Human metabolomics: strategies to understand biology

Metabolomics provides a direct functional read-out of the physiological status of an organism and is in principle ideally suited to describe someone's health status. Whereas only a limited number of small metabolites are used in the clinics, in inborn errors of metabolism an extensive repertoire of metabolites are used as biomarkers. We discuss that the proper clinical phenotyping is crucial to find biomarkers and obtain biological insights for multifactorial diseases. This requires to study the phenotype dynamics including the concepts of homeostasis and allostasis, that is, the ability to adapt and cope with a challenge. We also elaborate that biology-driven metabolomics platforms (i.e. development of metabolomics technology driven by the need of studying and answering important biomedical questions) addressing clinically relevant pathways and at the same time providing absolute concentrations are key to allow discovery and validation of biomarkers across studies and labs. Following individuals over years will require high throughput metabolomics approaches, which are emerging for nuclear magnetic resonance spectroscopy and direct-infusion mass spectrometry, but should also include the biochemical networks needed for personalized health monitoring

Über schwindende Gemeinsamkeiten - Ausländer- versus Migrantenforschung: die Notwendigkeit eines Perspektivenwechsels zur Erforschung ethnischer Minderheiten in Deutschland am Beispiel des Projekts "Die Qualität der multikulturellen Demokratie in Amsterdam und Berlin"

"Das Bild ethnischer Minderheiten in Deutschland beruht vornehmlich auf der medialen Darstellung, der politischen Perzeption und der sozialstatistischen Erfassung von 'Ausländern'. Dabei sind Ausländer im formellen Sinne spätestens seit der verstärkten Zuwanderung 'volksdeutscher' Spätaussiedler und verschiedener Reformen des Staatsbürgerschaftsrechts in den neunziger Jahren nur noch eine, zudem schrumpfende, Teilmenge der Wohnbevölkerung nichtdeutscher Herkunft. Eine wissenschaftlich bisher zu wenig diskutierte Frage ist, ob man Erkenntnisse, die auf der Untersuchung von Personen ohne deutsche Staatsbürgerschaft beruhen, auf die eigentlich im Fokus der politischen Diskussion stehenden Gruppe, die hier zusammenfassend 'Migranten' genannt wird, noch verallgemeinern kann. Das Projekt 'Die Qualität der multikulturellen Demokratie in Amsterdam und Berlin' berücksichtigt die veränderten Rahmenbedingungen, indem es die politische und zivilgesellschaftliche Integration von 'Allochthonen' untersucht. Diese amtliche niederländische Definition bezeichnet alle Personen, die entweder selbst oder von denen mindestens einer ihrer Elternteile außerhalb ihres momentanen Aufenthaltslandes geboren wurden. Basis des vorliegenden Papiers ist die Feldarbeit der Berliner Teilstudie des Projekts in Form einer telefonischen Befragung von Deutschen, Türken, Italienern und Zuwanderern aus dem Gebiet der ehemaligen Sowjetunion, einschließlich deutschstämmiger Aussiedler und jüdischer Kontingentflüchtlinge. Es wird die Frage erörtert, ob eine solche Perspektivenerweiterung bei der Bestimmung der Grundgesamtheit, mit der Folge methodischer Innovationen bei Stichprobenkonzept und Befragungstechnik, inhaltlich notwendig ist, um die politische und zivilgesellschaftliche Integration ethnischer Minderheiten realitätsnah abbilden zu können. Die Autoren kommen zu dem Schluss, dass auf Basis von Ausländerbefragungen gewonnene Erkenntnisse nicht länger repräsentativ für die in Deutschland lebenden Migranten sind." (Autorenreferat)"The view on ethnic minorities in Germany is predominantly determined by medial presentation, political perception and statistical registration of 'foreigners'. In a legal sense, however, foreigners are only a declining subset of the population of non-German origin, this has been the case at least since the increasing immigration of so-called 'ethnic Germans' and several reforms of citizenship rights in the 1990s. A widely neglected question pertaining to migrants in Germany is whether and to what extent persons of non-German nationality can be assigned to the group of so-called migrants; this is the intended focus of the political discourse. The project 'The Quality of Multicultural Democracy in Amsterdam and Berlin' takes the changing conditions into account when examining the political and civil integration of 'allochthonous individuals'. This official Dutch term refers to all persons who are born outside their actual country of residence, or for whom this was the case of at least one of their parents. This paper focuses on the empirical fieldwork for the Berlin part of the project, based on telephone interviews with German, Turkish, and Italian respondents, as well as on immigrants from the former Soviet Union, including ethnic Germans and Jewish 'contingency refugees'. The question is posed whether - in order to obtain a realistic view on the political and civil integration of ethnic minorities - such an extended definition (resulting from the methodological consequences of the sampling procedure and interview techniques) of the basic population is in fact necessary. The authors conclude that research findings that are based on foreign population surveys are no longer representative for migrants living in Germany." (author's abstract

