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951.
952.
Coassin S Schweiger M Kloss-Brandstätter A Lamina C Haun M Erhart G Paulweber B Rahman Y Olpin S Wolinski H Cornaciu I Zechner R Zimmermann R Kronenberg F 《PLoS genetics》2010,6(12):e1001239
Recent studies demonstrated a strong influence of rare genetic variants on several lipid-related traits. However, their impact on free fatty acid (FFA) plasma concentrations, as well as the role of rare variants in a general population, has not yet been thoroughly addressed. The adipose triglyceride lipase (ATGL) is encoded by the PNPLA2 gene and catalyzes the rate-limiting step of lipolysis. It represents a prominent candidate gene affecting FFA concentrations. We therefore screened the full genomic region of ATGL for mutations in 1,473 randomly selected individuals from the SAPHIR (Salzburg Atherosclerosis Prevention program in subjects at High Individual Risk) Study using a combined Ecotilling and sequencing approach and functionally investigated all detected protein variants by in-vitro studies. We observed 55 novel mostly rare genetic variants in this general population sample. Biochemical evaluation of all non-synonymous variants demonstrated the presence of several mutated but mostly still functional ATGL alleles with largely varying residual lipolytic activity. About one-quarter (3 out of 13) of the investigated variants presented a marked decrease or total loss of catalytic function. Genetic association studies using both continuous and dichotomous approaches showed a shift towards lower plasma FFA concentrations for rare variant carriers and an accumulation of variants in the lower 10%-quantile of the FFA distribution. However, the generally rather small effects suggest either only a secondary role of rare ATGL variants on the FFA levels in the SAPHIR population or a recessive action of ATGL variants. In contrast to these rather small effects, we describe here also the first patient with "neutral lipid storage disease with myopathy" (NLSDM) with a point mutation in the catalytic dyad, but otherwise intact protein. 相似文献
953.
Stenting of the Shelhigh pulmonary conduit was performed 2 years after a Ross procedure because of a stenosis of the distal segment. We used the new Siemens Artis Zeego technology. A precise placement of the stent to release the stenosis within the distal segment simultaneously retaining a competent valve was possible by using the Dyna-computed tomography technology. The early onset of a stenosis of the Shelhigh xenograft in the pulmonary position is alarming, thus, its use can not be recommended for a replacement of the pulmonary valve. 相似文献
954.
Wei Fan Stefan A. W. Bouwense Ross Crawford Yin Xiao 《Journal of molecular histology》2010,41(1):51-60
Despite the important physiological role of periosteum in the pathogenesis and treatment of osteoporosis, little is known
about the structural and cellular characteristics of periosteum in osteoporosis. To study the structural and cellular differences
in both diaphyseal and metaphyseal periosteum of osteoporotic rats, samples from the right femur of osteoporotic and normal
female Lewis rats were collected and tissue sections were stained with hematoxylin and eosin, antibodies or staining kit against
tartrate resistant acid phosphatase (TRAP), alkaline phosphatase (ALP), vascular endothelial growth factor (VEGF), von Willebrand
(vWF), tyrosine hydroxylase (TH) and calcitonin gene-related peptide (CGRP). The results showed that the osteoporotic rats
had much thicker and more cellular cambial layer of metaphyseal periosteum compared with other periosteal areas and normal
rats (P < 0.001). The number of TRAP+ osteoclasts in bone resorption pits, VEGF+ cells and the degree of vascularization were found to be greater in the cambial layer of metaphyseal periosteum of osteoporotic
rats (P < 0.05), while no significant difference was detected in the number of ALP+ cells between the two groups. Sympathetic nerve fibers identified by TH staining were predominantly located in the cambial
layer of metaphyseal periosteum of osteoporotic rats. No obvious difference in the expression of CGRP between the two groups
was found. In conclusion, periosteum may play an important role in the cortical bone resorption in osteoporotic rats and this
pathological process may be regulated by the sympathetic nervous system. 相似文献
955.
