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Showing papers by "Uppsala University published in 2008"


Journal ArticleDOI
TL;DR: In this article, an extensive grid of spherically-symmetric models (supplemented with plane-parallel ones for the highest surface gravities), built on up-to-date atomic and molecular data, is presented.
Abstract: Context. In analyses of stellar spectra and colours, and for the analysis of integrated light from galaxies, a homogeneous grid of model atmospheres of late-type stars and corresponding flux spectra is needed. Aims. We construct an extensive grid of spherically-symmetric models (supplemented with plane-parallel ones for the highest surface gravities), built on up-to-date atomic and molecular data, and make it available for public use. Methods. The most recent version of the MARCS program is used. Results. We present a grid of about 104 model atmospheres for stars with 2500K <= T-eff <= 8000 K, -1 <= log g = log (GM/R-2) <= 5 (cgs) with various masses and radii, -5 <= [Me/H] <= + 1, with [alpha/Fe] = 0.0 and 0.4 and different choices of C and N abundances. This includes "CN-cycled" models with C/N=4.07 (solar), 1.5 and 0.5, C/O ranging from 0.09 to (normally) 5.0 to also represent stars of spectral types R, S and N, and with 1.0 <= xi(t) = 5km s(-1). We also list thermodynamic quantities (T, P-g, P-e, rho, partial pressures of molecules, etc.) and provide them on the World Wide Web, as well as calculated fluxes in approximately 108 000 wavelength points. Underlying assumptions in addition to 1D stratification (spherical or plane-parallel) include hydrostatic equilibrium, mixing-length convection and local thermodynamic equilibrium. We discuss a number of general properties of the models, in particular in relation to the effects of changing abundances, of blanketing, and of sphericity. We illustrate positive and negative feedbacks between sphericity and molecular blanketing. We compare the models with those of other available grids and find excellent agreement with planeparallel models of Castelli & Kurucz (if convection is treated consistently) within the overlapping parameter range. Although there are considerable departures from the spherically-symmetric NextGen models, the agreement with more recent PHOENIX models is gratifying. Conclusions. The models of the grid show considerable regularities, but some interesting departures from general patterns occur for the coolest models due to the molecular opacities. We have tested a number of approximate "rules of thumb" concerning effects of blanketing and sphericity and often found them to be astonishingly accurate. Some interesting new phenomena have been discovered and explored, such as the intricate coupling between blanketing and sphericity, and the strong effects of carbon enhancement on metal-poor models. We give further details of line absorption data for molecules, as well as details of models and comparisons with observations in subsequent papers.

2,411 citations



Journal ArticleDOI
TL;DR: To improve outcome from GEP NETs, a better understanding of their biology is needed, with emphasis on molecular genetics and disease modeling, and more-reliable serum markers, better tumour localisation and identification of small lesions, and histological grading systems and classifications with prognostic application are needed.
Abstract: Gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) are fairly rare neoplasms that present many clinical challenges. They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects. Investigation and management should be highly individualised for a patient, taking into consideration the likely natural history of the tumour and general health of the patient. Management strategies include surgery for cure (which is achieved rarely) or for cytoreduction, radiological intervention (by chemoembolisation and radiofrequency ablation), chemotherapy, and somatostatin analogues to control symptoms that result from release of peptides and neuroamines. New biological agents and somatostatin-tagged radionuclides are under investigation. The complexity, heterogeneity, and rarity of GEP NETs have contributed to a paucity of relevant randomised trials and little or no survival increase over the past 30 years. To improve outcome from GEP NETs, a better understanding of their biology is needed, with emphasis on molecular genetics and disease modeling. More-reliable serum markers, better tumour localisation and identification of small lesions, and histological grading systems and classifications with prognostic application are needed. Comparison between treatments is currently very difficult. Progress is unlikely to occur without development of centers of excellence, with dedicated combined clinical teams to coordinate multicentre studies, maintain clinical and tissue databases, and refine molecularly targeted therapeutics.

