全文获取类型
收费全文 | 241篇 |
免费 | 32篇 |
国内免费 | 2篇 |
专业分类
耳鼻咽喉 | 3篇 |
儿科学 | 28篇 |
妇产科学 | 4篇 |
基础医学 | 33篇 |
口腔科学 | 10篇 |
临床医学 | 37篇 |
内科学 | 49篇 |
皮肤病学 | 1篇 |
神经病学 | 7篇 |
外科学 | 12篇 |
综合类 | 9篇 |
预防医学 | 39篇 |
药学 | 18篇 |
肿瘤学 | 25篇 |
出版年
2023年 | 2篇 |
2022年 | 3篇 |
2021年 | 8篇 |
2020年 | 6篇 |
2019年 | 5篇 |
2018年 | 7篇 |
2017年 | 9篇 |
2016年 | 4篇 |
2015年 | 7篇 |
2014年 | 12篇 |
2013年 | 10篇 |
2012年 | 9篇 |
2011年 | 9篇 |
2010年 | 4篇 |
2009年 | 7篇 |
2008年 | 12篇 |
2007年 | 26篇 |
2006年 | 8篇 |
2005年 | 6篇 |
2004年 | 15篇 |
2003年 | 10篇 |
2002年 | 6篇 |
2001年 | 2篇 |
2000年 | 4篇 |
1999年 | 3篇 |
1998年 | 3篇 |
1997年 | 3篇 |
1996年 | 2篇 |
1994年 | 2篇 |
1992年 | 6篇 |
1991年 | 7篇 |
1990年 | 7篇 |
1989年 | 8篇 |
1988年 | 2篇 |
1987年 | 7篇 |
1986年 | 9篇 |
1985年 | 3篇 |
1984年 | 3篇 |
1982年 | 4篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1974年 | 2篇 |
1973年 | 3篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1969年 | 2篇 |
排序方式: 共有275条查询结果,搜索用时 15 毫秒
1.
Pathogenic capacity of proteases from Serratia marcescens and Pseudomonas aeruginosa and their suppression by chicken egg white ovomacroglobulin. 总被引:1,自引:3,他引:1
下载免费PDF全文
![点击此处可从《Infection and immunity》网站下载免费的PDF全文](/ch/ext_images/free.gif)
The pathogenicities of three proteases from Serratia marcescens, two proteases from Pseudomonas aeruginosa, and one thermolysin from Bacillus stearothermophilus were examined. All proteases tested caused acute liquefactive necrosis of the cornea and descemetocele formation in guinea pig eyes after intrastromal injection, with the exception of the 60-kilodalton protease from S. marcescens, which produced only an opaque lesion. When injected into guinea pig skin, the protease also enhanced vascular permeability, which was followed by edema formation. The permeability-enhancing activity of the proteases increased in parallel with the concentration of the enzymes. When tested in vitro for its effect on these bacterial proteases, chicken egg white ovomacroglobulin (ovoM) inhibited the enzymatic activity of all the proteases after a short incubation period at an enzyme/inhibitor ratio (molar) of 1:1 to 1:4 or at a lower concentration after a longer incubation period. Such treatment of the proteases with chicken egg white ovoM before injection intrastromally into the eyes or intradermally into the clipped flanks of guinea pigs protected the cornea from destruction or completely prevented the permeability reaction and edema formation. No inhibitory effects of plasma protease inhibitors against these bacterial proteases were noted. Since the proteases are critical in the pathogenic processes caused by the bacteria, these results suggest a beneficial effect of ovoM against bacterial infections. 相似文献
2.
