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101.
Jan N Hansen Fabian Kaiser Philipp Leyendecker Birthe Stüven JensHenning Krause Fatemeh Derakhshandeh Jaazba Irfan Tommy J Sroka Kenley M Preval Paurav B Desai Michael Kraut Heidi Theis AnnaDorothee Drews Elena DeDomenico Kristian Hndler Gregory J Pazour David J P Henderson David U Mick Dagmar Wachten 《EMBO reports》2022,23(8)
The primary cilium constitutes an organelle that orchestrates signal transduction independently from the cell body. Dysregulation of this intricate molecular architecture leads to severe human diseases, commonly referred to as ciliopathies. However, the molecular underpinnings how ciliary signaling orchestrates a specific cellular output remain elusive. By combining spatially resolved optogenetics with RNA sequencing and imaging, we reveal a novel cAMP signalosome that is functionally distinct from the cytoplasm. We identify the genes and pathways targeted by the ciliary cAMP signalosome and shed light on the underlying mechanisms and downstream signaling. We reveal that chronic stimulation of the ciliary cAMP signalosome transforms kidney epithelia from tubules into cysts. Counteracting this chronic cAMP elevation in the cilium by small molecules targeting activation of phosphodiesterase‐4 long isoforms inhibits cyst growth. Thereby, we identify a novel concept of how the primary cilium controls cellular functions and maintains tissue integrity in a specific and spatially distinct manner and reveal novel molecular components that might be involved in the development of one of the most common genetic diseases, polycystic kidney disease. 相似文献
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104.
Intracellular Mg(2+) buffering and Mg(2+) extrusion were investigated in Xenopus laevis oocytes. Mg(2+) or EDTA were pressure injected and the resulting changes in the intracellular Mg(2+) concentration were measured simultaneously with Mg(2+)-selective microelectrodes. In the presence of extracellular Na(+), injected Mg(2+) was extruded from the oocytes with an estimated v(max) and K(M) of 74 pmol cm(-2)s(-1) and 1.28 mM, respectively. To investigate genuine cytosolic Mg(2+) buffering, measurements were carried out in the nominal absence of extracellular Na(+) to block Mg(2+) extrusion, and during the application of CCCP (inhibiting mitochondrial uptake). Under these conditions, Mg(2+) buffering calculated after both MgCl(2) and EDTA injections could be described by a buffer equivalent with a concentration of 9.8mM and an apparent dissociation constant, K(d-app), of 0.6mM together with an [ATP](i) of 0.9 mM with a K(d-app) 0.12 mM. Xenopus oocytes thus possess highly efficient mechanisms to maintain their intracellular Mg(2+) concentration. 相似文献
105.
Profile of cholesterol-related sterols in aged amyloid precursor protein transgenic mouse brain 总被引:1,自引:0,他引:1
Lütjohann D Brzezinka A Barth E Abramowski D Staufenbiel M von Bergmann K Beyreuther K Multhaup G Bayer TA 《Journal of lipid research》2002,43(7):1078-1085
Cholesterol is implicated to play a role in Alzheimer disease pathology. Therefore, the concentrations of cholesterol, its precursors, and its degradation products in brain homogenates of aging wild-type and beta-amyloid precursor protein transgenic mice carrying the Swedish mutation (APP23) were analyzed. Among the sterols measured, lanosterol is the first common intermediate of two different pathways, which use either desmosterol or lathosterol as the predominant precursors for de novo synthesis of brain cholesterol. In young mice, cholesterol is mainly synthesized via the desmosterol pathway, while in aged mice, lathosterol is the major precursor. 24S-hydroxycholesterol (cerebrosterol), which plays a key role in the removal of cholesterol from the brain, modestly increased during aging. No differences in the levels of cholesterol, its precursors, or its metabolites were found between wild-type and APP23 transgenic mice. Moreover, the levels of the exogenous plant sterols campesterol and sitosterol were significantly elevated in the brains of APP23 animals at age 12 and 18 months. This time point coincides with abundant plaque formation. 相似文献
106.
