全文获取类型
收费全文 | 241篇 |
免费 | 34篇 |
出版年
2023年 | 2篇 |
2021年 | 6篇 |
2020年 | 3篇 |
2019年 | 3篇 |
2018年 | 2篇 |
2017年 | 2篇 |
2016年 | 4篇 |
2015年 | 8篇 |
2014年 | 7篇 |
2013年 | 12篇 |
2012年 | 8篇 |
2011年 | 9篇 |
2009年 | 13篇 |
2008年 | 11篇 |
2007年 | 18篇 |
2006年 | 5篇 |
2005年 | 11篇 |
2004年 | 9篇 |
2003年 | 4篇 |
2002年 | 6篇 |
2001年 | 12篇 |
2000年 | 5篇 |
1999年 | 6篇 |
1997年 | 2篇 |
1996年 | 4篇 |
1994年 | 2篇 |
1992年 | 9篇 |
1990年 | 5篇 |
1989年 | 4篇 |
1988年 | 4篇 |
1987年 | 5篇 |
1986年 | 5篇 |
1985年 | 3篇 |
1984年 | 3篇 |
1983年 | 7篇 |
1982年 | 5篇 |
1981年 | 2篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 5篇 |
1975年 | 3篇 |
1972年 | 6篇 |
1971年 | 2篇 |
1969年 | 6篇 |
1968年 | 9篇 |
1966年 | 1篇 |
1962年 | 3篇 |
1955年 | 2篇 |
1926年 | 1篇 |
1903年 | 1篇 |
排序方式: 共有275条查询结果,搜索用时 15 毫秒
101.
Ilia V. Baskakov Byron Caughey Alejandro M. Sevillano Witold K. Surewicz Holger Wille 《朊病毒》2019,13(1):46-52
Understanding the structure of PrPSc is without doubt a sine qua non to understand not only PrPSc propagation, but also critical features of that process such as the strain phenomenon and transmission barriers. While elucidation of the PrPSc structure has been full of difficulties, we now have a large amount of structural information that allows us to begin to understand it. This commentary article summarizes a round table that took place within the Prion 2018 meeting held in Santiago de Compostela to discuss the state of the art in this matter. Two alternative models of PrPSc exist: the PIRIBS and the 4-rung β-solenoid models. Both of them have relevant features. The 4-rung β-solenoid model agrees with experimental constraints of brain derived PrPSc obtained from cryo-EM and X-ray fiber diffraction studies. Furthermore, it allows facile accommodation of the bulky glycans that decorate brain-derived PrPSc. On the other hand, the infectious PrP23-144 amyloid exhibits a PIRIBS architecture. Perhaps, both types of structure co-exist. 相似文献
102.
103.
104.
Cleren C Yang L Lorenzo B Calingasan NY Schomer A Sireci A Wille EJ Beal MF 《Journal of neurochemistry》2008,104(6):1613-1621
Coenzyme Q10 (CoQ10 ) is a promising agent for neuroprotection in neurodegenerative diseases. We tested the effects of various doses of two formulations of CoQ10 in food and found that administration in the diet resulted in significant protection against loss of dopamine (DA), which was accompanied by a marked increase in plasma concentrations of CoQ10 . We further investigated the neuroprotective effects of CoQ10 , reduced CoQ10 (ubiquinol), and CoQ10 emulsions in the (MPTP) model of Parkinson's disease (PD). We found neuroprotection against MPTP induced loss of DA using both CoQ10 , and reduced CoQ10 , which produced the largest increases in plasma concentrations. Lastly, we administered CoQ10 in the diet to test its effects in a chronic MPTP model induced by administration of MPTP by Alzet pump for 1 month. We found neuroprotective effects against DA depletion, loss of tyrosine hydroxylase neurons and induction of alpha-synuclein inclusions in the substantia nigra pars compacta. The finding that CoQ10 is effective in a chronic dosing model of MPTP toxicity, is of particular interest, as this may be more relevant to PD. These results provide further evidence that administration of CoQ10 is a promising therapeutic strategy for the treatment of PD. 相似文献
105.
106.
Although chemotherapy with procarbazine, lomustine and vincristine (PCV) is considered to be well tolerated, side effects
frequently lead to dose reduction or even discontinuation of treatment of oligodendroglial brain tumors. The primary objective
of the analysis was to retrospectively compare progression-free survival (PFS) after PCV vs. PC chemotherapy (without vincristine
to avoid side effects). Patients were retrospectively identified from a database containing our patients between 1990 and
2003. For the selected cases, all histopathology reports were re-evaluated by a local neuropathologist. Based on the updated
histology data, patients were included in the study if they had at least one histological diagnosis of an oligodendroglial
tumor. PFS after start of PCV (n = 61) and PC (n = 84) chemotherapy identical (median 30 months). Multivariate analysis adjusting
for prognostic imbalances favouring the PC group showed a minor, statistically non-significant benefit for PCV (hazard ratio
0.81, 95% confidence interval 0.53–1.25; p = 0.346). Younger age (< 50 y) was a statistically significant predictor of longer
PFS. Significant advantages in terms of overall survival after first diagnosis of oligodendroglial tumor (OS, n = 315) were
found for patients < 50 y (p < 0.001), oligodendrogliomas versus oligoastrocytomas (p = 0.002), and WHO°II vs. °III (p < 0.001).
