Three Landscapes For Orchestra

Three Landscapes for Orchestra is a three-movement orchestral suite, with music composed based on corresponding artworks. Each movement is inspired by an abstract painting by Samantha Keely Smith. Stylistically, the focus of these pieces is on color and mood, and the emulation of the atmosphere and emotions elicited by the source material. As such, the music either takes a literal approach to musical representations of certain aesthetic features, or an abstract approach wherein the music conveys a similar emotion or mood as the painting. Musically, the approach taken is an amalgamation of Late-Romantic, twentieth century, and twelve-tone styles, with influences from composers such as Gustav Mahler, Benjamin Britten, John Adams, and Arnold Schoenberg

Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis

Ras is phosphorylated on a conserved tyrosine at position 32 within the switch I region via Src kinase. This phosphorylation inhibits the binding of effector Raf while promoting the engagement of GTPase-activating protein (GAP) and GTP hydrolysis. Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. In comparison to normal astrocytes, SHP2 activity is elevated in astrocytes isolated from glioblastoma multiforme (GBM)-prone H-Ras(12V) knock-in mice as well as in glioma cell lines and patient-derived GBM specimens exhibiting hyperactive Ras. Pharmacologic inhibition of SHP2 activity attenuates cell proliferation, soft-agar colony formation and orthotopic GBM growth in NOD/SCID mice and decelerates the progression of low-grade astrocytoma to GBM in a spontaneous transgenic glioma mouse model. These results identify SHP2 as a direct activator of Ras and a potential therapeutic target for cancers driven by a previously 'undruggable' oncogenic or hyperactive Ras

Global analysis of SUMO chain function reveals multiple roles in chromatin regulation.

Like ubiquitin, the small ubiquitin-related modifier (SUMO) proteins can form oligomeric chains, but the biological functions of these superstructures are not well understood. Here, we created mutant yeast strains unable to synthesize SUMO chains (smt3(allR)) and subjected them to high-content microscopic screening, synthetic genetic array (SGA) analysis, and high-density transcript profiling to perform the first global analysis of SUMO chain function. This comprehensive assessment identified 144 proteins with altered localization or intensity in smt3(allR) cells, 149 synthetic genetic interactions, and 225 mRNA transcripts (primarily consisting of stress- and nutrient-response genes) that displayed a \u3e1.5-fold increase in expression levels. This information-rich resource strongly implicates SUMO chains in the regulation of chromatin. Indeed, using several different approaches, we demonstrate that SUMO chains are required for the maintenance of normal higher-order chromatin structure and transcriptional repression of environmental stress response genes in budding yeast

The maintenance of centriole appendages and motile cilia basal body anchoring relies on TBCCD1

Centrosomes are organelles consisting of two structurally and functionally distinct centrioles, with the mother centriole having complex distal (DA) and subdistal appendages (SDA). Despite their importance, how appendages are assembled and maintained remains unclear. This study investigated human TBCCD1, a centrosomal protein essential for centrosome positioning, to uncover its localization and role at centrioles. We found that TBCCD1 localizes at both proximal and distal regions of the two centrioles, forming a complex structure spanning from SDA to DA and extending inside and outside the centriole lumen. TBCCD1 depletion caused centrosome mispositioning, which was partially rescued by taxol, and the loss of microtubules (MTs) anchored to centrosomes. TBCCD1 depletion also reduced levels of SDA proteins involved in MT anchoring such as Centriolin/CEP110, Ninein, and CEP170. Additionally, TBCCD1 was essential for the correct positioning of motile cilia basal bodies and associated structures in Paramecium. This study reveals that TBCCD1 is an evolutionarily conserved protein essential for centriole and basal body localization and appendage assembly and maintenance. A BioID screening also linked TBCCD1 to ciliopathy-associated protein networks.info:eu-repo/semantics/publishedVersio

Analysis of the Saccharomyces cerevisiae proteome with PeptideAtlas

We present the Saccharomyces cerevisiae PeptideAtlas composed from 47 diverse experiments and 4.9 million tandem mass spectra. The observed peptides align to 61% of Saccharomyces Genome Database (SGD) open reading frames (ORFs), 49% of the uncharacterized SGD ORFs, 54% of S. cerevisiae ORFs with a Gene Ontology annotation of 'molecular function unknown', and 76% of ORFs with Gene names. We highlight the use of this resource for data mining, construction of high quality lists for targeted proteomics, validation of proteins, and software development

