Construction and Preparation of the Novel ADN/CL-20 Cocrystal via Directional Hydrogen Bonding Design for Turning Hygroscopicity.

Ammonium dinitramide (ADN), as a novel and environmentally friendly oxidizer, has strong hygroscopicity when exposed to high-humidity air, which seriously hinders its application in solid propellants. Modification of oxidizers by cocrystallization is an effective strategy to improve the hygroscopicity of energetic components. In this paper, the theoretical simulation of ADN/CL-20 cocrystals was developed via a directional hydrogen bonding design to establish a cocrystal with improved hygroscopicity. Intermolecular interaction analyses reveal that hydrogen bonds and van der Waals interactions synergistically lead to the formation of cocrystals. The ADN/CL-20 cocrystal was prepared experimentally by the spray drying self-assembly technique, and the corresponding thermal analysis and sensitivity properties were conducted to illustrate the thermal stability and high safety. Furthermore, the critical relative humidity (CRH) measurement was carried out to evaluate the hygroscopicity of the cocrystal, exhibiting a certain degree of antihygroscopic effect with a CRH of 65%. The hydrogen bonds formed between ADN and CL-20 saturate the ammonium ions of ADN, further preventing ADN from absorbing water molecules in the air. The ADN/CL-20 cocrystal has high specific impulse characteristics (Isp: 272.6 s). Accordingly, this work clearly demonstrates that the ADN/CL-20 cocrystal is expected to be used in a solid propellant to make up for the deficiency of the ADN oxidizer.

Forsythoside B, the active component of Frosythiae fructuse water extract, alleviates Streptococcus pneumoniae virulence by targeting pneumolysin.

AIMS: To explore the therapeutic potential of Forsythoside B in treating Streptococcus pneumoniae (S. pneumoniae) infections, focusing on its ability to inhibit pneumolysin activity and protect cells from damage. METHODS AND RESULTS: Hemolysis tests were used to evaluate Forsythoside B's inhibitory effect on pneumolysin activity, while growth curve analysis assessed its impact on S. pneumoniae growth. Western blotting and oligomerization analysis were conducted to examine its influence on pneumolysin oligomerization. Cytotoxicity assays, including LDH release and live/dead cell staining, evaluated the protective effects of Forsythoside B against pneumolysin-induced damage in A549 cells. Additionally, a mouse model was employed to test the effects on survival rates, lung bacterial load, and inflammation. The results showed that Forsythoside B significantly inhibited pneumolysin activity, reduced its oligomerization, and protected A549 cells from damage without affecting bacterial growth. In the mouse model, it improved survival rates and reduced lung inflammation, indicating its potential as a therapeutic agent against S. pneumoniae infections. CONCLUSIONS: Forsythoside B shows potential as a therapeutic agent for treating pneumonia, particularly in infections caused by S. pneumoniae.

YiQi GuBen capsule alleviates OVA-induced asthma through improving mitochondrial dysfunction.

Objective: This study aims to explore the effect of YiQi GuBen capsule on improving mitochondrial dysfunction in an animal model of asthma.Methods: The mice (n = 8) were divided into four groups including control (NC), ovalbumin (OVA), dexamethasone (OVA + DEX), and YiQi GuBen (OVA + YQGB) groups. Firstly, we established an OVA-induced mouse asthma model except for the NC group, which then were treated with dexamethasone and YiQi GuBen capsule. Subsequently, HE staining and Masson staining were used for pathological analysis of mice lung tissues. Next, we used transmission electron microscopy (TEM) to observe the effect of the Yiqi Guben capsule on the ultrastructure of mitochondria. Flow cytometry was used to analyze the ROS level, membrane potential, and the number of mitochondria in lung tissue. Moreover, we analyzed the copy number of mitochondrial DNA (mtDNA) and the expression levels of activator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitochondrial transcription factor A (TFAM).Results: The results of the pathological analysis showed that after treatment with the YiQi GuBen capsule, the lung tissue damage was significantly reduced. In addition, we observed that the ultrastructural damage of mitochondria was improved. Flow cytometry proved that after treatment with the YiQi GuBen capsule, the level of ROS in the mitochondria was effectively reduced, while the mitochondrial membrane potential decreased and the number increased significantly. Moreover, we found that the copy number of mtDNA was significantly increased and the expression levels of PGC-1α and TFAM were significantly upgraded.Conclusion: This study suggests YiQi GuBen capsule can effectively improve mitochondrial dysfunction in the OVA-induced mouse model.

