全文获取类型
收费全文 | 3971篇 |
免费 | 241篇 |
国内免费 | 2篇 |
出版年
2022年 | 21篇 |
2021年 | 37篇 |
2020年 | 16篇 |
2019年 | 34篇 |
2018年 | 36篇 |
2017年 | 29篇 |
2016年 | 71篇 |
2015年 | 92篇 |
2014年 | 127篇 |
2013年 | 363篇 |
2012年 | 190篇 |
2011年 | 191篇 |
2010年 | 132篇 |
2009年 | 127篇 |
2008年 | 172篇 |
2007年 | 209篇 |
2006年 | 213篇 |
2005年 | 244篇 |
2004年 | 243篇 |
2003年 | 239篇 |
2002年 | 221篇 |
2001年 | 120篇 |
2000年 | 98篇 |
1999年 | 80篇 |
1998年 | 55篇 |
1997年 | 33篇 |
1996年 | 41篇 |
1995年 | 46篇 |
1994年 | 46篇 |
1993年 | 43篇 |
1992年 | 62篇 |
1991年 | 52篇 |
1990年 | 45篇 |
1989年 | 57篇 |
1988年 | 44篇 |
1987年 | 42篇 |
1986年 | 31篇 |
1985年 | 33篇 |
1984年 | 23篇 |
1983年 | 33篇 |
1982年 | 36篇 |
1981年 | 24篇 |
1980年 | 16篇 |
1979年 | 18篇 |
1978年 | 14篇 |
1977年 | 19篇 |
1976年 | 13篇 |
1975年 | 18篇 |
1974年 | 10篇 |
1972年 | 8篇 |
排序方式: 共有4214条查询结果,搜索用时 31 毫秒
991.
Shinozuka T Shimada K Matsui S Yamane T Ama M Fukuda T Taki M Naito S 《Bioorganic & medicinal chemistry letters》2006,16(6):1502-1505
We have designed and synthesized a novel series of 3-biphenylamino acid amides as cathepsin K inhibitors based on compound I. In these inhibitors, we have discovered 4-aminophenoxyacetic acids 43 and 47 with good IC(50) values, although lipophilic groups are favorable for the hydrophobic S1' pocket. 相似文献
992.
993.
Kunihiko Hinohara Toshiaki Nakajima Michio Yasunami Shigeru Houda Taishi Sasaoka Ken Yamamoto Bok-Soo Lee Hiroki Shibata Yumiko Tanaka-Takahashi Megumi Takahashi Takuro Arimura Akinori Sato Taeko Naruse Jimin Ban Hidetoshi Inoko Yoshiji Yamada Motoji Sawabe Jeong-Euy Park Toru Izumi Akinori Kimura 《Human genetics》2009,126(4):539-547
Coronary artery disease (CAD) is based on the atherosclerosis of coronary artery and may manifest with myocardial infarction or angina pectoris. Although it is widely accepted that genetic factors are linked to CAD and several disease-related genes have been reported, only a few could be replicated suggesting that there might be some other CAD-related genes. To identify novel susceptibility loci for CAD, we used microsatellite markers in the screening and found six different candidate CAD loci. Subsequent single nucleotide polymorphism (SNP) association studies revealed an association between CAD and megakaryoblastic leukemia factor-1 gene (MKL1). The association with a promoter SNP of MKL1, ?184C > T, was found in a Japanese population and the association was replicated in another Japanese population and a Korean population. Functional analysis of the MKL1 promoter SNP suggested that the higher MKL1 expression was associated with CAD. These findings suggest that MKL1 is involved in the pathogenesis of CAD. 相似文献
994.
