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941.
Familial hypercholesterolemia (FH) is a dominantly inherited disorder principally due to mutations in the low-density lipoprotein (LDL) receptor that classically cause markedly elevated plasma LDL cholesterol concentrations and premature coronary heart disease (CHD). However, elevated plasma LDL cholesterol alone does not fully account for the increase or variation in risk of CHD. We propose a hypothetical model for the role of postprandial dyslipoproteinemia based on the overproduction and decreased catabolism of triglyceride-rich lipoproteins, which may be a consequence of LDL receptor deficiency. Expression of postprandial dyslipoproteinemia in FH may also depend on the type of pathogenic gene variants and on coexistent conditions, particularly obesity and insulin resistance. Further research is required to investigate our model proposed and to test whether treating postprandial dyslipoproteinemia decreases CHD risk in FH incremental to standard therapy. 相似文献
942.
Seymour DK Filiault DL Henry IM Monson-Miller J Ravi M Pang A Comai L Chan SW Maloof JN 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(11):4227-4232
Quantitative trait loci (QTL) mapping is a powerful tool for investigating the genetic basis of natural variation. QTL can be mapped using a number of different population designs, but recombinant inbred lines (RILs) are among the most effective. Unfortunately, homozygous RIL populations are time consuming to construct, typically requiring at least six generations of selfing starting from a heterozygous F(1). Haploid plants produced from an F(1) combine the two parental genomes and have only one allele at every locus. Converting these sterile haploids into fertile diploids (termed "doubled haploids," DHs) produces immortal homozygous lines in only two steps. Here we describe a unique technique for rapidly creating recombinant doubled haploid populations in Arabidopsis thaliana: centromere-mediated genome elimination. We generated a population of 238 doubled haploid lines that combine two parental genomes and genotyped them by reduced representation Illumina sequencing. The recombination rate and parental allele frequencies in our population are similar to those found in existing RIL sets. We phenotyped this population for traits related to flowering time and for petiole length and successfully mapped QTL controlling each trait. Our work demonstrates that doubled haploid populations offer a rapid, easy alternative to RILs for Arabidopsis genetic analysis. 相似文献
943.
Volkmer JP Sahoo D Chin RK Ho PL Tang C Kurtova AV Willingham SB Pazhanisamy SK Contreras-Trujillo H Storm TA Lotan Y Beck AH Chung BI Alizadeh AA Godoy G Lerner SP van de Rijn M Shortliffe LD Weissman IL Chan KS 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(6):2078-2083
Current clinical judgment in bladder cancer (BC) relies primarily on pathological stage and grade. We investigated whether a molecular classification of tumor cell differentiation, based on a developmental biology approach, can provide additional prognostic information. Exploiting large preexisting gene-expression databases, we developed a biologically supervised computational model to predict markers that correspond with BC differentiation. To provide mechanistic insight, we assessed relative tumorigenicity and differentiation potential via xenotransplantation. We then correlated the prognostic utility of the identified markers to outcomes within gene expression and formalin-fixed paraffin-embedded (FFPE) tissue datasets. Our data indicate that BC can be subclassified into three subtypes, on the basis of their differentiation states: basal, intermediate, and differentiated, where only the most primitive tumor cell subpopulation within each subtype is capable of generating xenograft tumors and recapitulating downstream populations. We found that keratin 14 (KRT14) marks the most primitive differentiation state that precedes KRT5 and KRT20 expression. Furthermore, KRT14 expression is consistently associated with worse prognosis in both univariate and multivariate analyses. We identify here three distinct BC subtypes on the basis of their differentiation states, each harboring a unique tumor-initiating population. 相似文献
944.
P Wang CM Chan D Christensen C Zhang K Selvadurai RH Huang 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(33):13248-13253
Ribotoxins cleave essential RNAs for cell killing in vivo, and the bacterial polynucleotide kinase-phosphatase (Pnkp)/hua enhancer 1 (Hen1) complex has been shown to repair ribotoxin-cleaved RNAs in vitro. Bacterial Pnkp/Hen1 is distinguished from other RNA repair systems by performing 3'-terminal 2'-O-methylation during RNA repair, which prevents the repaired RNA from repeated cleavage at the same site. To ensure the opportunity of 2'-O-methylation by bacterial Hen1 during RNA repair and, therefore, maintain the quality of the repaired RNA, Pnkp/Hen1 has evolved to require the participation of Hen1 in RNA ligation, because Pnkp alone is unable to carry out the reaction despite possessing all signature motifs of an RNA ligase. However, the precise role of Hen1 in RNA ligation is unknown. Here, we present the crystal structure of an active RNA ligase consisting of the C-terminal half of Pnkp (Pnkp-C) and the N-terminal half of Hen1 (Hen1-N) from Clostridium thermocellum. The structure reveals that the N-terminal domain of Clostridium thermocellum (Cth) Hen1, shaped like a left hand, grabs the flexible insertion module of CthPnkp and locks its conformation via further interaction with the C-terminal addition module of CthPnkp. Formation of the CthPnkp-C/Hen1-N heterodimer creates a ligation pocket with a width for two strands of RNA, depth for two nucleotides, and the adenosine monophosphate (AMP)-binding pocket at the bottom. The structure, combined with functional analyses, provides insight into the mechanism of how Hen1 activates the RNA ligase activity of Pnkp for RNA repair. 相似文献
945.
