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91.
Spontaneous mutational correlations for life-history, morphological and behavioral characters in Caenorhabditis elegans 下载免费PDF全文
The pattern of mutational covariance among traits plays a central, but largely untested, role in many theories in evolutionary genetics. Here we estimate the pattern of phenotypic, environmental, and mutational correlations for a set of life-history, behavioral, and morphological traits using 67 self-fertilizing lines of Caenorhabditis elegans, each having independently experienced an average of 370 generations of spontaneous mutation accumulation. Bivariate relationships of mutational effects indicate the existence of extensive pleiotropy. We find that mutations may tend to produce manifold effects on suites of functionally related traits; however, our data do not support the idea of completely parcelated pleiotropy, in which functional units are separately affected by mutations. Positive net phenotypic and mutational correlations are common for life-history traits, with environmental correlations being comparatively smaller and of the same sign for most pairs of traits. Observed mutational correlations are shown to be higher than those produced by the chance accumulation of nonpleiotropic mutations in the same lines. 相似文献
92.
Age-related macular degeneration: a high-resolution genome scan for susceptibility loci in a population enriched for late-stage disease 总被引:13,自引:0,他引:13 下载免费PDF全文
Abecasis GR Yashar BM Zhao Y Ghiasvand NM Zareparsi S Branham KE Reddick AC Trager EH Yoshida S Bahling J Filippova E Elner S Johnson MW Vine AK Sieving PA Jacobson SG Richards JE Swaroop A 《American journal of human genetics》2004,74(3):482-494
Age-related macular degeneration (AMD) is a complex multifactorial disease that affects the central region of the retina. AMD is clinically heterogeneous, leading to geographic atrophy (GA) and/or choroidal neovascularization (CNV) at advanced stages. Considerable data exists in support of a genetic predisposition for AMD. Recent linkage studies have provided evidence in favor of several AMD susceptibility loci. We have performed a high-resolution (5-cM) genome scan of 412 affected relative pairs that were enriched for late-stage disease (GA and/or CNV). Nonparametric linkage analysis was performed using two different diagnostic criteria and also by dividing the affected individuals according to GA or CNV phenotype. Our results demonstrate evidence of linkage in regions that were suggested in at least one previous study at chromosomes 1q (236-240 cM in the Marshfield genetic map), 5p (40-50 cM), and 9q (111 cM). Multipoint analysis of affected relatives with CNV provided evidence of additional susceptibility loci on chromosomes 2p (10 cM) and 22q (25 cM). A recently identified Gln5345Arg change in HEMICENTIN-1 on chromosome 1q25 was not detected in 274 affected members in the restricted group with AMD, 346 additional patients with AMD, and 237 unaffected controls. Our results consolidate the chromosomal locations of several AMD susceptibility loci and, together with previous reports, should facilitate the search for disease-associated sequence variants. 相似文献
93.
Protease-activated receptor signaling increases epithelial antimicrobial peptide expression 总被引:7,自引:0,他引:7
Chung WO Hansen SR Rao D Dale BA 《Journal of immunology (Baltimore, Md. : 1950)》2004,173(8):5165-5170
Epithelial tissues provide both a physical barrier and an antimicrobial barrier. Antimicrobial peptides of the human beta-defensin (hBD) family are part of the innate immune responses that play a role in mucosal defense. hBDs are made in epithelia including oral epithelium where the bacterial load is particularly great. hBD-2 and hBD-3 are up-regulated in response to bacterial stimuli. Previous studies show that hBD-2 expression in human gingival epithelial cells (GEC) is stimulated by both nonpathogenic and pathogenic bacteria, including Porphyromonas gingivalis, a Gram-negative pathogen associated with periodontitis. Present evidence suggests that hBD-2 expression in GEC uses several signaling pathways, including an NF-kappaB-mediated pathway but without apparent LPS-TLR4 signaling. Protease-activated receptors (PAR) are G-protein-coupled receptors that mediate cellular responses to extracellular proteinases. P. gingivalis secretes multiple proteases that contribute to its virulence mechanisms. To determine whether PAR signaling is used in hBD-2 induction, GEC were stimulated with wild-type P. gingivalis or mutants lacking one or more proteases. hBD-2 mRNA expression was reduced in GEC stimulated with single protease mutants (11-67% compared with wild type), strongly reduced in double mutants (0.1-16%), and restored to wild-type levels (93%) in mutant with restored protease activity. Stimulation by wild type was partially blocked by inhibitors of phospholipase C, a main signaling pathway for PARs. Expression of hBD-3 was unaffected. Peptide agonist of PAR-2, but not PAR-1 activator, also induced hBD-2 in GEC. Thus, P. gingivalis proteases are directly involved in regulation of hBD-2 in cultured GEC, and this induction partially uses the PAR-2 receptor and signaling pathway. 相似文献
94.
