全文获取类型
收费全文 | 559篇 |
免费 | 33篇 |
出版年
2022年 | 4篇 |
2020年 | 7篇 |
2018年 | 6篇 |
2017年 | 14篇 |
2016年 | 16篇 |
2015年 | 17篇 |
2014年 | 22篇 |
2013年 | 34篇 |
2012年 | 40篇 |
2011年 | 33篇 |
2010年 | 17篇 |
2009年 | 19篇 |
2008年 | 26篇 |
2007年 | 17篇 |
2006年 | 17篇 |
2005年 | 7篇 |
2004年 | 11篇 |
2003年 | 12篇 |
2002年 | 17篇 |
2001年 | 17篇 |
2000年 | 7篇 |
1999年 | 13篇 |
1998年 | 9篇 |
1996年 | 7篇 |
1995年 | 7篇 |
1994年 | 4篇 |
1993年 | 8篇 |
1992年 | 7篇 |
1991年 | 9篇 |
1990年 | 5篇 |
1989年 | 8篇 |
1988年 | 4篇 |
1987年 | 5篇 |
1986年 | 4篇 |
1985年 | 5篇 |
1984年 | 6篇 |
1983年 | 6篇 |
1982年 | 11篇 |
1981年 | 5篇 |
1980年 | 6篇 |
1979年 | 11篇 |
1978年 | 6篇 |
1977年 | 11篇 |
1976年 | 7篇 |
1975年 | 5篇 |
1974年 | 9篇 |
1973年 | 5篇 |
1972年 | 12篇 |
1971年 | 7篇 |
1969年 | 6篇 |
排序方式: 共有592条查询结果,搜索用时 156 毫秒
111.
Regulation of insulin resistance and type II diabetes by hepatitis C virus infection: A driver function of circulating miRNAs 下载免费PDF全文
Adit Singhal Aniruddh Agrawal Jun Ling 《Journal of cellular and molecular medicine》2018,22(4):2071-2085
Hepatitis C virus (HCV) infection is a serious worldwide healthcare issue. Its association with various liver diseases including hepatocellular carcinoma (HCC) is well studied. However, the study on the relationship between HCV infection and the development of insulin resistance and diabetes is very limited. Current research has already elucidated some underlying mechanisms, especially on the regulation of metabolism and insulin signalling by viral proteins. More studies have emerged recently on the correlation between HCV infection‐derived miRNAs and diabetes and insulin resistance. However, no studies have been carried out to directly address if these miRNAs, especially circulating miRNAs, have causal effects on the development of insulin resistance and diabetes. Here, we proposed a new perspective that circulating miRNAs can perform regulatory functions to modulate gene expression in peripheral tissues leading to insulin resistance and diabetes, rather than just a passive factor associated with these pathological processes. The detailed rationales were elaborated through comprehensive literature review and bioinformatic analyses. miR‐122 was identified to be one of the most potential circulating miRNAs to cause insulin resistance. This result along with the idea about the driver function of circulating miRNAs will promote further investigations that eventually lead to the development of novel strategies to treat HCV infection‐associated extrahepatic comorbidities. 相似文献
112.
Rates of weight loss and release of nutrients during different phases of decomposition in young water hyacinth leaves were
determined under laboratory conditions. The leaves decomposed solely by physical leaching during the initial 4-day phase and
later by microbial processes. The largest part of weight loss and nutrient release by physical leaching took place within
the first 4 h of incubation and thereafter the decomposition rate declined. Microbial processes decayed leaves at a significantly
higher rate than that by physical leaching. The overall decay rate constants were related inversely and the release of nutrients
directly to the levels of leaf additions in the lake water. The dissolved inorganic and organic nutrients were released chiefly
by abiotic processes during the initial as well as later phases of decay. The release was significantly higher during the
initial phase in comparison with that during the later phase. Microbes utilized only a small amount of nutrients that were
released during decomposition of water hyacinth leaves. The % release of various elements from the decaying leaves was in
the order of K > P > C > Na > N. 相似文献
113.
Development of antioxidative defense system of wheat seedlings in response to high light 总被引:15,自引:0,他引:15
Changes in the activities of enzymes involved in the detoxification of reactive oxygen species in wheat seedlings ( Triticum aestivum L.) in response to variations in the light environment were studied. Activities of ascorbate peroxidase, superoxide dismutase, monodehydroascorbate reductase, dehydroascorbate reductase, glutalhione reductase and catalase were much lower in seedlings grown under low-light conditions than in those grown under high-light conditions. Activities of all these enzymes significantly increased within 24 h of transfer of the low-light-grown seedlings to the high-light regime. The results suggest that the increase in enzyme activities was an adaptive response of the plants to higher amounts of active oxygen species generated at higher light intensities. An accumulation of glutathione was also observed, which could also be a part of the defense strategy to meet the increased generation of active oxygen species upon transfer of low-light-grown plants to high-light conditions. 相似文献
114.
