Noncommutative solitons on Kahler manifolds

We construct a new class of scalar noncommutative multi-solitons on an arbitrary Kahler manifold by using Berezin's geometric approach to quantization and its generalization to deformation quantization. We analyze the stability condition which arises from the leading 1/hbar correction to the soliton energy and for homogeneous Kahler manifolds obtain that the stable solitons are given in terms of generalized coherent states. We apply this general formalism to a number of examples, which include the sphere, hyperbolic plane, torus and general symmetric bounded domains. As a general feature we notice that on homogeneous manifolds of positive curvature, solitons tend to attract each other, while if the curvature is negative they will repel each other. Applications of these results are discussed.Comment: 26 pages, 3 figures, harvmac; references adde

Suppression of Mcl-1 via RNA interference sensitizes human hepatocellular carcinoma cells towards apoptosis induction

BACKGROUND: Hepatocelluar carcinoma (HCC) is one of the most common cancers worldwide and a major cause of cancer-related mortality. HCC is highly resistant to currently available chemotherapeutic drugs. Defects in apoptosis signaling contribute to this resistance. Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 protein family which interferes with mitochondrial activation. In a previous study we have shown that Mcl-1 is highly expressed in tissues of human HCC. In this study, we manipulated expression of the Mcl-1 protein in HCC cells by RNA interference and analyzed its impact on apoptosis sensitivity of HCC cells in vitro. METHODS: RNA interference was performed by transfecting siRNA to specifically knock down Mcl-1 expression in HCC cells. Mcl-1 expression was measured by quantitative real-time PCR and Western blot. Induction of apoptosis and caspase activity after treatment with chemotherapeutic drugs and different targeted therapies were measured by flow cytometry and fluorometric analysis, respectively. RESULTS: Here we demonstrate that Mcl-1 expressing HCC cell lines show low sensitivity towards treatment with a panel of chemotherapeutic drugs. However, treatment with the anthracycline derivative epirubicin resulted in comparatively high apoptosis rates in HCC cells. Inhibition of the kinase PI3K significantly increased apoptosis induction by chemotherapy. RNA interference efficiently downregulated Mcl-1 expression in HCC cells. Mcl-1 downregulation sensitized HCC cells to different chemotherapeutic agents. Sensitization was accompanied by profound activation of caspase-3 and -9. In addition, Mcl-1 downregulation also increased apoptosis rates after treatment with PI3K inhibitors and, to a lower extent, after treatment with mTOR, Raf I and VEGF/PDGF kinase inhibitors. TRAIL-induced apoptosis did not markedly respond to Mcl-1 knockdown. Additionally, knockdown of Mcl-1 efficiently enhanced apoptosis sensitivity towards combined treatment modalities: Mcl-1 knockdown significantly augmented apoptosis sensitivity of HCC cells towards chemotherapy combined with PI3K inhibition. CONCLUSION: Our data suggest that specific downregulation of Mcl-1 by RNA interference is a promising approach to sensitize HCC cells towards chemotherapy and molecularly targeted therapies

An acetylation-mediated chromatin switch governs H3K4 methylation read-write capability

In nucleosomes, histone N-terminal tails exist in dynamic equilibrium between free/accessible and collapsed/DNA-bound states. The latter state is expected to impact histone N-termini availability to the epigenetic machinery. Notably, H3 tail acetylation (e.g. K9ac, K14ac, K18ac) is linked to increased H3K4me3 engagement by the BPTF PHD finger, but it is unknown if this mechanism has a broader extension. Here, we show that H3 tail acetylation promotes nucleosomal accessibility to other H3K4 methyl readers, and importantly, extends to H3K4 writers, notably methyltransferase MLL1. This regulation is not observed on peptide substrates yet occurs on the cis H3 tail, as determined with fully-defined heterotypic nucleosomes. In vivo, H3 tail acetylation is directly and dynamically coupled with cis H3K4 methylation levels. Together, these observations reveal an acetylation ‘chromatin switch’ on the H3 tail that modulates read-write accessibility in nucleosomes and resolves the long-standing question of why H3K4me3 levels are coupled with H3 acetylation

On-entry assessment of school competencies and academic achievement: a comparison between Slovenia and Germany

The foundation of school success is laid early in children\u27s lives. Consequently, assessments of academic precursors may help to identify children in need of additional support. Such early assessments could also be interesting from an international perspective when educational systems are compared. This analysis is used to inform on the comparability of Slovenian and German versions of the English on-school-entry assessment tool "Performance Indicators in Primary School" (PIPS; Tymms and Albone 2002). PIPS was also used to predict later academic achievement in the two national samples. The German sample consisted of 468 children with a mean age of about 6;6 years at school entry (48.7 % girls). In Slovenia, 328 children (49 % girls) were assessed (mean age of about 6;3 years at school entry). Multi-group confirmatory factor analyses for PIPS did not support weak measurement invariance. However, results indicated that the number of factors as well as the pattern of loadings seems to be comparable. Further research is needed to examine in which respects PIPS might work as a tool for international comparisons. Structural equation modelling indicated that PIPS can be used as a predictor of academic achievement and that overall academic achievement could be predicted best by early numeracy. PIPS measures of literacy and numeracy skills were specific and significant predictors of children\u27s later language and math achievement in grade 1. (DIPF/Orig.

Nucleosome conformation dictates the histone code

Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has been proposed that these PTMs form localized ‘codes’ that are read by specialized regions (reader domains) in chromatin-associated proteins (CAPs) to regulate downstream function. Substantial effort has been made to define [CAP: histone PTM] specificities, and thus decipher the histone code and guide epigenetic therapies. However, this has largely been done using the reductive approach of isolated reader domains and histone peptides, which cannot account for any higher-order factors. Here, we show that the [BPTF PHD finger and bromodomain: histone PTM] interaction is dependent on nucleosome context. The tandem reader selectively associates with nucleosomal H3K4me3 and H3K14ac or H3K18ac, a combinatorial engagement that despite being in cis is not predicted by peptides. This in vitro specificity of the BPTF tandem reader for PTM-defined nucleosomes is recapitulated in a cellular context. We propose that regulatable histone tail accessibility and its impact on the binding potential of reader domains necessitates we refine the ‘histone code’ concept and interrogate it at the nucleosome level