Clinical Applicable Carboxymethyl Chitosan with Gel-Forming and Stabilizing Properties Based on Terminal Sterilization Methods of Electron Beam Irradiation.

Carboxymethyl chitosan (CMC)-based hydrogels have great potential for clinical applications, but a critical sterilization process must be addressed to bring them to market. Compared to ethylene oxide sterilization or heat sterilization, irradiation sterilization avoids alkylation and heat damage, while available studies on γ-irradiated other polysaccharides show that solution polysaccharides are susceptible to degradation or cross-linking. Aiming at the challenges brought by the γ-irradiation process of polysaccharide aqueous solution, this paper innovatively proposes the lyophilized CMC using electron beam (EB) irradiation, which not only avoids the generation of free radicals in the irradiated water leading to the degradation and cross-linking of polysaccharides but also retains the properties of CMC in terms of gel formation, stabilization, and clinical application. We used FTIR, TG, GPC, and microbial load tests to demonstrate that lyophilized CMC did not have significant changes in structure and molecular weight after EB irradiation, complied with the requirements for sterilization, and still had gel stability, thus proving that lyophilized CMC could be used for EB irradiation and met the requirements for clinical application. Therefore, this work is expected to further advance CMC injectable hydrogels toward clinical applications and provide a new direction for the sterilization processes of other polysaccharide hydrogels.

Cross-regulation between proteome reallocation and metabolic flux redistribution governs bacterial growth transition kinetics.

Bacteria need to adjust their metabolism and protein synthesis simultaneously to adapt to changing nutrient conditions. It's still a grand challenge to predict how cells coordinate such adaptation due to the cross-regulation between the metabolic fluxes and the protein synthesis. Here we developed a dynamic Constrained Allocation Flux Balance Analysis method (dCAFBA), which integrates flux-controlled proteome allocation and protein limited flux balance analysis. This framework can predict the redistribution dynamics of metabolic fluxes without requiring detailed enzyme parameters. We reveal that during nutrient up-shifts, the calculated metabolic fluxes change in agreement with experimental measurements of enzyme protein dynamics. During nutrient down-shifts, we uncover a switch of metabolic bottleneck from carbon uptake proteins to metabolic enzymes, which disrupts the coordination between metabolic flux and their enzyme abundance. Our method provides a quantitative framework to investigate cellular metabolism under varying environments and reveals insights into bacterial adaptation strategies.

Simply and Cheaply Prepared Liposomal Membrane for Nanocarriers: High Encapsulation Efficiency Based on Broad Regulation of Surface Charges and pH-Switchable Performance.

The zeta potential of nanoparticles impacts their distribution and metabolism in the body as well as their interaction with medications of varying charges, hence altering therapeutic efficacy and safety. In this paper, the external charges of liposomes were regulated by utilizing a simple and economical method based on competition for protons of cationic chitosan (CS) and anion hyaluronic acid (HA). The charge regulation of a liposomal membrane is generally accomplished by adjusting the ratio of charged lipids within a liposome (e.g., cationic DOTAP or anionic DOPS), the stability of which was maintained by the coating materials of cationic chitosan (CS) or anion hyaluronic acid (HA). A series of nanoparticles could respond to pH-stimulation with adjustable surface charge. Moreover, the sizes of liposomes coated with CS and HA remain within a narrow range. In vitro cytotoxicity tests revealed that the nanocarriers were safe, and the nanoparticles containing antitumor medicines were efficient in tumor therapy. Considering liposomes with different external surface charges could be aimed at diverse therapy purposes. The strategies for regulating liposomal surface charges with high encapsulation rates and certain release cycles reported here could provide a versatile platform as carriers for the delivery of drugs and other macromolecules into human bodies.

The role and regulatory mechanism of HIF-1α in myocardial injury in rats undergoing cardiopulmonary bypass.

