| 1. |
- Serwas, NK, et al.
(författare)
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Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3106-
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Tidskriftsartikel (refereegranskat)abstract
- Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11+CTLA-4+ vesicles in DEF6-mutated cells. One of the patients has been treated with CTLA-4-Ig and achieved sustained remission. Collectively, we uncover DEF6 as player in immune homeostasis ensuring availability of the checkpoint protein CTLA-4 at T-cell surface, identifying a potential target for autoimmune and/or cancer therapy.
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| 6. |
- Permyakov, E A, et al.
(författare)
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Interaction of alpha-lactalbumin with Cu2+.
- 1988
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Ingår i: Biophysical Chemistry. - 0301-4622 .- 1873-4200. ; 32:1, s. 37-42
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Tidskriftsartikel (refereegranskat)abstract
- It has been shown by intrinsic fluorescence spectroscopy that alpha-lactalbumin has several Cu2+ -binding sites per molecule. The Ca2+ -loaded protein binds two or more Cu2+ per molecule with an association constant of about 3 X 10(3) M-1. Apo-alpha-lactalbumin binds one Cu2+ per molecule with association constant 8 X 10(4) M-1 and from two to three Cu2+ with an association constant of about 4 X 10(3) M-1. The results obtained from spectrofluorometric pH titration of alpha-lactalbumin in the acidic pH region show the possible involvement of histidine residues in the coordination of Cu2+. The binding of Cu2+ to alpha-lactalbumin lowers significantly its thermostability and stability towards urea denaturation. The stability of Cu2+, Ca2+-alpha-lactalbumin against thermal and urea denaturation is similar to that of the apo protein. The thermal transition in Cu2+, Ca2+-alpha-lactalbumin occurs within the region of physiological temperatures which may suggest the existence of some thermal regulation of its functioning in vivo.
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| 7. |
- Permyakov, Eugene A, et al.
(författare)
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Ultraviolet illumination-induced reduction of alpha-lactalbumin disulfide bridges
- 2003
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Ingår i: Proteins: Structure, Function, and Bioinformatics. - : Wiley. - 0887-3585. ; 51:4, s. 498-503
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Tidskriftsartikel (refereegranskat)abstract
- Prolonged exposure of Ca2+-loaded or Ca2+-depleted human -lactalbumin to ultraviolet light (270-290 nm, 1 mW/cm2, for 2 to 4 h) results in a 10-nm red shift of its tryptophan fluorescence spectrum. Gel chromatography of the UV-illuminated samples reveals two non-native protein forms: (1) a component with a red-shifted tryptophan fluorescence spectrum; and (2) a component with kynurenine-like fluorescent properties. The first component has from 0.6 to 0.9 free DTNB-reactive SH groups per protein molecule, which are absent in the native protein and is characterized by slightly lowered Ca2+-affinity (2 × 108 M-1 versus 8 × 108 M-1 for the native protein) and absence of observable thermal transition. The second component corresponds to the protein with photochemically modified tryptophan residues. It is assumed that the UV excitation of tryptophan residue(s) in -lactalbumin is followed by a transfer of electrons to the SS bonds, resulting in their reduction. Mass spectrometry data obtained for trypsin-fragmented UV-illuminated -lactalbumin with acrylodan-modified free thiol groups reveal the reduction of the 61-77 and 73-91 disulfide bridges. The effect observed has to be taken into account in any UV-region spectral studies of -lactalbumin. Proteins 2003;51:498-503.
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| 8. |
- Kalinichenko, A, et al.
(författare)
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RhoG deficiency abrogates cytotoxicity of human lymphocytes and causes hemophagocytic lymphohistiocytosis
- 2021
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 137:15, s. 2033-2045
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Tidskriftsartikel (refereegranskat)abstract
- Exocytosis of cytotoxic granules (CG) by lymphocytes is required for the elimination of infected and malignant cells. Impairments in this process underly a group of diseases with dramatic hyperferritinemic inflammation termed hemophagocytic lymphohistiocytosis (HLH). Although genetic and functional studies of HLH have identified proteins controlling distinct steps of CG exocytosis, the molecular mechanisms that spatiotemporally coordinate CG release remain partially elusive. We studied a patient exhibiting characteristic clinical features of HLH associated with markedly impaired cytotoxic T lymphocyte (CTL) and natural killer (NK) cell exocytosis functions, who beared biallelic deleterious mutations in the gene encoding the small GTPase RhoG. Experimental ablation of RHOG in a model cell line and primary CTLs from healthy individuals uncovered a hitherto unappreciated role of RhoG in retaining CGs in the vicinity of the plasma membrane (PM), a fundamental prerequisite for CG exocytotic release. We discovered that RhoG engages in a protein–protein interaction with Munc13-4, an exocytosis protein essential for CG fusion with the PM. We show that this interaction is critical for docking of Munc13-4+ CGs to the PM and subsequent membrane fusion and release of CG content. Thus, our study illuminates RhoG as a novel essential regulator of human lymphocyte cytotoxicity and provides the molecular pathomechanism behind the identified here and previously unreported genetically determined form of HLH.
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- Silveira, Semida, 1961-, et al.
(författare)
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Opportunities for bioenergy in the Baltic Sea Region
- 2017
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Ingår i: International Scientific Conference “Environmental and Climate Technologies”, CONECT 2017, 10-12 May 2017, Riga, Latvia. - : Elsevier. ; , s. 157-164
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Konferensbidrag (refereegranskat)abstract
- Security of energy supply, promotion of the bio-economy, nutrient recycling, and innovation are prioritized policy areas in the EU Strategy for the Baltic Sea Region (EUBSR). The Baltic Sea Region (BSR) has a great bioenergy potential worth exploring in this context. This paper explores the state-of-art of bioenergy systems and synergies with eco-systems services in the BSR region in the context of developing the region's bio-economy. In this brief assessment, we consider 8 countries (i.e. Sweden, Finland, Estonia, Latvia, Lithuania, Poland, Denmark, and Belarus) in the region. While the production and use of modern bioenergy can help reduce greenhouse gas (GHG) emissions, promote energy security, diversify energy resources, and contribute to a successful circular economy and rural development, it is important to find a balance between the exploration of resources and the management of eco-systems services. In addition, both climate change vulnerability and bioenergy production may affect the environment and the capacity of the BSR to deliver ecosystem services (ESS). We recommend integrated strategies for optimal use of bioresources in the region. Bioeconomy can be realized by innovative approaches, establishing cross-cutting institutional and policy linkages for increased prosperity and green growth in the Baltic Sea Region.
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