全文获取类型
收费全文 | 4044篇 |
免费 | 288篇 |
国内免费 | 1篇 |
出版年
2024年 | 3篇 |
2023年 | 21篇 |
2022年 | 67篇 |
2021年 | 124篇 |
2020年 | 69篇 |
2019年 | 94篇 |
2018年 | 98篇 |
2017年 | 83篇 |
2016年 | 163篇 |
2015年 | 224篇 |
2014年 | 233篇 |
2013年 | 337篇 |
2012年 | 356篇 |
2011年 | 350篇 |
2010年 | 215篇 |
2009年 | 162篇 |
2008年 | 275篇 |
2007年 | 252篇 |
2006年 | 261篇 |
2005年 | 196篇 |
2004年 | 189篇 |
2003年 | 150篇 |
2002年 | 118篇 |
2001年 | 34篇 |
2000年 | 28篇 |
1999年 | 23篇 |
1998年 | 29篇 |
1997年 | 22篇 |
1996年 | 15篇 |
1995年 | 20篇 |
1994年 | 19篇 |
1993年 | 16篇 |
1992年 | 11篇 |
1991年 | 20篇 |
1990年 | 11篇 |
1989年 | 9篇 |
1988年 | 10篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 4篇 |
1983年 | 2篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1978年 | 2篇 |
1976年 | 1篇 |
1975年 | 2篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1910年 | 2篇 |
排序方式: 共有4333条查询结果,搜索用时 568 毫秒
261.
Coassin S Schweiger M Kloss-Brandstätter A Lamina C Haun M Erhart G Paulweber B Rahman Y Olpin S Wolinski H Cornaciu I Zechner R Zimmermann R Kronenberg F 《PLoS genetics》2010,6(12):e1001239
Recent studies demonstrated a strong influence of rare genetic variants on several lipid-related traits. However, their impact on free fatty acid (FFA) plasma concentrations, as well as the role of rare variants in a general population, has not yet been thoroughly addressed. The adipose triglyceride lipase (ATGL) is encoded by the PNPLA2 gene and catalyzes the rate-limiting step of lipolysis. It represents a prominent candidate gene affecting FFA concentrations. We therefore screened the full genomic region of ATGL for mutations in 1,473 randomly selected individuals from the SAPHIR (Salzburg Atherosclerosis Prevention program in subjects at High Individual Risk) Study using a combined Ecotilling and sequencing approach and functionally investigated all detected protein variants by in-vitro studies. We observed 55 novel mostly rare genetic variants in this general population sample. Biochemical evaluation of all non-synonymous variants demonstrated the presence of several mutated but mostly still functional ATGL alleles with largely varying residual lipolytic activity. About one-quarter (3 out of 13) of the investigated variants presented a marked decrease or total loss of catalytic function. Genetic association studies using both continuous and dichotomous approaches showed a shift towards lower plasma FFA concentrations for rare variant carriers and an accumulation of variants in the lower 10%-quantile of the FFA distribution. However, the generally rather small effects suggest either only a secondary role of rare ATGL variants on the FFA levels in the SAPHIR population or a recessive action of ATGL variants. In contrast to these rather small effects, we describe here also the first patient with "neutral lipid storage disease with myopathy" (NLSDM) with a point mutation in the catalytic dyad, but otherwise intact protein. 相似文献
262.
263.
José A. Donázar Ainara Cortés-Avizanda Martina Carrete 《European Journal of Wildlife Research》2010,56(4):613-621
Among vertebrates, specialization in scavenging has appeared only in “true” Gyps vultures, which usually base their diet almost exclusively on carcasses of medium and large-sized mammals, whereas all other
scavengers rely on broader ranges of prey. The availability of food for scavengers in Western Europe has not been limited
during recent decades permitting the existence and growth of huge vulture populations. From 2000 onwards, however, EU sanitary
legislation has progressively limited the abandonment of dead animals in the field resulting in a sudden reduction of food
availability with unknown ecological and conservation consequences. Here, we examine the dietary response of a tandem of carrion
eaters, the griffon vulture (Gyps fulvus) and the Egyptian vulture (Neophron percnopterus), showing different degrees of dietary specialization. Our results showed that after the reduction in numbers of supplementary
feeding stations (vulture restaurants) the niche breadth of the griffon vulture has broadened and now includes significant
amounts of wild rabbits (Oryctolagus cuniculus) and garbage. The diet of the Egyptian vulture, on the contrary, did not vary substantially. The diet overlap showed patterns
probably conditioned by interspecific competition and the progressive exploitation of unpredictable carcasses. On a short-term
scale, consequences for smaller scavengers could be negative due to the monopolization of resources by the dominant and much
more abundant griffon vulture, however in the long-term all guild species would benefit from the exploitation of unpredictable
carcasses, which could enhance the possibilities of coexistence. 相似文献
264.
