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51.
Ulrich Reineke Jens Schneider‐Mergener Ralf W. Glaser Rolf‐Dietrich Stigler Martina Seifert Hans‐Dieter Volk Robert Sabat 《Journal of molecular recognition : JMR》1999,12(4):242-248
We present the mapping of two anti‐human interleukin‐10 (hIL‐10) antibodies (CB/RS/2 and CB/RS/11) which have been described as binding their antigen cooperatively. The epitopes were identified using hIL‐10‐derived overlapping peptide scans prepared by spot synthesis. To identify residues essential for binding within the two epitopes, each position was replaced by all other L ‐amino acids. The epitope‐derived peptides were further characterized with respect to antibody affinity and their inhibition of the antibody–hIL‐10 interaction. One antibody (CB/RS/11) binds to residues which are completely buried in the X‐ray structure of IL‐10. Accessibility of this hidden epitope is enhanced upon binding of the antibody CB/RS/2, which recognizes a discontinuous epitope located nearby. The recognition of the hidden CB/RS/11 epitope, as well as the cooperative binding behaviour of the two antibodies, provides evidence that IL‐10 can adopt a conformational state other than that observed in the crystal structure. Copyright © 1999 John Wiley & Sons, Ltd. 相似文献
52.
Zacharia S. Cheruvallath Stephen L. Gwaltney Mark Sabat Mingnam Tang Haixia Wang Andy Jennings David Hosfield Bumsup Lee Yiqin Wu Petro Halkowycz Charles E. Grimshaw 《Bioorganic & medicinal chemistry letters》2017,27(12):2678-2682
Guided by co-crystal structural information obtained from a different series we were exploring, a scaffold morphing and SBDD approach led to the discovery of the 1,4-disubstituted indazole series as a novel class of GKAs that potently activate GK in enzyme and cell assays. anti-diabetic OGTT efficacy was demonstrated with 29 in a rodent models of type 2 diabetes. 相似文献
53.
Artur J Sabat Benedykt Wladyka Klaudia Kosowska-Shick Hajo Grundmann Jan Maarten van Dijl Julia Kowal Peter C Appelbaum Adam Dubin Waleria Hryniewicz 《BMC microbiology》2008,8(1):129
Background
Staphylococcus aureus expresses several proteases, which are thought to contribute to the virulence of this bacterium. Here we focus on aureolysin, the major thermolysin-like metalloprotease. Despite the importance of aureolysin in the physiology and pathogenesis of S. aureus, relatively little information was so far available concerning the aur gene diversity and mobility within and between the major subdivisions of the S. aureus population. Therefore, an epidemiologically and genetically diverse collection of S. aureus strains was used to determine the range of aureolysin (aur) gene polymorphism. 相似文献54.
Naya DE Ebensperger LA Sabat P Bozinovic F 《Physiological and biochemical zoology : PBZ》2008,81(2):186-194
Lactation is the most energetically demanding period in the life cycle of female mammals, and its effects on digestive flexibility and the size of internal organs have been extensively studied in laboratory mice and rats since the early 1900s. However, there have been only two studies on this topic for wild rodent species. Here, we analyzed digestive flexibility--that is, changes in gut content, activity of digestive enzymes, and gut morphology--during lactation in the caviomorph rodent Octodon degus. In addition, we evaluated changes in the size of other internal organs and analyzed their relationship with the resting metabolic rate. We found that gut content, the dry masses of digestive chambers, the dry mass of liver, and resting metabolic rate were greater in lactating than in nonbreeding control females. In contrast, fat stores were higher in control subjects. Maltase and aminopeptidase-N specific activity did not change with lactation, and both enzymes had greater activity values in the middle portion of the small intestine. Thus, our data indicate that the previously reported increase in food assimilation that occurs during lactation in O. degus is related to a mass increase in several central organs, leading, in turn, to higher energetic costs. Fat stores may help to mitigate these costs, but, as expected for small animals, to a limited extent. Our study reveals a complex interplay among energy acquisition, storage, and expenditure processes that ultimately determine an organism's fitness. 相似文献
55.
