全文获取类型
收费全文 | 419篇 |
免费 | 33篇 |
出版年
2023年 | 2篇 |
2022年 | 3篇 |
2021年 | 8篇 |
2020年 | 5篇 |
2019年 | 10篇 |
2018年 | 9篇 |
2017年 | 8篇 |
2016年 | 17篇 |
2015年 | 25篇 |
2014年 | 22篇 |
2013年 | 28篇 |
2012年 | 20篇 |
2011年 | 28篇 |
2010年 | 15篇 |
2009年 | 11篇 |
2008年 | 27篇 |
2007年 | 25篇 |
2006年 | 21篇 |
2005年 | 14篇 |
2004年 | 11篇 |
2003年 | 13篇 |
2002年 | 9篇 |
2001年 | 13篇 |
2000年 | 3篇 |
1999年 | 5篇 |
1997年 | 3篇 |
1996年 | 6篇 |
1995年 | 2篇 |
1994年 | 10篇 |
1993年 | 7篇 |
1992年 | 12篇 |
1990年 | 4篇 |
1989年 | 2篇 |
1987年 | 6篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1982年 | 4篇 |
1981年 | 2篇 |
1980年 | 3篇 |
1979年 | 2篇 |
1978年 | 3篇 |
1972年 | 2篇 |
1971年 | 2篇 |
1969年 | 4篇 |
1967年 | 3篇 |
1960年 | 2篇 |
1958年 | 2篇 |
1950年 | 1篇 |
1928年 | 1篇 |
排序方式: 共有452条查询结果,搜索用时 15 毫秒
381.
Mierau V Anke T Sterner O 《Zeitschrift für Naturforschung. C, Journal of biosciences》2003,58(7-8):541-546
Two new antibiotic metabolites, dacrymenone (1) and VM 3298-2 (2), were isolated from fermentations of a Dacrymyces sp., and their structures were determined by spectroscopic techniques. Dacrymenone (1) is a new eremophilane sesquiterpenoid while VM 3298-2 (2) is a bis-enol ether between methyl pyruvate and 4,6-dihydroxycyclohexan-1,3-dione. Dacrymenone (1) shows weak antibacterial and antifungal activity while VM 3298-2 (2) exhibits cytotoxic and antifungal activities. 相似文献
382.
Ridderbusch DC Weber RW Anke T Sterner O 《Zeitschrift für Naturforschung. C, Journal of biosciences》2004,59(5-6):379-383
Tulasnein (1), a new metabolite with strong antimicrobial and weaker cytotoxic and phytotoxic activity, was isolated from culture filtrates of three strains of the xylariaceous coprophilous fungus Podosordaria tulasnei. The producing strains were identified by their rhizomorphs and by ITS rDNA sequence analysis. A second new metabolite, podospirone (2), was also produced by all three strains whereas the weakly cytotoxic (+)-3,4-anhydroshikimic acid methyl ester (3) was detected in only one strain. 相似文献
383.
Lamar J Hu J Bueno AB Yang HC Guo D Copp JD McGee J Gitter B Timm D May P McCarthy J Chen SH 《Bioorganic & medicinal chemistry letters》2004,14(1):239-243
We describe herein the syntheses and evaluation of a series of C-termini pyridyl containing Phe*-Ala-based BACE inhibitors (5-19). In conjunction with four fixed residues at the P1 (Phe), P1' (Ala), P2' (Val), and P2' cap (Pyr.), rather detailed SAR modifications at P2 and P3 positions were pursued. The promising inhibitors emerging from this SAR investigation, 12 and 17 demonstrated very good enzyme potency (IC(50)=45 nM) and cellular activity (IC(50)=0.4 microM). 相似文献
384.