1,494 citations


Journal ArticleDOI
Jennifer Stone1, Jennifer Stone2, Jennifer Stone3, Michael Conlon O'Donovan4, Hugh Gurling5, George Kirov4, Douglas Blackwood6, Aiden Corvin7, Nicholas John Craddock4, Michael Gill7, Christina M. Hultman8, Christina M. Hultman9, Paul Lichtenstein8, Andrew McQuillin5, Carlos N. Pato10, Douglas M. Ruderfer2, Douglas M. Ruderfer3, Douglas M. Ruderfer1, Michael John Owen4, David St Clair11, Patrick F. Sullivan12, Pamela Sklar2, Pamela Sklar3, Pamela Sklar1, Shaun Purcell3, Shaun Purcell1, Shaun Purcell2, Joshua M. Korn2, Joshua M. Korn1, Stuart MacGregor13, Derek W. Morris7, Colm O'Dushlaine7, Mark J. Daly2, Mark J. Daly3, Mark J. Daly1, Peter M. Visscher13, Peter Holmans4, Edward M. Scolnick3, Edward M. Scolnick1, Nigel Williams4, Lucy Georgieva4, Ivan Nikolov4, Nadine Norton4, Hywel Williams4, Draga Toncheva, Vihra Milanova, Emma Flordal Thelander8, Patrick Sullivan12, Elaine Kenny7, John L. Waddington14, Khalid Choudhury5, Susmita Datta5, Jonathan Pimm5, Srinivasa Thirumalai15, Vinay Puri5, Robert Krasucki5, Jacob Lawrence5, Digby Quested16, Nicholas Bass5, David Curtis17, Caroline Crombie11, Gillian Fraser11, Soh Leh Kwan11, Nicholas Walker, Walter J. Muir6, Kevin A. McGhee6, Ben S. Pickard6, P. Malloy6, Alan W Maclean6, Margaret Van Beck6, Michele T. Pato10, Helena Medeiros10, Frank A. Middleton18, Célia Barreto Carvalho10, Christopher P. Morley18, Ayman H. Fanous, David V. Conti10, James A. Knowles10, Carlos Ferreira, António Macedo19, M. Helena Azevedo19, Steve McCarroll1, Steve McCarroll2, Mark J. Daly1, Mark J. Daly2, Mark J. Daly3, Kimberly Chambert1, Kimberly Chambert3, Casey Gates1, Stacey Gabriel1, Scott Mahon1, Kristen Ardlie1 
11 Sep 2008-Nature
TL;DR: A genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls provides strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome- wide and at specific loci.
Abstract: Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73 - 90% ( ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants ( CNVs) have been identified in individual patients with schizophrenia(2-7) and also in neurodevelopmental disorders(8-11), but large- scale genome- wide surveys have not been performed. Here we report a genome- wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high- density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15- fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single- occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo- cardio- facial syndrome, which includes psychotic symptoms in 30% of patients(12). Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome- wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome- wide and at specific loci.

1,465 citations


Journal ArticleDOI
TL;DR: It is concluded that music evokes emotions through mechanisms that are not unique to music, and that the study of musical emotions could benefit the emotion field as a whole by providing novel paradigms for emotion induction.
Abstract: Research indicates that people value music primarily because of the emotions it evokes. Yet, the notion of musical emotions remains controversial, and researchers have so far been unable to offer a satisfactory account of such emotions. We argue that the study of musical emotions has suffered from a neglect of underlying mechanisms. Specifically, researchers have studied musical emotions without regard to how they were evoked, or have assumed that the emotions must be based on the "default" mechanism for emotion induction, a cognitive appraisal. Here, we present a novel theoretical framework featuring six additional mechanisms through which music listening may induce emotions: (1) brain stem reflexes, (2) evaluative conditioning, (3) emotional contagion, (4) visual imagery, (5) episodic memory, and (6) musical expectancy. We propose that these mechanisms differ regarding such characteristics as their information focus, ontogenetic development, key brain regions, cultural impact, induction speed, degree of volitional influence, modularity, and dependence on musical structure. By synthesizing theory and findings from different domains, we are able to provide the first set of hypotheses that can help researchers to distinguish among the mechanisms. We show that failure to control for the underlying mechanism may lead to inconsistent or non-interpretable findings. Thus, we argue that the new framework may guide future research and help to resolve previous disagreements in the field. We conclude that music evokes emotions through mechanisms that are not unique to music, and that the study of musical emotions could benefit the emotion field as a whole by providing novel paradigms for emotion induction.

