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201.
Frequent genes in rare diseases: panel‐based next generation sequencing to disclose causal mutations in hereditary neuropathies
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Maike F. Dohrn Nicola Glöckle Lejla Mulahasanovic Corina Heller Julia Mohr Christine Bauer Erik Riesch Andrea Becker Florian Battke Konstanze Hörtnagel Thorsten Hornemann Saranya Suriyanarayanan Markus Blankenburg Jörg B. Schulz Kristl G. Claeys Burkhard Gess Istvan Katona Andreas Ferbert Debora Vittore Alexander Grimm Stefan Wolking Ludger Schöls Holger Lerche G. Christoph Korenke Dirk Fischer Bertold Schrank Urania Kotzaeridou Gerhard Kurlemann Bianca Dräger Anja Schirmacher Peter Young Beate Schlotter‐Weigel Saskia Biskup 《Journal of neurochemistry》2017,143(5):507-522
202.
Joachim Mariën Benny Borremans Sophie Gryseels Bram Vanden Broecke Beate Becker-Ziaja Rhodes Makundi Apia Massawe Jonas Reijniers Herwig Leirs 《EcoHealth》2017,14(3):463-473
Infectious diseases of wildlife are typically studied using data on antibody and pathogen levels. In order to interpret these data, it is necessary to know the course of antibodies and pathogen levels after infection. Such data are typically collected using experimental infection studies in which host individuals are inoculated in the laboratory and sampled over an extended period, but because laboratory conditions are controlled and much less variable than natural conditions, the immune response and pathogen dynamics may differ. Here, we compared Morogoro arenavirus infection patterns between naturally and experimentally infected multimammate mice (Mastomys natalensis). Longitudinal samples were collected during three months of bi-weekly trapping in Morogoro, Tanzania, and antibody titer and viral RNA presence were determined. The time of infection was estimated from these data using a recently developed Bayesian approach, which allowed us to assess whether the natural temporal patterns match the previously observed patterns in the laboratory. A good match was found for 52% of naturally infected individuals, while most of the mismatches can be explained by the presence of chronically infected individuals (35%), maternal antibodies (10%), and an antibody detection limit (25%). These results suggest that while laboratory data are useful for interpreting field samples, there can still be differences due to conditions that were not tested in the laboratory. 相似文献
203.
Yeast and human Clp1 proteins are homologous components of the mRNA 3′-cleavage-polyadenylation machinery. Recent studies highlighting an association of human Clp1 (hClp1) with tRNA splicing endonuclease and an intrinsic RNA-specific 5′-OH polynucleotide kinase activity of hClp1 have prompted speculation that Clp1 might play a catalytic role in tRNA splicing in animal cells. Here, we show that expression of hClp1 in budding yeast can complement conditional and lethal mutations in the essential 5′-OH RNA kinase module of yeast or plant tRNA ligases. The tRNA splicing activity of hClp1 in yeast is abolished by mutations in the kinase active site. In contrast, overexpression of yeast Clp1 (yClp1) cannot rescue kinase-defective tRNA ligase mutants, and, unlike hClp1, the purified recombinant yClp1 protein has no detectable RNA kinase activity in vitro. Mutations of the yClp1 ATP-binding site do not affect yeast viability. These findings, and the fact that hClp1 cannot complement growth of a yeast clp1Δ strain, indicate that yeast and human Clp1 proteins are not functional orthologs, despite their structural similarity. Although hClp1 can perform the 5′-end-healing step of a yeast-type tRNA splicing pathway in vivo, it is uncertain whether its kinase activity is necessary for tRNA splicing in human cells, given that other mammalian counterparts of yeast-type tRNA repair enzymes are nonessential in vivo. 相似文献
204.
Conformational transitions are a crucial factor in the vast majority of protein misfolding diseases. In most of these cases, the change in conformation is accompanied by the formation of insoluble aggregates, which often precludes a detailed characterization at the molecular level. Therefore, much effort has been put into the development of simplified, easy-to-synthesize peptide models that can be used to elucidate the molecular processes that underlie the conformational switch. For a design to be successful, two, sometimes concomitantly fulfilled, requirements are of importance. First, it is essential to create inherent structural ambiguity. This is usually achieved by combining the most prominent characteristics of different folds within a consensus sequence. Second, a stimulus-sensitive functionality that responds to alterations in the environment, such as pH, ionic strength or the presence of metal ions, is often needed to control structural conversion and to shift the equilibrium in either direction. 相似文献
205.
