全文获取类型
收费全文 | 1979篇 |
免费 | 189篇 |
专业分类
2168篇 |
出版年
2021年 | 23篇 |
2019年 | 22篇 |
2018年 | 22篇 |
2017年 | 18篇 |
2016年 | 31篇 |
2015年 | 49篇 |
2014年 | 50篇 |
2013年 | 78篇 |
2012年 | 94篇 |
2011年 | 83篇 |
2010年 | 50篇 |
2009年 | 57篇 |
2008年 | 76篇 |
2007年 | 76篇 |
2006年 | 71篇 |
2005年 | 80篇 |
2004年 | 57篇 |
2003年 | 77篇 |
2002年 | 82篇 |
2001年 | 69篇 |
2000年 | 54篇 |
1999年 | 45篇 |
1998年 | 30篇 |
1997年 | 29篇 |
1996年 | 18篇 |
1995年 | 19篇 |
1994年 | 16篇 |
1993年 | 20篇 |
1992年 | 41篇 |
1991年 | 32篇 |
1990年 | 28篇 |
1989年 | 16篇 |
1988年 | 32篇 |
1987年 | 35篇 |
1986年 | 35篇 |
1985年 | 36篇 |
1984年 | 30篇 |
1983年 | 37篇 |
1982年 | 28篇 |
1981年 | 31篇 |
1980年 | 16篇 |
1979年 | 17篇 |
1978年 | 21篇 |
1977年 | 21篇 |
1976年 | 17篇 |
1975年 | 21篇 |
1974年 | 20篇 |
1973年 | 17篇 |
1972年 | 25篇 |
1968年 | 18篇 |
排序方式: 共有2168条查询结果,搜索用时 15 毫秒
141.
Action potentials initiate in the axon initial segment (AIS), a specialized compartment enriched with Na(+) and K(+) channels. Recently, we found that T- and R-type Ca(2+) channels are concentrated in the AIS, where they contribute to local subthreshold membrane depolarization and thereby influence action potential initiation. While periods of high-frequency activity can alter availability of AIS voltage-gated channels, mechanisms for long-term modulation of AIS channel function remain unknown. Here, we examined the regulatory pathways that control AIS Ca(2+) channel activity in brainstem interneurons. T-type Ca(2+) channels were downregulated by dopamine receptor activation acting via protein kinase C, which in turn reduced neuronal output. These effects occurred without altering AIS Na(+) or somatodendritic T-type channel activity and could be mediated by endogenous dopamine sources present in the auditory brainstem. This pathway represents a new mechanism to inhibit neurons by specifically regulating Ca(2+) channels directly involved in action potential initiation. 相似文献
142.
Camilla L. Nesb? Rajkumari Kumaraswamy Marlena Dlutek W. Ford Doolittle Julia Foght 《Applied and environmental microbiology》2010,76(14):4896-4900
All cultivated Thermotogales are thermophiles or hyperthermophiles. However, optimized 16S rRNA primers successfully amplified Thermotogales sequences from temperate hydrocarbon-impacted sites, mesothermic oil reservoirs, and enrichment cultures incubated at <46°C. We conclude that distinct Thermotogales lineages commonly inhabit low-temperature environments but may be underreported, likely due to “universal” 16S rRNA gene primer bias.Thermotogales, a bacterial group in which all cultivated members are anaerobic thermophiles or hyperthermophiles (5), are rarely detected in anoxic mesothermic environments, yet their presence in corresponding enrichment cultures, bioreactors, and fermentors has been observed using metagenomic methods and 16S rRNA gene amplification (6) (see Table S1 in the supplemental material). The most commonly detected lineage is informally designated here “mesotoga M1” (see Table S1 in the supplemental material). PCR experiments indicated that mesotoga M1 sequences amplified inconsistently using “universal” 16S rRNA gene primers, perhaps explaining their poor detection in DNA isolated from environmental samples (see text and Table S2 in the supplemental material). We therefore designed three 16S rRNA PCR primer sets (Table (Table1)1) targeting mesotoga M1 bacteria and their closest cultivated relative, Kosmotoga olearia. Primer set A was the most successful set, detecting a wider diversity of Thermotogales sequences than set B and being more Thermotogales-specific than primer set C (Table (Table22).
