全文获取类型
收费全文 | 8267篇 |
免费 | 709篇 |
国内免费 | 3篇 |
出版年
2023年 | 29篇 |
2022年 | 69篇 |
2021年 | 108篇 |
2020年 | 69篇 |
2019年 | 76篇 |
2018年 | 113篇 |
2017年 | 103篇 |
2016年 | 181篇 |
2015年 | 319篇 |
2014年 | 367篇 |
2013年 | 444篇 |
2012年 | 565篇 |
2011年 | 564篇 |
2010年 | 416篇 |
2009年 | 356篇 |
2008年 | 501篇 |
2007年 | 505篇 |
2006年 | 460篇 |
2005年 | 482篇 |
2004年 | 506篇 |
2003年 | 445篇 |
2002年 | 476篇 |
2001年 | 70篇 |
2000年 | 56篇 |
1999年 | 116篇 |
1998年 | 139篇 |
1997年 | 56篇 |
1996年 | 79篇 |
1995年 | 64篇 |
1994年 | 73篇 |
1993年 | 85篇 |
1992年 | 79篇 |
1991年 | 61篇 |
1990年 | 74篇 |
1989年 | 47篇 |
1988年 | 61篇 |
1987年 | 59篇 |
1986年 | 55篇 |
1985年 | 49篇 |
1984年 | 69篇 |
1983年 | 48篇 |
1982年 | 65篇 |
1981年 | 73篇 |
1980年 | 46篇 |
1979年 | 46篇 |
1978年 | 40篇 |
1977年 | 43篇 |
1976年 | 35篇 |
1975年 | 25篇 |
1974年 | 27篇 |
排序方式: 共有8979条查询结果,搜索用时 93 毫秒
941.
Human patients with renal disease frequently develop disturbed sleep and severe fatigue. To develop a model for studying factors that contribute to these symptoms, we characterized the sleep patterns of various strains of mice after acute challenge with the fungal organism Candida albicans. After intravenous administration to mice, C. albicans typically colonizes the kidney, producing acute pyelonephritis. Various strains of inbred mice demonstrate marked variation in the temperature and sleep responses that develop after challenge, with individual strains generally showing increased or reduced somnolence in association with fever or hypothermia, respectively. C. albicans-infected mice may be a useful model for identifying the genes and mechanisms that link sleep, temperature, fatigue, and the immune response. 相似文献
942.
Lipid raft-based membrane compartmentation of a plant transport protein expressed in Saccharomyces cerevisiae
下载免费PDF全文
![点击此处可从《Eukaryotic cell》网站下载免费的PDF全文](/ch/ext_images/free.gif)
The hexose-proton symporter HUP1 shows a spotty distribution in the plasma membrane of the green alga Chlorella kessleri. Chlorella cannot be transformed so far. To study the membrane localization of the HUP1 protein in detail, the symporter was fused to green fluorescent protein (GFP) and heterologously expressed in Saccharomyces cerevisiae and Schizosaccharomyces pombe. In these organisms, the HUP1 protein has previously been shown to be fully active. The GFP fusion protein was exclusively targeted to the plasma membranes of both types of fungal cells. In S. cerevisiae, it was distributed nonhomogenously and concentrated in spots resembling the patchy appearance observed previously for endogenous H(+) symporters. It is documented that the Chlorella protein colocalizes with yeast proteins that are concentrated in 300-nm raft-based membrane compartments. On the other hand, it is completely excluded from the raft compartment housing the yeast H(+)/ATPase. As judged by their solubilities in Triton X-100, the HUP1 protein extracted from Chlorella and the GFP fusion protein extracted from S. cerevisiae are detergent-resistant raft proteins. S. cerevisiae mutants lacking the typical raft lipids ergosterol and sphingolipids showed a homogenous distribution of HUP1-GFP within the plasma membrane. In an ergosterol synthesis (erg6) mutant, the rate of glucose uptake was reduced to less than one-third that of corresponding wild-type cells. In S. pombe, the sterol-rich plasma membrane domains can be stained in vivo with filipin. Chlorella HUP1-GFP accumulated exactly in these domains. Altogether, it is demonstrated here that a plant membrane protein has the property of being concentrated in specific raft-based membrane compartments and that the information for its raft association is retained between even distantly related organisms. 相似文献
943.
944.
945.
