首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   1797篇
  免费   93篇
  国内免费   58篇
耳鼻咽喉   8篇
儿科学   19篇
妇产科学   5篇
基础医学   495篇
口腔科学   25篇
临床医学   67篇
内科学   269篇
皮肤病学   15篇
神经病学   295篇
特种医学   35篇
外科学   56篇
综合类   174篇
预防医学   76篇
眼科学   18篇
药学   210篇
中国医学   18篇
肿瘤学   163篇
  2024年   12篇
  2023年   16篇
  2022年   32篇
  2021年   41篇
  2020年   33篇
  2019年   44篇
  2018年   33篇
  2017年   33篇
  2016年   30篇
  2015年   52篇
  2014年   67篇
  2013年   103篇
  2012年   67篇
  2011年   93篇
  2010年   78篇
  2009年   98篇
  2008年   97篇
  2007年   94篇
  2006年   93篇
  2005年   62篇
  2004年   73篇
  2003年   63篇
  2002年   57篇
  2001年   51篇
  2000年   42篇
  1999年   29篇
  1998年   44篇
  1997年   40篇
  1996年   38篇
  1995年   33篇
  1994年   29篇
  1993年   23篇
  1992年   19篇
  1991年   12篇
  1990年   19篇
  1989年   19篇
  1988年   20篇
  1987年   24篇
  1986年   17篇
  1985年   18篇
  1984年   16篇
  1983年   15篇
  1982年   15篇
  1981年   20篇
  1980年   11篇
  1979年   6篇
  1978年   6篇
  1977年   4篇
  1974年   2篇
  1970年   3篇
排序方式: 共有1948条查询结果,搜索用时 14 毫秒
51.
Zhang X  Kielian M 《Virology》2005,337(2):344-352
Semliki Forest virus (SFV) membrane fusion is mediated by the viral E1 protein at acidic pH and regulated by the dimeric interaction of E1 with the E2 membrane protein. During low pH-triggered fusion, the E2/E1 heterodimer dissociates, freeing E1 to drive membrane fusion. E2 is synthesized as a precursor, p62, which is processed to mature E2 by the cellular protease furin. Both the dissociation of the p62/E1 dimer and the fusion reaction of p62 virus have a more acidic pH threshold than that of the mature E2 virus. We have previously isolated SFV mutations that allow virus growth in furin-deficient cells. Here we have used such pci mutations to compare the interactions of the p62/E1 and E2/E1 dimers. Our data suggest that there is an important p62/E1 dimer interaction site identified by an E2 R250G mutation and that this interaction is maintained after processing to the mature E2 protein.  相似文献   
52.
The long-term efficacy of lamivudine therapy in patients with hepatitis B virus (HBV) infection is still not clear. In this study, 20 non-cirrhotic Japanese patients infected with HBV received lamivudine therapy for more than 1 year and were followed for a median period of 8.5 years (range, 6.7-8.7 years). The rates of HBe antigen (HbeAg) negative, HBV-DNA undetectable, and alanine aminotransferase (ALT) normal level at the start of lamivudine were 55%, 25%, and 20% and 85%, 80%, and were 80%, respectively, at the last visit, including patients who received additional treatment. The values at the last visit tended to and were significantly higher than those at the start. The values improved at the last visit regardless of the emergence of YMDD motif mutant and continuation of lamivudine. YMDD mutant and biochemical relapse with mutant virus (breakthrough hepatitis) appeared in 65% and 45% during follow-up, respectively, but severe breakthrough hepatitis occurred in only 5%. Furthermore, 80% of patients who received additional treatment for breakthrough hepatitis, regardless of continuation of lamivudine, were ALT normal level at the last visit, in contrast to 25% untreated. HBsAg clearance occurred in two patients of the discontinuous lamivudine group with non-vertical transmission, who were relatively young. One was infected with HBV genotype C with breakthrough hepatitis and the other had no YMDD mutant and was infected with genotype D, a rare type in Japan. None developed cirrhosis or hepatocellular carcinoma (HCC) during follow-up. Our results suggest that long-term lamivudine therapy improves long-term prognosis, especially when additional treatment for breakthrough hepatitis is used.  相似文献   
53.
Bovine mastitis is responsible of major economic losses on dairy farms worldwide. In Argentine dairy herds, Staphylococcus aureus is the main causative agent of the disease.  相似文献   
54.
