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Joost Smolders Ester B. M. Remmerswaal Karianne G. Schuurman Jeroen Melief Corbert G. van Eden René A. W. van Lier Inge Huitinga Jörg Hamann 《Acta neuropathologica》2013,126(4):525-535
Immune surveillance of the central nervous system (CNS) by T cells is important to keep CNS-trophic viruses in a latent state, yet our knowledge of the characteristics of CNS-populating T cells is incomplete. We performed a comprehensive, multi-color flow-cytometric analysis of isolated T cells from paired corpus callosum (CC) and peripheral blood (PB) samples of 20 brain donors. Compared to PB, CC T cells, which were mostly located in the perivascular space and sporadically in the parenchyma, were enriched for cells expressing CD8. Both CD4+ and CD8+ T cells in the CC had a late-differentiated phenotype, as indicated by lack of expression of CD27 and CD28. The CC contained high numbers of T cells expressing chemokine receptor CX3CR1 and CXCR3 that allow for homing to inflamed endothelium and tissue, but hardly cells expressing the lymph node-homing receptor CCR7. Despite the late-differentiated phenotype, CC T cells had high expression of the IL-7 receptor α-chain CD127 and did not contain the neurotoxic cytolytic enzymes perforin, granzyme A, and granzyme B. We postulate that CNS T cells make up a population of tissue-adapted differentiated cells, which use CX3CR1 and CXCR3 to home into the perivascular space, use IL-7 for maintenance, and lack immediate cytolytic activity, thereby preventing immunopathology in response to low or non-specific stimuli. The presence of these cells in this tightly regulated environment likely enables a fast response to local threats. Our results will enable future detailed exploration of T-cell subsets in the brain involved in neurological diseases. 相似文献
34.
Properties of global‐ and local‐ancestry adjustments in genetic association tests in admixed populations 下载免费PDF全文
Eden R. Martin Ilker Tunc Zhi Liu Susan H. Slifer Ashley H. Beecham Gary W. Beecham 《Genetic epidemiology》2018,42(2):214-229
Population substructure can lead to confounding in tests for genetic association, and failure to adjust properly can result in spurious findings. Here we address this issue of confounding by considering the impact of global ancestry (average ancestry across the genome) and local ancestry (ancestry at a specific chromosomal location) on regression parameters and relative power in ancestry‐adjusted and ‐unadjusted models. We examine theoretical expectations under different scenarios for population substructure; applying different regression models, verifying and generalizing using simulations, and exploring the findings in real‐world admixed populations. We show that admixture does not lead to confounding when the trait locus is tested directly in a single admixed population. However, if there is more complex population structure or a marker locus in linkage disequilibrium (LD) with the trait locus is tested, both global and local ancestry can be confounders. Additionally, we show the genotype parameters of adjusted and unadjusted models all provide tests for LD between the marker and trait locus, but in different contexts. The local ancestry adjusted model tests for LD in the ancestral populations, while tests using the unadjusted and the global ancestry adjusted models depend on LD in the admixed population(s), which may be enriched due to different ancestral allele frequencies. Practically, this implies that global‐ancestry adjustment should be used for screening, but local‐ancestry adjustment may better inform fine mapping and provide better effect estimates at trait loci. 相似文献
35.
Karen Nuytemans PhD Vanessa Inchausti BS Gary W. Beecham PhD Liyong Wang PhD Dennis W. Dickson MD John Q. Trojanowski MD PhD Virginia M.‐Y. Lee PhD Deborah C. Mash PhD Matthew P. Frosch MD PhD Tatiana M. Foroud PhD Lawrence S. Honig MD PhD Thomas J. Montine MD PhD Ted M. Dawson MD PhD Eden R. Martin PhD William K. Scott PhD Jeffery M. Vance MD PhD 《Movement disorders》2014,29(6):827-830
36.
Adriana Caballero Daniel R. Thomases Eden Flores-Barrera Daryn K. Cass Kuei Y. Tseng 《Psychopharmacology》2014,231(8):1789-1796
Objective
The prefrontal cortex (PFC) receives multiple cortical and subcortical afferents that regulate higher order cognitive functions, many of which emerge late in adolescence. However, it remains unclear how these afferents influence PFC processing, especially in light of the protracted, late adolescent maturation of prefrontal GABAergic function. Here we investigated the role of PFC GABAergic transmission in regulating plasticity elicited from the ventral hippocampus and basolateral amygdala, and how such modulation undergoes functional changes during adolescence in rats.Methods
In vivo local field potential recordings, combined with prefrontal microinfusion of the GABA-A receptor antagonist picrotoxin, were employed to study the impact of ventral hippocampal and basolateral amygdala high-frequency stimulation on PFC plasticity.Results
Ventral hippocampal-induced PFC plasticity begins to appear only by postnatal days (P) 45–55 with a transient suppression of the evoked response. A switch from transient to long-lasting depression (LTD) of the PFC response emerges after P55 and throughout adulthood (P65–120). Recordings conducted in the presence of picrotoxin revealed that PFC GABAergic transmission is critical for the expression of LTD. In contrast, basolateral amygdala stimulation resulted in PFC long-term potentiation, a form of plasticity that is already enabled by P30 and is insensitive to picrotoxin.Conclusions
The development of ventral hippocampal-dependent PFC LTD is contingent upon the recruitment of local prefrontal GABAergic transmission during adolescence whereas plasticity elicited from the basolateral amygdala is not. Thus, different mechanisms contribute to the refinement of prefrontal plasticity during adolescence as inputs from these two regions are critical for shaping PFC functions. 相似文献37.