A meta-analysis of the effects of vitamin C supplementation for pregnant smokers on the pulmonary function of their offspring.

BACKGROUND: At present, the need for vitamin C supplementation for pregnant smokers has not been fully studied. This study is aimed at investigating whether vitamin C supplementation for pregnant smoking women can improve the pulmonary function of their offspring. METHODS: Four databases were searched from inception to April 1, 2023 for studies on the effect of vitamin C supplementation to pregnant smokers on the pulmonary function of their offspring. Meanwhile, the reference lists of relevant studies were manually searched. The risk of bias in the included studies was assessed using the Cochrane Collaboration tool, and the data was analyzed using STATA/SE 17.0. RESULTS: Four randomized controlled trials (RCTs), all of high quality, were enrolled in this meta-analysis, including 787 pregnant women. The offspring of pregnant smokers who received vitamin C supplementation exhibited improved Forced Expiratory Flow between 25 and 75% (FEF25-75), FEF50, FEF75, and Forced Vital Capacity (FVC) compared to those who did not receive vitamin C supplementation. However, there was no statistically significant difference in Forced Expiratory Volume at 0.5 s (FEV0.5) and the ratio of FEV0.5 to FVC between the offspring of pregnant smokers who received vitamin C and the control group. CONCLUSION: Vitamin C supplementation for smoking pregnant women may enhance the pulmonary function of their offspring, particularly in FEF25-75, FEF50, FEF75, and FVC. Nevertheless, there are no significant differences in FEV0.5 and the FEV0.5/FVC ratio. These findings suggest that vitamin C supplementation has potential benefits for specific pulmonary function. Further studies are needed to comprehensively assess the effects of vitamin C on pulmonary function in the context of maternal smoking during pregnancy.

A new strategy to prepare high-performance copper azide film for micro-initiator.

Copper azide (CA) has gradually become the chosen priming agent for microexplosive devices as a lead-free green priming agent. However, charge loading is challenging due to its high electrostatic sensitivity, severely limiting its practical application. In this study, copper hydroxide particles were evenly coated on the surface of carbon fiber using electrospinning and quick hot-pressing, and CA-based composites with uniform load were created using thein situazide technique while keeping good film characteristics. The produced CA-HP film has an electroostatic sensitivity of 3.8 mJ, which is much higher than the raw material of 0.05 mJ. The flame sensitivity has also been increased from 45 to 51 cm, and the use safety has been considerably enhanced. Furthermore, hot-pressed CA-HP films can improve the film's qualities, such as easy cutting and processing into the required shape, compatibility with MEMS processes, and the ability to successfully detonate secondary explosives with only 1 mg. This novel coupling technology expands the possibilities for developing high-safety primers for micro-initiator.

Effect of hydrogen/oxygen therapy for ordinary COVID-19 patients: a propensity-score matched case-control study.

