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101.
Prof. Dr. Arun K. Ghosh Dr. Margherita Brindisi Dr. Yu-Chen Yen Emma K. Lendy Dr. Satish Kovela Emilio Leal Cárdenas Dr. Bhavanam Sekhara Reddy Dr. Kalapala Venketeswara Rao Deborah Downs Dr. Xiangping Huang Dr. Jordan Tang Prof. Dr. Andrew D. Mesecar 《ChemMedChem》2019,14(5):545-560
Herein we present the design, synthesis, and biological evaluation of potent and highly selective β-secretase 2 (memapsin 1, beta-site amyloid precursor protein cleaving enzyme 2, or BACE 2) inhibitors. BACE2 has been recognized as an exciting new target for type 2 diabetes. The X-ray structure of BACE1 bound to inhibitor 2 a {N3-[(1S,2R)-1-benzyl-2-hydroxy-3-[[(1S,2S)-2-hydroxy-1-(isobutylcarbamoyl)propyl]amino]propyl]-5-[methyl(methylsulfonyl)amino]-N1-[(1R)-1-phenylpropyl]benzene-1,3-dicarboxamide} containing a hydroxyethylamine isostere was determined. Based on this structure, a computational docking study was performed which led to inhibitor 2 a -bound BACE2 models. These were used to optimize the potency and selectivity of inhibitors. A systematic structure–activity relationship study led to the identification of determinants of the inhibitors’ potency and selectivity toward the BACE2 enzyme. Inhibitors 2 d [N3-[(1S,2R)-1-benzyl-2-hydroxy-3-[[(1S,2S)-2-hydroxy-1-(isobutylcarbamoyl)pentyl]amino]propyl]-N1-methyl-N1-[(1R)-1-phenylpropyl]benzene-1,3-dicarboxamide; Ki=0.031 nm , selectivity over BACE1: ≈174 000-fold] and 3 l [N1-((2S,3R)-3-hydroxy-1-phenyl-4-((3-(trifluoromethyl)benzyl)amino)butan-2-yl)-N3,5-dimethyl-N3-((R)-1-phenylethyl)isophthalamide; Ki=1.6 nm , selectivity over BACE1: >500-fold] displayed outstanding potency and selectivity. Inhibitor 3 l is nonpeptide in nature and may pave the way to the development of a new class of potent and selective BACE2 inhibitors with clinical potential. 相似文献
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目的:探讨膳食丙烯酰胺暴露对2型糖尿病大鼠病程进展的影响。方法:对糖尿病模型GK大鼠给予低剂量丙烯酰胺(2 mg/(kg mb·d))8周后,研究其对大鼠空腹血糖、空腹糖耐量和胰岛素敏感性等血糖代谢相关指标的影响,同时测定血清生化指标、氧化和炎症因子水平,并对肝脏、肾脏、胰腺和腓肠肌进行苏木精-伊红染色,观察病理变化情况,分析丙烯酰胺暴露对GK大鼠脏器组织功能的影响。最后采用气相色谱-质谱联用仪对大鼠血清和尿液中的代谢物进行检测,筛选膳食丙烯酰胺暴露对GK大鼠造成影响的主要差异代谢物,分析其关联的代谢通路。结果:与对照组(灌胃去离子水)相比,膳食丙烯酰胺暴露进一步通过损伤GK大鼠胰腺、促进氧化炎症应激、影响胰岛β细胞功能和磷酸戊糖代谢通路等作用,导致糖尿病模型GK大鼠血糖代谢紊乱加重,具体表现为空腹血糖水平明显上升、空腹糖耐量受损和胰岛素敏感性降低。此外,膳食丙烯酰胺暴露的GK大鼠体内显著改变的差异代谢物有L-酪氨酸、肌醇、马尿酸、柠康酸、苯乙酰甘氨酸、N-乙酰基亮氨酸、喹啉酸、L-色氨酸以及5-羟甲基色胺等,与精氨酸和脯氨酸代谢、色氨酸代谢、磷酸肌醇代谢、苯丙氨酸、酪氨酸和色氨酸代谢... 相似文献
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Pamela Senesi Anna Ferrulli Livio Luzi Ileana Terruzzi 《International journal of molecular sciences》2021,22(15)
Type 2 diabetes (T2DM) and cardiovascular disease (CVD) are closely associated and represent a key public health problem worldwide. An excess of adipose tissue, NAFLD, and gut dysbiosis establish a vicious circle that leads to chronic inflammation and oxidative stress. Caloric restriction (CR) is the most promising nutritional approach capable of improving cardiometabolic health. However, adherence to CR represents a barrier to patients and is the primary cause of therapeutic failure. To overcome this problem, many different nutraceutical strategies have been designed. Based on several data that have shown that CR action is mediated by AMPK/SIRT1 activation, several nutraceutical compounds capable of activating AMPK/SIRT1 signaling have been identified. In this review, we summarize recent data on the possible role of berberine, resveratrol, quercetin, and L-carnitine as CR-related nutrients. Additionally, we discuss the limitations related to the use of these nutrients in the management of T2DM and CVD. 相似文献