BACKGROUND: Hypoxia-inducible factor-1alpha (HIF-1α) is a transcription factor implicated in physiological and pathological responses to hypoxia. The present study aims to investigate the effect and mechanism of HIF-1α on cardiopulmonary bypass (CPB)-related myocardial injury, thereby conferring a theoretical basis for the clinical treatment of myocardial injury in CPB. METHODS: An experimental model of CPB was established in rats by surgery. Adenovirus-packaged overexpression vectors and antiagomiRNA were used to overexpress HIF-1α and NR4A1 or inhibit miR-124-3p expression in rat myocardial tissues, respectively. qRT-PCR and Western blot detected HIF-1α, miR-124-3p, and NR4A1 expression in myocardial tissues. The rat cardiac function was monitored through an echocardiogram. The rat plasma at different stages of CPB was collected, followed by the detection of IL-6, cTnT, CK-MB, and IL-1ß. TUNEL staining measured apoptosis in myocardial tissues. ChIP assay analysed the enrichment of HIF-1α on the miR-124-3p promoter. The binding relationships between HIF-1α and miR-124-3p promoter sequence and between miR-124-3p and NR4A1 3'UTR sequence were confirmed by dual-luciferase reporter assay. RESULTS: HIF-1α expression had no significant change after CPB modelling. Overexpression of HIF-1α improved the cardiac function of CPB rats, decreased plasma IL-6, cTnT, CK-MB, and IL-1ß levels, and reduced TUNEL-positive myocardial cells. HIF-1α was enriched on the miR-124-3p promoter and promoted miR-124-3p expression. miR-124-3p bound to NR4A1 3'UTR sequence and targeted NR4A1 expression. Inhibition of miR-124-3p or overexpression of NR4A1 partially reversed the ameliorative effect of HIF-1α overexpression on myocardial injury in CPB rats. CONCLUSION: Overexpression of HIF-1α can improve myocardial injury in CPB rats via the miR-124-3p/NR4A1 axis.

A powerful antitumor "trident": the combination of radio-, immuno- and anti-angiogenesis therapy based on mesoporous silica single coated gold nanoparticles.

Although immunotherapy in combination with anti-angiogenesis therapy has made a breakthrough in the first-line treatment of cancer, considering the low responder rate and the adverse events, it is vital to propose a new combination modality. In this study, we report single encapsulated mesoporous silica coated gold nanoparticles that synergize sensitizing radiotherapy with the current combination therapy. Distinguished from simply combining two treatments, the nanoparticle-mediated "trident" therapy resolved the problem of matching the dose between radiation and drug, which determines the outcome since drug demand rises with immunosuppression from increased sensitivity to radiotherapy. The nanomedicine produced energy depositions when radiation was introduced, and released the loaded toripalimab and bevacizumab, exhibiting significant anti-tumor properties. In vitro tumor cell viability results indicated the highest inhibition by the "trident" therapy and in vivo animal models also revealed the earliest decrease in tumor tissue volume. As a result, the "trident" therapy is expected to further improve the anti-tumor benefits of the combination of immunotherapy and anti-angiogenesis therapy and provides a versatile perspective on cancer treatment.

A novel hydrogel orthotopic injection model in moderately hypofractionated radiation therapy for prostate cancer: Adaptive degradation and durable imaging.

Purpose: Moderately hypofractionated radiotherapy (MHRT) holds an important position in prostate cancer management. Existing hydrogel spacers can protect the rectum from radiation damage, but need improvement. We explored the application of a novel hydrogel in MHRT with adaptive degradation and durable imaging functions. Methods and materials: The hydrogels were irradiated with 6MV x-ray to detect the radio-resistance property. Male SD rats (n=45) underwent hydrogel injection between the prostate and rectum. CT was used for investigating the novel spacer's degradation and imaging functions over three months. The hydrogel's radiation-attenuation properties and biocompatibility were further assessed. Results: Hydrogel weight and volume remained stable for six weeks post-injection. After MHRT ended, the hydrogel showed accelerated degradation characteristics and remained in the body for at most three months. CT values of hydrogels exceeded 300 Hounsfield units (HU) throughout treatment, significantly higher than in surrounding normal tissues. A significant dose drop behind the hydrogel was observed post-implantation. Biocompatibility tests of hydrogel found it safe enough for living organisms. Conclusions: The novel hydrogel application was fully adaptable to prostate cancer MHRT modalities, largely stable during treatment, rapidly degraded after radiotherapy ended, and consistently maintained superior imaging performance and biocompatibility. This novel spacer will be an effective tool in the era of hypofractionated radiotherapy.

