Polyethylenimine-modified graphene quantum dots promote endothelial cell proliferation.

Endothelial cell proliferation plays an important role in angiogenesis and treatment of related diseases. The aim of this study was to evaluate the effect of polyethylenimine (PEI)-modified graphene quantum dots (GQDs) gene vectors on endothelial cell proliferation. The GQDs-cationic polymer gene vectors were synthesized by amidation reaction, and used to deliver pZNF580 gene to Human umbilical vein endothelial cells (HUVECs) for promoting their proliferation. The chemical modification of GQDs can adjust gene vectors' surface properties and charge distribution, thereby enhancing their interaction with gene molecules, which could effectively compress the pZNF580 gene. The CCK-8 assay showed that the cell viability was higher than 80% at higher vector concentration (40 µg/mL), demonstrating that the GQDs-cationic polymer gene vectors and their gene complex nanoparticles (NPs) having low cytotoxicity. The results of the live/dead cell double staining assay were consistent with those of the CCK-8 assay, in which the cell viability of the A-GQDs/pZNF580 (94.38 ± 6.39%), C-GQDs-PEI- polylactic acid-co-polyacetic acid (PLGA)/pZNF580 (98.65 ± 6.60%) and N-GQDs-PEI-PLGA/pZNF580 (90.08 ± 1.60%) groups was significantly higher than that of the Lipofectamine 2000/pZNF580 (71.98 ± 3.53%) positive treatment group. The results of transfection and western blot experiments showed that the vector significantly enhanced the delivery of plasmid to HUVECs and increased the expression of pZNF580 in HUVECs. In addition, the gene NPs better promote endothelial cell migration and proliferation. The cell migration rate and proliferation ability of C-GQDs-PEI-PLGA/pZNF580 and N-GQDs-PEI-PLGA/pZNF580 treatment groups were higher than those of Lipofectamine 2000/pDNA treatment group. Modified GQDs possess the potential to serve as efficient gene carriers. They tightly bind gene molecules through charge and other non-covalent interactions, significantly improving the efficiency of gene delivery and ensuring the smooth release of genes within the cell. This innovative strategy provides a powerful means to promote endothelial cell proliferation.

A gender recognition method based on EEG microstates.

BACKGROUND: Gender carries important information related to male and female characteristics, and a large number of studies have attempted to use physiological measurement methods for gender classification. Although previous studies have shown that there exist statistical differences in some Electroencephalographic (EEG) microstate parameters between males and females, it is still unknown that whether these microstate parameters can be used as potential biomarkers for gender classification based on machine learning. METHODS: We used two independent resting-state EEG datasets: the first dataset included 74 females and matched 74 males, and the second one included 42 males and matched 42 females. EEG microstate analysis based on modified k-means clustering method was applied, and temporal parameter and nonlinear characteristics (sample entropy and Lempel-Ziv complexity) of EEG microstate sequences were extracted to compare between males and females. More importantly, these microstate temporal parameters and complexity were tried to train six machine learning methods for gender classification. RESULTS: We obtained five common microstates for each dataset and each group. Compared with the male group, the female group has significantly higher temporal parameters of microstate B, C, E and lower temporal parameters of microstate A and D, and higher complexity of microstate sequence. When using combination of microstate temporal parameters and complexity or only microstate temporal parameters as classification features in an independent test set (the second dataset), we achieved 95.2% classification accuracy. CONCLUSION: Our research findings indicate that the dynamics of microstate have considerable Gender-specific alteration. EEG microstates can be used as neurophysiological biomarkers for gender classification.

ROS-Responsive Poly(α-l-lysine)-Based Nanoparticles Loaded with Doxycycline Combat Oxidative Stress and Bacterial Infection.

Bacterial pneumonia is one of the major threats in clinical practice, and the reactive oxygen species (ROS) generated at the infection site can exacerbate the damage. Currently, conventional antibiotic therapies have low utilization, and their excessive use can result in substantial toxicity. Nanocarrier systems provide an ideal approach for treating bacterial infection by facilitating more efficient utilization of antibiotics. In this study, the ROS-responsive amphiphilic nanoparticles (NPs) are developed and used to encapsulate the antibiotic doxycycline (DOXY) to achieve antibacterial and antioxidant functionalities. The NPs are prepared from poly(α-l-lysine) (α-PLL) and phenylboronic acid pinacol ester simultaneously conjugated carbonyldiimidazole (abbreviated as CDIPB). The phenylboronic acid ester groups on CDIPB could react with excessive ROS to suppress oxidative damage at the infection site. The ROS-responsive degradation of CDIPB also facilitates the rapid release of internal DOXY, effectively killing the accumulated bacteria. Additionally, in vitro cell experiments demonstrate the good biocompatibility of the NPs. These results suggest that the ROS-responsive amphiphilic nanoparticles can serve as a novel nanoplatform for the treatment of bacterial pneumonia.

