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B cells have a central role in the pathogenesis of collagen-induced arthritis CIA , an animal model of the autoimmune disease rheumatoid arthritis. In this report, a specific subset of an innate type of B cells, B-1 B cells, have been studied for the involvement in CIA.

The B-1 B cells were shown to produce small amounts of collagen-specific antibodies upon stimulation in vitro, suggesting that they play a minor role in the development of CIA. This report also includes how marginal zone B cells, another innate type of B cells with natural collagen-reactivity, can be identified in the medullary sinuses of lymph nodes of collagen-immunized mice, implying involvement in auto antigen trapping.

The fungal wall is pivotal for cell shape and function, and in interfacial protection during host infection and environmental challenge. Here, we provide the first description of the carbohydrate composition and structure of the cell wall of the rice blast fungus Magnaporthe oryzae.

We focus on the family of glucan elongation proteins Gels and characterize five putative beta-1,3-glucan glucanosyltransferases that each carry the Glycoside Hydrolase 72 signature. We reveal that M. Further, we demonstrated that Delta gel1 Delta gel3 Delta gel4 null mutant has a modified cell wall in which 1,3-glucans have a higher degree of polymerization and are less branched than the wild-type strain. The mutant showed significant differences in global patterns of gene expression, a hyper-branching phenotype and no sporulation, and thus was unable to cause rice blast lesions except via wounded tissues.

We conclude that Gel proteins play significant roles in structural modification of the fungal cell wall during appressorium-mediated plant infection. Sox2 is a master transcriptional regulator of embryonic development. In this study, we determined the protein interactome of Sox2 in the chromatin and nucleoplasm of mouse embryonic stem mES cells.

Apart from canonical interactions with pluripotency-regulating transcription factors, we identified interactions with several chromatin modulators, including members of the heterochromatin protein 1 HP1 family, suggesting a role for Sox2 in chromatin-mediated transcriptional repression. Thus, our results show that Sox2 extensively interacts with RBPs, and suggest that Sox2 and 7SK co-exist in a ribonucleoprotein complex whose function is not to regulate chromatin recruitment, but could rather regulate other processes in the nucleoplasm.

Apart from dominantly inherited mutations, age is the major risk factor and as life expectancy increases the prevalence for AD escalates dramatically. AD causes substantial problems for the affected persons and their families, and the society suffers economically. To date the available treatments only temporarily relieve the symptoms, wherefore the development of a cure is of utmost importance. The etiology of AD is still inconclusive but many believe that small aggregates oligomers of the protein amyloid-β Aβ are central for the onset of AD.

The aims of this thesis were to investigate how different molecules affect the aggregation and toxicity of Aβ. Differentiated neuroblastoma cells and Drosophila melanogaster were used as models of AD to address the issue. Various biophysical studies show that the co-aggregation increases the formation of fibrillar Aβ structures rich in β-sheets.

Noteworthy, these Aβ fibrils were more resistant to both degradation and denaturation, and less prone to propagate seeding from Aβ monomers. Lysozyme levels were increased in CSF from patients that were both biochemically and clinically diagnosed with AD. In mice models of AD it was revealed that the mRNA increase in lysozyme correlates to increased Aβ pathology, but not to tau pathology, indicating that Aβ could drive the expression of lysozyme.

To evaluate the effect for increased expression of lysozyme, co-expression of lysozyme was achieved in flies that expressed Aβ in the retina of the eyes, or in flies that expressed AβArc in the central nervous system. In all AD fly models, co-expression of lysozyme protected the cells from the Aβ induced toxicity. Of note, flies that expressed the toxic AβArc in the CNS of the flies showed an improvement in both lifespan and activity.

Finally, we demonstrate that Aβ aggregating in the presence of lysozyme inhibits the cellular uptake of Aβ and also the cytotoxic effect of Aβ. The work included in this thesis demonstrates that the oligothiophenes p-FTAA and h-FTAA, and also lysozyme have the potential to be used as treatment strategies for sporadic AD, but remarkable, also in familial AD with the highly toxic Arctic mutation. The protective mechanism of p-FTAA seems to be attributed to the ability to generate stable Aβ fibrils with reduced seeding capacity, and that lysozyme inhibits the neuronal uptake of Aβ, which could prevent both the intracellular toxicity and cell-to-cell transmission of Aβ.

A link between amyloid pathology and immune gene expression was suggested in a genome-wide gene expression study of transgenic amyloid mouse models. In this study, the gene expression of lysozyme, a major player in the innate immune system, was found to be increased in a comparable pattern as the amyloid pathology developed in transgenic mouse models of AD.

A similar pattern was seen at protein levels of lysozyme in human AD brain and CSF, but this lysozyme pattern was not seen in a tau transgenic mouse model. Lysozyme was demonstrated to be beneficial for different Drosophila melanogaster models of AD. In flies that expressed Aβ or AβPP together with BACE1 in the eyes, the rough eye phenotype indicative of toxicity was completely rescued by coexpression of lysozyme.

