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901.
Weeks CS Tanabe H Cummings JE Crampton SP Sheynis T Jelinek R Vanderlick TK Cocco MJ Ouellette AJ 《The Journal of biological chemistry》2006,281(39):28932-28942
Small intestinal Paneth cells secrete alpha-defensin microbicidal peptides as mediators of innate enteric immunity. In mice, production of mature Paneth cell alpha-defensins, termed cryptdins (Crps), requires proteolytic activation of inactive precursors (pro-Crps) by the convertase matrix metalloproteinase-7. Proteolysis of mouse (pro-Crp4)(20-92) produces the specific cleavage intermediates pro-Crp4(44-92), pro-Crp4(54-92), and pro-Crp4(59-92). To identify which cleavage event enables bactericidal activity, recombinant pro-Crp4-processing intermediates were purified to homogeneity and assayed for bactericidal peptide activity. The in vitro bactericidal activities of pro-Crp4-processing intermediates were very similar to fully processed Crp4, contrasting the lack of bactericidal and membrane-disruptive activity shown by pro-Crp4(20-92). Thus, cleavage of pro-Crp4(20-92) at Ser(43) downward arrowIle(44) is sufficient to activate bactericidal activity, and amino acids in the pro-Crp4(20-43) of the proregion maintain the precursor in an inactive state. Because cationic Arg residues are determinants of Crp4 bactericidal peptide activity, we hypothesized that Asp and Glu residues in pro-Crp4(20-43) neutralize Crp4 Arg side chains in pro-Crp4(20-92). Therefore, a pro-Crp4(20-92) variant with Gly substitutions at all pro-Crp4(20-43) Asp and Glu positions ((DE/G)-pro-Crp4) was prepared, and it was bactericidal and lysed phospholipid vesicles under conditions where native pro-Crp4(20-92) lacks activity. These findings show that MMP-7 proteolysis of pro-Crp4(20-92) at Ser(43) downward arrowIle(44) converts inactive precursors to bactericidal forms by removal of covalently associated, inhibitory acidic amino acids from proximity with the Crp4 component of the molecule. 相似文献
902.
Notch signaling in cancer 总被引:3,自引:0,他引:3
The evolutionarily conserved developmental pathway driven by Notch receptors and ligands has acquired multiple post-natal homeostatic functions in vertebrates. Potential roles in human physiology and pathology are being studied by an increasingly large number of investigators. While the canonical Notch signaling pathway is deceptively simple, the consequences of Notch activation on cell fate are complex and context-dependent. The manner in which other signaling pathways cross-talk with Notch signaling appears to be extraordinarily complex. Recent observations have demonstrated the importance of endocytosis, multiple ubiquitin ligases, non-visual beta-arrestins and hypoxia in modulating Notch signaling. Structural biology is shedding light on the molecular mechanisms whereby Notch interacts with its nuclear partners. Genomics is slowly unraveling the puzzle of Notch target genes in several systems. At the same time, interest in modulating Notch signaling for medical purposes has dramatically increased. Over the last few years we have learned much about Notch signaling in cancer, immune disorders, neurological disorders and most recently, stroke. The role of Notch signaling in normal and transformed stem cells is under intense investigation. Some Notch-modulating drugs are already in clinical trials, and others at various stages of development. This review will focus on the most recent findings on Notch signaling in cancer and discuss their potential clinical implications. 相似文献
903.
Lucio G. Costa Rebecca J. Richter Wan-Fen Li Toby Cole Marina Guizzetti Clement E. Furlong 《Biomarkers》2003,8(1):1-12
Paraoxonase (PON1) is an A-esterase capable of hydrolysing the active metabolites (oxons) of a number of organophosphorus (OP) insecticides such as parathion, diazinon and chlorpyrifos. PON1 activity is highest in liver and plasma, and among animal species significant differences exist, with birds and rabbits displaying very low and high activity, respectively. Human PON1 has two polymorphisms in the coding region (Q192R and L55M) and five polymorphisms in the promoter region. The Q192R polymorphism imparts different catalytic activity toward some OP substrates, while the polymorphism at position -108 (C/T) is the major contributor to differences in the level of PON1 expression. Animal studies have shown that PON1 is an important determinant of OP toxicity, with animal species with a low PON1 activity having an increased sensitivity to OPs. Administration of exogenous PON1 to rats or mice protects them from the toxicity of OPs. PON1 knockout mice display a high sensitivity to the toxicity of diazoxon and chlorpyrifos oxon, but not paraoxon. In vitro assayed catalytic efficiencies of purified PON192 isoforms for hydrolysis of specific oxon substrates accurately predict the degree of in vivo protection afforded by each isoform. Low PON1 activity may also contribute to the higher sensitivity of newborns to OP toxicity. 相似文献
904.
