全文获取类型
收费全文 | 1009篇 |
免费 | 45篇 |
专业分类
1054篇 |
出版年
2022年 | 14篇 |
2021年 | 20篇 |
2020年 | 11篇 |
2019年 | 15篇 |
2018年 | 18篇 |
2017年 | 21篇 |
2016年 | 18篇 |
2015年 | 40篇 |
2014年 | 53篇 |
2013年 | 53篇 |
2012年 | 88篇 |
2011年 | 75篇 |
2010年 | 41篇 |
2009年 | 32篇 |
2008年 | 50篇 |
2007年 | 56篇 |
2006年 | 48篇 |
2005年 | 52篇 |
2004年 | 48篇 |
2003年 | 38篇 |
2002年 | 47篇 |
2001年 | 21篇 |
2000年 | 14篇 |
1999年 | 9篇 |
1998年 | 5篇 |
1996年 | 6篇 |
1995年 | 7篇 |
1994年 | 5篇 |
1993年 | 4篇 |
1992年 | 6篇 |
1990年 | 9篇 |
1989年 | 8篇 |
1988年 | 5篇 |
1987年 | 6篇 |
1986年 | 6篇 |
1985年 | 5篇 |
1984年 | 8篇 |
1983年 | 4篇 |
1979年 | 6篇 |
1978年 | 5篇 |
1977年 | 7篇 |
1973年 | 4篇 |
1972年 | 6篇 |
1971年 | 5篇 |
1970年 | 5篇 |
1969年 | 4篇 |
1968年 | 8篇 |
1967年 | 5篇 |
1966年 | 6篇 |
1965年 | 3篇 |
排序方式: 共有1054条查询结果,搜索用时 12 毫秒
11.
Csaba Polgár Levente Jánváry Tibor Major András Somogyi Zoltán Takácsi-Nagy Georgina Fröhlich János Fodor 《Reports of Practical Oncology and Radiotherapy》2010,15(1):1-7
AimTo report the long-term results of high-dose-rate (HDR) brachytherapy (BT) boost for breast cancer patients treated with conservative surgery and radiotherapy.Materials and methodsBetween 1995 and 2007, 100 early-stage breast cancer patients received an HDR BT boost after conservative surgery and whole breast irradiation. Ten patients (10%) received a single-fraction HDR boost of 8–10.35 Gy using rigid needles, while 90 (90%) were treated with a fractionated multi-catheter HDR BT boost. The latter consisted of 3 × 4 Gy (n = 19), 3 × 4.75 Gy (n = 70), and 2 × 6.4 Gy (n = 1). Breast cancer related events, cosmetic results and side effects were assessed.ResultsAt a median follow-up time of 94 months (range: 8–152) only 7 (7%) ipsilateral breast failures were observed for a 5- and 8-year actuarial rate of 4.5 and 7.0%, respectively. The 8-year disease-free, cancer-specific, and overall survival was 76.1, 82.8, and 80.4%, respectively. Cosmetic outcome was rated excellent in 17%, good in 39%, fair in 33%, and poor in 11%. Data on late radiation side effects were available for 91 patients (91%). Grade 3 fibrosis and grade 3 telangiectasia occurred in 6 (6.6%) and 2 (2.2%) patients, respectively. In univariate analysis only positive margin status had a significant negative effect on local control.ConclusionsHDR BT boost using multi-catheter implants produce excellent long-term local tumour control with acceptable cosmetic outcome and low rate of grade 3 late radiation side effects. 相似文献
12.
Rogier M. Thurlings Carla A. Wijbrandts Roelof J. Bennink Serge E. Dohmen Carlijn Voermans Diana Wouters Elena S. Izmailova Danielle M. Gerlag Berthe L. F. van Eck-Smit Paul P. Tak 《PloS one》2009,4(11)
Background
Macrophages are principal drivers of synovial inflammation in rheumatoid arthritis (RA), a prototype immune-mediated inflammatory disease. Conceivably, synovial macrophages are continuously replaced by circulating monocytes in RA. Animal studies from the 1960s suggested that macrophage replacement by monocytes is a slow process in chronic inflammatory lesions. Translation of these data into the human condition has been hampered by the lack of available techniques to analyze monocyte migration in man.Methods/Principal Findings
We developed a technique that enabled us to analyze the migration of labelled autologous monocytes in RA patients using single photon emission computer tomography (SPECT). We isolated CD14+ monocytes by CliniMACS in 8 patients and labeled these with technetium-99m (99mTc-HMPAO). Monocytes were re-infused into the same patient. Using SPECT we calculated that a very small but specific fraction of 3.4×10−3 (0.95−5.1×10−3) % of re-infused monocytes migrated to the inflamed joints, being detectable within one hour after re-infusion.Conclusions/Significance
The results indicate monocytes migrate continuously into the inflamed synovial tissue of RA patients, but at a slow macrophage-replacement rate. This suggests that the rapid decrease in synovial macrophages that occurs after antirheumatic treatment might rather be explained by an alteration in macrophage retention than in monocyte influx and that RA might be particularly sensitive to treatments targeting inflammatory cell retention. 相似文献13.
