全文获取类型
收费全文 | 2323篇 |
免费 | 87篇 |
国内免费 | 3篇 |
出版年
2023年 | 23篇 |
2022年 | 46篇 |
2021年 | 114篇 |
2020年 | 39篇 |
2019年 | 75篇 |
2018年 | 76篇 |
2017年 | 72篇 |
2016年 | 82篇 |
2015年 | 116篇 |
2014年 | 122篇 |
2013年 | 174篇 |
2012年 | 166篇 |
2011年 | 134篇 |
2010年 | 75篇 |
2009年 | 84篇 |
2008年 | 101篇 |
2007年 | 86篇 |
2006年 | 115篇 |
2005年 | 84篇 |
2004年 | 83篇 |
2003年 | 65篇 |
2002年 | 51篇 |
2001年 | 29篇 |
2000年 | 35篇 |
1999年 | 22篇 |
1998年 | 13篇 |
1997年 | 20篇 |
1996年 | 17篇 |
1995年 | 12篇 |
1994年 | 21篇 |
1993年 | 12篇 |
1992年 | 13篇 |
1991年 | 17篇 |
1990年 | 8篇 |
1989年 | 7篇 |
1988年 | 9篇 |
1987年 | 11篇 |
1986年 | 10篇 |
1985年 | 19篇 |
1984年 | 9篇 |
1983年 | 16篇 |
1982年 | 15篇 |
1981年 | 22篇 |
1980年 | 17篇 |
1979年 | 9篇 |
1978年 | 8篇 |
1977年 | 8篇 |
1975年 | 8篇 |
1974年 | 6篇 |
1973年 | 10篇 |
排序方式: 共有2413条查询结果,搜索用时 812 毫秒
91.
Bardet–Biedl Syndrome is a multisystem autosomal recessive disorder characterized by central obesity, polydactyly, hypogonadism, learning difficulties, rod-cone dystrophy and renal dysplasia. Bardet–Biedl Syndrome has a prevalence rate ranging from 1 in 100,000 to 1 in 160,000 births although there are communities where Bardet–Biedl Syndrome is found at a higher frequency due to consanguinity. We report here a Pakistani consanguineous family with two affected sons with typical clinical features of Bardet–Biedl Syndrome, in addition to abnormal liver functioning and bilateral basal ganglia calcification, the latter feature being typical of Fahr's disease. Homozygous regions obtained from SNP array depicted three known genes BBS10, BBS14 and BBS2. Bidirectional sequencing of all coding exons by traditional sequencing of all these three genes showed a homozygous deletion of 10 nucleotides (c.1958_1967del), in BBS10 in both affected brothers. The segregation analysis revealed that the parents, paternal grandfather, maternal grandmother and an unaffected sister were heterozygous for the deletion. Such a large deletion in BBS10 has not been reported previously in any population and is likely to be contributing to the phenotype of Bardet–Biedl Syndrome in this family. 相似文献
92.
Yimei Jia Dongling Zhang Robert Monette Umar Iqbal Maria Moreno 《Journal of liposome research》2013,23(4):305-314
AbstractArchaeosomes composed of archaeal total polar lipids (TPL) or semi-synthetic analog vesicles have been used as vaccine adjuvants and delivery systems in animal models for many years. Typically administered by intramuscular or subcutaneous injections, archaeosomes can induce robust, long-lasting humoral and cell-mediated immune responses against entrapped antigens and provide protection in murine models of infectious disease and cancer. Herein, we evaluated various archaeosomes for transdermal delivery, since this route may help eliminate needle-stick injuries and needle re-use, and therefore increase patient compliance. Archaeosomes composed of TPL from different archaea (Halobacterium salinarum, Methanobrevibacter smithii, Haloferax volcanii) and various semi-synthetic glycolipid combinations were evaluated for their ability to diffuse across the skin barrier using an ex vivo pig skin model and the results were compared to conventional synthetic ester liposomes. Physicochemical characteristics were determined for selected formulations including vesicle size, size distribution, zeta potential, fluidity, antigen (ovalbumin) incorporation efficiency and release. Archaeosomes, in particular those composed of M. smithii TPL or the synthetic glycolipid sulfated S-lactosylarchaeol (SLA) mixed with uncharged glycolipid lactosyl archaeol (LA), appeared to be effective carriers for ovalbumin, achieving much better antigen distribution and vesicle accumulation in the skin epidermis than conventional liposomes. The enhanced skin permeation of archaeosomes may be attributed to their chemical structure and physicochemical properties such as particle size, surface charge, stability, and fluidity of their lipid bilayer. 相似文献
93.
