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排序方式: 共有7624条查询结果,搜索用时 11 毫秒
101.
Ewa Witkowska Magda Godlewska Jowita Osiejuk Sandra Gtarz Beata Wileska Katarzyna Kosiska Joanna Starnowska-Sok Anna Piotrowska Piotr F. J. Lipiski Joanna Mataliska Jolanta Dyniewicz Pawe K. Halik Ewa Gniazdowska Barbara Przewlocka Aleksandra Misicka 《International journal of molecular sciences》2022,23(2)
Based on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist, and the second pharmacophore is an antagonist of the pronociceptive system, i.e., an antagonist of the melanocortin-4 receptor. The results of tests in acute and neuropathic pain models of the obtained compounds have shown that the type of linker used to connect pharmacophores had an effect on antinociceptive activity. Peptidomimetics containing longer flexible linkers were very effective at low doses in the neuropathic pain model. To elucidate the effect of linker lengths, two hybrids showing very high activity and two hybrids with lower activity were further tested for affinity for opioid (mu, delta) and melanocortin-4 receptors. Their complexes with the target receptors were also studied by molecular modelling. Our results do not show a simple relationship between linker length and affinity for particular receptor types but suggest that activity in neuropathic pain is related to a proper balance of receptor affinity rather than maximum binding to any or all of the target receptors. 相似文献
102.
目的 基于全基因组测序(WGS)比较分析2019—2022年聊城市单核细胞增生李斯特菌(Lm)食品和病例分离株基因组特征、毒力性、耐药性以及遗传多样性。方法 对聊城市33株市售食品和临床病例中Lm分离株开展抗生素敏感性试验和WGS。利用MGAP对WGS数据进行拼接组装,对组装基因组进行基因预测和功能注释、MLST,制作cg MLST最小生成树图,并与美国国家生物信息中心(NCBI)上获取的18株国内外Lm构建wg-SNP进化树。结果 33株Lm分离株的基因组大小为2.89~3.41 Mb,CG含量为37.81%~37.97%,可分为6个ST型(ST9、ST121、ST8、ST87、ST155、ST101),分别属于6个克隆复合群(CC9、CC121、CC8、CC87、CC155、CC101);分离株均携带fosX和mprF耐药基因,此外还携带lplA1、prsA2等其他18个毒力基因,有不同程度的毒力基因缺失情况。2株菌对四环素耐药,1株菌对林可霉素耐药。均携带毒力岛LIPI-1和LIPI-2,未检测到毒力岛LIPI-3和LIPI-4。wg-SNPs、cgMLST和基于单拷贝核心蛋白序列的系统发育树遗传进化分析显示,33株Lm分子分型呈现高度多样性,病例来源菌株与食品分离株亲缘关系密切,食品分离株与国外暴发分离株在进化关系上密切相关。结论 山东省聊城市食品和病例中分离的单增李斯特菌均携带毒力基因,具有一定的潜在致病能力,耐药情况尚不严重。分子型别呈现出多样性,食品来源菌株和病例分离株具有较近的亲缘关系,提示市售食品有食源性感染的潜在风险。 相似文献
103.
Giulia Fiscon Federica Conte Lorenzo Farina Paola Paci 《International journal of molecular sciences》2022,23(7)
Drug repurposing strategy, proposing a therapeutic switching of already approved drugs with known medical indications to new therapeutic purposes, has been considered as an efficient approach to unveil novel drug candidates with new pharmacological activities, significantly reducing the cost and shortening the time of de novo drug discovery. Meaningful computational approaches for drug repurposing exploit the principles of the emerging field of Network Medicine, according to which human diseases can be interpreted as local perturbations of the human interactome network, where the molecular determinants of each disease (disease genes) are not randomly scattered, but co-localized in highly interconnected subnetworks (disease modules), whose perturbation is linked to the pathophenotype manifestation. By interpreting drug effects as local perturbations of the interactome, for a drug to be on-target effective against a specific disease or to cause off-target adverse effects, its targets should be in the nearby of disease-associated genes. Here, we used the network-based proximity measure to compute the distance between the drug module and the disease module in the human interactome by exploiting five different metrics (minimum, maximum, mean, median, mode), with the aim to compare different frameworks for highlighting putative repurposable drugs to treat complex human diseases, including malignant breast and prostate neoplasms, schizophrenia, and liver cirrhosis. Whilst the standard metric (that is the minimum) for the network-based proximity remained a valid tool for efficiently screening off-label drugs, we observed that the other implemented metrics specifically predicted further interesting drug candidates worthy of investigation for yielding a potentially significant clinical benefit. 相似文献
104.
Martina Magni Chiara Paolizzi Chiara Monfrini Cristina Vella Paolo Corradini Cristiana Carniti 《International journal of molecular sciences》2022,23(7)
Mature T-cell lymphomas (MTCLs) represent a heterogeneous group of aggressive non-Hodgkin lymphomas comprising different entities. Anthracycline-based regimens are considered the standard of care in the front-line treatment. However, responses to these approaches have been neither adequate nor durable, and new treatment strategies are urgently needed to improve survival. Genomic instability is a common feature of cancer cells and can be caused by aberrations in the DNA damage response (DDR) and DNA repair mechanisms. Consistently, molecules involved in DDR are being targeted to successfully sensitize cancer cells to chemotherapy. Recent studies showed that some hematological malignancies display constitutive DNA damage and intrinsic DDR activation, but these features have not been investigated yet in MTCLs. In this study, we employed a panel of malignant T cell lines, and we report for the first time the characterization of intrinsic DNA damage and basal DDR activation in preclinical models in T-cell lymphoma. Moreover, we report the efficacy of targeting the apical kinase ATM using the inhibitor AZD0156, in combination with standard chemotherapy to promote apoptotic cell death. These findings suggest that DDR is an attractive pathway to be pharmacologically targeted when developing novel therapies and improving MTCL patients’ outcomes. 相似文献
105.
