Mixed state non-Abelian holonomy for subsystems

Non-Abelian holonomy in dynamical systems may arise in adiabatic transport of energetically degenerate sets of states. We examine such a holonomy structure for mixtures of energetically degenerate quantal states. We demonstrate that this structure has a natural interpretation in terms of the standard Wilczek-Zee holonomy associated with a certain class of Hamiltonians that couple the system to an ancilla. The mixed state holonomy is analysed for holonomic quantum computation using ion traps.Comment: Minor changes, journal reference adde

Stratification of responders towards eculizumab using a structural epitope mapping strategy

The complement component 5 (C5)-binding antibody eculizumab is used to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical haemolytic uremic syndrome (aHUS). As recently reported there is a need for a precise classification of eculizumab responsive patients to allow for a safe and cost-effective treatment. To allow for such stratification, knowledge of the precise binding site of the drug on its target is crucial. Using a structural epitope mapping strategy based on bacterial surface display, flow cytometric sorting and validation via haemolytic activity testing, we identified six residues essential for binding of eculizumab to C5. This epitope co-localizes with the contact area recently identified by crystallography and includes positions in C5 mutated in non-responders. The identified epitope also includes residue W917, which is unique for human C5 and explains the observed lack of cross-reactivity for eculizumab with other primates. We could demonstrate that Ornithodorus moubata complement inhibitor (OmCI), in contrast to eculizumab, maintained anti-haemolytic function for mutations in any of the six epitope residues, thus representing a possible alternative treatment for patients non-responsive to eculizumab. The method for stratification of patients described here allows for precision medicine and should be applicable to several other diseases and therapeutics

Exploring the potential of ancestral phenylalanine/tyrosine ammonia-lyases for therapeutic applications

Phenylalanine/tyrosine ammonia-lyases (PAL/TAL) have been approved by the FDA for treatment of phenylketonuria and may also harbor potential for complimentary treatment of hereditary tyrosinemia type II. Herein, we explore ancestral sequence reconstruction as an enzyme engineering tool to increase stability and alter substrate specificity, which could enhance the therapeutic potential of these enzymes. We used MEGA and PAML to reconstruct putative ancestors of PAL/TAL from fungi and compared them to two modern enzymes that have a relatively low PAL/TAL activity ratio. The majority of ancestors could be functionally expressed in E. coli and showed activity towards both phenylalanine and tyrosine. All ancestral enzymes displayed increased thermostability compared to both modern enzymes, however, the increase in thermostability was accompanied by a loss in activity when going back in the phylogenetic tree. One reconstructed ancestral enzyme could be interesting for further development, as its catalytic turnover of tyrosine is slightly higher than one of the modern enzymes and it is significantly more thermostable than both modern enzymes. More detailed characterization of the ancestral variants with a focus on stability is currently ongoing. Our results indicate that ancestral sequence reconstruction programs are robust in terms of stability, whereas activity of ancestral variants seems to vary depending on the reconstruction method. We believe that this approach has great potential for enhancing the properties of therapeutic enzymes and biocatalysts for various applications

Interactions between Glutathione S-Transferase P1, Tumor Necrosis Factor, and Traffic-Related Air Pollution for Development of Childhood Allergic Disease

