Scalable iterative methods for sampling from massive Gaussian random vectors

Sampling from Gaussian Markov random fields (GMRFs), that is multivariate Gaussian ran- dom vectors that are parameterised by the inverse of their covariance matrix, is a fundamental problem in computational statistics. In this paper, we show how we can exploit arbitrarily accu- rate approximations to a GMRF to speed up Krylov subspace sampling methods. We also show that these methods can be used when computing the normalising constant of a large multivariate Gaussian distribution, which is needed for both any likelihood-based inference method. The method we derive is also applicable to other structured Gaussian random vectors and, in particu- lar, we show that when the precision matrix is a perturbation of a (block) circulant matrix, it is still possible to derive O(n log n) sampling schemes.Comment: 17 Pages, 4 Figure

The Way of the Artist Educator: Understanding the Fusion of Artistic Studio Practice and Teaching Pedagogy of K-12 Visual Arts Educators

The purpose of this autoethnographic study was to examine the experiences of Artist Educators and how they perceive the fusion of their artistic studio practice and teaching pedagogy impacts their creative and teaching practices. This study involved a focus group of six individuals, including the researcher. All the participants were practicing artists, currently employed or recently retired K-12 Visual Arts Education certified in the states of Maine or New Hampshire and members of the Kittery Art Association. This study used a combination of interviews and an arts-based method for data collection. All the data were analyzed and resulted in the following seven findings: (1) The identity of an Artist Educator is synchronized with a call to a vocation. (2) The necessity to create art and teach art simultaneously was intrinsic for Artist Educators. (3) Artist Educators lived a creative life and believed it to be a personal practice that cannot be taught. (4) Both extrinsic and intrinsic factors and conditions can inhibit an Artist Educator’s practice. (5) Both intrinsic and extrinsic factors and conditions supported the practice of an Artist Educator. (6) Artist Educators cultivated quality relationships for teaching and learning by fusing their artistic studio practice and teaching pedagogy. (7) Artist Educators fostered life lessons and embodied wisdom from the fusion of their artistic studio practice and teaching pedagogy. These findings and insights acquired have implications for visual arts education practice and arts educator professional development programs. The Way of the Artist Educator paradigm offers an alternative approach for a quality and holistic 21st Century Visual Arts Education. Key words: Artist Educator, identity, motivation, creativity, fusion, practic

Fission yeast 26S proteasome mutants are multi-drug resistant due to stabilization of the pap1 transcription factor

Here we report the result of a genetic screen for mutants resistant to the microtubule poison methyl benzimidazol-2-yl carbamate (MBC) that were also temperature sensitive for growth. In total the isolated mutants were distributed in ten complementation groups. Cloning experiments revealed that most of the mutants were in essential genes encoding various 26S proteasome subunits. We found that the proteasome mutants are multi-drug resistant due to stabilization of the stress-activated transcription factor Pap1. We show that the ubiquitylation and ultimately the degradation of Pap1 depend on the Rhp6/Ubc2 E2 ubiquitin conjugating enzyme and the Ubr1 E3 ubiquitin-protein ligase. Accordingly, mutants lacking Rhp6 or Ubr1 display drug-resistant phenotypes

Comparative venom-gland transcriptomics and venom proteomics of four Sidewinder Rattlesnake (\u3ci\u3eCrotalus cerastes\u3c/i\u3e) lineages reveal little differential expression despite individual variation

Changes in gene expression can rapidly influence adaptive traits in the early stages of lineage diversification. Venom is an adaptive trait comprised of numerous toxins used for prey capture and defense. Snake venoms can vary widely between conspecific populations, but the influence of lineage diversification on such compositional differences are unknown. To explore venom differentiation in the early stages of lineage diversification, we used RNA-seq and mass spectrometry to characterize Sidewinder Rattlesnake (Crotalus cerastes) venom. We generated the first venom-gland transcriptomes and complementary venom proteomes for eight individuals collected across the United States and tested for expression differences across life history traits and between subspecific, mitochondrial, and phylotranscriptomic hypotheses. Sidewinder venom was comprised primarily of hemorrhagic toxins, with few cases of differential expression attributable to life history or lineage hypotheses. However, phylotranscriptomic lineage comparisons more than doubled instances of significant expression differences compared to all other factors. Nevertheless, only 6.4% of toxins were differentially expressed overall, suggesting that shallow divergence has not led to major changes in Sidewinder venom composition. Our results demonstrate the need for consensus venom-gland transcriptomes based on multiple individuals and highlight the potential for discrepancies in differential expression between different phylogenetic hypotheses

