全文获取类型
收费全文 | 1344篇 |
免费 | 136篇 |
国内免费 | 55篇 |
专业分类
化学 | 1124篇 |
力学 | 14篇 |
综合类 | 39篇 |
数学 | 129篇 |
物理学 | 229篇 |
出版年
2024年 | 9篇 |
2023年 | 44篇 |
2022年 | 188篇 |
2021年 | 168篇 |
2020年 | 116篇 |
2019年 | 47篇 |
2018年 | 41篇 |
2017年 | 48篇 |
2016年 | 68篇 |
2015年 | 66篇 |
2014年 | 64篇 |
2013年 | 81篇 |
2012年 | 54篇 |
2011年 | 66篇 |
2010年 | 35篇 |
2009年 | 43篇 |
2008年 | 43篇 |
2007年 | 48篇 |
2006年 | 32篇 |
2005年 | 29篇 |
2004年 | 27篇 |
2003年 | 23篇 |
2002年 | 13篇 |
2001年 | 17篇 |
2000年 | 32篇 |
1999年 | 20篇 |
1998年 | 21篇 |
1997年 | 30篇 |
1996年 | 15篇 |
1995年 | 13篇 |
1994年 | 11篇 |
1993年 | 3篇 |
1992年 | 1篇 |
1991年 | 7篇 |
1990年 | 3篇 |
1988年 | 1篇 |
1985年 | 2篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1976年 | 1篇 |
排序方式: 共有1535条查询结果,搜索用时 15 毫秒
61.
Francisco Salgado Julio Caballero Reinaldo Vargas Alberto Cornejo 《Natural product research》2020,34(5):646-650
AbstractAlzheimer´s disease (AD) is the most common form of dementia involving Aβ and tau protein. So far, AD cure remains elusive, but considering that AD progresses throughout tau pathology, which turns tau protein an appropriate target, besides tau is also included in other neurodegenerative disorders named as tauopathies. Here, we have isolated seventeen compounds belonging to six lichens species. Due to scarce of spectroscopic data of the compound 5,7-dihydroxy-6-methylphthalide, we explained their structural elucidation based on NMR data. In this study, we show that only tenuiorin from Umbilicaria antarctica inhibited 50% of tau 4R at 100?µM. Then, we shown that molecular interactions of tenuiorin with the steric zipper model of the hexapeptide 306VQIVYK311 were studied by docking calculations and the results suggested that tenuiorin forms both hydrogen bonds with lysine and glutamine side chains and forms several hydrophobic interactions with valine and lysine from 306VQIVYK311 motif. 相似文献
62.
本研究以亲油性的双面胶作为基底,利用滴涂二乙炔单体结合紫外光聚合来制备均匀的聚二乙炔(PDA)薄膜,通过荧光和颜色两种信号变化模式(即"双模光学检测")研究了PDA薄膜对VOC气体的响应性,发现制备的PDA薄膜在2 min内就可以实现明显的荧光和颜色变化,有效解决了目前PDA薄膜在VOC气体检测方面存在响应速度慢、薄膜均一性差等问题.此外,为解决单一PDA薄膜的交叉响应性问题,本研究制备了四种不同的基于双面胶基底的PDA薄膜,并将制备的4种PDA薄膜集成到一片PDMS薄膜基底上来构建柔性的传感阵列,利用阵列的颜色变化结合模式识别技术,实现了对8种VOC气体的快速、灵敏区分.进一步将制备的PDA薄膜阵列用于健康人、模拟糖尿病及肾病患者呼出气体中VOC标志物的辨别和分析研究,发现可以将三类人的呼出气体清晰地区分,说明了该阵列在呼气疾病诊断中的应用前景.与目前报道的PDA薄膜阵列相比,本研究中基于双面胶基底的PDA薄膜阵列具有气体响应速度快、灵敏性高、柔韧性好、制备工艺简单、成本低、易于大规模制备等优点,有望用于实VOC气体检测研究中. 相似文献
63.
