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91.
Kurosaki Yoshifumi Imoto Akemi Kawakami Fumitaka Ouchi Motoshi Morita Asuka Yokoba Masanori Takenaka Tsuneo Ichikawa Takafumi Katagiri Masato Nielsen Rikke Ishii Naohito 《Molecular and cellular biochemistry》2022,477(3):689-699
Molecular and Cellular Biochemistry - Bardoxolone methyl [methyl-2-cyano-3, 12-dioxooleana-1, 9(11)dien-28-oate (CDDO-Me)], an activator of the nuclear factor erythroid-derived 2-related factor2... 相似文献
92.
Rikke Holm Anja P. Einholm Jens P. Andersen Bente Vilsen 《The Journal of biological chemistry》2015,290(15):9801-9811
The Na+,K+-ATPase binds Na+ at three transport sites denoted I, II, and III, of which site III is Na+-specific and suggested to be the first occupied in the cooperative binding process activating phosphorylation from ATP. Here we demonstrate that the asparagine substitution of the aspartate associated with site III found in patients with rapid-onset dystonia parkinsonism or alternating hemiplegia of childhood causes a dramatic reduction of Na+ affinity in the α1-, α2-, and α3-isoforms of Na+,K+-ATPase, whereas other substitutions of this aspartate are much less disruptive. This is likely due to interference by the amide function of the asparagine side chain with Na+-coordinating residues in site III. Remarkably, the Na+ affinity of site III aspartate to asparagine and alanine mutants is rescued by second-site mutation of a glutamate in the extracellular part of the fourth transmembrane helix, distant to site III. This gain-of-function mutation works without recovery of the lost cooperativity and selectivity of Na+ binding and does not affect the E1-E2 conformational equilibrium or the maximum phosphorylation rate. Hence, the rescue of Na+ affinity is likely intrinsic to the Na+ binding pocket, and the underlying mechanism could be a tightening of Na+ binding at Na+ site II, possibly via movement of transmembrane helix four. The second-site mutation also improves Na+,K+ pump function in intact cells. Rescue of Na+ affinity and Na+ and K+ transport by second-site mutation is unique in the history of Na+,K+-ATPase and points to new possibilities for treatment of neurological patients carrying Na+,K+-ATPase mutations. 相似文献
93.
Jette G. Petersen Rikke Bergmann Povl Krogsgaard-Larsen Thomas Balle Bente Frølund 《Neurochemical research》2014,39(6):1005-1015
The ionotropic GABAA receptors (GABAARs) are widely distributed in the central nervous system where they play essential roles in numerous physiological and pathological processes. A high degree of structural heterogeneity of the GABAAR has been revealed and extensive effort has been made to develop selective and potent GABAAR agonists. This review investigates the use of heterocyclic carboxylic acid bioisosteres within the GABAAR area. Several heterocycles including 3-hydroxyisoxazole, 3-hydroxyisoxazoline, 3-hydroxyisothiazole, and the 1- and 3-hydroxypyrazole rings have been employed in order to map the orthosteric binding site. The physicochemical properties of the heterocyclic moieties making them suitable for bioisosteric replacement of the carboxylic acid in the molecule of GABA are discussed. A variety of synthetic strategies for synthesis of the heterocyclic scaffolds are available. Likewise, methods for introduction of substituents into specific positions of the heterocyclic scaffolds facilitate the investigation of different regions in the orthosteric binding pocket in close vicinity of the core scaffolds of muscimol/GABA. The development of structural models, from pharmacophore models to receptor homology models, has provided more insight into the molecular basis for binding. Similar binding modes are proposed for the heterocyclic GABA analogues covered in this review by use of ligand–receptor docking into the receptor homology model and the presented structure–activity relationships. A network of interactions between the analogues and the binding pocket is leaving no room for substituents and underline the limited space in the GABAAR orthosteric binding site when in the agonist conformation. 相似文献
94.
