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Presents a duality theory and a nonlinear dual transformation method for solving a fully nonlinear, nonconvex parametric variational problem and associated nonlinear boundary-value problems. Associated partial differential equations; Proofs for complementary extremum principles in finite deformation theory; Method to obtain dual variational principles in n-dimensional problems.

Purpose: Rapid diagnosis of acute ischemic stroke (AIS) is critical to achieve positive outcomes and prognosis. This study aimed to construct a model to automatically identify the infarct core based on non-contrast-enhanced CT images, especially for small infarcts., Methods: The baseline CT scans of AIS patients, who had DWI scans obtained within less than 2 h apart, were included in this retrospective study. A modified Target-based deep learning model of YOLOv5 was developed to detect infarctions on CT. Randomly selected CT images were used for testing and evaluated by neuroradiologists and the model, using the DWI as a reference standard. Intraclass correlation coefficient (ICC) and weighted kappa were calculated to assess the agreement. The paired chi-square test was used to compare the diagnostic efficacy of physician groups and automated models in subregions. p  < 0.05 was considered statistically significant., Results: Five hundred and eighty four AIS patients were enrolled in total, finally 275 cases were eligible. Modified YOLOv5 perform better with increased precision (0.82), recall (0.81) and mean average precision (0.79) than original YOLOv5. Model showed higher consistency to the DWI-ASPECTS scores (ICC = 0.669, κ  = 0.447) than neuroradiologists (ICC = 0.452, κ = 0.247). The sensitivity (75.86% vs. 63.79%), specificity (98.87% vs. 95.02%), and accuracy (96.20% vs. 91.40%) were better than neuroradiologists. Automatic model had better diagnostic efficacy than physician diagnosis in the M6 region ( p  = 0.039)., Conclusion: The deep learning model was able to detect small infarct core on CT images more accurately. It provided the infarct portion and extent, which is valuable in assessing the severity of disease and guiding treatment procedures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Qu, Tang, Gao, Li, Zhao, Ban, Chen, Lu and Wang.)

Background: The effectiveness and safety of using Brucea javanica oil (BJO) in combination with Transarterial Chemoembolization (TACE) for liver cancer treatment are subjects of debate. This study aims to assess the comparative effectiveness and safety of BJO-assisted TACE versus TACE alone and quantifies the differences between these two treatment methods. Methods: A systematic search was conducted in multiple databases including PubMed, Cochrane, CNKI, and Wanfang, until 1 July 2023. Meta-analysis was conducted, and the results were presented as mean difference (MD), risk ratio (RR), and 95% confidence intervals (CI). Results: The search yielded 11 RCTs, with a combined sample size of 1054 patients. Meta-analysis revealed that BJO-assisted TACE exhibited superior outcomes compared to standalone TACE. Specific data revealed that BJO-assisted TACE improves clinical benefit rate by 22% [RR = 1.22, 95% CI (1.15, 1.30)], increases the number of people with improved quality of life by 32%, resulting in an average score improvement of 9.53 points [RR = 1.32, 95% CI (1.22, 1.43); MD = 9.53, 95% CI (6.95, 12.10)]. Furthermore, AFP improvement rate improved significantly by approximately 134% [RR = 2.34, 95% CI (1.58, 3.46)], accompanied by notable improvements in liver function indicators, with an average reduction of 27.19 U/L in AST [MD = -27.19, 95% CI (-40.36, -14.02)], 20.77 U/L in ALT [MD = -20.77, 95% CI (-39.46, -2.08)], 12.17 μmol/L in TBIL [MD = -12.17, 95% CI (-19.38, -4.97)], and a decrease of 43.72 pg/mL in VEGF [MD = -43.72, 95% CI (-63.29, -24.15)]. Most importantly, there was a 29% reduction in the occurrence of adverse reactions [RR = 0.71, 95% CI (0.60, 0.84)]. Conclusion: These findings indicate that BJO-assisted TACE may be considered as a potentially beneficial treatment option for liver cancer patients when compared to standalone TACE. It appears to contribute to improved treatment outcomes, enhanced quality of life, and potentially reduced adverse reactions, suggesting it warrants further investigation as a promising approach for liver cancer treatment. Systematic Review Registration: identifier CRD42023428948., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wu, Zhang, Li, Diao, Huang, Gao, Liang and Luo.)

