全文获取类型
收费全文 | 584篇 |
免费 | 34篇 |
专业分类
电工技术 | 1篇 |
化学工业 | 223篇 |
金属工艺 | 11篇 |
机械仪表 | 12篇 |
建筑科学 | 31篇 |
能源动力 | 13篇 |
轻工业 | 99篇 |
水利工程 | 7篇 |
石油天然气 | 2篇 |
无线电 | 29篇 |
一般工业技术 | 92篇 |
冶金工业 | 35篇 |
原子能技术 | 2篇 |
自动化技术 | 61篇 |
出版年
2024年 | 3篇 |
2023年 | 7篇 |
2022年 | 60篇 |
2021年 | 57篇 |
2020年 | 21篇 |
2019年 | 23篇 |
2018年 | 23篇 |
2017年 | 27篇 |
2016年 | 25篇 |
2015年 | 10篇 |
2014年 | 28篇 |
2013年 | 46篇 |
2012年 | 38篇 |
2011年 | 43篇 |
2010年 | 29篇 |
2009年 | 26篇 |
2008年 | 21篇 |
2007年 | 22篇 |
2006年 | 12篇 |
2005年 | 7篇 |
2004年 | 19篇 |
2003年 | 7篇 |
2002年 | 4篇 |
2001年 | 3篇 |
2000年 | 4篇 |
1999年 | 3篇 |
1998年 | 10篇 |
1997年 | 5篇 |
1996年 | 4篇 |
1995年 | 2篇 |
1994年 | 3篇 |
1993年 | 4篇 |
1992年 | 1篇 |
1991年 | 1篇 |
1990年 | 3篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1971年 | 1篇 |
排序方式: 共有618条查询结果,搜索用时 15 毫秒
481.
Sofia Barluenga Dr. Rajamalleswaramma Jogireddy Dr. Girish K. Koripelly Dr. Nicolas Winssinger Prof. 《Chembiochem : a European journal of chemical biology》2010,11(12):1692-1699
Hypothemycin and related resorcylic acid lactones (RAL) bearing a cis‐enone moiety have emerged as an alternative pharmacophore to heterocyclic motifs for kinase inhibition, and are endowed with a unique selectivity filter based on the irreversible reaction with a subset of the kinome bearing a suitably positioned cysteine residue. Two prototypical examples of “edited” RAL were evaluated for antitumoral, antimetastatic and antiangiogenic efficacy in an orthotopic murine renal cell carcinoma (RENCA) model. Both compounds ( 3 and 5 ) are good inhibitors of VEGFRs in vitro, and inhibited tumor growth in vivo with comparable efficacy to sunitinib, an FDA‐approved VEGFRs inhibitor. Compound 3 promoted lung metastasis to a similar extent as sunitinib, while compound 5 strongly inhibited lung metastasis. This study attests to the potential of irreversible kinase inhibitors and molecular editing of natural pharmacophores and provides encouraging results to a clinically significant problem. 相似文献
482.
Sofia Raftopoulou Paulina Valadez-Cosmes Zala Nikita Mihalic Rudolf Schicho Julia Kargl 《International journal of molecular sciences》2022,23(6)
Neutrophils are immune cells with reported phenotypic and functional plasticity. Tumor-associated neutrophils display many roles during cancer progression. Several tumor microenvironment (TME)-derived factors orchestrate neutrophil release from the bone marrow, recruitment and functional polarization, while simultaneously neutrophils are active stimulators of the TME by secreting factors that affect immune interactions and subsequently tumor progression. Successful immunotherapies for many cancer types and stages depend on the targeting of tumor-infiltrating lymphocytes. Neutrophils impact the success of immunotherapies, such as immune checkpoint blockade therapies, by displaying lymphocyte suppressive properties. The identification and characterization of distinct neutrophil subpopulations or polarization states with pro- and antitumor phenotypes and the identification of the major TME-derived factors of neutrophil polarization would allow us to harness the full potential of neutrophils as complementary targets in anticancer precision therapies. 相似文献
483.
Olga A. Averina Ivan G. Laptev Mariia A. Emelianova Oleg A. Permyakov Sofia S. Mariasina Alyona I. Nikiforova Vasily N. Manskikh Olga O. Grigorieva Anastasia K. Bolikhova Gennady A. Kalabin Olga A. Dontsova Petr V. Sergiev 《International journal of molecular sciences》2022,23(11)
Mitochondrial translation is a unique relic of the symbiotic origin of the organelle. Alterations of its components cause a number of severe human diseases. Hereby we report a study of mice devoid of Mettl15 mitochondrial 12S rRNA methyltransferase, responsible for the formation of m4C839 residue (human numbering). Homozygous Mettl15−/− mice appeared to be viable in contrast to other mitochondrial rRNA methyltransferase knockouts reported earlier. The phenotype of Mettl15−/− mice is much milder than that of other mutants of mitochondrial translation apparatus. In agreement with the results obtained earlier for cell cultures with an inactivated Mettl15 gene, we observed accumulation of the RbfA factor, normally associated with the precursor of the 28S subunit, in the 55S mitochondrial ribosome fraction of knockout mice. A lack of Mettl15 leads to a lower blood glucose level after physical exercise relative to that of the wild-type mice. Mettl15−/− mice demonstrated suboptimal muscle performance and lower levels of Cox3 protein synthesized by mitoribosomes in the oxidative soleus muscles. Additionally, we detected decreased learning capabilities in the Mettl15−/− knockout mice in the tests with both positive and negative reinforcement. Such properties make Mettl15−/− knockout mice a suitable model for mild mitochondriopathies. 相似文献
484.
