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71.
Redesigning the DNA‐Targeted Chromophore in Platinum–Acridine Anticancer Agents: A Structure–Activity Relationship Study 下载免费PDF全文
Dr. Amanda J. Pickard Dr. Fang Liu Thomas F. Bartenstein Laura G. Haines Dr. Keith E. Levine Prof. Gregory L. Kucera Prof. Ulrich Bierbach 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(49):16174-16187
Platinum–acridine hybrid agents show low‐nanomolar potency in chemoresistant non‐small cell lung cancer (NSCLC), but high systemic toxicity in vivo. To reduce the promiscuous genotoxicity of these agents and improve their pharmacological properties, a modular build–click–screen approach was used to evaluate a small library of twenty hybrid agents containing truncated and extended chromophores of varying basicities. Selected derivatives were resynthesized and tested in five NSCLC cell lines representing large cell, squamous cell, and adenocarcinomas. 7‐Aminobenz[c]acridine was identified as a promising scaffold in a hybrid agent ( P1–B1 ) that maintained submicromolar activity in several of the DNA‐repair proficient and p53‐mutant cancer models, while showing improved tolerability in mice by 32‐fold compared to the parent platinum–acridine ( P1–A1 ). The distribution and DNA/RNA adduct levels produced by the acridine‐ and benz[c]acridine‐based analogues in NCI‐H460 cells (confocal microscopy, ICP‐MS), and their ability to bind G‐quadruplex forming DNA sequences (CD spectroscopy, HR‐ESMS) were studied. P1–B1 emerges as a less genotoxic, more tolerable, and potentially more target‐selective hybrid agent than P1–A1 . 相似文献
72.
Probing the Anticancer Mechanism of (−)‐Ainsliatrimer A through Diverted Total Synthesis and Bioorthogonal Ligation 下载免费PDF全文
Dr. Chao Li Ting Dong Qiang Li Prof. Dr. Xiaoguang Lei 《Angewandte Chemie (International ed. in English)》2014,53(45):12111-12115
Herein, we report an efficient approach for exploring the novel anticancer mechanism of (?)‐ainsliatrimer A, a structurally complex and unique trimeric sesquiterpenoid, through a combined strategy of diverted total synthesis (DTS) and bioorthogonal ligation (TQ ligation), which allowed us to visualize the subcellular localization of this natural product in live cells. Further biochemical studies facilitated by pretarget imaging revealed that PPARγ, a nucleus receptor, was a functional cellular target of ainsliatrimer A. We also confirmed that the anticancer activity of ainsliatrimer A was caused by the activation of PPARγ. 相似文献
73.
Yi-Fan Wang Yiyu Liang Yan-Fang Wu Jian Yang Xu Zhang Dr. Dandan Cai Dr. Xu Peng Dr. Mohamedally Kurmoo Prof. Dr. Ming-Hua Zeng 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(32):13334-13339
The in situ tracking of the pyrolysis of a binary molecular cluster [Zn7(μ3-CH3O)6(L)6][ZnLCl2]2 is presented with one brucite disk and two mononuclear fragments (L=mmimp: 2-methoxy-6-((methylimino)-methyl)phenolate) to porous carbon using TG-MS from 30 to 900 °C. Following up the spilled gas product during the decomposed reaction of zinc cluster along the temperature rising, and in conjunction with XRD, SEM, BET and other materials characterization, where three key steps were observed: 1) cleavage of the bulky external ligand; 2) reduction of ZnO and 3) volatilization of Zn. The real-time-dependent phase-sequential evolution of the remaining products and the processing of pore forming template transformation are proposed simultaneously. The porous carbon structure featuring a uniform nano-sized pore distribution synthesized at 900 °C with the highest surface area of 1644 m2 g−1 and pore volume of 0.926 cm3 g−1 exhibits the best known capacitance of 662 F g−1 at 0.5 A g−1. 相似文献
74.
