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761.
Zohreh Hosseinzadeh Dong Luo Mentor Sopjani Shefalee K. Bhavsar Florian Lang 《The Journal of membrane biology》2014,247(4):331-338
Janus kinase-2 (JAK2), a signaling molecule mediating effects of various hormones including leptin and growth hormone, has previously been shown to modify the activity of several channels and carriers. Leptin is known to inhibit and growth hormone to stimulate epithelial Na+ transport, effects at least partially involving regulation of the epithelial Na+ channel ENaC. However, no published evidence is available regarding an influence of JAK2 on the activity of the epithelial Na+ channel ENaC. In order to test whether JAK2 participates in the regulation of ENaC, cRNA encoding ENaC was injected into Xenopus oocytes with or without additional injection of cRNA encoding wild type JAK2, gain-of-function V617FJAK2 or inactive K882EJAK2. Moreover, ENaC was expressed with or without the ENaC regulating ubiquitin ligase Nedd4-2 with or without JAK2, V617FJAK2 or K882EJAK2. ENaC was determined from amiloride (50 μM)-sensitive current (I amil) in dual electrode voltage clamp. Moreover, I amil was determined in colonic tissue utilizing Ussing chambers. As a result, the I amil in ENaC-expressing oocytes was significantly decreased following coexpression of JAK2 or V617FJAK2, but not by coexpression of K882EJAK2. Coexpression of JAK2 and Nedd4-2 decreased I amil in ENaC-expressing oocytes to a larger extent than coexpression of Nedd4-2 alone. Exposure of ENaC- and JAK2-expressing oocytes to JAK2 inhibitor AG490 (40 μM) significantly increased I amil. In colonic epithelium, I amil was significantly enhanced by AG490 pretreatment (40 μM, 1 h). In conclusion, JAK2 is a powerful inhibitor of ENaC. 相似文献
762.
Puneet Juneja Florian Hubrich Kay Diederichs Wolfram Welte Jennifer N. Andexer 《Journal of molecular biology》2014
Chorismate-converting enzymes are involved in many biosynthetic pathways leading to natural products and can often be used as tools for the synthesis of chemical building blocks. Chorismatases such as FkbO from Streptomyces species catalyse the hydrolysis of chorismate yielding (dihydro)benzoic acid derivatives. In contrast to many other chorismate-converting enzymes, the structure and catalytic mechanism of a chorismatase had not been previously elucidated. Here we present the crystal structure of the chorismatase FkbO in complex with a competitive inhibitor at 1.08 Å resolution. FkbO is a monomer in solution and exhibits pseudo-3-fold symmetry; the structure of the individual domains indicates a possible connection to the trimeric RidA/YjgF family and related enzymes. The co-crystallised inhibitor led to the identification of FkbO's active site in the cleft between the central and the C-terminal domains. A mechanism for FkbO is proposed based on both interactions between the inhibitor and the surrounding amino acids and an FkbO structure with chorismate modelled in the active site. We suggest that the methylene group of the chorismate enol ether takes up a proton from an active-site glutamic acid residue, thereby initiating chorismate hydrolysis. A similar chemistry has been described for isochorismatases, albeit implemented in an entirely different protein scaffold. This reaction model is supported by kinetic data from active-site variants of FkbO derived by site-directed mutagenesis. 相似文献
763.
A first step toward the development of a barley NAM population and its utilization to detect QTLs conferring leaf rust seedling resistance 总被引:2,自引:0,他引:2
Florian Schnaithmann Doris Kopahnke Klaus Pillen 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2014,127(7):1513-1525
Key message
We suggest multi-parental nested association mapping as a valuable innovation in barley genetics, which increases the power to map quantitative trait loci and assists in extending genetic diversity of the elite barley gene pool.Abstract
Plant genetic resources are a key asset to further improve crop species. The nested association mapping (NAM) approach was introduced to identify favorable genes in multi-parental populations. Here, we report toward the development of the first explorative barley NAM population and demonstrate its usefulness in a study on mapping quantitative trait loci (QTLs) for leaf rust resistance. The NAM population HEB-5 was developed from crossing and backcrossing five exotic barley donors with the elite barley cultivar ‘Barke,’ resulting in 295 NAM lines in generation BC1S1. HEB-5 was genetically characterized with 1,536 barley SNPs. Across HEB-5 and within the NAM families, no deviation from the expected genotype and allele frequencies was detected. Genetic similarity between ‘Barke’ and the NAM families ranged from 78.6 to 83.1 %, confirming the backcrossing step during population development. To explore its usefulness, a screen for leaf rust (Puccinia hordei) seedling resistance was conducted. Resistance QTLs were mapped to six barley chromosomes, applying a mixed model genome-wide association study. In total, four leaf rust QTLs were detected across HEB-5 and four QTLs within family HEB-F23. Favorable exotic QTL alleles reduced leaf rust symptoms on two chromosomes by 33.3 and 36.2 %, respectively. The located QTLs may represent new resistance loci or correspond to new alleles of known resistance genes. We conclude that the exploratory population HEB-5 can be applied to mapping and utilizing exotic QTL alleles of agronomic importance. The NAM concept will foster the evaluation of the genetic diversity, which is present in our primary barley gene pool. 相似文献764.
