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- Battisti, U. M., et al.
(författare)
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Serendipitous Identification of a Covalent Activator of Liver Pyruvate Kinase
- 2023
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Ingår i: ChemBioChem. - : Wiley. - 1439-4227 .- 1439-7633. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Enzymes are effective biological catalysts that accelerate almost all metabolic reactions in living organisms. Synthetic modulators of enzymes are useful tools for the study of enzymatic reactions and can provide starting points for the design of new drugs. Here, we report on the discovery of a class of biologically active compounds that covalently modifies lysine residues in human liver pyruvate kinase (PKL), leading to allosteric activation of the enzyme (EC50=0.29 μM). Surprisingly, the allosteric activation control point resides on the lysine residue K282 present in the catalytic site of PKL. These findings were confirmed by structural data, MS/MS experiments, and molecular modelling studies. Altogether, our study provides a molecular basis for the activation mechanism and establishes a framework for further development of human liver pyruvate kinase covalent activators.
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- Kobiela, A, et al.
(författare)
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Exposure of Keratinocytes to Candida Albicans in the Context of Atopic Milieu Induces Changes in the Surface Glycosylation Pattern of Small Extracellular Vesicles to Enhance Their Propensity to Interact With Inhibitory Siglec Receptors
- 2022
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 13, s. 884530-
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Tidskriftsartikel (refereegranskat)abstract
- Candida albicans (C. albicans) infection is a potential complication in the individuals with atopic dermatitis (AD) and can affect clinical course of the disease. Here, using primary keratinocytes we determined that atopic milieu promotes changes in the interaction of small extracellular vesicles (sEVs) with dendritic cells and that this is further enhanced by the presence of C. albicans. sEV uptake is largely dependent on the expression of glycans on their surface; modelling of the protein interactions indicated that recognition of this pathogen through C. albicans-relevant pattern recognition receptors (PRRs) is linked to several glycosylation enzymes which may in turn affect the expression of sEV glycans. Here, significant changes in the surface glycosylation pattern, as determined by lectin array, could be observed in sEVs upon a combined exposure of keratinocytes to AD cytokines and C. albicans. This included enhanced expression of multiple types of glycans, for which several dendritic cell receptors could be proposed as binding partners. Blocking experiments showed predominant involvement of the inhibitory Siglec-7 and -9 receptors in the sEV-cell interaction and the engagement of sialic acid-containing carbohydrate moieties on the surface of sEVs. This pointed on ST6 β-Galactoside α-2,6-Sialyltransferase 1 (ST6GAL1) and Core 1 β,3-Galactosyltransferase 1 (C1GALT1) as potential enzymes involved in the process of remodelling of the sEV surface glycans upon C. albicans exposure. Our results suggest that, in combination with atopic dermatitis milieu, C. albicans promotes alterations in the glycosylation pattern of keratinocyte-derived sEVs to interact with inhibitory Siglecs on antigen presenting cells. Hence, a strategy aiming at this pathway to enhance antifungal responses and restrict pathogen spread could offer novel therapeutic options for skin candidiasis in AD.
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| 7. |
- Czekirda, M., et al.
(författare)
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Objective and Subjective Stress Parameters in Response to High and Low-Fidelity Simulation Activities
- 2022
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI AG. - 1660-4601. ; 19:5
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Tidskriftsartikel (refereegranskat)abstract
- Nursing graduates are required to have both excellent theoretical and practical skills that should be used during stressful emergency interventions. Since the received knowledge should be practiced to gain skills and trained to achieve competences, simulation exercises can be beneficial to even reduce the stress that each individual may face during emergency management of patients. A total of 146 first-year nursing students participated in the study, including 124 women and 22 men aged between 19 and 50 years, with a mean age of 32 years. The objective method estimated psychophysiological parameters (serum cortisol). Objective and subjective methods were used. The subjective method assessed stress experienced by students based on the standardized Stress Appraisal Questionnaire Version B for dispositional assessment. The study was conducted in the Monoprofile Medical Simulation Centre at the University of Economics and Innovation in Lublin, Poland and was approved by the University Research Ethics Committee. Both participants under and over 25 years of age showed increased levels of stress after low and high-fidelity simulations, with statistically significantly higher stress levels found for the low fidelity method. Low-fidelity simulation methods generated a greater increase in cortisol levels, indicating a higher stress level than the high-fidelity methods. The analysis of the scores obtained in the Stress Appraisal Questionnaire (KOS-B) showed that higher cortisol levels after the low-fidelity simulation reduced the subjective perception of a threat, while higher cortisol levels before the high-fidelity simulation promoted higher intellectual activity among the students. Levels of stress in the education of nursing students using low and high-fidelity methods can limit the sense of threat and activate professional task performance. The use of low and high-fidelity simulation does not generate destructive stress levels.
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