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991.
BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions 总被引:1,自引:0,他引:1
Whittle AJ Carobbio S Martins L Slawik M Hondares E Vázquez MJ Morgan D Csikasz RI Gallego R Rodriguez-Cuenca S Dale M Virtue S Villarroya F Cannon B Rahmouni K López M Vidal-Puig A 《Cell》2012,149(4):871-885
Thermogenesis in brown adipose tissue (BAT) is fundamental to energy balance and is also relevant for humans. Bone morphogenetic proteins (BMPs) regulate adipogenesis, and, here, we describe a role for BMP8B in the direct regulation of thermogenesis. BMP8B is induced by nutritional and thermogenic factors in mature BAT, increasing the response to noradrenaline through enhanced p38MAPK/CREB signaling and increased lipase activity. Bmp8b(-/-) mice exhibit impaired thermogenesis and reduced metabolic rate, causing weight gain despite hypophagia. BMP8B is also expressed in the hypothalamus, and Bmp8b(-/-) mice display altered neuropeptide levels and reduced phosphorylation of AMP-activated protein kinase (AMPK), indicating an anorexigenic state. Central BMP8B treatment increased sympathetic activation of BAT, dependent on the status of AMPK in key hypothalamic nuclei. Our results indicate that BMP8B is a thermogenic protein that regulates energy balance in partnership with hypothalamic AMPK. BMP8B may offer a mechanism to specifically increase energy dissipation by BAT. 相似文献
992.
Insulin resistance is a complex metabolic disorder that defies explanation by a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway, and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, these cellular changes may converge to promote the accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, a common final pathway leading to impaired insulin signaling and insulin resistance. 相似文献
993.
Marie-Agnès Jacques Karine Durand Geoffrey Orgeur Samuel Balidas Céline Fricot Sophie Bonneau Anne Quillévéré Corinne Audusseau Valérie Olivier Valérie Grimault René Mathis 《Applied and environmental microbiology》2012,78(23):8388-8402
The genus Clavibacter comprises one species and five subspecies of plant-pathogenic bacteria, four of which are classified as quarantine organisms due to the high economic threat they pose. Clavibacter michiganensis subsp. michiganensis is one of the most important pathogens of tomato, but the recommended diagnostic tools are not satisfactory due to false-negative and/or -positive results. To provide a robust analysis of the genetic relatedness among a worldwide collection of C. michiganensis subsp. michiganensis strains, relatives (strains from the four other C. michiganensis subspecies), and nonpathogenic Clavibacter-like strains isolated from tomato, we performed multilocus sequence-based analysis and typing (MLSA and MLST) based on six housekeeping genes (atpD, dnaK, gyrB, ppK, recA, and rpoB). We compared this “framework” with phenotypic and genotypic characteristics such as pathogenicity on tomato, reaction to two antisera by immunofluorescence and to five PCR identification tests, and the presence of four genes encoding the main C. michiganensis subsp. michiganensis pathogenicity determinants. We showed that C. michiganensis subsp. michiganensis is monophyletic and is distinct from its closest taxonomic neighbors. The nonpathogenic Clavibacter-like strains were identified as C. michiganensis using 16S rRNA gene sequencing. These strains, while cross-reacting with C. michiganensis subsp. michiganensis identification tools, are phylogenetically distinct from the pathogenic strains but belong to the C. michiganensis clade. C. michiganensis subsp. michiganensis clonal complexes linked strains from highly diverse geographical origins and also strains isolated over long periods of time in the same location. This illustrates the importance of seed transmission in the worldwide dispersion of this pathogen and its survival and adaptation abilities in a new environment once introduced. 相似文献
994.
Anatoly Peretyatko Samuel Teissier Sylvia De Backer Ludwig Triest 《Hydrobiologia》2012,689(1):131-146
Nutrient enrichment of aquatic ecosystems caused dramatic increase in the frequency, magnitude and duration of cyanobacterial
blooms. Such blooms may cause fish kills, have adverse health effects on humans and contribute to the loss of biodiversity
in aquatic ecosystems. Some 50 eutrophic to hypereutrophic ponds from the Brussels Capital Region (Belgium) were studied between
2003 and 2009. A number of the ponds studied are prone to persistent cyanobacterial blooms. Because of the related health
concerns and adverse effects on ecological quality of the affected ponds, a tool for assessment of the risk of cyanobacterial
bloom occurrence was needed. The data acquired showed that cyanobacteria have threshold relationships with most of the environmental
factors that control them. This is negatively reflected on the predictive capacity of conventional statistical methods based
on linear relationships. Therefore, classification trees designed for the treatment of complex data and non-linear relationships
were used to assess the risk of cyanobacterial bloom occurrence. The main factors determining cyanobacterial bloom development
appeared to be phytoplankton biomass, pH and, to a lesser degree, nitrogen availability. These results suggest that to outcompete
eukaryotic phytoplankters cyanobacteria need the presence of environmental constraints: carbon limitation, light limitation
and nitrogen limitation, for which they developed a number of adaptations. In the absence of constraints, eukaryotic phytoplankters
appear to be more competitive. Therefore, prior build up of phytoplankton biomass seems to be essential for cyanobacterial
dominance. Classification trees proved to be an efficient tool for the bloom risk assessment and allowed the main factors
controlling bloom development to be identified as well as the risk of bloom occurrence corresponding to the conditions determined
by these factors to be quantified. The results produced by the classification trees are consistent with those obtained earlier
by probabilistic approach to bloom risk assessment. They can facilitate planning management interventions and setting restoration
priorities. 相似文献
995.