56.
Pablo Sabat Sandra Gonzalez-Vejares Karin Maldonado 《Comparative biochemistry and physiology. Part A, Molecular & integrative physiology》2009,152(3):322-326
The urine field osmolality in Zonotrichia capensis along a latitudinal gradient in rainfall and temperature in Chile was examined. We also investigated latitudinal variation in the renal traits that mediate how these birds cope with dehydration. We used the δ15N of this species' tissue to investigate whether the reliance on animals and seeds varied among birds and if it had any effect on excretion and renal traits. We found a significant latitudinal variation in urine osmolality, a variable that was correlated with habitat aridity. We also found that the kidney size and proportion of kidney devoted to medullary tissue differed between birds from arid and mesic localities, but not in a lineal fashion with aridity. The increment in the position in the food web, as measured by δ15N, led to an increment in urine osmolality, without changes in kidney features. Our data suggested that differences in dietary habits in the field could be not extended enough to cause changes in the kidney structure in Rufous-collared sparrows. 相似文献
57.
58.
Mark AJ Roberts Elias August Abdullah Hamadeh Philip K Maini Patrick E McSharry Judith P Armitage Antonis Papachristodoulou 《BMC systems biology》2009,3(1):105-14
Background
Developing methods for understanding the connectivity of signalling pathways is a major challenge in biological research. For this purpose, mathematical models are routinely developed based on experimental observations, which also allow the prediction of the system behaviour under different experimental conditions. Often, however, the same experimental data can be represented by several competing network models. 相似文献59.
Luis AJ Mur Amanda J Lloyd Simona M Cristescu Frans JM Harren Michael A Hall Aileen R Smith 《Plant signaling & behavior》2009,4(7):610-613
The hypersensitive response (HR) is a cell death phenomenon associated with localized resistance to pathogens. Biphasic patterns in the generation of H2O2, salicylic acid and ethylene have been observed in tobacco during the early stages of the HR. These biphasic models reflect an initial elicitation by pathogen-associated molecular patterns followed by a second phase, induced by pathogen-encoded avirulence gene products. The first phase has been proposed to potentiate the second, to increase the efficacy of plant resistance to disease. This potentiation is comparable to the “priming” of plant defenses which is seen when plants display systemic resistance to disease. The events regulating the generation of the biphasic wave, or priming, remains obscure, however recently we demonstrated a key role for nitric oxide in this process in a HR occurring in tobacco. Here we use laser photoacoustic detection to demonstrate that biphasic ethylene production also occurs during a HR occurring in Arabidopsis. We suggest that ethylene emanation during the HR represents a ready means of visualising biphasic events during the HR and that exploiting the genomic resources offered by this model species will facilitate the development of a mechanistic understanding of potentiating/priming processes.Key words: hypersensitive response, biphasic patterns, potentiation, defense priming, ethylene, ArabidopsisThe Hypersensitive Response (HR) is a cell death process which occurs at the site of attempted pathogen attack and which has been associated with host resistance.1 Much work on the regulation of the HR has indicated the importance of H2O2,2 and NO.3 A feature of H2O2 generation during the HR is its biphasic pattern (Fig. 1A). The first rise reflects elicitation by pathogen-associated molecular patterns (PAMPs)4 and the second reflects the interaction between a pathogen-encoded avirulence (avr) gene product with a plant resistance (R) gene. A key aspect of the first rise is the initiation of salicylic acid (SA) synthesis which potentiates the second rise and hence the potency of plant defense and the HR.5Open in a separate windowFigure 1Patterns of defense signal generation during the Pseudomonas syringae pv. phaseolicola elicited-hypersensitive response in tobacco (Nicotiana tabacum). Generation of (A) H2O2 (●, Mur18); (B) nitric oxide (◇; Mur12 (C) salicylic acid (SA, ■19) and (D) ethylene (○ Mur9) during