Treatment outcomes and the role of the DES scheme in the appropriate treatment selection for high-grade dural arteriovenous fistulas.

OBJECTIVE: Endovascular and microsurgical treatment are viable options for the majority of Borden type III dural arteriovenous fistulas (dAVFs). The aim of this study was to examine treatment outcomes in a comparative analysis of endovascular and surgical treatment modalities for Borden type III fistulas and explore clinical implications of the DES scheme in selecting ideal candidates for surgical therapy. METHODS: Patients diagnosed with dAVFs with leptomeningeal venous drainage admitted to the Departments of Neurosurgery or Neuroradiology of the University Hospital Zurich between January 2014 and October 2021 were included in this study. Comprehensive patient data including demographics, clinical presentation, and dAVF characteristics, including established classifications, were collected. Treatment outcomes were assessed based on postinterventional angiography findings. In addition, treatment-related complications were assessed based on the Clavien-Dindo classification. RESULTS: Among all Borden type III dAVFs, 15 were initially treated endovascularly (60% complete occlusion rate) and 10 with microsurgical disconnection (90% complete occlusion rate) (p = 0.18). Subgroup analysis of dAVFs meeting the criteria for directness and exclusivity based on the DES scheme showed a 100% complete occlusion rate after microsurgical disconnection, whereas embolization achieved a complete occlusion rate of 60% (p = 0.06). There was no significant difference in the rate or severity of treatment-related complications between treatment modalities. CONCLUSIONS: This study suggests that microsurgical disconnection is a viable primary treatment modality for Borden type III dAVFs, particularly for dAVFs that meet the criteria of directness and exclusivity according to the DES scheme. The DES scheme demonstrates its relevance in selecting the most appropriate treatment strategy for affected patients.

Bisphenol A: Unveiling Its Role in Glioma Progression and Tumor Growth.

Gliomas represent the most common and lethal category of primary brain tumors. Bisphenol A (BPA), a widely recognized endocrine disruptor, has been implicated in the progression of cancer. Despite its established links to various cancers, the association between BPA and glioma progression remains to be clearly defined. This study aimed to shed light on the impact of BPA on glioma cell proliferation and overall tumor progression. Our results demonstrate that BPA significantly accelerates glioma cell proliferation in a time- and dose-dependent manner. Furthermore, BPA has been found to enhance the invasive and migratory capabilities of glioma cells, potentially promoting epithelial-mesenchymal transition (EMT) characteristics within these tumors. Employing bioinformatics approaches, we devised a risk assessment model to gauge the potential glioma hazards associated with BPA exposure. Our comprehensive analysis revealed that BPA not only facilitates glioma invasion and migration but also inhibits apoptotic processes. In summary, our study offers valuable insights into the mechanisms by which BPA may promote tumorigenesis in gliomas, contributing to the understanding of its broader implications in oncology.

Genome Editing of Pik3cd Impedes Abnormal Retinal Angiogenesis.

Abnormal angiogenesis is associated with myriad human diseases, including proliferative diabetic retinopathy (PDR). Signaling transduction through phosphoinositide 3-kinases (PI3Ks) plays a critical role in angiogenesis. Herein, we showed that p110δ, the catalytic subunit of PI3Kδ, was highly expressed in pathological retinal vascular endothelial cells (ECs) in a mouse model of oxygen-induced retinopathy (OIR) and in fibrovascular membranes from patients with PDR. To explore novel intervention with PI3Kδ expression, we developed a recombinant dual adeno-associated viral (rAAV) system for delivering CRISPR/Cas9 in which Streptococcus pyogenes (Sp) Cas9 expression was driven by an endothelial specific promoter of the intercellular adhesion molecule 2 (pICAM2) to edit genomic Pik3cd, the gene encoding p110δ. We then demonstrated that infection of cultured mouse vascular ECs with the dual rAAV1s of rAAV1-pICAM2-SpCas9 and rAAV1-SpGuide targeting genomic Pik3cd resulted in 80% DNA insertion/deletion in the locus of genomic Pik3cd and 70% depletion of p110δ expression. Furthermore, we showed that in the mouse model of OIR editing retinal Pik3cd with the dual rAAV1s resulted in not only a significant decrease in p110δ expression, and Akt activation, but also a dramatic reduction in pathological retinal angiogenesis. These findings reveal that Pik3cd editing is a novel approach to treating abnormal retinal angiogenesis.

Superstructure of a Metal-Organic Framework Derived from Microdroplet Flow Reaction: An Intermediate State of Crystallization by Particle Attachment.

