全文获取类型
收费全文 | 413篇 |
免费 | 35篇 |
出版年
2023年 | 4篇 |
2022年 | 13篇 |
2021年 | 19篇 |
2020年 | 10篇 |
2019年 | 18篇 |
2018年 | 17篇 |
2017年 | 14篇 |
2016年 | 15篇 |
2015年 | 16篇 |
2014年 | 20篇 |
2013年 | 24篇 |
2012年 | 34篇 |
2011年 | 36篇 |
2010年 | 22篇 |
2009年 | 12篇 |
2008年 | 17篇 |
2007年 | 19篇 |
2006年 | 15篇 |
2005年 | 8篇 |
2004年 | 13篇 |
2003年 | 14篇 |
2002年 | 10篇 |
2001年 | 8篇 |
2000年 | 4篇 |
1999年 | 6篇 |
1998年 | 4篇 |
1997年 | 2篇 |
1992年 | 3篇 |
1991年 | 4篇 |
1990年 | 3篇 |
1989年 | 2篇 |
1987年 | 1篇 |
1986年 | 5篇 |
1985年 | 1篇 |
1984年 | 4篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1981年 | 3篇 |
1978年 | 3篇 |
1976年 | 3篇 |
1972年 | 2篇 |
1968年 | 2篇 |
1953年 | 1篇 |
1944年 | 1篇 |
1933年 | 1篇 |
1928年 | 2篇 |
1927年 | 2篇 |
1923年 | 1篇 |
1920年 | 1篇 |
1909年 | 1篇 |
排序方式: 共有448条查询结果,搜索用时 15 毫秒
71.
Satyamitra M Lombardini E Graves J Mullaney C Ney P Hunter J Johnson K Tamburini P Wang Y Springhorn JP Srinivasan V 《Radiation research》2011,175(6):746-758
Thrombopoietin (TPO) receptor agonists lacking sequence homology to TPO were designed by grafting a known peptide sequence into the hinge and/or kappa constant regions of a human anti-anthrax antibody. Some of these proteins were equipotent to TPO in stimulating cMpl-r activity in vitro and in increasing platelet levels in vivo. ALXN4100TPO (4100TPO), the best agonist in this series with a K(d) of 30 nM for cMpl-r, exhibited potent activity as a radiation countermeasure in CD2F1 mice exposed to lethal total-body radiation from a cobalt-60 γ-ray source. 4100TPO (2 mg/kg, s.c.) administered once either 24 h before or 6 h after TBI showed superior protection to five daily doses given before or after TBI. Prophylactic administration (69 to 94% survival) was superior to therapeutic schedules (60% survival). 4100TPO conferred a significant survival benefit (P < 0.01) when administered 4 days before or even 12 h after exposure and across a dose range of 0.1 to 8 mg/kg. The dose reduction factors (DRFs) with a single dose of 1 mg/kg 4100TPO 24 h before or 12 h after TBI were 1.32 and 1.11, respectively (P < 0.0001). Furthermore, 4100TPO increased bone marrow cellularity and megakaryocytic development and accelerated multi-lineage hematopoietic recovery in irradiated mice, demonstrating the potential of 4100TPO as both a protector and a mitigator in the event of a radiological incident. 相似文献
72.
The osmotic activation of sigma B (σ(B)) in Listeria monocytogenes was studied by monitoring expression of four known σ(B)-dependent genes, opuCA, lmo2230, lmo2085, and sigB. Activation was found to be rapid, transient, and proportional to the magnitude of the osmotic stress applied, features that underpin the adaptability of this pathogen. 相似文献
73.
Mallikaratchy PR Ruggiero A Gardner JR Kuryavyi V Maguire WF Heaney ML McDevitt MR Patel DJ Scheinberg DA 《Nucleic acids research》2011,39(6):2458-2469
Long-term survival still eludes most patients with leukemia and non-Hodgkin's lymphoma. No approved therapies target the hallmark of the B cell, its mIgM, also known as the B-cell receptor (BCR). Aptamers are small oligonucleotides that can specifically bind to a wide range of target molecules and offer some advantages over antibodies as therapeutic agents. Here, we report the rational engineering of aptamer TD05 into multimeric forms reactive with the BCR that may be useful in biomedical applications. Systematic truncation of TD05 coupled with modification with locked nucleic acids (LNA) increased conformational stability and nuclease resistance. Trimeric and tetrameric versions with optimized polyethyleneglycol (PEG) linker lengths exhibited high avidity at physiological temperatures both in vitro and in vivo. Competition and protease studies showed that the multimeric, optimized aptamer bound to membrane-associated human mIgM, but not with soluble IgM in plasma, allowing the possibility of targeting leukemias and lymphomas in vivo. The B-cell specificity of the multivalent aptamer was confirmed on lymphoma cell lines and fresh clinical leukemia samples. The chemically engineered aptamers, with significantly improved kinetic and biochemical features, unique specificity and desirable pharmacological properties, may be useful in biomedical applications. 相似文献
74.