Takura SASAKI Junichiroh KANEKO Masahiro ISHIZAKA Naoya SUZUKI Syuichiro KIMURA 《Physical Therapy Research》2021,24(3):249
Objective: This study aimed to clarify the effects of pre- and postoperative physical function on the 6-minute walking distance (6MWD) in patients with peripheral arterial disease (PAD). Method: Forty-two elderly patients with PAD who were hospitalized for revascularization and able to walk independently were included in the study. The 6MWD, ankle brachial index (ABI), weight-bearing index (WBI), gait, and intermittent claudication distance (ICD) were measured before and after the surgery, and skeletal muscle index was measured only before surgery. Analyses were performed by comparing the pre- and postoperative values of each factor using a paired t-test. In addition, multiple regression analysis was performed with 6MWD as the dependent variable before and after surgery. Results: Postoperatively, pain disappeared in 22 patients, and ABI, ICD, 6MWD, and stride length improved significantly. ICD and stride length were extracted as factors related to 6MWD before and after surgery, and ABI, WBI, and stride length were extracted as factors related to 6MWD after surgery. Conclusion: The improvement of intermittent claudication associated with revascularization suggests a stronger influence of functional aspects on postoperative 6MWD. 相似文献
64.
Alba L. Montoya Eileni R. Gil Emily L. Heydemann Igor L. Estevao Bianca E. Luna Cameron C. Ellis Sohan R. Jankuru Belkisyol Alarcn de Noya Oscar Noya Maria Paola Zago Igor C. Almeida Katja Michael 《Molecules (Basel, Switzerland)》2022,27(2)
Chagas disease (CD) can be accurately diagnosed by detecting Trypanosoma cruzi in patients’ blood using polymerase chain reaction (PCR). However, parasite-derived biomarkers are of great interest for the serological diagnosis and early evaluation of chemotherapeutic efficacy when PCR may fail, owing to a blood parasite load below the method’s limit of detection. Previously, we focused on the detection of specific anti-α-galactopyranosyl (α-Gal) antibodies in chronic CD (CCD) patients elicited by α-Gal glycotopes copiously expressed on insect-derived and mammal-dwelling infective parasite stages. Nevertheless, these stages also abundantly express cell surface glycosylphosphatidylinositol (GPI)-anchored glycoproteins and glycoinositolphospholipids (GIPLs) bearing nonreducing terminal β-galactofuranosyl (β-Galf) residues, which are equally foreign to humans and, therefore, highly immunogenic. Here we report that CCD patients’ sera react specifically with synthetic β-Galf-containing glycans. We took a reversed immunoglycomics approach that entailed: (a) Synthesis of T. cruzi GIPL-derived Galfβ1,3Manpα-(CH2)3SH (glycan G29SH) and Galfβ1,3Manpα1,2-[Galfβ1,3]Manpα-(CH2)3SH (glycan G32SH); and (b) preparation of neoglycoproteins NGP29b and NGP32b, and their evaluation in a chemiluminescent immunoassay. Receiver-operating characteristic analysis revealed that NGP32b can distinguish CCD sera from sera of healthy individuals with 85.3% sensitivity and 100% specificity. This suggests that Galfβ1,3Manpα1,2-[Galfβ1,3]Manpα is an immunodominant glycotope and that NGP32b could potentially be used as a novel CCD biomarker. 相似文献
65.
Mengdie Gong Mingyan Tu Hongxia Sun Lu Li Lili Zhu Honglin Li Zhenjiang Zhao Shiliang Li 《Molecules (Basel, Switzerland)》2022,27(1)
Huntington’s disease (HD) is a rare single-gene neurodegenerative disease, which can only be treated symptomatically. Currently, there are no approved drugs for HD on the market. Studies have found that MAPK11 can serve as a potential therapeutic target for HD. Regrettably, no MAPK11 small molecule inhibitors have been approved at present. This paper presents three series of compounds that were designed and synthesized based on the structure of skepinone-L, a known MAPK14 inhibitor. Among the synthesized compounds, 13a and 13b, with IC50 values of 6.40 nM and 4.20 nM, respectively, displayed the best inhibitory activities against MAPK11. Furthermore, the structure–activity relationship (SAR) is discussed in detail, which is constructive in optimizing the MAPK11 inhibitors for better activity and effect against HD. 相似文献
66.
67.
Rosalba Leuci Leonardo Brunetti Antonio Laghezza Luca Piemontese Antonio Carrieri Leonardo Pisani Paolo Tortorella Marco Catto Fulvio Loiodice 《Molecules (Basel, Switzerland)》2022,27(3)
A new series of aryloxyacetic acids was prepared and tested as peroxisome proliferator-activated receptors (PPARs) agonists and fatty acid amide hydrolase (FAAH) inhibitors. Some compounds exhibited an interesting dual activity that has been recently proposed as a new potential therapeutic strategy for the treatment of Alzheimer’s disease (AD). AD is a multifactorial pathology, hence multi-target agents are currently one of the main lines of research for the therapy and prevention of this disease. Given that cholinesterases represent one of the most common targets of recent research, we decided to also evaluate the effects of our compounds on the inhibition of these specific enzymes. Interestingly, two of these compounds, (S)-5 and 6, showed moderate activity against acetylcholinesterase (AChE) and even some activity, although at high concentration, against Aβ peptide aggregation, thus demonstrating, in agreement with the preliminary dockings carried out on the different targets, the feasibility of a simultaneous multi-target activity towards PPARs, FAAH, and AChE. As far as we know, these are the first examples of molecules endowed with this pharmacological profile that might represent a promising line of research for the identification of novel candidates for the treatment of AD. 相似文献
68.