Allen IC Hartney JM Coffman TM Penn RB Wess J Koller BH 《American journal of physiology. Lung cellular and molecular physiology》2006,290(3):L526-L533
Thromboxane A2 (TXA2) is a potent lipid mediator released by platelets and inflammatory cells and is capable of inducing vasoconstriction and bronchoconstriction. In the airways, it has been postulated that TXA2 causes airway constriction by direct activation of thromboxane prostanoid (TP) receptors on airway smooth muscle cells. Here we demonstrate that although TXA2 can mediate a dramatic increase in airway smooth muscle constriction and lung resistance, this response is largely dependent on vagal innervation of the airways and is highly sensitive to muscarinic acetylcholine receptor (mAChR) antagonists. Further analyses employing pharmacological and genetic strategies demonstrate that TP-dependent changes in lung resistance and airway smooth muscle tension require expression of the M2 mAChR subtype. These results raise the possibility that some of the beneficial actions of anticholinergic agents used in the treatment of asthma and chronic obstructive pulmonary disease result from limiting physiological changes mediated through the TP receptor. Furthermore, these findings demonstrate a unique pathway for TP regulation of homeostatic mechanisms in the airway and suggest a paradigm for the role of TXA2 in other organ systems. 相似文献
95.
Allen IC Pace AJ Jania LA Ledford JG Latour AM Snouwaert JN Bernier V Stocco R Therien AG Koller BH 《American journal of physiology. Lung cellular and molecular physiology》2006,291(5):L1005-L1017
A genetic contribution to asthma susceptibility is well recognized, and linkage studies have identified a large number of genes associated with asthma pathogenesis. Recently, a locus encoding a seven-transmembrane protein was shown to be associated with asthma in founder populations. The expression of the protein GPRA (G protein-coupled receptor for asthma susceptibility) in human airway epithelia and smooth muscle, and its increased expression in a mouse model of asthma, suggested that a gain-of-function mutation in this gene increased the disease risk. However, we report here that the development of allergic lung disease in GPRA-deficient mice is unaltered. A possible explanation for this finding became apparent upon reexamination of the expression of this gene. In contrast to initial studies, our analyses failed to detect expression of GPRA in human lung tissue or in mice with allergic lung disease. We identify a single parameter that distinguishes GPRA-deficient and wild-type mice. Whereas the change in airway resistance in response to methacholine was identical in control and GPRA-deficient mice, the mutant animals showed an attenuated response to thromboxane, a cholinergic receptor-dependent bronchoconstricting agent. Together, our studies fail to support a direct contribution of GPRA to asthma pathogenesis. However, our data suggest that GPRA may contribute to the asthmatic phenotype by altering the activity of other pathways, such as neurally mediated mechanisms, that contribute to disease. This interpretation is supported by high levels of GPRA expression in the brain and its recent identification as the neuropeptide S receptor. 相似文献
96.
