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51.
52.
Qingjie Liu Douglas G. Batt Charu Chaudhry Jonathan S. Lippy Mark A. Pattoli Neha Surti Songmei Xu Percy H. Carter James R. Burke Joseph A. Tino 《Bioorganic & medicinal chemistry letters》2018,28(18):3080-3084
Incorporation of a suitably-placed electrophilic group transformed a series of reversible BTK inhibitors based on carbazole-1-carboxamide and tetrahydrocarbazole-1-carboxamide into potent, irreversible inhibitors. Removal of one ring from the core of these compounds provided a potent irreversible series of 2,3-dimethylindole-7-carboxamides having excellent potency and improved selectivity, with the additional advantages of reduced lipophilicity and molecular weight. 相似文献
53.
Two distinct dihydrolipoamide dehydrogenases (E3s, EC 1.8.1.4) have been detected in pea (Pisum sativum L. cv. Little Marvel) leaf extracts and purified to at or near homogeneity. The major enzyme, a homodimer with an apparent subunit Mr value 56 000 (80–90% of overall activity), corresponded to the mitochondrial isoform studied previously, as confirmed by electrospray mass spectrometry and N-terminal sequence analysis. The minor activity (10–20%), which also behaved as a homodimer, copurified with chloroplasts, and displayed a lower subunit Mr value of 52 000 which was close to the Mr value of 52 614±9.89 Da determined by electrospray mass spectrometry. The plastidic enzyme was also present at low levels in root extracts where it represented only 1–2% of total E3 activity. The specific activity of the chloroplast enzyme was three-to fourfold lower than its mitochondrial counterpart. In addition, it displayed a markedly higher affinity for NAD+ and was more sensitive to product inhibition by NADH. It exhibited no activity with NADP+ as cofactor nor was it inhibited by the presence of high concentrations of NADP+ or NADPH. Antibodies to the mitochondrial enzyme displayed little or no cross-reactivity with its plastidic counterpart and available amino acid sequence data were also suggestive of only limited sequence similarity between the two enzymes. In view of the dual location of the pyruvate dehydrogenase multienzyme complex (PDC) in plant mitochondria and chloroplasts, it is likely that the distinct chloroplastic E3 is an integral component of plastidic PDC, thus representing the first component of this complex to be isolated and characterised to date.Abbreviations E1
pyruvate dehydrogenase
- E2
dihydrolipoamide acetyltransferase
- E3
dihydrolipoamide dehydrogenase
- PDC
pyruvate dehydrogenase complex
- OGDC
2-oxoglutarate dehydrogenase complex
- GDC
glycine decarboxylase complex
- SDS-PAGE
sodium dodecyl sulphate/polyacrylamide gel electrophoresis
- TDP
thiamine diphosphate
- Mr
relative molecular mass
J.G.L. is grateful to the Biotechnology and Biological Sciences Research Council (BBSRC), U.K. for continuing financial support. M.C. is the holder of a BBSRC-funded earmarked Ph.D. studentship. 相似文献
54.
Matilde Fernández Bertrand Morel Andrés Corral‐Lugo Tino Krell 《Molecular microbiology》2016,99(1):34-42
Chemotaxis is an essential mechanism that enables bacteria to move toward favorable ecological niches. Escherichia coli, the historical model organism for studying chemotaxis, has five well‐studied chemoreceptors. However, many bacteria with different lifestyle have more chemoreceptors, most of unknown function. Using a high throughput screening approach, we identified a chemoreceptor from Pseudomonas putida KT2440, named McpH, which specifically recognizes purine and its derivatives, adenine, guanine, xanthine, hypoxanthine and uric acid. The latter five compounds form part of the purine degradation pathway, permitting their use as sole nitrogen sources. Isothermal titration calorimetry studies show that these six compounds bind McpH‐Ligand Binding Domain (LBD) with very similar affinity. In contrast, non‐metabolizable purine derivatives (caffeine, theophylline, theobromine), nucleotides, nucleosides or pyrimidines are unable to bind McpH‐LBD. Mutation of mcpH abolished chemotaxis toward the McpH ligands identified – a phenotype that is restored by complementation. This is the first report on bacterial chemotaxis to purine derivatives and McpH the first chemoreceptor described that responds exclusively to intermediates of a catabolic pathway, illustrating a clear link between metabolism and chemotaxis. The evolution of McpH may reflect a saprophytic lifestyle, which would have exposed the studied bacterium to high concentrations of purines produced by nucleic acid degradation. 相似文献
55.
