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51.
Brian P. Delisle Heather A. S. Underkofler Brooke M. Moungey Jessica K. Slind Jennifer A. Kilby Jabe M. Best Jason D. Foell Ravi C. Balijepalli Timothy J. Kamp Craig T. January 《The Journal of biological chemistry》2009,284(5):2844-2853
The pro-arrhythmic Long QT syndrome (LQT) is linked to 10 different genes
(LQT1–10). Approximately 40% of genotype-positive LQT patients
have LQT2, which is characterized by mutations in the human ether-a-go-go
related gene (hERG). hERG encodes the voltage-gated
K+ channel α-subunits that form the pore of the rapidly
activating delayed rectifier K+ current in the heart. The purpose
of this study was to elucidate the mechanisms that regulate the intracellular
transport or trafficking of hERG, because trafficking is impaired for about
90% of LQT2 missense mutations. Protein trafficking is regulated by small
GTPases. To identify the small GTPases that are critical for hERG trafficking,
we coexpressed hERG and dominant negative (DN) GTPase mutations in HEK293
cells. The GTPases Sar1 and ARF1 regulate the endoplasmic reticulum (ER)
export of proteins in COPII and COPI vesicles, respectively. Expression of DN
Sar1 inhibited the Golgi processing of hERG, decreased hERG current
(IhERG) by 85% (n ≥ 8 cells per group, *, p
< 0.01), and reduced the plasmalemmal staining of hERG. The coexpression of
DN ARF1 had relatively small effects on hERG trafficking. Surprisingly, the
coexpression of DN Rab11B, which regulates the endosomal recycling, inhibited
the Golgi processing of hERG, decreased IhERG by 79% (n
≥ 8 cells per group; *, p < 0.01), and reduced the plasmalemmal
staining of hERG. These data suggest that hERG undergoes ER export in COPII
vesicles and endosomal recycling prior to being processed in the Golgi. We
conclude that hERG trafficking involves a pathway between the ER and endosomal
compartments that influences expression in the plasmalemma.The human KCNH2 or ether-a-go-go related gene
(hERG)3
encodes the voltage-gated K+ channel α-subunits that
oligomerize to form the pore of the rapidly activating delayed rectifier
K+ current (IKr) in cardiac myocytes
(1–3).
Hundreds of hERG mutations are linked to the congenital
pro-arrhythmic Type 2 Long QT syndrome (LQT2) and functional studies suggest
that these mutations result in a loss of normal hERG K+ channel
(hERG) function (4,
5). In LQT2, missense mutations
are the dominant abnormality and many LQT2 missense mutations reduce hERG
K+ current (IhERG) by decreasing the intracellular
transport or trafficking of hERG to the Golgi apparatus (Golgi) and the cell
surface membrane (plasmalemma)
(6). Therefore, disruption of
hERG K+ channel trafficking appears to be a principal mechanism for
disease.Movement of proteins between membrane-bound intracellular compartments is
mediated by small transport vesicles, which bud from a donor compartment to
fuse with an appropriate acceptor compartment. The trafficking of many
transmembrane and secretory proteins between the ER and Golgi compartments is
dependent on the small GTPases ADP-ribosylation factor 1 (ARF1) and Sar1,
which regulate the formation of coat-associated protein complex I (COPI) and
II (COPII) vesicles, respectively
(7–19).
These small GTPases facilitate the polymerization of transport vesicle protein
coats on the donor membrane. Vesicular cargo selection, docking, and fusion to
the target membrane are regulated by adaptor proteins, SNARE proteins, and Rab
GTPases. To rationally develop novel therapeutic targets that may increase the
expression of trafficking-deficient LQT2 mutant channels, the molecular
mechanisms that regulate the trafficking of hERG need to be explored. The
purpose of this study is to identify transport proteins that regulate the
trafficking of wild type (WT) hERG. We used a strategy of testing specific WT
GTPases or ones containing dominant negative (DN) mutations to interfere with
their function. 相似文献
52.