Pediatric diffuse midline gliomas are devastating diseases. Among them, diffuse midline gliomas H3K27M‐mutant are associated with worse prognosis. However, recent studies have highlighted significant differences in clinical behavior and biological alterations within this specific subgroup. In this context, simple markers are needed to refine the prognosis of diffuse midline gliomas H3K27M‐mutant and guide the clinical management of patients. The aims of this study were (i) to describe the molecular, immunohistochemical and, especially, chromosomal features of a cohort of diffuse midline gliomas and (ii) to focus on H3K27M‐mutant tumors to identify new prognostic markers. Patients were retrospectively selected from 2001 to 2017. Tumor samples were analyzed by immunohistochemistry (including H3K27me3, EGFR, c‐MET and p53), next‐generation sequencing and comparative genomic hybridization array. Forty‐nine patients were included in the study. The median age at diagnosis was 9 years, and the median overall survival (OS) was 9.4 months. H3F3A or HIST1H3B mutations were identified in 80% of the samples. Within the H3K27M‐mutant tumors, PDGFRA amplification, loss of 17p and a complex chromosomal profile were significantly associated with worse survival. Three prognostic markers were identified in diffuse midline gliomas H3K27M‐mutant: PDGFRA amplification, loss of 17p and a complex chromosomal profile. These markers are easy to detect in daily practice and should be considered to refine the prognosis of this entity.  相似文献   
55.
In a multicenter study a new, fully automated Roche Diagnostics Elecsys HBsAg II screening assay with improved sensitivity to HBsAg mutant detection was compared to well-established HBsAg tests: AxSYM HBsAg V2 (Abbott), Architect HBsAg (Abbott), Advia Centaur HBsAg (Bayer) Enzygnost HBsAg 5.0 (Dade-Behring), and Vitros Eci HBsAg (Ortho). A total of 16 seroconversion panels, samples of 60 HBsAg native mutants, and 31 HBsAg recombinant mutants, dilution series of NIBSC and PEI standards, 156 HBV positive samples comprising genotypes A to G, 686 preselected HBsAg positive samples from different stages of infection, 3,593 samples from daily routine, and 6,360 unselected blood donations were tested to evaluate the analytical and clinical sensitivity, the detection of mutants, and the specificity of the new assay. Elecsys HBsAg II showed a statistically significant better sensitivity in seroconversion panels to the compared tests. Fifty-seven out of 60 native mutants and all recombinant mutants were found positive. Among 156 HBV samples with different genotypes and 696 preselected HBsAg positive samples Elecsys HBsAg II achieved a sensitivity of 100%. The lower detection limit for NIBSC standard was calculated to be 0.025 IU/ml and for the PEI standards ad and ay it was <0.001 and <0.005 U/ml, respectively. Within 2,724 daily routine specimens and 6.360 unselected blood donations Elecsys HBsAg II showed a specificity of 99.97 and 99.88%, respectively. In conclusion the new Elecsys HBsAg II shows a high sensitivity for the detection of all stages of HBV infection and HBsAg mutants paired together with a high specificity in blood donors, daily routine samples, and potentially interfering sera.  相似文献   
56.
Previous evidence demonstrates that TAR DNA binding protein (TDP-43) mislocalization is a key pathological feature of amyotrophic lateral sclerosis (ALS). TDP-43 normally shows nuclear localization, but in CNS tissue from patients who died with ALS this protein mislocalizes to the cytoplasm. Disease specific TDP-43 species have also been reported to include hyperphosphorylated TDP-43, as well as a C-terminal fragment. Whether these abnormal TDP-43 features are present in patients with SOD1-related familial ALS (fALS), or in mutant SOD1 over-expressing transgenic mouse models of ALS remains controversial. Here we investigate TDP-43 pathology in transgenic mice expressing the G93A mutant form of SOD1. In contrast to previous reports we observe redistribution of TDP-43 to the cytoplasm of motor neurons in mutant SOD1 transgenic mice, but this is seen only in mice having advanced disease. Furthermore, we also observe rounded TDP-43 immunoreactive inclusions associated with intense ubiquitin immunoreactivity in lumbar spinal cord at end stage disease in mSOD mice. These data indicate that TDP-43 mislocalization and ubiquitination are present in end stage mSOD mice. However, we do not observe C-terminal TDP-43 fragments nor TDP-43 hyperphosphorylated species in these end stage mSOD mice. Our findings indicate that G93A mutant SOD1 transgenic mice recapitulate some key pathological, but not all biochemical hallmarks, of TDP-43 pathology previously observed in human ALS. These studies suggest motor neuron degeneration in the mutant SOD1 transgenic mice is associated with TDP-43 histopathology.  相似文献   
57.