BACKGROUND: Air pollutants may induce airway inflammation and sensitization due to generation of reactive oxygen species. The genetic background to these mechanisms could be important effect modifiers. OBJECTIVE: Our goal was to assess interactions between exposure to air pollution and single nucleotide polymorphisms (SNPs) in the beta2-adrenergic receptor (ADRB2), glutathione S-transferase P1 (GSTP1), and tumor necrosis factor (TNF) genes for development of childhood allergic disease. METHODS: In a birth cohort originally of 4,089 children, we assessed air pollution from local traffic using nitrogen oxides (traffic NO(x)) as an indicator based on emission databases and dispersion modeling and estimated individual exposure through geocoding of home addresses. We measured peak expiratory flow rates and specific IgE for inhalant and food allergens at 4 years of age, and selected children with asthma symptoms up to 4 years of age (n = 542) and controls (n = 542) for genotyping. RESULTS: Interaction effects on allergic sensitization were indicated between several GSTP1 SNPs and traffic NO(x) exposure during the first year of life (p(nominal) < 0.001-0.06). Children with Ile105Val/Val105Val genotypes were at increased risk of sensitization to any allergen when exposed to elevated levels of traffic NO(x) (for a difference between the 5th and 95th percentile of exposure: odds ratio = 2.4; 95% confidence interval, 1.0-5.3). In children with TNF-308 GA/AA genotypes, the GSTP1-NO(x) interaction effect was even more pronounced. We observed no conclusive interaction effects for ADRB2. CONCLUSION: The effect of air pollution from traffic on childhood allergy appears to be modified by GSTP1 and TNF variants, supporting a role of genes controlling the antioxidative system and inflammatory response in allergy

Model of the complex of Parathyroid hormone-2 receptor and Tuberoinfundibular peptide of 39 residues

<p>Abstract</p> <p>Background</p> <p>We aim to propose interactions between the parathyroid hormone-2 receptor (PTH2R) and its ligand the tuberoinfundibular peptide of 39 residues (TIP39) by constructing a homology model of their complex. The two related peptides parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP) are compared with the complex to examine their interactions.</p> <p>Findings</p> <p>In the model, the hydrophobic N-terminus of TIP39 is buried in a hydrophobic part of the central cavity between helices 3 and 7. Comparison of the peptide sequences indicates that the main discriminator between the agonistic peptides TIP39 and PTH and the inactive PTHrP is a tryptophan-phenylalanine replacement. The model indicates that the smaller phenylalanine in PTHrP does not completely occupy the binding site of the larger tryptophan residue in the other peptides. As only TIP39 causes internalisation of the receptor and the primary difference being an aspartic acid in position 7 of TIP39 that interacts with histidine 396 in the receptor, versus isoleucine/histidine residues in the related hormones, this might be a trigger interaction for the events that cause internalisation.</p> <p>Conclusions</p> <p>A model is constructed for the complex and a trigger interaction for full agonistic activation between aspartic acid 7 of TIP39 and histidine 396 in the receptor is proposed.</p

Network modeling of the transcriptional effects of copy number aberrations in glioblastoma

DNA copy number aberrations (CNAs) are a characteristic feature of cancer genomes. In this work, Rebecka Jörnsten, Sven Nelander and colleagues combine network modeling and experimental methods to analyze the systems-level effects of CNAs in glioblastoma

A 150-Year Perspective on Swedish Capital Income Taxation

This paper describes the evolution of capital income taxation, including corporate, dividend, interest, capital gains and wealth taxation, in Sweden between 1862 and 2010. To illustrate the evolution, we present annual time-series data on the marginal effective tax rates on capital income (METR) for a marginal investment financed with new share issues, retained earnings or debt. Tax tables covering the period are presented. These data are unique in their consistency, thoroughness and time span covered. The METR is low, is stable and does not exceed five percent until World War I, when it starts to drift somewhat upward and vary depending on the source of finance. The outbreak of World War II starts a period when the magnitude and variation of the METR sharply increases. The METR peaks during the 1970s and 1980s and often exceeds 100 percent. The 1990-1991 tax reform and lower inflation reduce the magnitude and variation of the METR. The METR varies between 15 and 40 percent at the end of the examined period

