| 1. |
- Groenen, M. A., et al.
(author)
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Analyses of pig genomes provide insight into porcine demography and evolution
- 2012
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 491:7424, s. 393-398
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Journal article (peer-reviewed)abstract
- For 10,000 years pigs and humans have shared a close and complex relationship. From domestication to modern breeding practices, humans have shaped the genomes of domestic pigs. Here we present the assembly and analysis of the genome sequence of a female domestic Duroc pig (Sus scrofa) and a comparison with the genomes of wild and domestic pigs from Europe and Asia. Wild pigs emerged in South East Asia and subsequently spread across Eurasia. Our results reveal a deep phylogenetic split between European and Asian wild boars approximately 1 million years ago, and a selective sweep analysis indicates selection on genes involved in RNA processing and regulation. Genes associated with immune response and olfaction exhibit fast evolution. Pigs have the largest repertoire of functional olfactory receptor genes, reflecting the importance of smell in this scavenging animal. The pig genome sequence provides an important resource for further improvements of this important livestock species, and our identification of many putative disease-causing variants extends the potential of the pig as a biomedical model.
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| 2. |
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| 3. |
- Holmberg, M., et al.
(author)
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Treatment outcome 6-10 years after diagnosis of hyperthyroidism in 2916 patients : a longitudinal evaluation of a swedish incidence cohort
- 2018
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In: Thyroid. - : Mary Ann Liebert. - 1050-7256 .- 1557-9077. ; :S1
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Journal article (other academic/artistic)abstract
- Treatment of Graves’ disease (GD) and toxic nodular goiter (TNG) has the objectives to cure hyperthyroidism, prevent recurrent disease and preserve thyroid function. Treatment efficacies and long-termout comes of antithyroid drugs (ATD), radioactive iodine (RAI) or surgery varies in the literature. We report outcome of treatment, cure rate and risk factors for relapse for GD and TNG in an unselected cohort. A prospective incidence-cohort of de novo diagnosed GD and TNG patients (n = 2916) from 2003-05, were invited to a follow-up 6 - 10 years after diagnosis. Questionnaires were sent to 2430 patients regarding treatments, cure rate, recurrence, quality of life, demographic data, comorbidities and life-style factors. Patients were treated according to clinical routine with ATD, RAI or surgery. Of those included, 1186 (83.3%) had GD and 237 (16.7%) had TNG. In GD patients, 351 (45.3%), 264 (81.5%), and 52 (96.3%) were cured by ATD, RAI or surgery respectively as first line treatment. Of those, 77.0%, 15.4% and 3.8% respectively were without levothyr-oxine supplementation at follow-up at 8 – 0.9 years. Including all treatment modalities, 851 (71.8%) of GD patients were cured within one treatment period. At follow-up, 278 (23%) of GD patients had been operated. In TNG patients, RAI cured 88.6% and surgery 92.9%, whereof 52/154 (33.8%) and 3/15 (20%) had no levothyroxine supplementation post RAI and surgery, respectively.The proportion that did not feel fully recovered at follow-up was 25.3% of GD and 18.1% of the TNG patients. Overall, treatment of hyperthyroidism results in preserved thyroid function only in 35.3% and 44.7% of GD and TNG cases, respectively. As many as 23.4% of the GD patients end up with surgery although only 4.6% choose it from the beginning. Our treatment tradition cures 71.8% of GD patients and 78.1% of TNG patients within one treatment period. The high number of patients who do not feel recovered 6 -10 years after hyperthyroidism in GD and TNG is are minder of the chronic nature of hyperthyroidism.
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| 4. |
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| 5. |
- Berglund, Åsa M. M., 1978-, et al.