106.
Drug repositioning, the approach of discovering different uses for existing drugs, has gained enormous popularity in recent years in the anticancer drug discovery field due to the increasing demand for anticancer drugs. Additionally, the repurposing of veterinary antiparasitic drugs for the treatment of cancer is gaining traction, as supported by existing literature. A prominent example is the proposal to implement the use of veterinary antiparasitics such as benzimidazole carbamates and halogenated salicylanilides as novel anticancer drugs. These agents have revealed pronounced anti-tumor activities and gained special attention for “double repositioning”, as they are repurposed for different species and diseases simultaneously, acting via different mechanisms depending on their target. As anticancer agents, these compounds employ several mechanisms, including the inhibition of oncogenic signal transduction pathways of mitochondrial respiration and the inhibition of cellular stress responses. In this review, we summarize and provide valuable information about the experimental, preclinical, and clinical trials of veterinary antiparasitic drugs available for the treatment of various cancers in humans. This review suggests the possibility of new treatment options that could improve the quality of life and outcomes for cancer patients in comparison to the currently used treatments. 相似文献
107.
Maria A. Ortiz F. Javier Piedrafita Adel Nefzi 《International journal of molecular sciences》2022,23(8)
A growing body of evidence suggests a pathogenic role for pro-inflammatory T helper 17 cells (Th17) in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type I diabetes, and psoriasis—diseases for which no curative treatment is currently available. The nuclear retinoic acid receptor–related orphan receptors alpha and gamma (RORα/γ), in particular the truncated isoform RORγt that is specifically expressed in the thymus, play a critical role in the activation of a pro-inflammatory Th17 response, and RORγ inverse agonists have shown promise as negative regulators of Th17 for the treatment of autoimmune diseases. Our study underscores the screening of a large combinatorial library of 1,5-disubstituted acylated 2-amino-4,5-dihydroimidazoles using a demonstrated synthetic and screening approach and the utility of the positional scanning libraries strategy for the rapid identification of a novel class of ROR inhibitors. We identified compound 1295-273 with the highest activity against RORγ (3.3 µM IC50) in this series, and almost a two-fold selectivity towards this receptor isoform, with 5.3 and 5.8 µM IC50 against RORα and RORβ cells, respectively. 相似文献
108.
109.
Andrzej Gawor Zdzislaw Gajewski Leszek Paczek Bozena Czarkowska-Paczek Anna Konopka Grzegorz Wryk Ewa Bulska 《International journal of molecular sciences》2022,23(8)
In many pharmaceuticals, a hydrogen atom or hydroxyl group is replaced by a fluorine to increase bioavailability and biostability. The fate of fluorine released from fluorine-containing drugs is not well investigated. The aim of this study was to examine possible fluorination of proteins in rat liver and brain after administration of the fluorinated drug cinacalcet. We assigned 18 Wistar rats to a control group (n = 6) and a group treated with cinacalcet (2 mg kg−1/body weight, 5 days/week), divided into 7 day (n = 6) and 21 day (n = 6) treatment subgroups. Fluorinated proteins were identified using a free proteomics approach; chromatographic separation and analysis by high-resolution mass spectrometry; peptide/protein identification using the Mascot search algorithm; manual verification of an experimentally generated MS/MS spectrum with the theoretical MS/MS spectrum of identified fluorinated peptides. Three fluorinated proteins (spectrin beta chain; carbamoyl-phosphate synthase [ammonia], mitochondrial; 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 1) were identified in the liver and four (spectrin beta chain, dihydropyrimidinase-related protein 4, prominin-2, dihydropyrimidinase-related protein 4) in the brain tissue after 21 days of cinacalcet treatment, but not in the control group. Introduction of fluorine into an organism by administration of fluorinated drugs results in tissue-specific fluorination of proteins. 相似文献
110.
目的:对比单独降脂药物及药物联合饮食控制治疗高脂血症的临床疗效,以供参考。方法:将牡丹江医院红旗医院院2011年5月—2013年4月收治的高脂血症患者100例纳入本研究,根据随机原则分组。对照组接受单独降脂药物治疗,实验组接受药物联合饮食控制治疗。用药12w后对比两组患者血脂水平的变化和辛伐他汀日使用剂量的差异。结果:与治疗前对比,治疗后患者TC、TG、LDL-C等指标水平均有所下降,HDL-C水平有所上升,其中实验组各指标改善幅度明显大于对照组,组间差异经统计学分析后认为有意义(P0.05)。与对照组对比,实验组患者辛伐他汀日使用剂量明显较低,组间差异经统计学分析后认为有意义(P0.05)。结论:采用药物联合饮食控制治疗高脂血症的降脂效果优于单独药物治疗,同时可减少降脂药物使用剂量,对减少不良反应和降低医疗费用有益。 相似文献