Production and comprehension of prosodic boundary marking in persons with unilateral brain lesions

Purpose: Persons with unilateral brain damage in the right hemisphere (RH) or left hemisphere (LH) show limitations in processing linguistic prosody, with yet inconclusive results on their ability to process prosodically marked structural boundaries for syntactic ambiguity resolution. We aimed at systematically investigating production and comprehension of three prosodic cues (f 0 range, final lengthening, and pause) at structural boundaries in coordinate sequences in participants with right hemisphere brain damage (RHDP) and participants with left hemisphere brain damage (LHDP).Method: Twenty RHDP and 15 LHDP participated in our study. Comprehension experiment: Participants and a control group listened to coordinate name sequences with internal grouping by a prosodically marked structural boundary (grouped condition, e.g., "(Gabi und Leni) # und Nina") or without internal grouping (ungrouped condition, e.g., "Gabi und Leni und Nina") and had to identify the target condition. The strength and combinations of prosodic cues in the stimuli were manipulated. Production experiment: Participants were asked to produce coordinate sequences in the two conditions (grouped, ungrouped) in two different tasks: a Reading Aloud and a Repetition experiment. Accuracy of participants' productions was subsequently assessed in a rating study and productions were analyzed with respect to use of prosodic cues.Results: In the Comprehension experiment, RHDP and LHDP had overall lower identification accuracies than unimpaired control participants and LHDP were found to have particular problems with boundary identification when the pause cue was reduced. In production, LHDP and RHDP employed all three prosodic cues for boundary marking, but struggled to clearly mark prosodic boundaries in 28% of all productions. Both groups showed better performance in reading aloud than in repetition. LHDP relied more on using f 0 range and pause duration to prosodically mark structural boundaries, whereas RHDP employed final lengthening more vigorously than LHDP in reading aloud.Conclusions: We conclude that processing of linguistic prosody is affected in RHDP and LHDP, but not completely impaired. Therefore, prosody can serve as a relevant communicative resource. However, it should also be considered as a target area for assessment and treatment in both groups

The Use of Sodium Fluoride for Worming Hogs.

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The role of the cancer stem cell marker CD271 in DNA damage response and drug resistance of melanoma cells

Several lines of evidence have suggested that stemness and acquired resistance to targeted inhibitors or chemotherapeutics are mechanistically linked. Here we observed high cell surface and total levels of nerve growth factor receptor/CD271, a marker of melanoma-initiating cells, in sub-populations of chemoresistant cell lines. CD271 expression was increased in drug-sensitive cells but not resistant cells in response to DNA-damaging chemotherapeutics etoposide, fotemustine and cisplatin. Comparative analysis of melanoma cells engineered to stably express CD271 or a targeting short hairpin RNA by expression profiling provided numerous genes regulated in a CD271-dependent manner. In-depth analysis of CD271-responsive genes uncovered the association of CD271 with regulation of DNA repair components. In addition, gene set enrichment analysis revealed enrichment of CD271-responsive genes in drug- resistant cells, among them DNA repair components. Moreover, our comparative screen identified the fibroblast growth factor 13 (FGF13) as a target of CD271, highly expressed in chemoresistant cells. Further we show that levels of CD271 determine drug response. Knock-down of CD271 in fotemustine-resistant cells decreased expression of FGF13 and at least partly restored sensitivity to fotemustine. Together, we demonstrate that expression of CD271 is responsible for genes associated with DNA repair and drug response. Further, we identified 110 CD271-responsive genes predominantly expressed in melanoma metastases, among them were NEK2, TOP2A and RAD51AP1 as potential drivers of melanoma metastasis. In addition, we provide mechanistic insight in the regulation of CD271 in response to drugs. We found that CD271 is potentially regulated by p53 and in turn is needed for a proper p53-dependent response to DNA-damaging drugs. In summary, we provide for the first time insight in a CD271-associated signaling network connecting CD271 with DNA repair, drug response and metastasis

