全文获取类型
收费全文 | 217篇 |
免费 | 12篇 |
出版年
2021年 | 3篇 |
2020年 | 1篇 |
2019年 | 4篇 |
2018年 | 2篇 |
2017年 | 3篇 |
2016年 | 6篇 |
2015年 | 15篇 |
2014年 | 13篇 |
2013年 | 7篇 |
2012年 | 18篇 |
2011年 | 15篇 |
2010年 | 4篇 |
2009年 | 8篇 |
2008年 | 8篇 |
2007年 | 11篇 |
2006年 | 10篇 |
2005年 | 8篇 |
2004年 | 9篇 |
2003年 | 9篇 |
2002年 | 8篇 |
2001年 | 8篇 |
2000年 | 7篇 |
1999年 | 7篇 |
1998年 | 1篇 |
1997年 | 3篇 |
1996年 | 1篇 |
1995年 | 2篇 |
1994年 | 1篇 |
1993年 | 1篇 |
1992年 | 2篇 |
1991年 | 1篇 |
1990年 | 5篇 |
1989年 | 3篇 |
1987年 | 3篇 |
1986年 | 3篇 |
1984年 | 1篇 |
1983年 | 2篇 |
1982年 | 1篇 |
1981年 | 2篇 |
1980年 | 3篇 |
1978年 | 1篇 |
1976年 | 1篇 |
1974年 | 1篇 |
1967年 | 1篇 |
1952年 | 2篇 |
1951年 | 1篇 |
1950年 | 1篇 |
1934年 | 1篇 |
1924年 | 1篇 |
排序方式: 共有229条查询结果,搜索用时 15 毫秒
1.
Tallimustine (FCE 24517) is an AT-specific alkylating antitumor derivative of distamycin. This study examined levels of tallimustine lesions in intracellular DNA, their sequence- and region-specificity, and the long-range distribution of the drug binding motif. Tallimustine adducts in DNA converted to strand breaks by heating allowed the quantitation of drug lesions. In bulk DNA of intact human leukemia CEM cells, tallimustine formed 0.15 +/- 0.04 and 0.64 +/- 0.18 lesions/kbp at 5 and 50 microM, respectively. These lesions represent monoadducts as no interstrand cross-links or DNA-protein cross-links were detected. Tallimustine adducts in intracellularly treated DNA showed a general preference for sequences with T-tracts, suggesting a propensity for intrinsically bent motifs. Major drug-adducted sites identified by repetitive primer extension, included 5'-TTTTGPu-3' and 5'-TTTTGC-3' motif. Despite the high specificity at the nucleotide level, tallimustine did not differentiate among bulk DNA and three discrete AT-rich regions of genomic DNA examined by quantitative PCR stop assay with lesion frequencies ranging from 0.23 to 0.39 lesions/kbp at 25 microM drug. In comparisons of lesion frequencies and cytotoxicity, tallimustine adducts are approximately 50 times more lethal than relatively nonsequence specific cisplatin adducts but are >100 times less lethal than lesions by an unrelated AT-specific drug, bizelesin. However, the 5'-TTTTGPu-3' motifs targeted by tallimustine are relatively infrequent and scattered throughout the genome. In contrast, the motifs 5'-T(A/T)(4)A-3' motifs targeted by bizelesin, while also infrequent, cluster in defined AT-rich islands. The lack of region-specificity may be the reason tallimustine adducts, despite high AT-specificity at the nucleotide level, are less lethal than region-specific bizelesin adducts. 相似文献
2.
Endogenous CD8+ T cell expansion during regression of monoclonal EBV-associated posttransplant lymphoproliferative disorder. 总被引:5,自引:0,他引:5
V P Khatri R A Baiocchi R Peng A R Oberkircher J M Dolce P M Ward G P Herzig M A Caligiuri 《Journal of immunology (Baltimore, Md. : 1950)》1999,163(1):500-506
There are experimental data which suggest that the primary immune effector cell responsible for maintaining immune surveillance against the outgrowth of EBV-transformed B cells in humans is the CTL, but in vivo proof of this is lacking. In this study we perform a series of cellular and molecular assays to characterize an autologous, endogenous immune response against a transplantation-associated, monoclonal, EBV+ posttransplant lymphoproliferative disorder (PTLD). Following allogeneic bone marrow transplantation, a patient developed a monoclonal PTLD of donor B cell origin. With a decrease in immune suppression, we document the emergence of endogenous, donor-derived CD3+CD8+ CTLs, followed by regression of the PTLD. The TCR Vbeta repertoire went from a polyclonal pattern prior to the development of PTLD to a restricted TCR Vbeta pattern during the outgrowth and regression of PTLD. Donor-derived CD3+CD8+ T lymphocytes displayed MHC class I-restricted cytolytic activity against the autologous EBV+ B cells ex vivo without additional in vitro sensitization. The striking temporal relationship between the endogenous expansion of a TCR Vbeta-restricted, CD3+CD8+ population of MHC class I-restricted CTL, and the regression of an autologous monoclonal PTLD, provides direct evidence in humans that endogenous CD3+CD8+ CTLs can be responsible for effective immune surveillance against malignant transformation of EBV+ B cells. 相似文献
3.
