全文获取类型
收费全文 | 2172篇 |
免费 | 194篇 |
国内免费 | 2篇 |
专业分类
2368篇 |
出版年
2023年 | 7篇 |
2022年 | 15篇 |
2021年 | 34篇 |
2020年 | 28篇 |
2019年 | 19篇 |
2018年 | 31篇 |
2017年 | 25篇 |
2016年 | 51篇 |
2015年 | 98篇 |
2014年 | 98篇 |
2013年 | 130篇 |
2012年 | 184篇 |
2011年 | 162篇 |
2010年 | 101篇 |
2009年 | 116篇 |
2008年 | 136篇 |
2007年 | 154篇 |
2006年 | 116篇 |
2005年 | 118篇 |
2004年 | 122篇 |
2003年 | 101篇 |
2002年 | 92篇 |
2001年 | 23篇 |
2000年 | 26篇 |
1999年 | 26篇 |
1998年 | 28篇 |
1997年 | 18篇 |
1996年 | 19篇 |
1995年 | 16篇 |
1994年 | 14篇 |
1993年 | 17篇 |
1992年 | 10篇 |
1991年 | 11篇 |
1990年 | 10篇 |
1989年 | 15篇 |
1988年 | 8篇 |
1987年 | 8篇 |
1986年 | 9篇 |
1985年 | 9篇 |
1984年 | 8篇 |
1983年 | 10篇 |
1982年 | 7篇 |
1980年 | 7篇 |
1977年 | 7篇 |
1976年 | 6篇 |
1974年 | 7篇 |
1972年 | 6篇 |
1970年 | 8篇 |
1968年 | 6篇 |
1967年 | 6篇 |
排序方式: 共有2368条查询结果,搜索用时 15 毫秒
1.
2.
Shreaya Chakroborty Clark Briggs Megan B. Miller Ivan Goussakov Corinne Schneider Joyce Kim Jaime Wicks Jill C. Richardson Vincent Conklin Benjamin G. Cameransi Grace E. Stutzmann 《PloS one》2012,7(12)
Alzheimer’s disease (AD) is a devastating neurodegenerative condition with no known cure. While current therapies target late-stage amyloid formation and cholinergic tone, to date, these strategies have proven ineffective at preventing disease progression. The reasons for this may be varied, and could reflect late intervention, or, that earlier pathogenic mechanisms have been overlooked and permitted to accelerate the disease process. One such example would include synaptic pathology, the disease component strongly associated with cognitive impairment. Dysregulated Ca2+ homeostasis may be one of the critical factors driving synaptic dysfunction. One of the earliest pathophysiological indicators in mutant presenilin (PS) AD mice is increased intracellular Ca2+ signaling, predominantly through the ER-localized inositol triphosphate (IP3) and ryanodine receptors (RyR). In particular, the RyR-mediated Ca2+ upregulation within synaptic compartments is associated with altered synaptic homeostasis and network depression at early (presymptomatic) AD stages. Here, we offer an alternative approach to AD therapeutics by stabilizing early pathogenic mechanisms associated with synaptic abnormalities. We targeted the RyR as a means to prevent disease progression, and sub-chronically treated AD mouse models (4-weeks) with a novel formulation of the RyR inhibitor, dantrolene. Using 2-photon Ca2+ imaging and patch clamp recordings, we demonstrate that dantrolene treatment fully normalizes ER Ca2+ signaling within somatic and dendritic compartments in early and later-stage AD mice in hippocampal slices. Additionally, the elevated RyR2 levels in AD mice are restored to control levels with dantrolene treatment, as are synaptic transmission and synaptic plasticity. Aβ deposition within the cortex and hippocampus is also reduced in dantrolene-treated AD mice. In this study, we highlight the pivotal role of Ca2+ aberrations in AD, and propose a novel strategy to preserve synaptic function, and thereby cognitive function, in early AD patients. 相似文献
3.