Garnett JA Martínez-Santos VI Saldaña Z Pape T Hawthorne W Chan J Simpson PJ Cota E Puente JL Girón JA Matthews S 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(10):3950-3955
Bacteria have evolved a variety of mechanisms for developing community-based biofilms. These bacterial aggregates are of clinical importance, as they are a major source of recurrent disease. Bacterial surface fibers (pili) permit adherence to biotic and abiotic substrates, often in a highly specific manner. The Escherichia coli common pilus (ECP) represents a remarkable family of extracellular fibers that are associated with both disease-causing and commensal strains. ECP plays a dual role in early-stage biofilm development and host cell recognition. Despite being the most common fimbrial structure, relatively little is known regarding its biogenesis, architecture, and function. Here we report atomic-resolution insight into the biogenesis and architecture of ECP. We also derive a structural model for entwined ECP fibers that not only illuminates interbacteria communication during biofilm formation but also provides a useful foundation for the design of novel nanofibers. 相似文献
946.
Wei Qi HoMan Chan Lin Teng Ling Li Shannon Chuai Ruipeng Zhang Jue Zeng Min Li Hong Fan Ying Lin Justin Gu Ophelia Ardayfio Ji-Hu Zhang Xiaoxia Yan Jialuo Fang Yuan Mi Man Zhang Tao Zhou Grace Feng Zijun Chen Guobin Li Teddy Yang Kehao Zhao Xianghui Liu Zhengtian Yu Chris X. Lu Peter Atadja En Li 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(52):21360-21365
947.
Purpose The purpose of the study was to test the feasibility and efficacy of a diabetes self-management and education program for Chinese Americans in a support group format. The rationale for the study was to create culturally appropriate diabetes education and management programs in response to the growing diabetes prevalence among Chinese Americans. The investigators hypothesized that participants will have improved diabetes knowledge and practices, hemoglobin A1C, and social support. The study objectives were at least: 50% will have significant improvements in diabetes knowledge and practice activities, 30% of participants will have significant improvements in A1C, and 50% will report a gain in emotional support. Methods The program consisted of 12 90-minute diabetes education and support group sessions offered in a medical office setting. The sample included 23 Chinese Americans with either type 1 or type 2 diabetes. Using a single-group, pre-post test design, A1C and diabetes knowledge were assessed at baseline and 6 months. Data were collected through clinical assessments and written questionnaires. Results The results indicated high attendance and statistically significant increases in glycemic control and diabetes knowledge. Statistically insignificant differences were shown in diabetes management practices. Secondary outcomes assessed participants' perceived diabetes management and emotional and social support. Conclusions Diabetes Self-Management: A Cultural Approach (DSMCA) support group model demonstrates that a culturally tailored support group utilizing a community-based participatory research approach is an effective format to improve diabetes self-management skills among Chinese Americans. The program can be adapted for other ethnic populations. The efficacy of the intervention can be further tested in larger randomized trials. 相似文献
948.
Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disease commonly found among elderly. In addition
to cognitive and behavioral deficits, vision abnormalities are prevalent in AD patients. Recent studies investigating retinal
changes in AD double-transgenic mice have shown altered processing of amyloid precursor protein and accumulation of β-amyloid
peptides in neurons of retinal ganglion cell layer (RGCL) and inner nuclear layer (INL). Apoptotic cells were also detected
in the RGCL. Thus, the pathophysiological changes of retinas in AD patients are possibly resembled by AD transgenic models.
The retina is a simple model of the brain in the sense that some pathological changes and therapeutic strategies from the
retina may be observed or applicable to the brain. Furthermore, it is also possible to advance our understanding of pathological
mechanisms in other retinal degenerative diseases. Therefore, studying AD-related retinal degeneration is a promising way
for the investigation on (1) AD pathologies and therapies that would eventually benefit the brain and (2) cellular mechanisms
in other retinal degenerations such as glaucoma and age-related macular degeneration. This review will highlight the efforts
on retinal degenerative research using AD transgenic mouse models. 相似文献
949.
950.