In Drosophila flies bearing the Aβ variant with the Arctic gene mutation, lysozyme increased the fly survival and decreased locomotor dysfunction dose dependently. An interaction between lysozyme and Aβ in the Drosophila eye was discovered. We propose that the increased levels of lysozyme, seen in mouse models of AD and in human AD cases, were triggered by Aβ and caused a beneficial effect by binding of lysozyme to toxic species of Aβ, which prevented these from exerting their toxic effects.

These results emphasize the possibility of lysozyme as biomarker and therapeutic target for AD. Induced pluripotent stem cell iPSC technology has become an important tool for disease modeling. Insufficient data on the variability among iPSC lines derived from a single somatic parental cell line have in practice led to generation and analysis of several, usually three, iPSC sister lines from each parental cell line. All iPSC lines fulfilled stringent criteria for pluripotency.

In an unbiased cluster analysis, all stem cell lines four iPSCs and one ESC clustered together as opposed to the parental fibroblasts. The transcriptome profiles of the three iPSC sister lines were indistinguishable from each other, and functional pathway analysis did not reveal any significant hits. Differentiation to embryoid bodies and subsequent analysis of germ layer markers in the five stem cell clones confirmed that the distribution of their expression profiles was retained.

Taken together, our observations stress the importance of using iPSCs of different parental origin rather than several sister iPSC lines to distinguish disease-associated mechanisms from genetic background effects in disease modeling.

Protein engineering has had an immense impact on the development of biological drugs, including replacement therapies with engineered versions of insulin or factor VIII to treat diabetes or bleeding disorders, and monoclonal antibodies to treat cancer and various other malignancies.

Now, with the next generation of treatment modalities coming up, including monoclonal reagents based on alternative scaffolds, gene and cell therapies, the importance of protein engineering to tailor-make these treatments is likely to increase further.

The neonatal Fc receptor FcRn is widely expressed in the body. One of the receptor's interesting functions is to rescue immunoglobulin G IgG and serum albumin SA from degradation by cells in contact with blood. When serum proteins are endocytosed by a cell, they are transported via the endosome to the lysosome for degradation. However, IgG and SA associate with the FcRn already at the slightly acidic pH of the endosome followed by transport back to the cell surface. There the complex encounters the neutral pH of the blood, at which the binding affinity to FcRn is lost, and IgG and SA are released back into circulation.

In the main part of this thesis, efforts are described aiming to take use of, or block, the FcRn recycling mechanism to control the serum circulation half-life of proteins. In the first study Study I , a robust expression strategy for human FcRn was designed and evaluated.

The extracellular domain was produced in the human SKOV3 cell-line after facile lentiviral delivery of the expression cassettes. This lead to continuous expression of secreted protein that could be purified to homogeneity by a single affinity chromatographic step, using the intrinsic pH-dependent interaction between FcRn and IgG, where the latter was immobilized in a column. The amount of purified protein was 1.

The results suggested a fully functional and stable protein of high purity. In a following study Study II , the goal was to generate affinity proteins interacting with human FcRn in a pH-dependent manner similar to that of FcRn's natural ligands.

The affinity proteins used are denoted affibody molecules, a class of small alternative scaffold proteins with a three-helical structure.

Affibody molecules were selected from a combinatorial library displayed on phage where binding took place at pH 5. Selected variants were characterized by developed in vitro and cell based assays, and some were found to have the desired pH-dependent binding to FcRn.

In vivo studies in mice showed that the serum half-life of a model protein, genetically fused to the FcRn binding affibody molecules, was extended up to almost three-fold compared to a control protein from 33 to 91 hours. In a subsequent study Study III , the use of a FcRn binding affibody molecule to reduce, rather than prolong, the serum half-life of proteins was explored. Here, the rationale was to investigate if injection of a FcRn binding affibody could hinder endogenous IgG from being rescued by FcRn, which could lead to depletion of IgGs by lysosomal degradation.

In autoimmune diseases, such depletion of IgG would include also pathogenic IgG and could thus mitigate the symptoms of the disease. Using cell based assays, it was found that one affibody molecule, selected in Study II, could readily block IgG from binding both human and murine FcRn. In a fourth study Study IV , the goal was to use a different class of affinity proteins to regulate the level of an enzyme in the brain. More specifically, artificial zinc finger-based transcription factors regulating the level of GAD67, which is the rate-limiting enzyme in synthesis of gamma-aminobutyric acid GABA , were designed.

Imbalances in GABA-signaling is involved in different diseases, including Parkinson's disease and epilepsy, and regulation of GAD67 at particular sites in the brain might be a route to ameliorate symptoms associated with such diseases. A construct encoding G3 fused to a general transcriptional activator VP64 was delivered to PCcells, using a lentivirus-based gene delivery system, resulting in a significant up-regulation of endogenous GAD67 expression.

The same construct was subsequently delivered to the striatum of rats, with an induced disease model of Parkinson's disease. Western blot of striatal samples showed a significant up-regulation of GAD67 expression in lesioned striatum compared to intact striatum, and a tendency towards up-regulation compared to lesioned striatum.

