全文获取类型
收费全文 | 673篇 |
免费 | 49篇 |
出版年
2022年 | 4篇 |
2021年 | 12篇 |
2018年 | 5篇 |
2017年 | 12篇 |
2016年 | 16篇 |
2015年 | 15篇 |
2014年 | 23篇 |
2013年 | 50篇 |
2012年 | 44篇 |
2011年 | 36篇 |
2010年 | 17篇 |
2009年 | 10篇 |
2008年 | 24篇 |
2007年 | 30篇 |
2006年 | 47篇 |
2005年 | 49篇 |
2004年 | 49篇 |
2003年 | 38篇 |
2002年 | 52篇 |
2001年 | 13篇 |
2000年 | 5篇 |
1999年 | 18篇 |
1998年 | 11篇 |
1997年 | 10篇 |
1996年 | 11篇 |
1995年 | 12篇 |
1994年 | 8篇 |
1993年 | 10篇 |
1992年 | 7篇 |
1991年 | 8篇 |
1990年 | 5篇 |
1989年 | 6篇 |
1988年 | 3篇 |
1987年 | 3篇 |
1985年 | 2篇 |
1984年 | 8篇 |
1983年 | 6篇 |
1982年 | 5篇 |
1981年 | 5篇 |
1980年 | 4篇 |
1978年 | 3篇 |
1976年 | 7篇 |
1975年 | 2篇 |
1974年 | 3篇 |
1972年 | 2篇 |
1969年 | 3篇 |
1968年 | 1篇 |
1967年 | 1篇 |
1966年 | 1篇 |
1959年 | 1篇 |
排序方式: 共有722条查询结果,搜索用时 15 毫秒
141.
Naoko Matsushita Toshihide Kashihara Hisashi Shimojo Satoshi Suzuki Tsutomu Nakada Yasuchika Takeishi Ulrike Mende Eiichi Taira Mitsuhiko Yamada Atsushi Sanbe Masamichi Hirose 《PloS one》2014,9(8)
Background
Transgenic mice with transient cardiac expression of constitutively active Galpha q (Gαq-TG) exhibt progressive heart failure and ventricular arrhythmias after the initiating stimulus of transfected constitutively active Gαq becomes undetectable. However, the mechanisms are still unknown. We examined the effects of chronic administration of olmesartan on heart failure and ventricular arrhythmia in Gαq-TG mice.Methodology/Principal Findings
Olmesartan (1 mg/kg/day) or vehicle was chronically administered to Gαq-TG from 6 to 32 weeks of age, and all experiments were performed in mice at the age of 32 weeks. Chronic olmesartan administration prevented the severe reduction of left ventricular fractional shortening, and inhibited ventricular interstitial fibrosis and ventricular myocyte hypertrophy in Gαq-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 9 of 10 vehicle-treated Gαq-TG but in none of 10 olmesartan-treated Gαq-TG. The collected QT interval and monophasic action potential duration in the left ventricle were significantly shorter in olmesartan-treated Gαq-TG than in vehicle-treated Gαq-TG. CTGF, collagen type 1, ANP, BNP, and β-MHC gene expression was increased and olmesartan significantly decreased the expression of these genes in Gαq-TG mouse ventricles. The expression of canonical transient receptor potential (TRPC) 3 and 6 channel and angiotensin converting enzyme (ACE) proteins but not angiotensin II type 1 (AT1) receptor was increased in Gαq-TG ventricles compared with NTG mouse ventricles. Olmesartan significantly decreased TRPC6 and tended to decrease ACE expressions in Gαq-TG. Moreover, it increased AT1 receptor in Gαq-TG.Conclusions/Significance
These findings suggest that angiotensin II type 1 receptor activation plays an important role in the development of heart failure and ventricular arrhythmia in Gαq-TG mouse model of heart failure. 相似文献142.
