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Abstract: Exosomes, as nanoscale biological vesicles, have been shown to have great potential for biomedical applications. However, the low yield of exosomes limits their application. In this review, we focus on methods to increase exosome yield. Two main strategies are used to increase exosome production, one is based on genetic manipulation of the exosome biogenesis and release pathway, and the other is by pretreating parent cells, changing the culture method or adding different components to the medium. By applying these strategies, exosomes can be produced on a large scale to facilitate their practical application in the clinic.

Immune checkpoint inhibitors, a type of immunotherapy, have demonstrated optimal treatment efficacy in inducing durable antitumor responses in various cancers. Cytokine-release syndrome is a rare immune-related adverse event induced by immune checkpoint inhibitors. In our case, a patient with hypopharyngeal squamous cell carcinoma received toripalimab combined with chemotherapy. On the fourth day post treatment, the patient developed fever and hypotension. Laboratory examination indicated myelosuppression, acute kidney injury and disseminated intravascular coagulation. Meanwhile, serum cytokine levels of IL-6, IL-8, IL-10, IL-1β, IFN-γ and the level of hypersensitive C-reactive protein were markedly elevated. The patient was diagnosed with cytokine release syndrome, which progressed rapidly and led to the patient’s demise on the fifth day post treatment.

The first example of an acid-promoted difunctionalization of ketones to construct C–P and C–C bonds via a phospha-aldol-elimination is described under metal- and solvent-free conditions.

Due to the huge impact of temperature on mechanical and tribological properties of polymer composites, polyimide composites reinforced with glass fiber and aramid fiber were fabricated. The composites were treated by the alternate temperature from-50 °C to 150 °C with 200 cycles. The comparation of the test results were analyzed and discussed before and after alternate temperature treatment.

Shao-Long Chen,1 Hong Xiao,2 Guo-Jun Li,3 Yao-Jie Shen4 1Shulan International Medical College, Zhejiang Shuren University, Hangzhou, 310015, People’s Republic of China; 2Department of Infectious Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, People’s Republic of China; 3Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, 315100, People’s Republic of China; 4Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of ChinaCorrespondence: Shao-Long Chen, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, 310015, People’s Republic of China, Email chenshaolong@zjsru.edu.cnPurpose: Chronic hepatitis B virus (CHB) infection is a worldwide health problem. Polyethylene glycol (PEG)ylated interferon (PEG-IFN) is an available therapy for CHB that has antiviral and immunomodulatory effects. However, PEG-IFN therapy is limited by the fact that only a subset of patients show a sustained response, its severe side effects, and high cost. The aim of this study was to explore novel biomarkers for the early prediction of PEG-IFN treatment response and to uncover its underlying mechanism.Patients and Methods: We enrolled 10 paired patients with Hepatitis B e antigen (HBeAg)-positive CHB who received PEG-IFN-α 2a monotherapy. Patient serum samples were collected at 0, 4, 12, 24, and 48 weeks and serum samples were collected from eight healthy people as healthy controls. For confirmation, we enrolled 27 patients with HBeAg-positive CHB receiving PEG-IFN therapy and serum samples at 0 and 12 weeks were obtained. Serum samples were analyzed using Luminex technology.Results: Among 27 assessed cytokines, 10 cytokines were identified to have high expression levels. Among them, six cytokines had significant differences in their levels between the patients with HBeAg-positive CHB and the healthy controls (P < 0.05). Potentially, treatment response could be predicted using the early time points of 4, 12, and 24 weeks. Moreover, after 12 weeks of PEG-IFN treatment, increased levels of pro-inflammatory cytokines and decreased levels of anti-inflammatory cytokines were observed. The fold change of IP-10 between 12 weeks and 0 weeks correlated with the decrease in ALT levels from 0 to 12 weeks (r = 0.2675, P = 0.0024).Conclusion: In patients with CHB, we observed a certain pattern in the levels of cytokines during treatment with PEG-IFN, and the cytokine IP-10 might be a potential biomarker for treatment response.Keywords: chronic hepatitis B, PEGylated interferon, cytokine, chemokine, Luminex

Apolipoprotein E2 (ApoE2) is a pleiotropic protein that influences several aspects of cancer metabolism and development. Evading apoptosis is a vital factor for facilitating cancer cell growth. However, the role and mechanism of ApoE2 in regulating cell apoptosis of pancreatic cancer remain unclear.In this study, we firstly detected the mRNA and protein expressions of ApoE2 in PANC-1 and Capan-2 cells by real-time polymerase chain reaction and Western blotting. We then performed TUNEL and flow cytometric analyses to explore the role of recombinant human ApoE2, pCMV6-ApoE2 and siApoE2 in the apoptosis of PANC-1 and Capan-2 cells. Furthermore, we investigated the molecular mechanism through which ApoE2 affected apoptosis in PANC-1 cells using immunofluorescence, immunoprecipitation, Western blotting and co-immunoprecipitation analysis.ApoE2 phosphorylated ERK1/2 and inhibited pancreatic cancer cell apoptosis. In addition, our data showed that ApoE2/ERK1/2 altered the expression and mitochondrial localization of BCL-2 via activating CREB. ApoE2/ERK1/2/CREB also increased the total BCL-2/BAX ratio, inhibited the opening of the mitochondrial permeability transition pore and the depolarization of mitochondrial transmembrane potential, blocked the leakage of cytochrome-c and the formation of the apoptosome, and consequently, suppressed mitochondrial apoptosis.ApoE2 regulates the mitochondrial localization and expression of BCL-2 through the activation of the ERK1/2/CREB signaling cascade to evade the mitochondrial apoptosis of pancreatic cancer cells. ApoE2 may be a distinct prognostic marker and a potential therapeutic target for pancreatic cancer.

