全文获取类型
收费全文 | 861篇 |
免费 | 147篇 |
国内免费 | 1篇 |
出版年
2022年 | 5篇 |
2021年 | 14篇 |
2020年 | 5篇 |
2019年 | 6篇 |
2018年 | 11篇 |
2017年 | 8篇 |
2016年 | 14篇 |
2015年 | 29篇 |
2014年 | 33篇 |
2013年 | 39篇 |
2012年 | 45篇 |
2011年 | 42篇 |
2010年 | 37篇 |
2009年 | 23篇 |
2008年 | 36篇 |
2007年 | 32篇 |
2006年 | 48篇 |
2005年 | 37篇 |
2004年 | 24篇 |
2003年 | 34篇 |
2002年 | 42篇 |
2001年 | 42篇 |
2000年 | 40篇 |
1999年 | 40篇 |
1998年 | 26篇 |
1997年 | 20篇 |
1996年 | 17篇 |
1995年 | 12篇 |
1994年 | 11篇 |
1993年 | 7篇 |
1992年 | 21篇 |
1991年 | 10篇 |
1990年 | 18篇 |
1989年 | 22篇 |
1988年 | 15篇 |
1987年 | 15篇 |
1986年 | 14篇 |
1985年 | 9篇 |
1984年 | 15篇 |
1983年 | 9篇 |
1982年 | 16篇 |
1981年 | 6篇 |
1980年 | 8篇 |
1979年 | 4篇 |
1978年 | 7篇 |
1977年 | 6篇 |
1976年 | 6篇 |
1975年 | 6篇 |
1974年 | 5篇 |
1966年 | 3篇 |
排序方式: 共有1009条查询结果,搜索用时 15 毫秒
61.
Yurong Cheng Yong Li Nora Scherer Franziska Grundner-Culemann Terho Lehtimki Binisha H. Mishra Olli T. Raitakari Matthias Nauck Kai-Uwe Eckardt Peggy Sekula Ulla T. Schultheiss 《PLoS genetics》2022,18(4)
Osteopontin (OPN), encoded by SPP1, is a phosphorylated glycoprotein predominantly synthesized in kidney tissue. Increased OPN mRNA and protein expression correlates with proteinuria, reduced creatinine clearance, and kidney fibrosis in animal models of kidney disease. But its genetic underpinnings are incompletely understood. We therefore conducted a genome-wide association study (GWAS) of OPN in a European chronic kidney disease (CKD) population. Using data from participants of the German Chronic Kidney Disease (GCKD) study (N = 4,897), a GWAS (minor allele frequency [MAF]≥1%) and aggregated variant testing (AVT, MAF<1%) of ELISA-quantified serum OPN, adjusted for age, sex, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR) was conducted. In the project, GCKD participants had a mean age of 60 years (SD 12), median eGFR of 46 mL/min/1.73m2 (p25: 37, p75: 57) and median UACR of 50 mg/g (p25: 9, p75: 383). GWAS revealed 3 loci (p<5.0E-08), two of which replicated in the population-based Young Finns Study (YFS) cohort (p<1.67E-03): rs10011284, upstream of SPP1 encoding the OPN protein and related to OPN production, and rs4253311, mapping into KLKB1 encoding prekallikrein (PK), which is processed to kallikrein (KAL) implicated through the kinin-kallikrein system (KKS) in blood pressure control, inflammation, blood coagulation, cancer, and cardiovascular disease. The SPP1 gene was also identified by AVT (p = 2.5E-8), comprising 7 splice-site and missense variants. Among others, downstream analyses revealed colocalization of the OPN association signal at SPP1 with expression in pancreas tissue, and at KLKB1 with various plasma proteins in trans, and with phenotypes (bone disorder, deep venous thrombosis) in human tissue. In summary, this GWAS of OPN levels revealed two replicated associations. The KLKB1 locus connects the function of OPN with PK, suggestive of possible further post-translation processing of OPN. Further studies are needed to elucidate the complex role of OPN within human (patho)physiology. 相似文献
62.
63.
