全文获取类型
收费全文 | 271篇 |
免费 | 19篇 |
国内免费 | 3篇 |
专业分类
293篇 |
出版年
2022年 | 3篇 |
2021年 | 8篇 |
2020年 | 3篇 |
2019年 | 1篇 |
2018年 | 4篇 |
2017年 | 3篇 |
2016年 | 7篇 |
2015年 | 19篇 |
2014年 | 10篇 |
2013年 | 22篇 |
2012年 | 21篇 |
2011年 | 19篇 |
2010年 | 14篇 |
2009年 | 10篇 |
2008年 | 10篇 |
2007年 | 16篇 |
2006年 | 9篇 |
2005年 | 10篇 |
2004年 | 11篇 |
2003年 | 7篇 |
2002年 | 7篇 |
2001年 | 1篇 |
2000年 | 4篇 |
1999年 | 5篇 |
1998年 | 2篇 |
1997年 | 4篇 |
1996年 | 4篇 |
1995年 | 7篇 |
1994年 | 1篇 |
1992年 | 2篇 |
1991年 | 1篇 |
1990年 | 5篇 |
1989年 | 5篇 |
1988年 | 2篇 |
1987年 | 3篇 |
1986年 | 6篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1982年 | 6篇 |
1978年 | 2篇 |
1977年 | 4篇 |
1976年 | 2篇 |
1974年 | 1篇 |
1973年 | 2篇 |
1970年 | 1篇 |
1969年 | 1篇 |
1968年 | 1篇 |
1941年 | 1篇 |
排序方式: 共有293条查询结果,搜索用时 15 毫秒
51.
In this work, we describe the synthesis and characterization of a novel glycosylated hemoglobin (Hb) with high oxygen affinity as a potential Hb-based oxygen carrier. Site-selective glycosylation of bovine Hb was achieved by conjugating a lactose derivative to Cys 93 on the beta subunit of Hb. LC-MS analysis indicates that the reaction was quantitative, with no unmodified Hb present in the reaction product. The glycosylation site was identified by chymotrypsin digestion of the glycosylated bovine Hb followed with LC-MS/MS and from the X-ray crystal structure of the glycosylated Hb. The chemical conjugation of the lactose derivative at Cys beta93 yields an oxygen carrier with a high oxygen affinity (P(50) of 4.94 mmHg) and low cooperativity coefficient (n) of 1.20. Asymmetric flow field-flow fractionation (AFFFF) coupled with multiangle static light scattering (MASLS) was used to measure the absolute molecular weight of the glycosylated Hb. AFFFF-MASLS analysis indicates that glycosylation of Hb significantly altered the alpha(2)beta(2)-alphabeta equilibrium compared to native Hb. Subsequent X-ray analysis of the glycosylated Hb crystal showed that the covalently linked lactose derivative is sandwiched between the beta(1) and alpha(2) (and hence by symmetry the beta(2) and alpha(1)) subunits of the tetramer, and the interaction between the saccharide and amino acid residues located at the interface is apparently stabilized by hydrogen bonding interactions. The resultant structural analysis of the glycosylated Hb helps to explain the shift in the alpha(2)beta(2)-alphabeta equilibrium in terms of the hydrogen bonding interactions at the beta(1)alpha(2)/beta(2)alpha(1) interface. Taken together, all of these results indicate that it is feasible to site-specifically glycosylate Hb. This work has great potential in developing an oxygen carrier with defined chemistry that can target oxygen delivery to low pO(2) tissues and organs. 相似文献
52.
53.
Miriam H. P. van Lieshout Adam A. Anas Sandrine Florquin Baidong Hou Cornelis van't Veer Alex F. de Vos Tom van der Poll 《PLoS pathogens》2014,10(9)
Klebsiella pneumoniae is an important cause of sepsis. The common Toll-like receptor adapter myeloid differentiation primary response gene (MyD)88 is crucial for host defense against Klebsiella. Here we investigated the role of MyD88 in myeloid and endothelial cells during Klebsiella pneumosepsis. Mice deficient for MyD88 in myeloid (LysM-Myd88−/−) and myeloid plus endothelial (Tie2-Myd88−/−) cells showed enhanced lethality and bacterial growth. Tie2-Myd88−/− mice reconstituted with control bone marrow, representing mice with a selective MyD88 deficiency in endothelial cells, showed an unremarkable antibacterial defense. Myeloid or endothelial cell MyD88 deficiency did not impact on lung pathology or distant organ injury during late stage sepsis, while LysM-Myd88−/− mice demonstrated a strongly attenuated inflammatory response in the airways early after infection. These data suggest that myeloid but not endothelial MyD88 is important for host defense during gram-negative pneumonia derived sepsis. 相似文献
54.
