全文获取类型
收费全文 | 1556篇 |
免费 | 107篇 |
专业分类
1663篇 |
出版年
2023年 | 7篇 |
2022年 | 15篇 |
2021年 | 42篇 |
2020年 | 24篇 |
2019年 | 22篇 |
2018年 | 32篇 |
2017年 | 36篇 |
2016年 | 59篇 |
2015年 | 79篇 |
2014年 | 90篇 |
2013年 | 121篇 |
2012年 | 144篇 |
2011年 | 132篇 |
2010年 | 83篇 |
2009年 | 71篇 |
2008年 | 95篇 |
2007年 | 79篇 |
2006年 | 101篇 |
2005年 | 71篇 |
2004年 | 89篇 |
2003年 | 74篇 |
2002年 | 60篇 |
2001年 | 7篇 |
2000年 | 7篇 |
1999年 | 12篇 |
1998年 | 10篇 |
1997年 | 5篇 |
1996年 | 7篇 |
1995年 | 14篇 |
1994年 | 7篇 |
1993年 | 9篇 |
1992年 | 8篇 |
1991年 | 6篇 |
1990年 | 7篇 |
1989年 | 2篇 |
1987年 | 4篇 |
1985年 | 5篇 |
1984年 | 2篇 |
1983年 | 5篇 |
1982年 | 1篇 |
1980年 | 3篇 |
1979年 | 3篇 |
1978年 | 1篇 |
1977年 | 3篇 |
1975年 | 1篇 |
1974年 | 2篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1961年 | 1篇 |
1959年 | 1篇 |
排序方式: 共有1663条查询结果,搜索用时 10 毫秒
81.
Invasion history and demographic processes associated with rapid morphological changes in the Red‐whiskered bulbul established on tropical islands 下载免费PDF全文
Ariane Le Gros Philippe Clergeau Dario Zuccon Raphaël Cornette Blake Mathys Sarah Samadi 《Molecular ecology》2016,25(21):5359-5376
The Red‐whiskered bulbul is a very successful invasive bird species. Morphological differences have been reported among individuals inhabiting the humid and dry coasts of Reunion Island, in a 30‐year‐old population. This suggests a capacity for rapid local adaptation which could explain the general invasive success of this species. However, the origin and invasion history of this population is unknown. It is therefore not possible to establish with certainty the cause of these morphological differences. Here, we investigated the invasion history of populations of Red‐whiskered bulbul established on Reunion Island, Mauritius and Oahu (three geographically similar tropical islands) to assess the link between invasion history and morphological changes in these populations. We first assessed the source(s) of the invasive populations. We then compared the morphology of the individuals between the invasive and native populations and between the dry and humid coasts of invaded islands. Finally, we inferred the invasion history of the invasive populations to investigate the role of neutral processes (e.g. founder effect and drift) on morphology. We found that the invasive populations have a similar origin and that the morphology of the individuals in these populations has diverged in a similar way from the native range, suggesting a convergent adaptation to tropical islands. Like on Reunion, we found differences in morphology between the dry and humid coasts on Mauritius. These morphological differences can be explained by invasion history on Reunion but not on Mauritius. Both neutral evolution and adaptation thus shape the morphology of invasive Red‐whiskered bulbuls. 相似文献
82.
83.
