全文获取类型
收费全文 | 1546篇 |
免费 | 140篇 |
国内免费 | 1篇 |
专业分类
1687篇 |
出版年
2024年 | 2篇 |
2023年 | 15篇 |
2022年 | 35篇 |
2021年 | 74篇 |
2020年 | 36篇 |
2019年 | 43篇 |
2018年 | 61篇 |
2017年 | 26篇 |
2016年 | 66篇 |
2015年 | 89篇 |
2014年 | 116篇 |
2013年 | 109篇 |
2012年 | 123篇 |
2011年 | 145篇 |
2010年 | 82篇 |
2009年 | 73篇 |
2008年 | 82篇 |
2007年 | 79篇 |
2006年 | 77篇 |
2005年 | 56篇 |
2004年 | 54篇 |
2003年 | 59篇 |
2002年 | 45篇 |
2001年 | 12篇 |
2000年 | 9篇 |
1999年 | 10篇 |
1998年 | 7篇 |
1997年 | 7篇 |
1996年 | 9篇 |
1995年 | 5篇 |
1994年 | 10篇 |
1993年 | 4篇 |
1992年 | 3篇 |
1991年 | 4篇 |
1989年 | 2篇 |
1988年 | 3篇 |
1984年 | 3篇 |
1983年 | 4篇 |
1982年 | 7篇 |
1980年 | 2篇 |
1979年 | 3篇 |
1978年 | 2篇 |
1976年 | 4篇 |
1974年 | 3篇 |
1972年 | 2篇 |
1967年 | 2篇 |
1943年 | 2篇 |
1926年 | 2篇 |
1902年 | 2篇 |
1862年 | 1篇 |
排序方式: 共有1687条查询结果,搜索用时 15 毫秒
81.
Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60 总被引:20,自引:0,他引:20 下载免费PDF全文
Hansen JJ Dürr A Cournu-Rebeix I Georgopoulos C Ang D Nielsen MN Davoine CS Brice A Fontaine B Gregersen N Bross P 《American journal of human genetics》2002,70(5):1328-1332
SPG13, an autosomal dominant form of pure hereditary spastic paraplegia, was recently mapped to chromosome 2q24-34 in a French family. Here we present genetic data indicating that SPG13 is associated with a mutation, in the gene encoding the human mitochondrial chaperonin Hsp60, that results in the V72I substitution. A complementation assay showed that wild-type HSP60 (also known as "HSPD1"), but not HSP60 (V72I), together with the co-chaperonin HSP10 (also known as "HSPE1"), can support growth of Escherichia coli cells in which the homologous chromosomal groESgroEL chaperonin genes have been deleted. Taken together, our data strongly indicate that the V72I variation is the first disease-causing mutation that has been identified in HSP60. 相似文献
82.
Engrailed homeoprotein secretion is a regulated process 总被引:4,自引:0,他引:4
Maizel A Tassetto M Filhol O Cochet C Prochiantz A Joliot A 《Development (Cambridge, England)》2002,129(15):3545-3553
Chicken Engrailed 2 homeoprotein is transported between cells in culture. This intercellular transfer is based on unconventional secretion and internalisation mechanisms: Engrailed 2 has access to vesicles but lacks a signal sequence for secretion and is internalised by a non-endocytic process. We show that phosphorylation of a serine-rich domain within Engrailed 2 by the protein kinase CK2 specifically inhibits Engrailed 2 secretion. The availability of the serine-rich domain to CK2 is highly increased when it is displaced from its normal position to the C terminus of Engrailed 2, leading to a constitutive blockage of Engrailed 2 intercellular transfer. This indicates that intercellular transfer of Engrailed 2 is a highly regulated process. 相似文献
83.