Objective: Postoperative delirium (POD) has become a critical challenge with severe consequences and increased incidences as the global population ages. However, the underlying mechanism is yet unknown. Our study aimed to explore the changes in metabolites in three specific brain regions and saliva of older mice with postoperative delirium behavior and to identify potential non-invasive biomarkers., Methods: Eighteen-month-old male C57/BL6 mice were randomly assigned to the anesthesia/surgery or control group. Behavioral tests were conducted 24 h before surgery and 6, 9, and 24 h after surgery. Complement C3 (C3) and S100 calcium-binding protein B protein (S100beta) levels were measured in the hippocampus, and a metabolomics analysis was performed on saliva, hippocampus, cortex, and amygdala samples., Results: In total, 43, 33, 38, and 14 differential metabolites were detected in the saliva, hippocampus, cortex, and amygdala, respectively. "Pyruvate" "alpha-linolenic acid" and "2-oleoyl-1-palmitoy-sn-glycero-3-phosphocholine" are enriched in one common pathway and may be potential non-invasive biomarkers for POD. Common changes were observed in the three brain regions, with the upregulation of 1-methylhistidine and downregulation of D-glutamine., Conclusion: Dysfunctions in energy metabolism, oxidative stress, and neurotransmitter dysregulation are implicated in the development of POD. The identification of changes in the level of salivary metabolite biomarkers could aid in the development of noninvasive diagnostic methods for POD., (Copyright © 2024 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Objectives: The genus Streptococcus contains species of important zoonotic pathogens such as those that cause bovine mastitis. Unfortunately, many Streptococcus species have developed antibiotic resistance. Phage lysins are considered promising alternatives to antibiotics because it is difficult for bacteria to develop lysin resistance. However, there remains a lack of phage lysin resources for the treatment of streptococci-induced mastitis., Methods: We identified the prophage lysin Lys0859 from the genome of the Streptococcus suis SS0859 strain. Lys0859 was subsequently characterized to determine its host range, MIC, bactericidal activity in milk, and ability to clear biofilms in vitro. Finally, to determine the effects of Lys0859 on the treatment of both bovine mastitis and S. suis infection in vivo, we established models of Streptococcus agalactiae ATCC 13813-induced mastitis and S. suis serotype 2 SC19 systemic infection., Results: Our results demonstrate that Lys0859 possesses broad-spectrum lytic activity against Streptococcus and Staphylococcus species isolated from animals with bovine mastitis and 15 serotypes of S. suis isolated from swine. Intramammary and intramuscular injection of Lys0859 reduced the number of bacteria in mammary tissue by 3.75 and 1.45 logs compared with the PBS group, respectively. Furthermore, 100 μg/mouse of Lys0859 administered intraperitoneally at 1 h post-infection protected 83.3% (5/6) of mice from a lethal dose of S. suis infection., Conclusions: Overall, our results enhance the understanding and development of new strategies to combat both streptococci-induced mastitis and S. suis infection., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Lytic polysaccharide monooxygenase (LPMO) is known as an oxidatively cleaving enzyme in recalcitrant polysaccharide deconstruction. Herein, we report a novel AA10 LPMO derived from Bacillus subtilis (BsLPMO10A). A substrate specificity study revealed that the enzyme exhibited an extensive active-substrate spectrum, particularly for polysaccharides linked via β-1,4 glycosidic bonds, such as β-(Man1 → 4Man), β-(Glc1 → 4Glc) and β-(Xyl1 → 4Xyl). HPAEC-PAD and MALDI-TOF-MS analyses indicated that BsLPMO10A dominantly liberated native oligosaccharides with a degree of polymerization (DP) of 3-6 and C1-oxidized oligosaccharides ranging from DP3ox to DP6ox from mixed linkage glucans and beechwood xylan. Due to its synergistic action with a variety of glycoside hydrolases, including glucanase IDSGLUC5-38, xylanase TfXYN11-1, cellulase IDSGLUC5-11 and chitinase BtCHI18-1, BsLPMO10A dramatically accelerated glucan, xylan, cellulose and chitin saccharification. After co-reaction for 72 h, the reducing sugars in Icelandic moss lichenan, beechwood xylan, phosphoric acid swollen cellulose and chitin yielded 3176 ± 97, 7436 ± 165, 649 ± 44, and 2604 ± 130 μmol/L, which were 1.47-, 1.56-, 1.44- and 1.25-fold higher than those in the GHs alone groups, respectively (P < 0.001). In addition, the synergy of BsLPMO10A and GHs was further validated by the degradation of natural feedstuffs, the co-operation of BsLPMO10A and GHs released 3266 ± 182 and 1725 ± 107 μmol/L of reducing sugars from Oryza sativa L. and Arachis hypogaea L. straws, respectively, which were significantly higher than those produced by GHs alone (P < 0.001). Furthermore, BsLPMO10A also accelerated the liberation of reducing sugars from Celluclast® 1.5 L, a commercial cellulase cocktail, on filter paper, A. hypogaea L. and O. sativa L. straws by 49.58 % (P < 0.05), 72.19 % (P < 0.001) and 54.36 % (P < 0.05), respectively. This work has characterized BsLPMO10A with a broad active-substrate scope, providing a promising candidate for lignocellulosic biomass biorefinery., Competing Interests: Declaration of competing interest The authors report no declarations of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Pectate lyases (Pels) have a vital function in degradation of the primary plant cell wall and the middle lamella and have been widely used in the industry. In this study, two pectate lyase genes, IDSPel16 and IDSPel17, were cloned from a sheep rumen microbiome. The recombinant enzymes were expressed in Escherichia coli and functionally characterized. Both IDSPel16 and IDSPel17 proteins had an optimal temperature of 60 ℃, and an optimal pH of 10.0. IDSPel16 was relatively stable below 60 °C, maintaining 77.51% residual activity after preincubation at 60 °C for 1 h, whereas IDSPel17 denatured rapidly at 60 °C. IDSPel16 was relatively stable between pH 6.0 and 12.0, after pretreatment for 1 h, retaining over 60% residual activity. IDSPel16 had high activity towards polygalacturonic acid, with a V max of 942.90 ± 68.11, whereas IDSPel17 had a V max of only 28.19 ± 2.23 μmol/min/mg. Reaction product analyses revealed that IDSPel17 liberated unsaturated digalacturonate (uG 2 ) and unsaturated trigalacturonate (uG 3 ) from the substrate, indicating a typical endo-acting pectate lyase (EC 4.2.2.2). In contrast, IDSPel16 initially generated unsaturated oligogalacturonic acids, then converted these intermediates into uG 2 and unsaturated galacturonic acid (uG 1 ) as end products, a unique depolymerization profile among Pels. To the best of our knowledge, the IDSPel16 discovered with both endo-Pel (EC 4.2.2.2) and exo-Pel (EC 4.2.2.9) activities. These two pectate lyases, particularly the relatively thermo- and pH-stable IDSPel16, will be of interest for potential application in the textile, food, and feed industries. KEY POINTS: • Two novel pectate lyase genes, IDSPel16 and IDSPel17, were isolated and characterized from the sheep rumen microbiome. • Both IDSPel16 and IDSPel17 are alkaline pectate lyases, releasing unsaturated digalacturonate and unsaturated trigalacturonate from polygalacturonic acid. • IDSPel16, a bifunctional pectate lyase with endo-Pel (EC 4.2.2.2) and exo-Pel (EC 4.2.2.9) activities, could be a potential candidate for industrial application., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Occludin (OCLN) is a tight junction protein and Ocln deletion mutation causes male infertility in mice. However, the role of OCLN in male reproductive system remains unknown. In this study, we used an interdisciplinary approach to elucidate the underlying mechanism of male infertility in related to OCLN function, including Ocln knockout mice as well as a combined omics analysis and immunofluorescent labelling. Our results showed that the epididymis of Ocln -null mice displayed a phenomenon resembling epididymal sperm granuloma, which occurred especially in the junctional region between caput and corpus epididymidis. Sperm motility and fertilisation capacity were also impaired in these Ocln -null mice, accompanied by enlarged tubules in the proximal regions and degeneration in the distal regions of epididymis. Cellular localization analysis showed that OCLN immunofluorescence was enriched only in the apical junction of epithelial principal cells in the proximal regions of epididymis. Integrative omics analysis revealed the downregulation of gene clusters enriched in acid secretion and fatty acid metabolism in the Ocln -null epididymis, especially the enzymes related to the unsaturated arachidonic acid pathway. The number of proton-pump V-ATPase-expression clear cells, a key player of luminal acidification in the epididymis, declined drastically from prepubertal age before sperm arrival but not in the early postnatal age. This was accompanied by programmed cell death of clear cells and increased pH in the epididymal fluid of OCLN-deficient mice. The lipidomics results showed significantly increased levels of specific DAGs conjugated to unsaturated fatty acids in the Ocln-mutant. Immunofluorescent labelling showed that the arachidonic acid converting enzyme PTGDS and phospholipase PLA2g12a were prominently altered in the principal cells and luminal contents of the Ocln -mutant epididymis. Whereas the carboxylate ester lipase CES1, originally enriched in the WT basal cells, was found upregulated in the Ocln -mutant principal cells. Overall, this study demonstrates that OCLN is essential for maintaining caput-to-corpus epithelial integrity, survival of acid-secreting clear cells, and unsaturated fatty acid catabolism in the mouse epididymis, thereby ensuring sperm maturation and male fertility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Zhang, Gao, Li, Xu and Shum.)