Structural and functional differences between KRIT1A and KRIT1B isoforms: a framework for understanding CCM pathogenesis 总被引:1,自引:0,他引:1
Francalanci F Avolio M De Luca E Longo D Menchise V Guazzi P Sgrò F Marino M Goitre L Balzac F Trabalzini L Retta SF 《Experimental cell research》2009,315(2):285-2519
KRIT1 is a disease gene responsible for Cerebral Cavernous Malformations (CCM). It encodes for a protein containing distinct protein-protein interaction domains, including three NPXY/F motifs and a FERM domain. Previously, we isolated KRIT1B, an isoform characterized by the alternative splicing of the 15th coding exon and suspected to cause CCM when abnormally expressed.Combining homology modeling and docking methods of protein-structure and ligand binding prediction with the yeast two-hybrid assay of in vivo protein-protein interaction and cellular biology analyses we identified both structural and functional differences between KRIT1A and KRIT1B isoforms.We found that the 15th exon encodes for the distal β-sheet of the F3/PTB-like subdomain of KRIT1A FERM domain, demonstrating that KRIT1B is devoid of a functional PTB binding pocket. As major functional consequence, KRIT1B is unable to bind Rap1A, while the FERM domain of KRIT1A is even sufficient for this function. Furthermore, we found that a functional PTB subdomain enables the nucleocytoplasmic shuttling of KRIT1A, while its alteration confers a restricted cytoplasmic localization and a dominant negative role to KRIT1B. Importantly, we also demonstrated that KRIT1A, but not KRIT1B, may adopt a closed conformation through an intramolecular interaction involving the third NPXY/F motif at the N-terminus and the PTB subdomain of the FERM domain, and proposed a mechanism whereby an open/closed conformation switch regulates KRIT1A nuclear translocation and interaction with Rap1A in a mutually exclusive manner.As most mutations found in CCM patients affect the KRIT1 FERM domain, the new insights into the structure-function relationship of this domain may constitute a useful framework for understanding molecular mechanisms underlying CCM pathogenesis. 相似文献
84.
Ramirez DC Gomez-Mejiba SE Corbett JT Deterding LJ Tomer KB Mason RP 《The Biochemical journal》2009,417(1):341-353
The understanding of the mechanism, oxidant(s) involved and how and what protein radicals are produced during the reaction of wild-type SOD1 (Cu,Zn-superoxide dismutase) with H2O2 and their fate is incomplete, but a better understanding of the role of this reaction is needed. We have used immuno-spin trapping and MS analysis to study the protein oxidations driven by human (h) and bovine (b) SOD1 when reacting with H2O2 using HSA (human serum albumin) and mBH (mouse brain homogenate) as target models. In order to gain mechanistic information about this reaction, we considered both copper- and CO3(*-) (carbonate radical anion)-initiated protein oxidation. We chose experimental conditions that clearly separated SOD1-driven oxidation via CO(*-) from that initiated by copper released from the SOD1 active site. In the absence of (bi)carbonate, site-specific radical-mediated fragmentation is produced by SOD1 active-site copper. In the presence of (bi)carbonate and DTPA (diethylenetriaminepenta-acetic acid) (to suppress copper chemistry), CO(*-) produced distinct radical sites in both SOD1 and HSA, which caused protein aggregation without causing protein fragmentation. The CO(*-) produced by the reaction of hSOD1 with H2O2 also produced distinctive DMPO (5,5-dimethylpyrroline-N-oxide) nitrone adduct-positive protein bands in the mBH. Finally, we propose a biochemical mechanism to explain CO(*-) production from CO2, enhanced protein radical formation and protection by (bi)carbonate against H2O2-induced fragmentation of the SOD1 active site. Our present study is important for establishing experimental conditions for studying the molecular mechanism and targets of oxidation during the reverse reaction of SOD1 with H2O2; these results are the first step in analysing the critical targets of SOD1-driven oxidation during pathological processes such as neuroinflammation. 相似文献
85.
Brodehl A Hedde PN Dieding M Fatima A Walhorn V Gayda S Šarić T Klauke B Gummert J Anselmetti D Heilemann M Nienhaus GU Milting H 《The Journal of biological chemistry》2012,287(19):16047-16057
Mutations in the DES gene coding for the intermediate filament protein desmin may cause skeletal and cardiac myopathies, which are frequently characterized by cytoplasmic aggregates of desmin and associated proteins at the cellular level. By atomic force microscopy, we demonstrated filament formation defects of desmin mutants, associated with arrhythmogenic right ventricular cardiomyopathy. To understand the pathogenesis of this disease, it is essential to analyze desmin filament structures under conditions in which both healthy and mutant desmin are expressed at equimolar levels mimicking an in vivo situation. Here, we applied dual color photoactivation localization microscopy using photoactivatable fluorescent proteins genetically fused to desmin and characterized the heterozygous status in living cells lacking endogenous desmin. In addition, we applied fluorescence resonance energy transfer to unravel short distance structural patterns of desmin mutants in filaments. For the first time, we present consistent high resolution data on the structural effects of five heterozygous desmin mutations on filament formation in vitro and in living cells. Our results may contribute to the molecular understanding of the pathological filament formation defects of heterozygous DES mutations in cardiomyopathies. 相似文献
86.