1,381 citations


Journal ArticleDOI
TL;DR: The remaining challenges of understanding the relative roles of genes and ecology in determining variation between taxa in the rate of extra paternity are highlighted, and testing for differences between extra‐pair offspring and those sired within‐pair is highlighted.
Abstract: The application of molecular genetic techniques has revolutionized our view of avian mating systems. Contrary to prior expectations, birds are only very rarely sexually monogamous, with ‘extra-pair offspring’ found in approximately 90% of species. Even among socially monogamous species, over 11% of offspring are, on average, the result of extra-pair paternity (EPP). Based on over 150 molecular genetic studies of EPP in birds, we review two topical areas: (i) ecological explanations for interspecific variation in the rate of EPP; and (ii) evidence bearing on the adaptive function of EPP. We highlight the remaining challenges of understanding the relative roles of genes and ecology in determining variation between taxa in the rate of extra paternity, and testing for differences between extra-pair offspring and those sired within-pair.

1,360 citations


Journal ArticleDOI
TL;DR: The results show that numerous genes, some with known immune-related functions, predispose to SLE, and evidence of association with replication is found at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases.
Abstract: Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (lambda(S) = approximately 30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 x 10(-7) or =9 other loci (P < 2 x 10(-7)). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.

1,253 citations


Journal ArticleDOI
TL;DR: This article aims to provide a comprehensive overview of the five main human GPCR families with a focus on gene repertoire, general ligand preference, common and unique structural features, and the potential for future drug discovery.
Abstract: G protein-coupled receptors (GPCRs) are the largest family of membrane-bound receptors and also the targets of many drugs. Understanding of the functional significance of the wide structural diversity of GPCRs has been aided considerably in recent years by the sequencing of the human genome and by structural studies, and has important implications for the future therapeutic potential of targeting this receptor family. This article aims to provide a comprehensive overview of the five main human GPCR families--Rhodopsin, Secretin, Adhesion, Glutamate and Frizzled/Taste2--with a focus on gene repertoire, general ligand preference, common and unique structural features, and the potential for future drug discovery.

1,247 citations


Journal ArticleDOI
TL;DR: A mechanism whereby Kcnq1ot1 establishes lineage-specific transcriptional silencing patterns through recruitment of chromatin remodeling complexes and maintenance of these patterns through subsequent cell divisions occurs via targeting the associated regions to the perinucleolar compartment is described.

1,164 citations


Journal ArticleDOI
TL;DR: Using RNA interference against phenoloxidase or in specific host-pathogen interactions where the pathogen prevents melanin production by the host, convincing data have confirmed the importance of this cascade in invertebrate innate immunity.

1,047 citations


Journal ArticleDOI
30 Jul 2008-PLOS ONE
TL;DR: This work has employed 454-pyrosequencing of a hyper-variable region of the 16S rRNA gene in combination with sample-specific barcode sequences which enables parallel in-depth analysis of hundreds of samples with limited sample processing, and demonstrated that the method correctly describes microbial communities down to phylotypes below the genus level.
Abstract: Humans host complex microbial communities believed to contribute to health maintenance and, when in imbalance, to the development of diseases. Determining the microbial composition in patients and healthy controls may thus provide novel therapeutic targets. For this purpose, high-throughput, cost-effective methods for microbiota characterization are needed. We have employed 454-pyrosequencing of a hyper-variable region of the 16S rRNA gene in combination with sample-specific barcode sequences which enables parallel in-depth analysis of hundreds of samples with limited sample processing. In silico modeling demonstrated that the method correctly describes microbial communities down to phylotypes below the genus level. Here we applied the technique to analyze microbial communities in throat, stomach and fecal samples. Our results demonstrate the applicability of barcoded pyrosequencing as a high-throughput method for comparative microbial ecology.

