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991.
AS Vaidya B Karumudi E Mendonca A Madriaga H Abdelkarim RB van Breemen PA Petukhov 《Bioorganic & medicinal chemistry letters》2012,22(15):5025-5030
The design, modeling, synthesis, biological evaluation of a novel series of photoreactive benzamide probes for class I HDAC isoforms is reported. The probes are potent and selective for HDAC1 and 2 and are efficient in crosslinking to HDAC2 as demonstrated by photolabeling experiments. The probes exhibit a time-dependent inhibition of class I HDACs. The inhibitory activities of the probes were influenced by the positioning of the aryl and alkyl azido groups necessary for photocrosslinking and attachment of the biotin tag. The probes inhibited the deacetylation of H4 in MDA-MB-231 cell line, indicating that they are cell permeable and target the nuclear HDACs. 相似文献
992.
Ash Bahl Patrick Barton Keith Bowers Moya V. Caffrey Rebecca Denton Peter Gilmour Shaun Hawley Tero Linannen Christopher A. Luckhurst Tobias Mochel Matthew W.D. Perry Robert J. Riley Emma Roe Brian Springthorpe Linda Stein Peter Webborn 《Bioorganic & medicinal chemistry letters》2012,22(21):6694-6699
The discovery and optimisation of a series of zwitterionic CCR3 antagonists is described. Optimisation of the structure led to AZ12436092, a compound with excellent selectivity over activity at hERG and outstanding pharmacokinetics in preclinical species. 相似文献
993.
Aditya Sudheer Vaidya Raghupathi Neelarapu Antonett Madriaga He Bai Emma Mendonca Hazem Abdelkarim Richard B. van Breemen Sylvie Y. Blond Pavel A. Petukhov 《Bioorganic & medicinal chemistry letters》2012,22(21):6621-6627
A novel series of HDAC8 inhibitors without a zinc-chelating hydroxamic acid moiety is reported. Photoaffinity labeling and molecular modeling studies suggest that these ligands are likely to bind in an ‘upside-down’ fashion in a secondary binding site proximal to the main catalytic site. The most potent ligand in the series exhibits an IC50 of 28 μM for HDAC8 and is found to inhibit the deacetylation of H4 but not α-tubulin in SH-SY5Y cell line. 相似文献
994.
Z Yang EP Bennett B Jørgensen DP Drew E Arigi U Mandel P Ulvskov SB Levery H Clausen BL Petersen 《Plant physiology》2012,160(1):450-463
Glycosylation is the most abundant and complex posttranslational modification to be considered for recombinant production of therapeutic proteins. Mucin-type (N-acetylgalactosamine [GalNAc]-type) O-glycosylation is found in eumetazoan cells but absent in plants and yeast, making these cell types an obvious choice for de novo engineering of this O-glycosylation pathway. We previously showed that transient implementation of O-glycosylation capacity in plants requires introduction of the synthesis of the donor substrate UDP-GalNAc and one or more polypeptide GalNAc-transferases for incorporating GalNAc residues into proteins. Here, we have stably engineered O-glycosylation capacity in two plant cell systems, soil-grown Arabidopsis (Arabidopsis thaliana) and tobacco (Nicotiana tabacum) Bright Yellow-2 suspension culture cells. Efficient GalNAc O-glycosylation of two stably coexpressed substrate O-glycoproteins was obtained, but a high degree of proline hydroxylation and hydroxyproline-linked arabinosides, on a mucin (MUC1)-derived substrate, was also observed. Addition of the prolyl 4-hydroxylase inhibitor 2,2-dipyridyl, however, effectively suppressed proline hydroxylation and arabinosylation of MUC1 in Bright Yellow-2 cells. In summary, stably engineered mammalian type O-glycosylation was established in transgenic plants, demonstrating that plants may serve as host cells for the production of recombinant O-glycoproteins. However, the present stable implementation further strengthens the notion that elimination of endogenous posttranslational modifications may be needed for the production of protein therapeutics. 相似文献
995.
Aims
In the present study, we analysed the diversity of indigenous arbuscular mycorrhizal fungi (AMF) colonising both the roots and rhizosphere soil of an annual herbaceous species, Bromus rubens, and a perennial herbaceous species, Brachypodium retusum, co-occurring in the same Mediterranean, semiarid degraded area. The intention was to study whether these two species promoted the diversity of AM fungi in their rhizospheres differently and to ascertain whether the AMF community harboured by an annual plant species differed from that harboured by a perennial species when both grew in the same place.Methods
The AMF large subunit ribosomal RNA genes (LSU) were subjected to nested PCR, cloning, sequencing and phylogenetic analysis.Results
Twenty AMF sequence types belonging to Glomus group A, Glomus group B and Diversispora were identified. The two plant species differed in the AMF community composition in their roots, B. rubens showing a higher diversity of AMF than B. retusum. However the composition of the AMF communities associated with the two rhizosphere soils was similar.Conclusions
These results suggest that the management of these Mediterranean, semiarid degraded areas should include the promotion of annual herbaceous plant communities in order to maintain the sustainability and productivity of these ecosystems. 相似文献996.