β-Glucanases are a suite of glycoside hydrolases that depolymerize β-glucan into cellooligosaccharides and/or monosaccharides and have been widely used as feed additives in livestock. In this study, two novel glucanase genes, IDSGluc5-26 and IDSGluc5-37, derived from sheep rumen microbiota, were expressed and functionally characterized. The optimal temperatures/pH of recombinant IDSGLUC5-26 and IDSGLUC5-37 were 50 °C/5.0 and 40 °C/6.0, respectively. Notably, IDSGLUC5-26 showed considerable stability under acidic conditions. Both IDSGLUC5-26 and IDSGLUC5-37 showed the highest activities toward barley β-glucan, with V max values of 89.96 ± 9.19 µmol/min/mg and 459.50 ± 25.02 µmol/min/mg, respectively. Additionally, these two glucanases demonstrated hydrolysis of Icelandic moss lichenan and konjac gum, IDSGLUC5-26 releasing cellobiose (G2; occupying 17.37% of total reducing sugars), cellotriose (G3; 23.97%), and cellotetraose (G4; 30.93%) from barley β-glucan and Icelandic moss lichenan after 10 min and suggestive of a typical endo-β-1,4-glucanase (EC.3.2.1.4). In contrast, IDSGLUC5-37 was capable of liberating dominant G3 (64.11% or 67.55%) from barley β-glucan or Icelandic moss lichenan, suggesting that the enzyme was likely an endo-β-1,3 - 1,4-glucanases/lichenase (EC3.2.1.73). These findings describe the expression and characterization of two novel glucanase genes from sheep rumen microbiota. The two recombinant enzymes, particularly the acid-stable IDSGLUC5-26, will be of interest for potential application in food-/feed-additive development., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

This paper presents a new deterministic method and a polynomial-time algorithm for solving general huge-sized sensor network localization problems. The problem is first formulated as a nonconvex minimization, which was considered as an NP-hard based on conventional theories. However, by the canonical duality theory, this challenging problem can be equivalently converted into a convex dual problem. By introducing a new optimality measure, a powerful canonical primal-dual interior (CPDI) point algorithm is developed which can solve efficiently huge-sized problems with hundreds of thousands of sensors. The new method is compared with the popular methods in the literature. Results show that the CPDI algorithm is not only faster than the benchmarks but also much more accurate on networks affected by noise on the distances.

During October 2019 and March 2020, the luminous red supergiant Betelgeuse demonstrated an unusually deep minimum of its brightness. It became fainter by more than one magnitude and this is the most significant dimming observed in the recent decades. While the reason for the dimming is debated, pre-phase of supernova explosion, obscuring dust, or changes in the photosphere of the star were suggested scenarios. Here, we present spectroscopic studies of Betelgeuse using high-resolution and high signal-to-noise ratio near-infrared spectra obtained at Weihai Observatory on four epochs in 2020 covering the phases of during and after dimming. We show that the dimming episode is caused by the dropping of its effective temperature by at least 170 K on 2020 January 31, that can be attributed to the emergence of a large dark spot on the surface of the star., (© 2021. The Author(s).)

Obesity increases the risk of developing cardiovascular disease and other metabolic diseases. We intended to compare three different anthropometric indicators of obesity, in predicting the incidence of cardiovascular events in Chinese type 2 diabetes. Beijing Community Diabetes Study was a prospective multi-center study conducted in Beijing community health centers. Type 2 diabetes patients from fourteen community health centers were enrolled at baseline. The primary endpoint was cardiovascular events. The upper quartile of neck circumference (NC) was set as greater NC. A total of 3299 diabetes patients were enrolled. In which, 941 (28.52%) had cardiovascular disease at baseline. Logistic analysis showed that central obesity (waist circumference (WC) above 90 cm in men and 85 cm in women) and greater NC were all related to baseline cardiovascular disease (adjusted OR = 1.49, and 1.55). After 10-year follow-up, 340 (10.31%) had cardiovascular events. Compared with patients without cardiovascular events, those having cardiovascular events had higher BMI, larger WC and NC. Cox regression analysis showed that greater WC and NC were all associated with the occurrence of cardiovascular events (adjusted HR = 1.41, and 1.38). A higher NC and WC might increase the risk of cardiovascular events by about 40% in type 2 diabetes patients in Beijing communities.

Herbivores gastrointestinal microbiota is of tremendous interest for mining novel lignocellulosic enzymes for bioprocessing. We previously reported a set of potential carbohydrate-active enzymes from the metatranscriptome of the Hu sheep rumen microbiome. In this study, we isolated and heterologously expressed two novel glucanase genes, Cel5A-h38 and Cel5A-h49, finding that both recombinant enzymes showed the optimum temperatures of 50 °C. Substrate-specificity determination revealed that Cel5A-h38 was exclusively active in the presence of mixed-linked glucans, such as barley β-glucan and Icelandic moss lichenan, whereas Cel5A-h49 (EC 3.2.1.4) exhibited a wider substrate spectrum. Surprisingly, Cel5A-h38 initially released only cellotriose from lichenan and further converted it into an equivalent amount of glucose and cellobiose, suggesting a dual-function as both endo-β-1,3-1,4-glucanase (EC 3.2.1.73) and exo-cellobiohydrolase (EC 3.2.1.91). Additionally, we performed enzymatic hydrolysis of sheepgrass (Leymus chinensis) and rice (Orysa sativa) straw using Cel5A-h38, revealing liberation of 1.91 ± 0.30 mmol/mL and 2.03 ± 0.09 mmol/mL reducing sugars, respectively, including high concentrations of glucose and cellobiose. These results provided new insights into glucanase activity and lay a foundation for bioconversion of lignocellulosic biomass., Competing Interests: Declaration of competing interest The authors declared that they have no conflicts of interest to this work., (Copyright © 2021. Published by Elsevier B.V.)

To investigate the potential benefits of acarbose therapy on cardiovascular events (CVD) in Type 2 diabetes (T2DM) in an urban community over 10-year follow-up. The study population of Beijing Community Diabetes Study (BCDS) were type 2 diabetes (T2DM) living in 21 communities in Beijing. All patients received comprehensive intervention in accordance with the Chinese guidelines for the prevention and treatment of diabetes. Professors in endocrinology from top tier hospitals regularly visited the communities for consultations, which was a feature of this study. A total of 1797 T2DM in BCDS study had complete screening data, including blood glucose, blood pressure, lipid profiles and acarbose continuous therapy. After 10-year follow-up, the risks of CVD outcomes were assessed according to whether patients had received acarbose therapy or not. All patients were followed-up to assess the long-term effects of the multifactorial interventions. At baseline, compared with the acarbose therapy free in T2DM, there was no significant difference in achieving the joint target control in patients with acarbose therapy. From the beginning of 8th year follow-up, the joint target control rate in patients with acarbose therapy was significantly higher than that of acarbose therapy free. During the 10-year follow-up, a total of 446 endpoint events occurred, including all-cause death, cardiovascular events, cerebrovascular events. The incidences of myocardial infarction (from the 4th year of follow-up) and all-cause death (from the 2nd year of follow-up) in patients who received acarbose therapy were significantly lower than that of acarbose therapy free respectively. In Cox multivariate analyses, there were significant differences in incidences of myocardial infarction and all-cause death between afore two groups during the 10-year follow-up, and the adjusted HRs were 0.50 and 0.52, respectively. After multifactorial interventions, T2DM with acarbose therapy revealed significant reductions of myocardial infarction and all-cause death. The long-term effects of with acarbose therapy on improving joint target control might be one of the main reasons of myocardial infarction and all-cause death reduction.Trial Registration: ChiCTR-TRC-13003978, ChiCTR-OOC-15006090.

Antibody-dependent enhancement (ADE) refers to the process in which some virus-specific antibodies (generally non-neutralizing antibodies) bind to the virus and bind to some cells expressing FcR on the surface through their Fc segment, thereby mediating the endocytosis and replication of the virus and enhancing the infection of the virus. This review summarized experience of ADE in respiratory syncytial virus, dengue virus, influenza virus infection and explored the possible mechanism of COVID-19 high incidence and severity of the disease, which implied challenges in the process of vaccine development and provided some insights for COVID-19 pathogenesis.

