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21.
22.
Humans develop polyclonal, serotype-specific neutralizing antibody responses after dengue virus (DENV) infection. Many mouse antibodies that neutralize DENV bind to the lateral ridge or A strand epitopes on domain III of the viral envelope (EDIII) protein. It has been assumed that these epitopes are also the main target of human neutralizing antibodies. Using recombinant dengue serotype 2 viruses with altered EDIII epitopes, we demonstrate that EDIII epitopes are not the main target of human neutralizing antibody. 相似文献
23.
John Paul SanGiovanni Dan E. Arking Sudha K. Iyengar Michael Elashoff Traci E. Clemons George F. Reed Alice K. Henning Theru A. Sivakumaran Xuming Xu Andrew DeWan Elvira Agrón Elena Rochtchina Carolyn M. Sue Jie Jin Wang Paul Mitchell Josephine Hoh Peter J. Francis Michael L. Klein Emily Y. Chew Aravinda Chakravarti 《PloS one》2009,4(5)
Background
Age-related macular degeneration (AMD), a chronic neurodegenerative and neovascular retinal disease, is the leading cause of blindness in elderly people of western European origin. While structural and functional alterations in mitochondria (mt) and their metabolites have been implicated in the pathogenesis of chronic neurodegenerative and vascular diseases, the relationship of inherited variants in the mitochondrial genome and mt haplogroup subtypes with advanced AMD has not been reported in large prospective cohorts.Methodology/Prinicipal Findings
We examined the relationship of inherited mtDNA variants with advanced AMD in 1168 people using a three-stage design on samples from 12-year and 10-year prospective studies on the natural history of age-related eye disease. In Stage I we resequenced the entire genome in 99 elderly AMD-free controls and 215 people with advanced AMD from the 12-year study. A consistent association with AMD in 14 of 17 SNPs characterizing the mtDNA T haplogroup emerged. Further analysis revealed these associations were driven entirely by the T2 haplogroup, and characterized by two variants in Complex I genes (A11812G of MT-ND4 and A14233G of MT-ND6). We genotyped T haplogroups in an independent sample of 490 cases and 61 controls from the same study (Stage II) and in 56 cases and 246 controls from the 10-year study (Stage III). People in the T2 haplogroup were approximately 2.5 times more likely to have advanced AMD than their peers (odds ratio [OR] = 2.54, 95%CI 1.36–4.80, P≤0.004) after considering the totality of evidence. Findings persisted after considering the impact of AMD-associated variants A69S and Y402H (OR = 5.19, 95%CI 1.19–22.69, P≤0.029).Conclusion
Loci defining the mtDNA T2 haplogroup and Complex I are reasonable targets for novel functional analyses and therapeutic research in AMD. 相似文献24.
Ann Z. Moore Mary L. Biggs Amy Matteini Ashley O'Connor Sarah McGuire Brock A. Beamer M. Danielle Fallin Linda P. Fried Jeremy Walston Aravinda Chakravarti Dan E. Arking 《PloS one》2010,5(6)
Background
Mitochondria contribute to the dynamics of cellular metabolism, the production of reactive oxygen species, and apoptotic pathways. Consequently, mitochondrial function has been hypothesized to influence functional decline and vulnerability to disease in later life. Mitochondrial genetic variation may contribute to altered susceptibility to the frailty syndrome in older adults.Methodology/Principal Findings
To assess potential mitochondrial genetic contributions to the likelihood of frailty, mitochondrial DNA (mtDNA) variation was compared in frail and non-frail older adults. Associations of selected SNPs with a muscle strength phenotype were also explored. Participants were selected from the Cardiovascular Health Study (CHS), a population-based observational study (1989–1990, 1992–1993). At baseline, frailty was identified as the presence of three or more of five indicators (weakness, slowness, shrinking, low physical activity, and exhaustion). mtDNA variation was assessed in a pilot study, including 315 individuals selected as extremes of the frailty phenotype, using an oligonucleotide sequencing microarray based on the Revised Cambridge Reference Sequence. Three mtDNA SNPs were statistically significantly associated with frailty across all pilot participants or in sex-stratified comparisons: mt146, mt204, and mt228. In addition to pilot participants, 4,459 additional men and women with frailty classifications, and an overlapping subset of 4,453 individuals with grip strength measurements, were included in the study population genotyped at mt204 and mt228. In the study population, the mt204 C allele was associated with greater likelihood of frailty (adjusted odds ratio = 2.04, 95% CI = 1.07–3.60, p = 0.020) and lower grip strength (adjusted coefficient = −2.04, 95% CI = −3.33– −0.74, p = 0.002).Conclusions
This study supports a role for mitochondrial genetic variation in the frailty syndrome and later life muscle strength, demonstrating the importance of the mitochondrial genome in complex geriatric phenotypes. 相似文献25.