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Polyphenols, which are abundantly distributed in plants such as fruits, vegetables, and tea, constitute a large group of aromatic compounds, mainly including phenolic acids and flavonoids. These natural metabolites have been demonstrated to possess a wide range of biological activities associated with health benefits, including the α-glucosidase inhibitory activity. In contrast to the classical α-glucosidase inhibitors, e.g., aza/imino sugars, polyphenols serve as a new type of α-glucosidase inhibitor with different, yet unknown, mechanisms of action, which could lead to novel dietary supplements and therapeutic agents for the prevention and treatment of metabolic disorders. In this review, we report a collection of 137 naturally occurring phenolic acids and flavonoids with α-glucosidase inhibitory activities. 相似文献
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Macrophages are highly heterogeneous and plastic immune cells with peculiar characteristics dependent on their origin and microenvironment. Following pathogen infection or damage, circulating monocytes can be recruited in different tissues where they differentiate into macrophages. Stimuli present in the surrounding milieu induce the polarisation of macrophages towards a pro-inflammatory or anti-inflammatory profile, mediating inflammatory or homeostatic responses, respectively. However, macrophages can also derive from embryonic hematopoietic precursors and reside in specific tissues, actively participating in the development and the homeostasis in physiological conditions. Pancreatic islet resident macrophages are present from the prenatal stages onwards and show specific surface markers and functions. They localise in close proximity to β-cells, being exquisite sensors of their secretory ability and viability. Over the years, the crucial role of macrophages in β-cell differentiation and homeostasis has been highlighted. In addition, macrophages are emerging as central players in the initiation of autoimmune insulitis in type 1 diabetes and in the low-grade chronic inflammation characteristic of obesity and type 2 diabetes pathogenesis. The present work reviews the current knowledge in the field, with a particular focus on the mechanisms of communication between β-cells and macrophages that have been described so far. 相似文献
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Katarzyna Szkudelska Marzanna Deniziak Maciej Sassek Ignacy Szkudelski Wojciech Noskowiak Tomasz Szkudelski 《International journal of molecular sciences》2021,22(5)
Resveratrol is a biologically active diphenolic compound exerting multiple beneficial effects in the organism, including anti-diabetic properties. This action is, however, not fully elucidated. In the present study, we examined effects of resveratrol on some parameters related to insulin signaling, and also on diabetes-associated dysregulation in Goto-Kakizaki (GK) rats with congenital type 2 diabetes. Resveratrol was given at the dose of 20 mg/kg b.w. for 10 weeks. It was shown that the expression and phosphorylation levels of insulin receptor in the skeletal muscle of GK rats were significantly decreased, compared with control animals. However, these changes were totally prevented by resveratrol. Liver expression of the insulin receptor was also reduced, but in this case, resveratrol was ineffective. Resveratrol was also demonstrated to significantly influence parameters of insulin binding (dissociation constant and binding capacity) in the skeletal muscle and liver. Moreover, it was shown that the expression levels of proteins related to intracellular glucose transport (GLUT4 and TUG) in adipose tissue of GK rats were significantly decreased. However, treatment with resveratrol completely abolished these changes. Resveratrol was found to induce normalization of TUG expression in the skeletal muscle. Blood levels of insulin and GIP were elevated, whereas proinsulin and GLP-1 diminished in GK rats. However, concentrations of these hormones were not affected by resveratrol. These results indicate that resveratrol partially ameliorates diabetes-associated dysregulation in GK rats. The most relevant finding covers the normalization of the insulin receptor expression in the skeletal muscle and also GLUT4 and TUG in adipose tissue. 相似文献