全文获取类型
收费全文 | 1201篇 |
免费 | 123篇 |
出版年
2022年 | 14篇 |
2021年 | 14篇 |
2020年 | 16篇 |
2019年 | 19篇 |
2018年 | 15篇 |
2017年 | 22篇 |
2016年 | 25篇 |
2015年 | 48篇 |
2014年 | 40篇 |
2013年 | 59篇 |
2012年 | 68篇 |
2011年 | 63篇 |
2010年 | 40篇 |
2009年 | 54篇 |
2008年 | 57篇 |
2007年 | 45篇 |
2006年 | 50篇 |
2005年 | 44篇 |
2004年 | 30篇 |
2003年 | 46篇 |
2002年 | 41篇 |
2001年 | 39篇 |
2000年 | 31篇 |
1999年 | 29篇 |
1998年 | 19篇 |
1997年 | 9篇 |
1996年 | 17篇 |
1995年 | 15篇 |
1994年 | 19篇 |
1993年 | 14篇 |
1992年 | 24篇 |
1991年 | 26篇 |
1990年 | 14篇 |
1989年 | 12篇 |
1988年 | 14篇 |
1987年 | 12篇 |
1986年 | 11篇 |
1985年 | 18篇 |
1984年 | 10篇 |
1983年 | 10篇 |
1981年 | 14篇 |
1980年 | 9篇 |
1979年 | 10篇 |
1978年 | 10篇 |
1975年 | 9篇 |
1973年 | 9篇 |
1972年 | 8篇 |
1971年 | 10篇 |
1970年 | 7篇 |
1967年 | 7篇 |
排序方式: 共有1324条查询结果,搜索用时 15 毫秒
111.
Hagen SJ Wu H Morrison SW 《American journal of physiology. Gastrointestinal and liver physiology》2000,279(2):G400-G410
This study was undertaken to determine the mechanism by which ammonium chloride (NH(4)Cl) inhibits stimulated acid secretion in the bullfrog gastric mucosa. To this end, four possible pathways of inhibition were studied: 1) blockade of basolateral K(+) channel, 2) blockade of ion transport activity, 3) neutralization of secreted H(+) in the luminal solution, or 4) ATP depletion. Addition of nutrient 10 mM NH(4)Cl (calculated NH(3) concentration = 92.5 microM and NH(4)(+) concentration = 9.91 mM) inhibited acid secretion within 30 min. Inhibition of acid secretion did not occur by blockade of basolateral K(+) channel activity or ion transport activity or by neutralization of the luminal solution. Although ATP depletion occurred in the presence of NH(4)Cl, the magnitude of ATP depletion in 30 min was not sufficient to inhibit stimulated acid secretion. By comparing the effect of NH(4)Cl on the resistance of inhibited or stimulated tissues, we demonstrate that NH(4)Cl acts specifically on stimulated tissues. We propose that NH(4)Cl blocks activity of an apical K(+) channel present in stimulated oxyntic cells. Our data suggest that the activity of this channel is important for the regulation of acid secretion in bullfrog oxyntic cells. 相似文献
112.
Communication and reciprocal regulation between the nervous, endocrine and immune systems are essential for the stability of the organism. Among others, cytokines, hormones and neuropeptides have been identified as signalling molecules mediating the communication between the three systems. This review focuses on the role of the neuropeptide somatostatin as an intersystem signalling molecule, with emphasis on the immune system. Somatostatin down-modulates a number of immune functions, among others lymphocyte proliferation, immunoglobulin production and the release of proinflammatory cytokines such as IFN-g. Systemic or local treatment with somatostatin or somatostatin analogues has been shown to be beneficial in a number of in vivo models of autoimmune disease and chronic inflammation. In many of these models somatostatin appears to antagonise the effects of another neuropeptide, substance P. A somatostatin-substance P immunoregulatory circuit has been proposed to operate within murine Schistosoma mansoni-induced granulomas. In this review we extend the model of the somatostatin-substance P immunoregulatory circuit to include data derived from other biological systems, and those relying on human clinical situations. In addition, we present a hypothesis on the regulation of the default class of immune response within a tissue, based on the local balance of pro-and anti-inflammatory neuropeptides. 相似文献
113.
Grigelioniene G Eklöf O Ivarsson SA Westphal O Neumeyer L Kedra D Dumanski J Hagenäs L 《Human genetics》2000,107(2):145-149
Dyschondrosteosis (DCO) and hypochondroplasia (HCH) are common skeletal dysplasias characterized by disproportionate short stature. The diagnosis of these conditions might be difficult to establish especially in early childhood. Point mutations and deletions of the short stature homeobox containing gene (SHOX) are detected in DCO and idiopathic short stature with some rhizomelic body disproportion, whereas mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are found in 40-70% of HCH cases. In this study, we performed mutational analysis of the coding region of the SHOX gene in five DCO and 18 HCH patients, all of whom tested negative for the known HCH-associated FGFR3 mutations. The polymorphic CA-repeat analysis, direct sequencing and Southern blotting were used for detection of deletions and point mutations. The auxological and radiological phenotype of these patients was carefully determined. Three novel mutations in DCO patients were found: (1) a deletion of one base (de1272G) (according to GenBank accession nos. Y11536, Y11535), resulting in a premature stop codon at position 75 of the amino acid sequence; (2) the transversion C485G resulting in the substitution Leu132Val; and (3) the transversion G549T causing an Arg153Leu substitution. These substitutions segregate with the DCO phenotype and affect evolutionarily conserved homeodomain residues, based on a comparison of homeobox containing proteins in 13 species. Moreover, these changes were not found in 80 unrelated, unaffected individuals. This strongly suggests that these mutations are pathogenic. The phenotype of our patients with DCO and HCH varied from mild to severe shortness and body disproportion. These results further support clinical and genetic heterogeneity of dyschondrosteosis and hypochondroplasia. 相似文献
114.