Kaori Tanaka Tsukasa Hori Naoki Hatakeyama Masaki Yamamoto Rumiko Takayama Yuko Yoto Nobuhiro Suzuki Toshiaki Hayashi Yukiho Ikeda Hiroshi Ikeda Tadao Ishida Hiroyuki Tsutsumi 《Microbiology and immunology》2009,53(6):319-322
BK polyomavirus (BKV) is ubiquitous among humans, usually infecting them asymptomatically during childhood. BKV persists in renal tissue of individuals and their progeny are excreted in urine, particularly in immunocompromised patients. JC virus, another human polyomavirus, has been considered to be transmitted from parents to children during prolonged cohabitation. However, BKV has been supposed to be transmitted not only within but also outside the family. In the present study, to clarify this possibility, we analyzed phylogenetically 35 BKV which were excreted in the urine by Japanese children and adults undergoing stem cell transplantation. Subtypes I, III and IV were detected in 15, two and one children and in 15, one and one adults, respectively. Among 15 subtype I isolates from children, three, four and eight belonged to subgroups Ia, Ib-1 and Ic, respectively. All the three children from whom Ia was detected were less than 9 years old. In contrast in the adults, three subtype I belonged to Ib-1 and the other 12 to Ic. These findings may reflect the recent transmission of BKV Ia strains to Japanese children. 相似文献
995.
Tatsuya Maruyama Kenichi Onda Masahiko Hayakawa Norio Seki Takumi Takahashi Hiroyuki Moritomo Takayuki Suzuki Tetsuo Matsui Toshiyuki Takasu Itsuro Nagase Mitsuaki Ohta 《Bioorganic & medicinal chemistry》2009,17(9):3283-3294
In the search for potent and selective human β3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of phenoxypropanolamine derivatives containing acetanilides were prepared and their biological activities were evaluated at the human β3-, β2-, and β1-ARs. Several of the analogues (21a, 21b, and 27a) exhibited potent agonistic activity at the β3-AR. Among the compounds described herein, the N-methyl-1-benzylimidazol-2-ylacetanilide derivative (21b) was found to be the most potent and selective β3-AR agonist, with an EC50 value of 0.28 μM and no agonistic activity for either the β1- or β2-AR. In addition, 21b showed significant hypoglycemic activity in a rodent diabetic model. 相似文献
996.
Yasunori Yamamoto Sumiko Mochida Takao Kurooka Toshiaki Sakisaka 《The Journal of biological chemistry》2009,284(18):12480-12490
Neurotransmitter release from presynaptic nerve terminals is regulated by
SNARE complex-mediated synaptic vesicle fusion. Tomosyn, a negative regulator
of neurotransmitter release, which is composed of N-terminal WD40 repeats, a
tail domain, and a C-terminal VAMP-like domain, is known to inhibit SNARE
complex formation by sequestering target SNAREs (t-SNAREs) upon interaction of
its C-terminal VAMP-like domain with t-SNAREs. However, it remains unclear how
the inhibitory activity of tomosyn is regulated. Here we show that the tail
domain functions as a regulator of the inhibitory activity of tomosyn through
intramolecular interactions. The binding of the tail domain to the C-terminal
VAMP-like domain interfered with the interaction of the C-terminal VAMP-like
domain with t-SNAREs, and thereby repressed the inhibitory activity of tomosyn
on the SNARE complex formation. The repressed inhibitory activity of tomosyn
was restored by the binding of the tail domain to the N-terminal WD40 repeats.
These results indicate that the probable conformational change of tomosyn
mediated by the intramolecular interactions of the tail domain controls its
inhibitory activity on the SNARE complex formation, leading to a regulated
inhibition of neurotransmitter release.Synaptic vesicles are transported to the presynaptic plasma membrane where
Ca2+ channels are located. Depolarization induces Ca2+
influx into the cytosol of nerve terminals through the Ca2+
channels, and this Ca2+ influx initiates the fusion of the vesicles
with the plasma membrane, finally leading to exocytosis of neurotransmitters
(1). Soluble
N-ethylmaleimide-sensitive fusion protein attachment protein
(SNAP)2
receptors (SNAREs) are essential for synaptic vesicle exocytosis
(2-5).
Synaptic vesicles are endowed with vesicle-associated membrane protein 2
(VAMP-2) as a vesicular SNARE, whereas the presynaptic plasma membrane is
endowed with syntaxin-1 and SNAP-25 as target SNAREs. VAMP-2 interacts with
SNAP-25 and syntaxin-1 to form a stable SNARE complex
(6-9).
