全文获取类型
收费全文 | 1297篇 |
免费 | 101篇 |
出版年
2024年 | 1篇 |
2023年 | 5篇 |
2022年 | 35篇 |
2021年 | 55篇 |
2020年 | 32篇 |
2019年 | 30篇 |
2018年 | 54篇 |
2017年 | 26篇 |
2016年 | 63篇 |
2015年 | 84篇 |
2014年 | 75篇 |
2013年 | 89篇 |
2012年 | 100篇 |
2011年 | 116篇 |
2010年 | 71篇 |
2009年 | 54篇 |
2008年 | 78篇 |
2007年 | 95篇 |
2006年 | 70篇 |
2005年 | 70篇 |
2004年 | 59篇 |
2003年 | 58篇 |
2002年 | 35篇 |
2001年 | 2篇 |
2000年 | 4篇 |
1999年 | 8篇 |
1998年 | 9篇 |
1997年 | 4篇 |
1996年 | 2篇 |
1995年 | 3篇 |
1993年 | 2篇 |
1992年 | 1篇 |
1991年 | 2篇 |
1989年 | 1篇 |
1988年 | 2篇 |
1979年 | 1篇 |
1973年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有1398条查询结果,搜索用时 15 毫秒
1.
2.
Ekaterina Maidji Galina Kosikova Pheroze Joshi Cheryl A. Stoddart 《Journal of virology》2012,86(23):12795-12805
Human cytomegalovirus (HCMV) is the leading viral cause of birth defects and life-threatening lung-associated diseases in premature infants and immunocompromised children. Although the fetal lung is a major target organ of the virus, HCMV lung pathogenesis has remained unexplored, possibly as a result of extreme host range restriction. To overcome this hurdle, we generated a SCID-hu lung mouse model that closely recapitulates the discrete stages of human lung development in utero. Human fetal lung tissue was implanted into severe combined immunodeficient (CB17-scid) mice and inoculated by direct injection with the VR1814 clinical isolate of HCMV. Virus replication in the fetal lung was assessed by the quantification of infectious virus titers and HCMV genome copies and the detection of HCMV proteins by immunohistochemistry and Western blotting. We show that HCMV efficiently replicated in the lung implants during a 2-week period, forming large viral lesions. The virus productively infected alveolar epithelial and mesenchymal cells, imitating congenital infection of the fetal lung. HCMV replication triggered apoptosis near and within the viral lesions and impaired the production of surfactant proteins in the alveolar epithelium. Our findings highlight that congenital and neonatal HCMV infection can adversely impact lung development, leading to pneumonia and acute lung injury. We have successfully developed a small-animal model that closely recapitulates fetal and neonatal lung development and provides a valuable, biologically relevant tool for an understanding of the lung pathogenesis of HCMV as well as other human respiratory viruses. Additionally, this model would greatly facilitate the development and testing of new antiviral therapies for HCMV along with select human pulmonary pathogens. 相似文献
3.
Membrane preparations, capable of high rates of respiration-linked ATP synthesis, have been obtained from a gram-positive methylotrophic bacterium Bacillus sp. MGA3. NADH, succinate, reduced TMPD and methanol were shown to be suitable substrates for the oxidative phosphorylation. Esterification of orthophosphate was dependent on electron transfer, as evidenced by the requirement for both substrate and oxygen. Phosphorylation was also dependent on ADP and was destroyed by boiling the membrane preparation. The phosphorylation was markedly uncoupled by carbonyl cyanide p-(trichloromethoxy)-phenylhydrazone (CCCP) and was inhibited by N,N-dicyclohexylcarbodiimide (DCCD). KCN caused strong inhibition of substrate oxidation as well as phosphorylation for all substrates tested. Rotenone, amytal and antimycin A caused inhibition when NADH or methanol were used as substrates. Antimycin A inhibited respiration and ATP synthesis with succinate as substrate and had no effect on ascorbate —N,N,N,N-tetramethyl-p-phenylenediimide (TMPD) oxidation by membrane preparations of Bacillus sp. MGA3. P/O ratios determined were 2.4 with NADH, 1.7 with succinate and 0.8 with reduced TMPD. The measured P/O ratio with methanol-oxidizing system was similar to that with NADH (about 2.4).Abbreviations CCCP
Carbonyl cyanide p-(trichloromethoxy)-phenylhydrazone
- DCCD
N,N-dicyclohexylcarbodiimide
- TMPD
N,N,N,N-tetramethyl-p-phenylenediimide
- Q
ubiquinone Q 相似文献
4.