Hendrik Greve Ietidal E. Mohamed Alexander Pontius Stefan Kehraus Harald Gross Gabriele M. König 《Phytochemistry Reviews》2010,9(4):537-545
Natural products play an important role in the development of anticancer drugs. To date, predominantly metabolites from plants
and bacteria served as lead structures for anticancer agents. Fungal metabolites and derivatives thereof are much less investigated
for their potential in cancer therapy. There are, however, some promising candidates derived from fungi in clinical phases
I and II studies. This review gives an overview on the role of natural products in cancer therapy and summarises some of the
latest results of our group in this area. 相似文献
956.
Stefan Mittelmaier Michael Fünfrocken Dominik Fenn Thomas Fichert Monika Pischetsrieder 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2010,878(11-12):877-882
Glucose degradation products (GDPs) formed during heat sterilization of peritoneal dialysis (PD) fluids exert cytotoxic effects and promote the formation of advanced glycation end-products in the peritoneal cavity. As a result, long-term application of continuous ambulatory peritoneal dialysis is limited. The composition and concentration of GDPs in PD fluids must be known to evaluate their biological effects. The present study describes a targeted screening for novel GDPs in PD fluids. For this purpose, dicarbonyl compounds were converted with o-phenylenediamine to give the respective quinoxaline derivatives, which were selectively monitored by HPLC/diode array detector. Glucosone was thereby identified as a novel major GDP in PD fluids. Product identity was confirmed by LC/MSMS analysis using independently synthesized glucosone as a reference compound. Furthermore, a method was developed to quantify glucosone in PD fluids by HPLC/UV after derivatization with o-phenylenediamine. The method's limit of detection was 0.6 μM and the limit of quantitation 1.1 μM. A linear calibration curve was obtained between 1.1 and 113.9 μM (R2 = 0.9999). Analyzed at three different concentration levels, recovery varied between 95.6% and 102.0%. The coefficient of variation ranged between 0.4% and 4.7%. The method was then applied to the measurement of glucosone in typical PD fluids. Glucosone levels in double chamber bag PD fluids varied between not detectable and 6.7 μM. In single chamber bag fluids, glucosone levels ranged between 28.7 and 40.7 μM. 相似文献
957.
Stefan Sturm Felix Hammann Juergen Drewe Hans H. Maurer André Scholer 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2010,878(28):2726-2732
A fully automated screening using liquid chromatography–mass spectrometric method applying data-dependent acquisition was developed to identify toxicologically relevant substances in serum and urine. A library including more than 405 spectra of about 365 compounds (main drugs and important metabolites) was established. An easy to use program was created to automate and accelerate library search. Drugs were identified based on their relative retention times, molecular ions and fragment ions. Limits of detection were tested with 100 of the 365 compounds the majority of these were lower than 100 μg/l (67%). The developed LC–MS–MS system seems to be a valuable alternative to other general unknown screening methods allowing fast and specific identification of drugs in serum and urine samples. 相似文献
958.
Kathrin Rychli Christoph Kaun Philipp J. Hohensinner Adrian J. Dorfner Stefan Pfaffenberger Alexander Niessner Michael Bauer Wolfgang Dietl Bruno K. Podesser Gerald Maurer Kurt Huber Johann Wojta 《Journal of cellular and molecular medicine》2010,14(1-2):198-205
Cardiac diseases such as myocardial infarction and heart failure are among the leading causes of death in western societies. Therapeutic angiogenesis has been suggested as a concept to combat these diseases. The biology of angiogenic factors expressed in the heart such as vascular endothelial growth factor (VEGF) is well studied, whereas data on anti-angiogenic mediators in the heart are scarce. Here we study the expression of the anti-angiogenic factor pigment epithelium-derived factor (PEDF) in the human heart and in human cardiac cells. PEDF expression could be detected in human cardiac tissue on the protein and mRNA levels. PEDF mRNA levels were significantly lower in explanted human ischemic hearts as compared to healthy hearts. Our in vitro experiments showed that human adult cardiac myocytes and fibroblasts constitutively secrete PEDF. In addition to anoxic conditions, cobalt chloride, 2,2'dipyridyl and dimethoxally glycine, which stabilize hypoxia inducible factor-α decreased PEDF expression. Furthermore we show that PEDF inhibits VEGF-induced sprouting. We have identified PEDF in healthy and ischemic human hearts and we show that PEDF expression is down-regulated by low oxygen levels. Therefore, we suggest a role for PEDF in the regulation of angiogenesis in the heart and propose PEDF as a possible therapeutic target in heart disease. 相似文献
959.
