| 1. |
- Happonen, Lotta, et al.
(author)
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A quantitative Streptococcus pyogenes-human protein-protein interaction map reveals localization of opsonizing antibodies
- 2019
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2727-2727
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Journal article (peer-reviewed)abstract
- A fundamental challenge in medical microbiology is to characterize the dynamic protein-protein interaction networks formed at the host-pathogen interface. Here, we generate a quantitative interaction map between the significant human pathogen, Streptococcus pyogenes, and proteins from human saliva and plasma obtained via complementary affinity-purification and bacterial-surface centered enrichment strategies and quantitative mass spectrometry. Perturbation of the network using immunoglobulin protease cleavage, mixtures of different concentrations of saliva and plasma, and different S. pyogenes serotypes and their isogenic mutants, reveals how changing microenvironments alter the interconnectivity of the interaction map. The importance of host immunoglobulins for the interaction with human complement proteins is demonstrated and potential protective epitopes of importance for phagocytosis of S. pyogenes cells are localized. The interaction map confirms several previously described protein-protein interactions; however, it also reveals a multitude of additional interactions, with possible implications for host-pathogen interactions involving other bacterial species.
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| 2. |
- Birkedal, Lars, et al.
(author)
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Guarded Cubical Type Theory
- 2019
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In: Journal of Automated Reasoning. - : Springer Science and Business Media LLC. - 0168-7433 .- 1573-0670. ; 63:2, s. 211-253
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Journal article (peer-reviewed)abstract
- This paper improves the treatment of equality in guarded dependent type theory ((Formula presented.)), by combining it with cubical type theory ((Formula presented.)). (Formula presented.) is an extensional type theory with guarded recursive types, which are useful for building models of program logics, and for programming and reasoning with coinductive types. We wish to implement (Formula presented.) with decidable type checking, while still supporting non-trivial equality proofs that reason about the extensions of guarded recursive constructions. (Formula presented.) is a variation of Martin–Löf type theory in which the identity type is replaced by abstract paths between terms. (Formula presented.) provides a computational interpretation of functional extensionality, enjoys canonicity for the natural numbers type, and is conjectured to support decidable type-checking. Our new type theory, guarded cubical type theory ((Formula presented.)), provides a computational interpretation of extensionality for guarded recursive types. This further expands the foundations of (Formula presented.) as a basis for formalisation in mathematics and computer science. We present examples to demonstrate the expressivity of our type theory, all of which have been checked using a prototype type-checker implementation. We show that (Formula presented.) can be given semantics in presheaves on (Formula presented.), where (Formula presented.) is the cube category, and (Formula presented.) is any small category with an initial object. We then show that the category of presheaves on (Formula presented.) provides semantics for (Formula presented.).
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| 3. |
- Birkedal, Lars, et al.
(author)
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Guarded Cubical Type Theory: Path Equality for Guarded Recursion
- 2016
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In: Leibniz International Proceedings in Informatics, LIPIcs. - 1868-8969. - 9783959770224 ; 62, s. 23:1-23:17
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Conference paper (peer-reviewed)abstract
- This paper improves the treatment of equality in guarded dependent type theory (GDTT), by combining it with cubical type theory (CTT). GDTT is an extensional type theory with guarded recursive types, which are useful for building models of program logics, and for programming and reasoning with coinductive types. We wish to implement GDTT with decidable type checking, while still supporting non-trivial equality proofs that reason about the extensions of guarded recursive constructions. CTT is a variation of Martin-Löf type theory in which the identity type is replaced by abstract paths between terms. CTT provides a computational interpretation of functional extensionality, is conjectured to have decidable type checking, and has an implemented type checker. Our new type theory, called guarded cubical type theory, provides a computational interpretation of extensionality for guarded recursive types. This further expands the foundations of CTT as a basis for formalisation in mathematics and computer science. We present examples to demonstrate the expressivity of our type theory, all of which have been checked using a prototype type-checker implementation, and present semantics in a presheaf category.
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| 4. |
- Cheng, Fang, et al.
(author)
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Non-conserved, S-nitrosylated cysteines in glypican-1 react with N-unsubstituted glucosamines in heparan sulfate and catalyze deaminative cleavage.
