全文获取类型
收费全文 | 927篇 |
免费 | 83篇 |
出版年
2023年 | 10篇 |
2022年 | 8篇 |
2021年 | 14篇 |
2020年 | 8篇 |
2019年 | 10篇 |
2018年 | 13篇 |
2017年 | 9篇 |
2016年 | 20篇 |
2015年 | 33篇 |
2014年 | 47篇 |
2013年 | 41篇 |
2012年 | 50篇 |
2011年 | 60篇 |
2010年 | 36篇 |
2009年 | 37篇 |
2008年 | 36篇 |
2007年 | 58篇 |
2006年 | 49篇 |
2005年 | 48篇 |
2004年 | 24篇 |
2003年 | 40篇 |
2002年 | 47篇 |
2001年 | 22篇 |
2000年 | 17篇 |
1999年 | 24篇 |
1998年 | 17篇 |
1997年 | 6篇 |
1996年 | 5篇 |
1995年 | 7篇 |
1994年 | 4篇 |
1993年 | 14篇 |
1992年 | 20篇 |
1991年 | 12篇 |
1990年 | 12篇 |
1989年 | 15篇 |
1988年 | 12篇 |
1987年 | 6篇 |
1985年 | 7篇 |
1984年 | 7篇 |
1983年 | 9篇 |
1982年 | 10篇 |
1980年 | 7篇 |
1979年 | 16篇 |
1976年 | 4篇 |
1973年 | 4篇 |
1972年 | 4篇 |
1971年 | 4篇 |
1969年 | 4篇 |
1967年 | 7篇 |
1966年 | 5篇 |
排序方式: 共有1010条查询结果,搜索用时 31 毫秒
101.
Schäffer AA Salzer U Hammarström L Grimbacher B 《Current opinion in genetics & development》2007,17(3):201-212
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. Patients have recurrent bacterial infections and an increased risk of developing autoimmune diseases, lung damage, and selected cancers. Since 2003, four genes have been shown to be mutated in CVID patients: ICOS, TNFRSF13B (encoding TACI), TNFRSF13C (encoding BAFF-R) and CD19. Heterozygous mutations in TNFRSF13B are also associated with CVID, whereas the other three genes are purely recessive. Recent genetic linkage studies have also identified possible loci for dominant CVID genes on chromosomes 4q, 5p and 16q. These findings markedly improved the genetic diagnosis of CVID and point towards new strategies for future genetic studies. In addition, some CVID genes might be relevant to more common diseases such as asthma and stroke. 相似文献
102.
Carinci P Becchetti E Baroni T Carinci F Pezzetti F Stabellini G Locci P Scapoli L Tognon M Volinia S Bodo M 《European journal of histochemistry : EJH》2007,51(Z1):105-115
The normal development of cranial primordia and orofacial structures involves fundamental processes in which growth, morphogenesis, and cell differentiation take place and interactions between extracellular matrix (ECM) components, growth factors and embryonic tissues are involved. Biochemical and molecular aspects of craniofacial development, such as the biological regulation of normal or premature cranial suture fusion, has just begun to be understood, thanks mainly to studies performed in the last decade. Several mutations has been identified in both syndromic and non-syndromic craniosynostosis patients throwing new light onto the etiology, classification and developmental pathology of these diseases. In the more common craniosynostosis syndromes and other skeletal growth disorders, the mutations were identified in the genes encoding fibroblast growth factor receptor types 1-3 (FGFR1, 2 and 3) where they are dominantly acting and affect specific and important protein binding domain. The unregulated FGF signaling during intramembranous ossification is associated to the Apert and Crouzon syndrome. The non syndromic cleft of the lip and/or palate (CLP) has a more complex genetic background if compared to craniosynostosis syndrome because of the number of involved genes and type of inheritance. Moreover, the influence of environmental factor makes difficult to clarify the primary causes of this malformation. ECM represents cell environment and results mainly composed by collagens, fibronectin, proteoglycans (PG) and hyaluronate (HA). Cooperative effects of ECM and growth factors regulate regional matrix production during the morphogenetic events, connective tissue remodelling and pathological states. In the present review we summarize the studies we performed in the last years to better clarify the role of ECM and growth factors in the etiology and pathogenesis of craniosynostosis and CLP diseases. 相似文献
103.