Loughrey Chen S Huddleston MJ Shou W Deshaies RJ Annan RS Carr SA 《Molecular & cellular proteomics : MCP》2002,1(3):186-196
Prior to anaphase in Saccharomyces cerevisiae, Cdc14 protein phosphatase is sequestered within the nucleolus and inhibited by Net1, a component of the RENT complex in budding yeast. During anaphase the RENT complex disassembles, allowing Cdc14 to migrate to the nucleus and cytoplasm where it catalyzes exit from mitosis. The mechanism of Cdc14 release appears to involve the polo-like kinase Cdc5, which is capable of promoting the dissociation of a recombinant Net1.Cdc14 complex in vitro by phosphorylation of Net1. We report here the phosphorylation site mapping of recombinant Net1 (Net1N) and a mutant Net1N allele (Net1N-19m) with 19 serines or threonines mutated to alanine. A variety of chromatographic and mass spectrometric-based strategies were used, including immobilized metal-affinity chromatography, alkaline phosphatase treatment, matrix-assisted laser-desorption post-source decay, and a multidimensional electrospray mass spectrometry-based approach. No one approach was able to identify all phosphopeptides in the tryptic digests of these proteins. Most notably, the presence of a basic residue near the phosphorylated residue significantly hampered the ability of alkaline phosphatase to hydrolyze the phosphate moiety. A major goal of research in proteomics is to identify all proteins and their interactions and post-translational modification states. The failure of any single method to identify all sites in highly phosphorylated Net1N, however, raises significant concerns about how feasible it is to map phosphorylation sites throughout the proteome using existing technologies. 相似文献
84.
Semel AC Seales EC Singhal A Eklund EA Colley KJ Bellis SL 《The Journal of biological chemistry》2002,277(36):32830-32836
Despite numerous reports suggesting that beta(1) integrin receptors undergo differential glycosylation, the potential role of N-linked carbohydrates in modulating integrin function has been largely ignored. In the present study, we find that beta(1) integrins are differentially glycosylated during phorbol ester (PMA)-stimulated differentiation of myeloid cells along the monocyte/macrophage lineage. PMA treatment of two myeloid cell lines, U937 and THP-1, induces a down-regulation in expression of the ST6Gal I sialyltransferase. Correspondingly, the beta(1) integrin subunit becomes hyposialylated, suggesting that the beta(1) integrin is a substrate for this enzyme. The expression of hyposialylated beta(1) integrin isoforms is temporally correlated with enhanced binding of myeloid cells to fibronectin, and, importantly, fibronectin binding is inhibited when the Golgi disrupter, brefeldin A, is used to block the expression of the hyposialylated form. Consistent with the observation that cells with hyposialylated integrins are more adhesive to fibronectin, we demonstrate that the enzymatic removal of sialic acid residues from purified alpha(5)beta(1) integrins stimulates fibronectin binding by these integrins. These data support the hypothesis that unsialylated beta(1) integrins are more adhesive to fibronectin, although desialylation of alpha(5) subunits could also contribute to increased fibronectin binding. Collectively our results suggest a novel mechanism for regulation of the beta(1) integrin family of cell adhesion receptors. 相似文献
85.
Parkinson's disease is characterized by the progressive and selective loss of the dopaminergic neurons in the substantia nigra and the presence of ubiquitinated protein inclusions termed Lewy bodies. In the past six years, four genes involved in rare inherited forms of Parkinson's disease have been identified: mutations in the alpha-synuclein and ubiquitin carboxyterminal hydrolase L1 genes (UCH-L1) cause autosomal dominant forms, whereas mutations in the Parkin and DJ-1 genes are responsible for autosomal recessive forms of the disease. A toxic gain of function related to the ability of alpha-synuclein to assemble into insoluble amyloid fibrils may underlie neuronal cell death in parkinsonism due to alpha-synuclein gene mutations. In contrast, loss of protein function appears to be the cause of the disease in parkinsonism due to mutations in the genes encoding Parkin and UCH-L1, which are key enzymes of the ubiquitin-proteasome pathway. The presence of alpha-synuclein, Parkin and UCH-L1 in Lewy bodies suggests that dysfunction of pathways involved in protein folding and degradation is not only involved in the pathogenesis of familial Parkinson's disease, but could also play a role in the frequent sporadic form of the disease (idiopathic Parkinson's disease). 相似文献
86.