(author)
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Effects on the food-web structure and bioaccumulation patterns of organic contaminants in a climate-altered Bothnian Sea mesocosms
- 2023
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In: Frontiers in Marine Science. - : Frontiers Media S.A.. - 2296-7745. ; 10
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Journal article (peer-reviewed)abstract
- Climate change is expected to alter global temperature and precipitation patterns resulting in complex environmental impacts. The proposed higher precipitation in northern Scandinavia would increase runoff from land, hence increase the inflow of terrestrial dissolved organic matter (tDOM) in coastal regions. This could promote heterotrophic bacterial production and shift the food web structure, by favoring the microbial food web. The altered climate is also expected to affect transport and availability of organic micropollutants (MPs), with downstream effects on exposure and accumulation in biota. This study aimed to assess climate-induced changes in a Bothnian Sea food web structure as well as bioaccumulation patterns of MPs. We performed a mesocosms-study, focusing on aquatic food webs with fish as top predator. Alongside increased temperature, mesocosm treatments included tDOM and MP addition. The tDOM addition affected nutrient availability and boosted both phytoplankton and heterotrophic bacteria in our fairly shallow mesocosms. The increased tDOM further benefitted flagellates, ciliates and mesozooplankton, while the temperature increase and MP addition had minor effect on those organism groups. Temperature, on the other hand, had a negative impact on fish growth and survival, whereas tDOM and MP addition only had minor impact on fish. Moreover, there were indications that bioaccumulation of MPs in fish either increased with tDOM addition or decreased at higher temperatures. If there was an impact on bioaccumulation, moderately lipophilic MPs (log Kow 3.6 - 4.6) were generally affected by tDOM addition and more lipophilic MPs (log Kow 3.8 to 6.4) were generally affected by increased temperature. This study suggest that both increased temperatures and addition of tDOM likely will affect bioaccumulation patterns of MPs in shallow coastal regions, albeit with counteracting effects.
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| 6. |
- Byström, Sanna, et al.
(author)
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Affinity Proteomic Profiling of Plasma, Cerebrospinal Fluid, and Brain Tissue within Multiple Sclerosis
- 2014
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In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 13:11, s. 4607-4619
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Journal article (peer-reviewed)abstract
- The brain is a vital organ and because it is well shielded from the outside environment, possibilities for noninvasive analysis are often limited. Instead, fluids taken from the spinal cord or circulatory system are preferred sources for the discovery of candidate markers within neurological diseases. In the context of multiple sclerosis (MS), we applied an affinity proteomic strategy and screened 22 plasma samples with 4595 antibodies (3450 genes) on bead arrays, then defined 375 antibodies (334 genes) for targeted analysis in a set of 172 samples and finally used 101 antibodies (43 genes) on 443 plasma as well as 573 cerebrospinal spinal fluid (CSF) samples. This revealed alteration of protein profiles in relation to MS subtypes for IRF8, IL7, METTL14, SLC30A7, and GAP43. Respective antibodies were subsequently used for immunofluorescence on human post-mortem brain tissue with MS pathology for expression and association analysis. There, antibodies for IRF8, IL7, and METTL14 stained neurons in proximity of lesions, which highlighted these candidate protein targets for further studies within MS and brain tissue. The affinity proteomic translation of profiles discovered by profiling human body fluids and tissue provides a powerful strategy to suggest additional candidates to studies of neurological disorders.
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| 7. |
- Ekman-Ordeberg, G, et al.
(author)
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Low molecular weight heparin stimulates myometrial contractility and cervical remodeling in vitro
- 2009
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In: Acta Obstet Gynecol Scand. - : Wiley. ; 88:9, s. 984-989
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Journal article (peer-reviewed)abstract
- OBJECTIVES: The low molecular weight heparin, Dalteparin, shortens human labor time. The aim of this study was to investigate if the mechanism behind this effect involves myometrial contractility and cervical ripening and if the anticoagulative activity is necessary for its effect. DESIGN: Experimental in vitro study. SETTING: Lund University and Karolinska Institute, Sweden. METHODS: The effect of low molecular weight heparins with or without anticoagulative properties on myometrial contractility was measured in vitro on smooth muscle strips from biopsies obtained at elective cesarean sections. The effects on cervical ripening were assessed in cervical fibroblasts cultured from explants of cervical biopsies obtained at delivery. MAIN OUTCOME MEASURES: Mean force and number of contractions in uterine smooth muscle strips and interleukin-8 (IL-8) secretion in cervical fibroblasts. RESULTS: Myometrial smooth muscle strips pretreated with low molecular weight heparins showed increased contractile activity compared to untreated smooth muscle strips. Secretion of IL-8 from cultured cervical fibroblasts was significantly increased after treatment with low molecular weight heparin. Both these effects were independent of anticoagulative activity of the low molecular weight heparin. CONCLUSIONS: A possible underlying mechanism for the shortened labor time after low molecular weight heparin treatment is enhanced myometrial contractility and an increased IL-8 secretion in cervical fibroblast, mimicking the final cervical ripening in vivo. Our data support the notion that anticoagulant activity is not required to promote labor.