Neaves L Wapstra E Birch D Girling JE Joss JM 《Journal of experimental zoology. Part A, Comparative experimental biology》2006,305(1):74-82
The majority of research into the timing of gonad differentiation (and sex determination) in reptiles has focused on oviparous species. This is largely because: (1) most reptiles are oviparous; (2) it is easier to manipulate embryonic developmental conditions (e.g., temperature) of eggs than oviductal embryos and (3) modes of sex determination in oviparous taxa were thought to be more diverse since viviparity and environmental sex determination (ESD)/temperature-dependent sex determination (TSD) were considered incompatible. However, recent evidence suggests the two may well be compatible biological attributes, opening potential new lines of enquiry into the evolution and maintenance of sex determination. Unfortunately, the baseline information on embryonic development in viviparous species is lacking and information on gonad differentiation and sexual organ development is almost non-existent. Here we present an embryonic morphological development table (10 stages), the sequence of gonad differentiation and sexual organ development for the viviparous spotted snow skink (Niveoscincus ocellatus). Gonad differentiation in this species is similar to other reptilian species. Initially, the gonads are indifferent and both male and female accessory ducts are present. During stage 2, in the middle third of development, differentiation begins as the inner medulla regresses and the cortex thickens signaling ovary development, while the opposite occurs in testis formation. At this point, the Müllerian (female reproductive) duct regresses in males until it is lost (stage 6), while females retain both ducts until after birth. In the later stages of testis development, interstitial tissue forms in the medulla corresponding to maximum development of the hemipenes in males and the corresponding regression in the females. 相似文献
946.
Melissa A. Geller Sarah Cooley Peter A. Argenta Levi S. Downs Linda F. Carson Patricia L. Judson Rahel Ghebre Brenda Weigel Angela Panoskaltsis-Mortari Julie Curtsinger Jeffrey S. Miller 《Cancer immunology, immunotherapy : CII》2010,59(12):1877-1884
Background
The primary objective was to study the antitumor activity of prolonged subcutaneous dosing of systemic 852A, a Toll-like receptor-7 agonist (TLR-7), in recurrent breast, ovarian and cervix cancer. Secondary objectives included assessment of safety and immune system activation.Methods
Adults with recurrent breast, ovarian or cervix cancer failing multiple therapies received 0.6 mg/m2 of 852A subcutaneously twice weekly for 12 weeks. Doses increased by 0.2 mg/m2/week to a maximum of 1.2 mg/m2. Serum was collected to assess immune activation.Results
Fifteen patients enrolled: 10 ovarian, 2 cervix and 3 breast. Three completed all 24 injections. There were two grade 2 (decreased ejection fractions), nine grade 3 (1 cardiovascular, 1 anorexia, 3 dehydration, 2 infections, 2 renal) and two grade 4 (hepatic and troponin elevation) unanticipated toxicities. Cardiac toxicities included three cardiomyopathies (2 asymptomatic) and one stress-related non-ST elevated myocardial infarction. Five patients discontinued therapy due to possibly associated side effects. One who had stable disease (SD) following 24 doses received 17 additional doses. A cervix patient with SD following 24 doses received chemotherapy after progressing 3 months later, and remains disease free at 18 months. Immune activation, as evidenced by increased IP-10 and IL-1ra, was observed.Conclusions
In this first human experience of a TLR-7 agonist delivered subcutaneously using a prolonged dosing schedule, 852A demonstrated sustained tolerability in some patients. Clinical benefit was modest, but immune activation was seen suggesting further study of antitumor applications is warranted. Because of cardiac toxicity; 852A should be used cautiously in heavily pretreated patients. 相似文献947.