Lena Ebbers Somisetty V. Satheesh Katrin Janz Lukas Rüttiger Maren Blosa Franz Hofmann Markus Morawski Désirée Griesemer Marlies Knipper Eckhard Friauf Hans Gerd Nothwang 《The Journal of biological chemistry》2015,290(39):23692-23710
Cav1.2 and Cav1.3 are the major L-type voltage-gated Ca2+ channels in the CNS. Yet, their individual in vivo functions are largely unknown. Both channel subunits are expressed in the auditory brainstem, where Cav1.3 is essential for proper maturation. Here, we investigated the role of Cav1.2 by targeted deletion in the mouse embryonic auditory brainstem. Similar to Cav1.3, loss of Cav1.2 resulted in a significant decrease in the volume and cell number of auditory nuclei. Contrary to the deletion of Cav1.3, the action potentials of lateral superior olive (LSO) neurons were narrower compared with controls, whereas the firing behavior and neurotransmission appeared unchanged. Furthermore, auditory brainstem responses were nearly normal in mice lacking Cav1.2. Perineuronal nets were also unaffected. The medial nucleus of the trapezoid body underwent a rapid cell loss between postnatal days P0 and P4, shortly after circuit formation. Phosphorylated cAMP response element-binding protein (CREB), nuclear NFATc4, and the expression levels of p75NTR, Fas, and FasL did not correlate with cell death. These data demonstrate for the first time that both Cav1.2 and Cav1.3 are necessary for neuronal survival but are differentially required for the biophysical properties of neurons. Thus, they perform common as well as distinct functions in the same tissue. 相似文献
56.
Attitude to morality, reflecting cultural norms and values, is considered unique to human social behavior. Resulting moral behavior in a social environment is controlled by a widespread neural network including the dorsolateral prefrontal cortex (DLPFC), which plays an important role in decision making. In the present study we investigate the influence of neurophysiological modulation of DLPFC reactivity by means of transcranial direct current stimulation (tDCS) on moral reasoning. For that purpose we administered anodal, cathodal, and sham stimulation of the left DLPFC while subjects judged the appropriateness of hard moral personal dilemmas. In contrast to sham and cathodal stimulation, anodal stimulation induced a shift in judgment of personal moral dilemmas towards more non-utilitarian actions. Our results demonstrate that alterations of left DLPFC activity can change moral judgments and, in consequence, provide a causal link between left DLPFC activity and moral reasoning. Most important, the observed shift towards non-utilitarian actions suggests that moral decision making is not a permanent individual trait but can be manipulated; consequently individuals with boundless, uncontrollable, and maladaptive moral behavior, such as found in psychopathy, might benefit from neuromodulation-based approaches. 相似文献
57.
The carbon count of 2000 years of rice cultivation 总被引:2,自引:0,他引:2
Karsten Kalbitz Klaus Kaiser Sabine Fiedler Angelika Kölbl Wulf Amelung Tino Bräuer Zhihong Cao Axel Don Piet Grootes Reinhold Jahn Lorenz Schwark Vanessa Vogelsang Livia Wissing Ingrid Kögel‐Knabner 《Global Change Biology》2013,19(4):1107-1113
More than 50% of the world's population feeds on rice. Soils used for rice production are mostly managed under submerged conditions (paddy soils). This management, which favors carbon sequestration, potentially decouples surface from subsurface carbon cycling. The objective of this study was to elucidate the long‐term rates of carbon accrual in surface and subsurface soil horizons relative to those of soils under nonpaddy management. We assessed changes in total soil organic as well as of inorganic carbon stocks along a 2000‐year chronosequence of soils under paddy and adjacent nonpaddy management in the Yangtze delta, China. The initial organic carbon accumulation phase lasts much longer and is more intensive than previously assumed, e.g., by the Intergovernmental Panel on Climate Change (IPCC). Paddy topsoils accumulated 170–178 kg organic carbon ha?1 a?1 in the first 300 years; subsoils lost 29–84 kg organic carbon ha?1 a?1 during this period of time. Subsoil carbon losses were largest during the first 50 years after land embankment and again large beyond 700 years of cultivation, due to inorganic carbonate weathering and the lack of organic carbon replenishment. Carbon losses in subsoils may therefore offset soil carbon gains or losses in the surface soils. We strongly recommend including subsoils into global carbon accounting schemes, particularly for paddy fields. 相似文献
58.
