全文获取类型
收费全文 | 1082篇 |
免费 | 57篇 |
出版年
2024年 | 2篇 |
2023年 | 6篇 |
2022年 | 14篇 |
2021年 | 25篇 |
2020年 | 15篇 |
2019年 | 18篇 |
2018年 | 43篇 |
2017年 | 34篇 |
2016年 | 43篇 |
2015年 | 65篇 |
2014年 | 71篇 |
2013年 | 72篇 |
2012年 | 102篇 |
2011年 | 113篇 |
2010年 | 69篇 |
2009年 | 54篇 |
2008年 | 78篇 |
2007年 | 70篇 |
2006年 | 55篇 |
2005年 | 38篇 |
2004年 | 31篇 |
2003年 | 42篇 |
2002年 | 32篇 |
2001年 | 9篇 |
2000年 | 4篇 |
1999年 | 5篇 |
1998年 | 2篇 |
1997年 | 6篇 |
1996年 | 4篇 |
1995年 | 2篇 |
1994年 | 2篇 |
1993年 | 3篇 |
1991年 | 1篇 |
1990年 | 4篇 |
1986年 | 1篇 |
1982年 | 1篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有1139条查询结果,搜索用时 15 毫秒
101.
Schneider A Araújo GW Trajkovic K Herrmann MM Merkler D Mandelkow EM Weissert R Simons M 《The Journal of biological chemistry》2004,279(53):55833-55839
Axonal damage is a major morphological correlate and cause of permanent neurological deficits in patients with multiple sclerosis (MS), a multifocal, inflammatory and demyelinating disease of the central nervous system. Hyperphosphorylation and pathological aggregation of microtubule-associated protein tau is a common feature of many neurodegenerative diseases with axonal degeneration including Alzheimer's disease. We have therefore analyzed tau phosphorylation, solubility and distribution in the brainstem of rats with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Tau was hyperphosphorylated at several sites also phosphorylated in Alzheimer's disease and became partially detergent-insoluble in EAE brains. Morphological examination demonstrated accumulation of amorphous deposits of abnormally phosphorylated tau in the cell body and axons of neurons within demyelinating plaques. Hyperphosphorylation of tau was accompanied by up-regulation of p25, an activator of cyclin-dependent kinase 5. Phosphorylation of tau, activation of cdk5, and axonal pathology were significantly reduced when diseased rats were treated with prednisolone, a standard therapy of acute relapses in MS. Hyperphosphorylation of tau was not observed in a genetic or nutritional model of axonal degeneration or demyelination, suggesting that inflammation as detected in the brains of rats with EAE is the specific trigger of tau pathology. In summary, our data provide evidence that axonal damage in EAE and possibly MS is linked to tau pathology. 相似文献
102.
Scrapie protein degradation by cysteine proteases in CD11c+ dendritic cells and GT1-1 neuronal cells
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Luhr KM Nordström EK Löw P Ljunggren HG Taraboulos A Kristensson K 《Journal of virology》2004,78(9):4776-4782
Dendritic cells (DC) of the CD11c(+) myeloid phenotype have been implicated in the spread of scrapie in the host. Previously, we have shown that CD11c(+) DC can cause a rapid degradation of proteinase K-resistant prion proteins (PrP(Sc)) in vitro, indicating a possible role of these cells in the clearance of PrP(Sc). To determine the mechanisms of PrP(Sc) degradation, CD11c(+) DC that had been exposed to PrP(Sc) derived from a neuronal cell line (GT1-1) infected with scrapie (ScGT1-1) were treated with a battery of protease inhibitors. Following treatment with the cysteine protease inhibitors (2S,3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane (E-64c), its ethyl ester (E-64d), and leupeptin, the degradation of PrP(Sc) was inhibited, while inhibitors of serine and aspartic and metalloproteases (aprotinin, pepstatin, and phosphoramidon) had no effect. An endogenous degradation of PrP(Sc) in ScGT1-1 cells was revealed by inhibiting the expression of cellular PrP (PrP(C)) by RNA interference, and this degradation could also be inhibited by the cysteine protease inhibitors. Our data show that PrP(Sc) is proteolytically cleaved preferentially by cysteine proteases in both CD11c(+) DC and ScGT1-1 cells and that the degradation of PrP(Sc) by proteases is different from that of PrP(C). Interference by protease inhibitors with DC-induced processing of PrP(Sc) has the potential to modify prion spread, clearance, and immunization in a host. 相似文献
103.