Stabilizing the clear-water state in eutrophic ponds after biomanipulation: submerged vegetation versus fish recolonization 总被引:2,自引:0,他引:2
Biomanipulation through fish removal is a tool commonly used to restore a clear-water state in lakes. Biomanipulation of ponds
is, however, less well documented, although their importance for biodiversity conservation and public amenities is undisputed.
In ponds, a more complete fish removal can be carried out as compared to lakes and therefore a stronger response is expected.
Fish recolonization can, however, potentially compromise the longer term success of biomanipulation. Therefore, we investigated
the impact of fish recolonization on zooplankton, phytoplankton, and nutrients for several years after complete drawdown and
fish removal in function of submerged vegetation cover in 12 peri-urban eutrophic ponds situated in Brussels (Belgium). Fish
recolonization after biomanipulation had a considerable impact on zooplankton grazers, reducing their size and density substantially,
independent of the extent of submerged vegetation cover. Only ponds with <30% cover of submerged vegetation shifted back to
a turbid state after fish recolonization, coinciding with an increase in density of small cladocerans, rotifers, and cyclopoid
copepods. In ponds with >30% submerged vegetation cover, macrophytes prevented an increase in phytoplankton growth despite
the disappearance of large zooplankton grazers. Our results suggest that macrophytes, rather than by providing a refuge for
zooplankton grazers, control phytoplankton through other associated mechanisms and confirm that the recovery of submerged
macrophytes is essential for biomanipulation success. Although the longer term effect of biomanipulation is disputable, increased
ecological quality could be maintained for several years, which is particularly interesting in an urban area where nutrient
loading reduction is often not feasible. 相似文献
996.
Multiple new prokaryotic C-terminal protein-sorting signals were found that reprise the tripartite architecture shared by LPXTG and PEP-CTERM: motif, TM helix, basic cluster. Defining hidden Markov models were constructed for all. PGF-CTERM occurs in 29 archaeal species, some of which have more than 50 proteins that share the domain. PGF-CTERM proteins include the major cell surface protein in Halobacterium, a glycoprotein with a partially characterized diphytanylglyceryl phosphate linkage near its C terminus. Comparative genomics identifies a distant exosortase homolog, designated archaeosortase A (ArtA), as the likely protein-processing enzyme for PGF-CTERM. Proteomics suggests that the PGF-CTERM region is removed. Additional systems include VPXXXP-CTERM/archeaosortase B in two of the same archaea and PEF-CTERM/archaeosortase C in four others. Bacterial exosortases often fall into subfamilies that partner with very different cohorts of extracellular polymeric substance biosynthesis proteins; several species have multiple systems. Variant systems include the VPDSG-CTERM/exosortase C system unique to certain members of the phylum Verrucomicrobia, VPLPA-CTERM/exosortase D in several alpha- and deltaproteobacterial species, and a dedicated (single-target) VPEID-CTERM/exosortase E system in alphaproteobacteria. Exosortase-related families XrtF in the class Flavobacteria and XrtG in Gram-positive bacteria mark distinctive conserved gene neighborhoods. A picture emerges of an ancient and now well-differentiated superfamily of deeply membrane-embedded protein-processing enzymes. Their target proteins are destined to transit cellular membranes during their biosynthesis, during which most undergo additional posttranslational modifications such as glycosylation. 相似文献
997.
Tsiang M Jones GS Niedziela-Majka A Kan E Lansdon EB Huang W Hung M Samuel D Novikov N Xu Y Mitchell M Guo H Babaoglu K Liu X Geleziunas R Sakowicz R 《The Journal of biological chemistry》2012,287(25):21189-21203
tert-Butoxy-(4-phenyl-quinolin-3-yl)-acetic acids (tBPQA) are a new class of HIV-1 integrase (IN) inhibitors that are structurally distinct from IN strand transfer inhibitors but analogous to LEDGINs. LEDGINs are a class of potent antiviral compounds that interacts with the lens epithelium-derived growth factor (LEDGF) binding pocket on IN and were identified through competition binding against LEDGF. LEDGF tethers IN to the host chromatin and enables targeted integration of viral DNA. The prevailing understanding of the antiviral mechanism of LEDGINs is that they inhibit LEDGF binding to IN, which prevents targeted integration of HIV-1. We showed that in addition to the properties already known for LEDGINs, the binding of tBPQAs to the IN dimer interface inhibits IN enzymatic activity in a LEDGF-independent manner. Using the analysis of two long terminal repeat junctions in HIV-infected cells, we showed that the inhibition by tBPQAs occurs at or prior to the viral DNA 3'-processing step. Biochemical studies revealed that this inhibition operates by compound-induced conformational changes in the IN dimer that prevent proper assembly of IN onto viral DNA. For the first time, tBPQAs were demonstrated to be allosteric inhibitors of HIV-1 IN displaying a dual mode of action: inhibition of IN-viral DNA assembly and inhibition of IN-LEDGF interaction. 相似文献
998.
