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941.
Yi-Juan Hu Peizhou Liao H. Richard Johnston Andrew S. Allen Glen A. Satten 《PLoS genetics》2016,12(5)
Next-generation sequencing of DNA provides an unprecedented opportunity to discover rare genetic variants associated with complex diseases and traits. However, the common practice of first calling underlying genotypes and then treating the called values as known is prone to false positive findings, especially when genotyping errors are systematically different between cases and controls. This happens whenever cases and controls are sequenced at different depths, on different platforms, or in different batches. In this article, we provide a likelihood-based approach to testing rare variant associations that directly models sequencing reads without calling genotypes. We consider the (weighted) burden test statistic, which is the (weighted) sum of the score statistic for assessing effects of individual variants on the trait of interest. Because variant locations are unknown, we develop a simple, computationally efficient screening algorithm to estimate the loci that are variants. Because our burden statistic may not have mean zero after screening, we develop a novel bootstrap procedure for assessing the significance of the burden statistic. We demonstrate through extensive simulation studies that the proposed tests are robust to a wide range of differential sequencing qualities between cases and controls, and are at least as powerful as the standard genotype calling approach when the latter controls type I error. An application to the UK10K data reveals novel rare variants in gene BTBD18 associated with childhood onset obesity. The relevant software is freely available. 相似文献
942.
Andrew C. Huang John E. Elliott Kimberly M. Cheng Kermit Ritland Carol E. Ritland Sarah K. Thomsen Sofi Hindmarch Kathy Martin 《Conservation Genetics》2016,17(2):357-367
The barn owl (Tyto alba) is a non-migratory species widely distributed across much of North America in areas with extensive old-field and grassland habitat and without extensive winter snow cover. We investigated the genetic diversity and phylogeographic patterns of barn owl populations in western North America, ranging from British Columbia (BC) to southern California, and one eastern population from Pennsylvania. We also determined the genetic distinctiveness of a population off the coast of southern California, Santa Barbara Island, as management plans to control the local owl population are being considered to decrease predation rate on the now threatened Scripps’s Murrelet (Synthliboramphus scrippsi). Using 8 polymorphic microsatellite markers (N = 126) and ND2 mitochondrial sequences (N = 37), we found little to no genetic structure among all sampled regions, with the exception of Santa Barbara Island. The BC mainland population, despite its northwestern geographically peripheral location and ongoing habitat degradation, is not genetically depauperate. However, individuals from Vancouver Island, likewise a peripheral population in BC, exhibited the lowest genetic diversity of all sampled locations. The low global FST value (0.028) estimated from our study suggests that old-field agricultural habitats are well connected in North America. Since the BC population has declined by about 50 % within the last three decades, it is vital to focus on preserving the remaining barn owl habitats in BC to allow successful establishment from neighbouring populations. Additionally, our microsatellite data revealed that the population on Santa Barbara Island showed genetic divergence from its continental counterpart. Mitochondrial data, however, demonstrated that this island population is not a monophyletic lineage containing unique haplotypes, and hence cannot be designated as an Evolutionarily Significant Unit. 相似文献
943.
Megan A. Greischar Nicole Mideo Andrew F. Read Ottar N. Bj?rnstad 《PLoS computational biology》2016,12(2)
Many microparasites infect new hosts with specialized life stages, requiring a subset of the parasite population to forgo proliferation and develop into transmission forms. Transmission stage production influences infectivity, host exploitation, and the impact of medical interventions like drug treatment. Predicting how parasites will respond to public health efforts on both epidemiological and evolutionary timescales requires understanding transmission strategies. These strategies can rarely be observed directly and must typically be inferred from infection dynamics. Using malaria as a case study, we test previously described methods for inferring transmission stage investment against simulated data generated with a model of within-host infection dynamics, where the true transmission investment is known. We show that existing methods are inadequate and potentially very misleading. The key difficulty lies in separating transmission stages produced by different generations of parasites. We develop a new approach that performs much better on simulated data. Applying this approach to real data from mice infected with a single Plasmodium chabaudi strain, we estimate that transmission investment varies from zero to 20%, with evidence for variable investment over time in some hosts, but not others. These patterns suggest that, even in experimental infections where host genetics and other environmental factors are controlled, parasites may exhibit remarkably different patterns of transmission investment. 相似文献
944.