Marcelo N. Gomes Laura M. Alcântara Bruno J. Neves Cleber C. Melo-Filho Lucio H. Freitas-Junior Carolina B. Moraes Rui Ma Scott G. Franzblau Eugene Muratov Carolina Horta Andrade 《Bioorganic & medicinal chemistry letters》2017,27(11):2459-2464
Leishmaniasis are infectious diseases caused by parasites of genus Leishmania that affect affects 12 million people in 98 countries mainly in Africa, Asia, and Latin America. Effective treatments for this disease are urgently needed. In this study, we present a computer-aided approach to investigate a set of 32 recently synthesized chalcone and chalcone-like compounds to act as antileishmanial agents. As a result, nine most promising compounds and three potentially inactive compounds were experimentally evaluated against Leishmania infantum amastigotes and mammalian cells. Four compounds exhibited EC50 in the range of 6.2–10.98 μM. In addition, two compounds, LabMol-65 and LabMol-73, exhibited cytotoxicity in macrophages >50 μM that resulted in better selectivity compared to standard drug amphotericin B. These two compounds also demonstrated low cytotoxicity and high selectivity towards Vero cells. The results of target fishing followed by homology modeling and docking studies suggest that these chalcone compounds could act in Leishmania because of their interaction with cysteine proteases, such as procathepsin L. Finally, we have provided structural recommendations for designing new antileishmanial chalcones. 相似文献
905.
Lucio Andres Lombardo María Mercedes Nisi Nicolás Salines Celina Elena Ghione Marcelo Helguera 《Cytology and Genetics》2017,51(4):305-314
Bread wheat (Triticum aestivum L.) is a staple food crop eaten in different ways like pan and other food products. High molecular weight glutenin subunits (HMW-GS) are major determinants of the different wheat end-use qualities. Ethyl-methanesulfonate (EMS) mutagenized populations in plants can be used for the discovery of valuable mutants for basic research and breeding purposes. In this study, we report the identification of 27 HMW-GS M3 mutants based on SDS-PAGE patterns from an EMS mutagenized population of the cultivar Baguette Premium 11. Nine mutations were detected in Ax2*, five in Bx7, four in By8, six in Dx5 and three in Dy10 subunit. Two Ax2* null mutants were characterized at molecular level finding in both cases premature stop codons associated. EMS would tend to generate more premature stop codons in glutenins genes than in others because these have a high frequency of glutamine codons. This type of mutation generates null alleles, therefore they are easily detectable by a low cost protocol like SDS-PAGE. The potential use of knock-out (null alleles) and SDS-PAGE size altered mutants for HMW-GS in wheat quality and nutrition is discussed. 相似文献
906.
Alessandro Stella Nicoletta Resta Angela Polizzi Mariapina Montera Filomena Cariola Francesco Susca Viviana Gismondi Lucio Bertario Cristiana Marchese Romano Tenconi Maria Grazia Tibiletti Paola Izzo Mattia Gentile Fernando Prete Oronzo Pannarale Giovanni Di Matteo Paola Sala Liliana Varesco Cristina Mareni G. Guanti 《Human genetics》1998,102(6):624-628
In the present study, we used five different polymorphic markers to construct the haplotype at the adenomatous polyposis
coli (APC) locus in families with familial adenomatous polyposis (FAP) and in the normal Italian population. Non-ambiguous
haplotypes were reconstructed from 246 normal chromosomes and 65 FAP chromosomes. In the control population, the four polymorphisms
intragenic to APC gave rise to 16 haplotypes, the most common of which (II and XV) accounted for over 50% of all chromosomes.
