全文获取类型
收费全文 | 163篇 |
免费 | 42篇 |
出版年
2023年 | 1篇 |
2021年 | 1篇 |
2018年 | 2篇 |
2017年 | 5篇 |
2016年 | 2篇 |
2015年 | 6篇 |
2014年 | 8篇 |
2013年 | 8篇 |
2012年 | 9篇 |
2011年 | 12篇 |
2010年 | 6篇 |
2009年 | 4篇 |
2008年 | 9篇 |
2007年 | 12篇 |
2006年 | 8篇 |
2005年 | 7篇 |
2004年 | 11篇 |
2003年 | 7篇 |
2002年 | 8篇 |
2001年 | 8篇 |
2000年 | 10篇 |
1999年 | 7篇 |
1998年 | 3篇 |
1997年 | 2篇 |
1996年 | 3篇 |
1995年 | 2篇 |
1994年 | 1篇 |
1993年 | 3篇 |
1992年 | 3篇 |
1991年 | 3篇 |
1990年 | 2篇 |
1989年 | 3篇 |
1988年 | 5篇 |
1987年 | 4篇 |
1986年 | 2篇 |
1984年 | 1篇 |
1983年 | 2篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1977年 | 3篇 |
1974年 | 1篇 |
1972年 | 1篇 |
1968年 | 1篇 |
1964年 | 2篇 |
1962年 | 1篇 |
排序方式: 共有205条查询结果,搜索用时 31 毫秒
101.
Jones P Atack JR Braun MP Cato BP Chambers MS O'Connor D Cook SM Hobbs SC Maxey R Szekeres HJ Szeto N Wafford KA MacLeod AM 《Bioorganic & medicinal chemistry letters》2006,16(4):872-875
(3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine (1) was recently identified as a functionally selective, inverse agonist at the benzodiazepine site of GABA(A) alpha5 receptors and enhances performance in animal models of cognition. The routes of metabolism of this compound in vivo in rat have been well characterised, the identities of the major metabolites are confirmed by synthesis and their biological profiles were evaluated. An unusual oxidation of the pyrazolo[1,5-d][1,2,4]triazine core to the corresponding pyrazolo[1,5-d][1,2,4]triazin-4(5H)-one scaffold by aldehyde oxidase has been observed. 相似文献
102.
103.
The genome of Enterococcus faecalis 62, a commensal isolate from a healthy Norwegian infant, revealed multiple adaptive traits to the gastrointestinal tract (GIT) environment and the milk-containing diet of breast-fed infants. Adaptation to a commensal existence was emphasized by lactose and other carbohydrate metabolism genes within genomic islands, accompanied by the absence of virulence traits. 相似文献
104.
Borrero J Brede DA Skaugen M Diep DB Herranz C Nes IF Cintas LM Hernández PE 《Applied and environmental microbiology》2011,77(1):369-373
Lactococcus garvieae DCC43 produces a bacteriocin, garvicin ML (GarML), with a molecular mass of 6,004.2 Da. Data from de novo amino acid sequencing by tandem mass spectrometry and nucleotide sequencing by reverse genetics suggested that the bacteriocin is synthesized as a 63-amino-acid precursor with a 3-amino-acid leader peptide that is removed by cleavage. Subsequently, a covalent linkage between the N and C termini forms the mature version of this novel 60-amino-acid circular bacteriocin. 相似文献
105.
Wolkenberg SE Zhao Z Mulhearn JJ Harrison ST Sanders JM Cato MJ Jovanovska A Panigel J Cook SP Henze DA Kane SA Hartman GD Barrow JC 《Bioorganic & medicinal chemistry letters》2011,21(9):2646-2649
The Merck Fragment Library was screened versus acid-sensing ion channel 3 (ASIC3), a novel target for the treatment of pain. Fragment hits were optimized using two strategies, and potency was improved from 0.7 mM to 3 μM with retention of good ligand efficiency and incorporation of reasonable physical properties, off-target profile, and rat pharmacokinetics. 相似文献
106.
Lower urinary tract trauma, although relatively uncommon in blunt trauma, can lead to significant morbidity when diagnosed late or left untreated; urologists may only encounter a handful of these injuries in their career. This article reviews the literature and reports on the management of these injuries, highlighting the issues facing clinicians in this subspecialty. Also presented is a structured review detailing the mechanisms, classification, diagnosis, management, and complications of blunt trauma to the bladder and urethra. The prognosis for bladder rupture is excellent when treated. Significant intraperitoneal rupture or involvement of the bladder neck mandates surgical repair, whereas smaller extraperitoneal lacerations may be managed with catheterization alone. With the push for management of trauma patients in larger centers, urologists in these hospitals are seeing increasing numbers of lower urinary tract injuries. Prospective analysis may be achieved in these centers to address the current lack of Level 1 evidence. 相似文献
107.