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| 8. |
- Fredolini, Claudia, et al.
(author)
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Systematic assessment of antibody selectivity in plasma based on a resource of enrichment profiles
- 2019
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
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Journal article (peer-reviewed)abstract
- There is a strong need for procedures that enable context and application dependent validation of antibodies. Here, we applied a magnetic bead assisted workflow and immunoprecipitation mass spectrometry (IP-MS/MS) to assess antibody selectivity for the detection of proteins in human plasma. A resource was built on 414 IP experiments using 157 antibodies (targeting 120 unique proteins) in assays with heat-treated or untreated EDTA plasma. For each protein we determined their antibody related degrees of enrichment using z-scores and their frequencies of identification across all IP assays. Out of 1,313 unique endogenous proteins, 426 proteins (33%) were detected in >20% of IPs, and these background components were mainly comprised of proteins from the complement system. For 45% (70/157) of the tested antibodies, the expected target proteins were enriched (z-score >= 3). Among these 70 antibodies, 59 (84%) co-enriched other proteins beside the intended target and mainly due to sequence homology or protein abundance. We also detected protein interactions in plasma, and for IGFBP2 confirmed these using several antibodies and sandwich immunoassays. The protein enrichment data with plasma provide a very useful and yet lacking resource for the assessment of antibody selectivity. Our insights will contribute to a more informed use of affinity reagents for plasma proteomics assays.
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| 9. |
- Häggmark, Anna, et al.
(author)
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Antibody-based profiling of cerebrospinal fluid within multiple sclerosis
- 2013
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In: Proteomics. - : Wiley. - 1615-9853 .- 1615-9861. ; 13:15, s. 2256-2267
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Journal article (peer-reviewed)abstract
- Antibody suspension bead arrays have proven to enable multiplexed and high-throughput protein profiling in unfractionated plasma and serum samples through a direct labeling approach. We here describe the development and application of an assay for protein profiling of cerebrospinal fluid (CSF). While setting up the assay, systematic intensity differences between sample groups were observed that reflected inherent sample specific total protein amounts. Supplementing the labeling reaction with BSA and IgG diminished these differences without impairing the apparent sensitivity of the assay. We also assessed the effects of heat treatment on the analysis of CSF proteins and applied the assay to profile 43 selected proteins by 101 antibodies in 339 CSF samples from a multiple sclerosis (MS) cohort. Two proteins, GAP43 and SERPINA3 were found to have a discriminating potential with altered intensity levels between sample groups. GAP43 was detected at significantly lower levels in secondary progressive MS compared to early stages of MS and the control group of other neurological diseases. SERPINA3 instead was detected at higher levels in all MS patients compared to controls. The developed assay procedure now offers new possibilities for broad-scale protein profiling of CSF within neurological disorders.
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| 10. |
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| 11. |
- Sj?lin, G., et al.
