全文获取类型
收费全文 | 1068篇 |
免费 | 57篇 |
出版年
2023年 | 2篇 |
2022年 | 6篇 |
2021年 | 19篇 |
2020年 | 11篇 |
2019年 | 23篇 |
2018年 | 25篇 |
2017年 | 17篇 |
2016年 | 34篇 |
2015年 | 50篇 |
2014年 | 51篇 |
2013年 | 75篇 |
2012年 | 86篇 |
2011年 | 111篇 |
2010年 | 59篇 |
2009年 | 43篇 |
2008年 | 82篇 |
2007年 | 80篇 |
2006年 | 58篇 |
2005年 | 71篇 |
2004年 | 57篇 |
2003年 | 42篇 |
2002年 | 41篇 |
2001年 | 6篇 |
2000年 | 2篇 |
1999年 | 8篇 |
1998年 | 6篇 |
1997年 | 5篇 |
1996年 | 4篇 |
1995年 | 2篇 |
1994年 | 6篇 |
1993年 | 4篇 |
1992年 | 4篇 |
1991年 | 4篇 |
1990年 | 5篇 |
1989年 | 5篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1985年 | 5篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1982年 | 3篇 |
1981年 | 3篇 |
1979年 | 1篇 |
1975年 | 1篇 |
1974年 | 1篇 |
排序方式: 共有1125条查询结果,搜索用时 31 毫秒
991.
Dukat M El-Zahabi M Ferretti G Damaj MI Martin BR Young R Glennon RA 《Bioorganic & medicinal chemistry letters》2002,12(20):3005-3007
Several 6-alkyl analogues of nicotine were examined in radioligand binding and in vivo functional assays. Although (-)6-ethylnicotine (3) binds with high affinity at nACh receptors (Ki=5.6 nM) and produces nicotine-like actions, its n-propyl homologue (-)4 (Ki=22 nM) failed to produce such effects. In fact, (-)4 antagonized the antinociceptive effects of (-)nicotine in the tail-flick assay in mice, but not the spontaneous activity or discriminative stimulus effects of (-)nicotine. Compound (-)4 appears to selectively antagonize only one of the three effects examined and is an interesting cholinergic agent for subsequent investigation. 相似文献
992.
Malgorzata?LatalowaEmail author Monika?Badura Joanna?Jarosińska 《Vegetation History and Archaeobotany》2003,12(2):93-104
The botanical composition of samples from culture layers, explored in two medieval towns in northern Poland, is discussed with respect to their potential as a source of environmental data. The frequency of selected taxa and the proportion of their diaspores in the actualistic groups of weed and grassland species, as well as the distribution of indices for edaphic factors were used as indicators of the natural environment around and inside the towns, and of some aspects of agriculture. The comparison of the results from both towns affords new evidence for a better understanding of archaeobotanical data from culture layers of non-specific, complex origin. 相似文献
993.
An amino acid in the central catalytic domain of three retroviral integrases that affects target site selection in nonviral DNA
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Integrase can insert retroviral DNA into almost any site in cellular DNA; however, target site preferences are noted in vitro and in vivo. We recently demonstrated that amino acid 119, in the alpha2 helix of the central domain of the human immunodeficiency virus type 1 integrase, affected the choice of nonviral target DNA sites. We have now extended these findings to the integrases of a nonprimate lentivirus and a more distantly related alpharetrovirus. We found that substitutions at the analogous positions in visna virus integrase and Rous sarcoma virus integrase changed the target site preferences in five assays that monitor insertion into nonviral DNA. Thus, the importance of this protein residue in the selection of nonviral target DNA sites is likely to be a general property of retroviral integrases. Moreover, this amino acid might be part of the cellular DNA binding site on integrase proteins. 相似文献
994.