The Albumin-to-Fibrinogen Ratio Independently Predicts Acute Kidney Injury in Infants With Ventricular Septal Defect Undergoing Cardiac Surgery With Cardiopulmonary Bypass.

Background: Acute kidney injury (AKI) is a common and serious complication faced by children following ventricular septal defect (VSD) surgery with cardiopulmonary bypass (CPB). The objective of this study was to explore potential predictors inherent to AKI. Methods: VSD infants who were scheduled for elective cardiac surgery with CPB from 2017 to 2020 were enrolled in this study. Based on the Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease (pRIFLE) criteria, patients were divided into AKI and non-AKI groups. Univariate and multivariate logistic regression analyses were carried out in order to evaluate potential risk factors for AKI. Receiver operating characteristic (ROC) curves were generated to evaluate the predictive probabilities of risk factors for AKI. Results: Of all the 338 enrolled VSD infants, 49 manifested AKI with an incidence of 14.5% (49/338). The ROC curve indicated that albumin-to-fibrinogen ratio (AFR) during CPB was a significant predictor of AKI [area under the curve (AUC), 0.711; p < 0.001]. Based on the univariate and multivariate logistic analyses, AFR during CPB [odds ratio (OR), 1.89; 95% confidence interval (CI), 1.22-2.76, p = 0.011] was the only independent risk factor for AKI. Conclusions: This study demonstrated that a low AFR (<9.35) during CPB was an independent risk factor for AKI in VSD infants following cardiac surgery with CPB.

Circular Network of Coregulated Sphingolipids Dictates Chronic Hypoxia Damage in Patients With Tetralogy of Fallot.

Background: Tetralogy of Fallot (TOF) is the most common cyanotic heart disease. However, the association of cardiac metabolic reprogramming changes and underlying molecular mechanisms in TOF-related chronic myocardial hypoxia damage are still unclear. Methods: In this study, we combined microarray transcriptomics analysis with liquid chromatography tandem-mass spectrometry (LC-MS/MS) spectrum metabolomics analysis to establish the metabolic reprogramming that occurs in response to chronic hypoxia damage. Two Gene Expression Omnibus (GEO) datasets, GSE132176 and GSE141955, were downloaded to analyze the metabolic pathway in TOF. Then, a metabolomics analysis of the clinical samples (right atrial tissue and plasma) was performed. Additionally, an association analysis between differential metabolites and clinical phenotypes was performed. Next, four key genes related to sphingomyelin metabolism were screened and their expression was validated by real-time quantitative PCR (QT-PCR). Results: The gene set enrichment analysis (GSEA) showed that sphingolipid metabolism was downregulated in TOF and the metabolomics analysis showed that multiple sphingolipids were dysregulated. Additionally, genes related to sphingomyelin metabolism were identified. We found that four core genes, UDP-Glucose Ceramide Glucosyltransferase (UGCG), Sphingosine-1-Phosphate Phosphatase 2 (SGPP2), Fatty Acid 2-Hydroxylase (FA2H), and Sphingosine-1-Phosphate Phosphatase 1 (SGPP1), were downregulated in TOF. Conclusion: Sphingolipid metabolism was downregulated in TOF; however, the detailed mechanism needs further investigation.

The volume expansion effect of amine during CO2 adsorption process: An experimental study combined with theoretical calculations.