Romina Theiler Morihisa Fujita Masamichi Nagae Yoshiki Yamaguchi Yusuke Maeda Taroh Kinoshita 《The Journal of biological chemistry》2014,289(24):16835-16843
Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are group of proteins that depend on p24 cargo receptors for their transport from the endoplasmic reticulum to the Golgi apparatus. The GPI anchor is expected to act as a sorting and transport signal, but so far little is known about the recognition mechanism. In the present study we investigate the GPI-AP transport in cell knockdown of p24γ, the most diverse p24 subfamily. Knockdown of p24γ2 but not of other p24γ family members impaired the transport of a reporter GPI-AP. Restoration of the knockdown-induced phenotype using chimeric constructs between p24γ2 and the related p24γ1 further implied a role of the α-helical region of p24γ2 but not its GOLD domain in the specific binding of GPI-APs. We conclude that motifs in the membrane-adjacent α-helical region of p24γ2 are involved in recognition of GPI-APs and are consequently responsible for the incorporation of these proteins into coat protein complex II-coated transport vesicles. 相似文献
143.
Yu Qin Maoyong Fu Masamichi Takahashi Akio Iwanami Daisuke Kuga Rajiv G. Rao Deepthi Sudhakar Tiffany Huang Meagan Kiyohara Kathleen Torres Christen Dillard Akihito Inagaki Noriyuki Kasahara Lee Goodglick Jonathan Braun Paul S. Mischel Lynn K. Gordon Madhuri Wadehra 《The Journal of biological chemistry》2014,289(20):13974-13985
Despite recent advances in molecular classification, surgery, radiotherapy, and targeted therapies, the clinical outcome of patients with malignant brain tumors remains extremely poor. In this study, we have identified the tetraspan protein epithelial membrane protein-2 (EMP2) as a potential target for glioblastoma (GBM) killing. EMP2 had low or undetectable expression in normal brain but was highly expressed in GBM as 95% of patients showed some expression of the protein. In GBM cells, EMP2 enhanced tumor growth in vivo in part by up-regulating αvβ3 integrin surface expression, activating focal adhesion kinase and Src kinases, and promoting cell migration and invasion. Consistent with these findings, EMP2 expression significantly correlated with activated Src kinase in patient samples and promoted tumor cell invasion using intracranial mouse models. As a proof of principle to determine whether EMP2 could serve as a target for therapy, cells were treated using specific anti-EMP2 antibody reagents. These reagents were effective in killing GBM cells in vitro and in reducing tumor load in subcutaneous mouse models. These results support the role of EMP2 in the pathogenesis of GBM and suggest that anti-EMP2 treatment may be a novel therapeutic treatment. 相似文献
144.
FANCD2 is a product of one of the genes associated with Fanconi anemia (FA), a rare recessive disease characterized by bone marrow failure, skeletal malformations, developmental defects, and cancer predisposition. FANCD2 forms a complex with FANCI (ID complex) and is monoubiquitinated, which facilitates the downstream interstrand crosslink (ICL) repair steps, such as ICL unhooking and nucleolytic end resection. In the present study, we focused on the chicken FANCD2 (cFANCD2) mutant harboring the Leu234 to Arg (L234R) substitution. cFANCD2 L234R corresponds to the human FANCD2 L231R mutation identified in an FA patient. We found that cFANCD2 L234R did not complement the defective ICL repair in FANCD2−/− DT40 cells. Purified cFANCD2 L234R did not bind to chicken FANCI, and its monoubiquitination was significantly deficient, probably due to the abnormal ID complex formation. In addition, the histone chaperone activity of cFANCD2 L234R was also defective. These findings may explain some aspects of Fanconi anemia pathogenesis by a FANCD2 missense mutation. 相似文献
145.