Reactive oxygen species (ROS) play an important role in physiological processes, but - when being in excess - ROS cause oxidative damage to molecules. Under physiological conditions, the production and detoxification of ROS are more-or-less balanced. Also in the thyroid, ROS and free radicals participate in physiological and pathological processes in the gland. For example, hydrogen peroxide (H2O2) is crucial for thyroid hormone biosynthesis, acting at different steps of the process. Additionally, H2O2 is believed to participate in the Wolff-Chaikoff's effect, undergoing in conditions of iodide excess in the thyroid. Much evidence has been accumulated indicating that oxidative stress is involved in pathomechanism of thyroid disease, e.g., Graves' disease, goiter formation or thyroid cancer. Melatonin (N-acetyl-5-methoxytryptamine) - the main secretory product of the pineal gland - is a well-known antioxidant and free radical scavenger, widely distributed in the organism. Mutual relationships between the pineal gland and the thyroid have - for a long time - been a subject of intensive research. The abundant to-date's evidence relates mostly to the inhibitory action of melatonin on the thyroid growth and function and - to a lesser extent - to the stimulatory effects of thyroid hormones on the pineal gland. It is highly probable that under physiological conditions melatonin and, possibly, other antioxidants regulate ROS generation for thyroid hormone synthesis. We believe that melatonin may protect against extensive oxidative damage in the course of certain thyroid disorders or in case of a harmful action of some external factors on the thyroid. Thus, oxidative damage and the protective action of antioxidants, melatonin included, may occur during both physiological and pathological processes in the thyroid, however, this assumption, requires further studies. 相似文献
995.
Mahon GM Wang Y Korus M Kostenko E Cheng L Sun T Arlinghaus RB Whitehead IP 《Current biology : CB》2003,13(5):437-441
Bcr is a multifunctional protein that is the fusion partner for Abl (p210 Bcr-Abl) in Philadelphia chromosome positive leukemias. We have identified c-Myc as a binding partner for Bcr in both yeast and mammalian cells. We are also able to observe interactions between natively expressed c-Myc and Bcr in leukemic cell lines. Although Bcr and Max have overlapping binding sites on c-Myc, Bcr cannot interact with Max, or with the c-Myc.Max heterodimer. Bcr expression blocks activation of c-Myc-responsive genes, as well as the transformed phenotype induced by coexpression of c-Myc and H-Ras, and this finding suggests that one function of Bcr is to limit the activity of c-Myc. However, Bcr does not block c-Myc function by preventing its nuclear localization. Interestingly, increased Bcr dosage in COS-7 and K-562 cells correlates with a reduction in c-Myc protein levels, suggesting that Bcr may in fact be limiting c-Myc activity by regulating its stability. These data indicate that Bcr is a novel regulator of c-Myc function whose disrupted expression may contribute to the high level of c-Myc protein that is observed in Bcr-Abl transformed cells. 相似文献
996.
A redox-sensitive loop regulates plasminogen activator inhibitor type 2 (PAI-2) polymerization
下载免费PDF全文
![点击此处可从《The EMBO journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Plasminogen activator inhibitor type 2 (PAI-2) is the only wild-type serpin that polymerizes spontaneously under physiological conditions. We show that PAI-2 loses its ability to polymerize following reduction of thiol groups, suggesting that an intramolecular disulfide bond is essential for the polymerization. A novel disulfide bond was identified between C79 (in the CD-loop) and C161 (at the bottom of helix F). Substitution mutants in which this disulfide bond was broken did not polymerize. Reactive center loop peptide insertion experiments and binding of bis-ANS to hydrophobic cavities indicate that the C79-C161 disulfide bond stabilizes PAI-2 in a polymerogenic conformation with an open A-beta-sheet. Elimination of this disulfide bond causes A-beta-sheet closure and abrogates the polymerization. The finding that cytosolic PAI-2 is mostly monomeric, whereas PAI-2 in the secretory pathway is prone to polymerize, suggests that the redox status of the cell could regulate PAI-2 polymerization. Taken together, our data suggest that the CD-loop functions as a redox-sensitive switch that converts PAI-2 between an active stable monomeric and a polymerogenic conformation, which is prone to form inactive polymers. 相似文献
997.
Bovine ovarian antral follicles exhibit either one or the other of two patterns of granulosa cell death in atresia. Death can commence either from the antrum and progress toward the basal lamina (antral atresia) or the converse (basal atresia). In basal atresia, the remaining live antrally situated cells appeared to continue maturing. Beyond that, little is known about these distinct patterns of atresia. Healthy (nonatretic) follicles also exhibit either one or the other of two patterns of granulosa cell shape, follicular basal lamina ultrastructure or location of younger cells within the membrana granulosa. To examine these different phenotypes, the expression of the steroidogenic enzymes cholesterol side-chain cleavage cytochrome P450 (SCC) and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) in granulosa cells and concentrations of steroid hormones in follicular fluid were measured in individual histologically classified bovine antral follicles. Healthy follicles first expressed SCC and 3beta-HSD in granulosa cells only when the follicles reached an approximate threshold of 10 mm in diameter. The pattern of expression in antral atretic follicles was the same as healthy follicles. Basal atretic follicles were all <5 mm. In these, the surviving antral granulosa cells expressed SCC and 3beta-HSD. In examining follicles of 3-5 mm, basal atretic follicles were found to have substantially elevated progesterone (P < 0.001) and decreased androstenedione and testosterone compared to healthy and antral atretic follicles. Estradiol was highest in the large healthy follicles, lower in the small healthy follicles, lower still in the antral atretic follicles, and lowest in the basal atretic follicles. Our findings have two major implications. First, the traditional method of identifying atretic follicles by measurement of steroid hormone concentrations may be less valid with small bovine follicles. Second, features of the two forms of follicular atresia are so different as to imply different mechanisms of initiation and regulation. 相似文献
998.
