全文获取类型
收费全文 | 154篇 |
免费 | 12篇 |
专业分类
166篇 |
出版年
2020年 | 1篇 |
2017年 | 2篇 |
2016年 | 6篇 |
2015年 | 5篇 |
2014年 | 10篇 |
2013年 | 10篇 |
2012年 | 8篇 |
2011年 | 12篇 |
2010年 | 8篇 |
2009年 | 5篇 |
2008年 | 9篇 |
2007年 | 7篇 |
2006年 | 3篇 |
2005年 | 5篇 |
2004年 | 2篇 |
2003年 | 3篇 |
2002年 | 3篇 |
2001年 | 3篇 |
2000年 | 4篇 |
1999年 | 4篇 |
1998年 | 4篇 |
1996年 | 4篇 |
1995年 | 5篇 |
1994年 | 3篇 |
1993年 | 4篇 |
1992年 | 6篇 |
1991年 | 2篇 |
1990年 | 2篇 |
1989年 | 1篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1986年 | 3篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1982年 | 1篇 |
1980年 | 2篇 |
1978年 | 5篇 |
1977年 | 3篇 |
1976年 | 1篇 |
1974年 | 1篇 |
1965年 | 2篇 |
1964年 | 1篇 |
1958年 | 1篇 |
排序方式: 共有166条查询结果,搜索用时 15 毫秒
71.
Lu Sun Shirley Haun Richard C. Jones Ricky D. Edmondson Khaled Machaca 《The Journal of biological chemistry》2009,284(30):20184-20196
Fertilization induces a species-specific Ca2+ transient with specialized spatial and temporal dynamics, which are essential to temporally encode egg activation events such as the block to polyspermy and resumption of meiosis. Eggs acquire the competence to produce the fertilization-specific Ca2+ transient during oocyte maturation, which encompasses dramatic potentiation of inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ release. Here we show that increased IP3 receptor (IP3R) sensitivity is initiated at the germinal vesicle breakdown stage of maturation, which correlates with maturation promoting factor (MPF) activation. Extensive phosphopeptide mapping of the IP3R resulted in ∼70% coverage and identified three residues, Thr-931, Thr-1136, and Ser-114, which are specifically phos pho ryl a ted during maturation. Phospho-specific antibody analyses show that Thr-1136 phos pho ryl a tion requires MPF activation. Activation of either MPF or the mitogen-activated protein kinase cascade independently, functionally sensitizes IP3-dependent Ca2+ release. Collectively, these data argue that the kinase cascades driving meiotic maturation potentiates IP3-dependent Ca2+ release, possibly trough direct phos pho ryl a tion of the IP3R.Egg activation refers to the cellular and molecular events that take place immediately following fertilization, transitioning the zygote into embryogenesis. In vertebrates, egg activation encompasses the block to polyspermy and the completion of oocyte meiosis, which is coupled to the extrusion of the second polar body. Interestingly, in all sexually reproducing organisms tested to date the cellular events associated with egg activation are Ca2+-dependent (1). Importantly the Ca2+ signal at fertilization encodes the progression of these cellular events in a defined temporal sequence that ensures a functional egg-to-embryo transition (2, 3). The first order of business for the fertilized egg is to block polyspermy, which could be lethal to the embryo. This presents a particularly difficult problem for the large Xenopus oocyte. Therefore, this species employs a fast and slow blocks to polyspermy, both of which are Ca2+-dependent (4). In addition, the Ca2+ release wave at fertilization releases the metaphase II cytostatic factor-dependent arrest in Xenopus oocytes. As is the case in other vertebrates, Xenopus eggs arrest at metaphase of meiosis II, an event that marks the completion of maturation.Therefore, Ca2+ dynamics at fertilization initiate and temporally encode critical cellular events for the egg-to-embryo transition. Specificity in Ca2+ signaling is encoded to a large extent in the spatial, temporal, and amplitude features of the Ca2+ signal. This endows Ca2+ signaling with its versatility and specificity, where in the same cell Ca2+ signals can mediate distinct cellular responses (5, 6).Ca2+ signaling pathways and intracellular organelles remodel during oocyte maturation, a complex cellular differentiation that prepares the egg for fertilization and egg activation (7, 8). In Xenopus the activity and distribution of multiple essential Ca2+-transporting proteins is modulated dramatically during oocyte maturation (8). Functional studies and mathematical modeling support the conclusion that the two critical determinants of Ca2+ signaling remodeling during Xenopus oocyte maturation are the internalization of the plasma-membrane Ca2+-ATPase, and the sensitization of inositol 1,4,5-trisphosphate (IP3)2-dependent Ca2+ release (9–11). Indeed Ca2+ release from intracellular stores through the IP3 receptor (IP3R) represents the primary source for the initial Ca2+ rise at fertilization in vertebrates (12–14). The sensitivity of IP3-dependent Ca2+ release is enhanced during maturation (10, 15). The IP3R physically clusters during maturation (9, 16), and this is associated with functional clustering of elementary Ca2+ release events (10). IP3R clustering is important for the slow and continuous nature of Ca2+ wave propagation in Xenopus eggs (10). In fact the potentiation of IP3-dependent Ca2+ release is a hallmark of Ca2+ signaling differentiation during oocyte maturation in several vertebrate and invertebrate species (17–19). However, the mechanisms underlying enhanced IP3-dependent Ca2+ release are not well understood.An attractive mechanism to explain increased IP3R sensitivity during oocyte maturation is phosphorylation, given the critical role kinase cascades play in the initiation and progression of the meiotic cell cycle. Furthermore, the affinity of the IP3R increases during mitosis apparently due to direct phosphorylation by maturation-promoting factor (MPF) (20, 21). In contrast, in starfish eggs, although the increase in Ca2+ release was dependent on MPF activation, MPF does not directly phosphorylate the IP3R, but rather it appears to mediate its effect through the actin cytoskeleton (22, 23). More recently, the MAPK cascade has been shown to be important for shaping Ca2+ dynamics in mouse eggs (24). Together, these results argue that phosphorylation plays an important role in the sensitization of IP3-dependent Ca2+ release during M-phase.Xenopus oocyte maturation is initiated by steroids that appear to act on a cell surface receptor (25). An important kinase cascade activated during maturation is the MAPK cascade that is initiated through the accumulation of Mos (Fig. 1A). This cascade culminates in the inhibition of Myt1, which phosphorylates and inhibits MPF. MPF is the key regulator of entry into M-phase and is composed of a Ser/Thr kinase subunit (cdk1) and cyclin B as a regulatory subunit. In addition, activation of Cdc25C is essential for oocyte maturation, because it represents the rate-limiting step in MPF activation (26). Cdc25C is phosphorylated by polo-like kinase through unknown upstream steps. In this work we analyze the functional regulation and phosphorylation pattern of the IP3R during oocyte maturation to better understand the role of cell cycle kinases in modulating IP3-dependent Ca2+ release.Open in a separate windowFIGURE 1.IP3-dependent Ca2+ release dynamics during maturation. A, kinase cascades driving Xenopus oocyte maturation. B, oocytes were injected with caged-IP3 and Oregan Green 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis 1 before imaging. Maturation was induced with progesterone, and cells were collected at different time points as indicated. Cells were imaged in line scan mode on a Zeiss LSM510 with the near UV 450 nm laser continuously on, at low intensity to produce a slow gradual IP3 rise. After imaging each cell was lysed and analyzed individually for the activation state of MAPK and MPF. MPF was assayed using an anti-phospho-Tyr-15-cdk1 antibody (arrow). Dephosphorylation is indicative of MPF activation. MAPK activation was detected using a phospho-specific MAPK antibody (arrowhead). Tubulin was the loading control (dash). C, percent of cells at each time point that either exhibit no release for the duration of the line scan (No Rel., black), puffs only (puffs, green), puffs followed by a wave (Puff-Wave, blue), or only a Ca2+ wave (Wave, red). For each time point n = 11–23 cells. D, amplitude of the first peak during the line scan as compared with the maximal Ca2+ signal. Mean ± S.E. (n = 9–18). E, latency until the first Ca2+ signal (Time to first peak) as compared with the time required to reach maximal signal (Time to Max). Mean ± S.E. (n = 9–18). For C–E: oocytes (Ooc); cells treated with progesterone that have not undergone GVBD at 2 or more hours after progesterone (p > 2); cells at GVBD and up to 0.5 h after GVBD (GVBD 0–0.5); cells from 0.5 to 2.5 h after GVBD (GVBD 0.5–2.5); fully mature eggs at 3 or more hours after GVBD (>3 egg). 相似文献
72.
