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91.
Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule 总被引:10,自引:0,他引:10
Lalioti MD Zhang J Volkman HM Kahle KT Hoffmann KE Toka HR Nelson-Williams C Ellison DH Flavell R Booth CJ Lu Y Geller DS Lifton RP 《Nature genetics》2006,38(10):1124-1132
The mechanisms that govern homeostasis of complex systems have been elusive but can be illuminated by mutations that disrupt system behavior. Mutations in the gene encoding the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and hyperkalemia. We show that physiology in mice transgenic for genomic segments harboring wild-type (TgWnk4(WT)) or PHAII mutant (TgWnk4(PHAII)) Wnk4 is changed in opposite directions: TgWnk4(PHAII) mice have higher blood pressure, hyperkalemia, hypercalciuria and marked hyperplasia of the distal convoluted tubule (DCT), whereas the opposite is true in TgWnk4(WT) mice. Genetic deficiency for the Na-Cl cotransporter of the DCT (NCC) reverses phenotypes seen in TgWnk4(PHAII) mice, demonstrating that the effects of the PHAII mutation are due to altered NCC activity. These findings establish that Wnk4 is a molecular switch that regulates the balance between NaCl reabsorption and K+ secretion by altering the mass and function of the DCT through its effect on NCC. 相似文献
92.
A wiki for the life sciences where authorship matters 总被引:2,自引:0,他引:2
Hoffmann R 《Nature genetics》2008,40(9):1047-1051
WikiGenes is the first wiki system to combine the collaborative and largely altruistic possibilities of wikis with explicit authorship. In view of the extraordinary success of Wikipedia there remains no doubt about the potential of collaborative publishing, yet its adoption in science has been limited. Here I discuss a dynamic collaborative knowledge base for the life sciences that provides authors with due credit and that can evolve via continual revision and traditional peer review into a rigorous scientific tool. 相似文献
93.
Isabelle Callebaut Brice Hoffmann Pierre Lehn Jean-Paul Mornon 《Cellular and molecular life sciences : CMLS》2017,74(1):3-22
The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a member of the ATP-binding cassette (ABC) transporter superfamily that functions as an ATP-gated channel. Considerable progress has been made over the last years in the understanding of the molecular basis of the CFTR functions, as well as dysfunctions causing the common genetic disease cystic fibrosis (CF). This review provides a global overview of the theoretical studies that have been performed so far, especially molecular modelling and molecular dynamics (MD) simulations. A special emphasis is placed on the CFTR-specific evolution of an ABC transporter framework towards a channel function, as well as on the understanding of the effects of disease-causing mutations and their specific modulation. This in silico work should help structure-based drug discovery and design, with a view to develop CFTR-specific pharmacotherapeutic approaches for the treatment of CF in the context of precision medicine. 相似文献
94.
95.
X K Zhang J Lehmann B Hoffmann M I Dawson J Cameron G Graupner T Hermann P Tran M Pfahl 《Nature》1992,358(6387):587-591
Retinoid response pathways are mediated by two classes of receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). A central question is whether distinct response pathways are regulated by these two classes of receptors. The observation that the stereoisomer 9-cis-retinoic acid binds with high affinity to RXRs suggested that this retinoid has a distinct role in controlling RXR activity, but it was almost simultaneously discovered that RXRs function as auxiliary receptors for RARs and related receptors, and are essential for DNA binding and function of those receptors. Hence, although RARs seem to operate effectively only as heterodimeric RAR/RXR complexes, RXRs themselves apparently function predominantly, if not exclusively, as auxiliary receptors. Here we report that 9-cis-retinoic acid induces RXR homodimer formation. Our results demonstrate a new mechanism for retinoid action by which a ligand-induced homodimer mediates a distinct retinoid response pathway. 相似文献
96.