Understanding the crystallization pathway is of fundamental importance in controlling structures and functionalities for metal-organic frameworks (MOFs), but only few studies have been reported on the mechanism of crystallization for MOFs to date. Here, by using a microdroplet flow (MF) reaction technique, we successfully revealed the different status of HKUST-1 during its crystal growth process. The morphologies and structures of crystals at different stages were recorded and characterized by scanning electron microscopy, transmission electron microscopy, and small-angle X-ray diffraction. Experimental observations clearly demonstrate a process of crystallization by particle attachment (CPA) for crystal growth of HKUST-1 under MF conditions. The superstructure of HKUST-1, which is assembled from oriented attachment of nanosized particles of HKUST-1, is observed at early stage of crystal growth. This type of superstructure gradually transforms to true single crystals through a ripening effect upon increasing residence time, accompanied by increase in dimensions of crystals. Thus, the superstructure is the intermediate state during crystallization and acts as the bridge between disordered reactants and highly ordered single crystals. Based on these findings, the crystal growth of HKUST-1 in MF reaction can be elucidated as a process involving three steps: the generation of nanosized primary particles, the following assembly of the primary particles into a superstructure, and the ripening of superstructure into a crystal. Furthermore, the superstructure of HKUST-1 shows superior performance for CO2 and CH4 adsorptions. The CPA mechanism in the crystallization of HKUST-1 demonstrated in this work is in clear contrast to the monomer-by-monomer addition mechanism in classic models of crystal growth. This mechanism could have important reference meaning for understanding the crystal growth mechanism of other type of MOFs or other special morphologies.

Boosting ORR Catalytic Activity by Integrating Pyridine-N Dopants, a High Degree of Graphitization, and Hierarchical Pores into a MOF-Derived N-Doped Carbon in a Tandem Synthesis.

N-doped carbon materials represent promising metal-free electrocatalysts for the oxygen reduction reaction (ORR), the cathode reaction in fuel cells, metal-air batteries, and so on. A challenge for optimizing the ORR catalytic activities of these electrocatalysts is to tune their local structures and chemical compositions in a rational and controlled way that can achieve the synergistic function of each factor. Herein, we report a tandem synthetic strategy that integrates multiple contributing factors into an N-doped carbon. With an N-containing MOF (ZIF-8) as the precursor, carbonization at higher temperatures leads to a higher degree of graphitization. Subsequent NH3 etching of this highly graphitic carbon enabled the introduction of a higher content of pyridine-N sites and higher porosity. By optimizing these three factors, the resultant carbon materials displayed ORR activity that was far superior to that of carbon derived from a one-step pyrolysis. The onset potential of 0.955 V versus a reversible hydrogen electrode (RHE) and the half-wave potential of 0.835 V versus RHE are among the top ranks of metal-free ORR catalysts and are comparable to commercial Pt/C (20 wt %) catalysts. Kinetic studies revealed lower H2 O2 yields, higher electron-transfer numbers, and lower Tafel slopes for these carbon materials compared with that derived from a one-step carbonization. These findings verify the effectiveness of this tandem synthetic strategy to enhance the ORR activity of N-doped carbon materials.

Ru nanoparticles dispersed on magnetic yolk-shell nanoarchitectures with Fe3O4 core and sulfoacid-containing periodic mesoporous organosilica shell as bifunctional catalysts for direct conversion of cellulose to isosorbide.

A green and sustainable approach for biorefining involves the development of bifunctional catalysts for the one-pot conversion of cellulosic biomass to isosorbide. This requires highly efficient, easily separated and versatile metal-acid catalysts for hydrolysis-hydrogenation-dehydration cascade reactions. Herein, we report a new type of metal-acid bifunctional catalyst by dispersing Ru nanoparticles (NPs) on magnetic yolk-shell nanoarchitectures comprising an Fe3O4 core and a sulfoacid (SO3H)-containing periodic mesoporous organosilica shell. The resultant magnetic Ru-SO3H nanoreactors are highly porous and have large surface areas (>350 m2 g-1), uniform mesopores (∼3.8 nm), well-dispersed Ru NPs (<1.5 wt%) and superior magnetization. Tailoring the size of the Ru NPs and the amount of SO3H moieties produced a highly efficient Ru-SO3H nanocatalyst, which delivered a high yield of isosorbide of 58.1% with almost complete conversion of cellulose in 2 h and achieved maximum productivity of 2.19 molIsosor h-1 gRu-1, which was one order of magnitude higher than that achieved using other Ru-containing acidic catalysts. Moreover, the elaborately fabricated Ru-SO3H nanocatalyst can be easily separated by applying an external magnetic field and can be cycled four times. This work reveals new possibilities for the fabrication of highly efficient, easily separated metal-acid catalysts in virtue of the concept of nanoreactor design.

