全文获取类型
收费全文 | 1087篇 |
免费 | 54篇 |
出版年
2024年 | 4篇 |
2023年 | 7篇 |
2022年 | 10篇 |
2021年 | 19篇 |
2020年 | 18篇 |
2019年 | 28篇 |
2018年 | 25篇 |
2017年 | 33篇 |
2016年 | 44篇 |
2015年 | 46篇 |
2014年 | 51篇 |
2013年 | 76篇 |
2012年 | 100篇 |
2011年 | 92篇 |
2010年 | 56篇 |
2009年 | 46篇 |
2008年 | 83篇 |
2007年 | 60篇 |
2006年 | 54篇 |
2005年 | 57篇 |
2004年 | 52篇 |
2003年 | 50篇 |
2002年 | 40篇 |
2001年 | 17篇 |
2000年 | 14篇 |
1999年 | 6篇 |
1998年 | 3篇 |
1995年 | 4篇 |
1993年 | 1篇 |
1992年 | 5篇 |
1991年 | 3篇 |
1990年 | 3篇 |
1989年 | 2篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1984年 | 7篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 2篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1978年 | 1篇 |
1977年 | 2篇 |
1975年 | 1篇 |
1974年 | 1篇 |
1971年 | 2篇 |
1968年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有1141条查询结果,搜索用时 15 毫秒
961.
Toshihiro Sakamoto Minoru Moriya Hiroyasu Tsuge Toshiyuki Takahashi Yuji Haga Katsumasa Nonoshita Osamu Okamoto Hirobumi Takahashi Aya Sakuraba Tomoko Hirohashi Takunobu Shibata Tetsuya Kanno Junko Ito Hisashi Iwaasa Akira Gomori Akane Ishihara Takahiro Fukuroda Akio Kanatani Takehiro Fukami 《Bioorganic & medicinal chemistry》2009,17(14):5015-5026
Spiroindoline urea derivatives, designed to act as NPY Y5 receptor antagonists, were synthesized and their structure–activity relationships were investigated. Of these derivatives, compound 3a showed good Y5 binding affinity with favorable pharmacokinetic properties. Compound 3a significantly inhibited bPP Y5 agonist-induced food intake in rats, and suppressed body weight gain in DIO mice. 相似文献
962.
We investigated the spatial distribution and taxonomic identity of mycorrhizal fungi colonizing the root systems of two threatened
Cephalanthera species, C. falcata and C. erecta, in naturally regenerated forests. Peloton formation was observed in both plant species, confirming the existence of orchid
mycorrhizas. For C. falcata, mycorrhization was significantly different among individuals, ranging from 14 to 63%, and no significant difference among
C. erecta individuals was detected (57–68%). Mycorrhization among three growth directions of roots and between orchid species was not
significantly different. The spatial distribution of mycorrhizas in both orchids showed significant differences, being most
frequent at an apical position. Based on DNA sequencing and phylogenetic analyses, we inferred that the families Thelephoraceae
and Sebacinaceae were mycobionts for C. falcata and Thelephoraceae for C. erecta. Our findings indicated that mycorrhizal colonization occurs at a distal position from the base of these orchid root systems
and that mycorrhizal fungi are restricted to few ectomycorrhizal fungal families. 相似文献
963.
The attractiveness hypothesis predicts that females produce offspring with male-biased sex ratios when they mate with attractive males because their male offspring will inherit the paternal sexual attractiveness and may have high reproductive success. In this study, we examined the effect of the attractiveness of the male guppy Poecilia reticulata in terms of the conspicuousness of its orange spot patterns, important criteria affecting female choice in this species, on the offspring sex ratios. We found that food-manipulation treatment altered the conspicuousness of the orange spot patterns in a full-sibling male pair. When females were presented to these males, they showed a greater mate preference for males having brighter orange spots than for those having duller orange spots. Subsequently, half of the females were mated with the preferred males and the remaining females were mated with the less preferred males. When the females exhibited a greater preference for their mates, their offspring sex ratios were more male biased. These results appear to be consistent with the prediction of the attractiveness hypothesis. In the guppy, as male sexual attractiveness is heritable, the male-biased sex ratios of the broods of attractive males may be adaptive. 相似文献
964.
