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51.
Hugues Aschard Bjarni?J. Vilhjálmsson Nicolas Greliche Pierre-Emmanuel Morange David-Alexandre Trégou?t Peter Kraft 《American journal of human genetics》2014,94(5):662-676
Many human traits are highly correlated. This correlation can be leveraged to improve the power of genetic association tests to identify markers associated with one or more of the traits. Principal component analysis (PCA) is a useful tool that has been widely used for the multivariate analysis of correlated variables. PCA is usually applied as a dimension reduction method: the few top principal components (PCs) explaining most of total trait variance are tested for association with a predictor of interest, and the remaining components are not analyzed. In this study we review the theoretical basis of PCA and describe the behavior of PCA when testing for association between a SNP and correlated traits. We then use simulation to compare the power of various PCA-based strategies when analyzing up to 100 correlated traits. We show that contrary to widespread practice, testing only the top PCs often has low power, whereas combining signal across all PCs can have greater power. This power gain is primarily due to increased power to detect genetic variants with opposite effects on positively correlated traits and variants that are exclusively associated with a single trait. Relative to other methods, the combined-PC approach has close to optimal power in all scenarios considered while offering more flexibility and more robustness to potential confounders. Finally, we apply the proposed PCA strategy to the genome-wide association study of five correlated coagulation traits where we identify two candidate SNPs that were not found by the standard approach. 相似文献
52.
John C O'LearyIII Qingyou Li Paul Marinec Laura J Blair Erin E Congdon Amelia G Johnson Umesh K Jinwal John KorenIII Jeffrey R Jones Clara Kraft Melinda Peters Jose F Abisambra Karen E Duff Edwin J Weeber Jason E Gestwicki Chad A Dickey 《Molecular neurodegeneration》2010,5(1):45
Background
It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection.Results
Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember?, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced.Conclusions
Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.53.
Christoph Kleinschnitz Henrike Grund Kirstin Wingler Melanie E. Armitage Emma Jones Manish Mittal David Barit Tobias Schwarz Christian Geis Peter Kraft Konstanze Barthel Michael K. Schuhmann Alexander M. Herrmann Sven G. Meuth Guido Stoll Sabine Meurer Anja Schrewe Lore Becker Valérie Gailus-Durner Helmut Fuchs Thomas Klopstock Martin Hrabé de Angelis Karin Jandeleit-Dahm Ajay M. Shah Norbert Weissmann Harald H. H. W. Schmidt 《PLoS biology》2010,8(9)
Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4
−/−) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4
−/− mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy. 相似文献
54.
R Misselwitz R Kraft S Kostka H Fabian K Welfle W Pfeil H Welfle D Gerlach 《International journal of biological macromolecules》1992,14(2):107-116
Limited proteolysis of streptokinase (Sk) by trypsin and thermolysin was performed under various incubation conditions and analysed by polyacrylamide gel electrophoresis. Several fragments (Sk1, Tr27, Tr17, Th26, and Th16) were isolated and characterized further. The N-terminal sequences of Tr27, Tr17, Th26, Th16 and the C-terminal sequences of Tr27 and Th26 were determined by partial sequencing. The evidence available allows the positioning of these fragments within the Sk sequence. Fragment Sk1 is obtained by carefully standardized tryptic digestion of Sk and gel chromatography under non-denaturing conditions. Sk1 is formed by a large polypeptide Ser60-Lys293 and non-covalently bonded smaller polypeptides composed of amino acids from the N-terminal region Ile1-Lys59 of Sk. Fragment Tr27 consists of the large polypeptide Ser60-Lys293 of Sk1, and can be obtained from Sk1 by removal of the smaller N-terminal polypeptides under denaturing conditions. Fragment Th26 is composed of amino acids Phe63-His291. The N-termini of fragments Tr17 and Th16 start with Glu148 and Ile151. From their electrophoretically-determined sizes it can be concluded that they most probably have the same C-terminal amino acids, Lys293 and His291, as fragments Tr27 and Th26, respectively. Secondary structure elements of similar composition were found in all the fragments studied using circular dichroism (c.d.) and infrared (i.r.) measurements. Differential scanning calorimetric (d.s.c.) measurements were performed in order to correlate the sequence regions of Sk to energetic folding units of the protein. Fragments Sk1, Tr27, Th26, Tr17, and Th16 show one melting peak in the temperature range from 42.8 to 46.1 degrees C (thermal unfolding stage). For fragment Sk1, this melting peak can be separated by deconvolution into two transitions at T1 = 46.1 degree C and T2 = 47.3 degrees C with delta H1 = 450 kJ/mol and delta H2 = 219 kJ/mol, respectively. Fragments Tr17 and Th16 show one two-state transition at T = 42.8 degrees C with delta H = 326 kJ/mol. 相似文献
55.