(author)
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The Long-Term Outcome of Treatment for Graves' Hyperthyroidism
- 2019
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In: Thyroid. - : Mary Ann Liebert Inc. - 1050-7256 .- 1557-9077. ; 29:11, s. 1545-1557
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Journal article (peer-reviewed)abstract
- Background: The treatment efficacy of antithyroid drug (ATD) therapy, radioactive iodine (I-131), or surgery for Graves' hyperthyroidism is well described. However, there are a few reports on the long-term total outcome of each treatment modality regarding how many require levothyroxine supplementation, the need of thyroid ablation, or the individual patient's estimation of their recovery. Methods: We conducted a pragmatic trial to determine the effectiveness and adverse outcome in a patient cohort newly diagnosed with Graves' hyperthyroidism between 2003 and 2005 (n = 2430). The patients were invited to participate in a longitudinal study spanning 8 +/- 0.9 years (mean +/- standard deviation) after diagnosis. We were able to follow 1186 (60%) patients who had been treated with ATD, I-131, or surgery. We determined the mode of treatment, remission rate, recurrence, quality of life, demographic data, comorbidities, and lifestyle factors through questionnaires and a review of the individual's medical history records. Results: At follow-up, the remission rate after first-line treatment choice with ATD was 45.3% (351/774), with I-131 therapy 81.5% (324/264), and with surgery 96.3% (52/54). Among those patients who had a second course of ATD, 29.4% achieved remission (vs. the 45.3% after the first course of ATD). The total number of patients who had undergone ablative treatment was 64.3% (763/1186), of whom 23% (278/1186) had received surgery, 43% (505/1186) had received I-131 therapy, including 2% (20/1186) who had received both surgery and I-131. Patients who received ATD as first-line treatment and possibly additional ATD had 49.7% risk (385/774) of having undergone ablative treatment at follow-up. Levothyroxine replacement was needed in 23% (81/351) of the initially ATD treated in remission, in 77.3% (204/264) of the I-131 treated, and in 96.2% (50/52) of the surgically treated patients. Taken together after 6-10 years, and all treatment considered, normal thyroid hormone status without thyroxine supplementation was only achieved in 35.7% (423/1186) of all patients and in only 40.3% of those initially treated with ATD. The proportion of patients that did not feel fully recovered at follow-up was 25.3%. Conclusion: A patient selecting ATD therapy as the initial approach in the treatment of Graves' hyperthyroidism should be informed that they have only a 50.3% chance of ultimately avoiding ablative treatment and only a 40% chance of eventually being euthyroid without thyroid medication. Surprisingly, 1 in 4 patients did not feel fully recovered after 6-10 years. The treatment for Graves' hyperthyroidism, thus, has unexpected long-term consequences for many patients.
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| 12. |
- Åström, S U, et al.
(author)
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Genetic interactions between a null allele of the RIT1 gene encoding an initiator tRNA-specific modification enzyme and genes encoding translation factors in Saccharomyces cerevisiae
- 1999
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In: Molecular General Genetics. - : Springer. - 0026-8925 .- 1432-1874. ; 261:6, s. 967-976
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Journal article (peer-reviewed)abstract
- The Saccharomyces cerevisiae gene RIT1 encodes a phospho-ribosyl transferase that exclusively modifies the initiator tRNA (tRNAMet(i)) by the addition of a 2'-O-ribosyl phosphate group to Adenosine 64. As a result, tRNAMet(i) is prevented from participating in the elongation steps of protein synthesis. We previously showed that the modification is not essential for the function of tRNAMet(i) in the initiation of translation, since rit1 null strains are viable and show no obvious growth defects. Here, we demonstrate that yeast strains in which a rit1 null allele is combined with mutations in any of the genes for the three subunits of eukaryotic initiation factor-2 (eIF-2), or with disruption alleles of two of the four initiator methionine tRNA (IMT) genes, show synergistic growth defects. A multicopy plasmid carrying an IMT gene can alleviate these defects. On the other hand, introduction of a high-copy-number plasmid carrying the TEF2 gene, which encodes the eukaryotic elongation factor 1alpha (eEF-1alpha), into rit1 null strains with two intact IMT genes had the opposite effect, indicating that increased levels of eEF-1alpha are deleterious to these strains, presumably due to sequestration of the unmodified met-tRNAMet(i) for elongation. Thus, under conditions in which the components of the ternary met-tRNAMet(i):GTP:eIF-2 complex become limiting or are functionally impaired, the presence of the 2'-O-ribosyl phosphate modification in tRNAMet(i) is important for the provision of adequate amounts of tRNAMet(i) for formation of this ternary complex.
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| 13. |
- Andersson, Jens, et al.
