全文获取类型
收费全文 | 104篇 |
免费 | 20篇 |
出版年
2021年 | 2篇 |
2018年 | 1篇 |
2017年 | 1篇 |
2016年 | 2篇 |
2015年 | 7篇 |
2014年 | 4篇 |
2013年 | 8篇 |
2012年 | 7篇 |
2011年 | 4篇 |
2010年 | 6篇 |
2009年 | 4篇 |
2008年 | 5篇 |
2007年 | 5篇 |
2006年 | 2篇 |
2005年 | 5篇 |
2004年 | 5篇 |
2003年 | 6篇 |
2002年 | 3篇 |
2001年 | 1篇 |
2000年 | 3篇 |
1999年 | 5篇 |
1998年 | 1篇 |
1996年 | 1篇 |
1994年 | 3篇 |
1993年 | 1篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1989年 | 2篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1985年 | 1篇 |
1984年 | 2篇 |
1982年 | 2篇 |
1981年 | 2篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 3篇 |
1976年 | 1篇 |
1975年 | 4篇 |
1973年 | 1篇 |
1971年 | 5篇 |
排序方式: 共有124条查询结果,搜索用时 186 毫秒
1.
Polymer-level synthesis of oxopyrimidine deoxynucleotides by Bacillus subtilis phage SP10: characterization of modification-defective mutants. 下载免费PDF全文
Bacillus subtilis phage SP10 DNA has two oxopyrimidines, thymidine 5'-monophosphate (dTMP) and its hypermodified analog (YdTMP). Published data suggest that both are synthesized by postreplicational modification of 5-hydroxymethyldeoxyuridylate (HOMedUMP) in nascent DNA by the following pathway: HOMedUMP----PPOMedUMP----dTMP (85%) or YdTMP (15%); PPOMedUMP is 5-(hydroxymethyl-O-pyrophosphoryl)deoxyuridylate, the pyrophosphoric acid ester of the C5CH2OH function of HOMedUMP. This paper describes aberrant DNAs synthesized at nonpermissive temperatures by a complementary series of heat-sensitive, modification-defective (mod) mutants. Collectively, these mutants encompass the major steps in the complete modification of nascent SP10 DNA. DNA produced by modA phage retains HOMedUMP as its sole oxopyrimidine, implying that (i) this mutant is defective in the pyrophosphorylation step and (ii) formation of PPOMedUMP is required for any further modification. Furthermore, studies with double mutants indicated that modA is epistatic for all other mod mutants, which supports the hypothesis that modA controls the earliest step in the modification pathway. Since their DNAs contain no YdTMP, modC and modD are defective in hypermodification (i.e., PPOMedUMP----YdTMP). However, dTMP occupies the entire oxopyrimidine fraction of modC DNA, whereas modD DNA has a normal dTMP content, but the now-missing YdTMP is replaced by either PPOMedUMP or a byproduct of abortive hypermodification. It is proposed that the modD mutants are defective in the catalytic aspects of hypermodification and that modC are defective in some regulatory function that promotes hypermodification at the expense of reductive modification (i.e., PPOMedUMP----dTMP). Reductive modification is defective in modB phage, as evidenced by the absence of dTMP. In contrast to the others, modB DNA has a complex oxopyrimidine content: HOMedUMP, ca. 30%; PPOMedUMP, ca. 40%; and YdTMP, ca. 30%. The expanded level of YdTMP suggests that at certain sites, reductive modification and hypermodification are competing reactions. Interestingly, the PPOMedUMP content of modB DNA seemingly reflects the maximum degree to which phage DNA can be pyrophosphorylated, since the loss of YdTMP from modBmodC and modBmodD DNAs results in a unilateral increase in HOMedUMP content. 相似文献
2.
mtDNA diversity in rhesus monkeys reveals overestimates of divergence time and paraphyly with neighboring species 总被引:4,自引:0,他引:4
Reconstructions of the human-African great ape phylogeny by using
mitochondrial DNA (mtDNA) have been subject to considerable debate. One
confounding factor may be the lack of data on intraspecific variation. To
test this hypothesis, we examined the effect of intraspecific mtDNA
diversity on the phylogenetic reconstruction of another Plio- Pleistocene
radiation of higher primates, the fascicularis group of macaque (Macaca)
monkey species. Fifteen endonucleases were used to identify 10 haplotypes
of 40-47 restriction sites in M. mulatta, which were compared with similar
data for the other members of this species group. Interpopulational,
intraspecific mtDNA diversity was large (0.5%- 4.5%), and estimates of
divergence time and branching order incorporating this variation were
substantially different from those based on single representatives of each
species. We conclude that intraspecific mtDNA diversity is substantial in
at least some primate species. Consequently, without prior information on
the extent of genetic diversity within a particular species, intraspecific
variation must be assessed and accounted for when reconstructing primate
phylogenies. Further, we question the reliability of hominoid mtDNA
phylogenies, based as they are on one or a few representatives of each
species, in an already depauperate superfamily of primates.
相似文献
3.