Tabary O Corvol H Boncoeur E Chadelat K Fitting C Cavaillon JM Clément A Jacquot J 《American journal of physiology. Lung cellular and molecular physiology》2006,290(3):L588-L596
Persistent presence of PMN in airways is the hallmark of CF. Our aim was to assess PMN adherence, percentage of apoptotic airway PMN (aPMN), and IL-6 and IL-8 production when aPMN are in contact with airway epithelial cells. Before coculture, freshly isolated CF aPMN have greater spontaneous and TNF-alpha-induced apoptosis compared with blood PMN from the same CF patients and from aPMN of non-CF patients. We then examined cocultures of PMN isolated from CF and non-CF airways with bronchial epithelial cells bearing mutated cftr compared with cftr-corrected bronchial epithelial cells. After 18-h coculture, the number of CF aPMN adhered on cftr-deficient bronchial epithelial cells was 2.3-fold higher compared with the coculture of non-CF aPMN adhered on cftr-corrected bronchial epithelial cells. The percentage of CF apoptotic aPMN (9.5 +/- 0.2%) adhered on cftr-deficient bronchial epithelial cells was similar to the percentage of non-CF apoptotic aPMN adhered on cftr-corrected bronchial epithelial cells (10.3 +/- 0.7%). IL-6 and IL-8 levels were enhanced 6.5- and 2.9-fold, respectively, in coculture of CF aPMN adhered on cftr-deficient bronchial epithelial cells compared with coculture of non-CF aPMN adhered on cftr-corrected bronchial epithelial cells. Moreover, blocking surface adhesion molecules ICAM-1, VCAM-1, and E-selectin on cftr-deficient bronchial epithelial cells with specific MAbs inhibited the adherence of CF aPMN by 64, 51, and 50%, respectively. Our data suggest that in CF patients a high number of nonapoptotic PMN adhered on airway epithelium associated with elevated IL-6 and IL-8 levels may contribute to sustained and exaggerated inflammatory response in CF airways. 相似文献
104.
Katarina Jewgenow Frank Goeritz Katrin Neubauer Joerns Fickel Sergej V. Naidenko 《European Journal of Wildlife Research》2006,52(1):34-38
This study characterizes the reproductive activity of male European lynx kept in Central Russia. Four captive adult males
were subjected to an electroejaculation prior to (November), during (March) and after (June) the breeding season. Concentration,
motility and morphological integrity of spermatozoa as well as testis diameter and testosterone levels in serum were evaluated.
Additionally, fecal samples were collected for 2 years to determine the fecal testosterone secretion. Testis sizes and serum
testosterone concentrations were characterized by little changes with highest levels in March (2.98 mm3; 1.96 ng/ml testosterone) and lowest in June (2.34 mm3; 0.75 ng/ml testosterone). In faeces, the highest testosterone concentrations were measured in February followed by a second
increase in May. The volume of ejaculates and percentages of motile and intact spermatozoa reached the maxima in March. By
performing two-male mating experiments, we could prove multiple paternity within three litters. Paternity analysis of litter
also revealed that 26 of 31 cubs (84%) were sired from the same male, independently from being the first or second mating
partner of the respective female. This particular male showed the most developed and activated reproductive tract and also
had the best semen quality, which seems to be important for sperm competition. 相似文献
105.
Population size, one of the basic biological parameters is particularly difficult to estimate for nocturnal animals with cryptic life style and little individual distinctiveness like Eurasian otters (Lutra lutra). Because telemetric methods often fail and also expose the animals to a high risk of injuries and even mortality, we analysed DNA and hormones of spraints to obtain data on population density and structure of free-living otters in a Nature Park in north-eastern Germany. We were able to assign 53 different individual profiles from faecal samples and obtained six more profiles from animals found dead inside the park. The total population estimate (n=59) consisted of at least 32 males and 27 females; 33 animals were adult, 23 younger than 2 years (three of unknown age). Marking points were frequented by up to 12 individuals. Estimated density was one animal per 4.7 km of shoreline. The genotypically estimated total population size was more than 2.5 times as high as estimated in the past census. The method was also suited to compare otter population densities in different areas or at different times in the same area. 相似文献
106.
