全文获取类型
收费全文 | 320篇 |
免费 | 16篇 |
国内免费 | 1篇 |
出版年
2023年 | 1篇 |
2022年 | 4篇 |
2021年 | 6篇 |
2020年 | 3篇 |
2019年 | 1篇 |
2018年 | 4篇 |
2017年 | 5篇 |
2016年 | 11篇 |
2015年 | 22篇 |
2014年 | 23篇 |
2013年 | 29篇 |
2012年 | 33篇 |
2011年 | 29篇 |
2010年 | 27篇 |
2009年 | 16篇 |
2008年 | 15篇 |
2007年 | 20篇 |
2006年 | 12篇 |
2005年 | 18篇 |
2004年 | 16篇 |
2003年 | 14篇 |
2002年 | 10篇 |
2000年 | 1篇 |
1999年 | 2篇 |
1996年 | 1篇 |
1995年 | 2篇 |
1994年 | 3篇 |
1993年 | 4篇 |
1992年 | 1篇 |
1990年 | 1篇 |
1987年 | 1篇 |
1985年 | 1篇 |
1955年 | 1篇 |
排序方式: 共有337条查询结果,搜索用时 250 毫秒
51.
52.
Wei Zhang Nick Bansback Annelies Boonen Adam Young Amitabh Singh Aslam H Anis 《Arthritis research & therapy》2010,12(5):R177
Introduction
The Work Productivity and Activity Impairment (WPAI) questionnaire is a well validated instrument to measure impairments in work and activities. However, its validation among patients with rheumatoid arthritis (RA) has not been well established. The present study's purpose is to evaluate the construct validity of the WPAI-general health version among RA patients and its ability to differentiate between RA patients with varying health status. 相似文献53.
Maaike Schilperoort Jan Kroon Sander Kooijman Annelies E. Smit Max Gentenaar Kathrin Mletzko Felix N. Schmidt Leo van Ruijven Bjrn Busse Alberto M. Pereira Natasha M. AppelmanDijkstra Nathalie Bravenboer Patrick C.N. Rensen Onno C. Meijer Elizabeth M. Winter 《Aging cell》2021,20(10)
Glucocorticoid (GC)‐induced osteoporosis is a widespread health problem that is accompanied with increased fracture risk. Detrimental effects of anti‐inflammatory GC therapy on bone have been ascribed to the excess in GC exposure, but it is unknown whether there is also a role for disruption of the endogenous GC rhythm that is inherent to GC therapy. To investigate this, we implanted female C57Bl/6J mice with slow‐release corticosterone (CORT) pellets to blunt the rhythm in CORT levels without inducing hypercortisolism. Flattening of CORT rhythm reduced cortical and trabecular bone volume and thickness, whilst bone structure was maintained in mice injected with supraphysiologic CORT at the time of their endogenous GC peak. Mechanistically, mice with a flattened CORT rhythm showed disrupted circadian gene expression patterns in bone, along with changes in circulating bone turnover markers indicative of a negative balance in bone remodelling. Indeed, double calcein labelling of bone in vivo revealed a reduced bone formation in mice with a flattened CORT rhythm. Collectively, these perturbations in bone turnover and structure decreased bone strength and stiffness, as determined by mechanical testing. In conclusion, we demonstrate for the first time that flattening of the GC rhythm disrupts the circadian clock in bone and results in an osteoporotic phenotype in mice. Our findings indicate that at least part of the fracture risk associated with GC therapy may be the consequence of a disturbed GC rhythm, rather than excess GC exposure alone, and that a dampened GC rhythm may contribute to the age‐related risk of osteoporosis. 相似文献
54.
Annelies Onraedt Cassandra De Muynck Bart Walcarius Wim Soetaert Erick Vandamme 《Biotechnology letters》2005,26(19):1481-1485
As a halotolerant bacterial species, Brevibacterium epidermis DSM 20659 can grow at relatively high salinity, tolerating up to 2 m NaCl. It synthesizes ectoine and the intracellular content increases with the medium salinity, with a maximum of 0.14 g ectoine/g CDW at 1 m NaCl. Sugar-stressed cells do not synthesize ectoine. Ectoine synthesis is also affected by the presence of external osmolytes. Added betaine is taken up and completely replaced ectoine, while l-proline is only temporarily accumulated after which ectoine is synthesized. The strain can metabolize ectoine; l-glutamate is a better carbon source for ectoine synthesis than l-aspartate. 相似文献
55.
