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81.
Novel stop and frameshifting mutations in the autosomal dominant polycystic kidney disease 2 (PKD2) gene 总被引:3,自引:0,他引:3
Miguel Viribay Tomohito Hayashi Dolores Tellería Toshio Mochizuki David M. Reynolds Rafael Alonso Xose M. Lens Felipe Moreno Peter C. Harris Stefan Somlo José L. San Millán 《Human genetics》1997,101(2):229-234
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most frequent inherited disorders. The majority of cases
are due to mutation of the PKD1 gene, on 16p13.3, while in most of the remainder the disease maps to the PKD2 locus, at chromosome
4q21-q23. Recently, the PKD2 gene has been positionally cloned and three nonsense mutations within the coding sequence of
the gene identified. Here we report a systematic mutation screening of all 15 exons of the PKD2 gene in chromosome 4-linked
ADPKD families, using heteroduplex and SSCP analyses. We have identified and characterized seven novel mutations, with a detection
rate of approximately 90% in the population studied. All of the mutations result in the premature stop of translation: four
nonsense changes and three deletions. The deletions are all frameshifting, of four T nucleotides in one case and one G nucleotide
in the other two. All mutations are unique and are distributed throughout the gene without evidence of clustering. Comparison
of specific mutations with the clinical profile in ADPKD2 families shows no clear correlation.
Received: 5 April 1997 / Accepted: 31 July 1997 相似文献
82.
Shuichiro Gohda Akio Shimizu Masamichi Ikeguchi Shintaro Sugai 《The protein journal》1995,14(8):731-737
The disulfide reduction kinetics in equine lysozyme (ELZ), which is a Ca2+-binding lysozyme, and human (HLA) and equineα-lactalbumin (ELA) at pH 8.5 and 25°C by excess dithiothreitol were studied, and it was found that in ELZ there is no superreactive disulfide bond, while one of the disulfides is reduced very quickly by the reducing agent in HLA and ELA, as in bovineα-lactalbumin. The local conformation around the surface disulfide in ELZ seems to be more similar to that in hen egg-white lysozyme than inα-lactalbumin. The four disulfides in ELZ were reduced slowly in an apparently single-exponential form, and the bound Ca2+ lowered the reduction rate. The torsion energy on each of the disulfides in threeα-lactalbumin and eight c-type lysozymes whose native conformations have been experimentally or theoretically analyzed was calculated, and it was found that torsion imposed on the surface disulfide between Cys 6 and Cys 120 inα-lactalbumin is a main cause of the superreactivity and all of lysozymes, including the Ca2+-binding ones, have no such strained surface bond. 相似文献
83.
84.
Inhibition of DNA synthesis of adult rat hepatocytes in primary culture by dibutyrylcytidine 3', 5'-cyclic monophosphate 总被引:1,自引:0,他引:1
T Kubin M Yanagida S Mori Y Hayashi E Gohda I Yamamoto 《Cell biology international reports》1989,13(11):907-917
The effect of dibutyrylcytidine 3',5'-cyclic monophosphate (Bt2cCMP) on DNA synthesis of adult rat hepatocytes in primary culture was examined. Bt2cCMP caused dose-dependent inhibition of the DNA syntheses stimulated by various growth factors including human hepatocyte growth factor (hHGF). Dibutyryladenosine 3',5'-cyclic monophosphate (Bt2cAMP) inhibited the DNA synthesis more effectively than Bt2cCMP, but dibutyrylguanosine 3',5'-cyclic monophosphate (Bt2cGMP) and n-butyrate had a slight or null inhibitory effect. When added at the onset of DNA synthesis, Bt2cAMP was much less effective, but Bt2cCMP was still effective. Thus Bt2cCMP is able to inhibit growth factor-stimulated hepatocyte proliferation. 相似文献
85.