Andrew Chay Ilaria Zamparo Andreas Koschinski Manuela Zaccolo Kim T. Blackwell 《PLoS computational biology》2016,12(2)
Norepinephrine, a neuromodulator that activates β-adrenergic receptors (βARs), facilitates learning and memory as well as the induction of synaptic plasticity in the hippocampus. Several forms of long-term potentiation (LTP) at the Schaffer collateral CA1 synapse require stimulation of both βARs and N-methyl-D-aspartate receptors (NMDARs). To understand the mechanisms mediating the interactions between βAR and NMDAR signaling pathways, we combined FRET imaging of cAMP in hippocampal neuron cultures with spatial mechanistic modeling of signaling pathways in the CA1 pyramidal neuron. Previous work implied that cAMP is synergistically produced in the presence of the βAR agonist isoproterenol and intracellular calcium. In contrast, we show that when application of isoproterenol precedes application of NMDA by several minutes, as is typical of βAR-facilitated LTP experiments, the average amplitude of the cAMP response to NMDA is attenuated compared with the response to NMDA alone. Models simulations suggest that, although the negative feedback loop formed by cAMP, cAMP-dependent protein kinase (PKA), and type 4 phosphodiesterase may be involved in attenuating the cAMP response to NMDA, it is insufficient to explain the range of experimental observations. Instead, attenuation of the cAMP response requires mechanisms upstream of adenylyl cyclase. Our model demonstrates that Gs-to-Gi switching due to PKA phosphorylation of βARs as well as Gi inhibition of type 1 adenylyl cyclase may underlie the experimental observations. This suggests that signaling by β-adrenergic receptors depends on temporal pattern of stimulation, and that switching may represent a novel mechanism for recruiting kinases involved in synaptic plasticity and memory. 相似文献
945.
Matthew J. O’Brien Ji Young Lee Mercedes R. Carnethon Ronald T. Ackermann Maria C. Vargas Andrew Hamilton Nivedita Mohanty Sarah S. Rittner Jessica N. Park Amro Hassan David R. Buchanan Lei Liu Joseph Feinglass 《PLoS medicine》2016,13(7)
BackgroundIn 2015, the United States Preventive Services Task Force (USPSTF) recommended targeted screening for prediabetes and diabetes (dysglycemia) in adults who are aged 40 to 70 y old and overweight or obese. Given increasing prevalence of dysglycemia at younger ages and lower body weight, particularly among racial/ethnic minorities, we sought to determine whether the current screening criteria may fail to identify some high-risk population subgroups.ConclusionsTargeted diabetes screening based on new USPSTF criteria may detect approximately half of adult community health center patients with undiagnosed dysglycemia and proportionately fewer racial/ethnic minorities than whites. Future research is needed to estimate the performance of these screening criteria in population-based samples. 相似文献
946.
Quantifying heterogeneity in gene expression among single cells can reveal information inaccessible to cell-population averaged measurements. However, the expression level of many genes in single cells fall below the detection limit of even the most sensitive technologies currently available. One proposed approach to overcome this challenge is to measure random pools of k cells (e.g., 10) to increase sensitivity, followed by computational “deconvolution” of cellular heterogeneity parameters (CHPs), such as the biological variance of single-cell expression levels. Existing approaches infer CHPs using either single-cell or k-cell data alone, and typically within a single population of cells. However, integrating both single- and k-cell data may reap additional benefits, and quantifying differences in CHPs across cell populations or conditions could reveal novel biological information. Here we present a Bayesian approach that can utilize single-cell, k-cell, or both simultaneously to infer CHPs within a single condition or their differences across two conditions. Using simulated as well as experimentally generated single- and k-cell data, we found situations where each data type would offer advantages, but using both together can improve precision and better reconcile CHP information contained in single- and k-cell data. We illustrate the utility of our approach by applying it to jointly generated single- and k-cell data to reveal CHP differences in several key inflammatory genes between resting and inflammatory cytokine-activated human macrophages, delineating differences in the distribution of ‘ON’ versus ‘OFF’ cells and in continuous variation of expression level among cells. Our approach thus offers a practical and robust framework to assess and compare cellular heterogeneity within and across biological conditions using modern multiplexed technologies. 相似文献
947.
J. Pedro Fernández-Murray Sergey V. Prykhozhij J. Noelia Dufay Shelby L. Steele Daniel Gaston Gheyath K. Nasrallah Andrew J. Coombs Robert S. Liwski Conrad V. Fernandez Jason N. Berman Christopher R. McMaster 《PLoS genetics》2016,12(1)
Sideroblastic anemias are acquired or inherited anemias that result in a decreased ability to synthesize hemoglobin in red blood cells and result in the presence of iron deposits in the mitochondria of red blood cell precursors. A common subtype of congenital sideroblastic anemia is due to autosomal recessive mutations in the SLC25A38 gene. The current treatment for SLC25A38 congenital sideroblastic anemia is chronic blood transfusion coupled with iron chelation. The function of SLC25A38 is not known. Here we report that the SLC25A38 protein, and its yeast homolog Hem25, are mitochondrial glycine transporters required for the initiation of heme synthesis. To do so, we took advantage of the fact that mitochondrial glycine has several roles beyond the synthesis of heme, including the synthesis of folate derivatives through the glycine cleavage system. The data were consistent with Hem25 not being the sole mitochondrial glycine importer, and we identify a second SLC25 family member Ymc1, as a potential secondary mitochondrial glycine importer. Based on these findings, we observed that high levels of exogenous glycine, or 5-aminolevulinic acid (5-Ala) a metabolite downstream of Hem25 in heme biosynthetic pathway, were able to restore heme levels to normal in yeast cells lacking Hem25 function. While neither glycine nor 5-Ala could ameliorate SLC25A38 congenital sideroblastic anemia in a zebrafish model, we determined that the addition of folate with glycine was able to restore hemoglobin levels. This difference is likely due to the fact that yeast can synthesize folate, whereas in zebrafish folate is an essential vitamin that must be obtained exogenously. Given the tolerability of glycine and folate in humans, this study points to a potential novel treatment for SLC25A38 congenital sideroblastic anemia. 相似文献
948.
