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排序方式: 共有174条查询结果,搜索用时 16 毫秒
21.
Anders Sandberg Leila M. Luheshi Sofia S?llvander Teresa Pereira de Barros Bertil Macao Tuomas P. J. Knowles Henrik Biverst?l Christofer Lendel Frida Ekholm-Petterson Anatoly Dubnovitsky Lars Lannfelt Christopher M. Dobson Torleif H?rd 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(35):15595-15600
Soluble oligomeric aggregates of the amyloid-β peptide (Aβ) have been implicated in the pathogenesis of Alzheimer’s disease (AD). Although the conformation adopted by Aβ within these aggregates is not known, a β-hairpin conformation is known to be accessible to monomeric Aβ. Here we show that this β-hairpin is a building block of toxic Aβ oligomers by engineering a double-cysteine mutant (called Aβcc) in which the β-hairpin is stabilized by an intramolecular disulfide bond. Aβ40cc and Aβ42cc both spontaneously form stable oligomeric species with distinct molecular weights and secondary-structure content, but both are unable to convert into amyloid fibrils. Biochemical and biophysical experiments and assays with conformation-specific antibodies used to detect Aβ aggregates in vivo indicate that the wild-type oligomer structure is preserved and stabilized in Aβcc oligomers. Stable oligomers are expected to become highly toxic and, accordingly, we find that β-sheet-containing Aβ42cc oligomers or protofibrillar species formed by these oligomers are 50 times more potent inducers of neuronal apoptosis than amyloid fibrils or samples of monomeric wild-type Aβ42, in which toxic aggregates are only transiently formed. The possibility of obtaining completely stable and physiologically relevant neurotoxic Aβ oligomer preparations will facilitate studies of their structure and role in the pathogenesis of AD. For example, here we show how kinetic partitioning into different aggregation pathways can explain why Aβ42 is more toxic than the shorter Aβ40, and why certain inherited mutations are linked to protofibril formation and early-onset AD. 相似文献
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TM Sankary ; G Yang ; JM Romeo ; PP Ulrich ; MP Busch ; BD Rawal ; GN Vyas 《Transfusion》1994,34(8):656-660
BACKGROUND: Since screening for antibody to hepatitis C virus (HCV) was introduced in 1990, posttransfusion hepatitis has been reduced to nearly background levels. This has led to reconsideration of the value of testing donated blood for elevated alanine aminotransferase (ALT). The contribution of ALT testing in detecting seronegative infection was evaluated by the performance of polymerase chain reaction (PCR) for hepatitis B virus (HBV) or HCV in plasma from ALT-elevated blood units. STUDY DESIGN AND METHODS: Testing was performed on 375 units of plasma, derived from an equivalent of 47,500 blood donations, with a highly sensitive hemi-nested PCR procedure. Using a triplet of primers directed at the conserved regions of HBV DNA and 5'-noncoding regions of HCV RNA, the hemi-nested PCR assay can reliably amplify 10 viral molecules to levels detectable in ethidium bromide-stained agarose gels. Pools of plasma from groups of four donors were screened with hemi-nested PCR. For any reactive pools, the plasma from individual donors was retested twice on different aliquots. RESULTS: Two of 375 units, both with midrange ALT elevation, were repeatedly reactive in hemi-nested PCR (one each for HBV DNA and HCV RNA). However, samples from the two suspect donors tested 9 and 5 months later revealed no seroconversion, elevated ALT, or viral genomes in hemi-nested PCR. CONCLUSION: The lack of confirmed HBV or HCV infection in this study representing an estimated 47,500 voluntary blood donations suggests that routine ALT testing for further prevention of posttransfusion hepatitis after exclusion of HBV- and/or HCV-seropositive blood may be superfluous. 相似文献
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AI Zijlstra GD Offner NH Afdhal M van Overveld GN Tytgat AK Groen 《Gastroenterology》1996,110(6):1926-1935
BACKGROUND & AIMS: Many putative pronucleating proteins have been isolated from the biliary concanavalin A (con A)-binding fraction. The pronase resistance of the overall nucleating-promoting activity was almost never taken into consideration. The aim of this study was to identify the major pronase-resistant con A-binding glycoproteins. METHODS: Pronase-treated and -untreated con A-binding glycoproteins were separated on a Superose 12 gel permeation column (Pharmacia, Uppsala, Sweden) and tested in a crystal growth assay. Proteins were identified by amino-terminal sequencing. RESULTS: Con A-binding pronucleating activity eluted in two peaks on the Superose column. This activity was unaltered after pronase treatment. Activity peak I contained too little protein to allow amino-terminal sequencing. In activity peak II, the major pronase-resistant con A-binding glycoproteins were identified as alpha 1-antitrypsin and alpha 1- antichymotrypsin. The 130-kilodalton nucleation promoter was identified as aminopeptidase N, but the full pronase resistance of this protein, reported earlier, was not confirmed. Immunoabsorptive removal of alpha 1-antitrypsin and alpha 1-antichymotrypsin and immunopurification showed that only alpha 1-antichymotrypsin had pronucleating activity. CONCLUSIONS: The pronase resistance of the nucleating-promoting activity of the con A-binding glycoprotein fraction was confirmed. An important part of this activity could be attributed to alpha 1- antichymotrypsin. It is an acute-phase protein, as are many other pronucleating proteins, which might indicate a general mechanism of action in gallstone formation. (Gastroenterology 1996 Jun;110(6):1926-35) 相似文献