Objective: The aim of this study was to investigate the correlations of endothelin-1 (ET-1) gene polymorphisms with the occurrence of hypertensive intracerebral hemorrhage (HICH)., Patients and Methods: In this case-control study, 100 HICH patients and 100 controls with matched race, age and gender were enrolled as research subjects. Single nucleotide polymorphisms (rs1920453, rs1022436 and rs1035627) in the promoter region of ET-1 gene were typed via conformational difference gel electrophoresis. Whether the distribution frequency of ET-1 genotypes conformed to Hardy-Weinberg equilibrium was evaluated by chi-square test. The correlations of different gene polymorphisms and alleles in the promoter region of ET-1 gene with the occurrence of HICH were analyzed. Furthermore, the associations of rs1920453 polymorphism in the promoter region of ET-1 gene with neurological deficit scores and laboratory parameters of HICH patients were explored., Results: It was found that ET-1 gene polymorphisms (rs1920453, rs1022436 and rs1035627) conformed to Hardy-Weinberg equilibrium (p>0.05). Gene-based association analysis indicated that only rs1920453 polymorphism and alleles were correlated with the occurrence of HICH (p<0.05). However, rs1022436 and rs1035627 polymorphisms and alleles had no association with HICH (p>0.05). Additionally, NIHSS score and high-density lipoprotein cholesterol level were prominently higher in HICH patients with CG and GG genotypes of ET-1 gene polymorphism rs1920453 than those in patients with CC genotype (p<0.05)., Conclusions: Rs1920453 in the promoter region of ET-1 gene is correlated with the occurrence of HICH.

Herein multi-walled carbon nanotubes (MWCNTs) were processed by ultrasonication and freeze-drying method. The morphology of the processed MWCNTs was examined by scanning electron microscopy. An original electrochemical sensor for the simultaneous detection of levodapa (LD), paracetamol (PA) and l-tyrosine (Tyr) was developed by dropcasting a mixture of processed MWCNTs and Nafion on a glassy carbon electrode. The as-prepared sensor was studied by cyclic voltammetry and differential pulse voltammetry. The peak currents of LD, PA and Tyr significantly increased compared to those obtained at bare glassy carbon electrodes or unprocessed MWCNTs modified electrodes. The peaks of LD, PA and Tyr were well-defined and obviously separated from each other. The linear ranges for detection of LD, PA and Tyr were 2.0-300.0, 2.0-180.0, and 2.0-120.0 μM, with a detection limit of 0.6, 0.5 and 0.8 μM (S/N = 3), respectively. Finally, the sensor was applied to detect LD, PA and Tyr in serum samples, and the results were satisfactory., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Microbiota from herbivore rumen is of great interest for mining glycoside hydrolases for lignocellulosic biomass biorefinement. We previously isolated a highly active but poorly thermostable xylanase (LXY) from a rumen fluid fosmid library of Hu sheep, a local high-reproductive species in China. In this study, we used a universal enzyme-engineering strategy called SpyTag/SpyCatcher molecular cyclization to improve LXY stability via isopeptide-bond-mediated ligation. Both linear and cyclized LXY (L- and C-LXY, respectively) shared similar patterns of optimal pH and temperature, pH stability, and kinetic constants (k m and V max ). However, the C-LXY showed enhanced thermostability, ion stability, and resilience to aggregation and freeze-thaw treatment than L-LXY, without compromise of its catalytic efficiency. Circular dichroism and intrinsic and 8-anilino-1-naphthalenesulfonic acid-binding fluorescence analysis indicated that the cyclized enzyme was more capable of maintaining its secondary and tertiary structures than the linear enzyme. Taken together, these results promote the cyclized enzyme for potential applications in the feed, food, paper pulp, and bioenergy industries.

Waste concrete was recycled and crushed into fine aggregate to prepare a high ductility cementitious composite (HDCC) in this study, for helping dispose the massive amount of construction waste and for reserving natural resources. Firstly, the features of recycled fine aggregate (RFA) were analyzed in detail and compared with natural fine aggregate (NFA). After that, the mechanical properties, including compression, flexure, bending and tension, and the microstructure of high ductility cementitious composite (HDCC) prepared with RFA were systematically investigated and compared with that of HDCC prepared with NFA. The results show that, since RFA has a higher water absorption rate and contains 4.86 times as much crush dust as NFA, HDCC with RFA forms a denser matrix and a higher bond between fiber and matrix than HDCC with NFA. Thus, HDCC with RFA has higher compressive, flexural, bending and tensile strength. Meanwhile, the higher bond between the fiber and matrix of HDCC with RFA and the finer particle sizes of RFA can greatly promote the development of multiple cracking. As a result, HDCC with RFA exhibits more remarkable stain hardening, and presents 182.73% higher peak deflection in bending and 183.33% higher peak strain in tension than HDCC with NFA. Finally, with the consideration of fiber volume fraction, the prediction models for the peak strengths of HDCC with RFA were proposed. The prediction results show a good agreement with the test results., Competing Interests: The authors declare no conflict of interest.

Abnormal tumour vasculature has a significant impact on tumour progression and response to therapy. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis and, thus, can be delivered to normalize tumour vasculature. However, a NO-delivery system with a prolonged half-life and a sustained release mechanism is currently lacking. Here we report the development of NanoNO, a nanoscale carrier that enables sustained NO release to efficiently deliver NO into hepatocellular carcinoma. Low-dose NanoNO normalizes tumour vessels and improves the delivery and effectiveness of chemotherapeutics and tumour necrosis factor-related, apoptosis-inducing, ligand-based therapy in both primary tumours and metastases. Furthermore, low-dose NanoNO reprogrammes the immunosuppressive tumour microenvironment toward an immunostimulatory phenotype, thereby improving the efficacy of cancer vaccine immunotherapy. Our findings demonstrate the ability of nanoscale NO delivery to efficiently reprogramme tumour vasculature and immune microenvironments to overcome resistance to cancer therapy, resulting in a therapeutic benefit.

Background: Neck circumference (NC) was found to be related to the risk factors of cardiovascular disease. However, the effects of NC on cardiovascular disease are still controversial. A prospective study of Chinese patients with type 2 diabetes was performed to evaluate the relationship between NC and cardiovascular disease., Methods: A multicenter prospective study with eight-year follow-up was conducted in Beijing communities. Cardiovascular events were defined as myocardial infarction, unstable angina pectoris, hospitalization for heart failure, coronary revascularization, cardiac death, stroke, transient ischemic attack, and cerebral hemorrhage., Results: A total of 3,009 diabetic patients were recruited. Following an eight-year follow-up, 211 patients with cardiovascular events (105 in men and 106 in women) were identified. All patients were categorized into two groups according to the upper quartile of NC (43 cm in men and 39 cm in women). The prevalence of cardiovascular events in men with an NC >43 cm (16.48%) was higher than that in the group with an NC <43 cm (8.16%, p =0.007). The prevalence of cardiovascular events in women with the NC >39 cm (10.67%) was higher compared to the group with NC <39 cm (5.31%, p =0.004). The longitudinal prevalence of cardiovascular events in groups with different NC increased with the increasing duration of follow-up ( p < 0.001). Cox regression analysis showed that higher NC was associated with the occurrence of cardiovascular events after adjusting for confounding variables (adjusted HR = 2.305 (1.535-3.460))., Conclusions: NC was associated with the occurrence of cardiovascular events in type 2 diabetes in Chinese communities, and greater NC may increase the risk of cardiovascular events by about 2.3-fold., Competing Interests: Liyong Bai is an employee of Bayer Healthcare Company Limited, China. All other authors declare no conflicts of interest., (Copyright © 2019 Guang-Ran Yang et al.)