The novel compound Z060228 inhibits assembly of the HBV capsid.

AIMS: The effective anti-HBV drugs on the market are mainly immunomodulators or nucleoside analogs. The uses of INF-α and lamivudine (3TC) are considerably limited by their low response rate, side effects, drug resistance and HBV recurrence. Thus, new mechanism-based drugs remain in urgent need. This study aimed to investigate the anti-HBV effects of the novel compound Z060228 and to confirm its anti-HBV mechanisms. MAIN METHODS: HepG2.2.15 cells and HBV-transgenic mice were used to evaluate the anti-HBV activity of Z060228. Conformational changes of the capsid structure induced by Z060228 were detected with high-resolution electron microscopy (EM), size-exclusion chromatography (SEC), and atomic force microscopy (AFM). KEY FINDINGS: The HBV DNA replication in the supernatants of the HepG2.2.15 cells was effectively inhibited by Z060228 and Bay41-4109. In the liver of HBV-transgenic mice, the HBcAg content was significantly decreased and HBV DNA replication was also inhibited after high-dose (30 mg/kg) Z060228 treatment. Z060228 and Bay41-4109 exhibited similar effects on the self-assembly of Cp149. SEC data revealed that Z060228 altered the equilibrium (a state of stability) of Cp149 assembly. EM data further demonstrated that Z060228 could prevent Cp149 from self-assembling to the correct core particles. Additionally, AFM results showed that a low concentration of Z060228 caused Cp149 syncretizing, whereas a high concentration caused Cp149 to polymerize. SIGNIFICANCE: Z060228 was demonstrated to be a potential capsid targeting anti-HBV drug candidate. The methods employed here could be used as a general strategy to study mechanisms of self-assembling protein-targeted drugs.

A new series of HAPs as anti-HBV agents targeting at capsid assembly.

A series of novel Heteroaryldihydropyrimidines (HAPs) derivatives were designed and synthesized as potent inhibitors of HBV capsid assembly. These compounds were prepared from efforts to optimize an earlier series of HAPs, and compounds Mo1, Mo7, Mo8, Mo10, Mo12, and Mo13 demonstrated potent inhibition of HBV DNA replication at submicromolar range.

Listr1 locus regulates innate immunity against Listeria monocytogenes infection in the mouse liver possibly through Cxcl11 polymorphism.

Inbred stains of mice display differential susceptibility to infection with the common foodborne pathogen Listeria monocytogenes (Lm). Previously, Listr1 and Listr2, two genetic loci that control differential sensitivity to Lm infection between BALB/cByJ and C57BL/6ByJ mice, were identified. To analyze the role of Listr1 in innate immune responses, we employed congenic mice (C.B6By-Listr1/Rag2 (-/-) ) bearing the C57BL/6ByJ-derived Listr1 locus on a BALB/c-Rag2 (-/-) background. Consistent with the results of a previous genetic analysis, the congenic mice showed increased susceptibility to Lm infection. The bacterial burden in the liver between the congenic and control lines was significantly different (P < 0.05) from 24 h postinfection with Lm. Analysis of genes within the Listr1 locus identified a frameshift mutation in the Cxcl11 gene of the C57BL/6 strain that prevents production of the mature chemokine CXCL11. No differences in inflammatory cell infiltration or cells expressing CXCR3 and CXCR7 which are the receptors of CXCL11 occurred because of CXCL11 deficiency in the congenic mice spleens. However, these mice lacked a distinct population of CD14(+) positive resident mononuclear cells that express intermediate levels of CXCR3 and CXCR7 in the liver. There were fewer microabscesses in the liver of CXCL11-deficient mice during the early stage of infection, which is consistent with their decreased ability to resist Lm. Our results, when taken together, show that the Listr1 locus plays an important role in early control of Lm infection in the mouse liver and that Cxcl11 is a candidate gene for disease severity within this locus.

An efficient synthesis of enantiopure (R)-heteroarylpyrimidine analogs.

An efficient synthesis of enantiopure (R)-heteroarylpyrimidine analogs is described here, which involves introduction of a chiral group, formation and separation of diasteroisomers and final transformation of an amide to an ester. The absolute configuration of the enantiopure HAPs is confirmed by X-ray analysis of their intermediates.

Influence of oxidized starch on the properties of thermoplastic starch.

Thermoplastic starch was prepared by adding oxidized starches and glycerol together into starch. The addition of oxidized starch improved the rheological properties and also increased the toughness of thermoplastic starch. Compared with TPS30, the elongation at break increased from 126.8% to 152.5% when 5wt% OS 117% was added. Good compatibility of thermoplastic starch between the matrix and oxidized starch was confirmed by SEM. The addition of oxidized starch lowered the storage modulus and glass transition temperature (Tg) of thermoplastic starch, decreasing Tg from 34.1 to 30°C when 10 wt% OS117% was added. The thermal stability of blending was improved by adding oxidized starches, i.e. when 5 wt% OS70% was added, T5% increased from 134 to 156°C.

