A word by any other intonation: fMRI evidence for implicit memory traces for pitch contours of spoken words in adult brains.

OBJECTIVES: Intonation may serve as a cue for facilitated recognition and processing of spoken words and it has been suggested that the pitch contour of spoken words is implicitly remembered. Thus, using the repetition suppression (RS) effect of BOLD-fMRI signals, we tested whether the same spoken words are differentially processed in language and auditory brain areas depending on whether or not they retain an arbitrary intonation pattern. EXPERIMENTAL DESIGN: Words were presented repeatedly in three blocks for passive and active listening tasks. There were three prosodic conditions in each of which a different set of words was used and specific task-irrelevant intonation changes were applied: (i) All words presented in a set flat monotonous pitch contour (ii) Each word had an arbitrary pitch contour that was set throughout the three repetitions. (iii) Each word had a different arbitrary pitch contour in each of its repetition. PRINCIPAL FINDINGS: The repeated presentations of words with a set pitch contour, resulted in robust behavioral priming effects as well as in significant RS of the BOLD signals in primary auditory cortex (BA 41), temporal areas (BA 21 22) bilaterally and in Broca's area. However, changing the intonation of the same words on each successive repetition resulted in reduced behavioral priming and the abolition of RS effects. CONCLUSIONS: Intonation patterns are retained in memory even when the intonation is task-irrelevant. Implicit memory traces for the pitch contour of spoken words were reflected in facilitated neuronal processing in auditory and language associated areas. Thus, the results lend support for the notion that prosody and specifically pitch contour is strongly associated with the memory representation of spoken words

ROI analysis in STG-MTG in the two semantic categorization tasks, pooled together.

<p>Contrast values (CV) and SEM in the three repeating blocks of each of the three prosodic modulations (M, P, and V). (<b>A</b>) Left STG- MTG; (<b>B</b>) Right STG-MTG. Repetition suppression (RS) effects were found in the M and P modulations (*p<0.016, Bonferroni test for multiple comparisons).</p

Regions of activation induced by the semantic categorization tasks in all three prosodic modulations.

<p>(<b>A</b>) High threshold Map: p<0.05; FWE corrected, Extent threshold: k = 27 voxels. (<b>B</b>) Low threshold Map: p<0.001, non -corrected; Extent threshold: k = 27 voxels.</p

ROI analysis, left and right STG-MTG in the three repeating mini-blocks of the non-semantic task.

<p>Contrast values (CV) and SEM are shown. (A) During C modulation - constant pitch contour for all repetitions of the same word; (B) during V modulation - variable pitch contour between repetitions of the same word. Repetition suppression (RS) effect was found only in the C modulation (*p<0.016, Bonferroni test for multiple comparisons.</p

ROI analysis, left and right A1 in the three repeating mini-blocks of the non-semantic task Contrast values (CV) and SEM are shown.

<p>(A) during C modulation - single, constant pitch contour for all repetitions of the same word; (B) during V modulation - variable pitch contour between repetitions of the same word. Repetition suppression (RS) effect was found only in the C modulation (*p<0.016, Bonferroni test for multiple comparisons).</p

Breast-Specific Epigenetic Regulation of DeltaNp73 and Its Role in DNA-Damage-Response of BRCA1-Mutated Human Mammary Epithelial Cells

The function of BRCA1/2 proteins is essential for maintaining genomic integrity in all cell types. However, why women who carry deleterious germline mutations in BRCA face an extremely high risk of developing breast and ovarian cancers specifically has remained an enigma. We propose that breast-specific epigenetic modifications, which regulate tissue differentiation, could team up with BRCA deficiency and affect tissue susceptibility to cancer. In earlier work, we compared genome-wide methylation profiles of various normal epithelial tissues and identified breast-specific methylated gene promoter regions. Here, we focused on deltaNp73, the truncated isoform of p73, which possesses antiapoptotic and pro-oncogenic functions. We showed that the promoter of deltaNp73 is unmethylated in normal human breast epithelium and methylated in various other normal epithelial tissues and cell types. Accordingly, deltaNp73 was markedly induced by DNA damage in human mammary epithelial cells (HMECs) but not in other epithelial cell types. Moreover, the induction of deltaNp73 protected HMECs from DNA damage-induced cell death, and this effect was more substantial in HMECs from BRCA1 mutation carriers. Notably, when BRCA1 was knocked down in MCF10A, a non-malignant breast epithelial cell line, both deltaNp73 induction and its protective effect from cell death were augmented upon DNA damage. Interestingly, deltaNp73 induction also resulted in inhibition of BRCA1 and BRCA2 expression following DNA damage. In conclusion, breast-specific induction of deltaNp73 promotes survival of BRCA1-deficient mammary epithelial cells upon DNA damage. This might result in the accumulation of genomic alterations and allow the outgrowth of breast cancers. These findings indicate deltaNp73 as a potential modifier of breast cancer susceptibility in BRCA1 mutation carriers and may stimulate novel strategies of prevention and treatment for these high-risk women