Degradation of protease inhibitors, immunoglobulins, and other serum proteins by Serratia protease and its toxicity to fibroblast in culture 总被引:2,自引:4,他引:2
下载免费PDF全文
![点击此处可从《Infection and immunity》网站下载免费的PDF全文](/ch/ext_images/free.gif)
We investigated the effect of the extracellular protease of Serratia marcescens on human serum constituents such as immunoglobulins, fibronectin, alpha 1-protease inhibitor, alpha 2-macroglobulin, lysozyme, and transferrin. At a very low concentration of Serratia 56-kilodalton protease (56K protease), purified human plasma fibronectin was degraded rapidly into three structural domains or small fragments. Immunoglobulin G3 (IgG3) and IgA1 were also degraded within 30 min with 1 microgram of this protease per ml, more rapidly than their other subclass of IgG or IgA. alpha 1-Protease inhibitor, which did not inhibit the 56K protease, was degraded similarly by the protease. These events were demonstrated by fluorescence polarization and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The protease was considerably inhibited by human alpha 2-macroglobulin and chicken ovomacroglobulin. However, when there was a 2 M excess of ovomacroglobulin or a 4 M excess of alpha 2-macroglobulin over the 56K protease, about 25 or 40% proteolytic activity remained, respectively. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that the protease degraded the alpha 2-macroglobulin extensively during prolonged incubation, which paralleled with regeneration of the protease activity. The protease also cleaved human lysozyme, although moderately. Human serum transferrin was degraded slightly, and human serum albumin was almost resistant to the 56K protease. The enzyme seemed to have no effect on reconstituted collagen, but it degraded rat tropocollagen and yielded fragments of beta and gamma chains by cleaving the intramolecular cross-links. Most of the above proteolysis by the 56K protease appears to result in a limited type of substrate specificity. Thus, the present study demonstrates that the protease is capable of degrading defense-oriented humoral proteins and tissue constituents. Furthermore, it is toxic to fibroblasts. These findings also clarified the possible role of Serratia protease as a virulence factor in the pathogenesis of serratial infections. We recently demonstrated this notion in vivo with rabbit cornea (R. Kamata et al., Ophthalmology 92:1452-1459, 1985). 相似文献
3.
The effects of the 56-kilodalton protease (56K protease) from Serratia marcescens on complement-derived chemotactic activity were examined. Fresh human serum was incubated with zymosan to produce C5a. This activated serum was then incubated with various concentrations of 56K protease, and the chemotactic activity of mouse peritoneal exudate polymorphonuclear leukocytes (PMN) and macrophages was evaluated. A significant dose-dependent decrease of chemotactic activity was observed after protease treatment. Furthermore, treatment of human recombinant C5a with 56K protease at a dose of 1.0 microgram/ml resulted in a complete loss of chemotactic activity. When the living bacteria of the virulent strain, which produced about 10 times more protease than did the less virulent strain, were injected intraperitoneally into mice, the magnitude of infiltration of polymorphonuclear leukocytes into the peritoneal cavity was much lower than that caused by the less virulent strain. Because complement-dependent chemotactic activity is an initial response to bacterial infection, these results suggest indirect pathogenic functions of serratial proteases that suppress chemotactic activity. 相似文献
4.
Jorge I Gonzalez Borroto Amadeu Creus Ricard Marcos Ricard Molla Jorge Zapatero 《Toxicological sciences》2003,72(2):359-362
The compound 2-furyl-1-nitroethene (G-0) has been tested to determine its ability to induce clastogenic or aneugenic effects in vivo, through the induction of micronucleated polychromatic erythrocytes (MNPCE) in mouse bone marrow. Groups of five CD-1 male mice were administered once intraperitoneally at a dose range of 5-20 mg/kg and bone marrow was sampled at 24 and 48 h after the treatment. G-0 was dissolved in corn oil, thus a vehicle control group received only corn oil at 10 ml/kg. The positive control group was administered with cyclophosphamide (40 mg/kg). All animals dosed with the highest concentration of the test agent (20 mg/kg) showed evident clinical symptoms of toxicity. Although evidences of bone marrow toxicity were observed, no statistically significant increases in the incidence of MNPCE over the vehicle control group were observed at any sampling time with any of the assayed doses of the G-0 compound. Cyclophosphamide treatment increased the incidence of MNPCE in all treated animals, demonstrating the sensitivity of the assay conditions in which it was carried out. From the results obtained, it is concluded that the test agent G-0 is neither clastogenic nor aneugenic in the erythrocytes from the bone marrow of treated mice at the doses tested. 相似文献
5.
