The Structural and Molecular Biology of Type I Galactosemia: Enzymology of Galactose 1-phosphate Uridylyltransferase

Reduced galactose 1-phosphate uridylyltransferase (GAIT) activity is associated with the genetic disease type 1 galactosemia. This results in an increase in the cellular concentration of galactose 1-phosphate. The accumulation of this toxic metabolite, combined with aberrant glycoprotein and glycolipid biosynthesis, is likely to be the major factor in molecular pathology. The mechanism of GAIT was established through classical enzymological methods to be a substituted enzyme in which the reaction with UDP-glucose results in the formation of a covalent, UMP-histidine adduct in the active site. The uridylated enzyme can then react with galactose 1-phosphate to form UDP-galactose. The structure of the enzyme from Escherichia coli reveals a homodimer containing one zinc (II) and one iron (11) ion per subunit. This enzymological and structural knowledge provides the basis for understanding the biochemistry of this critical step in the Leloir pathway. However, a high-resolution crystal structure of human GAIT is required to assist greater understanding of the effects of disease-associated mutations. (C) 2011 IUBMB IUBMB Life, 63(9): 694-700, 2011

Improved prognosis for congenital nephrotic syndrome of the Finnish type in Irish families

Congenital nephrotic syndrome of the Finnish type is a rare autosomal recessive disease with a high infant mortality without aggressive treatment. The biochemical basis of the disease is not understood fully but the disease locus has been mapped recently to chromosome 19q12-q13.1 in Finnish families. This paper describes the clinical features and outcome of 20 patients in Ireland with congenital nephrotic syndrome of the Finnish type who have presented since 1980. Before 1987, all infants died by the age of 3 years. After the introduction of daily intravenous albumin infusion, nutritional support, elective bilateral nephrectomy, and renal transplantation, mortality in the past decade has fallen to 30%, with no deaths in the past five years. Genetic linkage analysis was performed in six families in whom DNA was available and the locus responsible was mapped to the same region on chromosome 19 as in Finnish families, suggesting that Irish families share the same disease locus.

Serine proteases in bone disease

Serine proteases are active in many physiological and pathological processes within bone tissue. Although essential to adequate maintenance of bone and cartilage, their inappropriate expression can lead to exacerbation of tissue destruction and inflammation. Their effects are exerted through multiple pathways, including interaction with signalling molecules such as transforming growth factor ß (TGFß), binding to protease-activated receptors (PARs), and direct proteolysis of extracellular matrix proteins, in some cases working synergistically with matrix metalloproteases in the remodelling of bone tissue. The overall effect of these interactions is not yet clear, but there are strong links between some serine proteases and arthropathies, in addition to metastatic bone invasion. Understanding the contribution of each of these enzymes to the molecular disease process is crucial to developing effective treatment based on inhibitors or agonists. Serine protease inhibitors have shown promise in reducing the severity of arthritis, but greater specificity is required to avoid undesired systemic effects. © 2009 Bentham Science Publishers Ltd.

Identification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families

A recent report showed significant associations between several SNPs in a previously unknown EST cluster with schizophrenia. (1). The cluster was identified as the human dystrobrevin binding protein 1 gene (DTNBP1) by sequence database comparisons and homology with mouse DTNBP1. (2). However, the linkage disequilibrium (LD) among the SNPs in DTNBP1 as well as the pattern of significant SNP-schizophrenia association was complex. This raised several questions such as the number of susceptibility alleles that may be involved and the size of the region where the actual disease mutation(s) could be located. To address these questions, we performed different single-marker tests on the 12 previously studied and 2 new SNPs in DTNBP1 that were re-scored using an improved procedure, and performed a variety of haplotype analyses. The sample consisted of 268 Irish multiplex families selected for high density of schizophrenia. Results suggested a simple structure where the LD in the target region could be explained by 6 haplotypes that together accounted for 96% of haplotype diversity in the whole sample. From these six, a single high-risk haplotype was identified that showed a significant association with schizophrenia and explained the pattern of significant findings in the analyses with individual markers. This haplotype was 30 kb long, had a large effect, could be measured with two tag SNPs only, had a frequency of 6% in our sample, seemed to be of relatively recent origin in evolutionary terms, and was equally distributed over Ireland. Implications of these findings for follow-up and replication studies are discussed.

Predicting the past: Understanding the causes of bank distress in the Netherlands in the 1920s

Why do some banks fail in financial crises while others survive? This article answers this question by analysing the effect of the Dutch financial crisis of the 1920s on 142 banks, of which 33 failed. We find that choices of balance sheet composition and product market strategy made in the lead-up to the crisis had a significant impact on banks’ subsequent chances of experiencing distress. We document that high-risk banks – those operating highly-leveraged portfolios and attracting large quantities of deposits – were more likely to fail. Branching and international activities also increased banks’ default probabilities. We measure the effects of board interlocks, which have been characterized in the extant literature as contributing to the Dutch crisis. We find that boards mattered: failing banks had smaller boards, shared directors with smaller and very profitable banks and had a lower concentration of interlocking directorates in non-financial firms.