Animals, including Humans, are prone to develop persistent maladaptive and suboptimal behaviours. Some of these behaviours have been suggested to arise from interactions between brain systems of Pavlovian conditioning, the acquisition of responses to initially neutral stimuli previously paired with rewards, and instrumental conditioning, the acquisition of active behaviours leading to rewards. However the mechanics of these systems and their interactions are still unclear. While extensively studied independently, few models have been developed to account for these interactions. On some experiment, pigeons have been observed to display a maladaptive behaviour that some suggest to involve conflicts between Pavlovian and instrumental conditioning. In a procedure referred as negative automaintenance, a key light is paired with the subsequent delivery of food, however any peck towards the key light results in the omission of the reward. Studies showed that in such procedure some pigeons persisted in pecking to a substantial level despite its negative consequence, while others learned to refrain from pecking and maximized their cumulative rewards. Furthermore, the pigeons that were unable to refrain from pecking could nevertheless shift their pecks towards a harmless alternative key light. We confronted a computational model that combines dual-learning systems and factored representations, recently developed to account for sign-tracking and goal-tracking behaviours in rats, to these negative automaintenance experimental data. We show that it can explain the variability of the observed behaviours and the capacity of alternative key lights to distract pigeons from their detrimental behaviours. These results confirm the proposed model as an interesting tool to reproduce experiments that could involve interactions between Pavlovian and instrumental conditioning. The model allows us to draw predictions that may be experimentally verified, which could help further investigate the neural mechanisms underlying theses interactions. 相似文献
765.
766.
Jérémy S. P. Froidevaux Florian Zellweger Kurt Bollmann Martin K. Obrist 《Ecology and evolution》2014,4(24):4690-4700
Passive acoustic methods are increasingly used in biodiversity research and monitoring programs because they are cost‐effective and permit the collection of large datasets. However, the accuracy of the results depends on the bioacoustic characteristics of the focal taxa and their habitat use. In particular, this applies to bats which exhibit distinct activity patterns in three‐dimensionally structured habitats such as forests. We assessed the performance of 21 acoustic sampling schemes with three temporal sampling patterns and seven sampling designs. Acoustic sampling was performed in 32 forest plots, each containing three microhabitats: forest ground, canopy, and forest gap. We compared bat activity, species richness, and sampling effort using species accumulation curves fitted with the clench equation. In addition, we estimated the sampling costs to undertake the best sampling schemes. We recorded a total of 145,433 echolocation call sequences of 16 bat species. Our results indicated that to generate the best outcome, it was necessary to sample all three microhabitats of a given forest location simultaneously throughout the entire night. Sampling only the forest gaps and the forest ground simultaneously was the second best choice and proved to be a viable alternative when the number of available detectors is limited. When assessing bat species richness at the 1‐km2 scale, the implementation of these sampling schemes at three to four forest locations yielded highest labor cost‐benefit ratios but increasing equipment costs. Our study illustrates that multiple passive acoustic sampling schemes require testing based on the target taxa and habitat complexity and should be performed with reference to cost‐benefit ratios. Choosing a standardized and replicated sampling scheme is particularly important to optimize the level of precision in inventories, especially when rare or elusive species are expected. 相似文献
767.
