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111.
Novel 3,4-diarylpyrazolines as potent cannabinoid CB1 receptor antagonists with lower lipophilicity 总被引:1,自引:0,他引:1
Lange JH van Stuivenberg HH Veerman W Wals HC Stork B Coolen HK McCreary AC Adolfs TJ Kruse CG 《Bioorganic & medicinal chemistry letters》2005,15(21):4794-4798
Novel 3,4-diarylpyrazolines 1 as potent CB1 receptor antagonists with lipophilicity lower than that of SLV319 are described. The key change is the replacement of the arylsulfonyl group in the original series by a dialkylaminosulfonyl moiety. The absolute configuration (4S) of eutomer 24 was established by X-ray diffraction analysis and 24 showed a close molecular fit with rimonabant in a CB1 receptor-based model. Compound 17 exhibited the highest CB1 receptor affinity (Ki = 24 nM) in this series, as well as very potent CB1 antagonistic activity (pA2 = 8.8) and a high CB1/CB2 subtype selectivity (approximately 147-fold). 相似文献
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113.
Role of phosphoinositide 3-kinase and endocytosis in nerve growth factor-induced extracellular signal-regulated kinase activation via Ras and Rap1 总被引:16,自引:0,他引:16 下载免费PDF全文
York RD Molliver DC Grewal SS Stenberg PE McCleskey EW Stork PJ 《Molecular and cellular biology》2000,20(21):8069-8083
Neurotrophins promote multiple actions on neuronal cells including cell survival and differentiation. The best-studied neurotrophin, nerve growth factor (NGF), is a major survival factor in sympathetic and sensory neurons and promotes differentiation in a well-studied model system, PC12 cells. To mediate these actions, NGF binds to the TrkA receptor to trigger intracellular signaling cascades. Two kinases whose activities mediate these processes include the mitogen-activated protein (MAP) kinase (or extracellular signal-regulated kinase [ERK]) and phosphoinositide 3-kinase (PI3-K). To examine potential interactions between the ERK and PI3-K pathways, we studied the requirement of PI3-K for NGF activation of the ERK signaling cascade in dorsal root ganglion cells and PC12 cells. We show that PI3-K is required for TrkA internalization and participates in NGF signaling to ERKs via distinct actions on the small G proteins Ras and Rap1. In PC12 cells, NGF activates Ras and Rap1 to elicit the rapid and sustained activation of ERKs respectively. We show here that Rap1 activation requires both TrkA internalization and PI3-K, whereas Ras activation requires neither TrkA internalization nor PI3-K. Both inhibitors of PI3-K and inhibitors of endocytosis prevent GTP loading of Rap1 and block sustained ERK activation by NGF. PI3-K and endocytosis may also regulate ERK signaling at a second site downstream of Ras, since both rapid ERK activation and the Ras-dependent activation of the MAP kinase kinase kinase B-Raf are blocked by inhibition of either PI3-K or endocytosis. The results of this study suggest that PI3-K may be required for the signals initiated by TrkA internalization and demonstrate that specific endocytic events may distinguish ERK signaling via Rap1 and Ras. 相似文献
114.
Isolation of TSH and LH/CG receptor cDNAs from human thyroid: regulation by tissue specific splicing 总被引:9,自引:0,他引:9
A L Frazier L S Robbins P J Stork R Sprengel D L Segaloff R D Cone 《Molecular endocrinology (Baltimore, Md.)》1990,4(8):1264-1276
A TSH receptor (TSH-R) cDNA has been isolated from a human thyroid lambda GT11 library. Unexpectedly, several cDNAs encoding the human LH/CG receptor (LH/CG-R), previously thought to be expressed solely in gonadal cells, were also isolated from the thyroid library. The receptors are structurally related, consisting of a signal sequence, a large extracellular amino terminal domain, seven membrane spanning domains, and a short carboxyl-terminal portion. The TSH-R is encoded by a single 4.2 kilobase mRNA specific to the thyroid. Introns were not present in any hTSH-R cDNAs examined, however, sequencing of several LH/CG-R cDNAs and RNase protection experiments demonstrated that the majority of hLH/CG-R mRNA in the thyroid is incompletely spliced. Consequently, tissue-specific splicing may be an important step in the regulation of the glycoprotein hormone receptor family. 相似文献
115.
