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1.
The alpha-like globin gene cluster in rabbits contains embryonic zeta-
globin genes, an adult alpha-globin gene, and theta-globin genes of
undetermined function. The basic arrangement of genes, deduced from
analysis of cloned DNA fragments, is 5'-zeta 0-zeta 1-alpha 1-theta 1- zeta
2-zeta 3-theta 2-3'. However, the pattern of restriction fragments
containing zeta- and theta-globin genes varies among individual rabbits.
Analysis of BamHI fragments of genomic DNA from 24 New Zealand white
rabbits revealed eight different patterns of fragments containing
zeta-globin genes. The large BamHI fragments containing genes zeta 0 and
zeta 1 are polymorphic in length, whereas a 1.9-kb fragment containing the
zeta 2 gene and the 3.5-kb fragment containing the zeta 3 gene do not vary
in size. In contrast to this constancy in the size of the restriction
fragments, the copy number of the zeta 2 and zeta 3 genes does vary among
different rabbits. No length polymorphism was detected in the BamHI
fragments containing the theta-globin genes, but again the copy number
varies for restriction fragments containing the theta 2 gene. The alpha 1-
and theta 1-globin genes are located in a nonpolymorphic 7.2-kb BamHI
fragment. The combined data from hybridization with both zeta and theta
probes shows that the BamHI cleavage pattern does not vary within the
region 5'-alpha 1-theta 1- zeta 2-zeta 3-theta 2-3', but the pattern
genomic blot-hybridization patterns for the progeny of parental rabbits
with different zeta-globin gene patterns shows that the polymorphic
patterns are inherited in a Mendelian fashion. Two different haplotypes
have been mapped based on the genomic blot-hybridization data. The
variation in the alpha-like globin gene cluster in the rabbit population
results both from differences in the copy number of the duplication block
containing the zeta-zeta-theta gene set and from the presence or absence of
polymorphic BamHI sites.
相似文献
2.
Assignment of orthologous relationships among mammalian alpha-globin genes by examining flanking regions reveals a rapid rate of evolution 总被引:1,自引:0,他引:1
In order to study the relationships among mammalian alpha-globin genes, we
have determined the sequence of the 3' flanking region of the human alpha 1
globin gene and have made pairwise comparisons between sequenced
alpha-globin genes. The flanking regions were examined in detail because
sequence matches in these regions could be interpreted with the least
complication from the gene duplications and conversions that have occurred
frequently in mammalian alpha-like globin gene clusters. We found good
matches between the flanking regions of human alpha 1 and rabbit alpha 1,
human psi alpha 1 and goat I alpha, human alpha 2 and goat II alpha, and
horse alpha 1 and goat II alpha. These matches were used to align the
alpha-globin genes in gene clusters from different mammals. This alignment
shows that genes at equivalent positions in the gene clusters of different
mammals can be functional or nonfunctional, depending on whether they
corrected against a functional alpha-globin gene in recent evolutionary
history. The number of alpha-globin genes (including pseudogenes) appears
to differ among species, although highly divergent pseudogenes may not have
been detected in all species examined. Although matching sequences could be
found in interspecies comparisons of the flanking regions of alpha- globin
genes, these matches are not as extensive as those found in the flanking
regions of mammalian beta-like globin genes. This observation suggests that
the noncoding sequences in the mammalian alpha-globin gene clusters are
evolving at a faster rate than those in the beta-like globin gene clusters.
The proposed faster rate of evolution fits with the poor conservation of
the genetic linkage map around alpha-globin gene clusters when compared to
that of the beta-like globin gene clusters. Analysis of the 3' flanking
regions of alpha-globin genes has revealed a conserved sequence
approximately 100-150 bp 3' to the polyadenylation site; this sequence may
be involved in the expression or regulation of alpha-globin genes.
相似文献
3.
Crystallographic determination of the structures of human alpha-thrombin complexed with BMS-186282 and BMS-189090. 总被引:1,自引:1,他引:0 下载免费PDF全文
M. F. Malley L. Tabernero C. Y. Chang S. L. Ohringer D. G. Roberts J. Das J. S. Sack 《Protein science : a publication of the Protein Society》1996,5(2):221-228
The crystallographic structures of the ternary complexes of human alpha-thrombin with hirugen (a sulfated hirudin fragment) and the small-molecule active site thrombin inhibitors BMS-186282 and BMS-189090 have been determined at 2.6 and 2.8 A. In both cases, the inhibitors, which adopt very similar bound conformations, bind in an antiparallel beta-strand arrangement relative to the thrombin main chain in a manner like that reported for PPACK, D-Phe-Pro-Arg-CH2Cl. They do, however, exhibit differences in the binding of the alkyl guanidine moiety in the specificity pocket. Numerous hydrophilic and hydrophobic interactions serve to stabilize the inhibitors in the binding pocket. Although PPACK forms covalent bonds to both serine and the histidine of the catalytic triad of thrombin, neither BMS-186282 nor BMS-189090 bind covalently and only BMS-186282 forms a hydrogen bond to the serine of the catalytic triad. Both inhibitors bind with high affinity (Ki = 79 nM and 3.6 nM, respectively) and are highly selective for thrombin over trypsin and other serine proteases. 相似文献
4.
