Fibromodulin Interacts with Collagen Cross-linking Sites and Activates Lysyl Oxidase

The hallmark of fibrotic disorders is a highly cross-linked and dense collagen matrix, a property driven by the oxidative action of lysyl oxidase. Other fibrosis-associated proteins also contribute to the final collagen matrix properties, one of which is fibromodulin - its interactions with collagen affect collagen cross-linking, packing, and fibril diameter. We investigated the possibility that a specific relationship exists between fibromodulin and lysyl oxidase, potentially imparting a specific collagen matrix phenotype. We mapped the fibromodulin-collagen interaction sites using the Collagen II and III Toolkit peptide libraries. Fibromodulin interacted with the peptides containing the known collagen cross-linking sites and the MMP-1 cleavage site in collagens I and II. Interestingly, the interaction sites are closely aligned within the quarter-staggered collagen fibril, suggesting a multivalent interaction between fibromodulin and several collagen helices. Furthermore, we detected an interaction between fibromodulin and lysyl oxidase - a major collagen cross-linking enzyme - and mapped the interaction site to 12 N-terminal amino acids on fibromodulin. This interaction also increases the activity of lysyl oxidase. Altogether, the data suggest a fibromodulin-modulated collagen cross-linking mechanism, where fibromodulin binds to a specific part of the collagen domain and also forms a complex together with lysyl oxidase, targeting the enzyme towards specific cross-linking sites.SK and KR were supported by grants from the Swedish Cancer Foundation, the Swedish Research Council, the Alfred Österlund Foundation, the Crafoord Foundation, the Magnus Bergvall Foundation, and the Åke Wiberg Foundation; AB, DB and RWF by grants from the Wellcome Trust (094470/Z/10/Z) and British Heart Foundation (RG/15/4/31268).This is the final version of the article. It first appeared from the American Society for Biochemistry and Molecular Biology] via http://dx.doi.org/10.1074/jbc.M115.69340

Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.publishedVersio

Assessment of Myocardial Function using Phase Based Motion Sensitive MRI

for provision of financial support and access to leading edge research infrastructure. Cover: DENSE encodes displacement into the phase of the MRI signal. The strength of the displacement encoding gradient in the DENSE acquisition determines the ratio between the displacement and the phase and is chosen to provide a favorable SNR. A side effect of this approach is wrapping of the phase as seen on the cover

Assessment of Myocardial Function using Phase Based Motion Sensitive MRI

Quantitative assessment of myocardial function is a valuable tool for clinical applications and physiological studies. This assessment can be acquired using phase based motion sensitive magnetic resonance imaging (MRI) techniques. In this thesis, the accuracy of these phase based motion sensitive MRI techniques is investigated, and modifications in acquisition and post-processing are proposed. The strain rate of the myocardium can be used to evaluate the myocardial function. However, the estimation of strain rate from the velocity data acquired with phase-contrast MRI (PC-MRI) is sensitive to noise. Estimation using normalized convolution showed, however, to reduce this sensitivity to noise and to minimize the influence of non-myocardial tissue which could impair the result. Strain of the myocardium is another measure to assess myocardial function. Strain can be estimated from the myocardial displacement acquired with displacement encoding with stimulated echo (DENSE). DENSE acquisition can be realized with several different encoding strategies. The choice of encoding scheme may make the acquisition more or less sensitive to different sources of error. Two potential sources of errors in DENSE acquisition are the influence of the FID and of  the off-resonance effects. Their influence on DENSE were investigated to determine suitable encoding strategies to reduce their influence and thereby improve the measurement accuracy acquired. The quality of the DENSE measurement is not only dependent on the accuracy, but also the precision of the measurement. The precision is affected by the SNR and thereby depends on flip angle strategies, magnetic field strength and spatial variation of the receiver coil sensitivity. A mutual comparison of their influence on SNR in DENSE was therefore performed and could serve as a guideline to optimize parameters for specific applications. The acquisition time is often an important factor, especially in clinical applications where it affects potential patient discomfort and patient through-put. A multiple-slice DENSE acquisition was therefore presented, which allows the acquisition of strain values according to the 16-segment cardiac model within a single breath-hold, instead of the conventional three breath-holds. The DENSE technique can also be adapted toward comprehensive evaluation of the heart in the form of full three-dimensional three-directional acquisition of the displacement. To estimate the full strain tensor from these data, a novel post-processing technique using a polynomial was investigated. The method yielded accurate results on an analytical model and \textit{in-vivo} strains obtained agreed with previously reported myocardial strains in normal volunteers