Jared M. Baeten Renee Heffron Lara Kidoguchi Nelly R. Mugo Elly Katabira Elizabeth A. Bukusi Stephen Asiimwe Jessica E. Haberer Jennifer Morton Kenneth Ngure Nulu Bulya Josephine Odoyo Edna Tindimwebwa Craig Hendrix Mark A. Marzinke Norma C. Ware Monique A. Wyatt Susan Morrison Harald Haugen Andrew Mujugira Deborah Donnell Connie Celum Partners Demonstration Project Team 《PLoS medicine》2016,13(8)
BackgroundAntiretroviral-based interventions for HIV-1 prevention, including antiretroviral therapy (ART) to reduce the infectiousness of HIV-1 infected persons and pre-exposure prophylaxis (PrEP) to reduce the susceptibility of HIV-1 uninfected persons, showed high efficacy for HIV-1 protection in randomized clinical trials. We conducted a prospective implementation study to understand the feasibility and effectiveness of these interventions in delivery settings.ConclusionsIntegrated delivery of time-limited PrEP until sustained ART use in African HIV-1-serodiscordant couples was feasible, demonstrated high uptake and adherence, and resulted in near elimination of HIV-1 transmission, with an observed HIV incidence of <0.5% per year compared to an expected incidence of >5% per year. 相似文献
949.
Rong Deng Daniela Bumbaca Cinthia V. Pastuskovas C. Andrew Boswell David West Kyra J. Cowan 《MABS-AUSTIN》2016,8(3):593-603
MPDL3280A is a human monoclonal antibody that targets programmed cell death-1 ligand 1 (PD-L1), and exerts anti-tumor activity mainly by blocking PD-L1 interaction with programmed cell death-1 (PD-1) and B7.1. It is being investigated as a potential therapy for locally advanced or metastatic malignancies. The purpose of the study reported here was to characterize the pharmacokinetics, pharmacodynamics, tissue distribution and tumor penetration of MPDL3280A and/or a chimeric anti-PD-L1 antibody PRO304397 to help further clinical development.The pharmacokinetics of MPDL3280A in monkeys at 0.5, 5 and 20 mg·kg?1 and the pharmacokinetics / pharmacodynamics of PRO304397 in mice at 1, 3 10 mg·kg?1 were determined after a single intravenous dose. Tissue distribution and tumor penetration for radiolabeled PRO304397 in tumor-bearing mouse models were determined.The pharmacokinetics of MPDL3280A and PRO304397 were nonlinear in monkeys and mice, respectively. Complete saturation of PD-L1 in blood in mice was achieved at serum concentrations of PRO304397 above ~0.5 µg·mL?1. Tissue distribution and tumor penetration studies of PRO304397 in tumor-bearing mice indicated that the minimum tumor interstitial to plasma radioactivity ratio was ~0.3; saturation of target-mediated uptake in non–tumor tissues and desirable exposure in tumors were achieved at higher serum concentrations, and the distribution into tumors was dose-and time-dependent.The biodistribution data indicated that the efficacious dose is mostly likely higher than that estimated based on simple pharmacokinetics/pharmacodynamics in blood. These data also allowed for estimation of the target clinical dose for further development of MPDL3280A. 相似文献
950.
Competitive diversification, that is, when increasing intraspecific competition promotes population niche expansion, is commonly invoked in evolutionary studies and currently plays a central role in how we conceptualize the process of adaptive diversification. Despite the frequency with which this idea is cited, the empirical evidence for the process is somewhat limited, and the findings of these studies have yet to be weighed objectively through synthesis. Here, we sought to fill this gap by reviewing the existing literature and collecting the data necessary to assess the evidence for competition as a diversifying force. Additionally, we sought to test a more recent hypothesis, which suggests that competition can act to both promote and inhibit dietary diversification depending on the degree to which a consumer depletes its resources. The surprising result of this synthesis was that increasing competition did not have a mean positive effect on population‐level diet breadth or the degree of individual specialization. Instead, we found that increasing intraspecific competition had a restricting effect on population‐level diet breadth in as many cases as it had a diversifying effect. This wide disparity in the effect of competition on consumer diet variation was negatively related to a metric for consumer resource depletion. Altogether, these findings call into question a long‐standing assumption of basic evolutionary models and lend some support to recent theoretical predictions. Specifically, these findings support the idea that competition is primarily diversifying for species with a small effect (per unit biomass) on their resources and that resource depletion limits the diversifying effect of competition for consumers with larger ecological effects. 相似文献