Maximal information component analysis: a novel non-linear network analysis method.

BackgroundNetwork construction and analysis algorithms provide scientists with the ability to sift through high-throughput biological outputs, such as transcription microarrays, for small groups of genes (modules) that are relevant for further research. Most of these algorithms ignore the important role of non-linear interactions in the data, and the ability for genes to operate in multiple functional groups at once, despite clear evidence for both of these phenomena in observed biological systems.ResultsWe have created a novel co-expression network analysis algorithm that incorporates both of these principles by combining the information-theoretic association measure of the maximal information coefficient (MIC) with an Interaction Component Model. We evaluate the performance of this approach on two datasets collected from a large panel of mice, one from macrophages and the other from liver by comparing the two measures based on a measure of module entropy, Gene Ontology (GO) enrichment, and scale-free topology (SFT) fit. Our algorithm outperforms a widely used co-expression analysis method, weighted gene co-expression network analysis (WGCNA), in the macrophage data, while returning comparable results in the liver dataset when using these criteria. We demonstrate that the macrophage data has more non-linear interactions than the liver dataset, which may explain the increased performance of our method, termed Maximal Information Component Analysis (MICA) in that case.ConclusionsIn making our network algorithm more accurately reflect known biological principles, we are able to generate modules with improved relevance, particularly in networks with confounding factors such as gene by environment interactions

Optical detection of single electron spin resonance in a quantum dot

We demonstrate optically detected spin resonance of a single electron confined to a self-assembled quantum dot. The dot is rendered dark by resonant optical pumping of the spin with a coherent laser. Contrast is restored by applying a radio frequency (rf) magnetic field at the spin resonance. The scheme is sensitive even to rf fields of just a few micro-T. In one case, the spin resonance behaves exactly as a driven 3-level quantum system (a lambda-system) with weak damping. In another, the dot exhibits remarkably strong (67% signal recovery) and narrow (0.34 MHz) spin resonances with fluctuating resonant positions, evidence of unusual dynamic processes of non-Markovian character.Comment: 4 pages, 5 figure

Analysis of the Host Transcriptome from Demyelinating Spinal Cord of Murine Coronavirus-Infected Mice

Persistent infection of the mouse central nervous system (CNS) with mouse hepatitis virus (MHV) induces a demyelinating disease pathologically similar to multiple sclerosis and is therefore used as a model system. There is little information regarding the host factors that correlate with and contribute to MHV-induced demyelination. Here, we detail the genes and pathways associated with MHV-induced demyelinating disease in the spinal cord. High-throughput sequencing of the host transcriptome revealed that demyelination is accompanied by numerous transcriptional changes indicative of immune infiltration as well as changes in the cytokine milieu and lipid metabolism. We found evidence that a Th1-biased cytokine/chemokine response and eicosanoid-derived inflammation accompany persistent MHV infection and that antigen presentation is ongoing. Interestingly, increased expression of genes involved in lipid transport, processing, and catabolism, including some with known roles in neurodegenerative diseases, coincided with demyelination. Lastly, expression of several genes involved in osteoclast or bone-resident macrophage function, most notably TREM2 and DAP12, was upregulated in persistently infected mouse spinal cord. This study highlights the complexity of the host antiviral response, which accompany MHV-induced demyelination, and further supports previous findings that MHV-induced demyelination is immune-mediated. Interestingly, these data suggest a parallel between bone reabsorption by osteoclasts and myelin debris clearance by microglia in the bone and the CNS, respectively. To our knowledge, this is the first report of using an RNA-seq approach to study the host CNS response to persistent viral infection

Identification of methylated proteins in the yeast small ribosomal subunit: A role for SPOUT methyltransferases in protein arginine methylation

We have characterized the posttranslational methylation of Rps2, Rps3, and Rps27a, three small ribosomal subunit proteins in the yeast Saccharomyces cerevisiae, using mass spectrometry and amino acid analysis. We found that Rps2 is substoichiometrically modified at arginine-10 by the Rmt1 methyltransferase. We demonstrated that Rps3 is stoichiometrically modified by ω- monomethylation at arginine-146 by mass spectrometric and site-directed mutagenic analyses. Substitution of alanine for arginine at position 146 is associated with slow cell growth, suggesting that the amino acid identity at this site may influence ribosomal function and/or biogenesis. Analysis of the three-dimensional structure of Rps3 in S. cerevisiae shows that arginine-146 makes contacts with the small subunit rRNA. Screening of deletion mutants encoding potential yeast methyltransferases revealed that the loss of the YOR021C gene results in the absence of methylation of Rps3. We demonstrated that recombinant Yor021c catalyzes ω-monomethylarginine formation when incubated with S-adenosylmethionine and hypomethylated ribosomes prepared from a YOR021C deletion strain. Interestingly, Yor021c belongs to the family of SPOUT methyltransferases that, to date, have only been shown to modify RNA substrates. Our findings suggest a wider role for SPOUT methyltransferases in nature. Finally, we have demonstrated the presence of a stoichiometrically methylated cysteine residue at position 39 of Rps27a in a zinc-cysteine cluster. The discovery of these three novel sites of protein modification within the small ribosomal subunit will now allow for an analysis of their functional roles in translation and possibly other cellular processes. © 2012 American Chemical Society

The structure of an NDR/LATS kinase – mob complex reveals a novel kinase-coactivator system and substrate docking mechanism.

