全文获取类型
收费全文 | 539篇 |
免费 | 30篇 |
国内免费 | 1篇 |
出版年
2023年 | 7篇 |
2022年 | 12篇 |
2021年 | 7篇 |
2020年 | 9篇 |
2019年 | 11篇 |
2018年 | 13篇 |
2017年 | 15篇 |
2016年 | 19篇 |
2015年 | 25篇 |
2014年 | 28篇 |
2013年 | 53篇 |
2012年 | 57篇 |
2011年 | 44篇 |
2010年 | 32篇 |
2009年 | 17篇 |
2008年 | 29篇 |
2007年 | 14篇 |
2006年 | 28篇 |
2005年 | 24篇 |
2004年 | 38篇 |
2003年 | 21篇 |
2002年 | 6篇 |
2001年 | 5篇 |
2000年 | 4篇 |
1999年 | 3篇 |
1998年 | 3篇 |
1997年 | 1篇 |
1995年 | 3篇 |
1994年 | 2篇 |
1993年 | 2篇 |
1992年 | 4篇 |
1991年 | 7篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1988年 | 4篇 |
1987年 | 1篇 |
1986年 | 5篇 |
1985年 | 2篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1981年 | 1篇 |
1979年 | 3篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1969年 | 1篇 |
排序方式: 共有570条查询结果,搜索用时 15 毫秒
61.
It is well-known that secondary metabolite production is repressed by excess nitrogen substrate available in the fermentation media. Although the nitrogen catabolite repression has been known, quantitative process models have not been reported to represent this phenomenon in complex medium. In this paper, we present a cybernetic model for rifamycin B production via Amycolatopsis mediterranei S699 in complex medium, which is typically used in industry. Nitrogen substrate is assumed to be present in two forms in the medium; available nitrogen (S
ANS) such as free amino acids and unavailable nitrogen (S
UNS) such as peptides and proteins. The model assumes that an inducible enzyme catalyzes the conversion of S
UNS to S
ANS. Although S
ANS is required for growth and product formation, high concentrations were found to inhibit rifamycin production. To experimentally validate the model, five different organic nitrogen sources were used that differ in the ratio of S
ANS/S
UNS. The model successfully predicts higher rifamycin B productivity for nitrogen sources that contain lower initial S
ANS. The higher productivity is attributed to the sustained availability of S
ANS at low concentration via conversion of S
UNS to S
ANS, thereby minimizing the effects of nitrogen catabolite repression on rifamycin production. The model can have applications in model-based optimization of substrate feeding recipe and in monitoring and control of fed batch processes. 相似文献
62.
Prashant M Bapat Debasish Das Sujata V Sohoni Pramod P Wangikar 《Microbial cell factories》2006,5(1):32-14
Background
Industrial fermentation typically uses complex nitrogen substrates which consist of mixture of amino acids. The uptake of amino acids is known to be mediated by several amino acid transporters with certain preferences. However, models to predict this preferential uptake are not available. We present the stoichiometry for the utilization of amino acids as a sole carbon and nitrogen substrate or along with glucose as an additional carbon source. In the former case, the excess nitrogen provided by the amino acids is excreted by the organism in the form of ammonia. We have developed a cybernetic model to predict the sequence and kinetics of uptake of amino acids. The model is based on the assumption that the growth on a specific substrate is dependent on key enzyme(s) responsible for the uptake and assimilation of the substrates. These enzymes may be regulated by mechanisms of nitrogen catabolite repression. The model hypothesizes that the organism is an optimal strategist and invests resources for the uptake of a substrate that are proportional to the returns. 相似文献63.
64.
