全文获取类型
收费全文 | 254篇 |
免费 | 18篇 |
出版年
2022年 | 1篇 |
2021年 | 1篇 |
2019年 | 1篇 |
2018年 | 2篇 |
2017年 | 4篇 |
2016年 | 4篇 |
2015年 | 14篇 |
2014年 | 10篇 |
2013年 | 6篇 |
2012年 | 14篇 |
2011年 | 9篇 |
2010年 | 11篇 |
2009年 | 7篇 |
2008年 | 6篇 |
2007年 | 10篇 |
2006年 | 13篇 |
2005年 | 10篇 |
2004年 | 8篇 |
2003年 | 12篇 |
2002年 | 11篇 |
2001年 | 9篇 |
2000年 | 9篇 |
1999年 | 9篇 |
1998年 | 10篇 |
1997年 | 8篇 |
1996年 | 8篇 |
1995年 | 6篇 |
1994年 | 1篇 |
1993年 | 3篇 |
1992年 | 2篇 |
1990年 | 5篇 |
1989年 | 2篇 |
1988年 | 3篇 |
1987年 | 1篇 |
1985年 | 7篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1982年 | 4篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 7篇 |
1976年 | 6篇 |
1975年 | 3篇 |
1974年 | 2篇 |
1973年 | 1篇 |
1972年 | 2篇 |
1971年 | 1篇 |
排序方式: 共有272条查询结果,搜索用时 328 毫秒
241.
PCR-based assays of mendelian polymorphisms from anonymous single-copy nuclear DNA: techniques and applications for population genetics 总被引:5,自引:0,他引:5
This paper outlines a PCR-based approach for population genetics that
offers several advantages over conventional Southern blotting methods for
revealing restriction-fragment-length polymorphisms (RFLPs) in nuclear DNA.
Primers are constructed from clones isolated from a nuclear DNA library,
and these primers subsequently are employed in in vitro syntheses of
homologous regions. Amplified products are then screened directly for RFLPs
by using gel-staining procedures. Population applications for this
PCR-based approach, including potential strengths and weaknesses, are
exemplified by two RFLP data sets generated to estimate (a) male-mediated
gene flow in the green turtle (Chelonia mydas) and (b) geographic
population genetic structure in the American oyster (Crassostrea
virginica). Restriction assays of amplified products from 14 or 15
independent primer pairs in each species revealed polymorphisms at several
loci that proved highly informative in the population genetic analyses. In
general, the Mendelian polymorphisms produced by this PCR-based approach
will provide useful genetic markers for population studies, particularly in
situations where simpler and less expensive allozyme methods have failed,
for whatever reason, to provide adequate information.
相似文献
242.
243.
DNA fingerprints from hypervariable mitochondrial genotypes 总被引:4,自引:0,他引:4
Conventional surveys of restriction-fragment polymorphisms in mitochondrial
DNA of menhaden fish (Brevoortia tyrannus/patronus complex) and chuckwalla
lizards (Sauromalus obesus) revealed exceptionally high levels of genetic
variation, attributable to differences in mtDNA size as well as in
restriction sites. The observed probabilities that any two randomly drawn
individuals differed detectably in mtDNA genotype were 0.998 and 0.983 in
the two species, respectively. Thus, the variable gel profiles provided
unique mtDNA "fingerprints" for most conspecific animals assayed. mtDNA
fingerprints differ from nuclear DNA fingerprints in several empirical
respects and should find special application in the genetic assessment of
maternity.
相似文献
244.
