Whole tumor RNA-sequencing and deconvolution reveal a clinically-prognostic PTEN/PI3K-regulated glioma transcriptional signature

The concept that solid tumors are maintained by a productive interplay between neoplastic and non-neoplastic elements has gained traction with the demonstration that stromal fibroblasts and immune system cells dictate cancer development and progression. While less studied, brain tumor (glioma) biology is likewise influenced by non-neoplastic immune system cells (macrophages and microglia) which interact with neoplastic glioma cells to create a unique physiological state (glioma ecosystem) distinct from that found in the normal tissue. To explore this neoplastic ground state, we leveraged several preclinical mouse models of neurofibromatosis type 1 (NF1) optic glioma, a low-grade astrocytoma whose formation and maintenance requires productive interactions between non-neoplastic and neoplastic cells, and employed whole tumor RNA-sequencing and mathematical deconvolution strategies to characterize this low-grade glioma ecosystem as an aggregate of cellular and acellular elements. Using this approach, we demonstrate that optic gliomas generated by altering the germlin

Estrogen activation of microglia underlies the sexually dimorphic differences in Nf1 optic glioma-induced retinal pathology

Children with neurofibromatosis type 1 (NF1) develop low-grade brain tumors throughout the optic pathway. Nearly 50% of children with optic pathway gliomas (OPGs) experience visual impairment, and few regain their vision after chemotherapy. Recent studies have revealed that girls with optic nerve gliomas are five times more likely to lose vision and require treatment than boys. To determine the mechanism underlying this sexually dimorphic difference in clinical outcome, we leveraged Nf1 optic glioma (Nf1-OPG) mice. We demonstrate that female Nf1-OPG mice exhibit greater retinal ganglion cell (RGC) loss and only females have retinal nerve fiber layer (RNFL) thinning, despite mice of both sexes harboring tumors of identical volumes and proliferation. Female gonadal sex hormones are responsible for this sexual dimorphism, as ovariectomy, but not castration, of Nf1-OPG mice normalizes RGC survival and RNFL thickness. In addition, female Nf1-OPG mice have threefold more microglia than their male counterparts, and minocycline inhibition of microglia corrects the retinal pathology. Moreover, pharmacologic inhibition of microglial estrogen receptor-β (ERβ) function corrects the retinal abnormalities in female Nf1-OPG mice. Collectively, these studies establish that female gonadal sex hormones underlie the sexual dimorphic differences in Nf1 optic glioma–induced retinal dysfunction by operating at the level of tumor-associated microglial activation

The cell of origin dictates the temporal course of neurofibromatosis-1 (Nf1) low-grade glioma formation.

Low-grade gliomas are one of the most common brain tumors in children, where they frequently form within the optic pathway (optic pathway gliomas; OPGs). Since many OPGs occur in the context of the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome, we have previously employed Nf1 genetically-engineered mouse (GEM) strains to study the pathogenesis of these low-grade glial neoplasms. In the light of the finding that human and mouse low-grade gliomas are composed of Olig2+ cells and that Olig2+ oligodendrocyte precursor cells (OPCs) give rise to murine high-grade gliomas, we sought to determine whether Olig2+ OPCs could be tumor-initiating cells for Nf1 optic glioma. Similar to the GFAP-Cre transgenic strain previously employed to generate Nf1 optic gliomas, Olig2+ cells also give rise to astrocytes in the murine optic nerve in vivo. However, in contrast to the GFAP-Cre strain where somatic Nf1 inactivation in embryonic neural progenitor/stem cells (Nf1flox/mut; GFAP-Cre mice) results in optic gliomas by 3 months of age in vivo, mice with Nf1 gene inactivation in Olig2+ OPCs (Nf1flox/mut; Olig2-Cre mice) do not form optic gliomas until 6 months of age. These distinct patterns of glioma latency do not reflect differences in the timing or brain location of somatic Nf1 loss. Instead, they most likely reflect the cell of origin, as somatic Nf1 loss in CD133+ neural progenitor/stem cells during late embryogenesis results in optic gliomas at 3 months of age. Collectively, these data demonstrate that the cell of origin dictates the time to tumorigenesis in murine optic glioma

Efficiency of self-cleaning properties in wheat (Triticum aestivum L.)

An experimental study was carried out to assess the efficiency of self-cleaning properties of three wheat cultivars and their potential in the protection against Blumeria graminis f. sp. tritici, a fungus that causes powdery mildew. Leaf samples with intact epicuticular structure were compared to such with wiped wax crystals. Contact angles were determined and the surfaces were subjected to a standardized contamination test with hydrophobic fluorescence powder. Another set of samples was inoculated with conidia of B. graminis and, after various time intervals, exposed to artificial fog or rain. For the intact surfaces of all cultivars contact angles of about 165° were measured. It is therefore suggested that wheat should be termed superhydrophobic. The wiping of the wax crystals led to a significant decrease of contact angles. This fact underlines the importance of surface roughness for achieving extreme water-repellency. In the standardized contamination test significantly more particles remained on the wiped surfaces than on those who had been left intact. This result was ascribed to increased adhesion on the smoothed samples.The inoculation with subsequent precipitation revealed a significantly better removal effect of conidia from intact than from wiped surfaces. This was irrespective of the wheat cultivar. In general, conidia were more effectively removed by rain than by fog. This was probably due to the higher kinetic energy and the greater amount of water when using rain. If fog application was delayed by 3 hours a higher percentage of conidia remained on the surface. As possible causes are discussed increased adhesion by conidia secretions or the development of primary germ tubes.Despite its highly efficient self-cleaning properties proved here, wheat is frequently infected by Blumeria graminis. We conclude that the high water content of the mildew conidia, the ability of Blumeria graminis to germinate at very low humidities and its rapid irreversible adhesion are effective adaptations in order to overcome the barrier of a superhydrophobic self-cleaning surface

Soziale Ungleichheit – Kein Schnee von gestern!

