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941.
Rice KD Wang VR Gangloff AR Kuo EY Dener JM Newcomb WS Young WB Putnam D Cregar L Wong M Simpson PJ 《Bioorganic & medicinal chemistry letters》2000,10(20):2361-2366
Detailed structure activity relationships (SARs) for a series of dibasic human tryptase inhibitors are presented. The structural requirements for potent inhibitory activity are remarkably broad with a range of core template modifications being well tolerated. Optimized inhibitors demonstrate potent anti-asthmatic activity in a sheep model of allergic asthma. APC-2059, a dibasic tryptase inhibitor with subnanomolar activity, has been advanced to phase II clinical trials for the treatment of both psoriasis and ulcerative colitis. 相似文献
942.
Tucker JA Clayton TL Chidester CG Schulz MW Harrington LE Conrad SJ Yagi Y Oien NL Yurek D Kuo MS 《Bioorganic & medicinal chemistry》2000,8(3):601-615
This paper describes the structure activity relationships of a new class of cytomegalovirus DNA polymerase inhibitors having two aryl groups joined by an acyloxyamidine linker. Examination of a series of analogues in which the terminal groups are varied revealed a very narrow SAR around the 2,4-dichlorophenyl group of the lead compound, but a variety of replacements for the benzothiazole ring are compatible with activity. The most notable of these is the isoxazole ring of compound 78, which provides a 30-fold enhancement in potency compared to the lead compound. We also describe the design, synthesis and evaluation of 10 analogues in which the acyloxyamidine linker is modified or replaced by an isosteric group. Structure-activity relationship studies identified the linker -NH2 group as a critical pharmacophoric element. Ab initio molecular orbital calculations combined with qualitative estimates of steric interaction energies suggest that the lowest energy conformations of the acyloxyamidine linker are characterized by an extended planar CAr-C=N-O-C arrangement and either a syn-periplanar or anti-periplanar N-O-C-C(Ar') arrangement. Only the anti-periplanar conformation was observed in the crystal structures of three acyloxyamidines. The most active of the linker-modified compounds designed on the basis of these studies is the amidine carbamate 20, which is approximately one-third as potent in the cytomegalovirus DNA polymerase inhibition assay as the comparator acyloxyamidine 53. The activity of 20 suggests that acyloxyamidines may bind to the cytomegalovirus DNA polymerase via an anti-periplanar conformation similar to that observed in the crystal structure of acyloxyamidine 36. 相似文献
943.
944.
The deep roots and wide branches of the K+ -channel family are evident from genome surveys and laboratory experimentation. K+ -channel genes are widespread and found in nearly all the free-living bacteria, archaea and eukarya. The conservation of basic structures and mechanisms such as the K+ filter, the gate, and some of the gate's regulatory domains have allowed general insights on animal K+ channels to be gained from crystal structures of prokaryotic channels. Since microbes are the great majority of life's diversity, it is not surprising that microbial genomes reveal structural motifs beyond those found in animals. There are open-reading frames that encode K+ -channel subunits with unconventional filter sequences, or regulatory domains of different sizes and numbers not previously known. Parasitic or symbiotic bacteria tend not to have K+ channels, while those showing lifestyle versatility often have more than one K+ -channel gene. It is speculated that prokaryotic K+ channels function to allow adaptation to environmental and metabolic changes, although the actual roles of these channels in prokaryotes are not yet known. Unlike enzymes in basic metabolism, K+ channel, though evolved early, appear to play more diverse roles than revealed by animal research. Finding and sorting out these roles will be the goal and challenge of the near future. 相似文献
945.