The biosynthesis of the volatiles 2,5‐ and 2,6‐diisopropylpyrazine ( 2 and 3 , resp.) released by the myxobacteria Nannocystis exedens subsp. cinnabarina (Na c29) and Chondromyces crocatus (strains Cm c2 and Cm c5) was studied. Isotopically labeled precursors and proposed pathway intermediates were fed to agar plate cultures of the myxobacteria. Subsequently, the volatiles were collected by use of a closed loop stripping apparatus (CLSA), and incorporation into the pyrazines was followed by GC/MS analysis. [2H8]Valine was smoothly incorporated into both pyrazines clearly establishing their origin from the amino acid pool. The cyclic dipeptide valine anhydride ( 16 ) – a potential intermediate on the biosynthetic pathway to branched dialkylpyrazines – was synthesized containing 2H1 labels in specific positions. Feeding of [2H16]‐ 16 and [2H12]‐ 16 in both valine subunits mainly resulted in the formation of pyrazines derived from only one labeled amino acid, whereas only traces of the expected pyrazines with two labeled subunits were found. To investigate the origin of nitrogen in the pyrazines, a feeding experiment with [15N]valine was performed, resulting in the incorporation of the 15N label. The results contradict a biosynthetic pathway via cyclic dipeptides, but rather point to a pathway on which valine is reduced to valine aldehyde. Its dimerization to 2,5‐diisopropyldihydropyrazine 36 and subsequent oxidation results in 2 . The proposed biosynthetic pathway neatly fits the results of earlier labeling studies and also explains the formation of the regioisomer 2,6‐diisopropylpyrazine 3 by isomerization during the first condensation step of two molecules valine aldehyde. A general biosynthetic pathway to different classes of pyrazines is presented. 相似文献
960.
Francesco Pampaloni Ernst H. K. Stelzer Stefan Leicht Marco Marcello 《Proteomics》2010,10(19):3394-3413
We investigate the influence of the dimensionality and the biochemistry of the culture system on the cellular functionality by analyzing the protein expression levels in Madin–Darby canine kidney (MDCK) cells grown in 3‐D and 2‐D substrates. We cultured MDCK cells on a hard and flat 2‐D uncoated plastic surface, on a 2‐D collagen‐coated plastic surface and in 3‐D collagen gel and employed 2‐D gel electrophoresis, MALDI‐TOF‐MS, and LC‐MS/MS analysis to identify the differentially regulated proteins. We found significant differences in the expression of antioxidant proteins, actin‐binding proteins, glycolytic enzymes, and heat‐shock proteins/chaperons among the three types of cultures. While MDCK cells cultured in 3‐D collagen up‐regulate antioxidant proteins and proteins involved in the dynamic remodeling of the actin cytoskeleton, 2‐D collagen‐coated plastic surfaces induce the up‐regulation of glycolytic enzymes. Our data shows that the culture conditions have profound effects on the physiology of the cell. Culture in 3‐D collagen induces a differentiated polarized phenotype. In contrast, collagen‐coated 2‐D substrates favor a tumor‐like phenotype with increased glycolysis. Thus, the suitability of 2‐D cultures to study the physiological behavior of cells, especially in drug discovery, bioprocessing, and toxicology, should be carefully reconsidered. 相似文献