Komninou D Ayonote A Richie JP Rigas B 《Experimental biology and medicine (Maywood, N.J.)》2003,228(4):396-405
The insulin resistance-colon cancer hypothesis, stating that insulin resistance may be associated with the development of colorectal cancer, represents a significant advance in colon cancer, as it emphasizes the potential for this cancer to become a modifiable disease. The fact that the incidence of insulin resistance has been increasing in the United States and much of the rest of the Western world where colon cancer remains the second leading cause of cancer death makes the exploration of the interrelationship of these conditions a subject of high priority. Here, we review the salient features of insulin resistance, defined as impaired biological response to the action of insulin. Recent epidemiological studies, evaluating potential associations between colon cancer risk and diabetes mellitus, dietary intake and metabolic factors, and IGF levels in several clinical settings, provide strong support of the insulin resistance-colon cancer hypothesis (without establishing causality). Mechanistically, insulin resistance has been associated with hyperinsulinemia, increased levels of growth factors including IGF-1, and alterations in NF-kappaB and peroxisome proliferator-activated receptor signaling, which may promote colon cancer through their effects on colonocyte kinetics. It is a reasonable expectation that in the not too distant future, critical interventions to the already mapped molecular sequence of events, which link two apparently disparate entities, combined with lifestyle changes could abrogate the development of colon cancer. 相似文献
87.
Edwin Ochong Alexis Nzila Serah Kimani Gilbert Kokwaro Theonest Mutabingwa William Watkins Kevin Marsh 《Malaria journal》2003,2(1):1-3
Background
Procalcitonin (PCT) is closely correlated with parasite burden and clinical outcome in falciparum malaria. The role of PCT in tertian malaria has not previously been investigated.Patients and methods
PCT serum levels in 37 patients with tertian malaria were analysed. Clinical and laboratory parameters were assessed and statistically correlated both to the initial PCT levels and during the course of the disease.Results
PCT levels rose for one day after commencing treatment and declined thereafter. However, there was no significant correlation with parasite burden, clinical parameters, laboratory values, or the presence of semi-immunity. Before treatment, the majority of patients showed normal or slightly elevated PCT levels (< 2.5 ng/ml), but PCT was markedly elevated (4.8 – 47 ng/ml) in one third of the population. The two groups did not differ by any other of the assessed parameters. Thus, while the post-treatment course of PCT resembles falciparum malaria, the lack of correlation between disease severity and even high PCT levels in a large proportion of patients is intriguing.Conclusions
There is a fundamental difference in the relationship of PCT with tertian malaria not seen in other infectious diseases in which elevated PCT levels have been observed. This suggests distinct pathophysiological pathways in malaria. 相似文献88.
The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP and cGMP-regulated chloride channel critical to the regulation of intestinal fluid, chloride, and bicarbonate secretion. In cystic fibrosis (CF), mutations in CFTR result in downregulation of CFTR function and small intestinal obstruction. Unlike the human CF intestine, severe gastrointestinal disease and lethal obstruction is common in transgenic mice deficient in CFTR. The relevance of the physiology of CFTR and pathophysiology of CF in genetically altered mice to that of human CF disease remains incompletely understood. We hypothesized that the expression and distribution of CFTR in mouse intestine may differ from that of human and may contribute to the variation in disease expression between the two species. Using immunocytochemical and immunoblot techniques and well-characterized anti-rodent anti-CFTR antibodies, we examined the cellular distribution of CFTR in the mouse intestinal tract. We identified significant differences in villus distribution for CFTR in the mouse proximal small intestine compared to those previously reported for human and rat. These observations are important to the understanding of CFTR pathophysiology in transgenic CF mouse model systems and bear relevance to the different phenotypic expression of disease in mice compared to human. 相似文献
89.
90.
Association between a school‐based intervention and adiposity outcomes in adolescents: The Italian “EAT” project 下载免费PDF全文