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91.
Vézina H Durocher F Dumont M Houde L Szabo C Tranchant M Chiquette J Plante M Laframboise R Lépine J Nevanlinna H Stoppa-Lyonnet D Goldgar D Bridge P Simard J 《Human genetics》2005,117(2-3):119-132
The Quebec population contains about six-million French Canadians, descended from the French settlers who colonized Nouvelle-France between 1608 and 1765. Although the relative genetic contribution of each of these founders is highly variable, altogether they account for the major part of the contemporary French-Canadian gene pool. This study was designed to analyze the role of this founder effect in the introduction and diffusion of the BRCA1 recurrent R1443X mutant allele. A highly conserved haplotype, observed in 18 French-Canadian families and generated using 17 microsatellite markers surrounding the BRCA1 locus, supports the fact that the R1443X mutation is a founder mutation in the Quebec population. We also performed haplotyping analysis of R1443X carriers on 19 other families from seven different nationalities; although the same alleles are shared for three markers surrounding the BRCA1 gene, distinct haplotypes were obtained in four families, suggesting multiple origins for the R1443X mutation. Ascending genealogies of the 18 French Canadian families and of controls were reconstructed on an average depth of 10 generations. We identified the founder couple with the highest probability of having introduced the mutation in the population. Based on the descending genealogy of this couple, we detected the presence of geographical concentration in the diffusion pattern of the mutation. This study demonstrates how molecular genetics and demogenetic analyses can complement each other to provide findings that could have an impact on public health. Moreover, this approach is certainly not unique to breast cancer genetics and could be used to understand other complex traits.Other members of the BCLC Haplotype Group involved in this study are listed in Appendix 1Other members of INHERIT BRCAs involved in this study are listed in Appendix 2H. Vézina and F. Durocher contributed equally to this work and should be regarded as joint first author 相似文献
92.
93.
Heli T. Viljakainen Yoav Ben-Shlomo Sanjay Kinra Shah Ebrahim Hannah Kuper K. V. Radhakrishna Bharati Kulkarni Jon H. Tobias 《PloS one》2015,10(10)
Background
Fracture risk is rising in countries undergoing rapid rural to urban migration, but whether this reflects an adverse effect of urbanization on intrinsic bone strength, as reflected by bone mineral density (BMD), is currently unknown.Methods
Lumbar spine (LS) and total hip (TH) BMD, and total body fat and lean mass, were obtained from DXA scans performed in the Hyderabad arm of the Indian Migration Study (54% male, mean age 49 years). Sib-pair comparisons were performed between rural-urban migrants (RUM) and rural non-migrated (RNM) siblings (N = 185 sib-pairs).Results
In analyses adjusted for height, gender, age and occupation, rural to urban migration was associated with higher lumbar and hip BMD and greater predicted hip strength; ΔLS BMD 0.030 (0.005, 0.055) g/cm2, ΔTH BMD 0.044 (0.024; 0.064) g/cm2, Δcross-sectional moment of inertia 0.162 (0.036, 0.289) cm4. These differences were largely attenuated after adjusting for body composition, insulin levels and current lifestyle factors ie. years of smoking, alcohol consumption and moderate to vigorous physical activity. Further analyses suggested that differences in lean mass, and to a lesser extent fat mass, largely explained the BMD differences which we observed.Conclusions
Rural to urban migration as an adult is associated with higher BMD and greater predicted hip strength, reflecting associated alterations in body composition. It remains to be seen how differences in BMD between migration groups will translate into fracture risk in becoming years. 相似文献94.
Iina Vainio Amna Abu Khamidakh Michelangelo Paci Heli Skottman Kati Juuti-Uusitalo Jari Hyttinen Soile Nymark 《PloS one》2015,10(6)
Objective
Computational models of calcium (Ca2+) signaling have been constructed for several cell types. There are, however, no such models for retinal pigment epithelium (RPE). Our aim was to construct a Ca2+ signaling model for RPE based on our experimental data of mechanically induced Ca2+ wave in the in vitro model of RPE, the ARPE-19 monolayer.Methods
We combined six essential Ca2+ signaling components into a model: stretch-sensitive Ca2+ channels (SSCCs), P2Y2 receptors, IP3 receptors, ryanodine receptors, Ca2+ pumps, and gap junctions. The cells in our epithelial model are connected to each other to enable transport of signaling molecules. Parameterization was done by tuning the above model components so that the simulated Ca2+ waves reproduced our control experimental data and data where gap junctions were blocked.Results
Our model was able to explain Ca2+ signaling in ARPE-19 cells, and the basic mechanism was found to be as follows: 1) Cells near the stimulus site are likely to conduct Ca2+ through plasma membrane SSCCs and gap junctions conduct the Ca2+ and IP3 between cells further away. 2) Most likely the stimulated cell secretes ligand to the extracellular space where the ligand diffusion mediates the Ca2+ signal so that the ligand concentration decreases with distance. 3) The phosphorylation of the IP3 receptor defines the cell’s sensitivity to the extracellular ligand attenuating the Ca2+ signal in the distance.Conclusions
The developed model was able to simulate an array of experimental data including drug effects. Furthermore, our simulations predict that suramin may interfere ligand binding on P2Y2 receptors or accelerate P2Y2 receptor phosphorylation, which may partially be the reason for Ca2+ wave attenuation by suramin. Being the first RPE Ca2+ signaling model created based on experimental data on ARPE-19 cell line, the model offers a platform for further modeling of native RPE functions. 相似文献95.
Background
Workplace contamination by the use of volatile anesthetic agents should be kept to a minimum if a potential health hazard is to be minimised. Mask induction of animals is a common procedure. The present study investigates the efficiency of a novel scavenging double mask in reducing waste gas concentrations in the breathing zone of the anesthetist performing this procedure. 相似文献96.