Hrebícek M Mrázová L Seyrantepe V Durand S Roslin NM Nosková L Hartmannová H Ivánek R Cízkova A Poupetová H Sikora J Urinovská J Stranecký V Zeman J Lepage P Roquis D Verner A Ausseil J Beesley CE Maire I Poorthuis BJ van de Kamp J van Diggelen OP Wevers RA Hudson TJ Fujiwara TM Majewski J Morgan K Kmoch S Pshezhetsky AV 《American journal of human genetics》2006,79(5):807-819
Mucopolysaccharidosis IIIC (MPS IIIC, or Sanfilippo C syndrome) is a lysosomal storage disorder caused by the inherited deficiency of the lysosomal membrane enzyme acetyl-coenzyme A: alpha -glucosaminide N-acetyltransferase (N-acetyltransferase), which leads to impaired degradation of heparan sulfate. We report the narrowing of the candidate region to a 2.6-cM interval between D8S1051 and D8S1831 and the identification of the transmembrane protein 76 gene (TMEM76), which encodes a 73-kDa protein with predicted multiple transmembrane domains and glycosylation sites, as the gene that causes MPS IIIC when it is mutated. Four nonsense mutations, 3 frameshift mutations due to deletions or a duplication, 6 splice-site mutations, and 14 missense mutations were identified among 30 probands with MPS IIIC. Functional expression of human TMEM76 and the mouse ortholog demonstrates that it is the gene that encodes the lysosomal N-acetyltransferase and suggests that this enzyme belongs to a new structural class of proteins that transport the activated acetyl residues across the cell membrane. 相似文献
53.
A commonly used paradigm to study motor imagery is the hand laterality judgment task. The present study aimed to determine which strategies young children employ to successfully perform this task. Children of 5 to 8 years old (N = 92) judged laterality of back and palm view hand pictures in different rotation angles. Response accuracy and response duration were registered. Response durations of the trials with a correct judgment were fitted to a-priori defined predictive sinusoid models, representing different strategies to successfully perform the hand laterality judgment task. The first model predicted systematic changes in response duration as a function of rotation angle of the displayed hand. The second model predicted that response durations are affected by biomechanical constraints of hand rotation. If observed data could be best described by the first model, this would argue for a mental imagery strategy that does not involve motor processes to solve the task. The second model reflects a motor imagery strategy to solve the task. In line with previous research, we showed an age-related increase in response accuracy and decrease in response duration in children. Observed data for both back and palm view showed that motor imagery strategies were used to perform hand laterality judgments, but that not all the children use these strategies (appropriately) at all times. A direct comparison of response duration patterns across age sheds new light on age-related differences in the strategies employed to solve the task. Importantly, the employment of the motor imagery strategy for successful task performance did not change with age. 相似文献
54.
Reconstructed human epidermis for skin absorption testing: results of the German prevalidation study
Schäfer-Korting M Bock U Gamer A Haberland A Haltner-Ukomadu E Kaca M Kamp H Kietzmann M Korting HC Krächter HU Lehr CM Liebsch M Mehling A Netzlaff F Niedorf F Rübbelke MK Schäfer U Schmidt E Schreiber S Schröder KR Spielmann H Vuia A 《Alternatives to laboratory animals : ATLA》2006,34(3):283-294
Exposure to chemicals absorbed by the skin can threaten human health. In order to standardise the predictive testing of percutaneous absorption for regulatory purposes, the OECD adopted guideline 428, which describes methods for assessing absorption by using human and animal skin. In this study, a protocol based on the OECD principles was developed and prevalidated by using reconstructed human epidermis (RHE). The permeation of the OECD standard compounds, caffeine and testosterone, through commercially available RHE models was compared to that of human epidermis and animal skin. In comparison to human epidermis, the permeation of the chemicals was overestimated when using RHE. The following ranking of the permeation coefficients for testosterone was obtained: SkinEthic > EpiDerm, EPISKIN > human epidermis, bovine udder skin, pig skin. The ranking for caffeine was: SkinEthic, EPISKIN > bovine udder skin, EpiDerm, pig skin, human epidermis. The inter-laboratory and intra-laboratory reproducibility was good. Long and variable lag times, which are a matter of concern when using human and pig skin, did not occur with RHE. Due to the successful transfer of the protocol, it is now in the validation process. 相似文献
55.