The feeding behaviour of Leptodora kindti and its impact on the zooplankton community of Neusiedler See (Austria) 总被引:1,自引:0,他引:1
Leptodora kindti is a very efficient invertebrate predator. Its searching mode of preying is tactile. The setae of the first thoracic limb act as mechanoreceptors, the other thoracic limbs, thorax and head together form the shape of an open basket in which after encounter the prey is pushed in by the aid of the first thoracic limbs and the furca. In Neusiedler See, small individuals of Diaphanosoma brachyurum (0.6–0.9 mm) are the preferred prey, rarely copepods are taken. The predation rate is influenced by temperature, prey density and predator size and varies between less than one and 12 prey items per predator per day. At high predator densities, Leptodora will have a substantial effect on the Diaphanosoma population of Neusiedler See. 相似文献
4.
Freshly extruded and hardened spermatophores of the spiny lobster, Panulirus interruptus, were compared using light and electron microscopy (EM). The spermatophore is composed of a sperm tube embedded in an acellular matrix. The sperm tube consists of tightly packed spherical cavities in an acellular material within which the sperm lie. The extruded spermatophore is white, soft, and sticky on all surfaces. The highly coiled sperm tube can be seen near the surface of the foot of the spermatophore, which is the side that will attach to the exoskeleton of the female. The opposite surface, the cap, will harden and darken after exposure to seawater. In the soft spermatophore, the matrix surrounding the sperm tube and extending from foot to cap is composed of small (2-μm) granules embedded in a loose weave of filaments. In the hardened spermatophore, the matrix is composed of small (4-μm) empty spheres. At the cap region the matrix darkens, and at the foot the granules dissolve to form a thick layer characterized by vertical striations. The structure of this spermatophore is compared to those spermatophores of other decapods that have been described at the EM level. The chemical composition and possible function(s) of the various components are discussed. 相似文献
5.
Maria Rohm Anke Sommerfeld Daniela Strzoda Allan Jones Tjeerd P. Sijmonsma Gottfried Rudofsky Christian Wolfrum Carsten Sticht Norbert Gretz Maximilian Zeyda Lukas Leitner Peter P. Nawroth Thomas M. Stulnig Mauricio Berriel Diaz Alexandros Vegiopoulos Stephan Herzig 《Cell metabolism》2013,17(4):575-585
Highlights? TBLR1 controls cAMP-dependent lipolysis in adipocytes ? Adipocyte-specific deletion of TBLR1 in mice impairs fasting-induced lipolysis ? Lack of TBLR1 in adipocytes aggravates diet-induced obesity and metabolic dysfunction ? TBLR1 mRNA levels in WAT are elevated under lipolytic conditions in mice and humans 相似文献
6.