Sköld K Svensson M Nilsson A Zhang X Nydahl K Caprioli RM Svenningsson P Andrén PE 《Journal of proteome research》2006,5(2):262-269
PEP-19 is a neuronal calmodulin-binding protein, and as such, a putative modulator of calcium regulated processes. In the present study, we used proteomics technology approaches such as peptidomics and imaging MALDI mass spectrometry, as well as traditional techniques (immunoblotting and in situ hybridization) to identify PEP-19 and, specifically, to measure PEP-19 mRNA and protein levels in an animal model of Parkinson's disease. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in mice resulted in a significant decrease in striatal PEP-19 mRNA. Capillary nano-flow liquid chromatography electrospray mass spectrometry analysis of striatal tissue revealed a significant decrease of the PEP-19 protein level. Moreover, imaging MALDI mass spectrometry also showed that PEP-19 protein was predominantly localized to the striatum of the brain tissue cross sections. After MPTP administration, PEP-19 levels were significantly reduced by 30%. We conclude that PEP-19 mRNA and protein expression are decreased in the striatum of a common animal model of Parkinson's disease. Further studies are needed to show the specific involvement of PEP-19 in the neurodegeneration seen in MPTP lesioned animals. Finally, this study has shown that the combination of traditional molecular biology techniques with novel, highly specific and sensitive mass spectrometry methods is advantageous in characterizing molecular events of many diseases, including Parkinson's disease. 相似文献
107.
Increased intracellular free zinc concentrations are associated with activation of several stress signaling pathways, specific
organelle injury and final cell death. In the present work we examined the involvement of mitochondria and lysosomes and their
crosstalk in free zinc-induced cell demise. We report that treatment of cervical tumor Hep-2 cells with zinc pyrithione leads
to an early appearance of cytoplasmic zinc-specific foci with corresponding accumulation of zinc first in mitochondria and
later in lysosomes. Concomitant with these changes, upregulation of expression of metallothionein II A gene as well as the
increased abundance of its protein occurs. Moreover, zinc activates p53 and its dependent genes including Puma and Bax and
they contribute to an observed loss of mitochondrial membrane potential and activation of apoptosis. Conversely, lysosomal
membrane permeabilization and its promoted cleavage of Bid occurs in a delayed manner in treated cells and their effect on
decrease of mitochondrial membrane potential is limited. The use of specific inhibitors as well as siRNA technology suggest
a crucial role of MT-IIA in trafficking of free zinc into mitochondria or lysosomes and regulation of apoptotic or necrotic
cell demise. 相似文献
108.
109.
110.
Praveen Papareddy Martina Kalle Gopinath Kasetty Matthias M?rgelin Victoria Rydeng?rd Barbara Albiger Katarina Lundqvist Martin Malmsten Artur Schmidtchen 《The Journal of biological chemistry》2010,285(36):28387-28398
Tissue factor pathway inhibitor (TFPI) inhibits tissue factor-induced coagulation, but may, via its C terminus, also modulate cell surface, heparin, and lipopolysaccharide interactions as well as participate in growth inhibition. Here we show that C-terminal TFPI peptide sequences are antimicrobial against the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, Gram-positive Bacillus subtilis and Staphylococcus aureus, as well as the fungi Candida albicans and Candida parapsilosis. Fluorescence studies of peptide-treated bacteria, paired with analysis of peptide effects on liposomes, showed that the peptides exerted membrane-breaking effects similar to those seen for the “classic” human antimicrobial peptide LL-37. The killing of E. coli, but not P. aeruginosa, by the C-terminal peptide GGLIKTKRKRKKQRVKIAYEEIFVKNM (GGL27), was enhanced in human plasma and largely abolished in heat-inactivated plasma, a phenomenon linked to generation of antimicrobial C3a and activation of the classic pathway of complement activation. Furthermore, GGL27 displayed anti-endotoxic effects in vitro and in vivo in a mouse model of LPS shock. Importantly, TFPI was found to be expressed in the basal layers of normal epidermis, and was markedly up-regulated in acute skin wounds as well as wound edges of chronic leg ulcers. Furthermore, C-terminal fragments of TFPI were associated with bacteria present in human chronic leg ulcers. These findings suggest a new role for TFPI in cutaneous defense against infections. 相似文献