Misra M Miller KK Kuo K Griffin K Stewart V Hunter E Herzog DB Klibanski A 《American journal of physiology. Endocrinology and metabolism》2005,289(2):E347-E356
Ghrelin is an orexigenic peptide and a growth hormone (GH) secretagogue. Secretory dynamics of ghrelin have not been characterized in adolescents with anorexia nervosa (AN). We hypothesized that, compared with healthy adolescents, girls with AN would have increased ghrelin concentrations measured over 12 h of nocturnal sampling from increased basal and pulsatile secretion, and endogenous ghrelin would independently predict GH and cortisol. We examined ghrelin concentration and secretory dynamics in 22 girls with AN and 18 healthy adolescents 12-18 yr old. Associations between ghrelin, various hormones, and measures of insulin resistance were examined. On Cluster analysis, girls with AN had higher ghrelin concentrations than controls, including total area under the curve (AUC) (P = 0.002), nadir (P = 0.0006), and valley levels (P = 0.002). On deconvolution analysis, secretory burst amplitude (P = 0.03) and burst mass (P = 0.04) were higher in AN, resulting in higher pulsatile (P = 0.05) and total ghrelin secretion (P = 0.03). Fasting ghrelin independently predicted GH burst frequency (r = 0.44, P = 0.005). The nutritional markers body mass index and body fat predicted postglucose and valley ghrelin but not fasting levels. Ghrelin parameters were inversely associated with fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), leptin, and IGF-I. HOMA-IR was the most significant predictor of most ghrelin parameters. Valley ghrelin independently predicted cortisol burst frequency (52% of variability), and ghrelin parameters independently predicted total triiodothyronine and LH levels. Higher ghrelin concentrations in adolescents with AN are a consequence of increased secretory burst mass and amplitude. The most important predictor of ghrelin concentration is insulin resistance, and ghrelin in turn predicts GH and cortisol burst frequency. 相似文献
946.
Involvement of hypothalamic neuropeptide Y in regulating the amphetamine-induced appetite suppression in streptozotocin diabetic rats 总被引:2,自引:0,他引:2
Kuo DY 《Regulatory peptides》2005,127(1-3):19-26
BACKGROUND AND AIM: Amphetamine (AMPH) is a well-known anorectic agent. In normal rats, AMPH-induced anorexia has been attributed to its inhibitory action on hypothalamic neuropeptide Y (NPY), an appetite stimulant in the brain. In diabetic rats, however, if this anorectic response of AMPH might still be observed was uncertain. METHODS: Rats (including normal, diabetic and insulin-treated diabetic rats) were given daily with saline or AMPH for 6 days. Changes in food intake, plasma glucose level (PGL) and NPY content of these rats were measured and compared. RESULTS: The AMPH-induced anorectic response was altered in diabetic rats. Although the anorectic effects of AMPH on the first day of dosing were similar between diabetic and control rats, diabetic rats developed tolerance to this anorexia more rapidly than control rats. This alteration was independent of PGL since PGL levels were not changed following AMPH treatment and PGL normalization induced by phlorizin could not restore the level of AMPH anorexia. On the other hand, this alteration was dependent on the action of NPY because NPY contents were decreased following AMPH treatment and the replacement of insulin in diabetic rats could restore both NPY content and AMPH anorexia. CONCLUSION: These results suggested that the elevated hypothalamic NPY content in diabetic rats was involved in modifying the anorectic response of AMPH. 相似文献
947.
Gagliardi AD Kuo EY Raulic S Wagner GF DiMattia GE 《American journal of physiology. Endocrinology and metabolism》2005,288(1):E92-105
Stanniocalcin (STC)-2 was discovered by its primary amino acid sequence identity to the hormone STC-1. The function of STC-2 has not been examined; thus we generated two lines of transgenic mice overexpressing human (h)STC-2 to gain insight into its potential functions through identification of overt phenotypes. Analysis of mouse Stc2 gene expression indicates that, unlike Stc1, it is not highly expressed during development but exhibits overlapping expression with Stc1 in adult mice, with heart and skeletal muscle exhibiting highest steady-state levels of Stc2 mRNA. Constitutive overexpression of hSTC-2 resulted in pre- and postnatal growth restriction as early as embryonic day 12.5, progressing such that mature hSTC-2-transgenic mice are approximately 45% smaller than wild-type littermates. hSTC-2 overexpression is sometimes lethal; we observed 26-34% neonatal morbidity without obvious dysmorphology. hSTC-2-induced growth retardation is associated with developmental delay, most notably cranial suture formation. Organ allometry studies show that hSTC-2-induced dwarfism is associated with testicular organomegaly and a significant reduction in skeletal muscle mass likely contributing to the dwarf phenotype. hSTC-2-transgenic mice are also hyperphagic, but this does not result in obesity. Serum Ca2+ and PO4 were unchanged in hSTC-2-transgenic mice, although STC-1 can regulate intra- and extracellular Ca2+ in mammals. Interestingly, severe growth retardation induced by hSTC-2 is not associated with a decrease in GH or IGF expression. Consequently, similar to STC-1, STC-2 can act as a potent growth inhibitor and reduce intramembranous and endochondral bone development and skeletal muscle growth, implying that these tissues are specific physiological targets of stanniocalcins. 相似文献
948.