Amphiphilic multi-targeting copolymer micelles efficiently deliver pZNF580 to promote endothelial cell proliferation and migration.

Cationic copolymers are widely used in gene delivery as a non-viral gene vector, but their applications are limited by low transfection efficiency and high cytotoxicity. In order to enhance the transfection efficiency of copolymer micelles to endothelial cells (HUVECs) and reduce their cytotoxicity, this study synthesized an amphipathic multi-targeted copolymer micelle delivery system PCLMD-PPEGMA-NLS-TAT-REDV (TCMs). Gel test results showed that TCMs showed good pZNF580 binding ability and could effectively load the pZNF580 plasmid. The CCK-8 results show that when the concentration of TCMs is greater than 60 µg mL-1, it will affect cell viability and have low cytotoxicity. We found that the multi-targeted copolymer micelles can be effectively taken up by HUVECs in vitro. The transfection efficiency of TCMs@pZNF580 (w/wpZNF580 = 3) to HUVECs was comparable to that of the positive control group lip2000@pZNF580, and WB also showed the same trend. In addition, the TCMs@pZNF580 complex also significantly enhanced the proliferation and migration of HUVECs. The experimental results on blood vessel formation showed that TCMs@pZNF580 accelerated the vascularization of HUVECs. This experiment provided a new technology platform for targeted gene therapy, especially for endothelialization and vascularization. The research results have important reference value for the treatment of cardiovascular diseases.

γ-Cyclodextrin metal-organic frameworks as the promising carrier for pulmonary delivery of cyclosporine A.

γ-Cyclodextrin metal-organic frameworks (CD-MOFs) are considered as a green and biocompatible material with great potential in drug delivery systems. Original CD-MOFs show the poor aerosol properties, which limit the application in pulmonary drug delivery. To improve the in vitro deposition properties, herein, we synthesized CD-MOFs by the vapor diffusion method using a series of modulators to achieve better pulmonary delivery of cyclosporine A (CsA). The results showed that blank CD-MOFs and drug loaded CD-MOFs prepared with different modulators all preserved the cubical shape, and exhibited the similar crystal form, structural characteristics, thermal behaviors and release properties. In addition, drug loaded CD-MOFs prepared with polyethylene glycol 10000 (PEG 10000) as a modulator exhibited better in vitro aerosol performance than those of synthesized using other modulators, and the in vivo pharmacokinetics data demonstrated that the bioavailability of CsA could be significantly enhanced by inhalation administration of drug loaded CD-MOFs compared with oral administration of Neoral®. The repeated dose inhalation toxicity also confirmed the fine biocompatibility of CD-MOFs as the carrier for pulmonary drug delivery. Therefore, the results demonstrated CD-MOFs as the promising carrier could be used for pulmonary drug delivery.

Hemoadsorption in acute respiratory distress syndrome patients requiring venovenous extracorporeal membrane oxygenation: a systematic review.

BACKGROUND: Venovenous extracorporeal membrane oxygenation (VV ECMO) has been widely used for severe acute respiratory distress syndrome (ARDS) in recent years. However, the role of hemoadsorption in ARDS patients requiring VV ECMO is unclear. METHODS: Therefore, we conducted a systematic review to describe the effect of hemoadsorption on outcomes of ARDS patients requiring VV ECMO and elucidate the risk factors for adverse outcomes. We conducted and reported a systematic literature review based on the principles derived from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The systematic review searched Embase, CINHAL, and Pubmed databases for studies on ARDS patients receiving hemoadsorption and VV ECMO. The demographic data, clinical data and biological data of the patients were collected. RESULTS: We ultimately included a total of 8 articles including 189 patients. We characterized the population both clinically and biologically. Our review showed most studies described reductions in inflammatory markers and fluid resuscitation drug dosage in ARDS patients with Coronavirus disease 2019 (COVID-19) or sepsis after hemoadsorption. CONCLUSION: Because most of the studies have the characteristics of high heterogeneity, we could only draw very cautious conclusions that hemoadsorption therapy may enhance hemodynamic stability in ARDS patients with COVID-19 or sepsis receiving VV ECMO support. However, our results do not allow us to draw conclusions that hemoadsorption could reduce inflammation and mortality. Prospective randomized controlled studies with a larger sample size are needed in the future to verify the role of hemoadsorption in ARDS patients requiring VV ECMO.