Evonne Low Sean R. Mathieson Nathan J. Stevenson Vicki Livingstone C. Anthony Ryan Conor O. Bogue Janet M. Rennie Geraldine B. Boylan 《PloS one》2014,9(7)
Background
Stroke is the second most common cause of seizures in term neonates and is associated with abnormal long-term neurodevelopmental outcome in some cases.Objective
To aid diagnosis earlier in the postnatal period, our aim was to describe the characteristic EEG patterns in term neonates with perinatal arterial ischaemic stroke (PAIS) seizures.Design
Retrospective observational study.Patients
Neonates >37 weeks born between 2003 and 2011 in two hospitals.Method
Continuous multichannel video-EEG was used to analyze the background patterns and characteristics of seizures. Each EEG was assessed for continuity, symmetry, characteristic features and sleep cycling; morphology of electrographic seizures was also examined. Each seizure was categorized as electrographic-only or electroclinical; the percentage of seizure events for each seizure type was also summarized.Results
Nine neonates with PAIS seizures and EEG monitoring were identified. While EEG continuity was present in all cases, the background pattern showed suppression over the infarcted side; this was quite marked (>50% amplitude reduction) when the lesion was large. Characteristic unilateral bursts of theta activity with sharp or spike waves intermixed were seen in all cases. Sleep cycling was generally present but was more disturbed over the infarcted side. Seizures demonstrated a characteristic pattern; focal sharp waves/spike-polyspikes were seen at frequency of 1–2 Hz and phase reversal over the central region was common. Electrographic-only seizure events were more frequent compared to electroclinical seizure events (78 vs 22%).Conclusions
Focal electrographic and electroclinical seizures with ipsilateral suppression of the background activity and focal sharp waves are strong indicators of PAIS. Approximately 80% of seizure events were the result of clinically unsuspected seizures in neonates with PAIS. Prolonged and continuous multichannel video-EEG monitoring is advocated for adequate seizure surveillance. 相似文献75.
Jason V. Rogers Conor McMahon Anastasia Baryshnikova Frederick M. Hughson Mark D. Rose 《Molecular biology of the cell》2014,25(21):3401-3412
The peripheral endoplasmic reticulum (ER) network is dynamically maintained by homotypic (ER–ER) fusion. In Saccharomyces cerevisiae, the dynamin-like GTPase Sey1p can mediate ER–ER fusion, but sey1Δ cells have no growth defect and only slightly perturbed ER structure. Recent work suggested that ER-localized soluble N-ethylmaleimide–sensitive factor attachment protein receptors (SNAREs) mediate a Sey1p-independent ER–ER fusion pathway. However, an alternative explanation—that the observed phenotypes arose from perturbed vesicle trafficking—could not be ruled out. In this study, we used candidate and synthetic genetic array (SGA) approaches to more fully characterize SNARE-mediated ER–ER fusion. We found that Dsl1 complex mutations in sey1Δ cells cause strong synthetic growth and ER structure defects and delayed ER–ER fusion in vivo, additionally implicating the Dsl1 complex in SNARE-mediated ER–ER fusion. In contrast, cytosolic coat protein I (COPI) vesicle coat mutations in sey1Δ cells caused no synthetic defects, excluding perturbed retrograde trafficking as a cause for the previously observed synthetic defects. Finally, deleting the reticulons that help maintain ER architecture in cells disrupted for both ER–ER fusion pathways caused almost complete inviability. We conclude that the ER SNAREs and the Dsl1 complex directly mediate Sey1p-independent ER–ER fusion and that, in the absence of both pathways, cell viability depends upon membrane curvature–promoting reticulons. 相似文献
76.
77.
Lawrence R. Heaney Joseph S. Walsh Jr A. Townsend Peterson 《Journal of Biogeography》2005,32(2):229-247
Aim To test hypotheses that: (1) late Pleistocene low sea‐level shorelines (rather than current shorelines) define patterns of genetic variation among mammals on oceanic Philippine islands; (2) species‐specific ecological attributes, especially forest fidelity and vagility, determine the extent to which common genetic patterns are exhibited among a set of species; (3) populations show reduced within‐population variation on small, isolated oceanic islands; (4) populations tend to be most highly differentiated on small, isolated islands; and (5) to assess the extent to which patterns of genetic differentiation among multiple species are determined by interactions of ecological traits and geological/geographic conditions. Location The Philippine Islands, a large group of oceanic islands in Southeast (SE) Asia with unusually high levels of endemism among mammals. Methods Starch‐gel electrophoresis of protein allozymes of six species of small fruit bats (Chiroptera, Pteropodidae) and one rodent (Rodentia, Muridae). Results Genetic distances between populations within all species are not correlated with distances between present‐day shorelines, but are positively correlated with distances between shorelines during the last Pleistocene period of low sea level; relatively little intraspecific variation was found within these ‘Pleistocene islands’. Island area and isolation of oceanic populations have only slight effects on standing genetic variation within populations, but populations on some isolated islands have heightened levels of genetic differentiation, and reduced levels of gene flow, relative to other islands. Species associated with disturbed habitat (all of which fly readily across open habitats) show more genetic variation within populations than species associated with primary rain forest (all of which avoid flying out from beneath forest canopy). Species associated with disturbed habitats, which tend to be widely distributed in SE Asia, also show higher rates of gene flow and less differentiation between populations than species associated with rain forest, which tend to be Philippine endemic species. One rain forest bat has levels of gene flow and heterozygosity similar to the forest‐living rodent in our study. Main conclusions The maximum limits of Philippine islands that were reached during Pleistocene periods of low sea level define areas of relative genetic homogeneity, whereas even narrow sea channels between adjacent but permanently isolated oceanic islands are associated with most genetic variation within the species. Moreover, the distance between ‘Pleistocene islands’ is correlated with the extent of genetic distances within species. The structure of genetic variation is strongly influenced by the ecology of the species, predominantly as a result of their varying levels of vagility and ability to tolerate open (non‐forested) habitat. Readily available information on ecology (habitat association and vagility) and geological circumstances (presence or absence of Pleistocene land‐bridges between islands, and distance between oceanic islands during periods of low sea level) are combined to produce a simple predictive model of likely patterns of genetic differentiation (and hence speciation) among these mammals, and probably among other organisms, in oceanic archipelagos. 相似文献
78.
