全文获取类型
收费全文 | 274篇 |
免费 | 11篇 |
专业分类
285篇 |
出版年
2022年 | 3篇 |
2021年 | 3篇 |
2020年 | 1篇 |
2019年 | 2篇 |
2018年 | 2篇 |
2017年 | 2篇 |
2016年 | 3篇 |
2015年 | 7篇 |
2014年 | 13篇 |
2013年 | 14篇 |
2012年 | 24篇 |
2011年 | 28篇 |
2010年 | 11篇 |
2009年 | 15篇 |
2008年 | 29篇 |
2007年 | 23篇 |
2006年 | 14篇 |
2005年 | 19篇 |
2004年 | 15篇 |
2003年 | 9篇 |
2002年 | 17篇 |
2001年 | 2篇 |
2000年 | 2篇 |
1999年 | 2篇 |
1998年 | 1篇 |
1997年 | 1篇 |
1996年 | 1篇 |
1995年 | 2篇 |
1994年 | 2篇 |
1993年 | 3篇 |
1992年 | 1篇 |
1991年 | 1篇 |
1989年 | 2篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1982年 | 2篇 |
1981年 | 3篇 |
1978年 | 1篇 |
排序方式: 共有285条查询结果,搜索用时 0 毫秒
191.
Takaaki Mizuguchi Hiromasa Uchimura Taeko Kakizawa Tooru Kimura Shigeyuki Yokoyama Yoshiaki Kiso Kazuki Saito 《Bioorganic & medicinal chemistry letters》2009,19(12):3279-3282
A cyclic decapeptide was chemically synthesized that mimics the loop structure of a β-hairpin arm of the EGF receptor, which is highly involved in receptor dimerization upon activation by ligand binding. This peptide was revealed to reduce dimer formation of the receptor in a detergent-solubilized extract of epidermoid carcinoma A431 cells and to inhibit receptor autophosphorylation at less than 10 μM in the intact cells. 相似文献
192.
Taeko Shigemoto Maiko Kageyama Reiko Hirai JiPing Zheng Mitsutoshi Yoneyama Takashi Fujita 《The Journal of biological chemistry》2009,284(20):13348-13354
Retinoic acid-inducible gene I (RIG-I) and melanoma
differentiation-associated gene 5 (MDA5) are essential for detecting viral RNA
and triggering antiviral responses, including production of type I interferon.
We analyzed the phenotype of non-synonymous mutants of human RIG-I and MDA5
reported in databases by functional complementation in cell cultures. Of seven
missense mutations of RIG-I, S183I, which occurs within the second caspase
recruitment domain repeat, inactivated this domain and conferred a dominant
inhibitory function. Of 10 mutants of MDA5, two exhibited loss of function. A
nonsense mutation, E627*, resulted in deletion of the C-terminal region and
double-stranded RNA (dsRNA) binding activity. Another loss of function
mutation, I923V, which occurs within the C-terminal domain, did not affect
dsRNA binding activity, suggesting a novel and essential role for this residue
in the signaling. Remarkably, these mutations are implicated in resistance to
type I diabetes. However, the A946T mutation of MDA5, which has been
implicated in type I diabetes by previous genetic analyses, affected neither
dsRNA binding nor IFN gene activation. These results provide new
insights into the structure-function relationship of RIG-I-like receptors as
well as into human RIG-I-like receptor polymorphisms, antiviral innate
immunity, and autoimmune diseases.Innate and adaptive immune systems constitute the defense against
infections by pathogens. Immediately after an infection occurs, various cells
in the body sense the virus and initiate antiviral responses in which type I
IFN2 plays a critical
role, both in viral inhibition and in the subsequent adaptive immune response
(1). The production of IFN is
initiated when sensor molecules such as Toll-like receptors (TLRs) and RLRs
detect virus-associated molecules. TLRs detect pathogen-associated molecular
patterns (PAMPs) at the cell surface or in the endosome in immune cells such
as dendritic cells and macrophages
(2). RLRs sense viral RNA in
the cytoplasm of most cell types and induce antiviral responses, including the
activation of IFN genes
(3). RLRs include RIG-I, MDA5,
and laboratory of genetics and physiology 2 (LGP2).It is proposed that RLRs sense and activate antiviral signals through the
coordination of their functional domains
(4). The N-terminal region of
RIG-I and MDA5 is characterized by two repeats of CARD and functions as an
activation domain (3). This
domain is responsible for the transduction of signals downstream to IFN-β
promoter stimulator 1 (IPS-1) (also known as MAVS, VISA, and Cardif). The
primary sequence of the CTD, consisting of ∼140 amino acids, is conserved
among RLRs. The CTD of RIG-I functions as a viral RNA-sensing domain as
revealed by biochemical and structural analyses
(5,
6). Both dsRNA and
5′-ppp-ssRNA, which are generated in the cytoplasm of virus-infected
cells, are recognized by a basic cleft structure of RIG-I CTD. In addition to
its RNA recognition function, the CTD of RIG-I and LGP2 functions as a
repression domain through interaction with the activation domain. The
repression domain is responsible for keeping RIG-I inactive in non-stimulated
cells (3,
7). The helicase domain, with
DEXD/H box-containing RNA helicase motifs, is the largest domain
found in RLRs. Once dsRNA or 5′-ppp-ssRNA is recognized by the CTD, the
helicase domain causes structural changes to release the activation domain.