The statin drug Simvastatin is a HMG-CoA reductase inhibitor that has been widely used to lower blood lipid. However, the drug is clinically observed to reposition a significant suppressing potency on glioblastoma (GBM) by unexpectedly targeting diverse kinase pathways involved in GBM tumorigensis. Here, an inverse screening strategy is described to discover potential kinase targets of Simvastatin. Various human protein kinases implicated in GBM are enriched to define a druggable kinome; the binding behavior of Simvastatin to the kinome is profiled systematically via an integrative computational approach, from which most kinases have only low or moderate binding potency to Simvastatin, while only few are identified as promising kinase hits. It is revealed that Simvastatin can potentially interact with certain known targets or key regulators of GBM such as ErbB, c-Src and FGFR signaling pathways, but exhibit low affinity to the well-established GBM target of PI3K/Akt/mTOR pathway. Further assays determine that Simvastatin can inhibit kinase hits EGFR, MET, SRC and HER2 at nanomolar level, which are comparable with those of cognate kinase inhibitors. Structural analyses reveal that the sophisticated T790 M gatekeeper mutation can considerably reduce Simvastatin sensitivity to EGFR by inducing the ligand change between different binding modes. 相似文献
75.
Deepak Singh Kapkoti Shilpi Singh Sarfaraz Alam Feroz Khan Suaib Luqman 《Natural product research》2020,34(12):1735-1742
AbstractNovel Mannich base derivatives of glabridin were synthesized and their antiproliferative activity were performed along with our previously reported glabridin-chalcone hybrids molecules (GCHMs) against various human cell lines MDA-MB-231 (breast adenocarcinoma), HEK-293 (embryonic kidney cell line), K562 (leukemia), MCF-7 (breast adenocarcinoma), HeLa (cervix adenocarcinoma), HepG2 (hepatocellular carcinoma) and WRL-68 (hepatic carcinoma). The result showed that the glabridin significantly reduced cell proliferation with IC50 ranges from 3.67 to 58.30?µM against all the tested cell lines. The remarkable reduction in antiproliferative activity 2’,4’-dimethoxyglabridin and GCHMs compounds with phenolic OH groups protected by methoxy (OCH3) groups suggested that the free OH groups are essential factor for the antiproliferative activity of glabridin and its derivatives. The Mannich base derivatives of glabridin showed moderate activity IC50 (2.20–>95.78?µM). Furthermore, in silico target identification analysis revealed that AKT1, DECR1 and NOS1 are the potential targets for glabridin and their derivatives. 相似文献
76.
I. E. BARTON 《国际流体数值方法杂志》1996,22(3):211-221
Particle-laden flows are calculated for a classical laminar backward- facing step problem. The particle tracks are calculated using a recently developed exponential Lagrangian tracking scheme. The behaviour of the particle-laden flow is considered for various inlet for Reynolds number, Stokes numbers and void fractions. Doping the flow with low-Stokes-number particles has the effect of increasing the inlet inertia of the flow and this increases the strength of the recirculation behind the step. High-Stokes- number particles are dominated by gravitational effects which affect the flow accordingly. Differences between the single-phase flow and the particle-laden flows are therefore dependent on the Stokes number and increase linearly with void fraction. 相似文献
77.
灰度人脸识别形态学相关的一般理论研究 总被引:5,自引:4,他引:1
提出一般形态学相关概念,并提出一种小型联合变换相关器的硬件设计以实现一般形态学相关.提出两种改进的一般形态学相关算法,灰度图像按某种分解方法分解成一系列二值图像片.在第一种算法中,每片二值联合图像片的边缘被检测,其功率谱求和.在第二种算法中,一种情况是每片的联合变换功率谱被二值化或细化再求和;另一种情况是这些片的联合变换功率谱的总和被二值化或细化.计算机模拟结果表明,改进后的算法能改善高相似度灰度人脸图像识别的鉴别率. 相似文献
78.
中高分辨力遥感图像中飞机目标自动识别算法研究 总被引:2,自引:0,他引:2
提出了一种中高分辨力的航空航天遥感图像中飞机目标快速自动识别的新算法。在分割和分类过程中充分利用飞机目标的先验知识,提出了一种改进区域分割方法,并应用树分类器对飞机目标进行自动识别。所提出的改进区域分割方法较好地实现了区域分割中阈值的准确自动选取,克服了复杂背景图像中小目标的全局阈值自动分割的失效问题。采用二叉树分类器,通过提取简单的目标几何特征,分层进行种类识别,提高了识别速度,降低了漏检率和虚警率。运用该方法进行了实验。结果表明,识别率达到了100%。 相似文献
79.
80.