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81.
We have engineered the Fc region of a human immunoglobulin G (IgG) to generate a mutated antibody that modulates the concentrations of endogenous IgGs in vivo. This has been achieved by targeting the activity of the Fc receptor, FcRn, which serves through its IgG salvage function to maintain and regulate IgG concentrations in the body. We show that an IgG whose Fc region was engineered to bind with higher affinity and reduced pH dependence to FcRn potently inhibits FcRn-IgG interactions and induces a rapid decrease of IgG levels in mice. Such FcRn blockers (or 'Abdegs,' for antibodies that enhance IgG degradation) may have uses in reducing IgG levels in antibody-mediated diseases and in inducing the rapid clearance of IgG-toxin or IgG-drug complexes. 相似文献
82.
83.
Gene-environment interaction effects on the development of immune responses in the 1st year of life 总被引:9,自引:0,他引:9 下载免费PDF全文
Hoffjan S Nicolae D Ostrovnaya I Roberg K Evans M Mirel DB Steiner L Walker K Shult P Gangnon RE Gern JE Martinez FD Lemanske RF Ober C 《American journal of human genetics》2005,76(4):696-704
Asthma is a common disease that results from both genetic and environmental risk factors. Children attending day care in the 1st year of life have lower risks for developing asthma, although the mechanism for this "day care" effect is largely unknown. We investigated the interactions between day care exposure in the 1st 6 mo of life and genotypes for 72 polymorphisms at 45 candidate loci and their effects on cytokine response profiles and on the development of atopic phenotypes in the 1st year of life in the Childhood Onset of Asthma (COAST) cohort of children. Six interactions (at four polymorphisms in three loci) with "day care" that had an effect on early-life immune phenotypes were significant at P<.001. The estimated false-discovery rate was 33%, indicating that an estimated four P values correspond to true associations. Moreover, the "day care" effect at some loci was accounted for by the increased number of viral infections among COAST children attending day care, whereas interactions at other loci were independent of the number of viral infections, indicating the presence of additional risk factors associated with day care environment. This study identified significant gene-environment interactions influencing the early patterning of the immune system and the subsequent development of asthma and highlights the importance of considering environmental risk factors in genetic analyses. 相似文献
84.
A recent genome-scan identified the Leu33Pro polymorphism in the 3 integrin (ITGB3) gene as a quantitative trait locus for whole blood serotonin level in a large Hutterite pedigree. Because both the Leu33Pro polymorphism and the serotonin system have been implicated in cardiovascular disease (CVD) risk and treatment response, we studied additional variation in ITGB3 and its relationship to intermediate phenotypes associated with CVD in the same population. We examined associations between 15 single nucleotide polymorphisms (SNPs) across ITGB3 and five CVD-related traits in the Hutterites: plasma levels of high density lipoprotein-cholesterol (HDL-c), triglycerides (TG), low density lipoprotein-cholesterol (LDL-c), and lipoprotein(a) [Lp(a)] and blood pressure or hypertension. Seven of these SNPs in ITGB3 were associated with whole blood serotonin. Among the intermediate CVD-related phenotypes, only Lp(a) was associated with multiple ITGB3 SNPs, five of which were also associated with serotonin. A sex-stratified analysis revealed that the association between ITGB3 and Lp(a) is present only in females, whereas the association between ITGB3 and serotonin is concentrated in males. Our results suggest that variation in ITGB3 in addition to Leu33Pro could contribute to susceptibility to CVD and serotonin in a sex-specific manner. 相似文献
85.
HLA and mate choice in humans. 总被引:13,自引:1,他引:12
C Ober L R Weitkamp N Cox H Dytch D Kostyu S Elias 《American journal of human genetics》1997,61(3):497-504
Evidence from studies in rodents suggests that mate selection is influenced by major-histocompatibility-complex haplotypes, with preferences for dissimilar partners. This study was initiated to determine whether avoidance of a mate with the same HLA haplotype as one's own might be occurring in the Hutterites, a North American reproductive isolate of European ancestry, notable for their large sibships, communal lifestyle, and limited number of five-locus HLA haplotypes (HLA-A, -B, -C, -DR, and -DQ). HLA haplotypes were known for 411 Hutterite couples. The number of couples expected to match for a haplotype was calculated in two ways: first, from population genotype frequencies, with account being taken of the nonrandom mating pattern with respect to colony lineages, and, second, from computer simulations using conservative founder assumptions and the exact genealogy of the 411 couples. We observed fewer matches for HLA haplotypes between spouses than expected (first method, P = .005; second method, P = .020-.067). Among couples who did match for a haplotype, the matched haplotype was inherited from the mother in 29 cases and from the father in 50 cases (P = .018). These results are consistent with the conclusion that Hutterite mate choice is influenced by HLA haplotypes, with an avoidance of spouses with haplotypes that are the same as one's own. 相似文献
86.