Ly-Thuy-Tram Le Morgane Couvet Bertrand Favier Jean-Luc Coll Chi-Hung Nguyen Annie Molla 《Oncotarget》2015,6(26):22152-22166
Aurora kinases play an essential role in mitotic progression and are attractive targets in cancer therapy. The first generation of benzo[e]pyridoindole exhibited powerful aurora kinase inhibition but their low solubility limited further development. Grafting a pyperidine-ethoxy group gives rise to a hydrosoluble inhibitor: compound C5M.C5M could efficiently inhibit the proliferation of cells from different origins. C5M prevented cell cycling, induced a strong mitotic arrest then, cells became polyploid and finally died. C5M did not impair the spindle checkpoint, the separation of the sister chromatids and the transfer of aurora B on the mid-zone. C5M prevented histone H3 phosphorylation at mitotic entry and erased AMPK-Thr172 phosphorylation in late mitosis. With this unique profile of inhibition, C5M could be useful for understanding the role of phospho-Thr172-AMPK, in abscission and the relationship between the chromosomal complex and the energy sensing machinery.C5M is a multikinase inhibitor with interesting preclinical characteristics: high hydro-solubility and a good stability in plasma. A single dose prevents the expansion of multicellular spheroids. C5M can safely be injected to mice and reduces significantly the development of xenograft. The next step will be to define the protocol of treatment and the cancer therapeutic field of this new anti-proliferative drug. 相似文献
6.
Salvatore Iovino Alison M. Burkart Kristina Kriauciunas Laura Warren Katelyn J. Hughes Michael Molla Youn-Kyoung Lee Mary-Elizabeth Patti C. Ronald Kahn 《Diabetes》2014,63(12):4130-4142
Insulin resistance is central to diabetes and metabolic syndrome. To define the consequences of genetic insulin resistance distinct from those secondary to cellular differentiation or in vivo regulation, we generated induced pluripotent stem cells (iPSCs) from individuals with insulin receptor mutations and age-appropriate control subjects and studied insulin signaling and gene expression compared with the fibroblasts from which they were derived. iPSCs from patients with genetic insulin resistance exhibited altered insulin signaling, paralleling that seen in the original fibroblasts. Insulin-stimulated expression of immediate early genes and proliferation were also potently reduced in insulin resistant iPSCs. Global gene expression analysis revealed marked differences in both insulin-resistant iPSCs and corresponding fibroblasts compared with control iPSCs and fibroblasts. Patterns of gene expression in patients with genetic insulin resistance were particularly distinct in the two cell types, indicating dependence on not only receptor activity but also the cellular context of the mutant insulin receptor. Thus, iPSCs provide a novel approach to define effects of genetically determined insulin resistance. This study demonstrates that effects of insulin resistance on gene expression are modified by cellular context and differentiation state. Moreover, altered insulin receptor signaling and insulin resistance can modify proliferation and function of pluripotent stem cell populations. 相似文献
7.
Neelima Afroz Molla Kabirul Ahsan Mollah Waranya Wongwit Oleg Shipin Pongrama Ramasoota 《Archives of environmental & occupational health》2017,72(6):336-342
This study quantifies the diarrhea burden among migrant children under age 5 (who have migrated due to environmental degradation) in Dhaka. We used a multifactor socioepidemiological as well as environmental approach with pretested questionnaires and observations. It was found that 52% of the children were affected by diarrhea. Disability-adjusted life years (DALYs) lost was reduced manifold with the increase of mothers' behavioral determinants. Health losses were 1,718 fold with significant coefficient (β) in the migrant group. DALYs lost were significantly associated with socioenvironmental factors such as mother's illiteracy (β = .18; p < .001), no hand wash before eating (β = .08; p = .004), and no hand wash after defecation (β = .10; p < .001). This puts emphasis clearly on the awareness at household level, especially of mothers and children under age 5 in Dhaka, Bangladesh, in formulating migration-related policies. 相似文献
8.
9.
