CiteULike: Author Björklund

Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen.

M Alimohammadi — 2008-03-10T10:10:13-00:00

N Engl J Med, Vol. 358, No. 10. (6 March 2008), pp. 1018-1028.

BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disorder caused by mutations in AIRE, the autoimmune regulator gene. Though recent studies concerning AIRE deficiency have begun to elucidate the molecular pathogenesis of organ-specific autoimmunity in patients with APS-1, the autoantigen responsible for hypoparathyroidism, a hallmark of APS-1 and its most common autoimmune endocrinopathy, has not yet been identified. METHODS: We performed immunoscreening of a human parathyroid complementary DNA library, using serum samples from patients with APS-1 and hypoparathyroidism, to identify patients with reactivity to the NACHT leucine-rich-repeat protein 5 (NALP5). Subsequently, serum samples from 87 patients with APS-1 and 293 controls, including patients with other autoimmune disorders, were used to determine the frequency and specificity of autoantibodies against NALP5. In addition, the expression of NALP5 was investigated in various tissues. RESULTS: NALP5-specific autoantibodies were detected in 49% of the patients with APS-1 and hypoparathyroidism but were absent in all patients with APS-1 but without hypoparathyroidism, in all patients with other autoimmune endocrine disorders, and in all healthy controls. NALP5 was predominantly expressed in the cytoplasm of parathyroid chief cells. CONCLUSIONS: NALP5 appears to be a tissue-specific autoantigen involved in hypoparathyroidism in patients with APS-1. Autoantibodies against NALP5 appear to be highly specific and may be diagnostic for this prominent component of APS-1.

The yeast Mediator complex and its regulation.

S Björklund — 2007-11-28T05:26:26-00:00

Trends Biochem Sci, Vol. 30, No. 5. (May 2005), pp. 240-244.

The Mediator complex acts as a bridge, conveying regulatory information from enhancers and other control elements to the basal RNA polymerase II transcription machinery. Mediator is required for the regulated transcription of nearly all RNA polymerase II-dependent genes in Saccharomyces cerevisiae, and post-translational modifications of specific Mediator subunits can affect global patterns of gene transcription.

Application of Active and Kinase-Deficient Kinome Collection for Identification of Kinases Regulating Hedgehog Signaling

Markku Varjosalo — 2008-05-05T17:16:49-00:00

Cell, Vol. 133, No. 3. (2 May 2008), pp. 537-548.

Summary To allow genome-scale identification of genes that regulate cellular signaling, we cloned >90% of all human full-length protein kinase cDNAs and constructed the corresponding kinase activity-deficient mutants. To establish the utility of this resource, we tested the effect of expression of the kinases on three different cellular signaling models. In all screens, many kinases had a modest but significant effect, apparently due to crosstalk between signaling pathways. However, the strongest effects were found with known regulators and novel components, such as MAP3K10 and DYRK2, which we identified in a mammalian Hedgehog (Hh) signaling screen. DYRK2 directly phosphorylated and induced the proteasome-dependent degradation of the key Hh pathway-regulated transcription factor, GLI2. MAP3K10, in turn, affected GLI2 indirectly by modulating the activity of DYRK2 and the known Hh pathway component, GSK3[beta]. Our results establish kinome expression screening as a highly effective way to identify physiological signaling pathway components and genes involved in pathological signaling crosstalk.

Quantification of the elevated rate of domain rearrangements in metazoa.

D Ekman — 2007-11-25T09:46:46-00:00

J Mol Biol, Vol. 372, No. 5. (5 October 2007), pp. 1337-1348.

Most eukaryotic proteins consist of multiple domains created through gene fusions or internal duplications. The most frequent change of a domain architecture (DA) is insertion or deletion of a domain at the N or C terminus. Still, the mechanisms underlying the evolution of multidomain proteins are not very well studied. Here, we have studied the evolution of multidomain architectures (MDA), guided by evolutionary information in the form of a phylogenetic tree. Our results show that Pfam domain families and MDAs have been created with comparable rates (0.1-1 per million years (My)). The major changes in DA evolution have occurred in the process of multicellularization and within the metazoan lineage. In contrast, creation of domains seems to have been frequent already in the early evolution. Furthermore, most of the architectures have been created from older domains or architectures, whereas novel domains are mainly found in single-domain proteins. However, a particular group of exon-bordering domains may have contributed to the rapid evolution of novel multidomain proteins in metazoan organisms. Finally, MDAs have evolved predominantly through insertions of domains, whereas domain deletions are less common. In conclusion, the rate of creation of multidomain proteins has accelerated in the metazoan lineage, which may partly be explained by the frequent insertion of exon-bordering domains into new architectures. However, our results indicate that other factors have contributed as well.

