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171.
Sarah M. McLeod Paul R. Fleming Kathleen MacCormack Robert E. McLaughlin James D. Whiteaker Shin-ichiro Narita Makiko Mori Hajime Tokuda Alita A. Miller 《Journal of bacteriology》2015,197(6):1075-1082
In Gram-negative bacteria, lipoproteins are transported to the outer membrane by the Lol system. In this process, lipoproteins are released from the inner membrane by the ABC transporter LolCDE and passed to LolA, a diffusible periplasmic molecular chaperone. Lipoproteins are then transferred to the outer membrane receptor protein, LolB, for insertion in the outer membrane. Here we describe the discovery and characterization of novel pyridineimidazole compounds that inhibit this process. Escherichia coli mutants resistant to the pyridineimidazoles show no cross-resistance to other classes of antibiotics and map to either the LolC or LolE protein of the LolCDE transporter complex. The pyridineimidazoles were shown to inhibit the LolA-dependent release of the lipoprotein Lpp from E. coli spheroplasts. These results combined with bacterial cytological profiling are consistent with LolCDE-mediated disruption of lipoprotein targeting to the outer membrane as the mode of action of these pyridineimidazoles. The pyridineimidazoles are the first reported inhibitors of the LolCDE complex, a target which has never been exploited for therapeutic intervention. These compounds open the door to further interrogation of the outer membrane lipoprotein transport pathway as a target for antimicrobial therapy. 相似文献
172.
Tatsuki Sugi Tatsunori Masatani Fumi Murakoshi Shin-ichiro Kawazu Kentaro Kato 《Analytical biochemistry》2014
Toxoplasma gondii can differentiate into tachyzoites or bradyzoites. To accelerate the investigation of bradyzoite differentiation mechanisms, we constructed a reporter parasite, PLK/DLUC_1C9, for a high-throughput assay. PLK/DLUC_1C9 expressed firefly luciferase under the bradyzoite-specific BAG1 promoter. Firefly luciferase activity was detected with a minimum of 102 parasites induced by pH 8.1. To normalize bradyzoite differentiation, PLK/DLUC_1C9 expressed Renilla luciferase under the parasite’s α-tubulin promoter. Renilla luciferase activity was detected with at least 102 parasites. By using PLK/DLUC_1C9 with this 96-well format screening system, we found that the protein kinase inhibitor analogs, bumped kinase inhibitors 1NM-PP1, 3MB-PP1, and 3BrB-PP1, had bradyzoite-inducing effects. 相似文献
173.
Andreas Gerondopoulos Ricardo Nunes Bastos Shin-ichiro Yoshimura Rachel Anderson Sarah Carpanini Irene Aligianis Mark T. Handley Francis A. Barr 《The Journal of cell biology》2014,205(5):707-720
The ancestral Rab GTPase Rab18 and both subunits of the Rab3GAP complex are mutated in the human neurological and developmental disorder Warburg Micro syndrome. Here, we demonstrate that the Rab3GAP complex is a specific Rab18 guanine nucleotide exchange factor (GEF). The Rab3GAP complex localizes to the endoplasmic reticulum (ER) and is necessary for ER targeting of Rab18. It is also sufficient to promote membrane recruitment of Rab18. Disease-associated point mutations of conserved residues in either the Rab3GAP1 (T18P and E24V) or Rab3GAP2 (R426C) subunits result in loss of the Rab18 GEF and membrane-targeting activities. Supporting the view that Rab18 activity is important for ER structure, in the absence of either Rab3GAP subunit or Rab18 function, ER tubular networks marked by reticulon 4 were disrupted, and ER sheets defined by CLIMP-63 spread out into the cell periphery. Micro syndrome is therefore a disease characterized by direct loss of Rab18 function or loss of Rab18 activation at the ER by its GEF Rab3GAP. 相似文献
174.
Hajime Honma Makoto Hirai Shota Nakamura Hassan Hakimi Shin-ichiro Kawazu Nirianne M.Q. Palacpac Hajime Hisaeda Hiroyuki Matsuoka Satoru Kawai Hiroyoshi Endo Teruo Yasunaga Jun Ohashi Toshihiro Mita Toshihiro Horii Mitsuru Furusawa Kazuyuki Tanabe 《DNA research》2014,21(4):439-446
Plasmodium falciparum malaria imposes a serious public health concern throughout the tropics. Although genetic tools are principally important to fully investigate malaria parasites, currently available forward and reverse tools are fairly limited. It is expected that parasites with a high mutation rate can readily acquire novel phenotypes/traits; however, they remain an untapped tool for malaria biology. Here, we generated a mutator malaria parasite (hereinafter called a ‘malaria mutator’), using site-directed mutagenesis and gene transfection techniques. A mutator Plasmodium berghei line with a defective proofreading 3′ → 5′ exonuclease activity in DNA polymerase δ (referred to as PbMut) and a control P. berghei line with wild-type DNA polymerase δ (referred to as PbCtl) were maintained by weekly passage in ddY mice for 122 weeks. High-throughput genome sequencing analysis revealed that two PbMut lines had 175–178 mutations and a 86- to 90-fold higher mutation rate than that of a PbCtl line. PbMut, PbCtl, and their parent strain, PbWT, showed similar course of infection. Interestingly, PbMut lost the ability to form gametocytes during serial passages. We believe that the malaria mutator system could provide a novel and useful tool to investigate malaria biology. 相似文献
175.