Cancer stem cells in melanoma

The identification of cancer stem cells in various malignancies led to the hypothesis that these cells have the exclusive ability of self-renewal, contribute to the plasticity of the tumours and may be the cause for ineffective cancer therapies. Several markers of melanoma stem cells have been described in recent studies including CD133, CD166, Nestin and BMI-1. Further studies are necessary to identify, better define and understand the origin and function of cancer stem cells. If confirmed that cancer stem cells play an important role in malignancy, therapeutic strategies may need to be redirected towards these cells to circumvent the failure of conventional therapies

Molecular characterization of signalling pathways in cancer stem cells

To avoid artefacts introduced by culturing cells for extended periods of time, it is crucial to use low-passage patient-derived tumour cells. The ability to enrich, isolate and assay sub-populations of cells that behave as cancer stem cells (CSCs) from these primary cell lines is essential before performing characterizations such as gene-expression profiling. We have isolated cells from glioblastomas which show characteristics of CSCs. Although glioblastomas contain only a relatively small amount of putative CSCs, these cells express many genes which seem to be worthy targets for future therapies

Antiferromagnetic interlayer exchange coupling across an amorphous metallic spacer layer

By means of magneto-optical Kerr effect we observe for the first time antiferromagnetic coupling between ferromagnetic layers across an amorphous metallic spacer layer. Biquadratic coupling occurs at the transition from a ferromagnetically to an antiferromagnetically coupled region. Scanning tunneling microscopy images of all involved layers are used to extract thickness fluctuations and to verify the amorphous state of the spacer. The observed antiferromagnetic coupling behavior is explained by RKKY interaction taking into account the amorphous structure of the spacer material.Comment: Typset using RevTex, 4 pages with 4 figures (.eps

Augmented reality meeting table: a novel multi-user interface for architectural design

Immersive virtual environments have received widespread attention as providing possible replacements for the media and systems that designers traditionally use, as well as, more generally, in providing support for collaborative work. Relatively little attention has been given to date however to the problem of how to merge immersive virtual environments into real world work settings, and so to add to the media at the disposal of the designer and the design team, rather than to replace it. In this paper we report on a research project in which optical see-through augmented reality displays have been developed together with prototype decision support software for architectural and urban design. We suggest that a critical characteristic of multi user augmented reality is its ability to generate visualisations from a first person perspective in which the scale of rendition of the design model follows many of the conventions that designers are used to. Different scales of model appear to allow designers to focus on different aspects of the design under consideration. Augmenting the scene with simulations of pedestrian movement appears to assist both in scale recognition, and in moving from a first person to a third person understanding of the design. This research project is funded by the European Commission IST program (IST-2000-28559)

Reflection of neuroblastoma intratumor heterogeneity in the new OHC-NB1 disease model

Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80-540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with 4 clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system

A RAS-independent biomarker panel to reliably predict response to MEK inhibition in colorectal cancer

BACKGROUND: In colorectal cancer (CRC), mutations of genes associated with the TGF-β/BMP signaling pathway, particularly affecting SMAD4, are known to correlate with decreased overall survival and it is assumed that this signaling axis plays a key role in chemoresistance. METHODS: Using CRISPR technology on syngeneic patient-derived organoids (PDOs), we investigated the role of a loss-of-function of SMAD4 in sensitivity to MEK-inhibitors. CRISPR-engineered SMAD4(R361H) PDOs were subjected to drug screening, RNA-Sequencing, and multiplex protein profiling (DigiWest(R)). Initial observations were validated on an additional set of 62 PDOs with known mutational status. RESULTS: We show that loss-of-function of SMAD4 renders PDOs sensitive to MEK-inhibitors. Multiomics analyses indicate that disruption of the BMP branch within the TGF-β/BMP pathway is the pivotal mechanism of increased drug sensitivity. Further investigation led to the identification of the SFAB-signature (SMAD4, FBXW7, ARID1A, or BMPR2), coherently predicting sensitivity towards MEK-inhibitors, independent of both RAS and BRAF status. CONCLUSION: We identified a novel mutational signature that reliably predicts sensitivity towards MEK-inhibitors, regardless of the RAS and BRAF status. This finding poses a significant step towards better-tailored cancer therapies guided by the use of molecular biomarkers