The Role of Long Noncoding RNAs in Intestinal Health and Diseases: A Focus on the Intestinal Barrier.

The gut is the body's largest immune organ, and the intestinal barrier prevents harmful substances such as bacteria and toxins from passing through the gastrointestinal mucosa. Intestinal barrier dysfunction is closely associated with various diseases. However, there are currently no FDA-approved therapies targeting the intestinal epithelial barriers. Long noncoding RNAs (lncRNAs), a class of RNA transcripts with a length of more than 200 nucleotides and no coding capacity, are essential for the development and regulation of a variety of biological processes and diseases. lncRNAs are involved in the intestinal barrier function and homeostasis maintenance. This article reviews the emerging role of lncRNAs in the intestinal barrier and highlights the potential applications of lncRNAs in the treatment of various intestinal diseases by reviewing the literature on cells, animal models, and clinical patients. The aim is to explore potential lncRNAs involved in the intestinal barrier and provide new ideas for the diagnosis and treatment of intestinal barrier damage-associated diseases in the clinical setting.

PTIR1 acts as an isoform of DDX58 and promotes tumor immune resistance through activation of UCHL5.

Cancer evades host immune surveillance by virtue of poor immunogenicity. Here, we report an immune suppressor, designated as PTIR1, that acts as a promotor of tumor immune resistance. PTIR1 is selectively induced in human cancers via alternative splicing of DDX58 (RIG-I), and its induction is closely related to poor outcome in patients with cancer. Through blocking the recruitment of leukocytes, PTIR1 facilitates cancer immune escape and tumor-intrinsic resistance to immunotherapeutic treatments. Unlike RIG-I, PTIR1 is capable of binding to the C terminus of UCHL5 and activates its ubiquitinating function, which in turn inhibits immunoproteasome activity and limits neoantigen processing and presentation, consequently blocking T cell recognition and attack against cancer. Moreover, we find that the adenosine deaminase ADAR1 induces A-to-I RNA editing on DDX58 transcript, thus triggering PTIR1 production. Collectively, our data uncover the immunosuppressive role of PTIR1 in tumorigenesis and propose that ADAR1-PTIR1-UCHL5 signaling is a potential cancer immunotherapeutic target.

Identification of potentially functional circRNAs and prediction of the circRNA-miRNA-hub gene network in mice with primary blast lung injury.

OBJECTIVES: Primary blast lung injury (PBLI) is the main cause of death in blast injury patients, and is often ignored due to the absence of a specific diagnosis. Circular RNAs (circRNAs) are becoming recognized as new regulators of various diseases, but the role of circRNAs in PBLI remain largely unknown. This study aimed to investigate PBLI-related circRNAs and their probable roles as new regulators in PBLI in order to provide new ideas for PBLI diagnosis and treatment. METHODS: The differentially expressed (DE) circRNA and mRNA profiles were screened by transcriptome high-throughput sequencing and validated by quantitative real-time PCR (qRT-PCR). The GO and KEGG pathway enrichment was used to investigate the potential function of DE mRNAs. The interactions between proteins were analyzed using the STRING database and hub genes were identified using the MCODE plugin. Then, Cytoscape software was used to illustrate the circRNA-miRNA-hub gene network. RESULTS: A total of 117 circRNAs and 681 mRNAs were aberrantly expressed in PBLI, including 64 up-regulated and 53 down-regulated circRNAs, and 315 up-regulated and 366 down-regulated mRNAs. GO and KEGG analysis revealed that the DE mRNAs might be involved in the TNF signaling pathway and Fanconi anemia pathway. Hub genes, including Cenpf, Ndc80, Cdk1, Aurkb, Ttk, Aspm, Ccnb1, Kif11, Bub1 and Top2a, were obtained using the MCODE plugin. The network consist of 6 circRNAs (chr18:21008725-21020999 + , chr4:44893533-44895989 + , chr4:56899026-56910247-, chr5:123709382-123719528-, chr9:108528589-108544977 + and chr15:93452117-93465245 +), 7 miRNAs (mmu-miR-3058-5p, mmu-miR-3063-5p, mmu-miR-668-5p, mmu-miR-7038-3p, mmu-miR-761, mmu-miR-7673-5p and mmu-miR-9-5p) and 6 mRNAs (Aspm, Aurkb, Bub1, Cdk1, Cenpf and Top2a). CONCLUSIONS: This study examined a circRNA-miRNA-hub gene regulatory network associated with PBLI and explored the potential functions of circRNAs in the network for the first time. Six circRNAs in the circRNA-miRNA-hub gene regulatory network, including chr18:21008725-21020999 + , chr4:44893533-44895989 + , chr4:56899026-56910247-, chr5:123709382-123719528-, chr9:108528589-108544977 + and chr15:93452117-93465245 + may play an essential role in PBLI.

