全文获取类型
收费全文 | 1181篇 |
免费 | 91篇 |
国内免费 | 2篇 |
出版年
2023年 | 3篇 |
2022年 | 5篇 |
2021年 | 9篇 |
2020年 | 7篇 |
2019年 | 12篇 |
2018年 | 15篇 |
2017年 | 4篇 |
2016年 | 16篇 |
2015年 | 31篇 |
2014年 | 33篇 |
2013年 | 56篇 |
2012年 | 51篇 |
2011年 | 58篇 |
2010年 | 36篇 |
2009年 | 45篇 |
2008年 | 70篇 |
2007年 | 60篇 |
2006年 | 64篇 |
2005年 | 69篇 |
2004年 | 60篇 |
2003年 | 53篇 |
2002年 | 62篇 |
2001年 | 59篇 |
2000年 | 48篇 |
1999年 | 43篇 |
1998年 | 12篇 |
1997年 | 20篇 |
1996年 | 6篇 |
1995年 | 14篇 |
1994年 | 5篇 |
1993年 | 11篇 |
1992年 | 23篇 |
1991年 | 27篇 |
1990年 | 19篇 |
1989年 | 19篇 |
1988年 | 23篇 |
1987年 | 16篇 |
1986年 | 12篇 |
1985年 | 13篇 |
1984年 | 12篇 |
1983年 | 10篇 |
1982年 | 9篇 |
1981年 | 8篇 |
1975年 | 9篇 |
1974年 | 6篇 |
1973年 | 3篇 |
1972年 | 3篇 |
1970年 | 3篇 |
1969年 | 3篇 |
1968年 | 4篇 |
排序方式: 共有1274条查询结果,搜索用时 15 毫秒
81.
Matsumoto N Tsuruoka S Iwamoto T Tomich JM Ito K Imai M Suzuki M 《The Journal of membrane biology》2003,193(3):195-200
To better understand the process of fluid movement driven by Cl– conductance, a Cl– channel-forming peptide was delivered to the luminal membrane of microperfused rabbit renal proximal tubules. When the peptide (NK4-M2GlyR) was perfused, a significant new conductance was observed within 3 min and stabilized at 10 min. Alteration of the ion composition revealed it to be a Cl–-specific conductance. Reabsorption of Cl– (J
Cl) was increased by NK4-M2GlyR, but not by a scramble NK4-M2GlyR sequence, suggesting that the active peptide formed de novo Cl– channels in the luminal membrane of the perfused tubules. In the presence of the peptide, reabsorption of fluid (J
v) was dramatically increased and J
Na and J
Ca were concomitantly increased. We propose that introduction of the new Cl– conductance in the luminal membrane leads to a coordinated efflux of water across the membrane and an increase in cation translocation via the paracellular pathway, resulting in an increase in J
v. This novel method could prove useful in characterizing mechanisms of fluid transport driven by Cl– gradients. 相似文献
82.
Seto Y Nakajima H Suto A Shimoda K Saito Y Nakayama KI Iwamoto I 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(2):1077-1083
Allergic inflammation is mediated by Th2 cell-derived cytokines, including IL-4, IL-5, and IL-13, and down-regulated by IFN-gamma and IL-12. Tyk2 is a member of the Janus family of protein tyrosine kinases and is activated by a variety of cytokines: IFN-alphabeta, IL-6, IL-10, IL-12, and IL-13. In this study, we investigated the role of Tyk2 in the regulation of Ag-induced Th cell differentiation and Ag-induced allergic inflammation in the airways using Tyk2-deficient (Tyk2(-/-)) mice. When splenocytes were stimulated with antigenic peptide, IL-12-mediated Th1 cell differentiation was decreased, but IL-4-mediated Th2 cell differentiation was increased in Tyk2(-/-) mice. In vivo, Ag-specific IgE and IgG1 production was increased, but Ag-specific IgG2a production was decreased in Tyk2(-/-) mice as compared with those in control mice. In addition, Ag-induced eosinophil and CD4(+) T cell recruitment, as well as the production of Th2 cytokines in the airways, was increased in Tyk2(-/-) mice. Adoptive transfer experiments revealed that CD4(+) T cells were responsible for the enhanced Ag-induced eosinophil recruitment in Tyk2(-/-) mice. In contrast, although the level of IL-13 was increased in the airways of Tyk2(-/-) mice after Ag inhalation, the number of goblet cells, as well as Muc5ac mRNA expression, was decreased in Tyk2(-/-) mice. Together, these results indicate that Tyk2 plays a bilateral role in the regulation of allergic inflammation in the airways: Tyk2 plays a role in the down-regulation of Th2 cell-mediated Ab production and eosinophil recruitment in the airways by regulating Th1/Th2 balance toward Th1-type, while Tyk2 is necessary for the induction of IL-13-mediated goblet cell hyperplasia in the airways. 相似文献
83.
