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141.
This paper describes the experimental and clinical findings of acrylamide intoxication in a human being. It is believed that this is the first such case to be recorded in the medical literature.Acrylamide is widely used as a “chemical grout”. It is pumped into dirt, clay and stone walls of excavations in a liquid state together with a catalyst, and it then polymerizes to make a watertight shield.This chemical is neurotoxic in its non-polymerized form and can be absorbed through the intact skin, mucous membranes and lungs. In spite of warnings with regard to its handling, this worker became careless, and developed a contact dermatitis and a polyneuropathy with bluish cold extremities which dripped perspiration.In six months'' time after his removal from contact with the chemical the patient made a complete clinical recovery. He was advised not to work with the chemical. 相似文献
142.
Walsh MJ Brimacombe KR Veith H Bougie JM Daniel T Leister W Cantley LC Israelsen WJ Vander Heiden MG Shen M Auld DS Thomas CJ Boxer MB 《Bioorganic & medicinal chemistry letters》2011,21(21):6322-6327
Compared to normal differentiated cells, cancer cells have altered metabolic regulation to support biosynthesis and the expression of the M2 isozyme of pyruvate kinase (PKM2) plays an important role in this anabolic metabolism. While the M1 isoform is a highly active enzyme, the alternatively spliced M2 variant is considerably less active and expressed in tumors. While the exact mechanism by which decreased pyruvate kinase activity contributes to anabolic metabolism remains unclear, it is hypothesized that activation of PKM2 to levels seen with PKM1 may promote a metabolic program that is not conducive to cell proliferation. Here we report the third chemotype in a series of PKM2 activators based on the 2-oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamide scaffold. The synthesis, structure activity relationships, selectivity and notable physiochemical properties are described. 相似文献
143.
Napier SE Letourneau JJ Ansari N Auld DS Baker J Best S Campbell-Wan L Chan JH Craighead M Desai H Goan KA Ho KK Hulskotte EG MacSweeney CP Milne R Morphy JR Neagu I Ohlmeyer MH Peeters AW Presland J Riviello C Ruigt GS Thomson FJ Zanetakos HA Zhao J Webb ML 《Bioorganic & medicinal chemistry letters》2011,21(6):1871-1875
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V1b (V3) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V1b receptor and good selectivity with respect to related receptors V1a, V2 and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction. 相似文献
144.
Rosenthal AS Tanega C Shen M Mott BT Bougie JM Nguyen DT Misteli T Auld DS Maloney DJ Thomas CJ 《Bioorganic & medicinal chemistry letters》2011,21(10):3152-3158
Continued examination of substituted 6-arylquinazolin-4-amines as Clk4 inhibitors resulted in selective inhibitors of Clk1, Clk4, Dyrk1A and Dyrk1B. Several of the most potent inhibitors were validated as being highly selective within a comprehensive kinome scan. 相似文献
145.
Napier SE Letourneau JJ Ansari N Auld DS Baker J Best S Campbell-Wan L Chan R Craighead M Desai H Ho KK MacSweeney C Milne R Richard Morphy J Neagu I Ohlmeyer MH Pick J Presland J Riviello C Zanetakos HA Zhao J Webb ML 《Bioorganic & medicinal chemistry letters》2011,21(12):3813-3817
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V1b antagonists are described. 2-(6-Aminomethylaryl-2-aryl-4-oxo-quinazolin-3(4H)-yl)acetamide have been identified with low nanomolar affinity for the V1b receptor and good selectivity with respect to related receptors V1a, V2 and OT. Optimised compound 16 shows a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction. 相似文献
146.
Sundaram Kuppu Julio Paez‐Valencia Marisol Mendoza Pei Hou Jian Chen Xiaoyun Qiu Longfu Zhu Xianlong Zhang Dick Auld Eduardo Blumwald Hong Zhang Roberto Gaxiola Paxton Payton 《Plant biotechnology journal》2011,9(1):88-99
The Arabidopsis gene AVP1 encodes a vacuolar pyrophosphatase that functions as a proton pump on the vacuolar membrane. Overexpression of AVP1 in Arabidopsis, tomato and rice enhances plant performance under salt and drought stress conditions, because up‐regulation of the type I H+‐PPase from Arabidopsis may result in a higher proton electrochemical gradient, which facilitates enhanced sequestering of ions and sugars into the vacuole, reducing water potential and resulting in increased drought‐ and salt tolerance when compared to wild‐type plants. Furthermore, overexpression of AVP1 stimulates auxin transport in the root system and leads to larger root systems, which helps transgenic plants absorb water more efficiently under drought conditions. Using the same approach, AVP1‐expressing cotton plants were created and tested for their performance under high‐salt and reduced irrigation conditions. The AVP1‐expressing cotton plants showed more vigorous growth than wild‐type plants in the presence of 200 mm NaCl under hydroponic growth conditions. The soil‐grown AVP1‐expressing cotton plants also displayed significantly improved tolerance to both drought and salt stresses in greenhouse conditions. Furthermore, the fibre yield of AVP1‐expressing cotton plants is at least 20% higher than that of wild‐type plants under dry‐land conditions in the field. This research indicates that AVP1 has the potential to be used for improving crop’s drought‐ and salt tolerance in areas where water and salinity are limiting factors for agricultural productivity. 相似文献
147.