Goeminne A Berg M McNaughton M Bal G Surpateanu G Van der Veken P De Prol S Versées W Steyaert J Haemers A Augustyns K 《Bioorganic & medicinal chemistry》2008,16(14):6752-6763
A key enzyme within the purine salvage pathway of parasites, nucleoside hydrolase, is proposed as a good target for new antiparasitic drugs. We have developed N-arylmethyl-iminoribitol derivatives as a novel class of inhibitors against a purine specific nucleoside hydrolase from Trypanosoma vivax. Several of our inhibitors exhibited low nanomolar activity, with 1,4-dideoxy-1,4-imino-N-(8-quinolinyl)methyl-d-ribitol (UAMC-00115, K(i) 10.8nM), N-(9-deaza-adenin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol (K(i) 4.1nM), and N-(9-deazahypoxanthin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol (K(i) 4.4nM) being the three most active compounds. Docking studies of the most active inhibitors revealed several important interactions with the enzyme. Among these interactions are aromatic stacking of the nucleobase mimic with two Trp-residues, and hydrogen bonds between the hydroxyl groups of the inhibitors and amino acid residues in the active site. During the course of these docking studies we also identified a strong interaction between the Asp40 residue from the enzyme and the inhibitor. This is an interaction which has not previously been considered as being important. 相似文献
56.
Annelies De Paepe Sylvie De Buck Katleen Hoorelbeke Jonah Nolf Ingrid Peck Anna Depicker 《The Plant journal : for cell and molecular biology》2009,59(4):517-527
For genetic transformation of plants, floral dip with Agrobacterium often results in integration of multiple T-DNA copies at a single locus and frequently in low and unstable transgene expression. To obtain efficient single-copy T-DNA transformants, two CRE/ loxP recombinase-based simplifying strategies for complex T-DNA loci were compared. A T-DNA vector with oppositely oriented loxP sites was transformed into CRE -expressing and wild-type control Arabidopsis thaliana plants. Of the primary CRE -expressing transformants, 55% harboured a single copy of the introduced T-DNA, but only 15% in the wild-type plants. However, 73% of the single-copy transformants in the CRE background showed continuous somatic inversion of the DNA segment between the two loxP sites. To avoid inversion of the loxP -flanked T-DNA segment, two T-DNA vectors harbouring only one loxP site were investigated for their suitability for CRE/ loxP recombinase-mediated resolution upon floral-dip transformation into CRE -expressing plants. On average, 70% of the transformants in the CRE background were single-copy transformants, whereas the single-copy T-DNA frequency was only 11% for both vectors in the wild-type background. Both resolution strategies yielded mostly Cre transformants in which the 35S-driven transgene expression was stable and uniform in the progeny and remarkably, also in Cre transformants with multiple T-DNA copies. Therefore, a role is proposed for the CRE recombinase in preventing inverted T-DNA repeat formation or modifying the locus chromatin structure, resulting in a reduced sensitivity for silencing. 相似文献
57.
Tomasz Jaworski Ilse Dewachter Benoit Lechat Sophie Croes Annelies Termont David Demedts Peter Borghgraef Herman Devijver Robert K. Filipkowski Leszek Kaczmarek Sebastian Kügler Fred Van Leuven 《PloS one》2009,4(10)
In Alzheimer''s disease tauopathy is considered secondary to amyloid, and the duality obscures their relation and the definition of their respective contributions.Transgenic mouse models do not resolve this problem conclusively, i.e. the relative hierarchy of amyloid and tau pathology depends on the actual model and the genes expressed or inactivated. Here, we approached the problem in non-transgenic models by intracerebral injection of adeno-associated viral vectors to express protein tau or amyloid precursor protein in the hippocampus in vivo. AAV-APP mutant caused neuronal accumulation of amyloid peptides, and eventually amyloid plaques at 6 months post-injection, but with only marginal hippocampal cell-death. In contrast, AAV-Tau, either wild-type or mutant P301L, provoked dramatic degeneration of pyramidal neurons in CA1/2 and cortex within weeks. Tau-mediated neurodegeneration proceeded without formation of large fibrillar tau-aggregates or tangles, but with increased expression of cell-cycle markers.We present novel AAV-based models, which demonstrate that protein tau mediates pyramidal neurodegeneration in vivo. The data firmly support the unifying hypothesis that post-mitotic neurons are forced to re-enter the cell-cycle in primary and secondary tauopathies, including Alzheimer''s disease. 相似文献
58.