Functional evolution of IGF2:IGF2R domain 11 binding generates novel structural interactions and a specific IGF2 antagonist

Among the 15 extracellular domains of the mannose 6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF2R), domain 11 has evolved a binding site for IGF2 to negatively regulate ligand bioavailability and mammalian growth. Despite the highly evolved structural loops of the IGF2:domain 11 binding site, affinity-enhancing AB loop mutations suggest that binding is modifiable. Here we examine the extent to which IGF2:domain 11 affinity, and its specificity over IGF1, can be enhanced, and we examine the structural basis of the mechanistic and functional consequences. Domain 11 binding loop mutants were selected by yeast surface display combined with high-resolution structure-based predictions, and validated by surface plasmon resonance. We discovered previously unidentified mutations in the ligand-interacting surface binding loops (AB, CD, FG, and HI). Five combined mutations increased rigidity of the AB loop, as confirmed by NMR. When added to three independently identified CD and FG loop mutations that reduced the koff value by twofold, these mutations resulted in an overall selective 100-fold improvement in affinity. The structural basis of the evolved affinity was improved shape complementarity established by interloop (AB-CD) and intraloop (FG-FG) side chain interactions. The high affinity of the combinatorial domain 11 Fc fusion proteins functioned as ligand-soluble antagonists or traps that depleted pathological IGF2 isoforms from serum and abrogated IGF2-dependent signaling in vivo. An evolved and reengineered high-specificity M6P/IGF2R domain 11 binding site for IGF2 may improve therapeutic targeting of the frequent IGF2 gain of function observed in human cancer

A Census of the High-Density Molecular Gas in M82

We present a three-pointing study of the molecular gas in the starburst nucleus of M82 based on 190 - 307 GHz spectra obtained with Z-Spec at the Caltech Submillimeter Observatory. We present intensity measurements, detections and upper limits, for 20 transitions, including several new detections of CS, HNC, C2H, H2CO, and CH3CCH lines. We combine our measurements with previously-published measurements at other frequencies for HCN, HNC, CS, C34S, and HCO+ in a multi-species likelihood analysis constraining gas mass, density and temperature, and the species' relative abundances. We find some 1.7 - 2.7 x 10^8 M_sun of gas with n_H2 between 1 - 6 x 10^4 cm^-3 and T > 50 K. While the mass and temperature are comparable to values inferred from mid-J CO transitions, the thermal pressure is a factor of 10 - 20 greater. The molecular interstellar medium is largely fragmented and is subject to ultraviolet irradiation from the star clusters. It is also likely subject to cosmic rays and mechanical energy input from the supernovae, and is warmer on average than the molecular gas in the massive star formation regions in the Milky Way. The typical conditions in the dense gas in M82's central kpc appear unfavorable for further star formation; if any appreciable stellar populations are currently forming, they are likely biased against low mass stars, producing a top-heavy initial mass function.Comment: 15 pages (using emulateapj.cls), 6 figures, Astrophysical Journal, in pres

PIP5KIβ Selectively Modulates Apical Endocytosis in Polarized Renal Epithelial Cells