(author)
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Plastic reources polymorphism : effects or resource availability on Arctic char (Salvelinus alpinus) morphology
- 2005
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In: Biological Journal of the Linnean Society. - London : Acad. P.. - 0024-4066 .- 1095-8312. ; 85:3, s. 341-351
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Journal article (peer-reviewed)abstract
- Resource polymorphism has been suggested to be a platform for speciation. In some cases resource polymorphism depends on phenotypic plasticity but in other cases on genetic differences between morphotypes, which in turn has been suggested to be the ongoing development of a species pair. Here we study environmentally induced morphological differences in two age classes of Arctic char (Salvelinus alpinus) influencing char performance and diet in relation to resource availability. We found that structurally complex habitats with relatively lower zooplankton densities gave rise to individuals with a deeper body, and a downward positioned tip of the snout compared with individuals from structurally simple habitats with relatively higher zooplankton densities for both age classes. Environment also had an effect on foraging efficiency on zooplankton, with fish from structurally simple habitats had a higher foraging rate than fish from structurally complex habitats. Diet analyses showed that resource use in char mainly depends on the relative abundance of different resources. Therefore, to gain further understanding of resource polymorphism we suggest that future studies must include population dynamic feedbacks by the resources on the consumers.
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| 14. |
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| 15. |
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| 16. |
- Björk, Glenn R, et al.
(author)
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Prevention of translational frameshifting by the modified nucleoside 1-methylguanosine
- 1989
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In: Science. - 0036-8075 .- 1095-9203. ; 244:4907, s. 986-989
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Journal article (peer-reviewed)abstract
- The methylated nucleoside 1-methylguanosine (m1G) is present next to the 3' end of the anticodon (position 37) in all transfer RNAs (tRNAs) that read codons starting with C except in those tRNAs that read CAN codons. All of the three proline tRNA species, which read CCN codons in Salmonella typhimurium, have been sequenced and shown to contain m1G in position 37. A mutant of S. typhimurium that lacks m1G in its tRNA when grown at temperatures above 37 degrees C, has now been isolated. The mutation (trmD3) responsible for this methylation deficiency is in the structural gene (trmD) for the tRNA(m1G37)methyltransferase. Therefore, the three proline tRNAs in the trmD3 mutant have an unmodified guanosine at position 37. Furthermore, the trmD3 mutation also causes at least one of the tRNAPro species to frequently shift frame when C's are present successively in the message. Thus, m1G appears to prevent frameshifting. The data from eubacteria apply to both eukaryotes and archaebacteria.
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| 17. |
- Braendengen, Morten, et al.
(author)
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Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer
- 2008
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In: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 26:22, s. 3687-3694
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Journal article (peer-reviewed)abstract
- PURPOSE: Preoperative chemoradiotherapy is considered standard treatment for locally advanced rectal cancer, although the scientific evidence for the chemotherapy addition is limited. This trial investigated whether chemotherapy as part of a multidisciplinary treatment approach would improve downstaging, survival, and relapse rate. PATIENTS AND METHODS: The randomized study included 207 patients with locally nonresectable T4 primary rectal carcinoma or local recurrence from rectal carcinoma in the period 1996 to 2003. The patients received either chemotherapy (fluorouracil/leucovorin) administered concurrently with radiotherapy (50 Gy) and adjuvant for 16 weeks after surgery (CRT group, n = 98) or radiotherapy alone (50 Gy; RT group, n = 109). RESULTS: The two groups were well balanced according to pretreatment characteristics. An R0 resection was performed in 82 patients (84%) in the CRT group and in 74 patients (68%) in the RT group (P = .009). Pathologic complete response was seen in 16% and 7%, respectively. After an R0 + R1 resection, local recurrence was found in 5% and 7%, and distant metastases in 26% and 39%, respectively. Local control (82% v 67% at 5 years; log-rank P = .03), time to treatment failure (63% v 44%; P = .003), cancer-specific survival (72% v 55%; P = .02), and overall survival (66% v 53%; P = .09) all favored the CRT group. Grade 3 or 4 toxicity, mainly GI, was seen in 28 (29%) of 98 and six (6%) of 109, respectively (P = .001). There was no difference in late toxicity. CONCLUSION: CRT improved local control, time to treatment failure, and cancer-specific survival compared with RT alone in patients with nonresectable rectal cancer. The treatments were well tolerated.
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| 18. |
- Byström, Jonas, et al.
(author)
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Inducible CYP2J2 and its product 11,12-EET promotes bacterial phagocytosis : a role for CYP2J2 deficiency in the pathogenesis of Crohn's disease?