Mannooligosaccharides are released by mannan-degrading endo-β-1,4-mannanase and are known as functional additives in human and animal diets. To satisfy demands for biocatalysis and bioprocessing in crowed environments, in this study, we employed a recently developed enzyme-engineering system, isopeptide bond-mediated molecular cyclization, to modify a mesophilic mannanase from Bacillus subtilis. The results revealed that the cyclized enzymes showed enhanced thermostability and ion stability and resilience to aggregation and freeze-thaw treatment by maintaining their conformational structures. Additionally, by using the SpyTag/SpyCatcher system, we generated a mannanase-xylanase bifunctional enzyme that exhibited a synergistic activity in substrate deconstruction without compromising substrate affinity. Interestingly, the dual-enzyme ring conformation was observed to be more robust than the linear enzyme but inferior to the single-enzyme ring conformation. Taken together, these findings provided new insights into the mechanisms of molecular cyclization on stability improvement and will be useful in the production of new functional oligosaccharides and feed additives.

A low-calcium microenvironment is essential for spermatozoa to mature in the epididymis; however, it remains unclear how dysregulation of epididymal luminal calcium is associated with male infertility. Using a warfarin-induced vitamin K2 deficiency rat model, we found that vitamin-K-dependent γ-glutamyl carboxylase (GGCX) and matrix Gla protein (MGP) were essential in extracellular calcium signaling of the intercellular communication required for epididymal sperm maturation. We found that GGCX and MGP co-localized in the vesicular structures of epididymal cells and spermatozoa. Calcium-regulated MGP binds to proteins in a biphasic manner; sub-millimolar calcium enhances, whereas excessive calcium inhibits, the binding. Bioinformatic analysis of the calcium-dependent MGP-bound proteome revealed that vesicle-mediated transport and membrane trafficking underlie the intercellular communication networks. We also identified an SNP mutation, rs699664, in the GGCX gene of infertile men with asthenozoospermia. Overall, we revealed that the GGCX-MGP system is integrated with the intercellular calcium signaling to promote sperm maturation., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The capacities for thermal and inhibitor tolerance are critical for industrial enzymes and loss of activity is a major challenge in deploying natural enzymes for commercial applications. Protein engineering approaches, such as site-directed mutagenesis and directed evolution, have been devoted to modifying natural enzymes. Recently, a post-translation protein engineering strategy, the SpyTag/SpyCatcher system, was introduced. Here, we have generated a thermo- and ion-tolerant cyclized xylanase (C-TFX) by fusing the SpyTag and SpyCatcher peptides to its N- and C- terminus respectively. Compared with the linear enzyme, C-TFX retained greater residual activity after heating or metal ion exposure. Intrinsic fluorescence and circular dichroism analysis revealed that the isopeptide bond mediated by SpyTag/SpyCatcher cyclization contributed to enhanced thermo- and ion-stability, probably by stabilizing its secondary and conformational structure. In addition, the heat-challenged C-TFX was observed to degrade natural lignocellulosic substrates efficiently. The cyclized xylanase was more stable and resistent to denaturation and aggregation than the linear enzyme. The "superglue" SpyTag/SpyCatcher cyclization system enables the enzyme to maintain its structural conformation, which will be of particular interest in engineering of enzymes for industrial application such as feed additives and functional oligosaccharides production., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Regulation of α-glucosidase (EC 3.2.1.20) and its inhibitors is of great interest to researchers due to its clinical relevance as a target enzyme for the treatment of α-glucosidase-mediated diseases, such as type 2 diabetes mellitus and Pompe disease. In this study, we conducted a phloroglucinol-induced inhibition kinetics assay and performed computational molecular dynamics (MD) simulations to assess binding manner in α-glucosidase. The results showed that phloroglucinol reversibly inhibited α-glucosidase in a dose-dependent but non-competitive manner (K i =2.07±0.16mM). Interestingly, the maximum peak wavelength and the hydrophobic surface remained unchanged during the inhibition reaction, with computational MD simulations further revealing that phloroglucinol bound in front of the active site pocket rather than in the α-glucosidase active site. Therefore, we speculate that phloroglucinol-specific inhibition is mild and the inhibitor likely binds to a single binding site near but not in the active site. Our study provided insight into the effects and mechanisms associated with a mild inhibitor of α-glucosidase activity and promotes fundamental research and potential applications of inhibitors for treatment of α-glucosidase-mediated clinical disease., (Copyright © 2018. Published by Elsevier B.V.)

Objective: We investigated the prognostic significance of metabolic risk scores and aspirin with respect to cerebrovascular events., Methods: A total of 25 communities of diabetic patients were enrolled in Beijing Community Diabetes Study (BCDS) from 2008. 3413 patients with T2DM in BCDS have complete screening data, including blood glucose, blood pressure, lipid profiles and anti-platelet therapy, which were assigned metabolic score (MS) and add up to the total metabolic score (TMS). According to the total metabolic score (TMS), the patients were divided into four equal groups: Group 1 (24 < TMS < 40), Group 2 (40 < TMS < 47), Group 3 (47 < TMS < 55) and Group 4 (55 < TMS < 87). After 96 months, patients were followed-up to assess the long-term effects of the multifactorial interventions., Results: During 96-months follow-up, a total of 91 cerebrovascular events occurred, including acute cerebral infarction, acute cerebral hemorrhage and transient ischemic attack (TIA). The incidence of cerebrovascular events was higher in the Group 4 than in the Group 1. In Cox multivariate analyses, there are significant differences in incidences of cerebral infarction events among the four groups during the 96-months follow-up. Cox proportional hazards analysis revealed that, HbA1c (p ≤ 0.001), systolic pressure (p ≤ 0.001), aspirin free treatment (P = 0.0023) are independent predictor for cerebrovascular events in diabetic patients., Conclusions: This study indicates that total metabolic score (TMS) influences the incidence of cerebrovascular events in diabetic patients. In addition to good control of blood glucose, blood pressure and lipid profiles, anti-platelet therapy is important for the prevention of cerebrovascular events in T2DM., Trial Registration: ChiCTR-TRC-13003978, ChiCTR-OOC-15006090., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Motivation: Toehold switches are a class of RNAs with a hairpin loop that can be unfolded upon binding a trigger RNA, thereby exposing a ribosome binding site (RBS) and permitting translation of the reporter protein. They have been shown very useful in detecting a variety of targets including RNAs from Zika and Ebola viruses. The base complementation between the toehold switch and the trigger RNA also makes it sensitive to sequence variations. Design of toehold switches involves a series of considerations related to their sequence properties, structures and specificities., Results: Here we present the first comprehensive web tool for designing toehold switches. We also propose a score for predicting the efficacy of designed toehold switches based on properties learned from ∼180 experimentally tested switches., Availability and Implementation: The toehold switch web tool is available at https://yiplab.cse.cuhk.edu.hk/toehold/.