Yayoi Kamata Aya Taniguchi Mami Yamamoto Junko Nomura Kazuhiko Ishihara Hidenari Takahara Toshihiko Hibino Atsushi Takeda 《The Journal of biological chemistry》2009,284(19):12829-12836
Filaggrin is a component of the cornified cell envelope and the precursor
of free amino acids acting as a natural moisturizing factor in the stratum
corneum. Deimination is critical for the degradation of filaggrin into free
amino acids. In this study, we tried to identify the enzyme(s) responsible for
the cleavage of deiminated filaggrin in vitro. First, we investigated
citrulline aminopeptidase activity in the extract of newborn rat epidermis by
double layer fluorescent zymography and detected strong activity at neutral
pH. Monitoring the citrulline-releasing activity, we purified an enzyme of 280
kDa, comprised of six identical subunits of 48 kDa. The NH2
terminus of representative tryptic peptides perfectly matched the sequence of
rat bleomycin hydrolase (BH). The enzyme released various amino acids except
Pro from β-naphthylamide derivatives and hydrolyzed
citrulline-β-naphthylamide most effectively. Thus, to break down
deiminated filaggrin, another protease would be required. Among proteases
tested, calpain I degraded the deiminated filaggrin effectively into many
peptides of different mass on the matrix-assisted laser
desorption/ionization-time of flight mass spectrum. We confirmed that various
amino acids including citrulline were released by BH from those peptides. On
the other hand, caspase 14 degraded deiminated filaggrin into a few peptides
of limited mass. Immunohistochemical analysis of normal human skin revealed
co-localization of BH and filaggrin in the granular layer. Collectively, our
results suggest that BH is essential for the synthesis of natural moisturizing
factors and that calpain I would play a role as an upstream protease in the
degradation of filaggrin.The mammalian epidermal keratinocytes arise from proliferating basal cells
and move outward through a series of distinct differentiation events to form
the stratum corneum (1,
2). During this progressive
epidermal differentiation, keratinocytes express different proteins such as
keratins, profilaggrin/filaggrin, involucrin, small proline-rich proteins,
loricrin, cystatin A, and elafin, which form the cornified envelope of mature
corneocytes
(3–7).
Profilaggrin is synthesized as a large, extremely insoluble phosphoprotein
that consists of a unique NH2-terminal Ca2+-binding
protein of the S-100 family, linked to 10–20 tandem filaggrin monomer
repeats
(8–10).
Each individual filaggrin repeat is completely removed by proteolysis to
generate the mature filaggrin monomer (a molecular mass of 37 kDa in human).
Then, filaggrin is completely degraded in the uppermost layer of the stratum
corneum to produce a mixture of free and modified hygroscopic amino acids that
are important for maintaining epidermal hydration
(2,
11–13).
In addition, a number of proteins are subjected to various post-translational
modifications such as disulfide bonding, N-(γ-glutamyl)-lysine
isopeptide cross-linking, and deimination during the terminal differentiation
of epidermal keratinocytes (4,
6,
14,
15). Deimination is catalyzed
by peptidylarginine deiminase
(PAD),2 which converts
arginine to citrulline in proteins
(17–19).
The modification seems essential for the processing into free amino acids
including citrulline.Several proteases reportedly participate in the processing of profilaggrin.
Furin, a member of the proprotein convertase family, has been proposed to
cleave the NH2 terminus of profilaggrin, facilitating the release
of the NH2-terminal S-100 protein
(20,
21). In contrast, calpain I
and profilaggrin endopeptidase I (PEP-I) were implicated in the processing of
the linker regions between the filaggrin monomer repeats to generate the
filaggrin monomer
(22–25).
Recently, significant results regarding the conversion of profilaggrin to
filaggrin have been obtained with the knock-out of matriptase/MT-SP1,
prostasin/channel-activating serine protease 1/Prss 8, and caspase 14
in mice
(26–28).
These proteases were a key component of the profilaggrin-processing pathway in
terminal epidermal differentiation. However, although the signal initiating
the degradation of profilaggrin at a defined stage of the maturation of the
stratum corneum was found to be the water gradient within the stratum corneum
itself (11), the proteases for
the processing of filaggrin and/or the deiminated form into peptides following
the breakdown of these peptides to amino acids including citrulline remain
unknown.In this study, we have purified a novel aminopeptidase using a deiminated
substrate from rat skin homogenate and identified it as a neutral cysteine
protease, bleomycin hydrolase (BH). Furthermore, we investigated the
processing of the deiminated filaggrin by calpain I or caspase 14. Based on
these results, we proposed that calpain I participated preferentially in the
processing of deiminated filaggrin into peptides and then BH appeared
essential for the breakdown of the peptides into amino acids. 相似文献
965.
Aya Shinozaki Tetsuo Ushiku Teppei Morikawa Rumi Hino Takashi Sakatani Hiroshi Uozaki Masashi Fukayama 《The journal of histochemistry and cytochemistry》2009,57(8):775-785
Epstein-Barr virus (EBV)-associated gastric carcinoma (GC) is a distinct subtype with characteristic clinicopathological features. To better characterize its cellular characteristics, 43 cases of EBV-associated GC, 68 cases of EBV-negative GC, and non-neoplastic gastric mucosa in adults and fetuses were examined immunohistochemically. We quantified the expression of the major tight-junction protein claudin (CLDN) -1, -3, -4, -7, and -18 together with gastric mucins (MUC5AC and MUC6), intestinal mucin (MUC2), and CD10. EBV-associated GC showed a high frequency of CLDN18 expression (84%) and a low frequency of CLDN3 expression (5%). This expression profile corresponded to that of normal gastric epithelium in adults and fetuses. Almost half of the EBV-associated GC cases demonstrated gastric mucin expression, whereas the other half lacked mucin or CD10 expression. In contrast, as demonstrated by the expression profiles of CLDN3 and CLDN18, EBV-negative GC comprised a heterogeneous group of four different CLDN phenotypes: gastric, intestinal, mixed, and an undifferentiated type with variable expression patterns of mucins. These results indicate that EBV-associated GC is considerably homogenous with regard to cellular differentiation and that it preserves well the nature of the cells of origin. EBV-associated GC may undergo distinct carcinogenic processes, which differ from those of EBV-negative GC. (J Histochem Cytochem 57:775–785, 2009) 相似文献
966.