Open in a separate windowaHeterogeneity hot spots identified in reference 1.
Open in a separate windowaSee the supplemental material for site and methodological details. NA, not applicable; ND, not determined.bThe number of OTUs observed at a 0.01 distance cutoff is given for each primer set. The numbers of clones with Thermotogales sequences are in parentheses. —, PCR was attempted but no Thermotogales sequences were obtained or the PCR consistently failed.c+, sequence(s) detected; −, not detected. For more information on the enrichments, see the text and Table S3 in the supplemental material.dFrom April to May 2004, the temperature at the depth where the sample was taken was 12°C (7).eThere were no water samples from DWH and HSAT available for enrichment cultures, and no DNA was available from HWH.fThis reservoir has been treated with biocides; moreover, at this site, the water is filtered before being reinjected into the reservoir.gTemperatures of the oil pool where the water sample was obtained. The HSAT facility receives water from two oil pools, one at 41°C and one at 50°C.hWe screened DNA from samples taken in 2006 and 2008 but detected the same sequences in both, so sequences from the two samples were pooled.iThe mesotoga M1 and Kosmotoga sequences from DWH and DF were >99% similar and were assembled into one sequence in Fig. Fig.11.jThis reservoir has been injected with water from a neighboring oil reservoir.Since the putative mesophilic Thermotogales have been overwhelmingly associated with polluted and hydrocarbon-impacted environments and mesothermic oil reservoirs are the only natural environments where mesotoga M1 sequences previously were detected (see Table S1 in the supplemental material), we selected four oil reservoirs with in situ temperatures of 14°C to 53°C and two temperate, chronically hydrocarbon-impacted sites for analysis (Table (Table2).2). Total community DNA was extracted, the 16S rRNA genes were amplified, cloned, and sequenced as described in the supplemental material. 相似文献
TABLE 1.
Primers targeting mesotoga M1 bacteria constructed and used in this studyPrimer | Sequence (5′ to 3′) | Position in mesotoga 16S rRNA gene | No. of heterogeneity hot spotsa | Potential primer match in other Thermotogales lineages |
---|---|---|---|---|
Primer set A | 1 (helix 17) | |||
NMes16S.286F | CGGCCACAAGGAYACTGAGA | 286 | Perfect match in Kosmotoga olearia. The last 7 or 8 nucleotides at the 3′ end are conserved in other Thermotogales lineages. | |
NMes16S.786R | TGAACATCGTTTAGGGCCAG | 786 | One 5′ mismatch in Kosmotoga olearia and Petrotoga mobilis; 2-4 internal and 5′ mismatches in other lineages | |
Primer set B | None | |||
BaltD.42F | ATCACTGGGCGTAAAGGGAG | 540 | Perfect match in Kosmotoga olearia; one or two 3′ mismatches in most other Thermotogales lineages | |
BaltD.494R | GTGGTCGTTCCTCTTTCAAT | 992 | No match in other Thermotogaleslineages. The primer is located in heterogeneity hot spot helices 33 and 34. This primer also fails to amplify some mesotoga M1 sequences. | |
Primer set C | 9 (all 9 regions) | |||
TSSU-3F | TATGGAGGGTTTGATCCTGG | 3 | Perfect match in Thermotoga spp., Kosmotoga olearia, and Petrotoga mobilis; two or three 5′ mismatches in other Thermotogales lineages; one 5′ mismatch to mesotoga M1 16S rRNA genes | |
Mes16S.R | ACCAACTCGGGTGGCTTGAC | 1390 | One 5′ mismatch in Kosmotoga olearia; 1-3 internal or 5′ mismatches in other Thermotogales lineages |
TABLE 2.
