全文获取类型
收费全文 | 559篇 |
免费 | 45篇 |
出版年
2023年 | 6篇 |
2022年 | 12篇 |
2021年 | 24篇 |
2020年 | 15篇 |
2019年 | 26篇 |
2018年 | 20篇 |
2017年 | 9篇 |
2016年 | 16篇 |
2015年 | 29篇 |
2014年 | 25篇 |
2013年 | 35篇 |
2012年 | 48篇 |
2011年 | 36篇 |
2010年 | 25篇 |
2009年 | 22篇 |
2008年 | 25篇 |
2007年 | 41篇 |
2006年 | 23篇 |
2005年 | 24篇 |
2004年 | 13篇 |
2003年 | 21篇 |
2002年 | 11篇 |
2001年 | 5篇 |
2000年 | 7篇 |
1999年 | 7篇 |
1998年 | 7篇 |
1997年 | 3篇 |
1996年 | 4篇 |
1995年 | 3篇 |
1994年 | 6篇 |
1993年 | 3篇 |
1992年 | 2篇 |
1991年 | 7篇 |
1990年 | 3篇 |
1989年 | 3篇 |
1988年 | 3篇 |
1987年 | 2篇 |
1986年 | 3篇 |
1985年 | 3篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1974年 | 2篇 |
1973年 | 2篇 |
1972年 | 1篇 |
1971年 | 2篇 |
1968年 | 4篇 |
1967年 | 1篇 |
1966年 | 2篇 |
1965年 | 1篇 |
1950年 | 1篇 |
排序方式: 共有604条查询结果,搜索用时 203 毫秒
261.
Martin G. De Kauwe Belinda E. Medlyn Anna M. Ukkola Mengyuan Mu Manon E. B. Sabot Andrew J. Pitman Patrick Meir Lucas A. Cernusak Sami W. Rifai Brendan Choat David T. Tissue Chris J. Blackman Ximeng Li Michael Roderick Peter R. Briggs 《Global Change Biology》2020,26(10):5716-5733
South‐East Australia has recently been subjected to two of the worst droughts in the historical record (Millennium Drought, 2000–2009 and Big Dry, 2017–2019). Unfortunately, a lack of forest monitoring has made it difficult to determine whether widespread tree mortality has resulted from these droughts. Anecdotal observations suggest the Big Dry may have led to more significant tree mortality than the Millennium drought. Critically, to be able to robustly project future expected climate change effects on Australian vegetation, we need to assess the vulnerability of Australian trees to drought. Here we implemented a model of plant hydraulics into the Community Atmosphere Biosphere Land Exchange (CABLE) land surface model. We parameterized the drought response behaviour of five broad vegetation types, based on a common garden dry‐down experiment with species originating across a rainfall gradient (188–1,125 mm/year) across South‐East Australia. The new hydraulics model significantly improved (~35%–45% reduction in root mean square error) CABLE’s previous predictions of latent heat fluxes during periods of water stress at two eddy covariance sites in Australia. Landscape‐scale predictions of the greatest percentage loss of hydraulic conductivity (PLC) of about 40%–60%, were broadly consistent with satellite estimates of regions of the greatest change in both droughts. In neither drought did CABLE predict that trees would have reached critical PLC in widespread areas (i.e. it projected a low mortality risk), although the model highlighted critical levels near the desert regions of South‐East Australia where few trees live. Overall, our experimentally constrained model results imply significant resilience to drought conferred by hydraulic function, but also highlight critical data and scientific gaps. Our approach presents a promising avenue to integrate experimental data and make regional‐scale predictions of potential drought‐induced hydraulic failure. 相似文献
262.
Maria De Risi Giulia Torromino Michele Tufano Stphanie Moriceau Annabella Pignataro Manon Rivagorda Nicol Carrano Silvia Middei Carmine Settembre Martine Ammassari‐Teule Fabrizio Gardoni Andrea Mele Franck Oury Elvira De Leonibus 《Aging cell》2020,19(9)
Autophagy agonists have been proposed to slow down neurodegeneration. Spermidine, a polyamine that acts as an autophagy agonist, is currently under clinical trial for the treatment of age‐related memory decline. How Spermidine and other autophagy agonists regulate memory and synaptic plasticity is under investigation. We set up a novel mouse model of mild cognitive impairment (MCI), in which middle‐aged (12‐month‐old) mice exhibit impaired memory capacity, lysosomes engulfed with amyloid fibrils (β‐amyloid and α‐synuclein) and impaired task‐induced GluA1 hippocampal post‐translation modifications. Subchronic treatment with Spermidine as well as the autophagy agonist TAT‐Beclin 1 rescued memory capacity and GluA1 post‐translational modifications by favouring the autophagy/lysosomal‐mediated degradation of amyloid fibrils. These findings provide new mechanistic evidence on the therapeutic relevance of autophagy enhancers which, by improving the degradation of misfolded proteins, slow down age‐related memory decline. 相似文献
263.