- 2013
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In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:9
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Journal article (peer-reviewed)abstract
- The epoxygenase CYP2J2 has an emerging role in inflammation and vascular biology. The role of CYP2J2 in phagocytosis is not known and its regulation in human inflammatory diseases is poorly understood. Here we investigated the role of CYP2J2 in bacterial phagocytosis and its expression in monocytes from healthy controls and Crohns disease patients. CYP2J2 is anti-inflammatory in human peripheral blood monocytes. Bacterial LPS induced CYP2J2 mRNA and protein. The CYP2J2 arachidonic acid products 11,12-EET and 14,15-EET inhibited LPS induced TNFα release. THP-1 monocytes were transformed into macrophages by 48h incubation with phorbol 12-myristate 13-acetate. Epoxygenase inhibition using a non-selective inhibitor SKF525A or a selective CYP2J2 inhibitor Compound 4, inhibited E. coli particle phagocytosis, which could be specifically reversed by 11,12-EET. Moreover, epoxygenase inhibition reduced the expression of phagocytosis receptors CD11b and CD68. CD11b also mediates L. monocytogenes phagocytosis. Similar, to E. coli bioparticle phagocytosis, epoxygenase inhibition also reduced intracellular levels of L. monocytogenes, which could be reversed by co-incubation with 11,12-EET. Disrupted bacterial clearance is a hallmark of Crohn's disease. Unlike macrophages from control donors, macrophages from Crohn's disease patients showed no induction of CYP2J2 in response to E. coli. These results demonstrate that CYP2J2 mediates bacterial phagocytosis in macrophages, and implicates a defect in the CYP2J2 pathway may regulate bacterial clearance in Crohn's disease.
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| 19. |
- Byström, JW, et al.
(author)
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Serological assessment of SARS-CoV-2 exposure in northern Sweden by the use of at-home sampling to meet geographical challenges in rural regions
- 2022
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In: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory.
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Journal article (other academic/artistic)abstract
- The current SARS-CoV-2 pandemic has highlighted a need for easy and safe blood sampling in combination with accurate serological methodology. Venipuncture is usually performed by trained staff at health care centers. Long travel distances may introduce a bias of testing towards relatively large communities with close access to health care centers. Rural regions may thus be overlooked. Here, we demonstrate a sensitive method to measure antibodies to the S-protein of SARS-CoV-2. We adapted and optimized this assay for clinical use together with capillary blood sampling to meet the geographical challenges of serosurveillance. Finally, we tested remote at-home capillary blood sampling together with centralized assessment of S-specific IgG in a rural region of northern Scandinavia that encompasses 55,185 sq kilometers. We conclude that serological assessment from capillary blood sampling gives comparable results as analysis of venous blood. Importantly, at-home sampling enabled citizens living in remote rural areas access to centralized and sensitive laboratory antibody tests.
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| 20. |
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| 21. |
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| 22. |
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| 23. |
- Byström, Roberth, et al.
(author)
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SOD1 mutations targeting surface hydrogen bonds promote ALS without reducing apo-state stability
- 2010
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In: Journal of Biological Chemistry. - : The American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 285:25, s. 19544-52
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Journal article (peer-reviewed)abstract
- In good accord with the protein-aggregation hypothesis for neurodegenerative diseases, ALS-associated SOD1 mutations are found to reduce structural stability or net repulsive charge. Moreover there are weak indications that the ALS disease progression rate is correlated with the degree of mutational impact on the apo-SOD1 structure. A bottleneck for obtaining more conclusive information about these structure-disease relationships, however, is the large intrinsic variability in patient survival times and insufficient disease statistics for the majority of ALS-provoking mutations. As an alternative test of the structure-disease relationship we focus here on the SOD1 mutations that appear to be outliers in the data set. The results identify several ALS-provoking mutations whose only effect on apo SOD1 is the elimination or introduction of a single charge, i.e., D76V/Y, D101N and N139D/K. The thermodynamic stability and folding behaviour of these mutants are indistinguishable from the wildtype control. Moreover, D101N is an outlier in the plot of stability loss vs. patient survival time by having rapid disease progression. Common to the identified mutations is that they truncate conserved salt-links and/or H-bond networks in the functional loops IV or VII. The results show that the local impact of ALS-associated mutations on the SOD1 molecule can sometimes overrun their global effects on apo-state stability and net repulsive charge, and point at the analysis of property outliers as an efficient strategy for mapping out new ALS-provoking features.
