全文获取类型
收费全文 | 947篇 |
免费 | 59篇 |
出版年
2022年 | 5篇 |
2021年 | 15篇 |
2020年 | 9篇 |
2019年 | 16篇 |
2018年 | 18篇 |
2017年 | 10篇 |
2016年 | 24篇 |
2015年 | 41篇 |
2014年 | 47篇 |
2013年 | 61篇 |
2012年 | 78篇 |
2011年 | 61篇 |
2010年 | 22篇 |
2009年 | 37篇 |
2008年 | 45篇 |
2007年 | 55篇 |
2006年 | 51篇 |
2005年 | 28篇 |
2004年 | 44篇 |
2003年 | 33篇 |
2002年 | 36篇 |
2001年 | 19篇 |
2000年 | 24篇 |
1999年 | 17篇 |
1998年 | 14篇 |
1997年 | 7篇 |
1996年 | 8篇 |
1994年 | 8篇 |
1993年 | 6篇 |
1992年 | 9篇 |
1991年 | 8篇 |
1990年 | 9篇 |
1989年 | 11篇 |
1988年 | 6篇 |
1987年 | 8篇 |
1985年 | 6篇 |
1984年 | 6篇 |
1983年 | 6篇 |
1982年 | 6篇 |
1981年 | 9篇 |
1980年 | 6篇 |
1979年 | 11篇 |
1978年 | 5篇 |
1977年 | 5篇 |
1975年 | 7篇 |
1974年 | 4篇 |
1973年 | 4篇 |
1969年 | 7篇 |
1968年 | 5篇 |
1967年 | 4篇 |
排序方式: 共有1006条查询结果,搜索用时 15 毫秒
921.
Tate CM Pallini R Ricci-Vitiani L Dowless M Shiyanova T D'Alessandris GQ Morgante L Giannetti S Larocca LM di Martino S Rowlinson SW De Maria R Stancato L 《Cell death and differentiation》2012,19(10):1644-1654
Glioblastoma multiforme (GBM) is among the most aggressive tumor types and is essentially an incurable malignancy characterized by resistance to chemo-, radio-, and immunotherapy. GBM is maintained by a hierarchical cell organization that includes stem-like, precursor, and differentiated cells. Recurrence and maintenance of the tumor is attributed to a small population of undifferentiated tumor-initiating cells, defined as glioblastoma stem-like cells (GSLCs). This cellular hierarchy offers a potential treatment to induce differentiation of GSLCs away from tumor initiation to a more benign phenotype or to a cell type more amenable to standard therapies. Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, have numerous biological activities including control of growth and differentiation. In vitro, a BMP7 variant (BMP7v) decreased primary human GSLC proliferation, endothelial cord formation, and stem cell marker expression while enhancing neuronal and astrocyte differentiation marker expression. In subcutaneous and orthotopic GSLC xenografts, which closely reproduce the human disease, BMP7v decreased tumor growth and stem cell marker expression, while enhancing astrocyte and neuronal differentiation compared with control mice. In addition, BMP7v reduced brain invasion, angiogenesis, and associated mortality in the orthotopic model. Inducing differentiation of GSLCs and inhibiting angiogenesis with BMP7v provides a potentially powerful and novel approach to the treatment of GBM. 相似文献
922.
Alejandra González-Loyola Gonzalo Fernández-Miranda Marianna Trakala David Partida Kumiko Samejima Hiromi Ogawa Marta Ca?amero Alba de Martino ángel Martínez-Ramírez Guillermo de Cárcer Ignacio Pérez de Castro William C. Earnshaw Marcos Malumbres 《Molecular and cellular biology》2015,35(20):3566-3578
Aurora kinase B, one of the three members of the mammalian Aurora kinase family, is the catalytic component of the chromosomal passenger complex, an essential regulator of chromosome segregation in mitosis. Aurora B is overexpressed in human tumors although whether this kinase may function as an oncogene in vivo is not established. Here, we report a new mouse model in which expression of the endogenous Aurkb locus can be induced in vitro and in vivo. Overexpression of Aurora B in cultured cells induces defective chromosome segregation and aneuploidy. Long-term overexpression of Aurora B in vivo results in aneuploidy and the development of multiple spontaneous tumors in adult mice, including a high incidence of lymphomas. Overexpression of Aurora B also results in a reduced DNA damage response and decreased levels of the p53 target p21Cip1
in vitro and in vivo, in line with an inverse correlation between Aurora B and p21Cip1 expression in human leukemias. Thus, overexpression of Aurora B may contribute to tumor formation not only by inducing chromosomal instability but also by suppressing the function of the cell cycle inhibitor p21Cip1. 相似文献
923.
Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice 总被引:37,自引:0,他引:37 下载免费PDF全文
Klaman LD Boss O Peroni OD Kim JK Martino JL Zabolotny JM Moghal N Lubkin M Kim YB Sharpe AH Stricker-Krongrad A Shulman GI Neel BG Kahn BB 《Molecular and cellular biology》2000,20(15):5479-5489
Protein-tyrosine phosphatase 1B (PTP-1B) is a major protein-tyrosine phosphatase that has been implicated in the regulation of insulin action, as well as in other signal transduction pathways. To investigate the role of PTP-1B in vivo, we generated homozygotic PTP-1B-null mice by targeted gene disruption. PTP-1B-deficient mice have remarkably low adiposity and are protected from diet-induced obesity. Decreased adiposity is due to a marked reduction in fat cell mass without a decrease in adipocyte number. Leanness in PTP-1B-deficient mice is accompanied by increased basal metabolic rate and total energy expenditure, without marked alteration of uncoupling protein mRNA expression. In addition, insulin-stimulated whole-body glucose disposal is enhanced significantly in PTP-1B-deficient animals, as shown by hyperinsulinemic-euglycemic clamp studies. Remarkably, increased insulin sensitivity in PTP-1B-deficient mice is tissue specific, as insulin-stimulated glucose uptake is elevated in skeletal muscle, whereas adipose tissue is unaffected. Our results identify PTP-1B as a major regulator of energy balance, insulin sensitivity, and body fat stores in vivo. 相似文献
924.
Tissue glucocorticoid resistance/hypersensitivity syndromes 总被引:12,自引:0,他引:12
925.
Tissot S Oberbek A Reclari M Dreyer M Hacker DL Baldi L Farhat M Wurm FM 《New biotechnology》2011,28(4):382-390
Bioprocesses for recombinant protein production with mammalian cells are typically controlled for several physicochemical parameters including the pH and dissolved oxygen concentration (DO) of the culture medium. Here we studied whether these controls are necessary for efficient and reproducible bioprocesses in an orbitally shaken bioreactor (OSR). Mixing, gas transfer, and volumetric power consumption (P(V)) were determined in both a 5-L OSR and a 3-L stirred-tank bioreactor (STR). The two cultivation systems had a similar mixing intensity, but the STR had a lower volumetric mass transfer coefficient of oxygen (k(L)a) and a higher P(V) than the OSR. Recombinant CHO cell lines expressing either tumor necrosis factor receptor as an Fc fusion protein (TNFR:Fc) or an anti-RhesusD monoclonal antibody were cultivated in the two systems. The 5-L OSR was operated in an incubator shaker with 5% CO(2) in the gas environment but without pH and DO control whereas the STR was operated with or without pH and DO control. Higher cell densities and recombinant protein titers were obtained in the OSR as compared to both the controlled and the non-controlled STRs. To test the reproducibility of a bioprocess in a non-controlled OSR, the two CHO cell lines were each cultivated in parallel in six 5-L OSRs. Similar cell densities, cell viabilities, and recombinant protein titers along with similar pH and DO profiles were achieved in each group of replicates. Our study demonstrated that bioprocesses can be performed in OSRs without pH or DO control in a highly reproducible manner, at least at the scale of operation studied here. 相似文献
926.