BACKGROUND: Hydrogen/oxygen therapy contribute to ameliorate dyspnea and disease progression in patients with respiratory diseases. Therefore, we hypothesized that hydrogen/oxygen therapy for ordinary coronavirus disease 2019 (COVID-19) patients might reduce the length of hospitalization and increase hospital discharge rates. METHODS: This retrospective, propensity-score matched (PSM) case-control study included 180 patients hospitalized with COVID-19 from 3 centers. After assigned in 1:2 ratios by PSM, 33 patients received hydrogen/oxygen therapy and 55 patients received oxygen therapy included in this study. Primary endpoint was the length of hospitalization. Secondary endpoints were hospital discharge rates and oxygen saturation (SpO2). Vital signs and respiratory symptoms were also observed. RESULTS: Findings confirmed a significantly lower median length of hospitalization (HR = 1.91; 95% CIs, 1.25-2.92; p < 0.05) in the hydrogen/oxygen group (12 days; 95% CI, 9-15) versus the oxygen group (13 days; 95% CI, 11-20). The higher hospital discharge rates were observed in the hydrogen/oxygen group at 21 days (93.9% vs. 74.5%; p < 0.05) and 28 days (97.0% vs. 85.5%; p < 0.05) compared with the oxygen group, except for 14 days (69.7% vs. 56.4%). After 5-day therapy, patients in hydrogen/oxygen group exhibited a higher level of SpO2 compared with that in the oxygen group (98.5%±0.56% vs. 97.8%±1.0%; p < 0.001). In subgroup analysis of patients received hydrogen/oxygen, patients aged < 55 years (p = 0.028) and without comorbidities (p = 0.002) exhibited a shorter hospitalization (median 10 days). CONCLUSION: This study indicated that hydrogen/oxygen might be a useful therapeutic medical gas to enhance SpO2 and shorten length of hospitalization in patients with ordinary COVID-19. Younger patients or those without comorbidities are likely to benefit more from hydrogen/oxygen therapy.

Evaluating the ability of the NLHA2 and artificial neural network models to predict COVID-19 severity, and comparing them with the four existing scoring systems.

To improve the identification and subsequent intervention of COVID-19 patients at risk for ICU admission, we constructed COVID-19 severity prediction models using logistic regression and artificial neural network (ANN) analysis and compared them with the four existing scoring systems (PSI, CURB-65, SMARTCOP, and MuLBSTA). In this prospective multi-center study, 296 patients with COVID-19 pneumonia were enrolled and split into the General-Ward-Care group (N = 238) and the ICU-Admission group (N = 58). The PSI model (AUC = 0.861) had the best results among the existing four scoring systems, followed by SMARTCOP (AUC = 0.770), motified-MuLBSTA (AUC = 0.761), and CURB-65 (AUC = 0.712). Data from 197 patients (training set) were analyzed for modeling. The beta coefficients from logistic regression were used to develop a severity prediction model and risk score calculator. The final model (NLHA2) included five covariates (consumes alcohol, neutrophil count, lymphocyte count, hemoglobin, and AKP). The NLHA2 model (training: AUC = 0.959; testing: AUC = 0.857) had similar results to the PSI model, but with fewer variable items. ANN analysis was used to build another complex model, which had higher accuracy (training: AUC = 1.000; testing: AUC = 0.907). Discrimination and calibration were further verified through bootstrapping (2000 replicates), Hosmer-Lemeshow goodness of fit testing, and Brier score calculation. In conclusion, the PSI model is the best existing system for predicting ICU admission among COVID-19 patients, while two newly-designed models (NLHA2 and ANN) performed better than PSI, and will provide a new approach for the development of prognostic evaluation system in a novel respiratory viral epidemic.

Heterogeneity of T cells and macrophages in chlorine-induced acute lung injury in mice using single-cell RNA sequencing.

OBJECTIVE: Chlorine (Cl2), as an asphyxiant toxicant, induced poisoning incidents and acute lung injury (ALI) occur frequently. The specific pathogenesis of Cl2-induced ALI remains unclear. Immune cells play an important role in the process of lung damage. We used single-cell RNA sequencing (scRNA-seq) technology to explore T cells and macrophages molecular mechanism. METHODS: Female BALB/c mice were exposed to 400 ppm Cl2 for 15 min. scRNA-seq technology was used to observe the heterogeneity of T cells and macrophages. Hematoxylin-eosin (H&E) staining was used to evaluate the degree of lung injury. Immunofluorescence was used to verify the highly expressed genes of our interest. RESULTS: A total of 5316 to 7742 cells were classified into eight different cell types. Several new highly expressed anti-inflammatory and pro-inflammatory genes were found in T cells and macrophages, which were further verified in vitro. Through the pseudotime analysis of macrophages, it was found that the expression of pro-inflammatory and anti-inflammatory genes showed opposite trends in the development of Cl2-induced ALI. This study also mapped T cells-macrophage communication and identified the development of several important receptor-ligand complexes in Cl2-induced ALI. CONCLUSIONS: These findings are worthy of further exploration and provide new resources and directions for the study of Cl2-induced ALI in mice, especially in immune and inflammation mechanisms.

