全文获取类型
收费全文 | 880篇 |
免费 | 67篇 |
出版年
2023年 | 4篇 |
2022年 | 9篇 |
2021年 | 27篇 |
2020年 | 6篇 |
2019年 | 12篇 |
2018年 | 9篇 |
2017年 | 16篇 |
2016年 | 26篇 |
2015年 | 38篇 |
2014年 | 44篇 |
2013年 | 83篇 |
2012年 | 90篇 |
2011年 | 80篇 |
2010年 | 52篇 |
2009年 | 36篇 |
2008年 | 66篇 |
2007年 | 60篇 |
2006年 | 51篇 |
2005年 | 53篇 |
2004年 | 49篇 |
2003年 | 47篇 |
2002年 | 38篇 |
2001年 | 5篇 |
2000年 | 1篇 |
1999年 | 6篇 |
1998年 | 8篇 |
1997年 | 7篇 |
1996年 | 2篇 |
1995年 | 4篇 |
1994年 | 2篇 |
1993年 | 2篇 |
1992年 | 1篇 |
1991年 | 1篇 |
1990年 | 3篇 |
1989年 | 2篇 |
1988年 | 1篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1981年 | 3篇 |
1976年 | 1篇 |
排序方式: 共有947条查询结果,搜索用时 15 毫秒
151.
Evolution of the Hepatitis C Virus Second Envelope Protein Hypervariable Region in Chronically Infected Patients Receiving Alpha Interferon Therapy 总被引:8,自引:0,他引:8
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)
Jean-Michel Pawlotsky Georgios Germanidis Pierre-Olivier Frainais Magali Bouvier Alexandre Soulier Muriel Pellerin Daniel Dhumeaux 《Journal of virology》1999,73(8):6490-6499
Sustained hepatitis C virus (HCV) RNA clearance is achieved in 8 to 12% of patients with chronic HCV infection treated with alpha interferon (IFN-alpha) at the approved dose of 3 MU three times a week for 6 months and in about 25% of those receiving this treatment for 12 months. We used single-strand conformation polymorphism analysis combined with cloning and sequencing strategies to characterize the genetic evolution of HCV second envelope gene hypervariable region 1 (HVR1) quasispecies during and after IFN therapy in patients who failed to clear HCV RNA. Sustained HCV RNA clearance was achieved in 6% of patients. Profound changes in HVR1 quasispecies major variants were estimated to occur in 70% of the patients during and after therapy. These changes were evolutionary and were characterized by shifts in the virus population, related to selection and subsequent diversification of minor pretreatment variants. The quasispecies changes appeared to be induced by changes in the host environment likely resulting from the IFN-induced enhancement and post-IFN attenuation of neutralizing and possibly cytotoxic responses against HVR1. The remaining patients had no apparent changes in HVR1 quasispecies major variants, suggesting selection of major pretreatment variants, but some changes were observed in other genomic regions. We conclude that IFN-alpha administration and withdrawal profoundly alters the nature of circulating HCV quasispecies, owing to profound changes in virus-host interactions, in patients in whom sustained HCV RNA clearance fails to occur. These changes are associated with profound alterations of the natural outcome of HCV-related liver disease, raising the hypothesis of a causal relationship. 相似文献
152.
153.