The metastability of human UDP-galactose 4'-epimerase (GALE) is increased by variants associated with type III galactosemia but decreased by substrate and cofactor binding

Type III galactosemia is an inherited disease caused by mutations which affect the activity of UDP-galactose 4'-epimerase (GALE). We evaluated the impact of four disease-associated variants (p.N34S, p.G90E, p.V94M and p.K161N) on the conformational stability and dynamics of GALE. Thermal denaturation studies showed that wild-type GALE denatures at temperatures close to physiological, and disease-associated mutations often reduce GALE's thermal stability. This denaturation is under kinetic control and results partly from dimer dissociation. The natural ligands, NAD(+) and UDP-glucose, stabilize GALE. Proteolysis studies showed that the natural ligands and disease-associated variations affect local dynamics in the N-terminal region of GALE. Proteolysis kinetics followed a two-step irreversible model in which the intact protein is cleaved at Ala38 forming a long-lived intermediate in the first step. NAD(+) reduces the rate of the first step, increasing the amount of undigested protein whereas UDP-glucose reduces the rate of the second step, increasing accumulation of the intermediate. Disease-associated variants affect these rates and the amounts of protein in each state. Our results also suggest communication between domains in GALE. We hypothesize that, in vivo, concentrations of natural ligands modulate GALE stability and that it should be possible to discover compounds which mimic the stabilising effects of the natural ligands overcoming mutation-induced destabilization.

Female narratives of ‘new’ citizens’ belonging(s) and identities in Europe: case studies from the Netherlands and Britain

Public discourses on citizenship, identity and nationality, which link geographical borders and the political boundaries of a community, are infused with tensions and contradictions. This paper illustrates how these tensions are interwoven with multilayered notions of home, belonging, migration, citizenship and individual’s ‘longing just to be’, focusing on the Dutch and the British context. The narratives of a number of Dutch and British women, who either immigrated to the respective countries or were born to immigrants, illustrate how the growing rigid integration and assimilative discourses in Europe contradict an individual anchoring in national and local communities. The narratives of women participating in these studies show multilayered angles of belonging presenting an alternative to the increasing strong argument for a fixed notion of positioning and national belonging. The female ‘new’ citizens in our study tell stories of individual choices, social mobility and a sense of multiple belonging in and across different communities.

Forced Displacement, Suffering and the Aesthetics of Loss

This article investigates how artists have addressed shocking experiences of displacement in different political contexts. Drawing on the notion of ‘the aesthetics of loss’ (Köstlin, 2010), it examines and compares the different aims, desires and strategies that have shaped the histories and social lives of paintings, memorial statues, installations and other artefacts. The analysis identifies a mode of artistic engagement with the sense of a ‘loss of homeland’ that has been commonly felt amongst Sudeten German expellees, namely the production and framing of visual images as markers of collective trauma. These aesthetics of loss are contrasted with the approach taken by the Dutch artist Sophie Ernst in her project entitled HOME. Working with displaced people from Pakistan, India, Palestine, Israel and Iraq, she created a mnemonic space to stimulate a more individualistic, exploratory engagement with the loss of home, which aimed, in part, to elicit interpersonal empathy. To simply oppose these two modes of aesthetic engagement, however, would ignore the ways in which artefacts are drawn into different discursive, affective and spatial formations. This article argues for the need to expose such dynamic processes of framing and reframing by focusing on the processual aspects of aestheticisation with attention to the perspective of loss.

Stratified analysis reveals chemokine-like factor (CKLF) as a potential prognostic marker in the MSI-immune consensus molecular subtype CMS1 of colorectal cancer

The Colorectal Cancer (CRC) Subtyping Consortium (CRCSC) recently published four consensus molecular subtypes (CMS’s) representing the underlying biology in CRC. The Microsatellite Instable (MSI) immune group, CMS1, has a favorable prognosis in early stage disease, but paradoxically has the worst prognosis following relapse, suggesting the presence of factors enabling neoplastic cells to circumvent this immune response. To identify the genes influencing subsequent poor prognosis in CMS1, we analyzed this subtype, centered on risk of relapse.
In a cohort of early stage colon cancer (n=460), we examined, in silico, changes in gene expression within the CMS1 subtype and demonstrated for the first time the favorable prognostic value of chemokine-like factor (CKLF) gene expression in the adjuvant disease setting [HR=0.18, CI=0.04-0.89]. In addition, using transcription profiles originating from cell sorted CRC tumors, we delineated the source of CKLF transcription within the colorectal tumor microenvironment to the leukocyte component of these tumors. Further to this, we confirmed that CKLF gene expression is confined to distinct immune subsets in whole blood samples and primary cell lines, highlighting CKLF as a potential immune cell-derived factor promoting tumor immune-surveillance of nascent neoplastic cells, particularly in CMS1 tumors. Building on the recently reported CRCSC data, we provide compelling evidence that leukocyte-infiltrate derived CKLF expression is a candidate biomarker of favorable prognosis, specifically in MSI-immune stage II/III disease.

