首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   454篇
  免费   41篇
  2020年   2篇
  2019年   3篇
  2018年   5篇
  2017年   7篇
  2016年   8篇
  2015年   19篇
  2014年   16篇
  2013年   31篇
  2012年   29篇
  2011年   26篇
  2010年   22篇
  2009年   28篇
  2008年   22篇
  2007年   27篇
  2006年   20篇
  2005年   11篇
  2004年   19篇
  2003年   16篇
  2002年   12篇
  2001年   12篇
  2000年   12篇
  1999年   12篇
  1998年   11篇
  1997年   5篇
  1996年   5篇
  1995年   4篇
  1994年   2篇
  1993年   6篇
  1992年   10篇
  1991年   9篇
  1990年   8篇
  1989年   3篇
  1988年   5篇
  1987年   6篇
  1986年   4篇
  1985年   6篇
  1984年   4篇
  1983年   3篇
  1982年   6篇
  1981年   2篇
  1977年   4篇
  1976年   5篇
  1975年   2篇
  1974年   2篇
  1973年   3篇
  1969年   2篇
  1966年   2篇
  1962年   2篇
  1938年   2篇
  1877年   1篇
排序方式: 共有495条查询结果,搜索用时 15 毫秒
101.
In an endotoxaemic mouse model of sepsis, a tissue-based proteomics approach for biomarker discovery identified long pentraxin 3 (PTX3) as the lead candidate for inflamed myocardium. When the redox-sensitive oligomerization state of PTX3 was further investigated, PTX3 accumulated as an octamer as a result of disulfide-bond formation in heart, kidney, and lung—common organ dysfunctions seen in patients with sepsis. Oligomeric moieties of PTX3 were also detectable in circulation. The oligomerization state of PTX3 was quantified over the first 11 days in critically ill adult patients with sepsis. On admission day, there was no difference in the oligomerization state of PTX3 between survivors and non-survivors. From day 2 onward, the conversion of octameric to monomeric PTX3 was consistently associated with a greater survival after 28 days of follow-up. For example, by day 2 post-admission, octameric PTX3 was barely detectable in survivors, but it still constituted more than half of the total PTX3 in non-survivors (p < 0.001). Monomeric PTX3 was inversely associated with cardiac damage markers NT-proBNP and high-sensitivity troponin I and T. Relative to the conventional measurements of total PTX3 or NT-proBNP, the oligomerization of PTX3 was a superior predictor of disease outcome.Severe sepsis is a common acute illness in intensive care units (ICUs)1 and is associated with high mortality rates and chronic morbidity. When it is associated with hypotension (termed septic shock), the mortality rate is very high (50% to 80%). Cardiovascular dysfunction during sepsis is multifactorial and often associated with minimal loss of myocardial tissue, but with the release of myocardial-specific markers such as troponins. A key unmet clinical need is the availability of a biomarker that predicts myocardial dysfunction early, monitors response to treatment, and thus identifies a cohort of patients at higher risk of septic shock to aid in targeted interventions and improve outcome (1).In the present study, we used proteomics for biomarker discovery. Over the past decade, the field of proteomics has made impressive progress. Plasma and serum, however, are the most complex proteomes of the human body (2), and less abundant proteins tend to be missed in untargeted proteomics analyses of body fluids (3). Thus, we pursued an alternative strategy: the application of proteomics to diseased tissue (4), in which the potential biomarkers are less dilute and have a less uncertain cellular origin (57). We employed a solubility-based protein-subfractionation methodology to analyze inflammatory proteins that are retained with sepsis tissue. This innovative proteomics approach shall reveal inflammatory molecules that reside and persist within inflamed tissue. We hypothesized that proteins that accumulate in the susceptible tissues are more likely to be biomarker candidates for organ dysfunction than proteins that just circulate in plasma or serum. We then validated our proteomics findings in the preclinical model using samples from sepsis patients admitted to ICUs.  相似文献   
102.
103.
We describe an open-source kPAL package that facilitates an alignment-free assessment of the quality and comparability of sequencing datasets by analyzing k-mer frequencies. We show that kPAL can detect technical artefacts such as high duplication rates, library chimeras, contamination and differences in library preparation protocols. kPAL also successfully captures the complexity and diversity of microbiomes and provides a powerful means to study changes in microbial communities. Together, these features make kPAL an attractive and broadly applicable tool to determine the quality and comparability of sequence libraries even in the absence of a reference sequence. kPAL is freely available at https://github.com/LUMC/kPAL.

