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\"The catalogue raisonnâe covers Sage's mature style of work from 1934 to 1961. Separated into four sections, the book features over 230 entries with full-page, color reproductions throughout: 138 paintings, 22 collages, 51 works on paper, and 23 constructions. A number of works are presented for the first time. Also included is a small group of Sage's rarely seen, earlier academic work produced in Italy. A poetic and thoughtful essay by Mary Ann Caws delves into the Sage's life, bringing to light new insight into the artist's very personal practice. A chronology by Sage scholar Stephen Robeson Miller provides new research and documentation. Both are fully illustrated\"-- Provided by publisher.

Purpose To examine the dose–response effects of acute glutamine supplementation on markers of gastrointestinal (GI) permeability, damage and, secondary, subjective symptoms of GI discomfort in response to running in the heat. Methods Ten recreationally active males completed a total of four exercise trials; a placebo trial and three glutamine trials at 0.25, 0.5 and 0.9 g kg −1 of fat-free mass (FFM) consumed 2 h before exercise. Each exercise trial consisted of a 60-min treadmill run at 70% of V ˙ O 2max in an environmental chamber set at 30 °C. GI permeability was measured using ratio of lactulose to rhamnose (L:R) in serum. Plasma glutamine and intestinal fatty acid binding protein (I-FABP) concentrations were determined pre and post exercise. Subjective GI symptoms were assessed 45 min and 24 h post-exercise. Results Relative to placebo, L:R was likely lower following 0.25 g kg −1 (mean difference: − 0.023; ± 0.021) and 0.5 g kg −1 (− 0.019; ± 0.019) and very likely following 0.9 g kg − 1 (− 0.034; ± 0.024). GI symptoms were typically low and there was no effect of supplementation. Discussion Acute oral glutamine consumption attenuates GI permeability relative to placebo even at lower doses of 0.25 g kg −1 , although larger doses may be more effective. It remains unclear if this will lead to reductions in GI symptoms. Athletes competing in the heat may, therefore, benefit from acute glutamine supplementation prior to exercise in order to maintain gastrointestinal integrity.

Thermal transitions of polyisocyanide single molecules to polymer bundles and finally networks lead to hydrogels mimicking the properties of biopolymer intermediate-filament networks; their analysis shows that bundling and chain stiffness are crucial design parameters for hydrogels. Biomimetic polymer networks This paper describes a new class of water-soluble, relatively stiff polymers that bundle in a controlled manner on heating to produce very stiff fibres. These fibres, in turn, form hydrogels that very closely mimic components of the cell cytoskeleton, intermediate filaments. Synthesis involves the thermal transition of polyisocyanide polymers from single molecules to bundles of polymer chains. Networks made with this material demonstrate a stress-stiffening behaviour that is usually absent in synthetic polymer gels, and their mechanical properties can be modified by altering the chemical structure of the polymer, offering greater versatility than biopolymer networks. Mechanical responsiveness is essential to all biological systems down to the level of tissues and cells 1 , 2 . The intra- and extracellular mechanics of such systems are governed by a series of proteins, such as microtubules, actin, intermediate filaments and collagen 3 , 4 . As a general design motif, these proteins self-assemble into helical structures and superstructures that differ in diameter and persistence length to cover the full mechanical spectrum 1 . Gels of cytoskeletal proteins display particular mechanical responses (stress stiffening) that until now have been absent in synthetic polymeric and low-molar-mass gels. Here we present synthetic gels that mimic in nearly all aspects gels prepared from intermediate filaments. They are prepared from polyisocyanopeptides 5 , 6 , 7 grafted with oligo(ethylene glycol) side chains. These responsive polymers possess a stiff and helical architecture, and show a tunable thermal transition where the chains bundle together to generate transparent gels at extremely low concentrations. Using characterization techniques operating at different length scales (for example, macroscopic rheology, atomic force microscopy and molecular force spectroscopy) combined with an appropriate theoretical network model 8 , 9 , 10 , we establish the hierarchical relationship between the bulk mechanical properties and the single-molecule parameters. Our results show that to develop artificial cytoskeletal or extracellular matrix mimics, the essential design parameters are not only the molecular stiffness, but also the extent of bundling. In contrast to the peptidic materials, our polyisocyanide polymers are readily modified, giving a starting point for functional biomimetic hydrogels with potentially a wide variety of applications 11 , 12 , 13 , 14 , in particular in the biomedical field.