Chronic liver diseases have recently garnered substantial attention as a leading cause of death around the world. During the progression of liver fibrosis/cirrhosis induced by chronic liver injury, hepatic stellate cells (HSCs) play key roles in the regulation of liver fibrogenesis and can even accelerate the progression of hepatocellular carcinoma (HCC). Thus, inhibition of HSC activation or suppression of inflammatory cytokine secretion by HSCs may be an efficient therapeutic strategy to ameliorate liver fibrosis/cirrhosis. In this study, we demonstrated that Cellax NPs (Carboxymethylcellulose - docetaxel-conjugated nanoparticles), which are nanoscale Pegylated carboxymethylcellulose - DTX conjugates, selectively target activated HSCs and abrogate their fibrogenic properties in vitro. Furthermore, Cellax NPs alleviated CCl 4 -induced hepatic fibrosis and suppressed HCC progression in a clinically relevant HCC model associated with underlying liver fibrosis in vivo. Taken together, Cellax NPs demonstrate great therapeutic promise as a treatment for liver fibrosis and cancer.

The gametocyte-specific factor 1 (GTSF1) gene participates in DNA methylation and retrotransposon activation in germ cells, particularly during cell proliferation. The present study aimed to assess the level of GTSF1 gene expression in liver cancer tumor tissues, and its role in human hepatoma cell lines in vitro and in a nude mouse model in vivo . GTSF1 gene expression was detected in liver cancer tumor tissues, compared with in healthy controls, via reverse transcription quantitative polymerase chain reaction. An adeno-associated virus vector was used to study tumor stem cell proliferation in vivo . A plasmid expressing GTSF1 was constructed and transfected into various human hepatoma cell lines, in order to analyze the cellular proliferation and apoptosis of liver cancer cells using small interfering (si)RNAs in vitro . In the present study, GTSF1 gene expression was detected in 18/24 (75.0%) liver cancer tumor tissues from patients with hepatocellular carcinoma (HCC), and elevated GTSF1 expression was identified in the tissue of one of 32 healthy control samples (3.13%; P<0.05). Notably, the GTSF1 gene was expressed at a higher frequency in AFP-positive HCC samples (14/16, 87.50%) compared with in AFP-negative HCC samples (4/8, 50.0%; P=0.129). In addition, there was no statistical significance between GTSF1 expression in non-HBV-infected (71.42%) and HBV-infected HCC specimens (76.47%), as determined by a χ 2 test (P=0.921). It was demonstrated that GTSF1 significantly increased the tumorigenicity of Ad-shNC-transfected (GTSF1-positive) HepG2 cells in the nude mouse xenograft model, whereas the sizes and weights of the tumors in the GTSF1-negative group were dercreased in comparison with the GTSF1-positive group (P<0.05). Reduced levels of GTSF1 mRNA, along with fewer and smaller colonies, were identified in two groups of human liver cancer cells treated with with GTSF1-targeting siRNA, when compared with cells without GTSF1 mRNA interference (P<0.05). In summary, the present study elucidated the GTSF1 mRNA expression pattern in liver cancer, and investigated the potential role of GTSF1 in tumorigenesis. The data suggest an important role for the GTSF1 gene in the molecular etiology of hepatocarcinogenesis, and indicate a potential application of GTSF1 mRNA expression in liver cancer diagnosis and therapy.

The rapid rise of drug- and multi-drug resistant pathogenic bacteria constitutes an increasing risk to global public health. Thus, it is essential to develop new agents and/or strategies to overcome the antibiotic resistance crisis. Herein, ultra-small protein-based nanoparticles (NPs) with absorption covering both the near-infrared (NIR) I and II windows were constructed as novel antibacterial agents, which introduced a killing strategy utilizing the synergistic photothermal and photodynamic effects. The agent engineered by the conjugation of Ce6 molecules to ultra-small hydrophilic protein-modified copper sulfide NPs can transfer light energy into thermal energy for photothermal therapy and produce reactive oxygen species for photodynamic therapy. Under the irradiation of both NIR I and II lasers, the agent demonstrated a potent bacteria killing activity on both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) in vitro bacteria with high efficacy and safety. Furthermore, the as-prepared NPs also displayed an efficient in vivo bactericidal activity in a mouse model as monitored by measuring the photoacoustic signals of the blood vessels around the infection site. Consequently, leveraging the synergistic photothermal and photodynamic effects, the as-designed ultra-small NIR NPs may eliminate the emergence of drug resistance due to the mechanical destruction of the bacteria cell, thus representing a promising approach to control the antibiotic resistance crisis.

Liver damage and fibrosis are precursors of hepatocellular carcinoma (HCC). In HCC patients, sorafenib-a multikinase inhibitor drug-has been reported to exert anti-fibrotic activity. However, incomplete inhibition of RAF activity by sorafenib may also induce paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in malignant cells. The consequence of this effect in non-malignant disease (hepatic fibrosis) remains unknown. This study aimed to examine the effects of sorafenib on activated hepatic stellate cells (HSCs), and develop effective therapeutic approaches to treat liver fibrosis and prevent cancer development. Methods: We first examined the effects of sorafenib in combination with MEK inhibitors on fibrosis pathogenesis in vitro and in vivo . To improve the bioavailability and absorption by activated HSCs, we developed CXCR4-targeted nanoparticles (NPs) to co-deliver sorafenib and a MEK inhibitor to mice with liver damage. Results: We found that sorafenib induced MAPK activation in HSCs, and promoted their myofibroblast differentiation. Combining sorafenib with a MEK inhibitor suppressed both paradoxical MAPK activation and HSC activation in vitro , and alleviated liver fibrosis in a CCl 4 -induced murine model of liver damage. Furthermore, treatment with sorafenib/MEK inhibitor-loaded CXCR4-targeted NPs significantly suppressed hepatic fibrosis progression and further prevented fibrosis-associated HCC development and liver metastasis. Conclusions: Our results show that combined delivery of sorafenib and a MEK inhibitor via CXCR4-targeted NPs can prevent activation of ERK in activated HSCs and has anti-fibrotic effects in the CCl 4 -induced murine model. Targeting HSCs represents a promising strategy to prevent the development and progression of fibrosis-associated HCC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

The epididymis is an essential organ for sperm maturation and reproductive health. The epididymal epithelium consists of intricately connected cell types that are distinct not only in molecular and morphological features but also in physiological properties. These differences reflect their diverse functions, which together establish the necessary microenvironment for the post-testicular sperm development in the epididymal lumen. The understanding of the biophysical properties of the epididymal epithelial cells is critical for revealing their functions in sperm and reproductive health, under both physiological and pathophysiological conditions. While their functional properties have yet to be fully elucidated, the epididymal epithelial cells can be studied using the patch-clamp technique, a tool for measuring the cellular events and the membrane properties of single cells. Here, we describe the methods of cell isolation and whole-cell patch-clamp recording to measure the electrical properties of primary dissociated epithelial cells from the rat cauda epididymides.

