Complex-based analysis of dysregulated cellular processes in cancer

Background: Differential expression analysis of (individual) genes is often used to study their roles in diseases. However, diseases such as cancer are a result of the combined effect of multiple genes. Gene products such as proteins seldom act in isolation, but instead constitute stable multi-protein complexes performing dedicated functions. Therefore, complexes aggregate the effect of individual genes (proteins) and can be used to gain a better understanding of cancer mechanisms. Here, we observe that complexes show considerable changes in their expression, in turn directed by the concerted action of transcription factors (TFs), across cancer conditions. We seek to gain novel insights into cancer mechanisms through a systematic analysis of complexes and their transcriptional regulation. Results: We integrated large-scale protein-interaction (PPI) and gene-expression datasets to identify complexes that exhibit significant changes in their expression across different conditions in cancer. We devised a log-linear model to relate these changes to the differential regulation of complexes by TFs. The application of our model on two case studies involving pancreatic and familial breast tumour conditions revealed: (i) complexes in core cellular processes, especially those responsible for maintaining genome stability and cell proliferation (e.g. DNA damage repair and cell cycle) show considerable changes in expression; (ii) these changes include decrease and countering increase for different sets of complexes indicative of compensatory mechanisms coming into play in tumours; and (iii) TFs work in cooperative and counteractive ways to regulate these mechanisms. Such aberrant complexes and their regulating TFs play vital roles in the initiation and progression of cancer.Comment: 22 pages, BMC Systems Biolog

Magnetic induction mapping of magnetite chains in magnetotactic bacteria at room temperature and close to the Verwey transition using electron holography

Off-axis electron holography in the transmission electron microscope is used to record magnetic induction maps of closely spaced magnetite crystals in magnetotactic bacteria at room temperature and after cooling the sample using liquid nitrogen. The magnetic microstructure is related to the morphology and crystallography of the particles, and to interparticle interactions. At room temperature, the magnetic signal is dominated by interactions and shape anisotropy, with highly parallel and straight field lines following the axis of each chain of crystals closely. In contrast, at low temperature the magnetic induction undulates along the length of the chain. This behaviour may result from a competition between interparticle interactions and an easy axis of magnetisation that is no longer parallel to the chain axis. The quantitative nature of electron holography also allows the change in magnetisation in the crystals with temperature to be measured

The detection and photometric redshift determination of distant galaxies using SIRTF's Infrared Array Camera

We investigate the ability of the Space Infrared Telescope Facility's Infrared Array Camera to detect distant (z ~ 3)galaxies and measure their photometric redshifts. Our analysis shows that changing the original long wavelength filter specifications provides significant improvements in performance in this and other areas.Comment: 28 pages incl 12 figures; to appear in June 1999 PASP. Fig.12 replaced with corrected versio

Nanopore direct RNA sequencing maps the complexity of Arabidopsis mRNA processing and m6A modification

Understanding genome organization and gene regulation requires insight into RNA transcription, processing and modification. We adapted nanopore direct RNA sequencing to examine RNA from a wild-type accession of the model plant Arabidopsis thaliana and a mutant defective in mRNA methylation (m6A). Here we show that m6A can be mapped in full-length mRNAs transcriptome-wide and reveal the combinatorial diversity of cap-associated transcription start sites, splicing events, poly(A) site choice and poly(A) tail length. Loss of m6A from 3’ untranslated regions is associated with decreased relative transcript abundance and defective RNA 30 end formation. A functional consequence of disrupted m6A is a lengthening of the circadian period. We conclude that nanopore direct RNA sequencing can reveal the complexity of mRNA processing and modification in full-length single molecule reads. These findings can refine Arabidopsis genome annotation. Further, applying this approach to less well-studied species could transform our understanding of what their genomes encode

Substrate-guided optimization of the syringolins yields potent proteasome inhibitors with activity against leukemia cell lines

Natural products that inhibit the proteasome have been fruitful starting points for the development of drug candidates. Those of the syringolin family have been underexploited in this context. Using the published model for substrate mimicry by the syringolins and knowledge about the substrate preferences of the proteolytic subunits of the human proteasome, we have designed, synthesized, and evaluated syringolin analogs. As some of our analogs inhibit the activity of the proteasome with second-order rate constants 5-fold greater than that of the methyl ester of syringolin B, we conclude that the substrate mimicry model for the syringolins is valid. The improvements in in vitro potency and the activities of particular analogs against leukemia cell lines are strong bases for further development of the syringolins as anti-cancer drugs.National Institutes of Health (U.S.) (Grant AI-16892

Maximal surface group representations in isometry groups of classical Hermitian symmetric spaces