Novel product specificity toward erlose and panose exhibited by multisite engineered mutants of amylosucrase
下载免费PDF全文
![点击此处可从《Protein science : a publication of the Protein Society》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Alizée Vergès Emmanuelle Cambon Sophie Barbe Claire Moulis Magali Remaud‐Siméon Isabelle André 《Protein science : a publication of the Protein Society》2017,26(3):566-577
A computer‐aided engineering approach recently enabled to deeply reshape the active site of N. polysaccharea amylosucrase for recognition of non‐natural acceptor substrates. Libraries of variants were constructed and screened on sucrose allowing the identification of 17 mutants able to synthesize molecules from sole sucrose, which are not synthesized by the parental wild‐type enzyme. Three of the isolated mutants as well as the new products synthesized were characterized in details. Mutants contain between 7 and 11 mutations in the active site and the new molecules were identified as being a sucrose derivative, named erlose (α‐d ‐glucopyranosyl‐(1→4)‐α‐d ‐glucopyranosyl‐(1→2)‐β‐d ‐Fructose), and a new malto‐oligosaccharide named panose (α‐d ‐glucopyranosyl‐(1→6)‐α‐d ‐glucopyranosyl‐(1→4)‐α‐d ‐Glucose). These product specificities were never reported for none of the amylosucrases characterized to date, nor their engineered variants. Optimization of the production of these trisaccharides of potential interest as sweeteners or prebiotic molecules was carried out. Molecular modelling studies were also performed to shed some light on the molecular factors involved in the novel product specificities of these amylosucrase variants. 相似文献
154.
155.
Dendritic cells and innate defense against tumor cells 总被引:1,自引:0,他引:1
Ullrich E Ménard C Flament C Terme M Mignot G Bonmort M Plumas J Chaperot L Chaput N Zitvogel L 《Cytokine & growth factor reviews》2008,19(1):79-92
Tumor growth results from a delicate balance between intrinsic dysregulation of oncogenes, tumor suppressor and stability genes counteracted by extrinsic defenses composed of immune cells shaping tumor immunogenicity. Although immune subversion might be the ultimate outcome of this process, a complex network of cellular interactions take place eventually leading to tumor specific cognate immune responses. The links between innate and cognate antitumor immunity eliciting protective T cell responses are instigated by cytokines, chemokines and damage associated molecular patterns. The intricate differentiation pathway whereby dendritic cells could undergo an efficient maturation program in the tumor microenvironment appears crucial. We will discuss the role of innate effectors and cancer therapies in the process of defense against tumor cells. 相似文献
156.
Salma Hazgui Arnaud Bonnomet Béatrice Nawrocki-Raby Magali Milliot Christine Terryn Jér?me Cutrona Myriam Polette Philippe Birembaut Jean-Marie Zahm 《Respiratory research》2008,9(1):33
Background
Many studies associated the main polyphenolic constituent of green tea, (-)-Epigallocatechin-3-gallate (EGCG), with inhibition of cancers, invasion and metastasis. To date, most of the studies have focused on the effect of EGCG on cell proliferation or death. Since cell migration is an important mechanism involved in tumor invasion, the aim of the present work was to target another approach of the therapeutic effect of EGCG, by investigating its effect on the cell migratory behavior.Methods
The effect of EGCG (at concentrations lower than 10 μg/ml) on the migration speed of invasive cells was assessed by using 2D and 3D models of cell culture. We also studied the effects of EGCG on proteinases expression by RT-PCR analysis. By immunocytochemistry, we analyzed alterations of vimentin organization in presence of different concentrations of EGCG.Results
We observed that EGCG had an inhibitory effect of cell migration in 2D and 3D cell culture models. EGCG also inhibited MMP-2 mRNA and protein expression and altered the intermediate filaments of vimentin.Conclusion
Taken together, our results demonstrate that EGCG is able to inhibit the migration of bronchial tumor cells and could therefore be an attractive candidate to treat tumor invasion and cell migration. 相似文献157.
