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1.
R W Lambert J A Martin G J Thomas I B Duncan M J Hall E P Heimer 《Journal of medicinal chemistry》1989,32(2):367-374
Phosphonoacetic acid (PAA, 1) was coupled with various acyclonucleosides, 2'-deoxyuridines, cytidines, and arabinosyluracils, with 2,4,6-triisopropylbenzenesulfonyl chloride (TPS) or dicyclohexylcarbodiimide (DCCI) as condensing agents, to give a range of phosphonate esters. The carboxylic ester linkage of PAA to the 5'-position of 5-bromo-2'-deoxyuridine (BUdR, 3) was achieved via the mixed anhydride formed from (diethylphosphono)acetic acid and trifluoroacetic anhydride. Phosphonoformic acid (PFA, 2) was coupled with BUdR by using the DCCI method to give the phosphonate ester. Of these compounds only phosphonate esters in the 2'-deoxyuridine series showed significant activity against herpes simplex virus types 1 and 2. The BUdR-PAA derivative and the BUdR-PFA derivative were highly active, especially the latter, which was more active than the parent nucleoside BUdR against the type 2 virus. The active compounds may exert their effects by extracellular or intracellular hydrolysis to the corresponding antiviral agents, but an intrinsic component of antiviral activity may also be involved. 相似文献
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Dahl N; Pigg M; Ristoff E; Gali R; Carlsson B; Mannervik B; Larsson A; Board P 《Human molecular genetics》1997,6(7):1147-1152
Severe glutathione synthetase (GS) deficiency is a rare genetic disorder
with neonatal onset. The enzymatic block of the gamma-glutamyl cycle leads
to a generalized glutathione deficiency. Clinically affected patients
present with severe metabolic acidosis, 5- oxoprolinuria, increased rate of
hemolysis and defective function of the central nervous system. The
disorder is inherited in an autosomal recessive mode and, until recently,
the molecular basis has remained unknown. We have sequenced 18 GS alleles
associated with enzyme deficiency and we detected missense mutations by
direct sequencing of cDNAs and genomic DNA. In total, 13 different
mutations were identified. Four patients were found to be compound
heterozygotes and two individuals were apparently homozygous. Reduced
enzymatic activities were demonstrated in recombinant protein expressed
from cDNAs in four cases with different missense mutations. The results
from biochemical analysis of patient specimens, supported by the properties
of the expressed mutant proteins, indicate that a residual activity is
present in affected individuals. Our results suggest that complete loss of
function of both GS alleles is probably lethal. It is postulated that
missense mutations will account for the phenotype in the majority of
patients with severe GS deficiency.
相似文献
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Celiac disease (CD) is a chronic disease treated by maintaining and managing a lifelong restrictive gluten-free diet. The purpose of this study was to develop a mobile application, Plan My C-Day, to promote self-management skills among youth with CD during adolescence—a time when decreased adherence often occurs—and examine its usability among adolescents with CD. Plan My C-Day contains three simulations of activities involving eating out and actions to take when preparing for these events. It was developed and pilot tested by 13 adolescents with CD. Application use and user perception data were collected and analyzed. Participants chose 160 actions within the simulations. For over 75% of participants, the time to complete the simulation decreased from the first to the third (last) simulation by an average of 50%. The average reported usability perception was 3.71 on a scale of 1 to 5, with system ease of use and ease of learning obtaining the highest scores. This study demonstrated that the Plan My C-Day mobile application’s self-management content, features, and functions operated well and that the simulations were easy to understand and complete. Further development will include the option to add self-created activities and adaptation to different languages and cultures. 相似文献
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Methotrexate pretreatment of L1210 cells had been shown previously by us to cause an enhancement of the intracellular accumulation of 5-fluorouracil and of the formation of 5-fluorouracil nucleotides which was correlated with synergistic cytotoxicity. This effect of methotrexate was associated with increases in 5-phosphoribosyl-1-pyrophosphate, the cofactor required for the conversion of 5-fluorouracil to 5-fluorouridine-5'-monophosphate (FUMP). Because these influences on 5-fluorouracil metabolism were most likely mediated by the activity of methotrexate as an inhibitor of purine synthesis, the effects of other agents that inhibit purine synthesis were examined. An inhibitor of amidophosphoribosyltransferase, 6-methylmercaptopurine ribonucleoside, the glutamine antagonists, azaserine and 6-diazo-5-oxo-L-norleucine (DON), and the L-aspartate analogue inhibitor of adenylsuccinate synthetase, L-alanosine, all reduced the incorporation of [1-14C]glycine into adenine and guanine bases isolated from nucleic acids. Each drug also resulted in intracellular elevations of 5-phosphoribosyl-1-pyrophosphate that were 15- to 25-fold greater than control levels. These alterations in de novo purine nucleotide synthesis were associated with enhanced intracellular 5-fluorouracil accumulation and synergistic cytotoxicity. 相似文献
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Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge 下载免费PDF全文
Lin PF Nowicka-Sans B Terry B Zhang S Wang C Fan L Dicker I Gali V Higley H Parkin N Tenney D Krystal M Colonno R 《Antimicrobial agents and chemotherapy》2008,52(5):1759-1767
Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients. 相似文献
10.
Changes in virulence and fitness during an epidemic are common among pathogens. Several studies have shown that HIV fitness increases within a patient during disease progression, while bottlenecks, such as sexual transmission, immune pressure and drug treatment can reduce fitness. In this study, we analyzed how these opposing forces have shaped HIV-1 fitness over time. Therefore, we compared the replicative fitness of HIV-1 isolates from newly infected untreated individuals, diagnosed for HIV-1 infection early in the AIDS epidemic in Amsterdam, the Netherlands, with more recent isolates. Twenty-five early and late HIV-1 isolates, carefully matched for seroconversion time, were competed head-to-head in a dual infection/competition assay, employing peripheral blood mononuclear cells. In contrast with previous studies, we observed a trend of increasing fitness over time in the HIV epidemic of Amsterdam. Apparently, the bottleneck, occurring with each transmission event, does not completely reset the fitness increase acquired during disease progression. 相似文献