Liquidity, Inflation and Asset Prices in a Time-Varying Framework for the Euro Area

In this paper, we investigate how the dynamic effects of excess liquidity shocks on economic activity, asset prices and inflation differ over time. We show that the impact varies considerably over time, depends on the source of increased liquidity (M1, M3-M1 or credit) and the underlying state of the economy (asset price boom-bust, business cycle, inflation cycle, credit cycle and monetary policy stance).Liquidity, asset prices, inflation, time-varying coefficients.

Liquidity, inflation and asset prices in a time-varying framework for the euro area

In this paper, we investigate how the dynamic effects of excess liquidity shocks on economic activity, asset prices and inflation differ over time. We show that the impact varies considerably over time, depends on the source of increased liquidity (M1, M3-M1 or credit) and the underlying state of the economy (asset price boom-bust, business cycle, inflation cycle, credit cycle and monetary policy stance).Liquidity, asset prices, inflation, time-varying coefficients

GenomeGraphs: integrated genomic data visualization with R.

BackgroundBiological studies involve a growing number of distinct high-throughput experiments to characterize samples of interest. There is a lack of methods to visualize these different genomic datasets in a versatile manner. In addition, genomic data analysis requires integrated visualization of experimental data along with constantly changing genomic annotation and statistical analyses.ResultsWe developed GenomeGraphs, as an add-on software package for the statistical programming environment R, to facilitate integrated visualization of genomic datasets. GenomeGraphs uses the biomaRt package to perform on-line annotation queries to Ensembl and translates these to gene/transcript structures in viewports of the grid graphics package. This allows genomic annotation to be plotted together with experimental data. GenomeGraphs can also be used to plot custom annotation tracks in combination with different experimental data types together in one plot using the same genomic coordinate system.ConclusionGenomeGraphs is a flexible and extensible software package which can be used to visualize a multitude of genomic datasets within the statistical programming environment R

Functional dissection of transcriptional regulation during normal and malignant T-cell development : an integrative (epi)genomic approach

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive malignant disorder. While originally associated with poor prognosis, more recent intensified T-ALL therapy has led to remarkable improvements in survival of these patients. Unfortunately, these therapeutic schemes are associated with severe acute and long-term toxicities, thus demanding for further research in order to design more precision medicine oriented treatment. Importantly, for T-ALL patients with relapsed and refractory T-ALL, outcome remains extremely poor, thus urging further investigations to design therapies with further reduced relapse risk and/or novel treatment to cure relapsed cases. To shift towards this personalized medicine approach, a more profound understanding of the molecular basis of T-ALL progression is required. Several decades of genetic studies in T-ALL have uncovered a remarkable heterogeneous and complex landscape of combined oncogenic and loss-of-function mutations that contribute to malignant thymocyte transformation. One of the major challenges in T-ALL research is to unravel in detail how the diverse complement of oncogenes and tumor suppressors functionally contribute to T-ALL pathogenesis and response to therapy. To this end, I have studied the functional properties and cooperation of several key players that participate in normal and malignant T-cell development at the level of transcriptional regulatory networks. TLX1 is a major driver oncogene causing transformation of immature thymocytes towards T-ALL. Previous pioneering work partly uncovered its mode of action in relation to T-ALL formation, showing that ectopic overexpression of TLX1 in immature thymocytes causes repression of multiple T-ALL tumor suppressor genes. The study performed during this doctoral mandate, led to the observation of an unexpected antagonism between the TLX1 and NOTCH1 oncogenes, with activated TLX1 suppressing NOTCH1 and key NOTCH1 target genes. Based on this finding, we hypothesized that this unique interaction between both oncogenes could explain the presence of NOTCH1 mutations in most TLX1 driven T-ALL. Furthermore, the required cooperativity of NOTCH1 (pathway) activating mutations can also explain the very long latency of T-ALL development in a TLX1 driven leukemia mouse model (paper 1). In addition to NOTCH1 mutations, PHF6 loss-of-function mutations are also frequently observed, pointing at a further putative required cooperative genetic lesion for full-blown TLX1 driven T-ALL formation. Given the lack of insight into the normal cellular function of the epigenetic reader protein PHF6, I investigated its role during normal hematopoiesis and observed a profound effect of PHF6 loss on hematopoietic lineage development (paper 2). Moreover, in the context of TLX1 driven T-ALL formation, I identified the tyrosine kinase ‘interleukine-7 receptor’ (IL7R) as a robustly upregulated gene upon PHF6 knockdown. Given the role of IL7R signaling in survival of maturing thymocytes, this observation opens an exciting perspective that PHF6 loss is required as an essential cooperative event in TLX1 driven T-ALL pathogenesis by re-installment of TLX1 repressed IL7R expression. Importantly, in addition to paving the way for further animal modeling and mechanistic studies, this finding is also highly relevant in the context of design of novel therapies targeting IL7R downstream JAK-STAT signaling (paper 3). Until recently, transcriptional regulatory networks were mainly studied from a ‘gene-protein coding’ genomic viewpoint. Several studies have challenged this central dogma based on the proven role of non-coding RNAs in control of normal cellular behavior. Given this exciting new perspective on further expanding complexity of gene regulation during normal development and malignant transformation, I decided to study the role of such micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs) in T-ALL perturbed transcriptional networks. More specifically, I studied the role of miRNAs under control of TAL1 (paper 4), unraveled the landscape of lncRNAs implicated in the NOTCH1 signaling pathway (paper 5) and performed the first landscaping of the TLX1 lncRNAome (paper 6). In conclusion, my work has contributed to novel insights into transcriptional networks in normal and malignant T-cell development, revealing several novel nodes for therapeutic intervention in the pursuit of personalized medicine development in the field of T-ALL research