Chai W Chan KY de Vries R van den Bogeardt AJ de Maeyer JH Schuurkes JA Villalón CM Saxena PR Danser AH MaassenVanDenBrink A 《Life sciences》2012,90(13-14):538-544
AimsBesides acting as gastrointestinal prokinetic agents, 5-hydroxytryptamine4 (5-HT4) receptor agonists can induce positive inotropism in human isolated atrium, but not in ventricles. We pharmacologically evaluated the gastroprokinetic 5-HT4 receptor agonists tegaserod, prucalopride, R199715, cisapride, the cisapride metabolite norcisapride, and the 5-HT3 receptor agonist MKC773 on human isolated myocardial trabeculae, and compared their effects with those induced by 5-HT and 5-methoxytryptamine (5-MeOT).Main methodsAtrial and ventricular trabeculae were paced and changes in contractile force were studied in the absence or presence of the 5-HT4 receptor antagonist GR113808. Partial agonism was assessed using 5-HT4 receptor agonists as antagonists against 5-HT. To test the contribution of L-type calcium channels, the inotropic responses to 5-HT and 5-MeOT were studied in the absence or presence of verapamil.Key findingsLike 5-HT and 5-MeOT, cisapride and tegaserod, but not prucalopride, R19971 and MKC733, induced concentration-dependent positive inotropic responses on atrial trabeculae, which were abolished by GR113808. The L-type calcium channel blocker verapamil attenuated inotropic responses to 5-HT and 5-MeOT. None of the agonists affected the contraction of left ventricular trabeculae. Concentration response curves to 5-HT were shifted to the right in the presence of prucalopride, cisapride, tegaserod and R199715, but not MKC-773.SignificanceWe conclude that (i) inotropic responses to 5-HT and 5-MeOT seem to depend on L-type calcium channels, (ii) tegaserod and cisapride behave as partial 5-HT4 receptor agonists, while prucalopride, norcisapride and MKC-733 cause no significant effects on human atrial trabeculae, (iii) R199715 seems to behave as a 5-HT4 receptor antagonist. 相似文献
65.
Srivastava AK Srivastava PK Al-Khedhairy AA Musarrat J Shukla Y 《Mutation research》2012,747(1):22-28
Allethrin (C(19)H(26)O(3)) is non-cyano-containing pyrethroid insecticide that is used extensively for controlling flies and mosquitoes. Apart from its neurotoxic effects in non-target species, allethrin is reported to be mutagenic in bacterial systems. In this study, we observed oxidative damage-mediated genotoxicity caused by allethrin in Swiss albino mice. The genotoxic potential of allethrin was evaluated using chromosome aberrations (CAs) and a micronuclei (MN) induction assay as genetic end-points. The oral intubation of allethrin (25 and 50mg/kg b.wt.) significantly induces CAs and MN in mouse bone marrow cells. The DNA-damaging potential of allethrin was estimated in mouse liver using the DNA alkaline unwinding assay (DAUA) and by measuring the levels of 8-hydroxy-2'-deoxy-guanosine (8-OH-dG). Furthermore, a dose-dependent increase in reactive oxygen species (ROS) generation and lipid peroxidation (LPO), with a concurrent decrease in superoxide dismutase (SOD) and catalase, confirm its pro-oxidant potential. The DNA-damaging potential of allethrin was found to be mediated through the modulation of p53, p21, GADD45α and MDM-2. These results confirm the genotoxic and the pro-oxidant potential of allethrin in Swiss albino mice. 相似文献
66.
Phylogenetic footprinting is a method for the discovery of regulatory elements in a set of homologous regulatory regions, usually collected from multiple species. It does so by identifying the best conserved motifs in those homologous regions. There are two popular sets of methods-alignment-based and motif-based, which are generally employed for phylogenetic methods. However, serious efforts have lacked to develop a tool exclusively for phylogenetic footprinting, based on either of these methods. Nevertheless, a number of software and tools exist that can be applied for prediction of phylogenetic footprinting with variable degree of success. The output from these tools may get affected by a number of factors associated with current state of knowledge, techniques and other resources available. We here present a critical apprehension of various phylogenetic approaches with reference to prokaryotes outlining the available resources and also discussing various factors affecting footprinting in order to make a clear idea about the proper use of this approach on prokaryotes. 相似文献
67.