Human metapneumovirus (HMPV) is an important cause of upper and lower respiratory tract disease in individuals of all ages. It is estimated that most individuals will be infected by HMPV by the age of five years old. Despite this burden of disease, there remain caveats in our knowledge of global genetic diversity due to a lack of HMPV sequencing, particularly at the whole-genome scale. The purpose of this study was to create a simple and robust approach for HMPV whole-genome sequencing to be used for genomic epidemiological studies. To design our assay, all available HMPV full-length genome sequences were downloaded from the National Center for Biotechnology Information (NCBI) GenBank database and used to design four primer sets to amplify long, overlapping amplicons spanning the viral genome and, importantly, specific to all known HMPV subtypes. These amplicons were then pooled and sequenced on an Illumina iSeq 100 (Illumina, San Diego, CA, USA); however, the approach is suitable to other common sequencing platforms. We demonstrate the utility of this method using a representative subset of clinical samples and examine these sequences using a phylogenetic approach. Here we present an amplicon-based method for the whole-genome sequencing of HMPV from clinical extracts that can be used to better inform genomic studies of HMPV epidemiology and evolution. 相似文献
38.
Geographical and ecological analyses of childhood acute leukaemias and lymphomas in north-west England 总被引:3,自引:0,他引:3
Childhood leukaemias and lymphomas have been associated with exposure to environmental factors, including infections, which show geographical variation. This study examined the geographical distribution of the incidence of acute leukaemia and lymphoma using Manchester Children's Tumour Registry (MCTR) data 1976-2000. A total of 910 children were included, all of whom had histologically and/or cytologically verified leukaemia or lymphoma. At the time of their diagnoses, all the children were aged 0-14 years and were resident in the counties of Greater Manchester or Lancashire. Standardized morbidity ratios were calculated. Poisson regression was used to examine the relationship between incidence rates and small-area (census ward) population density, ethnic composition and deprivation index. There was a monotonic relationship between acute lymphoblastic leukaemia (ALL) incidence and population density (P = 0.05). Higher rates were seen in more densely populated areas. There was evidence for a monotonic relationship between the incidence of the mixed cellularity subtype of Hodgkin's disease (HD) and the Townsend deprivation score (P = 0.001). Markedly higher incidence was associated with greater levels of unemployment and household overcrowding. The results for ALL and mixed cellularity HD support the involvement of environmental factors, such as infections, in disease aetiology. 相似文献
39.
K. Langlands O. B. Eden † P. Micallef-Eynaud A. C. Parker R. S. Anthony 《British journal of haematology》1993,84(4):648-655
Summary. T cell receptor δ chain (TCRδ) gene rearrangements were studied by Southern blot analysis in 36 patients with common acute lymphoblastic leukaemia, including 14 adults and 22 children. The majority of patients (68%) had either a rearrangement or deletion of one or more TCRδ genes. The most frequent rearrangement involved a partial recombination of Vδ2 to Dδ3 (55%). Dδ2–Dδ3 rearrangements were present in five patients (14%). To investigate the TCRδ rearrangement as a tumour marker in minimal residual disease studies, presentation samples from 18 patients were amplified by PCR and directly sequenced. Although the size of the Vδ2–Dδ3 junction varied by only 40 bp, sequence analysis showed extensive diversity. This was derived from four factors: deletion of the 5'end of Dδ3 gene (15/18) and 3'end of Vδ2 gene (16/18); the presence of Dδ2 sequences (6/18); insertion of N nucleotides (15/18); association of P nucleotides with intact Vδ2 and Dδ3 genes (5/18). N nucleotides were the major feature, contributing to 75% of the junction. Dδ1 sequences were not involved. Twenty base oligonucleotide probes, constructed from the junctional sequences, were capable of detecting residual tumour cells at the 10−4 sensitivity level. Cross hybridization studies confirmed the probes to be clone specific. Longitudinal studies on patients undergoing treatment were capable of detecting tumour in remission samples. 相似文献
40.
How ‘love’ and ‘hate’ differ from ‘sleep’: Using combined electro/magnetoencephalographic data to reveal the sources of early cortical responses to emotional words 下载免费PDF全文
Kati Keuper Peter Zwanzger Marisa Nordt Annuschka Eden Inga Laeger Pienie Zwitserlood Johanna Kissler Markus Junghöfer Christian Dobel 《Human brain mapping》2014,35(3):875-888
Emotional words—as symbols for biologically relevant concepts—are preferentially processed in brain regions including the visual cortex, frontal and parietal regions, and a corticolimbic circuit including the amygdala. Some of the brain structures found in functional magnetic resonance imaging are not readily apparent in electro‐ and magnetoencephalographic (EEG; MEG) measures. By means of a combined EEG/MEG source localization procedure to fully exploit the available information, we sought to reduce these discrepancies and gain a better understanding of spatiotemporal brain dynamics underlying emotional‐word processing. Eighteen participants read high‐arousing positive and negative, and low‐arousing neutral nouns, while EEG and MEG were recorded simultaneously. Combined current‐density reconstructions (L2‐minimum norm least squares) for two early emotion‐sensitive time intervals, the P1 (80–120 ms) and the early posterior negativity (EPN, 200–300 ms), were computed using realistic individual head models with a cortical constraint. The P1 time window uncovered an emotion effect peaking in the left middle temporal gyrus. In the EPN time window, processing of emotional words was associated with enhanced activity encompassing parietal and occipital areas, and posterior limbic structures. We suggest that lexical access, being underway within 100 ms, is speeded and/or favored for emotional words, possibly on the basis of an “emotional tagging” of the word form during acquisition. This gives rise to their differential processing in the EPN time window. The EPN, as an index of natural selective attention, appears to reflect an elaborate interplay of distributed structures, related to cognitive functions, such as memory, attention, and evaluation of emotional stimuli. Hum Brain Mapp 35:875–888, 2014. © 2012 Wiley Periodicals, Inc. 相似文献