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排序方式: 共有463条查询结果,搜索用时 31 毫秒
71.
Menear KA Adcock C Alonso FC Blackburn K Copsey L Drzewiecki J Fundo A Le Gall A Gomez S Javaid H Lence CF Martin NM Mydlowski C Smith GC 《Bioorganic & medicinal chemistry letters》2008,18(14):3942-3945
We have previously described poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors based on a substituted benzyl-phthalazinone scaffold. As an alternative chemical template, a novel series of alkoxybenzamides were developed with restricted conformation through intramolecular hydrogen bond formation; the compounds exhibit low nM enzyme and cellular activity as PARP-1 inhibitors. 相似文献
72.
73.
Staphylococcus epidermidis polysaccharide intercellular adhesin induces IL-8 expression in human astrocytes via a mechanism involving TLR2 总被引:1,自引:0,他引:1
Niall T. Stevens Irina Sadovskaya Said Jabbouri Tafiq Sattar James P. O'Gara Hilary Humphreys Catherine M. Greene 《Cellular microbiology》2009,11(3):421-432
Staphylococcus epidermidis is an opportunistic biofilm-forming pathogen associated with neurosurgical device-related meningitis. Expression of the polysaccharide intercellular adhesin (PIA) on its surface promotes S. epidermidis biofilm formation. Here we investigated the pro-inflammatory properties of PIA against primary and transformed human astrocytes. PIA induced IL-8 expression in a dose- and/or time-dependent manner from U373 MG cells and primary normal human astrocytes. This effect was inhibited by depletion of N -acetyl-β- d -glucosamine polymer from the PIA preparation with Lycopersicon esculentum lectin or sodium meta -periodate. Expression of dominant-negative versions of the TLR2 and TLR4 adaptor proteins MyD88 and Mal in U373 MG cells inhibited PIA-induced IL-8 production. Blocking IL-1 had no effect. PIA failed to induce IL-8 production from HEK293 cells stably expressing TLR4. However, in U373 MG cells which express TLR2, neutralization of TLR2 impaired PIA-induced IL-8 production. In addition to IL-8, PIA also induced expression of other cytokines from U373 MG cells including IL-6 and MCP-1. These data implicate PIA as an important immunogenic component of the S. epidermidis biofilm that can regulate pro-inflammatory cytokine production from human astrocytes, in part, via TLR2. 相似文献
74.
Manuel Garber Michael C Zody Harindra M Arachchi Aaron Berlin Sante Gnerre Lisa M Green Niall Lennon Chad Nusbaum 《Genome biology》2009,10(6):R60-6
The most recent release of the finished human genome contains 260 euchromatic gaps (excluding chromosome Y). Recent work has
helped explain a large number of these unresolved regions as 'structural' in nature. Another class of gaps is likely to be
refractory to clone-based approaches, and cannot be approached in ways previously described. We present an approach for closing
these gaps using 454 sequencing. As a proof of principle, we closed all three remaining non-structural gaps in chromosome
15. 相似文献
75.
Niall De Lappe Jean O Connor Geraldine Doran Genevieve Devane Martin Cormican 《BMC microbiology》2009,9(1):155-6
Background
With the exception of M. tuberculosis, little has been published on the problems of cross-contamination in bacteriology laboratories. We performed a retrospective analysis of subtyping data from the National Salmonella Reference Laboratory (Ireland) from 2000–2007 to identify likely incidents of laboratory cross contamination. 相似文献76.
Niall J Lennon Robert E Lintner Scott Anderson Pablo Alvarez Andrew Barry William Brockman Riza Daza Rachel L Erlich Georgia Giannoukos Lisa Green Andrew Hollinger Cindi A Hoover David B Jaffe Frank Juhn Danielle McCarthy Danielle Perrin Karen Ponchner Taryn L Powers Kamran Rizzolo Dana Robbins Elizabeth Ryan Carsten Russ Todd Sparrow John Stalker Scott Steelman Michael Weiand Andrew Zimmer Matthew R Henn Chad Nusbaum Robert Nicol 《Genome biology》2010,11(2):1-9
We present an automated, high throughput library construction process for 454 technology. Sample handling errors and cross-contamination are minimized via end-to-end barcoding of plasticware, along with molecular DNA barcoding of constructs. Automation-friendly magnetic bead-based size selection and cleanup steps have been devised, eliminating major bottlenecks and significant sources of error. Using this methodology, one technician can create 96 sequence-ready 454 libraries in 2 days, a dramatic improvement over the standard method. 相似文献
77.