High-resolution functional MRI (fMRI) is largely hindered by random thermal noise. Random matrix theory (RMT)-based principal component analysis (PCA) is promising to reduce such noise in fMRI data. However, there is no consensus about the optimal strategy and practice in implementation. In this work, we propose a comprehensive RMT-based denoising method that consists of 1) rank and noise estimation based on a set of newly derived multiple criteria, and 2) optimal singular value shrinkage, with each module explained and implemented based on the RMT. By incorporating the variance stabilizing approach, the denoising method can deal with low signal-to-noise ratio (SNR) (such as5) magnitude fMRI data with favorable performance compared to other state-of-the-art methods. Results from both simulation and in-vivo high-resolution fMRI data show that the proposed denoising method dramatically improves image restoration quality, promoting functional sensitivity at the same level of functional mapping blurring compared to existing denoising methods. Moreover, the denoising method can serve as a drop-in step in data preprocessing pipelines along with other procedures aimed at removal of structured physiological noises. We expect that the proposed denoising method will play an important role in leveraging high-quality, high-resolution task fMRI, which is desirable in many neuroscience and clinical applications.

Biopolymer-scaffold modification is widely used to enhance enzyme catalysis. A central challenge is predicting the effects of scaffold position on enzyme properties. Here, we use a computational-experimental approach to develop a model for the effects of DNA scaffold position on enzyme kinetics. Using phosphotriesterase modified with a 20bp dsDNA, we demonstrate that conjugation position is as important as the scaffold's chemistry and structure. Multiscale simulations predict the effective substrate concentration increases close to the scaffold, which has μM-strength binding to the substrate. Kinetic analysis shows that the effective concentration that the scaffold provides is best utilized when positioned next to, but not blocking, the active site. At ~5Å distance between scaffold and active site a 7-fold increase in

To solve the problem of stall warning for axial compressors, this paper proposes a stall warning algorithm based on the sparrow search algorithm, which optimizes the deep belief network. The deep belief network is trained by using deep learning to extract the FFT spectrum of compressor stall experiment data directly as the feature vector. To improve the accuracy of DBN classification, parameters of hidden layer nodes n and initial weights w of DBN were optimized by SSA algorithm, and stall warning algorithm model of SSA-DBN axial-flow compressor was established. The experimental results of the algorithms show that the stall data at each speed is at least 0.1～0.3s in advance for early warning. This method is 0.075~0.281s ahead of the various models from the past to the present, and noise is superimposed on the experimental data to verify the Robustness of the way, better surge warning margin performance, and engineering practicability. &nbsp

Arabidopsis RESISTANCE TO POWDERY MILDEW 8.2 (RPW8.2) is specifically induced by the powdery mildew (PM) fungus (Golovinomyces cichoracearum) in the infected epidermal cells to activate immunity. However, the mechanism of RPW8.2-induction is not well understood. Here, we identify a G. cichoracearum effector that interacts with RPW8.2, named Gc-RPW8.2 interacting protein 1 (GcR8IP1), by a yeast two-hybrid screen of an Arabidopsis cDNA library. GcR8IP1 physically associated with RPW8.2 with its RING finger domain that is essential and sufficient for the association. GcR8IP1 was secreted and translocated into the nucleus of host cell infected with PM. Association of GcR8IP1 with RPW8.2 led to an increase of RPW8.2 in the nucleus. In turn, the nucleus-localised RPW8.2 promoted the activity of the RPW8.2 promoter, resulting in transcriptional self-amplification of RPW8.2 to boost immunity at infection sites. Additionally, ectopic expression or host-induced gene silencing of GcR8IP1 supported its role as a virulence factor in PM. Altogether, our results reveal a mechanism of RPW8.2-dependent defense strengthening via altered partitioning of RPW8.2 and transcriptional self-amplification triggered by a PM fungal effector, which exemplifies an atypical form of effector-triggered immunity.