Alle Menschen gehören sozialen Gruppen an. Wir unterscheiden etwa zwischen höheren und niedrigen Schichten, zwischen hoch und gering qualifizierten Personen oder Männern und Frauen. Die Zugehörigkeit zu sozialen Gruppen ist häufig mit sozialen Ungleichheiten verbunden. Was unter sozialer Ungleichheit zu verstehen ist und welche Erklärungen es dafür gibt, ist das Thema dieses Readers. Er versammelt zentrale theoretische Texte zur Sozialstrukturanalyse, die jeder Studierende der Sozialwissenschaften während des Studiums lesen sollte. Nach der Einleitung, in der die wichtigsten Grundbegriffe vorgestellt werden, folgt eine Zusammenstellung der klassischen Theorien zur sozialen Ungleichheit etwa von Davis/Moore, Marx, Weber und Bourdieu. Danach zeichnen unter anderen Texte von Dahrendorf, Schelsky und Beck die Debatten um Klasse und Schicht nach. Es folgen Beiträge zu neueren Theorien und Lebens(ver)laufsansätzen. In seiner knappen und dennoch umfassenden Anlage eignet sich dieser Reader zum Selbststudium und als Lektüregrundlage für Seminare zur Sozialstrukturanalyse

Systems analysis of the transcriptional response of human ileocecal epithelial cells to Clostridium difficile toxins and effects on cell cycle control

<p>Abstract</p> <p>Background</p> <p>Toxins A and B (TcdA and TcdB) are <it>Clostridium difficile</it>'s principal virulence factors, yet the pathways by which they lead to inflammation and severe diarrhea remain unclear. Also, the relative role of either toxin during infection and the differences in their effects across cell lines is still poorly understood. To better understand their effects in a susceptible cell line, we analyzed the transciptome-wide gene expression response of human ileocecal epithelial cells (HCT-8) after 2, 6, and 24 hr of toxin exposure.</p> <p>Results</p> <p>We show that toxins elicit very similar changes in the gene expression of HCT-8 cells, with the TcdB response occurring sooner. The high similarity suggests differences between toxins are due to events beyond transcription of a single cell-type and that their relative potencies during infection may depend on differential effects across cell types within the intestine. We next performed an enrichment analysis to determine biological functions associated with changes in transcription. Differentially expressed genes were associated with response to external stimuli and apoptotic mechanisms and, at 24 hr, were predominately associated with cell-cycle control and DNA replication. To validate our systems approach, we subsequently verified a novel G₁/S and known G₂/M cell-cycle block and increased apoptosis as predicted from our enrichment analysis.</p> <p>Conclusions</p> <p>This study shows a successful example of a workflow deriving novel biological insight from transcriptome-wide gene expression. Importantly, we do not find any significant difference between TcdA and TcdB besides potency or kinetics. The role of each toxin in the inhibition of cell growth and proliferation, an important function of cells in the intestinal epithelium, is characterized.</p

Is an ecosystem services-based approach developed for setting specific protection goals for plant protection products applicable to other chemicals?

Clearly defined protection goals specifying what to protect, where and when, are required for designing scientifically sound risk assessments and effective risk management of chemicals. Environmental protection goals specified in EU legislation are defined in general terms, resulting in uncertainty in how to achieve them. In 2010, the European Food Safety Authority (EFSA) published a framework to identify more specific protection goals based on ecosystem services potentially affected by plant protection products. But how applicable is this framework to chemicals with different emission scenarios and receptor ecosystems? Four case studies used to address this question were: (i) oil refinery waste water exposure in estuarine environments; (ii) oil dispersant exposure in aquatic environments; (iii) down the drain chemicals exposure in a wide range of ecosystems (terrestrial and aquatic); (iv) persistent organic pollutant exposure in remote (pristine) Arctic environments. A four-step process was followed to identify ecosystems and services potentially impacted by chemical emissions and to define specific protection goals. Case studies demonstrated that, in principle, the ecosystem services concept and the EFSA framework can be applied to derive specific protection goals for a broad range of chemical exposure scenarios. By identifying key habitats and ecosystem services of concern, the approach offers the potential for greater spatial and temporal resolution, together with increased environmental relevance, in chemical risk assessments. With modifications including improved clarity on terminology/definitions and further development/refinement of the key concepts, we believe the principles of the EFSA framework could provide a methodical approach to the identification and prioritization of ecosystems, ecosystem services and the service providing units that are most at risk from chemical exposure

Adult Cognitive and Non-cognitive Skills: An Overview of Existing PIAAC Data

As of summer 2019, more than 60 PIAAC datasets from participating countries worldwide were available for research purposes. These datasets can be differentiated, for example, in terms of their accessibility, the extent of the information provided, the population group in focus, and the design of the underlying study. PIAAC Public Use Files, for instance, are freely available and are therefore highly anonymised, whereas PIAAC Scientific Use Files are available only for scientific research purposes and provide access to more detailed variables. The majority of the PIAAC data are available as public use files, but some participating countries (e.g. Germany and the United States) have also made several scientific use files or other extended file versions available to the research community. Some of the available PIAAC datasets focus on specific population groups - for example, the incarcerated adult population in the United States. Regarding the design of the underlying studies, most available datasets are cross-sectional, but some longitudinal data already exist (e.g. PIAAC-L in Germany). The present chapter provides an overview of the structure, accessibility, and use of the PIAAC datasets available worldwide