The evolution of C4 photosynthesis in many taxa involves the establishment of a two-celled photorespiratory CO 2 pump, termed C 2 photosynthesis. How C 3 species evolved C 2 metabolism is critical to understanding the initial phases of C 4 plant evolution. To evaluate early events in C 4 evolution, we compared leaf anatomy, ultrastructure, and gas-exchange responses of closely related C 3 and C 2 species of Flaveria, a model genus for C 4 evolution. We hypothesized that Flaveria pringlei and Flaveria robusta, two C 3 species that are most closely related to the C 2 Flaveria species, would show rudimentary characteristics of C 2 physiology. Compared with less-related C 3 species, bundle sheath (BS) cells of F. pringlei and F. robusta had more mitochondria and chloroplasts, larger mitochondria, and proportionally more of these organelles located along the inner cell periphery. These patterns were similar, although generally less in magnitude, than those observed in the C 2 species Flaveria angustifolia and Flaveria sonorensis. In F. pringlei and F. robusta, the CO 2 compensation point of photosynthesis was slightly lower than in the less-related C 3 species, indicating an increase in photosynthetic efficiency. This could occur because of enhanced refixation of photorespired CO 2 by the centripetally positioned organelles in the BS cells. If the phylogenetic positions of F. pringlei and F. robusta reflect ancestral states, these results support a hypothesis that increased numbers of centripetally located organelles initiated a metabolic scavenging of photorespired CO 2 within the BS. This could have facilitated the formation of a glycine shuttle between mesophyll and BS cells that characterizes C 2 photosynthesis.

Betalain pigments are unique to the Caryophyllales and structurally and biosynthetically distinct from anthocyanins. Two key enzymes within the betalain synthesis pathway have been identified: 4,5-dioxygenase (DODA) that catalyzes the formation of betalamic acid and CYP76AD1, a cytochrome P450 gene that catalyzes the formation of cyclo-DOPA. We performed phylogenetic analyses to reveal the evolutionary history of the DODA and CYP76AD1 lineages and in the context of an ancestral reconstruction of pigment states we explored the evolution of these genes in relation to the complex evolution of pigments in Caryophylalles. Duplications within the CYP76AD1 and DODA lineages arose just before the origin of betalain pigmentation in the core Caryophyllales. The duplications gave rise to DODA-α and CYP76AD1-α isoforms that appear specific to betalain synthesis. Both betalain-specific isoforms were then lost or downregulated in the anthocyanicMolluginaceae and Caryophyllaceae. Our findings suggest a single origin of the betalain synthesis pathway, with neofunctionalization following gene duplications in the CYP76AD1 and DODA lineages. Loss of DODA-α and CYP76AD1-α in anthocyanic taxa suggests that betalain pigmentation has been lost twice in Caryophyllales, and exclusion of betalain pigments from anthocyanic taxa is mediated through gene loss or downregulation. [Correction added after online publication 13 May 2015: in the last two paragraphs of the Summary the gene name CYP761A was changed to CYP76AD1.]

DNA double-strand breaks (DSBs) are perhaps the most toxic of all DNA lesions, with defects in the DNA-damage response to DSBs being associated with various human diseases. Although it is known that DSB repair pathways are tightly regulated by ubiquitylation, we do not yet have a comprehensive understanding of how deubiquitylating enzymes (DUBs) function in DSB responses. Here, by carrying out a multidimensional screening strategy for human DUBs, we identify several with hitherto unknown links to DSB repair, the G2/M DNA-damage checkpoint and genome-integrity maintenance. Phylogenetic analyses reveal functional clustering within certain DUB subgroups, suggesting evolutionally conserved functions and/or related modes of action. Furthermore, we establish that the DUB UCHL5 regulates DSB resection and repair by homologous recombination through protecting its interactor, NFRKB, from degradation. Collectively, our findings extend the list of DUBs promoting the maintenance of genome integrity, and highlight their potential as therapeutic targets for cancer. Systematic characterization of deubiquitylating enzymes in the DNA-damage response identifies UCHL5 as promoting DNA-end resection.