Florian Binetruy Marie Buysse Quentin Lejarre Roxanne Barosi Manon Villa Nil Rahola Christophe Paupy Diego Ayala Olivier Duron 《Molecular ecology》2020,29(5):1016-1029
Mutualistic interactions with microbes have facilitated the adaptation of major eukaryotic lineages to restricted diet niches. Hence, ticks with their strictly blood‐feeding lifestyle are associated with intracellular bacterial symbionts through an essential B vitamin supplementation. In this study, examination of bacterial diversity in 25 tick species of the genus Amblyomma showed that three intracellular bacteria, Coxiella‐like endosymbionts (LE), Francisella‐LE and Rickettsia, are remarkably common. No other bacterium is as uniformly present in Amblyomma ticks. Almost all Amblyomma species were found to harbour a nutritive obligate symbiont, Coxiella‐LE or Francisella‐LE, that is able to synthesize B vitamins. However, despite the co‐evolved and obligate nature of these mutualistic interactions, the structure of microbiomes does not mirror the Amblyomma phylogeny, with a clear exclusion pattern between Coxiella‐LE and Francisella‐LE across tick species. Coxiella‐LE, but not Francisella‐LE, form evolutionarily stable associations with ticks, commonly leading to co‐cladogenesis. We further found evidence for symbiont replacements during the radiation of Amblyomma, with recent, and probably ongoing, invasions by Francisella‐LE and subsequent replacements of ancestral Coxiella‐LE through transient co‐infections. Nutritional symbiosis in Amblyomma ticks is thus not a stable evolutionary state, but instead arises from conflicting origins between unrelated but competing symbionts with similar metabolic capabilities. 相似文献
264.
265.
Frank G. van Steenbeek Bart Spee Louis C. Penning Anne Kummeling Ingrid H. M. van Gils Guy C. M. Grinwis Dik Van Leenen Frank C. P. Holstege Manon Vos-Loohuis Jan Rothuizen Peter A. J. Leegwater 《PloS one》2013,8(3)
The aryl hydrocarbon receptor (AHR) mediates biological responses to toxic chemicals. An unexpected role for AHR in vascularization was suggested when mice lacking AHR displayed impaired closure of the ductus venosus after birth, as did knockout mice for aryl hydrocarbon receptor interacting protein (AIP) and aryl hydrocarbon receptor nuclear translocator (ARNT). The resulting intrahepatic portosystemic shunts (IHPSS) are frequently diagnosed in specific dog breeds, such as the Irish wolfhound. We compared the expression of components of the AHR pathway in healthy Irish wolfhounds and dogs with IHPSS. To this end, we analyzed the mRNA expression in the liver of AHR,AIP, ARNT, and other genes involved in this pathway, namely, those for aryl hydrocarbon receptor nuclear translocator 2 (ARNT2), hypoxia inducible factor 1alpha (HIF1A), heat shock protein 90AA1 (HSP90AA1), cytochromes P450 (CYP1A1, CYP1A2, and CYP1B1), vascular endothelial growth factor A (VEGFA), nitric oxide synthesase 3 (NOS3), and endothelin (EDN1). The observed low expression of AHR mRNA in the Irish wolfhounds is in associated with a LINE-1 insertion in intron 2, for which these dogs were homozygous. Down regulation in Irish wolfhounds was observed for AIP, ARNT2, CYP1A2, CYP1B1 and HSP90AA1 expression, whereas the expression of HIF1A was increased. Immunohistochemistry revealed lower levels of AHR, HIF1A, and VEGFA protein in the nucleus and lower levels of ARNT and HSP90AA1 protein in the cytoplasm of the liver cells of Irish wolfhounds. The impaired expression of HSP90AA1 could trigger the observed differences in mRNA and protein levels and therefore explain the link between two very different functions of AHR: regulation of the closure of the ductus venosus and the response to toxins. 相似文献
266.
267.
