全文获取类型
收费全文 | 564篇 |
免费 | 69篇 |
国内免费 | 1篇 |
出版年
2021年 | 12篇 |
2020年 | 7篇 |
2019年 | 4篇 |
2018年 | 4篇 |
2017年 | 12篇 |
2016年 | 10篇 |
2015年 | 20篇 |
2014年 | 14篇 |
2013年 | 21篇 |
2012年 | 31篇 |
2011年 | 30篇 |
2010年 | 30篇 |
2009年 | 16篇 |
2008年 | 16篇 |
2007年 | 26篇 |
2006年 | 25篇 |
2005年 | 23篇 |
2004年 | 24篇 |
2003年 | 23篇 |
2002年 | 19篇 |
2001年 | 19篇 |
2000年 | 17篇 |
1999年 | 18篇 |
1998年 | 6篇 |
1997年 | 7篇 |
1996年 | 9篇 |
1995年 | 9篇 |
1994年 | 6篇 |
1993年 | 3篇 |
1992年 | 10篇 |
1991年 | 8篇 |
1990年 | 4篇 |
1989年 | 4篇 |
1988年 | 5篇 |
1987年 | 8篇 |
1986年 | 8篇 |
1985年 | 7篇 |
1983年 | 6篇 |
1982年 | 10篇 |
1980年 | 9篇 |
1979年 | 10篇 |
1978年 | 5篇 |
1977年 | 3篇 |
1976年 | 7篇 |
1975年 | 6篇 |
1974年 | 5篇 |
1973年 | 4篇 |
1972年 | 4篇 |
1971年 | 7篇 |
1970年 | 7篇 |
排序方式: 共有634条查询结果,搜索用时 15 毫秒
51.
52.
Corbett JW Rauckhorst MR Qian F Hoffman RL Knauer CS Fitzgerald LW 《Bioorganic & medicinal chemistry letters》2007,17(22):6250-6256
Low nanomolar corticotropin releasing factor type-1 (CRF(1)) receptor antagonists containing unique indanylamines were identified from the heteroatom-linked pyrazine chemotype. The most potent indanylpyrazine had a K(i)=11+/-1 nM. The oxygen-linked pyrazinyl derivatives were prepared through a copper-catalyzed coupling of a pyridinone to a bromo- or iodopyrazine. 相似文献
53.
Bommarius B Maxwell D Swimm A Leung S Corbett A Bornmann W Kalman D 《Molecular microbiology》2007,63(6):1748-1768
Enteropathogenic Escherichia coli (EPEC) cause intestinal inflammation, severe diarrhoea and mortality, particularly among children in developing nations. Upon attachment to intestinal epithelial cells, EPEC induces actin-filled membrane protrusions called 'pedestals' and disrupts microvilli to form attaching and effacing (A/E) lesions. EPEC also disrupts epithelial barrier function and causes colitis. Here we have investigated how virulence factors which orchestrate formation of actin pedestals interface with host tyrosine kinases. We show that Tec-family tyrosine kinases localize beneath EPEC and, with Abl-family kinases, comprise a set of redundant host kinases utilized by EPEC to form actin pedestals. We also show that Tir, a virulence factor required for pathogenesis, contains a polyproline region (PPR) that interacts with SH3 domains of redundant kinases, and a phosphorylation site (Y474) that interacts with kinase SH2 domains. These interactions are essential for pedestal formation, and mimic activation of kinases by cellular ligands. Our results suggest that a positive feedback loop exists in which initial phosphorylation of Tir on Y474 by tyrosine kinases causes recruitment of additional redundant kinases via PPR-SH3 interactions and PO(3)-Y474-SH2 interactions, which in turn phosphorylate other Tir molecules as well as proteins that catalyse formation of actin pedestals. 相似文献
54.