Qian Yang Yiqiong Ma Yipeng Liu Wei Liang Xinghua Chen Zhilong Ren Huiming Wang Pravin C. Singhal Guohua Ding 《Molecular biology of the cell》2016,27(1):197-208
Recent studies have shown that nephrin plays a vital role in angiotensin II (Ang II)–induced podocyte injury and thus contributes to the onset of proteinuria and the progression of renal diseases, but its specific mechanism remains unclear. c-Abl is an SH2/SH3 domain–containing nonreceptor tyrosine kinase that is involved in cell survival and regulation of the cytoskeleton. Phosphorylated nephrin is able to interact with molecules containing SH2/SH3 domains, suggesting that c-Abl may be a downstream molecule of nephrin signaling. Here we report that Ang II–infused rats developed proteinuria and podocyte damage accompanied by nephrin dephosphorylation and minimal interaction between nephrin and c-Abl. In vitro, Ang II induced podocyte injury and nephrin and Akt dephosphorylation, which occurred in tandem with minimal interaction between nephrin and c-Abl. Moreover, Ang II promoted c-Abl phosphorylation and interaction between c-Abl and SH2 domain–containing 5′-inositol phosphatase 2 (SHIP2). c-Abl small interfering RNA (siRNA) and STI571 (c-Abl inhibitor) provided protection against Ang II–induced podocyte injury, suppressed the Ang II-induced c-Abl–SHIP2 interaction and SHIP2 phosphorylation, and maintained a stable level of nephrin phosphorylation. These results indicate that c-Abl is a molecular chaperone of nephrin signaling and the SHIP2-Akt pathway and that the released c-Abl contributes to Ang II–induced podocyte injury. 相似文献
115.
Pavel V. Belichenko Rime Madani Lorianne Rey-Bellet Maria Pihlgren Ann Becker Adeline Plassard Stephanie Vuillermot Valérie Giriens Rachel L. Nosheny Alexander M. Kleschevnikov Janice S. Valletta Sara K. S. Bengtsson Gordon R. Linke Michael T. Maloney David T. Hickman Pedro Reis Anne Granet Dorin Mlaki Maria Pilar Lopez-Deber Long Do Nishant Singhal Eliezer Masliah Matthew L. Pearn Andrea Pfeifer Andreas Muhs William C. Mobley 《PloS one》2016,11(3)
In Down syndrome (DS) or trisomy of chromosome 21, the β-amyloid (Aβ) peptide product of the amyloid precursor protein (APP) is present in excess. Evidence points to increased APP gene dose and Aβ as playing a critical role in cognitive difficulties experienced by people with DS. Particularly, Aβ is linked to the late-life emergence of dementia as associated with neuropathological markers of Alzheimer’s disease (AD). At present, no treatment targets Aβ–related pathogenesis in people with DS. Herein we used a vaccine containing the Aβ 1–15 peptide embedded into liposomes together with the adjuvant monophosphoryl lipid A (MPLA). Ts65Dn mice, a model of DS, were immunized with the anti-Aβ vaccine at 5 months of age and were examined for cognitive measures at 8 months of age. The status of basal forebrain cholinergic neurons and brain levels of APP and its proteolytic products were measured. Immunization of Ts65Dn mice resulted in robust anti-Aβ IgG titers, demonstrating the ability of the vaccine to break self-tolerance. The vaccine-induced antibodies reacted with Aβ without detectable binding to either APP or its C-terminal fragments. Vaccination of Ts65Dn mice resulted in a modest, but non-significant reduction in brain Aβ levels relative to vehicle-treated Ts65Dn mice, resulting in similar levels of Aβ as diploid (2N) mice. Importantly, vaccinated Ts65Dn mice showed resolution of memory deficits in the novel object recognition and contextual fear conditioning tests, as well as reduction of cholinergic neuron atrophy. No treatment adverse effects were observed; vaccine did not result in inflammation, cellular infiltration, or hemorrhage. These data are the first to show that an anti-Aβ immunotherapeutic approach may act to target Aβ-related pathology in a mouse model of DS. 相似文献
116.
BackgroundReports including our own describe that intravascular hemolysis increases the risk of thrombosis in hemolytic disorders. Our recent study shows that plasma Hb concentrations correlate directly with platelet activation in patients with paroxysmal nocturnal hemoglobinuria (PNH). The binding of Hb to glycoprotein1bα (GP1bα) increases platelet activation. A peptide AA1-50, designed from N-terminal amino acid sequence of GP1bα significantly inhibits the Hb binding to GP1bα as well as Hb-induced platelet activation. This study further examined if the Hb-mediated platelet activation plays any significant role in thrombus formation on subendothelium matrix under physiological flow shear stresses and the inhibition of Hb-platelet interaction can abrogate the above effects of Hb.
