全文获取类型
收费全文 | 444篇 |
免费 | 37篇 |
专业分类
481篇 |
出版年
2022年 | 5篇 |
2021年 | 6篇 |
2020年 | 6篇 |
2019年 | 4篇 |
2018年 | 6篇 |
2017年 | 4篇 |
2016年 | 5篇 |
2015年 | 8篇 |
2014年 | 13篇 |
2013年 | 12篇 |
2012年 | 27篇 |
2011年 | 27篇 |
2010年 | 10篇 |
2009年 | 8篇 |
2008年 | 16篇 |
2007年 | 26篇 |
2006年 | 20篇 |
2005年 | 24篇 |
2004年 | 18篇 |
2003年 | 13篇 |
2002年 | 16篇 |
2001年 | 21篇 |
2000年 | 11篇 |
1999年 | 16篇 |
1998年 | 6篇 |
1996年 | 5篇 |
1995年 | 6篇 |
1994年 | 3篇 |
1992年 | 9篇 |
1991年 | 9篇 |
1989年 | 8篇 |
1988年 | 5篇 |
1987年 | 8篇 |
1986年 | 5篇 |
1985年 | 4篇 |
1984年 | 6篇 |
1983年 | 4篇 |
1982年 | 4篇 |
1981年 | 5篇 |
1980年 | 3篇 |
1979年 | 4篇 |
1978年 | 5篇 |
1977年 | 6篇 |
1976年 | 6篇 |
1975年 | 3篇 |
1974年 | 3篇 |
1971年 | 3篇 |
1962年 | 3篇 |
1942年 | 3篇 |
1930年 | 2篇 |
排序方式: 共有481条查询结果,搜索用时 0 毫秒
91.
In Swedish families with hereditary prostate cancer, linkage to the HPC1 locus on chromosome 1q24-25 is restricted to families with early-onset prostate cancer.
下载免费PDF全文
![点击此处可从《American journal of human genetics》网站下载免费的PDF全文](/ch/ext_images/free.gif)
H Grnberg J Smith M Emanuelsson B A Jonsson A Bergh J Carpten W Isaacs J Xu D Meyers J Trent J E Damber 《American journal of human genetics》1999,65(1):134-140
Prostate cancer clusters in some families, and an estimated 5%-10% of all cases are estimated to result from inheritance of prostate cancer-susceptibility genes. We previously reported evidence of linkage to the 1q24-25 region (HPC1) in 91 North American and Swedish families each with multiple cases of prostate cancer (Smith et al. 1996). In the present report we analyze 40 (12 original and 28 newly identified) Swedish families with hereditary prostate cancer (HPC) that, on the basis of 40 markers spanning a 25-cM interval within 1q24-25, have evidence of linkage. In the complete set of families, a maximum two-point LOD score of 1.10 was observed at D1S413 (at a recombination fraction [theta] of.1), with a maximum NPL (nonparametric linkage) Z score of 1.64 at D1S202 (P=.05). The evidence of linkage to this region originated almost exclusively from the subset of 12 early-onset (age <65 years) families, which yielded a maximum LOD score of 2.38 at D1S413 (straight theta=0) and an NPL Z score of 1.95 at D1S422 (P=.03). Estimates from heterogeneity tests suggest that, within Sweden, as many as 50% of early-onset families had evidence of linkage to the HPC1 region. These results are consistent with the hypothesis of linkage to HPC1 in a subset of families with prostate cancer, particularly those with an early age at diagnosis. 相似文献
92.
Isaacs RC Solinsky MG Cutrona KJ Newton CL Naylor-Olsen AM McMasters DR Krueger JA Lewis SD Lucas BJ Kuo LC Yan Y Lynch JJ Lyle EA 《Bioorganic & medicinal chemistry letters》2008,18(6):2062-2066
Guided by X-ray crystallography of thrombin-inhibitor complexes and molecular modeling, alkylation of the N1 nitrogen of the imidazole P1 ligand of the pyridinoneacetamide thrombin inhibitor 1 with various acetamide moieties furnished inhibitors with significantly improved thrombin potency, trypsin selectivity, functional in vitro anticoagulant potency and in vivo antithrombotic efficacy. In the pyrazinoneacetamide series, oral bioavailability was also improved. 相似文献
93.