What properties characterize the hub proteins of the protein-protein interaction network of Saccharomyces cerevisiae?

Diana Ekman — 2006-06-18T14:25:30-00:00

Genome Biology, Vol. 7, No. 6. (16 June 2006), R45.

BACKGROUND:Most proteins interact with only a few other proteins while a small number of proteins (hubs) have many interaction partners. Hub proteins and non-hub proteins differ in several respects; however, understanding is not complete about what properties characterize the hubs and set them apart from proteins of low connectivity. Therefore, we have investigated what differentiates hubs from non-hubs and static hubs (party hubs) from dynamic hubs (date hubs) in the protein-protein interaction network of Saccharomyces cerevisiae.RESULTS:The many interactions of hub proteins can only partly be explained by bindings to similar proteins or domains. It is evident that domain repeats, which are associated with binding, are enriched in hubs. Moreover, there is an over representation of multi-domain proteins and long proteins among the hubs. In addition, there are clear differences between party hubs and date hubs. Fewer of the party hubs contain long disordered regions compared to date hubs, indicating that these regions are important for flexible binding but less so for static interactions. Furthermore, party hubs interact to a large extent with each other, supporting the idea of party hubs as the cores of highly clustered functional modules. In addition, hub proteins, and in particular party hubs, are more often ancient. Finally, the more recent paralogs of party hubs are underrepresented.CONCLUSION:Our results indicate that multiple and repeated domains are enriched in hub proteins and, further, that long disordered regions, which are common in date hubs, are particularly important for flexible binding.

A high-throughput strategy for protein profiling in cell microarrays using automated image analysis.

S Strömberg — 2008-01-18T02:11:25-00:00

Proteomics, Vol. 7, No. 13. (June 2007), pp. 2142-2150.

Advances in antibody production render a growing supply of affinity reagents for immunohistochemistry (IHC), and tissue microarray (TMA) technologies facilitate simultaneous analysis of protein expression in a multitude of tissues. However, collecting validated IHC data remains a bottleneck problem, as the standard method is manual microscopical analysis. Here we present a high-throughput strategy combining IHC on a recently developed cell microarray with a novel, automated image-analysis application (TMAx). The software was evaluated on 200 digital images of IHC-stained cell spots, by comparing TMAx annotation with manual annotation performed by seven human experts. A high concordance between automated and manual annotation of staining intensity and fraction of IHC-positive cells was found. In a limited study, we also investigated the possibility to assess the correlation between mRNA and protein levels, by using TMAx output results for relative protein quantification and quantitative real-time PCR for the quantification of corresponding transcript levels. In conclusion, automated analysis of immunohistochemically stained in vitro-cultured cells in a microarray format can be used for high-throughput protein profiling, and extraction of RNA from the same cell lines provides a basis for comparing transcription and protein expression on a global scale.

Accumulation of nonphosphorylated beta-catenin and c-myc in primary and uremic secondary hyperparathyroid tumors.

P Björklund — 2008-01-03T04:33:45-00:00

J Clin Endocrinol Metab, Vol. 92, No. 1. (January 2007), pp. 338-344.