14.
LTP inhibits LTD in the hippocampus via regulation of GSK3beta 总被引:2,自引:0,他引:2
Peineau S Taghibiglou C Bradley C Wong TP Liu L Lu J Lo E Wu D Saule E Bouschet T Matthews P Isaac JT Bortolotto ZA Wang YT Collingridge GL 《Neuron》2007,53(5):703-717
Glycogen synthase kinase-3 (GSK3) has been implicated in major neurological disorders, but its role in normal neuronal function is largely unknown. Here we show that GSK3beta mediates an interaction between two major forms of synaptic plasticity in the brain, N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) and NMDA receptor-dependent long-term depression (LTD). In rat hippocampal slices, GSK3beta inhibitors block the induction of LTD. Furthermore, the activity of GSK3beta is enhanced during LTD via activation of PP1. Conversely, following the induction of LTP, there is inhibition of GSK3beta activity. This regulation of GSK3beta during LTP involves activation of NMDA receptors and the PI3K-Akt pathway and disrupts the ability of synapses to undergo LTD for up to 1 hr. We conclude that the regulation of GSK3beta activity provides a powerful mechanism to preserve information encoded during LTP from erasure by subsequent LTD, perhaps thereby permitting the initial consolidation of learnt information. 相似文献
15.
Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner 总被引:11,自引:0,他引:11 下载免费PDF全文
Hirao A Cheung A Duncan G Girard PM Elia AJ Wakeham A Okada H Sarkissian T Wong JA Sakai T De Stanchina E Bristow RG Suda T Lowe SW Jeggo PA Elledge SJ Mak TW 《Molecular and cellular biology》2002,22(18):6521-6532
In response to ionizing radiation (IR), the tumor suppressor p53 is stabilized and promotes either cell cycle arrest or apoptosis. Chk2 activated by IR contributes to this stabilization, possibly by direct phosphorylation. Like p53, Chk2 is mutated in patients with Li-Fraumeni syndrome. Since the ataxia telangiectasia mutated (ATM) gene is required for IR-induced activation of Chk2, it has been assumed that ATM and Chk2 act in a linear pathway leading to p53 activation. To clarify the role of Chk2 in tumorigenesis, we generated gene-targeted Chk2-deficient mice. Unlike ATM(-/-) and p53(-/-) mice, Chk2(-/-) mice do not spontaneously develop tumors, although Chk2 does suppress 7,12-dimethylbenzanthracene-induced skin tumors. Tissues from Chk2(-/-) mice, including those from the thymus, central nervous system, fibroblasts, epidermis, and hair follicles, show significant defects in IR-induced apoptosis or impaired G(1)/S arrest. Quantitative comparison of the G(1)/S checkpoint, apoptosis, and expression of p53 proteins in Chk2(-/-) versus ATM(-/-) thymocytes suggested that Chk2 can regulate p53-dependent apoptosis in an ATM-independent manner. IR-induced apoptosis was restored in Chk2(-/-) thymocytes by reintroduction of the wild-type Chk2 gene but not by a Chk2 gene in which the sites phosphorylated by ATM and ataxia telangiectasia and rad3(+) related (ATR) were mutated to alanine. ATR may thus selectively contribute to p53-mediated apoptosis. These data indicate that distinct pathways regulate the activation of p53 leading to cell cycle arrest or apoptosis. 相似文献
16.
Gergely Losonczy Attila Vajas Lili Takács Erika Dzsudzsák ágnes Fekete éva Márhoffer László Kardos éva Ajzner Bego?a Hurtado Pablo Garcia de Frutos András Berta István Balogh 《PloS one》2012,7(11)
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. Numerous genetic factors contribute to the development of the multifactorial disease. We performed a case-control study to assess the risk conferred by known and candidate genetic polymorphisms on the development of AMD. We searched for genetic interactions and for differences in dry and wet AMD etiology. We enrolled 213 patients with exudative, 67 patients with dry AMD and 106 age and ethnically matched controls. Altogether 12 polymorphisms in Apolipoprotein E, complement factor H, complement factor I, complement component 3, blood coagulation factor XIII, HTRA1, LOC387715, Gas6 and MerTK genes were tested. No association was found between either the exudative or the dry form and the polymorphisms in the Apolipoprotein E, complement factor I, FXIII and MerTK genes. Gas6 c.834+7G>A polymorphism was found to be significantly protective irrespective of other genotypes, reducing the odds of wet type AMD by a half (OR = 0.50, 95%CI: 0.26–0.97, p = 0.04). Multiple regression models revealed an interesting genetic interaction in the dry AMD subgroup. In the absence of C3 risk allele, mutant genotypes of both CFH and HTRA1 behaved as strongly significant risk factors (OR = 7.96, 95%CI: 2.39 = 26.50, p = 0.0007, and OR = 36.02, 95%CI: 3.30–393.02, p = 0.0033, respectively), but reduced to neutrality otherwise. The risk allele of C3 was observed to carry a significant risk in the simultaneous absence of homozygous CFH and HTRA1 polymorphisms only, in which case it was associated with a near-five-fold relative increase in the odds of dry type AMD (OR = 4.93, 95%CI: 1.98–12.25, p = 0.0006). Our results suggest a protective role of Gas6 c.834+7G>A polymorphism in exudative AMD development. In addition, novel genetic interactions were revealed between CFH, HTRA1 and C3 polymorphisms that might contribute to the pathogenesis of dry AMD. 相似文献
17.