C. A. Mills S. I. Heaney C. Butterwick J. E. Corry J.M. Elliott 《Journal of fish biology》1990,37(SA):167-174
All English populations of Arctic charr, Salvelinus alpinus (L.), are found in the Lake District (northwest England). There are at least four races of charr in Windermere, the largest lake in England; the North and South basins of the lake each contain two distinct races that spawn in autumn and spring respectively. The spring spawners in both basins probably represent less than 15% of the total population in the lake.
Changes in the population density of charr in the lake are described briefly and examined in relation to the trophic status of the lake. Other factors that could possibly affect the charr population are reviewed, especially the influence of climate change. 相似文献
Changes in the population density of charr in the lake are described briefly and examined in relation to the trophic status of the lake. Other factors that could possibly affect the charr population are reviewed, especially the influence of climate change. 相似文献
79.
David McAteer Ian J. Godwin Zheng Ling Andrew Harvey Lily He Conor S. Boland Victor Vega‐Mayoral Beata Szydłowska Aurélie A. Rovetta Claudia Backes John B. Boland Xin Chen Michael E. G. Lyons Jonathan N. Coleman 《Liver Transplantation》2018,8(15)
Identifying cheap, yet effective, oxygen evolution catalysts is critical to the advancement of water splitting. Using liquid exfoliated Co(OH)2 nanosheets as a model system, a simple procedure is developed to maximize the activity of any oxygen evolution reaction nanocatalyst. First the nanosheet edges are confirmed as the active areas by analyzing the catalytic activity as a function of nanosheet size. This allows the authors to select the smallest nanosheets (length ≈50 nm) as the best performing catalysts. While the number of active sites per unit electrode area can be increased via the electrode thickness, this is found to be impossible beyond ≈10 µm due to mechanical instabilities. However, adding carbon nanotubes increases both toughness and conductivity significantly. These enhancements mean that composite electrodes consisting of small Co(OH)2 nanosheets and 10 wt% nanotubes can be made into freestanding films with thickness of up to 120 µm with no apparent electrical limitations. The presence of diffusion limitations results in an optimum electrode thickness of 70 µm, yielding a current density of 50 mA cm?2 at an overpotential of 235 mV, close to the state of the art in the field. Applying this procedure to a high‐performance catalyst such as NiFeOx should significantly surpass the state of the art. 相似文献
80.
John J. Ferrie Conor M. Haney Jimin Yoon Buyan Pan Yi-Chih Lin Zahra Fakhraai Elizabeth Rhoades Abhinav Nath E. James Petersson 《Biophysical journal》2018,114(1):53-64
We describe a strategy for experimentally-constraining computational simulations of intrinsically disordered proteins (IDPs), using α-synuclein, an IDP with a central role in Parkinson’s disease pathology, as an example. Previously, data from single-molecule Förster Resonance Energy Transfer (FRET) experiments have been effectively utilized to generate experimentally constrained computational models of IDPs. However, the fluorophores required for single-molecule FRET experiments are not amenable to the study of short-range (<30 Å) interactions. Using ensemble FRET measurements allows one to acquire data from probes with multiple distance ranges, which can be used to constrain Monte Carlo simulations in PyRosetta. To appropriately employ ensemble FRET data as constraints, we optimized the shape and weight of constraining potentials to afford ensembles of structures that are consistent with experimental data. We also used this approach to examine the structure of α-synuclein in the presence of the compacting osmolyte trimethylamine-N-oxide. Despite significant compaction imparted by 2 M trimethylamine-N-oxide, the underlying ensemble of α-synuclein remains largely disordered and capable of aggregation, also in agreement with experimental data. These proof-of-concept experiments demonstrate that our modeling protocol enables one to efficiently generate experimentally constrained models of IDPs that incorporate atomic-scale detail, allowing one to study an IDP under a variety of conditions. 相似文献