Troubled waters: an institutional analysis of ageing Dutch and American waterway infrastructure

Waterways are one of the oldest systems for the transportation of cargo and continue to play a vital role in the economies of some countries. Due to societal change, climate change and the ageing of assets, the conditions influencing the effective functioning of these systems seem to be changing. These changing conditions require measures to renew, adapt or renovate these waterway systems. However, measures with the sole aim of improving navigation conditions have encountered resistance, as the general public, and stakeholders in particular, value these waters in many more ways than navigation alone. Therefore, a more inclusive, integrated approach is required, rather than a sectoral one. Addressing these contemporary challenges requires a shift in the traditional waterway authorities' regimes. The aim of this study is to identify elements in the institutional setting where obstacles and opportunities for a more inclusive approach can be found. Two major waterway systems, the American and the Dutch, have been analyzed using the Institutional Analysis and Development framework to reveal those obstacles and opportunities. The results show that horizontal coordination and a low pay-off for an inclusive approach is particularly problematic. The American case also reveals a promising aspect – mandatory local co-funding for federal navigation projects acts as a stimulus for broad stakeholder involvement. Improving horizontal coordination and seizing opportunities for multifunctional development can open pathways to optimize the value of waterway systems for society.

Cultural adaptation of websites: a comparative study of portuguese and dutch corporate websites

Master Thesis Presented at Instituto de Contabilidade e Administração do Porto for obtaining the Master’s degree in Digital Marketing under the supervision of Professor José de Freitas Santos

Hand Involvement in Ollier Disease and Maffucci Syndrome: a Case Series

Ollier Disease and Maffucci Syndrome are two rare diseases that can cause tumors in several organs, having a special predilection for the hand. However, there have been very few reports in the literature focusing on hand manifestations of these diseases. We report the cases of three female patients: one with Ollier Disease, and two other with Maffucci Syndrome. All patients had hand involvement as their initial primary complaint. The Ollier Disease patient developed chondrosarcomas of two digits and had to have these fingers amputated. One of the Maffucci patients died one year after presentation from a brain glioblastoma. These cases emphasize the importance of early diagnosis of Ollier Disease and Maffucci Syndrome, as these two conditions are associated not only to crippling hand deformity, but also to a significant risk of chondrosarcoma, and other malignant tumors.

Disease-Gene Association Using a Genetic Algorithm

Understanding the relationship between genetic diseases and the genes associated with them is an important problem regarding human health. The vast amount of data created from a large number of high-throughput experiments performed in the last few years has resulted in an unprecedented growth in computational methods to tackle the disease gene association problem. Nowadays, it is clear that a genetic disease is not a consequence of a defect in a single gene. Instead, the disease phenotype is a reflection of various genetic components interacting in a complex network. In fact, genetic diseases, like any other phenotype, occur as a result of various genes working in sync with each other in a single or several biological module(s). Using a genetic algorithm, our method tries to evolve communities containing the set of potential disease genes likely to be involved in a given genetic disease. Having a set of known disease genes, we first obtain a protein-protein interaction (PPI) network containing all the known disease genes. All the other genes inside the procured PPI network are then considered as candidate disease genes as they lie in the vicinity of the known disease genes in the network. Our method attempts to find communities of potential disease genes strongly working with one another and with the set of known disease genes. As a proof of concept, we tested our approach on 16 breast cancer genes and 15 Parkinson's Disease genes. We obtained comparable or better results than CIPHER, ENDEAVOUR and GPEC, three of the most reliable and frequently used disease-gene ranking frameworks.

Disease-Gene Association Using Genetic Programming

As a result of mutation in genes, which is a simple change in our DNA, we will have undesirable phenotypes which are known as genetic diseases or disorders. These small changes, which happen frequently, can have extreme results. Understanding and identifying these changes and associating these mutated genes with genetic diseases can play an important role in our health, by making us able to find better diagnosis and therapeutic strategies for these genetic diseases. As a result of years of experiments, there is a vast amount of data regarding human genome and different genetic diseases that they still need to be processed properly to extract useful information. This work is an effort to analyze some useful datasets and to apply different techniques to associate genes with genetic diseases. Two genetic diseases were studied here: Parkinson’s disease and breast cancer. Using genetic programming, we analyzed the complex network around known disease genes of the aforementioned diseases, and based on that we generated a ranking for genes, based on their relevance to these diseases. In order to generate these rankings, centrality measures of all nodes in the complex network surrounding the known disease genes of the given genetic disease were calculated. Using genetic programming, all the nodes were assigned scores based on the similarity of their centrality measures to those of the known disease genes. Obtained results showed that this method is successful at finding these patterns in centrality measures and the highly ranked genes are worthy as good candidate disease genes for being studied. Using standard benchmark tests, we tested our approach against ENDEAVOUR and CIPHER - two well known disease gene ranking frameworks - and we obtained comparable results.