The formation of the SNARE complex then brings synaptic vesicles and the
plasma membrane into close apposition, and provides the energy that drives the
mixing of the two lipid bilayers
(3-5,
9).Tomosyn is a syntaxin-1-binding protein that we originally identified
(10). Tomosyn contains
N-terminal WD40 repeats, a tail domain, and a C-terminal domain homologous to
VAMP-2. The C-terminal VAMP-like domain (VLD) of tomosyn acts as a SNARE
domain that competes with VAMP-2. Indeed, a structural study of the VLD
revealed that the VLD, syntaxin-1, and SNAP-25 assemble into a SNARE
complex-like structure (referred to as tomosyn complex hereafter)
(11). Tomosyn inhibits SNARE
complex formation by sequestering t-SNAREs through the tomosyn complex
formation, and thereby inhibits SNARE-dependent neurotransmitter release. The
large N-terminal region of tomosyn shares similarity to the
Drosophila tumor suppressor lethal giant larvae (Lgl), the mammalian
homologues M-Lgl1 and M-Lgl2, and yeast proteins Sro7p and Sro77p
(12,
13). Consistent with the
function of tomosyn, Lgl family members play an important role in polarized
exocytosis by regulating SNARE function on the plasma membrane in yeast and
epithelial cells (12,
13). However, only tomosyn,
Sro7, and Sro77 have the tail domains and the VLDs, suggesting that their
structural regulation is evolutionally conserved. Recently, the crystal
structure of Sro7 was solved and revealed that the tail domain of Sro7 binds
its WD40 repeats (14). Sec9, a
yeast counterpart of SNAP-25, also binds the WD40 repeats of Sro7. This
binding inhibits the SNARE complex formation and exocytosis by sequestering
Sec9. In addition, binding of the tail domain to the WD40 repeats causes a
conformational change of Sro7 and prevents the interaction of the WD40 repeats
with Sec9, leading to regulation of the inhibitory activity of Sro7 on the
SNARE complex formation (14).
However, the solved structure of Sro7 lacks its VLD. Therefore, involvement of
the activity of the VLD in the conformational change of Sro7 remains
elusive.Genetic studies in Caenorhabditis elegans showed that TOM-1, an
ortholog of vertebrate tomosyn, inhibits the priming of synaptic vesicles, and
that this priming is modulated by the balance between TOM-1 and UNC-13
(15,
16). Tomosyn was also shown to
be involved in inhibition of the exocytosis of dense core granules in adrenal
chromaffin cells and PC12 cells
(17,
18). Thus, evidence is
accumulating that tomosyn acts as a negative regulator for formation of the
SNARE complex, thereby inhibiting various vesicle fusion events. However, the
precise molecular mechanism regulating the inhibitory action of tomosyn has
yet to be elucidated.In the present study, we show that the tail domain of tomosyn binds both
the WD40 repeats and the VLD and functions as a regulator for the inhibitory
activity of tomosyn on the SNARE complex formation. Our results indicate that
the probable conformational change of tomosyn mediated by the intramolecular
interactions of the tail domain serves for controlling the inhibitory activity
of the VLD. 相似文献
997.
Daisuke Matsui Tadao Oikawa Noriaki Arakawa Shintaro Osumi Frank Lausberg Norma Stäbler Roland Freudl Lothar Eggeling 《Applied microbiology and biotechnology》2009,83(6):1045-1054
The pyridoxal-5′-phosphate (PLP)-dependent amino acid racemases occur in almost every bacterium but may differ considerably
with respect to substrate specificity. We here isolated the cloned broad substrate specificity racemase ArgR of Pseudomonas taetrolens from Escherichia coli by classical procedures. The racemase was biochemically characterized and amongst other aspects it was confirmed that it
is mostly active with lysine, arginine and ornithine, but merely weakly active with alanine, whereas the alanine racemase
of the same organism studied in comparison acts on alanine only. Unexpectedly, sequencing the amino-terminal end of ArgR revealed
processing of the protein, with a signal peptide cleaved off. Subsequent localization studies demonstrated that in both P. taetrolens and E. coli ArgR activity was almost exclusively present in the periplasm, a feature so far unknown for any amino acid racemase. An ArgR-derivative
carrying a carboxy-terminal His-tag was made and this was demonstrated to localize even in an E. coli mutant devoid of the twin-arginine translocation (Tat) pathway in the periplasm. These data indicate that ArgR is synthesized
as a prepeptide and translocated in a Tat-independent manner. We therefore propose that ArgR translocation depends on the
Sec system and a post-translocational insertion of PLP occurs. As further experiments showed, ArgR is necessary for the catabolism
of d-arginine and d-lysine by P. taetrolens. 相似文献
998.