T-ALL and thymocytes : a message of noncoding RNAs

In the last decade, the role for noncoding RNAs in disease was clearly established, starting with microRNAs and later expanded towards long noncoding RNAs. This was also the case for T cell acute lymphoblastic leukemia, which is a malignant blood disorder arising from oncogenic events during normal T cell development in the thymus. By studying the transcriptomic profile of protein-coding genes, several oncogenic events leading to T cell acute lymphoblastic leukemia (T-ALL) could be identified. In recent years, it became apparent that several of these oncogenes function via microRNAs and long noncoding RNAs. In this review, we give a detailed overview of the studies that describe the noncoding RNAome in T-ALL oncogenesis and normal T cell development

Thick-billed Murre Hunting in West Greenland, 1988-89

Thick-billed murre (Uria lomyia) hunting by Inuit of West Greenland was surveyed during the winter and spring of 1988/89. Kill toll levels and age structure of the kill were determined for districts between Upernavik (73 degrees N) and Nanortalik (60 degrees N). Based on counts of the numbers of birds available for purchase at markets and on information from processing companies, an estimated 100,000 murres were killed for commercial trading purposes in 1988/89. Non-commercial hunting is harder to assess, but estimates based on the number of licences issued and the mean number of murres killed per day by non-commercial hunters indicate that between 190,000 and 293,000 murres are killed per annum. Thus the total kill toll is estimated to be between 283,000 and 386,000 murres annually. In Central West and Southwest Greenland the peak hunting period was November and December, but hunting continued to 15 March or until ice conditions prevented sailing. Age distribution of the kill was determined by classifying 6278 murres as "first-year" or "older" by the development of the cranium. In Southwest Greenland the proportion of older birds in the kill was always below 9%, whereas in Central West Greenland (Nuuk) the value increased from 27.5% in October to 75.8% old birds in March. About 90% of the murres killed in spring near major breeding colonies in Upernavik were adult breeding birds, and hunting near the breeding grounds is considered the major cause for population reductions. Murres shot in winter are mostly birds from colonies outside Greenland, but though it has yet to be proved, the immense kill of murres during the winter hunt probably affects the populations involved.Key words: thick-billed murre, Uria lomvia, Greenland, Inuit, hunting, seabirds, population structure, resource management, hunting legislationRÉSUMÉ. Au cours de l’hiver et de l’été de 1988-89, on a effectué des relevés portant sur la chasse à la marmette de Brünnich (Uria lomvia) par les Inuit de l’ouest du Groenland. Le taux des oiseaux abattus et leur structure d’âge ont été déterminés pour les districts situés entre Upernavik (73” N.) et Nanortalik (60’ N.). En s’appuyant sur le comptage du nombre d’oiseaux mis en vente sur les marchés ainsi que sur l’information obtenue auprès des compagnies de conditionnement, on a évalué à 100 000 le nombre de marmettes de Brünnich tuées à des fins commerciales en 1988-89. La chasse non commerciale est plus difficile à évaluer, mais les estimations fondées sur le nombre de permis issus et la moyenne de marmettes tuées chaque jour par des chasseurs non commerciaux indiquent qu’entre 190 000 et 293 000 marmettes sont tuées chaque année. Le nombre total de marmettes tuées annuellement se situerait donc entre 283 000 et 386 000. Dans le centre-ouest et le sud-ouest du Groenland, la saison de chasse battait son plein en novembre et décembre, mais la chasse continuait jusqu’au 15 mars ou jusqu’à ce que les conditions des glaces empêchent la navigation. On a déterminé la distribution d’âge des oiseaux tués en classant 6278 marmettes dans deux catégories, soit <<première année>> ou <<plus âgée>>, d’après le développement de la boîte cranienne. Dans le sud-ouest du Groenland, la proportion d’oiseaux plus âgés parmi les oiseaux tués était toujours inférieure à 9 p. cent, tandis que dans le centre-ouest du Groenland (Nuuk), la proportion augmentait de 273 p. cent en octobre à 75,8 p. cent au mois de mars. Près de 90 p. cent des marmettes de Brünnich tuées au printemps à proximité d’importantes colonies reproductrices à Upemavik étaient des adultes en âge de se reproduire, et c’est la chasse près des sites de nidification qui serait tenue en grande partie responsable de la diminution de leur population. Les marmettes abattues en hiver sont surtout des oiseaux venant de colonies situées hors du Groenland, mais, bien que cela reste encore à prouver, l’abattage massif des marmettes durant la chasse hivernale affecte probablement les populations concernées. Les recommandations en vue d’améliorer la gestion des populations de marmettes de Brünnich au Groenland comprennent des programmes éducatifs et l’application stricte des lois, la réduction du nombre de chasseurs et le raccourcissement de la saison de chasse hivernale. D’autres recherches sont nécessaires concernant l’ampleur et la variation de la chasse non commerciale, une surveillance détaillée de la population reproductrice et la provenance des oiseaux tués.Mots clés: marmette de Briinnich, Uria lomvia, Groenland, Inuit, chasse, oiseaux marins, structure de la population, gestion des ressources, législation concernant la chass

