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1.
AIDS and Behavior - Pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV but requires sustained adherence. Conditional economic incentives (CEIs) can improve medication-taking...  相似文献   
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BackgroundThe aim of this study was to predict the presence of esophageal varices (EVs) by noninvasive tools combined with 2-dimensional shear wave elastography (2D-SWE), and to compare the diagnostic capabilities of 2D-SWE with those of transient elastography (TE).MethodsBetween January 2015 and December 2017, 289 patients with compensated advanced chronic liver disease (cACLD) who underwent consecutive 2D-SWE and EGD were enrolled. Capabilities for predicting the presence of EVs of 2D-SWE and models combining 2D-SWE with other noninvasive tools (modified LS-spleen-diameter-to-platelet-ratio score [mLSPS], platelet-spleen ratio score) were compared. A subgroup analysis was performed on 177 patients who also underwent simultaneous TE.ResultsThe area under receiver operating characteristics (AUROCs) for detecting EVs for 2D-SWE alone vs. mLSPS, which included 2D-SWE, were 0.757 (95% confidence interval [CI], 0.701–0.810) and 0.813 (95% CI, 0.763–.857), respectively. The AUROCs for predicting varices needing treatment (VNT) for 2D-SWE and mLSPS were 0.712 (95% CI, 0.621–0.738) and 0.834 (95% CI, 0.785–0.875), respectively. For the 195 patients who underwent simultaneous TE and 2D-SWE, no differences in diagnostic performance were observed.ConclusionsThe diagnostic performance of 2D-SWE is similar to that of TE for predicting the presence of EVs. The mLSPS, which includes 2D-SWE, seemed to be useful for predicting EVs.  相似文献   
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Background

Recent conceptual models argue that early life adversity (ELA) accelerates development, which may contribute to poor mental and physical health outcomes. Evidence for accelerated development in youths comes from studies of telomere shortening or advanced pubertal development following circumscribed ELA experiences and neuroimaging studies of circuits involved in emotional processing. It is unclear whether all ELA is associated with accelerated development across global metrics of biological aging or whether this pattern emerges following specific adversity types.

Methods

In 247 children and adolescents 8 to 16 years of age with wide variability in ELA exposure, we evaluated the hypothesis that early environments characterized by threat, but not deprivation, would be associated with accelerated development across two global biological aging metrics: DNA methylation (DNAm) age and pubertal stage relative to chronological age. We also examined whether accelerated development explained associations of ELA with depressive symptoms and externalizing problems.

Results

Exposure to threat-related ELA (e.g., violence) was associated with accelerated DNAm age and advanced pubertal stage, but exposure to deprivation (e.g., neglect, food insecurity) was not. In models including both ELA types, threat-related ELA was uniquely associated with accelerated DNAm age (β = .18) and advanced pubertal stage (β = .28), whereas deprivation was uniquely associated with delayed pubertal stage (β = ?.21). Older DNAm age was related to greater depressive symptoms, and a significant indirect effect of threat exposure on depressive symptoms was observed through DNAm age.

