全文获取类型
收费全文 | 386篇 |
免费 | 70篇 |
国内免费 | 1篇 |
专业分类
综合类 | 3篇 |
化学工业 | 319篇 |
机械仪表 | 9篇 |
建筑科学 | 2篇 |
轻工业 | 43篇 |
无线电 | 17篇 |
一般工业技术 | 51篇 |
冶金工业 | 7篇 |
自动化技术 | 6篇 |
出版年
2024年 | 2篇 |
2023年 | 9篇 |
2022年 | 51篇 |
2021年 | 91篇 |
2020年 | 25篇 |
2019年 | 22篇 |
2018年 | 22篇 |
2017年 | 25篇 |
2016年 | 21篇 |
2015年 | 21篇 |
2014年 | 20篇 |
2013年 | 28篇 |
2012年 | 19篇 |
2011年 | 15篇 |
2010年 | 18篇 |
2009年 | 19篇 |
2008年 | 11篇 |
2007年 | 21篇 |
2006年 | 4篇 |
2005年 | 4篇 |
2004年 | 2篇 |
2003年 | 4篇 |
2002年 | 1篇 |
1997年 | 1篇 |
1987年 | 1篇 |
排序方式: 共有457条查询结果,搜索用时 406 毫秒
71.
72.
Bartolini M Pistolozzi M Andrisano V Egea J López MG Iriepa I Moraleda I Gálvez E Marco-Contelles J Samadi A 《ChemMedChem》2011,6(11):1990-1997
73.
Surface Binding of TOTAPOL Assists Structural Investigations of Amyloid Fibrils by Dynamic Nuclear Polarization NMR Spectroscopy
下载免费PDF全文
![点击此处可从《Chembiochem : a European journal of chemical biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Dr. Madhu Nagaraj Dr. Trent W. Franks Siavash Saeidpour Dr. Tobias Schubeis Dr. Hartmut Oschkinat Dr. Christiane Ritter Dr. Barth‐Jan van Rossum 《Chembiochem : a European journal of chemical biology》2016,17(14):1308-1311
Dynamic nuclear polarization (DNP) NMR can enhance sensitivity but often comes at the price of a substantial loss of resolution. Two major factors affect spectral quality: low‐temperature heterogeneous line broadening and paramagnetic relaxation enhancement (PRE) effects. Investigations by NMR spectroscopy, isothermal titration calorimetry (ITC), and EPR revealed a new substantial affinity of TOTAPOL to amyloid surfaces, very similar to that shown by the fluorescent dye thioflavin‐T (ThT). As a consequence, DNP spectra with remarkably good resolution and still reasonable enhancement could be obtained at very low TOTAPOL concentrations, typically 400 times lower than commonly employed. These spectra yielded several long‐range constraints that were difficult to obtain without DNP. Our findings open up new strategies for structural studies with DNP NMR spectroscopy on amyloids that can bind the biradical with affinity similar to that shown towards ThT. 相似文献
74.
Michalis Michailidis Despina A. Tata Despina Moraitou Dimitrios Kavvadas Sofia Karachrysafi Theodora Papamitsou Patroklos Vareltzis Vasileios Papaliagkas 《International journal of molecular sciences》2022,23(9)
The public health burden of type 2 diabetes mellitus and Alzheimer’s disease is steadily increasing worldwide, especially in the population of older adults. Epidemiological and clinical studies suggest a possible shared pathophysiology between the two diseases and an increased risk of AD in patients with type 2 diabetes mellitus. Therefore, in recent years, there has been a substantial interest in identifying the mechanisms of action of antidiabetic drugs and their potential use in Alzheimer’s disease. Human studies in patients with mild cognitive impairment and Alzheimer’s disease have shown that administration of some antidiabetic medications, such as intranasal insulin, metformin, incretins, and thiazolidinediones, can improve cognition and memory. This review aims to examine the latest evidence on antidiabetic medications as a potential candidate for the treatment of Alzheimer’s disease. 相似文献
75.
Inhibition of hIAPP Amyloid Aggregation and Pancreatic β‐Cell Toxicity by OH‐Terminated PAMAM Dendrimer
下载免费PDF全文
![点击此处可从《Small (Weinheim an der Bergstrasse, Germany)》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Esteban N. Gurzov Bo Wang Emily H. Pilkington Pengyu Chen Aleksandr Kakinen William J. Stanley Sara A. Litwak Eric G. Hanssen Thomas P. Davis Feng Ding Pu Chun Ke 《Small (Weinheim an der Bergstrasse, Germany)》2016,12(12):1615-1626
Human islet amyloid polypeptide (hIAPP, or amylin) forms amyloid deposits in the islets of Langerhans, a phenomenon that is associated with type‐2 diabetes impacting millions of people worldwide. Accordingly, strategies against hIAPP aggregation are essential for the prevention and eventual treatment of the disease. Here, it is shown that generation‐3 OH‐terminated poly(amidoamine) dendrimer, a polymeric nanoparticle, can effectively halt the aggregation of hIAPP and shut down hIAPP toxicity in pancreatic MIN6 and NIT‐1 cells as well as in mouse islets. This finding is supported by high‐throughput dynamic light scattering experiment and thioflavin T assay, where the rapid evolution of hIAPP nucleation and elongation processes is halted by the addition of the dendrimer up to 8 h. Discrete molecular dynamics simulations further reveal that hIAPP residues bound strongly with the dendrimer near the c‐terminal portion of the peptide, where the amyloidogenic sequence (residues 22–29) locates. Furthermore, simulations of hIAPP dimerization reveal that binding with the dendrimer significantly reduces formation of interpeptide contacts and hydrogen bonds, thereby prohibiting peptide self‐association and amyloidosis. This study points to a promising nanomedicinal strategy for combating type‐2 diabetes and may have broader implications for targeting neurological disorders whose distinct hallmark is also amyloid fibrillation. 相似文献
76.