Recently, it has emerged that palindrome-mediated genomic instability contributes to a diverse group of genomic rearrangements including translocations, deletions, and amplifications. One of the best studied examples is the recurrent t(11;22) constitutional translocation in humans that has been well documented to be mediated by palindromic AT-rich repeats (PATRRs) on chromosomes 11q23 and 22q11. De novo examples of the translocation are detected at a high frequency in sperm samples from normal healthy males, but not in lymphoblasts or fibroblasts. Cloned breakpoint sequences preferentially form a cruciform configuration in vitro. Analysis of the junction fragments implicates frequent double-strand-breaks (DSBs) at the center of both palindromic regions, followed by repair through the non-homologous end joining (NHEJ) pathway. We propose that the PATRR adopts a cruciform structure in male meiotic cells, creating genomic instability that leads to the recurrent translocation. 相似文献
97.
Wittenburg H Lyons MA Li R Kurtz U Wang X Mössner J Churchill GA Carey MC Paigen B 《Journal of lipid research》2006,47(8):1780-1790
To identify additional loci that influence lipoprotein cholesterol levels, we performed quantitative trait locus (QTL) mapping in offspring of PERA/EiJxI/LnJ and PERA/EiJxDBA/2J intercrosses and in a combined data set from both crosses after 8 weeks of consumption of a high fat-diet. Most QTLs identified were concordant with homologous chromosomal regions that were associated with lipoprotein levels in human studies. We detected significant new loci for HDL cholesterol levels on chromosome (Chr) 5 (Hdlq34) and for non-HDL cholesterol levels on Chrs 15 (Nhdlq9) and 16 (Nhdlq10). In addition, the analysis of combined data sets identified a QTL for HDL cholesterol on Chr 17 that was shared between both crosses; lower HDL cholesterol levels were conferred by strain PERA. This QTL colocalized with a shared QTL for cholesterol gallstone formation detected in the same crosses. Haplotype analysis narrowed this QTL, and sequencing of the candidate genes Abcg5 and Abcg8 confirmed shared alleles in strains I/LnJ and DBA/2J that differed from the alleles in strain PERA/EiJ. In conclusion, our analysis furthers the knowledge of genetic determinants of lipoprotein cholesterol levels in inbred mice and substantiates the hypothesis that polymorphisms of Abcg5/Abcg8 contribute to individual variation in both plasma HDL cholesterol levels and susceptibility to cholesterol gallstone formation. 相似文献
98.
Involvement of ERK1/2 and p38 in Mg2+ accumulation in liver cells 总被引:10,自引:0,他引:10
Activation of PKC signaling induces Mg2+ accumulation in liver cells. To test the hypothesis that PKC induces Mg2+ accumulation via MAPKs activation, hepatocytes were incubated in the presence of PD98059 and SB202190 as specific inhibitors of ERK1/2 and p38, respectively, and stimulated for Mg2+ accumulation by addition of PMA or OAG. Accumulation of Mg2+ within the cells was measured by atomic absorbance spectrophotometry in the acid extract of cell pellet. The presence of either inhibitor completely abolished Mg2+ accumulation irrespective of the dose of agonist utilized while having no discernible effect on β -adrenoceptor mediated Mg2+ extrusion. A partial inhibition on α 1-adrenoceptor mediated Mg2+ extrusion was observed only in cells treated with PD98059. To confirm the inhibitory effect of PD98509 and SB202190, total and basolateral liver plasma membrane vesicles were purified in the presence of either MAPK inhibitor during the isolation procedure. Consistent with the data obtained in intact cells, liver plasma membrane vesicles purified in the presence of PD98509 or SB202190 lost the ability to accumulate Mg2+in exchange for intra-vesicular entrapped Na+ while retaining the ability to extrude entrapped Mg2+ in exchange for extra-vesicular Na+. These data indicate that ERK1/2 and p38 are involved in mediating Mg2+ accumulation in liver cells following activation of PKC signaling. The absence of a detectable effect of either inhibitor on β -adrenoceptor induced, Na+-dependent Mg2+ extrusion in intact cells and in purified plasma membrane vesicles further support the hypothesis that Mg2+ extrusion and accumulation occur through distinct and differently regulated transport mechanisms. 相似文献
99.
