全文获取类型
收费全文 | 814篇 |
免费 | 73篇 |
出版年
2023年 | 5篇 |
2022年 | 12篇 |
2021年 | 30篇 |
2020年 | 11篇 |
2019年 | 22篇 |
2018年 | 33篇 |
2017年 | 22篇 |
2016年 | 46篇 |
2015年 | 67篇 |
2014年 | 65篇 |
2013年 | 77篇 |
2012年 | 94篇 |
2011年 | 84篇 |
2010年 | 35篇 |
2009年 | 28篇 |
2008年 | 53篇 |
2007年 | 42篇 |
2006年 | 29篇 |
2005年 | 35篇 |
2004年 | 20篇 |
2003年 | 21篇 |
2002年 | 20篇 |
2001年 | 3篇 |
2000年 | 5篇 |
1999年 | 4篇 |
1998年 | 3篇 |
1996年 | 1篇 |
1995年 | 3篇 |
1994年 | 1篇 |
1992年 | 1篇 |
1991年 | 2篇 |
1989年 | 1篇 |
1988年 | 2篇 |
1987年 | 2篇 |
1986年 | 1篇 |
1985年 | 2篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1979年 | 1篇 |
1970年 | 1篇 |
排序方式: 共有887条查询结果,搜索用时 15 毫秒
41.
Whole‐cell biotransformation of oleanolic acid by free and immobilized cells of Nocardia iowensis: Characterization of new metabolites 下载免费PDF全文
Benjamin Ludwig Doris Geib Christiane Haas Juliane Steingroewer Thomas Bley Kai Muffler Roland Ulber 《Engineering in Life Science》2015,15(1):108-115
In this study, Nocardia iowensis was used to transform oleanolic acid (OA) into oleanane derivatives. The first derivative, which was found after 24 h of cultivation, was the known and already described OA methyl ester. After 1 week, two other derivatives (oleanonic acid methyl ester and an unknown metabolite) were identified as new products of a biotransformation by N. iowensis. These oleanane metabolites were characterized by HPLC, HPLC‐ESI‐MS, and HPLC‐1H NMR spectroscopy. The biotransformation was performed by suspended and immobilized cells (ICs) of N. iowensis. Cells immobilized in alginate beads were used in order to prepare a continuous process. The substrate uptake of free and ICs was similar, whereas the peak area of OA methyl ester of the ICs was only about 10% of the native cells. However, the final product (oleanonic acid methyl ester) concentrations were similar in both approaches, whereas the unknown metabolite 3 was only detected transiently in the medium of ICs. Based on these results, a new biosynthetic pathway for the biotechnological production of oleanonic acid methyl ester is proposed. 相似文献
42.
43.
Juliane Dinter Jessica Mühlhaus Carolin Leonie Wienchol Chun-Xia Yi Daniela Nürnberg Silke Morin Annette Grüters Josef K?hrle Torsten Sch?neberg Matthias Tsch?p Heiko Krude Gunnar Kleinau Heike Biebermann 《PloS one》2015,10(2)
ObjectiveApplication of 3-iodothyronamine (3-T1AM) results in decreased body temperature and body weight in rodents. The trace amine-associated receptor (TAAR) 1, a family A G protein-coupled receptor, is a target of 3-T1AM. However, 3-T1AM effects still persist in mTaar1 knockout mice, which suggest so far unknown further receptor targets that are of physiological relevance. TAAR5 is a highly conserved TAAR subtype among mammals and we here tested TAAR5 as a potential 3-T1AM target. First, we investigated mouse Taar5 (mTaar5) expression in several brain regions of the mouse in comparison to mTaar1. Secondly, to unravel the full spectrum of signaling capacities, we examined the distinct Gs-, Gi/o-, G12/13-, Gq/11- and MAP kinase-mediated signaling pathways of mouse and human TAAR5 under ligand-independent conditions and after application of 3-T1AM. We found overlapping localization of mTaar1 and mTaar5 in the amygdala and ventromedial hypothalamus of the mouse brain. Second, the murine and human TAAR5 (hTAAR5) display significant basal activity in the Gq/11 pathway but show differences in the basal activity in Gs and MAP kinase signaling. In contrast to mTaar5, 3-T1AM application at hTAAR5 resulted in significant reduction in basal IP3 formation and MAP kinase signaling. In conclusion, our data suggest that the human TAAR5 is a target for 3-T1AM, exhibiting inhibitory effects on IP3 formation and MAP kinase signaling pathways, but does not mediate Gs signaling effects as observed for TAAR1. This study also indicates differences between TAAR5 orthologs with respect to their signaling profile. In consequence, 3-T1AM-mediated effects may differ between rodents and humans. 相似文献
44.