ATP binding and/or its hydrolysis is essential for the conformational change
because Walker''s ATP-binding site within the helicase domain is essential for
signaling by RIG-I and MDA5.Analyses of knock-out mice have revealed that RIG-I and MDA5 recognize
distinct RNA viruses (8,
9). Picornaviruses are detected
by MDA5, but many other viruses such as influenza A, Sendai, vesicular
stomatitis, and Japanese encephalitis are detected by RIG-I. The difference is
based on the distinct non-self RNA patterns generated by viruses, as
demonstrated by the finding that RIG-I is selectively activated by dsRNA or
5′-ppp ssRNA, whereas MDA5 is activated by long dsRNA
(10–12).Single nucleotide polymorphisms (SNPs) of the human RIG-I and
MDA5 genes including several non-synonymous SNPs (nsSNPs), which
potentially alter the function of the proteins encoded, are reported in
databases. In this report, we investigated the functions of nsSNPs of RIG-I
and MDA5 by functional complementation using respective knock-out cells. We
identified loss of function mutations of RIG-I and MDA5. Notably, two MDA5
mutations, E627* and I923V, recently reported to have a strong association
with resistance to T1D (13),
were severely inactive. The results suggest a novel molecular mechanism for
the activation of RLRs and will contribute to our understanding of the
functional effects of RLR polymorphisms and the critical relationship between
RLR nsSNPs and diseases. 相似文献
193.
Morita I Nakagaki H Kato K Murakami T Tsuboi S Hayashizaki J Toyama A Hashimoto M Simozato T Morishita N Kawanaga T Igo J Sheiham A 《Gerodontology》2006,23(4):214-218
Objectives: The objective of this study was to assess whether elderly people with 20 or more natural teeth were more likely to live longer than a cohort with less than 20 teeth. Materials and methods: Groups of elderly people over 80 years of age (24 males and 35 females) with 20 or more teeth (≥20 group) were compared with elderly people (24 males and 35 females) with less than 20 teeth (<20 group). Follow‐up studies were conducted at regular intervals for 10 years from July 1992 to July 2002. The cumulative survival rate of the ≥20 group (average ± SE tooth number of teeth – males, 23.9 ± 0.6; females, 23.8 ± 0.4) was compared with the <20 group (average number of teeth – males, 3.8 ± 1.1; females, 2.6 ± 0.8). The multivariate Cox proportional hazard models with the number of teeth in a group (≥20 group or <20 group). Smoking status and alcohol intake as covariates were used to adjust the cumulative survival rate. Results: The male participants in the ≥20 group had a significantly higher cumulative survival rates (p < 0.05) than the <20 group at 18 and 21 months from baseline. There were no significant differences in survival rates between the female groups. Adjusted cumulative survival rate was significantly different at 72, 75 and 78 months between the ≥20 group and <20 group for males but not for females. Conclusion: Having 20 or more natural teeth was associated with increased survival rate in elderly males, but not among the elderly females. 相似文献
194.