MOTIVATION: Missing data in genotyping single nucleotide polymorphism (SNP) spots are common. High-throughput genotyping methods usually have a high rate of missing data. For example, the published human chromosome 21 data by Patil et al. contains about 20% missing SNPs. Inferring missing SNPs using the haplotype block structure is promising but difficult because the haplotype block boundaries are not well defined. Here we propose a global algorithm to overcome this difficulty. RESULTS: First, we propose to use entropy as a measure of haplotype diversity. We show that the entropy measure combined with a dynamic programming algorithm produces better haplotype block partitions than other measures. Second, based on the entropy measure, we propose a two-step iterative partition-inference algorithm for the inference of missing SNPs. At the first step, we apply the dynamic programming algorithm to partition haplotypes into blocks. At the second step, we use an iterative process similar to the expectation-maximization algorithm to infer missing SNPs in each haplotype block so as to minimize the block entropy. The algorithm iterates these two steps until the total block entropy is minimized. We test our algorithm in several experimental data sets. The results show that the global approach significantly improves the accuracy of the inference. AVAILABILITY: Upon request. 相似文献
949.
Lin CF Yang JS Chang CY Kuo SC Lee MR Huang LJ 《Bioorganic & medicinal chemistry》2005,13(5):1537-1544
A series of benzyloxybenzaldehyde derivatives were prepared and tested against the HL-60 cell line for anticancer activity. Preliminary structure-activity relationships were established. It was discovered that 2-(benzyloxy)benzaldehyde (17), 2-(benzyloxy)-4-methoxybenzaldehyde (26), 2-(benzyloxy)-5-methoxybenzaldehyde (27), 2-(benzyloxy)-5-chlorobenzaldehyde (28), 2-[(3-methoxybenzyl)oxy]benzaldehyde (29), 2-[(2-chlorobenzyl)oxy]benzaldehyde (30), and 2-[(4-chlorobenzyl)oxy]benzaldehyde (31) exhibited significant activity at 1-10 microM. Among them, compound 29 was the most potent one. The morphological assessment and DNA fragmentation analysis indicated that these compounds arrested cell cycle progression at G2/M phase and induced cell apoptosis. They resulted in the loss of mitochondrial membrane potential after 12h of treatment. 相似文献
950.
Summary Due to their similarity to type IV pilus (Tfp) subunits, the pseudopilins, XpsG, -H, -I, -J and -K, have been predicted to
form a pilus-like structure in the type II secretion (T2S) pathway. While overexpression of GspG can result in the formation
of bundle structures, the functions of other pseudopilin are not known yet. In this study, we investigate the mutual interaction
among the pseudopilins and characterize the specialized minor pseudopilin, XpsJ. By using gel filtration and Ni-NTA affinity
chromatography, a linearly ordered interactive relationship is revealed among the four pseudopilins, XpsG-XpsI-XpsH-XpsJ.
Notably, unlike the mutant XpsJ194 staying in the inner membrane, wild type XpsJ stayed in the outer membrane and blocked
the extension of overexpressed XpsG to outside of the cell. By analogy with the Type I pilus structures, we hypothesize that
the XpsH and XpsI might act as an adaptor to connect XpsJ with the major pseudopilin XpsG, and XpsJ might act as a tip to
restrict the out-growth of XpsG in the pilus-like structure of the T2S pathway. 相似文献