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

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

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)

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

A combined computational and functional approach identifies IGF2BP2 as a driver of chemoresistance in a wide array of pre-clinical models of colorectal cancer

Aim Chemoresistance is a major cause of treatment failure in colorectal cancer (CRC) therapy. In this study, the impact of the IGF2BP family of RNA-binding proteins on CRC chemoresistance was investigated using in silico, in vitro, and in vivo approaches. Methods Gene expression data from a well-characterized cohort and publicly available cross-linking immunoprecipi‑ tation sequencing (CLIP-Seq) data were collected. Resistance to chemotherapeutics was assessed in patient-derived xenografts (PDXs) and patient-derived organoids (PDOs). Functional studies were performed in 2D and 3D cell culture models, including proliferation, spheroid growth, and mitochondrial respiration analyses. Results We identifed IGF2BP2 as the most abundant IGF2BP in primary and metastastatic CRC, correlating with tumor stage in patient samples and tumor growth in PDXs. IGF2BP2 expression in primary tumor tissue was signif‑ cantly associated with resistance to selumetinib, geftinib, and regorafenib in PDOs and to 5-fuorouracil and oxalipl‑ atin in PDX in vivo. IGF2BP2 knockout (KO) HCT116 cells were more susceptible to regorafenib in 2D and to oxaliplatin, selumitinib, and nintedanib in 3D cell culture. Further, a bioinformatic analysis using CLIP data suggested stabiliza‑ tion of target transcripts in primary and metastatic tumors. Measurement of oxygen consumption rate (OCR) and extracellular acidifcation rate (ECAR) revealed a decreased basal OCR and an increase in glycolytic ATP production rate in IGF2BP2 KO. In addition, real-time reverse transcriptase polymerase chain reaction (qPCR) analysis confrmed decreased expression of genes of the respiratory chain complex I, complex IV, and the outer mitochondrial membrane in IGF2BP2 KO cells. Conclusions IGF2BP2 correlates with CRC tumor growth in vivo and promotes chemoresistance by altering mito‑ chondrial respiratory chain metabolism. As a druggable target, IGF2BP2 could be used in future CRC therapy to overcome CRC chemoresistance

Age-related transcriptional changes in gene expression in different organs of mice support the metabolic stability theory of aging

Individual differences in the rate of aging are determined by the efficiency with which an organism transforms resources into metabolic energy thus maintaining the homeostatic condition of its cells and tissues. This observation has been integrated with analytical studies of the metabolic process to derive the following principle: The metabolic stability of regulatory networks, that is the ability of cells to maintain stable concentrations of reactive oxygen species (ROS) and other critical metabolites is the prime determinant of life span. The metabolic stability of a regulatory network is determined by the diversity of the metabolic pathways or the degree of connectivity of genes in the network. These properties can be empirically evaluated in terms of transcriptional changes in gene expression. We use microarrays to investigate the age-dependence of transcriptional changes of genes in the insulin signaling, oxidative phosphorylation and glutathione metabolism pathways in mice. Our studies delineate age and tissue specific patterns of transcriptional changes which are consistent with the metabolic stability–longevity principle. This study, in addition, rejects the free radical hypothesis which postulates that the production rate of ROS, and not its stability, determines life span

Stemming Cancer: Functional Genomics of Cancer Stem Cells in Solid Tumors

Cancer stem cells (CSCs) were discovered about 15 years ago in hematopoietic cancers. Subsequently, cancer stem cells were discovered in various solid tumors. Based on parallels with normal stem cells, a developmental process of cancer stem cells follows paths of organized, hierarchical structure of cells with different degrees of maturity. While some investigators have reported particular markers as identification of cancer stem cells, these markers require further research. In this review, we focus on the functional genomics of cancer stem cells. Functional genomics provides useful information on the signaling pathways which are consecutively activated or inactivated amongst those cells. This information is of particular importance for cancer research and clinical treatment in many respects. (1) Understanding of self-renewal mechanisms crucial to tumor growth. (2) Allow the identification of new, more specific marker for CSCs, and (3) pathways that are suitable as future targets for anti-cancer drugs. This is of particular importance, because today’s chemotherapy targets the proliferating cancer cells sparing the relatively slow dividing cancer stem cells. The first step on this long road therefore is to analyze genome-wide expression-profiles within the same type of cancer and then between different types of cancer, encircling those target genes and pathways, which are specific to these cells

Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells

Genomic instability is a common feature of cancer etiology. This provides an avenue for therapeutic intervention, since cancer cells are more susceptible than normal cells to DNA damaging agents. However, there is growing evidence that the epigenetic mechanisms that impact DNA methylation and histone status also contribute to genomic instability. The DNA damage response, for example, is modulated by the acetylation status of histone and non-histone proteins, and by the opposing activities of histone acetyltransferase and histone deacetylase (HDAC) enzymes. Many HDACs overexpressed in cancer cells have been implicated in protecting such cells from genotoxic insults. Thus, HDAC inhibitors, in addition to unsilencing tumor suppressor genes, also can silence DNA repair pathways, inactivate non-histone proteins that are required for DNA stability, and induce reactive oxygen species and DNA double-strand breaks. This review summarizes how dietary phytochemicals that affect the epigenome also can trigger DNA damage and repair mechanisms. Where such data is available, examples are cited from studies in vitro and in vivo of polyphenols, organosulfur/organoselenium compounds, indoles, sesquiterpene lactones, and miscellaneous agents such as anacardic acid. Finally, by virtue of their genetic and epigenetic mechanisms, cancer chemopreventive agents are being redefined as chemo- or radio-sensitizers. A sustained DNA damage response coupled with insufficient repair may be a pivotal mechanism for apoptosis induction in cancer cells exposed to dietary phytochemicals. Future research, including appropriate clinical investigation, should clarify these emerging concepts in the context of both genetic and epigenetic mechanisms dysregulated in cancer, and the pros and cons of specific dietary intervention strategies