Cockcroft XL Dillon KJ Dixon L Drzewiecki J Kerrigan F Loh VM Martin NM Menear KA Smith GC 《Bioorganic & medicinal chemistry letters》2006,16(4):1040-1044
We have previously described the discovery of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors based on a phthalazinone scaffold. Subsequent optimisation of inhibitory activity, metabolic stability and pharmacokinetic parameters has led to a novel series of meta-substituted 4-benzyl-2H-phthalazin-1-one PARP-1 inhibitors which retain low nM cellular activity and show good stability in vivo and efficacy in cell based models. 相似文献
78.
Hall LM Moran CN Milne GR Wilson J MacFarlane NG Forouhi NG Hariharan N Salt IP Sattar N Gill JM 《PloS one》2010,5(12):e14197
Background
South Asians are more insulin resistant than Europeans, which cannot be fully explained by differences in adiposity. We investigated whether differences in oxidative capacity and capacity for fatty acid utilisation in South Asians might contribute, using a range of whole-body and skeletal muscle measures.Methodology/Principal Findings
Twenty men of South Asian ethnic origin and 20 age and BMI-matched men of white European descent underwent exercise and metabolic testing and provided a muscle biopsy to determine expression of oxidative and lipid metabolism genes and of insulin signalling proteins. In analyses adjusted for age, BMI, fat mass and physical activity, South Asians, compared to Europeans, exhibited; reduced insulin sensitivity by 26% (p = 0.010); lower VO2max (40.6±6.6 vs 52.4±5.7 ml.kg−1.min−1, p = 0.001); and reduced fat oxidation during submaximal exercise at the same relative (3.77±2.02 vs 6.55±2.60 mg.kg−1.min−1 at 55% VO2max, p = 0.013), and absolute (3.46±2.20 vs 6.00±1.93 mg.kg−1.min−1 at 25 ml O2.kg−1.min−1, p = 0.021), exercise intensities. South Asians exhibited significantly higher skeletal muscle gene expression of CPT1A and FASN and significantly lower skeletal muscle protein expression of PI3K and PKB Ser473 phosphorylation. Fat oxidation during submaximal exercise and VO2max both correlated significantly with insulin sensitivity index and PKB Ser473 phosphorylation, with VO2max or fat oxidation during exercise explaining 10–13% of the variance in insulin sensitivity index, independent of age, body composition and physical activity.Conclusions/Significance
These data indicate that reduced oxidative capacity and capacity for fatty acid utilisation at the whole body level are key features of the insulin resistant phenotype observed in South Asians, but that this is not the consequence of reduced skeletal muscle expression of oxidative and lipid metabolism genes. 相似文献79.
80.
Devaney JM Gordish-Dressman H Harmon BT Bradbury MK Devaney SA Harris TB Thompson PD Clarkson PM Price TB Angelopoulos TJ Gordon PM Moyna NM Pesca LS VIsich PS Zoeller RF Seip RL Seo J Kim BH Tosi LL Garcia M Li R Zmuda J Delmonico MJ Lindsay RS Howard BV Kraus WE Hoffman EP 《Human genetics》2011,129(2):129-139
Converging lines of evidence suggest that AKT1 is a major mediator of the responses to insulin,insulin-like growth factor 1 (IGF1), and glucose. AKT1 also plays a key role in the regulation of both muscle cell hypertrophy and atrophy. We hypothesized that AKT1 variants may play a role in the endophenotypes that makeup metabolic syndrome. We studied a 12-kb region including the ?rst exon of the AKT1 gene for association with metabolic syndrome-related phenotypes in four study populations [FAMUSS cohort (n = 574; age 23.7 ± 5.7 years), Strong Heart Study (SHS) (n = 2,134; age 55.5 ± 7.9 years), Dynamics of Health, Aging and Body Composition (Health ABC) (n = 3,075; age 73.6 ± 2.9 years), and Studies of a Targeted Risk Reduction Intervention through De?ned Exercise (STRRIDE)(n = 175; age 40–65 years)]. We identi?ed a three SNP haplotype that we call H1, which represents the ancestral alleles eles at the three loci and H2, which represents the derived alleles at the three loci. In young adult European Americans (FAMUSS), H1 was associated with higher fasting glucose levels in females. In middle age Native Americans (SHS), H1 carriers showed higher fasting insulin and HOMA in males, and higher BMI in females. Inolder African-American and European American subjects(Health ABC) H1 carriers showed a higher incidence of metabolic syndrome. Homozygotes for the H1 haplotype showed about twice the risk of metabolic syndrome in both males and females (p\0.001). In middle-aged European Americans with insulin resistance (STRRIDE) studied by intravenous glucose tolerance test (IVGTT), H1 carriers showed increased insulin resistance due to the Sg component (p = 0.021). The 12-kb haplotype is a risk factor for metabolic syndrome and insulin resistance that needs to be explored in further populations. 相似文献