Hermann Russ Michele Mazzanti Chris Parsons Katrin Riemann Alexander Gebauer Gerhard Rammes 《International journal of molecular sciences》2022,23(10)
Soluble amyloid β (Aβ) oligomers have been shown to be highly toxic to neurons and are considered to be a major cause of the neurodegeneration underlying Alzheimer’s disease (AD). That makes soluble Aβ oligomers a promising drug target. In addition to eliminating these toxic species from the patients’ brain with antibody-based drugs, a new class of drugs is emerging, namely Aβ aggregation inhibitors or modulators, which aim to stop the formation of toxic Aβ oligomers at the source. Here, pharmacological data of the novel Aβ aggregation modulator GAL-201 are presented. This small molecule (288.34 g/mol) exhibits high binding affinity to misfolded Aβ1-42 monomers (KD = 2.5 ± 0.6 nM). Pharmacokinetic studies in rats using brain microdialysis are supportive of its oral bioavailability. The Aβ oligomer detoxifying potential of GAL-201 has been demonstrated by means of single cell recordings in isolated hippocampal neurons (perforated patch experiments) as well as in vitro and in vivo extracellular monitoring of long-term potentiation (LTP, in rat transverse hippocampal slices), a cellular correlate for synaptic plasticity. Upon preincubation, GAL-201 efficiently prevented the detrimental effect on LTP mediated by Aβ1-42 oligomers. Furthermore, the potential to completely reverse an already established neurotoxic process could also be demonstrated. Of particular note in this context is the self-propagating detoxification potential of GAL-201, leading to a neutralization of Aβ oligomer toxicity even if GAL-201 has been stepwise removed from the medium (serial dilution), likely due to prion-like conformational changes in Aβ1-42 monomer aggregates (trigger effect). The authors conclude that the data presented strongly support the further development of GAL-201 as a novel, orally available AD treatment with potentially superior clinical profile. 相似文献
77.
Kamile Mikalauskaite Mantas Ziaunys Vytautas Smirnovas 《International journal of molecular sciences》2022,23(10)
Amyloid fibril formation is associated with several amyloidoses, including neurodegenerative Alzheimer’s or Parkinson’s diseases. The process of such fibrillar structure formation is still not fully understood, with new mechanistic insights appearing on a regular basis. This, in turn, has limited the development of potential anti-amyloid compounds, with only a handful of effective cures or treatment modalities available. One of the multiple amyloid aggregation factors that requires further examination is the ability of proteins to form multiple, structurally distinct aggregates, based on the environmental conditions. In this work, we examine how the initial folding state affects the fibrilization of lysozyme—an amyloidogenic protein, often used in protein aggregation studies. We show that there is a correlation between the initial state of the protein and the aggregate formation lag time, rate of elongation, resulting aggregate structural variability and dye-binding properties, as well as formation lag time and rate of elongation. 相似文献
78.
Da Yeon Cheong Wonseok Lee Insu Park Jinsung Park Gyudo Lee 《International journal of molecular sciences》2022,23(10)
Processes that monitor the nucleation of amyloids and characterize the formation of amyloid fibrils are vital to medicine and pharmacology. In this study, we observe the nucleation and formation of lysozyme amyloid fibrils using a facile microfluidic system to generate nanoliter droplets that can control the flow rate and movement of monomer-in-oil emulsion droplets in a T-junction microchannel. Using a fluorescence assay, we monitor the nucleation and growth process of amyloids based on the volume of droplets. Using the microfluidic system, we demonstrate that the lag phase, which is vital to amyloid nucleation and growth, is reduced at a lower droplet volume. Furthermore, we report a peculiar phenomenon of high amyloid formation at the edge of a bullet-shaped droplet, which is likely due to the high local monomer concentration. Moreover, we discovered that amyloid fibrils synthesized in the nanoliter droplets are shorter and thicker than fibrils synthesized from a bulk solution via the conventional heating method. Herein, a facile procedure to observe and characterize the nucleation and growth of amyloid fibrils using nanoliter droplets is presented, which is beneficial for investigating new features of amyloid fibril formation as an unconventional synthetic method for amyloid fibrils. 相似文献
79.
80.
Lukas Babylon Fabian Schmitt Yannik Franke Tim Hubert Gunter P. Eckert 《International journal of molecular sciences》2022,23(15)
Increased amyloid beta (Aβ) levels and mitochondrial dysfunction (MD) in the human brain characterize Alzheimer disease (AD). Folic acid, magnesium and vitamin B6 are essential micro-nutrients that may provide neuroprotection. Bioenergetic parameters and amyloid precursor protein (APP) processing products were investigated in vitro in human neuroblastoma SH-SY5Y-APP695 cells, expressing neuronal APP, and in vivo, in the invertebrate Caenorhabditis elegans (CL2006 & GMC101) expressing muscular APP. Model organisms were incubated with either folic acid and magnesium-orotate (ID63) or folic acid, magnesium-orotate and vitamin B6 (ID64) in different concentrations. ID63 and ID64 reduced Aβ, soluble alpha APP (sAPPα), and lactate levels in SH-SY5Y-APP695 cells. The latter might be explained by enhanced expression of lactate dehydrogenase (LDHA). Micronutrient combinations had no effects on mitochondrial parameters in SH-SY5Y-APP695 cells. ID64 showed a significant life-prolonging effect in C. elegans CL2006. Incubation of GMC101 with ID63 significantly lowered Aβ aggregation. Both combinations significantly reduced paralysis and thus improved the phenotype in GMC101. Thus, the combinations of the tested biofactors are effective in pre-clinical models of AD by interfering with Aβ related pathways and glycolysis. 相似文献