485.
Andrea Mammoli Elisa Bianconi Luana Ruta Alessandra Riccio Carlo Bigiotti Maria Souma Andrea Carotti Sofia Rossini Chiara Suvieri Maria Teresa Pallotta Ursula Grohmann Emidio Camaioni Antonio Macchiarulo 《International journal of molecular sciences》2022,23(7)
Over the last two decades, indoleamine 2,3-dioxygenase 1 (IDO1) has attracted wide interest as a key player in immune regulation, fostering the design and development of small molecule inhibitors to restore immune response in tumor immunity. In this framework, biochemical, structural, and pharmacological studies have unveiled peculiar structural plasticity of IDO1, with different conformations and functional states that are coupled to fine regulation of its catalytic activity and non-enzymic functions. The large plasticity of IDO1 may affect its ligand recognition process, generating bias in structure-based drug design campaigns. In this work, we report a screening campaign of a fragment library of compounds, grounding on the use of three distinct conformations of IDO1 that recapitulate its structural plasticity to some extent. Results are instrumental to discuss tips and pitfalls that, due to the large plasticity of the enzyme, may influence the identification of novel and differentiated chemical scaffolds of IDO1 ligands in structure-based screening campaigns. 相似文献
486.
Tatiana Maurício Susana Aveiro Sofia Guedes Diana Lopes Tnia Melo Bruno M. Neves Rosrio Domingues Pedro Domingues 《International journal of molecular sciences》2022,23(4)
In recent years, several studies have demonstrated that polyunsaturated fatty acids have strong immunomodulatory properties, altering several functions of macrophages. In the present work, we sought to provide a multi-omic approach combining the analysis of the lipidome, the proteome, and the metabolome of RAW 264.7 macrophages supplemented with phospholipids containing omega-3 (PC 18:0/22:6; ω3-PC) or omega-6 (PC 18:0/20:4; ω6-PC) fatty acids, alone and in the presence of lipopolysaccharide (LPS). Supplementation of macrophages with ω3 and ω6 phospholipids plus LPS produced a significant reprogramming of the proteome of macrophages and amplified the immune response; it also promoted the expression of anti-inflammatory proteins (e.g., pleckstrin). Supplementation with the ω3-PC and ω6-PC induced significant changes in the lipidome, with a marked increase in lipid species linked to the inflammatory response, attributed to several pro-inflammatory signalling pathways (e.g., LPCs) but also to the pro-resolving effect of inflammation (e.g., PIs). Finally, the metabolomic analysis demonstrated that supplementation with ω3-PC and ω6-PC induced the expression of several metabolites with a pronounced inflammatory and anti-inflammatory effect (e.g., succinate). Overall, our data show that supplementation of macrophages with ω3-PC and ω6-PC effectively modulates the lipidome, proteome, and metabolome of these immune cells, affecting several metabolic pathways involved in the immune response that are triggered by inflammation. 相似文献
487.
Sofia Valenti Luis Javier del Valle Michela Romanini Meritxell Mitjana Jordi Puiggalí Josep Lluís Tamarit Roberto Macovez 《International journal of molecular sciences》2022,23(5)
Amorphous molecule-macromolecule mixtures are ubiquitous in polymer technology and are one of the most studied routes for the development of amorphous drug formulations. For these applications it is crucial to understand how the preparation method affects the properties of the mixtures. Here, we employ differential scanning calorimetry and broadband dielectric spectroscopy to investigate dispersions of a small-molecule drug (the Nordazepam anxiolytic) in biodegradable polylactide, both in the form of solvent-cast films and electrospun microfibres. We show that the dispersion of the same small-molecule compound can have opposite (plasticizing or antiplasticizing) effects on the segmental mobility of a biopolymer depending on preparation method, temperature, and polymer enantiomerism. We compare two different chiral forms of the polymer, namely, the enantiomeric pure, semicrystalline L-polymer (PLLA), and a random, fully amorphous copolymer containing both L and D monomers (PDLLA), both of which have lower glass transition temperature (Tg) than the drug. While the drug has a weak antiplasticizing effect on the films, consistent with its higher Tg, we find that it actually acts as a plasticizer for the PLLA microfibres, reducing their Tg by as much as 14 K at 30%-weight drug loading, namely, to a value that is lower than the Tg of fully amorphous films. The structural relaxation time of the samples similarly depends on chemical composition and morphology. Most mixtures displayed a single structural relaxation, as expected for homogeneous samples. In the PLLA microfibres, the presence of crystalline domains increases the structural relaxation time of the amorphous fraction, while the presence of the drug lowers the structural relaxation time of the (partially stretched) chains in the microfibres, increasing chain mobility well above that of the fully amorphous polymer matrix. Even fully amorphous homogeneous mixtures exhibit two distinct Johari–Goldstein relaxation processes, one for each chemical component. Our findings have important implications for the interpretation of the Johari–Goldstein process as well as for the physical stability and mechanical properties of microfibres with small-molecule additives. 相似文献
488.