Metabolic characterization of the natural progression of chronic hepatitis B

Background: Worldwide, over 350 million people are chronically infected with the hepatitis B virus (HBV) and are at increased risk of developing progressive liver diseases. The confinement of HBV replication to the liver, which also acts as the central hub for metabolic and nutritional regulation, emphasizes the interlinked nature of host metabolism and the disease. Still, the metabolic processes operational during the distinct clinical phases of a chronic HBV infection-immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis phases-remains unexplored. Methods: To investigate this, we conducted a targeted metabolomics approach on serum to determine the metabolic progression over the clinical phases of chronic HBV infection, using patient samples grouped based on their HBV DNA, alanine aminotransferase, and HBeAg serum levels. Results: Our data illustrate the strength of metabolomics to provide insight into the metabolic dysregulation experienced during chronic HBV. The immune tolerant phase is characterized by the speculated viral hijacking of the glycerol-3-phosphate-NADH shuttle, explaining the reduced glycerophospholipid and increased plasmalogen species, indicating a strong link to HBV replication. The persisting impairment of the choline glycerophospholipids, even during the inactive carrier phase with minimal HBV activity, alludes to possible metabolic imprinting effects. The progression of chronic HBV is associated with increased concentrations of very long chain triglycerides together with citrulline and ornithine, reflective of a dysregulated urea cycle peaking in the HBV envelope antigen-negative phase. Conclusions: The work presented here will aid in future studies to (i) validate and understand the implication of these metabolic changes using a thorough systems biology approach, (ii) monitor and predict disease severity, as well as (iii) determine the therapeutic value of the glycerol-3-phosphate-NADH shuttle

Dietary supplementation with multiple micronutrients: No beneficial effects in pediatric cystic fibrosis patients

AbstractBackgroundCystic fibrosis (CF) patients are subjected to increased oxidative stress due to chronic pulmonary inflammation and recurrent infections. Additionally, these patients have diminished skeletal muscle performance and exercise capacity. We hypothesize that a mixture of multiple micronutrients could have beneficial effects on pulmonary function and muscle performance.MethodsA double-blind, randomized, placebo controlled, cross-over trial with a mixture of multiple micronutrients (ML1) was performed in 22 CF patients (12.9±2.5 yrs) with predominantly mild lung disease. Anthropometric measures, pulmonary function, exercise performance by bicycle ergometry, muscular strength and vitamins A and E were determined.ResultsAnalysis was performed using the paired Student t-test comparing the change in each parameter during ML1 and placebo. Plasma vitamin E and A levels increased during ML1 when compared to placebo. However, no significant difference between the effect of the ML1 or placebo was observed neither for FEV1, FVC, anthropometry, nor for the parameters for muscle performance.ConclusionsThe micronutrient mixture was not superior to placebo with respect to changes in pulmonary function or muscle performance in pediatric CF patients, despite a significant increase in plasma vitamin E concentrations

Political integration by a detour? Ethnic communities and social capital of migrants in Berlin

This article investigates the impact of associational participation of migrants on their political integration in Berlin. Using survey data, we focus on the individual level to see whether migrants who are active in German and/or ethnic organisations are better integrated politically. We test the social capital argument that participation in voluntary organisations is beneficial for political integration and investigate the empirical side of the often normatively-based fear that ethnic self-organisation is a danger to the integration of ethnic groups in the receiving society. We could not find a clear-cut answer to this question. Participation in German organisations does indeed support integration, but the effects of participation in ethnic organisations are more ambiguous: migrants active in ethnic organisations are more politically active, but not more interested in German politics, than migrants who are not active in ethnic organisations. Furthermore, we conclude that the mechanisms behind the social capital argument are different for the ethnic groups under study. © 2004 Taylor and Francis Ltd

The Copper Metabolism MURR1 Domain Protein 1 (COMMD1) Modulates the Aggregation of Misfolded Protein Species in a Client-Specific Manner

The Copper Metabolism MURR1 domain protein 1 (COMMD1) is a protein involved in multiple cellular pathways, including copper homeostasis, NF-kappa B and hypoxia signalling. Acting as a scaffold protein, COMMD1 mediates the levels, stability and proteolysis of its substrates (e.g. the copper-transporters ATP7B and ATP7A, RELA and HIF-1 alpha). Recently, we established an interaction between the Cu/Zn superoxide dismutase 1 (SOD1) and COMMD1, resulting in a decreased maturation and activation of SOD1. Mutations in SOD1, associated with the progressive neurodegenerative disorder Amyotrophic Lateral Sclerosis (ALS), cause misfolding and aggregation of the mutant SOD1 (mSOD1) protein. Here, we identify COMMD1 as a novel regulator of misfolded protein aggregation as it enhances the formation of mSOD1 aggregates upon binding. Interestingly, COMMD1 co-localizes to the sites of mSOD1 inclusions and forms high molecular weight complexes in the presence of mSOD1. The effect of COMMD1 on protein aggregation is client-specific as, in contrast to mSOD1, COMMD1 decreases the abundance of mutant Parkin inclusions, associated with Parkinson's disease. Aggregation of a polyglutamine-expanded Huntingtin, causative of Huntington's disease, appears unaltered by COMMD1. Altogether, this study offers new research directions to expand our current knowledge on the mechanisms underlying aggregation disease pathologies.</p