Tiana Baqueiro Momtchilo Russo Virgínia MG Silva Thayna Meirelles Pablo RS Oliveira Eliane Gomes Renato Barboza Ana T Cerqueira-Lima Camila A Figueiredo Lain Pontes-de-Carvalho Neuza M Alcantara-Neves 《Respiratory research》2010,11(1):51
Background
The dust mite Blomia tropicalis is an important source of aeroallergens in tropical areas. Although a mouse model for B. tropicalis extract (BtE)-induced asthma has been described, no study comparing different mouse strains in this asthma model has been reported. The relevance and reproducibility of experimental animal models of allergy depends on the genetic background of the animal, the molecular composition of the allergen and the experimental protocol.Objectives
This work had two objectives. The first was to study the anti-B. tropicalis allergic responses in different mouse strains using a short-term model of respiratory allergy to BtE. This study included the comparison of the allergic responses elicited by BtE with those elicited by ovalbumin in mice of the strain that responded better to BtE sensitization. The second objective was to investigate whether the best responder mouse strain could be used in an experimental model of allergy employing relatively low BtE doses.Methods
Groups of mice of four different syngeneic strains were sensitized subcutaneously with 100 μg of BtE on days 0 and 7 and challenged four times intranasally, at days 8, 10, 12, and 14, with 10 μg of BtE. A/J mice, that were the best responders to BtE sensitization, were used to compare the B. tropicalis-specific asthma experimental model with the conventional experimental model of ovalbumin (OVA)-specific asthma. A/J mice were also sensitized with a lower dose of BtE.Results
Mice of all strains had lung inflammatory-cell infiltration and increased levels of anti-BtE IgE antibodies, but these responses were significantly more intense in A/J mice than in CBA/J, BALB/c or C57BL/6J mice. Immunization of A/J mice with BtE induced a more intense airway eosinophil influx, higher levels of total IgE, similar airway hyperreactivity to methacholine but less intense mucous production, and lower levels of specific IgE, IgG1 and IgG2 antibodies than sensitization with OVA. Finally, immunization with a relatively low BtE dose (10 μg per subcutaneous injection per mouse) was able to sensitize A/J mice, which were the best responders to high-dose BtE immunization, for the development of allergy-associated immune and lung inflammatory responses.Conclusions
The described short-term model of BtE-induced allergic lung disease is reproducible in different syngeneic mouse strains, and mice of the A/J strain was the most responsive to it. In addition, it was shown that OVA and BtE induce quantitatively different immune responses in A/J mice and that the experimental model can be set up with low amounts of BtE. 相似文献73.
