全文获取类型
收费全文 | 2749篇 |
免费 | 177篇 |
出版年
2023年 | 15篇 |
2022年 | 39篇 |
2021年 | 69篇 |
2020年 | 58篇 |
2019年 | 58篇 |
2018年 | 47篇 |
2017年 | 54篇 |
2016年 | 92篇 |
2015年 | 135篇 |
2014年 | 162篇 |
2013年 | 203篇 |
2012年 | 265篇 |
2011年 | 252篇 |
2010年 | 145篇 |
2009年 | 110篇 |
2008年 | 195篇 |
2007年 | 156篇 |
2006年 | 142篇 |
2005年 | 139篇 |
2004年 | 115篇 |
2003年 | 103篇 |
2002年 | 80篇 |
2001年 | 18篇 |
2000年 | 12篇 |
1999年 | 21篇 |
1998年 | 22篇 |
1997年 | 15篇 |
1996年 | 8篇 |
1995年 | 14篇 |
1994年 | 11篇 |
1993年 | 9篇 |
1992年 | 4篇 |
1991年 | 7篇 |
1990年 | 5篇 |
1989年 | 4篇 |
1988年 | 9篇 |
1984年 | 5篇 |
1982年 | 8篇 |
1981年 | 5篇 |
1978年 | 6篇 |
1976年 | 6篇 |
1975年 | 6篇 |
1973年 | 6篇 |
1968年 | 11篇 |
1966年 | 4篇 |
1965年 | 3篇 |
1964年 | 5篇 |
1962年 | 5篇 |
1957年 | 5篇 |
1955年 | 3篇 |
排序方式: 共有2926条查询结果,搜索用时 31 毫秒
101.
102.
Erika Reus-Chavarría Ivette Martínez-Vieyra Cristina Salinas-Nolasco Araceli Evangelina Chávez-Piña Juan Vicente Méndez-Méndez Edgar Oliver López-Villegas Alejandro Sosa-Peinado Doris Cerecedo 《生物化学与生物物理学报:生物膜》2019,1861(2):387-402
Hypertension (HTN), i.e. abnormally high blood pressure, is a major risk factor for heart attack, stroke, and kidney failure. The Epithelial Sodium Channel (ENaC), one of the main transporters regulates blood pressure by tightly controlling the sodium reabsorption along the nephron. Recently, we have shown an α-ENaC overexpression in platelets from hypertensive patients compared to platelets from normotensive subjects, suggesting it makes a contribution to the activation state of platelets and the physiopathology of hypertension. However, the involvement of the α-ENaC localized in neutrophils to this disease remains unknown. Neutrophils are the first leukocytes to be recruited to an inflammatory site and are equipped with a strong ability to eliminate intra- or extracellular pathogens using reactive oxygen species or antibacterial proteins contained in their granules.Using the Western blotting (Wb), flow cytometry, and qRT-PCR approaches; we determined α-ENaC neutrophil overexpression at the protein and messenger RNA (mRNA) levels. By confocal and cytometry analysis, we determined the α-ENaC distribution and the heterogeneity of HTN neutrophils population, respectively. Immunoprecipitation and Wb assays demonstrated the presence of both α-ENaC and caveolin-1 phosphorylated forms, compared with neutrophils from healthy individuals. Although neutrophils from hypertensive subjects circulating in an activated state were exhibiting important oxidative stress and modifications registered by confocal, atomic force, and scanning electron microscope, they conserved their defense capabilities. The features described above for neutrophils from hypertensive patients could be attributed to α-ENaC overexpression, as its drug inhibition diminished their activation state modulating the actin cytoskeleton reorganization triggered during the activation process. 相似文献
103.
Zenas George Yusuf Omosun Anthony A. Azenabor Jason Goldstein James Partin Kahaliah Joseph Debra Ellerson Qing He Francis Eko Melissa A. McDonald Matthew Reed Pavel Svoboda Olga Stuchlik Jan Pohl Erika Lutter Claudiu Bandea Carolyn M. Black Joseph U. Igietseme 《Biochemical and biophysical research communications》2019,508(2):421-429
The unfolded protein response (UPR) contributes to chlamydial pathogenesis, as a source of lipids and ATP during replication, and for establishing the initial anti-apoptotic state of host cell that ensures successful inclusion development. The molecular mechanism(s) of UPR induction by Chlamydia is unknown. Chlamydia use type III secretion system (T3SS) effector proteins (e.g, the Translocated Actin-Recruiting Phosphoprotein (Tarp) to stimulate host cell's cytoskeletal reorganization that facilitates invasion and inclusion development. We investigated the hypothesis that T3SS effector-mediated assembly of myosin-II complex produces activated non-muscle myosin heavy chain II (NMMHC-II), which then binds the UPR master regulator (BiP) and/or transducers to induce UPR. Our results revealed the interaction of the chlamydial effector proteins (CT228 and Tarp) with components of the myosin II complex and UPR regulator and transducer during infection. These interactions caused the activation and binding of NMMHC-II to BiP and IRE1α leading to UPR induction. In addition, specific inhibitors of myosin light chain kinase, Tarp oligomerization and myosin ATPase significantly reduced UPR activation and Chlamydia replication. Thus, Chlamydia induce UPR through T3SS effector-mediated activation of NMMHC-II components of the myosin complex to facilitate infectivity. The finding provides greater insights into chlamydial pathogenesis with the potential to identify therapeutic targets and formulations. 相似文献
104.