94.
Qudsia Rashid Charu Kapil Poonam Singh Vineeta Kumari 《Journal of biomolecular structure & dynamics》2013,31(6):1352-1362
Serpins such as antithrombin, heparin cofactor II, plasminogen activator inhibitor, antitrypsin, antichymotrypsin, and neuroserpin are involved in important biological processes by inhibiting specific serine proteases. Initially, the protease recognizes the mobile reactive loop of the serpin eliciting conformational changes, where the cleaved loop together with the protease inserts into β-sheet A, translocating the protease to the opposite side of inhibitor leading to its inactivation. Serpin interaction with proteases is governed mainly by the reactive center loop residues (RCL). However, in some inhibitory serpins, exosite residues apart from RCL have been shown to confer protease specificity. Further, this forms the basis of multi-specificity of some serpins, but the residues and their dimension at interface in serpin-protease complexes remain elusive. Here, we present a comprehensive structural analysis of the serpin-protease interfaces using bio COmplexes COntact MAPS (COCOMAPS), PRotein Interface Conservation and Energetics (PRICE), and ProFace programs. We have carried out interface, burial, and evolutionary analysis of different serpin-protease complexes. Among the studied complexes, non-inhibitory serpins exhibit larger interface region with greater number of residue involvement as compared to the inhibitory serpins. On comparing the multi-specific serpins (antithrombin and antitrypsin), a difference in the interface area and residue number was observed, suggestive of a differential mechanism of action of these serpins in regulating their different target proteases. Further, detailed study of these multi-specific serpins listed few essential residues (common in all the complexes) and certain specificity (unique to each complex) determining residues at their interfaces. Structural mapping of interface residues suggested that individual patches with evolutionary conserved residues in specific serpins determine their specificity towards a particular protease. 相似文献
95.
M. Iqbal Hossain Carli L. Roulston M. Aizuddin Kamaruddin Percy W. Y. Chu Dominic C. H. Ng Gregory J. Dusting Jeffrey D. Bjorge Nicholas A. Williamson Donald J. Fujita Steve N. Cheung Tung O. Chan Andrew F. Hill Heung-Chin Cheng 《The Journal of biological chemistry》2013,288(14):9696-9709
Excitotoxicity resulting from overstimulation of glutamate receptors is a major cause of neuronal death in cerebral ischemic stroke. The overstimulated ionotropic glutamate receptors exert their neurotoxic effects in part by overactivation of calpains, which induce neuronal death by catalyzing limited proteolysis of specific cellular proteins. Here, we report that in cultured cortical neurons and in vivo in a rat model of focal ischemic stroke, the tyrosine kinase Src is cleaved by calpains at a site in the N-terminal unique domain. This generates a truncated Src fragment of ∼52 kDa, which we localized predominantly to the cytosol. A cell membrane-permeable fusion peptide derived from the unique domain of Src prevents calpain from cleaving Src in neurons and protects against excitotoxic neuronal death. To explore the role of the truncated Src fragment in neuronal death, we expressed a recombinant truncated Src fragment in cultured neurons and examined how it affects neuronal survival. Expression of this fragment, which lacks the myristoylation motif and unique domain, was sufficient to induce neuronal death. Furthermore, inactivation of the prosurvival kinase Akt is a key step in its neurotoxic signaling pathway. Because Src maintains neuronal survival, our results implicate calpain cleavage as a molecular switch converting Src from a promoter of cell survival to a mediator of neuronal death in excitotoxicity. Besides unveiling a new pathological action of Src, our discovery of the neurotoxic action of the truncated Src fragment suggests new therapeutic strategies with the potential to minimize brain damage in ischemic stroke. 相似文献
96.
