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- Ng, Bobby G, et al.
(författare)
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ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.
- 2016
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794.
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Tidskriftsartikel (refereegranskat)abstract
- Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over one hundred genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate (DLO) required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date thirteen mutations in eighteen patients from fourteen families have been described with varying degrees of clinical severity. We identified and characterized thirty-nine previously unreported cases of ALG1-CDG from thirty-two families and add twenty-six new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all twenty-seven patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder. This article is protected by copyright. All rights reserved.
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| 4. |
- Strittmatter, Nicole, et al.
(författare)
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Holistic Characterization of a Salmonella Typhimurium Infection Model Using Integrated Molecular Imaging
- 2021
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Ingår i: Journal of the American Society for Mass Spectrometry. - : American Chemical Society (ACS). - 1044-0305 .- 1879-1123. ; 32:12, s. 2791-2802
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Tidskriftsartikel (refereegranskat)abstract
- A more complete and holistic view on host-microbe interactions is needed to understand the physiological and cellular barriers that affect the efficacy of drug treatments and allow the discovery and development of new therapeutics. Here, we developed a multimodal imaging approach combining histopathology with mass spectrometry imaging (MSI) and same section imaging mass cytometry (IMC) to study the effects of Salmonella Typhimurium infection in the liver of a mouse model using the S. Typhimurium strains SL3261 and SL1344. This approach enables correlation of tissue morphology and specific cell phenotypes with molecular images of tissue metabolism. IMC revealed a marked increase in immune cell markers and localization in immune aggregates in infected tissues. A correlative computational method (network analysis) was deployed to find metabolic features associated with infection and revealed metabolic clusters of acetyl carnitines, as well as phosphatidylcholine and phosphatidylethanolamine plasmalogen species, which could be associated with pro-inflammatory immune cell types. By developing an IMC marker for the detection of Salmonella LPS, we were further able to identify and characterize those cell types which contained S. Typhimurium.
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| 5. |
- Strittmatter, Nicole, et al.
(författare)
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Method To Visualize the Intratumor Distribution and Impact of Gemcitabine in Pancreatic Ductal Adenocarcinoma by Multimodal Imaging
- 2022
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 94:3, s. 1795-1803
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Tidskriftsartikel (refereegranskat)abstract
- Gemcitabine (dFdC) is a common treatment for pancreatic cancer; however, it is thought that treatment may fail because tumor stroma prevents drug distribution to tumor cells. Gemcitabine is a pro-drug with active metabolites generated intracellularly; therefore, visualizing the distribution of parent drug as well as its metabolites is important. A multimodal imaging approach was developed using spatially coregistered mass spectrometry imaging (MSI), imaging mass cytometry (IMC), multiplex immunofluorescence microscopy (mIF), and hematoxylin and eosin (H&E) staining to assess the local distribution and metabolism of gemcitabine in tumors from a genetically engineered mouse model of pancreatic cancer (KPC) allowing for comparisons between effects in the tumor tissue and its microenvironment. Mass spectrometry imaging (MSI) enabled the visualization of the distribution of gemcitabine (100 mg/kg), its phosphorylated metabolites dFdCMP, dFdCDP and dFdCTP, and the inactive metabolite dFdU. Distribution was compared to small-molecule ATR inhibitor AZD6738 (25 mg/kg), which was codosed. Gemcitabine metabolites showed heterogeneous distribution within the tumor, which was different from the parent compound. The highest abundance of dFdCMP, dFdCDP, and dFdCTP correlated with distribution of endogenous AMP, ADP, and ATP in viable tumor cell regions, showing that gemcitabine active metabolites are reaching the tumor cell compartment, while AZD6738 was located to nonviable tumor regions. The method revealed that the generation of active, phosphorylated dFdC metabolites as well as treatment-induced DNA damage primarily correlated with sites of high proliferation in KPC PDAC tumor tissue, rather than sites of high parent drug abundance.
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| 6. |
- Topping, Matthew, et al.
(författare)
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The effect of iron on dislocation evolution in model and commercial zirconium alloys
- 2018
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Ingår i: ASTM Special Technical Publication. - 0066-0558. ; STP 1597, s. 796-822
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Konferensbidrag (refereegranskat)abstract
- Although the evolution of irradiation-induced dislocation loops has been well correlated with irradiation-induced growth phenomena, the effect of alloying elements on this evolution remains elusive, especially at low fluences. To develop a more mechanistic understanding of the role iron has on loop formation, we used state-of-the-art techniques to study a proton-irradiated Zr-0.1Fe alloy and proton- and neutron-irradiated Zircaloy-2. The two alloys were irradiated with 2-MeV protons up to 7 dpa at 350°C and Zircaloy-2 up to 14.7 × 1025n • m-2, approximately 24 dpa, in a boiling water reactor at approximately 300°C. Baseline transmission electron microscopy showed that the Zr3Fe secondary-phase particles in the binary system were larger and fewer in number than the Zr (Fe, Cr)2and Zr2(Fe, Ni) particles in Zircaloy-2. An analysis of the irradiated binary alloy revealed only limited dissolution of Ze3Fe, suggesting little dispersion of iron into the matrix, while at the same time a higher 〈a〉-loop density was observed compared with Zircaloy-2 at equivalent proton dose levels. We also found that the redistribution of iron during irradiation led to the formation of iron nanoclusters. A delay in the onset of 〈c〉-loop nucleation in proton-irradiated Zircaloy-2 compared with the binary alloy was observed. The effect of iron redistributed from secondary-phase particles because of dissolution on the density and morphology of 〈a〉 and 〈c〉 loops is described. The implication this may have on irradiation-induced growth of zirconium fuel cladding is also discussed.
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