Biophysical computational models are complementary to experiments and theories, providing powerful tools for the study of neurological diseases. The focus of this review is the dynamic modeling and control strategies of Parkinson's disease (PD). In previous studies, the development of parkinsonian network dynamics modeling has made great progress. Modeling mainly focuses on the cortex-thalamus-basal ganglia (CTBG) circuit and its sub-circuits, which helps to explore the dynamic behavior of the parkinsonian network, such as synchronization. Deep brain stimulation (DBS) is an effective strategy for the treatment of PD. At present, many studies are based on the side effects of the DBS. However, the translation from modeling results to clinical disease mitigation therapy still faces huge challenges. Here, we introduce the progress of DBS improvement. Its specific purpose is to develop novel DBS treatment methods, optimize the treatment effect of DBS for each patient, and focus on the study in closed-loop DBS. Our goal is to review the inspiration and insights gained by combining the system theory with these computational models to analyze neurodynamics and optimize DBS treatment. 相似文献
69.
Parkinson’s disease (PD) is characterized by the decrease of dopamine (DA) production and release in the substantia nigra and striatum regions of the brain. Transcranial ultrasound has been exploited recently for neuromodulation of the brain in a number of fields. We have stimulated DA release in PC12 cells using low-intensity continuous ultrasound (0.1 W/cm2 − 0.3 W/cm2, 1 MHz), 12 h after exposure at 0.2 W/cm2, 40 s, the amount of DA content eventually increased 78.5% (p = 0.004). After 10-day ultrasonic treatment (0.3 W/cm2, 5 min/d), the DA content in the striatum of PD mice model restored to 81.07% of the control (vs 43.42% in the untreated PD mice model). In addition to this the locomotion activity was restored to the normal level after treatment. We suggest that the low intensity ultrasound-induced DA release can be attributed to a combination of neuron regeneration and improved membrane permeability produced by the mechanical force of ultrasound. Our study indicates that the application of transcranial ultrasound applied below FDA limits, could provide a candidate for relatively safe and noninvasive PD therapy through an amplification of DA levels and the stimulation of dopaminergic neuron regeneration without contrast agents. 相似文献
70.
Hongfa Lv Lianping Wang Shuang Liu Wei Hu Jianfeng Wang Xuming Deng Jinying Gao 《Molecules (Basel, Switzerland)》2022,27(7)
Listeria monocytogenes (L. monocytogenes) is an important Gram-positive food-borne pathogen that severely threatens public health. A checkerboard microdilution method was performed to evaluate the synergistic effect of lithocholic acid (LCA) with Gentamicin (Genta) against L. monocytogenes. BacLight LIVE/DEAD staining, scanning electron microscopy and biofilm inhibition assays were further used to explore the bactericidal effect and antibiofilm effect of this combination on L. monocytogenes. Additionally, the synergistic effects of LCA derivatives with Genta were also evaluated against L. monocytogenes, S. aureus and S. suis. The results indicated that a synergistic bactericidal effect was observed for the combined therapy of LCA at the concentration without affecting bacteria viability, with Genta. Additionally, LCA in combination with Genta had a synergistic effect against Gram-positive bacteria (L. monocytogenes, S. aureus and S. suis) but not against Gram-negative bacteria (E. coli, A. baumannii and Salmonella). BacLight LIVE/DEAD staining and scanning electron microscopy analysis revealed that the combination of LCA with Genta caused L. monocytogenes membrane injury, leading to bacteria death. We found that 8 μg/mL LCA treatment effectively improved the ability of Genta to eradicate L. monocytogenes biofilms. In addition, we found that chenodeoxycholic acid, as a cholic acid derivative, also improved the bactericidal effect of Genta against Gram-positive bacteria. Our results indicate that LCA represents a broad-spectrum adjuvant with Genta for infection caused by L. monocytogenes and other Gram-positive pathogens. 相似文献