Female fecundity, oviposition preference and specificity on one normal and two novel food media were assayed on four laboratory
populations ofDrosophila melanogaster, revealing considerable among- and within-population variation in oviposition preference. Overall, there was a significant
tendency of females to prefer novel media to their normal banana food as an oviposition substrate. Specificity in the populations
was fairly high, implying that a large proportion of females tended to lay the majority of their eggs on the preferred medium.
The results showed that oviposition preference for a given food medium could be affected by the alternative provided, and
that, consequently, oviposition preference for a given food medium versus another cannot be predicted based upon a knowledge
of what the preference for each of the two media was versus a common third medium. Specificity, on the other hand, was not
significantly affected by the type of alternative food media provided in a given trial. Moreover, comparison of results from
fecundity and oviposition preference assays also showed that the egg laying behaviour ofDrosophila females in response to different food media may be different in choice versus no-choice situations. Thus, a substrate on
which fecundity is higher than on another, when assayed in a no-choice situation, may not be preferred over the other substrate
when a choice between the two is provided to the ovipositing females. The latter two results point to possible complexity
in the responses of females to various oviposition substrates based upon the overall setting of the assay, including the alternative
substrates present for egg laying. 相似文献
26.
Misha Angrist Shuqian Jing Stacey Bolk Kimberly Bentley Sudha Nallasamy Marc Halushka Gary M. Fox Aravinda Chakravarti 《Genomics》1998,48(3):354
Congenital aganglionic megacolon, commonly known as Hirschsprung disease (HSCR), is the most frequent cause of congenital bowel obstruction. Germline mutations in theRETreceptor tyrosine kinase have been shown to cause HSCR. Knockout mice forRETand for its ligand, glial cell line-derived neurotrophic factor (GDNF), exhibit both complete intestinal aganglionosis and renal defects. Recently, GDNF and GFRA1 (GDNF family receptor, also known as GDNFR-α), its GPI-linked coreceptor, were demonstrated to be components of a functional ligand for RET. Moreover,GDNFhas been implicated in rare cases of HSCR. We have mappedGFRA1to human chromosome 10q25, isolated human and mouse genomic clones, determined the gene's intron–exon boundaries, isolated a highly polymorphic microsatellite marker adjacent to exon 7, and scanned forGFRA1mutations in a large panel of HSCR patients. No evidence of linkage was detected in HSCR kindreds, and no sequence variants were found to be in significant excess in patients. These data suggest thatGFRA1's role in enteric neurogenesis in humans remains to be elucidated and that RET signaling in the gut may take place via alternate pathways, such as the recently described GDNF-related molecule neurturin and its GFRA1-like coreceptor, GFRA2. 相似文献
27.
A Prem Kumar Anirudra Ghorai Vasudev Kriplani Rabindra Kumar Dash J Aravinda Paramesh Shamanna TK Sabeer Abdul Hannan Mahesh Abhyankar Santosh Revankar 《Bioinformation》2021,17(6):652
It is of interest to evaluate the clinical characteristics, treatment patterns, clinical effectiveness, and safety of telmisartan as a monotherapy or as part of combination therapy in Indian adults (>18 years old) with hypertension. All patients were receiving telmisartan as monotherapy, or as a combination therapy for hypertension management. Demographics, risk factors, existing comorbidity, and ongoing medical therapies were retrieved from the patients’ medical records. A total of 8607 patients with hypertension (median age, 51.0 years) were part of the study. The gender distribution suggested, 5534(64.3%) patients were male, and 3073 (35.7%) were female patients. The excess salt intake (39.0%) was the most common risk factor according to the results. The analysis revealed telmisartan dual therapy (57.9%) as the most prescribed therapy, followed by monotherapy (32.5%), and triple therapy (9.6%). Further, telmisartan 40mg (21.3%) and telmisartan 40mg plus amlodipine 5mg (17.6%) were the most commonly prescribed therapies. The data suggested that only 17.2% of patients required dose titration. The mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) (mmHg) were significantly decreased with monotherapy (mean change: 19.8 [15.1] mmHg and 8.8[8.2] mmHg), dual therapy (mean change: 23.7 [16.6] mmHg and 10.3[8.5] mmHg), and triple therapy (mean change: 28.6 [19.0] mmHg and 12.1[10.8] mmHg) after the treatment (P<0.001). A total of 98.4% of the patients were compliant, and 97.6% achieved the target blood pressure goal with telmisartan-based therapy. There were 157 adverse events reported altogether. The Physicians'' global evaluation of efficacy and tolerability showed the majority of the patients receiving telmisartan-based therapy on a good to excellent scale. Telmisartan used as a monotherapeutic agent or as a part of combination therapy was successful and effective in reducing blood pressure and achieving the blood pressure target. Irrespective of the patient’s age, duration, and stages of hypertension, the study resulted in a good to excellent scale in efficacy and tolerability in the Indian patients having hypertension. 相似文献
28.
