全文获取类型
收费全文 | 172篇 |
免费 | 18篇 |
出版年
2023年 | 1篇 |
2022年 | 1篇 |
2021年 | 6篇 |
2020年 | 3篇 |
2019年 | 4篇 |
2018年 | 4篇 |
2017年 | 2篇 |
2016年 | 4篇 |
2015年 | 9篇 |
2014年 | 9篇 |
2013年 | 10篇 |
2012年 | 14篇 |
2011年 | 15篇 |
2010年 | 9篇 |
2009年 | 4篇 |
2008年 | 9篇 |
2007年 | 4篇 |
2006年 | 10篇 |
2005年 | 12篇 |
2004年 | 10篇 |
2003年 | 7篇 |
2002年 | 14篇 |
2001年 | 1篇 |
2000年 | 2篇 |
1999年 | 2篇 |
1998年 | 5篇 |
1996年 | 1篇 |
1995年 | 1篇 |
1994年 | 1篇 |
1993年 | 1篇 |
1992年 | 1篇 |
1989年 | 1篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1983年 | 1篇 |
1981年 | 1篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1974年 | 2篇 |
1971年 | 1篇 |
1969年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有190条查询结果,搜索用时 343 毫秒
101.
Rosie M. A. Maddock Gregory J. Pollard Nicolette G. Moreau Justin J. Perry Paul R. Race 《Biopolymers》2020,111(9):e23390
Intermolecular cross-linking is one of the most important techniques that can be used to fundamentally alter the material properties of a polymer. The introduction of covalent bonds between individual polymer chains creates 3D macromolecular assemblies with enhanced mechanical properties and greater chemical or thermal tolerances. In contrast to many chemical cross-linking reactions, which are the basis of thermoset plastics, enzyme catalysed processes offer a complimentary paradigm for the assembly of cross-linked polymer networks through their predictability and high levels of control. Additionally, enzyme catalysed reactions offer an inherently ‘greener’ and more biocompatible approach to covalent bond formation, which could include the use of aqueous solvents, ambient temperatures, and heavy metal-free reagents. Here, we review recent progress in the development of biocatalytic methods for polymer cross-linking, with a specific focus on the most promising candidate enzyme classes and their underlying catalytic mechanisms. We also provide exemplars of the use of enzyme catalysed cross-linking reactions in industrially relevant applications, noting the limitations of these approaches and outlining strategies to mitigate reported deficiencies. 相似文献
102.
Elodie Bousquet Min Zhao André Ly Guillaume Leroux les Jardins Brigitte Goldenberg Marie-Christine Naud Laurent Jonet Bernadette Besson-Lescure Frederic Jaisser Nicolette Farman Yvonne De Kozak Francine Behar-Cohen 《PloS one》2012,7(11)
We have previously shown that the eye is a mineralocorticoid-sensitive organ and we now question the role of mineralocorticoid receptor (MR) in ocular inflammation. The endotoxin-induced uveitis (EIU), a rat model of human intraocular inflammation, was induced by systemic administration of lipopolysaccharide (LPS). Evaluations were made 6 and 24 hours after intraocular injection of aldosterone (simultaneous to LPS injection). Three hours after onset of EIU, the MR and the glucocorticoid metabolizing enzyme 11-beta hydroxysteroid dehydrogenase type 2 (11β-HSD2) expression were down-regulated in iris/ciliary body and the corticosterone concentration was increased in aqueous humor, altering the normal MR/glucocorticoid receptor (GR) balance. At 24 hours, the GR expression was also decreased. In EIU, aldosterone reduced the intensity of clinical inflammation in a dose-dependent manner. The clinical benefit of aldosterone was abrogated in the presence of the MR antagonist (RU26752) and only partially with the GR antagonist (RU38486). Aldosterone reduced the release of inflammatory mediators (6 and 24 hours: TNF-α, IFN-γ, MIP-1α) in aqueous humor and the number of activated microglia/macrophages. Aldosterone partly prevented the uveitis-induced MR down-regulation. These results suggest that MR expression and activation in iris/ciliary body could protect the ocular structures against damages induced by EIU. 相似文献
103.
104.
Synthetic progestins are used by millions of women as contraceptives and in hormone replacement therapy (HRT), although their molecular mechanisms of action are not well understood. The importance of investigating these mechanisms, as compared to those of progesterone, has been highlighted by clinical evidence showing that medroxyprogesterone acetate (MPA), a first generation progestin, increases the risk of breast cancer and coronary heart disease in HRT users. A diverse range of later generation progestins with varying structures and pharmacological properties is available for therapeutic use and it is becoming clear that different progestins elicit beneficial and adverse effects to different extents. These differences in biological activity are likely to be due to many factors including variations in dose, metabolism, pharmacokinetics, bioavailability, and regulation of, and/or binding, to serum-binding proteins and steroidogenic enzymes. Since the intracellular effects on gene expression and cell signaling of steroids are mediated via intracellular steroid receptors, differential actions via the progesterone and other steroid receptors and their isoforms, are likely to be the major cause of differential intracellular actions of progestins. Since many progestins bind not only to the progesterone receptor, but also to the glucocorticoid, androgen, mineralocorticoid, and possibly the estrogen receptors, it is plausible that synthetic progestins exert therapeutic actions as well as side-effects via some of these receptors. Here we review the molecular mechanisms of intracellular actions of old (MPA, norethisterone, levonorgestrel, gestodene) vs. new (drospirenone, dienogest, trimegestone) generation progestins, via steroid receptors. 相似文献
105.