105.
Bhanupriya Madarampalli Gerald F.M. Watts Paul M. Panipinto Hung N. Nguygen Michael B. Brenner Erika H. Noss 《生物化学与生物物理学报:疾病的分子基础》2019,1865(6):1516-1524
Cadherins are homophilic cell-to-cell adhesion molecules that help cells respond to environmental changes. Newly formed cadherin junctions are associated with increased cell phosphorylation, but the pathways driving this signaling response are largely unknown. Since cadherins have no intrinsic signaling activity, this phosphorylation must occur through interactions with other signaling molecules. We previously reported that cadherin-11 engagement activates joint synovial fibroblasts, promoting inflammatory and degradative pathways important in rheumatoid arthritis (RA) pathogenesis. Our objective in this study was to discover interacting partners that mediate cadherin-11 signaling. Protein array screening showed that cadherin-11 extracellular binding domains linked to an Fc domain (cad11Fc) induced platelet-derived growth factor (PDGFR)-α phosphorylation in synovial fibroblasts and glioblastoma cells. PDGFRs are growth factor receptor tyrosine kinases that promote cell proliferation, survival, and migration in mesodermally derived cells. Increased PDGFR activity is implicated in RA pathology and associates with poor prognosis in several cancers, including sarcoma and glioblastoma. PDGFRα activation by cadherin-11 signaling promoted fibroblast proliferation, a signaling pathway independent from cadherin-11-stimulated IL-6 or matrix metalloproteinase (MMP)-3 release. PDGFRα phosphorylation mediated most of the cad11Fc-induced phosphatidyl-3-kinase (PI3K)/Akt activation, but only part of the mitogen-activated protein kinase (MAPK) response. PDGFRα-dependent signaling did not require cell cadherin-11 expression. Rather, cad11Fc immunoprecipitated PDGFRα, indicating a direct interaction between cadherin-11 and PDGFRα extracellular domains. This study is the first to report an interaction between cadherin-11 and PDGFRα and adds to our growing understanding that cadherin-growth factor receptor interactions help balance the interplay between tissue growth and adhesion. 相似文献
106.
Ralph Gradisch Dniel Szllsi Marco Niello Erika Lazzarin Harald H. Sitte Thomas Stockner 《The Journal of biological chemistry》2022,298(3)
The human serotonin transporter (hSERT) terminates neurotransmission by removing serotonin (5HT) from the synaptic cleft, an essential process for proper functioning of serotonergic neurons. Structures of the hSERT have revealed its molecular architecture in four conformations, including the outward-open and occluded states, and show the transporter’s engagement with co-transported ions and the binding mode of inhibitors. In this study, we investigated the molecular mechanism by which the hSERT occludes and sequesters the substrate 5HT. This first step of substrate uptake into cells is a structural change consisting of the transition from the outward-open to the occluded state. Inhibitors such as the antidepressants citalopram, fluoxetine, and sertraline inhibit this step of the transport cycle. Using molecular dynamics simulations, we reached a fully occluded state, in which the transporter-bound 5HT becomes fully shielded from both sides of the membrane by two closed hydrophobic gates. Analysis of 5HT-triggered occlusion showed that bound 5HT serves as an essential trigger for transporter occlusion. Moreover, simulations revealed a complex sequence of steps and showed that movements of bundle domain helices are only partially correlated. 5HT-triggered occlusion is initially dominated by movements of transmembrane helix 1b, while in the final step, only transmembrane helix 6a moves and relaxes an intermediate change in its secondary structure. 相似文献
107.