Type-2 innate lymphoid cells (ILC2) are a prominent source of type II cytokines and are found constitutively at mucosal surfaces and in visceral adipose tissue. Despite their role in limiting obesity, how ILC2s respond to high fat feeding is poorly understood, and their direct influence on the development of atherosclerosis has not been explored. Here, we show that ILC2 are present in para-aortic adipose tissue and lymph nodes and display an inflammatory-like phenotype atypical of adipose resident ILC2. High fat feeding alters both the number of ILC2 and their type II cytokine production. Selective genetic ablation of ILC2 in Ldlr −/− mice accelerates the development of atherosclerosis, which is prevented by reconstitution with wild type but not Il5 −/− or Il13 −/− ILC2. We conclude that ILC2 represent a major innate cell source of IL-5 and IL-13 required for mounting atheroprotective immunity, which can be altered by high fat diet. Type-2 innate lymphoid cells (ILC2) affect adipose tissue metabolism and function. Here the authors show that the ILC2 are present in para-aortic adipose tissue and represent a major source of IL-5 and IL-13 required for mounting atheroprotective immunity, which can be altered by high fat diet.

The RNA-guided Cas9 nuclease is being widely employed to engineer the genomes of various cells and organisms. Despite the efficient mutagenesis induced by Cas9, off-target effects have raised concerns over the system’s specificity. Recently a “double-nicking” strategy using catalytic mutant Cas9 D10A nickase has been developed to minimise off-target effects. Here, we describe a Cas9 D10A -based screening approach that combines an All-in-One Cas9 D10A nickase vector with fluorescence-activated cell sorting enrichment followed by high-throughput genotypic and phenotypic clonal screening strategies to generate isogenic knockouts and knock-ins highly efficiently, with minimal off-target effects. We validated this approach by targeting genes for the DNA-damage response (DDR) proteins MDC1, 53BP1, RIF1 and P53, plus the nuclear architecture proteins Lamin A/C, in three different human cell lines. We also efficiently obtained biallelic knock-in clones, using single-stranded oligodeoxynucleotides as homologous templates, for insertion of an EcoRI recognition site at the RIF1 locus and introduction of a point mutation at the histone H2AFX locus to abolish assembly of DDR factors at sites of DNA double-strand breaks. This versatile screening approach should facilitate research aimed at defining gene functions, modelling of cancers and other diseases underpinned by genetic factors and exploring new therapeutic opportunities.

Many phylogenomic studies based on transcriptomes have been limited to “single-copy” genes due to methodological challenges in homology and orthology inferences. Only a relatively small number of studies have explored analyses beyond reconstructing species relationships. We sampled 69 transcriptomes in the hyperdiverse plant clade Caryophyllales and 27 outgroups from annotated genomes across eudicots. Using a combined similarity- and phylogenetic tree-based approach, we recovered 10,960 homolog groups, where each was represented by at least eight ingroup taxa. By decomposing these homolog trees, and taking gene duplications into account, we obtained 17,273 ortholog groups, where each was represented by at least ten ingroup taxa. We reconstructed the species phylogeny using a 1,122-gene data set with a gene occupancy of 92.1%. From the homolog trees, we found that both synonymous and nonsynonymous substitution rates in herbaceous lineages are up to three times as fast as in their woody relatives. This is the first time such a pattern has been shown across thousands of nuclear genes with dense taxon sampling. We also pinpointed regions of the Caryophyllales tree that were characterized by relatively high frequencies of gene duplication, including three previously unrecognized whole-genome duplications. By further combining information from homolog tree topology and synonymous distance between paralog pairs, phylogenetic locations for 13 putative genome duplication events were identified. Genes that experienced the greatest gene family expansion were concentrated among those involved in signal transduction and oxidoreduction, including a cytochrome P450 gene that encodes a key enzyme in the betalain synthesis pathway. Our approach demonstrates a new approach for functional phylogenomic analysis in nonmodel species that is based on homolog groups in addition to inferred ortholog groups.