CONTEXT: Primary hyperparathyroidism (pHPT) resulting from parathyroid tumors is a common endocrine disorder with incompletely understood etiology, affecting about 1% of the adult population, with an even higher prevalence for elderly individuals. In renal failure, secondary hyperparathyroidism (sHPT) occurs with multiple tumor development as a result of calcium and vitamin D regulatory disturbance. OBJECTIVE: Aberrant Wnt/beta-catenin signaling with accumulation of beta-catenin in the cytoplasm/nucleus is involved in the development of a variety of neoplasms. The aim of this study was to evaluate whether the Wnt/beta-catenin signaling pathway is activated in parathyroid adenomas of pHPT and in hyperplastic glands from uremic patients with sHPT. DESIGN: Immunohistochemistry, Western blotting, real-time quantitative RT-PCR, and DNA sequencing were performed. RESULTS: beta-Catenin was accumulated in all analyzed parathyroid tumors (n = 47) from patients with pHPT and from patients with HPT secondary to uremia. The accumulation included nonphosphorylated, stabilized (transcriptionally active) beta-catenin. The overexpression was not related to increased beta-catenin mRNA levels. A protein-stabilizing mutation in exon 3 of beta-catenin (S37A) was detected in three of 20 pHPT tumors (15%). No mutation was detected in secondary hyperplastic glands (n = 20), and no evidence for truncated adenomatosis polyposis coli proteins was found in adenomas and secondary hyperplastic glands. Mutations in other Wnt signaling components leading to beta-catenin accumulation, other than in beta-catenin itself, are therefore anticipated. The beta-catenin target gene c-myc was overexpressed in a substantial fraction of the parathyroid tumors. CONCLUSION: Our results strongly suggest that modifications in the Wnt/beta-catenin signaling pathway may be involved in the development of hyperparathyroidism.

The Market Comes to Education in Sweden: An Evaluation of Sweden's Surprising School Reforms

Anders Björklund — 2007-08-07T23:34:04-00:00

(30 January 2006)

A large central government providing numerous public services has long been a hallmark of Swedish society, which is also well-known for its pursuit of equality. Yet in the 1990s, Sweden moved away from this tradition in education, introducing market-oriented reforms that decentralized authority over public schools and encouraged competition between private and public schools. Many wondered if this approach would improve educational quality, or if it might expand inequality that Sweden has fought so hard to hold down. In The Market Comes to Education in Sweden, economists Anders BjÃ¶rklund, Melissa A. Clark, Per-Anders Edin, Peter Fredriksson, and Alan Krueger measure the impact of Sweden's bold experiment in governing and help answer the questions that societies across the globe have been debating as they try to improve their children's education. The Market Comes to Education in Sweden injects some much-needed objectivity into the heavily politicized debate about the effectiveness of educational reform. While advocates for reform herald the effectiveness of competition in improving outcomes, others suggest that the reforms will grossly increase educational inequality for young people. The authors find that increased competition did help improve students' math and language skills, but only slightly, and with no effect on the performance of foreign-born students and those with low-educated parents. They also find some signs of increasing school segregation and wider inequality in student performance, but nothing near the doomsday scenarios many feared. In fact, the authors note that the relationship between family background and school performance has hardly budged since before the reforms were enacted. The authors conclude by providing valuable recommendations for school reform, such as strengthening school evaluation criteria, which are essential for parents, students, and governments to make competent decisions regarding education. Whether or not the market-oriented reforms to Sweden's educational system succeed will have far reaching implications for other countries considering the same course of action. The Market Comes to Education in Sweden offers firm empirical answers to the questions raised by school reform and brings crucial facts to the debate over the future of schooling in countries across the world.

A Unified Approach to Code Generation from Behavioral Diagrams

Dag Björklund — 2007-07-20T20:32:53-00:00

Languages for System Specification (2004), pp. 20-34.

In this article we show how to use the Rialto intermediate language, to capture the semantics of UML behavioral diagrams. The Rialto language has a formal semantics given as structural operational rules and it supports semantic variations. It can be used to uniformly describe the behavior of a combination of several diagrams and as a bridge from UML models to animation and production code.

Expression of genetic and environmental variation during ageing

G Engström — 2007-05-16T12:02:18-00:00

TAG Theoretical and Applied Genetics, Vol. 77, No. 1. (1 January 1989), pp. 119-122.

