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Lalith K. Kummari Mark S. Butler Emily Furlong Ross Blundell Amanda Nouwens Alberto B. Silva Ulrike Kappler James A. Fraser Bostjan Kobe Matthew A. Cooper Avril A.B. Robertson 《Bioorganic & medicinal chemistry》2018,26(20):5408-5419
Fungi cause serious life-threatening infections in immunocompromised individuals and current treatments are now complicated by toxicity issues and the emergence of drug resistant strains. Consequently, there is a need for development of new antifungal drugs. Inosine monophosphate dehydrogenase (IMPDH), a key component of the de novo purine biosynthetic pathway, is essential for growth and virulence of fungi and is a potential drug target. In this study, a high-throughput screen of 114,000 drug-like compounds against Cryptococcus neoformans IMPDH was performed. We identified three 3-((5-substituted)-1,3,4-oxadiazol-2-yl)thio benzo[b]thiophene 1,1-dioxides that inhibited Cryptococcus IMPDH and also possessed whole cell antifungal activity. Analogs were synthesized to explore the SAR of these hits. Modification of the fifth substituent on the 1,3,4-oxadiazole ring yielded compounds with nanomolar in vitro activity, but with associated cytotoxicity. In contrast, two analogs generated by substituting the 1,3,4-oxadiazole ring with imidazole and 1,2,4-triazole gave reduced IMPDH inhibition in vitro, but were not cytotoxic. During enzyme kinetic studies in the presence of DTT, nucleophilic attack of a free thiol occurred with the benzo[b]thiophene 1,1-dioxide. Two representative compounds with substitution at the 5 position of the 1,3,4-oxadiazole ring, showed mixed inhibition in the absence of DTT. Incubation of these compounds with Cryptococcus IMPDH followed by mass spectrometry analysis showed non-specific and covalent binding with IMPDH at multiple cysteine residues. These results support recent reports that the benzo[b]thiophene 1,1-dioxides moiety as PAINS (pan-assay interference compounds) contributor. 相似文献
134.
John A. M. Gall Daine Alcorn Aldona Butkus John P. Coghlan Professor Graeme B. Ryan 《Cell and tissue research》1986,244(1):203-208
Summary Peripolar cells are granulated glomerular epithelial cells that form a cuff around the vascular pole of the glomerulus. Quantitation of these cells in 17 species of mammals (including man, several laboratory animals and a variety of other species) indicated that they were detectable by light microscopy in all but one of the mammals that were examined (the Australian hopping mouse). In adult mammals with detectable peripolar cells, the peripolar cell index (the percentage of randomly sectioned glomeruli that displayed peripolar cells in histological sections of kidney) ranged from 0.15 (for echidna) to 11.86 (for sheep). Newborn lambs and rats showed strikingly high values (23.30 and 10.76, respectively) compared with their adult counterparts. Using electron microscopy, peripolar cells were observed in all species that were examined, including the Australian hopping mouse. Morphologically, peripolar cells were similar in all species although their size and granule population varied. They showed a predominantly outer cortical glomerular distribution and a close anatomical relationship with the renin-containing myoepithelioid cells. These findings indicate that peripolar cells are present in a wide variety of species and support the view that such cells may play a significant role in the regulation of normal renal function. 相似文献
135.
Tissue and species distribution of the secreted carbonic anhydrase isoenzyme. 总被引:2,自引:0,他引:2
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The secreted carbonic anhydrases, CA VI, are high molecular mass, oligomeric enzymes originally found in the sheep parotid gland and saliva. The enzymes have been purified from the saliva or parotid glands of several different species. All the CA VI enzymes studied have an apparent subunit Mr of about 45,000 as previously reported for the sheep enzyme. By Western analysis, CA VI from human, cow and dog cross-reacted with antibody raised against the purified sheep enzyme whereas that of the mouse did not. The N-terminal sequences of the sheep, human, cow and mouse enzymes are reported. The sheep, cow and human N-terminal sequences are similar to one another while the mouse sequence is substantially different. Nevertheless, the amino acids in the aromatic cluster I (Trp-5, Tyr-7, Trp-16 and Tyr/Phe-20) have all been conserved, as is the case with the cytoplasmic carbonic anhydrases. Eighteen tissues from the sheep have been examined for the presence of CA VI by Western analysis but it has been found only in the salivary glands. Northern analysis and hybridization histochemistry show that the mRNA for CA VI in sheep is expressed specifically in the acinar cells of the parotid and submandibular glands. 相似文献
136.
