全文获取类型
收费全文 | 273篇 |
免费 | 29篇 |
出版年
2022年 | 1篇 |
2021年 | 7篇 |
2020年 | 3篇 |
2019年 | 4篇 |
2018年 | 4篇 |
2017年 | 5篇 |
2016年 | 6篇 |
2015年 | 17篇 |
2014年 | 16篇 |
2013年 | 20篇 |
2012年 | 20篇 |
2011年 | 17篇 |
2010年 | 16篇 |
2009年 | 8篇 |
2008年 | 27篇 |
2007年 | 23篇 |
2006年 | 17篇 |
2005年 | 14篇 |
2004年 | 8篇 |
2003年 | 5篇 |
2002年 | 12篇 |
2001年 | 8篇 |
2000年 | 5篇 |
1999年 | 2篇 |
1997年 | 2篇 |
1996年 | 1篇 |
1995年 | 2篇 |
1992年 | 2篇 |
1991年 | 4篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1986年 | 4篇 |
1985年 | 2篇 |
1984年 | 1篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1977年 | 2篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1970年 | 1篇 |
1969年 | 1篇 |
1967年 | 1篇 |
1966年 | 1篇 |
1965年 | 4篇 |
排序方式: 共有302条查询结果,搜索用时 31 毫秒
41.
42.
Corona C Frazzini V Silvestri E Lattanzio R La Sorda R Piantelli M Canzoniero LM Ciavardelli D Rizzarelli E Sensi SL 《PloS one》2011,6(3):e17971
Background
The pathogenic road map leading to Alzheimer''s disease (AD) is still not completely understood; however, a large body of studies in the last few years supports the idea that beside the classic hallmarks of the disease, namely the accumulation of amyloid-β (Aβ) and neurofibrillary tangles, other factors significantly contribute to the initiation and the progression of the disease. Among them, mitochondria failure, an unbalanced neuronal redox state, and the dyshomeostasis of endogenous metals like copper, iron, and zinc have all been reported to play an important role in exacerbating AD pathology. Given these factors, the endogenous peptide carnosine may be potentially beneficial in the treatment of AD because of its free-radical scavenger and metal chelating properties.Methodology
In this study, we explored the effect of L-carnosine supplementation in the 3xTg-AD mouse, an animal model of AD that shows both Aβ- and tau-dependent pathology.Principal Findings
We found that carnosine supplementation in 3xTg-AD mice promotes a strong reduction in the hippocampal intraneuronal accumulation of Aβ and completely rescues AD and aging-related mitochondrial dysfunctions. No effects were found on tau pathology and we only observed a trend toward the amelioration of cognitive deficits.Conclusions and Significance
Our data indicate that carnosine can be part of a combined therapeutic approach for the treatment of AD. 相似文献43.
Divergent host responses during primary simian immunodeficiency virus SIVsm infection of natural sooty mangabey and nonnatural rhesus macaque hosts 下载免费PDF全文
Silvestri G Fedanov A Germon S Kozyr N Kaiser WJ Garber DA McClure H Feinberg MB Staprans SI 《Journal of virology》2005,79(7):4043-4054
To understand how natural sooty mangabey hosts avoid AIDS despite high levels of simian immunodeficiency virus (SIV) SIVsm replication, we inoculated mangabeys and nonnatural rhesus macaque hosts with an identical inoculum of uncloned SIVsm. The unpassaged virus established infection with high-level viral replication in both macaques and mangabeys. A species-specific, divergent immune response to SIV was evident from the first days of infection and maintained in the chronic phase, with macaques showing immediate and persistent T-cell proliferation, whereas mangabeys displayed little T-cell proliferation, suggesting subdued cellular immune responses to SIV. Importantly, only macaques developed (CD4+)-T-cell depletion and AIDS, thus indicating that in mangabeys limited immune activation is a key mechanism to avoid immunodeficiency despite high levels of SIVsm replication. These studies demonstrate that it is the host response to infection, rather than properties inherent to the virus itself, that causes immunodeficiency in SIV-infected nonhuman primates. 相似文献
44.