Electronic supplementary material

The online version of this article (doi:10.1186/s13059-014-0555-3) contains supplementary material, which is available to authorized users.  相似文献   
104.
H D Zeller  R Hille  M S Jorns 《Biochemistry》1989,28(12):5145-5154
Corynebacterial sarcosine oxidase contains both covalently and noncovalently bound FAD and forms complexes with various heterocyclic carboxylic acids (D-proline and 2-furoic, 2-pyrrolecarboxylic, and 2-thiophenecarboxylic acids). 2-Furoic acid, a competitive inhibitor with respect to sarcosine, selectively perturbs the absorption spectrum of the noncovalent flavin, suggesting that the enzyme has a single sarcosine binding site near the noncovalent flavin. Several heterocyclic amines have been identified as new substrates for the enzyme. Similar reactivity is observed with L-proline and L-pipecolic acid whereas L-2-azetidine-carboxylic acid is less reactive. Turnover with L-proline is slow (TN = 4.4 min-1) as compared with sarcosine (TN = 1000 min-1). Anaerobic reduction of the enzyme with heterocyclic amine substrates at pH 8.0 occurs as a biphasic reaction. A similar long-wavelength intermediate is formed in the initial fast phase of each reaction and then decays in a slower second phase to yield 1,5-dihydroFAD. The slow phase is not kinetically significant during aerobic turnover at pH 8.0 and is absent when the anaerobic reactions are conducted at pH 7.0. EPR and other studies at pH 7.0 show that the long-wavelength species is a half-reduced form of the enzyme (1 electron/substrate-reducible flavin) containing 0.9 mol of flavin radical/mol of substrate-reducible flavin. This biradical intermediate exhibits an absorption spectrum similar to that expected for a 50:50 mixture of red anionic and blue neutral flavin radicals. A similar long-wavelength species is observed during titration of the enzyme with sarcosine and other reductants. Studies with L-proline suggest that reduction of the enzyme involves initial transfer of two electrons to the noncovalent flavin. The covalent flavin is not required and can be complexed with sulfite without affecting the rate of electron transfer. The initial half-reduced form of the enzyme appears to be rapidly converted to the biradical form via comproportionation of the reduced noncovalent flavin with the oxidized covalent flavin.  相似文献   
105.

Background  

Campylobacter jejuni is the predominant cause of antecedent infection in post-infectious neuropathies such as the Guillain-Barré (GBS) and Miller Fisher syndromes (MFS). GBS and MFS are probably induced by molecular mimicry between human gangliosides and bacterial lipo-oligosaccharides (LOS). This study describes a new C. jejuni-specific high-throughput AFLP (htAFLP) approach for detection and identification of DNA polymorphism, in general, and of putative GBS/MFS-markers, in particular.  相似文献   
106.
107.
Molecular and developmental studies of limb pattern formation have recently gained widespread attention. The fact that vertebrate limbs are amenable to both genetic and embryological manipulations has established this model system as a valuable paradigm for studying vertebrate development. Limb buds are polarised along all three major axes and the establishment of the dorso-ventral (DV) polarity is dependent upon cues localised in the trunk, where a DV ectodermal interface is produced by confrontation of dorsal and ventral identities. By analogy to Drosophila imaginal disc development, this interface has been proposed to determine and position an ectodermal organising centre, the Apical Ectodermal Ridge (AER), controlling limb bud outgrowth. Recent fate mapping studies(1) and studies of genes regulating DV limb polarity(2-6), AER formation(7,8) and differentiation(9) suggest, however, that DV patterning and AER induction, though coordinately regulated during limb bud outgrowth, may early on be more dissociated than expected.  相似文献   
108.
The influence of dopamine as compared with dobutamine on glucose homeostasis has been assessed in thyroidectomized euthyroid rats. Both sympathomimetic agents were given intravenously over 6 h at four dosages, varying from 2 to 30 micrograms.kg-1.min-1. Immediately before the end of the infusion period, serum concentrations of glucose and insulin as well as plasma glucagon concentrations were measured. Dobutamine infusions did not exert any influence on these parameters. At a dose of 7.5 micrograms.kg-1.min-1, dopamine infusion caused a decrease in glucose concentrations, accompanied by a rise of glucagon and insulin levels. Glucose levels were significantly increased in the presence of unaltered insulin and decreasing glucagon levels at higher dopamine doses. The rise in glucose levels was reversed by 8 micrograms.kg-1.min-1 and inverted to a decrease by 12 micrograms.kg-1.min-1 of the alpha-adrenergic blocking agent phentolamine, simultaneously infused with 15 micrograms.kg-1.min-1 dopamine, while the insulin levels were increased and glucagon levels remained elevated. These findings demonstrate that dopamine acts on glucoregulation divergently, according to the dosage applied. The data suggest that dopamine rather than dobutamine treatment may disturb glucose homeostasis.  相似文献   
109.
Reductive cleavage of fully methylated, partially O-carboxymethylated cellulose had previously been shown to produce 4-O-acetyl-1,5-anhydro-2,3,6-tri-O-methyl-, -2-O-(methoxycarbonylmethyl)-3,6-di-O-methyl-, -3-O-(methoxycarbonylmethyl)-2,6-di-O-methyl-, -6-O-(methoxycarbonylmethyl)-2,3-di-O-methyl-, -2,3-di-O-(methoxycarbonylmethyl)-6-O-methyl-, -2,6-di-O-(methoxycarbonylmethyl)-3-O-methyl-, -3,6-di-O-(methoxycarbonylmethyl)-2-O-methyl-, and -2,3,6-tri-O-(methoxycarbonylmethyl)-D-glucitol. Described herein is the independent synthesis of these derivatives, except for the first, which had been reported. In addition, their 1H-n.m.r. spectra, chemical-ionization (NH3) mass spectra, and electronionization mass spectra are tabulated.  相似文献   
110.
RFLP markers for the wheat powdery mildew resistance genes Pm1 and Pm2 were tagged by means of near-isogenic lines. The probe Whs178 is located 3 cM from the Pm1 gene. For the powdery mildew resistance gene Pm2, two markers were identified. The linkage between the Pm2 resistance locus and one of these two probes was estimated to be 3 cM with a F2 population. Both markers can be used to detect the presence of the corresponding resistance gene in commercial cultivars. Bulked segregant analysis was applied to identify linkage disequillibrium between the resistance gene Pm18 and the abovementioned marker, which was linked to this locus at a distance of 4 cM. Furthermore, the RAPD marker OPH-111900 (5-CTTCCGCAGT-3) was selected with pools created from a population segregating for the resistance of Trigo BR 34. The RAPD marker was mapped about 13 cM from this resistance locus.  相似文献   
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号