全文获取类型
收费全文 | 214篇 |
免费 | 6篇 |
专业分类
220篇 |
出版年
2022年 | 3篇 |
2021年 | 3篇 |
2020年 | 3篇 |
2019年 | 3篇 |
2018年 | 2篇 |
2017年 | 2篇 |
2016年 | 7篇 |
2015年 | 8篇 |
2014年 | 11篇 |
2013年 | 15篇 |
2012年 | 13篇 |
2011年 | 15篇 |
2010年 | 11篇 |
2009年 | 9篇 |
2008年 | 13篇 |
2007年 | 10篇 |
2006年 | 8篇 |
2005年 | 9篇 |
2004年 | 6篇 |
2003年 | 6篇 |
2000年 | 7篇 |
1999年 | 4篇 |
1998年 | 6篇 |
1997年 | 2篇 |
1996年 | 1篇 |
1995年 | 3篇 |
1993年 | 1篇 |
1991年 | 3篇 |
1989年 | 2篇 |
1988年 | 3篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 1篇 |
1984年 | 2篇 |
1982年 | 1篇 |
1981年 | 2篇 |
1980年 | 1篇 |
1978年 | 1篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1973年 | 1篇 |
1972年 | 4篇 |
1971年 | 1篇 |
1970年 | 1篇 |
1969年 | 2篇 |
1967年 | 1篇 |
1958年 | 1篇 |
1957年 | 1篇 |
1955年 | 1篇 |
1939年 | 1篇 |
排序方式: 共有220条查询结果,搜索用时 15 毫秒
61.
62.
Mark S. Plummer Joseph Cornicelli Howard Roark Donald J. Skalitzky Charles J. Stankovic Susan Bove Jayvardhan Pandit Annise Goodman James Hicks Aurash Shahripour David Beidler Xiao Kang Lu Brian Sanchez Christopher Whitehead Ron Sarver Timothy Braden Richard Gowan Xi Qiang Shen Sandra Lightle 《Bioorganic & medicinal chemistry letters》2013,23(11):3438-3442
We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of PDE4 inhibitors, while simultaneously minimizing PDE4 activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like mode in contrast to the cAMP-like binding mode found in PDE4. Structure activity relationship studies coupled with an inhibitor bound crystal structure in the active site of the catalytic domain of PDE2 identified structural features required to minimize PDE4 inhibition while simultaneously maximizing PDE2 inhibition. 相似文献
63.
Susan M. Samuel Luz Palacios-Derflingher Marcello Tonelli Braden Manns Lynden Crowshoe Sofia B. Ahmed Min Jun Nathalie Saad Brenda R. Hemmelgarn 《CMAJ》2014,186(2):E86-E94
Background:
Despite a low prevalence of chronic kidney disease (estimated glomerular filtration rate [GFR] < 60 mL/min per 1.73 m2), First Nations people have high rates of kidney failure requiring chronic dialysis or kidney transplantation. We sought to examine whether the presence and severity of albuminuria contributes to the progression of chronic kidney disease to kidney failure among First Nations people.Methods:
We identified all adult residents of Alberta (age ≥ 18 yr) for whom an outpatient serum creatinine measurement was available from May 1, 2002, to Mar. 31, 2008. We determined albuminuria using urine dipsticks and categorized results as normal (i.e., no albuminuria), mild, heavy or unmeasured. Our primary outcome was progression to kidney failure (defined as the need for chronic dialysis or kidney transplantation, or a sustained doubling of serum creatinine levels). We calculated rates of progression to kidney failure by First Nations status, by estimated GFR and by albuminuria category. We determined the relative hazard of progression to kidney failure for First Nations compared with non–First Nations participants by level of albuminuria and estimated GFR.Results:
Of the 1 816 824 participants we identified, 48 669 (2.7%) were First Nations. First Nations people were less likely to have normal albuminuria compared with non–First Nations people (38.7% v. 56.4%). Rates of progression to kidney failure were consistently 2- to 3-fold higher among First Nations people than among non–First Nations people, across all levels of albuminuria and estimated GFRs. Compared with non–First Nations people, First Nations people with an estimated GFR of 15.0–29.9 mL/min per 1.73 m2 had the highest risk of progression to kidney failure, with similar hazard ratios for those with normal and heavy albuminuria.Interpretation:
Albuminuria confers a similar risk of progression to kidney failure for First Nations and non–First Nations people.Severe chronic kidney disease (estimated glomerular filtration rate [GFR] < 30 mL/min per 1.73 m2) is almost 2-fold higher, and rates of end-stage kidney disease (defined as the need for chronic dialysis or kidney transplantation) are 4-fold higher, among First Nations people compared with non–First Nations people in Canada.1,2 The reasons for the higher rate of end-stage kidney disease when there is a lower prevalence of earlier stages of chronic kidney disease in First Nations people (estimated GFR 30–60 mL/min per 1.73 m2) are unclear. The rising incidence of diabetes is seen as the major cause of kidney failure among First Nations people;3 however, First Nations people without diabetes are also 2–3 times more likely to eventually have kidney failure.4 These observations suggest that diabetes is not the sole determinant of risk for kidney failure and that there are yet undefined factors that may accelerate the progression of chronic kidney disease in the First Nations population.5Recent studies have highlighted the prognostic importance of albuminuria as a risk factor for kidney failure.6 Although ethnic variations in the prevalence and severity of albuminuria and their association with renal outcomes have been reported, these studies are primarily limited to non–First Nations populations.7 A limited number of studies have reported an increased prevalence of albuminuria among First Nations people, suggesting the potential association between albuminuria and risk of kidney failure.8,9 We sought to measure the presence and severity of albuminuria and estimate the risk of progression to kidney failure for First Nations people compared with non–First Nations people using a community-based cohort. 相似文献64.
