An Investigation in the Measurable Differences between Pitch Perception in the Voice and Pitch Perception of External Sound Sources.

OBJECTIVES: Pitch perception is an important part of accurate singing. Therefore, accurate singing requires the ability to accurately assess the pitch in one's own voice.There are two objectives of this study the first was to investigate whether there is a measurable difference in perceived pitch in one's voice to the pitch one perceives from an external sound source. The second, to measure the effects of occlusion on pitch accuracy over a melodic phrase. STUDY DESIGN: We recruited 16 participants for this study. The study that was designed to investigate the perceptual difference was split into two parts. The first is a one-to-one pitch matching test where they would recreate a pitch with singing and matching external pitches. The second was singing the familiar song 'Happy Birthday' which was used to measure pitch accuracy over a melodic phrase and to measure the effects of occlusion on pitch accuracy while singing. METHODS: The one-to-one study involved singing back a series of 5 notes to a set vowel which were the same 5 notes used when matching them to a series of possible pitches on the button test. The melodic test was to sing 'Happy Birthday' 3 times, the first normally, the second wearing headphones to occlude the ear to reduce air conductive hearing and the third time with white noise to mask all hearing. RESULTS: The results showed a higher accuracy of pitch matching with external sounds over using their voice, and some form of occlusion (wearing headphones or headphones with white noise) showed the version with higher pitch accuracy. CONCLUSIONS: The results of this study showed that there was improved pitch accuracy when comparing two external sounds in pitch and when singing occlusion of some form improved pitch accuracy. This could suggest a difference when recreating pitch between the voice and matching external sound sources. Furthermore, with the improvements shown from occluding the ears, it could further suggest a difference in pitch perception abilities between the voice and external sound sources. This could have implications of improving pitch accuracy in a studio environment.

Fragment-Derived Selective Inhibitors of Dual-Specificity Kinases DYRK1A and DYRK1B.

The serine/threonine kinase DYRK1A has been implicated in regulation of a variety of cellular processes associated with cancer progression, including cell cycle control, DNA damage repair, protection from apoptosis, cell differentiation, and metastasis. In addition, elevated-level DYRK1A activity has been associated with increased severity of symptoms in Down's syndrome. A selective inhibitor of DYRK1A could therefore be of therapeutic benefit. We have used fragment and structure-based discovery methods to identify a highly selective, well-tolerated, brain-penetrant DYRK1A inhibitor which showed in vivo activity in a tumor model. The inhibitor provides a useful tool compound for further exploration of the effect of DYRK1A inhibition in models of disease.

Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors.

The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma.

Specific oncogenic activity of the Src-family tyrosine kinase c-Yes in colon carcinoma cells.

c-Yes, a member of the Src tyrosine kinase family, is found highly activated in colon carcinoma but its importance relative to c-Src has remained unclear. Here we show that, in HT29 colon carcinoma cells, silencing of c-Yes, but not of c-Src, selectively leads to an increase of cell clustering associated with a localisation of ß-catenin at cell membranes and a reduction of expression of ß-catenin target genes. c-Yes silencing induced an increase in apoptosis, inhibition of growth in soft-agar and in mouse xenografts, inhibition of cell migration and loss of the capacity to generate liver metastases in mice. Re-introduction of c-Yes, but not c -Src, restores transforming properties of c-Yes depleted cells. Moreover, we found that c-Yes kinase activity is required for its role in ß-catenin localisation and growth in soft agar, whereas kinase activity is dispensable for its role in cell migration. We conclude that c-Yes regulates specific oncogenic signalling pathways important for colon cancer progression that is not shared with c-Src.

A novel non-phosphorylated potential antitumoral peptide inhibits STAT3 biological activity.

STAT3 (Signal Transducer and Activator of Transcription 3) is an SH2 (Src Homology 2)-domain containing transcription factor that plays a key role in cancer, by regulating as a dimer the expression of genes implicated in the main processes of the tumorigenesis. Therefore, STAT3 and more particularly its dimeric form has emerged as promising targets for cancer therapy. STAT3 dimerization occurs through reciprocal interaction between the SH2 domain of one monomer and the phosphorylated tyrosine residue of a second one. One strategy to design small inhibitors of STAT3 dimerization, consists in using phosphotyrosine-based peptidomimetics targeted to the SH2 domain. We have tested whether a high affinity phosphotyrosyl peptide ligand P1 (AYRNRY( *)RRQYRY) (K(d) = 0.34 microM), issued from combinatorial chemistry, could inhibit STAT3 dimerization and biological activity. This ligand was found to disrupt dimerization with an IC(50) of 9 microM. Further biological evaluation using a STAT3-dependent cell line demonstrated that its Antennapedia-vectorized form P1a interacted with STAT3 within the cell, resulting in a significant effect on cell proliferation and expression of cell cycle and apoptosis regulators controlled by STAT3. More importantly, these studies identified unexpectedly a non-phosphorylated vectorized peptide P2a, as another potent inhibitor of STAT3 biological activity and thus give further insight for the development of novel inhibitors.

Synthesis, in vitro antiproliferative activities, and Chk1 inhibitory properties of indolylpyrazolones and indolylpyridazinedione.

The synthesis of 5-indolylpyrazol-3-one, 4-indolylpyrazol-3-one and 4-indolyl-pyridazin-3,6-dione is reported. Their Chk1 inhibitory properties have been evaluated and their in vitro antiproliferative activities toward three tumor cell lines: murine leukemia L1210, human colon carcinoma HT29 and HCT116 have been determined. 4-Indolyl-pyridazin-3,6-dione is inactive against Chk1 and exhibits weak cytotoxicities toward the tumor cell lines tested. The IC(50) values toward Chk1 of the two indolylpyrazolones are identical and are in the micromolar range, but the cytotoxicities of 4-indolylpyrazol-3-one are significantly stronger than those of 5-indolylpyrazol-3-one. Since 4-indolylpyrazol-3-one and 5-indolylpyrazol-3-one can present several conformers and tautomeric forms, molecular modelling in the ATP binding site of Chk1 has been carried out to investigate which form could induce the best stabilization in the active site of the enzyme. To get an insight into the kinase selectivity of these compounds, their inhibitory activities toward Src kinase were evaluated.

Synthesis and primary cytotoxicity evaluation of arylmethylenenaphthofuranones derivatives.

New series of 2(or 3)-arylmethylenenaphtho[2,1-b]furan-3(or 2)-ones were synthesized, characterized and tested for anticancer properties in vitro. The target compounds were prepared by Knoevenagel coupling between the naphthofuranones 3, 28-30 and formyl derivatives. 2-(4-Oxo-1-benzopyran-3-ylmethylene)naphtho[2,1-b]furan-3-one 36 was the most active compound (IC50 (L1210) = 1.6 microM). These compounds were also evaluated, in an independent manner, as inhibitors of Src protein tyrosine kinase, but only minor activity was observed.