Marhaba Hojahmat David B. Horton Seth D. Norrholm Dennis K. Miller Vladimir P. Grinevich Agripina Gabriela Deaciuc Linda P. Dwoskin Peter A. Crooks 《Bioorganic & medicinal chemistry》2010,18(2):640-649
Vesicular monoamine transporter-2 (VMAT2) is a viable target for development of pharmacotherapies for psychostimulant abuse. Lobeline (1) is a potent antagonist at α4β21 nicotinic acetylcholine receptors, has moderate affinity (Ki = 5.46 μM) for VMAT2, and is being investigated currently as a clinical candidate for treatment of psychostimulant abuse. A series of carboxylic acid and sulfonic acid ester analogs 2–20 of lobeline were synthesized and evaluated for interaction with α4β21 and α71 neuronal nicotinic acetylcholine receptors (nAChRs), the dopamine transporter (DAT), serotonin transporter (SERT) and VMAT2. Both carboxylic acid and sulfonic acid esters had low affinity at α71 nAChRs. Similar to lobeline (Ki = 4 nM), sulfonic acid esters had high affinity at α4β21 (Ki = 5–17 nM). Aromatic carboxylic acid ester analogs of lobeline (2–4) were 100–1000-fold less potent than lobeline at α4β21 nAChRs, whereas aliphatic carboxylic acid ester analogs were 10–100-fold less potent than lobeline at α4β21. Two representative lobeline esters, the 10-O-benzoate (2) and the 10-O-benzenesulfonate (10) were evaluated in the 36Rb+ efflux assay using rat thalamic synaptosomes, and were shown to be antagonists with IC50 values of 0.85 μM and 1.60 μM, respectively. Both carboxylic and sulfonic acid esters exhibited a range of potencies (equipotent to 13–45-fold greater potency compared to lobeline) for inhibiting DAT and SERT, respectively, and like lobeline, had moderate affinity (Ki = 1.98–10.8 μM) for VMAT2. One of the more interesting analogs, p-methoxybenzoic acid ester 4, had low affinity at α4β21 nAChRs (Ki = 19.3 μM) and was equipotent with lobeline, at VMAT2 (Ki = 2.98 μM), exhibiting a 6.5-fold selectivity for VMAT2 over α4β2 nAChRs. Thus, esterification of the lobeline molecule may be a useful structural modification for the development of lobeline analogs with improved selectivity at VMAT2. 相似文献
948.
Woldeamanuel Birru Ross T. Fernley Lloyd D. Graham Julian Grusovin Ronald J. Hill Albert Hofmann Linda Howell Peter J. James Karen E. Jarvis Wynona M. Johnson Dionne A. Jones Christa Leitner Andris J. Liepa George O. Lovrecz Louis Lu Roland H. Nearn Brian J. O’Driscoll Tram Phan Matthew Pollard Kathleen A. Turner David A. Winkler 《Bioorganic & medicinal chemistry》2010,18(15):5647-5660
Nuclear hormone receptors, such as the ecdysone receptor, often display a large amount of induced fit to ligands. The size and shape of the binding pocket in the EcR subunit changes markedly on ligand binding, making modelling methods such as docking extremely challenging. It is, however, possible to generate excellent 3D QSAR models for a given type of ligand, suggesting that the receptor adopts a relatively restricted number of binding site configurations or ‘attractors’. We describe the synthesis, in vitro binding and selected in vivo toxicity data for γ-methylene γ-lactams, a new class of high-affinity ligands for ecdysone receptors from Bovicola ovis (Phthiraptera) and Lucilia cuprina (Diptera). The results of a 3D QSAR study of the binding of methylene lactams to recombinant ecdysone receptor protein suggest that this class of ligands is indeed recognised by a single conformation of the EcR binding pocket. 相似文献
949.
Fuquan Zhang Alice Moon Kay Childs Stephen Goodbourn Linda K. Dixon 《Journal of virology》2010,84(20):10681-10689
950.
Shruthi S. Vembar Martin C. Jonikas Linda M. Hendershot Jonathan S. Weissman Jeffrey L. Brodsky 《The Journal of biological chemistry》2010,285(29):22484-22494
Hsp70 chaperones can potentially interact with one of several J domain-containing Hsp40 co-chaperones to regulate distinct cellular processes. However, features within Hsp70s that determine Hsp40 specificity are undefined. To investigate this question, we introduced mutations into the ER-lumenal Hsp70, BiP/Kar2p, and found that an R217A substitution in the J domain-interacting surface of BiP compromised the physical and functional interaction with Sec63p, an Hsp40 required for ER translocation. In contrast, interaction with Jem1p, an Hsp40 required for ER-associated degradation, was unaffected. Moreover, yeast expressing R217A BiP exhibited defects in translocation but not in ER-associated degradation. Finally, the genetic interactions of the R217A BiP mutant were found to correlate with those of known translocation mutants. Together, our results indicate that residues within the Hsp70 J domain-interacting surface help confer Hsp40 specificity, in turn influencing distinct chaperone-mediated cellular activities. 相似文献