Kenji Gomi Masaru Satoh Rika Ozawa Yumi Shinonaga Sachiyo Sanada Katsutomo Sasaki Masaya Matsumura Yuko Ohashi Hiroo Kanno Kazuya Akimitsu Junji Takabayashi 《The Plant journal : for cell and molecular biology》2010,61(1):46-57
A pre-infestation of the white-backed planthopper (WBPH), Sogatella furcifera Horváth, conferred resistance to bacterial blight caused by Xanthomonas oryzae pv. oryzae ( Xoo ) in rice ( Oryza sativa L.) under both laboratory and field conditions. The infestation of another planthopper species, the brown planthopper (BPH) Nilaparvata lugens Stål, did not significantly reduce the incidence of bacterial blight symptoms. A large-scale screening using a rice DNA microarray and quantitative RT-PCR revealed that WBPH infestation caused the upregulation of more defence-related genes than did BPH infestation. Hydroperoxide lyase 2 ( OsHPL2 ), an enzyme for producing C6 volatiles, was upregulated by WBPH infestation, but not by BPH infestation. One C6 volatile, ( E )-2-hexenal, accumulated in rice after WBPH infestation, but not after BPH infestation. A direct application of ( E )-2-hexenal to a liquid culture of Xoo inhibited the growth of the bacterium. Furthermore, a vapour treatment of rice plants with ( E )-2-hexenal induced resistance to bacterial blight. OsHPL2 -overexpressing transgenic rice plants exhibited increased resistance to bacterial blight. Based on these data, we conclude that OsHPL2 and its derived ( E )-2-hexenal play some role in WBPH-induced resistance in rice. 相似文献
195.
Sharma R Buras E Terashima T Serrano F Massaad CA Hu L Bitner B Inoue T Chan L Pautler RG 《PloS one》2010,5(10):e13463
Background
While hyperglycemia-induced oxidative stress damages peripheral neurons, technical limitations have, in part, prevented in vivo studies to determine the effect of hyperglycemia on the neurons in the central nervous system (CNS). While olfactory dysfunction is indicated in diabetes, the effect of hyperglycemia on olfactory receptor neurons (ORNs) remains unknown. In this study, we utilized manganese enhanced MRI (MEMRI) to assess the impact of hyperglycemia on axonal transport rates in ORNs. We hypothesize that (i) hyperglycemia induces oxidative stress and is associated with reduced axonal transport rates in the ORNs and (ii) hyperglycemia-induced oxidative stress activates the p38 MAPK pathway in association with phosphorylation of tau protein leading to the axonal transport deficits.Research Design and Methods
T1-weighted MEMRI imaging was used to determine axonal transport rates post-streptozotocin injection in wildtype (WT) and superoxide dismutase 2 (SOD2) overexpressing C57Bl/6 mice. SOD2 overexpression reduces mitochondrial superoxide load. Dihydroethidium staining was used to quantify the reactive oxygen species (ROS), specifically, superoxide (SO). Protein and gene expression levels were determined using western blotting and Q-PCR analysis, respectively.Results
STZ-treated WT mice exhibited significantly reduced axonal transport rates and significantly higher levels of ROS, phosphorylated p38 MAPK and tau protein as compared to the WT vehicle treated controls and STZ-treated SOD2 mice. The gene expression levels of p38 MAPK and tau remained unchanged.Conclusion
Increased oxidative stress in STZ-treated WT hyperglycemic mice activates the p38 MAPK pathway in association with phosphorylation of tau and attenuates axonal transport rates in the olfactory system. In STZ-treated SOD-overexpressing hyperglycemic mice in which superoxide levels are reduced, these deficits are reversed. 相似文献196.