Conclusions

Early threat-related experiences are particularly associated with accelerated biological aging in youths, which may be a mechanism linking ELA with depressive symptoms.  相似文献   
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Aureobasidium pullulans is a yeast-like fungus that produces volatile organic compounds (VOCs) with antifungal properties. VOCs have the potential to trigger the production of intracellular reactive oxygen species (ROS), lipid peroxidation and electrolyte loss in microorganisms. The relationship among A. pullulans VOCs, induced ROS accumulation and electrolyte leakage was investigated in Botrytis cinerea and Alternaria alternata in vitro. Exposure to a mixture of A. pullulans VOCs: ethanol, 2-methyl-1-propanol, 3-methyl-1-butanol and 2-phenylethanol, resulted in electrolyte leakage in both B. cinerea and A. alternata. Fluorescence microscopy using 2′,7′-dichlorofluorescein diacetate indicated triggered ROS accumulation in exposed fungal mycelia and the presence of the superoxide radical was evident by intense red fluorescence with dihydroethidium. Partial inhibition of enzymes of the mitochondrial respiratory chain complex I of B. cinerea and A. alternata by pre-treatment with rotenone reduced ROS accumulation in hypha exposed to A. pullulans VOCs and reversed the VOCs inhibition of fungal growth. Scanning electron micrographs revealed that B. cinerea and A. alternata hypha exposed to A. pullulans VOCs had altered cell wall structures. Our findings give insights into the potential mechanisms involved in the antifungal properties of A. pullulans in the suppression of B. cinerea and A. alternata growth in vitro.  相似文献   
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An aneuploid-immune paradox encompasses somatic copy-number alterations (SCNAs), unleashing a cytotoxic response in experimental precancer systems, while conversely being associated with immune suppression and cytotoxic-cell depletion in human tumors, especially head and neck cancer (HNSC). We present evidence from patient samples and cell lines that alterations in chromosome dosage contribute to an immune hot-to-cold switch during human papillomavirus-negative (HPV) head and neck tumorigenesis. Overall SCNA (aneuploidy) level was associated with increased CD3+ and CD8+ T cell microenvironments in precancer (mostly CD3+, linked to trisomy and aneuploidy), but with T cell-deficient tumors. Early lesions with 9p21.3 loss were associated with depletion of cytotoxic T cell infiltration in TP53 mutant tumors; and with aneuploidy were associated with increased NK-cell infiltration. The strongest driver of cytotoxic T cell and Immune Score depletion in oral cancer was 9p-arm level loss, promoting profound decreases of pivotal IFN-γ-related chemokines (e.g., CXCL9) and pathway genes. Chromosome 9p21.3 deletion contributed mainly to cell-intrinsic senescence suppression, but deletion of the entire arm was necessary to diminish levels of cytokine, JAK-STAT, and Hallmark NF-κB pathways. Finally, 9p arm-level loss and JAK2-PD-L1 codeletion (at 9p24) were predictive markers of poor survival in recurrent HPV HNSC after anti–PD-1 therapy; likely amplified by independent aneuploidy-induced immune-cold microenvironments observed here. We hypothesize that 9p21.3 arm-loss expansion and epistatic interactions allow oral precancer cells to acquire properties to overcome a proimmunogenic aneuploid checkpoint, transform and invade. These findings enable distinct HNSC interception and precision-therapeutic approaches, concepts that may apply to other CN-driven neoplastic, immune or aneuploid diseases, and immunotherapies.

The genetic bases for predisposition, and neoplastic transformation, to cancer have been increasingly well described. However, it remains less clear how early, precancer cells employ these genetic alterations to acquire the characteristic features and properties (1) of malignant disease. For example, studies of the immune landscape led to breakthrough trials of programmed death-1 (PD-1) inhibitors for recurrent, metastatic head and neck squamous cell carcinoma (HNSC) therapy (24). This underscores the importance of immune modulation in these tumors, despite a still suboptimal overall response rate of less than 20% in advanced cancers. Immune response within tumors has been observed to be strongest at the earliest neoplastic stages, as reported recently in lung adenocarcinoma precursors (5). As such, new, immune-based strategies could be developed to reduce the high global burden of HNSC, by intercepting the most common precursor of the most common HNSC presentation: HPV oral squamous cell carcinomas (68).Studies of chromosome somatic copy-number (CN) alteration (SCNA) profiles have reported the impact of 3p14, 9p21, or 17p13 loss in molecular models of HNSC progression (9) and risk (1015). Early studies reported that patients with oral precancers harboring 9p21 and/or 3p14 loss were at significantly greater cancer risk than those with retention at these loci (10, 16). A comprehensive, prospective validation study examined the relative contribution of six candidate chromosome-arm regions. 9p21 loss had the greatest influence on cancer risk (13). The mechanism underlying the association between CN and malignant transformation of precancers, however, is unclear (1720). Studies of CN-altered neoplastic cells have shown that SCNAs can trigger a cytotoxic response in experimental precancer systems (21, 22) but, paradoxically, were associated with immune evasion (23) and suppression (24) in computational studies of naturally occurring human cancers. The latter, in melanoma, found that nonresponders to PD-1 and CTLA-4 blockade had higher CN alteration and loss burdens, which correlated with immunologically cold tumors, characterized by cytotoxic-cell, marker, and metric reductions, and suppressive microenvironment cell, network, and signal increases (2326). This SCNA-cold association was particularly strong in our previous, pan-The Cancer Genome Atlas (TCGA) computational study in HNSC (23). These data point to a putative in vivo switch from immune hot-to-cold in the precancer–cancer transition, and raise the hypothesis that SCNAs in precursor lesions contribute to malignant transformation through genomic events and mechanisms that enable the acquisition of immune-suppressive, evasive properties. To test this hypothesis, we evaluated CN influence on immune profiles and outcomes in a large prospective oral precancer patient cohort, and HPV HNSC (tissue specimens and cell lines) and anti–PD-1–treated recurrent-disease cohorts.  相似文献   
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