全文获取类型
收费全文 | 239篇 |
免费 | 3篇 |
专业分类
系统科学 | 3篇 |
教育与普及 | 1篇 |
理论与方法论 | 1篇 |
现状及发展 | 48篇 |
研究方法 | 52篇 |
综合类 | 136篇 |
自然研究 | 1篇 |
出版年
2021年 | 2篇 |
2018年 | 8篇 |
2017年 | 6篇 |
2016年 | 5篇 |
2015年 | 3篇 |
2014年 | 9篇 |
2013年 | 6篇 |
2012年 | 30篇 |
2011年 | 26篇 |
2010年 | 10篇 |
2009年 | 3篇 |
2008年 | 20篇 |
2007年 | 13篇 |
2006年 | 28篇 |
2005年 | 25篇 |
2004年 | 18篇 |
2003年 | 14篇 |
2002年 | 9篇 |
1999年 | 1篇 |
1990年 | 1篇 |
1982年 | 1篇 |
1978年 | 1篇 |
1976年 | 1篇 |
1969年 | 1篇 |
1967年 | 1篇 |
排序方式: 共有242条查询结果,搜索用时 31 毫秒
61.
Tommy Baumann Urs Kämpfer Stefan Schürch Johann Schaller Carlo Largiadèr Wolfgang Nentwig Lucia Kuhn-Nentwig 《Cellular and molecular life sciences : CMLS》2010,67(16):2787-2798
Three novel glycine-rich peptides, named ctenidin 1–3, with activity against the Gram-negative bacterium E. coli, were isolated and characterized from hemocytes of the spider Cupiennius salei. Ctenidins have a high glycine content (>70%), similarly to other glycine-rich peptides, the acanthoscurrins, from another spider, Acanthoscurria gomesiana. A combination of mass spectrometry, Edman degradation, and cDNA cloning revealed the presence of three isoforms of ctenidin, at least two of them originating from simple, intronless genes. The full-length sequences of the ctenidins consist of a 19 amino acid residues signal peptide followed by the mature peptides of 109, 119, or 120 amino acid residues. The mature peptides are post-translationally modified by the cleavage of one or two C-terminal cationic amino acid residue(s) and amidation of the newly created mature C-terminus. Tissue expression analysis revealed that ctenidins are constitutively expressed in hemocytes and to a small extent also in the subesophageal nerve mass. 相似文献
62.
Alexandr V. Bazhin Vojtech Tambor Boyan Dikov Pavel P. Philippov Dirk Schadendorf Stefan B. Eichmüller 《Cellular and molecular life sciences : CMLS》2010,67(5):817-828
Malignant melanoma is one of the most aggressive human neoplasms which develop from the malignant transformation of normal
epithelial melanocytes and share the lineage with retinal cells. cGMP-phosphodiesterase 6 (PDE6) is one of the cancer-retina
antigens newly identified in melanoma cells. Normally, PDE6 hydrolyzes the photoreceptor second messenger cGMP allowing the
visual signal transduction in photoreceptor cells. cGMP also play an important signaling role in stimulating melanogenesis
in human melanocytes. Here, we present evidence that PDE6 is a key enzyme regulating the cGMP metabolism in melanoma cells.
Decrease in intracellular cGMP leads to calcium accumulation in melanoma cells. In these cells, cGMP-phosphodiesterase 6 can
be activated by another cancer-retina antigen, transducin, through Wnt5a–Frizzled-2 cascade, which leads to a lowering of
cGMP and an increase in intracellular calcium mobilization. Thus, the aberrant expression of PDE6 may control cGMP metabolism
and calcium homeostasis in melanoma cells. 相似文献
63.
Ellinghaus E Ellinghaus D Stuart PE Nair RP Debrus S Raelson JV Belouchi M Fournier H Reinhard C Ding J Li Y Tejasvi T Gudjonsson J Stoll SW Voorhees JJ Lambert S Weidinger S Eberlein B Kunz M Rahman P Gladman DD Gieger C Wichmann HE Karlsen TH Mayr G Albrecht M Kabelitz D Mrowietz U Abecasis GR Elder JT Schreiber S Weichenthal M Franke A 《Nature genetics》2010,42(11):991-995
64.