Targeted thrombolysis by using c-RGD-modified N,N,N-Trimethyl Chitosan nanoparticles loaded with lumbrokinase.

Lumbrokinase (LK) has strong fibrinolytic and thrombolytic activities, but it has a short half-life, can be easily inactivated, and may cause hemorrhage as a side effect. This study develops a potential thrombolytic therapy by fabricating N,N,N-Trimethyl Chitosan (TMC) nanoparticles modified with the cyclic Arg-Gly-Asp-Phe-Lys peptide (c-RGD) and loaded with LK (i.e. c-RGD-LK-NPs). The binding of c-RGD to platelet membrane GPIIb/IIIa receptors is expected to enable targeted delivery of the c-RGD-conjugated TMC to the thrombus. The synthesized c-RGD-LK-NPs had a mean particle size of 232.0 nm, zeta potential of 19.8 mV, entrapment efficiency of 52.7% ± 2.5%, and loading efficiency of 17.4% ± 0.65%. Transmission electron microscopy showed that they were generally spherical. The c-RGD-LK-NPs gave a cumulative in vitro LK release of 80.6% over 8 h, and the activity of LK was close to 80%, indicating that the nanoparticles protected the activity of LK. In vitro blood clot lysis assays were carried out and in vivo thrombolysis effect was tested in Sprague-Dawley rats carotid artery thrombus model. In all cases, the c-RGD-LK-NPs showed superior performance compared with the free LK and the unmodified TMC nanoparticles loaded with LK. The c-RGD-LK-NPs reagent is expected to be potentially useful in treating thromboembolic diseases.

Annexin V-Conjugated Mixed Micelles as a Potential Drug Delivery System for Targeted Thrombolysis.

To alleviate the hemorrhagic side effect of thrombolysis therapy, a thrombus targeted drug delivery system based on the specific affinity of Annexin V to phosphatidylserine exposed on the membrane surface of activated platelet was developed. The amphiphilic and biodegradable biomaterial, polycaprolactone-block-poly(2-(dimethylamino)ethyl methacrylate)-block-poly(2-hydroxyethyl methacrylate) (PCL-b-PDMAEMA-b-PHEMA (PCDH)) triblock polymer, was synthesized via ring opening polymerization (ROP) and atom transfer radical polymerization (ATRP) to use as the nanocarriers of thrombolytic drug. In order to conjugate Annexin V to the polymer, PCDH was modified by succinic anhydride via ring-opening reaction to introduce the carboxyl group (PCDH-COOH). After preparation of PCDH/PCDH-COOH (9/1, m/m) mixed micelles, Annexin V was coupled with the micelles using carbodiimide chemistry. The blood clot lysis assay in vitro confirmed that lumbrokinase-loaded targeted micelles (LKTM) had stronger thrombolysis potency than free lumbrokinase (LK) and LK-loaded nontargeted micelles (LKM, P < 0.05). In vivo thrombolytic assay, multispectral, optoacoustic tomography (MSOT) was used to assess the target ability of LKTM. The results of MSOT images indicated the fluorescence intensity of the LKTM group located in the blood clot position were significantly stronger than the LKM group. A 5 mm of carotid artery containing blood clot was cut out 24 h later after administration to assess the degree of thrombolysis. The results of thrombolytic assay in vivo were consistent with the assay in vitro, which the differences between LK, LKM, and LKTM groups were both statistically significant. All the results of thrombolysis assays above proved that the capacity of thrombolysis in the LKTM group was optimal. It suggested that Annexin V-conjugated micelles will be a potential drug delivery system for targeted thrombolysis.