Rosado CJ Kondos S Bull TE Kuiper MJ Law RH Buckle AM Voskoboinik I Bird PI Trapani JA Whisstock JC Dunstone MA 《Cellular microbiology》2008,10(9):1765-1774
Pore-forming toxins (PFTs) are commonly associated with bacterial pathogenesis. In eukaryotes, however, PFTs operate in the immune system or are deployed for attacking prey (e.g. venoms). This review focuses upon two families of globular protein PFTs: the cholesterol-dependent cytolysins (CDCs) and the membrane attack complex/perforin superfamily (MACPF). CDCs are produced by Gram-positive bacteria and lyse or permeabilize host cells or intracellular organelles during infection. In eukaryotes, MACPF proteins have both lytic and non-lytic roles and function in immunity, invasion and development. The structure and molecular mechanism of several CDCs are relatively well characterized. Pore formation involves oligomerization and assembly of soluble monomers into a ring-shaped pre-pore which undergoes conformational change to insert into membranes, forming a large amphipathic transmembrane β-barrel. In contrast, the structure and mechanism of MACPF proteins has remained obscure. Recent crystallographic studies now reveal that although MACPF and CDCs are extremely divergent at the sequence level, they share a common fold. Together with biochemical studies, these structural data suggest that lytic MACPF proteins use a CDC-like mechanism of membrane disruption, and will help understand the roles these proteins play in immunity and development. 相似文献
245.
Zhang Q Law RH Bottomley SP Whisstock JC Buckle AM 《Journal of molecular biology》2008,376(5):1348-1359
In this study, we report the X-ray crystal structure of an N-terminally truncated variant of the bacterial serpin, tengpin (tengpinΔ42). Our data reveal that tengpinΔ42 adopts a variation of the latent conformation in which the reactive center loop is hyperinserted into the A β-sheet and removed from the vicinity of the C-sheet. This conformational change leaves the C β-sheet completely exposed and permits antiparallel edge-strand interactions between the exposed portion of the reactive center loop of one molecule and strand s2C of the C β-sheet of the neighboring molecule in the crystal lattice. Our structural data thus reveal that tengpinΔ42 forms a loop C-sheet polymer in the crystal lattice. In vivo serpins have a propensity to misfold and form long-chain polymers, a process that underlies serpinopathies such as emphysema, thrombosis and dementia. Native serpins are thought to polymerize via a loop A-sheet mechanism. However, studies on plasminogen activator inhibitor 1 and the S49P variant of human neuroserpin reveal that the latent form of these molecules can also polymerize. Polymerization of latent neuroserpin may be important for the development of familial encephalopathy with neuroserpin inclusion bodies. Our structural data provide a possible mechanism for polymerization by latent serpins. 相似文献
246.
The concentrations of Fe, Mn, Ni, Pb and V in water, sediment and the gill, liver and muscle tissues of Synodontis resupinatus, Heterotis niloticus and Clarias gariepinus, all commercially important fish species of the lower Niger River, were investigated in 2015. Water, sediment and fish samples were collected for six months and heavy metals were determined using an Atomic Absorption Spectrometer. Fe ranked highest in water and sediment, with concentrations of 2.74 mg l?1 and 61.60 mg kg?1, respectively. Metals followed the magnitude of Fe > Mn > Ni > V > Pb in the water and Fe > Mn > V > Ni > Pb in the sediments. Metal concentrations were higher in the tissues of S. resupinatus compared with H. niloticus and C. gariepinus. Fe was also highest in the gills, liver and muscle of the three fish species. Its highest concentration of 132.97 mg kg?1 dry weight was recorded in the gills of S. resupinatus. Bioconcentration factors of metals ranged from 8.79 for Mn in H. niloticus muscle to 67.99 for Ni in S. resupinatus gills. The fish species studied pose no health risk for all metals studied, because the target hazard quotient was less than 1 and the estimated daily intakes of the metals were below the reference doses. 相似文献
247.
