全文获取类型
收费全文 | 390篇 |
免费 | 25篇 |
出版年
2023年 | 2篇 |
2022年 | 4篇 |
2021年 | 5篇 |
2020年 | 3篇 |
2019年 | 6篇 |
2018年 | 11篇 |
2017年 | 7篇 |
2016年 | 14篇 |
2015年 | 18篇 |
2014年 | 22篇 |
2013年 | 27篇 |
2012年 | 30篇 |
2011年 | 32篇 |
2010年 | 25篇 |
2009年 | 21篇 |
2008年 | 18篇 |
2007年 | 21篇 |
2006年 | 18篇 |
2005年 | 18篇 |
2004年 | 24篇 |
2003年 | 18篇 |
2002年 | 11篇 |
2001年 | 6篇 |
2000年 | 3篇 |
1999年 | 6篇 |
1998年 | 2篇 |
1997年 | 3篇 |
1996年 | 2篇 |
1995年 | 5篇 |
1994年 | 1篇 |
1993年 | 2篇 |
1992年 | 5篇 |
1991年 | 2篇 |
1990年 | 4篇 |
1989年 | 1篇 |
1986年 | 3篇 |
1978年 | 3篇 |
1977年 | 2篇 |
1976年 | 1篇 |
1975年 | 2篇 |
1974年 | 1篇 |
1972年 | 2篇 |
1971年 | 1篇 |
1970年 | 1篇 |
1968年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有415条查询结果,搜索用时 15 毫秒
1.
Susanne Berglund Bryan J. Egner Henrik Gradén Joakim Gradén David G.A. Morgan Tord Inghardt Fabrizio Giordanetto 《Bioorganic & medicinal chemistry letters》2009,19(15):4268-4273
Herein, we disclose the discovery and optimization of 2-piperidin-4-yl-acetamide derivatives as MCH-R1 antagonists. Structural investigation of piperidin-4-yl-amide and piperidin-4-yl-ureas identified 2-piperidin-4-yl-acetamide-based MCH-R1 antagonists with outstanding in vivo efficacy but flawed with high affinity towards the hERG potassium channel. While existing hERG SAR information was employed to discover highly potent MCH-R1 antagonists with minimized hERG inhibition, additional hurdles prevented their subsequent clinical exploration. 相似文献
2.
Joakim Galli Urban Lendahl Gabrielle Paulsson Christer Ericsson Tomas Bergman Mats Carlquist Lars Wieslander 《Journal of molecular evolution》1990,31(1):40-50
Summary We describe the structure of a gene expressed in the salivary gland cells of the dipteranChironomus tentans and show that it encodes 1 of the approximately 15 secretory proteins exported by the gland cells. This sp115,140 gene consists of approximately 65 copies of a 42-bp sequence in a central uninterrupted core block, surrounded by short nonrepetitive regions. The repeats within the gene are highly similar to each other, but divergent repeats are present in a pattern which suggests that the repeat structure has been remodeled during evolution. The 42-bp repeat in the gene is a simple variant of the more complex repeat unit present in the Balbiani ring genes, encoding four of the other secretory proteins. The structure of the sp115,140 gene suggests that related repeat structures have evolved from a common origin and resulted in the set of genes whose secretory proteins interact in the assembly of the secreted protein fibers. 相似文献
3.
Humoral anti-idiotypic and anti-anti-idiotypic immune response in cancer patients treated with monoclonal antibody 17-1A 总被引:4,自引:0,他引:4
Peter Ragnhammar Maria Liljefors Anna-Lena Hjelm Håkan Mellstedt Jan-Erik Frödin J. Fagersberg 《Cancer immunology, immunotherapy : CII》1996,42(2):81-87
A group of 96 patients with advanced colorectal carcinoma were treated with the mouse (m) or chimeric (c) (mouse variable
regions × human IgG1 constant regions) monoclonal antibody (mAb) 17-1A recognizing the tumour-associated antigen GA733-2.