Recruitment in plant populations is often tightly coupled to major disturbances such as fires. For species with persistent
seed banks, fire-related cues may allow or enhance germination. The litter layer influences germination and may modify the
impact of seed predators on seeds and seedlings. The litter layer is obviously affected by fire, providing one mechanism by
which disturbance can determine recruitment. We tested the role of litter in the disturbance–recruitment coupling of two species
with contrasting seed release timing after fire—Banksia serrata (canopy seed bank) and Telopea speciosissima (transient seed bank) by planting their seeds both early and late in the post-fire recruitment period (PRP) and manipulating
litter density in orthogonal treatments. Vertebrate seed predators were excluded. Both species established more seedlings
late in the PRP, although results were strongly influenced by very poor establishment at one site. Invertebrate seed predators
consumed more T. speciosissima seeds in sites early (69.5%) than late in the PRP (51.2%), while consumption of B. serrata seeds was lower overall and comparable across sites (average 47.3%). Surprisingly, litter had very little effect on establishment
and none on invertebrate seed predation, suggesting that other factors are more important. Recruitment was only loosely coupled
to disturbance for the canopy seed bank species; for the transient seed bank species, the coupling was tighter but separated
in time from the disturbance. Understanding both the strength and temporal aspects of the disturbance–recruitment coupling
is necessary for appropriate management of plant functional diversity in fire-prone habitats. 相似文献
148.
Heidi C. Zimmer Tony D. Auld John Benson Patrick J. Baker 《Biodiversity and Conservation》2014,23(1):203-215
Seedling survival plays a critical role in maintaining a supply of potential recruits. We examined seedling recruitment, survival and growth in Wollemia nobilis, a rare, long-lived Australian conifer. Wollemia nobilis seedlings and juveniles were monitored for 16 years (1996–2011). While W. nobilis can recruit from seed and, unlike most conifers, persist through resprouting, seed-based recruitment was the primary focus of this study. Sixty-five per cent of new seedlings died within their first year and only 7 % persisted for the 16-year monitoring period. However, 44 % of established juvenile plants (of unknown age at the beginning of the study) persisted throughout the 16-year monitoring period. Growth of seedlings and juveniles was very slow; growth estimates for most individuals had 95 % confidence intervals that included zero. The recruitment strategy of W. nobilis may be to maintain a slow-growing juvenile bank—a strategy typical of other shade-tolerant rainforest trees, including other Araucariaceae. Seedling recruitment in W. nobilis may act together with resprouting to maintain the population. 相似文献
149.
Ajit G. Thomas Camilo Rojas Cordelle Tanega Min Shen Anton Simeonov Matthew B. Boxer Douglas S. Auld Dana V. Ferraris Takashi Tsukamoto Barbara S. Slusher 《Biochemical and biophysical research communications》2013
Glutaminase catalyzes the hydrolysis of glutamine to glutamate and plays a central role in the proliferation of neoplastic cells via glutaminolysis, as well as in the generation of excitotoxic glutamate in central nervous system disorders such as HIV-associated dementia (HAD) and multiple sclerosis. Both glutaminase siRNA and glutaminase inhibition have been shown to be effective in in vitro models of cancer and HAD, suggesting a potential role for small molecule glutaminase inhibitors. However, there are no potent, selective inhibitors of glutaminase currently available. The two prototypical glutaminase inhibitors, BPTES and DON, are either insoluble or non-specific. In a search for more drug-like glutaminase inhibitors, we conducted a screen of 1280 in vivo active drugs (Library of Pharmacologically Active Compounds (LOPAC1280)) and identified ebselen, chelerythrine and (R)-apomorphine. The newly identified inhibitors exhibited 10 to 1500-fold greater affinities than DON and BPTES and over 100-fold increased efficiency of inhibition. Although non-selective, it is noteworthy that the affinity of ebselen for glutaminase is more potent than any other activity yet described. It is possible that the previously reported biological activity seen with these compounds is due, in part, to glutaminase inhibition. Ebselen, chelerythrine and apomorphine complement the armamentarium of compounds to explore the role of glutaminase in disease. 相似文献
150.
The spectra of neocarzinostatin (NCS) chromophore during its reversible association with poly(dA-dT).poly(dA-dT) [poly(dA-dT)] were recorded (at intervals of 17 ms or more) by a cryospectroscopic method. Examination of the spectral changes of a drug during its interaction with DNA has not been previously reported. Such studies indicate binding of chromophore to poly(dA-dT) is a two-step process in which the spectral properties of the intermediate poly(dA-dT). NCS chromophore species closely resemble those of the final equilibrium species. On the basis of cryokinetic studies (at single wavelengths) carried out at low temperature (2 degrees C), the following proposed mechanism of the DNA-drug (PD) interaction was quantitated: (Formula: see text). In analogy with the other reports on the kinetics of drug-DNA interaction, (PD)I and (PD)II could represent externally bound and intercalated complexes, respectively. However, since the spectra of (PD)I and (PD)II are closely similar, it can also be proposed that (PD)I and (PD)II represent two forms of an intercalated complex. The rate and equilibrium constant for each step were determined by examining the kinetics of the forward and reverse reactions. This was accomplished by determining the polynucleotide concentration dependence of the apparent fast and slow first-order rate constants observed during a double-exponential increase in transmittance (at 330 nm) associated with the binding and the apoprotein-induced dissociation rate constant of the chromophore from poly(dA-dT). The opportunity to use apoprotein, instead of a detergent, to follow the kinetics of the reverse reaction provides a novel approach to these studies.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献