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81.
Nonhuman primates contribute unique understanding to anovulatory infertility in women 总被引:2,自引:0,他引:2
Abbott DH Foong SC Barnett DK Dumesic DA 《ILAR journal / National Research Council, Institute of Laboratory Animal Resources》2004,45(2):116-131
Anovulatory infertility affects a large proportion of reproductive-aged women. Major improvements in successful clinical treatment of this prevalent disorder in women's health have been made possible because of biomedical research employing nonhuman primates. Experiments on female rhesus monkeys were the first to demonstrate that the key hypothalamic neurotransmitter, gonadotropin-releasing hormone, involved in stimulating pituitary gonadotropin synthesis, storage, and release was bioactive only when released in approximately hourly bursts. This breakthrough in understanding gonadotropin regulation enabled identification of hypogonadotropic, apparently normogonadotropic, and hypergonadotropic forms of anovulatory infertility, and development of appropriate stimulatory or inhibitory gonadotropin therapies. Treatments to overcome anovulatory infertility represent one of the major advances in clinical reproductive endocrinology during the last 25 yr. The future promise of nonhuman primate models for human ovulatory dysfunction, however, may be based on an increased understanding of molecular and physiological mechanisms responsible for fetal programming of adult metabolic and reproductive defects and for obesity-related, hyperinsulinemic impairment of oocyte development. 相似文献
82.
Two antineoplastic agents, chlornaphazine (CN) and chlorambucil (CHL), were tested for the induction of dominant lethal mutations in male mice. Both compounds are nitrogen mustard derivatives and have been shown to be genotoxic in a variety of organisms. CN was administered intraperitoneally to DBA/2J male mice at a dosage of 0, 500, 1000, or 1500 mg/kg body weight (bw). Immediately following treatment, each male was mated at 4-day intervals to two virgin C57BL/6J females. CHL was administered intraperitoneally to C3H/HeJ and DBA/2J males at a dosage of 0, 2.5, or 5.0 mg/kg bw. These males were mated at weekly intervals to two virgin T-stock females. CN and CHL clearly induced dominant lethal mutations. CN induced dominant lethal effects in all post-meiotic germ-cell stages of treated DBA males, with a clear dose-response relationship. The results with CHL-treated DBA males indicated that all post-meiotic germ-cell stages, except late-spermatids, were affected by CHL treatment, while in C3H males, CHL induced dominant lethal effects in all post-meiotic germ-cell stages. A dose-response relationship was also observed with CHL in C3H male mice. In the present experiments, regardless of the agent or the mouse strain used, spermatids appeared to be the germ-cell stage most sensitive to dominant lethal induction. 相似文献
83.
84.
Ward SM Desgrosellier JS Zhuang X Barnett JV Galper JB 《The Journal of biological chemistry》2002,277(51):50183-50189
Little is known regarding factors that induce parasympathetic responsiveness during cardiac development. We demonstrated previously that in atrial cells cultured from chicks 14 days in ovo, transforming growth factor beta (TGFbeta) decreased parasympathetic inhibition of beat rate by the muscarinic agonist, carbamylcholine, by 5-fold and decreased expression of Galpha(i2). Here in atrial cells 5 days in ovo, TGFbeta increased carbamylcholine inhibition of beat rate 2.5-fold and increased expression of Galpha(i2). TGFbeta also stimulated Galpha(i2) mRNA expression and promoter activity at day 5 while inhibiting them at day 14 in ovo. Over the same time course expression of type I TGFbeta receptors, chick activin receptor-like kinase 2 and 5 increased with a 2.3-fold higher increase in activin receptor-like kinase 2. Constitutively active activin receptor-like kinase 2 inhibited Galpha(i2) promoter activity, whereas constitutively active activin receptor-like kinase 5 stimulated Galpha(i2) promoter activity independent of embryonic age. In 5-day atrial cells, TGFbeta stimulated the p3TP-lux reporter, which is downstream of activin receptor-like kinase 5 and had no effect on the activity of the pVent reporter, which is downstream of activin receptor-like kinase 2. In 14-day cells, TGFbeta stimulated both pVent and p3TP-lux. Thus TGFbeta exerts opposing effects on parasympathetic response and Galpha(i2) expression by activating different type I TGFbeta receptors at distinct stages during cardiac development. 相似文献
85.
Barnett JV Desgrosellier JS 《Birth defects research. Part C, Embryo today : reviews》2003,69(1):58-72
The proper formation and function of the vertebrate heart requires a multitude of specific cell and tissue interactions. These interactions drive the early specification and assembly of components of the cardiovascular system that lead to a functioning system before the attainment of the definitive cardiac and vascular structures seen in the adult. Many of these adult structures are hypothesized to require both proper molecular and physical cues to form correctly. Unlike any other organ system in the embryo, the cardiovascular system requires concurrent function and formation for the embryo to survive. An example of this complex interaction between molecular and physical cues is the formation of the valves of the heart. Both molecular cues that regulate cell transformation, migration, and extracellular matrix deposition, and physical cues emanating from the beating heart, as well as hemodynamic forces, are required for valvulogenesis. This review will focus on molecules and emerging pathways that guide early events in valvulogenesis. 相似文献
86.