Angela Smilansky Liron Dangoor Itay Nakdimon Danya Ben-Hail Dario Mizrachi Varda Shoshan-Barmatz 《The Journal of biological chemistry》2015,290(52):30670-30683
The voltage-dependent anion channel 1 (VDAC1), found in the mitochondrial outer membrane, forms the main interface between mitochondrial and cellular metabolisms, mediates the passage of a variety of molecules across the mitochondrial outer membrane, and is central to mitochondria-mediated apoptosis. VDAC1 is overexpressed in post-mortem brains of Alzheimer disease (AD) patients. The development and progress of AD are associated with mitochondrial dysfunction resulting from the cytotoxic effects of accumulated amyloid β (Aβ). In this study we demonstrate the involvement of VDAC1 and a VDAC1 N-terminal peptide (VDAC1-N-Ter) in Aβ cell penetration and cell death induction. Aβ directly interacted with VDAC1 and VDAC1-N-Ter, as monitored by VDAC1 channel conductance, surface plasmon resonance, and microscale thermophoresis. Preincubated Aβ interacted with bilayer-reconstituted VDAC1 and increased its conductance ∼2-fold. Incubation of cells with Aβ resulted in mitochondria-mediated apoptotic cell death. However, the presence of non-cell-penetrating VDAC1-N-Ter peptide prevented Aβ cellular entry and Aβ-induced mitochondria-mediated apoptosis. Likewise, silencing VDAC1 expression by specific siRNA prevented Aβ entry into the cytosol as well as Aβ-induced toxicity. Finally, the mode of Aβ-mediated action involves detachment of mitochondria-bound hexokinase, induction of VDAC1 oligomerization, and cytochrome c release, a sequence of events leading to apoptosis. As such, we suggest that Aβ-mediated toxicity involves mitochondrial and plasma membrane VDAC1, leading to mitochondrial dysfunction and apoptosis induction. The VDAC1-N-Ter peptide targeting Aβ cytotoxicity is thus a potential new therapeutic strategy for AD treatment. 相似文献
87.
Control of AMPK-related kinases by USP9X and atypical Lys(29)/Lys(33)-linked polyubiquitin chains 总被引:1,自引:0,他引:1
Al-Hakim AK Zagorska A Chapman L Deak M Peggie M Alessi DR 《The Biochemical journal》2008,411(2):249-260
AMPK (AMP-activated protein kinase)-related kinases regulate cell polarity as well as proliferation and are activated by the LKB1-tumour suppressor kinase. In the present study we demonstrate that the AMPK-related kinases, NUAK1 (AMPK-related kinase 5) and MARK4 (microtubule-affinity-regulating kinase 4), are polyubiquitinated in vivo and interact with the deubiquitinating enzyme USP9X (ubiquitin specific protease-9). Knockdown of USP9X increased polyubiquitination of NUAK1 and MARK4, whereas overexpression of USP9X inhibited ubiquitination. USP9X, catalysed the removal of polyubiquitin chains from wild-type NUAK1, but not from a non-USP9X-binding mutant. Topological analysis revealed that ubiquitin monomers attached to NUAK1 and MARK4 are linked by Lys(29) and/or Lys(33) rather than the more common Lys(48)/Lys(63). We find that AMPK and other AMPK-related kinases are also polyubiquitinated in cells. We identified non-USP9X-binding mutants of NUAK1 and MARK4 and find that these are hyper-ubiquitinated and not phosphorylated at their T-loop residue targeted by LKB1 when expressed in cells, suggesting that polyubiquitination may inhibit these enzymes. The results of the present study demonstrate that NUAK1 and MARK4 are substrates of USP9X and provide the first evidence that AMPK family kinases are regulated by unusual Lys(29)/Lys(33)-linked polyubiquitin chains. 相似文献
88.