Biocomputational studies on protein structures

Biology in the post-genomic era produces large amount of data. This, in combination with the need for efficient algorithms to find genes in the genomic material, has brought a renaissance into the field of computational biology. Methods now range from lead discovery in the drug discovery process, by virtual ligand screening, through sequence comparisons and homology searches, to micro array data analysis and visualisation. This thesis primarily deals with sequence analysis, different aspects of protein structure prediction and ligand--enzyme complex characterisation, I have applied bioinformatic techniques on the enzyme families of medium- chain dehydrogenases/reductases (MDR), short-chain dehydrogenases/reductases (SDR) and biologically active peptides Sequence analysis of the MDR superfamily extends the evolutionary context of this superfamily, as MDR enzymes were collected from completely sequenced genomes. The analysis reveals the presence of eight families whereof several were previously uncharacterised. Three families are formed by dimeric alcohol dehydrogenases (ADH), cinnamyl alcohol dehydrogenases (CAD) and tetrameric alcohol dehydrogenases (YADH). Three further families are centred on forms initially detected as mitochondrial respiratory function proteins (MRF), acetyl-CoA reductases of fatty acid synthases (ACR), and leukotriene B4 dehydrogenases (LTD). The two remaining families, with polyol dehydrogenases (PDH) and quinone reductases (QOR), are also distinct but with variable sequences. The analysis also suggests that new functions have evolved in this superfamily in higher organisms. Factors that govern the substrate specificity of gammagammaADH were investigated with docking calculations and can be traced to active site characteristics, most notably the Ser48/thr48 replacement between gammagammaADH and betabetaADH, which allow the oxidation of 3beta-hydroxy bile acids, such as isoUDCA, in gammagammaADH, while both enzymes are inactive versus 3alpha-hydroxy bile acids. A homology model of type 10 17beta-hydroxysteroid dehydrogenase was constructed from 7alpha-hydroxysteroid dehydrogenase. The validity of the model was investigated by its ability to distinguish between active and inactive using docking calculations. Substrates tested ranged from steroids and bile acids to L- and D-hydroxyacyl CoA. Ligands with 17P or 3alpha hydroxy groups and L-hydroxyacyl CoA could achieve interactions favourable for catalysis at the active site. A crystallographically determined structure published after the submission of our paper verified large portions of our model. The role of a conserved asparagine in the short-chain dehydrogenase/reductase (SDR) fold is investigated through structural comparisons of 21 members with experimentally verified structures. An extensive hydrogen-bonding network including parts of the active site is revealed in 16 out of 21 SDR forms. Molecular dynamics simulations were employed to study the effect of deleterious mutants and replacements, known to diminish fibrillation, to the stability of the helical region of the amyloidogenic peptides amyloid beta-peptide (AP) and surfactant protein-C (SP-C). The effects in SP-C are quantitatively distinguishable, while the noise ratio in the AP simulations makes valid predictions somewhat difficult. Sequence comparisons of the C-peptide of proinsulin displays a sequence variability that is 1 to 2 orders of magnitude greater than that of insulin, but in the same order of magnitude as the well established peptide hormones relaxin and parathormone, which in conjunction with functional reports may indicate a hormonal function for the C-peptide

A generalized framework for controlling FDR in gene regulatory network inference

Motivation: Inference of gene regulatory networks (GRNs) from perturbation data can give detailed mechanistic insights of a biological system. Many inference methods exist, but the resulting GRN is generally sensitive to the choice of method-specific parameters. Even though the inferred GRN is optimal given the parameters, many links may be wrong or missing if the data is not informative. To make GRN inference reliable, a method is needed to estimate the support of each predicted link as the method parameters are varied. Results: To achieve this we have developed a method called nested bootstrapping, which applies a bootstrapping protocol to GRN inference, and by repeated bootstrap runs assesses the stability of the estimated support values. To translate bootstrap support values to false discovery rates we run the same pipeline with shuffled data as input. This provides a general method to control the false discovery rate of GRN inference that can be applied to any setting of inference parameters, noise level, or data properties. We evaluated nested bootstrapping on a simulated dataset spanning a range of such properties, using the LASSO, Least Squares, RNI, GENIE3 and CLR inference methods. An improved inference accuracy was observed in almost all situations. Nested bootstrapping was incorporated into the GeneSPIDER package, which was also used for generating the simulated networks and data, as well as running and analyzing the inferences