Rhonda Christiane Meyer Barbara Kusterer Jan Lisec Matthias Steinfath Martina Becher Hanno Scharr Albrecht E. Melchinger Joachim Selbig Ulrich Schurr Lothar Willmitzer Thomas Altmann 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2010,120(2):227-237
The main objective of this study was to identify genomic regions involved in biomass heterosis using QTL, generation means, and mode-of-inheritance classification analyses. In a modified North Carolina Design III we backcrossed 429 recombinant inbred line and 140 introgression line populations to the two parental accessions, C24 and Col-0, whose F 1 hybrid exhibited 44% heterosis for biomass. Mid-parent heterosis in the RILs ranged from ?31 to 99% for dry weight and from ?58 to 143% for leaf area. We detected ten genomic positions involved in biomass heterosis at an early developmental stage, individually explaining between 2.4 and 15.7% of the phenotypic variation. While overdominant gene action was prevalent in heterotic QTL, our results suggest that a combination of dominance, overdominance and epistasis is involved in biomass heterosis in this Arabidopsis cross. 相似文献
265.
Martin Rudwaleit Filip Van den Bosch Martina Kron Sonja Kary Hartmut Kupper 《Arthritis research & therapy》2010,12(3):R117
Introduction
Tumor necrosis factor (TNF) antagonists reduce the signs and symptoms of spondyloarthritides, including ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Our objective was to evaluate the effectiveness and safety of adalimumab, 40 mg every other week, for patients with AS or PsA and prior treatment with infliximab (IFX) and/or etanercept (ETN). 相似文献266.
The branch point (BP) is one of the three obligatory signals required for pre-mRNA splicing. In mammals, the degeneracy of the motif combined with the lack of a large set of experimentally verified BPs complicates the task of modeling it in silico, and therefore of predicting the location of natural BPs. Consequently, BPs have been disregarded in a considerable fraction of the genome-wide studies on the regulation of splicing in mammals. We present a new computational approach for mammalian BP prediction. Using sequence conservation and positional bias we obtained a set of motifs with good agreement with U2 snRNA binding stability. Using a Support Vector Machine algorithm, we created a model complemented with polypyrimidine tract features, which considerably improves the prediction accuracy over previously published methods. Applying our algorithm to human introns, we show that BP position is highly dependent on the presence of AG dinucleotides in the 3' end of introns, with distance to the 3' splice site and BP strength strongly correlating with alternative splicing. Furthermore, experimental BP mapping for five exons preceded by long AG-dinucleotide exclusion zones revealed that, for a given intron, more than one BP can be chosen throughout the course of splicing. Finally, the comparison between exons of different evolutionary ages and pseudo exons suggests a key role of the BP in the pathway of exon creation in human. Our computational and experimental analyses suggest that BP recognition is more flexible than previously assumed, and it appears highly dependent on the presence of downstream polypyrimidine tracts. The reported association between BP features and the splicing outcome suggests that this, so far disregarded but yet crucial, element buries information that can complement current acceptor site models. 相似文献
267.
Jos H.M. Lange Martina A.W. van der Neut Arnold P. den Hartog Henri C. Wals Jan Hoogendoorn Herman H. van Stuivenberg Bernard J. van Vliet Chris G. Kruse 《Bioorganic & medicinal chemistry letters》2010,20(5):1752-1757
The synthesis, structure–activity relationship (SAR) studies and intramolecular hydrogen bonding pattern of 1,3,5-trisubstituted 4,5-dihydropyrazoles are described. The target compounds 6–18 represent a novel class of potent and selective CB1 receptor antagonists. Based on X-ray diffraction data, the orally active 17 is shown to elicit a different intramolecular H-bonding mode as compared to ibipinabant (3) and SLV330 (4). 相似文献
268.