Speliotes EK Willer CJ Berndt SI Monda KL Thorleifsson G Jackson AU Lango Allen H Lindgren CM Luan J Mägi R Randall JC Vedantam S Winkler TW Qi L Workalemahu T Heid IM Steinthorsdottir V Stringham HM Weedon MN Wheeler E Wood AR Ferreira T Weyant RJ Segrè AV Estrada K Liang L Nemesh J Park JH Gustafsson S Kilpeläinen TO Yang J Bouatia-Naji N Esko T Feitosa MF Kutalik Z Mangino M Raychaudhuri S Scherag A Smith AV Welch R Zhao JH Aben KK Absher DM Amin N Dixon AL Fisher E Glazer NL Goddard ME 《Nature genetics》2010,42(11):937-948
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10??), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation. 相似文献
65.
Tamara Jefferson Ulrich auf dem Keller Caroline Bellac Verena V. Metz Claudia Broder Jana Hedrich Anke Ohler Wladislaw Maier Viktor Magdolen Erwin Sterchi Judith S. Bond Arumugam Jayakumar Heiko Traupe Athena Chalaris Stefan Rose-John Claus U. Pietrzik Rolf Postina Christopher M. Overall Christoph Becker-Pauly 《Cellular and molecular life sciences : CMLS》2013,70(2):309-333
The in vivo roles of meprin metalloproteases in pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human meprin α and β we employed TAILS (terminal amine isotopic labeling of substrates), a proteomics approach that enriches for N-terminal peptides of proteins and cleavage fragments. Of the 151 new extracellular substrates we identified, it was notable that ADAM10 (a disintegrin and metalloprotease domain-containing protein 10)—the constitutive α-secretase—is activated by meprin β through cleavage of the propeptide. To validate this cleavage event, we expressed recombinant proADAM10 and after preincubation with meprin β, this resulted in significantly elevated ADAM10 activity. Cellular expression in murine primary fibroblasts confirmed activation. Other novel substrates including extracellular matrix proteins, growth factors and inhibitors were validated by western analyses and enzyme activity assays with Edman sequencing confirming the exact cleavage sites identified by TAILS. Cleavages in vivo were confirmed by comparing wild-type and meprin?/? mice. Our finding of cystatin C, elafin and fetuin-A as substrates and natural inhibitors for meprins reveal new mechanisms in the regulation of protease activity important for understanding pathophysiological processes. 相似文献
66.
Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction 总被引:9,自引:0,他引:9
Raeder H Johansson S Holm PI Haldorsen IS Mas E Sbarra V Nermoen I Eide SA Grevle L Bjørkhaug L Sagen JV Aksnes L Søvik O Lombardo D Molven A Njølstad PR 《Nature genetics》2006,38(1):54-62
Dysfunction of the exocrine pancreas is observed in diabetes, but links between concurrent exocrine and endocrine pancreatic disease and contributing genetic factors are poorly characterized. We studied two families with diabetes and exocrine pancreatic dysfunction by genetic, physiological and in vitro functional studies. A genome-wide screen in Family 1 linked diabetes to chromosome 9q34 (maximal lod score 5.07). Using fecal elastase deficiency as a marker of exocrine pancreatic dysfunction refined the critical chromosomal region to 1.16 Mb (maximal lod score 11.6). Here, we identified a single-base deletion in the variable number of tandem repeats (VNTR)-containing exon 11 of the carboxyl ester lipase (CEL) gene, a major component of pancreatic juice and responsible for the duodenal hydrolysis of cholesterol esters. Screening subjects with maturity-onset diabetes of the young identified Family 2, with another single-base deletion in CEL and a similar phenotype with beta-cell failure and pancreatic exocrine disease. The in vitro catalytic activities of wild-type and mutant CEL protein were comparable. The mutant enzyme was, however, less stable and secreted at a lower rate. Furthermore, we found some evidence for an association between common insertions in the CEL VNTR and exocrine dysfunction in a group of 182 unrelated subjects with diabetes (odds ratio 4.2 (1.6, 11.5)). Our findings link diabetes to the disrupted function of a lipase in the pancreatic acinar cells. 相似文献
67.
