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121.
Kevin J. Filipski Angel Guzman-Perez Jianwei Bian Christian Perreault Gary E. Aspnes Mary T. Didiuk Robert L. Dow Richard F. Hank Christopher S. Jones Robert J. Maguire Meihua Tu Dongxiang Zeng Shenping Liu John D. Knafels John Litchfield Karen Atkinson David R. Derksen Francis Bourbonais Jeffrey A. Pfefferkorn 《Bioorganic & medicinal chemistry letters》2013,23(16):4571-4578
Glucokinase activators are a class of experimental agents under investigation as a therapy for Type 2 diabetes mellitus. An X-ray crystal structure of a modestly potent agent revealed the potential to substitute the common heterocyclic amide donor–acceptor motif for a pyridone moiety. We have successfully demonstrated that both pyridone and pyrimidone heterocycles can be used as a potent donor–acceptor substituent. Several sub-micromolar analogs that possess the desired partial activator profile were synthesized and characterized. Unfortunately, the most potent activators suffered from sub-optimal pharmacokinetic properties. Nonetheless, these donor–acceptor motifs may find utility in other glucokinase activator series or beyond. 相似文献
122.
Pinguan Zheng Brian P. Lieberman Karl Ploessl Laetitia Lemoine Sara Miller Hank F. Kung 《Bioorganic & medicinal chemistry letters》2013,23(3):869-872
New ligands for in vivo brain imaging of serotonin transporter (SERT) with single photon emission tomography (SPECT) were prepared and evaluated. An efficient synthesis and radiolabeling of a biphenylthiol, FLIP-IDAM, 4, was accomplished. The affinity of FLIP-IDAM was evaluated by an in vitro inhibitory binding assay using [125I]-IDAM as radioligand in rat brain tissue homogenates (Ki = 0.03 nM). New [125I]Flip-IDAM exhibited excellent binding affinity to SERT binding sites with a high hypothalamus to cerebellum ratio of 4 at 30 min post iv injection. The faster in vivo kinetics for brain uptake and a rapid washout from non-specific regions provide excellent signal to noise ratio. This new agent, when labeled with 123I, may be a useful imaging agent for mapping SERT binding sites in the human brain. 相似文献
123.
Kentaro Futatsugi Vincent Mascitti Cristiano R.W. Guimarães Nao Morishita Cuiman Cai Michael P. DeNinno Hua Gao Michael D. Hamilton Richard Hank Anthony R. Harris Daniel W. Kung Sophie Y. Lavergne Bruce A. Lefker Michael G. Lopaze Kim F. McClure Michael J. Munchhof Cathy Preville Ralph P. Robinson Amit S. Kalgutkar 《Bioorganic & medicinal chemistry letters》2013,23(1):194-197
A novel GPR119 agonist based on the 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole scaffold was designed through lead optimization starting from pyrazole-based GPR119 agonist 1. The design is centered on the conformational restriction of the core scaffold, while minimizing the change in spatial relationships of two key pharmacophoric elements (piperidine-carbamate and aryl sulfone). 相似文献
124.
Liu J Zhu L Plössl K Lieberman BP Kung HF 《Bioorganic & medicinal chemistry letters》2011,21(10):2962-2965
A series of novel N-fluoropyridyl-containing tropane derivatives were synthesized and their binding affinities for the dopamine transporter (DAT), serotonin transporter (SERT) and norepinephrine (NET) were determined via competitive radioligand binding assays. Among these derivatives, compound 6d showed the highest binding affinity to DAT (Ki = 4.1 nM), and selectivity for DAT over SERT (5-fold) and NET (16-fold). Compound 6d was radiolabeled with Fluorine-18 in two steps. Regional brain distribution and ex vivo autoradiography studies of [18F]6d demonstrated that the ligand was selectively localized in the striatum region, where DAT binding sites are highly expressed. [18F]6d may be useful as a potential radioligand for imaging DATs with PET. 相似文献
125.
126.