Mesotoga clade sequences detected in environmental samples and enrichment cultures screened in this studyaSite (abbreviation) | Temp in situ(°C) | Waterflooded | Environmental samplesb | Enrichment cultures | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Primer set A | Primer set B | Primer set C | Thermotogalesdetected by primer setc: | Lineage(s) detected | ||||||||
No. of OTUs (no. of clones) | Lineage | No. of OTUs (no. of clones) | Lineage | No. of OTUs (no. of clones) | Lineage | A | B | C | ||||
Sidney Tar Ponds sediment (TAR) | Temperate | NA | 1 (5) | M1 | 1 | M1 | — | — | + | + | + | M1, M2, M5 |
Oil sands settling basin tailings (05mlsb) | ∼12d | NA | — | — | 1 (6) | M1 | — | — | − | + | − | M1 |
Grosmont A produced water (GrosA) | 20 | No | 1 (15) | M1 | 1 (22) | M1 | 2 (14) | M1 | + | + | + | M1 |
Foster Creek produced water (FC) | 14 | No | 1 (21) | M1 | 1 (23) | M1 | 1 (1) | M1 | + | ND | − | M1 |
Oil field D wellhead water (DWH)e,f | 52-53g | Yes | 1 (14) | Kosmotogai | 1 (6) | M1i | 1 (1) | Kosmotogai | NA | NA | NA | NA |
Oil field D FWKO water (DF)f,h | 20-30 | Yes | 1 (45) | Kosmotogai | 1 (17) | M1i | — | — | + | + | − | M1, Kosmotoga, Petrotoga |
Oil field H FWKO water (HF)j | 30-32 | Yes | 7 (59) | M1, M2, M3, M4, Kosmotoga | 1 (29) | M1 | — | — | + | + | − | M1, Petrotoga |
Oil field H satellite water (HSAT)e,j | 41 and 50g | Yes | 1 (8) | M1 | — | — | 2 (16) | Kosmotoga, Thermotoga | NA | NA | NA | NA |
Oil field H wellhead water (HWH)e,j | 41 and 50g | Yes | NA | — | — | NA | NA | NA | + | + | + | M1, Petrotoga |
143.
Ford DA 《Clinical lipidology.》2010,5(6):835-852
Leukocytes, containing myeloperoxidase (MPO), produce the reactive chlorinating species, HOCl, and they have important roles in the pathophysiology of cardiovascular disease. Leukocyte-derived HOCl can target primary amines, alkenes and vinyl ethers of lipids, resulting in chlorinated products. Plasmalogens are vinyl ether-containing phospholipids that are abundant in tissues of the cardiovascular system. The HOCl oxidation products derived from plasmalogens are α-chlorofatty aldehyde and unsaturated molecular species of lysophosphatidylcholine. α-chlorofatty aldehyde is the precursor of both α-chlorofatty alcohol and α-chlorofatty acid. Both α-chlorofatty aldehyde and α-chlorofatty acid accumulate in activated neutrophils and have disparate chemotactic properties. In addition, α-chlorofatty aldehyde increases in activated monocytes, human atherosclerotic lesions and rat infarcted myocardium. This article addresses the pathways for the synthesis of these lipids and their biological targets. 相似文献
144.
