Wilson Disease at a Single Cell Level Ralle, Martina; Huster, Dominik; Vogt, Stefan ...
The Journal of biological chemistry,
10/2010, Letnik:
285, Številka:
40
Journal Article
Recenzirano
Odprti dostop
Wilson disease (WD) is a severe hepato-neurologic disorder that affects primarily children and young adults. WD is caused by mutations in ATP7B and subsequent copper overload. However, copper levels ...alone do not predict severity of the disease. We demonstrate that temporal and spatial distribution of copper in hepatocytes may play an important role in WD pathology. High resolution synchrotron-based x-ray fluorescence imaging in situ indicates that copper does not continuously accumulate in Atp7b−/− hepatocytes, but reaches a limit at 90–300 fmol. The lack of further accumulation is associated with the loss of copper transporter Ctr1 from the plasma membrane and the appearance of copper-loaded lymphocytes and extracellular copper deposits. The WD progression is characterized by changes in subcellular copper localization and transcriptome remodeling. The synchrotron-based x-ray fluorescence imaging and mRNA profiling both point to the key role of nucleus in the initial response to copper overload and suggest time-dependent sequestration of copper in deposits as a protective mechanism. The metabolic pathways, up-regulated in response to copper, show compartmentalization that parallels changes in subcellular copper concentration. In contrast, significant down-regulation of lipid metabolism is observed at all stages of WD irrespective of copper distribution. These observations suggest new stage-specific as well as general biomarkers for WD. The model for the dynamic role of copper in WD is proposed.
The subject of geometry in the curriculum continues to be an area of concern among mathematics educators. The gap between standards expectations and actual textbook content continues to reflect the ...need for substantial change. In this study, the geometry language introduced in K‐6 textbooks was carefully examined and compared to the language used in the Curriculum and Evaluation Standards for School Mathematics (National Council of Teachers of Mathematics, 1989), Principles and Standards for School Mathematics (NCTM, 1999), and New Standards Elementary School Mathematics Performance Standards (National Center for Education and the Economy, 1997). The. logic followed was that the language in textbooks reflects the content presented in the textbook, and the language in the standards reflects what should be presented. The results of the study clearly indicate that there is a substantial misalignment between the geometry presented in the textbooks, the. geometry expected to be taught by groups such as NCTM, and the geometry being assessed in student performance measures as suggested by NCEE. Specific areas of misalignment are identified, along with implications, and some areas in which the curriculum should be revised are identified.
New observations of Orion Molecular Cloud 2 have been made from 1 to 100 microns using the NASA Infrared Telescope Facility and the Kuiper Airborne Observatory. An extensive program of polarimetry, ...photometry, and spectrophotometry has shown that the extended emission regions associated with two of the previously known near-infrared sources, IRS 1 and IRS 4, are infrared reflection nebulae, and that the compact sources IRS 1 and IRS 4 are the main luminosity sources in the cloud. The constraints from the far-infrared observations and an analysis of the scattered light from the IRS 1 nebula show that OMC-2/IRS 1 can be characterized by L of 500 solar luminosities or less and T of roughly 1000 K. The near-infrared albedo of the grains in the IRS 1 nebula is greater than 0.08.
Objective
Methotrexate (MTX) enters cells through the reduced folate carrier (RFC‐1) and exerts part of its effects through polyglutamation to MTX polyglutamates (MTXPGs) and inhibition of ...5‐aminoimidazole‐4‐carboxamide ribonucleotide transformylase (ATIC) and thymidylate synthase (TS). We investigated the contribution of common genetic polymorphisms in RFC‐1 (G80A), ATIC (C347G), and TS (28‐bp tandem repeats located in the TS enhancer region TSER*2/*3) and of MTXPGs to the effect of MTX in patients with rheumatoid arthritis.
Methods
The study was cross‐sectional. All patients received MTX for at least 3 months. The numbers of tender and swollen joints, the Visual Analog Scale (VAS) scores for the physician's global assessment of disease activity, and the modified Health Assessment Questionnaire scores were collected. Using the VAS score for the physician's assessment of patient's response to MTX, the population of patients was dichotomized into responders to MTX (VAS score ≤2 cm) and nonresponders to MTX (VAS score >2 cm). A pharmacogenetic index was calculated as the sum of homozygous variant genotypes (RFC‐1 AA + ATIC 347GG + TSER *2/*2) carried by the patients. MTXPG concentrations were measured in red blood cells (RBCs) by high‐performance liquid chromatography.
Results
The dose of MTX was not associated with the effects of MTX (P > 0.05). In contrast, increased RBC long‐chain MTXPG concentrations (median 40 nmoles/liter; range <5–131 nmoles/liter) and an increased pharmacogenetic index were associated with a lower number of tender and swollen joints (P < 0.05) and a lower score for the physician's global assessment of disease activity (P ≤ 0.001). Patients with RBC MTXPG levels of >60 nmoles/liter and carriers of a homozygous variant genotype were 14.0‐fold (95% confidence interval 95% CI 3.6–53.8) and 3.7‐fold (95% CI 1.7–9.1), respectively, more likely to have a good response to MTX (P ≤ 0.01).
Conclusion
These data suggest that measuring RBC MTXPG levels and/or the common polymorphisms in the folate–purine–pyrimidine pathway may help in monitoring MTX therapy.
Near-infrared imaging of Lynds 1551 IRS 5 Hodapp, Klaus-Werner; Capps, Richard W.; Strom, Stephen E. ...
The Astrophysical journal,
12/1988, Letnik:
335, Številka:
2
Journal Article
Recenzirano
High-spatial-resolution 1.6-micron (H) and 2.2-micron (K) images of the well-known young stellar object (YSO) L1551 IRS 5 reveal an extended, conically-shaped reflection nebula. The comparison of the ...images at the two wavelengths shows a shift in the position of the flux maximum, demonstrating that the H band maximum is not identical with the illuminating star. Morphological differences between the H band and K band images as well as a color map indicate that extinction effects in the reflection nebula are important. The results support a model that posits that, at H and K, the star in IRS 5 is surrounded by an optically thick disk and illuminates the inner wall of the nozzle created by the anisotropic mass outflow from the embedded young star.
A coordinated program to observe Jupiter at high spatial resolution in the 5-micrometer wavelength region was undertaken to support Voyager 1 imaging and infrared radiation experiment targeting. ...Jupiter was observed over a 5-month period from Palomar and Mauna Kea observatories. The frequency of observations allowed the selection of interesting areas for closer Voyager examination and also provided good short-term monitoring of variations in cloud morphology. Significant global changes in the 5-micrometer distribution are seen over this time period.
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