Machiko Kanzaki Yoshihiro Asano Hatsue Ishibashi-Ueda Eiji Oiki Tomoki Nishida Hiroshi Asanuma Hisakazu Kato Toru Oka Tomohito Ohtani Osamu Tsukamoto Shuichiro Higo Hidetaka Kioka Ken Matsuoka Yoshiki Sawa Issei Komuro Masafumi Kitakaze Seiji Takashima Yasushi Sakata 《PloS one》2016,11(2)
Background
Accurate prediction of both mortality and morbidity is of significant importance, but it is challenging in patients with severe heart failure. It is especially difficult to detect the optimal time for implanting mechanical circulatory support devices in such patients. We aimed to analyze the morphometric ultrastructure of nuclear chromatin in cardiomyocytes by developing an original clinical histopathological method. Using this method, we developed a biomarker to predict poor outcome in patients with dilated cardiomyopathy (DCM).Methods and Results
As a part of their diagnostic evaluation, 171 patients underwent endomyocardial biopsy (EMB). Of these, 63 patients diagnosed with DCM were included in this study. We used electron microscopic imaging of cardiomyocyte nuclei and an automated image analysis software program to assess whether it was possible to detect discontinuity of the nuclear periphery. Twelve months after EMB, all patients with a discontinuous nuclear periphery (Group A, n = 11) died from heart failure or underwent left ventricular assist device (VAD) implantation. In contrast, in patients with a continuous nuclear periphery (Group N, n = 52) only 7 patients (13%) underwent VAD implantation and there were no deaths (p<0.01). We then evaluated chromatin particle density (Nuc-CS) and chromatin thickness in the nuclear periphery (Per-CS) in Group N patients; these new parameters were able to identify patients with poor prognosis.Conclusions
We developed novel morphometric methods based on cardiomyocyte nuclear chromatin that may provide pivotal information for early prediction of poor prognosis in patients with DCM. 相似文献86.
87.
88.
Takashi Nishina Jin Gohda Jun-ichiro Inoue 《Biochemical and biophysical research communications》2009,388(1):96-260
Pancreatic cancer has one of the poorest prognoses among human neoplasms. Constitutive activation of NF-κB is frequently observed in pancreatic cancer cells and is involved in their malignancy. However, little is known about the molecular mechanism of this constitutive NF-κB activation. Here, we show that the alternative pathway is constitutively activated and NF-κB-inducing kinase (NIK), a mediator of the alternative pathway, is significantly expressed in pancreatic cancer cells. siRNA-mediated silencing of NIK expression followed by subcellular fractionation revealed that NIK is constitutively involved in the processing of p100 and nuclear transport of p52 and RelB in pancreatic cancer cells. In addition, NIK silencing significantly suppressed proliferation of pancreatic cancer cells. These results clearly indicate that NIK is involved in the constitutive activation of the alternative pathway and controls cell proliferation in pancreatic cancer cells. Therefore, NIK might be a novel target for the treatment of pancreatic cancer. 相似文献
89.
Gohda K 《Journal of enzyme inhibition and medicinal chemistry》2006,21(5):609-615
In this study, we investigated by linear regression model the SAR data of the 15 HIV-1 protease inhibitors possessing structurally diverse scaffolds. First, a regression model was developed only using the enzyme-inhibitor interaction energy as a term of the model, but did not provide a good correlation with the inhibitory activity (R2 = 0.580 and Q2 = 0.500). Then, we focused on the conformational flexibility of the inhibitors which may represent the diversity of the inhibitors, and added two conformational parameters into the model, respectively: the number of rotatable bonds of ligands (deltaSrot) and the distortion energy of ligands (deltaElig). The regression model by adding deltaElig successfully improved the quality of the model (R2 = 0.771 and Q2 = 0.713) while the model with deltaSrot was unsuccessful. The prediction for a training inhibitor by the deltaElig model also showed good agreement with experimental activity. These results suggest that the conformational flexibility of HIV-1 protease inhibitors directly contributes to the enzyme inhibition. 相似文献
90.
Song Y Matsumoto K Yamada M Gohda A Brigham CJ Sinskey AJ Taguchi S 《Applied microbiology and biotechnology》2012,93(5):1917-1925
The first biosynthetic system for lactate (LA)-based polyesters was previously created in recombinant Escherichia coli (Taguchi et al. 2008). Here, we have begun efforts to upgrade the prototype polymer production system to a practical stage by using metabolically
engineered Gram-positive bacterium Corynebacterium glutamicum as an endotoxin-free platform. We designed metabolic pathways in C. glutamicum to generate monomer substrates, lactyl-CoA (LA-CoA), and 3-hydroxybutyryl-CoA (3HB-CoA), for the copolymerization catalyzed
by the LA-polymerizing enzyme (LPE). LA-CoA was synthesized by D-lactate dehydrogenase and propionyl-CoA transferase, while 3HB-CoA was supplied by β-ketothiolase (PhaA) and NADPH-dependent
acetoacetyl-CoA reductase (PhaB). The functional expression of these enzymes led to a production of P(LA-co-3HB) with high LA fractions (96.8 mol%). The omission of PhaA and PhaB from this pathway led to a further increase in LA
fraction up to 99.3 mol%. The newly engineered C. glutamicum potentially serves as a food-grade and biomedically applicable platform for the production of poly(lactic acid)-like polyester. 相似文献