In FAP patients, 13 haplotypes were found but their distribution was not statistically different from normal subjects. Eighty
complete chromosomal haplotypes (many fewer than the theoretical maximum of 208) for the five polymorphic sites assayed were
observed in the control population, 35 being found in the FAP patients. We compared the distribution of these haplotypes within
the two groups; no statistically significant differences between normal and FAP chromosomes were found. The elevated heterogeneity
of FAP chromosomes was clearly confirmed by the observation that 19 patients who carried one or other of the two most common
APC mutations (nt 3183 and nt 3927) showed 18 different haplotypes. On the basis of these results, we were not able to identify
a founder FAP chromosome. Various mechanisms are presented to explain this observation.
Received: 5 November 1997 / Accepted: 3 February 1998 相似文献
907.
Lucio Aliperti Ariel A. Aptekmann Gonzalo Farfañuk Luciana L. Couso Alfonso Soler-Bistué Ignacio E. Sánchez 《Environmental microbiology》2023,25(12):3255-3268
The guanine/cytosine (GC) content of prokaryotic genomes is species-specific, taking values from 16% to 77%. This diversity of selection for GC content remains contentious. We analyse the correlations between GC content and a range of phenotypic and genotypic data in thousands of prokaryotes. GC content integrates well with these traits into r/K selection theory when phenotypic plasticity is considered. High GC-content prokaryotes are r-strategists with cheaper descendants thanks to a lower average amino acid metabolic cost, colonize unstable environments thanks to flagella and a bacillus form and are generalists in terms of resource opportunism and their defence mechanisms. Low GC content prokaryotes are K-strategists specialized for stable environments that maintain homeostasis via a high-cost outer cell membrane and endospore formation as a response to nutrient deprivation, and attain a higher nutrient-to-biomass yield. The lower proteome cost of high GC content prokaryotes is driven by the association between GC-rich codons and cheaper amino acids in the genetic code, while the correlation between GC content and genome size may be partly due to functional diversity driven by r/K selection. In all, molecular diversity in the GC content of prokaryotes may be a consequence of ecological r/K selection. 相似文献
908.
909.
Mariarosaria Boccellino Raffaele La Porta Mario Coppola Pasquale Petronella Fulvio Freda Vincenzo Calderaro Lucio Quagliuolo 《Apoptosis : an international journal on programmed cell death》2013,18(1):43-56
A larger diffusion of peritoneal dialysis (PD) is limited by the progressive deterioration of the dialysis membrane structure and function, characterized in vitro and in vivo by mesothelial cell loss and closely related to the use of bioincompatible dialysis solutions. The apoptosis rate of rat and human mesothelial cells incubated in commercial PD fluid (PDF, 4.25 g/dL dextrose) became significant as early as 1 h after PDF addition and reached a plateau at 4–5 h. This pattern was unchanged after exposure to 1.5 g/dL dextrose PDF or freshly prepared PDF, indicating that effects were independent on the dextrose strength and manufacturing procedures but strictly dependent on PDF composition. Molecular studies revealed that PDF exposure inactivated the physiological volume recovery from hypertonic shrinkage, accompanied by an abnormal Ca2+ signaling: a progressive intracellular Ca2+ ([Ca2+]i) rise resulting from an increased Ca2+ entry. PDF also affected cytoskeleton integrity: early dissolution of actin filaments occurred well before the appearance of typical apoptosis features. Lastly, the PDF dependent apoptosis was almost completely prevented by the contemporary Ca2+ concentration decrease and K+ addition. This study suggests that the PDF dependent apoptosis arises from the extreme volume perturbations in mesothelial cells, turned out unable to regulate their volume back once exposed to a hyperosmolal medium containing high Ca2+ levels in the absence of K+, such PDF. 相似文献
910.
(+)-Epoxydon, together with the new (+)-epoxydon monoacetate, 3-methylidene-6-methoxy-1,4-benzodioxan-2-one and 2-(2-hydroxy-5-methoxyphenoxy)-acrylic acid, has been isolated and identified from the mycelium of Mycosphaerella ligulicola grown on Sabouraud-maltose 4 %-agar. 相似文献