Development of Large Hollow Particles for Pulmonary Delivery of Cyclosporine A.

The purpose of this study was to prepare large hollow particles (LHPs) by spray drying for pulmonary delivery of cyclosporine A (CsA), using L-Leucine (LEU) and hydroxypropyl methylcellulose (HPMC) as excipients and ammonium bicarbonate (AB) as a porogen. The prepared LHPs were spherical particles composed of both CsA and LEU on the surface and HPMC on the inner layer. The formulation of CsA-LEU-0.8HPMC-AB as typical LHPs showed excellent in vitro aerodynamic performance with a minimum mass median aerodynamic diameter (MMAD) of 1.15 µm. The solubility of CsA-LEU-0.8HPMC-AB was about 5.5-fold higher than that of raw CsA, and the dissolution of CsA-LEU-0.8HPMC-AB suggested that the drug was released within 1 h. The cell viability of the A549 cell line showed that CsA-LEU-0.8HPMC-AB was safe for delivering CsA to the lungs. In addition, inhalation administration of CsA-LEU-0.8HPMC-AB with the Cmax and AUC0-∞ increasing by about 2-fold and 2.8-fold compared with the oral administration of Neoral® could achieve therapeutic drug concentrations with lower systemic exposure and significantly improve the in vivo bioavailability of CsA. From these findings, the LHPs, with the advantage of avoiding alveolar macrophage clearance, could be a viable choice for delivering CsA by inhalation administration relative to oral administration.

Cyclosporine A-loaded chitosan extra-fine particles for deep pulmonary drug delivery: In vitro and in vivo evaluation.

In this study, the extra-fine dry powder inhalers (DPIs) with chitosan (CS) as carrier were successfully prepared by ionic gel method combined with spray drying technique for deep pulmonary drug delivery of Cyclosporine A (CsA), using sodium hyaluronate (SHA) and sodium polyglutamate (SPGA) as polyanions. The CsA-loaded DPIs of CS-SHA-CsA and CS-SPGA-CsA were spherical particles with wrinkles on the surface, which were more conducive to improving the aerosol properties. The aerodynamic evaluation of CS-SHA-CsA and CS-SPGA-CsA showed that the fine particle fraction (FPF) reached up to 79.22 ± 2.12% and 81.55 ± 0.43%, while the emitted fraction (EF) reached 77.15 ± 1.46% and 78.29 ± 2.10%. In addition, the mass median aerodynamic diameter (MMAD) was calculated as 1.58 ± 0.04 µm and 1.94 ± 0.02 µm for CS-SHA-CsA and CS-SPGA-CsA, indicating that they were all extra-fine particles (d < 2 µm). These in vitro aerodynamic results showed that CS-SHA-CsA and CS-SPGA-CsA could reach the smaller airways, further improving therapeutic efficiency. The cell viability on A549 cell line results showed that CS-SHA-CsA and CS-SPGA-CsA were safe to deliver CsA to lungs. The in vivo pharmacokinetics consequence proved that inhalation administration of CS-SHA-CsA and CS-SPGA-CsA could significantly improve the bioavailability of CsA in vivo compared with oral administration of Neoral®, effectively reducing the risk of a series of adverse effects caused by systemic overexposure. In addition, the safety and compatibility of DPIs using SHA, SPGA, and CS as carriers for pulmonary drug delivery was verified by in vivo repeated dose inhalation toxicity. From these findings, the extra-fine DPIs with CS as carrier could be a viable delivery option for the deep pulmonary drug delivery of CsA relative to orally administered drug.