Separation of ionic liquid [Mmim][DMP] and glucose from enzymatic hydrolysis mixture of cellulose using alumina column chromatography.

Pretreatment of cellulose with ionic liquids (ILs) can improve the efficiency of the hydrolysis by increasing the surface area of the substrates accessible to solvents and cellulases. However, the IL methods are facing challenges to separate the hydrolyzed sugar products as well as the renewable ILs from the complex hydrolysis mixtures. In this study, an alumina column chromatography (ACC) method was developed for the separation of hydrophilic IL N-methyl-N-methylimidazolium dimethyl phosphate ([Mmim][DMP]) and glucose, which was the main ingredient of the monosaccharide hydrolyzate. The processing parameters involved in ACC separation were investigated in detail. Our results showed that the recovery yields of [Mmim][DMP] and glucose can reach up to 93.38% and 90.14%, respectively, under the optimized parameters: the sampling ratio of 1:20 between the applied sample volume and the bed volume of the column; a gradient elution using methanol (100%, 150 ml) and then water (170 ml) as eluents with 1 ml/min flow rate. The recovered [Mmim][DMP] showed qualified property and was effective in a new hydrolysis reaction. In addition, scale-up ACC separations were successfully done with satisfied separation performance. The results indicated that the ACC is one of the available methods for the separation of ILs and monosaccharides from the hydrolysis mixtures.

2,4-Diaryl-4,6,7,8-tetrahydroquinazolin-5(1H)-one derivatives as anti-HBV agents targeting at capsid assembly.

A series of novel 2,4-diaryl-4,6,7,8-tetrahydroquinazolin-5(1H)-one derivatives were designed and synthesized as potent inhibitors of HBV capsid assembly. These compounds arose from efforts to rigidify an earlier series of heteroaryldihydropyrimidines (HAPs), and compounds 12, 13, 20, 24, 30 and 32 showed potent inhibition of HBV capsid assembly, especially 24 with IC(50) value at sub-micromolar range.

Novel fatty acid synthase (FAS) inhibitors: design, synthesis, biological evaluation, and molecular docking studies.

Several novel series of C75 derivatives were synthesized and evaluated for their FAS inhibitory activities. The results showed compound 4-methylene-2-octyl-5-oxo-tetrahydro-thiophene-3-carboxylic acid (1c) had more effective FAS inhibitory (IC(50) was 2.56 microM and T.I. was 9.26) and potent anti-tumor activities on HL60 and Hela cells in vitro (IC(50) were 5.38 microM and 46.10 microM, respectively).

1-Oxo-3-substitute-isothiochroman-4-carboxylic acid compounds: synthesis and biological activities of FAS inhibition.

A new series 1-oxo-3-substitute-isothiochroman-4-carboxylic acid compounds have been designed and synthesized. Screening of these molecules for FAS inhibition in vitro has indicated that compounds 2c and 2d showed more effective FAS inhibition activities and higher therapeutic index than C75.

Effect of hepatocyte apoptosis induced by TNF-alpha on acute severe hepatitis in mouse models.

AIM:To study the effect of hepatocyte apoptosis and necrosis induced by TNF-alpha on the pathogenesis of acute severe hepatitis (ASH).METHODS:The model of ASH was prepared in D-galactosamine (GalN) sensitized BALB/c mice by injection of either endotoxin (ET) or tumor necrosis factor-alpha(TNF-alpha. Morphological changes of apoptotic hepatocytes were studied by both light and electron microscope and in site end labeling method (ISEL). Molecular biological changes of DNA ladder were observed by electrophoresis of extract from liver tissues. Biochemical changes were measured by alanine aminotransferase (ALT), aspartic aminotransferase (AST) and TNF-alpha. The relation between apoptosis and necrosis was evaluated simultaneously.RESULTS:The sequence of hepatocyte apoptosis, necrosis, and final death from ASH was observed both in GalN/ET and GalN/TNF-alpha group. Apoptosis was prominent at 3.5h and 6h after injection of inducer, while necrosis became dominant at 9h after challenge. The appearance of apoptosis was earlier in GalN/TNF-alpha group than that in GalN/ET group. Pretreatment of mice with antiTNF IgG1 may completely prevent the liver injury induced by GalN/ET.CONCLUSION:TNF-alpha can cause liver amage by inducing hepatic apoptosis and necrosis in mice with endotoxemia.