Kwaks TH Barnett P Hemrika W Siersma T Sewalt RG Satijn DP Brons JF van Blokland R Kwakman P Kruckeberg AL Kelder A Otte AP 《Nature biotechnology》2003,21(5):553-558
The expression of transgenic proteins is often low and unstable over time, a problem that may be due to integration of the transgene in repressed chromatin. We developed a screening technology to identify genetic elements that efficiently counteract chromatin-associated repression. When these elements were used to flank a transgene, we observed a substantial increase in the number of mammalian cell colonies that expressed the transgenic protein. Expression of the shielded transgene was, in a copy number-dependent fashion, substantially higher than the expression of unprotected transgenes. Also, protein production remained stable over an extended time period. The DNA elements are small, not exceeding 2,100 base pairs (bp), and they are highly conserved between human and mouse, at both the functional and sequence levels. Our results demonstrate the existence of a class of genetic elements that can readily be applied to more efficient transgenic protein production in mammalian cells. 相似文献
87.
O'Harte FP Boyd AC McKillop AM Abdel-Wahab YH McNulty H Barnett CR Conlon JM Højrup P Flatt PR 《Peptides》2000,21(10):1519-1526
Human insulin was glycated under hyperglycemic reducing conditions and a novel diglycated form (M(r) 6135.1 Da) was purified by RP-HPLC. Endoproteinase Glu-C digestion combined with mass spectrometry and automated Edman degradation localized glycation to Gly(1) and Phe(1) of the insulin A- and B-chains, respectively. Intraperitoneal (i.p.) administration of diglycated insulin to mice alone or in combination with glucose (7 nmol/kg) resulted in a 43-61% and 11-34% reduction in glucose lowering activity, respectively, compared with native insulin. Consistent with these findings, diglycated insulin (10(-9) to 10(-7) mol/liter) was 22-38% less effective (P < 0.001) than native insulin in stimulating glucose uptake, glucose oxidation and glycogen production in isolated mouse abdominal muscle. 相似文献
88.
Hempel N Barnett AC Bolton-Grob RM Liyou NE McManus ME 《Biochemical and biophysical research communications》2000,276(1):224-230
The sulfonation of estrogens by human estrogen sulfotransferase (humSULT1E1) plays a vital role in controlling the active levels of these hormones in the body. To understand more fully the structural and functional characteristics of humSULT1E1, we have carried out site-directed mutagenesis of critical amino acids found in the substrate-binding cleft. Three single amino acid mutations of humSULT1E1 (V145E, H107A, and K85A) were created in this study. Kinetic studies were used to provide information about the importance of these residues in substrate specificity and catalysis, using a variety of substrates. Lysine at position 85 has been proposed to be within hydrogen bonding distance to the 3alpha-phenol group of beta-estradiol, thereby stabilising the substrate in the active site. However, substitution to a neutral alanine at this position improved substrate specificity of humSULT1E1 for beta-estradiol, estrone, and dehydroepiandrosterone (DHEA). The exchange of valine 145 for negatively charged glutamic acid markedly improved the ability of humSULT1E1 to sulfonate dopamine, but caused a reduction in specificity constants toward steroids tested, in particular DHEA. The presence of a histidine residue at position 107 was shown to be essential for the production of a functional protein, as substitution of this amino acid to alanine resulted in complete loss of activity of humSULT1E1 towards all substrates tested. 相似文献
89.
Stanley EG Biben C Allison J Hartley L Wicks IP Campbell IK McKinley M Barnett L Koentgen F Robb L Harvey RP 《Genesis (New York, N.Y. : 2000)》2000,26(4):259-264
The mouse Cer1 (mCer1, Cer-l, Cerr1) gene encodes one member of a family of cytokines structurally and functionally related to the Xenopus head-inducing factor, Cerberus (xCer). We generated a mouse line in which the Cer1 gene was inactivated by replacing the first coding exon with a lacZ reporter gene. Mice homozygous for this allele (Cer1(lacZ)) showed no apparent perturbation of embryogenesis or later development. However, the lacZ reporter revealed a number of hitherto uncharacterised sites of Cer1 expression in late fetal and adult tissues. Preliminary analysis suggests that Cer1 is not essential for their morphogenesis, differentiation, or homeostasis. 相似文献
90.
Barnett SS Smolinski P Vorp DA 《Computer methods in biomechanics and biomedical engineering》2000,3(4):287-296
The finite element method was used to analyze heat transfer within a section of the forearm while exposed to different ambient conditions and with different metabolic states. The three-dimensional model accounts for the different material properties of bone, muscle and blood and incorporates a single artery-vein pair for counter-current heat exchange. The geometry of the model was developed from anatomical cross-sectional images of the forearm. The model was used to determine the effects or rest vs. exercise, free vs. forced surface convection and 0 degrees C vs. -20 degrees C external temperatures. The results of the model were compared to experimental data and the model exhibits qualitatively correct behaviour. This model can be used to study hyperthermia, burns and cryogenic freezing of tissue. 相似文献