Brison Y Pijning T Malbert Y Fabre É Mourey L Morel S Potocki-Véronèse G Monsan P Tranier S Remaud-Siméon M Dijkstra BW 《The Journal of biological chemistry》2012,287(11):7915-7924
ΔN123-glucan-binding domain-catalytic domain 2 (ΔN123-GBD-CD2) is a truncated form of the bifunctional glucansucrase DSR-E from Leuconostoc mesenteroides NRRL B-1299. It was constructed by rational truncation of GBD-CD2, which harbors the second catalytic domain of DSR-E. Like GBD-CD2, this variant displays α-(1→2) branching activity when incubated with sucrose as glucosyl donor and (oligo-)dextran as acceptor, transferring glucosyl residues to the acceptor via a ping-pong bi-bi mechanism. This allows the formation of prebiotic molecules containing controlled amounts of α-(1→2) linkages. The crystal structure of the apo α-(1→2) branching sucrase ΔN123-GBD-CD2 was solved at 1.90 Å resolution. The protein adopts the unusual U-shape fold organized in five distinct domains, also found in GTF180-ΔN and GTF-SI glucansucrases of glycoside hydrolase family 70. Residues forming subsite −1, involved in binding the glucosyl residue of sucrose and catalysis, are strictly conserved in both GTF180-ΔN and ΔN123-GBD-CD2. Subsite +1 analysis revealed three residues (Ala-2249, Gly-2250, and Phe-2214) that are specific to ΔN123-GBD-CD2. Mutation of these residues to the corresponding residues found in GTF180-ΔN showed that Ala-2249 and Gly-2250 are not directly involved in substrate binding and regiospecificity. In contrast, mutant F2214N had lost its ability to branch dextran, although it was still active on sucrose alone. Furthermore, three loops belonging to domains A and B at the upper part of the catalytic gorge are also specific to ΔN123-GBD-CD2. These distinguishing features are also proposed to be involved in the correct positioning of dextran acceptor molecules allowing the formation of α-(1→2) branches. 相似文献
999.
Mingjian Shi Vadim Pedchenko Briana H. Greer Wade D. Van Horn Samuel A. Santoro Charles R. Sanders Billy G. Hudson Brandt F. Eichman Roy Zent Ambra Pozzi 《The Journal of biological chemistry》2012,287(42):35139-35152
Integrin α1β1 binding to collagen IV, which is mediated by the α1-inserted (I) domain, down-regulates collagen synthesis. When unligated, a salt bridge between Arg287 and Glu317 is thought to keep this domain in a low affinity conformation. Ligand binding opens the salt bridge leading to a high-affinity conformation. How modulating integrin α1β1 affinity alters collagen homeostasis is unknown. To address this question, we utilized a thermolysin-derived product of the α1α2α1 network of collagen IV (α1α2α1(IV) truncated protomer) that selectively binds integrin α1β1. We show that an E317A substitution enhanced binding to the truncated protomer, consistent with a previous finding that this substitution eliminates the salt bridge. Surprisingly, we show that an R287A substitution did not alter binding, whereas R287E/E317R substitutions enhanced binding to the truncated protomer. NMR spectroscopy and molecular modeling suggested that eliminating the Glu317 negative charge is sufficient to induce a conformational change toward the open state. Thus, the role played by Glu317 is largely independent of the salt bridge. We further show that cells expressing E317A or R287E/E317R substitutions have enhanced down-regulation of collagen IV synthesis, which is mediated by the ERK/MAPK pathway. In conclusion, we have demonstrated that modulating the affinity of the extracellular α1 I domain to collagen IV enhances outside-in signaling by potentiating ERK activation and enhancing the down-regulation of collagen synthesis. 相似文献
1000.
One of the most recognised and studied family of peptide hormones is the insulin superfamily. Within this family is the relaxin subfamily which comprises seven members: relaxin-1, -2 and -3 and insulin-like peptides 3, 4, 5 and 6. Besides exhibiting sequence similarities, each member exists as an active A-B heterodimer linked by three disulfide bonds. This mini-review is divided into three broad themes: an overview of all insulin superfamily members (including structural similarities); roles of each superfamily member and finally, a focus on the pleiotropic peptide hormone, human relaxin-2. In addition to promoting vasodilatory effects leading to evaluation in Phase III clinical trials for the treatment of acute heart failure, relaxin has recently been shown to be highly expressed by cancer cells, aiding in their proliferation, invasiveness and metastasis. These contrary effects of relaxin are discussed together with current efforts in the development of relaxin antagonists that may possess future therapeutic potential for the treatment of certain cancers. 相似文献