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141.
Shefer K Brown Y Gorkovoy V Nussbaum T Ulyanov NB Tzfati Y 《Molecular and cellular biology》2007,27(6):2130-2143
Telomerase copies a short template within its integral telomerase RNA onto eukaryotic chromosome ends, compensating for incomplete replication and degradation. Telomerase action extends the proliferative potential of cells, and thus it is implicated in cancer and aging. Nontemplate regions of telomerase RNA are also crucial for telomerase function. However, they are highly divergent in sequence among species, and their roles are largely unclear. Using in silico three-dimensional modeling, constrained by mutational analysis, we propose a three-dimensional model for a pseudoknot in telomerase RNA of the budding yeast Kluyveromyces lactis. Interestingly, this structure includes a U-A.U major-groove triple helix. We confirmed the triple-helix formation in vitro using oligoribonucleotides and showed that it is essential for telomerase function in vivo. While triplex-disrupting mutations abolished telomerase function, triple compensatory mutations that formed pH-dependent G-C.C(+) triples restored the pseudoknot structure in a pH-dependent manner and partly restored telomerase function in vivo. In addition, we identified a novel type of triple helix that is formed by G-C.U triples, which also partly restored the pseudoknot structure and function. We propose that this unusual structure, so far found only in telomerase RNA, provides an essential and conserved telomerase-specific function. 相似文献
142.
The BsmI vitamin D receptor gene polymorphism is associated with ulcerative colitis in Jewish Ashkenazi patients 总被引:4,自引:0,他引:4
Dresner-Pollak R Ackerman Z Eliakim R Karban A Chowers Y Fidder HH 《Genetic testing》2004,8(4):417-420
Susceptibility to inflammatory bowel disease (IBD) has a strong genetic component. The vitamin D receptor (VDR) gene maps to a region on chromosome 12 shown to be associated with IBD in some studies. In this case-control study we determined the association between the BsmI VDR gene polymorphism and IBD in patients with Crohn's disease (CD) and ulcerative colits (UC). Three hundred seventy-nine Jewish Israeli patients with IBD, 228 with CD (129 Ashkenazi and 99 non-Ashkenazi), and 151 patients with UC (72 Ashkenazi, 79 non-Ashkenazi) were studied. The control group included 495 healthy blood donors (352 non-Ashkenazi and 143 Ashkenazi). All subjects were genotyped for the BsmI VDR gene polymorphism. The frequency of the BB genotype was higher in Ashkenazi patients with UC compared to Ashkenazi controls (0.21 vs. 0.11, p = 0.042, odds ratio 2.27, 95% confidence interval [CI] 1.06-4.9). There were no differences in the prevalence of the BB genotype or the B allele between ethnically matched patients with CD and UC. Nor were there differences in the BB genotype or B allele frequencies between CD patients and ethnically matched controls. The BsmI VDR gene polymorphism is associated with increased susceptibility to UC in Israeli Ashkenazi patients with UC. 相似文献
143.
Ayelet Zauberman Yehuda Flashner Yinon Levy Yaron Vagima Avital Tidhar Ofer Cohen Erez Bar-Haim David Gur Moshe Aftalion Gideon Halperin Avigdor Shafferman Emanuelle Mamroud 《PloS one》2013,8(12)
Plague, initiated by Yersinia pestis infection, is a rapidly progressing disease with a high mortality rate if not quickly treated. The existence of antibiotic-resistant Y. pestis strains emphasizes the need for the development of novel countermeasures against plague. We previously reported the generation of a recombinant Y. pestis strain (Kim53ΔJ+P) that over-expresses Y. enterocolitica YopP. When this strain was administered subcutaneously to mice, it elicited a fast and effective protective immune response in models of bubonic, pneumonic and septicemic plague. In the present study, we further characterized the immune response induced by the Kim53ΔJ+P recombinant strain. Using a panel of mouse strains defective in specific immune functions, we observed the induction of a prompt protective innate immune response that was interferon-γ dependent. Moreover, inoculation of mice with Y. pestis Kim53ΔJ+P elicited a rapid protective response against secondary infection by other bacterial pathogens, including the enteropathogen Y. enterocolitica and the respiratory pathogen Francisella tularensis. Thus, the development of new therapies to enhance the innate immune response may provide an initial critical delay in disease progression following the exposure to highly virulent bacterial pathogens, extending the time window for successful treatment. 相似文献
144.
Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux 下载免费PDF全文
Bartels CF Bükülmez H Padayatti P Rhee DK van Ravenswaaij-Arts C Pauli RM Mundlos S Chitayat D Shih LY Al-Gazali LI Kant S Cole T Morton J Cormier-Daire V Faivre L Lees M Kirk J Mortier GR Leroy J Zabel B Kim CA Crow Y Braverman NE van den Akker F Warman ML 《American journal of human genetics》2004,75(1):27-34
The homodimeric transmembrane receptor natriuretic peptide receptor B (NPR-B [also known as guanylate cyclase B, GC-B, and GUC2B]; gene name NPR2) produces cytoplasmic cyclic GMP from GTP on binding its extracellular ligand, C-type natriuretic peptide (CNP). CNP has previously been implicated in the regulation of skeletal growth in transgenic and knockout mice. The autosomal recessive skeletal dysplasia known as "acromesomelic dysplasia, type Maroteaux" (AMDM) maps to an interval that contains NPR2. We sequenced DNA from 21 families affected by AMDM and found 4 nonsense mutations, 4 frameshift mutations, 2 splice-site mutations, and 11 missense mutations. Molecular modeling was used to examine the putative protein change brought about by each missense mutation. Three missense mutations were tested in a functional assay and were found to have markedly deficient guanylyl cyclase activity. We also found that obligate carriers of NPR2 mutations have heights that are below the mean for matched controls. We conclude that, although NPR-B is expressed in a number of tissues, its major role is in the regulation of skeletal growth. 相似文献
145.
Administration of several doses of MIF-I or alpha-MSH did not modify colonic temperature or the level of motor activity of rats in ambient temperatures of 4 degree or 20 degrees C. However, the thermoregulatory but not motor effects of the interaction between MIF-I or alpha-MSH with d-amphetamine were dependent upon ambient temperature. At 4 degree C, 1.0 mg/kg of both peptides enhanced the d-amphetamine-induced hypothermia, but at 20 degrees C both peptides blocked the hyperthermic effects of d-amphetamine. The hypothermic effect of chlorpromazine (CPZ) at 4 degree C and 20 degrees C was blocked by 1.0 mg/kg MIF-I but not by 1.0 mg/kg alpha-MSH. No linear dose response relationships between various doses of MIF-I or alpha-MSH and thermal responses were found. Administration of melanin or the use of hypophysectomized rats did not alter the significant interactions observed after peripheral injections. 相似文献
146.
Han G. Ron Yair Mordish Avi Eisenthal Yehuda Skornick Moshe J. Inbar Samario Chaitchik 《Cancer immunology, immunotherapy : CII》1994,38(6):379-384
Chemotherapy and interleukin-2 (IL-2) and/or interferon (IFN) produce objective responses in a proportion of patients with advanced malignant melanoma. The duration of response to chemotherapy is usually less than 4 months, and immunotherapy has resulted in longlasting remissions in a small number of patients with metastatic melanoma. The current study was conducted to improve the antitumor efficacy and the interactions between recombinant (r) IL-2, rIFN2a and chemotherapy. A total of 16 evaluable patients with metastatic malignant melanoma were entered into a phase-II study designed to assess the response rate and therapeutic efficacy of dacarbazine and carboplatin followed by rIL-2 and rIFN2a. Patients received 750 mg/m2 dacarbazine with 400 mg/m2 carboplatin each by intravenous bolus on days 1 and 22. Recombinant IL-2 and IFN2a were administered on an outpatient basis (home therapy) subcutaneously for 6 consecutive weeks: 4.8×106 IU/m2 rIL-2 daily, 5 days a week; 6.0×106 IU/m2 rIFN2a thrice weekly. There were responses in 6 of the 16 enrolled patients with an overall response rate of 37.5% (95% confidence interval: 14%–61%). All responding patients had partial responses. The median survival time of the responding patients was significantly better than that of patients with progressive and stable disease (P=0.03). The median duration of response was 11 months (range 2–24 months). Responses in lung, liver, soft tissue and lymph-node sites were noted. 相似文献
147.