Schultz-Heienbrok R Maier T Sträter N 《Protein science : a publication of the Protein Society》2004,13(7):1811-1822
Engineering disulfide bridges is a common technique to lock a protein movement in a defined conformational state. We have designed two double mutants of Escherichia coli 5'-nucleotidase to trap the enzyme in both an open (S228C, P513C) and a closed (P90C, L424C) conformation by the formation of disulfide bridges. The mutant proteins have been expressed, purified, and crystallized, to structurally characterize the designed variants. The S228C, P513C is a double mutant crystallized in two different crystal forms with three independent conformers, which differ from each other by a rotation of up to 12 degrees of the C-terminal domain with respect to the N-terminal domain. This finding, as well as an analysis of the domain motion in the crystal, indicates that the enzyme still exhibits considerable residual domain flexibility. In the double mutant that was designed to trap the enzyme in the closed conformation, the structure analysis reveals an unexpected intermediate conformation along the 96 degrees rotation trajectory between the open and closed enzyme forms. A comparison of the five independent conformers analyzed in this study shows that the domain movement of the variant enzymes is characterized by a sliding movement of the residues of the domain interface along the interface, which is in contrast to a classical closure motion where the residues of the domain interface move perpendicular to the interface. 相似文献
385.
Titus GP Mueller HA Burgner J Rodríguez De Córdoba S Peñalva MA Timm DE 《Nature structural biology》2000,7(7):542-546
Homogentisate dioxygenase (HGO) cleaves the aromatic ring during the metabolic degradation of Phe and Tyr. HGO deficiency causes alkaptonuria (AKU), the first human disease shown to be inherited as a recessive Mendelian trait. Crystal structures of apo-HGO and HGO containing an iron ion have been determined at 1.9 and 2.3 A resolution, respectively. The HGO protomer, which contains a 280-residue N-terminal domain and a 140-residue C-terminal domain, associates as a hexamer arranged as a dimer of trimers. The active site iron ion is coordinated near the interface between subunits in the HGO trimer by a Glu and two His side chains. HGO represents a new structural class of dioxygenases. The largest group of AKU associated missense mutations affect residues located in regions of contact between subunits. 相似文献
386.
Photorespiration is a Janus-headed metabolic process: it makes oxygenic photosynthesis possible by scavenging its major toxic by-product, 2-phosphoglycolate, but also leads to high losses of freshly assimilated CO(2) from most land plants. Photorespiration has been often classified as a wasteful process but is now increasingly appreciated as a key ancillary component of photosynthesis and therefore the global carbon cycle. As such, the photorespiratory cycle is one of the major highways for the flow of carbon in the terrestrial biosphere. Recent research revealed that this important pathway originated as a partner of oxygenic photosynthesis billions of years ago and is multiply linked to other pathways of central metabolism of contemporary land plants. 相似文献
387.
S Timm M Mielewczik A Florian S Frankenbach A Dreissen N Hocken AR Fernie A Walter H Bauwe 《PloS one》2012,7(8):e42809
Background
Photorespiratory carbon metabolism was long considered as an essentially closed and nonregulated pathway with little interaction to other metabolic routes except nitrogen metabolism and respiration. Most mutants of this pathway cannot survive in ambient air and require CO2-enriched air for normal growth. Several studies indicate that this CO2 requirement is very different for individual mutants, suggesting a higher plasticity and more interaction of photorespiratory metabolism as generally thought. To understand this better, we examined a variety of high- and low-level parameters at 1% CO2 and their alteration during acclimation of wild-type plants and selected photorespiratory mutants to ambient air.Methodology and Principal Findings
The wild type and four photorespiratory mutants of Arabidopsis thaliana (Arabidopsis) were grown to a defined stadium at 1% CO2 and then transferred to normal air (0.038% CO2). All other conditions remained unchanged. This approach allowed unbiased side-by-side monitoring of acclimation processes on several levels. For all lines, diel (24 h) leaf growth, photosynthetic gas exchange, and PSII fluorescence were monitored. Metabolite profiling was performed for the wild type and two mutants. During acclimation, considerable variation between the individual genotypes was detected in many of the examined parameters, which correlated with the position of the impaired reaction in the photorespiratory pathway.Conclusions
Photorespiratory carbon metabolism does not operate as a fully closed pathway. Acclimation from high to low CO2 was typically steady and consistent for a number of features over several days, but we also found unexpected short-term events, such as an intermittent very massive rise of glycine levels after transition of one particular mutant to ambient air. We conclude that photorespiration is possibly exposed to redox regulation beyond known substrate-level effects. Additionally, our data support the view that 2-phosphoglycolate could be a key regulator of photosynthetic-photorespiratory metabolism as a whole. 相似文献388.