Eukaryotic cells commonly use protein kinases in signaling systems that relay information and control a wide range of processes. These enzymes have a fundamentally similar structure, but achieve functional diversity through variable regions that determine how the catalytic core is activated and recruited to phosphorylation targets. "Hippo" pathways are ancient protein kinase signaling systems that control cell proliferation and morphogenesis; the NDR/LATS family protein kinases, which associate with "Mob" coactivator proteins, are central but incompletely understood components of these pathways. Here we describe the crystal structure of budding yeast Cbk1-Mob2, to our knowledge the first of an NDR/LATS kinase-Mob complex. It shows a novel coactivator-organized activation region that may be unique to NDR/LATS kinases, in which a key regulatory motif apparently shifts from an inactive binding mode to an active one upon phosphorylation. We also provide a structural basis for a substrate docking mechanism previously unknown in AGC family kinases, and show that docking interaction provides robustness to Cbk1's regulation of its two known in vivo substrates. Co-evolution of docking motifs and phosphorylation consensus sites strongly indicates that a protein is an in vivo regulatory target of this hippo pathway, and predicts a new group of high-confidence Cbk1 substrates that function at sites of cytokinesis and cell growth. Moreover, docking peptides arise in unstructured regions of proteins that are probably already kinase substrates, suggesting a broad sequential model for adaptive acquisition of kinase docking in rapidly evolving intrinsically disordered polypeptides

Solution structure of an ultra-stable single-chain insulin analog connects protein dynamics to a novel mechanism of receptor binding

Domain-minimized insulin receptors (IRs) have enabled crystallographic analysis of insulin-bound "micro-receptors." In such structures, the C-terminal segment of the insulin B chain inserts between conserved IR domains, unmasking an invariant receptor-binding surface that spans both insulin A and B chains. This "open" conformation not only rationalizes the inactivity of single-chain insulin (SCI) analogs (in which the A and B chains are directly linked), but also suggests that connecting (C) domains of sufficient length will bind the IR. Here, we report the high-resolution solution structure and dynamics of such an active SCI. The hormone's closed-to-open transition is foreshadowed by segmental flexibility in the native state as probed by heteronuclear NMR spectroscopy and multiple conformer simulations of crystallographic protomers as described in the companion article. We propose a model of the SCI's IR-bound state based on molecular-dynamics simulations of a micro-receptor complex. In this model, a loop defined by the SCI's B and C domains encircles the C-terminal segment of the IR α-subunit. This binding mode predicts a conformational transition between an ultra-stable closed state (in the free hormone) and an active open state (on receptor binding). Optimization of this switch within an ultra-stable SCI promises to circumvent insulin's complex global cold chain. The analog's biphasic activity, which serendipitously resembles current premixed formulations of soluble insulin and microcrystalline suspension, may be of particular utility in the developing world

Accretion of Planetary Material onto Host Stars

Accretion of planetary material onto host stars may occur throughout a star's life. Especially prone to accretion, extrasolar planets in short-period orbits, while relatively rare, constitute a significant fraction of the known population, and these planets are subject to dynamical and atmospheric influences that can drive significant mass loss. Theoretical models frame expectations regarding the rates and extent of this planetary accretion. For instance, tidal interactions between planets and stars may drive complete orbital decay during the main sequence. Many planets that survive their stars' main sequence lifetime will still be engulfed when the host stars become red giant stars. There is some observational evidence supporting these predictions, such as a dearth of close-in planets around fast stellar rotators, which is consistent with tidal spin-up and planet accretion. There remains no clear chemical evidence for pollution of the atmospheres of main sequence or red giant stars by planetary materials, but a wealth of evidence points to active accretion by white dwarfs. In this article, we review the current understanding of accretion of planetary material, from the pre- to the post-main sequence and beyond. The review begins with the astrophysical framework for that process and then considers accretion during various phases of a host star's life, during which the details of accretion vary, and the observational evidence for accretion during these phases.Comment: 18 pages, 5 figures (with some redacted), invited revie

Welwitindolinone C synthetic studies. Construction of the welwitindolinone carbon skeleton via a transannular nitrone cycloaddition

Described is the construction of the N-methylwelwitindolinone C core via an efficient strategy that employs a sequential rhodium carbenoid-mediated O–H insertion, Claisen rearrangement and transannular [3+2] nitrone cycloaddition

Transmission of HIV-1 infection in sub-Saharan Africa and effect of elimination of unsafe injections

During the past year, a group has argued that unsafe injections are a major if not the main mode of HIV-1 transmission\ud in sub-Saharan Africa. We review the main arguments used to question the epidemiological interpretations on the lead\ud role of unsafe sex in HIV-1 transmission, and conclude there is no compelling evidence that unsafe injections are a\ud predominant mode of HIV-1 transmission in sub-Saharan Africa. Conversely, though there is a clear need to eliminate\ud all unsafe injections, epidemiological evidence indicates that sexual transmission continues to be by far the major\ud mode of spread of HIV-1 in the region. Increased efforts are needed to reduce sexual transmission of HIV-1