Leys D Backers K Meyer TE Hagen WR Cusanovich MA Van Beeumen JJ 《The Journal of biological chemistry》2000,275(21):16050-16056
The photosynthetic bacterium Rhodobacter sphaeroides produces a heme protein (SHP), which is an unusual c-type cytochrome capable of transiently binding oxygen during autooxidation. Similar proteins have not only been observed in other photosynthetic bacteria but also in the obligate methylotroph Methylophilus methylotrophus and the metal reducing bacterium Shewanella putrefaciens. A three-dimensional structure of SHP was derived using the multiple isomorphous replacement phasing method. Besides a model for the oxidized state (to 1.82 A resolution), models for the reduced state (2.1 A resolution), the oxidized molecule liganded with cyanide (1. 90 A resolution), and the reduced molecule liganded with nitric oxide (2.20 A resolution) could be derived. The SHP structure represents a new variation of the class I cytochrome c fold. The oxidized state reveals a novel sixth heme ligand, Asn(88), which moves away from the iron upon reduction or when small molecules bind. The distal side of the heme has a striking resemblance to other heme proteins that bind gaseous compounds. In SHP the liberated amide group of Asn(88) stabilizes solvent-shielded ligands through a hydrogen bond. 相似文献
115.
Energy metabolism in uncoupling protein 3 gene knockout mice 总被引:27,自引:0,他引:27
Vidal-Puig AJ Grujic D Zhang CY Hagen T Boss O Ido Y Szczepanik A Wade J Mootha V Cortright R Muoio DM Lowell BB 《The Journal of biological chemistry》2000,275(21):16258-16266
Uncoupling protein 3 (UCP3) is a member of the mitochondrial anion carrier superfamily. Based upon its high homology with UCP1 and its restricted tissue distribution to skeletal muscle and brown adipose tissue, UCP3 has been suggested to play important roles in regulating energy expenditure, body weight, and thermoregulation. Other postulated roles for UCP3 include regulation of fatty acid metabolism, adaptive responses to acute exercise and starvation, and prevention of reactive oxygen species (ROS) formation. To address these questions, we have generated mice lacking UCP3 (UCP3 knockout (KO) mice). Here, we provide evidence that skeletal muscle mitochondria lacking UCP3 are more coupled (i.e. increased state 3/state 4 ratio), indicating that UCP3 has uncoupling activity. In addition, production of ROS is increased in mitochondria lacking UCP3. This study demonstrates that UCP3 has uncoupling activity and that its absence may lead to increased production of ROS. Despite these effects on mitochondrial function, UCP3 does not seem to be required for body weight regulation, exercise tolerance, fatty acid oxidation, or cold-induced thermogenesis. The absence of such phenotypes in UCP3 KO mice could not be attributed to up-regulation of other UCP mRNAs. However, alternative compensatory mechanisms cannot be excluded. The consequence of increased mitochondrial coupling in UCP3 KO mice on metabolism and the possible role of yet unidentified compensatory mechanisms, remains to be determined. 相似文献
116.
Phylogenetic utility of the nuclear gene arginine decarboxylase: an example from Brassicaceae 总被引:10,自引:2,他引:8
Arginine decarboxylase (ADC) is an important enzyme in the production of
putrescine and polyamines in plants. It is encoded by a single or low-copy
nuclear gene that lacks introns in sequences studied to date. The rate of
Adc amino acid sequence evolution is similar to that of ndhF for the
angiosperm family studied. Highly conserved regions provide several target
sites for PCR priming and sequencing and aid in nucleotide and amino acid
sequence alignment across a range of taxonomic levels, while a variable
region provides an increased number of potentially informative characters
relative to ndhF for the taxa surveyed. The utility of the Adc gene in
plant molecular systematic studies is demonstrated by analysis of its
partial nucleotide sequences obtained from 13 representatives of
Brassicaceae and 3 outgroup taxa, 2 from the mustard oil clade (order
Capparales) and 1 from the related order Malvales. Two copies of the Adc
gene, Adc1 and Adc2, are found in all members of the Brassicaceae studied
to data except the basal genus Aethionema. The resulting Adc gene tree
provides robust phylogenetic data regarding relationships within the
complex mustard family, as well as independent support for proposed tribal
realignments based on other molecular data sets such as those from
chloroplast DNA.