Root Growth and Oxygen Relations at Low Water Potentials. Impact
of Oxygen Availability in Polyethylene Glycol
Solutions 总被引:13,自引:1,他引:12 下载免费PDF全文
Polyethylene glycol (PEG), which is often used to impose low water potentials (ψw) in solution culture, decreases O2 movement by increasing solution viscosity. We investigated whether this property causes O2 deficiency that affects the elongation or metabolism of maize (Zea mays L.) primary roots. Seedlings grown in vigorously aerated PEG solutions at ambient solution O2 partial pressure (pO2) had decreased steady-state root elongation rates, increased root-tip alanine concentrations, and decreased root-tip proline concentrations relative to seedlings grown in PEG solutions of above-ambient pO2 (alanine and proline accumulation are responses to hypoxia and low ψw, respectively). Measurements of root pO2 were made using an O2 microsensor to ensure that increased solution pO2 did not increase root pO2 above physiological levels. In oxygenated PEG solutions that gave maximal root elongation rates, root pO2 was similar to or less than (depending on depth in the tissue) pO2 of roots growing in vermiculite at the same ψw. Even without PEG, high solution pO2 was necessary to raise root pO2 to the levels found in vermiculite-grown roots. Vermiculite was used for comparison because it has large air spaces that allow free movement of O2 to the root surface. The results show that supplemental oxygenation is required to avoid hypoxia in PEG solutions. Also, the data suggest that the O2 demand of the root elongation zone may be greater at low relative to high ψw, compounding the effect of PEG on O2 supply. Under O2-sufficient conditions root elongation was substantially less sensitive to the low ψw imposed by PEG than that imposed by dry vermiculite. 相似文献
87.
Proline Accumulation in Maize (Zea mays L.) Primary Roots at Low Water Potentials (I. Requirement for Increased Levels of Abscisic Acid) 总被引:8,自引:2,他引:6 下载免费PDF全文
We have characterized sulfate transport in the unicellular green alga Chlamydomonas reinhardtii during growth under sulfur-sufficient and sulfur-deficient conditions. Both the Vmax and the substrate concentration at which sulfate transport is half of the maximum velocity of the sulfate transport (K1/2) for uptake were altered in starved cells: the Vmax increased approximately 10-fold, and the K1/2 decreased approximately 7-fold. This suggests that sulfur-deprived C. reinhardtii cells synthesize a new, high-affinity sulfate transport system. This system accumulated rapidly; it was detected in cells within 1 h of sulfur deprivation and reached a maximum by 6 h. A second response to sulfur-limited growth, the production of arylsulfatase, was apparent only after 3 h of growth in sulfur-free medium. The enhancement of sulfate transport upon sulfur starvation was prevented by cycloheximide, but not by chloramphenicol, demonstrating that protein synthesis on 80S ribosomes was required for the development of the new, high-affinity system. The transport of sulfate into the cells occurred in both the light and the dark. Inhibition of ATP formation by the antibiotics carbonylcyanide m-chlorophenylhydrazone and gramicidin-S and inhibition of either F- or P-type ATPases by N,N-dicyclohexylcarbodiimide and vanadate completely abolished sulfate uptake. Furthermore, nigericin, a carboxylate ionophore that exchanges H+ for K+, inhibited transport in both the light and the dark. Finally, uptake in the dark was strongly inhibited by valinomycin. These results suggest that sulfate transport in C. reinhardtii is an energy-dependent process and that it may be driven by a proton gradient generated by a plasma membrane ATPase. 相似文献
88.
