全文获取类型
收费全文 | 612篇 |
免费 | 56篇 |
专业分类
668篇 |
出版年
2023年 | 4篇 |
2022年 | 7篇 |
2021年 | 13篇 |
2020年 | 7篇 |
2018年 | 8篇 |
2017年 | 7篇 |
2016年 | 16篇 |
2015年 | 24篇 |
2014年 | 26篇 |
2013年 | 38篇 |
2012年 | 60篇 |
2011年 | 40篇 |
2010年 | 27篇 |
2009年 | 19篇 |
2008年 | 31篇 |
2007年 | 33篇 |
2006年 | 35篇 |
2005年 | 37篇 |
2004年 | 28篇 |
2003年 | 38篇 |
2002年 | 45篇 |
2001年 | 3篇 |
2000年 | 3篇 |
1999年 | 4篇 |
1998年 | 6篇 |
1997年 | 8篇 |
1996年 | 7篇 |
1995年 | 6篇 |
1994年 | 3篇 |
1993年 | 2篇 |
1992年 | 4篇 |
1991年 | 4篇 |
1990年 | 3篇 |
1989年 | 6篇 |
1988年 | 3篇 |
1987年 | 3篇 |
1986年 | 4篇 |
1985年 | 4篇 |
1984年 | 3篇 |
1983年 | 3篇 |
1982年 | 5篇 |
1981年 | 3篇 |
1980年 | 4篇 |
1979年 | 6篇 |
1978年 | 5篇 |
1977年 | 7篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1974年 | 2篇 |
1973年 | 4篇 |
排序方式: 共有668条查询结果,搜索用时 0 毫秒
101.
Carbohydrates present on cell surfaces participate in numerous biological recognition phenomena including cell–cell interactions,
cancer metastasis and pathogen invasion. Therefore, synthetic carbohydrates have a potential to act as pharmaceutical substances
for treatment of various pathological phenomena by inhibiting specifically the interaction between cell surface carbohydrates
and their protein receptors (lectins). However, the inherently low affinity of carbohydrate-protein interactions has often
been an obstacle for successful generation of carbohydrate based pharmaceuticals. Multivalent glycoconjugates, i.e. structures
carrying several copies of the active carbohydrate sequence in a carrier molecule, have been constructed to overcome this
problem. Here we present two novel types of multivalent carbohydrate conjugates based on chondroitin oligomer and cyclodextrin
carriers. These carriers were modified to express primary amino groups, and oligosaccharides were then bound to carrier molecules
by reductive amination. Multivalent conjugates were produced using the human milk type oligosaccharides LNDFH I (Lewis-b hexasaccharide),
LNnT, and GlcNAcβ1-3Galβ1-4GlcNAcβ1-3Galβ1-4Glc. 相似文献
102.
Background
Progestins as respiratory stimulants in chronic obstructive pulmonary disease (COPD) have been investigated in males and during wakefulness. However, sleep and gender may influence therapeutic responses. We investigated the effects of a 2-week medroxyprogesterone acetate (MPA) therapy on sleep and nocturnal breathing in postmenopausal women.Methods
A single-blind placebo-controlled trial was performed in 15 postmenopausal women with moderate to severe COPD. A 12-week trial included 2-week treatment periods with placebo and MPA (60 mg/d/14 days). All patients underwent a polysomnography with monitoring of SaO2 and transcutaneous PCO2 (tcCO2) at baseline, with placebo, with medroxyprogesterone acetate (MPA 60 mg/d/14 days), and three and six weeks after cessation of MPA.Results
Thirteen patients completed the trial. At baseline, the average ± SD of SaO2 mean was 90.6 ± 3.2 % and the median of SaO2 nadir 84.8 % (interquartile range, IQR 6.1). MPA improved them by 1.7 ± 1.6 %-units (95 % confidence interval (CI) 0.56, 2.8) and by 3.9 %-units (IQR 4.9; 95% CI 0.24, 10.2), respectively. The average of tcCO2 median was 6.0 ± 0.9 kPa and decreased with MPA by 0.9 ± 0.5 kPa (95% CI -1.3, -0.54). MPA improved SaO2 nadir and tcCO2 median also during REM sleep. Three weeks after cessation of MPA, the SaO2 mean remained 1.4 ± 1.8 %-units higher than at baseline, the difference being not significant (95% CI -0.03, 2.8). SaO2 nadir was 2.7 %-units (IQR 4.9; 95% CI 0.06, 18.7) higher than at baseline. Increases in SaO2 mean and SaO2 nadir during sleep with MPA were inversely associated with baseline SaO2 mean (r = -0.70, p = 0.032) and baseline SaO2 nadir (r = -0.77, p = 0.008), respectively. Treatment response in SaO2 mean, SaO2 nadir and tcCO2 levels did not associate with pack-years smoked, age, BMI, spirometric results or sleep variables.Conclusion
MPA-induced respiratory improvement in postmenopausal women seems to be consistent and prolonged. The improvement was greater in patients with lower baseline SaO2 values. Long-term studies in females are warranted. 相似文献103.