967.
968.
Jun Kimura Hiroyuki Abe Shigeki Kamitani Hirono Toshima Aya Fukui Masami Miyake Yoichi Kamata Yoshiko Sugita-Konishi Shigeki Yamamoto Yasuhiko Horiguchi 《The Journal of biological chemistry》2010,285(1):401-408
Clostridium perfringens enterotoxin (CPE), a causative agent of food poisoning, is a pore-forming toxin disrupting the selective permeability of the plasma membrane of target cells, resulting in cell death. We previously identified claudin as the cell surface receptor for CPE. Claudin, a component of tight junctions, is a tetratransmembrane protein and constitutes a large family of more than 20 members, not all of which serve as the receptor for CPE. The mechanism by which the toxin distinguishes the sensitive claudins is unknown. In this study, we localized the region of claudin responsible for interaction with CPE to the C-terminal part of the second extracellular loop and found that the isoelectric point of this region in sensitive claudins was higher than insensitive claudins. Amino acid substitutions to lower the pI resulted in reduced sensitivity to CPE among sensitive claudins, whereas substitutions to raise the pI endowed CPE-insensitive claudins with sensitivity. The steric structure of the claudin-binding domain of CPE reveals an acidic cleft surrounded by Tyr306, Tyr310, Tyr312, and Leu315, which were reported to be essential for interaction with the sensitive claudins. These results imply that an electrostatic attraction between the basic claudin region and the acidic CPE cleft is involved in their interaction. 相似文献
969.
Naoto Watanabe Shizuka Takagi Aya Tominaga Taisuke Tomita Takeshi Iwatsubo 《The Journal of biological chemistry》2010,285(26):19738-19746
γ-Secretase is a multimeric membrane protein complex composed of presenilin (PS), nicastrin, Aph-1, and Pen-2, which mediates intramembrane proteolysis of a range of type I transmembrane proteins. We previously analyzed the functional roles of the N-terminal transmembrane domains (TMDs) 1–6 of PS1 in the assembly and proteolytic activity of the γ-secretase using a series of TMD-swap PS1 mutants. Here we applied the TMD-swap method to all the TMDs of PS1 for the structure-function analysis of the proteolytic mechanism of γ-secretase. We found that TMD2- or -6-swapped mutant PS1 failed to bind the helical peptide-based, substrate-mimic γ-secretase inhibitor. Cross-linking experiments revealed that both TMD2 and TMD6 of PS1 locate in proximity to the TMD9, the latter being implicated in the initial substrate binding. Taken together, our data suggest that TMD2 and the luminal side of TMD6 are involved in the formation of the initial substrate-binding site of the γ-secretase complex. 相似文献
970.
Kitamura S Hida A Watanabe M Enomoto M Aritake-Okada S Moriguchi Y Kamei Y Mishima K 《Chronobiology international》2010,27(9-10):1797-1812
Although evening preference has recently been identified as a risk factor for depression, it has not been substantiated whether evening preference is a direct risk factor for depressive states, or if it is associated secondarily through other factors, such as delayed sleep timing and shortened sleep duration. The objective of this study is to investigate associations in Japanese adult subjects between evening preference and incidence of depressive states, adjusting for various sleep parameters related to depressive states. The Morningness-Eveningness Questionnaire (MEQ), the Pittsburgh Sleep Quality Index (PSQI), and the Center for Epidemiologic Studies Depression Scale (CES-D) were administered to 1170 individuals (493 males/677 females; mean and range 38.5 and 20-59 yrs) to assess their diurnal preferences, sleeping states, and presence of depression symptoms. Subjects were classified into five chronotypes based on MEQ scores. Evening preference was associated with delayed sleep timing, shortened sleep duration, deteriorated subjective sleep quality, and worsened daytime sleepiness. Logistic regression analysis demonstrated that the extreme evening type (odds ratio [OR]?=?1.926, p?=?.018) was associated with increased incidence of depressive states and that the extreme morning type (OR?=?0.342, p?=?.038) was associated with the decreased incidence of depressive states, independent of sleep parameters, such as nocturnal awakening (OR?=?1.844, p?.001), subjective sleep quality (OR?=?2.471, p?.001), and daytime sleepiness (OR?=?1.895, p?=?.001). However, no significant associations were observed between the incidence of depressive states and sleep duration, sleep timing, and sleep debt (levels of insufficient sleep). Although the findings of this study do not demonstrate a causative relationship between evening preference and depression, they do suggest the presence of functional associations between mood adjustment and biological clock systems that regulate diurnal preference. They also suggest that evening preference might increase susceptibility to the induction of mood disorders. 相似文献