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排序方式: 共有307条查询结果,搜索用时 15 毫秒
1.
Dr. Li Di Prof. Per Artursson Dr. Alex Avdeef Prof. Leslie Z. Benet Prof. J. Brian Houston Dr. Manfred Kansy Edward H. Kerns Prof. Hans Lennernäs Dr. Dennis A. Smith Prof. Kiyohiko Sugano 《ChemMedChem》2020,15(20):1862-1874
Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients. 相似文献
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Damage detection of CFRP using fiber Bragg gratings 总被引:1,自引:0,他引:1
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K Toyama K Ohyashiki Y Yoshida T Abe S Asano H Hirai K Hirashima T Hotta A Kuramoto S Kuriya 《Canadian Metallurgical Quarterly》1993,7(4):499-508
It is well known that cytogenetic analysis in patients with myelodysplastic syndrome (MDS) provides information useful in determining their prognosis. Based on the chromosomal results obtained from 401 MDS patients by a multicentric study in Japan, we studied correlations between chromosomal findings and prognosis or leukemic transformation in MDS patients. Patients with complex aberrations (cytogenetic abnormalities at more than three chromosomes), of any subtype, had a poor prognosis; for example, > 60% of patients with refractory anemia (RA) showing complex aberrations died within one year, but only 11% of them developed leukemia. In patients with RA with ringed sideroblasts (RARS), > 70% of those with complex aberrations evolved into the leukemic phase and survived for less than one year, suggesting a biologic heterogeneity in RARS patients. By contrast, about 5% of patients with RA or RARS exhibiting chromosomal findings other than -7/7q-, +8, two aberrations, and complex aberrations, developed leukemia and had a favorable prognosis. Therefore, the presence of chromosome abnormalities alone in patients with RA or RARS is not a factor in predicting leukemic transformation or poor prognosis. In patients with refractory anemia with an excess of blasts (RAEB), the presence of chromosome aberrations at MDS diagnosis affected the occurrence of leukemic transformation (24% versus 43%), however, no particular difference was noted in patients with RAEB in transformation with regard to whether they had chromosome changes or not, and about 60% of them evolved into leukemia. The poor prognosis related to complex aberrations was consistently noted in all MDS subtypes or age-matched groups, indicating that this cytogenetic anomaly is an independent risk factor for a poor prognosis in MDS patients. The duration between MDS diagnosis and development of the leukemic phase and that between the latter and death were significantly shorter in patients with complex aberrations than those without this change. Although the clinical significance of certain chromosomal abnormalities differs among subtypes of MDS, a new scoring system for predicting prognosis by cytogenetic changes, in combination with hematologic parameters, was proposed. 相似文献
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Postnatal development and myocardial hypertrophy are associated with alterations in cardiac voltage-gated K+ channels. To investigate mechanisms underlying this K+ channel remodeling, expression of Kv4.2 and Kv1.4 K+ channel alpha-subunits was examined in cultured newborn rat ventricular myocytes by Western blot analysis using polyclonal antibodies against each of the subunits. At day 5 of cell culture, Kv1.4 protein was expressed at higher level than Kv4.2; as the age of culture progressed, Kv1.4 was significantly diminished while Kv4.2 increased with time in culture and became the predominant K+ channel protein. Such K+ channel isoform switch from Kv1.4 to Kv4.2 resembles that of the development in vivo. A 72-h treatment with exogenous triiodothyronine (T3, 0.1 microM) to cultured neonatal myocytes enhanced the expression of Kv4.2 by 73% and decreased the Kv1.4 expression by 22%. The effects of T3 were associated with an increase in the protein-to-DNA ratio indicating myocyte hypertrophy. On the other hand, a 72-h treatment with cardiac non-myocyte cell (NMC)-conditioned growth medium (NCGM) or phenylephrine (20 microM) induced similar cell hypertrophy, but in sharp contrast to T3, both markedly suppressed the Kv4.2 channel protein level. In addition, the trophic and the Kv4.2-downregulating effects of NCGM could be mimicked by exogenous endothelin-1 (0.1 microM), a paracrine factor secreted from cardiac NMCs. Our observations for the first time suggest that cardiac Kv4.2 and Kv1.4 K+ channel alpha-subunits are differentially regulated by a variety of myocardial hypertrophic factors. That T3 accelerated the developmental K+ channel isoform switch from Kv1.4 to Kv4.2 in vitro indicates the critical importance of thyroid hormone in postnatal K+ channel remodeling. Cardiac NMCs and alpha-adrenoceptor activation may contribute to the reduced outward K+ channel density in hypertrophied cardiomyocytes. 相似文献
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Toyama Mitsutoshi; Yamashita Mitsuo; Yoneda Morihide; Zaborowski Andrzej; Nagato Masaki; Ono Hisayo; Hirayama Noriaki; Murooka Yoshikatsu 《Protein engineering, design & selection : PEDS》2002,15(6):477-483