The role of disease in the long-term dynamics of threatened species is poorly quantified, as well as being under-represented
in ecology and conservation management. To understand persistent host–pathogen interaction operating in a vulnerable habitat,
we quantified dynamics driving patterns of seagrass density using a longitudinal study in a relatively pristine site (Isles
of Scilly, UK). Replicated samples of eelgrass (Zostera marina) density and wasting disease prevalence, presumably caused by Labyrinthula zosterae, were taken from five meadows at the height of the growing season, over the years 1997–2010. Data were used to parameterise
a population dynamic model, incorporating density-dependent factors and sea temperature records. We found that direct density
and disease-mediated feedback operate within a network of local populations. Furthermore, our results indicate that the strength
of limitation to seagrass growth by disease was increased at higher temperatures. This modification of the coupled host–pathogen
dynamics forms a novel hypothesis to account for dramatic die-backs of Z. marina widely reported elsewhere. Our findings highlight the importance of disease in structuring distributions of vulnerable species,
as well as the application of population modelling in order to reveal ecological processes and prioritise future mechanistic
investigation. 相似文献
997.
Emma Granqvist Derin Wysham Saul Hazledine Wojciech Kozlowski Jongho Sun Myriam Charpentier Teresa Vaz Martins Pauline Haleux Krasimira Tsaneva-Atanasova J. Allan Downie Giles E.D. Oldroyd Richard J. Morris 《Plant physiology》2012,160(4):2300-2310
Legumes form symbioses with rhizobial bacteria and arbuscular mycorrhizal fungi that aid plant nutrition. A critical component in the establishment of these symbioses is nuclear-localized calcium (Ca2+) oscillations. Different components on the nuclear envelope have been identified as being required for the generation of the Ca2+ oscillations. Among these an ion channel, Doesn''t Make Infections1, is preferentially localized on the inner nuclear envelope and a Ca2+ ATPase is localized on both the inner and outer nuclear envelopes. Doesn''t Make Infections1 is conserved across plants and has a weak but broad similarity to bacterial potassium channels. A possible role for this cation channel could be hyperpolarization of the nuclear envelope to counterbalance the charge caused by the influx of Ca2+ into the nucleus. Ca2+ channels and Ca2+ pumps are needed for the release and reuptake of Ca2+ from the internal store, which is hypothesized to be the nuclear envelope lumen and endoplasmic reticulum, but the release mechanism of Ca2+ remains to be identified and characterized. Here, we develop a mathematical model based on these components to describe the observed symbiotic Ca2+ oscillations. This model can recapitulate Ca2+ oscillations, and with the inclusion of Ca2+-binding proteins it offers a simple explanation for several previously unexplained phenomena. These include long periods of frequency variation, changes in spike shape, and the initiation and termination of oscillations. The model also predicts that an increase in buffering capacity in the nucleoplasm would cause a period of rapid oscillations. This phenomenon was observed experimentally by adding more of the inducing signal.Plant growth is frequently limited by the essential nutrients nitrogen and phosphorus. Several plant species have established symbiotic relationships with microorganisms to overcome such limitations. In addition to the symbiotic relationship with arbuscular mycorrhizal fungi that many plants establish in order to secure their uptake of water, phosphorus, and other nutrients (Harrison, 2005; Parniske, 2008), legumes have developed interactions with bacteria called rhizobia, resulting in the fixation of atmospheric nitrogen within the plant root (Lhuissier et al., 2001; Gage, 2004; Riely et al., 2006).Root symbioses initiate with signal exchanges in the soil. Plant signals are perceived by the symbionts, triggering the successive release of microbial signals. For rhizobia, the signal molecules are lipochitooligosaccharides termed Nod factors (Dénarié et al., 1996), and the release of lipochitooligosaccharides has also been found in the fungal interaction (Maillet et al., 2011). Upon receiving diffusible signals from the microsymbionts, the plant roots initiate developmental programs that lead to infection by rhizobia or arbuscular mycorrhizal fungi. Both programs employ the same signaling pathway with several components being common to both mycorrhizal and rhizobial interactions (Kistner and Parniske, 2002; Lima et al., 2009). In particular, both the symbioses show characteristic perinuclear and nucleoplasmic localized calcium (Ca2+) oscillations, so-called Ca2+ spiking (Oldroyd and Downie, 2006; Sieberer et al., 2009). It has been suggested that Ca2+ is released from an internal store, most likely the nuclear lumen and associated endoplasmic reticulum (ER; Matzke et al., 2009), with targeted release in the nuclear region (Capoen et al., 2011).Genetic screens in the model legume Medicago truncatula have identified several genes that are required