This paper describes the fabrication of paper-based plasmonic refractometric sensors through the embedding of metal nanoparticles (NPs) onto flexible papers using reversal nanoimprint lithography. The NP-embedded papers can serve as gas sensors for the detection of volatile biogenic amines (BAs) released from spoiled food. Commercial inkjet papers were employed as sensor substrates-their high reflectance (>80%) and smooth surfaces (roughness: ca. 4.9 nm) providing significant optical signals for reflection-mode plasmonic refractometric sensing and high particle transfer efficiency, respectively; in addition, because inkjet papers have lightweight and are burnable and flexible, they are especially suitable for developing portable, disposable, cost-effective, eco-friendly sensing platforms. Solid silver NPs (SNPs), solid gold NPs (GNPs), and hollow Au-Ag alloyed NPs (HGNs) were immobilized on a solid mold and then transferred directly onto the softened paper surfaces. The particle number density and exposure height of the embedded NPs were dependent on two imprinting parameters: applied pressure and temperature. The optimal samples exhibited high particle transfer efficiency (ca. 85%), a sufficient exposure surface area (ca. 50% of particle surface area) presented to the target molecules, and a strong resonance reflectance dip for detection. Moreover, the HGN-embedded paper displayed a significant wavelength dip shift upon the spontaneous adsorption of BA vapors (e.g., Δλ = 33 nm for putrescine; Δλ = 24 nm for spermidine), indicating high refractometric sensitivity; in contrast, no visible spectroscopic responses were observed with respect to other possibly coexisting gases (e.g., air, N 2 , CO 2 , water vapor) during the food storage process, indicating high selectivity. Finally, the plasmonic sensing papers were used to monitor the freshness of a food product (salmon).

Sorafenib is a RAF inhibitor approved for several cancers, including hepatocellular carcinoma (HCC). Inhibition of RAF kinases can induce a dose-dependent "paradoxical" upregulation of the downstream mitogen-activated protein kinase (MAPK) pathway in cancer cells. It is unknown whether "paradoxical" ERK activation occurs after sorafenib therapy in HCC, and if so, if it impacts the therapeutic efficacy. Here, we demonstrate that RAF inhibition by sorafenib rapidly leads to RAF dimerization and ERK activation in HCCs, which contributes to treatment evasion. The transactivation of RAF dimers and ERK signaling promotes HCC cell survival, prevents apoptosis via downregulation of BIM and achieves immunosuppression by MAPK/NF-kB-dependent activation of PD-L1 gene expression. To overcome treatment evasion and reduce systemic effects, we developed CXCR4-targeted nanoparticles to co-deliver sorafenib with the MEK inhibitor AZD6244 in HCC. Using this approach, we preferentially and efficiently inactivated RAF/ERK, upregulated BIM and down-regulated PD-L1 expression in HCC, and facilitated intra-tumoral infiltration of cytotoxic CD8+ T cells. These effects resulted in a profound delay in tumor growth. Thus, this nano-delivery strategy to selectively target tumors and prevent the paradoxical ERK activation could increase the feasibility of dual RAF/MEK inhibition to overcome sorafenib treatment escape in HCC.

The objective of the study is to investigate potential citrullinated autoantigens as targets of anti-citrullinated protein antibodies (ACPAs) response in synovial fluids (SFs) of patients with rheumatoid arthritis (RA). SFs from six RA patients and six osteoarthritis (OA) patients as controls were collected. The citrullinated proteins in SFs were extracted by immunoprecipitation with rabbit anti-citrulline antibodies. Matrix-assisted laser desorption/ionization time of flight mass spectrometry/time of flight mass spectrometry (MALDI-TOF/TOF) mass spectrometry was subsequently performed to discover a characteristic neutral loss to finally determine citrullinated autoantigens. A total of 182 citrullinated peptides and 200 citrullinated sites were identified in RA SFs, while 3 citrullinated peptides and 4 citrullinated sites were identified in OA SFs. The 182 citrullinated peptides from RA SFs and the 3 citrullinated peptides from OA SFs were derived from 83 and 3 autoantigens, respectively. Eighty-three autoantigens except protein-arginine deiminase type-2 (PADI2) and protein-arginine deiminase type-2 (PADI4) were over-citrullinated compared with controls, and the citrullinated sites of PADI2 and PADI4 were different in two groups. Interestingly, citrullinated histone H3.3 (H3F3A) was found in OA controls, but not in RA groups. The differential citrullinated proteins identified in RA SFs suggested potential autoantigens were targeted for ACPAs response and might contribute to the induction and perpetuation of complement activation and joint inflammation in RA.

Numerous hybrid white organic light-emitting diodes (WOLEDs) have recently been developed. However, their efficiency is not comparable to that of their best all-phosphorescent WOLED counterparts, and the structures are usually complicated, restricting their further development. Herein, a novel concept is used to achieve a hybrid WOLED, whose crucial feature is the exploitation of double multifunctional blue emitting layers. The three-organic-layer WOLED exhibits a total efficiency of 89.3 and 65.1 lm W -1 at 100 and 1000 cd m -2 , respectively, making it the most efficient hybrid WOLED reported in the literature so far. Significantly, the efficiencies of hybrid WOLEDs have, for the first time, been demonstrated to be comparable to those of the best all-phosphorescent WOLEDs. In addition, the device exhibits the lowest voltages among hybrid WOLEDs (i.e., 2.4, 2.7 and 3.1 V for 1, 100 and 1000 cd m -2 , respectively). Such remarkable performance achieved from such an ultrasimplified structure opens a new path toward low-cost commercialization., Competing Interests: The authors declare no conflict of interest.

The urotensin II/urotensin receptor (UII/UT) system can mediate inflammatory liver injury in acute liver failure (ALF); however; the related mechanism is not clear. In this study, we confirmed that lipopolysaccharide/D-galactosamine (LPS/D-GalN) induced up-regulation of liver interferon regulatory factor 3 (IRF3) in ALF mice, whereas the UT antagonist urantide inhibited the up-regulated liver IRF3. LPS stimulation induced IRF3 transcription and nuclear translocation and promoted the secretion of interleukin-6 (IL-6), interferon (IFN)-β, and IFN-γ in Kupffer cells (KCs); these effects in LPS-stimulated KCs were inhibited by urantide. Knockdown of IRF3 using an adenovirus expressing an IRF3 shRNA inhibited IFN-β transcription and secretion as well as tumor necrosis factor (TNF)-α and IL-1β secretion from LPS-stimulated KCs; additionally, IL-10 transcription and secretion were promoted in response to LPS. However, LPS-stimulated TNF-α and IL-1β mRNA was not affected in the KCs. The IRF3 shRNA also did not have a significant effect on the NF-κB p65 subunit and p38MAPK protein phosphorylation levels in the nuclei of LPS-stimulated KCs. Therefore, IRF3 expression and activation depended on the signal transduction of the UII/UT system, and played important roles in UII/UT-mediated immune inflammatory injury in the liver but did not affect NF-κB and p38 MAPK activity., Competing Interests: The authors have declared that no competing interest exist.

The accuracy of the calibration reference source polarization states directly influences the precision of the polarized optical remote sensor calibration, and thus affects the inversion accuracy of the characteristics of targets. In this paper, 870 nm horizontal linear polarized light has been chosen as the tested calibration reference light, modulated by rotating quarter-wave plate(QWP). The intensity as a Fourier series of the rotation angle of the plate and its coefficients were demodulated with the Fourier transform method, Stokes parameters can be calculated with these coefficients. The mean, standard deviation, composite uncertainty and relative deviation of measured data compared with the theoretical value of the ten measurement results were presented. In order to improve the accuracy of the measurement, the correction model for the quarter-wave plate retardance deviation Δδ, fast axis angle deviation Δα and the transmission axis alignment deviation Δβ of analyzing polarizer has been constructed. In this model, detection deviation of Stokes parameters is described as a function of Δδ and Δβ, Δδ and Δβ were determined by the function and magnitude of the deviation. Combined with quarter-wave plate fast axis angle deviation which was the result of simulation to adjust the experiment device, and then detecting the calibration reference source polarization states again. The experimental results show that, the difference between measured value and theoretical value of Stokes parameters reduced to less than 1.41% from 3.77% relative to without correction. The experiment principle, device and deviation correction model of this research can significantly improve the accuracy of detecting the polarization state of the calibration reference light source.