A peptide isolated from porcine gut according to its glucagon-like activity in liver (bioactive enteroglucagon) has been characterized immunologically, biologically and chemically: its potency relative to pancreatic glucagon in interacting with an antiglucagon antibody, hepatic glucagon-binding sites and hepatic adenylate cyclase was ~100%, 20% and 10%, respectively. In contrast, it is ~20-times more potent than glucagon in oxyntic glands, justifying the term ‘oxyntomodulin’. Chemically, it consists in the 29 amino acid-peptide glucagon elongated at its C-terminal end by the octapeptide Lys—Arg—Asn—Lys—Asn—Asn—Ile &;—Ala; accordingly, it is called ‘glucagon-37’ 相似文献
104.
Enerly E Steinfeld I Kleivi K Leivonen SK Aure MR Russnes HG Rønneberg JA Johnsen H Navon R Rødland E Mäkelä R Naume B Perälä M Kallioniemi O Kristensen VN Yakhini Z Børresen-Dale AL 《PloS one》2011,6(2):e16915
Introduction
Few studies have performed expression profiling of both miRNA and mRNA from the same primary breast carcinomas. In this study we present and analyze data derived from expression profiling of 799 miRNAs in 101 primary human breast tumors, along with genome-wide mRNA profiles and extensive clinical information.Methods
We investigate the relationship between these molecular components, in terms of their correlation with each other and with clinical characteristics. We use a systems biology approach to examine the correlative relationship between miRNA and mRNAs using statistical enrichment methods.Results
We identify statistical significant differential expression of miRNAs between molecular intrinsic subtypes, and between samples with different levels of proliferation. Specifically, we point to miRNAs significantly associated with TP53 and ER status. We also show that several cellular processes, such as proliferation, cell adhesion and immune response, are strongly associated with certain miRNAs. We validate the role of miRNAs in regulating proliferation using high-throughput lysate-microarrays on cell lines and point to potential drivers of this process.Conclusion
This study provides a comprehensive dataset as well as methods and system-level results that jointly form a basis for further work on understanding the role of miRNA in primary breast cancer. 相似文献105.
The proportion in which carbon and growth-limiting nutrients are exported from the oceans’ productive surface layer to the deep sea is a crucial parameter in models of the biological carbon pump. Based on >400 vertical flux observations of particulate organic carbon (POC) and nitrogen (PON) from the European Arctic Ocean we show the common assumption of constant C:N stoichiometry not to be met. Exported POC:PON ratios exceeded the classical Redfield atomic ratio of 6.625 in the entire region, with the largest deviation in the deep Central Arctic Ocean. In this part the mean exported POC:PON ratio of 9.7 (a:a) implies c. 40% higher carbon export compared to Redfield-based estimates. When spatially integrated, the potential POC export in the European Arctic was 10–30% higher than suggested by calculations based on constant POC:PON ratios. We further demonstrate that the exported POC:PON ratio varies regionally in relation to nitrate-based new production over geographical scales that range from the Arctic to the subtropics, being highest in the least productive oligotrophic Central Arctic Ocean and subtropical gyres. Accounting for variations in export stoichiometry among systems of different productivity will improve the ability of models to resolve regional patterns in carbon export and, hence, the oceans’ contribution to the global carbon cycle will be predicted more accurately. 相似文献
106.