James A. Franke Christoph Müller Sara Minoli Joshua Elliott Christian Folberth Charles Gardner Tobias Hank Roberto Cesar Izaurralde Jonas Jgermeyr Curtis D. Jones Wenfeng Liu Stefan Olin Thomas A.M. Pugh Alex C. Ruane Haynes Stephens Florian Zabel Elisabeth J. Moyer 《Global Change Biology》2022,28(1):167-181
Modern food production is spatially concentrated in global “breadbaskets.” A major unresolved question is whether these peak production regions will shift poleward as the climate warms, allowing some recovery of potential climate-related losses. While agricultural impacts studies to date have focused on currently cultivated land, the Global Gridded Crop Model Intercomparison Project (GGCMI) Phase 2 experiment allows us to assess changes in both yields and the location of peak productivity regions under warming. We examine crop responses under projected end of century warming using seven process-based models simulating five major crops (maize, rice, soybeans, and spring and winter wheat) with a variety of adaptation strategies. We find that in no-adaptation cases, when planting date and cultivar choices are held fixed, regions of peak production remain stationary and yield losses can be severe, since growing seasons contract strongly with warming. When adaptations in management practices are allowed (cultivars that retain growing season length under warming and modified planting dates), peak productivity zones shift poleward and yield losses are largely recovered. While most growing-zone shifts are ultimately limited by geography, breadbaskets studied here move poleward over 600 km on average by end of the century under RCP 8.5. These results suggest that agricultural impacts assessments can be strongly biased if restricted in spatial area or in the scope of adaptive behavior considered. Accurate evaluation of food security under climate change requires global modeling and careful treatment of adaptation strategies. 相似文献
127.
Ming-Lung Yu Chen-Hua Liu Chung-Feng Huang Tai-Chung Tseng Jee-Fu Huang Chia-Yen Dai Zu-Yau Lin Shinn-Cherng Chen Liang-Yen Wang Suh-Hang Hank Juo Wan-Long Chuang Jia-Horng Kao 《PloS one》2012,7(12)
Background
The current stopping rule for peginterferon/ribavirin therapy in hepatitis C virus genotype-1 (HCV-1) patients is based on an early virological response (EVR, defined as >2 log10 viral reduction at treatment week 12). We aimed to explore rapid stopping rules at week 4.Methods
We randomly allocated 528 HCV-1 patients into training and validation sets (at a 1∶2 ratio). The interleukin-28B rs8099917 genotypes and on-treatment virological responses were evaluated to determine the negative predictive value (NPV) for achieving a sustained virological response (SVR, defined as undetectable HCV RNA 24 weeks after end-of-treatment). The study was approved by the ethics committees of the participating hospitals. All of the patients gave written informed consent before enrollment.Results
A poor week 4 response (W4R), defined as a HCV RNA reduction of <1 log10 IU/mL at week 4 or a week 4 HCV RNA>10,000 IU/mL with interleukin-28B non-TT genotype, had the highest NPV (95%). In the complete sample, poor W4R could identify 43.4% (59/136) of the non-responders, with an NPV of 95% and a false negative rate of only 0.8% (3/396). The multivariate analysis revealed that a poor W4R was the most important negative predictor (odds ratio/95% confidence intervals: 49.01/13.70–175.37), followed by the lack of an EVR. In addition to HCV RNA<1 log10 IU/mL reduction, using the criteria of HCV RNA>10,000 IU/mL/non-TT genotype helped identifying an additional one-third of non-SVR patients at W4.Using the strategy of sequential rapid stopping rule strategy could identify 53.7% (73/136) of the non-responders (43.4% at week 4 and an addition 11.3% at week 12), as compared to 40.4% for the classical week-12 early stopping rule.Conclusions
Sequential rapid stopping rules using on-treatment virological responses and interleukin-28B genotype can rapidly identify additional peginterferon/ribavirin non-responders. 相似文献128.