Localized synthesis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] at clathrin coated pits (CCPs) is crucial for the recruitment of adaptors and other components of the internalization machinery, as well as for regulating actin dynamics during endocytosis. PtdIns(4,5)P2 is synthesized from phosphatidylinositol 4-phosphate by any of three phosphatidylinositol 5-kinase type I (PIP5KI) isoforms (α, β or γ). PIP5KIβ localizes almost exclusively to the apical surface in polarized mouse cortical collecting duct cells, whereas the other isoforms have a less polarized membrane distribution. We therefore investigated the role of PIP5KI isoforms in endocytosis at the apical and basolateral domains. Endocytosis at the apical surface is known to occur more slowly than at the basolateral surface. Apical endocytosis was selectively stimulated by overexpression of PIP5KIβ whereas the other isoforms had no effect on either apical or basolateral internalization. We found no difference in the affinity for PtdIns(4,5)P2-containing liposomes of the PtdIns(4,5)P2 binding domains of epsin and Dab2, consistent with a generic effect of elevated PtdIns(4,5)P2 on apical endocytosis. Additionally, using apical total internal reflection fluorescence imaging and electron microscopy we found that cells overexpressing PIP5KIβ have fewer apical CCPs but more internalized coated structures than control cells, consistent with enhanced maturation of apical CCPs. Together, our results suggest that synthesis of PtdIns(4,5)P2 mediated by PIP5KIβ is rate limiting for apical but not basolateral endocytosis in polarized kidney cells. PtdIns(4,5)P2 may be required to overcome specific structural constraints that limit the efficiency of apical endocytosis. © 2013 Szalinski et al

Ubiquitous outflows in DEEP2 spectra of star-forming galaxies at z=1.4

Galactic winds are a prime suspect for the metal enrichment of the intergalactic medium and may have a strong influence on the chemical evolution of galaxies and the nature of QSO absorption line systems. We use a sample of 1406 galaxy spectra at z~1.4 from the DEEP2 redshift survey to show that blueshifted Mg II 2796, 2803 A absorption is ubiquitous in starforming galaxies at this epoch. This is the first detection of frequent outflowing galactic winds at z~1. The presence and depth of absorption are independent of AGN spectral signatures or galaxy morphology; major mergers are not a prerequisite for driving a galactic wind from massive galaxies. Outflows are found in coadded spectra of galaxies spanning a range of 30x in stellar mass and 10x in star formation rate (SFR), calibrated from K-band and from MIPS IR fluxes. The outflows have column densities of order N_H ~ 10^20 cm^-2 and characteristic velocities of ~ 300-500 km/sec, with absorption seen out to 1000 km/sec in the most massive, highest SFR galaxies. The velocities suggest that the outflowing gas can escape into the IGM and that massive galaxies can produce cosmologically and chemically significant outflows. Both the Mg II equivalent width and the outflow velocity are larger for galaxies of higher stellar mass and SFR, with V_wind ~ SFR^0.3, similar to the scaling in low redshift IR-luminous galaxies. The high frequency of outflows in the star-forming galaxy population at z~1 indicates that galactic winds occur in the progenitors of massive spirals as well as those of ellipticals. The increase of outflow velocity with mass and SFR constrains theoretical models of galaxy evolution that include feedback from galactic winds, and may favor momentum-driven models for the wind physics.Comment: Accepted by ApJ. 25 pages, 17 figures. Revised to add discussions of intervening absorbers and AGN-driven outflows; conclusions unchange

Evidence for divergent patterns of local selection driving venom variation in Mojave Rattlesnakes (\u3ci\u3eCrotalus scutulatus\u3c/i\u3e)

Snake venoms represent an enriched system for investigating the evolutionary processes that lead to complex and dynamic trophic adaptations. It has long been hypothesized that natural selection may drive geographic variation in venom composition, yet previous studies have lacked the population genetic context to examine these patterns. We leverage range-wide sampling of Mojave Rattlesnakes (Crotalus scutulatus) and use a combination of venom, morphological, phylogenetic, population genetic, and environmental data to characterize the striking dichotomy of neurotoxic (Type A) and hemorrhagic (Type B) venoms throughout the range of this species. We find that three of the four previously identified major lineages within C. scutulatus possess a combination of Type A, Type B, and a ‘mixed’ Type A + B venom phenotypes, and that fixation of the two main venom phenotypes occurs on a more fine geographic scale than previously appreciated. We also find that Type A + B individuals occur in regions of inferred introgression, and that this mixed phenotype is comparatively rare. Our results support strong directional local selection leading to fixation of alternative venom phenotypes on a fine geographic scale, and are inconsistent with balancing selection to maintain both phenotypes within a single population. Our comparisons to biotic and abiotic factors further indicate that venom phenotype correlates with fang morphology and climatic variables. We hypothesize that links to fang morphology may be indicative of co-evolution of venom and other trophic adaptations, and that climatic variables may be linked to prey distributions and/or physiology, which in turn impose selection pressures on snake venoms