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| 24. |
- Byström, Roberth, et al.
(author)
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SOD1 Mutations Targeting Surface Hydrogen Bonds Promote Amyotrophic Lateral Sclerosis without Reducing Apo-state Stability
- 2010
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 285:25, s. 19544-19552
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Journal article (peer-reviewed)abstract
- In good accord with the protein aggregation hypothesis for neurodegenerative diseases, ALS-associated SOD1 mutations are found to reduce structural stability or net repulsive charge. Moreover there are weak indications that the ALS disease progression rate is correlated with the degree of mutational impact on the apoSOD1 structure. A bottleneck for obtaining more conclusive information about these structure-disease relationships, however, is the large intrinsic variability in patient survival times and insufficient disease statistics for the majority of ALS- provoking mutations. As an alternative test of the structure- disease relationship we focus here on the SOD1 mutations that appear to be outliers in the data set. The results identify several ALS- provoking mutations whose only effect on apoSOD1 is the elimination or introduction of a single charge, i.e. D76V/Y, D101N, and N139D/K. The thermodynamic stability and folding behavior of these mutants are indistinguishable from the wild-type control. Moreover, D101N is an outlier in the plot of stability loss versus patient survival time by having rapid disease progression. Commonto the identified mutations is that they truncate conserved salt-links and/or H-bond networks in the functional loops IV or VII. The results show that the local impact of ALS- associated mutations on the SOD1 molecule can sometimes overrun their global effects on apo-state stability and net repulsive charge, and point at the analysis of property outliers as an efficient strategy for mapping out new ALS- provoking features.
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| 25. |
- Byström, Sanna
(author)
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Affinity assays for profiling disease-associated proteins in human plasma
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Affinity-based proteomics offers opportunities for the discovery and validation of disease-associated proteins in human body fluids. This thesis describes the use of antibody-based immunoassays for multiplexed analysis of proteins in human plasma, serum and cerebrospinal fluid (CSF). This high-throughput method was applied with the objective to identify proteins associated to clinical variables. The main work in this thesis was conducted within the diseases of multiple sclerosis and malignant melanoma, as well as mammographic density, a risk factor for breast cancer.The suspension bead array (SBA) technology has been the main method for the work presented in this thesis (Paper I-IV). SBA assays and other affinity proteomic technologies were introduced for protein profiling of sample material obtained from clinical collaborators and biobanks. Perspectives on the validation of antibody selectivity by means of e.g. immuno-capture mass spectrometry are also provided.Paper I describes the development and application of a protocol for multiplexed pro- tein profiling of CSF. The analysis of 340 CSF samples from patients with multiple sclerosis and other neurological disease revealed proteins with potential association to disease progression (GAP43) and inflammation (SERPINA3). Paper II continued on this work with an extended investigation of more than 1,000 clinical samples and included both plasma and CSF collected from the same patients. Comparison of disease subtypes and controls revealed five plasma proteins of potential diagnostic relevance, such as IRF8 and GAP43. The previously reported associations for GAP43 and SERPINA3 in CSF was confirmed. Subsequent immunohistochemical analysis of post-mortem brain tissue revealed differential protein expression in disease affected areas. In Paper III, 150 serum samples from patients with cutaneous malignant melanoma were analyzed. Protein profiles from antibody bead arrays suggested three proteins (RGN, MTHFD1L, STX7) of differential abundance between patients with no disease recurrence and low tumor thickness (T-stage 1 and 2) compared to patients with high tumor thickness (T-stage 3 and 4) and disease recurrence. We observed MTHFD1L expression in tissue of a majority of patients, while expression of STX7 in melanoma tissue had been reported previously. Paper IV describes the analysis of protein in plasma in relation to mammographic breast density (MD), one of the strongest risk factors for the development of breast cancers. More than 1,300 women without prior history of breast cancer were screened. Linear associations to MD in two independent sample sets were found for 11 proteins, which are expressed in the breast and involved in tissue homeostasis, DNA repair, cancer development and/or progression in MD.In conclusion, this thesis describes the use of multiplexed antibody bead arrays for protein profiling of serum, plasma and CSF, and it shortlists disease associated proteins for further validation studies.
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