Dr. Hans-Jürgen Stork 《Zoomorphology》1972,73(1):81-94
Summary Brain-pan pneumatisation in pigeons and songbirds is explored by metrical and histological methods. By thickening and pneumatisation of skull dermal bones pigeons show an increase of neurocranium breadth and height without any change of brain case capacity. In comparison with this songbirds have a decrease of brain case capacity without any change in neurocranium breadth and height. This phenomen in songbirds is correlated with a diminution of brain weight by water loss.Histogenesis of dermal bone pneumatisation show corresponding differences to the metrical explorations. In pigeons the primarily grown dermal bone is excavated by osteoclasts and has growth of bone by osteoblasts in the outer periost. In songbirds primarily grown dermal bone remains untouched by osteoclasts and excavation and pneumatisation occurs within a new-grown inner layer of dermal bone.The function of brain-pan pneumatisation is discussed.
Die Untersuchungen zu dieser Arbeit wurden noch am Anatomischen Institut der Universität München (Direktor: Prof. Dr. med. Hans Frick) durchgeführt. Für die Herstellung der Zeichnungen danke ich Herrn Rust. 相似文献
Zur entwicklung pneumatischer räume im neurocranium der vögel (Aves)
Zusammenfassung Die Pneumatisation der Schädeldecke von Tauben und Singvögeln wird mit metrischen und histologischen Methoden untersucht. Bei Tauben führt die Verdickung und Pneumatisation zu einer Vergrößerung des Neurocraniums nach außen. Eine Veränderung der Hirnschädelkapazität, die von einem vollentwickelten Gehirn erfüllt ist, tritt nicht ein. Bei Singvögeln führt die Verdickung und Pneumatisation der Deckknochen zu einer Verringerung der Hirnschädelkapazität bei gleichbleibenden Außenmaßen. Eine gleichzeitig ablaufende Massenverringerung des Gehirns ermöglicht eine Verdickung der Schädeldecke hirnu ärts.Die Histogenese der in der Pneumatisation befindlichen Deckknochen ist bei Tauben und Singvögeln entsprechend verschieden. Bei Tauben wird der primäre Deckknochen ausgehählt und nach außen verdickt. Bei Singvögeln bleibt die primäre Schädeldecke unberührt, und die Pneumatisation erfolgt durch Aushöhlung einer hirnwärts neugebildeten Knochenschicht.Überlegungen zur Funktion der Lufträume in der Schädelkapsel werden angestellt.
Die Untersuchungen zu dieser Arbeit wurden noch am Anatomischen Institut der Universität München (Direktor: Prof. Dr. med. Hans Frick) durchgeführt. Für die Herstellung der Zeichnungen danke ich Herrn Rust. 相似文献
116.
Daniel LaCasse Scott Lute Marcus Fiadeiro Jonida Basha Matthew Stork Kurt Brorson Ranga Godavarti Chris Gallo 《Biotechnology progress》2016,32(4):959-970
Virus retentive filters are a key product safety measure for biopharmaceuticals. A simplistic perception is that they function solely based on a size‐based particle removal mechanism of mechanical sieving and retention of particles based on their hydrodynamic size. Recent observations have revealed a more nuanced picture, indicating that changes in viral particle retention can result from process pressure and/or flow interruptions. In this study, a mechanistic investigation was performed to help identify a potential mechanism leading to the reported reduced particle retention in small virus filters. Permeate flow rate or permeate driving force were varied and analyzed for their impact on particle retention in three commercially available small virus retentive filters. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:959–970, 2016 相似文献
117.
G protein-coupled receptors can induce cellular proliferation by stimulating the mitogen-activated protein (MAP) kinase cascade. Heterotrimeric G proteins are composed of both alpha and betagamma subunits that can signal independently to diverse intracellular signaling pathways including those that activate MAP kinases. In this study, we examined the ability of isoproterenol, an agonist of the beta(2)-adrenergic receptor (beta(2)AR), to stimulate extracellular signal-regulated kinases (ERKs). Using HEK293 cells, which express endogenous beta(2)AR, we show that isoproterenol stimulates ERKs via beta(2)AR. This action of isoproterenol requires cAMP-dependent protein kinase and is insensitive to pertussis toxin, suggesting that Galpha(s) activation of cAMP-dependent protein kinase is required. Interestingly, beta(2)AR activates both the small G proteins Rap1 and Ras, but only Rap1 is capable of coupling to Raf isoforms. beta(2)AR inhibits the Ras-dependent activation of both Raf isoforms Raf-1 and B-Raf, whereas Rap1 activation by isoproterenol recruits and activates B-Raf. beta(2)AR activation of ERKs is not blocked by expression of RasN17, an interfering mutant of Ras, but is blocked by expression of either RapN17 or Rap1GAP1, both of which interfere with Rap1 signaling. We propose that isoproterenol can activate ERKs via Rap1 and B-Raf in these cells. 相似文献
118.
