全文获取类型
收费全文 | 1541篇 |
免费 | 118篇 |
专业分类
1659篇 |
出版年
2024年 | 3篇 |
2023年 | 6篇 |
2022年 | 11篇 |
2021年 | 31篇 |
2020年 | 15篇 |
2019年 | 22篇 |
2018年 | 22篇 |
2017年 | 21篇 |
2016年 | 47篇 |
2015年 | 66篇 |
2014年 | 75篇 |
2013年 | 102篇 |
2012年 | 143篇 |
2011年 | 149篇 |
2010年 | 91篇 |
2009年 | 79篇 |
2008年 | 98篇 |
2007年 | 112篇 |
2006年 | 88篇 |
2005年 | 88篇 |
2004年 | 70篇 |
2003年 | 76篇 |
2002年 | 77篇 |
2001年 | 9篇 |
2000年 | 16篇 |
1999年 | 7篇 |
1998年 | 15篇 |
1997年 | 9篇 |
1996年 | 14篇 |
1995年 | 5篇 |
1994年 | 6篇 |
1993年 | 5篇 |
1992年 | 6篇 |
1991年 | 3篇 |
1990年 | 4篇 |
1988年 | 4篇 |
1987年 | 3篇 |
1985年 | 3篇 |
1984年 | 5篇 |
1981年 | 5篇 |
1977年 | 2篇 |
1974年 | 2篇 |
1970年 | 4篇 |
1960年 | 2篇 |
1958年 | 3篇 |
1957年 | 2篇 |
1955年 | 2篇 |
1954年 | 2篇 |
1951年 | 2篇 |
1949年 | 2篇 |
排序方式: 共有1659条查询结果,搜索用时 0 毫秒
81.
Seidl-Seiboth V Gruber S Sezerman U Schwecke T Albayrak A Neuhof T von Döhren H Baker SE Kubicek CP 《Journal of molecular evolution》2011,72(4):339-351
Hydrophobins are small proteins, characterised by the presence of eight positionally conserved cysteine residues, and are
present in all filamentous asco- and basidiomycetes. They are found on the outer surfaces of cell walls of hyphae and conidia,
where they mediate interactions between the fungus and the environment. Hydrophobins are conventionally grouped into two classes
(class I and II) according to their solubility in solvents, hydropathy profiles and spacing between the conserved cysteines.
Here we describe a novel set of hydrophobins from Trichoderma spp. that deviate from this classification in their hydropathy, cysteine spacing and protein surface pattern. Phylogenetic
analysis shows that they form separate clades within ascomycete class I hydrophobins. Using T. atroviride as a model, the novel hydrophobins were found to be expressed under conditions of glucose limitation and to be regulated
by differential splicing. 相似文献
82.
Fredenburgh LE Velandia MM Ma J Olszak T Cernadas M Englert JA Chung SW Liu X Begay C Padera RF Blumberg RS Walsh SR Baron RM Perrella MA 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(10):5255-5267
Sepsis remains the leading cause of death in critically ill patients, despite modern advances in critical care. Intestinal barrier dysfunction may lead to secondary bacterial translocation and the development of the multiple organ dysfunction syndrome during sepsis. Cyclooxygenase (COX)-2 is highly upregulated in the intestine during sepsis, and we hypothesized that it may be critical in the maintenance of intestinal epithelial barrier function during peritonitis-induced polymicrobial sepsis. COX-2(-/-) and COX-2(+/+) BALB/c mice underwent cecal ligation and puncture (CLP) or sham surgery. Mice chimeric for COX-2 were derived by bone marrow transplantation and underwent CLP. C2BBe1 cells, an intestinal epithelial cell line, were treated with the COX-2 inhibitor NS-398, PGD(2), or vehicle and stimulated with cytokines. COX-2(-/-) mice developed exaggerated bacteremia and increased mortality compared with COX-2(+/+) mice following CLP. Mice chimeric for COX-2 exhibited the recipient phenotype, suggesting that epithelial COX-2 expression in the ileum attenuates bacteremia following CLP. Absence of COX-2 significantly increased epithelial permeability of the ileum and reduced expression of the tight junction proteins zonula occludens-1, occludin, and claudin-1 in the ileum following CLP. Furthermore, PGD(2) attenuated cytokine-induced hyperpermeability and zonula occludens-1 downregulation in NS-398-treated C2BBe1 cells. Our findings reveal that absence of COX-2 is associated with enhanced intestinal epithelial permeability and leads to exaggerated bacterial translocation and increased mortality during peritonitis-induced sepsis. Taken together, our results suggest that epithelial expression of COX-2 in the ileum is a critical modulator of tight junction protein expression and intestinal barrier function during sepsis. 相似文献
83.