Vanadyl caused a time- and dose-dependent degradation of deoxyribose to carbonyl products detectable with thiobarbituric acid. This process was inhibited by catalase, ethanol or HEPES; whereas superoxide dismutase was without effect. Vanadate did not substitute for vanadyl even in the presence of a source of O2- plus H2 O 2; but it did so in the presence of reductants such as thiols or NADH. It appears that hydrogen peroxide, generated by the autoxidation of vanadyl, is reduced by vanadyl to the hydroxyl radical; which, in turn, was responsible for the degradation of deoxyribose. A similar process might contribute to the toxic and pharmacological effects of vanadium salts. 相似文献
5.
Chromosome polymorphism in populations of the grasshopper Trimerotropis pallidipennis from southern Argentina 总被引:1,自引:0,他引:1
Three populations of the grasshopper Trimerotropis pallidipennis from southern Argentina have been studied cytologically. A very characteristic B-chromosome was found in all three. They also showed geographical variability in respect of the presence of pericentric inversions, and the inversion system was found to influence chiasma frequency. The Laguna Blanca population, which is on the hypothetical pathway the species is believed to have followed during its migration from northern to southern latitudes, has the same karyotype composition as the N. American form, with fixed inversions in the 3 largest autosomes and the X-chromosome. Its members have a high total chiasma frequency and a great number of interstitial chiasmata. The Sierra de la Ventana population, situated at the absolute eastern border of the species distribution is highly polymorphic with respect to the presence of inversions in the medium chromosomes. Its members have the lowest total chiasma frequency and a greatly reduced number of interstitial chiasmata. Situated geographically between the other two, the Choele-Choel population has the highest frequency of inversions and many of them are homozygous. Its members have a higher total chiasma frequency than that observed in specimens from Sierra de la Ventana, and a greatly reduced number of interstitial chiasmata, similar to that observed in individuals from the latter population. 相似文献
6.
Iliana Ionkova Aleksandar Shkondrov Yancho Zarev Ekaterina Kozuharova Ilina Krasteva 《Current issues in molecular biology》2022,44(9):3884
Some of the most effective anticancer compounds are still derived from plants since the chemical synthesis of chiral molecules is not economically efficient. Rapid discovery of lead compounds with pronounced biological activity is essential for the successful development of novel drug candidates. This work aims to present the chemical diversity of antitumor bioactive compounds and biotechnological approaches as alternative production and sustainable plant biodiversity conservation. Astragalus spp., (Fabaceae) and Gloriosa spp. (Liliaceae) are selected as research objects within this review because they are known for their anticancer activity, because they represent two of the largest families respectively in dicots and monocots, and also because many of the medicinally important plants are rare and endangered. We summarized the ethnobotanical data concerning their anticancer application, highlighted the diversity of their secondary metabolites possessing anticancer properties such as saponins, flavonoids, and alkaloids, and revealed the potential of the in vitro cultures as an alternative way of their production. Since the natural supply is limited, it is important to explore the possibility of employing plant cell or organ in vitro cultures for the biotechnological production of these compounds as an alternative. 相似文献
7.
Lichens and mosses promote alternate stable plant communities in the New Jersey Pinelands 总被引:13,自引:0,他引:13
Severely burned areas in the pitch pine-dominated forests of the New Jersey Pinelands may remain open and only vegetated with mats of lichens and mosses and sparse, scattered vascular plants for many decades. We hypothesize that climate-driven alternation between moss and lichen domination of the cryptogam mats may foster and inhibit, respectively, vascular plant development. We propose that these processes are mediated by the inhibitory effects of lichens on seed germination and seedling establishment versus a facilitating effect of mosses. We tested the hypothesis by 1) detailed surveys of the composition of cryptogam mats and their association with vascular plants, 2) experimental studies of the effects of tissue leachates on seed germination, 3) observations of mycorrhizal infection in field-collected plants, and 4) experimental tests of seedling emergence from mats. Lichen dominance in the mats was correlated with low densities of vascular plants (graminoids and ericoid shrubs), thin organic horizons on the soil, and high levels of light availability; moss dominance was correlated with higher vascular plant densities, thicker organic horizons, and lower light. Tissue extracts of lichens strongly inhibited seed germination, while moss extracts had no effect. Similarly, mycorrhizal infection by both ecto- and endomycorrhizae was lower in plants growing within lichen mats than in moss mats or in bare soil. However, thick mats of both types of cryptogam inhibited seedling emergence. We observed that moss-dominated patches became overgrown with lichens during a series of very dry, hot summers during the study. These observations all support the hypothesis that fluctuating warm and dry versus cool and moist conditions allow alternative stable states (open cryptogam mats vs succession to pine forest) to develop. 相似文献
8.