Natália Bromberg Juliana L. Dreyfuss Caio V. Regatieri Marcelly V. Palladino Nelson Durán Helena B. Nader Marcela Haun Giselle Z. Justo 《Chemico-biological interactions》2010,186(1):43-52
The continuing threat to biodiversity lends urgency to the need of identification of sustainable source of natural products. This is not so much trouble if there is a microbial source of the compound. Herein, violacein, a natural indolic pigment extracted from Chromobacterium violaceum, was evaluated for its antitumoral potential against the Ehrlich ascites tumor (EAT) in vivo and in vitro. Evaluation of violacein cytotoxicity using different endpoints indicated that EAT cells were twofold (IC50 = 5.0 μM) more sensitive to the compound than normal human peripheral blood lymphocytes. In vitro studies indicated that violacein cytotoxicity to EAT cells is mediated by a rapid (8–12 h) production of reactive oxygen species (ROS) and a decrease in intracellular GSH levels, probably due to oxidative stress. Additionally, apoptosis was primarily induced, as demonstrated by an increase in Annexin-V positive cells, concurrently with increased levels of DNA fragmentation and increased caspase-2, caspase-9 and caspase-3 activities up to 4.5-, 6.0- and 5.5-fold, respectively, after 72 h of treatment. Moreover, doses of 0.1 and 1.0 μg kg?1 violacein, administered intraperitoneally (i.p.) to EAT-bearing mice throughout the lifespan of the animals significantly inhibited tumor growth and increased survival of mice. In view of these results, a 35-day toxicity study was conducted in vivo. Complete hematology, biochemistry (ALT, AST and creatinine levels) and histopathological analysis of liver and kidney indicated that daily doses of violacein up to 1000 μg kg?1 for 35 days are well tolerated and did not cause hematotoxicity nor renal or hepatotoxicity when administered i.p. to mice. Altogether, these results indicate that violacein causes oxidative stress and an imbalance in the antioxidant defense machinery of cells culminating in apoptotic cell death. Furthermore, this is the first report of its antitumor activity in vivo, which occurs in the absence of toxicity to major organs. 相似文献
74.
Background
The image formed by the eye''s optics is blurred by the ocular aberrations, specific to each eye. Recent studies demonstrated that the eye is adapted to the level of blur produced by the high order aberrations (HOA). We examined whether visual coding is also adapted to the orientation of the natural HOA of the eye.Methods and Findings
Judgments of perceived blur were measured in 5 subjects in a psychophysical procedure inspired by the “Classification Images” technique. Subjects were presented 500 pairs of images, artificially blurred with HOA from 100 real eyes (i.e. different orientations), with total blur level adjusted to match the subject''s natural blur. Subjects selected the image that appeared best focused in each random pair, in a 6-choice ranked response. Images were presented through Adaptive Optics correction of the subject''s aberrations. The images selected as best focused were identified as positive, the other as negative responses. The highest classified positive responses correlated more with the subject''s Point Spread Function, PSF, (r = 0.47 on average) than the negative (r = 0.34) and the difference was significant for all subjects (p<0.02). Using the orientation of the best fitting ellipse of angularly averaged integrated PSF intensities (weighted by the subject''s responses) we found that in 4 subjects the positive PSF response was close to the subject''s natural PSF orientation (within 21 degrees on average) whereas the negative PSF response was almost perpendicularly oriented to the natural PSF (at 76 degrees on average).Conclusions
The Classification-Images inspired method is very powerful in identifying the internally coded blur of subjects. The consistent bias of the Positive PSFs towards the natural PSF in most subjects indicates that the internal code of blur appears rather specific to each subject''s high order aberrations and reveals that the calibration mechanisms for normalizing blur also operate using orientation cues. 相似文献75.
1. We aimed to demonstrate reproducible nutrition and growth of macrophytes in non‐axenic laboratory cultures preventing growth of phytoplankton and epiphytes. 2. Macrophyte shoot segments were planted in a mixture of commercial acid‐washed silica sand with crystalline tricalcium phosphate, and this artificial sediment was covered with a layer of pure silica sand. The liquid mineral media used did not contain phosphorus but were rich in all other nutrient elements. A CO2 reservoir provided sustainable CO2 supply to macrophyte cultures by gas diffusion through a polyethylene membrane. 3. Chara hispida, Chara tomentosa, Chara baltica, Elodea canadensis, Potamogeton pectinatus and Zanichellia palustris could be cultivated for long term without medium exchange and aeration. Microalgae growth was prevented by the absence of phosphate in the water column. Mobilisation of tricalcium phosphate and phosphate uptake by the rhizoids of C. hispida enabled sustainable rapid shoot growth and increased the concentration of inorganic phosphate in the shoot dry weight by five to six times in comparison with plants cultivated on pure silica sand. A significant growth support from tricalcium phosphate was also observed for E. canadensis, but the rate of phosphate uptake by the roots was not sufficient to maintain a storage pool of inorganic phosphate (Pi) in the growing shoots of this plant. 4. Membrane‐controlled CO2 supply from a reservoir and artificial sediments like the one described provide attractive options for the laboratory culture of macrophytes. 相似文献
76.