Association between parental occupational exposure and the risk of asthma in offspring: A meta-analysis and systematic review.

BACKGROUND: Previous epidemiological studies have shown inconsistent results regarding the relation between the risk of asthma in offspring and parental occupational exposure. Therefore, we conducted a comprehensive and systematic collection of currently available epidemiological data to quantify the correlation between the 2. METHODS: Related studies published before March 2023 were identified through searches of the Cochrane Library, Embase, PubMed, and Web of Science databases. The quality of included studies was assessed using the Newcastle-Ottawa Scale, while pooled odds ratios (ORs) with 95% confidence intervals (CIs) were computed using fixed-effect or random-effects models. RESULTS: This systematic review included 10 cohort studies, with a total of 89,571 parent-child pairs included in the quantitative analysis. The results exhibited a substantial association between parental occupational exposure to allergens (OR = 1.11; 95% CI: 1.00, 1.23; P = .051) and irritants (OR = 1.19; 95% CI: 1.07, 1.32; P = .001) and an increased risk of asthma in offspring. This association was also observed in the analysis of wheezing (OR = 1.22; 95% CI: 1.11, 1.35; P < .001 and OR = 1.19; 95% CI: 1.08, 1.32; P = .001). Subgroup analysis demonstrated that maternal occupational exposure to allergens (OR = 1.07; 95% CI: 1.02, 1.12; P = .008) and irritants (OR = 1.13; 95% CI: 1.05, 1.21; P = .001) significantly increased the risk of childhood asthma. Furthermore, parental postnatal occupational exposure to allergens (OR = 1.26; 95% CI: 1.10, 1.46; P = .001) and irritants (OR = 1.26; 95% CI: 1.06, 1.49; P = .009) had a more pronounced impact on childhood asthma. Higher levels of exposure (OR = 1.26; 95% CI: 1.10, 1.46; P = .001 and OR = 1.30; 95% CI: 1.16, 1.47; P < .001) were recognized as significant risk factors for childhood asthma. CONCLUSION: Parental occupational exposure to allergens and irritants increases the risk of asthma and wheezing in offspring, with maternal exposure, postnatal exposure, and high-dose exposure being the primary risk factors for childhood asthma.

Diffusion simulation and risk assessment model establishment of chlorine gas leakage based on terrain conditions.

This study researches the impact of terrain factors on chlorine gas diffusion processes based on SLAB model. Simulating the law of wind speed changing with altitude by calculating the real-time speed with vertical height combing actual terrain data, and integrating the influence of terrain on wind speed by using Reynolds Average Navier-Stokes (RANS) algorithm, K-turbulence model, and standard wall functions, then plotting the gas diffusion range in the map with terrain data according to the Gaussian-Cruger projection algorithm and dividing the hazardous areas according to the public exposure guidelines (PEG). The accidental chlorine gas releases near Lishan Mountain, Xi'an City, were simulated by the improved SLAB model. The results show that there are obvious differences analyzing contrastively the endpoint distance and area of chlorine gas dispersion under real terrain condition and ideal condition at different times; it can be found that the endpoint distance of the real terrain conditions is 1.34 km shorter than that of the ideal conditions at 300 s with terrain factors, and also the thermal area is 3,768,026m2 less than that of the ideal conditions. In addition, it can predict the specific number of casualties within different levels of harm at 2 min after chlorine gas dispersion, and casualties are constantly changing over time. The fusion of terrain factors can be used to optimize the SLAB model, which is expected to provide an important reference for effective rescue.

Enhanced Thermal Decomposition and Safety of Spherical CL-20@MOF-199 Composites via Micro-Nanostructured Self-Assembly Regulation.

