全文获取类型
收费全文 | 350篇 |
免费 | 43篇 |
出版年
2022年 | 3篇 |
2021年 | 5篇 |
2020年 | 6篇 |
2017年 | 4篇 |
2016年 | 6篇 |
2015年 | 12篇 |
2014年 | 13篇 |
2013年 | 14篇 |
2012年 | 17篇 |
2011年 | 27篇 |
2010年 | 9篇 |
2009年 | 11篇 |
2008年 | 16篇 |
2007年 | 19篇 |
2006年 | 9篇 |
2005年 | 10篇 |
2004年 | 14篇 |
2003年 | 18篇 |
2002年 | 13篇 |
2001年 | 12篇 |
2000年 | 7篇 |
1999年 | 8篇 |
1998年 | 3篇 |
1997年 | 4篇 |
1996年 | 3篇 |
1992年 | 10篇 |
1991年 | 4篇 |
1990年 | 6篇 |
1989年 | 6篇 |
1988年 | 5篇 |
1987年 | 6篇 |
1986年 | 4篇 |
1985年 | 5篇 |
1984年 | 5篇 |
1983年 | 3篇 |
1981年 | 2篇 |
1979年 | 4篇 |
1978年 | 5篇 |
1977年 | 5篇 |
1976年 | 5篇 |
1975年 | 6篇 |
1974年 | 6篇 |
1973年 | 3篇 |
1972年 | 3篇 |
1971年 | 4篇 |
1970年 | 2篇 |
1968年 | 7篇 |
1966年 | 4篇 |
1965年 | 3篇 |
1959年 | 2篇 |
排序方式: 共有393条查询结果,搜索用时 21 毫秒
11.
Stephen P. Muench Jozef Stec Ying Zhou Gustavo A. Afanador Martin J. McPhillie Mark R. Hickman Patty J. Lee Susan E. Leed Jennifer M. Auschwitz Sean T. Prigge David W. Rice Rima McLeod 《Bioorganic & medicinal chemistry letters》2013,23(12):3551-3555
The enoyl acyl-carrier protein reductase (ENR) enzyme is harbored within the apicoplast of apicomplexan parasites providing a significant challenge for drug delivery, which may be overcome through the addition of transductive peptides, which facilitates crossing the apicoplast membranes. The binding site of triclosan, a potent ENR inhibitor, is occluded from the solvent making the attachment of these linkers challenging. Herein, we have produced 3 new triclosan analogs with bulky A- and B-ring motifs, which protrude into the solvent allowing for the future attachment of molecular transporters for delivery. 相似文献
12.
Umashankar Das Ravi S.P. Singh Jane Alcorn Mark R. Hickman Richard J. Sciotti Susan E. Leed Patricia J. Lee Norma Roncal Jonathan R. Dimmock 《Bioorganic & medicinal chemistry》2013,21(23):7250-7256
Drug resistance is a major challenge in antimalarial chemotherapy. In addition, a complete cure of malaria requires intervention at various stages in the development of the parasite within the host. There are only a few antimalarials that target the liver stage of the Plasmodium species which is an essential part of the life cycle of the malarial parasite. We report a series of antimalarial 3,5-bis(benzylidene)-4-piperidones and related N-acyl analogs 1–5, a number of which exhibit potent in vitro growth-inhibiting properties towards drug-sensitive D6 and drug-resistant C235 strains of Plasmodium falciparum as well as inhibiting the liver stage development of the malarial life cycle. The compounds 2b (IC50: 165 ng/mL), 3b (IC50: 186 ng/mL), 5c (IC50: 159 ng/mL) and 5d (IC50: 93.5 ng/mL) emerged as lead molecules that inhibit liver stage Plasmodium berghei and are significantly more potent than chloroquine (IC50: >2000 ng/mL) and mefloquine (IC50: >2000 ng/mL) in this screen. All the compounds that showed potent inhibitory activity against the P. berghei liver stage were nontoxic to human HepG2 liver cells (IC50: >2000 ng/mL). The compounds 5a and 5b exhibit comparable metabolic stability as chloroquine and mefloquine in human plasma and the most potent compound 5d demonstrated suitable permeability characteristics using the MDCK monolayer. These results emphasize the value of 3,5-bis(benzylidene)-4-piperidones as novel antimalarials for further drug development. 相似文献
13.