Journal ArticleDOI
TL;DR: The authors identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM-ITGAX region.
Abstract: Background Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility genes; there is strong evidence for the existence of additional risk loci Methods We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent Genotypes from 1557 additional control subjects were obtained from public data repositories We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden Results Genetic variation in the region upstream from the transcription initiation site of the gene encod

Journal ArticleDOI
TL;DR: It is suggested that in elderly men with or without prevalent cardiovascular disease, the simultaneous addition of several biomarkers of cardiovascular and renal abnormalities substantially improves the risk stratification for death from cardiovascular causes beyond that of a model that is based only on established risk factors.
Abstract: Background The incremental usefulness of adding multiple biomarkers from different disease pathways for predicting the risk of death from cardiovascular causes has not, to our knowledge, been evaluated among the elderly. Methods We used data from the Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based cohort of elderly men, to investigate whether a combination of biomarkers that reflect myocardial cell damage, left ventricular dysfunction, renal failure, and inflammation (troponin I, N-terminal pro–brain natriuretic peptide, cystatin C, and C-reactive protein, respectively) improved the risk stratification of a person beyond an assessment that was based on the established risk factors for cardiovascular disease (age, systolic blood pressure, use or nonuse of antihypertensive treatment, total cholesterol, high-density lipoprotein cholesterol, use or nonuse of lipid-lowering treatment, presence or absence of diabetes, smoking status, and body-mass index). Results During follow-up (median, 10.0 years), 315 of the 1135 participants in our study (mean age, 71 years at baseline) died; 136 deaths were the result of cardiovascular disease. In Cox proportional-hazards models adjusted for established risk factors, all of the biomarkers significantly predicted the risk of death from cardiovascular causes. The C statistic increased significantly when the four biomarkers were incorporated into a model with established risk factors, both in the whole cohort (C statistic with biomarkers vs. without biomarkers, 0.766 vs. 0.664; P<0.001) and in the group of 661 participants who did not have cardiovascular disease at baseline (0.748 vs. 0.688, P=0.03). The improvement in risk assessment remained strong when it was estimated by other statistical measures of model discrimination, calibration, and global fit. Conclusions Our data suggest that in elderly men with or without prevalent cardiovascular disease, the simultaneous addition of several biomarkers of cardiovascular and renal abnormalities substantially improves the risk stratification for death from cardiovascular causes beyond that of a model that is based only on established risk factors.

Journal ArticleDOI
TL;DR: In this paper, a systematic review aims to describe longitudinal evidence on the effects of father involvement on children's developmental outcomes, focusing on social, behavioural and psychological outcomes, and concluding that active and regular engagement with the child predicts a range of positive outcomes.
Abstract: Objective: This systematic review aims to describe longitudinal evidence on the effects of father involvement on children’s developmental outcomes. Methods: Father involvement was conceptualized as accessibility (cohabitation), engagement, responsibility or other complex measures of involvement. Both biological fathers and father figures were included. We searched all major databases from the first dates. Data on father involvement had to be generated at least 1 year before measuring offspring outcomes. Results: N = 24 publications were included in the overview: 22 of these described positive effects of father involvement, whereof 16 studies had controlled for SES and 11 concerned the study population as a whole [five socio-economic status (SES)-controlled]. There is certain evidence that cohabitation with the mother and her male partner is associated with less externalising behavioural problems. Active and regular engagement with the child predicts a range of positive outcomes, although no specific form of engagement has been shown to yield better outcomes than another. Father engagement seems to have differential effects on desirable outcomes by reducing the frequency of behavioural problems in boys and psychological problems in young women, and enhancing cognitive development, while decreasing delinquency and economic disadvantage in low SES families. Conclusions: There is evidence to support the positive influence of father engagement on offspring social, behavioural and psychological outcomes. Although the literature only provides sufficient basis for engagement (direct interaction with the child) as the specific form of ‘effective’ father involvement, there is enough support to urge both professionals and policy makers to improve circumstances for involved fathering.