Gustavo Basurto-Islas Inge Grundke-Iqbal Yunn Chyn Tung Fei Liu Khalid Iqbal 《The Journal of biological chemistry》2013,288(24):17495-17507
Neurofibrillary pathology of abnormally hyperphosphorylated Tau is a key lesion of Alzheimer disease and other tauopathies, and its density in the brain directly correlates with dementia. The phosphorylation of Tau is regulated by protein phosphatase 2A, which in turn is regulated by inhibitor 2, I2PP2A. In acidic conditions such as generated by brain ischemia and hypoxia, especially in association with hyperglycemia as in diabetes, I2PP2A is cleaved by asparaginyl endopeptidase at Asn-175 into the N-terminal fragment (I2NTF) and the C-terminal fragment (I2CTF). Both I2NTF and I2CTF are known to bind to the catalytic subunit of protein phosphatase 2A and inhibit its activity. Here we show that the level of activated asparaginyl endopeptidase is significantly increased, and this enzyme and I2PP2A translocate, respectively, from neuronal lysosomes and nucleus to the cytoplasm where they interact and are associated with hyperphosphorylated Tau in Alzheimer disease brain. Asparaginyl endopeptidase from Alzheimer disease brain could cleave GST-I2PP2A, except when I2PP2A was mutated at the cleavage site Asn-175 to Gln. Finally, an induction of acidosis by treatment with kainic acid or pH 6.0 medium activated asparaginyl endopeptidase and consequently produced the cleavage of I2PP2A, inhibition of protein phosphatase 2A, and hyperphosphorylation of Tau, and the knockdown of asparaginyl endopeptidase with siRNA abolished this pathway in SH-SY5Y cells. These findings suggest the involvement of brain acidosis in the etiopathogenesis of Alzheimer disease, and asparaginyl endopeptidase-I2PP2A-protein phosphatase 2A-Tau hyperphosphorylation pathway as a therapeutic target. 相似文献
97.
Rashid Nazir Jan A. Warmink David C. Voordes Henk H. van de Bovenkamp Jan Dirk van Elsas 《Microbial ecology》2013,65(1):245-254
We investigated the ecological strategies exerted by the soil bacterium Burkholderia terrae BS001 at the hyphae of the soil saprotrophic fungus Lyophyllum sp. strain Karsten. Recently, this bacterium has been reported to form biofilms around, and to comigrate with, growing hyphae of Lyophyllum sp. strain Karsten. In addition, it was found to be able to utilize fungal metabolites. Here, we extend this work to shed some light on the interactions between the bacterial and fungal partner which allow ecological success for the former. In standing liquid microcosms inoculated with Lyophyllum sp. strain Karsten, we detected, upon prolonged incubation, the formation of a mycelial mat at the liquid–air interface. From this mat, primordia were formed after 4–6 weeks, which eventually resulted in mushrooms. However, upon addition of strain BS001 to the bulk liquid, mushroom formation from the fungal mat was clearly inhibited, as evidenced by (1) the formation of significantly lower numbers of primordia and (2) a delay of the onset of primordia formation. Moreover and importantly, the presence of strain BS001 caused the fungus to secrete large amounts of exudates at the mycelial mat, whereas such exudation was absent from control (uninoculated) or Escherichia coli K12- or Variovorax paradoxus BS64-inoculated microcosms. In the exudates, glycerol was the main carbonaceous component, and this compound could be easily utilized by strain BS001. Thus, in different experimental set-ups with the fungal partner, strain BS001 was shown to grow in the fungal exudates on the mat. The two fungal-interactive phenotypes were specific for B. terrae strain BS001, as the other bacteria used in our study, i.e. E. coli K12 and V. paradoxus BS64, did not exhibit any of these phenomena. 相似文献
98.