Taken together, the protein engineering efforts described in this thesis concerning affinity proteins binding other proteins or DNA, has the potential to find use in drug development and may benefit patients in the future. High-throughput drug screening HTS in live cells is often a vital part of the preclinical anticancer drug discovery process.

So far, two-dimensional 2D monolayer cell cultures have been the most prevalent model in HTS endeavors. However, 2D cell cultures often fail to recapitulate the complex microenvironments of in vivo tumors.

Monolayer cultures are highly proliferative and generally do not contain quiescent cells, thought to be one of the main reasons for the anticancer therapy failure in clinic. Thus, there is a need for in vitro cellular models that would increase predictive value of preclinical research results. The utilization of more complex three-dimensional 3D cell cultures, such as multicellular tumor spheroids MCTS , which contain both proliferating and quiescent cells, has therefore been proposed.

We also set out to identify cellular processes that could be targeted to selectively eradicate quiescent cancer cells. This led to discovery that quiescent cells up-regulate the mevalonate pathway upon OXPHOS inhibition and that the combination of OXPHOS inhibitors and mevalonate pathway inhibitors statins results in synergistic toxicity in this cell population.

In Paper III, we developed a novel spheroid-based drug combination-screening platform and identified a set of molecules that synergize with nitazoxanide to eradicate quiescent cancer cells.

In summary, this work illustrates how MCTS-based HTS yields potential to reveal and exploit previously unrecognized tumor-specific vulnerabilities. It also underscores the importance of cell culture conditions in preclinical drug discovery endeavors. The dynamin-related Epshomology domain-containing protein 2 EHD2 is a membrane-remodeling ATPase that regulates the dynamics of caveolae. Here, we established an electron paramagnetic resonance EPR approach to characterize structural features of membrane-bound EHD2.

We show that residues at the tip of the helical domain can insert into the membrane and may create membrane curvature by a wedging mechanism. Using EPR and X-ray crystallography, we found that the N terminus is folded into a hydrophobic pocket of the GTPase domain in solution and can be released into the membrane.

Cryoelectron microscopy demonstrated that the N terminus is not essential for oligomerization of EHD2 into a membrane-anchored scaffold. Instead, we found a function of the N terminus in regulating targeting and stable association of EHD2 to caveolae. Our data uncover an unexpected, membrane-induced regulatory switch in EHD2 and demonstrate the versatility of EPR to study structure and function of dynamin superfamily proteins. Mitochondria fulfill central functions in cellular energetics, metabolism, and signaling.

The outer membrane translocator complex the TOM complex imports most mitochondrial proteins, but its architecture is unknown. Using a cross-linking approach, we mapped the active translocator down to single amino acid residues, revealing different transport paths for preproteins through the Tom40 channel. An N-terminal segment of Tom40 passes from the cytosol through the channel to recruit chaperones fromthe intermembrane space that guide the transfer of hydrophobic preproteins.

The translocator contains three Tom40 beta-barrel channels sandwiched between a central alpha-helical Tom22 receptor cluster and external regulatory Tom proteins.

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  • Knockdown of Met had in part the opposite effects, indicating that Met inhibitors might be useful in the treatment of TNBC. Twelve endocannabinoids and related compounds 2— nM and 31 oxylipins 1. The overall aim of this thesis work has been to develop new strategies for triggering and controlling changes in lipid membrane integrity and to study the interactions of membrane active peptides with model lipid membranes using both de novo designed and biologically derived synthetic amphipathic cationic peptides. Despite microsurgical repair, healing is slow and incomplete, with lasting functional deficit. Taken together, the protein engineering efforts described in this thesis concerning affinity proteins binding other proteins or DNA, has the potential to find use in drug development and may benefit patients in the future.
  • Massage gärdet erotik spel Nuru massage gift mogen kvinna söker sexträffar i. These case-only variants are significantly more common in high OCD risk breeds compared to breeds with no known psychiatric problems. Both LPSs were isolated [ 1 ] from the C. To exemplify this flowchart, we used the recently characterized organellar oligopeptidase of Arabidopsis Arabidopsis thaliana , an enzyme that takes part in degradation of short peptides within mitochondria and chloroplasts. Fagerberg, Linn.
  • Gamla gratis porn bäckebo deting pa arabiska facesitting södra bröst. Western blot of striatal samples showed a significant up-regulation of GAD67 expression in lesioned striatum compared to intact striatum, and a tendency towards up-regulation compared to lesioned striatum. Tissue-based map of the human proteome Uhlen, Mathias et al. We used immunohistochemistry to identify neutrophils, macrophages, mast cells, and T lymphocytes surrounding necrotic adipocytes in PVAT together with increased gene expression of IL-6 and cathepsin K and S. The assay was applied to a HER2-binding Affibody variant that was efficiently retained by HER2-expressing cells, although characterized by a slow internalization rate.

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