Biosynthesis and maturation of alpha-N-acetylglucosaminidase in normal and Sanfilippo B-fibroblasts 总被引:3,自引:0,他引:3 下载免费PDF全文
K von Figura A Hasilik F Steckel J van de Kamp 《American journal of human genetics》1984,36(1):93-100
The biosynthesis of alpha-N-acetylglucosaminidase in normal and Sanfilippo B fibroblasts was studied by labeling cells with [35S]methionine and isolation of the enzyme by immunoprecipitation. The immunoprecipitated polypeptides were separated by polyacrylamide gel electrophoresis and visualized by fluorography. alpha-N-acetylglucosaminidase is synthesized as a precursor of an apparent mol. wt. of 87,000. Intracellular processing of the precursor yields two polypeptides of apparent mol. wts. of 73,000 and 76,000 via several intermediates. It is accomplished within 3 days after synthesis. Less than 30% of the newly synthesized precursor is secreted. In the presence of 10 mM NH4Cl, secretion is enhanced to more than 80%. In our study, no alpha-N-acetylglucosaminidase polypeptides could be detected in fibroblasts from patients affected with either the severe or mild form of Sanfilippo disease, type B. 相似文献
56.
A Reuser D Halley E de Wit A Hoogeveen M van der Kamp M Mulder H Galjaard 《Biochemical and biophysical research communications》1976,69(2):311-318
Intercellular exchange of N-acetyl-β-D-glucosaminidase (EC 3.2.1.30) β-galactosidase (EC 3.2.1.23) and acid α-glucosidase (EC 3.2.1.20) was studied after cocultivation of normal and enzyme deficient human fibroblasts in confluent cultures. Enzyme activities were measured in single cells using microchemical procedures. After co-cultivation of normal control fibroblasts and those from a patient with Sandhoff's disease an increase of activity of N-acetyl-β-D-glucosaminidase was found in Sandhoff cells, together with a decrease of activity in normal control cells. After co-cultivation of normal fibroblasts and those from patients with glycogenosis II and GM1-gangliosidosis, no indication was found for intercellular transfer of acid α-glucosidase and β-galactosidase respectively. The significance of the results is discussed in respect of the hypothesis of Hickman and Neufeld about secretion and uptake of lysosomal enzymes. 相似文献
57.
Habitat Association in Two Genetic Groups of the Insect-Pathogenic Fungus Metarhizium anisopliae: Uncovering Cryptic Species? 总被引:1,自引:0,他引:1 下载免费PDF全文
Michael J. Bidochka Andrena M. Kamp T. Michael Lavender Jason Dekoning J. N. Amritha De Croos 《Applied microbiology》2001,67(3):1335-1342
Strains of insect-pathogenic fungi with high virulence toward certain pest insects have great potential for commercial biological control applications. Identifying such strains has been a central theme in using fungi for biological control. This theme is supported by a persistent paradigm in insect pathology which suggests that the host insect is the predominant influence on the population genetics of insect-pathogenic fungi. In this study, a population genetics analysis of the insect-pathogenic fungus Metarhizium anisopliae from forested and agricultural habitats in Ontario, Canada, showed a nonrandom association of alleles between two distinct, reproductively isolated groups (index of multilocus association = 1.2). Analyses of the mitochondrial DNA showed no differences between the groups. The two groups were associated with different habitat types, and associations with insect hosts were not found. The group from forested areas showed an ability for cold-active growth (i.e., 8°C), while the group from the agricultural area showed an ability for growth at high temperatures (i.e., 37°C) and resilience to UV exposure. These results represent a significant paradigm shift; habitat selection, not host insect selection, drives the population structure of these insect-pathogenic deuteromycetous fungi. With each group we observed recombining population structures as well as clonally reproducing lineages. We discuss whether these groups may represent cryptic species. Worldwide, M. anisopliae may be an assembly of cryptic species, each adapted to certain environmental conditions. The association of fungal genotypes with habitat but not with host insects has implications on the criteria for utility of this, and perhaps other, fungal biocontrol agents. 相似文献
58.
G Kamp 《Biological chemistry Hoppe-Seyler》1989,370(6):565-573
1) Glycogen is degraded in the abdominal muscle of the shrimp Crangon crangon (Decapoda, Crustacea) during the recovery period following work. The regulation of post-exercise glycogen breakdown and the properties of glycogen phosphorylase (EC 2.4.1.1) have been studied: 2) Glycogen phosphorylase exists as unphosphorylated b-form and phosphorylated a-form, the latter contains 1 molecule phosphate/subunit. Both forms of phosphorylase are dimers, isoenzymes have not been detected. 3) The purified b-form is inactive in absence of AMP and has very low affinities for AMP and Pi. For half-maximum activation 0.33 +/- 0.04 mM AMP is necessary, and the Km-value for Pi at 1 mM AMP is 48 +/- 5 mM. IMP does not affect the activity of the b-form. 4) The a-form is active without effectors, its Km-value for Pi is 5.3 +/- 1.5 mM. The proportion of phosphorylase a increases in vivo, from about 25% at rest, to approximately 90% upon work and remains at this high level during the first minutes of recovery. 5) It is concluded that the glycogenolytic flux in the abdominal muscle of the shrimp even during post-exercise periods depends on the level of the a-form the activity of which is restricted in time and extent by the cytoplasmic Pi concentration (Kamp, G. & Juretschke, H. P. (1987) Biochim. Biophys. Acta 929, 121-127). 相似文献
59.