Pesce A De Sanctis D Nardini M Dewilde S Moens L Hankeln T Burmester T Ascenzi P Bolognesi M 《IUBMB life》2004,56(11-12):657-664
Neuroglobin (Ngb) and cytoglobin (Cygb) are two recently discovered intracellular members of the vertebrate hemoglobin (Hb) family. Ngb, predominantly expressed in nerve cells, is of ancient evolutionary origin and is homologous to nerve-globins of invertebrates. Cygb, present in many different tissues, shares common ancestry with myoglobin (Mb) and can be traced to early vertebrate evolution. Ngb is held to facilitate O2 diffusion to the mitochondria and to protect neuronal cells from hypoxic-ischemic insults, may be an oxidative stress-responsive sensor protein for signal transduction, and may carry out enzymatic activities, such as NO/O2 scavenging. Cygb is linked to collagen synthesis, may provide O2 for enzymatic reactions, and may be involved in a ROS(NO)-signaling pathway(s). Ngb and Cgb display the classical three-over-three alpha-helical fold of Hb and Mb, and are endowed with a hexa-coordinate heme-Fe atom, in their ferrous and ferric forms, having the heme distal HisE7 residue as the endogenous ligand. Reversible hexa- to penta-coordination of the heme Fe atom modulates ligand binding properties of Ngb and Cygb. Moreover, Ngb and Cygb display a tunnel/cavity system within the protein matrix held to facilitate ligand channeling to/from the heme, multiple ligand copies storage, multi-ligand reactions, and conformational transitions supporting ligand binding. 相似文献
927.
Cross-linking of the mannose receptor on monocyte-derived dendritic cells activates an anti-inflammatory immunosuppressive program 总被引:13,自引:0,他引:13
Chieppa M Bianchi G Doni A Del Prete A Sironi M Laskarin G Monti P Piemonti L Biondi A Mantovani A Introna M Allavena P 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(9):4552-4560
Immature monocyte-derived dendritic cells (DC) strongly express the endocytic mannose receptor (MR). Addition of a specific anti-MR mAb (clone PAM-1) for 24 h to cultures of immature DC induced phenotypical and functional maturation of the cells, assessed as up-regulation of costimulatory molecules and CD83, and chemotactic response to CCL19. A different isotype-matched anti-MR mAb (clone 19.2) had no significant effect. Engagement of MR with mAb PAM-1 induced the production of the anti-inflammatory cytokines IL-10, IL-1R antagonist, and of the nonsignaling IL-1R type II. In contrast IL-1beta, TNF, and IL-12 were not produced. PAM-1-treated DC were unable to polarize Th1 effector cells and did not secrete the chemokines CXCL10 and CCL19; in turn, they produced large amounts of CCL22 and CCL17, thus favoring the amplification of Th2 circuits. T cells cocultured with PAM-1-matured DC initially proliferated but later became anergic and behaved as suppressor/regulatory cells. Natural ligands binding to MR had differential effects. MUC III (a partially purified mucin), biglycan (a purified complex proteoglycan), and mannosylated lipoarabinomannan from Mycobacterium tuberculosis affected cytokine production with high IL-10, IL-1R antagonist, IL-1R type II, and inhibition of IL-12. In contrast, mannan, dextran, and thyroglobulin had no significant effect. In conclusion, the appropriate engagement of the MR by mAb PAM-1 and selected natural ligands elicit a secretory program in mono-derived DC characterized by a distinct profile of cytokines/chemokines with the ability to dampen inflammation and to inhibit the generation of Th1-polarized immune responses. 相似文献
928.
Jari Syv?ranta Aurélia Martino Dorothée Kopp Régis Céréghino Frédéric Santoul 《Hydrobiologia》2011,658(1):383-388
We tested the impacts of most common sample preservation methods used for aquatic sample materials on the stable isotope ratios
of carbon and nitrogen in clams, a typical baseline indicator organism for many aquatic food web studies utilising stable
isotope analysis (SIA). In addition to common chemical preservatives ethanol and formalin, we also assessed the potential
impacts of freezing on δ13C and δ15N values and compared the preserved samples against freshly dried and analysed samples. All preservation methods, including
freezing, had significant impacts on δ13C and δ15N values and the effects in general were greater on the carbon isotope values (1.3–2.2‰ difference) than on the nitrogen isotope
values (0.9–1.0‰ difference). However, the impacts produced by the preservation were rather consistent within each method
during the whole 1 year experiment allowing these to be accounted for, if clams are intended for use in retrospective stable
isotope studies. 相似文献
929.
930.