for the plant in the establishment of both symbioses. Two of these, Doesn’t Make Infections1 (DMI1) and DMI2, are essential for the induction of the Ca2+ oscillations, yet the precise roles and mechanisms of these components remain to be determined. DMI2 codes for a plasma membrane receptor-like kinase (Endre et al., 2002; Stracke et al., 2002) that is required to facilitate further signal transduction in the cell (Bersoult et al., 2005). DMI1 is a cation channel located preferentially on the inner nuclear envelope (Ané et al., 2004; Edwards et al., 2007; Riely et al., 2007; Charpentier et al., 2008; Capoen et al., 2011; Venkateshwaran et al., 2012). DMI3 encodes a calcium calmodulin-dependent protein kinase that interacts with downstream components and is thought to be the decoder of the Ca2+ oscillations (Lévy et al., 2004; Mitra et al., 2004; Hayashi et al., 2010). Additional genes coding for three nucleoporins called NUP85, NUP133, and NENA are also required for Ca2+ oscillations (Kanamori et al., 2006; Saito et al., 2007; Groth et al., 2010). The nuclear pore might be involved in trafficking secondary signals and/or ion channels to the inner nuclear membrane. These shared signaling components are collectively referred to as the common Sym pathway.DMI1 plays a key role in the production of Ca2+ oscillations, but its exact mechanism is still unknown. Orthologs of DMI1 have been found; in Lotus japonicus, they are called CASTOR and POLLUX (Charpentier et al., 2008), and in pea (Pisum sativum), SYM8 (Edwards et al., 2007). CASTOR and POLLUX, as well as calcium calmodulin-dependent protein kinase, are highly conserved both in legumes and nonlegumes (Banba et al., 2008; Chen et al., 2009). This highlights the essential role of the Ca2+ oscillations in mycorrhizal signaling.DMI1 is not the channel responsible for the release of Ca2+ (Charpentier et al., 2008; Parniske, 2008; Venkateshwaran et al., 2012) but probably influences the activity of Ca2+ channels. This is similar to how some K+ channels act in other plants and yeast (Peiter et al., 2007). Indeed, DMI1 is possibly a K+-permeable channel, based on the observation that POLLUX complements K+ transport in yeast (Charpentier et al., 2008). In symbiosis, the mode of action of DMI1 could be to allow cations into the nuclear envelope and in that way counterbalance the transmembrane charge that would occur following the release of Ca2+ into the nucleoplasm and cytoplasm. The cation channel could thus change the electrical potential across the nuclear membranes, affecting the opening of the voltage-activated Ca2+ channels (Edwards et al., 2007). This hypothesis is supported by a study reporting a membrane potential over the nuclear envelope in plants (Matzke and Matzke, 1986).Pharmacological evidence and the characteristics of the Ca2+ oscillations supports the involvement of Ca2+ pumps and Ca2+ channels (Engstrom et al., 2002). The pumps are needed to resequester Ca2+ after each release event, actively transporting Ca2+ against the concentration gradient using ATP. A recent study found a SERCA-type Ca2+ ATPase, MCA8, that is located on the inner and outer nuclear envelope of M. truncatula and is required for the symbiotic Ca2+ oscillations (Capoen et al., 2011). Such SERCA pumps are widely distributed on plant membranes, and the variation in their structure points to them being differentially regulated (Sze et al., 2000).Ca2+ channels release Ca2+ from the store, and the mechanism of activating these Ca2+ channels has been hypothesized to be voltage gated (Edwards et al., 2007; Oldroyd and Downie, 2008), but this remains to be verified experimentally. After release of Ca2+ into the cytosol and nucleoplasm, buffers quickly bind to and remove these free ions due to their toxicity to the cell (Sanders et al., 2002). Buffers, i.e. molecules that can bind Ca2+, may play an important role in determining the nonlinear behavior of the oscillatory system for Ca2+ signaling (Falcke, 2004). As numerous Ca2+ buffers are present in cells, it is important to take their contribution into account. Such buffers can also include experimentally introduced dyes and Ca2+ chelators.In Capoen et al. (2011), we investigated the establishment and transmission of spatial waves across the nuclear envelope and demonstrated that the key components for Ca2+ spiking reside on the inner and outer surface of the nuclear membrane. The computational framework we employed for this analysis makes a number of approximations in order to provide the computational efficiency required to perform spatiotemporal simulations. Here, a main focus is to understand the effect of buffers on the Ca2+ oscillations.In this article, we propose a mathematical model based on three key proteins; a Ca2+ ATPase, a voltage-gated Ca2+ channel, and the cation channel DMI1. The model reproduces the symbiotic Ca2+ oscillations, and we further demonstrate that Ca2+-binding proteins can explain initiation, termination, and experimentally observed variation in oscillation patterns. Furthermore, the model predicts that increases in buffering capacity can cause a period of rapid oscillations, and these were observed experimentally. 相似文献
998.