Selenium (Se) is a nutritional trace mineral essential for various aspects of human health that exerts its effects mainly
through its incorporation into selenoproteins as the amino acid, selenocysteine. Twenty-five selenoprotein genes have been
identified in humans and several selenoproteins are broadly classified as antioxidant enzymes. As progress is made on characterizing
the individual members of this protein family, however, it is becoming clear that their properties and functions are quite
diverse. This review summarizes recent insights into properties of individual selenoproteins such as tissue distribution,
subcellular localization, and regulation of expression. Also discussed are potential roles the different selenoproteins play
in human health and disease. 相似文献
97.
Christian Feißt Carlo Pergola Marija Rakonjac Antonietta Rossi Andreas Koeberle Gabriele Dodt Marika Hoffmann Christina Hoernig Lutz Fischer Dieter Steinhilber Lutz Franke Gisbert Schneider Olof Rådmark Lidia Sautebin Oliver Werz 《Cellular and molecular life sciences : CMLS》2009,66(16):2759-2771
We previously showed that, in vitro, hyperforin from St. John’s wort (Hypericum perforatum) inhibits 5-lipoxygenase (5-LO), the key enzyme in leukotriene biosynthesis. Here, we demonstrate that hyperforin possesses
a novel and unique molecular pharmacological profile as a 5-LO inhibitor with remarkable efficacy in vivo. Hyperforin (4 mg/kg, i.p.) significantly suppressed leukotriene B4 formation in pleural exudates of carrageenan-treated rats associated with potent anti-inflammatory effectiveness. Inhibition
of 5-LO by hyperforin, but not by the iron-ligand type 5-LO inhibitor BWA4C or the nonredox-type inhibitor ZM230487, was abolished
in the presence of phosphatidylcholine and strongly reduced by mutation (W13A-W75A-W102A) of the 5-LO C2-like domain. Moreover,
hyperforin impaired the interaction of 5-LO with coactosin-like protein and abrogated 5-LO nuclear membrane translocation
in ionomycin-stimulated neutrophils, processes that are typically mediated via the regulatory 5-LO C2-like domain. Together,
hyperforin is a novel type of 5-LO inhibitor apparently acting by interference with the C2-like domain, with high effectiveness
in vivo. 相似文献
98.
Michael Hoffmann 《Foundations of Science》1999,4(3):271-305
Abductive reasoning takes place in forming``hypotheses' in order to explain ``facts.' Thus, theconcept of abduction promises an understanding ofcreativity in science and learning. It raises,however, also a lot of problems. Some of them will bediscussed in this paper. After analyzing thedifference between induction and abduction (1), Ishall discuss Peirce's claim that there is a ``logic'of abduction (2). The thesis is that this claim can beunderstood, if we make a clear distinction betweeninferential elements and perceptive elements ofabductive reasoning. For Peirce, the creative act offorming explanatory hypotheses and the emergence of``new ideas' belongs exclusively to the perceptive sideof abduction. Thus, it is necessary to study the roleof perception in abductive reasoning (3). A furtherproblem is the question whether there is arelationship between abduction and Peirce's concept of``theorematic reasoning' in mathematics (4). Both formsof reasoning could be connected, because both arebased on perception. The last problem concerns therole of instincts in explaining the success ofabductive reasoning in science, and the questionwhether the concept of instinct might be replaced bymethods of inquiry (5). 相似文献
99.
K Hoffmann 《Experientia》1979,35(11):1529-1530
In male Djungarian hamsters (Phodopus sungorus) short photoperiods (L/D 8/16) with additional 1- or 5-min light-pulses 8 h after light-off were as effective as long photoperiods (L/D 16/8) in stimulating testicular recrudescence, increase in body weight and moult into summer pelage. The results are discussed with regard to the hypothesis that the pattern of melatonin release from the pineal gland is important in mediating photoperiodic effects in mammals. 相似文献
100.
Zusammenfassung
d-Amphetamin (2–4 mg i.v.) verstärkt bei Neuronen des Tectum opticum der Katze die Reizantwort auf optische Bewegungsreize und vermindert oder beseitigt die während einer Reizfolge auftretende neuronale Adaptation. 相似文献