Leblond J Le Pessot F Hubert-Buron A Duclos C Vuichoud J Faure M Breuillé D Déchelotte P Coëffier M 《Experimental biology and medicine (Maywood, N.J.)》2008,233(2):219-228
Mucositis, a common toxic side effect of chemotherapy, is characterized by an arrest of cell proliferation and a loss of gut barrier function, which may cause treatment reduction or withdrawal. Gut integrity depends on nutritional and metabolic factors, including the balance between protein synthesis and proteolysis. The effects of methotrexate (MTX; a frequently used chemotherapeutic agent) on intestinal proteolysis and gut barrier function were investigated in rats. Male Sprague-Dawley rats received 2.5 mg/kg of MTX subcutaneously during 3 days and were euthanized at Day 4 (D4) or Day 7 (D7). We observed at D4 that MTX induced mucosal damage and increased intestinal permeability (7-fold) and the mucosal concentration of interleukin (IL)-1beta and IL-6 (4- to 6-fold). In addition, villus height and glutathione content significantly decreased. Intestinal proteolysis was also affected by MTX as cathepsin D activity increased at D4, whereas chymotrypsin-like proteasome activity decreased and calpain activities remained unaffected. At D7, cathepsin D activity was restored to control levels, but proteasome activity remained reduced. This disruption of proteolysis pathways strongly contributed to mucositis and requires further study. Lysosomal proteolytic activity may be considered the main proteolytic pathway responsible for alteration of mucosal integrity and intestinal permeability during mucositis, as cathepsin D activity was found to be correlated with mucosal atrophy and intestinal permeability. Proteasome regulation could possibly be an adaptive process for survival. Future investigation is warranted to target proteolytic pathways with protective nutritional or pharmacological therapies during mucositis. 相似文献
158.
Hervé Rhinn Céline Largeau Pascal Bigey René Lai Kuen Magali Richard Daniel Scherman Virginie Escriou 《Biochimica et Biophysica Acta (BBA)/General Subjects》2009
Background
We recently reported an efficient formulation of siRNA targeting TNF-α, that was able to restore immunological balance in a mouse arthritis model following intravenous injection.Method
Since this efficient formulation included the pre association of siRNA with a DNA cargo, we decided to extensively characterise siRNA lipoplexes with or without DNA cargo, in order to better understand the DNA cargo enhancing effect.Results
We showed that addition of DNA cargo to siRNA lipoplexes led to specific gene extinction in vitro, using reduced siRNA concentration. This procedure is also applicable to other lipid vectors, like Lipofectamine or DMRIE-C. No structural modification could be observed in siRNA lipoplexes upon addition of DNA cargo using dynamic light scattering or transmission electronic microscopy. Nevertheless, we observed some slight differences, in the amount of lipid required to obtain neutrality of the complex and in stability of the complex towards incubation with heparan sulfate.Conclusions
These results suggest that the addition of DNA cargo to siRNA complexes is an easy procedure that leads to more efficient complexes to transfer siRNA at low concentration and in the presence of serum. 相似文献159.
Campylobacter jejuni represents one of the leading causes of bacterial enteritis throughout the world. Poultry is an important source of C. jejuni. Despite hygiene measures taken in the production chain, C. jejuni is frequently isolated from poultry meat. C. jejuni is a microaerophilic pathogen, affected by oxidative stress. Freeze-thaw treatment induces cell death by several mechanisms,
including oxidative stress. In this article, we investigate the role of oxidative stress in C. jejuni sensitivity during and after a freeze-thaw treatment. This treatment results in dead and sublethally injured cells. The latter
population might have an increased sensitivity to oxidative stress. To test this, cells were stored for another 24 h at 4°C
under aerobic conditions and compared to cells that were not treated. C. jejuni survival was measured in different media (water, BHI broth, chicken juice, and chicken fillets) to test the environment protective
effect. Different strains were tested, including sodB (encoding the superoxide dismutase) and cj1371 (encoding a periplasmic protein) mutants. Cell death was particularly important in water but similar in BHI, chicken juice,
and chicken fillets. The sodB mutant was more sensitive to freeze-thaw treatment, suggesting that the killing mechanism involves production of superoxide
anions. On the contrary, the cj1371 mutant was more sensitive to storage at 4°C, suggesting that it does not play a role in the detoxification of reactive oxygen
species. Storage at 4°C after freeze-thaw treatment increases cell death of oxidative stress-sensitive populations. Sensitization
to oxidative stress, freeze-thaw treatment, and further storage at 4°C could be a way to reduce C. jejuni populations on carcasses. 相似文献
160.