Rock-eating mycorrhizas: their role in plant nutrition and biogeochemical cycles

A decade ago, tunnels inside mineral grains were found that were likely formed by hyphae of ectomycorrhizal (EcM) fungi. This observation implied that EcM fungi can dissolve mineral grains. The observation raised several questions on the ecology of these ¿rock-eating¿ fungi. This review addresses the roles of these rock-eating EcM associations in plant nutrition, biogeochemical cycles and pedogenesis. Research approaches ranged from molecular to ecosystem level scales. Nutrient deficiencies change EcM seedling exudation patterns of organic anions and thus their potential to mobilise base cations from minerals. This response was fungal species-specific. Some EcM fungi accelerated mineral weathering. While mineral weathering could also increase the concentrations of phytotoxic aluminium in the soil solution, some EcM fungi increase Al tolerance through an enhanced exudation of oxalate. Through their contribution to Al transport, EcM hyphae could be agents in pedogenesis, especially podzolisation. A modelling study indicated that mineral tunnelling is less important than surface weathering by EcM fungi. With both processes taken together, the contribution of EcM fungi to weathering may be significant. In the field vertical niche differentiation of EcM fungi was shown for EcM root tips and extraradical mycelium. In the field EcM fungi and tunnel densities were correlated. Our results support a role of rock-eating EcM fungi in plant nutrition and biogeochemical cycles. EcM fungal species-specific differences indicate the need for further research with regard to this variation in functional traits

Targeting the NG2/CSPG4 Proteoglycan Retards Tumour Growth and Angiogenesis in Preclinical Models of GBM and Melanoma

Aberrant expression of the progenitor marker Neuron-glia 2 (NG2/CSPG4) or melanoma proteoglycan on cancer cells and angiogenic vasculature is associated with an aggressive disease course in several malignancies including glioblastoma multiforme (GBM) and melanoma. Thus, we investigated the mechanism of NG2 mediated malignant progression and its potential as a therapeutic target in clinically relevant GBM and melanoma animal models. Xenografting NG2 overexpressing GBM cell lines resulted in increased growth rate, angiogenesis and vascular permeability compared to control, NG2 negative tumours. The effect of abrogating NG2 function was investigated after intracerebral delivery of lentivirally encoded shRNAs targeting NG2 in patient GBM xenografts as well as in established subcutaneous A375 melanoma tumours. NG2 knockdown reduced melanoma proliferation and increased apoptosis and necrosis. Targeting NG2 in two heterogeneous GBM xenografts significantly reduced tumour growth and oedema levels, angiogenesis and normalised vascular function. Vascular normalisation resulted in increased tumour invasion and decreased apoptosis and necrosis. We conclude that NG2 promotes tumour progression by multiple mechanisms and represents an amenable target for cancer molecular therapy

Causal and associational language in observational health research: A systematic evaluation.

This is the final version. Available from Oxford University Press via the DOI in this record. Data, data analysis code, and materials are available on the Open Science Framework project https://osf.io/jtdaz/.We estimated the degree to which language used in the high profile medical/public health/epidemiology literature implied causality using language linking exposures to outcomes and action recommendations; examined disconnects between language and recommendations; identified the most common linking phrases; and estimated how strongly linking phrases imply causality. We searched and screened for 1,170 articles from 18 high-profile journals (65 per journal) published from 2010-2019. Based on written framing and systematic guidance, three reviewers rated the degree of causality implied in abstracts and full text for exposure/outcome linking language and action recommendations. Reviewers rated the causal implication of exposure/outcome linking language as None (no causal implication) in 13.8%, Weak 34.2%, Moderate 33.2%, and Strong 18.7% of abstracts. The implied causality of action recommendations was higher than the implied causality of linking sentences for 44.5% or commensurate for 40.3% of articles. The most common linking word in abstracts was "associate" (45.7%). Reviewers' ratings of linking word roots were highly heterogeneous; over half of reviewers rated "association" as having at least some causal implication. This research undercuts the assumption that avoiding "causal" words leads to clarity of interpretation in medical research.Marie Skłodowska-Curie grantAustralian Research CouncilNational Institute of Mental HealthNational Institute of Mental HealthNational Institute of Biomedical Imaging and BioengineeringNational Center for Advancing Translational Sciences UCLA Clinical Translational Science InstituteBloomberg American Health InitiativeKaren Toffler Charity Trus

Epigenome Mapping Reveals Distinct Modes of Gene Regulation and Widespread Enhancer Reprogramming by the Oncogenic Fusion Protein {EWS}-{FLI1}

SummaryTranscription factor fusion proteins can transform cells by inducing global changes of the transcriptome, often creating a state of oncogene addiction. Here, we investigate the role of epigenetic mechanisms in this process, focusing on Ewing sarcoma cells that are dependent on the EWS-FLI1 fusion protein. We established reference epigenome maps comprising DNA methylation, seven histone marks, open chromatin states, and RNA levels, and we analyzed the epigenome dynamics upon downregulation of the driving oncogene. Reduced EWS-FLI1 expression led to widespread epigenetic changes in promoters, enhancers, and super-enhancers, and we identified histone H3K27 acetylation as the most strongly affected mark. Clustering of epigenetic promoter signatures defined classes of EWS-FLI1-regulated genes that responded differently to low-dose treatment with histone deacetylase inhibitors. Furthermore, we observed strong and opposing enrichment patterns for E2F and AP-1 among EWS-FLI1-correlated and anticorrelated genes. Our data describe extensive genome-wide rewiring of epigenetic cell states driven by an oncogenic fusion protein

An electrochemiluminescence based assay for quantitative detection of endogenous and exogenously applied MeCP2 protein variants

Methyl-CpG-binding protein 2 (MeCP2) is a multifunctional chromosomal protein that plays a key role in the central nervous system. Its levels need to be tightly regulated, as both deficiency and excess of the protein can lead to severe neuronal dysfunction. Loss-of-function mutations affecting MeCP2 are the primary cause of Rett syndrome (RTT), a severe neurological disorder that is thought to result from absence of functional protein in the brain. Several therapeutic strategies for the treatment of RTT are currently being developed. One of them is the use of stable and native TAT-MeCP2 fusion proteins to replenish its levels in neurons after permeation across the blood-brain barrier (BBB). Here we describe the expression and purification of various transactivator of transcription (TAT)-MeCP2 variants and the development of an electrochemiluminescence based assay (ECLIA) that is able to measure endogenous MeCP2 and recombinant TAT-MeCP2 fusion protein levels in a 96-well plate format. The MeCP2 ECLIA produces highly quantitative, accurate and reproducible measurements with low intra- and inter-assay error throughout a wide working range. To underline its broad applicability, this assay was used to analyze brain tissue and study the transport of TAT-MeCP2 variants across an in vitro model of the blood-brain barrier