The volume expansion effect of amine supported on mesoporous silica during CO2 adsorption process was found for the first time through well-designed experiments and was further confirmed by theoretical calculations. It was found that the residual pore volume of mesocellular silica foam (MCF) based solid amine sorbent (tetraethylenepentamine (TEPA) supported on MCF) gradually decreased with the increase of CO2 uptake. Moreover, the surface area, the average diameters of window and cell of MCF show a similar changing trend. This is due to the volume expansion effect of TEPA during CO2 adsorption process, i.e., the total volume of reaction products of TEPA and CO2 is larger than that of pure TEPA. The products are very sticky and almost lose the liquidity totally even at 80 °C. The sticky products and the volume expansion effect may increase the mass transfer resistance and are not beneficial to higher CO2 uptakes especially for solid amine sorbent with higher amine loading due to the decrease of pore size and the residual pore volume. DFT calculations based on simple models also indicate that the total volume of the generated products is much larger than that of unreacted amine, further confirming the volume expansion effect of amine during CO2 adsorption process. DFT calculations also indicate that the volume is even doubled in the presence of moisture. The volume expansion effect of solid amine sorbent found in this study may help to design the sorbent with high CO2 capture performance and less the mass transfer resistance.

Compositional data network analysis via lasso penalized D-trace loss.

MOTIVATION: With the development of high-throughput sequencing techniques for 16S-rRNA gene profiling, the analysis of microbial communities is becoming more and more attractive and reliable. Inferring the direct interaction network among microbial communities helps in the identification of mechanisms underlying community structure. However, the analysis of compositional data remains challenging by the relative information conveyed by such data, as well as its high dimensionality. RESULTS: In this article, we first propose a novel loss function for compositional data called CD-trace based on D-trace loss. A sparse matrix estimator for the direct interaction network is defined as the minimizer of lasso penalized CD-trace loss under positive-definite constraint. An efficient alternating direction algorithm is developed for numerical computation. Simulation results show that CD-trace compares favorably to gCoda and that it is better than sparse inverse covariance estimation for ecological association inference (SPIEC-EASI) (hereinafter S-E) in network recovery with compositional data. Finally, we test CD-trace and compare it to the other methods noted above using mouse skin microbiome data. AVAILABILITY AND IMPLEMENTATION: The CD-trace is open source and freely available from https://github.com/coamo2/CD-trace under GNU LGPL v3. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

[Moxibustion Plus Medication Can Relieve Refractory Nausea and Vomiting and Improve Quality of Life of Advanced Cancer Patients Undergoing Chemical Therapy].

OBJECTIVE: To explore the efficacy of moxibustion combined with medication in the treatment of refractory nausea and vomiting and quality of life (QOL) in advanced cancer patients. METHODS: A total of 266 advanced cancer patients with nausea and vomiting were randomly assigned to Metoclopramide group (M group, n＝70), Metoclopramide plus Haloperidol group (MH group, n＝65), moxibustion ＋ M group (n＝63), and moxibustion ＋ MH group (n＝68). Moxibustion was applied to bilateral Zusanli (ST 36), and Guanyuan (CV 4), Qihai (CV 6) for 20 min every time, twice a day for 2 weeks. The Rhodes' Index of nausea, Vomiting and Retching (INVR) was used for assessing the state of these symptoms in duration, frequency and severity (40 points), the 24-item Hamilton Depression Rating Scale (HAMD, 0－76 points) was employed to measure the patients' depression severity, and the Functional Assessment of Cancer Therapy-General (FACT-G, including physical, social/family, emotional, and functional dimensions, 27 items, 108 points) was adopted to measure the cancer patients' QOL. RESULTS: Following the treatment, the INVR and HAMD scores were significantly decreased in the M, MH, moxibusion＋M and moxibustion＋MH groups in comparison with their own pretreatment (P<0.05) and were significantly lower in the moxibustion＋MH group than in the M, MH and moxibustion＋M groups (P<0.05). The FACT-G scoring outcomes showed that the scores of physical well-being, emotional well-being, and total score of QOL were significantly higher in the MH, moxibustion＋M and moxibustion＋MH groups than in the M group, and were significantly higher in the moxibustion＋MH group than in the MH and moxibustion＋M groups (P<0.05). No significant differences were found between the MH and moxibustion＋M groups in the INVR and HAMD scores, and in the scores of physical well-being, emotional well-being and total score of QOL (P>0.05)．. CONCLUSION: Moxibustion plus Metoclopramide and Haloperidol can relieve refractory nausea and vomiting, and better depression and QOL in advanced cancer patients, being worthy of popularization in clinical practice.