- 2012
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In: Glycobiology. - : Oxford University Press (OUP). - 1460-2423 .- 0959-6658. ; 22:11, s. 1480-1485
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Journal article (peer-reviewed)abstract
- The membrane lipid-anchored glypicans (heparan sulfate proteoglycans) are present in both vertebrates and invertebrates and serve as important modulators of growth factors and morphogens during development. Their core proteins are similar and consist of a large N-terminal domain comprising 14 evolutionary conserved cysteines and a C-terminal stalk carrying the heparan sulfate side-chains and the lipid anchor. Cysteines in glypican-1 can be S-nitrosylated but their positions have not been identified. The recently determined crystal structure of the N-terminal domain of glypican-1 has revealed that all the evolutionary conserved cysteines form intramolecular disulfide bonds. However, glypican-1 contains two more, non-conserved cysteines in the C-terminal stalk, located near the heparan sulfate attachment sites. We show here that the non-conserved cysteines are free thiols as a glypican-1 core protein containing the C-terminal stalk could be biotinylated by biotin-BMCC. After S-nitrosylation by using an NO-donor and copper ions, the glypican-1 core protein was retained on an affinity matrix substituted with heparan sulfate oligosaccharides containing N-unsubstituted glucosamines. The protein was displaced with 0.2 M glucosamine but also by 2 mM ascorbate. In the latter case, the heparan sulfate of the affinity matrix was simultaneously cleaved into fragments containing anhydromannose. We propose that the S-nitrosocysteine residues interact with closely located N-unsubstituted glucosamines in the heparan sulfate side-chains of the glypican-1 proteoglycan. Addition of ascorbate induces a series of reactions that eventually releases heparan sulfate fragments with reducing terminal anhydromannose, presumably without the formation of free nitric oxide.
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| 5. |
- Cheng, Fang, et al.
(author)
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Suppression of amyloid beta a11-immunoreactivity by vitamin C: possible role of heparan sulfate oligosaccharides derived from glypican-1 by ascorbate-induced, no-catalyzed degradation.
- 2011
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In: Journal of Biological Chemistry. - 1083-351X. ; 286:31, s. 27559-27572
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Journal article (peer-reviewed)abstract
- Amyloid beta is generated from the copper- and heparan sulfate (HS)-binding amyloid precursor protein (APP) by proteolytic processing. APP supports S-nitrosylation of the HS-proteoglycan glypican-1 (Gpc-1). In the presence of ascorbate there is NO-catalyzed release of anhydromannose (anMan)-containing oligosaccharides from Gpc-1-SNO. We have investigated whether these oligosaccharides interact with amyolid beta during APP processing and plaque formation. anMan-Immunoreactivity was detected in amyloid plaques of Alzheimer (AD) and APP transgenic (Tg2576) mouse brains by immunofluorescence microscopy. APP/APP degradation products detected by antibodies to the C-terminus of APP, but not amyolid beta oligomers detected by the anti-amyloid beta A11 antibody, colocalized with anMan-immunoreactivity in Tg2576 fibroblasts. A 50-55-kDa anionic, SDS-stable, anMan- and amyloid beta-immunoreactive species was obtained from Tg2576 fibroblasts using immunoprecipitation with anti-APP (C-terminal). anMan-Containing HS oligo- and disaccharide preparations modulated or suppressed A11-immunoreactivity and oligomerization of amyloid beta 42 peptide in an in vitro assay. A11 immunoreactivity increased in Tg2576 fibroblasts when Gpc-1 autoprocessing was inhibited by U18666A, and decreased when Gpc-1 autoprocessing was stimulated by ascorbate. Neither overexpression of Gpc-1 in Tg2576 fibroblasts nor addition of copper ion and NO-donor to hippocampal slices from 3xTg-AD mice affected A11 immunoreactivity levels. However, A11 immunoreactivity was greatly suppressed by the subsequent addition of ascorbate. We speculate that temporary interaction between the amyolid beta domain and small, anMan-containing oligosaccharides may preclude formation of toxic amyloid beta oligomers. A portion of the oligosaccharides co-secrete with the amyloid beta peptides and are deposited in plaques. These results support the notion that inadequate supply of vitamin C could contribute to late onset AD in humans.
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| 6. |
- Gratzer, Daniel, et al.
(author)
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Modalities and Parametric Adjoints
- 2022
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In: ACM Transactions on Computational Logic. - : Association for Computing Machinery (ACM). - 1529-3785 .- 1557-945X. ; 23:3
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Journal article (peer-reviewed)abstract
- Birkedal et al. recently introduced dependent right adjoints as an important class of (non-fibered) modalities in type theory. We observe that several aspects of their calculus are left underdeveloped and that it cannot serve as an internal language. We resolve these problems by assuming that the modal context operator is a parametric right adjoint. We show that this hitherto unrecognized structure is common. Based on these discoveries we present a new well-behaved Fitch-style multimodal type theory, which can be used as an internal language. Finally, we apply this syntax to guarded recursion and parametricity.