a HR elicited by Pseudomonas syringae pv. phaseolicola (Psph) in tobacco cv. Samsun NN. In (A) a phase where SA acts to augment the second rise in H2O2—the potentiation phase—is highlighted. The potentiation phase is likely to be similar to defense “priming”.6 Methodological details are contained within the appropriate references. (E) A possible model for biphasic defense signal regulation during the Psph-elicited HR in tobacco. During an initial phase NO and H2O2 act to initiate SA biosynthesis, where SA and NO act to initiate a “H2O2 biphasic switch”. This could initially suppress both SA and the H2O2 generation but subsequently acts to potentiate a second phase of H2O2 generation. This in turn increases SA biosynthesis which could act with NO to initiate the “C2H4 biphasic switch” to potentiate ethylene production. These (and other) signals contribute to initiation of the HR and SAR.This potentiation mechanism appears to be similar to defense priming; when whole plants display systemic resistance to disease as opposed to a localized resistance against pathogens. Priming can be initiated (the “primary stimulus”) following attack with a necrotizing pathogen (leading to “systemic acquired resistance”, SAR) or non-pathogenic rhizosphere bacteria (to confer “induced systemic resistance”, ISR). In the primed state a plant stimulates a range of plant defense genes, produces anti-microbial phytoalexins and deposits cell wall strengthening molecules, but only on imposition of a “secondary stimulus”.6 Such secondary stimuli include SA3 or PAMPs7 and is likely to be mechanistically similar to the potentiation step in the biphasic pattern of H2O2 generation (shaded in Fig. 1A). Accordingly, the two phases in the biphasic wave represent primary and secondary stimuli in priming.Highlighting a similarity between local HR-based events and priming, adds further impetus to efforts aiming to describe the underlying mechanism(s), however both phenomena remain poorly understood. Besides SA, both jasmonates and abscisic acid (ABA) have been shown to prime defenses as have a range of non-plant chemicals, with β-aminobutyric acid (BABA) being perhaps most widely used.6,8 Mutants which fail to exhibit BABA-mediated potentiation were defective in either a cyclin-dependent kinase-like protein, a polyphosphoinositide phosphatase or an ABA biosynthetic enzyme.8We have recently investigated biphasic ethylene production during the HR in tobacco elicited by the nonhost HR-eliciting bacterial pathogen Pseudomonas syringae pv. phaseolicola.9 As with H2O2 generation, this pattern reflected PAMP-and AVR-dependent elicitation events and included a SA-mediated potentiation stage. Crucially, we also showed that NO was a vital component in the SA-potentiation mechanism. When this finding is integrated with our other measurements of defense signal generation in the same host-pathogen system the complexity in the signaling network is revealed (Fig. 1). NO generation (Fig. 1B) appeared to be coincident with the first rise in H2O2 (Fig. 1A) which initiated SA biosynthesis10,11 and together would contribute to the first small, but transient, rise in that hormone (Fig. 1C). In line with established models5 this momentary rise in SA coincides with the potentiation phase (shaded in Fig. 1A) required to augment the second rise in ROS. However, ethylene production seems to be correlated poorly with the patterns of NO, H2O2 and SA (Fig. 1D). Nevertheless, biphasic ethylene production was found to reflect PAMP and AVR-dependent recognition and included a SA-mediated potentiation step.9 Hence, ethylene production could be used as a post-hoc indicator of the potentiation mechanism. Therefore, our discovery that the second wave of ethylene production—a “biphasic switch”—is influenced by NO acting with SA could also be relevant to the H2O2 generation. Significantly, the second phases in both H2O2 and ethylene production occur exactly where SA and NO production coincides; in the case of H2O2 generation 2–4 h post challenge and with ethylene 6 h onwards (Fig. 1E).Thus, ethylene production represents a readily assayable marker to indicate perturbations in the underlying biphasic and possible priming mechanisms. As we have demonstrated, laser photoacoustic detection (LAPD) is a powerful on-line approach to determine in planta ethylene production