Flux Balance Analysis of Plant Metabolism: The Effect of Biomass Composition and Model Structure on Model Predictions.

The biomass composition represented in constraint-based metabolic models is a key component for predicting cellular metabolism using flux balance analysis (FBA). Despite major advances in analytical technologies, it is often challenging to obtain a detailed composition of all major biomass components experimentally. Studies examining the influence of the biomass composition on the predictions of metabolic models have so far mostly been done on models of microorganisms. Little is known about the impact of varying biomass composition on flux prediction in FBA models of plants, whose metabolism is very versatile and complex because of the presence of multiple subcellular compartments. Also, the published metabolic models of plants differ in size and complexity. In this study, we examined the sensitivity of the predicted fluxes of plant metabolic models to biomass composition and model structure. These questions were addressed by evaluating the sensitivity of predictions of growth rates and central carbon metabolic fluxes to varying biomass compositions in three different genome-/large-scale metabolic models of Arabidopsis thaliana. Our results showed that fluxes through the central carbon metabolism were robust to changes in biomass composition. Nevertheless, comparisons between the predictions from three models using identical modeling constraints and objective function showed that model predictions were sensitive to the structure of the models, highlighting large discrepancies between the published models.

A network based covariance test for detecting multivariate eQTL in saccharomyces cerevisiae.

BACKGROUND: Expression quantitative trait locus (eQTL) analysis has been widely used to understand how genetic variations affect gene expressions in the biological systems. Traditional eQTL is investigated in a pair-wise manner in which one SNP affects the expression of one gene. In this way, some associated markers found in GWAS have been related to disease mechanism by eQTL study. However, in real life, biological process is usually performed by a group of genes. Although some methods have been proposed to identify a group of SNPs that affect the mean of gene expressions in the network, the change of co-expression pattern has not been considered. So we propose a process and algorithm to identify the marker which affects the co-expression pattern of a pathway. Considering two genes may have different correlations under different isoforms which is hard to detect by the linear test, we also consider the nonlinear test. RESULTS: When we applied our method to yeast eQTL dataset profiled under both the glucose and ethanol conditions, we identified a total of 166 modules, with each module consisting of a group of genes and one eQTL where the eQTL regulate the co-expression patterns of the group of genes. We found that many of these modules have biological significance. CONCLUSIONS: We propose a network based covariance test to identify the SNP which affects the structure of a pathway. We also consider the nonlinear test as considering two genes may have different correlations under different isoforms which is hard to detect by linear test.

A genome-scale metabolic network reconstruction of tomato (Solanum lycopersicum L.) and its application to photorespiratory metabolism.