Increased concentrations of both NMDA receptor co-agonists D-serine and glycine in global ischemia:A potential novel treatment target for perinatal asphyxia

Worldwide, perinatal asphyxia is an important cause of morbidity and mortality among term-born children. Overactivation of the N-methyl-d-aspartate receptor (NMDAr) plays a central role in the pathogenesis of cerebral hypoxia–ischemia, but the role of both endogenous NMDAr co-agonists d-serine and glycine remains largely elusive. We investigated d-serine and glycine concentration changes in rat glioma cells, subjected to oxygen and glucose deprivation (OGD) and CSF from piglets exposed to hypoxia–ischemia by occlusion of both carotid arteries and hypoxia. We illustrated these findings with analyses of cerebrospinal fluid (CSF) from human newborns affected by perinatal asphyxia. Extracellular concentrations of glycine and d-serine were markedly increased in rat glioma cells exposed to OGD, presumably through increased synthesis from l-serine. Upon reperfusion glycine concentrations normalized and d-serine concentrations were significantly lowered. The in vivo studies corroborated the finding of initially elevated and then normalizing concentrations of glycine and decreased d-serine concentrations upon reperfusion These significant increases of both endogenous NMDAr co-agonists in combination with elevated glutamate concentrations, as induced by global cerebral ischemia, are bound to lead to massive NMDAr activation, excitotoxicity and neuronal damage. Influencing these NMDAr co-agonist concentrations provides an interesting treatment target for this common, devastating and currently poorly treatable condition

Resilient or adaptable Islam? Multiculturalism, religion and migrants' claims-making for group demands in Britain, the Netherlands and France

This article investigates multiculturalism by examining the relationship between migrants’ group demands and liberal states’ policies for politically accommodating cultural and religious difference. It focuses especially on Islam. The empirical research compares migrants’ claims-making for group demands in countries with different traditions for granting recognition to migrants’ cultural difference – Britain, France and the Netherlands. Overall, we find very modest levels of group demands indicating that the challenge of group demands to liberal democracies is quantitatively less than the impression given by much multicultural literature. Group demands turn out to be significant only for Muslims, which holds across different countries. Qualitative analysis reveals problematic relationships between Islam and the state, in the overtly multicultural Dutch approach, within British race relations, and French civic universalism. This implies that there is no easy blueprint for politically accommodating Islam, whose public and religious nature makes it especially resilient to political adaptation

Benign recurrent intrahepatic cholestasis (BRIC): Evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disease characterized by multiple episodes of cholestasis without progression to chronic liver disease. The gene was previously assigned to chromosome 18q21, using a shared segment analysis in three families from the Netherlands. In the present study we report the linkage analysis of an expanded sample of 14 BRIC families, using 15 microsatellite markers from the 18q21 region. Obligate recombinants in two families place the gene in a 7-cM interval, between markers D18S69 and D18S64. All intervening markers had significant LOD scores in two-point linkage analysis. More over, we identified one family in which the BRIC gene seems to be unlinked to the 18q21 region, or that represents incomplete penetrance of the BRIC genotype

Simplivariate Models: Ideas and First Examples

One of the new expanding areas in functional genomics is metabolomics: measuring the metabolome of an organism. Data being generated in metabolomics studies are very diverse in nature depending on the design underlying the experiment. Traditionally, variation in measurements is conceptually broken down in systematic variation and noise where the latter contains, e.g. technical variation. There is increasing evidence that this distinction does not hold (or is too simple) for metabolomics data. A more useful distinction is in terms of informative and non-informative variation where informative relates to the problem being studied. In most common methods for analyzing metabolomics (or any other high-dimensional x-omics) data this distinction is ignored thereby severely hampering the results of the analysis. This leads to poorly interpretable models and may even obscure the relevant biological information. We developed a framework from first data analysis principles by explicitly formulating the problem of analyzing metabolomics data in terms of informative and non-informative parts. This framework allows for flexible interactions with the biologists involved in formulating prior knowledge of underlying structures. The basic idea is that the informative parts of the complex metabolomics data are approximated by simple components with a biological meaning, e.g. in terms of metabolic pathways or their regulation. Hence, we termed the framework ‘simplivariate models’ which constitutes a new way of looking at metabolomics data. The framework is given in its full generality and exemplified with two methods, IDR analysis and plaid modeling, that fit into the framework. Using this strategy of ‘divide and conquer’, we show that meaningful simplivariate models can be obtained using a real-life microbial metabolomics data set. For instance, one of the simple components contained all the measured intermediates of the Krebs cycle of E. coli. Moreover, these simplivariate models were able to uncover regulatory mechanisms present in the phenylalanine biosynthesis route of E. coli