Juliane I. Beier Jenny D. Jokinen Gretchen E. Holz Patrick S. Whang Amah M. Martin Nikole L. Warner Gavin E. Arteel Igor S. Lukashevich 《PloS one》2015,10(3)
Viral hemorrhagic fevers (VHFs) encompass a group of diseases with cardinal symptoms of fever, hemorrhage, and shock. The liver is a critical mediator of VHF disease pathogenesis and high levels of ALT/AST transaminases in plasma correlate with poor prognosis. In fact, Lassa Fever (LF), the most prevalent VHF in Africa, was initially clinically described as hepatitis. Previous studies in non-human primate (NHP) models also correlated LF pathogenesis with a robust proliferative response in the liver. The purpose of the current study was to gain insight into the mechanism of liver injury and to determine the potential role of proliferation in LF pathogenesis. C57Bl/6J mice were infected with either the pathogenic (for NHPs) strain of lymphocytic choriomeningitis virus (LCMV, the prototypic arenavirus), LCMV-WE, or with the non-pathogenic strain, LCMV-ARM. As expected, LCMV-WE, but not ARM, caused a hepatitis-like infection. LCMV-WE also induced a robust increase in the number of actively cycling hepatocytes. Despite this increase in proliferation, there was no significant difference in liver size between LCMV-WE and LCMV-ARM, suggesting that cell cycle was incomplete. Indeed, cells appeared arrested in the G1 phase and LCMV-WE infection increased the number of hepatocytes that were simultaneously stained for proliferation and apoptosis. LCMV-WE infection also induced expression of a non-conventional virus receptor, AXL-1, from the TAM (TYRO3/AXL/MERTK) family of receptor tyrosine kinases and this expression correlated with proliferation. Taken together, these results shed new light on the mechanism of liver involvement in VHF pathogenesis. Specifically, it is hypothesized that the induction of hepatocyte proliferation contributes to expansion of the infection to parenchymal cells. Elevated levels of plasma transaminases are likely explained, at least in part, by abortive cell cycle arrest induced by the infection. These results may lead to the development of new therapies to prevent VHF progression. 相似文献
45.
Thomas McNerney Anne Thomas Anna Senczuk Krista Petty Xiaoyang Zhao Rob Piper Juliane Carvalho Matthew Hammond Satin Sawant Jeanine Bussiere 《MABS-AUSTIN》2015,7(2):413-427
High titer (>10 g/L) monoclonal antibody (mAb) cell culture processes are typically achieved by maintaining high viable cell densities over longer culture durations. A corresponding increase in the solids and sub-micron cellular debris particle levels are also observed. This higher burden of solids (≥15%) and sub-micron particles typically exceeds the capabilities of a continuous centrifuge to effectively remove the solids without a substantial loss of product and/or the capacity of the harvest filtration train (depth filter followed by membrane filter) used to clarify the centrate. We discuss here the use of a novel and simple two-polymer flocculation method used to harvest mAb from high cell mass cell culture processes. The addition of the polycationic polymer, poly diallyldimethylammonium chloride (PDADMAC) to the cell culture broth flocculates negatively-charged cells and cellular debris via an ionic interaction mechanism. Incorporation of a non-ionic polymer such as polyethylene glycol (PEG) into the PDADMAC flocculation results in larger flocculated particles with faster settling rate compared to PDADMAC-only flocculation. PDADMAC also flocculates the negatively-charged sub-micron particles to produce a feed stream with a significantly higher harvest filter train throughput compared to a typical centrifuged harvest feed stream. Cell culture process variability such as lactate production, cellular debris and cellular densities were investigated to determine the effect on flocculation. Since PDADMAC is cytotoxic, purification process clearance and toxicity assessment were performed. 相似文献
46.