Stephan Koblmüller Nina Duftner Kristina M Sefc Ursula Aigner Martina Rogetzer Christian Sturmbauer 《Zoologica scripta》2009,38(3):257-268
One of the most fragmented habitats in freshwater lakes is the rocky littoral zone, where the already richly structured habitat is frequently interspersed with more pronounced barriers such as sandy bays, river estuaries and deep slopes. Although habitat fragmentation generally constrains the dispersal of specialized rock-dwelling species, patterns of population structure vary in sympatric taxa due to species-specific traits. In the present study, we examine the phylogeographic and population genetic structure of Perissodus microlepis , a presumptively highly mobile scale-eating cichlid fish endemic to Lake Tanganyika with a lake-wide distribution in the rocky littoral zone and no obvious geographical colour variation. Analysis of the mitochondrial DNA of six populations in the southern end of the lake suggests isolation by distance along rocky shoreline. Across a large muddy bay, a phylogeographic break indicates that environmental barriers restrict gene flow even in this highly mobile species. Restricted dispersal across the bay is not necessarily a consequence of an intrinsic propensity to avoid sand, but may be connected with the association between P. microlepis and other rock-dwelling fish, which the scale-eaters mimic and intermingle in order to be able to approach other fish to rip off scales from their bodies. 相似文献
269.
Brockmeyer J Bielaszewska M Fruth A Bonn ML Mellmann A Humpf HU Karch H 《Applied and environmental microbiology》2007,73(20):6351-6359
We investigated the prevalence, distribution, and structure of espP in Shiga toxin-producing Escherichia coli (STEC) and assessed the secretion and proteolytic activity of the encoded autotransporter protein EspP (extracellular serine protease, plasmid encoded). espP was identified in 56 of 107 different STEC serotypes. Sequencing of a 3,747-bp region of the 3,900-bp espP gene distinguished four alleles (espPalpha, espPbeta, espPgamma, and espPdelta), with 99.9%, 99.2%, 95.3%, and 95.1% homology, respectively, to espP of E. coli O157:H7 strain EDL933. The espPbeta, espPgamma, and espPdelta genes contained unique insertions and/or clustered point mutations that enabled allele-specific PCRs; these demonstrated the presence of espPalpha, espPbeta, espPgamma, and espPdelta in STEC isolates belonging to 17, 16, 15, and 8 serotypes, respectively. Among four subtypes of EspP encoded by these alleles, EspPalpha (produced by enterohemorrhagic E. coli [EHEC] O157:H7 and the major non-O157 EHEC serotypes) and EspPgamma cleaved pepsin A, human coagulation factor V, and an oligopeptide alanine-alanine-proline-leucine-para-nitroaniline, whereas EspPbeta and EspPdelta either were not secreted or were proteolytically inactive. The lack of proteolysis correlated with point mutations near the active serine protease site. We conclude that espP is widely distributed among STEC strains and displays genetic heterogeneity, which can be used for subtyping and which affects EspP activity. The presence of proteolytically active EspP in EHEC serogroups O157, O26, O111, and O145, which are bona fide human pathogens, suggests that EspP might play a role as an EHEC virulence factor. 相似文献
270.
Kienesberger S Gorkiewicz G Joainig MM Scheicher SR Leitner E Zechner EL 《Applied and environmental microbiology》2007,73(14):4619-4630
Molecular analysis of the virulence mechanisms of the emerging pathogen Campylobacter fetus has been hampered by the lack of genetic tools. We report the development and functional analysis of Escherichia coli-Campylobacter shuttle vectors that are appropriate for C. fetus. Some vectors were constructed based on the known Campylobacter coli plasmid pIP1455 replicon, which confers a wide host range in Campylobacter spp. Versatility in directing gene expression was achieved by introducing a strong C. fetus promoter. The constructions carry features necessary and sufficient to detect the expression of phenotypic markers, including molecular reporter genes in both subspecies of C. fetus, while retaining function in C. jejuni. The capacity to express several gene products from different vectors in a single host can be advantageous but requires distinct plasmid replicons. To this end, replication features derived from a cryptic plasmid of C. fetus subsp. venerealis strain 4111/108, designated pCFV108, were adapted for a compatible series of constructions. The substitution of the C. coli replication elements reduced vector size while apparently limiting the host range to C. fetus. The complementation of a ciprofloxacin-resistant mutant phenotype via vector-driven gyrA expression was verified. Cocultivation demonstrated that shuttle vectors based on the pCFV108 replicon were compatible with pIP1455 replication functions, and the stable maintenance of two plasmids in a C. fetus subsp. venerealis host over several months was observed. The application of both vector types will facilitate the investigation of the genetics and cellular interactions of the emerging pathogen C. fetus. 相似文献