Katarzyna A. Broniowska Bryndon J. Oleson Jennifer McGraw Aaron Naatz Clayton E. Mathews John A. Corbett 《The Journal of biological chemistry》2015,290(12):7952-7960
Cytokines impair the function and decrease the viability of insulin-producing β-cells by a pathway that requires the expression of inducible nitric oxide synthase (iNOS) and generation of high levels of nitric oxide. In addition to nitric oxide, excessive formation of reactive oxygen species, such as superoxide and hydrogen peroxide, has been shown to cause β-cell damage. Although the reaction of nitric oxide with superoxide results in the formation of peroxynitrite, we have shown that β-cells do not have the capacity to produce this powerful oxidant in response to cytokines. When β-cells are forced to generate peroxynitrite using nitric oxide donors and superoxide-generating redox cycling agents, superoxide scavenges nitric oxide and prevents the inhibitory and destructive actions of nitric oxide on mitochondrial oxidative metabolism and β-cell viability. In this study, we show that the β-cell response to nitric oxide is regulated by the location of superoxide generation. Nitric oxide freely diffuses through cell membranes, and it reacts with superoxide produced within cells and in the extracellular space, generating peroxynitrite. However, only when it is produced within cells does superoxide attenuate nitric oxide-induced mitochondrial dysfunction, gene expression, and toxicity. These findings suggest that the location of radical generation and the site of radical reactions are key determinants in the functional response of β-cells to reactive oxygen species and reactive nitrogen species. Although nitric oxide is freely diffusible, its biological function can be controlled by the local generation of superoxide, such that when this reaction occurs within β-cells, superoxide protects β-cells by scavenging nitric oxide. 相似文献
55.
Francine Z Marques Simon PR Romaine Matthew Denniff James Eales John Dormer Ingrid M Garrelds Lukasz Wojnar Katarzyna Musialik Barbara Duda-Raszewska Bartlomiej Kiszka Magdalena Duda Brian J Morris Nilesh J Samani AH Jan Danser Pawel Bogdanski Ewa Zukowska-Szczechowska Fadi J Charchar Maciej Tomaszewski 《Molecular medicine (Cambridge, Mass.)》2015,21(1):739-748
MicroRNA-181a binds to the 3′ untranslated region of messenger RNA (mRNA) for renin, a rate-limiting enzyme of the renin-angiotensin system. Our objective was to determine whether this molecular interaction translates into a clinically meaningful effect on blood pressure and whether circulating miR-181a is a measurable proxy of blood pressure. In 200 human kidneys from the TRANScriptome of renaL humAn TissuE (TRANSLATE) study, renal miR-181a was the sole negative predictor of renin mRNA and a strong correlate of circulating miR-181a. Elevated miR-181a levels correlated positively with systolic and diastolic blood pressure in TRANSLATE, and this association was independent of circulating renin. The association between serum miR-181a and systolic blood pressure was replicated in 199 subjects from the Genetic Regulation of Arterial Pressure of Humans In the Community (GRAPHIC) study. Renal immunohistochemistry and in situ hybridization showed that colocalization of miR-181a and renin was most prominent in collecting ducts where renin is not released into the systemic circulation. Analysis of 69 human kidneys characterized by RNA sequencing revealed that miR-181a was associated with downregulation of four mitochondrial pathways and upregulation of 41 signaling cascades of adaptive immunity and inflammation. We conclude that renal miR-181a has pleiotropic effects on pathways relevant to blood pressure regulation and that circulating levels of miR-181a are both a measurable proxy of renal miR-181a expression and a novel biochemical correlate of blood pressure. 相似文献
56.
Nick R Love Yaoyao Chen Boyan Bonev Michael J Gilchrist Lynne Fairclough Robert Lea Timothy J Mohun Roberto Paredes Leo AH Zeef Enrique Amaya 《BMC developmental biology》2011,11(1):1-15
Background
During liver development, intrahepatic bile ducts are thought to arise by a unique asymmetric mode of cholangiocyte tubulogenesis characterized by a series of remodeling stages. Moreover, in liver diseases, cells lining the Canals of Hering can proliferate and generate new hepatic tissue. The aim of this study was to develop protocols for three-dimensional visualization of protein expression, hepatic portal structures and human hepatic cholangiocyte tubulogenesis.Results
Protocols were developed to digitally visualize portal vessel branching and protein expression of hepatic cell lineage and extracellular matrix deposition markers in three dimensions. Samples from human prenatal livers ranging from 7 weeks + 2 days to 15½ weeks post conception as well as adult normal and acetaminophen intoxicated liver were used. The markers included cytokeratins (CK) 7 and 19, the epithelial cell adhesion molecule (EpCAM), hepatocyte paraffin 1 (HepPar1), sex determining region Y (SRY)-box 9 (SOX9), laminin, nestin, and aquaporin 1 (AQP1). Digital three-dimensional reconstructions using CK19 as a single marker protein disclosed a fine network of CK19 positive cells in the biliary tree in normal liver and in the extensive ductular reactions originating from intrahepatic bile ducts and branching into the parenchyma of the acetaminophen intoxicated liver. In the developing human liver, three-dimensional reconstructions using multiple marker proteins confirmed that the human intrahepatic biliary tree forms through several developmental stages involving an initial transition of primitive hepatocytes into cholangiocytes shaping the ductal plate followed by a process of maturation and remodeling where the intrahepatic biliary tree develops through an asymmetrical form of cholangiocyte tubulogenesis.Conclusions
The developed protocols provide a novel and sophisticated three-dimensional visualization of vessels and protein expression in human liver during development and disease. 相似文献57.