MDHM, a macrophage-activating product of Mycoplasma fermentans, stimulates murine macrophages to synthesize nitric oxide and become tumoricidal 总被引:1,自引:0,他引:1
Dorothee Ruschmeyer Hansjörg Thude Peter F. Mühlradt 《FEMS immunology and medical microbiology》1993,7(3):223-230
Abstract In continuation of previous work on macrophage activation by a Mycoplasma fermentans -derived product, originally named “mycoplasma-derived high mol. wt. material” (MDHM), we have investigated whether MDHM was capable of inducing synthesis of the reactive nitrogen intermediate nitric oxide (NO), thus rendering macrophages cytocidal. Mycoplasmas were first delipidated with acetone, and MDHM activity was then extracted with 50 mM 1-O-octyl-β- d -glucopyranoside to yield a particularly active new preparation of MDHM which we have named MDHM-D (D for detergent). In combination with IFN-γ, MDHM-D activated macrophages to produce reactive nitrogen intermediates and kill P815 mastocytoma cells in co-culture. P815 target cells were chosen because they are TNF-resistant. Macrophages from the LPS-low responder strain C3H/HeJ were used to minimize interference from possible LPS contamination. MDHM-D activity in this system was strictly IFN-γ-dependent. In the presence of 25 U/ml IFN-γ MDHM-D gave a half maximal response at a dilution of 1/100 000, showing a parallel concentration dependency for nitrite production and cytocidal activity. 相似文献
107.
Racemic synthetic 3HC18 juvenile hormone, dissolved in paraffin oil, was injected into adult Locusta migratoria and the excreted radioactive material in the faeces was determined. Within 48 hr two-thirds of the injected radioactivity can be recovered in the frass, half of it within 3 hr. The remaining one-third of the injected label is incorporated or is released as water. Adult locusts of either sex or of different ages show no difference in the metabolic pathways of the JH and its excretion rate.The excreta contain as a degradation product 7-ethyl-3,11-dimethyl-cis-10,11-epoxy-trans, trans-2,6 trideca-dienoic acid, the corresponding dioldienoic acid and the dioldienoic methyl ester. Unchanged Cecropia JH was also found in the frass. The radioactive hormone, as well as the metabolites, were excreted mainly by the Malpighian tubules; smaller amounts of the radioactive material were also found in the fore-, mid, and hindgut. 相似文献
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109.
Markus Anton Michael Passreiter Dorothee Lay Thanh-Phuong Thai Karin Gorgas Wilhelm W. Just 《Cell biochemistry and biophysics》2000,32(1-3):27-36
The authors characterized on a molecular level the clofibrate-inducible 26-kDa integral peroxisomal membrane protein (Pmp26p,
Pex11-1p) of rat liver. By screening cDNA databases with the obtained Pex11-1p-cDNA, a second homologous cDNA was identified
that codes for a polypeptide with slightly larger molecular mass than Pex11-1p. The authors call this polypeptide Pex11-2p.
Studies on the topology of Pex11-1p revealed two transmembrane domains with the N- and C-terminus facing the cytoplasm. The
C-terminal tail of Pex11-1p ends in a consensus dilysine motif of the type-KXKXX-COOH, which is known to be involved in the
ADP-ribosylation factor (ARF)1-coat protein (COP) I coat (ARF)1-dependent membrane recruitment to Golgi membranes. Studies
with isolated peroxisomes incubated in the presence of cytosol, adenosine triphosphate and GTPγS, indeed, provided evidence
for specific binding of ARF and coatomer to peroxisomes. Expression of Pex11-1p in Chinese hamster ovary (CHO) wild-type cells
led to a twofold increase in the number of peroxisomes, but expression in a temperature-sensitive CHO mutant, defective in
coatomer, induced elongation and tubulation of peroxisomal structures, rather than numerical proliferation. The obtained results
for the first time offer a mechanism explaining Pex11-1p-, as well as ARF- and coatomer-mediated peroxisomal vesiculation.
Two models are presented that may explain how these observations fit in with peroxisome biogenesis. 相似文献