An interpretation of postglacial change in water quality and productivity has been made for two shallow lakes in Central Alberta, Canada, namely Hastings Lake (longitude 113° 00′ W; latitude 53° 30′ N) and Lac Ste. Anne (longitude 114° 21′ W; latitude 53° 41′ N). Erosion rates around Lac Ste. Anne have remained constant. Similarly productivity has changed little although macrophytes contributed more to total production during the early stages. Hastings Lake has responded more sensitively to changes in the balance of precipitation and evaporation. From 5500 to 4000 year B. P. it was shallower than at present. Productivity during this early phase was less but macrophytes and allochthonous organic matter (i. e., leaf litter) probably contributed a greater proportion of the organic influx. After water levels rose productivity increased remaining steady until 2500 year B. P. when a slight decline occurred. Throughout the high water period oxygen depletion has not been serious. Any period of reducing conditions has been brief. Productivity has never been nutrient-limited. Elevation of the lake surface increased potential volume for production and reduced turbulent resuspension of bottom sediments permitting greater light penetration, and enhanced algal production. Difference between the sedimentary record of these two lakes, as well as the two basins of Hastings Lake, demonstrates the individualistic responses of basins and lakes to climatic events. 相似文献
14.
Mark R. Hickman David L. Saunders Catherine A. Bigger Christopher D. Kane Patrick L. Iversen 《PLoS neglected tropical diseases》2022,16(3)
The Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND) began development of a broad-spectrum antiviral countermeasure against deliberate use of high-consequence viral hemorrhagic fevers (VHFs) in 2016. The effort featured comprehensive preclinical research, including laboratory testing and rapid advancement of lead molecules into nonhuman primate (NHP) models of Ebola virus disease (EVD). Remdesivir (GS-5734, Veklury, Gilead Sciences) was the first small molecule therapeutic to successfully emerge from this effort. Remdesivir is an inhibitor of RNA-dependent RNA polymerase, a viral enzyme that is essential for viral replication. Its robust potency and broad-spectrum antiviral activity against certain RNA viruses including Ebola virus and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) led to its clinical evaluation in randomized, controlled trials (RCTs) in human patients during the 2018 EVD outbreak in the Democratic Republic of the Congo (DRC) and the ongoing Coronavirus Disease 2019 (COVID-19) pandemic today. Remdesivir was recently approved by the US Food and Drug Administration (FDA) for the treatment of COVID-19 requiring hospitalization. Substantial gaps remain in improving the outcomes of acute viral infections for patients afflicted with both EVD and COVID-19, including how to increase therapeutic breadth and strategies for the prevention and treatment of severe disease. Combination therapy that joins therapeutics with complimentary mechanisms of action appear promising, both preclinically and in RCTs. Importantly, significant programmatic challenges endure pertaining to a clear drug and biological product development pathway for therapeutics targeting biodefense and emerging pathogens when human efficacy studies are not ethical or feasible. For example, remdesivir’s clinical development was facilitated by outbreaks of Ebola and SARS-CoV-2; as such, the development pathway employed for remdesivir is likely to be the exception rather than the rule.The current regulatory licensure pathway for therapeutics targeting rare, weaponizable VHF agents is likely to require use of FDA’s established Animal Rule (21 CFR 314.600–650 for drugs; 21 CFR 601.90–95 for biologics). The FDA may grant marketing approval based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is safe and likely to produce clinical benefit in humans. In practical terms, this is anticipated to include a series of rigorous, well-documented, animal challenge studies, to include aerosol challenge, combined with human safety data. While small clinical studies against naturally occurring, high-consequence pathogens are typically performed where possible, approval for the therapeutics currently under development against biodefense pathogens will likely require the Animal Rule pathway utilizing studies in NHPs. We review the development of remdesivir as illustrative of the effort that will be needed to field future therapeutics against highly lethal, infectious agents. 相似文献
15.
Urvater JA Hickman H Dzuris JL Prilliman K Allen TM Schwartz KJ Lorentzen D Shufflebotham C Collins EJ Neiffer DL Raphael B Hildebrand W Sette A Watkins DI 《Journal of immunology (Baltimore, Md. : 1950)》2001,166(5):3334-3344
The human MHC class I gene, HLA-B27, is a strong risk factor for susceptibility to a group of disorders termed spondyloarthropathies (SpAs). HLA-B27-transgenic rodents develop SpAs, implicating HLA-B27 in the etiology of these disorders. Several nonhuman primates, including gorillas, develop signs of SpAs indistinguishable from clinical signs of humans with SpAs. To determine whether SpAs in gorillas have a similar HLA-B27-related etiology, we analyzed the MHC class I molecules expressed in four affected gorillas. Gogo-B01, isolated from three of the animals, has only limited similarity to HLA-B27 at the end of the alpha1 domain. It differs by several residues in the B pocket, including differences at positions 45 and 67. However, the molecular model of Gogo-B*0101 is consistent with a requirement for positively charged residues at the second amino acid of peptides bound by the MHC class I molecule. Indeed, the peptide binding motif and sequence of individual ligands eluted from Gogo-B*0101 demonstrate that, like HLA-B27, this gorilla MHC class I molecule binds peptides with arginine at the second amino acid position of peptides bound by the MHC class I molecule. Furthermore, live cell binding assays show that Gogo-B*0101 can bind HLA-B27 ligands. Therefore, although most gorillas that develop SpAs express an MHC class I molecule with striking differences to HLA-B27, this molecule binds peptides similar to those bound by HLA-B27. 相似文献
16.