Tiziana Filardi Giuseppina Catanzaro Giuseppina Emanuela Grieco Elena Splendiani Sofia Trocchianesi Carmela Santangelo Roberto Brunelli Elisa Guarino Guido Sebastiani Francesco Dotta Susanna Morano Elisabetta Ferretti 《International journal of molecular sciences》2022,23(8)
Gestational diabetes mellitus (GDM) causes both maternal and fetal adverse outcomes. The deregulation of microRNAs (miRNAs) in GDM suggests their involvement in GDM pathogenesis and complications. Exosomes are extracellular vesicles (EVs) of endosomal origin, released via exocytosis into the extracellular compartment. Through EVs, miRNAs are delivered in distant target cells and are able to affect gene expression. In this study, miRNA expression was analyzed to find new miRNAs that could improve GDM classification and molecular characterization. MiRNA were profiled in total plasma and EVs in GDM patients and normal glucose tolerance (NGT) women. Samples were collected at third trimester of gestation from two diabetes centers. MiRNA expression was profiled in a discovery cohort using the multiplexed NanoString nCounter Human v3 miRNA. Validation analysis was performed in a second independent cohort using RT-qPCR. A set of miRNAs resulted to be differentially expressed (DE) in total plasma and EVs in GDM. Among them, total plasma miR-222-3p and miR-409-3p were validated in the independent cohort. MiR-222-3p levels correlated with fasting plasma glucose (FPG) (p < 0.001) and birth weight (p = 0.012), whereas miR-409-3p expression correlated with FPG (p < 0.001) and inversely with gestational age (p = 0.001). The major validated target genes of the deregulated miRNAs were consistently linked to type 2 diabetes and GDM pathophysiology. MiR-222-3p and miR-409-3p are two circulating biomarkers that could improve GDM classification power and act in the context of the molecular events leading to the metabolic alterations observed in GDM. 相似文献
489.
Sofia Oliveira Sofia S. Pereira Madalena M. Costa Mariana P. Monteiro Duarte Pignatelli 《International journal of molecular sciences》2022,23(10)
The differential diagnosis between adrenocortical adenomas (ACAs) and adrenocortical carcinomas (ACCs) relies on unspecific clinical, imaging and histological features, and, so far, no single molecular biomarker has proved to improve diagnostic accuracy. Similarly, prognostic factors have an insufficient capacity to predict the heterogeneity of ACC clinical outcomes, which consequently lead to inadequate treatment strategies. Angiogenesis is a biological process regulated by multiple signaling pathways, including VEGF and the Ang–Tie pathway. Many studies have stressed the importance of angiogenesis in cancer development and metastasis. In the present study, we evaluated the expression of VEGF and Ang–Tie pathway mediators in adrenocortical tumors (ACTs), with the ultimate goal of assessing whether these molecules could be useful biomarkers to improve diagnostic accuracy and/or prognosis prediction in ACC. The expression of the proteins involved in angiogenesis, namely CD34, VEGF, VEGF-R2, Ang1, Ang2, Tie1 and Tie2, was assessed by immunohistochemistry in ACC (n = 22), ACA with Cushing syndrome (n = 8) and non-functioning ACA (n = 13). ACC presented a significantly higher Ang1 and Ang2 expression when compared to ACA. Tie1 expression was higher in ACC with venous invasion and in patients with shorter overall survival. In conclusion, although none of these biomarkers showed to be useful for ACT diagnosis, the Ang–Tie pathway is active in ACT and may play a role in regulating ACT angiogenesis. 相似文献
490.
Elizaveta Gordeliy Steven L. Crouch Sofia G. Mogilevskaya 《International journal for numerical methods in engineering》2009,77(6):751-775
This paper considers a transient heat conduction problem for an infinite medium with multiple non‐overlapping spherical cavities. Suddenly applied, steady Dirichlet‐, Neumann‐ or Robin‐type boundary conditions are assumed. The approach is based on the use of the general solution to the problem of a single cavity and superposition. Application of the Laplace transform and the so‐called addition theorem results in a semi‐analytical transformed solution for the case of multiple cavities. The solution in the time domain is obtained by performing a numerical inversion of the Laplace transform. A large‐time asymptotic series for the temperature is obtained. The limiting case of infinitely large time results in the solution for the corresponding steady‐state problem. Several numerical examples that demonstrate the accuracy and the efficiency of the method are presented. Copyright © 2008 John Wiley & Sons, Ltd. 相似文献