Mirabelli D Chiusolo M Ferrante D Balzola F Merletti F Petroni ML 《Obesity (Silver Spring, Md.)》2008,16(8):1920-1925
Few large studies on Northern European or US populations reported on mortality of severely obese individuals (BMI > or = 40 kg/m(2)). We studied a historical cohort in Italy to compare its mortality with previous findings, to investigate its relationship with BMI in the >40 range, and to provide evidence useful for clinical decision-making on treatment. The cohort comprised 4,837 persons with a BMI > or =40 kg/m(2) and aged > or =18 at first consultation, referred to six centers for obesity treatment between 1975 and 1996. After exclusion of persons with missing personal identification data or those untraceable, 4,498 (972 men, 3,526 women) remained for analyses. We calculated standardized mortality ratios (SMRs) and carried out Cox proportional hazards modeling. General mortality (484 deaths: 153 men, 331 women) was in excess, with SMRs (95% confidence intervals) of 2.78 (2.36-3.26) for men and 2.10 (1.88-2.34) for women. Excess mortality (i) was observed in all BMI categories, except among women weighing 40-42.4 kg/m(2); (ii) increased with increasing BMI; (iii) increased less among persons recruited in recent calendar periods; (iv) was inversely related to age attained at follow-up; and (v) was due to cardiovascular and respiratory diseases and violent deaths but not malignant neoplasms. Excess mortality was similar to that observed in Northern European and US cohorts. Its steady increase with BMI levels > or =40 suggests that benefits proportional to weight reduction are expected and that even limited control may be beneficial. The smaller excess among persons recruited most recently might reflect better treatment. 相似文献
89.
Species traits explain variation in detectability of UK birds 总被引:1,自引:0,他引:1
Alison Johnston Stuart E. Newson Kate Risely Andy J. Musgrove Dario Massimino Stephen R. Baillie 《Bird Study》2013,60(3):340-350
Capsule Heterogeneous detectability amongst species may impact multi-species bird surveys and if not accounted for, may bias community level conclusions. Estimates of detectability were produced for 195 UK bird species, and detectability was significantly affected by bird size, diet and habitat specialization.Aims To estimate detectability and understand which species traits may impact detectability.Methods We estimated the detectability of 195 species of birds in the UK using distance sampling methods and examined the average detectability of genetically related groups. We tested the significance of species traits in describing variation in detectability, whilst controlling for phylogenetic relationships.Results Passeriformes had the lowest median detectability of 0.37 and Charadriiformes the highest median detectability of 0.65, of the seven largest orders considered. Species most associated with closed habitats such as woodland and urban areas had the lowest detectability. Smaller species had lower detectability than larger species.Conclusion Heterogeneity in species detectability could lead to biased conclusions, particularly when calculating multi-species indices such as species richness or diversity. Accounting for detectability will be most important in studies that cover a wide range of habitat types or a diverse spread of taxa. 相似文献
90.
Magdalena Witek Luca Pietro Casacci Francesca Barbero Dario Patricelli Marco Sala Simone Bossi Massimo Maffei Michal Woyciechowski Emilio Balletto Simona Bonelli 《Biological journal of the Linnean Society. Linnean Society of London》2013,109(3):699-709
Myrmica ant colonies host numerous insect species, including the larvae of Maculinea butterflies and Microdon myrmicae hoverflies. Little is known about the interspecific relationships among these social parasites and their host ants occurring in sympatric populations. We investigated communities of social parasites to assess the strategies allowing them to share the same pool of resources (i.e. Myrmica colonies). The present study was carried out at five sites inhabited by different social parasite communities, each comprising varying proportions of Maculinea teleius, Maculinea nausithous, Maculinea alcon, and Microdon myrmicae. We investigated their spatial distributions, host segregation, the degree of chemical similarity between social parasites and hosts, and temporal overlaps in colony resource exploitation. Spatial segregation among social parasites was found in two populations and it arises from microhabitat preferences and biological interactions. Local conditions can drive selection on one social parasite to use a Myrmica host species that is not exploited by other social parasites. Myrmica scabrinodis and Myrmica rubra nests infested by larvae of two social parasite species were found and the most common co‐occurrence was between Ma. teleius and Mi. myrmicae. The successful coexistence of these two species derives from their exploitation of the host colony resources at different times of the year. © 2013 The Linnean Society of London, Biological Journal of the Linnean Society, 2013, 109 , 699–709. 相似文献