Respiratory syncytial virus (RSV) causes recurrent infections throughout life. Vaccine development may depend upon understanding the molecular basis for induction of ineffective immunity. Because dendritic cells (DCs) are critically involved in early responses to infection, their interaction with RSV may determine the immunological outcome of RSV infection. Therefore, we investigated the ability of RSV to infect and activate primary mDCs and pDCs using recombinant RSV expressing green fluorescent protein (GFP). At a multiplicity of infection of 5, initial studies demonstrated ~6.8% of mDC1 and ~0.9% pDCs were infected. We extended these studies to include CD1c(-)CD141(+) mDC2, finding mDC2 infected at similar frequencies as mDC1. Both infected and uninfected cells upregulated phenotypic markers of maturation. Divalent cations were required for infection and maturation, but maturation did not require viral replication. There is evidence that attachment and entry/replication processes exert distinct effects on DC activation. Cell-specific patterns of RSV-induced maturation and cytokine production were detected in mDC1, mDC2, and pDC. We also demonstrate for the first time that RSV induces significant TIMP-2 production in all DC subsets. Defining the influence of RSV on the function of selected DC subsets may improve the likelihood of achieving protective vaccine-induced immunity. 相似文献
58.
Background
Autism is a neurodevelopmental disorder characterized by impairments in social behavior, communication difficulties and the occurrence of repetitive or stereotyped behaviors. There has been substantial evidence for dysregulation of the immune system in autism.Methods
We evaluated differences in the number and phenotype of circulating blood cells in young children with autism (n = 70) compared with age-matched controls (n = 35). Children with a confirmed diagnosis of autism (4–6 years of age) were further subdivided into low (IQ<68, n = 35) or high functioning (IQ≥68, n = 35) groups. Age- and gender-matched typically developing children constituted the control group. Six hundred and forty four primary and secondary variables, including cell counts and the abundance of cell surface antigens, were assessed using microvolume laser scanning cytometry.Results
There were multiple differences in immune cell populations between the autism and control groups. The absolute number of B cells per volume of blood was over 20% higher for children with autism and the absolute number of NK cells was about 40% higher. Neither of these variables showed significant difference between the low and high functioning autism groups. While the absolute number of T cells was not different across groups, a number of cellular activation markers, including HLA-DR and CD26 on T cells, and CD38 on B cells, were significantly higher in the autism group compared to controls.Conclusions
These results support previous findings that immune dysfunction may occur in some children with autism. Further evaluation of the nature of the dysfunction and how it may play a role in the etiology of autism or in facets of autism neuropathology and/or behavior are needed. 相似文献59.
Burgess KL Corbett MS Eugenio P Lajkiewicz NJ Liu X Sanyal A Yan W Yuan Q Snyder JK 《Bioorganic & medicinal chemistry》2005,13(17):5299-5309
The development of chiral anthracene templates for use in Diels-Alder/retro Diels-Alder sequences is described. A summary of past results and new progress is reported. 相似文献
60.
Corbett DF Heightman TD Moss SF Bromidge SM Coggon SA Longley MJ Roa AM Williams JA Thomas DR 《Bioorganic & medicinal chemistry letters》2005,15(18):4014-4018
High-throughput screening of an array of biphenylmethylamines synthesised by high-throughput solid-phase chemistry resulted in the identification of compounds with high-affinity for the 5-ht5A receptor. The structure-activity relationship within this series and further array synthesis led to the identification of the biphenylmethylamine derivative 11, a potent and selective 5-ht5A receptor antagonist. 相似文献