Journal ArticleDOI
TL;DR: In this paper, the authors present a more synthetic picture of the present and future role of peatlands in the global C cycle and their interactions with the climate system, focusing on small-scale processes, fluxes at the landscape scale, and peatland and climate.
Abstract: Although peatlands cover only 3% of the Earth's land surface, boreal and subarctic peatlands store about 15?30% of the world's soil carbon as peat. Despite their potential for large positive feedbacks to the climate system through sequestration and emission of greenhouse gases, peatlands are not explicitly included in global climate models and therefore in predictions of future climate change. In April 2007 a symposium was held in Wageningen, the Netherlands, to advance our understanding of peatland C cycling through integration across disciplines and research approaches and to develop a more synthetic picture of the present and future role of peatlands in the global C cycle and their interactions with the climate system. This paper aims to synthesize the main findings of the symposium, focusing on (i) small-scale processes, (ii) C fluxes at the landscape scale, and (iii) peatlands and climate. The paper concludes with a summary of the main drivers of the C balance of peatlands, and proposes directions for new research to reduce key uncertainties in our knowledge of C cycling in peatlands in order to facilitate the explicit inclusion of these ecosystems in a new generation of earth system models.

Journal ArticleDOI
TL;DR: A revised classification system that takes into account the new advances, as well as encompassing other inherited diseases that should also be included within the EB spectrum, based on the presence of blistering and mechanical fragility is presented.
Abstract: BACKGROUND: Since publication in 2000 of the Second International Consensus Report on Diagnosis and Classification of Epidermolysis Bullosa, many advances have been made to our understanding of this group of diseases, both clinically and molecularly. At the same time, new epidermolysis bullosa (EB) subtypes have been described and similarities with some other diseases have been identified. OBJECTIVE: We sought to arrive at a new consensus of the classification of EB subtypes. RESULTS: We now present a revised classification system that takes into account the new advances, as well as encompassing other inherited diseases that should also be included within the EB spectrum, based on the presence of blistering and mechanical fragility. Current recommendations are made on the use of specific diagnostic tests, with updates on the findings known to occur within each of the major EB subtypes. Electronic links are also provided to informational and laboratory resources of particular benefit to clinicians and their patients. LIMITATIONS: As more becomes known about this disease, future modifications may be needed. The classification system has been designed with sufficient flexibility for these modifications. CONCLUSION: This revised classification system should assist clinicians in accurately diagnosing and subclassifying patients with EB.

Journal ArticleDOI
TL;DR: An immunohistochemistry‐based map of protein expression profiles in normal tissues, cancer and cell lines is generated and the presented Human Protein Atlas provides a resource for pathology‐based biomedical research, including protein science and biomarker discovery.
Abstract: Tissue-based diagnostics and research is incessantly evolving with the development of new molecular tools. It has long been realized that immunohistochemistry can add an important new level of information on top of morphology and that protein expression patterns in a cancer may yield crucial diagnostic and prognostic information. We have generated an immunohistochemistry-based map of protein expression profiles in normal tissues, cancer and cell lines. For each antibody, altogether 708 spots of tissues and cells are analysed and the resulting images and data are presented as freely available in the Human Protein Atlas (www.proteinatlas.org). The new version 4 of the atlas, including more than 5 million images of immunohistochemically stained tissues and cells, is based on 6122 antibodies, representing 5011 human proteins encoded by approximately 25% of the human genome. The gene-centric database includes a putative classification of proteins in various protein classes, both functional classes, such as kinases or transcription factors and project-related classes, such as candidate genes for cancer or cardiovascular diseases. For each of the internally generated antibodies, the exact antigen sequence is presented, together with a visualization of application-specific validation data, including a protein array assay, western blot analysis, immunohistochemistry and, in most cases, immunofluorescent-based confocal microscopy. The updated version also includes new search algorithms to allow complex queries regarding expression profiles, protein classes and chromosome location. Thus, the presented Human Protein Atlas provides a resource for pathology-based biomedical research, including protein science and biomarker discovery.