Marek Straczkowski Irina Kowalska Agnieszka Nikolajuk Stella Dzienis-Straczkowska Malgorzata Szelachowska Ida Kinalska 《Cardiovascular diabetology》2003,2(1):1-5
Background
Left ventricular hypertrophy (LVH) is a powerful independent risk factor for cardiovascular morbidity and mortality among hypertensive patients. Data regarding relationships between diabetes and LVH are controversial and inconclusive, whereas possible gender differences were not specifically investigated. The goal of this work was to investigate whether gender differences in left heart structure and mass are present in hypertensive patients with type 2 diabetes.Methods
Five hundred fifty hypertensive patients with at least one additional cardiovascular risk factor (314 men and 246 women, age 52 to 81, mean 66 ± 6 years), were enrolled in the present analysis. In 200 (36%) of them – 108 men and 92 women – type 2 diabetes mellitus was found upon enrollment. End-diastolic measurements of interventricular septal thickness (IVS), LV internal diameter, and posterior wall thickness were performed employing two-dimensionally guided M-mode echocardiograms. LVH was diagnosed when LV mass index (LVMI) was >134 g/m2 in men and >110 g/m2 in women.Results
Mean LVMI was significantly higher among diabetic vs. nondiabetic women (112.5 ± 29 vs. 105.6 ± 24, p = 0.03). In addition, diabetic women presented a significantly higher prevalence of increased IVS thickness, LVMI and left atrial diameter on intra-gender comparisons. The age adjusted relative risk for increased LVMI in diabetics vs. nondiabetics was 1.47 (95% CI: 1.0–2.2) in females and only 0.8 (0.5–1.3) in males.Conclusion
Type 2 diabetes mellitus was associated with a significantly higher prevalence of LVH and left atrial enlargement in hypertensive women. 相似文献999.
Activation and caspase-mediated inhibition of PARP: a molecular switch between fibroblast necrosis and apoptosis in death receptor signaling 总被引:19,自引:0,他引:19
下载免费PDF全文
![点击此处可从《Molecular biology of the cell》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Los M Mozoluk M Ferrari D Stepczynska A Stroh C Renz A Herceg Z Wang ZQ Schulze-Osthoff K 《Molecular biology of the cell》2002,13(3):978-988
Death ligands not only induce apoptosis but can also trigger necrosis with distinct biochemical and morphological features. We recently showed that in L929 cells CD95 ligation induces apoptosis, whereas TNF elicits necrosis. Treatment with anti-CD95 resulted in typical apoptosis characterized by caspase activation and DNA fragmentation. These events were barely induced by TNF, although TNF triggered cell death to a similar extent as CD95. Surprisingly, whereas the caspase inhibitor zVAD prevented CD95-mediated apoptosis, it potentiated TNF-induced necrosis. Cotreatment with TNF and zVAD was characterized by ATP depletion and accelerated necrosis. To investigate the mechanisms underlying TNF-induced cell death and its potentiation by zVAD, we examined the role of poly(ADP-ribose)polymerase-1 (PARP-1). TNF but not CD95 mediated PARP activation, whereas a PARP inhibitor suppressed TNF-induced necrosis and the sensitizing effect of zVAD. In addition, fibroblasts expressing a noncleavable PARP-1 mutant were more sensitive to TNF than wild-type cells. Our results indicate that TNF induces PARP activation leading to ATP depletion and subsequent necrosis. In contrast, in CD95-mediated apoptosis caspases cause PARP-1 cleavage and thereby maintain ATP levels. Because ATP is required for apoptosis, we suggest that PARP-1 cleavage functions as a molecular switch between apoptotic and necrotic modes of death receptor-induced cell death. 相似文献
1000.