全文获取类型
收费全文 | 324篇 |
免费 | 21篇 |
出版年
2023年 | 2篇 |
2022年 | 4篇 |
2021年 | 5篇 |
2020年 | 2篇 |
2019年 | 6篇 |
2018年 | 9篇 |
2017年 | 7篇 |
2016年 | 13篇 |
2015年 | 15篇 |
2014年 | 20篇 |
2013年 | 26篇 |
2012年 | 29篇 |
2011年 | 30篇 |
2010年 | 21篇 |
2009年 | 19篇 |
2008年 | 16篇 |
2007年 | 20篇 |
2006年 | 15篇 |
2005年 | 15篇 |
2004年 | 20篇 |
2003年 | 16篇 |
2002年 | 9篇 |
2001年 | 5篇 |
2000年 | 2篇 |
1999年 | 3篇 |
1998年 | 2篇 |
1997年 | 1篇 |
1996年 | 1篇 |
1995年 | 4篇 |
1993年 | 2篇 |
1992年 | 2篇 |
1990年 | 3篇 |
1976年 | 1篇 |
排序方式: 共有345条查询结果,搜索用时 15 毫秒
21.
Experimental exploration of equipment for stereotactic functional neurosurgery based on heating induced by radio-frequency current is most often carried out prior to surgery in order to secure a correct function of the equipment. The experiments are normally conducted in an experimental model including an albumin solution in which the treatment electrode is submerged, followed by a heating session during which a protein clot is generated around the electrode tip. The clot is believed to reflect the lesion generated in the brain during treatment. It is thereby presupposed that both the thermal and electric properties of the model are similar to brain tissue. This study investigates the presence of convective movements in the albumin solution using laser Doppler velocimetry. The result clearly shows that convective movements that depend on the time dependent heating characteristics of the equipment arise in the solution upon heating. The convective movements detected show a clear discrepancy compared with the in vivo situation that the experimental model tries to mimic; both the velocity (maximum velocity of about 5 mms) and mass flux are greater in this experimental setting. Furthermore the flow geometry is completely different since only a small fraction of the tissue surrounding the electrode in vivo consists of moving blood, whereas the entire surrounding given by the albumin solution in the experimental model is moving. Earlier investigations by our group (Eriksson et al., 1999, Med. Biol. Eng. Comput. 37, pp. 737-741; Wren, 2001, Ph.D. thesis; and Wren et al., 2001, Med. Biol. Eng. Comput. 39, pp. 255-262) indicate that the heat flux is an essential parameter for the lesion growth and final size, and that presence of convective movements in the model might substantially increase the heat flux. Thus, convective movements of the magnitude presented here will very likely underestimate the size of the brain lesion, a finding that definitely should be taken into consideration when using the model prior to patient treatment. 相似文献
22.
23.
Joakim Hjältén Lena Niemi ers Wennström Lars Ericson Heikki Roininen Riitta Julkunen-Tiitto 《Oikos》2007,116(5):751-758
Plant phenotypes often differ in their resistance to natural enemies, but the mechanism for this has seldom been identified. The aim of this study was to determine if the spatial patterns of phenotype use of a highly specialized insect herbivore (the galling sawfly Pontania triandrae ) in a natural willow population can be related to phenotypic variation in plant secondary chemistry. Furthermore, we tested if traits that confer resistance to one type of natural enemy, i.e. the galling sawfly, also confer resistance to others, in our case a leaf beetle Gonioctena linnaeana and the rust fungus Melampsora amygdalinae . We identified 18 phenotypes with high and 18 phenotypes with low gall density in our field population and determined gall densities, the degree of leaf damage and rust infection on each phenotype and collected leaves for chemical analyses. The concentration of phenolics was higher in phenotypes with high density of galls suggesting that this galling sawfly may use phenolics as oviposition cues. Rust infection showed the opposite pattern, with lower levels on clones with high concentration of phenolics, while leaf damage by G. linnaeana did not differ between clone types. This indicates that these important natural enemies may assert divergent selection on willow phenotypes and that this might provide a mechanism for maintaining phenotypic variation within willow populations. 相似文献
24.