Valuable biological information can be obtained by monitoring the movement of organisms. However, the choice of monitoring
method becomes highly restricted when following small organisms (<100 mm), especially in aquatic ecosystems. Stable isotopes
are being increasingly used in this respect but rarely at the local spatial scale, i.e. 10–1000 s of metres. We sought to
identify movement of small fishes between a main river channel and its tributary. Little overlap in isotope baseline was detected
between the two channels despite some temporal variability in δ15N of baseline indicator organisms in the main river. The individuals of two small cyprinid fish species (Leuciscus souffia and Alburnoides bipunctatus) of all the size classes (40–100 mm) caught within the tributary showed considerable heterogeneity in δ15N values. Classification and discriminant analysis on isotope-derived data distinguished two significantly different groups.
Moreover, this result was supported by further sampling of fish caught in the main river (in May and December 2006). Alternative
hypotheses, such as dietary differences, biological factors, temporal shifts and spatial differences in diet, did not explain
δ15N variability. This application of stable isotopes at a relatively small spatial and temporal scales further demonstrates
its potential as a tool for ecologists. 相似文献
4.
Studies on the mechanism of stimulation of T cells by the Mycoplasma arthritidis-derived mitogen. Role of class II IE molecules 总被引:8,自引:0,他引:8
A mitogen derived from the supernatant of broth cultures of Mycoplasma arthritidis (MAS-P) stimulates a proliferative response by normal, unprimed T cells and interleukin 2 production by some, but not all, T cell hybridomas. The response requires an IE-positive accessory cell (AC). The direct participation of IE, and not IA, in this system was confirmed by two sets of experiments. First, L cells transfected with IE, but not IA, provided effective AC function for both normal T cells and the T cell hybridoma DO-11.10. Second, we have taken a more direct approach by showing that purified IE incorporated in liposomes and used to coat glass beads can support the MAS-P response of the DO-11.10 T cell hybridoma in the absence of intact AC or other AC molecules. Although the receptor for IE-MAS-P has not been identified, we have eliminated from consideration two potential T cell recognition structures. Monoclonal antibody to the antigen-major histocompatibility complex specific receptor failed to inhibit the MAS-P response of DO-11.10 or the T cell line LBRM-33. Furthermore, the L3T4 molecule did not appear to be involved since an L3T4-negative variant of DO-11.10 responded well to the mitogen. In addition, we show that both Lyt-2-positive and L3T4-positive T cells respond to this class II-restricted stimulus. Thus, we postulate the existence of a non-T cell receptor, non-L3T4 receptor that recognizes MAS-P in association with a presumed nonpolymorphic region of IE. 相似文献
5.
The solution conformation of model compounds for the tri'-antennary and tetraantennary (six-arm) branch point of N-linked glycans has been determined through the use of chemical shift, relaxation, and nuclear Overhauser enhancement data. The object was to establish the conformation about the glycosidic linkages in the N-linked substructure GlcNAc(beta 1,6) [GlcNAc(beta 1,2)] Man(alpha)- by estimation of values for the appropriate glycosidic torsional angles. The GlcNAc(beta 1,6) linkage in a trisaccharide model compound was found to be constrained to a narrow rotameric subpopulation about the substituted Man C5-C6 bond (omega = -60 degrees) and a narrow range of possible phi - psi values. Free rotation about the Man C5-C6 bond was obstructed by unfavorable steric interactions between the GlcNAc(beta 1,6) and GlcNAc(beta 1,2) residues. A phi, psi value of 55 degrees, 190 degrees was found to be consistent with the NMR data for the GlcNAc(beta 1,6) linkage. However, the value of psi appears to be "virtual" in that the molecule is in equilibrium between two different values (90 degrees and 252 degrees). For the GlcNAc(beta 1,2) linkage, complete agreement between all the observed NMR parameters and all the calculated ensemble average values could only be obtained with a set of potential energy functions which included hydrogen bonding. Other choices of potentials yielded calculated values that disagreed with at least two of the observed quantities. As a result, we infer that an interresidue hydrogen bond is formed, and we find it to be between the GlcNAc(beta 1,2) ring oxygen and the Man C3 hydroxyl.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
6.