To test for different gene activity during ageing, an experiment was set up to determine whether or not genetic variation and genetic correlations between fitness traits at different ages change in a systematic way through time. Additive genetic and environmental variance components as well as genetic correlations between different age periods were calculated for the fitness trait “number of adult offspring” in a population of Drosophila melanogaster. Genetic correlations between age periods were all positive and, hence, did not support the theory postulating that genes with beneficial effects on early fitness have pleiotropic unfavourable effects on late fitness. The environmental variation as well as the additive genetic variance showed a clear increase with age. The increase of environmental variation is probably a result of the individuals' increasing difficulties in coping with environmental stress due to physiological deterioration with age. Increased additive genetic variation may be explained by more and more genes being “turned on” with age. Alternatively, it could be caused by accumulation of deleterious mutations with different effects and may reflect the individuals' capacity of DNA repair.

Expression of genetic and environmental variation during ageing

G Engström — 2007-05-16T11:57:14-00:00

TAG Theoretical and Applied Genetics, Vol. 85, No. 1. (1 October 1992), pp. 26-32.

A selection experiment with Drosophila melanogaster was carried out to test some theories of ageing by calculating genetic parameters for a reproductive fitness trait at different ages. Successful selection for increased lifespan showed that longevity is a trait under genetic control. Positive genetic correlations between early and late fitness were found. These results do not support the pleiotropy theory of ageing which predicts a negative genetic correlation. Both environmental and additive genetic variation clearly increased with age. Increased environmental variation probably reflects the individuals' difficulties in coping with environmental stress. The increase in additive genetic variation supports the mutation accumulation theory of ageing, as well as other theories that postulate increased additive genetic variation with age.

Supervised identification of allergen-representative peptides for in silico detection of potentially allergenic proteins.

AK Björklund — 2006-09-19T07:26:34-00:00

Bioinformatics, Vol. 21, No. 1. (1 January 2005), pp. 39-50.

MOTIVATION: Identification of potentially allergenic proteins is needed for the safety assessment of genetically modified foods, certain pharmaceuticals and various other products on the consumer market. Current methods in bioinformatic allergology exploit common features among allergens for the detection of amino acid sequences of potentially allergenic proteins. Features for identification still unexplored include the motifs occurring commonly in allergens, but rarely in ordinary proteins. In this paper, we present an algorithm for the identification of such motifs with the purpose of biocomputational detection of amino acid sequences of potential allergens. RESULTS: Identification of allergen-representative peptides (ARPs) with low or no occurrence in proteins lacking allergenic properties is the essential component of our new method, designated DASARP (Detection based on Automated Selection of Allergen-Representative Peptide). This approach consistently outperforms the criterion based on identical peptide match for predicting allergenicity recommended by ILSI/IFBC and FAO/WHO and shows results comparable to the alignment-based criterion as outlined by FAO/WHO. AVAILABILITY: The detection software and the ARP set needed for the analysis of a query protein reported here are properties of the Swedish National Food Agency and are available upon request. The protein sequence sets used in this work are publicly available on http://www.slv.se/templatesSLV/SLV_Page____9343.asp. Allergenicity assessment for specific protein sequences of interest is also possible via ulfh@slv.se

External cross-validation for unbiased evaluation of protein family detectors: application to allergens.

D Soeria-Atmadja — 2006-08-10T08:36:04-00:00

Proteins, Vol. 61, No. 4. (1 December 2005), pp. 918-925.

Key issues in protein science and computational biology are design and evaluation of algorithms aimed at detection of proteins that belong to a specific family, as defined by structural, evolutionary, or functional criteria. In this context, several validation techniques are often used to compare different parameter settings of the detector, and to subsequently select the setting that yields the smallest error rate estimate. A frequently overlooked problem associated with this approach is that this smallest error rate estimate may have a large optimistic bias. Based on computer simulations, we show that a detector's error rate estimate can be overly optimistic and propose a method to obtain unbiased performance estimates of a detector design procedure. The method is founded on an external 10-fold cross-validation (CV) loop that embeds an internal validation procedure used for parameter selection in detector design. The designed detector generated in each of the 10 iterations are evaluated on held-out examples exclusively available in the external CV iterations. Notably, the average of these 10 performance estimates is not associated with a final detector, but rather with the average performance of the design procedure used. We apply the external CV loop to the particular problem of detecting potentially allergenic proteins, using a previously reported design procedure. Unbiased performance estimates of the allergen detector design procedure are presented together with information about which algorithms and parameter settings that are most frequently selected.