Jim M Dunwell Mike J Wilkinson Stephen Nelson Sri Wening Andrew C Sitorus Devi Mienanti Yuzer Alfiko Adam E Croxford Caroline S Ford Brian P Forster Peter DS Caligari 《BMC plant biology》2010,10(1):1-25
Background
Studies on host-pathogen interactions in a range of pathosystems have revealed an array of mechanisms by which plants reduce the efficiency of pathogenesis. While R-gene mediated resistance confers highly effective defense responses against pathogen invasion, quantitative resistance is associated with intermediate levels of resistance that reduces disease progress. To test the hypothesis that specific loci affect distinct stages of fungal pathogenesis, a set of maize introgression lines was used for mapping and characterization of quantitative trait loci (QTL) conditioning resistance to Setosphaeria turcica, the causal agent of northern leaf blight (NLB). To better understand the nature of quantitative resistance, the identified QTL were further tested for three secondary hypotheses: (1) that disease QTL differ by host developmental stage; (2) that their performance changes across environments; and (3) that they condition broad-spectrum resistance.Results
Among a set of 82 introgression lines, seven lines were confirmed as more resistant or susceptible than B73. Two NLB QTL were validated in BC4F2 segregating populations and advanced introgression lines. These loci, designated qNLB1.02 and qNLB1.06, were investigated in detail by comparing the introgression lines with B73 for a series of macroscopic and microscopic disease components targeting different stages of NLB development. Repeated greenhouse and field trials revealed that qNLB1.06 Tx303 (the Tx303 allele at bin 1.06) reduces the efficiency of fungal penetration, while qNLB1.02 B73 (the B73 allele at bin 1.02) enhances the accumulation of callose and phenolics surrounding infection sites, reduces hyphal growth into the vascular bundle and impairs the subsequent necrotrophic colonization in the leaves. The QTL were equally effective in both juvenile and adult plants; qNLB1.06 Tx303 showed greater effectiveness in the field than in the greenhouse. In addition to NLB resistance, qNLB1.02 B73 was associated with resistance to Stewart's wilt and common rust, while qNLB1.06 Tx303 conferred resistance to Stewart's wilt. The non-specific resistance may be attributed to pleiotropy or linkage.Conclusions
Our research has led to successful identification of two reliably-expressed QTL that can potentially be utilized to protect maize from S. turcica in different environments. This approach to identifying and dissecting quantitative resistance in plants will facilitate the application of quantitative resistance in crop protection. 相似文献145.
The amyloid-beta rise and gamma-secretase inhibitor potency depend on the level of substrate expression 总被引:2,自引:0,他引:2
Burton CR Meredith JE Barten DM Goldstein ME Krause CM Kieras CJ Sisk L Iben LG Polson C Thompson MW Lin XA Corsa J Fiedler T Pierdomenico M Cao Y Roach AH Cantone JL Ford MJ Drexler DM Olson RE Yang MG Bergstrom CP McElhone KE Bronson JJ Macor JE Blat Y Grafstrom RH Stern AM Seiffert DA Zaczek R Albright CF Toyn JH 《The Journal of biological chemistry》2008,283(34):22992-23003
The amyloid-beta (Abeta) peptide, which likely plays a key role in Alzheimer disease, is derived from the amyloid-beta precursor protein (APP) through consecutive proteolytic cleavages by beta-site APP-cleaving enzyme and gamma-secretase. Unexpectedly gamma-secretase inhibitors can increase the secretion of Abeta peptides under some circumstances. This "Abeta rise" phenomenon, the same inhibitor causing an increase in Abeta at low concentrations but inhibition at higher concentrations, has been widely observed. Here we show that the Abeta rise depends on the beta-secretase-derived C-terminal fragment of APP (betaCTF) or C99 levels with low levels causing rises. In contrast, the N-terminally truncated form of Abeta, known as "p3," formed by alpha-secretase cleavage, did not exhibit a rise. In addition to the Abeta rise, low betaCTF or C99 expression decreased gamma-secretase inhibitor potency. This "potency shift" may be explained by the relatively high enzyme to substrate ratio under conditions of low substrate because increased concentrations of inhibitor would be necessary to affect substrate turnover. Consistent with this hypothesis, gamma-secretase inhibitor radioligand occupancy studies showed that a high level of occupancy was correlated with inhibition of Abeta under conditions of low substrate expression. The Abeta rise was also observed in rat brain after dosing with the gamma-secretase inhibitor BMS-299897. The Abeta rise and potency shift are therefore relevant factors in the development of gamma-secretase inhibitors and can be evaluated using appropriate choices of animal and cell culture models. Hypothetical mechanisms for the Abeta rise, including the "incomplete processing" and endocytic models, are discussed. 相似文献
146.