Water as an Essential Resource: Orb Web Spiders Cannot Balance Their Water Budget by Prey Alone 总被引:1,自引:0,他引:1
André Walter Natasha Cadenhead Valerie Sze Weii Lee Charlie Dove Emma Milley Mark A. Elgar 《Ethology : formerly Zeitschrift fur Tierpsychologie》2012,118(6):534-542
Water is essential for all living organisms because it acts as a major solvent and reaction medium. Terrestrial animals may lose water through evaporation and excretion and consequently have evolved strategies to balance their water budget by either minimising losses or by gaining water. The major pathway to gain water is via food intake, although many animals additionally drink free water. Spiders acquire substantial amounts of water by ingesting enzymatically liquefied prey. However, this may not account for the water needs of some species. We tested whether drinking is essential for orb web spiders of the genus Argiope by experimentally manipulating the diet (flies or crickets) and water supply (no water or a daily shower) to females and then measuring their subsequent drinking behaviour. Individuals of Argiope trifasciata, which are typically found in dry habitats, increased their body mass when fed crickets but not when fed flies. However, spiders deprived of water subsequently ingested significantly more water than spiders that received water every day, regardless of their feeding regime. This pattern was replicated in Argiope aetherea, which is found in the tropics and perhaps less likely to be water deprived in natural populations. Our results reveal that drinking allows these spiders to realise their water balance independent from the nutritional status. We suggest that the spiders may need to drink fresh water to process ingested nutrients. 相似文献
999.
Methane emissions have been previously detected from orangutans, but characterization of the diversity of methanogens in this species has yet to be completed. This preliminary study identified methanogen producing microorganims, also called methanogens, present in the feces from a colony of captive Sumatran orangutans at the Perth Zoo. All animals were housed in the same enclosure and were fed primarily a frugivorous diet. Methanogens were detected using a 16S rRNA gene clone library. A total of 207 clones were examined, revealing 37 different methanogen 16S rRNA sequences, or phylotypes. Of these, 31 phylotypes represented by 170 clones had 96.4-100% sequence identity to Methanosphaera stadtmanae, four phylotypes (32 clones) had 95.1-100% sequence identity to Methanobrevibacter smithii, while two phylotypes (five clones) had 95.9-97.7% sequence identity to Methanobacterium beijingense. Overall, five possible new species were identified from the clone library. This represents the first report of Msp. stadtmanae, a methanol utilizer, as the most predominant methanogen in the gastrointestinal tract of animals. This is likely due to the increased availability of methanol from the highly frugivorous diet of the orangutans. Further studies are warranted to properly assess the effects of frugivorous diets on the methanogen population. 相似文献
1000.
Mercer JR Yu E Figg N Cheng KK Prime TA Griffin JL Masoodi M Vidal-Puig A Murphy MP Bennett MR 《Free radical biology & medicine》2012,52(5):841-849
A number of recent studies suggest that mitochondrial oxidative damage may be associated with atherosclerosis and the metabolic syndrome. However, much of the evidence linking mitochondrial oxidative damage and excess reactive oxygen species (ROS) with these pathologies is circumstantial. Consequently the importance of mitochondrial ROS in the etiology of these disorders is unclear. Furthermore, the potential of decreasing mitochondrial ROS as a therapy for these indications is not known. We assessed the impact of decreasing mitochondrial oxidative damage and ROS with the mitochondria-targeted antioxidant MitoQ in models of atherosclerosis and the metabolic syndrome (fat-fed ApoE(-/-) mice and ATM(+/-)/ApoE(-/-) mice, which are also haploinsufficient for the protein kinase, ataxia telangiectasia mutated (ATM). MitoQ administered orally for 14weeks prevented the increased adiposity, hypercholesterolemia, and hypertriglyceridemia associated with the metabolic syndrome. MitoQ also corrected hyperglycemia and hepatic steatosis, induced changes in multiple metabolically relevant lipid species, and decreased DNA oxidative damage (8-oxo-G) in multiple organs. Although MitoQ did not affect overall atherosclerotic plaque area in fat-fed ATM(+/+)/ApoE(-/-) and ATM(+/-)/ApoE(-/-) mice, MitoQ reduced the macrophage content and cell proliferation within plaques and 8-oxo-G. MitoQ also significantly reduced mtDNA oxidative damage in the liver. Our data suggest that MitoQ inhibits the development of multiple features of the metabolic syndrome in these mice by affecting redox signaling pathways that depend on mitochondrial ROS such as hydrogen peroxide. These findings strengthen the growing view that elevated mitochondrial ROS contributes to the etiology of the metabolic syndrome and suggest a potential therapeutic role for mitochondria-targeted antioxidants. 相似文献