Three risk groups regarding OS were identified. Findings support the hypothesis that PC may be as effective as PCV chemotherapy,
while avoiding the additonal risks of vincristine. Younger age, lower tumor grade and histology of an oligodendroglioma were
identified to be favorable prognostic factors. 相似文献
107.
17α-ethinylestradiol cometabolism by bacteria degrading estrone, 17β-estradiol and estriol 总被引:2,自引:0,他引:2
Pauwels B Wille K Noppe H De Brabander H Van de Wiele T Verstraete W Boon N 《Biodegradation》2008,19(5):683-693
17alpha-ethinylestradiol (EE2), the active compound of the contraceptive pill, is a recalcitrant estrogen, which is encountered at ng/l levels in wastewater treatment plant (WWTP) effluents and rivers and can cause feminization of aquatic organisms. The aim of this study was to isolate micro-organisms that could remove such low EE2 concentrations. In this study, six bacterial strains were isolated from compost that cometabolize EE2 when metabolizing estrone (E1), 17beta-estradiol (E2) and estriol (E3). The strains belong to the alpha, beta and gamma-Proteobacteria. All six strains metabolize E2 over E1, at mug/l to ng/l concentrations. In 4 days, initial concentrations of 0.5 mug E2/l and 0.6 mug EE2/l were degraded to 1.8 +/- 0.4 ng E2/l and 85 +/- 16 ng EE2/l, respectively. No other metabolites besides E1, E2, E3 or EE2 were detected, suggesting that total degradation and cleavage of the aromatic ring occurred. This is the first study describing that bacteria able to metabolize E2, can subsequently cometabolize EE2 at low mug/l levels. 相似文献
108.
Gold MC Ehlinger HD Cook MS Smyk-Pearson SK Wille PT Ungerleider RM Lewinsohn DA Lewinsohn DM 《PLoS pathogens》2008,4(2):e39
The control of Mycobacterium tuberculosis (Mtb) infection is heavily dependent on the adaptive Th1 cellular immune response. Paradoxically, optimal priming of the Th1 response requires activation of priming dendritic cells with Th1 cytokine IFN-gamma. At present, the innate cellular mechanisms required for the generation of an optimal Th1 T cell response remain poorly characterized. We hypothesized that innate Mtb-reactive T cells provide an early source of IFN-gamma to fully activate Mtb-exposed dendritic cells. Here, we report the identification of a novel population of Mtb-reactive CD4(-) alphabetaTCR(+) innate thymocytes. These cells are present at high frequencies, respond to Mtb-infected cells by producing IFN-gamma directly ex vivo, and display characteristics of effector memory T cells. This novel innate population of Mtb-reactive T cells will drive further investigation into the role of these cells in the containment of Mtb following infectious exposure. Furthermore, this is the first demonstration of a human innate pathogen-specific alphabetaTCR(+) T cell and is likely to inspire further investigation into innate T cells recognizing other important human pathogens. 相似文献
109.
Sandra Wille Sabine Sydow Monika R Palchaudhuri Joachim Spiess & Frank M. Dautzenberg† 《Journal of neurochemistry》1999,72(1):388-395
Abstract : The aim of the present study was to identify the N-terminal regions of human corticotropin-releasing factor (CRF) receptor type 1 (hCRF-R1) that are crucial for ligand binding. Mutant receptors were constructed by replacing specific residues in hCRF-R1 with amino acids from the corresponding position in the N-terminal region of the human vasoactive intestinal peptide receptor type 2 (hVIP-R2). In cyclic AMP stimulation and CRF binding assays, it was established that two regions within the N-terminal domain were crucial for the binding of CRF receptor agonists and antagonists : one region mapping to amino acids 43-50 and a second amino acid sequence extending from position 76 to 84 of hCRF-R1. Recently, it was found that the latter sequence plays a very important role in determining the high ligand selectivity of the Xenopus CRF-R1 (xCRF-R1). Replacement of amino acids 76-84 of hCRF-R1 with residues from the same segment of the hVIP-R2 N terminus markedly reduced the binding affinity of CRF ligands. Mutation of Arg76 or Asn81 but not Gly83 of hCRF-R1 to the corresponding amino acids of xCRF-R1 or hVIP-R2 resulted in 100-1,000-fold lower affinities for human/rat CRF, rat urocortin, and astressin. These data underline the importance of the N-terminal domain of CRF-R1 in high-affinity ligand binding. 相似文献
110.