Integrating high-throughput genetic interaction mapping and high-content screening to explore yeast spindle morphogenesis

A combination of yeast genetics, synthetic genetic array analysis, and high-throughput screening reveals that sumoylation of Mcm21p promotes disassembly of the mitotic spindle

drr-2 encodes an eIF4H that acts downstream of TOR in diet-restriction-induced longevity of C. elegans

Dietary restriction (DR) results in a robust increase in lifespan while maintaining the physiology of much younger animals in a wide range of species. Here, we examine the role of drr-2 , a DR-responsive gene recently identified, in determining the longevity of Caenorhabditis elegans . Inhibition of drr-2 has been shown to increase longevity. However, the molecular mechanisms by which drr-2 influences longevity remain unknown. We report here that drr-2 encodes an ortholog of human eukaryotic translation initiation factor 4H (eIF4H), whose function is to mediate the initiation step of mRNA translation. The molecular function of DRR-2 is validated by the association of DRR-2 with polysomes and by the decreased rate of protein synthesis observed in drr-2 knockdown animals. Previous studies have also suggested that DR might trigger a regulated reduction in drr-2 expression to initiate its longevity response. By examining the effect of increasing drr-2 expression on DR animals, we find that drr-2 is essential for a large portion of the longevity response to DR. The nutrient-sensing target of rapamycin (TOR) pathway has been shown to mediate the longevity effects of DR in C. elegans . Results from our genetic analyses suggest that eIF4H/DRR-2 functions downstream of TOR, but in parallel to the S6K/PHA-4 pathway to mediate the lifespan effects of DR. Together, our findings reveal an important role for eIF4H/drr-2 in the TOR-mediated longevity responses to DR.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79256/1/ACEL_580_sm_tableS1-3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/79256/2/j.1474-9726.2010.00580.x.pd

Unraveling the role of TBCCD1 protein on cell size control: the regulation of cytoskeleton dynamics and cell junctions

During their lifetime most cells maintain their size. There is increasing evidence showing that this process may be dynamic and that cells can adapt their size in response to external signals and changes in the environment [1], which strongly suggests that cell size is regulated. Both Hippo and IGF/PI3K/AKT/mTORC1 pathways have been described as being involved in cell size/growth control [1]. Interestingly, these pathways are in a cross-talk with others involved and/or dependent on cellular polarity [2]. Our group characterized a centrosomal protein, TBCCD1 (TBCC domain – containing human protein 1) which, when depleted in human retinal epithelial (RPE–1) cells, leads to an abnormal localization of the centrosome at the cell periphery accompanied by the fragmentation of the Golgi apparatus, resulting in the disruption of the intrinsic cell polarity axis “Nucleus-Centrosome-Golgi Apparatus”. Moreover, TBCCD1 – depleted cells are larger, slower and have a lower efficiency in primary cilia assembly than control cells [3]. We identified the TBCCD1 interactome that showed that most of its partners are involved in cell polarity. Furthermore, most of them participate in the formation/maintenance of cell junctions, which are main regulators of cell polarity in epithelia and are upstream of pathways, like Hippo pathway. We also observed that TBCCD1 overexpression affects tubulin acetylation, which supports our results showing that some of the partners are involved in the regulation of the cytoskeleton dynamics, which may affect cell size. Therefore, it is tempting to hypothesize that the mechanisms involved in the establishment of intrinsic cell polarity may also directly/indirectly participate in the regulation of cell size.info:eu-repo/semantics/publishedVersio

The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability

Neurolysin (NLN) is a zinc metallopeptidase whose mitochondrial function is unclear. We found that NLN was overexpressed in almost half of patients with acute myeloid leukemia (AML), and inhibition of NLN was selectively cytotoxic to AML cells and stem cells while sparing normal hematopoietic cells. Mechanistically, NLN interacted with the mitochondrial respiratory chain. Genetic and chemical inhibition of NLN impaired oxidative metabolism and disrupted the formation of respiratory chain supercomplexes (RCS). Furthermore, NLN interacted with the known RCS regulator, LETM1, and inhibition of NLN disrupted LETM1 complex formation. RCS were increased in patients with AML and positively correlated with NLN expression. These findings demonstrate that inhibiting RCS formation selectively targets AML cells and stem cells and highlights the therapeutic potential of pharmacologically targeting NLN in AML