Wilfried Paarmann Burkhard Gutzmann Philipp Stumpe Hubertus Bolte Steffen Küppers Karsten Holzkamp Clemens Niers Joachim Adis Nigel E. Stork Claudlo R. V. da Fonseca 《Biotropica》2002,34(3):368-375
Although most Carabidae are recognized as predacious, recent studies have shown that some tropical rain forest Carabidae use the small seeds of fallen fruit from some tree species as a key food resource (particularly figs [Moraceae] but also those from other families). Assemblages of carabid beetles (Coleoptera: Carabidae) at fruit falls of the Melastomataceae tree genera, Bellucia, Loreya, and Miconia, were studied in a terra firme rain forest near Manaus (Amazonia, Brazil) from February 1992 to August 1996. Of 5483 specimens of 14 carabid species collected at 53 fruit falls, 98.2 percent of the collected beetles represented the seed-feeding genus Notiobia. Four of the 7 Notiobia species were found to reproduce at Melastomataceae fruit falls. The most abundant species, N. glabrata, was found to be a Melastomataceae seed generalise while N. maxima seemed to prefer the seeds of Bellucia, and N. aulica and Af. umbrifera the seeds of Miconia. The presence of larvae indicated reproduction of N. glabrata at fruit falls of all three tree genera and reproduction of N. maxima at those of Bellucia. Fruit falls of different species and genera of Melastomataceae appeared to occur at different times of die year and not continuously throughout the year. The seed-feeding Notiobia species, which specialize on Melastomataceae, used fruit falls of figs as migratory “stepping stones” during periods when there were no Melastomataceae fruit falls. The comparable suite of fig seed-feeding specialist species of Notiobia did not appear to do the reverse and seemed to avoid Melastomataceae fruit falls. The carabid assemblage at fig fruit falls was more diverse than the assemblage at those of Melastomataceae. Among the Melastomataceae, carabid species richness was highest at Miconia fruit falls and lowest at Loreya fruit falls. The three most common predatory species caught at Ficus fruit falls were also caught at those of Melastomataceae and appeared to reproduce at both fruit fall types. The proportion of the carabid assemblage accounted by predatory species was much lower at Melastomataceae (1.8%) than at fig fruit falls (8%). 相似文献
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120.
Oliver Stork Hans Welzl Carsten T. Wotjak Daniel Hoyer Markus Delling Harold Cremer Melitta Schachner 《Developmental neurobiology》1999,40(3):343-355
Mice deficient in the neural cell adhesion molecule (NCAM) show behavioral abnormalities as adults, including altered exploratory behavior, deficits in spatial learning, and increased intermale aggression. Here, we report increased anxiety‐like behavior of homozygous (NCAM−/−) and heterozygous (NCAM+/−) mutant mice in a light/dark avoidance test, independent of genetic background and gender. Anxiety‐like behavior was reduced in both NCAM+/+ and NCAM−/− mice by systemic administration of the benzodiazepine agonist diazepam and the 5‐HT1A receptor agonists buspirone and 8‐OH‐DPAT. However, NCAM−/− mice showed anxiolytic‐like effects at lower doses of buspirone and 8‐OH‐DPAT than NCAM+/+ mice. Such increased response to 5‐HT1A receptor stimulation suggests a functional change in the serotonergic system of NCAM−/− mice, likely involved in the control of anxiety and aggression. However, 5‐HT1A receptor binding and tissue content of serotonin and its metabolite 5‐hydroxyindolacetic acid were found unaltered in every brain area of NCAM−/− mice investigated, indicating that expression of 5‐HT1A receptors as well as synthesis and release of serotonin are largely unchanged in NCAM−/− mice. We hypothesize a critical involvement of endogenous NCAM in serotonergic transmission via 5‐HT1A receptors and inwardly rectifying K+ channels as the respective effector systems. © 1999 John Wiley & Sons, Inc. J Neurobiol 40: 343–355, 1999 相似文献