Since the tax of carbon emission is popular and consumers are exhibiting low-carbon preference, a manufacturer may invest to adopt carbon emission reduction (CER) technologies to produce green products. In face of high cost of CER investment and random yield in low carbon production processes for the manufacturer, this paper explores the incentive role of the contracts of revenue-sharing (RS) and cost-sharing with subsidy (CSS) offered by a retailer in a low-carbon supply chain. Theoretical analysis and numerical experiments show that both RS and CSS can promote the manufacturer’s Carbon Emission Reduction (CER) efforts and improve the efficiency of the supply chain, and RS boosts these more than CSS. RS and CSS can also decrease firms’ profit losses due to yield uncertainty, and RS also decreases firms’ profit losses more than CSS. Moreover, to motivate manufacturer’s CER efforts, the government should levy the highest-possible carbon tax under RS, the medium-level carbon tax under CSS, and the lowest-possible carbon tax for the decentralized case, and levy the same carbon tax on the centralized case with that under RS.

Only a small proportion of patients with triple-negative breast cancer benefit from immune checkpoint inhibitor (ICI) targeting PD-1/PD-L1 signaling in combination with chemotherapy. Here, we discovered that therapeutic response to ICI plus paclitaxel was associated with subcellular redistribution of PD-L1. In our immunotherapy cohort of ICI in combination with nab-paclitaxel, tumor samples from responders showed significant distribution of PD-L1 at mitochondria, while non-responders showed increased accumulation of PD-L1 on tumor cell membrane instead of mitochondria. Our results also revealed that the distribution pattern of PD-L1 was regulated by an ATAD3A-PINK1 axis. Mechanistically, PINK1 recruited PD-L1 to mitochondria for degradation via a mitophagy pathway. Importantly, paclitaxel increased ATAD3A expression to disrupt proteostasis of PD-L1 by restraining PINK1-dependent mitophagy. Clinically, patients with tumors exhibiting high expression of ATAD3A detected before the treatment with ICI in combination with paclitaxel had markedly shorter progression-free survival compared with those with ATAD3A-low tumors. Preclinical results further demonstrated that targeting ATAD3A reset a favorable antitumor immune microenvironment and increased the efficacy of combination therapy of ICI plus paclitaxel. In summary, our results indicate that ATAD3A serves not only as a resistant factor for the combination therapy of ICI plus paclitaxel through preventing PD-L1 mitochondrial distribution, but also as a promising target for increasing the therapeutic responses to chemoimmunotherapy.

Two-dimensional TiCl2 as a high-performance anode material for Na-ion batteries with high capacity and fast diffusion.

The unprecedented catalytic performance of micro-sized Co-ZIF-L for the decomposition of RDX was deeply explored and reveals its 2D-structure-induced ability to reverse the commonly advantageous N–N fission pathway in the low-temperature stage.

In this review, we summarized the mechanism and recent progress of conformational isomeric TADF emitters, and classified them according to their different applications, along with an outlook on their perspectives.

Two multi-resonance thermally activated delayed fluorescence analogous materials respectively integrating oxygen and sulfur atoms were compared to investigate the pro and cons of introducing elements of different periods.

Motility and spreading of nasopharyngeal carcinoma (NPC) cells were enhanced when co-cultured with nasopharyngeal epithelial cells in microwells with different sizes and topographies, which would provide insight for the study of NPC progression.

Strain leads to a rich magnetic phase transition in PC3NR, that is, from bandgap-tunable bipolar magnetic semiconductors to spin-gapless semiconductors to ferromagnetic metals or half-metal magnets and ±100% SP over a wide energy interval around EF.

To investigate microvascular alterations in the Glisson system of biliary atresia (BA) patients after Kasai portoenterostomy (KP) using three-dimensional (3D) virtual histopathology based on X-ray phase-contrast CT (PCCT).Liver explants from BA patients were imaged using PCCT, and 32 subjects were included and divided into two groups: KP (n = 16) and non-KP (n = 16). Combined with histological analysis and 3D visualization technology, 3D virtual histopathological assessment of the biliary, arterial, and portal venous systems was performed. According to loop volume ratio, 3D spatial density, relative surface area, tortuosity, and other parameters, pathological changes of microvasculature in the Glisson system were investigated.In the non-KP group, bile ducts mostly manifested as radial multifurcated hyperplasia and twisted into loops. In the KP group, the bile duct hyperplasia was less, and the loop volume ratio of bile ducts decreased by 13.89%. Simultaneously, the arterial and portal venous systems presented adaptive alterations in response to degrees of bile duct hyperplasia. Compared with the non-KP group, the 3D spatial density of arteries in the KP group decreased by 3.53%, and the relative surface area decreased from 0.088 ± 0.035 to 0.039 ± 0.015 (p.01). Deformed portal branches gradually recovered after KP, with a 2.93% increase in 3D spatial density and a decrease in tortuosity from 1.17 ± 0.06 to 1.14 ± 0.04 (p.01) compared to the non-KP group.3D virtual histopathology via PCCT clearly reveals the microvascular structures in the Glisson system of BA patients and provides key insights into the morphological mechanism of microvascular adaptation induced by biliary tract dredging after KP in BA disease.• 3D virtual histopathology via X-ray phase-contrast computed tomography clearly presented the morphological structures and pathological changes of microvasculature in the Glisson system of biliary atresia patients. • The morphological alterations of microvasculature in the Glisson system followed the competitive occupancy mechanism in the process of biliary atresia.