Kandiba L Aitio O Helin J Guan Z Permi P Bamford DH Eichler J Roine E 《Molecular microbiology》2012,84(3):578-593
VP4, the major structural protein of the haloarchaeal pleomorphic virus, HRPV‐1, is glycosylated. To define the glycan structure attached to this protein, oligosaccharides released by β‐elimination were analysed by mass spectrometry and nuclear magnetic resonance spectroscopy. Such analyses showed that the major VP4‐derived glycan is a pentasaccharide comprising glucose, glucuronic acid, mannose, sulphated glucuronic acid and a terminal 5‐N‐formyl‐legionaminic acid residue. This is the first observation of legionaminic acid, a sialic acid‐like sugar, in an archaeal‐derived glycan structure. The importance of this residue for viral infection was demonstrated upon incubation with N‐acetylneuraminic acid, a similar monosaccharide. Such treatment reduced progeny virus production by half 4 h post infection. LC‐ESI/MS analysis confirmed the presence of pentasaccharide precursors on two different VP4‐derived peptides bearing the N‐glycosylation signal, NTT. The same sites modified by the native host, Halorubrum sp. strain PV6, were also recognized by the Haloferax volcanii N‐glycosylation apparatus, as determined by LC‐ESI/MS of heterologously expressed VP4. Here, however, the N‐linked pentasaccharide was the same as shown to decorate the S‐layer glycoprotein in this species. Hence, N‐glycosylation of the haloarchaeal viral protein, VP4, is host‐specific. These results thus present additional examples of archaeal N‐glycosylation diversity and show the ability of Archaea to modify heterologously expressed proteins. 相似文献
107.
Jouni Smed Kari Salonen Mika Johnsson Tommi Johtela Olli S. Nevalainen 《Flexible Services and Manufacturing Journal》2003,15(1):19-35
In printed circuit board (PCB) assembly, the majority of electronic components are inserted by high-speed placement machines. Although the efficient utilization of the machinery is important for a manufacturer, it is hard to fully realize in high-mix low-volume production environments. On the machine level, the component setup strategy adopted by the manufacturer has a significant impact on the overall production efficiency. Usually, the setup strategy is formulated as a part type grouping problem or a minimum setup problem. In this article, we consider a hybridization of these two problems for the single machine case: The object function to be minimized includes a weighted sum of the number of part type groups (giving the number of setup occasions) and the number of feeder changeovers. We present algorithms for the problem and compare their efficiency. 相似文献
108.
Variability of the distribution of differentiation pathway choices regulated by a multipotent delayed stochastic switch 总被引:1,自引:1,他引:0
We study the plasticity of a delayed stochastic model of a genetic toggle switch as a multipotent differentiation pathway switch, at the single cell and cell population levels, by observing distributions of differentiation pathways choices of genetically homogeneous cell populations. Assuming a model of stochastic pathway determination of cell differentiation that is regulated by the proteins of the switch, we vary the proteins’ expression level and degradation rates, which cells are known to be able to regulate, to vary mean level, noise, and bias of the proteins’ expression levels. It is shown that small changes in each of these dynamical features significantly and distinctively affects the dynamics of the switch at the single cell level and thus, the cell differentiation patterns. The regulation of these features allows cells to regulate their pluripotency and cell populations’ distribution of lineage choice, suggesting that the stochastic switch has high plasticity regarding differentiation pathway choice regulation, thus providing adaptability to environmental stresses and changes. 相似文献
109.
Oresmaa L Kotikoski H Haukka M Oksala O Pohjala E Vapaatalo H Vainiotalo P Aulaskari P 《Bioorganic & medicinal chemistry letters》2006,16(8):2144-2147
Esters of 1-(H)-imidazole-5-nitrolic acid and 1-methyl-imidazole-5-carboxamide oxime were prepared to study the effect of esterification on the ocular effects of these compounds. Esterifications were performed with acid chloride. Acid chloride also reacts with the ring nitrogen of 1-(H)-imidazole-5-nitrolic acid, but the desired esters could be selectively prepared by adjustment of the reaction conditions. Esterification led to loss of the ocular effects exhibited by the parent compounds. 相似文献
110.
Veikko Salomaa Aki Havulinna Olli Saarela Tanja Zeller Pekka Jousilahti Antti Jula Thomas Muenzel Arpo Aromaa Alun Evans Kari Kuulasmaa Stefan Blankenberg 《PloS one》2010,5(4)