The Pro-rich, PH, and SH2 domain containing mitogenic signaling adapter PSM/SH2-B has been implicated as a cellular partner of various mitogenic receptor tyrosine kinases and related signaling mechanisms. Here, we report in a direct comparison of three peptide hormones, that PSM participates in the assembly of distinct mitogenic signaling complexes in response to insulin or IGF-I when compared to PDGF in cultured normal fibroblasts. The complex formed in response to insulin or IGF-I involves the respective peptide hormone receptor and presumably the established components leading to MAP kinase activation. However, our data suggest an alternative link from the PDGF receptor via PSM directly to MEK1/2 and consequently also to p44/42 activation, possibly through a scaffold protein. At least two PSM domains participate, the SH2 domain anticipated to link PSM to the respective receptor and the Pro-rich region in an association with an unidentified downstream component resulting in direct MEK1/2 and p44/42 regulation. The PDGF receptor signaling complex formed in response to PDGF involves PI 3-kinase in addition to the same components and interactions as described for insulin or IGF-I. PSM associates with PI 3-kinase via p85 and in addition the PSM PH domain participates in the regulation of PI 3-kinase activity, presumably through membrane interaction. In contrast, the PSM Pro-rich region appears to participate only in the MAP kinase signal. Both pathways contribute to the mitogenic response as shown by cell proliferation, survival, and focus formation. PSM regulates p38 MAP kinase activity in a pathway unrelated to the mitogenic response. 相似文献
104.
105.
Nils Kost Sophie Kaiser Yogesh Ostwal Dietmar Riedel Alexandra Stützer Miroslav Nikolov Christina Rathke Renate Renkawitz-Pohl Wolfgang Fischle 《Nucleic acids research》2015,43(6):3033-3045
Despite insights on the cellular level, the molecular details of chromatin reorganization in sperm development, which involves replacement of histone proteins by specialized factors to allow ultra most condensation of the genome, are not well understood. Protamines are dispensable for DNA condensation during Drosophila post-meiotic spermatogenesis. Therefore, we analyzed the interaction of Mst77F, another very basic testis-specific protein with chromatin and DNA as well as studied the molecular consequences of such binding. We show that Mst77F on its own causes severe chromatin and DNA aggregation. An intrinsically unstructured domain in the C-terminus of Mst77F binds DNA via electrostatic interaction. This binding results in structural reorganization of the domain, which induces interaction with an N-terminal region of the protein. Via putative cooperative effects Mst77F is induced to multimerize in this state causing DNA aggregation. In agreement, overexpression of Mst77F results in chromatin aggregation in fly sperm. Based on these findings we postulate that Mst77F is crucial for sperm development by giving rise to a unique condensed chromatin structure. 相似文献
106.
Abderamane B Tih AE Ghogomu RT Blond A Bodo B 《Zeitschrift für Naturforschung. C, Journal of biosciences》2011,66(3-4):87-92
Six isoflavonoid derivatives among which three are new have been isolated from the stem heartwood of Lophira alata. The structures were elucidated from spectroscopic and chemical evidences. Two have unusual carbon skeletons, possibly resulting from a variant of isoflavonoid biogenesis. The two compounds form the first members of a new subclass of flavonoid compounds which we call "isobiflavonoids". The presence of these isoflavonoid compounds in this plant of the Ochnaceae family has important chemotaxonomic implications since it modifies the botanic distribution of isoflavonoid compounds in non-leguminous plants. 相似文献
107.
Bioluminescence is a process during which light in the visible spectrum is emitted as a consequence of an enzymatic reaction catalyzed by luciferases. Luciferases have been identified mainly in marine organisms and are used for several biological purposes include camouflage, repulsion, attraction, communication and illumination. Some of the currently known luciferases have become indispensible tools in modern molecular biology and are used for diverse applications such as autoinducer-1 activity assays, promoter test assays in both prokaryotes and eukaryotes, imaging of bacterial infections in live animals, in vivo activity assays genes involved in host response and disease and monitoring of bacterial contaminations of food products. With the present review, the authors intend to give an overview on the currently used bacterial luciferase reporter systems, their methodologies and applications and compare them to other reporter systems. 相似文献
108.