Anna Geueke Giada Mantellato Florian Kuester Peter Schettina Melanie Nelles Jens Michael Seeger Hamid Kashkar Catherin Niemann 《EMBO reports》2021,22(10)
Maintaining the architecture, size and composition of an intact stem cell (SC) compartment is crucial for tissue homeostasis and regeneration throughout life. In mammalian skin, elevated expression of the anti‐apoptotic Bcl‐2 protein has been reported in hair follicle (HF) bulge SCs (BSCs), but its impact on SC function is unknown. Here, we show that systemic exposure of mice to the Bcl‐2 antagonist ABT‐199/venetoclax leads to the selective loss of suprabasal BSCs (sbBSCs), thereby disrupting cyclic HF regeneration. RNAseq analysis shows that the pro‐apoptotic BH3‐only proteins BIM and Bmf are upregulated in sbBSCs, explaining their addiction to Bcl‐2 and the marked susceptibility to Bcl‐2 antagonism. In line with these observations, conditional knockout of Bcl‐2 in mouse epidermis elevates apoptosis in BSCs. In contrast, ectopic Bcl‐2 expression blocks apoptosis during HF regression, resulting in the accumulation of quiescent SCs and delaying HF growth in mice. Strikingly, Bcl‐2‐induced changes in size and composition of the HF bulge accelerate tumour formation. Our study identifies a niche‐instructive mechanism of Bcl‐2‐regulated apoptosis response that is required for SC homeostasis and tissue regeneration, and may suppress carcinogenesis. 相似文献
768.
769.
Coralie E. Salesse‐Smith Robert E. Sharwood Florian A. Busch David B. Stern 《Plant biotechnology journal》2020,18(6):1409-1420
Many C4 plants, including maize, perform poorly under chilling conditions. This phenomenon has been linked in part to decreased Rubisco abundance at lower temperatures. An exception to this is chilling‐tolerant Miscanthus, which is able to maintain Rubisco protein content under such conditions. The goal of this study was to investigate whether increasing Rubisco content in maize could improve performance during or following chilling stress. Here, we demonstrate that transgenic lines overexpressing Rubisco large and small subunits and the Rubisco assembly factor RAF1 (RAF1‐LSSS), which have increased Rubisco content and growth under control conditions, maintain increased Rubisco content and growth during chilling stress. RAF1‐LSSS plants exhibited 12% higher CO2 assimilation relative to nontransgenic controls under control growth conditions, and a 17% differential after 2 weeks of chilling stress, although assimilation rates of all genotypes were ~50% lower in chilling conditions. Chlorophyll fluorescence measurements showed RAF1‐LSSS and WT plants had similar rates of photochemical quenching during chilling, suggesting Rubisco may not be the primary limiting factor that leads to poor performance in maize under chilling conditions. In contrast, RAF1‐LSSS had improved photochemical quenching before and after chilling stress, suggesting that increased Rubisco may help plants recover faster from chilling conditions. Relatively increased leaf area, dry weight and plant height observed before chilling in RAF1‐LSSS were also maintained during chilling. Together, these results demonstrate that an increase in Rubisco content allows maize plants to better cope with chilling stress and also improves their subsequent recovery, yet additional modifications are required to engineer chilling tolerance in maize. 相似文献
770.
Jiannong Li Keiryn Bennett Alexey Stukalov Bin Fang Guolin Zhang Takeshi Yoshida Isamu Okamoto Jae‐Young Kim Lanxi Song Yun Bai Xiaoning Qian Bhupendra Rawal Michael Schell Florian Grebien Georg Winter Uwe Rix Steven Eschrich Jacques Colinge John Koomen Giulio Superti‐Furga Eric B Haura 《Molecular systems biology》2013,9(1)
We hypothesized that elucidating the interactome of epidermal growth factor receptor (EGFR) forms that are mutated in lung cancer, via global analysis of protein–protein interactions, phosphorylation, and systematically perturbing the ensuing network nodes, should offer a new, more systems‐level perspective of the molecular etiology. Here, we describe an EGFR interactome of 263 proteins and offer a 14‐protein core network critical to the viability of multiple EGFR‐mutated lung cancer cells. Cells with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) had differential dependence of the core network proteins based on the underlying molecular mechanisms of resistance. Of the 14 proteins, 9 are shown to be specifically associated with survival of EGFR‐mutated lung cancer cell lines. This included EGFR, GRB2, MK12, SHC1, ARAF, CD11B, ARHG5, GLU2B, and CD11A. With the use of a drug network associated with the core network proteins, we identified two compounds, midostaurin and lestaurtinib, that could overcome drug resistance through direct EGFR inhibition when combined with erlotinib. Our results, enabled by interactome mapping, suggest new targets and combination therapies that could circumvent EGFR TKI resistance. 相似文献