Mechanistic insights into the inhibition of prostate specific antigen by beta-lactam class compounds
Singh P Williams SA Shah MH Lectka T Pritchard GJ Isaacs JT Denmeade SR 《Proteins》2008,70(4):1416-1428
Prostate Specific Antigen (PSA) is a biomarker used in the diagnosis of prostate cancer and to monitor therapeutic response. However, its precise role in prostate carcinogenesis and metastasis remains largely unknown. A number of studies arguing in the favor of an active role of PSA in prostate cancer development and progression have implicated this serine protease in the release and activation of growth factors such as insulin-like growth factor 1 (IGF1) through cleavage of insulin like growth factor binding protein 3 and Transforming Growth Factor beta (TGF-beta) through cleavage of Latent TGF-beta. In contrast, other studies suggest that PSA activity might hinder tumor development and progression. In light of these contradictory findings, efficient inhibitors of PSA are needed for exploring its biological role in tumor development and metastasis. Towards the goal of developing potent inhibitors of PSA, we have explored the molecular mechanism of a series of beta-lactam based compounds on binding to PSA using activity assays, matrix assisted laser desorption ionization with a time-of-flight mass spectrometry, and GOLD docking methodology. The mass spectrometry experiments and the activity assays confirmed the time-dependent and covalent nature of beta-lactam binding. To gain insights on the reaction intermediates at the molecular level, we docked beta-lactam inhibitors to a homology modeled PSA using the GOLD docking program in noncovalent and covalent binding modes. The docking studies elucidated the molecular details of the early noncovalent Michaelis complex, the acyl-enzyme covalent complex, and the nature of conformational reorganization required for the long term stability of the covalent complex. Additionally, the molecular basis for the effect of stereochemistry of the lactam ring on the inhibitory potency was elucidated through docking of beta-lactam enantiomers. As a validation of our docking methodology, two novel enantiomers were synthesized and evaluated for their inhibitory potency using fluorogenic substrate based activity assays. Additionally, cis enantiomers of eight beta-lactam compounds reported in a previous study were docked and their GOLD scores and binding modes were analyzed in order to assess the general applicability of our docking results. The close agreement of our docking results with the experimental data validates the mechanistic insights revealed through the docking studies and paves the way for the design and development of potent and specific inhibitors of PSA. 相似文献
94.
95.
96.
Elvira Valera Michael J. Isaacs Yasuhiko Kawakami Juan Carlos Izpisúa Belmonte Senyon Choe 《PloS one》2010,5(6)
Background
Bone Morphogenetic Protein (BMP) signaling pathways are involved in differentiation of stem cells into diverse cell types, and thus BMPs can be used as main guidance molecules for in vitro differentiation of human stem cells.Methodology/Principal Findings
We have analyzed the ability for inducing differentiation of the heterodimer BMP-2/BMP-6 (BMP-2/6) compared to the homodimers BMP-2 or BMP-6, using human embryonic stem (hES) cells H9 as model system. When incubated in a medium with high concentration of basic fibroblastic growth factor (FGF2), 100 ng/ml of human recombinant BMPs induced morphological changes and differentiation of hES cells in 24 to 48 hours. After 5 days, expression of differentiation markers was induced and quantified by quantitative PCR (qPCR) and flow cytometry. BMP-2/6 exhibited stronger activity for the induction of the expression of trophectodermal (CDX2) and endodermal (SOX17, GATA4, AFP) markers than BMP-2 or BMP-6 homodimers. BMP-2/6 also induced the expression of BMPR2 gene more effectively than BMP-2 or BMP-6 when used at the same concentration and time. Moreover, the percentage of cells expressing the surface endodermal marker CXCR4 was also increased for the heterodimer when compared to both homodimers. BMP-2/6 was a more potent activator of Smad-dependent (SMAD1/5) and Smad-independent signaling (mitogen-activated protein kinases ERK and p38) than BMP-2 and BMP-6, and the activation of these pathways might play a role in its increased potency for inducing hES cell differentiation.Conclusions/Significance
Therefore, we conclude that BMP-2/6 is more potent than BMP-2 or BMP-6 for inducing differentiation of hES cells, and it can be used as a more powerful substitute of these BMPs in in vitro differentiation guidance. 相似文献97.
Mhaka A Denmeade SR Yao W Isaacs JT Khan SR 《Bioorganic & medicinal chemistry letters》2002,12(17):2459-2461
A method for targeted delivery of the cytotoxic agent 5-fluorodeoxyuridine (FudR) (1) to sites of metastatic prostate cancer is described. The prodrug was synthesized by coupling the active drug (FudR) to the PSA-peptide via a self-cleaving diamino acid linker to produce HSSKLQ-Leu-Aib-FudR. This prodrug serves as a substrate for prostate specific antigen (PSA). This approach permitted efficient conversion of the inactive prodrug back to the active cytotoxic state by the enzymatic activity of PSA which is highly expressed by prostate cells. 相似文献
98.