相似文献
117.
Alexander F. Arendsen Jonathan Hadden Graeme Card Alan S. McAlpine Susan Bailey Vjacheslav Zaitsev Elizabeth H. M. Duke P. F. Lindley Monika Kröckel Alfred X. Trautwein Martinus C. Feiters John M. Charnock C. David Garner Sophie J. Marritt Andrew J. Thomson Ingeborg M. Kooter Michael K. Johnson Willy A. M. van den Berg Walter M. A. M. van Dongen W. R. Hagen 《Journal of biological inorganic chemistry》1998,3(1):81-95
The three-dimensional structure of the native "putative prismane" protein from Desulfovibrio vulgaris (Hildenborough) has been solved by X-ray crystallography to a resolution of 1.72?Å. The molecule does not contain a [6Fe-6S] prismane cluster, but rather two 4Fe clusters some 12?Å apart and situated close to the interfaces formed by the three domains of the protein. Cluster 1 is a conventional [4Fe-4S] cubane bound, however, near the N-terminus by an unusual, sequential arrangement of four cysteine residues (Cys 3, 6, 15, 21). Cluster 2 is a novel 4Fe structure with two μ2-sulfido bridges, two μ2-oxo bridges, and a partially occupied, unidentified μ2 bridge X. The protein ligands of cluster 2 are widely scattered through the second half of the sequence and include three cysteine residues (Cys 312, 434, 459), one persulfido-cysteine (Cys 406), two glutamates (Glu 268, 494), and one histidine (His 244). With this unusual mixture of bridging and external type of ligands, cluster 2 is named the "hybrid" cluster, and its asymmetric, open structure suggests that it could be the site of a catalytic activity. X-ray absorption spectroscopy at the Fe K-edge is readily interpretable in terms of the crystallographic model when allowance is made for volume contraction at 10?K; no Fe··Fe distances beyond 3.1?Å could be identified. EPR, Mössbauer and MCD spectroscopy have been used to define the oxidation states and the magnetism of the clusters in relation to the crystallographic structure. Reduced cluster 1 is a [4Fe-4S]1+ cubane with S?=?3/2; it is the first biological example of a "spin-admixed" iron-sulfur cluster. The hybrid cluster 2 has four oxidation states from (formally) all FeIII to three FeII plus one FeIII. The four iron ions are exchange coupled resulting in the system spins S?=?0, 9/2, 0 (and 4), 1/2, respectively, for the four redox states. Resonance Raman spectroscopy suggests that the bridging ligand X which could not be identified unambiguously in the crystal structure is a solvent-exchangeable oxygen. 相似文献
118.
119.
Niels Wessel Shishir Dash Jürgen Kurths Robert Bauernschmitt Hagen Malberg 《Biomedizinische Technik》2007,52(3):264-266
In this letter, we explain the role of acceleration and deceleration capacities as novel risk predictors after myocardial infarction and their relation to the occurrence of ventricular premature complexes. 相似文献
120.
Paolo Denti Kidola Jeremiah Emmanuel Chigutsa Daniel Faurholt-Jepsen George PrayGod Nyagosya Range Sandra Castel Lubbe Wiesner Christian Munch Hagen Michael Christiansen John Changalucha Helen McIlleron Henrik Friis Aase Bengaard Andersen 《PloS one》2015,10(10)
Exposure to lower-than-therapeutic levels of anti-tuberculosis drugs is likely to cause selection of resistant strains of Mycobacterium tuberculosis and treatment failure. The first-line anti-tuberculosis (TB) regimen consists of rifampicin, isoniazid, pyrazinamide, and ethambutol, and correct management reduces risk of TB relapse and development of drug resistance. In this study we aimed to investigate the effect of standard of care plus nutritional supplementation versus standard care on the pharmacokinetics of isoniazid, pyrazinamide and ethambutol among sputum smear positive TB patients with and without HIV. In a clinical trial in 100 Tanzanian TB patients, with or without HIV infection, drug concentrations were determined at 1 week and 2 months post initiation of anti-TB medication. Data was analysed using population pharmacokinetic modelling. The effect of body size was described using allometric scaling, and the effects of nutritional supplementation, HIV, age, sex, CD4+ count, weight-adjusted dose, NAT2 genotype, and time on TB treatment were investigated. The kinetics of all drugs was well characterised using first-order elimination and transit compartment absorption, with isoniazid and ethambutol described by two-compartment disposition models, and pyrazinamide by a one-compartment model. Patients with a slow NAT2 genotype had higher isoniazid exposure and a lower estimate of oral clearance (15.5 L/h) than rapid/intermediate NAT2 genotype (26.1 L/h). Pyrazinamide clearance had an estimated typical value of 3.32 L/h, and it was found to increase with time on treatment, with a 16.3% increase after the first 2 months of anti-TB treatment. The typical clearance of ethambutol was estimated to be 40.7 L/h, and was found to decrease with age, at a rate of 1.41% per year. Neither HIV status nor nutritional supplementations were found to affect the pharmacokinetics of these drugs in our cohort of patients. 相似文献