Danilo Maddalo Antje Neeb Katja Jehle Katja Schmitz Claudia Muhle-Goll Liubov Shatkina Tamara Vanessa Walther Anja Bruchmann Srinivasa M. Gopal Wolfgang Wenzel Anne S. Ulrich Andrew C. B. Cato 《PloS one》2012,7(10)
The molecular chaperone GRP78/BiP is a key regulator of protein folding in the endoplasmic reticulum, and it plays a pivotal role in cancer cell survival and chemoresistance. Inhibition of its function has therefore been an important strategy for inhibiting tumor cell growth in cancer therapy. Previous efforts to achieve this goal have used peptides that bind to GRP78/BiP conjugated to pro-drugs or cell-death-inducing sequences. Here, we describe a peptide that induces prostate tumor cell death without the need of any conjugating sequences. This peptide is a sequence derived from the cochaperone Bag-1. We have shown that this sequence interacts with and inhibits the refolding activity of GRP78/BiP. Furthermore, we have demonstrated that it modulates the unfolded protein response in ER stress resulting in PARP and caspase-4 cleavage. Prostate cancer cells stably expressing this peptide showed reduced growth and increased apoptosis in in vivo xenograft tumor models. Amino acid substitutions that destroyed binding of the Bag-1 peptide to GRP78/BiP or downregulation of the expression of GRP78 compromised the inhibitory effect of this peptide. This sequence therefore represents a candidate lead peptide for anti-tumor therapy. 相似文献
108.
Matta R Barnard JA Wancket LM Yan J Xue J Grieves J Frazier WJ Nelin L Cato AC Liu Y 《American journal of physiology. Gastrointestinal and liver physiology》2012,302(11):G1322-G1335
Il-10-deficient mice develop colitis associated with exaggerated Th1/Th17 responses and are a valuable model of inflammatory bowel disease. Mkp-1 is a major negative regulator of MAPKs, and its expression is enhanced by IL-10. To understand the role of Mkp-1 in the regulation of intestinal mucosal immune responses, we studied the effect of Mkp-1 deletion on the pathogenesis of colitis in Il-10(-/-) mice. We found that knockout of Mkp-1 on an Il-10(-/-) background accelerated the development of colitis. Compared with Il-10(-/-) mice, colitis not only appeared earlier but also was more severe in Il-10(-/-)/Mkp-1(-/-) mice. Il-10(-/-) mice exhibited a mild intestinal inflammation in the specific pathogen-free environment, and rectal prolapse rarely appeared before 6 mo of age. In contrast, the majority of Il-10(-/-)/Mkp-1(-/-) mice developed severe colitis rapidly and presented with rectal prolapse after only 2-3 mo. The colon of Il-10(-/-)/Mkp-1(-/-) mice showed diffuse transmural chronic inflammation and mucosal hyperplasia, with significantly more proliferating crypt epithelial cells than those of Il-10(-/-) mice. In addition to the severe colitis, Il-10(-/-)/Mkp-1(-/-) mice also developed conjunctivitis and blepharitis. The colon of Il-10(-/-)/Mkp-1(-/-) mice contained significantly higher levels of proinflammatory cytokines and exhibited greater MAPK activities than did the colon of Il-10(-/-) mice. Splenocytes and lymphocytes from Il-10(-/-)/Mkp-1(-/-) mice produced higher levels of Th1 cytokines ex vivo upon activation than did cells from Il-10(-/-) mice. Our studies support a pivotal role of Mkp-1 as a negative regulator of mucosal immune responses and highlight its protective function against inflammatory bowel disease. 相似文献
109.
Simone S. Riedel Anja Mottok Christian Brede Carina A. B?uerlein Ana-Laura Jordán Garrote Miriam Ritz Katharina Mattenheimer Andreas Rosenwald Hermann Einsele Bjarne Bogen Andreas Beilhack 《PloS one》2012,7(12)
Background
Multiple myeloma (MM) is a B-cell malignancy, where malignant plasma cells clonally expand in the bone marrow of older people, causing significant morbidity and mortality. Typical clinical symptoms include increased serum calcium levels, renal insufficiency, anemia, and bone lesions. With standard therapies, MM remains incurable; therefore, the development of new drugs or immune cell-based therapies is desirable. To advance the goal of finding a more effective treatment for MM, we aimed to develop a reliable preclinical MM mouse model applying sensitive and reproducible methods for monitoring of tumor growth and metastasis in response to therapy.Material and Methods
A mouse model was created by intravenously injecting bone marrow-homing mouse myeloma cells (MOPC-315.BM) that expressed luciferase into BALB/c wild type mice. The luciferase in the myeloma cells allowed in vivo tracking before and after melphalan treatment with bioluminescence imaging (BLI). Homing of MOPC-315.BM luciferase+ myeloma cells to specific tissues was examined by flow cytometry. Idiotype-specific myeloma protein serum levels were measured by ELISA. In vivo measurements were validated with histopathology.Results
Strong bone marrow tropism and subsequent dissemination of MOPC-315.BM luciferase+ cells in vivo closely mimicked the human disease. In vivo BLI and later histopathological analysis revealed that 12 days of melphalan treatment slowed tumor progression and reduced MM dissemination compared to untreated controls. MOPC-315.BM luciferase+ cells expressed CXCR4 and high levels of CD44 and α4β1 in vitro which could explain the strong bone marrow tropism. The results showed that MOPC-315.BM cells dynamically regulated homing receptor expression and depended on interactions with surrounding cells.Conclusions
This study described a novel MM mouse model that facilitated convenient, reliable, and sensitive tracking of myeloma cells with whole body BLI in living animals. This model is highly suitable for monitoring the effects of different treatment regimens. 相似文献110.