Le Diguarher T Ortuno JC Shanks D Guilbaud N Pierré A Raimbaud E Fauchère JL Hickman JA Tucker GC Casara PJ 《Bioorganic & medicinal chemistry letters》2004,14(3):767-771
A structure-activity study was performed by synthesis on N,N'-disubstitution of 3-aminobenzo[c] and [d]azepin-2-one 2 and 3 to afford potent and specific farnesyl transferase inhibitors with low nM enzymatic and cellular activities. 相似文献
17.
Le Diguarher T Ortuno JC Dorey G Shanks D Guilbaud N Pierré A Fauchère JL Hickman JA Tucker GC Casara PJ 《Bioorganic & medicinal chemistry》2003,11(14):3193-3204
A rapid structure-activity study was performed by parallel liquid synthesis on N,N'-disubstitution of 3-amino azepin-2-one to afford potent and specific farnesyl transferase inhibitors with low nM enzymatic and cellular activities. The activities of the selected compounds were validated in vivo, and compounds 41a and 44a presented significant antitumour activity. 相似文献
18.
Hickman HD Luis AD Bardet W Buchli R Battson CL Shearer MH Jackson KW Kennedy RC Hildebrand WH 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(1):22-26
Class I MHC molecules bind intracellular peptides for presentation to cytotoxic T lymphocytes. Identification of peptides presented by class I molecules during infection is therefore a priority for detecting and targeting intracellular pathogens. To understand which host-encoded peptides distinguish HIV-infected cells, we have developed a mass spectrometric approach to characterize HLA-B*0702 peptides unique to or up-regulated on infected T cells. In this study, we identify 15 host proteins that are differentially presented on infected human T cells. Peptides with increased expression on HIV-infected cells were derived from multiple categories of cellular proteins including RNA binding proteins and cell cycle regulatory proteins. Therefore, comprehensive analysis of the B*0702 peptide repertoire demonstrates that marked differences in host protein presentation occur after HIV infection. 相似文献
19.
Edmonston measles virus prevents increased cell surface expression of peptide-loaded major histocompatibility complex class II proteins in human peripheral monocytes
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)
Gamma interferon (IFN-gamma) induces expression of the gene products of the major histocompatibility complex (MHC), whereas IFN-alpha/beta can interfere with or suppress class II protein expression. In separate studies, measles virus (MV) was reported to induce IFN-alpha/beta and to up-regulate MHC class II proteins. In an attempt to resolve this paradox, we examined the surface expression of MHC class I and class II proteins in MV-infected peripheral monocytes in the presence and absence of IFN-alpha/beta. Infection of purified monocytes with Edmonston B MV resulted in an apparent increase in cell surface expression of HLA-A, -B, and -C class I proteins, but it had no effect on the expression of HLA-DR class II proteins. MV-infected purified monocytes expressed IFN-alpha/beta, but no measurable IFN-gamma expression was detected in supernatant fluids. Class II protein expression could be enhanced by coculture of purified monocytes with uninfected peripheral blood mononuclear cell (PBMC) supernatant. MV infection of PBMCs also did not affect expression of class II proteins, but the expression of HLA-A, -B, and -C class I proteins was increased two- to threefold in most donor cells. A direct role for IFN-alpha/beta suppression of MHC class II protein expression was not evident in monocytes since MV suppressed class II protein expression in the absence of IFN-alpha/beta. Taken together, these data suggest that MV interferes with the expression of peptide-loaded class II complexes, an effect that may potentially alter CD4(+)-T-cell proliferation and the cell-mediated immune responses that they help to regulate. 相似文献
20.
Turnquist HR Schenk EL McIlhaney MM Hickman HD Hildebrand WH Solheim JC 《Immunogenetics》2002,53(10-11):830-834
We examined chaperone association with subtypes of HLA-A68 differing at positions 116 and/or 70, and analyzed the surface expression of each A68 subtype. Our findings with A68 indicate that certain subtypes have inefficient association with the assembly complex and correspondingly high surface expression, dependent on the character of position 116. Specifically, poor association of A68 subtypes with the transporter associated with antigen processing correlated with a comparatively high level of W6/32(+) forms at the cell surface. This observation suggests that intracellular retention is a dominant function of the assembly complex and that natural differences in assembly complex interaction may dictate the level of surface expression of MHC class I molecules. We also found that position 116 was crucial for HLA-A68 subtype association with the assembly complex. Our data contrast with results we obtained previously with HLA-B7 in that an aspartic acid at position 116 abrogated chaperone association for HLA-A68, whereas it increased association for HLA-B7. In total, HLA-A molecules exhibit natural allele-specific distinctions in chaperone association that correlate with differences in cell surface expression and with the identity of amino acid position 116. 相似文献