Matsugami A Kobayashi S Ouhashi K Uesugi S Yamamoto R Taira K Nishikawa S Kumar PK Katahira M 《Structure (London, England : 1993)》2003,11(5):533-545
An RNA aptamer containing two binding sites exhibits extremely high affinity to the HIV Tat protein. We have determined the structure of the aptamer complexed with two argininamide molecules. Two adjacent U:A:U base triples were formed, which widens the major groove to make space for the two argininamide molecules. The argininamide molecules bind to the G bases through hydrogen bonds. The binding is stabilized through stacking interactions. The structure of the aptamer complexed with a Tat-derived arginine-rich peptide was also characterized. It was suggested that the aptamer structure is similar for both complexes and that the aptamer interacts with two different arginine residues of the peptide simultaneously at the two binding sites, which could explain the high affinity to Tat. 相似文献
176.
Moriyama H Tsukida T Inoue Y Kondo H Yoshino K Nishimura S 《Bioorganic & medicinal chemistry letters》2003,13(16):2741-2744
In order to verify whether azasugar would be a useful scaffold for inhibitory activity against metalloproteinases, we synthesized some azasugar-based compounds. As a result, it is clarified that azasugar moiety could function as successful inhibitor of matrix metalloproteinase-1, -3 and -9 and TACE. 相似文献
177.
Early ontogeny of the big roughy Gephyroberyx japonicus (Beryciformes: Trachichthyidae) in captivity
Development of eggs and larvae of the big roughy Gephyroberyx japonicus are described on the basis of specimens reared in captivity. Spherical eggs (diameter 1.26–1.35?mm) with a single oil globule were pelagic. Newly hatched larvae (2.8–3.1?mm in body length, BL) had strong linear pigmentation on the head and trunk. The mouth opened at ca. 3.5?mm BL; thereafter the yolk was absorbed. Notochord flexion started at ca. 4.5?mm BL when body depth increased rapidly, and melanophores spread to all of the body. Notochord flexion was completed at ca. 5.0?mm BL. Head spination and pelvic fins began to develop during the flexion stage. 相似文献
178.
Yusuke Nakatsu Yuichiro Otani Hideyuki Sakoda Jun Zhang Ying Guo Hirofumi Okubo Akifumi Kushiyama Midori Fujishiro Takako Kikuch Toshiaki Fukushima Haruya Ohno Yoshihiro Tsuchiya Hideaki Kamata Akiko Nagamachi Toshiya Inaba Fusanori Nishimura Hideki Katagiri Shin-ichiro Takahashi Hiroki Kurihara Takafumi Uchida Tomoichiro Asano 《The Journal of biological chemistry》2012,287(53):44526-44535
Nonalcoholic steatohepatitis (NASH) is a disorder characterized by simultaneous fat accumulation and chronic inflammation in the liver. In this study, Pin1 expression was revealed to be markedly increased in the livers of mice with methionine choline-deficient (MCD) diet-induced NASH, a rodent model of NASH. In addition, Pin1 KO mice were highly resistant to MCD-induced NASH, based on a series of data showing simultaneous fat accumulation, chronic inflammation, and fibrosis in the liver. In terms of Pin1-induced fat accumulation, it was revealed that the expression levels of peroxisome proliferator-activated receptor α and its target genes were higher in the livers of Pin1 KO mice than in controls. Thus, resistance of Pin1 KO mice to hepatic steatosis is partially attributable to the lack of Pin1-induced down-regulation of peroxisome proliferator-activated receptor α, although multiple other mechanisms are apparently involved. Another mechanism involves the enhancing effect of hematopoietic Pin1 on the expressions of inflammatory cytokines such as tumor necrosis factor and monocyte chemoattractant protein 1 through NF-κB activation, eventually leading to hepatic fibrosis. Finally, to distinguish the roles of hematopoietic or nonhematopoietic Pin1 in NASH development, mice lacking Pin1 in either nonhematopoietic or hematopoietic cells were produced by bone marrow transplantation between wild-type and Pin1 KO mice. The mice having nonhematopoietic Pin1 exhibited fat accumulation without liver fibrosis on the MCD diet. Thus, hepatic Pin1 appears to be directly involved in the fat accumulation in hepatocytes, whereas Pin1 in hematopoietic cells contributes to inflammation and fibrosis. In summary, this is the first study to demonstrate that Pin1 plays critical roles in NASH development. This report also raises the possibility that hepatic Pin1 inhibition to the appropriate level might provide a novel therapeutic strategy for NASH. 相似文献
179.
Kozako T Matsumoto N Kuramoto Y Sakata A Motonagare R Aikawa A Imoto M Toda A Honda S Shimeno H Soeda S 《FEBS letters》2012,586(7):1067-1072
Vasohibin is thought to be an important negative feedback regulator of angiogenesis that is selectively induced in endothelial cells by VEGF. Here, we assessed the role of vasohibin on HIF-1α expression under oxidative stress induced by hydrogen peroxide (H2O2) in HUVEC. VEGF induced significant cell growth that was associated with an increase in vasohibin expression. Following H2O2-pretreatment, VEGF further increased cell growth but this was contrastingly associated with a decrease in vasohibin expression when compared with VEGF alone. Interestingly, vasohibin inhibited cell proliferation through degradation of HIF-1α expression during H2O2-pretreatment. Furthermore, vasohibin elevated the expression of prolyl hydroxylase (PHD). These results suggest that vasohibin plays crucial roles as a negative feedback regulator of angiogenesis through HIF-1α degradation via PHD. 相似文献
180.