Syed Ghulam Musharraf Arslan Ali Naik Tameem Khan Maria Yousuf Muhammad Iqbal Choudhary 《Steroids》2013,78(2):171-181
Electrospray ionization tandem mass spectrometry (ESI-MS/MS) was used to investigate the effect of different substitutions introduced during metabolism on fragmentation patterns of four anabolic steroids including methyltestosterone, methandrostenolone, cis-androsterone and adrenosterone, along with their metabolites. Collision-induced dissociation (CID) analysis was performed to correlate the major product ions of 19 steroids with structural features. The analysis is done to portray metabolic alteration, such as incorporation or reduction of double bonds, hydroxylations, and/or oxidation of hydroxyl moieties to keto functional group on steroidal skeleton which leads to drastically changed product ion spectra from the respective classes of steroids, therefore, making them difficult to identify. The comparative ESI-MS/MS study also revealed some characteristic peaks to differentiate different steroidal metabolites and can be useful for the unambiguous identification of anabolic steroids in biological fluid. Moreover, LC–ESI-MS/MS analysis of fermented extract of methyltestosterone, obtained by Macrophomina phaseolina was also investigated. 相似文献
99.
Mikhail V. Pugachev Nikita V. Shtyrlin Lubov P. Sysoeva Elena V. Nikitina Timur I. Abdullin Alfiya G. Iksanova Alina A. Ilaeva Rashid Z. Musin Eugeny A. Berdnikov Yurii G. Shtyrlin 《Bioorganic & medicinal chemistry》2013,21(14):4388-4395
A series of 13 phosphonium salts on the basis of pyridoxine derivatives were synthesized and their antibacterial activity against clinically relevant strains was tested in vitro. All compounds were almost inactive against gram-negative bacteria and exhibited structure-dependent activity against gram-positive bacteria. A crucial role of ketal protection group in phosphonium salts for their antibacterial properties was demonstrated. Among synthesized compounds 5,6-bis[triphenylphosphonio(methyl)]-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine dichloride (compound 20) was found to be the most effective towards Staphylococcus aureus and Staphylococcus epidermidis strains (MIC 5 μg/ml). The mechanism of antibacterial activity of this compound probably involves cell penetration and interaction with genomic and plasmid DNA. 相似文献
100.
Wiesław Włoch Anna Wilczek Joanna Jura-Morawiec Paweł Kojs Muhammad Iqbal 《Trees - Structure and Function》2013,27(4):879-893
In contrast to common belief, recent studies have confirmed that intrusive growth of fusiform cambial initials has a significant role in the rearrangement of the initials, but does not contribute to the cambial circumference increment. We observed a rapid rearrangement of cambial initials on a long series of transverse sections of the vascular cambium and the wood of a 50-year-old pine (Pinus sylvestris L.) tree. A comparison of cell arrangement in consecutive sections, as well as a critical analysis of tangential reconstructions, has confirmed that changes in cell locations in a group of cells on the tangential surface caused no change in the total tangential width of the whole group. Models illustrating changes in locations of the initials have been proposed, assuming that intrusive growth, which makes the growing initials intrude between the neighbouring initials and their immediate derivatives, is localized on the longitudinal edges of cells. We infer that intrusive growth of the cambial initials in P. sylvestris is not involved in the cambial circumference increment, but plays a significant role in the rearrangement of the initials, probably allowing for a relaxation of shearing strains generated during radial growth. The relationship of intrusive growth with the elimination of initials has been discussed with reference to the frequency of anticlinal divisions. It has been proposed that the occurrence of anticlinal divisions in excess over the actual requirement for increase in the cambial circumference could be due to internal shearing strains. 相似文献