Thyroid-hormone effects on putative biochemical pathways involved in UCP3 activation in rat skeletal muscle mitochondria 总被引:2,自引:0,他引:2
Silvestri E Moreno M Lombardi A Ragni M de Lange P Alexson SE Lanni A Goglia F 《FEBS letters》2005,579(7):1639-1645
In vitro, uncoupling protein 3 (UCP3)-mediated uncoupling requires cofactors [e.g., superoxides, coenzyme Q (CoQ) and fatty acids (FA)] or their derivatives, but it is not yet clear whether or how such activators interact with each other under given physiological or pathophysiological conditions. Since triiodothyronine (T3) stimulates lipid metabolism, UCP3 expression and mitochondrial uncoupling, we examined its effects on some biochemical pathways that may underlie UCP3-mediated uncoupling. T3-treated rats (Hyper) showed increased mitochondrial lipid-oxidation rates, increased expression and activity of enzymes involved in lipid handling and increased mitochondrial superoxide production and CoQ levels. Despite the higher mitochondrial superoxide production in Hyper, euthyroid and hyperthyroid mitochondria showed no differences in proton-conductance when FA were chelated by bovine serum albumin. However, mitochondria from Hyper showed a palmitoyl-carnitine-induced and GDP-inhibited increased proton-conductance in the presence of carboxyatractylate. We suggest that T3 stimulates the UCP3 activity in vivo by affecting the complex network of biochemical pathways underlying the UCP3 activation. 相似文献
45.
Loss of CD127 expression defines an expansion of effector CD8+ T cells in HIV-infected individuals 总被引:15,自引:0,他引:15
Paiardini M Cervasi B Albrecht H Muthukumar A Dunham R Gordon S Radziewicz H Piedimonte G Magnani M Montroni M Kaech SM Weintrob A Altman JD Sodora DL Feinberg MB Silvestri G 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(5):2900-2909
The immunodeficiency that follows HIV infection is related to the virus-mediated killing of infected CD4(+) T cells, the chronic activation of the immune system, and the impairment of T cell production. In this study we show that in HIV-infected individuals the loss of IL-7R (CD127) expression defines the expansion of a subset of CD8(+) T cells, specific for HIV as well as other Ags, that show phenotypic (i.e., loss of CCR7 and CD62 ligand expression with enrichment in activated and/or proliferating cells) as well as functional (i.e., production of IFN-gamma, but not IL-2, decreased ex vivo proliferative potential and increased susceptibility to apoptosis) features of effector T cells. Importantly, in HIV-infected individuals the levels of CD8(+)CD127(-) T cells are directly correlated with the main markers of disease progression (i.e., plasma viremia and CD4(+) T cell depletion) as well as with the indices of overall T cell activation. In all, these results identify the expansion of CD8(+)CD127(-) effector-like T cells as a novel feature of the HIV-associated immune perturbation. Further studies are thus warranted to determine whether measurements of CD127 expression on CD8(+) T cells may be useful in the clinical management of HIV-infected individuals. 相似文献
46.
De Silvestri A Guglielmino CR 《Human biology; an international record of research》2004,76(6):901-920
The Sicilian population has a complex history of colonization and invasions that have influenced the genetic composition of the nine provinces of the island. Because surnames are patrilineally inherited, they simulate a Y-chromosome nonrecombinant genetic locus. We used surname data and a specific sampling strategy to describe the major subdivisions in each province and for the whole island of Sicily. The high number of families per surname in two provinces can be related to inbreeding as a result of founder events. Each province shows a major division, which, according to local historical events, likely represents cultural and probably genetic differences between east and west, between north and south, or between the inner regions and the coastal area. On the island level surnames reproduce the same separation, obtained by others with genes, of the eastern area from the western area. The separation is attributed to Greek influence in the east and to Phoenician-Carthaginian-Norman influence in the west. This separation crosses the two central provinces of Agrigento and Caltanissetta. 相似文献
47.