Journal ArticleDOI
TL;DR: Based on systematic review and consensus of experts, core domains and measures for clinical trials to treat pain in children and adolescents were defined to assist in comparison and pooling of data and promote evidence-based treatment.

Journal ArticleDOI
TL;DR: Correlations were observed in the MCI patients between PIB retention and CSF Abeta(1-42), total Tau and episodic memory, respectively, and the P IB retention in MCI converters was comparable to AD patients.

Journal ArticleDOI
TL;DR: The results suggest that the CD association at IRGM arises from an alteration in IRGM regulation that affects the efficacy of autophagy and a common deletion polymorphism is identified as a likely causal variant.
Abstract: Following recent success in genome-wide association studies, a critical focus of human genetics is to understand how genetic variation at implicated loci influences cellular and disease processes. Crohn's disease (CD) is associated with SNPs around IRGM, but coding-sequence variation has been excluded as a source of this association. We identified a common, 20-kb deletion polymorphism, immediately upstream of IRGM and in perfect linkage disequilibrium (r2 = 1.0) with the most strongly CD-associated SNP, that causes IRGM to segregate in the population with two distinct upstream sequences. The deletion (CD risk) and reference (CD protective) haplotypes of IRGM showed distinct expression patterns. Manipulation of IRGM expression levels modulated cellular autophagy of internalized bacteria, a process implicated in CD. These results suggest that the CD association at IRGM arises from an alteration in IRGM regulation that affects the efficacy of autophagy and identify a common deletion polymorphism as a likely causal variant.

Journal ArticleDOI
TL;DR: A new version (4.0) of the Human Protein Atlas has been developed in a genecentric manner with the inclusion of all human genes and splice variants predicted from genome efforts together with a visualization of each protein with characteristics such as predicted membrane regions, signal peptide, and protein domains and new plots showing the uniqueness of every fraction of eachprotein toward all other human proteins.

Journal ArticleDOI
TL;DR: During the last decade, the efforts to combat multidrug-resistant (MDR) microorganisms mainly focused on gram-positive bacteria, namely, methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci.
Abstract: During the last decade, the efforts to combat multidrug-resistant (MDR) microorganisms mainly focused on gram-positive bacteria, namely, methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. While a large number of hospitals have implemented more rigorous infection


Book ChapterDOI
29 Mar 2008
TL;DR: Turn-based stochastic games on infinite graphs induced by game probabilistic lossy channel systems (GPLCS) are decidable, which generalizes the decidability result for PLCS-induced Markov decision processes in [10].
Abstract: We consider turn-based stochastic games on infinite graphs induced by game probabilistic lossy channel systems (GPLCS), the game version of probabilistic lossy channel systems (PLCS). We study games with Buchi (repeated reachability) objectives and almost-sure winning conditions. These games are pure memoryless determined and, under the assumption that the target set is regular, a symbolic representation of the set of winning states for each player can be effectively constructed. Thus, turn-based stochastic games on GPLCS are decidable. This generalizes the decidability result for PLCS-induced Markov decision processes in [10].

Journal ArticleDOI
TL;DR: It is suggested that CNV analysis in phenotypically discordant monozygotic twins may provide a powerful tool for identifying disease-predisposition loci and that caution should be exercised when interpreting disease causality of de novo CNVs found in patients based on analysis of a single tissue in routine disease-related DNA diagnostics.
Abstract: The exploration of copy-number variation (CNV), notably of somatic cells, is an understudied aspect of genome biology. Any differences in the genetic makeup between twins derived from the same zygote represent an irrefutable example of somatic mosaicism. We studied 19 pairs of monozygotic twins with either concordant or discordant phenotype by using two platforms for genome-wide CNV analyses and showed that CNVs exist within pairs in both groups. These findings have an impact on our views of genotypic and phenotypic diversity in monozygotic twins and suggest that CNV analysis in phenotypically discordant monozygotic twins may provide a powerful tool for identifying disease-predisposition loci. Our results also imply that caution should be exercised when interpreting disease causality of de novo CNVs found in patients based on analysis of a single tissue in routine disease-related DNA diagnostics.