Epigenetic regulation of neuroblastoma development

In recent years, technological advances have enabled a detailed landscaping of the epigenome and the mechanisms of epigenetic regulation that drive normal cell function, development and cancer. Rather than merely a structural entity to support genome compaction, we now look at chromatin as a very dynamic and essential constellation that is actively participating in the tight orchestration of transcriptional regulation as well as DNA replication and repair. The unique feature of chromatin flexibility enabling fast switches towards more or less restricted epigenetic cellular states is, not surprisingly, intimately connected to cancer development and treatment resistance, and the central role of epigenetic alterations in cancer is illustrated by the finding that up to 50% of all mutations across cancer entities affect proteins controlling the chromatin status. We summarize recent insights into epigenetic rewiring underlying neuroblastoma (NB) tumor formation ranging from changes in DNA methylation patterns and mutations in epigenetic regulators to global effects on transcriptional regulatory circuits that involve key players in NB oncogenesis. Insights into the disruption of the homeostatic epigenetic balance contributing to developmental arrest of sympathetic progenitor cells and subsequent NB oncogenesis are rapidly growing and will be exploited towards the development of novel therapeutic strategies to increase current survival rates of patients with high-risk NB

Early and late effects of pharmacological ALK inhibition on the neuroblastoma transcriptome

Background: Neuroblastoma is an aggressive childhood malignancy of the sympathetic nervous system. Despite multi-modal therapy, survival of high-risk patients remains disappointingly low, underscoring the need for novel treatment strategies. The discovery of ALK activating mutations opened the way to precision treatment in a subset of these patients. Previously, we investigated the transcriptional effects of pharmacological ALK inhibition on neuroblastoma cell lines, six hours after TAE684 administration, resulting in the 77-gene ALK signature, which was shown to gradually decrease from 120 minutes after TAE684 treatment, to gain deeper insight into the molecular effects of oncogenic ALK signaling. Aim: Here, we further dissected the transcriptional dynamic profiles of neuroblastoma cells upon TAE684 treatment in a detailed timeframe of ten minutes up to six hours after inhibition, in order to identify additional early targets for combination treatment. Results: We observed an unexpected initial upregulation of positively regulated MYCN target genes following subsequent downregulation of overall MYCN activity. In addition, we identified adrenomedullin (ADM), previously shown to be implicated in sunitinib resistance, as the earliest response gene upon ALK inhibition. Conclusions: We describe the early and late effects of ALK inhibitor TAE684 treatment on the neuroblastoma transcriptome. The observed unexpected upregulation of ADM warrants further investigation in relation to putative ALK resistance in neuroblastoma patients currently undergoing ALK inhibitor treatment