Seebohm G Scherer CR Busch AE Lerche C 《The Journal of biological chemistry》2001,276(17):13600-13605
KCNQ1 inactivation bears electrophysiological characteristics different from classical N- and C-type inactivation in Shaker-like potassium channels. However, the molecular site of KCNQ1 inactivation has not yet been determined. KCNQ2 channels do not exert a fast inactivation in contrast to KCNQ1 channels. By expressing functional chimeras between KCNQ1 and KCNQ2 in Xenopus oocytes, we mapped the region of this inactivation to transmembrane domain S5 and the pore loop H5 and finally narrowed down the site to positions Gly(272) and Val(307) in KCNQ1. Exchanging these two amino acids individually with the analogous KCNQ2 residue abolished inactivation. Furthermore, a KCNQ1-like inactivation was introduced into KCNQ2 by mutagenesis in the corresponding region, confirming its relevance for the inactivation process. As KCNQ1 inactivation involves the regions S5 and H5, it exhibits a geography distinct from N- or C-type inactivation. Native cardiac I(Ks) channels comprising KCNQ1 and accessory MinK subunits do not inactivate because of the functional interaction of KCNQ1 with MinK. Mutations in KCNQ1 can lead to long QT1 syndrome, an inherited form of arrhythmia. The long QT1 mutant KCNQ1(L273F) displays a pronounced KCNQ1 inactivation. Here we show that when expressing mutant I(Ks) channels formed from KCNQ1(L273F) and MinK, MinK association no longer eliminates KCNQ1 inactivation. This results in smaller repolarizing currents in the heart and therefore represents a novel mechanism leading to long QT syndrome. 相似文献
64.
65.
Constitutively active mitogen-activated protein kinase kinase 6 (MKK6) or salicylate induces spontaneous 3T3-L1 adipogenesis 总被引:5,自引:0,他引:5
Engelman JA Berg AH Lewis RY Lin A Lisanti MP Scherer PE 《The Journal of biological chemistry》1999,274(50):35630-35638
Although much has been learned regarding the importance of p38 mitogen-activated protein kinase in inflammatory and stress responses, relatively little is known concerning its role in differentiation processes. Recently, we demonstrated that p38 mitogen-activated protein kinase activity is necessary for the differentiation of 3T3-L1 fibroblasts into adipocytes (Engelman, J. A., Lisanti, M. P., and Scherer, P. E. (1998) J. Biol. Chem. 273, 32111-32120). p38 activity is high during the initial stages of differentiation but decreases drastically as the fibroblasts undergo terminal differentiation into adipocytes. However, it remains unknown whether activation of p38 is sufficient to stimulate adipogenesis and whether the down-regulation of p38 activity in mature adipocytes is critical for maintaining adipocyte homeostasis. In this report, we have directly addressed these questions by analyzing 3T3-L1 cell lines harboring a specific upstream activator of p38 (a constitutively active mitogen-activated protein kinase kinase 6 (MKK6) mutant, MKK6(Glu)) under the control of an inducible promoter. Induction of MKK6(Glu) in 3T3-L1 fibroblasts spurs adipocyte conversion in the absence of the hormonal mixture normally required for efficient differentiation of wild-type cells. However, activation of p38 in adipocytes leads to cell death. Furthermore, treatment of 3T3-L1 fibroblasts with salicylate, a potent stimulator of p38, produces adipocyte-specific changes consistent with those observed with induction of MKK6(Glu). Expression of MKK6(Glu) in NIH-3T3 fibroblasts (cells that do not differentiate into adipocytes under normal conditions) is capable of converting these fibroblasts into lipid-laden fat cells following hormonal stimulation. Thus, p38 activation has pro-adipogenic effects in multiple fibroblast cell lines. 相似文献
66.
67.
68.
69.
Until now, the predominant use cases of industrial robots have been routine handling tasks in the automotive industry. In biotechnology and tissue engineering, in contrast, only very few tasks have been automated with robots. New developments in robot platform and robot sensor technology, however, make it possible to automate plants that largely depend on human interaction with the production process, e.g., for material and cell culture fluid handling, transportation, operation of equipment, and maintenance. In this paper we present a robot system that lends itself to automating routine tasks in biotechnology but also has the potential to automate other production facilities that are similar in process structure. After motivating the design goals, we describe the system and its operation, illustrate sample runs, and give an assessment of the advantages. We conclude this paper by giving an outlook on possible further developments. 相似文献
70.
Roberto?H?Higa Roberto?C?Togawa Arnaldo?J?Montagner Juliana?CF?Palandrani Igor?KS?Okimoto Paula?R?Kuser Michel?EB?Yamagishi Adauto?L?Mancini Goran?NeshichEmail author 《BMC bioinformatics》2004,5(1):107