Costly choices for treating Wilson's disease

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110871/1/hep27663.pd

Intimal smooth muscle cells are a source but not a sensor of anti-inflammatory CYP450 derived oxylipins

AbstractVascular pathologies are associated with changes in the presence and expression of morphologically distinct vascular smooth muscle cells. In particular, in complex human vascular lesions and models of disease in pigs and rodents, an intimal smooth muscle cell (iSMC) which exhibits a stable epithelioid or rhomboid phenotype in culture is often found to be present in high numbers, and may represent the reemergence of a distinct developmental vascular smooth muscle cell phenotype. The CYP450-oxylipin - soluble epoxide hydrolase (sEH) pathway is currently of great interest in targeting for cardiovascular disease. sEH inhibitors limit the development of hypertension, diabetes, atherosclerosis and aneurysm formation in animal models. We have investigated the expression of CYP450-oxylipin-sEH pathway enzymes and their metabolites in paired intimal (iSMC) and medial (mSMC) cells isolated from rat aorta. iSMC basally released significantly larger amounts of epoxy-oxylipin CYP450 products from eicosapentaenoic acid > docosahexaenoic acid > arachidonic acid > linoleic acid, and expressed higher levels of CYP2C12, CYP2B1, but not CYP2J mRNA compared to mSMC. When stimulated with the pro-inflammatory TLR4 ligand LPS, epoxy-oxylipin production did not change greatly in iSMC. In contrast, LPS induced epoxy-oxylipin products in mSMC and induced CYP2J4. iSMC and mSMC express sEH which metabolizes primary epoxy-oxylipins to their dihydroxy-counterparts. The sEH inhibitors TPPU or AUDA inhibited LPS-induced NFκB activation and iNOS induction in mSMC, but had no effect on NFκB nuclear localization or inducible nitric oxide synthase in iSMC; effects which were recapitulated in part by addition of authentic epoxy-oxylipins. iSMCs are a rich source but not a sensor of anti-inflammatory epoxy-oxylipins. Complex lesions that contain high levels of iSMCs may be more resistant to the protective effects of sEH inhibitors

Basal and inducible anti-inflammatory epoxygenase activity in endothelial cells

The roles of CYP lipid-metabolizing pathways in endothelial cells are poorly understood. Human endothelial cells expressed CYP2J2 and soluble epoxide hydrolase (sEH) mRNA and protein. The TLR-4 agonist LPS (1 μg/ml; 24 h) induced CYP2J2 but not sEH mRNA and protein. LC–MS/MS analysis of the stable commonly used human endothelial cell line EA.Hy926 showed active epoxygenase and epoxide hydrolase activity: with arachidonic acid (stable epoxide products 5,6-DHET, and 14,15-DHET), linoleic acid (9,10-EPOME and 12,13-EPOME and their stable epoxide hydrolase products 9,10-DHOME and 12,13-DHOME), docosahexaenoic acid (stable epoxide hydrolase product 19,20-DiHDPA) and eicosapentaenoic acid (stable epoxide hydrolase product 17,18-DHET) being formed. Inhibition of epoxygenases using either SKF525A or MS-PPOH induced TNFα release, but did not affect LPS, IL-1β, or phorbol-12-myristate-13-acetate (PMA)-induced TNFα release. In contrast, inhibition of soluble epoxide hydrolase by AUDA or TPPU inhibited basal, LPS, IL-1β and PMA induced TNFα release, and LPS-induced NFκB p65 nuclear translocation. In conclusion, human endothelial cells contain a TLR-4 regulated epoxygenase CYP2J2 and metabolize linoleic acid > eicosapentaenoic acid > arachidonic acid > docosahexaenoic acid to products with anti-inflammatory activity

Structure and Mechanism of Ergothionase from Treponema denticola

Ergothioneine is a sulfur-containing histidine derivative that emerges from microbial biosynthesis and enters the human body through intestinal uptake and regulated distribution into specific tissues. Although the proteins involved in biosynthesis and uptake are well characterized, less is known about the degradative pathways of ergothioneine. This report describes the crystal structure of the active form of ergothionase from the oral pathogen Treponema denticola complexed with the substrate analogue desmethyl-ergothioneine sulfonic acid. This enzyme catalyzes the 1,2-elimination of trimethylamine from ergothioneine and ergothioneine sulfonic acid by using a unique mode of substrate activation combined with acid/base catalysis. This structural and mechanistic investigation revealed four essential catalytic residues, which are strictly conserved in homologous proteins from common gastrointestinal bacteria and numerous pathogenic bacteria, suggesting that bacterial activity may play an important role in determining the availability of ergothioneine in healthy and diseased human tissue

Empowering students with geospatial solutions through challenge-based learning

Today, the field of Geospatial Solutions primarily focuses on spatial and mapping data, analysis, and technologies that primarily revolve around place and space. It is considered more as a tool or means rather than the ultimate objective of various interdisciplinary activities, where minimal attention is given to theoretical aspects, equations, and underlying principles of the subject. Conversely, despite advancements in science and technology and a broader audience for geospatial subjects, it is predominantly taught conventionally, disregarding the diverse needs and expectations of students. In recent years, there has been an exploration of innovative educational methods to utilize new pedagogical frameworks and enhance academic performance among students. The present study aims to develop a framework and provide guidelines for the integration of Challenge Based Learning into Geomatics education. This framework consists of three interconnected phases: engage, investigate, and act. Subsequently, an educational pilot program is created and implemented to apply the designed framework to key topics such as food security and cultural heritage. Finally, the project refines the educational framework based on real pilot attempts and evaluation results, identifying potential issues and making necessary adjustments. The designed framework and the attained results are made publicly available for reference and utilization.</p