Frank Lennartz Karen Bayer Nadine Czerwonka Yinghui Lu Kristine Kehr Manuela Hirz Torsten Steinmetzer Wolfgang Garten Christiane Herden 《Cellular microbiology》2016,18(3):340-354
Borna disease virus (BDV) is a non‐segmented negative‐stranded RNA virus that maintains a strictly neurotropic and persistent infection in affected end hosts. The primary target cells for BDV infection are brain cells, e.g. neurons and astrocytes. The exact mechanism of how infection is propagated between these cells and especially the role of the viral glycoprotein (GP) for cell–cell transmission, however, are still incompletely understood. Here, we use different cell culture systems, including rat primary astrocytes and mixed cultures of rat brain cells, to show that BDV primarily spreads through cell–cell contacts. We employ a highly stable and efficient peptidomimetic inhibitor to inhibit the furin‐mediated processing of GP and demonstrate that cleaved and fusion‐active GP is strictly necessary for the cell‐to‐cell spread of BDV. Together, our quantitative observations clarify the role of Borna disease virus‐glycoprotein for viral dissemination and highlight the regulation of GP expression as a potential mechanism to limit viral spread and maintain persistence. These findings furthermore indicate that targeting host cell proteases might be a promising approach to inhibit viral GP activation and spread of infection. 相似文献
84.
The anaerobic veratrol O-demethylase mediates the transfer of the methyl group of the phenyl methyl ether veratrol to tetrahydrofolate. The primary
methyl group acceptor is the cobalt of a corrinoid protein, which has to be in the +1 oxidation state to bind the methyl group.
Due to the negative redox potential of the cob(II)/cob(I)alamin couple, autoxidation of the cobalt may accidentally occur.
In this study, the reduction of the corrinoid to the superreduced [CoI] state was investigated. The ATP-dependent reduction of the corrinoid protein of the veratrol O-demethylase was shown to be dependent on titanium(III) citrate as electron donor and on an activating enzyme. In the presence
of ATP, activating enzyme, and Ti(III), the redox potential versus the standard hydrogen electrode (E
SHE) of the cob(II)alamin/cob(I)alamin couple in the corrinoid protein was determined to be −290 mV (pH 7.5), whereas E
SHE at pH 7.5 was lower than −450 mV in the absence of either activating enzyme or ATP. ADP, AMP, or GTP could not replace ATP
in the activation reaction. The ATP analogue adenosine-5′-(β,γ-imido)triphosphate (AMP-PNP, 2–4 mM) completely inhibited the
corrinoid reduction in the presence of ATP (2 mM). 相似文献
85.
Placental‐Specific Overexpression of sFlt‐1 Alters Trophoblast Differentiation and Nutrient Transporter Expression in an IUGR Mouse Model 下载免费PDF全文
86.
87.
Juan Manuel Iglesias Claire J. Cairney Roderick K. Ferrier Laura McDonald Kelly Soady Howard Kendrick Marie-Anne Pringle Reginald O. Morgan Finian Martin Matthew J. Smalley Karen Blyth Torsten Stein 《PloS one》2015,10(3)
We have previously shown that Annexin A8 (ANXA8) is strongly associated with the basal-like subgroup of breast cancers, including BRCA1-associated breast cancers, and poor prognosis; while in the mouse mammary gland AnxA8 mRNA is expressed in low-proliferative isolated pubertal mouse mammary ductal epithelium and after enforced involution, but not in isolated highly proliferative terminal end buds (TEB) or during pregnancy. To better understand ANXA8’s association with this breast cancer subgroup we established ANXA8’s cellular distribution in the mammary gland and ANXA8’s effect on cell proliferation. We show that ANXA8 expression in the mouse mammary gland was strong during pre-puberty before the expansion of the rudimentary ductal network and was limited to a distinct subpopulation of ductal luminal epithelial cells but was not detected in TEB or in alveoli during pregnancy. Similarly, during late involution its expression was found in the surviving ductal epithelium, but not in the apoptotic alveoli. Double-immunofluorescence (IF) showed that ANXA8 positive (+ve) cells were ER-alpha negative (−ve) and mostly quiescent, as defined by lack of Ki67 expression during puberty and mid-pregnancy, but not terminally differentiated with ∼15% of ANXA8 +ve cells re-entering the cell cycle at the start of pregnancy (day 4.5). RT-PCR on RNA from FACS-sorted cells and double-IF showed that ANXA8+ve cells were a subpopulation of c-kit +ve luminal progenitor cells, which have recently been identified as the cells of origin of basal-like breast cancers. Over expression of ANXA8 in the mammary epithelial cell line Kim-2 led to a G0/G1 arrest and suppressed Ki67 expression, indicating cell cycle exit. Our data therefore identify ANXA8 as a potential mediator of quiescence in the normal mouse mammary ductal epithelium, while its expression in basal-like breast cancers may be linked to ANXA8’s association with their specific cells of origin. 相似文献
88.