Mads F. Hjorth Jean-Philippe Chaput Camilla T. Damsgaard Stine-Mathilde Dalskov Rikke Andersen Arne Astrup Kim F. Michaelsen Inge Tetens Christian Ritz Anders Sj?din 《PloS one》2014,9(8)
Background
As cardio-metabolic risk tracks from childhood to adulthood, a better understanding of the relationship between movement behaviors (physical activity, sedentary behavior and sleep) and cardio-metabolic risk in childhood may aid in preventing metabolic syndrome (MetS) in adulthood.Objective
To examine independent and combined cross-sectional and longitudinal associations between movement behaviors and the MetS score in 8-11 year old Danish children.Design
Physical activity, sedentary time and sleep duration (seven days and eight nights) were assessed by accelerometer and fat mass index (fat mass/height2) was assessed using Dual-energy X-ray absorptiometry. The MetS-score was based on z-scores of waist circumference, mean arterial blood pressure, homeostatic model assessment of insulin resistance, triglycerides and high density lipoprotein cholesterol. All measurements were taken at three time points separated by 100 days. Average of the three measurements was used as habitual behavior in the cross-sectional analysis and changes from first to third measurement was used in the longitudinal analysis.Results
723 children were included. In the cross-sectional analysis, physical activity was negatively associated with the MetS-score (P<0.03). In the longitudinal analysis, low physical activity and high sedentary time were associated with an increased MetS-score (all P<0.005); however, after mutual adjustments for movement behaviors, physical activity and sleep duration, but not sedentary time, were associated with the MetS-score (all P<0.03). Further adjusting for fat mass index while removing waist circumference from the MetS-score rendered the associations no longer statistically significant (all P>0.17). Children in the most favorable tertiles of changes in moderate-to-vigorous physical activity, sleep duration and sedentary time during the 200-day follow-up period had an improved MetS-score relative to children in the opposite tertiles (P = 0.005).Conclusion
The present findings indicate that physical activity, sedentary time and sleep duration should all be targeted to improve cardio-metabolic risk markers in childhood; this is possibly mediated by adiposity. 相似文献95.
Dennis Trolle Peter A. Staehr Thomas A. Davidson Rikke Bjerring Torben L. Lauridsen Martin S?ndergaard Erik Jeppesen 《Ecosystems》2012,15(2):336-347
We used data collected from 1989 to 2009 from 151 shallow (mean depth < 3 m) temperate lakes in Denmark to explore the influence
of lake trophic status, surface area and catchment size on the seasonal dynamics of the air–water flux of CO2. Monthly CO2 fluxes were derived from measurements of acid neutralizing capacity (ANC), pH, ionic strength, temperature, and wind speed.
CO2 fluxes exhibited large seasonal variability, in particular in oligo-mesotrophic lakes. Most of the lakes emitted CO2 during winter (median rates ranging 300–1,900 mg C m−2 day−1), and less CO2 during summer or, in the case of some of the highly eutrophic lakes, retained CO2 during summer. We found that seasonal CO2 fluxes were strongly negatively correlated with pH (r = −0.65, P < 0.01), which in turn was correlated with chlorophyll a concentrations (r = 0.48, P < 0.01). Our analysis suggests that lake trophic status (a proxy for pelagic production) interacts with the lake ANC to drive
the seasonal dynamics of CO2 fluxes, largely by changing pH and thereby the equilibrium of the free CO2 and bicarbonate relation. Long-term observations from four lakes, which have all undergone a period of oligotrophication
during the past two decades, provide further evidence that CO2 efflux generally increases as trophic status decreases, as a consequence of decreased pH. Across these four lakes, the annual
average CO2 emission has increased by 32% during the past two decades, thus, demonstrating the strong link between lake trophic status
and CO2 flux. 相似文献
96.
Nilsson L Madsen K Topcu SO Jensen BL Frøkiær J Nørregaard R 《American journal of physiology. Renal physiology》2012,302(11):F1430-F1439
Bilateral ureteral obstruction (BUO) in rats is associated with increased cyclooxygenase type 2 (COX-2) expression, and selective COX-2 inhibition prevents downregulation of aquaporins (AQPs) in response to BUO. It was hypothesized that a murine model would display similar changes in renal COX-2 and AQPs upon BUO and that targeted disruption of COX-2 protects against BUO-induced suppression of collecting duct AQPs. COX-2(-/-) and wild-type littermates (C57BL/6) were employed to determine COX-1, -2, AQP2, and AQP3 protein abundances and localization after BUO. In a separate series, sham and BUO wild-type mice were treated with a selective COX-2 inhibitor, parecoxib. The COX-2 protein level increased in wild-type mice in response to BUO and was not detectable in COX-2(-/-). COX-1 protein abundance was increased in sham-operated and BUO mice. Total AQP2 and -3 mRNA and protein levels decreased significantly after BUO in the cortex+outer medulla (C+OM) and inner medulla (IM). The decrease in C+OM AQP2 and -3 levels was attenuated/prevented in COX-2(-/-) mice, whereas there was no change in the IM. In parallel, inhibition of COX-2 by parecoxib rescued C+OM AQP3 and IM AQP2 protein level in wild-type mice subjected to BUO. In summary, 1) In C57BL/6 mice, ureteral obstruction increases renal COX-2 expression in interstitial cells and lowers AQP2/-3 abundance and 2) inhibition of COX-2 activity by targeted disruption or pharmacological blockade attenuates obstruction-induced AQP downregulation. In conclusion, COX-2-derived prostaglandins contribute to downregulation of transcellular water transporters in the collecting duct and likely to postobstruction diureses in the mouse. 相似文献
97.