The correlated photon technique makes it possible to achieve a radiation calibration processing without chain transferring. The study of the spectral radiation character and time correlation of the photon is of great significance for broad-band radiometric calibration. To absolutely calibrate quantum efficiency of photoelectric detector, it is necessary to extend calibration band from single band to more bands. According to the phase-matching condition of the spontaneous parametric down-conversion, non-collinear angle formula of correlated photon in the crystal is derived. The distribution of the photon spectrum is simulated. Meanwhile, the phase-matching angle of the crystal is optimized. The photon generated by the spontaneous parameters down-conversion has a broad spectral distribution and the correlated photon wavelength is corresponding to its emission angle. Based on the result of the simulation, the experimental measurement system of the spectral distribution and time-correlation of the correlated photon is established. The spectral distribution, the time-correlation and the polarization properties of the four pair photon were measured by using this system. The experimental results show that, (1) the spectral distribution of the measurements is 633~808 nm, where the maximum spectral distribution measurement bias is 1.51 mm. The experiment result is highly consistent with theoretical ones; (2) the correlation time of four pairs correlated photon is measured, during which “three coincidence-peaks” is observed and the minimum correlation time was 0.32 ns; (3) single photon count rate along with coincidence count rate of correlated photon vary with the polarization direction of the pump as sine function. The experimental result is shown that the correlated photon pairs are ranging from the visible to near infrared band distribution, and that the spectrum has time-correlation and polarization characteristic. The research result is firstly reported at home and abroad, and the results are promising for the application of the photoelectric detector in the multi-band radiometric calibration.

Sorafenib is a tyrosine kinase inhibitor that has recently been shown to be a potential antifibrotic agent. However, a narrow therapeutic window limits the clinical use and therapeutic efficacy of sorafenib. Herein, we have developed and optimized nanoparticle (NP) formulations prepared from a mixture of poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (PEG-PLGA) copolymers with poly(lactic-co-glycolic acid) (PLGA) for the systemic delivery of sorafenib into the fibrotic livers of CCl4-induced fibrosis mouse models. We characterized and compared the pharmaceutical and biological properties of two different PLGA nanoparticles (NPs)--PEG-PLGA NPs (PEG-PLGA/PLGA=10/0) and PEG-PLGA/PLGA NPs (PEG-PLGA/PLGA=5/5). Increasing the PLGA content in the PEG-PLGA/PLGA mixture led to increases in the particle size and drug encapsulation efficacy and a decrease in the drug release rate. Both PEG-PLGA and PEG-PLGA/PLGA NPs significantly prolonged the blood circulation of the cargo and increased the uptake by the fibrotic livers. The systemic administration of PEG-PLGA or PEG-PLGA/PLGA NPs containing sorafenib twice per week for a period of 4 weeks efficiently ameliorated liver fibrosis, as indicated by decreased α-smooth muscle actin (α-SMA) content and collagen production in the livers of CCl4-treated mice. Furthermore, sorafenib-loaded PLGA NPs significantly shrank the abnormal blood vessels and decreased microvascular density (MVD), leading to vessel normalization in the fibrotic livers. In conclusion, our results reflect the clinical potential of sorafenib-loaded PLGA NPs for the prevention and treatment of liver fibrosis., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Antiangiogenic therapy has recently emerged as a highly promising therapeutic strategy for treating hepatocellular carcinoma (HCC). However, the only clinically approved systemic antiangiogenic agent for advanced HCC is sorafenib, which exerts considerable toxicity. Moreover, acquired resistance to antiangiogenic therapy often develops and restricts the therapeutic efficacy of this treatment. Hence, in this study, we develop a CXCR4-targeted lipid-based nanoparticle (NP) formulation to specifically deliver vascular endothelial growth factor (VEGF) siRNA as an antiangiogenic substance into HCC. AMD3100, a CXCR4 antagonist, is added into NPs to serve as both a targeting moiety and a sensitizer to antiangiogenic therapy. We demonstrate that AMD-modified NPs (AMD-NPs) can efficiently deliver VEGF siRNAs into HCC and downregulate VEGF expression in vitro and in vivo. Despite the upregulation of the SDF1α/CXCR4 axis upon the induction of hypoxia after antiangiogenic therapy, CXCR4 inhibition by AMD-NPs in combination with either conventional sorafenib treatment or VEGF siRNA prevents the infiltration of tumor-associated macrophages. These dual treatments also induce synergistic antiangiogenic effects and suppress local and distant tumor growth in HCC. In conclusion, the tumor-targeted multifunctional AMD-NPs that co-deliver VEGF siRNA and AMD3100 provide an effective approach for overcoming tumor evasion of antiangiogenic therapy, leading to delayed tumor progression in HCC.

Sorafenib, a multikinase inhibitor, has been used as an anti-angiogenic agent against highly vascular hepatocellular carcinoma (HCC) - yet associated with only moderate therapeutic effect and the high incidence of HCC recurrence. We have shown intratumoral hypoxia induced by sorafenib activated C-X-C receptor type 4 (CXCR4)/stromal-derived factor 1α (SDF1α) axis, resulting in polarization toward a tumor-promoting microenvironment and resistance to anti-angiogenic therapy in HCC. Herein, we formulated sorafenib in CXCR4-targeted lipid-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) modified with a CXCR4 antagonist, AMD3100 to systemically deliver sorafenib into HCC and sensitize HCC to sorafenib treatment. We demonstrated that CXCR4-targeted NPs efficiently delivered sorafenib into HCCs and human umbilical vein endothelial cells (HUVECs) to achieve cytotoxicity and anti-angiogenic effect in vitro and in vivo. Despite the increased expression of SDF1α upon the persistent hypoxia induced by sorafenib-loaded CXCR4-targeted NPs, AMD3100 attached to the NPs can block CXCR4/SDF1α, leading to the reduced infiltration of tumor-associated macrophages, enhanced anti-angiogenic effect, a delay in tumor progression and increased overall survival in the orthotopic HCC model compared with other control groups. In conclusion, our results highlight the clinical potential of CXCR4-targeted NPs for delivering sorafenib and overcoming acquired drug resistance in liver cancer., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

MicroRNAs (miRNAs), small non-coding RNAs, can regulate post-transcriptional gene expressions and silence a broad set of target genes. miRNAs, aberrantly expressed in cancer cells, play an important role in modulating gene expressions, thereby regulating downstream signaling pathways and affecting cancer formation and progression. Oncogenes or tumor suppressor genes regulated by miRNAs mediate cell cycle progression, metabolism, cell death, angiogenesis, metastasis and immunosuppression in cancer. Recently, miRNAs have emerged as therapeutic targets or tools and biomarkers for diagnosis and therapy monitoring in cancer. Since miRNAs can regulate multiple cancer-related genes simultaneously, using miRNAs as a therapeutic approach plays an important role in cancer therapy. However, one of the major challenges of miRNA-based cancer therapy is to achieve specific, efficient and safe systemic delivery of therapeutic miRNAs in vivo. This review discusses the key challenges to the development of the carriers for miRNA-based therapy and explores current strategies to systemically deliver miRNAs to cancer without induction of toxicity., (Copyright © 2014 Elsevier B.V. All rights reserved.)