Heather A Huet Joseph D Growney Jennifer A Johnson Jing Li Sanela Bilic Lance Ostrom Mohammad Zafari Colleen Kowal Guizhi Yang Axelle Royo Michael Jensen Bruno Dombrecht Kris RA Meerschaert Joost A Kolkman Karen D Cromie Rebecca Mosher Hui Gao Alwin Schuller Randi Isaacs William R Sellers Seth A Ettenberg 《MABS-AUSTIN》2014,6(6):1560-1570
Multiple therapeutic agonists of death receptor 5 (DR5) have been developed and are under clinical evaluation. Although these agonists demonstrate significant anti-tumor activity in preclinical models, the clinical efficacy in human cancer patients has been notably disappointing. One possible explanation might be that the current classes of therapeutic molecules are not sufficiently potent to elicit significant response in patients, particularly for dimeric antibody agonists that require secondary cross-linking via Fcγ receptors expressed on immune cells to achieve optimal clustering of DR5. To overcome this limitation, a novel multivalent Nanobody approach was taken with the goal of generating a significantly more potent DR5 agonist. In the present study, we show that trivalent DR5 targeting Nanobodies mimic the activity of natural ligand, and furthermore, increasing the valency of domains to tetramer and pentamer markedly increased potency of cell killing on tumor cells, with pentamers being more potent than tetramers in vitro. Increased potency was attributed to faster kinetics of death-inducing signaling complex assembly and caspase-8 and caspase-3 activation. In vivo, multivalent Nanobody molecules elicited superior anti-tumor activity compared to a conventional DR5 agonist antibody, including the ability to induce tumor regression in an insensitive patient-derived primary pancreatic tumor model. Furthermore, complete responses to Nanobody treatment were obtained in up to 50% of patient-derived primary pancreatic and colon tumor models, suggesting that multivalent DR5 Nanobodies may represent a significant new therapeutic modality for targeting death receptor signaling. 相似文献
99.
Qiang Wang Peng Xu Felipe Andreazza Yahui Liu Yoshiko Nomura Phil Duran Lan Jiang Mengli Chen Genki Takamatsu Makoto Ihara Kazuhiko Matsuda Rufus Isaacs Eugenio E. Oliveira Yuzhe Du Ke Dong 《PLoS genetics》2021,17(7)
Pyrethrum extract from dry flowers of Tanacetum cinerariifolium (formally Chrysanthemum cinerariifolium) has been used globally as a popular insect repellent against arthropod pests for thousands of years. However, the mechanistic basis of pyrethrum repellency remains unknown. In this study, we found that pyrethrum spatially repels and activates olfactory responses in Drosophila melanogaster, a genetically tractable model insect, and the closely-related D. suzukii which is a serious invasive fruit crop pest. The discovery of spatial pyrethrum repellency and olfactory response to pyrethrum in D. melanogaster facilitated our identification of four odorant receptors, Or7a, Or42b, Or59b and Or98a that are responsive to pyrethrum. Further analysis showed that the first three Ors are activated by pyrethrins, the major insecticidal components in pyrethrum, whereas Or98a is activated by (E)-β-farnesene (EBF), a sesquiterpene and a minor component in pyrethrum. Importantly, knockout of Or7a, Or59b or Or98a individually abolished fly avoidance to pyrethrum, while knockout of Or42b had no effect, demonstrating that simultaneous activation of Or7a, Or59b and Or98a is required for pyrethrum repellency in D. melanogaster. Our study provides insights into the molecular basis of repellency of one of the most ancient and globally used insect repellents. Identification of pyrethrum-responsive Ors opens the door to develop new synthetic insect repellent mixtures that are highly effective and broad-spectrum. 相似文献
100.
Dumisani Mnkandhla Michelle Isaacs Heinrich C. Hoppe Perry T. Kaye 《Bioorganic & medicinal chemistry letters》2018,28(6):1067-1070
A series of readily accessible 4-arylimino-3-hydroxybutanoic acids have been prepared and evaluated as potential HIV-1 Integrase inhibitors. None of the ligands exhibited significant toxicity against human embryonic kidney (HEK 293) cells, while five of them showed activity against HIV-1 integrase – the most active (6c) with an IC50 value of 3.5?μM. In silico docking studies indicate the capacity of ligand 6c to interact with several amino acid residues and the two Mg2+ cations in the HIV-1 integrase receptor cavity. 相似文献