in tobacco9,12 but any mechanistic investigations would be greatly facilitated if the genetic resources offered by the model species Arabidopsis could be exploited.To address this, Arabidopsis Col-0 rosettes were vacuum infiltrated with either Pseudomonas syringae pv. tomato (Pst) avrRpm1 (HR-eliciting), the virulent Pst strain and the non-HR eliciting and non-virulent Pst hrpA strain. Ethylene production was monitored by LAPD (Fig. 2A). Significantly, Pst avrRpm1 initiated a biphasic pattern of ethylene production whose kinetics were very similar to that seen in tobacco (compare Figs. 2A with with1D).1D). Inoculations with Pst and Pst hrpA only displayed the first PAMP-dependent rise in ethylene production. Thus, these data establish that Arabidopsis can be used to investigate biphasic switch mechanism(s) in ethylene production during the HR and possibly defense priming. When considering such mechanisms, it is relevant to highlight the work of Foschi et al.13 who observed that biphasic activation of a monomeric G protein to cause phase-specific activation of different kinase cascades. Interestingly, ethylene has been noted to initiate biphasic activation of G proteins and kinases in Arabidopsis, although differing in kinetics to the phases seen during the HR.14 Further, plant defense priming has been associated with the increased accumulation of MAP kinase protein.6Open in a separate windowFigure 2Ethylene in the Pseudomonas syringae pv. tomato elicited-hypersensitive response in Arabidopsis thaliana. (A) Ethylene production from 5 week old short day (8 h light 100 µmol.m2.sec−1) grown Arabidopsis rosette leaves which were vacuum infiltrated with bacterial suspensions (2 × 106 colony forming units.ml−1) of Pseudomonas syringae pv. tomato (Pst) strains detected using laser photoacoustic detection (LAPD). Experimental details of the ethylene detection by LAPD are detailed in Mur et al.9 The intercellular spaces in leaves were infiltrated with the HR-eliciting strain Pst avrRpm1, (■), the virulent strain Pst (△) or the non-virulent and non-HR eliciting derivative, Pst hrpA (◇). (B) The appearance of Arabidopsis Col-0 and etr1-1 leaves at various h following injection with 2 × 106 c.f.u.mL−1 with of Pst avrRpm1. (C) Explants (1 cm diameter discs) from Arabidopsis leaf areas infiltrated with suspensions of Pst avrRpm1 were placed in a 1.5 cm diameter well, bathed in 1 mL de-ionized H2O. Changes in the conductivity of the bathing solution, as an indicator of electrolyte leakage from either wild type Col-0 (◆), mutants which were compromised in ethylene signaling; etr1-1 (□), ein2-2 (▲) or which overproduced ethylene; eto2-1 (●) were measured using a conductivity meter. Methodological details are set out in Mur et al.9A further point requires consideration; the role of ethylene as a direct contributor to plant defense.15 The contribution of ethylene to the HR has been disputed,16 but in tobacco we have observed that altered ethylene production influenced the formation of a P. syringae pv. phaseolicola elicited HR.9 In Arabidopsis, cell death in the ethylene receptor mutant etr1-1 following inoculation with Pst avrRpm1 is delayed compared to wild type (Fig. 2B). When electrolyte leakage was used to quantify Pst avrRpm1 cell death, both etr1-1 and the ethylene insensitive signaling mutant ein2-1 exhibited slower death than wild-type but in the ethylene overproducing mutant eto2, cell death was augmented (Fig. 2C). These data indicate that ethylene influences the kinetics of the HR.Taking these data together we suggest that the complexity of signal interaction during the HR or in SAR/ISR could be further dissected by combining the genetic resources of Arabidopsis with measurements of ethylene production using such sensitive approaches as LAPD. 相似文献
60.
Sabat M VanRens JC Laufersweiler MJ Brugel TA Maier J Golebiowski A De B Easwaran V Hsieh LC Walter RL Mekel MJ Evdokimov A Janusz MJ 《Bioorganic & medicinal chemistry letters》2006,16(23):5973-5977
This communication details the synthesis, biological activity, and binding mode of a novel class of 2-benzimidazole substituted pyrimidines. The most potent analogs disclosed showed low nanomolar activity for the inhibition of Lck kinase and a representative analog was co-crystallized with Hck (a structurally related member of the Src family kinases). 相似文献