von Oheimb PV Albrecht C Riedel F Du L Yang J Aldridge DC Bössneck U Zhang H Wilke T 《PloS one》2011,6(10):e26307
Background
The Tibetan Plateau is not only the highest and largest plateau on earth; it is also home to numerous freshwater lakes potentially harbouring endemic faunal elements. As it remains largely unknown whether these lakes have continuously existed during the Last Glacial Maximum (LGM), questions arise as to whether taxa have been able to exist on the plateau since before the latest Pleistocene, from where and how often the plateau was colonized, and by which mechanisms organisms conquered remote high altitude lentic freshwater systems. In this study, species of the plateau-wide distributed freshwater gastropod genus Radix are used to answer these biogeographical questions.Methodology/Principal Findings
Based on a broad spatial sampling of Radix spp. on the Tibetan Plateau, and phylogenetic analyses of mtDNA sequence data, three probably endemic and one widespread major Radix clade could be identified on the plateau. Two of the endemic clades show a remarkably high genetic diversity, indicating a relatively great phylogenetic age. Phylogeographical analyses of individuals belonging to the most widely distributed clade indicate that intra-plateau distribution cannot be explained by drainage-related dispersal alone.Conclusions/Significance
Our study reveals that Radix spp. persisted throughout the LGM on the Tibetan Plateau. Therefore, we assume the continuous existence of suitable water bodies during that time. The extant Radix diversity on the plateau might have been caused by multiple colonization events combined with a relatively long intra-plateau evolution. At least one colonization event has a Palaearctic origin. In contrast to freshwater fishes, passive dispersal, probably by water birds, might be an important mechanism for conquering remote areas on the plateau. Patterns found in Radix spp. are shared with some terrestrial plateau taxa, indicating that Radix may be a suitable model taxon for inferring general patterns of biotic origin, dispersal and survival on the Tibetan Plateau. 相似文献109.
Quiroz TS Nieto PA Tobar HE Salazar-Echegarai FJ Lizana RJ Quezada CP Santiviago CA Araya DV Riedel CA Kalergis AM Bueno SM 《PloS one》2011,6(10):e26031
The availability of the complete genome sequence of several Salmonella enterica serovars has revealed the presence of unstable genetic elements in these bacteria, such as pathogenicity islands and prophages. This is the case of Salmonella enterica serovar Enteritidis (S. Enteritidis), a bacterium that causes gastroenteritis in humans and systemic infection in mice. The whole genome sequence analysis for S. Enteritidis unveiled the presence of several genetic regions that are absent in other Salmonella serovars. These regions have been denominated "regions of difference" (ROD). In this study we show that ROD21, one of such regions, behaves as an unstable pathogenicity island. We observed that ROD21 undergoes spontaneous excision by two independent recombination events, either under laboratory growth conditions or during infection of murine cells. Importantly, we also found that one type of excision occurred at higher rates when S. Enteritidis was residing inside murine phagocytic cells. These data suggest that ROD21 is an unstable pathogenicity island, whose frequency of excision depends on the environmental conditions found inside phagocytic cells. 相似文献
110.
Estradiol protects cultured articular chondrocytes from oxygen-radical-induced damage 总被引:3,自引:0,他引:3
Osteoarthritis (OA) is aggravated in menopausal women possibly because of changed serum estrogen levels. Estradiol has been postulated to affect oxidative stress induced by reactive oxygen species (ROS) in articular chondrocytes. We generated ROS in cultured bovine articular chondrocytes by incubating them with combined Fe2SO4, vitamin C, and hydrogen peroxide. The release of thiobarbituric-acid-reactive substances (TBARS, lipid peroxidation) and lactate dehydrogenase (LDH, membrane damage) was measured photometrically. Various estradiol doses and vitamin E, serving as control with an established anti-oxidative capacity, were applied either upon each exchange of medium and during radical production (strategy 1) or only during radical production (strategy 2). In chondrocytes incubated according to strategy 1, the production of TBARS and LDH release were significantly suppressed by 10–10–10–4 M estradiol or by vitamin E. Under strategy 2, the production of TBARS was significantly suppressed at estradiol concentrations higher than 10–6 M, whereas LDH release was inhibited at concentrations of 10–6–10–4 M. Vitamin E showed no significant effects. As repeated application of estradiol and vitamin E produced the best results, estradiol, like vitamin E, was speculated to accumulate in the plasma membrane and to decrease membrane fluidity resulting in protection against lipid peroxidation (non-genomic effect). Thus, in contrast to the neuroprotective effect of 17-estradiol in supraphysiological doses reported recently, the anti-oxidative potential of estradiol appears to protect articular chondrocytes from ROS-induced damage when the hormone is given repeatedly in a physiological range. Decreased estradiol levels may therefore contribute to menopausal OA in the long term. 相似文献