Wakana Saso Masako Yamasaki Shin-ichi Nakakita Shuetsu Fukushi Kana Tsuchimoto Noriyuki Watanabe Nongluk Sriwilaijaroen Osamu Kanie Masamichi Muramatsu Yoshimasa Takahashi Tetsuro Matano Makoto Takeda Yasuo Suzuki Koichi Watashi 《PLoS pathogens》2022,18(6)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been transmitted across all over the world, in contrast to the limited epidemic of genetically- and virologically-related SARS-CoV. However, the molecular basis explaining the difference in the virological characteristics among SARS-CoV-2 and SARS-CoV has been poorly defined. Here we identified that host sialoglycans play a significant role in the efficient spread of SARS-CoV-2 infection, while this was not the case with SARS-CoV. SARS-CoV-2 infection was significantly inhibited by α2-6-linked sialic acid-containing compounds, but not by α2–3 analog, in VeroE6/TMPRSS2 cells. The α2-6-linked compound bound to SARS-CoV-2 spike S1 subunit to competitively inhibit SARS-CoV-2 attachment to cells. Enzymatic removal of cell surface sialic acids impaired the interaction between SARS-CoV-2 spike and angiotensin-converting enzyme 2 (ACE2), and suppressed the efficient spread of SARS-CoV-2 infection over time, in contrast to its least effect on SARS-CoV spread. Our study provides a novel molecular basis of SARS-CoV-2 infection which illustrates the distinctive characteristics from SARS-CoV. 相似文献
146.
The fatty acid composition of the lipid of yellowfin tuna (Thunnus albacares) caught in two different localities, Philippine Sea (a tropical zone) and the Pacific coast area of Japan (a temperate zone) is described. The total lipids of various organs (dorsal ordinary muscle, ventral ordinary muscle, dark muscle, liver, heart, pyloric cecum, and orbital region) and of the stomach contents were extracted, and the fatty acid comosition was analyzed by gas-liquid chromatography (GLC).Docosahexaenoic acid (DHA; 22:6n-3) was the major unsaturated fatty acid in the lipid of all organs in the specimens examined from both localities, the mean DHA content accounting for more than 25% (mean ± S.D. of 26.9 ±5.7%) of the total fatty acids. This value is markedly different from the fatty acid profile of other fish species, because, in general, the fatty acid composition of other species is variable and the DHA content is less than 20% of total fatty acids.Although the mean DHA content of the total fatty acids in the lipid of yellowfin tuna caught in the tropical and temperate zones was markedly higher than that in other fish species, there was a small difference between that in the northern samples (temperate waters, 30.5 ±6.1%) and the southern samples (tropical waters, 25.9 ± 5.2%). It is suggested that this difference may be due to environmental effects, e.g., the fatty acid composition of the lipids of prey organisms, because there is also a small difference between the mean DHA content of northern prey fish (22.7 ±6.1%) and that of southern prey fish (19.2 ±4.0%). 相似文献
147.
Bongjin Shin Jungeun Yu Eui-Soon Park Seunga Choi Jiyeon Yu Jung Me Hwang Hyeongseok Yun Young-Ho Chung Kwan Soo Hong Jong-Soon Choi Masamichi Takami Jaerang Rho 《The Journal of biological chemistry》2014,289(52):35868-35881
Genetic mutations in osteoclastogenic genes are closely associated with osteopetrotic bone diseases. Genetic defects in OSTM1 (osteopetrosis-associated transmembrane protein 1) cause autosomal recessive osteopetrosis in humans. In particular, OSTM1 mutations that exclude the transmembrane domain might lead to the production of a secreted form of truncated OSTM1. However, the precise role of the secreted form of truncated OSTM1 remains unknown. In this study, we analyzed the functional role of truncated OSTM1 in osteoclastogenesis. Here, we showed that a secreted form of truncated OSTM1 binds to the cell surface of osteoclast (OC) precursors and inhibits the formation of multinucleated OCs through the reduction of cell fusion and survival. Truncated OSTM1 significantly inhibited the expression of OC marker genes through the down-regulation of the BLIMP1 (B lymphocyte-induced maturation protein 1)-NFATc1 (nuclear factor of activated T cells c1) axis. Finally, we demonstrated that truncated OSTM1 reduces lipopolysaccharide-induced bone destruction in vivo. Thus, these findings suggest that autosomal recessive osteopetrosis patients with an OSTM1 gene mutation lacking the transmembrane domain produce a secreted form of truncated OSTM1 that inhibits osteoclastogenesis. 相似文献
148.