97.
Amankwah EK Wang Q Schildkraut JM Tsai YY Ramus SJ Fridley BL Beesley J Johnatty SE Webb PM Chenevix-Trench G;Australian Ovarian Cancer Study Group Dale LC Lambrechts D Amant F Despierre E Vergote I Gayther SA Gentry-Maharaj A Menon U Chang-Claude J Wang-Gohrke S Anton-Culver H Ziogas A Dörk T Dürst M Antonenkova N Bogdanova N Brown R Flanagan JM Kaye SB Paul J Bützow R Nevanlinna H Campbell I Eccles DM Karlan BY Gross J Walsh C Pharoah PD Song H Krüger Kjær S Høgdall E Høgdall C Lundvall L 《PloS one》2011,6(5):e19642
Alterations in stromal tissue components can inhibit or promote epithelial
tumorigenesis. Decorin (DCN) and lumican (LUM)
show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We
hypothesized that common variants in these genes associate with risk.
Associations with sEOC among Caucasians were estimated with odds ratios (OR)
among 397 cases and 920 controls in two U.S.-based studies (discovery set), 436
cases and 1,098 controls in Australia (replication set 1) and a consortium of 15
studies comprising 1,668 cases and 4,249 controls (replication set 2). The
discovery set and replication set 1 (833 cases and 2,013 controls) showed
statistically homogeneous (Pheterogeneity≥0.48) decreased risks of
sEOC at four variants: DCN rs3138165, rs13312816 and rs516115,
and LUM rs17018765 (OR = 0.6 to 0.9;
Ptrend = 0.001 to 0.03). Results from
replication set 2 were statistically homogeneous
(Pheterogeneity≥0.13) and associated with increased risks at
DCN rs3138165 and rs13312816, and LUM
rs17018765: all ORs = 1.2; Ptrend≤0.02. The
ORs at the four variants were statistically heterogeneous across all 18 studies
(Pheterogeneity≤0.03), which precluded combining. In post-hoc
analyses, interactions were observed between each variant and recruitment period
(Pinteraction≤0.003), age at diagnosis
(Pinteraction = 0.04), and year of diagnosis
(Pinteraction = 0.05) in the five studies
with available information (1,044 cases, 2,469 controls). We conclude that
variants in DCN and LUM are not directly
associated with sEOC, and that confirmation of possible effect modification of
the variants by non-genetic factors is required. 相似文献
98.
Elovaara H Kidron H Parkash V Nymalm Y Bligt E Ollikka P Smith DJ Pihlavisto M Salmi M Jalkanen S Salminen TA 《Biochemistry》2011,50(24):5507-5520
Human membrane primary amine oxidase (hAOC3; also known as vascular adhesion protein-1, VAP-1) is expressed upon inflammation in most tissues, where its enzymatic activity plays a crucial role in leukocyte trafficking. We have determined two new structures of a soluble, proteolytically cleaved form of hAOC3 (sAOC3), which was extracted from human plasma. In the 2.6 ? sAOC3 structure, an imidazole molecule is hydrogen bonded to the topaquinone (TPQ) cofactor, which is in an inactive on-copper conformation, while in the 2.95 ? structure, an imidazole molecule is covalently bound to the active off-copper conformation of TPQ. A second imidazole bound by Tyr394 and Thr212 was identified in the substrate channel. We furthermore demonstrated that imidazole has an inhibitory role at high concentrations used in crystallization. A triple mutant (Met211Val/Tyr394Asn/Leu469Gly) of hAOC3 was previously reported to change substrate preferences toward those of hAOC2, another human copper-containing monoamine oxidase. We now mutated these three residues and Thr212 individually to study their distinct role in the substrate specificity of hAOC3. Using enzyme activity assays, the effect of the four single mutations was tested with four different substrates (methylamine, benzylamine, 2-phenylethylamine, and p-tyramine), and their binding modes were predicted by docking studies. As a result, Met211 and Leu469 were shown to be key residues for substrate specificity. The native structures of sAOC3 and the mutational data presented in this study will aid the design of hAOC3 specific inhibitors. 相似文献
99.
In this issue of Molecular Ecology, Kent et al. (2011) describe the adaptive evolution of honey bee vitellogenin that belongs to a phylogenetically conserved group of egg yolk precursors. This glyco‐lipoprotein leads a double life: it is central to egg production in the reproductive queen caste, and a regulator of social behaviour in the sterile worker caste. Does such social pleiotropy constrain molecular evolution? To the contrary; Kent et al. show that the vitellogenin gene is under strong positive selection in honey bees. Rapid change has taken place in specific protein regions, shedding light on the evolution of novel vitellogenin functions. 相似文献
100.
松材线虫(Bursaphelenchus xylophilus)是一种松树上发生严重的有害生物,它不仅改变了生态系统的结构和功能,而且改变了系统内生物的原有特性和地理分布。松材线虫及其引起的松树萎蔫病已对中国马尾松林(Pinus massoniana)的树木成长产生了巨大影响。基于此,使用"每木调查法"和"样方法",对松材线虫入侵后的马尾松林内松树的各项生长指标因子进行了调查分析,其结果表明:自松材线虫1996年入侵所调查地区的松林后,对于受害松树不管是伐倒木(被伐倒)还是倒木(自然倒地),其对周围马尾松胸径生长的影响是显著的,而对树高生长的影响不显著。最后建立了一系列的灰色和灰色-马尔可夫链数学模型,其预测结果精度高,可用于今后受害和未受害区马尾松林分因子的生长预测。 相似文献