Journal ArticleDOI
TL;DR: The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology, and two uncorrelated disease markers at 5p15.33 are detected.
Abstract: We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P - 2 x 10(-7) and P = 4 x 10(-6)) and replicated by the independent study series (P = 7 x 10(-5) and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.

Journal ArticleDOI
01 Jul 2008-Methods
TL;DR: The in situ proximity ligation assays (in situ PLA) are described, a method that is suitable for visualizing protein interactions in both tissue sections and in vitro cell lines, and research tasks when this or other method may be selected are discussed.

Proceedings ArticleDOI
16 Aug 2008
TL;DR: This shared task not only unifies the shared tasks of the previous four years under a unique dependency-based formalism, but also extends them significantly: this year's syntactic dependencies include more information such as named-entity boundaries; the semantic dependencies model roles of both verbal and nominal predicates.
Abstract: The Conference on Computational Natural Language Learning is accompanied every year by a shared task whose purpose is to promote natural language processing applications and evaluate them in a standard setting. In 2008 the shared task was dedicated to the joint parsing of syntactic and semantic dependencies. This shared task not only unifies the shared tasks of the previous four years under a unique dependency-based formalism, but also extends them significantly: this year's syntactic dependencies include more information such as named-entity boundaries; the semantic dependencies model roles of both verbal and nominal predicates. In this paper, we define the shared task and describe how the data sets were created. Furthermore, we report and analyze the results and describe the approaches of the participating systems.

Journal ArticleDOI
TL;DR: It is reported that the ubiquitin ligase (E3) TRAF6 interacts with a consensus motif present in TβRI, which is required for TGF-β-induced autoubiquitylation of TRAF 6 and subsequent activation of the TAK1–p38/JNK pathway, which leads to apoptosis.
Abstract: Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates embryonic development and tissue homeostasis; however, aberrations of its activity occur in cancer. TGF-beta signals through its Type II and Type I receptors (TbetaRII and TbetaRI) causing phosphorylation of Smad proteins. TGF-beta-associated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, was originally identified as an effector of TGF-beta-induced p38 activation. However, the molecular mechanisms for its activation are unknown. Here we report that the ubiquitin ligase (E3) TRAF6 interacts with a consensus motif present in TbetaRI. The TbetaRI-TRAF6 interaction is required for TGF-beta-induced autoubiquitylation of TRAF6 and subsequent activation of the TAK1-p38/JNK pathway, which leads to apoptosis. TbetaRI kinase activity is required for activation of the canonical Smad pathway, whereas E3 activity of TRAF6 regulates the activation of TAK1 in a receptor kinase-independent manner. Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6.

Journal ArticleDOI
TL;DR: In this article, the N = 2 superspace formulation of the Bagger-Lambert-Gustavsson theory was studied and the full SU(4)R-symmetry of the ABJM theory was proved.
Abstract: We discuss the N = 2 superspace formulation of the N = 8 superconformal Bagger-Lambert-Gustavsson theory, and of the N = 6 superconformal Aharony-Bergman-Jafferis-Maldacena U(N) x U(N) Chern-Simons theory. In particular, we prove the full SU(4)R-symmetry of the ABJM theory. We then consider orbifold projections of this theory that give non-chiral and chiral (U( N) x U(N))(n) superconformal quiver gauge theories. We argue that these theories are dual to certain AdS(4) x S-7/(Z(n) x Z (k$) over tilde) backgrounds of M-theory. We also study a SU(3) invariant mass term in the superpotential that makes the N = 8 theory flow to a N = 2 superconformal gauge theory with a sextic superpotential. We conjecture that this gauge theory is dual to the U(1)(R) x SU(3) invariant extremum of the N = 8 gauged supergravity, which was discovered by N. Warner 25 years ago and whose uplifting to 11 dimensions was found more recently.