Kraft M Knüpfer U Wenderoth R Kacholdt A Pietschmann P Hock B Horn U 《Applied microbiology and biotechnology》2007,76(6):1413-1422
The functional analysis of individual proteins or of multiprotein complexes—since the completion of several genome sequencing
projects—is in focus of current scientific work. Many heterologous proteins contain disulfide-bonds, required for their correct
folding and activity, and therefore, need to be transported to the periplasm. The production of soluble and functional protein
in the periplasm often needs target-specific regulatory genetic elements, leader peptides, and folding regimes. Usually, the
optimization of periplasmic expression is a step-wise and time-consuming procedure. To overcome this problem we developed
a dual expression system, containing a degP-promoter-based reporter system and a highly versatile plasmid set. This combines the differential protein expression with
the selection of a target-specific expression plasmid. For the validation of this expression tool, two different molecular
formats of a recombinant antibody directed to the human epidermal growth factor receptor and human 11β-hydroxysteroid dehydrogenase
type 2 (11β-HSD2) were used. By application of this expression system we demonstrated that the amount of functional protein
is inversely proportional to the on-line luciferase signal. We showed that this technology offers a simple tool to evaluate
and improve the yield of functionally expressed proteins in the periplasm, which depends on the used regulatory elements and
folding strategies. 相似文献
56.
57.
Complex disease by definition results from the interplay of genetic and environmental factors. However, it is currently unclear how gene-environment interaction can best be used to locate complex disease susceptibility loci, particularly in the context of studies where between 1,000 and 1,000,000 markers are scanned for association with disease. We present a joint test of marginal association and gene-environment interaction for case-control data. We compare the power and sample size requirements of this joint test to other analyses: the marginal test of genetic association, the standard test for gene-environment interaction based on logistic regression, and the case-only test for interaction that exploits gene-environment independence. Although for many penetrance models the joint test of genetic marginal effect and interaction is not the most powerful, it is nearly optimal across all penetrance models we considered. In particular, it generally has better power than the marginal test when the genetic effect is restricted to exposed subjects and much better power than the tests of gene-environment interaction when the genetic effect is not restricted to a particular exposure level. This makes the joint test an attractive tool for large-scale association scans where the true gene-environment interaction model is unknown. 相似文献
58.
Journal of Applied Phycology - Marine macroalgae such as Ulva intestinalis have promising properties as feedstock for cosmetics and pharmaceuticals. However, since the quantity and quality of... 相似文献
59.
Sun‐induced fluorescence – a new probe of photosynthesis: First maps from the imaging spectrometer HyPlant 下载免费PDF全文
U. Rascher L. Alonso A. Burkart C. Cilia S. Cogliati R. Colombo A. Damm M. Drusch L. Guanter J. Hanus T. Hyvärinen T. Julitta J. Jussila K. Kataja P. Kokkalis S. Kraft T. Kraska M. Matveeva J. Moreno O. Muller C. Panigada M. Pikl F. Pinto L. Prey R. Pude M. Rossini A. Schickling U. Schurr D. Schüttemeyer J. Verrelst F. Zemek 《Global Change Biology》2015,21(12):4673-4684
Variations in photosynthesis still cause substantial uncertainties in predicting photosynthetic CO2 uptake rates and monitoring plant stress. Changes in actual photosynthesis that are not related to greenness of vegetation are difficult to measure by reflectance based optical remote sensing techniques. Several activities are underway to evaluate the sun‐induced fluorescence signal on the ground and on a coarse spatial scale using space‐borne imaging spectrometers. Intermediate‐scale observations using airborne‐based imaging spectroscopy, which are critical to bridge the existing gap between small‐scale field studies and global observations, are still insufficient. Here we present the first validated maps of sun‐induced fluorescence in that critical, intermediate spatial resolution, employing the novel airborne imaging spectrometer HyPlant. HyPlant has an unprecedented spectral resolution, which allows for the first time quantifying sun‐induced fluorescence fluxes in physical units according to the Fraunhofer Line Depth Principle that exploits solar and atmospheric absorption bands. Maps of sun‐induced fluorescence show a large spatial variability between different vegetation types, which complement classical remote sensing approaches. Different crop types largely differ in emitting fluorescence that additionally changes within the seasonal cycle and thus may be related to the seasonal activation and deactivation of the photosynthetic machinery. We argue that sun‐induced fluorescence emission is related to two processes: (i) the total absorbed radiation by photosynthetically active chlorophyll; and (ii) the functional status of actual photosynthesis and vegetation stress. 相似文献
60.
Wang Y Voelker DR Lugogo NL Wang G Floros J Ingram JL Chu HW Church TD Kandasamy P Fertel D Wright JR Kraft M 《American journal of physiology. Lung cellular and molecular physiology》2011,301(4):L598-L606
Surfactant protein A (SP-A) regulates a variety of immune cell functions. We determined the ability of SP-A derived from normal and asthmatic subjects to modulate the inflammatory response elicited by Mycoplasma pneumoniae, a pathogen known to exacerbate asthma. Fourteen asthmatic and 10 normal control subjects underwent bronchoscopy with airway brushing and bronchoalveolar lavage (BAL). Total SP-A was extracted from BAL. The ratio of SP-A1 to total SP-A (SP-A1/SP-A) and the binding of total SP-A to M. pneumoniae membranes were determined. Airway epithelial cells from subjects were exposed to either normal or asthmatic SP-A before exposure to M. pneumoniae. IL-8 protein and MUC5AC mRNA were measured. Total BAL SP-A concentration did not differ between groups, but the percentage SP-A1 was significantly increased in BAL of asthmatic compared with normal subjects. SP-A1/SP-A significantly correlated with maximum binding of total SP-A to M. pneumoniae, but only in asthma. SP-A derived from asthmatic subjects did not significantly attenuate IL-8 and MUC5AC in the setting of M. pneumoniae infection compared with SP-A derived from normal subjects. We conclude that SP-A derived from asthmatic subjects does not abrogate inflammation effectively, and this dysfunction may be modulated by SP-A1/SP-A. 相似文献