Roldan M de Guia Adam J Rose Anke Sommerfeld Oksana Seibert Daniela Strzoda Annika Zota Yvonne Feuchter Anja Krones‐Herzig Tjeerd Sijmonsma Milen Kirilov Carsten Sticht Norbert Gretz Geesje Dallinga‐Thie Sven Diederichs Nora Klöting Matthias Blüher Mauricio Berriel Diaz Stephan Herzig 《The EMBO journal》2015,34(3):344-360
In mammals, glucocorticoids (GCs) and their intracellular receptor, the glucocorticoid receptor (GR), represent critical checkpoints in the endocrine control of energy homeostasis. Indeed, aberrant GC action is linked to severe metabolic stress conditions as seen in Cushing's syndrome, GC therapy and certain components of the Metabolic Syndrome, including obesity and insulin resistance. Here, we identify the hepatic induction of the mammalian conserved microRNA (miR)‐379/410 genomic cluster as a key component of GC/GR‐driven metabolic dysfunction. Particularly, miR‐379 was up‐regulated in mouse models of hyperglucocorticoidemia and obesity as well as human liver in a GC/GR‐dependent manner. Hepatocyte‐specific silencing of miR‐379 substantially reduced circulating very‐low‐density lipoprotein (VLDL)‐associated triglyceride (TG) levels in healthy mice and normalized aberrant lipid profiles in metabolically challenged animals, mediated through miR‐379 effects on key receptors in hepatic TG re‐uptake. As hepatic miR‐379 levels were also correlated with GC and TG levels in human obese patients, the identification of a GC/GR‐controlled miRNA cluster not only defines a novel layer of hormone‐dependent metabolic control but also paves the way to alternative miRNA‐based therapeutic approaches in metabolic dysfunction. 相似文献
7.
8.
Jennifer Hochscherf Dirk Lindenblatt Michaela Steinkrüger Eungyoung Yoo Özlem Ulucan Stefan Herzig Olaf-Georg Issinger Volkhard Helms Claudia Götz Ines Neundorf Karsten Niefind Markus Pietsch 《Analytical biochemistry》2015
Increased activity of protein kinase CK2 is associated with various types of cancer, neurodegenerative diseases, and chronic inflammation. In the search for CK2 inhibitors, attention has expanded toward compounds disturbing the interaction between CK2α and CK2β in addition to established active site-directed approaches. The current article describes the development of a fluorescence anisotropy-based assay that mimics the principle of CK2 subunit interaction by using CK2α1–335 and the fluorescent probe CF-Ahx-Pc as a CK2β analog. In addition, we identified new inhibitors able to displace the fluorescent probe from the subunit interface on CK2α1–335. Both CF-Ahx-Pc and the inhibitors I-Pc and Cl-Pc were derived from the cyclic peptide Pc, a mimetic of the C-terminal CK2α-binding motif of CK2β. The design of the two inhibitors was based on docking studies using the known crystal structure of the Pc/CK2α1–335 complex. The dissociation constants obtained in the fluorescence anisotropy assay for binding of all compounds to human CK2α1–335 were validated by isothermal titration calorimetry. I-Pc was identified as the tightest binding ligand with a KD value of 240 nM and was shown to inhibit the CK2 holoenzyme-dependent phosphorylation of PDX-1, a substrate requiring the presence of CK2β, with an IC50 value of 92 μM. 相似文献
9.
Alexis Jourdain Mariusz Karbowski Yves Mattenberger Sébastien Herzig Pascaline Clerc Ines Raschke Carsten Merkwirth Sarah Ehses Frank Krause David C Chan Christiane Alexander Christoph Bauer Richard Youle Thomas Langer Jean‐Claude Martinou 《The EMBO journal》2009,28(11):1589-1600
Mitochondria are dynamic organelles, the morphology of which results from an equilibrium between two opposing processes, fusion and fission. Mitochondrial fusion relies on dynamin‐related GTPases, the mitofusins (MFN1 and 2) in the outer mitochondrial membrane and OPA1 (optic atrophy 1) in the inner mitochondrial membrane. Apart from a role in the maintenance of mitochondrial DNA, little is known about the physiological role of mitochondrial fusion. Here we report that mitochondria hyperfuse and form a highly interconnected network in cells exposed to selective stresses. This process precedes mitochondrial fission when it is triggered by apoptotic stimuli such as UV irradiation or actinomycin D. Stress‐induced mitochondrial hyperfusion (SIMH) is independent of MFN2, BAX/BAK, and prohibitins, but requires L‐OPA1, MFN1, and the mitochondrial inner membrane protein SLP‐2. In the absence of SLP‐2, L‐OPA1 is lost and SIMH is prevented. SIMH is accompanied by increased mitochondrial ATP production and represents a novel adaptive pro‐survival response against stress. 相似文献
10.
Heidi Hintsala Tuomas V. Kentt? Mikko Tulppo Antti Kiviniemi Heikki V. Huikuri Matti M?ntysaari Sirkka Kein?nen-Kiukaannemi Risto Bloigu Karl-Heinz Herzig Riitta Antikainen Hannu Rintam?ki Jouni J. K. Jaakkola Tiina M. Ik?heimo 《PloS one》2014,9(7)