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Morphological variation of layer III pyramidal neurones in the occipitotemporal pathway of the macaque monkey visual cortex 总被引:5,自引:5,他引:0
We compared the morphological characteristics of layer III pyramidal
neurones in different visual areas of the occipitotemporal cortical
'stream', which processes information related to object recognition in the
visual field (including shape, colour and texture). Pyramidal cells were
intracellularly injected with Lucifer Yellow in cortical slices cut
tangential to the cortical layers, allowing quantitative comparisons of
dendritic field morphology, spine density and cell body size between the
blobs and interblobs of the primary visual area (V1), the interstripe
compartments of the second visual area (V2), the fourth visual area (V4)
and cytoarchitectonic area TEO. We found that the tangential dimension of
basal dendritic fields of layer III pyramidal neurones increases from
caudal to rostral visual areas in the occipitotemporal pathway, such that
TEO cells have, on average, dendritic fields spanning an area 5-6 times
larger than V1 cells. In addition, the data indicate that V1 cells located
within blobs have significantly larger dendritic fields than those of
interblob cells. Sholl analysis of dendritic fields demonstrated that
pyramidal cells in V4 and TEO are more complex (i.e. exhibit a larger
number of branches at comparable distances from the cell body) than cells
in V1 or V2. Moreover, this analysis demonstrated that the dendrites of
many cells in V1 cluster along specific axes, while this tendency is less
marked in extrastriate areas. Most notably, there is a relatively large
proportion of neurones with 'morphologically orientation-biased' dendritic
fields (i.e. branches tend to cluster along two diametrically opposed
directions from the cell body) in the interblobs in V1, as compared with
the blobs in V1 and extrastriate areas. Finally, counts of dendritic spines
along the length of basal dendrites revealed similar peak spine densities
in the blobs and the interblobs of V1 and in the V2 interstripes, but
markedly higher spine densities in V4 and TEO. Estimates of the number of
dendritic spines on the basal dendritic fields of layer III pyramidal cells
indicate that cells in V2 have on average twice as many spines as V1 cells,
that V4 cells have 3.8 times as many spines as V1 cells, and that TEO cells
have 7.5 times as many spines as V1 cells. These findings suggest the
possibility that the complex response properties of neurones in rostral
stations in the occipitotemporal pathway may, in part, be attributed to
their larger and more complex basal dendritic fields, and to the increase
in both number and density of spines on their basal dendrites.
相似文献
29.
Maternal infection during pregnancy has been associated with an increased risk for the development of schizophrenia, a disorder characterized by abnormalities in hippocampal morphology and function. Neurogenesis occurs in the hippocampus throughout development into adulthood and is believed to modulate hippocampal function. This study used a rat model in which bacterial endotoxin, lipopolysaccharide (LPS), is administered to pregnant dams, to test if prenatal immune activation has acute and/or long term effects on various phases of neurogenesis (proliferation, survival, differentiation) in the hippocampal dentate gyrus of offspring. When LPS was administered to dams on gestation days (GD) 15 and 16, there was decreased proliferation of dentate cells at postnatal day (PD) 14 and decreased survival of cells generated at PD14 in offspring. When prenatal exposure to LPS was later in pregnancy (GD 18 and 19), offspring showed decreased survival of cells generated both at the time of LPS exposure and at PD14. There was no change in cell proliferation or survival in adult offspring at PD60, with prenatal LPS exposure. Co-administration of the cyclo-oxygenase inhibitor, ibuprofen (IBU), together with prenatal LPS on GD 15 and 16, was unable to prevent the deficit in neuronal survival at PD14. IBU blocked LPS-induced fever but did not block LPS-induced increases in plasma cytokines and corticosterone in the pregnant dam. This indicates that deficits in neurogenesis caused by prenatal LPS are not mediated by LPS-induced fever or eicosanoid induction, but could be mediated by LPS-induced increases in maternal cytokines or corticosterone. 相似文献
30.