Mitsui T Shimaoka K Tsuzuku S Kajioka T Sakakibara H 《Journal of physiological anthropology》2008,27(4):179-184
Recently, many cross-sectional studies observed that body mass index (BMI) and percentage of body fat (%BF) were inversely associated with pedometer-determined physical activities, but studies on Asian populations, including the Japanese, are sparse. Height, weight, body fat percentage (%BF, bioelectrical impedance analyzer), and waist circumference were measured on 117 women (62.8+/-4.5 years, 22.2+/-2.2 kg/m(2)) and 62 men (64.0+/-4.6 years, 23.6+/-2.5 kg/m(2)). Pearson correlations and partial correlation coefficients after controlling for age were calculated between steps/day and variables. Furthermore, participants were classified into four groups as follows: <5,000, 5,000-7,499, 7,500-9,999, and >or=10,000 steps/day, and analyzed using ANOVA across activity groups. In women, a significant correlation was found between steps/day and BMI (r=-0.217, p=0.018), %BF (r=-0.292, p=0.0014), and the relationship was still significant after controlling for age. The relationship between steps/day and waist circumference was not significant. In men, a significant relationship was not observed between steps/day and obesity indices. The correlations between steps/day and both BMI and %BF were significant in Japanese women, but weak compared with Caucasian and African-American women as reported previously. A possible cause is racial difference in degree of obesity and body shape. The effects of physical activity on body shape and composition may differ according to race. 相似文献
197.
Phylogenetic analysis of penguin (Spheniscidae) species based on sequence variation in MHC class II genes 总被引:2,自引:2,他引:0
198.
Aberrant sialylation in cancer cells is thought to be a characteristic feature associated with malignant properties including
invasiveness and metastatic potential. Sialidase which catalyzes the removal of sialic acid residues from glycoproteins and
glycolipids, has been suggested to play important roles in many biological processes through regulation of cellular sialic
acid contents. The altered expression of sialidase observed in cancer would, therefore, suggest its involvement in the malignant
process. In mammalian cells, three types of sialidase cloned and characterized to date were found to behave in different manners
during carcinogenesis. Recent progress in molecular cloning of these sialidases has facilitated elucidation of the molecular
mechanisms and significance of these alterations. Herein we briefly describe our own studies on sialidase changes associated
with malignant transformation and summarize the topic from both a retrospective and a prospective viewpoint. Sialidases are
indeed closely related to malignancy and are thus potential targets for cancer diagnosis and therapy. Published in 2004.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献
199.
200.
The antiviral efficacy of simian immunodeficiency virus-specific CD8+ T cells is unrelated to epitope specificity and is abrogated by viral escape 下载免费PDF全文
Loffredo JT Burwitz BJ Rakasz EG Spencer SP Stephany JJ Vela JP Martin SR Reed J Piaskowski SM Furlott J Weisgrau KL Rodrigues DS Soma T Napoé G Friedrich TC Wilson NA Kallas EG Watkins DI 《Journal of virology》2007,81(6):2624-2634
CD8(+) T lymphocytes appear to play a role in controlling human immunodeficiency virus (HIV) replication, yet routine immunological assays do not measure the antiviral efficacy of these cells. Furthermore, it has been suggested that CD8+ T cells that recognize epitopes derived from proteins expressed early in the viral replication cycle can be highly efficient. We used a functional in vitro assay to assess the abilities of different epitope-specific CD8+ T-cell lines to control simian immunodeficiency virus (SIV) replication. We compared the antiviral efficacies of 26 epitope-specific CD8+ T-cell lines directed against seven SIV epitopes in Tat, Nef, Gag, Env, and Vif that were restricted by either Mamu-A*01 or Mamu-A*02. Suppression of SIV replication varied depending on the epitope specificities of the CD8+ T cells and was unrelated to whether the targeted epitope was derived from an early or late viral protein. Tat(28-35)SL8- and Gag(181-189)CM9-specific CD8+ T-cell lines were consistently superior at suppressing viral replication compared to the other five SIV-specific CD8+ T-cell lines. We also investigated the impact of viral escape on antiviral efficacy by determining if Tat(28-35)SL8- and Gag(181-189)CM9-specific CD8+ T-cell lines could suppress the replication of an escaped virus. Viral escape abrogated the abilities of Tat(28-35)SL8- and Gag(181-189)CM9-specific CD8+ T cells to control viral replication. However, gamma interferon (IFN-gamma) enzyme-linked immunospot and IFN-gamma/tumor necrosis factor alpha intracellular-cytokine-staining assays detected cross-reactive immune responses against the Gag escape variant. Understanding antiviral efficacy and epitope variability, therefore, will be important in selecting candidate epitopes for an HIV vaccine. 相似文献