Sandra Dunning Atta ur Rehman Marjolein H. Tiebosch Rebekka A. Hannivoort Floris W. Haijer Jannes Woudenberg Fiona A.J. van den Heuvel Manon Buist-Homan Klaas Nico Faber Han Moshage 《生物化学与生物物理学报:疾病的分子基础》2013,1832(12):2027-2034
BackgroundIn chronic liver disease, hepatic stellate cells (HSCs) are activated, highly proliferative and produce excessive amounts of extracellular matrix, leading to liver fibrosis. Elevated levels of toxic reactive oxygen species (ROS) produced during chronic liver injury have been implicated in this activation process. Therefore, activated hepatic stellate cells need to harbor highly effective anti-oxidants to protect against the toxic effects of ROS.AimTo investigate the protective mechanisms of activated HSCs against ROS-induced toxicity.MethodsCulture-activated rat HSCs were exposed to hydrogen peroxide. Necrosis and apoptosis were determined by Sytox Green or acridine orange staining, respectively. The hydrogen peroxide detoxifying enzymes catalase and glutathione-peroxidase (GPx) were inhibited using 3-amino-1,2,4-triazole and mercaptosuccinic acid, respectively. The anti-oxidant glutathione was depleted by L-buthionine-sulfoximine and repleted with the GSH-analogue GSH-monoethylester (GSH-MEE).ResultsUpon activation, HSCs increase their cellular glutathione content and GPx expression, while MnSOD (both at mRNA and protein level) and catalase (at the protein level, but not at the mRNA level) decreased. Hydrogen peroxide did not induce cell death in activated HSCs. Glutathione depletion increased the sensitivity of HSCs to hydrogen peroxide, resulting in 35% and 75% necrotic cells at 0.2 and 1 mmol/L hydrogen peroxide, respectively. The sensitizing effect was abolished by GSH-MEE. Inhibition of catalase or GPx significantly increased hydrogen peroxide-induced apoptosis, which was not reversed by GSH-MEE.ConclusionActivated HSCs have increased ROS-detoxifying capacity compared to quiescent HSCs. Glutathione levels increase during HSC activation and protect against ROS-induced necrosis, whereas hydrogen peroxide-detoxifying enzymes protect against apoptotic cell death. 相似文献
268.
269.
Residues surrounding and interacting with the heme proximal ligand are important for efficient catalysis by heme proteins. The nitric oxide synthases (NOSs) are thiolate-coordinated enzymes that catalyze the hydroxylation of l-Arg in the first of the two catalytic cycles needed to synthesize nitric oxide. In NOSs, the indole NH group of a conserved tryptophan [W56 of the bacterial NOS-like protein from Staphylococcus aureus (saNOS)] forms a hydrogen bond with the heme proximal cysteinate ligand. The purpose of this study was to determine the impact of increasing (W56F and W56Y variants) or decreasing (W56H variant) the electron density of the proximal cysteinate ligand on molecular oxygen (O(2)) activation using saNOS as a model. We show that the removal of the indole NH···S(-) bond for W56F and W56Y caused an increase in the electron density of the cysteinate. This was probed by the decrease of the midpoint reduction potential (E(1/2)) along with weakened σ-bonding and strengthened π-backbonding with distal ligands (CO and O(2)). On the other hand, the W56H variant showed stronger Fe-OO and Fe-CO bonds (strengthened σ-bonding) along with an elevated E(1/2), which is consistent with the formation of a strong NH···S(-) hydrogen bond from H56. We also show here that changing the electron density of the proximal thiolate controls its "push effect"; whereas the rates of both O(2) activation and autoxidation of the Fe(II)O(2) complex increase with the stronger push effect created by removing the indole NH···S(-) hydrogen bond (W56F and W56Y variants), the W56H variant showed an increased stability of the complex against autoxidation and a slower rate of O(2) activation. These results are discussed with regard to the roles played by the conserved tryptophan-cysteinate interaction in the first catalytic cycle of NOS. 相似文献
270.
Veit G Zwolanek D Eckes B Niland S Käpylä J Zweers MC Ishada-Yamamoto A Krieg T Heino J Eble JA Koch M 《The Journal of biological chemistry》2011,286(31):27804-27813
Cellular receptors for collagens belong to the family of β(1) integrins. In the epidermis, integrin α(2)β(1) is the only collagen-binding integrin present. Its expression is restricted to basal keratinocytes with uniform distribution on the cell surface of those cells. Although α(2)β(1) receptors localized at the basal surface interact with basement membrane proteins collagen IV and laminin 111 and 332, no interaction partners have been reported for these integrin molecules at the lateral and apical membranes of basal keratinocytes. Solid phase binding and surface plasmon resonance spectroscopy demonstrate that collagen XXIII, a member of the transmembrane collagens, directly interacts with integrin α(2)β(1) in an ion- and conformation-dependent manner. The two proteins co-localize on the surface of basal keratinocytes. Furthermore, collagen XXIII is sufficient to induce adhesion and spreading of keratinocytes, a process that is significantly reduced in the absence of functional integrin α(2)β(1). 相似文献