Beni Lestari Satomi Naito Akinori Endo Hidenori Nishihara Akira Kato Erika Watanabe Kimitoshi Denda Masayuki Komada Toshiaki Fukushima 《Molecular biology and evolution》2022,39(2)
The molecular evolution processes underlying the acquisition of the placenta in eutherian ancestors are not fully understood. Mouse NCK-interacting kinase (NIK)-related kinase (NRK) is expressed highly in the placenta and plays a role in preventing placental hyperplasia. Here, we show the molecular evolution of NRK, which confers its function for inhibiting placental cell proliferation. Comparative genome analysis identified NRK orthologs across vertebrates, which share the kinase and citron homology (CNH) domains. Evolutionary analysis revealed that NRK underwent extensive amino acid substitutions in the ancestor of placental mammals and has been since conserved. Biochemical analysis of mouse NRK revealed that the CNH domain binds to phospholipids, and a region in NRK binds to and inhibits casein kinase-2 (CK2), which we named the CK2-inhibitory region (CIR). Cell culture experiments suggest the following: 1) Mouse NRK is localized at the plasma membrane via the CNH domain, where the CIR inhibits CK2. 2) This mitigates CK2-dependent phosphorylation and inhibition of PTEN and 3) leads to the inhibition of AKT signaling and cell proliferation. Nrk deficiency increased phosphorylation levels of PTEN and AKT in mouse placenta, supporting our hypothesis. Unlike mouse NRK, chicken NRK did not bind to phospholipids and CK2, decrease phosphorylation of AKT, or inhibit cell proliferation. Both the CNH domain and CIR have evolved under purifying selection in placental mammals. Taken together, our study suggests that placental mammals acquired the phospholipid-binding CNH domain and CIR in NRK for regulating the CK2–PTEN–AKT pathway and placental cell proliferation. 相似文献
108.
Jos Antonio García-Espinoza Jos Francisco Muoz-Valle Mariel García-Chagolln Jorge Hernndez-Bello Claudia Azucena Palafox-Snchez Erika Fabiola Lpez-Villalobos Gabriela Athziri Snchez-Zuno Gloria Esther Martínez-Bonilla Sergio Cerpa-Cruz Francisco Josue Carrillo-Ballesteros Edith Oregon-Romero 《Current issues in molecular biology》2022,44(2):764
Background: Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease, which affects exocrine glands. T cell activation is a trigger mechanism in the immune response. Hyperreactivity of T cells and antibody production are features in pSS. ICOS can be critical in the pathogenesis of pSS. Methods: A total of 134 pSS patients and 134 control subjects (CS) were included. Genotyping was performed by PCR-RFLP. ICOS mRNA expression was quantified by real-time PCR, and CD4+ ICOS+ T cells were determined by flow cytometry. Results: The ICOS IVS1 + 173 T>C polymorphisms were not associated with susceptibility to pSS (p = 0.393, CI = 0.503–1.311). However, the c.1624 C>T polymorphism was associated with a reduction in the risk of development of pSS (p = 0.015, CI = 0.294–0.884). An increase in ICOS mRNA expression in patients was observed (3.7-fold). Furthermore, pSS patients showed an increase in membranal-ICOS expression (mICOS). High expression of mICOS (MFI) was associated with lymphocytic infiltration. Conclusions: The IVS1 + 173 polymorphism is not a genetic marker for the development of pSS, while c.1624 T allele was associated with a low risk. However, elevated mICOS expression in pSS patients with high lymphocytic infiltration was found. ICOS may have an important role in the immunopathogenesis of pSS and should be analyzed in T cell subsets in pSS patients as a possible disease marker. 相似文献
109.
Some ultrastructural characteristics of cell types in barley root tip and root cap were recorded and compared with the aim to identify these cells by electron microscopy, even if positional information is limited in the ultrathin section. Root cap and root body initials could be distinguished according to the type of proplastids. Cap and apical cells also differed at the level of dictyosomes and the relative quantity of the dense substance in the enlarging vacuoles. The maturity of cap cells could be judged from the degree of vacuolization and the size of starch grains (statoliths) in the plastids. 相似文献
110.
Production of recombinant human type I procollagen homotrimer in the mammary gland of transgenic mice 总被引:8,自引:0,他引:8
Toman PD Pieper F Sakai N Karatzas C Platenburg E de Wit I Samuel C Dekker A Daniels GA Berg RA Platenburg GJ 《Transgenic research》1999,8(6):415-427
The large scale production of recombinant collagen for use in biomaterials requires an efficient expression system capable of processing a large (>400Kd) multisubunit protein requiring post-translational modifications. To investigate whether the mammary gland of transgenic animals fulfills these requirements, transgenic mice were generated containing the S1-casein mammary gland-specific promoter operatively linked to 37Kb of the human 1(I) procollagen structural gene and 3 flanking region. The frequency of transgenic lines established was 12%. High levels of soluble triple helical homotrimeric [(1)3] type I procollagen were detected (up to 8mg/ml) exclusively in the milk of six out of 9 lines of lactating transgenic mice. The transgene-derived human procollagen chains underwent efficient assembly into a triple helical structure. Although proline or lysine hydroxylation has never been described for any milk protein, procollagen was detected with these post-translational modifications. The procollagen was stable in mil; minimal degradation was observed. These results show that the mammary gland is capable of expressing a large procollagen gene construct, efficiently assembling the individual polypeptide chains into a stable triple helix, and secreting the intact molecule into the milk. 相似文献