Design and development of high precision four roll CNC roll bending machine and automatic control model.

In recent years, advancements in industries such as aerospace, military weaponry, automobiles, locomotives, and shipbuilding have led to a surge in the demand for bent and rolled components, along with increasingly stringent requirements for rolling precision. However, the traditional hydraulic cylinder feeding solution has hindered further enhancements in the accuracy of rolled profile contours. Additionally, owing to variations in profile specifications, material properties, and an assortment of random factors during the forming process, the applicability of existing forming formulas remains limited, rendering them suitable only for profile processing under specific circumstances. To address these challenges, servo electric cylinders have been introduced as a replacement for traditional hydraulic cylinders, and the mechanical structure of a four-roll bending machine has been re-engineered. This innovation has demonstrated the feasibility of employing servo electric cylinders in four-roll CNC bending machines for profile bending, resulting in higher control precision and faster response times, ultimately providing a comprehensive design solution for four-roll CNC bending machines. In response to the limited universality of existing forming formulas, the actual R (profile forming curvature) and d (servo electric cylinder feed) values from the four-roll CNC bending machine have been utilized, and curve fitting methods have been implemented as the foundation for the automatic control model. This approach offers a high degree of universality, making it suitable for a wide range of applications. Moreover, as the number of trials increased, forming precision progressively improved.

Shear-induced acquired von Willebrand syndrome: an accomplice of bleeding events in adults on extracorporeal membrane oxygenation support.

Extracorporeal membrane oxygenation (ECMO) is an increasingly acceptable life-saving mechanical assistance system that provides cardiac and/or respiratory support for several reversible or treatable diseases. Despite important advances in technology and clinical management, bleeding remains a significant and common complication associated with increased morbidity and mortality. Some studies suggest that acquired von Willebrand syndrome (AVWS) is one of the etiologies of bleeding. It is caused by shear-induced deficiency of von Willebrand factor (VWF). VWF is an important glycoprotein for hemostasis that acts as a linker at sites of vascular injury for platelet adhesion and aggregation under high shear stress. AVWS can usually be diagnosed within 24 h after initiation of ECMO and is always reversible after explantation. Nonetheless, the main mechanism for the defect in the VWF multimers under ECMO support and the association between AVWS and bleeding complications remains unknown. In this review, we specifically discuss the loss of VWF caused by shear induction in the context of ECMO support as well as the current diagnostic and management strategies for AVWS.

Clinical applications of graph neural networks in computational histopathology: A review.

Pathological examination is the optimal approach for diagnosing cancer, and with the advancement of digital imaging technologies, it has spurred the emergence of computational histopathology. The objective of computational histopathology is to assist in clinical tasks through image processing and analysis techniques. In the early stages, the technique involved analyzing histopathology images by extracting mathematical features, but the performance of these models was unsatisfactory. With the development of artificial intelligence (AI) technologies, traditional machine learning methods were applied in this field. Although the performance of the models improved, there were issues such as poor model generalization and tedious manual feature extraction. Subsequently, the introduction of deep learning techniques effectively addressed these problems. However, models based on traditional convolutional architectures could not adequately capture the contextual information and deep biological features in histopathology images. Due to the special structure of graphs, they are highly suitable for feature extraction in tissue histopathology images and have achieved promising performance in numerous studies. In this article, we review existing graph-based methods in computational histopathology and propose a novel and more comprehensive graph construction approach. Additionally, we categorize the methods and techniques in computational histopathology according to different learning paradigms. We summarize the common clinical applications of graph-based methods in computational histopathology. Furthermore, we discuss the core concepts in this field and highlight the current challenges and future research directions.

Green space exposure on depression and anxiety outcomes: A meta-analysis.