Comparison of different algorithms to map hydrothermal alteration zones using ASTER remote sensing data for polymetallic Vein-Type ore exploration: Toroud-Chahshirin Magmatic Belt (TCMB), north Iran

© 2019 by the authors. Polymetallic vein-type ores are important sources of precious metal and a principal type of orebody for various base-metals. In this research, Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) remote sensing data were used for mapping hydrothermal alteration zones associated with epithermal polymetallic vein-type mineralization in the Toroud-Chahshirin Magmatic Belt (TCMB), North of Iran. The TCMB is the largest known goldfield and base metals province in the central-north of Iran. Propylitic, phyllic, argillic, and advanced argillic alteration and silicification zones are typically associated with Au-Cu, Ag, and/or Pb-Zn mineralization in the TCMB. Specialized image processing techniques, namely Selective Principal Component Analysis (SPCA), Band Ratio Matrix Transformation (BRMT), Spectral Angle Mapper (SAM) and Mixture Tuned Matched Filtering (MTMF) were implemented and compared to map hydrothermal alteration minerals at the pixel and sub-pixel levels. Subtle differences between altered and non-altered rocks and hydrothermal alteration mineral assemblages were detected and mapped in the study area. The SPCA and BRMT spectral transformation algorithms discriminated the propylitic, phyllic, argillic and advanced argillic alteration and silicification zones as well as lithological units. The SAM and MTMF spectral mapping algorithms detected spectrally dominated mineral groups such as muscovite/montmorillonite/illite, hematite/jarosite, and chlorite/epidote/calcite mineral assemblages, systematically. Comprehensive fieldwork and laboratory analysis, including X-ray diffraction (XRD), petrographic study, and spectroscopy were conducted in the study area for verifying the remote sensing outputs. Results indicate several high potential zones of epithermal polymetallic vein-type mineralization in the northeastern and southwestern parts of the study area, which can be considered for future systematic exploration programs. The approach used in this research has great implications for the exploration of epithermal polymetallic vein-type mineralization in other base metals provinces in Iran and semi-arid regions around the world

Availability Evaluation of Service Function Chains Under Different Protection Schemes

Network Function Virtualization (NFV) calls for a new resource management approach where virtualized network functions (VNFs) replace traditional network hardware appliances. Thanks to NFV, operators are given a much greater flexibility, as these VNFs can be deployed as virtual nodes and chained together to form Service Function Chains (SFCs). An SFC represents a set of dedicated virtualized resources deployed to provide a certain service to the consumer. One of its most important performance requirements is availability. In this paper, the availability achieved by SFCs is evaluated analytically, by modelling several protection schemes and given different availability values for the network components. The cost of each protection scheme, based on its network resource consumption, is also taken into account. Extensive numerical results are reported, considering various SFC characteristics, such as availability requirements, number of NFV nodes and availability values of network components. The lowest-cost protection strategy, in terms of number of occupied network components, which meets availability requirement, is identified. Our analysis demonstrates that, in most cases, resource-greedy protection schemes, such as end-to-end protection, can be replaced by less aggressive schemes, even when availability requirements are in the order of five or six nines, depending on the number of elements in the service function chain

Trapped air metamaterial concept for ultrasonic sub-wavelength imaging in water

Acoustic metamaterials constructed from conventional base materials can exhibit exotic phenomena not commonly found in nature, achieved by combining geometrical and resonance effects. However, the use of polymer-based metamaterials that could operate in water is difficult, due to the low acoustic impedance mismatch between water and polymers. Here we introduce the concept of “trapped air” metamaterial, fabricated via vat photopolymerization, which makes ultrasonic sub-wavelength imaging in water using polymeric metamaterials highly effective. This concept is demonstrated for a holey-structured acoustic metamaterial in water at 200–300 kHz, via both finite element modelling and experimental measurements, but it can be extended to other types of metamaterials. The new approach, which outperforms the usual designs of these structures, indicates a way forward for exploiting additive-manufacturing for realising polymer-based acoustic metamaterials in water at ultrasonic frequencies

An ultrasonic metallic Fabry–Pérot metamaterial for use in water

Fabry-Pérot ultrasonic metamaterials have been additively manufactured using laser powder bed fusion to contain subwavelength holes with a high aspect-ratio of width to depth. Such metamaterials require the acoustic impedance mismatch between the structure and the immersion medium to be large. It is shown for the first time that metallic structures fulfil this criterion for applications in water over the 200–800 kHz frequency range. It is also demonstrated that laser powder bed fusion is a flexible fabrication method for the ceration of structures with different thicknesses, hole geometry and tapered openings, allowing the acoustic properties to be modified. It was confirmed via both finite element simulation and practical measurements that these structures supported Fabry-Pérot resonances, needed for metamaterial operation, at ultrasonic frequencies in water. It was also demonstrated the the additively-manufactured structures detected the presence of a sub-wavelength slit aperture in water