance the stability of the integrated distribution transformer system (IDTS), a fault-tolerant topology of the high-frequency (HF) isolated energy conversion link which features a multi-winding HF transformer and two multi-arm converters are proposed in this paper. The operation process of the HF-isolated energy conversion link with an open-circuit fault in the power electronic switching devices is analysed in detail, and the fault characteristics are researched. Through modifying the operation modes of the proposed topology, the damaged part of the circuit can be replaced with the redundant transformer windings and bridge arms, maintaining the continuous operation of the IDTS. The theoretical analyses are verified by the simulated operation waveforms

Differential roles of CaMKII isoforms in phase separation with NMDA receptors and in synaptic plasticity

Summary: Calcium calmodulin-dependent kinase II (CaMKII) is critical for synaptic transmission and plasticity. Two major isoforms of CaMKII, CaMKIIα and CaMKIIβ, play distinct roles in synaptic transmission and long-term potentiation (LTP) with unknown mechanisms. Here, we show that the length of the unstructured linker between the kinase domain and the oligomerizing hub determines the ability of CaMKII to rescue the basal synaptic transmission and LTP defects caused by removal of both CaMKIIα and CaMKIIβ (double knockout [DKO]). Remarkably, although CaMKIIβ binds to GluN2B with a comparable affinity as CaMKIIα does, only CaMKIIα with the short linker forms robust dense clusters with GluN2B via phase separation. Lengthening the linker of CaMKIIα with unstructured “Gly-Gly-Ser” repeats impairs its phase separation with GluN2B, and the mutant enzyme cannot rescue the basal synaptic transmission and LTP defects of DKO mice. Our results suggest that the phase separation capacity of CaMKII with GluN2B is critical for its cellular functions in the brain

Soft start-up scheme for the hybrid distribution transformer

Hybrid distribution transformer (HDT) is an integrated system of the conventional distribution transformer and the PWM converters, which can greatly enhance the controllability of the conventional distribution transformer and is important for the intelligence of the future distribution network, since HDT can support the AC–DC power network and control the voltage and current in real time. However, the impact current, over voltage, and saturation will lead to the start-up failure when an incorrect start-up scheme is adopted in HDT. Therefore, it is significant to design a reliable start-up scheme to guarantee a safe operation for HDT. Here, a three-phase circuit scheme and the control system of HDT are proposed. Then, a soft start-up scheme that can realise the constant-current charging for the DC bus capacitor is proposed. Specifically, the soft start-up scheme is based on the following measures, bypassing the DC-bus current-limiting resistors when the voltage of DC-bus capacitor exceeds the threshold, limiting the output of PI controllers during the start-up, separating the integral coefficient according to the DC-bus voltage error. Finally, the proposed start-up scheme is verified in MATLAB, which lays the foundation for the optimal design of the start-up scheme of HDT

Insulin-Loaded Soybean Trypsin Inhibitor-Chitosan Nanoparticles: Preparation, Characterization, and Protective Effect Evaluation

The aim of this work was to prepare insulin-loaded nanoparticles using soybean trypsin inhibitor (STI) and chitosan (CS) as a potential coating. The nanoparticles were prepared by complex coacervation, and characterized for their particle size, polydispersity index (PDI), and encapsulation efficiency. In addition, the insulin release and enzymatic degradation of nanoparticles in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) were evaluated. The results showed that the optimal conditions for preparing insulin-loaded soybean trypsin inhibitor-chitosan (INs-STI-CS) nanoparticles were as follows: CS concentration of 2.0 mg/mL, STI concentration of 1.0 mg/mL, and pH 6.0. The INs-STI-CS nanoparticles prepared at this condition had a high insulin encapsulation efficiency of 85.07%, the particle diameter size was 350 ± 5 nm, and the PDI value was 0.13. The results of the in vitro evaluation of simulated gastrointestinal digestion showed that the prepared nanoparticles could improve the stability of insulin in the gastrointestinal tract. Compared with free insulin, the insulin loaded in INs-STI-CS nanoparticles was retained at 27.71% after 10 h of digestion in the intestinal tract, while free insulin was completely digested. These findings will provide a theoretical basis for improving the stability of oral insulin in the gastrointestinal tract