BACKGROUND: The development of urbanization has led to emerging mental health issues. Green space was becoming increasingly important for mental health. Previous studies have demonstrated the value of green space for a variety of outcomes connected to mental health. However, uncertainty remains regarding the association between green spaces and the risk of depression and anxiety outcomes. This study aimed to integrate present evidence from observational studies to define the association of exposure to green space with depression and anxiety. METHODS: A thorough electronic search of PubMed, Web of Science and Embase database was performed. We transformed the odds ratio (OR) of different green increments into per 0.1 unit increase in normalized difference vegetation index (NDVI) and per 10% increase in percentage of green space. Cochrane's Q and I2 statistics were used to assess study heterogeneity, and random-effects models were employed to calculate combined effect estimation OR with 95% confidence intervals (CIs). Pooled analysis was completed using Stata 15.0. RESULTS: According to this meta-analysis, a 10% increase in the proportion of green space was linked to a lower risk of depression (merged OR (95% CI) = 0.963 (0.948, 0.979)) and anxiety (merged OR (95% CI) = 0.938 (0.858, 1.025)) and a 0.1 unit increase in NDVI was linked to a lower risk of depression (merged OR (95% CI) = 0.931 (0.887, 0.977)). CONCLUSIONS: Results of this meta-analysis supported improving green space exposure in preventing depression and anxiety. Higher green space exposure might be helpful for depression and anxiety disorders. Therefore, improving or preserving green space should be regarded as a promising intervention for public health.

Compact optical convolution processing unit based on multimode interference.

Convolutional neural networks are an important category of deep learning, currently facing the limitations of electrical frequency and memory access time in massive data processing. Optical computing has been demonstrated to enable significant improvements in terms of processing speeds and energy efficiency. However, most present optical computing schemes are hardly scalable since the number of optical elements typically increases quadratically with the computational matrix size. Here, a compact on-chip optical convolutional processing unit is fabricated on a low-loss silicon nitride platform to demonstrate its capability for large-scale integration. Three 2 × 2 correlated real-valued kernels are made of two multimode interference cells and four phase shifters to perform parallel convolution operations. Although the convolution kernels are interrelated, ten-class classification of handwritten digits from the MNIST database is experimentally demonstrated. The linear scalability of the proposed design with respect to computational size translates into a solid potential for large-scale integration.

The effects of ECMO on neurological function recovery of critical patients: A double-edged sword.

Extracorporeal membrane oxygenation (ECMO) played an important role in the treatment of patients with critical care such as cardiac arrest (CA) and acute respiratory distress syndrome. ECMO is gradually showing its advantages in terms of speed and effectiveness of circulatory support, as it provides adequate cerebral blood flow (CBF) to the patient and ensures the perfusion of organs. ECMO enhances patient survival and improves their neurological prognosis. However, ECMO-related brain complications are also important because of the high risk of death and the associated poor outcomes. We summarized the reported complications related to ECMO for patients with CA, such as north-south syndrome, hypoxic-ischemic brain injury, cerebral ischemia-reperfusion injury, impaired intracranial vascular autoregulation, embolic stroke, intracranial hemorrhage, and brain death. The exact mechanism of ECMO on the role of brain function is unclear. Here we review the pathophysiological mechanisms associated with ECMO in the protection of neurologic function in recent years, as well as the ECMO-related complications in brain and the means to improve it, to provide ideas for the treatment of brain function protection in CA patients.

Can Stringent Government Initiatives Lead to Global Economic Recovery Rapidly during the COVID-19 Epidemic?

This paper investigates the effectiveness of government measures implemented against COVID-19 and the factors influencing a country's economic growth from a global perspective. With the help of the data of the Government Response Stringency Index (GRSI), Google mobility, and confirmed COVID-19 daily cases, we conducted a panel model for 105 countries and regions from 11 March 2020 to 31 June 2021 to explore the effects of response policies in different countries against the pandemic. First, the results showed that staying in residential places had the strongest correlation with confirmed cases. Second, in countries with higher government stringency, stay-at-home policies carried out in the early spread of the pandemic had the most effective the impact. In addition, the results have also been strictly robustly analyzed by applying the propensity score matching (PSM) method. Third, after reconstructing a panel data of 47 OECD countries, we further concluded that governments should take stricter restrictive measures in response to COVID-19. Even though it may also cause a shock to the market in the short term, this may not be sustainable. As long as the policy response is justified, it will moderate the negative effect on the economy over time, and finally have a positive effect.

[Rapid and simultaneous determination of two immunosuppressants in whole blood by high performance liquid chromatography].