Zhu Z Burnett CM Maksymov G Stepniak E Sierra A Subbotina E Anderson ME Coetzee WA Hodgson-Zingman DM Zingman LV 《Biochemical and biophysical research communications》2011,(4):637-641
The cardiovascular system operates under demands ranging from conditions of rest to extreme stress. One mechanism of cardiac stress tolerance is action potential duration shortening driven by ATP-sensitive potassium (KATP) channels. KATP channel expression has a significant physiologic impact on action potential duration shortening and myocardial energy consumption in response to physiologic heart rate acceleration. However, the effect of reduced channel expression on action potential duration shortening in response to severe metabolic stress is yet to be established. Here, transgenic mice with myocardium-specific expression of a dominant negative KATP channel subunit were compared with littermate controls. Evaluation of KATP channel whole cell current and channel number/patch was assessed by patch clamp in isolated ventricular cardiomyocytes. Monophasic action potentials were monitored in retrogradely perfused, isolated hearts during the transition to hypoxic perfusate. An 80–85% reduction in cardiac KATP channel current density results in a similar magnitude, but significantly slower rate, of shortening of the ventricular action potential duration in response to severe hypoxia, despite no significant difference in coronary flow. Therefore, the number of functional cardiac sarcolemmal KATP channels is a critical determinant of the rate of adaptation of myocardial membrane excitability, with implications for optimization of cardiac energy consumption and consequent cardioprotection under conditions of severe metabolic stress. 相似文献
9.
The mechanism of the vanadate (V(v))-dependent oxidation of NADH was different in phosphate buffers and in phosphate-free media. In phosphate-free media (aqueous medium or HEPES buffer) the vanadyl (V(v)) generated by the direct V(v)-dependent oxidation of NADH formed a complex with V(v). In phosphate buffers V(v) autoxidized instead of forming a complex with V(v). The generated superoxide radical (O2−) initiated, in turn, a high-rate free radical chain oxidation of NADH. Phosphate did not stimulate the V(v)-dependent NADH oxidation catalyzed by O2−-generating systems. Monovanadate proved to be a stronger catalyzer of NADH oxidation as compared to polyvanadate. 相似文献
10.
Murray E McKenna EO Burch LR Dillon J Langridge-Smith P Kolch W Pitt A Hupp TR 《Biochemistry》2007,46(48):13742-13751
Anterior gradient-2 protein was identified using proteomic technologies as a p53 inhibitor which is overexpressed in human cancers, and this protein presents a novel pro-oncogenic target with which to develop diagnostic assays for biomarker detection in clinical tissue. Combinatorial phage-peptide libraries were used to select 12 amino acid polypeptide aptamers toward anterior gradient-2 to determine whether methods can be developed to affinity purify the protein from clinical biopsies. Selecting phage aptamers through four rounds of screening on recombinant human anterior gradient-2 protein identified two classes of peptide ligand that bind to distinct epitopes on anterior gradient-2 protein in an immunoblot. Synthetic biotinylated peptide aptamers bound in an ELISA format to anterior gradient-2, and substitution mutagenesis further minimized one polypeptide aptamer to a hexapeptide core. Aptamers containing this latter consensus sequence could be used to affinity purify to homogeneity human anterior gradient-2 protein from a single clinical biopsy. The spotting of a panel of peptide aptamers onto a protein microarray matrix could be used to quantify anterior gradient-2 protein from crude clinical biopsy lysates, providing a format for quantitative screening. These data highlight the utility of peptide combinatorial libraries to acquire rapidly a high-affinity ligand that can selectively bind a target protein from a clinical biopsy and provide a technological approach for clinical biomarker assay development in an aptamer microarray format. 相似文献