Nitrogen deposition and grass encroachment in calcareous and acidic Grey dunes (H2130) in NW-Europe

We present an overview of high nitrogen deposition effects on coastal dune grasslands in NW-Europe (H2130), especially concerning grass encroachment in calcareous and acidic Grey Dunes. The problem is larger than previously assumed, because critical loads are still too high, and extra N-input from the sea may amount to 10 kg ha−1 yr−1. Grass encroachment clearly leads to loss of characteristic plant species, from approximately 16 in open dune grassland to 2 in tall-grass vegetation. Dune zones differ in grass encroachment, due to the chemical status of the soil. In calcareous and iron-rich dunes (Renodunal district), grass encroachment showed a clear gradient over the dune area. Grass encroachment is low in calcareous foredunes, due to low P-availability, and large grazers were not needed to counteract grass encroachment after 2001. In partly decalcified middle dunes, P-availability and grass encroachment are high due to dissolution of calcium phosphates, and grazing only partially helped to control this. In acidic, iron-rich hinterdunes, grass encroachment gradually increased between 1990 and 2014, possibly because P-availability increased with time due to increased soil organic matter content. In acidic, iron-poor dunes (Wadden district), grass encroachment is a large problem, because chemical P-fixation with Ca or Fe does not occur. Large grazers may however reduce tall-grass cover. High cumulative N-deposition could theoretically lead to increased N-storage and N-mineralization in the soil. Mineralization indeed increased with N-deposition, but in 15N experiments, most ammonium was converted to nitrate, and storage in soil organic matter was low. Soil N-storage is probably reduced by high nitrate leaching, which will favour dune restoration when N-deposition levels decrease

TNFR2 maintains adequate IL-12 production by dendritic cells in inflammatory responses by regulating endogenous TNF levels

Sepsis-induced immune reactions are reduced in TNF receptor 2 (TNFR2)-deficient mice as previously shown. In order to elucidate the underlying mechanisms, the functional integrity of myeloid cells of TNFR2-deficient mice was analyzed and compared to wild type (WT) mice. The capacity of dendritic cells to produce IL-12 was strongly impaired in TNF-deficient mice, mirroring impaired production of IL-12 by WT dendritic cells in sepsis or after LPS or TNF pre-treatment. In addition, TNFR2-deficient mice were refractory to LPS pre-treatment and also to hyper-sensitization by inactivated Propionibacterium acnes, indicating habituation to inflammatory stimuli by the immune response when TNFR2 is lacking. Constitutive expression of TNF mRNA in kidney, liver, spleen, colon and lung tissue, and the presence of soluble TNFR2 in urine of healthy WT mice supported the conclusion that TNF is continuously present in naïve mice and controlled by soluble TNFR2. In TNFR2-deficient mice endogenous TNF levels cannot be balanced and the continuous exposure to enhanced TNF levels impairs dendritic cell function. In conclusion, TNF pre-exposure suppresses secondary inflammatory reactions of myeloid cells; therefore, continuous control of endogenous TNF by soluble TNFR2 seems to be essential for the maintenance of adequate sensitivity to inflammatory stimuli

Molecular subgroups of medulloblastoma: the current consensus

Medulloblastoma, a small blue cell malignancy of the cerebellum, is a major cause of morbidity and mortality in pediatric oncology. Current mechanisms for clinical prognostication and stratification include clinical factors (age, presence of metastases, and extent of resection) as well as histological subgrouping (classic, desmoplastic, and large cell/anaplastic histology). Transcriptional profiling studies of medulloblastoma cohorts from several research groups around the globe have suggested the existence of multiple distinct molecular subgroups that differ in their demographics, transcriptomes, somatic genetic events, and clinical outcomes. Variations in the number, composition, and nature of the subgroups between studies brought about a consensus conference in Boston in the fall of 2010. Discussants at the conference came to a consensus that the evidence supported the existence of four main subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4). Participants outlined the demographic, transcriptional, genetic, and clinical differences between the four subgroups. While it is anticipated that the molecular classification of medulloblastoma will continue to evolve and diversify in the future as larger cohorts are studied at greater depth, herein we outline the current consensus nomenclature, and the differences between the medulloblastoma subgroups

Uitbreiding en herstel van Zuid-Limburgse hellingschraallanden. Eindrapportage 2e fase O + BN onderzoek

In het kader van Natura 2000 worden in Europees perspectief zeldzame soorten en zeldzame vegetatietypen in Nederland beschermd. In dit rapport staan de Zuid-Limburgse kalkgraslanden (H6210) en heischrale graslanden (H6230) centraal. Bijna alle nog bestaande hellingschraallanden in Nederland liggen binnen de als Natura2000 aangewezen gebieden. Beide habitattypen zijn prioritair en de opgave in deze gebieden bestaat uit uitbreiding van het oppervlak en verbetering van de kwaliteit. Uit de 1e fase van het O+BN onderzoek aan de Zuid-Limburgse hellingschraallanden is gebleken dat veel karakteristieke planten- en diersoorten binnen de huidige natuurreservaten nog steeds achteruitgaan. Een belangrijke oorzaak hiervoor is de verhoogde beschikbaarheid van stikstof

Defining the landscape of circular RNAs in neuroblastoma unveils a global suppressive function of MYCN

Circular RNAs (circRNAs) are a regulatory RNA class. While cancer-driving functions have been identified for single circRNAs, how they modulate gene expression in cancer is not well understood. We investigate circRNA expression in the pediatric malignancy, neuroblastoma, through deep whole-transcriptome sequencing in 104 primary neuroblastomas covering all risk groups. We demonstrate that MYCN amplification, which defines a subset of high-risk cases, causes globally suppressed circRNA biogenesis directly dependent on the DHX9 RNA helicase. We detect similar mechanisms in shaping circRNA expression in the pediatric cancer medulloblastoma implying a general MYCN effect. Comparisons to other cancers identify 25 circRNAs that are specifically upregulated in neuroblastoma, including circARID1A. Transcribed from the ARID1A tumor suppressor gene, circARID1A promotes cell growth and survival, mediated by direct interaction with the KHSRP RNA-binding protein. Our study highlights the importance of MYCN regulating circRNAs in cancer and identifies molecular mechanisms, which explain their contribution to neuroblastoma pathogenesis

Delineation of Two Clinically and Molecularly Distinct Subgroups of Posterior Fossa Ependymoma

Despite the histological similarity of ependymomas from throughout the neuroaxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis. Transcriptional profiling of two large independent cohorts of ependymoma reveals the existence of two demographically, transcriptionally, genetically, and clinically distinct groups of posterior fossa (PF) ependymomas. Group A patients are younger, have laterally located tumors with a balanced genome, and are much more likely to exhibit recurrence, metastasis at recurrence, and death compared with Group B patients. Identification and optimization of immunohistochemical (IHC) markers for PF ependymoma subgroups allowed validation of our findings on a third independent cohort, using a human ependymoma tissue microarray, and provides a tool for prospective prognostication and stratification of PF ependymoma patients

Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition.

Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common 'non-synonymous homozygous' deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3