Despite the structural similarities between cholesterol oxidasefrom Streptomyces and that from Brevibacterium, both enzymesexhibit different characteristics, such as catalytic activity,optimum pH and temperature. In attempts to define the molecularbasis of differences in catalytic activity or stability, substitutionsat six amino acid residues were introduced into cholesteroloxidase using site-directed mutagenesis of its gene. The aminoacid substitutions chosen were based on structural comparisonsof cholesterol oxidases from Streptomyces and Brevibacterium.Seven mutant enzymes were constructed with the following aminoacid substitutions: L117P, L119A, L119F, V145Q, Q286R, P357Nand S379T. All the mutant enzymes exhibited activity with theexception of that with the L117P mutation. The resulting V145Qmutant enzyme has low activities for all substrates examinedand the S379T mutant enzyme showed markedly altered substratespecificity compared with the wild-type enzyme. To evaluatethe role of V145 and S379 residues in the reaction, mutantswith two additional substitutions in V145 and four in S379 wereconstructed. The mutant enzymes created by the replacement ofV145 by Asp and Glu had much lower catalytic efficiency forcholesterol and pregnenolone as substrates than the wild-typeenzyme. From previous studies and this study, the V145 residueseems to be important for the stability and substrate bindingof the cholesterol oxidase. In contrast, the catalytic efficiencies(kcat/Km) of the S379T mutant enzyme for cholesterol and pregnenolonewere 1.8- and 6.0-fold higher, respectively, than those of thewild-type enzyme. The enhanced catalytic efficiency of the S379Tmutant enzyme for pregnenolone was due to a slightly high kcatvalue and a low Km value. These findings will provide severalideas for the design of more powerful enzymes that can be appliedto clinical determination of serum cholesterol levels and assterol probes. 相似文献
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Kiyohiko Hattori Eri Homma Toshinori Kagawa Masayuki Otani Naoki Tatebe Yasunori Owada Lin Shan Katsuhiro Temma Kiyoshi Hamaguchi 《Artificial Life and Robotics》2016,21(4):451-459
Recently, many extensive studies have been conducted on robot control via self-positioning estimation techniques. In the simultaneous localization and mapping (SLAM) method, which is one approach to self-positioning estimation, robots generally use both autonomous position information from internal sensors and observed information on external landmarks. SLAM can yield higher accuracy positioning estimations depending on the number of landmarks; however, this technique involves a degree of uncertainty and has a high computational cost, because it utilizes image processing to detect and recognize landmarks. To overcome this problem, we propose a state-of-the-art method called a generalized measuring-worm (GMW) algorithm for map creation and position estimation, which uses multiple cooperating robots that serve as moving landmarks for each other. This approach allows problems of uncertainty and computational cost to be overcome, because a robot must find only a simple two-dimensional marker rather than feature-point landmarks. In the GMW method, the robots are given a two-dimensional marker of known shape and size and use a front-positioned camera to determine the marker distance and direction. The robots use this information to estimate each other’s positions and to calibrate their movement. To evaluate the proposed method experimentally, we fabricated two real robots and observed their behavior in an indoor environment. The experimental results revealed that the distance measurement and control error could be reduced to less than 3 %. 相似文献
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Kikuta K Tochigi N Saito S Shimoda T Morioka H Toyama Y Hosono A Suehara Y Beppu Y Kawai A Hirohashi S Kondo T 《Proteomics. Clinical applications》2010,4(5):560-567
Purpose : We aimed to identify novel chemotherapy responsiveness biomarkers for osteosarcoma (OS) by investigating the global protein expression profile of 12 biopsy samples from OS patients. Experimental design : Six patients were classified as good responders and six as poor responders, according to the Huvos grading system. The protein expression profiles obtained by 2‐D DIGE consisted of 2250 protein spots. Results : Among them, we identified 55 protein spots whose intensity was significantly different (Bonferroni adjusted p‐value<0.01) between the two patient groups. Mass spectrometric protein identification demonstrated that the 55 spots corresponded to 38 distinct gene products including peroxiredoxin 2 (PRDX 2). Use of a specific antibody against PRDX 2 confirmed the differential expression of PRDX 2 between good and poor responders, while PRDX 2 levels as measured by Western blotting correlated highly with their corresponding 2‐D DIGE values. The predictive value of PRDX 2 expression was further confirmed by examining an additional four OS cases using Western blotting. Conclusions and clinical relevance : These results establish PRDX 2 as a candidate for chemotherapy responsiveness marker in OS. Measuring PRDX 2 in biopsy samples before treatment may contribute to more effective management of OS. 相似文献