Naoya Shinzato Tomoyuki Namihira Yasutomo Tamaki Masatoshi Tsukahara Toru Matsui 《Applied microbiology and biotechnology》2009,82(6):1187-1193
Monascus fungi are commonly used for a variety of food products in Asia, and are also known to produce some biologically active compounds.
Since the use of Monascus is expected to increase in food industries, strain-level identification and management of Monascus will be needed in the near future. In the present study, random amplified polymorphic DNA (RAPD) analysis coupled with microchip
electrophoresis was applied for this purpose. Evaluations of the analysis stability revealed that reproducible results could
be obtained, although template DNA fragmentation could influence the resulting RAPD pattern. RAPD analysis using 15 Monascus strains consisting of four species, M. ruber, M. pilosus, M. purpureus, and M. kaoliang showed that each strain generated a unique RAPD pattern, which allows strain-level identification of Monascus. In addition, the phylogenetic tree constructed from RAPD patterns reflected M. ruber–M. pilosus and M. purpureus–M. kaoliang clusters inferred from both ITS and β-tubulin gene sequences, which indicated that the RAPD pattern could reflect their phylogenetic
traits to a certain extent. On the other hand, RAPD analysis did not support the monophyletic clustering of the four Monascus species used in this study, which suggests the necessity of reexamination of species boundaries in Monascus. 相似文献
999.
Furubayashi T Ushiyama A Terao Y Mizuno Y Shirasawa K Pongpaibool P Simba AY Wake K Nishikawa M Miyawaki K Yasuda A Uchiyama M Yamashita HK Masuda H Hirota S Takahashi M Okano T Inomata-Terada S Sokejima S Maruyama E Watanabe S Taki M Ohkubo C Ugawa Y 《Bioelectromagnetics》2009,30(2):100-113
To investigate possible health effects of mobile phone use, we conducted a double-blind, cross-over provocation study to confirm whether subjects with mobile phone related symptoms (MPRS) are more susceptible than control subjects to the effect of electromagnetic fields (EMF) emitted from base stations. We sent questionnaires to 5,000 women and obtained 2,472 valid responses from possible candidates; from these, we recruited 11 subjects with MPRS and 43 controls. There were four EMF exposure conditions, each of which lasted 30 min: continuous, intermittent, and sham exposure with and without noise. Subjects were exposed to EMF of 2.14 GHz, 10 V/m (W-CDMA), in a shielded room to simulate whole-body exposure to EMF from base stations, although the exposure strength we used was higher than that commonly received from base stations. We measured several psychological and cognitive parameters pre- and post-exposure, and monitored autonomic functions. Subjects were asked to report on their perception of EMF and level of discomfort during the experiment. The MPRS group did not differ from the controls in their ability to detect exposure to EMF; nevertheless they consistently experienced more discomfort, regardless of whether or not they were actually exposed to EMF, and despite the lack of significant changes in their autonomic functions. Thus, the two groups did not differ in their responses to real or sham EMF exposure according to any psychological, cognitive or autonomic assessment. In conclusion, we found no evidence of any causal link between hypersensitivity symptoms and exposure to EMF from base stations. 相似文献
1000.
Many research groups have sought to measure phase response curves (PRCs) from real neurons. However, methods of estimating
PRCs from noisy spike-response data have yet to be established. In this paper, we propose a Bayesian approach for estimating
PRCs. First, we analytically obtain a likelihood function of the PRC from a detailed model of the observation process formulated
as Langevin equations. Then we construct a maximum a posteriori (MAP) estimation algorithm based on the analytically obtained
likelihood function. The MAP estimation algorithm derived here is equivalent to the spherical spin model. Moreover, we analytically
calculate a marginal likelihood corresponding to the free energy of the spherical spin model, which enables us to estimate
the hyper-parameters, i.e., the intensity of the Langevin force and the smoothness of the prior.
Action Editor: John Rinzel 相似文献