Chen W Ford MS Young KJ Cybulsky MI Zhang L 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(4):1846-1853
A novel subset of CD3(+)CD4(-)CD8(-) (double negative; DN) regulatory T cells has recently been shown to induce donor-specific skin allograft acceptance following donor lymphocyte infusion (DLI). In this study, we investigated the effect of DLI on rat to mouse cardiac xenotransplant survival and the ability of DN T cells to regulate xenoreactive T cells. B6 mice were given either DLI from Lewis rats, a short course of depleting anti-CD4 mAb, both DLI and anti-CD4 treatment together, or left untreated. DLI alone did not prolong graft survival when compared with untreated controls. Although anti-CD4-depleting mAb alone significantly prolonged graft survival, grafts were eventually rejected by all recipients. However, the combination of DLI and anti-CD4 treatment induced permanent cardiac xenograft survival. We demonstrate that recipients given both DLI and anti-CD4 treatment had a significant increase in the total number of DN T cells in their spleens when compared with all other treatment groups. Furthermore, DN T cells harvested from the spleens of DLI plus anti-CD4-treated mice could dose-dependently inhibit the proliferation of syngeneic antidonor T cells. Suppression mediated by these DN T cells was specific for antidonor T cells as T cells stimulated by third-party Ags were not suppressed. These results demonstrate for the first time that a combination of pretransplant DLI and anti-CD4-depleting mAb can induce permanent survival of rat to mouse cardiac xenografts and that DN T regulatory cells play an important role in preventing long-term concordant xenograft rejection through the specific suppression of antidonor T cells. 相似文献
147.
Ecology and conservation of insectivorous bats in fragmented areas of macadamia production in eastern Australia 下载免费PDF全文
Eduardo Crisol‐Martínez Greg Ford Finbarr G. Horgan Philip H. Brown Kevin R. Wormington 《Austral ecology》2017,42(5):597-610
Microbats perform important ecological services in agro‐ecosystems, but several species are globally threatened by loss of roosting and breeding habitats. The successful conservation of bats in agricultural land requires adequate knowledge of their ecology. Using ultrasonic recorders, we studied the activity of insectivorous bats in areas of macadamia production in eastern Australia at two spatial scales: across woodland‐orchard transects at the local scale and across three levels of fragmentation at the landscape scale. At the local scale, activity patterns of ‘clutter’ and ‘edge’ specialists were consistently higher in woodland patches, gradually decreasing towards isolated orchards, where only a few ‘open’ specialists were active. At the landscape scale, bat community activity was affected by the level of fragmentation, partly because three of the most recorded taxa (Austronomus australis, Saccolaimus flaviventris and Miniopterus australis) had their highest activity in less‐fragmented areas. A distance‐based model explained 24% of the bat community activity based on a combination of six environmental variables. Canonical correspondence analysis showed that a number of bat taxa were associated with open areas of macadamia, whereas other taxa were associated with increasing values of landscape composition, and arthropod and water availability. In addition, total bat activity was highly correlated with foraging rate. These results suggest that most bat taxa were influenced by proximity to woodland and the degree of fragmentation, and only few taxa were able to exploit isolated orchards. Environmental factors that promote bat activity could be exploited to strengthen conservation efforts. Preserving remnant woodland and promoting habitat heterogeneity will benefit several bat species. In particular, the foraging activity of ‘edge’ specialists could be fostered by increasing landscape connectivity and maintaining unobstructed water bodies near macadamia orchards. Considering that bats forage as they navigate these areas, conservation efforts could also bring benefits to farmers through pest‐reduction services. 相似文献
148.
149.
150.
Variation in age at maturity is an important contributor to life history and demographic variation within and among species. The optimal age at maturity can vary by sex, and the ability of each sex to evolve towards its fitness optimum depends on the genetic architecture of maturation. Using GWAS of RAD sequencing data, we show that age at maturity in Chinook salmon exhibits sex‐specific genetic architecture, with age at maturity in males influenced by large (up to 20 Mb) male‐specific haplotypes. These regions showed no such effect in females. We also provide evidence for translocation of the sex‐determining gene between two different chromosomes. This has important implications for sexually antagonistic selection, particularly that sex linkage of adaptive genes may differ within and among populations based on chromosomal location of the sex‐determining gene. Our findings will facilitate research into the genetic causes of shifting demography in Chinook salmon as well as a better understanding of sex determination in this species and Pacific salmon in general. 相似文献