Spatial development policy in the European Constitutional Treaty: position paper from the ARL, Hanover

As the implementation of the European single market has continued, it has become increasingly clear that a more closely integrated Europe cannot simply have an exclusively economic dimension. For a harmonious overall development, a large number of other policy areas clearly have to be included. One of these is spatial policy (spatial development policy), which aims to contribute to a more balanced spatial development. In the view of the ARL, the time has now come to initiate the institutional steps which have thus far emerged from the Europe-wide debate. The "territorial cohesion" of the Union cannot be achieved until we have clear legal foundations and definitions, which must also apply to spatial development policy in Europe. For that reason, the constitutional aspects of a European spatial development policy must form part of the agenda of the European Constitutional Convention.Mit der fortschreitenden Verwirklichung des Europäischen Binnenmarktes ist im Laufe der Zeit immer deutlicher geworden, dass das zusammenwachsende Europa nicht lediglich eine ökonomische Dimension haben kann, sondern dass für eine harmonische Gesamtentwicklung zahlreiche weitere Politikfelder einbezogen werden müssen. Dazu gehört auch die Raumpolitik (Raumentwicklungspolitik) mit dem Ziel einer ausgewogenen räumlichen Entwicklung. Nach Auffassung der Akademie ist es an der Zeit, aus dem bisherigen europaweiten Diskussionsstand endlich institutionelle Konsequenzen zu ziehen. Der "territoriale Zusammenhalt" der Union kann nicht gesichert werden, solange es keine klaren rechtlichen Grundlagen und Abgrenzungen auch für die Raumentwicklungspolitik in Europa gibt. Deshalb gehören die konstitutionellen Fragen einer europäischen Raumentwicklungspolitik auf die Agenda des Europäischen Verfassungskonvents.L'achèvement progressif du Grand marché intérieur de l'Union européenne a fait ressortir de plus en plus clairement au fil du temps que l'Europe, en s'intégrant, ne doit pas se limiter à la seule dimension économique. Son évolution harmonieuse globale requiert plutôt une approche qui englobe de nombreux autres champs politiques comme par exemple la politique spatiale (politique de développement de l'espace) envisageant un développement spatial équilibré. De l'avis de l'ARL, il est temps de tirer enfin des conclusions d'ordre institutionnel de l'état d'avancement des discussions en Europe. Il ne sera pas possible d'assurer la "cohésion territoriale" de l'Union européenne sans avoir créé des bases et des délimitations juridiques claires pour la politique du développement de l'espace européen. C'est pourquoi il appartient à la Convention européenne de traiter les questions constitutionnelles relatives à la politique européenne de développement de l'espace

Extensive alterations of the whole-blood transcriptome are associated with body mass index: results of an mRNA profiling study involving two large population-based cohorts

Background: Obesity, defined as pathologically increased body mass index (BMI),is strongly related to an increased risk for numerous common cardiovascular and metabolic diseases. It is particularly associated with insulin resistance, hyperglycemia, and systemic oxidative stress and represents the most important risk factor for type 2 diabetes (T2D). However, the pathophysiological mechanisms underlying these associations are still not completely understood. Therefore, in order to identify potentially disease-relevant BMI-associated gene expression signatures, a transcriptome-wide association study (TWAS) on BMI was performed. Methods: Whole-blood mRNA levels determined by array-based transcriptional profiling were correlated with BMI in two large independent population-based cohort studies (KORA F4 and SHIP-TREND) comprising a total of 1977 individuals. Results: Extensive alterations of the whole-blood transcriptome were associated with BMI: More than 3500 transcripts exhibited significant positive or negative BMI-correlation. Three major whole-blood gene expression signatures associated with increased BMI were identified. The three signatures suggested: i) a ratio shift from mature erythrocytes towards reticulocytes, ii) decreased expression of several genes essentially involved in the transmission and amplification of the insulin signal, and iii) reduced expression of several key genes involved in the defence against reactive oxygen species (ROS). Conclusions: Whereas the first signature confirms published results, the other two provide possible mechanistic explanations for well-known epidemiological findings under conditions of increased BMI, namely attenuated insulin signaling and increased oxidative stress. The putatively causative BMI-dependent down-regulation of the expression of numerous genes on the mRNA level represents a novel finding. BMI-associated negative transcriptional regulation of insulin signaling and oxidative stress management provide new insights into the pathogenesis of metabolic syndrome and T2D

Congener patterns of polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls as a useful aid to source identification during a contamination incident in the food chain

Polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs) are still considered among the most important groups of contaminants in the food chain. Self-control by food producers and official control by authorities are important activities that allow contaminant sources to be traced and promote further reduction in food and feed levels. Strict but feasible maximum levels were set by the EU Commission for food and feed to support this strategy, as well as action levels and thresholds. When products exceed these levels, it is important to trace the source of contamination and take measures to remove it. Congener patterns of PCDD/Fs and PCBs differ between sources and are important tools for source identification. Therefore, patterns associated with different sources and incidents relating to various feed matrices and certain agricultural chemicals were collated from published scientific papers, with additional ones available from some laboratories. The collection was evaluated for completeness by presentations at workshops and conferences. Primary sources appear to derive from 5 categories, i) by-products from production of organochlorine chemicals (e.g. PCBs, chlorophenols, chlorinated pesticides, polyvinyl chloride (PVC)), ii) the result of combustion of certain materials and accidental fires, iii) the use of inorganic chlorine, iv) recycling/production of certain minerals, and v) certain naturally occurring clays (ball clay, kaolinite). A decision tree was developed to assist in the identification of the source

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease

The serotonin receptor 3E variant is a risk factor for female IBS-D

Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT receptor family. 5-HT Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D. [Abstract copyright: © 2022. The Author(s).