Vikas Duhan Neha Joshi P. Nagarajan Pramod Upadhyay 《Journal of visualized experiments : JoVE》2012,(66)
Hyperthermia is a general term used to define the increase in core body temperature above normal. It is often used to describe the increased core body temperature that is observed during fever. The use of hyperthermia as an adjuvant has emerged as a promising procedure for tumor regression in the field of cancer biology. For this purpose, the most important requirement is to have reliable and uniform heating protocols. We have developed a protocol for hyperthermia (whole body) in mice. In this protocol, animals are exposed to cycles of hyperthermia for 90 min followed by a rest period of 15 min. During this period mice have easy access to food and water. High body temperature spikes in the mice during first few hyperthermia exposure cycles are prevented by immobilizing the animal. Additionally, normal saline is administered in first few cycles to minimize the effects of dehydration. This protocol can simulate fever like conditions in mice up to 12-24 hr. We have used 8-12 weeks old BALB/Cj female mice to demonstrate the protocol. 相似文献
68.
Srivastava RK Maiti SK Das D Bapat PM Batta K Bhushan M Wangikar PP 《Journal of industrial microbiology & biotechnology》2012,39(8):1227-1243
The metabolic reaction rate vector is a bridge that links gene and protein expression alterations to the phenotypic endpoint. We present a simple approach for the estimation of flux distribution at key branch points in the metabolic network by using substrate uptake, metabolite secretion rate, and biomass growth rate for transketolase (tkt) deficient Bacillus pumilus ATCC 21951. We find that the glucose-6-phosphate (G6P) and pseudo catabolic/anabolic branch points are flexible in the D: -ribose-producing tkt deficient strain of B. pumilus. The normalized flux through the pentose phosphate pathway (PPP) varied from 1.5 to 86?% under different growth conditions, thereby enabling substantial extracellular accumulation of D: -ribose under certain conditions. Interestingly, the flux through PPP was affected by the extracellular phosphate concentration and dissolved oxygen concentration. This metabolic flexibility may have been the underlying reason for this strain being selected from thousands of others in a screening for D: -ribose producers conducted in the 1970s. 相似文献
69.
Actinomycetes, a class of filamentous bacteria, are an important source of several industrially relevant secondary metabolites.
Several environmental factors including the media composition affect both biomass growth and product formation. Likewise,
several studies have shown that environmental factors cause changes in cellular morphology. However, the relationship between
morphology and product formation is not well understood. In this study, we first characterized the effect of varying concentrations
of phosphate and ammonia in defined media on pellet morphology for an actinomycete Amycolatopsis balhimycina DSM 5908, which produces balhimycin, a glycopeptide antibiotic. Our results show that higher balhimycin productivity is correlated
with the following morphological features: (1) higher pellet fraction in the biomass, (2) small elongated pellets, and (3)
shorter filaments in hyphal growth in the periphery of the pellets. The correlation between morphology and product formation
was also observed in industrially relevant complex media. Although balhimycin production starts after 72 h with maximum production
around 168 h, the morphological changes in pellets are observed as early as 24 h after commencing of the batch. Therefore,
morphology may be used as an early predictor of the end-of-batch productivity. We argue that a similar strategy can be developed
for other strains where morphological indicators may be used as a batch monitoring tool. 相似文献
70.
Protein therapeutics occupy a very significant position in the biopharmaceutical market. In addition to the preclinical, clinical and post marketing challenges common to other drugs, unwanted immunogenicity is known to affect efficacy and/or safety of most biotherapeutics. A standard set of immunogenicity risk factors are routinely used to inform monitoring strategies in clinical studies. A number of in-silico, in vivo and in vitro approaches have also been employed to predict immunogenicity of biotherapeutics, but with limited success. Emerging data also indicates the role of immune tolerance mechanisms and impact of several product-related factors on modulating host immune responses. Thus, a comprehensive discussion of the impact of innate and adaptive mechanisms and molecules involved in induction of host immune responses on immunogenicity of protein therapeutics is needed. A detailed understanding of these issues is essential in order to fully exploit the therapeutic potential of this class of drugs. This Roundtable Session was designed to provide a common platform for discussing basic immunobiological and pharmacological issues related to the role of biotherapeutic-associated risk factors, as well as host immune system in immunogenicity against protein therapeutics. The session included overview presentations from three speakers, followed by a panel discussion with audience participation. 相似文献