Methods and Results
Study performed thrombus formation assay in vitro by perfusing whole blood over immobilized VWF or collagen type I in presence of Hb under shear stresses simulating arterial or venous flow. The Hb concentrations ranging from 5 to 10 μM, commonly observed level in plasma of the hemolytic patients including PNH, dose-dependently increased thrombus formation on immobilized VWF under higher shear stress of 25 dyne/cm2, but not at 5 dyne/cm2. The above Hb concentrations also increased thrombus formation on immobilized collagen under both shear stresses of 5 and 25 dyne/cm2. The peptide AA1-50 abrogated invariably the above effects of Hb on thrombus formation.Conclusions and Significance
This study therefore indicates that the Hb-induced platelet activation plays a crucial role in thrombus formation on immobilized VWF or collagen under physiological flow shear stresses. Thus suggesting a probable role of this mechanism in facilitating thrombosis under hemolytic conditions. 相似文献117.
118.
119.
Immunoregulatory activity of human bone marrow. Identification of suppressor cells possessing OKM1, SSEA-1, and HNK-1 antigens 总被引:2,自引:0,他引:2
F Mortari M A Bains S K Singhal 《Journal of immunology (Baltimore, Md. : 1950)》1986,137(4):1133-1137
Human bone marrow contains natural regulatory cells capable of suppressing the in vitro primary IgM response of normal tonsillar cells. The suppression is mediated by non-T cells possessing Fc receptors, OKM1, SSEA-1, and HNK-1 antigens on their surface. The suppression was abrogated by treatment of bone marrow cells (BMC) with anti-HNK-1 or anti-SSEA-1 antisera and complement. Furthermore, BMC depleted of HNK-1+ cells could respond in a primary in vitro antibody response when provided with accessory T cells and macrophages from tonsillar cells. Our findings support the idea that HNK-1+ and HNK-1- BMC populations act antagonistically in the regulation of antibody synthesis. Further, the finding of HNK-1+, SSEA-1+, and OKM1+ suppressor cells in human bone marrow may represent a precursor phenotype of mature natural killer cells with potent immunoregulatory activity. 相似文献
120.
A novel cell surface antigen (T305) found in increased frequency on acute leukemia cells and in autoimmune disease states 总被引:4,自引:0,他引:4
R I Fox M Hueniken S Fong S Behar I Royston S K Singhal L Thompson 《Journal of immunology (Baltimore, Md. : 1950)》1983,131(2):762-767
Monoclonal antibody T305, prepared by immunizing mice with the T-ALL derived cell line RPMI-8402, immunoprecipitates a single chain glycoprotein with m.w. 160,000 daltons (under reducing conditions) or 180,000 daltons (under nonreducing conditions). In immunofluorescence assays, antibody T305 reacted with a subpopulation of T cells in normal blood (22 +/- 6%), thymus (28 +/- 11%), and lymph node (24 +/- 6%). Increased frequency of T cells reactive with antibody T305 was found in peripheral blood of patients with infectious mononucleosis (greater than 80%), graft-vs-host disease after bone marrow transplantation (65 +/- 11%), acquired immunodeficiency syndrome (53 +/- 12%). The T cells in synovial fluid of patients with rheumatoid arthritis had increased frequency of antibody T305 reactive cells (59 +/- 8%) as compared to their peripheral blood (18 +/- 7%). Two color immunofluorescent studies demonstrated that the T305+ T cells predominantly co-stained with antibody Leu 2a (suppressor/cytotoxic subset) in both normals and disease state blood. After cell sorting to obtain T305+ and T305- subpopulations, we demonstrated that a) natural killer and antibody-dependent cellular cytotoxicity activity in normal blood was in the T305+ but not T305- T cells; b) cytotoxic T cells induced by mixed lymphocyte reaction were predominantly T305+; c) T305- T cells could be induced in vitro to express T305 antigen by mitogens or allogeneic B cells; d) the DNA content of T305+ and T305- T cells in normal blood was similar (greater 95% of cells with G0/G1 level); e) after mitogen stimulation, T305 antigen induction on previously T305- cells occurs before S-phase; and f) significantly more [3H]-thymidine after mitogen stimulation was incorporated by originally T305- cells than by originally T305+ cells (p less than 0.001). The T305 antigen was not restricted to T cells because it was also found on myeloid precursors in bone marrow but was not present on polymorphonuclear leukocytes, red blood cells, platelets, muscle, liver, skin, kidney, lung, or brain. Antibody T305 was found on 24/25 cases of acute leukemia (6 T-ALL, 10/11 cALL, 7 AML, and 1 AMOL) but not on 18 cases of chronic leukemia (B-CLL, T-CLL, null CLL, CML). The importance of the T305 antigen is that it is present on a high number of T cells in certain autoimmune diseases and on virtually all acute leukemia cells. Its distribution on immature and in vitro activated cells suggests that it may represent a receptor for signals related to cellular replication or differentiation. 相似文献