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| 7. |
- Grünewald, Tilman A., et al.
(author)
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Mapping the 3D orientation of nanocrystals and nanostructures in human bone: Indications of novel structural features
- 2020
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In: Science advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 6:24
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Journal article (peer-reviewed)abstract
- Bone is built from collagen fibrils and biomineral nanoparticles. In humans, they are organized in lamellar twisting patterns on the microscale. It has been a central tenet that the biomineral nanoparticles are co-aligned with the bone nanostructure. Here, we reconstruct the three-dimensional orientation in human lamellar bone of both the nanoscale features and the biomineral crystal lattice from small-angle x-ray scattering and wide-angle x-ray scattering, respectively. While most of the investigated regions show well-aligned nanostructure and crystal structure, consistent with current bone models, we report a localized difference in orientation distribution between the nanostructure and the biomineral crystals in specific bands. Our results show a robust and systematic, but localized, variation in the alignment of the two signals, which can be interpreted as either an additional mineral fraction in bone, a preferentially aligned extrafibrillar fraction, or the result of transverse stacking of mineral particles over several fibrils.
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| 8. |
- Malmström, Lars, et al.
(author)
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Quantitative proteogenomics of human pathogens using DIA-MS.
- 2015
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In: Journal of Proteomics. - : Elsevier BV. - 1874-3919 .- 1876-7737. ; 129, s. 98-107
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Journal article (peer-reviewed)abstract
- The increasing number of bacterial genomes in combination with reproducible quantitative proteome measurements provides new opportunities to explore how genetic differences modulate proteome composition and virulence. It is challenging to combine genome and proteome data as the underlying genome influences the proteome. We present a strategy to facilitate the integration of genome data from several genetically similar bacterial strains with data-independent analysis mass spectrometry (DIA-MS) for rapid interrogation of the combined data sets. The strategy relies on the construction of a composite genome combining all genetic data in a compact format, which can accommodate the fusion with quantitative peptide and protein information determined via DIA-MS. We demonstrate the method by combining data sets from whole genome sequencing, shotgun MS and DIA-MS from 34 clinical isolates of Streptococcus pyogenes. The data structure allows for fast exploration of the data showing that undetected proteins are on average more amenable to amino acid substitution than expressed proteins. We identified several significantly differentially expressed proteins between invasive and non-invasive strains. The work underlines how integration of whole genome sequencing with accurately quantified proteomes can further advance the interpretation of the relationship between genomes, proteomes and virulence.
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| 9. |
- Mani, Katrin, et al.
(author)
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Tumor attenuation by 2(6-hydroxynaphthyl)-{beta}-D-xylopyranoside requires priming of heparan sulfate and nuclear targeting of the products.
- 2004
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In: Glycobiology. - : Oxford University Press (OUP). - 1460-2423. ; 14:5, s. 387-397
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Journal article (peer-reviewed)abstract
- We have previously reported that the heparan sulfate-priming glycoside 2-(6-hydroxynaphthyl)-ß-D-xylopyranoside selectively inhibits growth of transformed or tumor-derived cells. To investigate the specificity of this xyloside various analogs were synthesized and tested in vitro. Selective growth inhibition was dependent on the presence of a free 6-hydroxyl in the aglycon. Because cells deficient in heparan sulfate synthesis were insensitive to the xyloside, we conclude that priming of heparan sulfate synthesis was required for growth inhibition. In growth-inhibited cells, heparan sulfate chains primed by the active xyloside were degraded to products that contained anhydromannose and appeared in the nuclei. Hence the degradation products were generated by nitric oxide–dependent cleavage. Accordingly, nitric oxide depletion reduced nuclear localization of the degradation products and counteracted the growth-inhibitory effect of the xyloside. We propose that 2-(6-hydroxynaphthyl)-ß-D-xylopyranoside entered cells and primed synthesis of heparan sulfate chains that were subsequently degraded by nitric oxide into products that accumulated in the nucleus. In vivo experiments demonstrated that the xyloside administered subcutaneously, perorally, or intraperitoneally was adsorbed and made available to tumor cells located subcutaneously. Treatment with the xyloside reduced the average tumor load by 70–97% in SCID mice. The present xyloside may serve as a lead compound for the development of novel antitumor strategies.
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