Anton Orlin Dolan Sondhi Matthew T. Witmer Matthew M. Wessel Jason G. Mezey Stephen M. Kaminsky Neil R. Hackett Kaleb Yohay Barry Kosofsky Mark M. Souweidane Michael G. Kaplitt Donald J. D’Amico Ronald G. Crystal Szilárd Kiss 《PloS one》2013,8(8)
Background
Late infantile neuronal ceroid lipofuscinosis (LINCL), one form of Batten’s disease is a progressive neurodegenerative disorder resulting from a CLN2 gene mutation. The spectrum of ophthalmic manifestations of LINCL and the relationship with neurological function has not been previously described.Methods
Patients underwent ophthalmic evaluations, including anterior segment and dilated exams, optical coherence tomography, fluorescein and indocyanine green angiography. Patients were also assessed with the LINCL Neurological Severity Scale. Ophthalmic findings were categorized into one of five severity scores, and the association of the extent of ocular disease with neurological function was assessed.Results
Fifty eyes of 25 patients were included. The mean age at the time of exam was 4.9 years (range 2.5 to 8.1). The mean ophthalmic severity score was 2.6 (range 1 to 5). The mean neurological severity score was 6.1 (range 2 to 11). Significantly more severe ophthalmic manifestations were observed among older patients (p<0.005) and patients with more severe neurological findings (p<0.03). A direct correlation was found between the Ophthalmic Severity Scale and the Weill Cornell Neurological Scale (p<0.002). A direct association was also found between age and the ophthalmic manifestations (p<0.0002), with older children having more severe ophthalmic manifestations.Conclusions
Ophthalmic manifestations of LINCL correlate closely with the degree of neurological function and the age of the patient. The newly established LINCL Ophthalmic Scale may serve as an objective marker of LINCL severity and disease progression, and may be valuable in the evaluation of novel therapeutic strategies for LINCL, including gene therapy. 相似文献4.
Watterson SH Carlsen M Dhar TG Shen Z Pitts WJ Guo J Gu HH Norris D Chorba J Chen P Cheney D Witmer M Fleener CA Rouleau K Townsend R Hollenbaugh DL Iwanowicz EJ 《Bioorganic & medicinal chemistry letters》2003,13(3):543-546
A series of novel quinolone-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are described. 相似文献
5.
MicroRNA (miRNA) transcriptome of mouse retina and identification of a sensory organ-specific miRNA cluster 总被引:6,自引:0,他引:6
6.
Egbertson MS Moritz HM Melamed JY Han W Perlow DS Kuo MS Embrey M Vacca JP Zrada MM Cortes AR Wallace A Leonard Y Hazuda DJ Miller MD Felock PJ Stillmock KA Witmer MV Schleif W Gabryelski LJ Moyer G Ellis JD Jin L Xu W Braun MP Kassahun K Tsou NN Young SD 《Bioorganic & medicinal chemistry letters》2007,17(5):1392-1398
A 1,6-naphthyridine inhibitor of HIV-1 integrase has been discovered with excellent inhibitory activity in cells, good pharmacokinetics, and an excellent ability to inhibit virus with mutant enzyme. 相似文献
7.
8.
Zheng X Hudyma TW Martin SW Bergstrom C Ding M He F Romine J Poss MA Kadow JF Chang CH Wan J Witmer MR Morin P Camac DM Sheriff S Beno BR Rigat KL Wang YK Fridell R Lemm J Qiu D Liu M Voss S Pelosi L Roberts SB Gao M Knipe J Gentles RG 《Bioorganic & medicinal chemistry letters》2011,21(10):2925-2929
Herein, we present initial SAR studies on a series of bridged 2-arylindole-based NS5B inhibitors. The introduction of bridging elements between the indole N1 and the ortho-position of the 2-aryl moiety resulted in conformationally constrained heterocycles that possess multiple additional vectors for further exploration. The binding mode and pharmacokinetic (PK) properties of select examples, including: 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-d][1,4]benzodiazepine-10-carboxylic acid (7) (IC50 = 0.07 μM, %F = 18), are reported. 相似文献
9.
Embrey MW Wai JS Funk TW Homnick CF Perlow DS Young SD Vacca JP Hazuda DJ Felock PJ Stillmock KA Witmer MV Moyer G Schleif WA Gabryelski LJ Jin L Chen IW Ellis JD Wong BK Lin JH Leonard YM Tsou NN Zhuang L 《Bioorganic & medicinal chemistry letters》2005,15(20):4550-4554
Introduction of a 5,6-dihydrouracil functionality in the 5-position of N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide 1 led to a series of highly active HIV-1 integrase inhibitors. These compounds displayed low nanomolar activity in inhibiting both the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 11 is a 150-fold more potent antiviral agent than 1, with a CIC(95) of 40 nM in the presence of human serum. It displays good pharmacokinetics when dosed in rats and dogs. 相似文献
10.
Kornacker MG Lai Z Witmer M Ma J Hendrick J Lee VG Riexinger DJ Mapelli C Metzler W Copeland RA 《Biochemistry》2005,44(34):11567-11573
Beta-APP cleaving enzyme (BACE) is responsible for the first of two proteolytic cleavages of the APP protein that together lead to the generation of the Alzheimer's disease-associated Abeta peptide. It is widely believed that halting the production of Abeta peptide, by inhibition of BACE, is an attractive therapeutic modality for the treatment of Alzheimer's disease. BACE is an aspartyl protease, and there is significant effort in the pharmaceutical community to apply traditional design methods to the development of active site-directed inhibitors of this enzyme. We report here the discovery of a ligand binding pocket within the catalytic domain of BACE that is distinct from the enzymatic active site (i.e., an exosite). Peptides, initially identified from combinatorial phage peptide libraries, contain the sequence YPYF(I/L)P(L/I) and bind specifically to this exosite, even in the presence of saturating concentrations of active site-directed inhibitors. Binding of peptides to the BACE exosite leads to a concentration-dependent inhibition of proteolysis for APP-related, protein-based substrates of BACE. The discovery of this exosite opens new opportunities for the identification and development of novel and potentially selective small molecule inhibitors of BACE that act through exosite, rather than active site, binding interactions. 相似文献