A human protein atlas for normal and cancer tissues based on antibody proteomics.

M Uhlén — 2006-03-04T14:17:52-00:00

Mol Cell Proteomics, Vol. 4, No. 12. (December 2005), pp. 1920-1932.

Antibody-based proteomics provides a powerful approach for the functional study of the human proteome involving the systematic generation of protein-specific affinity reagents. We used this strategy to construct a comprehensive, antibody-based protein atlas for expression and localization profiles in 48 normal human tissues and 20 different cancers. Here we report a new publicly available database containing, in the first version, approximately 400,000 high resolution images corresponding to more than 700 antibodies toward human proteins. Each image has been annotated by a certified pathologist to provide a knowledge base for functional studies and to allow queries about protein profiles in normal and disease tissues. Our results suggest it should be possible to extend this analysis to the majority of all human proteins thus providing a valuable tool for medical and biological research.

Stabilization of the Activated alpha(M)beta(2) Integrin by a Small Molecule Inhibits Leukocyte Migration and Recruitment.

Mikael Björklund — 2006-03-02T13:12:51-00:00

Biochemistry, Vol. 45, No. 9. (7 March 2006), pp. 2862-2871.

Integrins are potential targets for the development of antiinflammatory agents. Here we develop a novel high-throughput assay by allowing a chemical library to compete with phage display peptide binding and identify a novel small-molecule ligand to the leukocyte-specific alpha(M)beta(2) integrin. The identified thioxothiazolidine-containing compound, IMB-10, had an unexpected activity in that it stabilized binding of alpha(M)beta(2) to its endogenous ligands proMMP-9 and fibrinogen. Single amino acid substitutions in the activity-regulating C-terminal helix and the underlying region in the ligand-binding I domain of the integrin suppressed the effect of IMB-10. A computational model indicated that IMB-10 occupies a distinct cavity present only in the activated form of the integrin I domain. IMB-10 inhibited alpha(M)beta(2)-dependent migration in vitro and inflammation-induced neutrophil emigration in vivo. Stabilization of integrin-mediated adhesion by a small molecule is a novel means to inhibit cell migration and may have a utility in treatment of inflammatory diseases involving leukocyte recruitment.

Spatial learning and motor deficits in aged rats.

FH Gage — 2005-12-11T05:00:25-00:00

Neurobiol Aging, Vol. 5, No. 1. (1984), pp. 43-48.

Young (3 months) and aged (24 months) rats were compared on a range of behavioural tests. The aged animals were impaired in their acquisition of a spatial learning task in the Morris water maze, as well as showing deficits in motor coordination, swimming efficiency, and spontaneous locomotion and exploration in an open field. Qualitative observation and correlation analyses indicated that the aged group was heterogeneous in the degree of impairments manifested by the individual animals, and suggested that the development of impairments may progress with aging at different rates in the various tasks and possibly in different underlying neuroanatomical systems.

Gelatinase-mediated migration and invasion of cancer cells.

M Björklund — 2005-05-25T06:40:24-00:00

Biochim Biophys Acta, Vol. 1755, No. 1. (25 May 2005), pp. 37-69.

The matrix metalloproteinases(MMP)-2 and -9, also known as the gelatinases have been long recognized as major contributors to the proteolytic degradation of extracellular matrix during tumor invasion. In the recent years, a plethora of non-matrix proteins have also been identified as gelatinase substrates thus significantly broadening our understanding of these enzymes as proteolytic executors and regulators in various physiological and pathological states including embryonic growth and development, angiogenesis and tumor progression, inflammation, infective diseases, degenerative diseases of the brain and vascular diseases. Although the effect of broad-spectrum inhibitors of MMPs in the treatment of cancer has been disappointing in clinical trials, novel mechanisms of gelatinase inhibition have been now identified. Inhibition of the association of the gelatinases with cell-surface integrins appears to offer highly specific means to target these enzymes without inhibiting their catalytic activity in multiple cell types including endothelial cells, tumor cells and leukocytes. Here, we review the multiple functions of the gelatinases in cancer, and especially their role in the tumor cell migration and invasion.