Annika S?derholm Xiaohu Guo Matilda S. Newton Gary B. Evans Joakim N?svall Wayne M. Patrick Maria Selmer 《The Journal of biological chemistry》2015,290(41):24657-24668
HisA is a (βα)8 barrel enzyme that catalyzes the Amadori rearrangement of N′-[(5′-phosphoribosyl)formimino]-5-aminoimidazole-4-carboxamide ribonucleotide (ProFAR) to N′-((5′-phosphoribulosyl) formimino)-5-aminoimidazole-4-carboxamide-ribonucleotide (PRFAR) in the histidine biosynthesis pathway, and it is a paradigm for the study of enzyme evolution. Still, its exact catalytic mechanism has remained unclear. Here, we present crystal structures of wild type Salmonella enterica HisA (SeHisA) in its apo-state and of mutants D7N and D7N/D176A in complex with two different conformations of the labile substrate ProFAR, which was structurally visualized for the first time. Site-directed mutagenesis and kinetics demonstrated that Asp-7 acts as the catalytic base, and Asp-176 acts as the catalytic acid. The SeHisA structures with ProFAR display two different states of the long loops on the catalytic face of the structure and demonstrate that initial binding of ProFAR to the active site is independent of loop interactions. When the long loops enclose the substrate, ProFAR adopts an extended conformation where its non-reacting half is in a product-like conformation. This change is associated with shifts in a hydrogen bond network including His-47, Asp-129, Thr-171, and Ser-202, all shown to be functionally important. The closed conformation structure is highly similar to the bifunctional HisA homologue PriA in complex with PRFAR, thus proving that structure and mechanism are conserved between HisA and PriA. This study clarifies the mechanistic cycle of HisA and provides a striking example of how an enzyme and its substrate can undergo coordinated conformational changes before catalysis. 相似文献
25.
26.
The HIV-1 epidemic in West Africa has been dominated by subtype A and the recombinant form CRF02_AG. Little is known about the origins and the evolutionary history of HIV-1 in this region. We employed Maximum likelihood and Bayesian methods in combination with temporal and spatial information to reconstruct the HIV-1 subtype distribution, demographic history and migration patterns over time in Guinea-Bissau, West Africa. We found that CRF02_AG and subsubtype A3 were the dominant forms of HIV-1 in Guinea-Bissau and that they were introduced into the country on at least six different occasions between 1976 and 1981. These estimates also corresponded well with the first reported HIV-1 cases in Guinea-Bissau. Migration analyses suggested that (1) the HIV-1 epidemic started in the capital Bissau and then dispersed into more rural areas, and (2) the epidemic in Guinea-Bissau was connected to both Cameroon and Mali. This is the first study that describes the HIV-1 molecular epidemiology in a West African country by combining the results of subtype distribution with analyses of epidemic origin and epidemiological linkage between locations. The multiple introductions of HIV-1 into Guinea-Bissau, during a short time-period of five years, coincided with and were likely influenced by the major immigration wave into the country that followed the end of the independence war (1963-1974). 相似文献
27.
Biomarker identification is of utmost importance for the development of novel diagnostics and therapeutics. Here we make use of a translational database selection strategy, utilizing data from the Human Protein Atlas (HPA) on differentially expressed protein patterns in healthy and breast cancer tissues as a means to filter out potential biomarkers for underlying genetic causatives of the disease. DNA was isolated from ten breast cancer biopsies, and the protein coding and flanking non-coding genomic regions corresponding to the selected proteins were extracted in a multiplexed format from the samples using a single DNA sequence capture array. Deep sequencing revealed an even enrichment of the multiplexed samples and a great variation of genetic alterations in the tumors of the sampled individuals. Benefiting from the upstream filtering method, the final set of biomarker candidates could be completely verified through bidirectional Sanger sequencing, revealing a 40 percent false positive rate despite high read coverage. Of the variants encountered in translated regions, nine novel non-synonymous variations were identified and verified, two of which were present in more than one of the ten tumor samples. 相似文献
28.