Joseph P. Stein James F. Catterall Paula Kristo Anthony R. Means Bert W. OMalley 《Cell》1980,21(3):681-687
Two thirds of the natural chicken ovomucoid gene has been sequenced, including all exons and the intron sequences surrounding all fourteen intron/ exon junctions. The junction sequences surrounding four of the introns are redundant; however, the sequences surrounding the other three introns contain no redundancies and thus the splicing sites at either end of these three introns are unambiguous. The splicing in all cases conforms to the GT-AG rule. The ovomucoid gene sequence around intron F can be used to predict the cause of an internal deletion polymorphism in the ovomucoid protein, which is an apparent error in the processing of the ovomucoid pre-mRNA. We also compare the structural organization of the ovomucoid gene with the ovomucoid protein sequence to examine theories of the evolution of ovomucoids as well as the origin of intervening sequences. This analysis suggests that the present ovomucoid gene evolved from a primordial ovomucoid gene by two separate intragenic duplications. Furthermore, sequence analyses suggest that introns were present in the primordial ovomucoid gene before birds and mammals diverged, about 300 million years ago. Finally, the positions of the introns within the ovomucoid gene support the theory that introns separate gene segments that code for functional domains of proteins and provide insight on the manner by which eucaryotic genes were constructed during the process of evolution. 相似文献
5.
D. F. Malley K. H. Mills 《Journal of Aquatic Ecosystem Stress and Recovery (Formerly Journal of Aquatic Ecosystem Health)》1992,1(3):159-174
The rationale and methods for and value of whole-lake experimentation are described using the Experimental Lakes Area (ELA), northwestern Ontario, as the example. The ELA consists of 46 lakes (< 100 ha in surface area), their watersheds, and several streams protected for research purposes in near-pristine boreal forest on the Precambrian Shield near Kenora, Ontario. Over more than 20 y, whole-lake experimentation has provided unique information on the effects on lakes of nutrient additions, acidification, Cd addition, and biomanipulation. Experiments are planned to study the effects of PCB addition and flooding. Recovery, mitigation, and remediation have been explored in some experiments. As well, the fate of radioactive metals in a lake and the effects of acidification on a poor fen and an upland watershed are studied. Comparison between the experimental systems and unmanipulated reference systems has proven to be essential. These reference systems also have a role in defining (absolute) aquatic ecosystem health for small, pristine Precambrian Shield lakes. The ELA experimental data base is available, as well, for calibrating indices of relative aquatic ecosystem health, i.e., environmental degradation, using the dose-responses of lakes to eutrophication, acidification, Cd addition, and other stressors. 相似文献
6.
The catalytic activity of the two stable aggregation states of arginine decarboxylase, a dimer and a decamer, has been examined under a variety of conditions. The specific activity of the dimer was determined at pH 5.2, the optimum pH, over a very broad range of protein concentrations. It was found to be independent of concentration only above 5 μg/ml, and decreased to 0 at 0.02 μg/ml, suggesting that a concentration-dependent reassociation was occurring in the assay. At 0.58 μg/ml, the restoration of activity was time dependent. We conclude that, at pH 5.2, the decamer is active and the dimer is essentially inactive. The activities of the dimer and the decamer were also compared at neutral pH, by using increasing concentrations of either Na+, arginine, or protein to induce reassociation. All of these experiments are consistent with the idea that both species are equally active at this pH. Furthermore, the dependence of activity on arginine concentration is not hyperbolic at pH 7.2. The arginine decarboxylase dimer was modified by allowing one sulfhydryl group per monomer to react with 5,5′-dithiobis(2-nitrobenzoic acid). The modified dimer reassociates less readily than the native form, requiring higher concentrations of any of the three associating agents tried. The modified decamer, at both pH 5.2 and 7.4, and the modified dimer, at pH 7.4, retain approximately 60% of the activity of the untreated enzyme. 相似文献
7.
Janis E. Lochner Geoffrey V. F. Seaman Philip Blume Arthur Malley 《Cell biochemistry and biophysics》1982,4(1):15-24
Concanavalin A, at extremely low concentrations, will produce significant increases in the electrophoretic mobility of murine
splenic T lymphocytes. It has been established that the alteration in cellular surface charge is mediated by a factor produced
by those lymphocytes that have reacted directly with con A. We originally conjectured that the mobility change might be the
consequence of an alteration in the distribution of the charged moieties of membrane glycoproteins. The results of experiments
conducted at low temperature raise some questions about this mechanism. Further experiments have been performed to establish
the nature of the physicochemical alterations in the peripheral zone of the factor-stimulated lymphocytes that are manifest
as changes in cellular surface charge. The results of these studies indicate that, subsequent to the interaction of T lymphocytes
with con A, there is a reduction in the number of positively charged amino groups effective at the electrophoretic surface
of the cells. 相似文献
8.
9.
10.
Chunjian Liu James Lin Gerry Everlof Christoph Gesenberg Hongjian Zhang Punit H. Marathe Mary Malley Michael A. Galella Murray Mckinnon John H. Dodd Joel C. Barrish Gary L. Schieven Katerina Leftheris 《Bioorganic & medicinal chemistry letters》2013,23(10):3028-3033
A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38α inhibitor, were synthesized and evaluated. Though the phosphoryloxymethylene carbamates (3, 4, and 5) and α-aminoacyloxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral conditions. Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values. At a solution dose of 14.2 mpk (equivalent to 10 mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10 mpk of 1 itself. At a suspension dose of 142 mpk (equivalent to 100 mpk of 1), 2 demonstrated that it could overcome the solubility issue associated with 1 and provide a much higher exposure of 1. To our knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could represent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug candidates. 相似文献