This study examines the effects of the intracellular protein FKBP12.6 on action potential and associated K+ currents in isolated adult rabbit ventricular cardiomyocytes. FKBP12.6 was over-expressed by ~6 times using a recombinant adenovirus coding for human FKBP12.6. This over-expression caused prolongation of action potential duration (APD) by ~30%. The amplitude of the transient outward current (I to) was unchanged, but rate of inactivation at potentials positive to +40 mV was increased. FKBP12.6 over-expression decreased the amplitude of the inward rectifier current (I K1) by ~25% in the voltage range −70 to −30 mV, an effect prevented by FK506 or lowering intracellular [Ca2+] below 1 nM. Over-expression of an FKBP12.6 mutant, which cannot bind calcineurin, prolonged APD and affected I to and I K1 in a similar manner to wild-type protein. These data suggest that FKBP12.6 can modulate APD via changes in I K1 independently of calcineurin binding, suggesting that FKBP12.6 may affect APD by direct interaction with I K1.  相似文献   
58.
Summary A virtually complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HPRT) causes Lesch-Nyhan syndrome. A novel mutation of HPRT gene in a Japanese Lesch-Nyhan family has been identified using mRNA and genomic DNA from peripheral blood cells. A single nucleotide substitution of T to C in exon 3 resulted in a mis-sensemutation, CTC (Leu) to CCC (Pro), at codon 65. Utilizing anMnlI restriction site which was lost in the mutation as an indicator,a family study showed that the mother was normal not having the mutant gene. The mutation was ade novo event that had occurred in the germ cells of the mother or in the proband during the early phase of fetal development.  相似文献   
59.
The evolution of precore stop codon mutation (A1896) and dinucleotide mutation (T1762/A1764) in the basic core promoter (BCP) of hepatitis B virus (HBV) genome during transient seroconversion and seroreversion of hepatitis B e antigen (HBeAg) remains unclarified. Five HBeAg-positive HBV carriers who experienced transient seroconversion followed by seroreversion of HBeAg (Group I, 3.3%) and 3 HBeAg-negative HBV carriers with documented reversion of HBeAg (Group II, 2.5%) in a prospective cohort of 272 patients with chronic hepatitis B were thus identified. The sequential changes at the precore nucleotide 1896 and BCP dinucleotide 1762/1764 were determined by polymerase chain reaction and direct sequencing. At enrollement, precore A1896 and BCP T1762/A1764 were noted in 4 (50%) and 1 (13%) of the eight patients. During a median follow-up period of 58 months (range: 31-76 months), 12 episodes of transient HBeAg seroconversion followed by seroreversion were encountered in Group I patients and 3 episodes of HBeAg seroreversion in Group II patients. Accompanying acute exacerbations were found in two-thirds of patients with either HBeAg seroconversion or seroreversion. Overall, precore nucleotide A1896 remained identical in 73% and 83% of the seroconversion and seroreversion events, respectively. BCP dinucleotide T1762/A1764 remained unchanged in 94% and 92% of the seroconversion and seroreversion events, respectively. At the end of follow-up, only one had both precore and BCP mutations. In conclusion, these data suggested that HBeAg seroreversion might be due to the lack of sustained precore and BCP mutations after HBeAg seroconversion. Although uncommon, HBeAg seroreversion can be associated with hepatitis exacerbation.  相似文献   
60.
冉瑞琼  付华 《现代免疫学》1996,16(5):257-260
本文采用放射配基结合分析法和蛋白合成抑制试验研究了肿瘤坏死因子突变体(TNF-m)对SGC7901细胞TNF受体的影响。结果表明,TNF-m可显著降低SGC7901细胞表面TNF受体数目并呈剂量、时间、温度依赖关系,对受体亲和力无影响,TNF-m可使胞浆TNF受体数目增加,去除TNF-m3h后,膜TNF受体大约可恢复60%,显著高于胰蛋白酶处理组TNF受体的恢复率,放线菌素D对TNF-m处理的细胞TNF受体的抑制作用显著低于对照组,且TNF受体的半衰期约为90min.据此认为,TNF-m通过介导TNF受体的内化从而使膜TNF受体数降低。  相似文献   
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号