Gu CC Chang YP Hunt SC Schwander K Arnett D Djousse L Heiss G Oberman A Lalouel JM Province M Chakravarti A Rao DC 《Human heredity》2005,60(3):164-176
OBJECTIVE: Function of the renin-angiotensin system is important to human hypertension, but its genetic etiology remains elusive. We set out to examine a hypothesis that multiple genetic variants in the system act together in blood pressure regulation, via intermediate phenotypes such as blood pressure reactivity. METHODS: A sample of 531 hypertensive cases and 417 controls was selected from the HyperGEN study. Hypertension-related traits including blood pressure responses to challenges to math test, handgrip and postural change (mathBP, gripBP, and postBP), and body mass index (BMI) were analyzed for association with 10 single nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT) gene. Single-marker and haplotype analyses were performed to examine the effects of both individual and multiple variants. Multiple-trait profiling was used to assess interaction of latent intermediate factors with susceptible haplotypes. RESULTS: In Blacks, two SNPs in exon 5 and 3'UTR showed significant association with gripBP, and two promoter SNPs were strongly associated with postBP. In Whites, only borderline association was found for 2 promoter SNPs with mathBP. Haplotype analyses in Blacks confirmed association with gripBP, and detected significant association of a haplotype to BMI (p=0.029). With the interactions modeled, haplotype associations found in Blacks remain significant, while significant associations to BMI (p=0.009) and gripSBP emerged in Whites. CONCLUSION: Genetic variants in regulatory regions of AGT showed strong association with blood pressure reactivity. Interaction of promoter and genic SNPs in AGT revealed collective action of multiple variants on blood pressure reactivity and BMI both in Blacks and in Whites, possibly following different pathways. 相似文献
29.
Protective and therapeutic capacity of human single-chain Fv-Fc fusion proteins against West Nile virus 总被引:5,自引:0,他引:5
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Gould LH Sui J Foellmer H Oliphant T Wang T Ledizet M Murakami A Noonan K Lambeth C Kar K Anderson JF de Silva AM Diamond MS Koski RA Marasco WA Fikrig E 《Journal of virology》2005,79(23):14606-14613
West Nile virus has spread rapidly across the United States, and there is currently no approved human vaccine or therapy to prevent or treat disease. Passive immunization with antibodies against the envelope protein represents a promising means to provide short-term prophylaxis and treatment for West Nile virus infection. In this study, we identified a panel of 11 unique human single-chain variable region antibody fragments (scFvs) that bind the envelope protein of West Nile virus. Selected scFvs were converted to Fc fusion proteins (scFv-Fcs) and were tested in mice for their ability to prevent lethal West Nile virus infection. Five of these scFv-Fcs, 11, 15, 71, 85, and 95, protected 100% of mice from death when given prior to infection with virus. Two of them, 11 and 15, protected 80% of mice when given at days 1 and 4 after infection. In addition, four of the scFv-Fcs cross-neutralized dengue virus, serotype 2. Binding assays using yeast surface display demonstrated that all of our scFvs bind to sites within domains I and II of West Nile virus envelope protein. These recombinant human scFvs are potential candidates for immunoprophylaxis and therapy of flavivirus infections. 相似文献
30.
The tick-borne bacterium Borrelia burgdorferi has over 20 different circular and linear plasmids. Some B. burgdorferi plasmids are readily lost during in vitro culture or genetic manipulation. Linear plasmid 25, which is often lost in laboratory strains, is required for the infection of mice. Strains missing linear plasmid 25 (lp25(-)) are able to infect mice if the BBE22 gene on lp25 is provided on a shuttle vector. In this study, we examined the role of lp25 and BBE22 in tick infections. We tested the hypothesis that complementation with BBE22 in spirochetes lacking lp25 would restore the ability of spirochetes to infect ticks. A natural tick infection cycle was performed by feeding larvae on mice injected with the parental, lp25(-), or lp25(-) BBE22-complemented spirochete strains. In addition, larvae and nymphs were artificially infected with different strains to study tick infections independent of mouse infections. B. burgdorferi missing lp25 was significantly impaired in its ability to infect larval and nymphal ticks. When an lp25(-) strain was complemented with BBE22, the ability to infect ticks was partially restored. Complementation with BBE22 allowed spirochetes lacking lp25 to establish short-term infections in ticks, but in most cases the infection prevalence was lower than that of the wild-type strain. In addition, the number of infected ticks decreased over time, suggesting that another gene(s) on lp25 is required for long-term persistence in ticks and completion of a natural infection cycle. 相似文献