Veenma D Beurskens N Douben H Eussen B Noomen P Govaerts L Grijseels E Lequin M de Krijger R Tibboel D de Klein A Van Opstal D 《PloS one》2010,5(12):e15348
In this paper we present the detailed clinical and cytogenetic analysis of a prenatally detected complex Congenital Diaphragmatic Hernia (CDH) patient with a mosaic unbalanced translocation (5;12). High-resolution whole genome SNP array confirmed a low-level mosaicism (20%) in uncultured cells, underlining the value of array technology for identification studies. Subsequently, targeted Fluorescence In-Situ Hybridization in postmortem collected tissues demonstrated a similar low-level mosaicism, independently of the affected status of the tissue. Thus, a higher incidence of the genetic aberration in affected organs as lung and diaphragm cannot explain the severe phenotype of this complex CDH patient. Comparison with other described chromosome 5p and 12p anomalies indicated that half of the features presented in our patient (including the diaphragm defect) could be attributed to both chromosomal areas. In contrast, a few features such as the palpebral downslant, the broad nasal bridge, the micrognathia, microcephaly, abnormal dermatoglyphics and IUGR better fitted the 5p associated syndromes only. This study underlines the fact that low-level mosaicism can be associated with severe birth defects including CDH. The contribution of mosaicism to human diseases and specifically to congenital anomalies and spontaneous abortions becomes more and more accepted, although its phenotypic consequences are poorly described phenomena leading to counseling issues. Therefore, thorough follow-up of mosaic aberrations such as presented here is indicated in order to provide genetic counselors a more evidence based prediction of fetal prognosis in the future. 相似文献
59.
Eduardo Massad Annelies Wilder-Smith Raphael Ximenes Marcos Amaku Luis Fernandez Lopez Francisco Antonio Bezerra Coutinho Giovanini Evelim Coelho Jarbas Barbosa da Silva Jr Claudio José Struchiner Marcelo Nascimento Burattini 《Memórias do Instituto Oswaldo Cruz》2014,109(3):394-397
Brazil will host the FIFA World Cup™, the biggest single-event competition in the
world, from June 12-July 13 2014 in 12 cities. This event will draw an estimated
600,000 international visitors. Brazil is endemic for dengue. Hence, attendees of the
2014 event are theoretically at risk for dengue. We calculated the risk of dengue
acquisition to non-immune international travellers to Brazil, depending on the
football match schedules, considering locations and dates of such matches for June
and July 2014. We estimated the average per-capita risk and expected
number of dengue cases for each host-city and each game schedule chosen based on
reported dengue cases to the Brazilian Ministry of Health for the period between
2010-2013. On the average, the expected number of cases among the 600,000 foreigner
tourists during the World Cup is 33, varying from 3-59. Such risk estimates will not
only benefit individual travellers for adequate pre-travel preparations, but also
provide valuable information for public health professionals and policy makers
worldwide. Furthermore, estimates of dengue cases in international travellers during
the World Cup can help to anticipate the theoretical risk for exportation of dengue
into currently non-infected areas. 相似文献
60.
Peeters A Fraisl P van den Berg S Ver Loren van Themaat E Van Kampen A Rider MH Takemori H van Dijk KW Van Veldhoven PP Carmeliet P Baes M 《The Journal of biological chemistry》2011,286(49):42162-42179
Hepatic peroxisomes are essential for lipid conversions that include the formation of mature conjugated bile acids, the degradation of branched chain fatty acids, and the synthesis of docosahexaenoic acid. Through unresolved mechanisms, deletion of functional peroxisomes from mouse hepatocytes (L-Pex5(-/-) mice) causes severe structural and functional abnormalities at the inner mitochondrial membrane. We now demonstrate that the peroxisomal and mitochondrial anomalies trigger energy deficits, as shown by increased AMP/ATP and decreased NAD(+)/NADH ratios. This causes suppression of gluconeogenesis and glycogen synthesis and up-regulation of glycolysis. As a consequence, L-Pex5(-/-) mice combust more carbohydrates resulting in lower body weights despite increased food intake. The perturbation of carbohydrate metabolism does not require a long term adaptation to the absence of functional peroxisomes as similar metabolic changes were also rapidly induced by acute elimination of Pex5 via adenoviral administration of Cre. Despite its marked activation, peroxisome proliferator-activated receptor α (PPARα) was not causally involved in these metabolic perturbations, because all abnormalities still manifested when peroxisomes were eliminated in a peroxisome proliferator-activated receptor α null background. Instead, AMP-activated kinase activation was responsible for the down-regulation of glycogen synthesis and induction of glycolysis. Remarkably, PGC-1α was suppressed despite AMP-activated kinase activation, a paradigm not previously reported, and they jointly contributed to impaired gluconeogenesis. In conclusion, lack of functional peroxisomes from hepatocytes results in marked disturbances of carbohydrate homeostasis, which are consistent with adaptations to an energy deficit. Because this is primarily due to impaired mitochondrial ATP production, these L-Pex5-deficient livers can also be considered as a model for secondary mitochondrial hepatopathies. 相似文献