Ultraviolet B (UVB) radiation may cause the inflammation of retinal pigment epithelium (RPE) cells and play a role in development of age-related macular degeneration (AMD). The activation of the complement factor B (CFB) gene has been shown to be involved in formation of AMD. Here our results revealed that UVB induces IL-6/STAT3 signaling activation and the UVB-induced STAT3 is able to regulate the CFB expression in ARPE-19 cells. Tannic acid (TA) is a kind of water-soluble polyphenol and may have anti-inflammation effects. We also found that TA attenuates the UVB-induced IL-6 protein production, the STAT3 phosphorylation and the CFB expression. Taken together, these findings suggest UVB-induced inflammation of RPE can be mediated through the IL-6/STAT3/CFB pathway, and TA has a protected effect via the inhibition to the inflammatory response. 相似文献
129.
Sylvie Carles Mohammed S. Lamhamedi Jean Beaulieu Debbie C. Stowe Hank A. Margolis 《Tree Genetics & Genomes》2012,8(1):39-51
The root systems of containerized seedlings must be sufficiently developed and have adequate root plug cohesion to permit
handling and the planting of the seedlings with minimal root damage. Genetic variability in morphological and physiological
seedling characteristics of 75 open-pollinated white spruce families was estimated to determine whether genetic selection
for improved seedling root systems is possible. Seedlings were grown for 2 years under standard cultural practices in a forest
nursery. Gas exchange measurements and seedling morphological characteristics (height, diameter, shoot and root dry mass,
root to shoot ratio) were measured at the end of the two growing seasons whereas seedling mineral (N, P, and K) status was
assessed at the end of the first growing season. Genetic parameters (heritabilities—h
2—and genetic correlations) were estimated for every seedling characteristic and a strong genetic control associated with a
large genetic variation was observed at both family (0.20 ≤ hf2 h_f^2 ≤ 0.88) and individual (0.21 ≤ hi2 h_i^2 ≤ 0.97) levels. A single, late-season measurement of physiological characteristics did not reveal physiological basis for
family variability in seedling root growth. Nevertheless, the family variation was large enough to permit genetic improvement
of 2-year-old seedling juvenile morphological characteristics. Strong, positive genetic correlations enable us to foresee
using root collar diameter as an effective method for indirectly selecting white spruce families with heavier root systems. 相似文献
130.
Fredriksson-Ahomaa M Bucher M Hank C Stolle A Korkeala H 《Systematic and applied microbiology》2001,24(3):457-463
Prevalence and contamination routes of pathogenic Yersinia enterocolitica were studied in Southern Germany. Tonsil and faeces samples of 50 fattening pigs, 140 offal samples and 120 minced meat samples were examined. Pig and offal samples were collected from a slaughterhouse approved by the European Union, and minced meat samples from two large meat factories. Yersinia enterocolitica was isolated using direct plating, overnight enrichment and selective enrichment in MRB and ITC broth. The isolates were bio- and serotyped, and pathogenicity was studied using two plasmid-encoded virulence markers: calcium dependence and Congo red absorption. The genotypes were studied with pulsed-field gel electrophoresis using NotI enzyme. Prevalence of pathogenic Y. enterocolitica 4:O3 was 60% and 10% in tonsils and faeces of fattening pigs, respectively. Besides tonsils, prevalence of pathogenic Y. enterocolitica 4:O3 was also high in other pluck set samples, including tongues, lungs, hearts, diaphragms and livers. However, the highest isolation rate was obtained from the tonsils. Kidneys, which were not attached to the pluck set and did not hang together with tonsils on the rack, had the lowest isolation rate. Yersinia enterocolitica 4:O3 was isolated from 12% of minced meat samples. A total of 25 NotI profiles were obtained from porcine samples. The most common genotype, NBI, found in tonsils was also the most common type recovered from offal and minced meat samples. The high contamination rate of tonsils, and the indistinguishable NotI profiles obtained from tonsils and offal indicate that the tonsils contaminate offal when they are removed and hung on the rack together. When the head, with the tonsils and tongue, is not removed prior to evisceration and is not handled and inspected separately, it is difficult to control the spread of Y. enterocolitica 4:O3 from tonsils to the carcass, and subsequently, to meat. 相似文献