Warren Kati Gennadiy Koev Michelle Irvin Jill Beyer Yaya Liu Preethi Krishnan Thomas Reisch Rubina Mondal Rolf Wagner Akhteruzzaman Molla Clarence Maring Christine Collins 《Antimicrobial agents and chemotherapy》2015,59(3):1505-1511
Dasabuvir (ABT-333) is a nonnucleoside inhibitor of the RNA-dependent RNA polymerase encoded by the hepatitis C virus (HCV) NS5B gene. Dasabuvir inhibited recombinant NS5B polymerases derived from HCV genotype 1a and 1b clinical isolates, with 50% inhibitory concentration (IC50) values between 2.2 and 10.7 nM, and was at least 7,000-fold selective for the inhibition of HCV genotype 1 polymerases over human/mammalian polymerases. In the HCV subgenomic replicon system, dasabuvir inhibited genotype 1a (strain H77) and 1b (strain Con1) replicons with 50% effective concentration (EC50) values of 7.7 and 1.8 nM, respectively, with a 13-fold decrease in inhibitory activity in the presence of 40% human plasma. This level of activity was retained against a panel of chimeric subgenomic replicons that contained HCV NS5B genes from 22 genotype 1 clinical isolates from treatment-naive patients, with EC50s ranging between 0.15 and 8.57 nM. Maintenance of replicon-containing cells in medium containing dasabuvir at concentrations 10-fold or 100-fold greater than the EC50 resulted in selection of resistant replicon clones. Sequencing of the NS5B coding regions from these clones revealed the presence of variants, including C316Y, M414T, Y448C, Y448H, and S556G, that are consistent with binding to the palm I site of HCV polymerase. Consequently, dasabuvir retained full activity against replicons known to confer resistance to other polymerase inhibitors, including the S282T variant in the nucleoside binding site and the M423T, P495A, P495S, and V499A single variants in the thumb domain. The use of dasabuvir in combination with inhibitors targeting HCV NS3/NS4A protease (ABT-450 with ritonavir) and NS5A (ombitasvir) is in development for the treatment of HCV genotype 1 infections. 相似文献
10.
Tami Pilot-Matias Rakesh Tripathi Daniel Cohen Isabelle Gaultier Tatyana Dekhtyar Liangjun Lu Thomas Reisch Michelle Irvin Todd Hopkins Ron Pithawalla Timothy Middleton Teresa Ng Keith McDaniel Yat Sun Or Rajeev Menon Dale Kempf Akhteruzzaman Molla Christine Collins 《Antimicrobial agents and chemotherapy》2015,59(2):988-997
The development of direct-acting antiviral agents is a promising therapeutic advance in the treatment of hepatitis C virus (HCV) infection. However, rapid emergence of drug resistance can limit efficacy and lead to cross-resistance among members of the same drug class. ABT-450 is an efficacious inhibitor of HCV NS3/4A protease, with 50% effective concentration values of 1.0, 0.21, 5.3, 19, 0.09, and 0.69 nM against stable HCV replicons with NS3 protease from genotypes 1a, 1b, 2a, 3a, 4a, and 6a, respectively. In vitro, the most common amino acid variants selected by ABT-450 in genotype 1 were located in NS3 at positions 155, 156, and 168, with the D168Y variant conferring the highest level of resistance to ABT-450 in both genotype 1a and 1b replicons (219- and 337-fold, respectively). In a 3-day monotherapy study with HCV genotype 1-infected patients, ABT-450 was coadministered with ritonavir, a cytochrome P450 3A4 inhibitor shown previously to markedly increase peak, trough, and overall drug exposures of ABT-450. A mean maximum HCV RNA decline of 4.02 log10 was observed at the end of the 3-day dosing period across all doses. The most common variants selected in these patients were R155K and D168V in genotype 1a and D168V in genotype 1b. However, selection of resistant variants was significantly reduced at the highest ABT-450 dose compared to lower doses. These findings were informative for the subsequent evaluation of ABT-450 in combination with additional drug classes in clinical trials in HCV-infected patients. (Study M11-602 is registered at ClinicalTrials.gov under registration no. .) NCT01074008相似文献