Masamichi Kato Ken-Ichi Honma Tsukasa Shigemitsu Yoichi Shiga 《Bioelectromagnetics》1993,14(2):97-106
We sought to determine whether a 6-week exposure to a 50-Hz rotating magnetic field influences melatonin synthesis by 11–18 week-old Wistar-King male rats. Rats were exposed continuously to a rotating magnetic field at 1, 5, 50, or 250 μT (spatial vector rms) for 6 weeks, except for twice-weekly breaks of about 2 h for cleaning of cages and feeding. The rats were housed in exposure and sham-exposure facilities, which were located in the same room, under a 12:12 light-dark photoperiod (lights on at 06:00 h). The room was constantly illuminated by 4 small, dim red lights (< 0.07 lux in dark period). Levels of plasma and pineal gland melatonin were determined by radioimmunoassay. A significant decrease of melatonin was observed between the control group and groups exposed to a magnetic field at a flux density in excess of l μT during the night time, but no statistical differences were found among the exposed groups. These results indicate that subchronic exposure of albino rats to a 50-Hz rotating magnetic field influences melatonin production and secretion by the pineal gland. © 1993 Wiley-Liss, Inc. 相似文献
149.
A requirement for the cooperation of macrophages (adherent cell population) in the process of the antigenic activation of immune lymphocytes for the production of migration inhibitory factor (MIF) has been demonstrated previously. It was found, in the present study, that the culture supernatant of peritoneal macrophages, which had been pulse-stimulated with a bacterial lipopolysaccharide (LPS), could be substituted for live macrophages. Fractionation of the supernatant by gel filtration revealed its activity in the fraction of 15,000–100,000 MW and the activity was completely abolished by heat treatment at 85°C for 30 min. These results distinguished the nature of the active component from that of LPS which was found to be present in a trace amount in the supernatant and strongly suggested the presence of a factor(s) derived from macrophages which effects, in some way, the process of the antigenic activation of immune lymphocytes. Our experiment showed that the cooperating function of macrophages was inhibited by the treatment of macrophages with vinblastine. It may be that vinblastine affects the release of an active factor(s) from macrophages although other possibilities remain that the inhibition resulted from its effects on other functioning processes of macrophages. 相似文献
150.
Hiroshi Ueda Hidemi Misawa Toshiaki Katada Michio Ui† Hiroshi Takagi Masamichi Satoh 《Journal of neurochemistry》1990,54(3):841-848
Functional coupling between mu-opioid receptors and GTP-binding regulatory proteins (G proteins) was investigated in reconstituted membranes of the guinea pig striatum. Selective mu-opioid agonists stimulated low-Km GTPase in striatal membranes, in a Na(+)-dependent manner. The same mu-opioid agonist [( D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAGO)] caused no stimulation when the membranes were exposed to islet-activating protein (IAP; pertussis toxin). There was also no DAGO stimulation in preparations pretreated with a lower concentration (5 microM) of N-ethylmaleimide (NEM), which abolished the ADP-ribosylation of purified Gi (the G protein that mediates inhibition of adenylate cyclase) and Go (a G protein of unknown function purified from bovine brain) by IAP. In addition, as the NEM treatment caused no change in the mu-agonist binding, NEM could probably substitute for IAP in inactivating native G proteins, without exhibiting effects on the receptor binding in membranes. The mu-agonist stimulation of low-Km GTPase activity in NEM-treated membranes was recovered by reconstitution with purified Gi or Go. The mu-agonist stimulation of low-Km GTPase was additive when Gi and Go were simultaneously reconstituted in NEM-treated membranes in amounts of 0.5 pmol/assay, which was required for maximal recovery, in either reconstitution experiment. The present findings provide the first evidence that the mu-opioid receptor may exist in at least two different forms, separately coupled to Gi or Go. 相似文献