Cyclosporine A and sirolimus are immunosuppressants that are widely used in many organ transplantation procedures. They exhibit some complementary mechanisms of action and interact synergistically when used together. However， they are critical-dose drugs and have a narrow therapeutic index. They provide the desired therapeutic effect with acceptable tolerability only within a specific range of blood concentrations. Therefore， the rapid and simultaneous detection of the concentrations of cyclosporine A and sirolimus in whole blood could provide valuable information on planning medicine administration after organ transplantations. In this study， firstly， the chromatographic behaviors of cyclosporine A and sirolimus on a biological liquid chromatography （BioLC） column and traditional liquid chromatography （TraLC） columns were investigated systematically under the same chromatographic conditions. The results suggested that the peak height and peak width of cyclosporine A and sirolimus on the BioLC column， ZORBAX 300SB C8 （250 mm×4.6 mm， 5.0 µm）， were the highest and narrowest， respectively. The number of theoretical plates of cyclosporine A and sirolimus on the ZORBAX 300SB C8 column increased significantly when the volume ratio of acetonitrile in the mobile phases was greater than 70%. Their retention time on the BioLC and TraLC columns was negligibly affected by the use of formic acid and trifluoroacetic acid as the mobile phases. In the range of the experimental column temperature， the number of theoretical plates of cyclosporine A and sirolimus on the ZORBAX 300SB C8 column was significantly higher than that on the two TraLC columns. Furthermore， the relationship between the retention factor and column temperature of cyclosporine A on the ZORBAX 300SB C8 column was different from that on the two TraLC columns. Subsequently， a high performance liquid chromatography method based on the ZORBAX 300SB C8 column was established for the rapid separation and determination of cyclosporin A and sirolimus in whole blood. A sample of whole blood with a volume of 50 µL was prepared by protein precipitation with 1 mol/L sodium hydroxide and then extracted into 500 µL of ether-methanol （95∶5， v/v）. After centrifugation at 14000 r/min for 10 min， the organic layer was removed and evaporated under a stream of nitrogen at 50 ℃. The residue was then reconstituted in 200 µL of methanol for use. Cyclosporin A and sirolimus were separated through isocratic elution on the ZORBAX 300SB C8 column. The column temperature was set at 60 ℃. The mobile phase was acetonitrile-water （70∶30， v/v） and the flow rate was 1.0 mL/min. The detection wavelengths were 205 nm for cyclosporine A and 278 nm for sirolimus. The injection volume was 20 µL. The external standard method was used to quantify cyclosporine A and sirolimus. Under the optimized conditions， cyclosporine A and sirolimus were well-separated within 6 min with a resolution of 3.7 at 205 nm. In addition， the endogenous substances in whole blood negligibly interfered in the detection of sirolimus， while two endogenous substances slightly affected the detection of cyclosporine A. Cyclosporine A and sirolimus both showed good linear relationships in their respective concentration （r>0.997）. The limits of detection （LODs） of cyclosporine A and sirolimus were respectively calculated to be 10 ng/mL and 1 ng/mL based on a signal-to-noise ratio of 3， and the limits of quantification （LOQs） were 30 ng/mL and 2 ng/mL based on a signal-to-noise ratio of 10. In the whole blood samples， the recoveries of cyclosporine A and sirolimus at three spiked levels were in the ranges of 83.5%-89.7% and 95.8%-97.8% with relative standard deviations （RSDs） of 3.2%-9.0% and 3.4%-6.7% （n=5）， respectively. The established method is simple in operation， can be performed with a simple mobile phase， has a short analysis time， and provides a wide linear range and high sensitivity； hence， it can be applied to the determination of cyclosporine A and sirolimus in whole blood.

Crosstalk between Inflammation and Hemorrhage/Coagulation Disorders in Primary Blast Lung Injury.

Primary blast lung injury (PBLI), caused by exposure to high-intensity pressure waves from explosions in war, terrorist attacks, industrial production, and life explosions, is associated with pulmonary parenchymal tissue injury and severe ventilation insufficiency. PBLI patients, characterized by diffused intra-alveolar destruction, including hemorrhage and inflammation, might deteriorate into acute respiratory distress syndrome (ARDS) with high mortality. However, due to the absence of guidelines about PBLI, emergency doctors and rescue teams treating PBLI patients rely on experience. The goal of this review is to summarize the mechanisms of PBLI and their cross-linkages, exploring potential diagnostic and therapeutic targets of PBLI. We summarize the pathophysiological performance and pharmacotherapy principles of PBLI. In particular, we emphasize the crosstalk between hemorrhage and inflammation, as well as coagulation, and we propose early control of hemorrhage as the main treatment of PBLI. We also summarize several available therapy methods, including some novel internal hemostatic nanoparticles to prevent the vicious circle of inflammation and coagulation disorders. We hope that this review can provide information about the mechanisms, diagnosis, and treatment of PBLI for all interested investigators.