Klinke S Zylberman V Bonomi HR Haase I Guimarães BG Braden BC Bacher A Fischer M Goldbaum FA 《Journal of molecular biology》2007,373(3):664-680
6,7-Dimethyl-8-ribityllumazine synthase (lumazine synthase; LS) catalyzes the penultimate step in the biosynthesis of riboflavin in plants and microorganisms. This protein is known to exhibit different quaternary assemblies between species, existing as free pentamers, decamers (dimers of pentamers) and icosahedrally arranged dodecamers of pentamers. A phylogenetic analysis on eubacterial, fungal and plant LSs allowed us to classify them into two categories: Type I LSs (pentameric or icosahedral) and Type II LSs (decameric). The Rhizobiales represent an order of alpha-proteobacteria that includes, among others, the genera Mesorhizobium, Agrobacterium and Brucella. Here, we present structural and kinetic studies on several LSs from Rhizobiales. Interestingly, Mesorhizobium and Brucella encode both a Type-I LS and a Type-II LS called RibH1 and RibH2, respectively. We show that Type II LSs appear to be almost inactive, whereas Type I LSs present a highly variable catalytic activity according to the genus. Additionally, we have solved four RibH1/RibH2 crystallographic structures from the genera Mesorhizobium and Brucella. The relationship between the active-site architecture and catalytic properties in these isoenzymes is discussed, and a model that describes the enzymatic behavior is proposed. Furthermore, sequence alignment studies allowed us to extend our results to the genus Agrobacterium. Our results suggest that the selective pressure controlling the riboflavin pathway favored the evolution of catalysts with low reaction rates, since the excess of flavins in the intracellular pool in Rhizobiales could act as a negative factor when these bacteria are exposed to oxidative or nitrosative stress. 相似文献
65.
Abrecht Mira Peinemann Viktor Nunes Yazaryan Ara Kevork Kestler Madeline DeMattei Braden Charles Hà Benjamin A. Ryznar Emily Jacobs David K. 《Coral reefs (Online)》2022,41(1):199-212
Coral Reefs - Rhodolith distribution, morphology, and cryptofauna have been minimally studied on fringing reefs. We present the first study to examine both rhodolith distribution and associated... 相似文献
66.
Braden TD 《Biology of reproduction》2012,87(1):21, 1-21, 2
67.
68.
MR Scrochi CN Zanuzzi N Fuentealba F Nishida ME Bravi ME Pacheco 《Biotechnic & histochemistry》2017,92(8):560-568
Many viruses alter different stages of apoptosis of infected cells as a strategy for successful infection. Few studies have addressed mechanisms of equine herpesvirus 1 (EHV-1) strain-induced cell death. We investigated the effect of an abortigenic strain (AR8 strain) on heterologous Madin–Darby bovine kidney cells and homologous equine dermis (ED) cells cell lines. We compared morphologic and biochemical features of early and late apoptosis at different postinfection times. We investigated translocation of phosphatidylserine to the cell surface, nuclear fragmentation and changes in the cytoskeleton using flow cytometry and annexin V/propidium iodide staining, DNA laddering, terminal deoxynucleotidyl transferase UTP nick-end labeling assay and immunofluorescence staining of cytokeratin 18 cleavage. AR8 EVH-1 strain interfered with apoptosis in both cell lines, particularly during the middle stage of the replication cycle; this was more evident in ED cells. Although this antiapoptotic effect has been reported for other alpha herpesviruses, our findings may help elucidate how EHV-1 improves its infectivity during its cycle. 相似文献
69.
Plemel RL Lobingier BT Brett CL Angers CG Nickerson DP Paulsel A Sprague D Merz AJ 《Molecular biology of the cell》2011,22(8):1353-1363
Traffic through late endolysosomal compartments is regulated by sequential signaling of small G proteins of the Rab5 and Rab7 families. The Saccharomyces cerevisiae Vps-C protein complexes CORVET (class C core vacuole/endosome tethering complex) and HOPS (homotypic fusion and protein transport) interact with endolysosomal Rabs to coordinate their signaling activities. To better understand these large and intricate complexes, we performed interaction surveys to assemble domain-level interaction topologies for the eight Vps-C subunits. We identified numerous intersubunit interactions and up to six Rab-binding sites. Functional modules coordinate the major Rab interactions within CORVET and HOPS. The CORVET-specific subunits, Vps3 and Vps8, form a subcomplex and physically and genetically interact with the Rab5 orthologue Vps21. The HOPS-specific subunits, Vps39 and Vps41, also form a subcomplex. Both subunits bind the Rab7 orthologue Ypt7, but with distinct nucleotide specificities. The in vivo functions of four RING-like domains within Vps-C subunits were analyzed and shown to have distinct functions in endolysosomal transport. Finally, we show that the CORVET- and HOPS-specific subunits Vps3 and Vps39 bind the Vps-C core through a common region within the Vps11 C-terminal domain (CTD). Biochemical and genetic experiments demonstrate the importance of these regions, revealing the Vps11 CTD as a key integrator of Vps-C complex assembly, Rab signaling, and endosomal and lysosomal traffic. 相似文献
70.
Sianos G Kay IP Carlier SG Lighart JM Wardeh AJ Coen VL Levendag PC Serruys PW 《International journal of cardiovascular interventions》2000,3(2):121-125
The application of beta-radiation in coronary arteries is a promising new technique for the treatment of in-stent restenosis. This is the first case in which the 5 F. delivery catheter of the Beta-Cath trade mark system was advanced through the struts of a stent, previously deployed in an adjacent branch, so as to deliver radiation to the target vessel. 相似文献