Eighty-two of the 83 patients treated with mmAb17-1A and 69% of the patients given cmAb17-1A (n = 13) developed anti-idiotypic antibodies (ab2). Auto-antibodies binding to tumour cells expressing GA733-2 were found in 7% of the patients. In a further 38 patients (40%)
antitumour-cell antibodies, i.e. anti-anti-idiotypic antibodies (ab3), were induced by the mAb17-1A therapy. Patients with detectable ab3 after treatment had significantly higher ab2 levels than those not developing ab3. Addition of granulocyte/macrophage-colony-stimulating factor (GM-CSF) to mmAb17-1A significantly enhanced the induction
of ab2 as well as induction of anti-anti-idiotypic antibodies (ab3), compared to mmAb17-1A alone. Patients with a high increase in antitumour-cell antibodies (ab3) induced by the therapy lived significantly longer than patients with no or a low level of induction of ab3 (P = 0.016). The results indicate that induction of an idiotypic network response might be an important effector mechanism in
mAb therapy.
Received: 20 October 1995 / Accepted: 18 December 1995 相似文献
4.
4-Thiaproline reduces heart lipid peroxidation and collagen accumulation in the diabetic db/db mouse
Summary Collagen accumulation is a main pathological feature of diabetic cardiomyopathy. The underlying mechanisms seem to be increased cross linking by reactive carbonyles. The purpose of the study was to decrease the collagen content of total ventricular tissue by the oral administration of thiaproline, which could reduce collagen due to its functions as a proline analogue, blocking collagen production and as a free oxygen radical scavenger, blocking reactive carbonyles and oxygen species and subsequently collagen cross linking.Thiaproline was administered to genetically diabetic db/db mice and compared to untreated animals. Total ventricular collagen as expressed by hydroxyproline was significantly lower in the treated group (means 0.23 micromoles/10 tissue in the treated vs 0.35 micromoles/100 mg tissue in the untreated group, p < 0.001). Significantly more collagen could be eluted in the treated group (p < 0.001) and carboxymethyllysine was significantly reduced in the treated group (p < 0.001). Di-tyrosine and glycemic control did not differ between the groups. Glutathione was significantly increased in the TP treated experimental group (p < 0.001) and lipid peroxidation products were significantly decreased (means 0.221 absorbance in the treated group versus 0.321 absorbance in the untreated diabetic group) correlating with total ventricular collagen content (r = 0.87, p < 0.01).We conclude that thiaproline reduced total ventricular collagen content by inhibiting collagen cross linking as reflected by increased solubility of collagen and expressed by higher elution quantity of collagen. Thiaproline, and/or its metabolites induced increase of heart glutathione which may well have been scavenging reactive carbonyles derived from lipid peroxidation and advanced stage nonenzymatic glycosylation as shown by decreased total ventricular carboxy-methyllysine and lipid peroxidation products paralleling reduced heart collagen content.It remains to be shown that the successful reduction of heart collagen by thiaproline is paralleled by improved functional properties. 相似文献
5.
Tom Thorvaldsen Harald Osnes Joakim Sundnes 《Computer methods in biomechanics and biomedical engineering》2013,16(6):369-379
In this paper we present a mixed finite element method for modeling the passive properties of the myocardium. The passive properties are described by a non-linear, transversely isotropic, hyperelastic material model, and the myocardium is assumed to be almost incompressible. Single-field, pure displacement-based formulations are known to cause numerical difficulties when applied to incompressible or slightly compressible material cases. This paper presents an alternative approach in the form of a mixed formulation, where a separately interpolated pressure field is introduced as a primary unknown in addition to the displacement field. Moreover, a constraint term is included in the formulation to enforce (almost) incompressibility. Numerical results presented in the paper demonstrate the difficulties related to employing a pure displacement-based method, applying a set of physically relevant material parameter values for the cardiac tissue. The same problems are not experienced for the proposed mixed method. We show that the mixed formulation provides reasonable numerical results for compressible as well as nearly incompressible cases, also in situations of large fiber stretches. There is good agreement between the numerical results and the underlying analytical models. 相似文献
6.
7.
Salvatore Vaccarella Anna S?derlund-Strand Silvia Franceschi Martyn Plummer Joakim Dillner 《PloS one》2013,8(8)
Background
To evaluate the pattern of co-infection of human papillomavirus (HPV) types in both sexes in Sweden.Methods
Cell samples from genital swabs, first-void urine, and genital swabs immersed in first-void urine were collected in the present cross-sectional High Throughput HPV Monitoring study. Overall, 31,717 samples from women and 9,949 from men (mean age 25) were tested for 16 HPV types using mass spectrometry. Multilevel logistic regression was used to estimate the expected number of multiple infections with specific HPV types, adjusted for age, type of sample, and accounting for correlations between HPV types due to unobserved risk factors using sample-level random effects. Bonferroni correction was used to allow for multiple comparisons (120).Results
Observed-to-expected ratio for any multiple infections was slightly above unity in both sexes, but, for most 2-type combinations, there was no evidence of significant departure from expected numbers. HPV6/18 was found more often and HPV51/68 and 6/68 less often than expected. However, HPV68 tended to be generally underrepresented in co-infections, suggesting a sub-optimal performance of our testing method for this HPV type.Conclusions
We found no evidence for positive or negative clustering between HPV types included in the current prophylactic vaccines and other untargeted oncogenic types, in either sex. 相似文献8.