The rate of uptake and efflux of phosphatidylcholine from human erythrocytes depends on the fatty acyl composition of the exchanging species 总被引:1,自引:0,他引:1
F A Kuypers X Andriesse P Child B Roelofsen J A Op den Kamp L L van Deenen 《Biochimica et biophysica acta》1986,857(1):75-84
The rate of uptake of radioactive phosphatidylcholine molecules of different fatty acid composition in intact erythrocytes as facilitated by a phosphatidylcholine-specific transfer protein has been studied. When trace amounts of radiolabeled phosphatidylcholine molecules are present in donor vesicles consisting of egg phosphatidylcholine and cholesterol, the transfer of the radiolabeled species depends strongly on their fatty acyl composition: dipalmitoylphosphatidylcholine is transferred at the lowest rate, 1-saturated-2-unsaturated species are transferred faster and the highest rate is observed for dioleoyl phosphatidylcholine. Transfer of the various phosphatidylcholine molecules was measured furthermore using donor systems in which the bulk phosphatidylcholine was varied in its fatty acyl composition. Also in this type of experiment, the transfer protein preferentially stimulated transfer of unsaturated phosphatidylcholine molecules, especially from an environment containing more saturated molecules. Finally, the efflux of labeled phosphatidylcholine from intact erythrocytes to plasma in the absence of the phosphatidylcholine-specific transfer protein was studied and it became clear that in this case the nature of the effused molecules itself, rather than the composition of the bulk lipids, determined the effuse rates. An important conclusion to be drawn from these experiments is that radiolabeled phosphatidylcholine molecules, when used as markers for phospholipid exchange or transfer, should resemble in their fatty acid composition the composition of the bulk lipid in order to provide reliable data on rates and extents of the process studied. 相似文献
60.
Gang Liu Rohinee Beri Amanda Mueller David W. Kamp 《Chemico-biological interactions》2010,188(2):309-318
Asbestos causes pulmonary fibrosis (asbestosis) and malignancies (bronchogenic lung cancer and mesothelioma) by mechanisms that are not fully elucidated. Accumulating evidence show that alveolar epithelial cell (AEC) apoptosis is a crucial initiating and perpetuating event in the development of pulmonary fibrosis following exposure to a wide variety of noxious stimuli, including asbestos. We review the important molecular mechanisms underlying asbestos-induced AEC apoptosis. Specifically, we focus on the role of asbestos in augmenting AEC apoptosis by the mitochondria- and p53-regulated death pathways that result from the production of iron-derived reactive oxygen species (ROS) and DNA damage. We summarize emerging evidence implicating the endoplasmic reticulum (ER) stress response in AEC apoptosis in patients with idiopathic pulmonary fibrosis (IPF), a disease with similarities to asbestosis. Finally, we discuss a recent finding that a mitochondrial oxidative DNA repair enzyme (8-oxoguanine DNA glycosylase; Ogg1) acts as a mitochondrial aconitase chaperone protein to prevent oxidant (asbestos and H2O2)-induced AEC mitochondrial dysfunction and intrinsic apoptosis. The coupling of mitochondrial Ogg1 to mitochondrial aconitase is a novel mechanism linking metabolism to mitochondrial DNA that may be important in the pathophysiologic events resulting in oxidant-induced toxicity as seen in tumors, aging, and respiratory disorders (e.g. asbestosis, IPF). Collectively, these studies are illuminating the molecular basis of AEC apoptosis following asbestos exposure that may prove useful for developing novel therapeutic strategies. Importantly, the asbestos paradigm is elucidating pathophysiologic insights into other more common pulmonary diseases, such as IPF and lung cancer, for which better therapy is required. 相似文献