68.
Helgadottir A Manolescu A Helgason A Thorleifsson G Thorsteinsdottir U Gudbjartsson DF Gretarsdottir S Magnusson KP Gudmundsson G Hicks A Jonsson T Grant SF Sainz J O'Brien SJ Sveinbjornsdottir S Valdimarsson EM Matthiasson SE Levey AI Abramson JL Reilly MP Vaccarino V Wolfe ML Gudnason V Quyyumi AA Topol EJ Rader DJ Thorgeirsson G Gulcher JR Hakonarson H Kong A Stefansson K 《Nature genetics》2006,38(1):68-74
Variants of the gene ALOX5AP (also known as FLAP) encoding arachidonate 5-lipoxygenase activating protein are known to be associated with risk of myocardial infarction. Here we show that a haplotype (HapK) spanning the LTA4H gene encoding leukotriene A4 hydrolase, a protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggest that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also show that HapK confers a modest relative risk (1.16) in European Americans, but it confers a threefold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Our analyses indicate that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group. 相似文献
69.
Müller M Mazur AJ Behrmann E Diensthuber RP Radke MB Qu Z Littwitz C Raunser S Schoenenberger CA Manstein DJ Mannherz HG 《Cellular and molecular life sciences : CMLS》2012,69(20):3457-3479
Inherited cardiomyopathies are caused by point mutations in sarcomeric gene products, including α-cardiac muscle actin (ACTC1). We examined the biochemical and cell biological properties of the α-cardiac actin mutations Y166C and M305L identified in hypertrophic cardiomyopathy (HCM). Untagged wild-type (WT) cardiac actin, and the Y166C and M305L mutants were expressed by the baculovirus/Sf9-cell system and affinity purified by immobilized gelsolin G4-6. Their correct folding was verified by a number of assays. The mutant actins also displayed a disturbed intrinsic ATPase activity and an altered polymerization behavior in the presence of tropomyosin, gelsolin, and Arp2/3 complex. Both mutants stimulated the cardiac β-myosin ATPase to only 50?% of WT cardiac F-actin. Copolymers of WT and increasing amounts of the mutant actins led to a reduced stimulation of the myosin ATPase. Transfection of established cell lines revealed incorporation of EGFP- and hemagglutinin (HA)-tagged WT and both mutant actins into cytoplasmic stress fibers. Adenoviral vectors of HA-tagged WT and Y166C actin were successfully used to infect adult and neonatal rat cardiomyocytes (NRCs). The expressed HA-tagged actins were incorporated into the minus-ends of NRC thin filaments, demonstrating the ability to form hybrid thin filaments with endogenous actin. In NRCs, the Y166C mutant led after 72?h to a shortening of the sarcomere length when compared to NRCs infected with WT actin. Thus our data demonstrate that a mutant actin can be integrated into cardiomyocyte thin filaments and by its reduced mode of myosin interaction might be the basis for the initiation of HCM. 相似文献
70.
Comas I Borrell S Roetzer A Rose G Malla B Kato-Maeda M Galagan J Niemann S Gagneux S 《Nature genetics》2012,44(1):106-110
Epidemics of drug-resistant bacteria emerge worldwide, even as resistant strains frequently have reduced fitness compared to their drug-susceptible counterparts. Data from model systems suggest that the fitness cost of antimicrobial resistance can be reduced by compensatory mutations; however, there is limited evidence that compensatory evolution has any significant role in the success of drug-resistant bacteria in human populations. Here we describe a set of compensatory mutations in the RNA polymerase genes of rifampicin-resistant M. tuberculosis, the etiologic agent of human tuberculosis (TB). M. tuberculosis strains harboring these compensatory mutations showed a high competitive fitness in vitro. Moreover, these mutations were associated with high fitness in vivo, as determined by examining their relative clinical frequency across patient populations. Of note, in countries with the world's highest incidence of multidrug-resistant (MDR) TB, more than 30% of MDR clinical isolates had this form of mutation. Our findings support a role for compensatory evolution in the global epidemics of MDR TB. 相似文献