Sam Nordfeldt Teresia ?ngarne-Lindberg Maria Nordwall Joakim Ekberg Carina Berter? 《PloS one》2013,8(6)
Background
Continued refinement of resources for patient information, education and support is needed. Considering the rapid development of new communication practices, the perspectives of young people themselves warrant more attention using a wide research focus. The purpose of this study was to understand information-seeking behaviours, Internet use and social networking online in adolescents with type 1 diabetes (T1DM). This applied to their everyday life, including the context of diabetes and their experiences and need of contact with T1DM peers.Methodology/Principal Findings
Twenty-four adolescents aged 10–17 years with T1DM were recruited from a county hospital in the south-east of Sweden. Qualitative data were obtained using eight focus groups, wherein each participant engaged in a 60–90 minute video/audio-recorded session. The focus group data were transcribed and analysed using qualitative content analysis. Some demographic and medical information was also collected. The three main categories that were identified; Aspects of Security, Updating, and Plainness and their sub-categories gave significant information about how to enhance information retrieval and peer contacts related to T1DM. Regarding the persons'' information-seeking behaviour, Internet use, and use of social media some differences could be identified depending on gender and age.Conclusions/Significance
Sensitivity and adaptation to users'' needs and expectations seem crucial in the development of future online resources for adolescents with T1DM. To start with, this could mean applying a wider range of already existing information and communication technologies. Health practitioners need to focus on the areas of security of information and communication, frequency of updating, and simplicity of design-less is more. 相似文献9.
Joakim Lundqvist Ilka Braumann Marzena Kurowska André H. Müller Mats Hansson 《The Journal of biological chemistry》2013,288(33):24012-24019
The ATP-dependent insertion of Mg2+ into protoporphyrin IX is the first committed step in the chlorophyll biosynthetic pathway. The reaction is catalyzed by magnesium chelatase, which consists of three gene products: BchI, BchD, and BchH. The BchI and BchD subunits belong to the family of AAA+ proteins (ATPases associated with various cellular activities) and form a two-ring complex with six BchI subunits in one layer and six BchD subunits in the other layer. This BchID complex is a two-layered trimer of dimers with the ATP binding site located at the interface between two neighboring BchI subunits. ATP hydrolysis by the BchID motor unit fuels the insertion of Mg2+ into the porphyrin by the BchH subunit. In the present study, we explored mutations that were originally identified in semidominant barley (Hordeum vulgare L.) mutants. The resulting recombinant BchI proteins have marginal ATPase activity and cannot contribute to magnesium chelatase activity although they apparently form structurally correct complexes with BchD. Mixing experiments with modified and wild-type BchI in various combinations showed that an exchange of BchI subunits in magnesium chelatase occurs during the catalytic cycle, which indicates that dissociation of the complex may be part of the reaction mechanism related to product release. Mixing experiments also showed that more than three functional interfaces in the BchI ring structure are required for magnesium chelatase activity. 相似文献
10.
The function of Notch signalling in segment formation in the crustacean Daphnia magna (Branchiopoda)
Ten years ago we showed for the first time that Notch signalling is required in segmentation in spiders, indicating the existence of similar mechanisms in arthropod and vertebrate segmentation. However, conflicting results in various arthropod groups hampered our understanding of the ancestral function of Notch in arthropod segmentation. Here we fill a crucial data gap in arthropods and analyse segmentation in a crustacean embryo. We analyse the expression of homologues of the Drosophila and vertebrate segmentation genes and show that members of the Notch signalling pathway are expressed at the same time as the pair-rule genes. Furthermore, inactivation of Notch signalling results in irregular boundaries of the odd-skipped-like expression domains and affects the formation of segments. In severe cases embryos appear unsegmented. We suggest two scenarios for the function of Notch signalling in segmentation. The first scenario agrees with a segmentation clock involving Notch signalling, while the second scenario discusses an alternative mechanism of Notch function which is integrated into a hierarchical segmentation cascade. 相似文献