Beate Knoke Marko Marhl Matjaž Perc Stefan Schuster 《Theorie in den Biowissenschaften》2008,127(1):1-14
Nonlinear oscillatory systems, playing a major role in biology, do not exhibit harmonic oscillations. Therefore, one might
assume that the average value of any of their oscillating variables is unequal to the steady-state value. For a number of
mathematical models of calcium oscillations (e.g. the Somogyi–Stucki model and several models developed by Goldbeter and co-workers),
the average value of the cytosolic calcium concentration (not, however, of the concentration in the intracellular store) does
equal its value at the corresponding unstable steady state at the same parameter values. The average value for parameter values
in the unstable region is even equal to the level at the stable steady state for other parameter values, which allow stability.
This holds for all parameters except those involved in the net flux across the cell membrane. We compare these properties
with a similar property of the Higgins–Selkov model of glycolytic oscillations and two-dimensional Lotka–Volterra equations.
Here, we show that this equality property is critically dependent on the following conditions: There must exist a net flux
across the model boundaries that is linearly dependent on the concentration variable for which the equality property holds
plus an additive constant, while being independent of all others. A number of models satisfy these conditions or can be transformed
such that they do so. We discuss our results in view of the question which advantages oscillations may have in biology. For
example, the implications of the findings for the decoding of calcium oscillations are outlined. Moreover, we elucidate interrelations
with metabolic control analysis.
This paper is dedicated to the memory of the late Reinhart Heinrich, who was the academic teacher of S.S. and, to a great
extent, also of M.M. 相似文献
206.
Sitara D Kim S Razzaque MS Bergwitz C Taguchi T Schüler C Erben RG Lanske B 《PLoS genetics》2008,4(8):e1000154
Maintenance of physiologic phosphate balance is of crucial biological importance, as it is fundamental to cellular function, energy metabolism, and skeletal mineralization. Fibroblast growth factor-23 (FGF-23) is a master regulator of phosphate homeostasis, but the molecular mechanism of such regulation is not yet completely understood. Targeted disruption of the Fgf-23 gene in mice (Fgf-23-/-) elicits hyperphosphatemia, and an increase in renal sodium/phosphate co-transporter 2a (NaPi2a) protein abundance. To elucidate the pathophysiological role of augmented renal proximal tubular expression of NaPi2a in Fgf-23-/- mice and to examine serum phosphate-independent functions of Fgf23 in bone, we generated a new mouse line deficient in both Fgf-23 and NaPi2a genes, and determined the effect of genomic ablation of NaPi2a from Fgf-23-/- mice on phosphate homeostasis and skeletal mineralization. Fgf-23-/-/NaPi2a-/- double mutant mice are viable and exhibit normal physical activities when compared to Fgf-23-/- animals. Biochemical analyses show that ablation of NaPi2a from Fgf-23-/- mice reversed hyperphosphatemia to hypophosphatemia by 6 weeks of age. Surprisingly, despite the complete reversal of serum phosphate levels in Fgf-23-/-/NaPi2a-/-, their skeletal phenotype still resembles the one of Fgf23-/- animals. The results of this study provide the first genetic evidence of an in vivo pathologic role of NaPi2a in regulating abnormal phosphate homeostasis in Fgf-23-/- mice by deletion of both NaPi2a and Fgf-23 genes in the same animal. The persistence of the skeletal anomalies in double mutants suggests that Fgf-23 affects bone mineralization independently of systemic phosphate homeostasis. Finally, our data support (1) that regulation of phosphate homeostasis is a systemic effect of Fgf-23, while (2) skeletal mineralization and chondrocyte differentiation appear to be effects of Fgf-23 that are independent of phosphate homeostasis. 相似文献
207.
Oxidative stress caused by pyocyanin impairs CFTR Cl(-) transport in human bronchial epithelial cells 总被引:1,自引:0,他引:1
Schwarzer C Fischer H Kim EJ Barber KJ Mills AD Kurth MJ Gruenert DC Suh JH Machen TE Illek B 《Free radical biology & medicine》2008,45(12):1653-1662
Pyocyanin (N-methyl-1-hydroxyphenazine), a redox-active virulence factor produced by the human pathogen Pseudomonas aeruginosa, is known to compromise mucociliary clearance. Exposure of human bronchial epithelial cells to pyocyanin increased the rate of cellular release of H(2)O(2) threefold above the endogenous H(2)O(2) production. Real-time measurements of the redox potential of the cytosolic compartment using the redox sensor roGFP1 showed that pyocyanin (100 microM) oxidized the cytosol from a resting value of -318+/-5 mV by 48.0+/-4.6 mV within 2 h; a comparable oxidation was induced by 100 microM H(2)O(2). Whereas resting Cl(-) secretion was slightly activated by pyocyanin (to 10% of maximal currents), forskolin-stimulated Cl(-) secretion was inhibited by 86%. The decline was linearly related to the cytosolic redox potential (1.8% inhibition/mV oxidation). Cystic fibrosis bronchial epithelial cells homozygous for DeltaF508 CFTR failed to secrete Cl(-) in response to pyocyanin or H(2)O(2), indicating that these oxidants specifically target the CFTR and not other Cl(-) conductances. Treatment with pyocyanin also decreased total cellular glutathione levels to 62% and cellular ATP levels to 46% after 24 h. We conclude that pyocyanin is a key factor that redox cycles in the cytosol, generates H(2)O(2), depletes glutathione and ATP, and impairs CFTR function in Pseudomonas-infected lungs. 相似文献
208.
