Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant brain tumor in infants that is characterized by loss of nuclear expression of SMARCB1 or SMARCA4 proteins. Recent studies show that AT/RTs comprise three molecular subgroups, namely AT/RT-TYR, AT/RT-MYC and AT/RT-SHH. The subgroups show distinct expression patterns of genes involved in ciliogenesis, however, little is known about the functional roles of primary cilia in the biology of AT/RT. Here, we show that primary cilia are present across all AT/RT subgroups with specific enrichment in AT/RT-TYR patient samples. Furthermore, we demonstrate that primary ciliogenesis contributes to AT/RT biology in vitro and in vivo. Specifically, we observed a significant decrease in proliferation and clonogenicity following disruption of primary ciliogenesis in AT/RT cell line models. Additionally, apoptosis was significantly increased via the induction of STAT1 and DR5 signaling, as detected by proteogenomic profiling. In a Drosophila model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with more than 20% of flies reaching adulthood. We also found significantly extended survival in an orthotopic xenograft mouse model of AT/RT upon disruption of primary ciliogenesis. Taken together, our findings indicate that primary ciliogenesis or its downstream signaling contributes to the aggressiveness of AT/RT and, therefore, may constitute a novel therapeutic target

Genome sequence analyses of two isolates from the recent Escherichia coli outbreak in Germany reveal the emergence of a new pathotype: Entero-Aggregative-Haemorrhagic Escherichia coli (EAHEC)

The genome sequences of two Escherichia coli O104:H4 strains derived from two different patients of the 2011 German E. coli outbreak were determined. The two analyzed strains were designated E. coli GOS1 and GOS2 (German outbreak strain). Both isolates comprise one chromosome of approximately 5.31 Mbp and two putative plasmids. Comparisons of the 5,217 (GOS1) and 5,224 (GOS2) predicted protein-encoding genes with various E. coli strains, and a multilocus sequence typing analysis revealed that the isolates were most similar to the entero-aggregative E. coli (EAEC) strain 55989. In addition, one of the putative plasmids of the outbreak strain is similar to pAA-type plasmids of EAEC strains, which contain aggregative adhesion fimbrial operons. The second putative plasmid harbors genes for extended-spectrum β-lactamases. This type of plasmid is widely distributed in pathogenic E. coli strains. A significant difference of the E. coli GOS1 and GOS2 genomes to those of EAEC strains is the presence of a prophage encoding the Shiga toxin, which is characteristic for enterohemorrhagic E. coli (EHEC) strains. The unique combination of genomic features of the German outbreak strain, containing characteristics from pathotypes EAEC and EHEC, suggested that it represents a new pathotype Entero-Aggregative-Haemorrhagic Escherichiacoli (EAHEC)

Small-Animal PET Imaging of Amyloid-Beta Plaques with [11C]PiB and Its Multi-Modal Validation in an APP/PS1 Mouse Model of Alzheimer's Disease

In vivo imaging and quantification of amyloid-β plaque (Aβ) burden in small-animal models of Alzheimer's disease (AD) is a valuable tool for translational research such as developing specific imaging markers and monitoring new therapy approaches. Methodological constraints such as image resolution of positron emission tomography (PET) and lack of suitable AD models have limited the feasibility of PET in mice. In this study, we evaluated a feasible protocol for PET imaging of Aβ in mouse brain with [11C]PiB and specific activities commonly used in human studies. In vivo mouse brain MRI for anatomical reference was acquired with a clinical 1.5 T system. A recently characterized APP/PS1 mouse was employed to measure Aβ at different disease stages in homozygous and hemizygous animals. We performed multi-modal cross-validations for the PET results with ex vivo and in vitro methodologies, including regional brain biodistribution, multi-label digital autoradiography, protein quantification with ELISA, fluorescence microscopy, semi-automated histological quantification and radioligand binding assays. Specific [11C]PiB uptake in individual brain regions with Aβ deposition was demonstrated and validated in all animals of the study cohort including homozygous AD animals as young as nine months. Corresponding to the extent of Aβ pathology, old homozygous AD animals (21 months) showed the highest uptake followed by old hemizygous (23 months) and young homozygous mice (9 months). In all AD age groups the cerebellum was shown to be suitable as an intracerebral reference region. PET results were cross-validated and consistent with all applied ex vivo and in vitro methodologies. The results confirm that the experimental setup for non-invasive [11C]PiB imaging of Aβ in the APP/PS1 mice provides a feasible, reproducible and robust protocol for small-animal Aβ imaging. It allows longitudinal imaging studies with follow-up periods of approximately one and a half years and provides a foundation for translational Alzheimer neuroimaging in transgenic mice

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Activation of phonological competitors in visual search

Item does not contain fulltextRecently, Meyer, Belke, Telling and Humphreys (2007) reported that competitor objects with homophonous names (e.g., boy) interfere with identifying a target object (e.g., buoy) in a visual search task, suggesting that an object name's phonology becomes automatically activated even in situations in which participants do not have the intention to speak. The present study explored the generality of this finding by testing a different phonological relation (rhyming object names, e.g., cat-hat) and by varying details of the experimental procedure. Experiment 1 followed the procedure by Meyer et al. Participants were familiarized with target and competitor objects and their names at the beginning of the experiment and the picture of the target object was presented prior to the search display on each trial. In Experiment 2, the picture of the target object presented prior to the search display was replaced by its name. In Experiment 3, participants were not familiarized with target and competitor objects and their names at the beginning of the experiment. A small interference effect from phonologically related competitors was obtained in Experiments 1 and 2 but not in Experiment 3, suggesting that the way the relevant objects are introduced to participants affects the chances of observing an effect from phonologically related competitors. Implications for the information flow in the conceptual-lexical system are discussed

Elongated giant seabed polygons and underlying polygonal faults as indicators of the creep deformation of Pliocene to recent sediments in the Grenada Basin, Caribbean Sea

Based on 2D seismic profiles, multibeam and seabed grab cores acquired during the Garanti cruise in 2017, 1-5 km wide seabed giant polygons were identified in the Grenada basin, covering a total area of ∼55000 km2, which is the largest area of outcropping polygonal faults (PF) ever found on Earth so far. They represent the top part of an active 700-1200 m thick underlying polygonal fault system (PFS) formed due to the volumetric contraction of clay- and smectite-rich sediments, initiated in the sub-surface at the transition between the Early to Middle Pliocene. The short axes of the best-fit ellipses obtained from a graphical centre-to-centre method were interpreted as the local orientation of a preferential contraction perpendicular to the creep deformation of slope sediments. In the North Grenada Basin, the polygons are relatively regular, but their short axes seem to be parallel to a N40°E extension recently evidenced in the forearc, possibly extending in the backarc, but not shown in the study area. They are most probably related to a progressive burial due to a homogeneous subsidence. In the South Grenada Basin, the polygons are more elongated and their axes are progressively rotating southeastward towards the depocenter, indicating a creep deformation towards the center of the basin created by a differential subsidence. Seabed polygons and underlying PF could thus be indicative of the deformation regime of shallow sediments related to main slopes controlled by two different basin architectures