Anin vitro procedure for large scale multiplication ofBoswellia serrata Roxb. has been developed using cotyledonary node segments. In average 4 shoots per node were obtained on Murashige and Skoog’s (MS) medium containing 0.5 mg dm?3 6-benzylaminopurine (BAP) and 0.05 mg dm?3 napthaleneacetic acid (NAA) within 22 d. By repeated subculture technique 90–100 shoots per node could be obtained after 88 d of initial culture. Shoots could be rooted on MS medium containing 1/4 salts, 1% saccharose, and a combination of 0.5 mg dm?3 indole-3-butyric acid (IBA) and 0.25 mg dm?3 indole-3-acetic acid (IAA). Addition of antioxidants like polyvinylpyrrolidone (PVP-50 mg dm?3) and ascorbic acid (100 mg dm?3) in both multiplication and rooting media prevented browning of cultures. Approximately 80% of shoots rooted within 8–10 d. Rooted plantlets were kept for 15 d in culture bottles containing SoilriteTM irrigated with a nutrient solution containing 1/4 MS salts and finally transferred to pots containing soil: SoilriteTM (1∶1), mixture with 70% transplantation success. 相似文献
18.
Vladimír Hrabovský Victoria Takáčová Eva Schréterová Lydia Pastvová Zuzana Hrabovská Katarina Čurová Leonard Siegfried 《Folia microbiologica》2017,62(6):525-530
Yeasts frequently colonize non-sterile sites in the body. The aim of the study was to determine distribution in clinical samples and antifungal susceptibility to five antifungals. From January 2013 through June 2015, 800 isolates were obtained from intensive care unit patients. Candida albicans (58.9%), Candida glabrata (20.4%), Candida krusei (8.6%), and Candida parapsilosis (3.6%) were the leading species. Majority of the C. albicans isolates were susceptible to the fluconazole. Elevated voriconazole minimal inhibitory concentrations (MICs) were observed in isolates exhibiting high fluconazole MICs, most frequently in C. glabrata. Isolates with echinocandins MICs suggesting reduced susceptibility were only sporadic cases with the exception of Trichosporon spp. The amphotericin B MICs were slightly higher for some C. krusei. 相似文献
19.
Rap1 signaling is required for suppression of Ras-generated reactive oxygen species and protection against oxidative stress in T lymphocytes 总被引:1,自引:0,他引:1
20.
Stress exerts a profound impact on learning and memory, in part, through the actions of adrenal corticosterone (CORT) on synaptic plasticity, a cellular model of learning and memory. Increasing findings suggest that CORT exerts its impact on synaptic plasticity by altering the functional properties of glutamate receptors, which include changes in the motility and function of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of glutamate receptor (AMPAR) that are responsible for the expression of synaptic plasticity. Here we provide evidence that CORT could also regulate synaptic plasticity by modulating the function of synaptic N-methyl-D-aspartate receptors (NMDARs), which mediate the induction of synaptic plasticity. We found that stress level CORT applied to adult rat hippocampal slices potentiated evoked NMDAR-mediated synaptic responses within 30 min. Surprisingly, following this fast-onset change, we observed a slow-onset (>1 hour after termination of CORT exposure) increase in synaptic expression of GluN2A-containing NMDARs. To investigate the consequences of the distinct fast- and slow-onset modulation of NMDARs for synaptic plasticity, we examined the formation of long-term potentiation (LTP) and long-term depression (LTD) within relevant time windows. Paralleling the increased NMDAR function, both LTP and LTD were facilitated during CORT treatment. However, 1-2 hours after CORT treatment when synaptic expression of GluN2A-containing NMDARs is increased, bidirectional plasticity was no longer facilitated. Our findings reveal the remarkable plasticity of NMDARs in the adult hippocampus in response to CORT. CORT-mediated slow-onset increase in GluN2A in hippocampal synapses could be a homeostatic mechanism to normalize synaptic plasticity following fast-onset stress-induced facilitation. 相似文献