The gene for human carbonic anhydrase VI(CA6) is on the tip of the short arm of chromosome 1 总被引:2,自引:0,他引:2
G R Sutherland E Baker K E Fernandez D F Callen P Aldred J P Coghlan R D Wright R T Fernley 《Cytogenetics and cell genetics》1989,50(2-3):149-150
The gene encoding the human secreted carbonic anhydrase isozyme CAVI(CA6) maps to chromosome 1 by Southern analysis of a somatic cell hybrid panel and to 1p36.22----p36.33 by in situ hybridization. CA6 is therefore not linked to the cytoplasmic carbonic anhydrase genes on chromosome 8 or to CA7 on chromosome 16. 相似文献
137.
Bersi Matthew R. Bellini Chiara Humphrey Jay D. Avril Stéphane 《Biomechanics and modeling in mechanobiology》2019,18(1):203-218
Biomechanics and Modeling in Mechanobiology - We recently developed an approach to characterize local nonlinear, anisotropic mechanical properties of murine arteries by combining biaxial... 相似文献
138.
Ambrose O Talisuna Penny Grevval Andrew Balyeku Timothy Egan Godfrey Bwire Bram Piot Renia Coghlan Maud Lugand John Bosco Rwakimari Richard Ndyomugyenyi Fred Kato Maria Byangire Paul Kagwa Fred Sebisubi David Nahamya Angela Bonabana Susan Mpanga-Mukasa Peter Buyungo Julius Lukwago Allan Batte Grace Nakanwagi James Tibenderana Kinny Nayer Kishore Reddy Nilesh Dokvval Sylvester Rugumambaju Saul Kidde Jaya Banerji George Jagoe 《Malaria journal》2012,11(Z1):O16
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The vertical distribution of the cyanobacterium Planktothrir(Oscillazoria) rubescens in Lake Zrich was investigated fromMarch 1993 to June 1995 by collecting filaments on filters andmeasuring them by epifluorescence microscopy and computer imageanalysis. The initial population, which began to stratify inApril, decreased by up to 99% by June. During the summer, thepopulation peaked at depths of 815 m; it reached a maximumareal filament-volume concentration of -60 cm 3 of lakesurface in early September and was then entrained in the deepeningsurface layer. It became mixed progressively deeper, to thelake bottom in the cold winter of 199394, but less completelyin the milder winter of 199495. Most of the filamentsremained viable during the winter. At the end of the mild winterof 19945, 70% of filaments in the water column retainedbuoyancy, but after the cold winter of 19967 only 22%were buoyant. Few remained buoyant below 80 m, where the hydrostaticpressure caused gas vesicle collapse. The proportion that remainbuoyant decreases with the depth and duration of winter mixing,and increases with the critical collapse pressure (Pc) of thegas vesicles, which provide buoyancy. Strains of P.rubescensisolated from Lake Zrich differed in mean (Pc) of their gasvesicles, from 0.9 to 1.1 MPa, the highest values in freshwatercyanobacteria. Allowing for a turgor pressure of 0.2 MPa. thesestrains would remain buoyant at depths down to 70 and 90 m,respectively. Natural selection for gas vesicles of high (Pc)will operate by increasing the proportion of filaments thatremain buoyant in the upper parts of the water column aftercirculation to various depths during the winter because onlybuoyant filaments will form the inoculum for the following season. 相似文献