Functional heterogeneity within stem and progenitor cells has been shown to influence cell fate decisions. Similarly, intracellular signaling activated by external stimuli is highly heterogeneous and its spatiotemporal activity is linked to future cell behavior. To quantify these heterogeneous states and link them to future cell fates, it is important to observe cell populations continuously with single cell resolution. Live cell imaging in combination with fluorescent biosensors for signaling activity serves as a powerful tool to study cellular and molecular heterogeneity and the long-term biological effects of signaling. Here, we describe these methodologies, their advantages over classical approaches, and we illustrate how they could be applied to improve our understanding of the importance of heterogeneous cellular and molecular responses to external signaling cues. 相似文献
389.
Mika Frankel Gabriel Bek? Michael Timm Sine Gustavsen Erik Wind Hansen Anne Mette Madsen 《Applied and environmental microbiology》2012,78(23):8289-8297
Indoor microbial exposure has been related to adverse pulmonary health effects. Exposure assessment is not standardized, and various factors may affect the measured exposure. The aim of this study was to investigate the seasonal variation of selected microbial exposures and their associations with temperature, relative humidity, and air exchange rates in Danish homes. Airborne inhalable dust was sampled in five Danish homes throughout the four seasons of 1 year (indoors, n = 127; outdoors, n = 37). Measurements included culturable fungi and bacteria, endotoxin, N-acetyl-beta-d-glucosaminidase, total inflammatory potential, particles (0.75 to 15 μm), temperature, relative humidity, and air exchange rates. Significant seasonal variation was found for all indoor microbial exposures, excluding endotoxin. Indoor fungi peaked in summer (median, 235 CFU/m3) and were lowest in winter (median, 26 CFU/m3). Indoor bacteria peaked in spring (median, 2,165 CFU/m3) and were lowest in summer (median, 240 CFU/m3). Concentrations of fungi were predominately higher outdoors than indoors, whereas bacteria, endotoxin, and inhalable dust concentrations were highest indoors. Bacteria and endotoxin correlated with the mass of inhalable dust and number of particles. Temperature and air exchange rates were positively associated with fungi and N-acetyl-beta-d-glucosaminidase and negatively with bacteria and the total inflammatory potential. Although temperature, relative humidity, and air exchange rates were significantly associated with several indoor microbial exposures, they could not fully explain the observed seasonal variations when tested in a mixed statistical model. In conclusion, the season significantly affects indoor microbial exposures, which are influenced by temperature, relative humidity, and air exchange rates. 相似文献
390.
Timm CD Irino K Gomes TA Vieira MM Guth BE Vaz TM Moreira CN Aleixo JA 《Letters in applied microbiology》2007,44(4):419-425
AIMS: To determine the prevalence of Shiga toxin-producing Escherichia coli (STEC) and serotypes and virulence markers of the STEC isolates from beef and dairy cattle in Rio Grande do Sul, Brazil. METHODS AND RESULTS: Faecal samples from beef cattle were collected at slaughterhouses. The isolates were submitted to colony hybridization assay with specific DNA probes for stx1, stx2 and eae genes, and serotyped for the identification of O and H antigens. Thirty-nine per cent of beef cattle surveyed harboured at least one STEC strain. Among the distinct serotypes identified, 10 were shared by both beef and dairy cattle. Most of the strains isolated harboured stx2. Genotypic and phenotypic profiles allowed the identification of 34 and 31 STEC strains, isolated from beef and dairy cattle, respectively. Serotypes O10:H14, O15:H21, O96:H21, O119:H4, O124:H11, O128:H21, O137:H-, O141:H19, O159:H42, O160:H2 and O177:H11, identified in this study, have not been previously reported as STEC isolated from cattle. CONCLUSIONS: Cattle are an important reservoir of STEC strains associated with human diseases in South America. SIGNIFICANCE AND IMPACT OF THE STUDY: Determining the prevalence, genotypic profile and serotypes of STEC strains isolated from cattle enables the prediction of possible risk for public health. 相似文献