The characteristics of high burning rate, high energy output, and low pressure exponent have always been the focus of development in the field of composite solid rocket propellants. In this paper, a metal-organic framework (MOF-199) compound is introduced to prepare micro-nanospherical CL-20@MOF-199 composites via the spray-drying self-assembly technique to reach the above goals. MOF-199, which acts as an attractive combustion catalyst and a safety regulator, is uniformly coated on the surface of CL-20 with close interface contact between particles, effectively accelerating the thermal decomposition of CL-20 and ensuring safety performance. The average noncovalent interaction (aNCI) analysis illustrates that there are strong C-H···O hydrogen bonds and van der Waals interaction between CL-20 and MOF-199 molecules, greatly enhancing the effect of interparticle assembly. The effects of different contents of MOF-199 on the thermal, safety, and energy properties of CL-20 were discussed. The thermal analysis demonstrates that MOF-199 has a significant thermal catalytic effect on CL-20, with an advanced peak temperature of thermal decomposition of 14.2 °C and a reduced activation energy barrier of 34.2 kJ·mol-1, mainly benefitting from more exposed catalytic active sites and close interface contact. In addition, CL-20@MOF-199 composites exhibit decreased mechanical sensitivity (IS: 21-40 cm, FS: 80-240 N) and excellent energy performance. This work clearly demonstrates that MOF-199 is both a superior combustion catalyst and a good safety buffer for CL-20, and it opens new potential for further applications of CL-20 in composite solid propellants.

Single-cell transcriptomes reveal heterogeneity of chlorine-induced mice acute lung injury and the inhibitory effect of pentoxifylline on ferroptosis.

To investigate the effect of pentoxifylline (PTX) on Chlorine (Cl2)-induced acute lung injury (ALI) by single-cell RNA sequencing (scRNA-seq). Female BALB/c mice were exposed to Cl2 at 400 ppm for 15 min. H&E staining was used to observe the degree of lung injury. scRNA-seq was conducted to analysis of normal and Cl2-exposed mice lung tissues. Immunofluorescence was used to observe genes of interest. Thirty-two mice were randomly divided into four groups: Control, Cl2, Cl2+Fer-1, Cl2+PTX. TEM, WB and ELISA were used to detect ferroptosis-related indicators. The 5, 8, 10, 12, 16, 20 clusters were epithelial cells and 4, 15, 18, 19, 21 clusters were endothelial cells. Pseudo-time analysis revealed the differentiation trajectory of epithelial cells and key regulatory genes (Gclc, Bpifa1, Dnah5 and Dnah9) during the process of injury. Cell-cell communication analysis identified several important receptor-ligand complexes (Nrp1-Vegfa, Nrp2-Vegfa, Flt1-Vegfa and Flt4-Vegfa). Ferroptosis were found up-regulated in epithelial and endothelial cells by GSVA analysis. Highly expressed genes to which closely related ferroptosis were found by SCENIC analysis. PTX could significantly decrease the levels of MDA and abnormal high expression of solute carrier family 7 member 11 (SLC7A11, the key transporter of cystine) as well as increase the expression of GSH/GSSG and glutathione peroxidase 4 (GPX4) (p < 0.05). This study revealed novel molecular features of Cl2-induced ALI. PTX may be a potential specific drug by inhibiting the process of ferroptosis in epithelial and endothelial cells.

Platinum-based adjuvant therapy was efficient for triple-negative breast cancer: a meta-analysis from randomized controlled trials.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer. Neoadjuvant chemotherapy was widely accepted for treating TNBC. This systematic review and meta-analysis aimed to evaluate the efficacy, safety, and survival benefit of platinum-based adjuvant therapy (PBAT) in treating TNBC. The keywords were searched in Medline, Embase, Pubmed, and Cochrane Library database up to July 24, 2022. All the randomized control trials (RCTs) comparing PBAT and non-PBAT in treating TNBC were included in our study. The pathological complete remission (pCR) and complications were compared by odds ratio (OR) and 95% confidence intervals (CIs). The overall survival (OS) and relapse-free survival (RFS) were compared by hazard ratio (HR) and 95% CIs. A total of 19 RCTs were included in our meta-analysis, among which 2,501 patients were treated with PBAT and 2,290 with non-PBAT. The patients treated with PBAT combined a significantly higher pCR rate compared to those patients treated with non-PBAT (49.8% versus 36.4%, OR = 1.27, 95%CI = 1.14-1.43, P < 0.001). Besides, patients treated with PBAT had a significantly better RFS (HR = 0.78, 95%CI = 0.63-0.95, P = 0.016), but not in OS (HR = 0.84, P = 0.304). Although the occurrence of neutropenia and nausea were slightly different between the PBAT group (51.5% and 24.4%) and the non-PBAT group (47.0% and 29.4%), the complications were acceptable in the two treatments groups. Our results demonstrated that TNBC patients treated with PBAT could achieve a higher pCR rate and better RFS benefit without a higher complication rate.Highlights Platinum-based adjuvant therapy provided a higher pCR rate for TNBC.Platinum-based adjuvant therapy prolonged the RFS but without prolongingthe OS.Neutropenia and nausea rate was different between group PBAT and non-PBAT.