Eva C. Schulte Maria Kousi Perciliz L. Tan Erik Tilch Franziska Knauf Peter Lichtner Claudia Trenkwalder Birgit Högl Birgit Frauscher Klaus Berger Ingo Fietze Magdolna Hornyak Wolfgang H. Oertel Cornelius G. Bachmann Alexander Zimprich Annette Peters Christian Gieger Thomas Meitinger Bertram Müller-Myhsok Nicholas Katsanis Juliane Winkelmann 《American journal of human genetics》2014
47.
48.
Juliane Mittasch Sabine Mikolajewski Frank Breuer Dieter Strack Carsten Milkowski 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2010,120(8):1485-1500
In oilseed rape (Brassica napus), the glucosyltransferase UGT84A9 catalyzes the formation of 1-O-sinapoyl-β-glucose, which feeds as acyl donor into a broad range of accumulating sinapate esters, including the major antinutritive
seed component sinapoylcholine (sinapine). Since down-regulation of UGT84A9 was highly efficient in decreasing the sinapate
ester content, the genes encoding this enzyme were considered as potential targets for molecular breeding of low sinapine
oilseed rape. B. napus harbors two distinguishable sequence types of the UGT84A9 gene designated as UGT84A9-1 and UGT84A9-2. UGT84A9-1 is the predominantly expressed variant, which is significantly up-regulated during the seed filling phase, when sinapate
ester biosynthesis exhibits strongest activity. In the allotetraploid genome of B. napus, UGT84A9-1 is represented by two loci, one derived from the Brassica C-genome (UGT84A9a) and one from the Brassica A-genome (UGT84A9b). Likewise, for UGT84A9-2 two loci were identified in B. napus originating from both diploid ancestor genomes (UGT84A9c, Brassica C-genome; UGT84A9d, Brassica A-genome). The distinct UGT84A9 loci were genetically mapped to linkage groups N15 (UGT84A9a), N05 (UGT84A9b), N11 (UGT84A9c) and N01 (UGT84A9d). All four UGT84A9 genomic loci from B. napus display a remarkably low micro-collinearity with the homologous genomic region of Arabidopsis thaliana chromosome III, but exhibit a high density of transposon-derived sequence elements. Expression patterns indicate that the
orthologous genes UGT84A9a and UGT84A9b should be considered for mutagenesis inactivation to introduce the low sinapine trait into oilseed rape. 相似文献
49.
50.
Ligation of B and T lymphocyte attenuator prevents the genesis of experimental cerebral malaria 总被引:2,自引:0,他引:2
Lepenies B Pfeffer K Hurchla MA Murphy TL Murphy KM Oetzel J Fleischer B Jacobs T 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(6):4093-4100
B and T lymphocyte attenuator (BTLA; CD272) is a coinhibitory receptor that is predominantly expressed on T and B cells and dampens T cell activation. In this study, we analyzed the function of BTLA during infection with Plasmodium berghei ANKA. Infection of C57BL/6 mice with this strain leads to sequestration of leukocytes in brain capillaries that is associated with a pathology resembling cerebral malaria in humans. During the course of infection, we found an induction of BTLA in several organs, which was either due to up-regulation of BTLA expression on T cells in the spleen or due to infiltration of BTLA-expressing T cells into the brain. In the brain, we observed a marked induction of BTLA and its ligand herpesvirus entry mediator during cerebral malaria, which was accompanied by an accumulation of predominantly CD8+ T cells, but also CD4+ T cells. Application of an agonistic anti-BTLA mAb caused a significantly reduced incidence of cerebral malaria compared with control mice. Treatment with this Ab also led to a decreased number of T cells that were sequestered in the brain of P. berghei ANKA-infected mice. Our findings indicate that BTLA-herpesvirus entry mediator interactions are functionally involved in T cell regulation during P. berghei ANKA infection of mice and that BTLA is a potential target for therapeutic interventions in severe malaria. 相似文献