Insulin improves contractile function after ischemia, but does not increase glucose uptake in the isolated working rat heart. We tested the hypothesis that the positive inotropic effect of insulin is independent of the signaling pathway responsible for insulin-stimulated glucose uptake. We inhibited this pathway at the level of phosphatidyl inositol 3-kinase (PI3K) with wortmannin. Hearts were perfused for 70 min at physiological workload with Krebs-Henseleit buffer containing [2-3H] glucose (5 mM, 0.05 Ci/ml) and oleate (0.4 mM, 1% BSA) in the presence (WM, n = 5) or absence (control, n = 7) of wortmannin (WM, 3 mol/L). After 20 min, hearts were subjected to 15 min of total global ischemia followed by 35 min of reperfusion. Insulin (1 mU/ml) was added at the beginning of reperfusion (WM + insulin n = 8, insulin n = 8). Cardiac power before ischemia was 8.1 ± 0.7 mW. Recovery of contractile function after ischemia was significantly increased in the presence of insulin (73.5 ± 8.9% vs. 38.5 ± 6.7%, p < 0.01). The addition of wortmannin completely abolished the effect of insulin on recovery (32.6 ± 6.4%). Glucose uptake was 1.84 ± 0.32 mol/min/g dry before ischemia and was slightly elevated during reperfusion (2.68 ± 0.35 mol/min/g dry, n.s.). Insulin did not affect postischemic glucose uptake. In the presence of wortmannin, glucose uptake was lowest during reperfusion (n.s.). The results suggest that PI3K is involved in the insulin-induced improvement in postischemic recovery of contractile function. This effect of insulin is independent of its effect on glucose uptake. 相似文献
89.
Hiller S Kohl A Fiorito F Herrmann T Wider G Tschopp J Grütter MG Wüthrich K 《Structure (London, England : 1993)》2003,11(10):1199-1205
Signaling in apoptosis and inflammation is often mediated by proteins of the death domain superfamily in the Fas/FADD/Caspase-8 or the Apaf-1/Caspase-9 pathways. This superfamily currently comprises the death domain (DD), death effector domain (DED), caspase recruitment domain (CARD), and pyrin domain (PYD) subfamilies. The PYD subfamily is most abundant, but three-dimensional structures are only available for the subfamilies DD, DED, and CARD, which have an antiparallel arrangement of six alpha helices as common fold. This paper presents the NMR structure of PYD of NALP1, a protein that is involved in the innate immune response and is a component of the inflammasome. The structure of NALP1 PYD differs from all other known death domain superfamily structures in that the third alpha helix is replaced by a flexibly disordered loop. This unique feature appears to relate to the molecular basis of familial Mediterranean fever (FMF), a genetic disease caused by single-point mutations. 相似文献
90.
Ryser-Degiorgis MP Jakubek EB af Segerstad CH Bröjer C Mörner T Jansson DS Lundén A Uggla A 《Journal of wildlife diseases》2006,42(1):182-187
To investigate the prevalence of Toxoplasma gondii infection in free-ranging Eurasian lynx (Lynx lynx) in Sweden, serosanguinous fluids and feces were collected from 207 carcasses of lynx killed or found dead from 1996 to 1998. Sera were tested for antibodies against T. gondii by the direct agglutination test, and 156 (75.4%) of the sera tested positive at antibody titers>or=40. Antibody prevalence was significantly lower in lynx originating from the northern parts of Sweden than in lynx from the more southern regions that are more densely populated by humans. Age-related differences also were found, with a significantly lower prevalence (55%) in juvenile (<1-yr-old) than in subadult and adult animals (82%). There was no significant difference in seroprevalence between males and females. Oocysts typical of T. gondii were not detected in any of the fecal samples. 相似文献