59.
Stoop R Albrecht D Gaissmaier C Fritz J Felka T Rudert M Aicher WK 《Arthritis research & therapy》2007,9(3):R60
Currently, autologous chondrocyte transplantation (ACT) is used to treat traumatic cartilage damage or osteochondrosis dissecans,
but not degenerative arthritis. Since substantial refinements in the isolation, expansion and transplantation of chondrocytes
have been made in recent years, the treatment of early stage osteoarthritic lesions using ACT might now be feasible. In this
study, we determined the gene expression patterns of osteoarthritic (OA) chondrocytes ex vivo after primary culture and subculture and compared these with healthy chondrocytes ex vivo and with articular chondrocytes expanded for treatment of patients by ACT. Gene expression profiles were determined using
quantitative RT-PCR for type I, II and X collagen, aggrecan, IL-1β and activin-like kinase-1. Furthermore, we tested the capability
of osteoarthritic chondrocytes to generate hyaline-like cartilage by implanting chondrocyte-seeded collagen scaffolds into
immunodeficient (SCID) mice. OA chondrocytes ex vivo showed highly elevated levels of IL-1β mRNA, but type I and II collagen levels were comparable to those of healthy chondrocytes.
After primary culture, IL-1β levels decreased to baseline levels, while the type II and type I collagen mRNA levels matched
those found in chondrocytes used for ACT. OA chondrocytes generated type II collagen and proteoglycan-rich cartilage transplants
in SCID mice. We conclude that after expansion under suitable conditions, the cartilage of OA patients contains cells that
are not significantly different from those from healthy donors prepared for ACT. OA chondrocytes are also capable of producing
a cartilage-like tissue in the in vivo SCID mouse model. Thus, such chondrocytes seem to fulfil the prerequisites for use in ACT treatment. 相似文献
60.
Hortencia Silva‐Jiménez Álvaro Ortega Cristina García‐Fontana Juan Luis Ramos Tino Krell 《Microbial biotechnology》2015,8(1):103-115
The reason for the existence of complex sensor kinases is little understood but thought to lie in the capacity to respond to multiple signals. The complex, seven‐domain sensor kinase TodS controls in concert with the TodT response regulator the expression of the toluene dioxygenase pathway in Pseudomonas putida F1 and DOT‐T1E. We have previously shown that some aromatic hydrocarbons stimulate TodS activity whereas others behave as antagonists. We show here that TodS responds in addition to the oxidative agent menadione. Menadione but no other oxidative agent tested inhibited TodS activity in vitro and reduced PtodX expression in vivo. The menadione signal is incorporated by a cysteine‐dependent mechanism. The mutation of the sole conserved cysteine of TodS (C320) rendered the protein insensitive to menadione. We evaluated the mutual opposing effects of toluene and menadione on TodS autophosphorylation. In the presence of toluene, menadione reduced TodS activity whereas toluene did not stimulate activity in the presence of menadione. It was shown by others that menadione increases expression of glucose metabolism genes. The opposing effects of menadione on glucose and toluene metabolism may be partially responsible for the interwoven regulation of both catabolic pathways. This work provides mechanistic detail on how complex sensor kinases integrate different types of signal molecules. 相似文献