Background
Diabetic retinopathy and retinopathy of prematurity are diseases caused by pathological angiogenesis in the retina as a consequence of local hypoxia. The underlying mechanism for epiretinal neovascularization (tuft formation), which contributes to blindness, has yet to be identified. Neural cell adhesion molecule (N-CAM) is expressed by Müller cells and astrocytes, which are in close contact with the retinal vasculature, during normal developmental angiogenesis.Methodology/Principal Findings
Notably, during oxygen induced retinopathy (OIR) N-CAM accumulated on astrocytes surrounding the epiretinal tufts. Here, we show that N-CAM ablation results in reduced vascular tuft formation due to reduced endothelial cell proliferation despite an elevation in VEGFA mRNA expression, whereas retinal developmental angiogenesis was unaffected.Conclusion/Significance
We conclude that N-CAM exhibits a regulatory function in pathological angiogenesis in OIR. This is a novel finding that can be of clinical relevance in diseases associated with proliferative vasculopathy. 相似文献29.
Näsström T Gonçalves S Sahlin C Nordström E Screpanti Sundquist V Lannfelt L Bergström J Outeiro TF Ingelsson M 《PloS one》2011,6(10):e27230
Recent research implicates soluble aggregated forms of α-synuclein as neurotoxic species with a central role in the pathogenesis of Parkinson's disease and related disorders. The pathway by which α-synuclein aggregates is believed to follow a step-wise pattern, in which dimers and smaller oligomers are initially formed. Here, we used H4 neuroglioma cells expressing α-synuclein fused to hemi:GFP constructs to study the effects of α-synuclein monoclonal antibodies on the early stages of aggregation, as quantified by Bimolecular Fluorescence Complementation assay. Widefield and confocal microscopy revealed that cells treated for 48 h with monoclonal antibodies internalized antibodies to various degrees. C-terminal and oligomer-selective α-synuclein antibodies reduced the extent of α-synuclein dimerization/oligomerization, as indicated by decreased GFP fluorescence signal. Furthermore, ELISA measurements on lysates and conditioned media from antibody treated cells displayed lower α-synuclein levels compared to untreated cells, suggesting increased protein turnover. Taken together, our results propose that extracellular administration of monoclonal antibodies can modify or inhibit early steps in the aggregation process of α-synuclein, thus providing further support for passive immunization against diseases with α-synuclein pathology. 相似文献
30.
Bäckvall H Asplund A Gustafsson A Sivertsson A Lundeberg J Ponten F 《Mutation research》2005,571(1-2):65-79
Carcinogenesis is a multi-step series of somatic genetic events. The complexity of this multi-hit process makes it difficult to determine each single event and the definitive outcome of such events. To investigate the genetic alterations in cancer-related genes, sensitive and reliable detection methods are of major importance for generating relevant results. Another critical issue is the quality of starting material which largely affects the outcome of the analysis. Microdissection of cells defined under the microscope ensures a selection of representative material for subsequent genetic analysis. Skin cancer provides an advantageous model for studying the development of cancer. Detectable lesions occur early during tumor progression, facilitating molecular analysis of the cell populations from both preneoplastic and neoplastic lesions. Alterations of the p53 tumor suppressor gene are very common in non-melanoma skin cancer, and dysregulation of p53 pathways appear to be an early event in the tumor development. A high frequency of epidermal p53 clones has been detected in chronically sun-exposed skin. The abundance of clones containing p53 mutated keratinocytes adjacent to basal cell (BCC) and squamous cell carcinoma (SCC) suggests a role in human skin carcinogenesis. Studies using p53 mutations as a clonality marker have suggested a direct link between actinic keratosis, SCC in situ and invasive SCC. Microdissection-based studies have also shown that different parts of individual BCC tumors can share a common p53 mutation yet differ with respect to additional alterations within the p53 gene, consistent with subclonal development within tumors. Here, we present examples of using well-defined cell populations, including single cells, from complex tissue in combination with molecular tools to reveal features involved in skin carcinogenesis. 相似文献