Extracellular Vesicle-Encapsulated MicroRNA-375 from Bone Marrow-Derived Mesenchymal Stem Cells Inhibits Hepatocellular Carcinoma Progression through Regulating HOXB3-Mediated Wnt/ß-Catenin Pathway.

Nowadays, microRNA-375 (miR-375) has been implicated in many types of cancers, including hepatocellular carcinoma (HCC), and the functions of miRNAs encapsulated by extracellular vesicles (EV) in HCC progression have also been extensively investigated. In this research, we aimed to probe into the mechanism of EV-encapsulated miR-375 from bone marrow-derived mesenchymal stem cells (BM-MSCs) in HCC progression. At first, miR-375 expression in HCC tissues and cells was detected using RT-qPCR, and miR-375 was overexpressed to specify the effects of miR-375 on the malignant phenotype of HCC cells. miR-375 was downregulated in HCC, and overexpression of miR-375 suppressed HCC cell growth. Then, BM-MSCs and EV were isolated and identified, and, EV were cocultured with HCC cells for further functional assays. It was found that miR-375 encapsulated by EV could restrict the malignant phenotypes of HCC cells. Furthermore, the downstream genes and signaling cascades involved in HCC growth were investigated. HOXB3 was determined to be a downstream target of miR-375, and upregulation of miR-375 decreased Wnt1 and ß-catenin protein expression. Furthermore, HOXB3 blocked the repressive effects of miR-375 on HCC cells and Wnt1 and ß-catenin expression. This study highlights that miR-375 encapsulated by EV inhibits HCC development via modulating the HOXB3/Wnt/ß-catenin axis.

Improving diacetyl production in Corynebacterium glutamicum via modifying respiratory chain.

To explore the suitability of Corynebacterium glutamicum as a chassis for diacetyl production from glucose, diacetyl metabolic pathway and the respiratory chain were linked to achieve redox balance. The carbon flux was redirected from pyruvate to diacetyl by overexpressing the α-acetolactate synthase, in combination with disruption the biosynthetic pathways of lactate, acetoin, 2,3-butanediol and acetate in C. glutamicum ATCC 13032. These modifications resulted in a sharp increase of the NADH/NAD+ ratio from 0.53 to 1.10, and produced 0.58 g/L diacetyl under aerobic conditions, representing a 58-fold increase over the wild type. Although the modification of the by-product pathways is an effective strategy, these disruption led to intracellular cofactor imbalance. NADH re-oxidization was further successfully solved by overexpressing of cytochrome bd oxidase. We constructed an efficient respiration-dependent cell factory by modification of the respiratory chain, improving diacetyl titer to 1.29 g/L in CGC11, decreased NADH/NAD+ ratio to 0.45, increased the ATP concentration from 8.51 to 10.64 µM/gDCW. To our best knowledge, this is the first report of diacetyl synthesis in C. glutamicum. Intracellular cofactor imbalance can be reduced by modification of the respiratory chain for production of diacetyl as well as other bio-based products with cofactor imbalance in C. glutamicum.

A randomized, double-blind, placebo-controlled, multicenter clinical trial for efficacy and safety of traditional Chinese medicine combined with antibiotics in the treatment of bacterial pneumonia in children.