Assortative mating preferences between colour morphs of the endemic Lake Tanganyika cichlid genus Tropheus 总被引:1,自引:1,他引:0
Bernd Egger Beate Obermüller Eva Eigner Christian Sturmbauer Kristina M. Sefc 《Hydrobiologia》2008,615(1):37-48
Female mate preferences effectuate reproductive isolation among and sexual selection within species. Both mechanisms have
been associated with the diversification and speciation of cichlid species flocks of the East African Great Lakes. In Lake
Tanganyika, the endemic genus Tropheus has diversified into >100 geographic colour morphs. Although distributed allopatrically at present, water level fluctuations
have repeatedly displaced and merged the benthic, rock-dwelling populations. Tests for assortative mating were performed to
explore the potential for reproductive isolation between morphs in secondary contact, and to assess the importance of sexual
selection for the diversification of this group. In contrast to other haplochromine cichlids, Tropheus is a sexually monochromatic, territorial and maternally mouthbrooding fish, which establishes temporary pair bonds prior
to spawning. Female mate preference trials involved two-way choices between a homotypic and a heterotypic male and were conducted
on allopatric populations of red and blue morphs from the southern part of Lake Tanganyika. Female affiliation time near each
male’s compartment did not predict the mate preferences subsequently expressed in unrestrained interactions after removal
of the compartment separators (spawning, pseudospawning and courtship). Consequently, mate preferences were inferred from
unrestrained interactions with one test male at a time in replicate observation sessions. Of the 23 females tested, 13 courted,
pseudospawned or spawned with the homotypic male, one blue female courted a red male, and nine females expressed no sexual
motivation. The assortative mate preferences in the experiments (P < 0.01) suggest that colour differentiation between Tropheus populations can effectuate reproductive isolation, and is consistent with the notion that sexual selection contributed to
the diversification of the genus.
Guest editors: T. Wilke, R. V?in?l? & F. Riedel
Patterns and Processes of Speciation in Ancient Lakes: Proceedings of the Fourth Symposium on Speciation in Ancient Lakes,
Berlin, Germany, September 4–8, 2006 相似文献
209.
As a first approach to establishing a three-dimensional culture infection model, we studied the growth behavior of the extracellular pathogen Yersinia enterocolitica in three-dimensional collagen gels (3D-CoG). Surprisingly, we observed that plasmidless Y. enterocolitica was motile in the 3D-CoG in contrast to its growth in traditional motility agar at 37 degrees C. Motility at 37 degrees C was abrogated in the presence of the virulence plasmid pYV or the exclusive expression of the pYV-located Yersinia adhesion gene yadA. YadA-producing yersiniae formed densely packed (dp) microcolonies, whereas pYVDelta yadA-carrying yersiniae formed loosely packed microcolonies at 37 degrees C in 3D-CoG. Furthermore, we demonstrated that the packing density of the microcolonies was dependent on the head domain of YadA. Moreover, dp microcolony formation did not depend on the capacity of YadA to bind to collagen fibers, as demonstrated by the use of yersiniae producing collagen nonbinding YadA. By using a yopE-gfp reporter, we demonstrated Ca(2+)-dependent expression of this pYV-localized virulence gene by yersiniae in 3D-CoG. In conclusion, this study revealed unique plasmid-dependent growth behavior of yersiniae in a three-dimensional matrix environment that resembles the behavior of yersiniae (e.g., formation of microcolonies) in infected mouse tissue. Thus, this 3D-CoG model may be a first step to a more complex level of in vitro infection models that mimic living tissue, enabling us to study the dynamics of pathogen-host cell interactions. 相似文献
210.
Visitor monitoring methods for managing public use pressures in the Danube Floodplains National Park, Austria 总被引:1,自引:0,他引:1
National parks in close proximity to large urban areas, such as the Danube Floodplains National Park near Vienna, need an intensive monitoring of recreational use due to the high number of visitors and the highly fragmented natural settings. Visitors in the National Park were monitored using an approach that integrated long-term video monitoring, counts by human observers, specific visitor interviews and route analysis by the application of GIS tools. The combination of monitoring and survey data allows a thorough analysis of public use patterns, as illustrated by a case study of dog walkers in the park. Results demonstrate the value of integrated monitoring approaches, and serve as a basis for improved sustainable management of the Danube Floodplains National Park. 相似文献