Jing Cheng Tamar Ringel-Kulka Ineke Heikamp-de Jong Yehuda Ringel Ian Carroll Willem M de Vos Jarkko Saloj?rvi Reetta Satokari 《The ISME journal》2016,10(4):1002-1014
The colonization pattern of intestinal microbiota during childhood may impact health later in life, but children older than 1 year are poorly studied. We followed healthy children aged 1–4 years (n=28) for up to 12 months, during which a synbiotic intervention and occasional antibiotics intake occurred, and compared them with adults from the same region. Microbiota was quantified with the HITChip phylogenetic microarray and analyzed with linear mixed effects model and other statistical approaches. Synbiotic administration increased the stability of Actinobacteria and antibiotics decreased Clostridium cluster XIVa abundance. Bacterial diversity did not increase in 1- to 5-year-old children and remained significantly lower than in adults. Actinobacteria, Bacilli and Clostridium cluster IV retained child-like abundances, whereas some other groups were converting to adult-like profiles. Microbiota stability increased, with Bacteroidetes being the main contributor. The common core of microbiota in children increased with age from 18 to 25 highly abundant genus-level taxa, including several butyrate-producing organisms, and developed toward an adult-like composition. In conclusion, intestinal microbiota is not established before 5 years of age and diversity, core microbiota and different taxa are still developing toward adult-type configuration. Discordant development patterns of bacterial phyla may reflect physiological development steps in children. 相似文献
148.
Methanogenesis in the hypersaline Solar Lake (Sinai) 总被引:2,自引:0,他引:2
Dieter Giani Luise Giani Yehuda Cohen Wolfgang E. Krumbein 《FEMS microbiology letters》1984,25(2-3):219-224
Abstract Enrichment studies on microbial mat sediments (potential stromatolites) from the hypersaline Solar Lake (Sinai) indicated high numbers of methanogenic bacteria (up to 105 ml−1 sediment) in spite of the high sulfate reduction rate, sulfate concentration and salinity. Among H2 /CO2 , acetate and monomethylamine, the methylated amine was the preferred substrate. The predominant species enriched was a Methanosarcina sp. The findings indicate that methanogenic bacteria play an important role in hypersaline sulfate-enriched anoxic sediments and stromatolithic microbial mats. 相似文献
149.
Hydrothermal synthesis has afforded a pair of divalent copper coordination polymers containing the kinked and hydrogen-bonding capable imine 4,4′-dipyridylamine (dpa) and aromatic dicarboxylates, {[Cu(iph)(dpa)]·0.5H2O}n (1, iph = isophthalate) and [Cu(tdc)(dpa)]n (2, tdc = 2,5-thiophenedicarboxylate). Compounds 1 and 2 contain orthogonally disposed parallel sets of 1-D [Cu(iph)]n and [Cu(tdc)]n chains, respectively, containing dicarboxylate-bridged dinuclear {CuOCO}2 units. The chain motifs are joined by tethering dpa ligands to construct uncommon non-interpenetrated 3-D CdSO4 lattices (658 topology) in both cases. Variable temperature magnetic studies show the presence of weak antiferromagnetic coupling within the {CuOCO}2 dimers in both complexes, with J = −2.66(3) and −1.68(5) cm−1 for 1 and 2, respectively. 相似文献
150.
Mahiuddin Ahmed Ming Cheng Qi Zhao Yehuda Goldgur Sarah M. Cheal Hong-Fen Guo Steven M. Larson Nai-Kong V. Cheung 《The Journal of biological chemistry》2015,290(50):30018-30029
B7-H3 (CD276) is both an inhibitory ligand for natural killer cells and T cells and a tumor antigen that is widely expressed among human solid tumors. Anti-B7-H3 mouse monoclonal antibody 8H9 has been successfully used for radioimmunotherapy for patients with B7-H3(+) tumors. We present the humanization, affinity maturation, and epitope mapping of 8H9 based on structure determination, modeling, and yeast display methods. The crystal structure of ch8H9 Fab fragment was solved to 2.5-Å resolution and used as a template for humanization. By displaying the humanized 8H9 single chain Fv (scFv) on the surface of yeast, the affinity was matured by sequential random mutagenesis and fluorescence-activated cell sorting. Six mutations (three in the complementarity-determining region and three in the framework regions) were identified and incorporated into an affinity-matured humanized 8H9 construct (hu8H9-6m) and an affinity-matured chimeric 8H9 construct (ch8H9-6m). The hu8H9-6m scFv had a 160-fold improvement in affinity (0.9 nm
KD) compared with parental hu8H9 scFv (144 nm
KD). The IgG formats of ch8H9-6m and hu8H9-6m (nanomolar to subnanomolar KD) had 2–9-fold enhancements in affinity compared with their parental forms, potent in vitro antibody-dependent cell-mediated cytotoxicity (0.1–0.3 μg/ml EC50), and high tumor uptake in mouse xenografts. Based on in silico docking studies and experimental validation, the molecular epitope of 8H9 was determined to be dependent on the FG loop of B7-H3, a region critical to its function in immunologic blockade and unique among anti-B7-H3 antibodies published to date. 相似文献