BACKGROUND: Pneumonia is the second leading cause of death in children worldwide after preterm birth and certification. Bacteria, viruses, mycoplasma, and other microorganisms are known to be the main causes of pneumonia, of which bacterial pathogenic factors account for 12.5% of cases. The invention and application of antibiotics have improved the prognosis of children with community-acquired bacterial pneumonia (CABP) to a certain extent, but with the emergence of antibiotic resistance worldwide, the mortality of children with CABP is still high. "Maxing Shigan Decoction" and "Qingfei Decoction" have significant efficacy in the treatment of CABP in children, but there is no standardized randomized controlled trial to systematically evaluate the outcomes. METHODS: This study is a randomized, double-blind, placebo-controlled, multicenter clinical trial that will randomize 240 patients with CABP to group of Oral Maxing Shigan Decoction, group of Qingfei Decoction or group of placebos administered 3 times a day for 7 days. This study will observe a wide range of clinically relevant endpoints that have been used in clinical trials of pneumonia, including but not limited to clinical cure rate, antibiotic application days, complete antipyretic rate, complete antipyretic days, disease efficacy, traditional Chinese medicine syndrome effect, and antibiotic upgrade treatment rates. Safety will be assessed by monitoring for the incidence of adverse events during the study. DISCUSSION: This clinical trial is the first to evaluate the efficacy and safety of "Maxing Shigan Decoction" and "Qingfei Decoction" in the treatment of children with CABP. The research results will provide a reference for future research design. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900025354. Registered on 14th October 2019-Retrospectively registered, http://www.chictr.org.cn/.

Development of carrier-free nanocrystals of poorly water-soluble drugs by exploring metastable zone of nucleation.

There has been increasing interest in research and development of nanocrystals for the delivery of poorly water-soluble drugs that can be directly produced from solution. Compared with traditional carrier-based or encapsulation designs, drug nanocrystals circumvent possible side-effects due to carrier polymers and poor stability issues associated with encapsulation. The production of carrier-free nanocrystals requires careful control of nucleation and thus a thorough understanding of the relevant solution's metastable zone. A solution may stay supersaturated without forming any nuclei and become metastable. The maximal degree of supersaturation is known as the metastable zone width. When nucleation is triggered directly from the metastable zone, it helps to produce homogeneous nuclei leading to uniform nanocrystals. Herein, we report a study in which the solubility and metastable limit of paclitaxel (PTX) in ethanol aqueous solution were measured at 40 °C. A wide range of metastable compositions were studied to prepare carrier-free PTX nanocrystals with particle size smaller than 250 nm and PDI less than 0.25. Compared with the raw material, dissolution rate of PTX nanocrystals was significantly increased. The study enables production of high-quality drug nanocrystals for treating patients.

Complex Neuromuscular Changes Post-Stroke Revealed by Clustering Index Analysis of Surface Electromyogram.

The objective of this paperwas to characterize complex neuromuscular changes induced by a hemisphere stroke through a novel clustering index (CI) analysis of surface electromyogram (EMG). The CI analysis was performed using surface EMG signals collected bilaterally from the thenar muscles of 17 subjects with stroke and 12 age-matched healthy controls during their performance of varying levels of isometric muscle contractions. Compared with the neurologically intact or contralateral muscles, mixed CI patterns were observed in the paretic muscles. Two paretic muscles showed significantly increased CI implying dominant neurogenic changes, whereas three paretic muscles had significantly reduced CI indicating dominantmyopathic changes; the other paretic muscles did not demonstrate a significant CI alternation, likely due to a deficit of descending central drive or a combined effect of neuromuscular factors. Such discrimination of paretic muscles was further highlighted using a modified CI method that emphasizes between-side comparison for each individual subject. The CI findings suggest that there appears to be different central and peripheral processes at work in varying degrees after stroke. This paper provides a convenient and quantitative analysis to assess the nature of neuromuscular changes after stroke, without using any special equipment but conventional surface EMG recording. Such assessment is helpful for the development of appropriate rehabilitation strategies for recovery of motor function.