N Freinkel B E Metzger R L Phelps J L Simpson A O Martin R Radvany C Ober S L Dooley R O Depp A Belton 《Hormones et métabolisme》1986,18(7):427-430
One hundred ninety-nine gravida with gestational diabetes mellitus (GDM) defined as "carbohydrate intolerance of varying severity with onset or first recognition during pregnancy" have been stratified into subgroups on the basis of fasting plasma glucose and evaluated for further phenotypic and genotypic heterogeneity. A significantly greater proportion of the women in all our groups were older and heavier than in a "control" population of 148 consecutive gravida with documented normal oral glucose tolerance. After correction for age and weight by covariate analysis, absolute insulinopenia in response to oral glucose could be demonstrated in all GDM groups, although exceptions were present in each. The incidence of diabetes in the mothers of our patients with GDM was 8-fold greater than in controls; the incidence in fathers did not deviate from control patterns. HLA-DR3 and DR4 antigens were more frequently present in GDM and the increase was statistically significant in blacks. At the time of diagnosis, cytoplasmic islet cell antibodies (ICA) were significantly more common in GDM associated with elevated fasting plasma glucose than in controls; the frequency of ICA was 18.4% (7/38) in women with fasting plasma glucose greater than or equal to 130 mg/dl. Our findings indicate that GDM entails genotypic as well as phenotypic diversity and may include patients with slowly-evolving Type I diabetes mellitus, as well as patients with Type II diabetes mellitus, and women with asymptomatic diabetes which antedated the pregnancy (i.e. pregestational diabetes mellitus). Appreciation of this heterogeneity should be incorporated into any evaluation of intervention strategies for women with GDM or into prognoses concerning their postpartum metabolic status. 相似文献
89.
Prior studies in the Schmiedeleut Hutterites of South Dakota have demonstrated associations between human leukocyte antigen
(HLA) haplotype matching and fetal loss (Ober et al. 1992) and mate preferences (Ober et al. 1997), as well as deficiencies of
homozygotes for HLA haplotypes (Kostyu et al. 1993). These studies were based on the serologically-defined five-locus HLA-A, -C, -B, -DR, -DQ haplotype. To further elucidate the effects of specific major histocompatibility (MHC) loci or regions on fetal loss and
mate choice, we genotyped a sample of Hutterites for 14 MHC loci by DNA or biochemical methods. Typing for additional loci
in the HLA-A to HLA-DPB1 region increased the number of recognized Hutterite MHC haplotypes to 67, and further localized the site of cross-over in
9 of 15 recombinant haplotypes. Hutterite MHC haplotype sequences are similar to those observed in outbred Caucasians, suggesting
that the influence of HLA haplotypes on fetal loss and mating structure may be general.
Received: 1 May 1998 / Revised: 2 December 1998 相似文献
90.
Wageesha Senaratne Prabuddha Sengupta Cindy Harnett Harold Craighead Barbara Baird Christopher K. Ober 《NanoBioTechnology》2005,1(1):23-33
Protein patterning has become an important topic as advances are made in biologically integrated devices and protein chip
technology. Versatile and effective patterning requires substrates that can be quantified, with active presentation of proteins
and control over protein density and orientation. Herein we describe a model system and the use of low-energy electron beam
lithography to pattern molecular templates for immobilization of antibodies through ligand recognition. The templates were
patterned over a background of poly(ethylene glycol) (PEG) modified silicon oxide (SiO
x
). These substrates were exposed to a low-voltage (2 keV) electron beam to remove PEG selectively from exposed regions. These
regions were then functionalized with a dinitrophenyl (DNP) ligand and tested for specific binding of fluorescently labeled
anti-DNP antibodies. The PEG modified regions in conjunction with ligand-presenting regions in the patterned arrays substantially
reduces non-specific adsorption of proteins, yielding a specific/nonspecific ratio of approx 10. The surface coverage of the
biologically active DNP groups on SiO
x
and the amount of immobilized antibody on DNP were measured with a fluorescence-based, enzyme-linked immunosorbent assay.
The specificity of the interaction between DNP ligand and fluorescently labeled anti-DNP antibodies was evaluated with fluorescence
microscopy. This approach to patterning of molecular templates and assays for quantification are generally applicable to immobilization
of any ligand-receptor pair on a wide range of substrates. 相似文献