Proteolytic action of kallikrein-related peptidase 7 produces unique active matrix metalloproteinase-9 lacking the C-terminal hemopexin domains 总被引:1,自引:0,他引:1
Vishnu C. Ramani Gur P. Kaushal Randy S. Haun 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2011,1813(8):1525-1531
The gelatinases, matrix metalloproteinase (MMP)-9 and -2, are produced as latent, inactive enzymes that can be proteolytically activated by a number of proteases. In many normal and pathological conditions, where the expression of MMPs is deregulated, changes in the expression of other proteases have also been reported. Human kallikrein-related peptidase 7 (KLK7), a chymotryptic-like serine protease, is overexpressed in many different types of neoplastic conditions, which have also been shown to express high levels of both MMP-9 and -2. Since the activation of MMPs by KLK7 has never been examined, we sought to determine whether KLK7 can activate these MMPs. To test this hypothesis KLK7 was incubated with the recombinant MMPs and the products of the reaction were analyzed for their activity. Incubation of proMMP-9 with KLK7 resulted in the production of a novel truncated, active MMP-9 lacking the C-terminal hemopexin domains. In contrast, KLK7 degraded, but did not activate, proMMP-2. The novel activation of proMMP-9 by KLK7 was further confirmed using conditioned medium prepared from an MMP-9-expressing cell line, MDA-MMP-9. Our results clearly establish that KLK7 activates proMMP-9 to produce a novel truncated, active MMP-9 product not generated by other proteases. These findings suggest that KLK7 may play an important role in the activation of MMP-9 in tumors that express high levels of both these proteases and the resulting truncated MMP may possess altered substrate specificities compared with full-length MMP-9 activated by other proteases. 相似文献
77.
Human societies are built on collaborative activities. Already from early childhood, human children are skillful and proficient collaborators. They recognize when they need help in solving a problem and actively recruit collaborators [1, 2]. The societies of other primates are also to some degree cooperative. Chimpanzees, for example, engage in a variety of cooperative activities such as border patrols, group hunting, and intra- and intergroup coalitionary behavior [3-5]. Recent studies have shown that chimpanzees possess many of the cognitive prerequisites necessary for human-like collaboration. Chimpanzees have been shown to recognize when they need help in solving a problem and to actively recruit good over bad collaborators [6, 7]. However, cognitive abilities might not be all that differs between chimpanzees and humans when it comes to cooperation. Another factor might be the motivation to engage in a cooperative activity. Here, we hypothesized that a key difference between human and chimpanzee collaboration-and so potentially a key mechanism in the evolution of human cooperation-is a simple preference for collaborating (versus acting alone) to obtain food. Our results supported this hypothesis, finding that whereas children strongly prefer to work together with another to obtain food, chimpanzees show no such preference. 相似文献
78.
79.
Böger CA Gorski M Li M Hoffmann MM Huang C Yang Q Teumer A Krane V O'Seaghdha CM Kutalik Z Wichmann HE Haak T Boes E Coassin S Coresh J Kollerits B Haun M Paulweber B Köttgen A Li G Shlipak MG Powe N Hwang SJ Dehghan A Rivadeneira F Uitterlinden A Hofman A Beckmann JS Krämer BK Witteman J Bochud M Siscovick D Rettig R Kronenberg F Wanner C Thadhani RI Heid IM Fox CS Kao WH;CKDGen Consortium 《PLoS genetics》2011,7(9):e1002292
Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m2 at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression. 相似文献
80.
I Curjuric M Imboden R Nadif A Kumar C Schindler M Haun F Kronenberg N Künzli H Phuleria DS Postma EW Russi T Rochat F Demenais NM Probst-Hensch 《PloS one》2012,7(7):e40175