Schaefer AV Leslie BA Rischke JA Stafford AR Fredenburgh JC Weitz JI 《Biochemistry》2006,45(13):4257-4265
Bleeding, the most serious complication of thrombolytic therapy with tissue-type plasminogen activator (t-PA), is thought to result from lysis of fibrin in hemostatic plugs and from the systemic lytic state caused by unopposed plasmin. One mechanism by which systemic plasmin can impair hemostasis is by partially degrading fibrinogen to fragment X, a product that retains clottability but forms clots with reduced tensile strength that stimulate plasminogen activation by t-PA more than fibrin clots. The purpose of this study was to elucidate potential mechanisms by which fragment X accelerates t-PA-mediated fibrinolysis. In the presence of t-PA, clots containing fragment X were degraded faster than fibrin clots and exhibited higher rates of plasminogen activation. Although treatment with carboxypeptidase B, an enzyme that reduces plasminogen binding to fibrin, prolonged the lysis times of fragment X and fibrin clots, clots containing fragment X still were degraded more rapidly. Furthermore, plasmin or trypsin also degraded clots containing fragment X more rapidly than fibrin clots, suggesting that this effect is largely independent of plasminogen activation. Fragment X-derived degradation products were not preferentially released by plasmin from clots composed of equal concentrations of fibrinogen and fragment X, indicating that fragment X does not constitute a preferential site for proteolysis. These data suggest that structural changes resulting from incorporation of fragment X into clots promote their lysis. Thus, attenuation of thrombolytic therapy-induced fragment X formation may reduce the risk of bleeding. 相似文献
100.
Polymorphisms in cytokine genes and risk of Helicobacter pylori infection among Jamaican children 总被引:2,自引:0,他引:2
Tseng FC Brown EE Maiese EM Yeager M Welch R Gold BD Owens M Cranston B Hanchard B El-Omar E Hisada M 《Helicobacter》2006,11(5):425-430
Background: Infection by Helicobacter pylori is often acquired during childhood. Recent studies suggest that inflammatory cytokines may play a role in susceptibility to, and disease phenotype caused by, H. pylori infection, but the association of host genetic variability with risk of H. pylori infection has not been studied in children. Methods: We investigated the relationship between the risk of H. pylori antibody positivity and cytokine gene polymorphisms among 199 two‐year‐old Jamaicans. H. pylori seropositivity was determined by a validated research enzyme‐linked immunosorbent assay. Real‐time Taqman® polymerase chain reaction was used to determine variants at 17 loci in 11 cytokine genes (IL1A, IL1B, IL2, TNF, TLR4, IL4, IL6, IL10, IL10RA, IL12A and IL13). We estimated the odds ratio and the 95% confidence interval for the association of genetic polymorphisms with H. pylori seropositivity, using logistic regression. Results: Forty (20.1%) of 199 children were seropositive. Children's H. pylori seropositivity correlated highly with maternal H. pylori seropositivity (OR = 7.98, 95% CI = 1.05–60.60, p = .02). Children carrying IL1A?889T had a lower risk of H. pylori positivity, compared to those carrying ?889C, with each T allele associated with 43% risk reduction (OR = 0.57, 95% CI = 0.33–0.99, p‐trend = .05). No other loci we examined were associated with the risk of H. pylori seropositivity. Conclusions: The IL1A?889 T allele, known to express a higher level of cytokine IL‐1α, is associated with a lower risk of H. pylori infection among Jamaican children. Our finding supports the hypothesis that an upregulation of pro‐inflammatory cytokines may protect against persistent H. pylori colonization. 相似文献