Keller MJ Madan RP Torres NM Fazzari MJ Cho S Kalyoussef S Shust G Mesquita PM Louissaint N Chen J Cohen HW Diament EC Lee AC Soto-Torres L Hendrix CW Herold BC 《PloS one》2011,6(1):e16475
Background
Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition.Methods
30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL) on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood.Results
A significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p<0.001) and fit a sigmoid Emax pharmacodynamic model. Anti-HIV activity in CVL from women who applied tenofovir persisted when virus was introduced in semen, whereas endogenous anti-HIV activity decreased. Tenofovir did not trigger an inflammatory response or induce sustained loss in endogenous antimicrobial activity or immune mediators.Conclusions
Tenofovir gel had no deleterious impact on soluble mucosal immunity. The increased anti-HIV activity in CVL, which persisted in the presence of semen and correlated with tenofovir concentration, is consistent with the efficacy observed in a recent clinical trial. These results promote quantified CVL anti-HIV activity as a surrogate of tissue pharmacodynamics and as a potential biomarker of adherence to product. This simple, feasible and inexpensive bioassay may promote the development of models more predictive of microbicide efficacy.Trial Registration
ClinicalTrials.gov NCT00594373相似文献106.
Hilde M. Buiting Wim Terpstra Floriske Dalhuisen Nicolette Gunnink-Boonstra Gabe S. Sonke Govert den Hartogh 《PloS one》2013,8(11)
Objective
To explore the extent to which patients have a directing role in decisions about chemotherapy in the palliative phase of cancer and (want to) anticipate on the last stage of life.Design
Qualitative interview study.Methods
In depth-interviews with 15 patients with advanced colorectal or breast cancer at the medical oncology department in a Dutch teaching hospital; interviews were analysed following the principles of thematic content-analysis.Results
All patients reported to know that the chemotherapy they received was with palliative intent. Most of them did not express the wish for information about (other) treatment options and put great trust in their physicians’ treatment advice. The more patients were aware of the severity of their disease, the more they seemed to ‘live their life’ in the present and enjoy things besides having cancer. Such living in the present seemed to be facilitated by the use of chemotherapy. Patients often considered the ‘chemotherapy-free period’ more stressful than periods when receiving chemotherapy despite their generally improved physical condition. Chemotherapy (regardless of side-effects) seemed to shift patients’ attention away from the approaching last stage of life. Interestingly, although patients often discussed advance care planning, they were reluctant to bring on end-of-life issues that bothered them at that specific moment. Expressing real interest in people ‘as a person’ was considered an important element of appropriate care.Conclusions
Fearing their approaching death, patients deliberately focus on living in the present. Active (chemotherapy) treatment facilitates this focus, regardless of the perceived side-effects. However, if anxiety for what lies ahead is the underlying reason for treatment, efforts should be made in assisting patients to find other ways to cope with this fear. Simultaneously, such an approach may reduce the use of burdensome and sometimes costly treatment in the last stage of life. 相似文献107.
108.
Mulaudzi T Ludidi N Ruzvidzo O Morse M Hendricks N Iwuoha E Gehring C 《FEBS letters》2011,585(17):2693-2697
While there is evidence of nitric oxide (NO)-dependent signalling via the second messenger cyclic guanosine 3',5'-monophosphate (cGMP) in plants, guanylate cyclases (GCs), enzymes that catalyse the formation of cGMP from guanosine 5'-triphosphate (GTP) have until recently remained elusive and none of the candidates identified to-date are NO-dependent. Using both a GC and heme-binding domain specific (H-NOX) search motif, we have identified an Arabidopsis flavin monooxygenase (At1g62580) and shown electrochemically that it binds NO, has a higher affinity for NO than for O(2) and that this molecule can generate cGMP from GTP in vitro in an NO-dependent manner. 相似文献
109.
Mikulski R Avvaru BS Tu C Case N McKenna R Silverman DN 《Archives of biochemistry and biophysics》2011,506(2):97-187
The rate limiting step in catalysis of bicarbonate dehydration by human carbonic anhydrase II (HCA II) is an intramolecular proton transfer from His64 to the zinc-bound hydroxide. We have examined the role of Tyr7 using site-specific mutagenesis and measuring catalysis by the 18O exchange method using membrane inlet mass spectrometry. The side chain of Tyr7 in HCA II extends into the active-site cavity about 7 Å from the catalytic zinc atom. Replacement of Tyr7 with eight other amino acids had no effect on the interconversion of bicarbonate and CO2, but in some cases caused enhancements in the rate constant of proton transfer by nearly 10-fold. The variant Y7I HCA II enhanced intramolecular proton transfer approximately twofold; its structure was determined by X-ray crystallography at 1.5 Å resolution. No changes were observed in the ordered solvent structure in the active-site cavity or in the conformation of the side chain of the proton shuttle His64. However, the first 11 residues of the amino-terminal chain in Y7I HCA II assumed an alternate conformation compared with the wild type. Differential scanning calorimetry showed variants at position 7 had a melting temperature approximately 8 °C lower than that of the wild type. 相似文献
110.
Timothy W. Kenealy Matthew J. G. Parsons A. Paul B. Rouse Robert N. Doughty Nicolette F. Sheridan Jennifer K. Harré Hindmarsh Sarah C. Masson Harry H. Rea 《PloS one》2015,10(3)