Kuo MR Morbidoni HR Alland D Sneddon SF Gourlie BB Staveski MM Leonard M Gregory JS Janjigian AD Yee C Musser JM Kreiswirth B Iwamoto H Perozzo R Jacobs WR Sacchettini JC Fidock DA 《The Journal of biological chemistry》2003,278(23):20851-20859
Tuberculosis and malaria together result in an estimated 5 million deaths annually. The spread of multidrug resistance in the most pathogenic causative agents, Mycobacterium tuberculosis and Plasmodium falciparum, underscores the need to identify active compounds with novel inhibitory properties. Although genetically unrelated, both organisms use a type II fatty-acid synthase system. Enoyl acyl carrier protein reductase (ENR), a key type II enzyme, has been repeatedly validated as an effective antimicrobial target. Using high throughput inhibitor screens with a combinatorial library, we have identified two novel classes of compounds with activity against the M. tuberculosis and P. falciparum enzyme (referred to as InhA and PfENR, respectively). The crystal structure of InhA complexed with NAD+ and one of the inhibitors was determined to elucidate the mode of binding. Structural analysis of InhA with the broad spectrum antimicrobial triclosan revealed a unique stoichiometry where the enzyme contained either a single triclosan molecule, in a configuration typical of other bacterial ENR:triclosan structures, or harbored two triclosan molecules bound to the active site. Significantly, these compounds do not require activation and are effective against wild-type and drug-resistant strains of M. tuberculosis and P. falciparum. Moreover, they provide broader chemical diversity and elucidate key elements of inhibitor binding to InhA for subsequent chemical optimization. 相似文献
84.
Yamazaki S Iwamoto R Saeki K Asakura M Takashima S Yamazaki A Kimura R Mizushima H Moribe H Higashiyama S Endoh M Kaneda Y Takagi S Itami S Takeda N Yamada G Mekada E 《The Journal of cell biology》2003,163(3):469-475
Heparin-binding EGF-like growth factor (HB-EGF) is first synthesized as a membrane-anchored form (proHB-EGF), and its soluble form (sHB-EGF) is released by ectodomain shedding from proHB-EGF. To examine the significance of proHB-EGF processing in vivo, we generated mutant mice by targeted gene replacement, expressing either an uncleavable form (HBuc) or a transmembrane domain-truncated form (HBdeltatm) of the molecule. HB(uc/uc) mice developed severe heart failure and enlarged heart valves, phenotypes similar to those in proHB-EGF null mice. On the other hand, mice carrying HBdeltatm exhibited severe hyperplasia in both skin and heart. These results indicate that ectodomain shedding of proHB-EGF is essential for HB-EGF function in vivo, and that this process requires strict control. 相似文献
85.
Yeh JK Niu Q Evans JF Iwamoto J Aloia JF 《Journal of musculoskeletal & neuronal interactions》2001,1(3):235-240
The aims of the study are to develop a non-invasive animal model of circular motion exercise and to evaluate the effect of this type of exercise on bone turnover in young rats. The circular motion exercise simulates isometric exercise using an orbital shaker that oscillates at a frequency of 50 Hz and is capable of speeds from 0-400 rpm. A cage is fixed on top of the shaker and the animals are placed inside. When the shaker is turned on, the oscillatory movement should encourage the animals to hold on to the cage and use various muscle forces to stabilize themselves. Rats at 8 weeks of age were trained on the shaker for 6 weeks and static and dynamic histomorphometric analyses were performed for the proximal tibial metaphysis and the tibial shaft. The exercise resulted in no significant effect on animal body weight, gastrocnemius muscle weight and femoral weight. Although the bone formation rate of cancellous and cortical periosteum was increased by the exercise, trabecular bone volume was decreased. The exercise increased periosteal and marrow perimeters and the cross-sectional diameter of cortical bone from medial to lateral without a significant increase in the cortical bone area. These results suggest that circular motion exercise under force without movement or additional weight loading will cause bone-modeling drift with an increase in bone turnover to reconstruct bone shape in adaptation to the demand in strength. Since there is no additional weight loading during circular motion exercise, the net mass of bone is not increased. The bone mass lost in trabecular bone could possibly be due to a re-distribution of mineral to the cortical bone. 相似文献
86.
Sugita-Konishi Y Hara-Kudo Y Iwamoto T Kondo K 《Bioscience, biotechnology, and biochemistry》2001,65(4):954-957
We studied the activity of wine against entero-pathogenic bacteria both in vitro and in vivo. The food-borne bacteria were killed in both red and white wine within 30 min. However, the results of a Salmonella infection experiment using mice suggested that wine was not effective in preventing food-borne diseases in vivo. 相似文献
87.