Welss T Sun J Irving JA Blum R Smith AI Whisstock JC Pike RN von Mikecz A Ruzicka T Bird PI Abts HF 《Biochemistry》2003,42(24):7381-7389
Hurpin (headpin/PI13/serpinB13) is an intracellular, differentially spliced member of the serpin superfamily that has been linked to differentiation and apoptosis of human keratinocytes. It is transiently downregulated by UV light and overexpressed in psoriatic skin lesions. Although it has all of the features of an inhibitory serpin, a productive interaction between hurpin and a proteinase has not yet been reported. Here we demonstrate that hurpin is a potent and selective inhibitor of the archetypal lysosomal cysteine proteinase cathepsin L (catL). Recombinant hurpin inhibits human catL with a stoichiometry of inhibition (SI) of 1.7 and a rate constant k(assoc) of (4.6 +/- 0.14) x 10(5) M(-1) s(-1). It inefficiently inhibits catV and does not inhibit papain, catB, or catK. To investigate the inhibitory mechanism, we determined the P1-P1' bond in the reactive center loop cleaved by catL ((356)Thr-(357)Ser) and expressed variants in which the proximal hinge, P1 residue, or differentially spliced CD loop was mutated. The results of assays using these proteins suggest that inhibition of catL by hurpin occurs via the conventional serpin inhibitory mechanism and that the CD loop plays no role in the process. Finally, it was found that the majority of hurpin is cytosolic and that its overexpression in human keratinocytes confers resistance to UV-induced apoptosis. Given that lysosomal disruption, release of catL, and catL-mediated caspase activation are known to occur in response to cellular stress, we propose that a physiological role of hurpin is to protect epithelial cells from ectopic catL. 相似文献
248.
Phosphoinositide signaling pathways regulate many essential cellular functions including proliferation, differentiation and survival, cytoskeletal organization, and vesicular trafficking. The inositol polyphosphate 5-phosphatases regulate the cellular levels of several bioactive phosphoinositide species. This review describes the structure and function of the 5-phosphatase and Sac1 catalytic domains of these enzymes. The crystal structure of the 5-phosphatase domain has been solved and shares homology with members of the AP endonuclease family. The phosphoinositide polyphosphatase activity of the Sac1 domain, found in some inositol polyphosphate 5-phosphatases, is defined by a motif, CX5 R(T/S), also found in both protein and lipid phosphatases. 相似文献
249.
Serine protease inhibitors (serpins) play very important roles in the maintenance of various physiologically important systems. As knowledge of the workings of proteins of this family grows, new understanding is gained of the mechanisms by which they inhibit target proteases, using conformational changes for which the structure of serpins is uniquely adapted. This finely balanced system is utilized to healthy benefit in the control of serpin function by modulators, arguably the most striking examples of which occur in the control of proteolytic cascades, such as the coagulation system. Serpins also play very important intracellular roles: one example is the protection of immune cells from their own cytotoxic proteases. The finely balanced serpin mechanism also means that it is prone to disastrous consequences if mutations should occur in vital positions in the serpin structure. Many examples of disease-associated mutations have been shown, which has the dual effect of highlighting how important these molecules are in the maintenance of health and the fine balance that must be maintained in order to preserve their active, inhibitory conformation. 相似文献
250.
Ludeman JP Pike RN Bromfield KM Duggan PJ Cianci J Le Bonniec B Whisstock JC Bottomley SP 《The international journal of biochemistry & cell biology》2003,35(2):221-225
Factor Xa is a central protease in the coagulation cascade and the target for many anticoagulant compounds currently under development. The preferences of the enzyme for substrates incorporating residues N-terminal to the cleavage site (P1, P2, etc.) have been elucidated, but little is known of its preferences for residues C-terminal to the cleavage site (P1', P2', etc.). The preferences of bovine factor Xa for substrate residues in the P1', P2' and P3' positions were mapped using fluorescence-quenched substrates. Bovine factor Xa, often used as a model for factor Xa, was most selective for the P2' position, less selective at the P1' position and almost completely non-selective at the P3' position. It appears that while the prime side subsites of factor Xa impose some selectivity towards substrates, the influence of these sites on factor Xa cleavage specificity is relatively low in comparison to related enzymes such as thrombin. 相似文献