Roles of target cells and virus-specific cellular immunity in primary simian immunodeficiency virus infection 下载免费PDF全文
Regoes RR Antia R Garber DA Silvestri G Feinberg MB Staprans SI 《Journal of virology》2004,78(9):4866-4875
There is an ongoing debate on whether acute human immunodeficiency virus infection is controlled by target cell limitation or by virus-specific cellular immunity. To resolve this question, we developed a novel mathematical modeling scheme which allows us to incorporate measurements of virus load, target cells, and virus-specific immunity and applied it to a comprehensive data set generated in an experiment involving rhesus macaques infected with simian immunodeficiency virus. Half of the macaques studied were treated during the primary infection period with reagents which block T-cell costimulation and as a result displayed severely impaired virus-specific immune responses. Our results show that early viral replication in normal infection is controlled to a large extent by virus-specific CD8(+) T cells and not by target cell limitation. 相似文献
48.
Rotavirus replication: plus-sense templates for double-stranded RNA synthesis are made in viroplasms 下载免费PDF全文
Rotavirus plus-strand RNAs not only direct protein synthesis but also serve as templates for the synthesis of the segmented double-stranded RNA (dsRNA) genome. In this study, we identified short-interfering RNAs (siRNAs) for viral genes 5, 8, and 9 that suppressed the expression of NSP1, a nonessential protein; NSP2, a component of viral replication factories (viroplasms); and VP7, an outer capsid protein, respectively. The loss of NSP2 expression inhibited viroplasm formation, genome replication, virion assembly, and synthesis of the other viral proteins. In contrast, the loss of VP7 expression had no effect on genome replication; instead, it inhibited only outer-capsid morphogenesis. Similarly, neither genome replication nor any other event of the viral life cycle was affected by the loss of NSP1. The data indicate that plus-strand RNAs templating dsRNA synthesis within viroplasms are not susceptible to siRNA-induced RNase degradation. In contrast, plus-strand RNAs templating protein synthesis in the cytosol are susceptible to degradation and thus are not the likely source of plus-strand RNAs for dsRNA synthesis in viroplasms. Indeed, immunofluorescence analysis of bromouridine (BrU)-labeled RNA made in infected cells provided evidence that plus-strand RNAs are synthesized within viroplasms. Furthermore, transfection of BrU-labeled viral plus-strand RNA into infected cells suggested that plus-strand RNAs introduced into the cytosol do not localize to viroplasms. From these results, we propose that plus-strand RNAs synthesized within viroplasms are the primary source of templates for genome replication and that trafficking pathways do not exist within the cytosol that transport plus-strand RNAs to viroplasms. The lack of such pathways confounds the development of reverse genetics systems for rotavirus. 相似文献
49.
50.
Cirioni O Giacometti A Ghiselli R Bergnach C Orlando F Mocchegiani F Silvestri C Licci A Skerlavaj B Zanetti M Saba V Scalise G 《Peptides》2006,27(9):2104-2110
An in vitro antibiotic susceptibility assay for Staphylococcus aureus biofilms developed on 96-well polystyrene tissue culture plates was performed to elucidate the activity of the 27 residues cathelicidin peptide BMAP-28, quinupristin/dalfopristin (Q/D), linezolid, and vancomycin. Efficacy studies were performed in a rat model of staphylococcal CVC infection. Silastic catheters were implanted into the superior cava. Twenty-four hours after implantation the catheters were filled with BMAP-28. Thirty minutes later rats were challenged via the CVC with 1.0x10(6) CFU of S. aureus strain Smith diffuse. Administration of antibiotics into the CVC at a concentration equal to the MBC observed using adherent cells, or at a much higher concentration (1024 microg/mL) began 24 h later. The inhibition activities of all antibiotics against adherent bacteria were at least two-four-fold lower that against freely growing cells. When antibiotics were used in BMAP-28 pre-treated wells, they showed higher activities. The in vivo studies showed that when CVCs were pre-treated with BMAP-28 or with a high dose of antibiotics, biofilm bacterial load was reduced from 10(7) to 10(3) CFU/mL and bacteremia reduced from 10(3) to 10(1) CFU/mL. When CVCs were treated with both BMAP-28 and antibiotics, biofilm bacterial load was further decreased to 10(1) CFU/mL and bacteremia was not detected. These results suggest that CVC pre-treated with BMAP-28 represents an attractive choice for the treatment of device-related infections caused by staphylococci. 相似文献