Higgs bundles and non-abelian Hodge theory provide holomorphic methods with which to study the moduli spaces of surface group representations in a reductive Lie group G. In this paper we survey the case in which G is the isometry group of a classical Hermitian symmetric space of non-compact type. Using Morse theory on the moduli spaces of Higgs bundles, we compute the number of connected components of the moduli space of representations with maximal Toledo invariant.Comment: v2: added due credits to the work of Burger, Iozzi and Wienhard. v3: corrected count of connected components for G=SU(p,q) (p \neq q); added due credits to the work of Xia and Markman-Xia; minor corrections and clarifications. 31 page

Rational Design of Selective and Bioactive Inhibitors of the Mycobacterium Tuberculosis Proteasome

The 20S core particle of the proteasome in Mycobacterium tuberculosis (Mtb) is a promising, yet unconventional, drug target. This multimeric peptidase is not essential, yet degrades proteins that have become damaged and toxic via reactions with nitric oxide (and/or the associated reactive nitrogen intermediates) produced during the host immune response. Proteasome inhibitors could render Mtb susceptible to the immune system, but they would only be therapeutically viable if they do not inhibit the essential 20S counterpart in humans. Selective inhibitors of the Mtb 20S were designed and synthesized on the bases of both its unique substrate preferences and the structures of substrate-mimicking covalent inhibitors of eukaryotic proteasomes called syringolins. Unlike the parent syringolins, the designed analogues weakly inhibit the human 20S (Hs 20S) proteasome and preferentially inhibit Mtb 20S over the human counterpart by as much as 74-fold. Moreover, they can penetrate the mycobacterial cell envelope and render Mtb susceptible to nitric oxide-mediated stress. Importantly, they do not inhibit the growth of human cell lines in vitro and thus may be starting points for tuberculosis drug development.National Institutes of Health (U.S.) (Grant AI-16892

Young stars and non-stellar emission in the aligned radio galaxy 3C 256

We present ground-based images of the z=1.824 radio galaxy 3C 256 in the standard BVRIJHK filters and an interference filter centered at 8800A, a Hubble Space Telescope image in a filter dominated by Ly-alpha emission (F336W), and spectra covering rest-frame wavelengths from Ly-alpha to [O III] 5007. Together with published polarimetry observations, we use these to decompose the overall spectral energy distribution into nebular continuum emission, scattered quasar light, and stellar emission. The nebular continuum and scattered light together comprise half (one third) of the V-band (K-band) light within a 4-arcsec aperture, and are responsible for the strong alignment between the optical/near-infrared light and the radio emission. The stellar emission is dominated by a population estimated to be 100-200 Myr old (assuming a Salpeter IMF), and formed in a short burst with a peak star formation rate of 1-4x10^3 Msun/yr. The total stellar mass is estimated to be no more than 2x10^{11} Msun, which is far less than other luminous radio galaxies at similar redshifts, and suggests that 3C 256 will undergo further star formation or mergers.Comment: 35 pages including 10 figures; to appear in Nov 10 Ap

Rank two quadratic pairs and surface group representations

Let $X$ be a compact Riemann surface. A quadratic pair on $X$ consists of a holomorphic vector bundle with a quadratic form which takes values in fixed line bundle. We show that the moduli spaces of quadratic pairs of rank 2 are connected under some constraints on their topological invariants. As an application of our results we determine the connected components of the $\mathrm{SO}_0(2,3)$-character variety of $X$.Comment: 37 pages, 1 figur

miR-139-5p is a regulator of metastatic pathways in breast cancer

Metastasis is a complex, multistep process involved in the progression of cancer from a localized primary tissue to distant sites, often characteristic of the more aggressive forms of this disease. Despite being studied in great detail in recent years, the mechanisms that govern this process remain poorly understood. In this study, we identify a novel role for miR-139-5p in the inhibition of breast cancer progression. We highlight its clinical relevance by reviewing miR-139-5p expression across a wide variety of breast cancer subtypes using in-house generated and online data sets to show that it is most frequently lost in invasive tumors. A biotin pull-down approach was then used to identify the mRNA targets of miR-139-5p in the breast cancer cell line MCF7. Functional enrichment analysis of the pulled-down targets showed significant enrichment of genes in pathways previously implicated in breast cancer metastasis (P < 0.05). Further bioinformatic analysis revealed a predicted disruption to the TGFβ, Wnt, Rho, and MAPK/PI3K signaling cascades, implying a potential role for miR-139-5p in regulating the ability of cells to invade and migrate. To corroborate this finding, using the MDA-MB-231 breast cancer cell line, we show that overexpression of miR-139-5p results in suppression of these cellular phenotypes. Furthermore, we validate the interaction between miR-139-5p and predicted targets involved in these pathways. Collectively, these results suggest a significant functional role for miR-139-5p in breast cancer cell motility and invasion and its potential to be used as a prognostic marker for the aggressive forms of breast cancer