Neural Network Ensembles and Combinatorial Optimization with Applications in Medicine

Artificial neural network (ANN) and combinatorial optimization algorithms are developed, and applied to the medical domain. A novel method for training an ensemble of ANN is presented, based on random weight updates alternated with replication of networks with low error. The evolution of the ensemble is explored, with particular emphasis on its diversity and internal correlation. The performance is tested on three datasets, and found comparable to a Bayesian algorithm and better than a Bagging ensemble. Hermite decomposition of ECGs is performed, and the coefficients are used as inputs to ANNs for predicting myocardial infarction, with good results. A case-based method for explaining the operation of the ANN is presented, based on perturbing a small number of inputs in a limited interval so as to maximize the change in output. A cost function for maximizing this change while satisfying the constraints is defined in a Potts spin formulation. After optimization using mean field annealing, a perturbed ECG is reconstructed from the perturbed Hermite coefficients. The perturbed ECG leads are found to match those deemed critical by a human expert in half of the cases. The question of what inputs features to use when training ANNs to interpret myocardial perfusion SPECT images is also studied. It is concluded that using additional clinical data as ANN input does not improve the predictive performance. A novel approach for multiple structure alignment of proteins is presented, based on fuzzy pairwise alignments of each protein to a virtual consensus chain. These alignments are alternated with translations and rotations of the proteins onto the consensus structure, and with updating the consensus chain. The pairwise alignments use mean-field annealing of fuzzy alignment variables, based on a cost expressed in terms of distances between aligned atoms and of gaps. Our approach is tested against a set of protein families from the HOMSTRAD database, and against another algorithm based on Monte Carlo, with good results

Assessment of Myocardial Function using Phase Based Motion Sensitive MRI

Quantitative assessment of myocardial function is a valuable tool for clinical applications and physiological studies. This assessment can be acquired using phase based motion sensitive magnetic resonance imaging (MRI) techniques. In this thesis, the accuracy of these phase based motion sensitive MRI techniques is investigated, and modifications in acquisition and post-processing are proposed. The strain rate of the myocardium can be used to evaluate the myocardial function. However, the estimation of strain rate from the velocity data acquired with phase-contrast MRI (PC-MRI) is sensitive to noise. Estimation using normalized convolution showed, however, to reduce this sensitivity to noise and to minimize the influence of non-myocardial tissue which could impair the result. Strain of the myocardium is another measure to assess myocardial function. Strain can be estimated from the myocardial displacement acquired with displacement encoding with stimulated echo (DENSE). DENSE acquisition can be realized with several different encoding strategies. The choice of encoding scheme may make the acquisition more or less sensitive to different sources of error. Two potential sources of errors in DENSE acquisition are the influence of the FID and of  the off-resonance effects. Their influence on DENSE were investigated to determine suitable encoding strategies to reduce their influence and thereby improve the measurement accuracy acquired. The quality of the DENSE measurement is not only dependent on the accuracy, but also the precision of the measurement. The precision is affected by the SNR and thereby depends on flip angle strategies, magnetic field strength and spatial variation of the receiver coil sensitivity. A mutual comparison of their influence on SNR in DENSE was therefore performed and could serve as a guideline to optimize parameters for specific applications. The acquisition time is often an important factor, especially in clinical applications where it affects potential patient discomfort and patient through-put. A multiple-slice DENSE acquisition was therefore presented, which allows the acquisition of strain values according to the 16-segment cardiac model within a single breath-hold, instead of the conventional three breath-holds. The DENSE technique can also be adapted toward comprehensive evaluation of the heart in the form of full three-dimensional three-directional acquisition of the displacement. To estimate the full strain tensor from these data, a novel post-processing technique using a polynomial was investigated. The method yielded accurate results on an analytical model and \textit{in-vivo} strains obtained agreed with previously reported myocardial strains in normal volunteers