Tomato (Solanum lycopersicum L.) has been studied extensively due to its high economic value in the market, and high content in health-promoting antioxidant compounds. Tomato is also considered as an excellent model organism for studying the development and metabolism of fleshy fruits. However, the growth, yield and fruit quality of tomatoes can be affected by drought stress, a common abiotic stress for tomato. To investigate the potential metabolic response of tomato plants to drought, we reconstructed iHY3410, a genome-scale metabolic model of tomato leaf, and used this metabolic network to simulate tomato leaf metabolism. The resulting model includes 3410 genes and 2143 biochemical and transport reactions distributed across five intracellular organelles including cytosol, plastid, mitochondrion, peroxisome and vacuole. The model successfully described the known metabolic behaviour of tomato leaf under heterotrophic and phototrophic conditions. The in silico investigation of the metabolic characteristics for photorespiration and other relevant metabolic processes under drought stress suggested that: (i) the flux distributions through the mevalonate (MVA) pathway under drought were distinct from that under normal conditions; and (ii) the changes in fluxes through core metabolic pathways with varying flux ratio of RubisCO carboxylase to oxygenase may contribute to the adaptive stress response of plants. In addition, we improved on previous studies of reaction essentiality analysis for leaf metabolism by including potential alternative routes for compensating reaction knockouts. Altogether, the genome-scale model provides a sound framework for investigating tomato metabolism and gives valuable insights into the functional consequences of abiotic stresses.

Tenuigenin protects dopaminergic neurons from inflammation-mediated damage induced by the lipopolysaccharide.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive death of dopaminergic neurons in the substantia nigra pars compacta (SNpc). AIMS: To study if tenuigenin (TEN), the main active component of Polygala tenuifolia, can protect dopaminergic neurons from inflammation-mediated damage in vivo. METHODS: We observed the effects of TEN on lipopolysaccharide (LPS) induced PD model by behavioral analysis, high-performance liquid chromatography, immunohistochemistry and enzyme-linked immunoadsorbent assay, etc. RESULTS: We showed that a single intranigral dose of LPSs (10 µg) induced microglial activation, reduced the survival ratio of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the SNpc and reduced dopamine (DA) content in the striatum. Treatment with 300 mg/kg TEN once per day over 14 weeks improved the survival rate of TH-ir neurons in the SNpc to 75%, on the non-injected side. Treatment with 200 or 300 mg/kg TEN once per day over 14 weeks significantly improved DA levels in the striatum to 73% and 81% on the non-injected side, respectively. The excessive production of cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, was abolished by TEN administration. CONCLUSION: Our results suggest that TEN may play a role in protecting dopaminergic neurons against inflammatory challenge.

Brassinosteroid alleviates phenanthrene and pyrene phytotoxicity by increasing detoxification activity and photosynthesis in tomato.

The present study was carried out to investigate the effects of exogenously applied 24-epibrassinolide (BR) on growth, gas exchange, chlorophyll fluorescence characteristics, lipid peroxidation and antioxidant systems of tomato seedlings grown under different levels (0, 10, 30, 100 and 300µM) of phenanthrene (PHE) and pyrene (PYR) in hydroponics. A concentration-dependent decrease in growth, photosynthetic pigment contents, net photosynthetic rate (Pn), stomatal conductance (Gs), maximal quantum yield of PSII (Fv/Fm), effective quantum yield of PSII (Φ(PSII)), photochemical quenching coefficient (qP) has been observed following PHE and PYR exposure. By contrast, non-photochemical quenching coefficient (NPQ) was increased. PHE was found to induce higher stress than PYR. However, foliar or root application of BR (50nM and 5nM, respectively) alleviated all those depressions with a sharp improvement in the activity of photosynthetic machinery. The activities of guaicol peroxidase (GPOD), catalase (CAT), ascorbate peroxidase (APX) and glutathione reductase (GR) as well as content of malondialdehyde (MDA) were increased in a dose-dependent manner under PHE or PYR treatments. Compared with control the highest increments of GPOD, CAT, APX, GR and MDA by PHE/PYR alone treatments were observed following 300µM concentration, which were 67%, 87%, 53%, 95% and 74% by PHE and 42%, 53%, 30%, 86% and 62% by PYR, respectively. In addition, both reduced glutathione (GSH) and oxidized glutathione (GSSG) were induced by PHE or PYR. Interestingly, BR application in either form further increased enzymatic and non enzymatic antioxidants in tomato roots treated with PHE or PYR. Our results suggest that BR has an anti-stress effect on tomato seedlings contaminated with PHE or PYR and this effect is mainly attributed by increased detoxification activity.