The mouse genomic sequence of the region containing the gene Rhced, the orthologue to the human gene RH30, was determined to elucidate the structure of Rhced and its flanking regions and to compare these with the corresponding human genomic region. Two genes, Smp1 and AK003528 (an orthologue of FLJ10747), flank Rhced. Neither sequences homologous to the characteristic nucleotide elements flanking the RHD gene in humans (rhesus boxes) nor an additional Rh gene were found within the mouse region sequenced. This result and that of a previous report demonstrate that this chromosomal region of the mouse comprises five genes (FLJ10747-RHCE-SMP1-NPD014-P29) that exhibit syntenic homology with the corresponding human region, which suggests that the RHD gene and rhesus boxes were inserted later. Evaluations of tissue distribution and subcellular localization of these genes indicate that the SMP1 orthologue has a ubiquitous tissue distribution and cytoplasmic localization, whereas AK003528 is expressed slightly higher in testis with a strong subcellular localization in the nucleus. Despite the steady improvements in the draft sequence of the human genome, this study demonstrates the continuing benefits of comparative genetic analyses in increasing our understanding of human genomic structure. 相似文献
88.
Iwamoto R Kubota H Hosoki T Ikehara K Tanaka M 《Archives of biochemistry and biophysics》2002,398(2):203-212
A glucosamine-induced novel alcohol dehydrogenase has been isolated from Agrobacterium radiobacter (tumefaciens) and its fundamental properties have been characterized. The enzyme catalyzes NAD-dependent dehydrogenation of aliphatic alcohols and amino alcohols. In this work, the complete amino acid sequence of the alcohol dehydrogenase was determined by PCR method using genomic DNA of A. radiobacter as template. The enzyme comprises 336 amino acids and has a molecular mass of 36 kDa. The primary structure of the enzyme demonstrates a high homology to structures of alcohol dehydrogenases from Shinorhizobium meliloti (83% identity, 90% positive) and Pseudomonas aeruginosa (65% identity, 76% positive). The two Zn(2+) ion binding sites, both the active site and another site that contributed to stabilization of the enzyme, are conserved in those enzymes. Sequences analysis of the NAD-dependent dehydrogenase family using a hypothetical phylogenetic tree indicates that these three enzymes form a new group distinct from other members of the Zn-containing long-chain alcohol dehydrogenase family. The physicochemical properties of alcohol dehydrogenase from A. radiobacter were characterized as follows. (1) Stereospecificity of the hydride transfer from ethanol to NADH was categorized as pro-R type by NMR spectra of NADH formed in the enzymatic reaction using ethanol-D(6) was used as substrate. (2) Optimal pH for all alcohols with no amino group examined was pH 8.5 (of the C(2)-C(6) alcohols, n-amyl alcohol demonstrated the highest activity). Conversely, glucosaminitol was optimally dehydrogenated at pH 10.0. (3) The rate-determining step of the dehydrogenase for ethanol is deprotonation of the enzyme-NAD-Zn-OHCH(2)CH(3) complex to enzyme-NAD-Zn-O(-)CH(2)CH(3) complex and that for glucosaminitol is H(2)O addition to enzyme-Zn-NADH complex. 相似文献
89.
Tao R Habu T Namba A Yamane H Fuyuhiro F Iwamoto K Sugiura A 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2002,105(2-3):222-228
Self-compatible cultivars of Japanese apricot ( Prunus mume Shieb. et Zucc.), a tree species that normally shows S-RNase-based self-incompatiblity, have a horticultural advantage over self-incompatible cultivars. Inheritance of self-compatibility and a common S(f)-RNase allele that is observed in self-compatible cultivars was investigated using progenies from controlled crosses. Total DNAs were isolated from the parents and progenies of seven crosses that included at least one self-compatible cultivar as a parent. These DNAs were PCR-amplified with the Pru-C2 and PCE-R primer pair to determine S-haplotypes of the parents and progenies. A novel S-haplotype, S(8), was found. In all crosses examined, the S(f)-RNase gene was inherited from either the seed or pollen parent as a pistil S-allele in a non-functional S-haplotype. Self-compatibility of about 20 trees each from reciprocal crosses of 'Benisashi ( S(7) S(f))' and 'Shinpeidayu ( S(3) S(f))', and 26 selections from 16 different crosses was tested by pollination and pollen-tube growth studies. Cosegregation of the S(f)-RNase allele and self-compatibility was confirmed with all but selection 1K0-26 ( S(3) S(7)). Selection 1K0-26 ( S(3) S(7)) that originated from 'Benisashi ( S(7) S(f))' x 'Koshinoume ( S(3) S(f))' appeared to be self-compatible even without the S(f)-RNase allele. The possible role of pollen- S, a presumably existing pollen component of gametophytic self-incompatibility, is discussed. 相似文献
90.