Larsson C Fink R Matthiesen CF Thomsen PD Tauson AH 《Archives of animal nutrition》2012,66(3):237-255
Growth performance and metabolism were investigated in mink kits (n = 210) exposed to the same dietary treatment as their dams (n = 30), i.e. high (HP; 61% of metabolisable energy, ME), medium (MP; 48% of ME) or low (LP; 30% of ME) protein supply, from birth until 10 weeks of age. The kits were weighed weekly, and were measured by means of balance experiment and indirect calorimetry, in weeks eight and nine post-partum (p.p.). At weaning (seven weeks p.p.) and 10 weeks p.p. one kit per litter was killed and blood, liver and kidneys were collected. Plasma amino acid profiles, and hepatic abundance of mRNA for phosphoenolpyruvate carboxykinase (PEPCK), fructose 1,6-biphosphatase, pyruvate kinase and glucose-6-phosphatase (G-6-Pase) by q-PCR, were determined. There were no differences in live weights among kits the first four weeks of life when kits solely consumed milk, but male LP kits were the heaviest. After transition to solid feed MP kits weighed most at nine weeks of age (p < 0.05). At eight weeks of age, the kits fed the LP diet retained less (p < 0.05) N than HP and MP kits. Heat production did not differ among kits, although protein oxidation was higher (p < 0.001) in HP kits than in LP kits. Kits fed the LP diet had lower (p < 0.05) plasma concentrations of lysine, methionine and leucine than MP kits. Dietary treatment was not reflected in the relative abundance of any of the studied mRNAs, but kits had significantly lower abundance of all studied mRNA than their dams, ranging from 83% less PEPCK abundance to 40% less for G-6-Pase. The kidney mass was smallest (p < 0.01) in kits fed the LP diet, and liver masses were largest (p < 0.001) in HP kits. The results indicate that the LP diet did not meet the protein requirements for mink kits in the transition period from milk to solid feed. The capacity to regulate the rate of gluconeogenesis was even more limited in young mink kits than in adult dams. However, young mink kits can regulate protein oxidation in response to dietary protein supply, probably by adapting the size of the liver and kidneys to the level of protein supply. 相似文献
98.
Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly 下载免费PDF全文
Møller RS Kübart S Hoeltzenbein M Heye B Vogel I Hansen CP Menzel C Ullmann R Tommerup N Ropers HH Tümer Z Kalscheuer VM 《American journal of human genetics》2008,82(5):1165-1170
We have identified and characterized two unrelated patients with prenatal onset of microcephaly, intrauterine growth retardation, feeding problems, developmental delay, and febrile seizures/epilepsy who both carry a de novo balanced translocation that truncates the DYRK1A gene at chromosome 21q22.2. DYRK1A belongs to the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family, which is highly conserved throughout evolution. Given its localization in both the Down syndrome critical region and in the minimal region for partial monosomy 21, the gene has been studied intensively in animals and in humans, and DYRK1A has been proposed to be involved in the neurodevelopmental alterations associated with these syndromes. In the present study, we show that truncating mutations of DYRK1A result in a clinical phenotype including microcephaly. 相似文献
99.
Coexistence between genetically modified (GM) and non-GM plants is a field of rapid development and considerable controversy. In crops, it is increasingly important to understand and predict the GM volunteer emergence in subsequent non-GM crops. Theoretical models suggest recruitment from the seedbank over extended periods, but empirical evidence matching these predictions has been scarce. Here, we provide evidence of long-term GM seed persistence in conventional agriculture. Ten years after a trial of GM herbicide-tolerant oilseed rape, emergent seedlings were collected and tested for herbicide tolerance. Seedlings that survived the glufosinate herbicide (15 out of 38 volunteers) tested positive for at least one GM insert. The resulting density was equivalent to 0.01 plants m-2, despite complying with volunteer reduction recommendations. These results are important in relation to debating and regulating coexistence of GM and non-GM crops, particularly for planting non-GM crops after GM crops in the same field. 相似文献
100.