Ariella Oppenheim Avi Yaari Deborah Rund Eliezer A. Rachmilewitz David Nathan Corinne Wong Haig H. Kazazian Jr. Barbara Miller 《Human genetics》1990,86(2):175-180
Summary The mechanism for elevated production of fetal hemoglobin (Hb F) in a Druze patient with °-thalassemia intermedia was investigated. Heterozygous family members exhibited normal Hb F levels, suggesting that the increase in -gene expression in the propositus may be partly due to anemic stress. Erythroid progenitors of these family members cultured in vitro [burst forming units (erythroid); (BFUe)] showed elevated synthesis of Hb F, indicating the existence of a genetically determined intrinsic capacity for high Hb F production in this family. The propositus was found to be homozygous for a IVS2-position 1 mutation, on the background of Mediterranean haplotype I, which is not known to be linked to high Hb F production. Moreover, extensive molecular studies of the -globin gene cluster, including sequence analysis of the promoter regions of the -globin genes, did not reveal any cisacting mechanism that could account for the high Hb F production in the propositus. A young niece of the propositus with °-thalassemia major was recently discovered, who was homozygous for the same -globin allele and haplotype as the propositus. However, unlike her uncle, she does not have a high Hb F level and presents with a severe clinical course. Her inability to produce high Hb F suggests that the genetic determinant for increased -gene expression in the propositus is unlinked to the -globin gene cluster. 相似文献
7.
Somatic or vegetative incompatibility is widespread in filamentous fungi. It prevents the coexistence of genetically different nuclei within a common cytoplasm. Cloning the het genes that control this process has been achieved in several species. This has provided essential information on the function of the genes in the biology of fungi and has also led to the formulation of models that may explain similar phenomena in other organisms. 相似文献
8.
Corinne Beaudouin Gisèle Haurat Jean Alex Laffitte Bernard Renaud 《Journal of neurochemistry》1993,61(3):928-935
Abstract: (+)-S-Adenosyl- l -methionine [(+)-SAM] was isolated from rat brain and was quantified by HPLC followed by UV spectrophotometric measurements and by 1 H-NMR. Its estimated ratio in brain is 3% of total SAM. Because of its commercial unavailability, (+)-SAM was also prepared from chemically synthesized SAM by separation of the two diastereoisomers on a preparative reverse-phase Nucleosil C8 column. The (+) diastereoisomer thus obtained was then assayed in vitro both as an inhibitor and a substrate of phenylethanolamine N -methyltransferase. Enzymatic activity was measured by HPLC analysis. It was shown that (+)-SAM has no effect on phenylethanolamine N -methyltransferase activity; therefore, it is unlikely that (+)-SAM plays any possible role in regulation of adrenaline synthesis in the brain. 相似文献
9.
Jeanne-Andrée Boudier Jacques Fantini Corinne Gerard Bernard Verrier 《Cell and tissue research》1993,271(1):23-31
Summary The fine structure of single identified muscle fibers and their nerve terminals in the limb closer muscle of the shore crab Eriphia spinifrons was examined, using a previous classification based on histochemical evidence which recognizes a slow (Type-I) fiber and three fast (Type-II, Type-III, Type-IV) fibers. All four fiber types have a fine structure characteristic of crustacean slow muscle, with 10–12 thin filaments surrounding each thick filament and sarcomere lengths of 6–13 m. Type-IV fibers have sarcomere lengths of 6 m while the other three types have substantially longer sarcomeres (10–13 m). Structural features of nerve terminals revealed excitatory innervation in all four fiber types but inhibitory innervation in Type-I, Type-II, and Type-III fibers only. Thus fibers with longer sarcomeres receive the inhibitor axon but those with shorter sarcomeres do not. Amongst the former, synaptic contact from an inhibitory nerve terminal onto an excitatory one, denoting presynaptic inhibition, was seen in Type-I and Type-II fibers but not in Type-III and Type-IV fibers. Inhibitory innervation of the walking leg closer muscle is therefore highly differentiated: some fibers lack inhibitory nerve terminals, some possess postsynaptic inhibition, and some possess both postsynaptic and presynaptic inhibition. 相似文献
10.