Renae K. Barr Giuseppe Verdile Linda K. Wijaya Michael Morici Kevin Taddei Veer B. Gupta Steve Pedrini Liang Jin Joseph A. Nicolazzo Erin Knock Paul E. Fraser Ralph N. Martins 《The Journal of biological chemistry》2016,291(2):547-559
Although the formation of β-amyloid (Aβ) deposits in the brain is a hallmark of Alzheimer disease (AD), the soluble oligomers rather than the mature amyloid fibrils most likely contribute to Aβ toxicity and neurodegeneration. Thus, the discovery of agents targeting soluble Aβ oligomers is highly desirable for early diagnosis prior to the manifestation of a clinical AD phenotype and also more effective therapies. We have previously reported that a novel 15-amino acid peptide (15-mer), isolated via phage display screening, targeted Aβ and attenuated its neurotoxicity (Taddei, K., Laws, S. M., Verdile, G., Munns, S., D''Costa, K., Harvey, A. R., Martins, I. J., Hill, F., Levy, E., Shaw, J. E., and Martins, R. N. (2010) Neurobiol. Aging 31, 203–214). The aim of the current study was to generate and biochemically characterize analogues of this peptide with improved stability and therapeutic potential. We demonstrated that a stable analogue of the 15-amino acid peptide (15M S.A.) retained the activity and potency of the parent peptide and demonstrated improved proteolytic resistance in vitro (stable to t = 300 min, c.f. t = 30 min for the parent peptide). This candidate reduced the formation of soluble Aβ42 oligomers, with the concurrent generation of non-toxic, insoluble aggregates measuring up to 25–30 nm diameter as determined by atomic force microscopy. The 15M S.A. candidate directly interacted with oligomeric Aβ42, as shown by coimmunoprecipitation and surface plasmon resonance/Biacore analysis, with an affinity in the low micromolar range. Furthermore, this peptide bound fibrillar Aβ42 and also stained plaques ex vivo in brain tissue from AD model mice. Given its multifaceted ability to target monomeric and aggregated Aβ42 species, this candidate holds promise for novel preclinical AD imaging and therapeutic strategies. 相似文献
55.
Veer. P. Bhavanandan Dwijendra Gupta Joseph Woitach Xiaoxuan Guo Weiping Jiang 《Bioscience reports》1999,19(3):209-217
Secreted epithelial mucins are large macromolecules which exhibit extreme polydispersity, the molecular basis of which is not fully understood. We have obtained partial sequences of two genes (BSM1 and BSM2) coding for two distinct molecules. This is the first time that such closely-related genes have been identified for any mucin from an animal. We propose that a combination of multiple homologous genes, alternative splicing, differential glycosylation, and additional post-translational processing all contribute to the extreme polydispersity of mucins. The multiple domain structure and non-identical tandem repeats are also very important for the generation of the saccharide diversities of mucins. 相似文献
56.
Saba Naz Shruti Dabral Sathya Narayanan Nagarajan Divya Arora Lakshya Veer Singh Pradeep Kumar Yogendra Singh Dhiraj Kumar Umesh Varshney Vinay Kumar Nandicoori 《PLoS pathogens》2021,17(3)
Tuberculosis caused by Mycobacterium tuberculosis (Mtb) is a significant public health concern, exacerbated by the emergence of drug-resistant TB. To combat the host’s dynamic environment, Mtb encodes multiple DNA repair enzymes that play a critical role in maintaining genomic integrity. Mtb possesses a GC-rich genome, rendering it highly susceptible to cytosine deaminations, resulting in the occurrence of uracils in the DNA. UDGs encoded by ung and udgB initiate the repair; hence we investigated the biological impact of deleting UDGs in the adaptation of pathogen. We generated gene replacement mutants of uracil DNA glycosylases, individually (RvΔung, RvΔudgB) or together (RvΔdKO). The double KO mutant, RvΔdKO exhibited remarkably higher spontaneous mutation rate, in the presence of antibiotics. Interestingly, RvΔdKO showed higher survival rates in guinea pigs and accumulated large number of SNPs as revealed by whole-genome sequence analysis. Competition assays revealed the superior fitness of RvΔdKO over Rv, both in ex vivo and in vivo conditions. We propose that compromised DNA repair results in the accumulation of mutations, and a subset of these drives adaptation in the host. Importantly, this property allowed us to utilize RvΔdKO for the facile identification of drug targets. 相似文献
57.
A. J. W. M. de Veer N. Bennaghmouch W. J. M. Dewilde J. M. ten Berg 《Netherlands heart journal》2021,29(3):135
BackgroundAntithrombotic treatment choices are complicated when patients have both atrial fibrillation (AF) and acute coronary syndrome and/or undergo percutaneous coronary intervention (PCI). In this study, we aimed to gain insight into antithrombotic management strategies in daily clinical practice.MethodsWe invited interventional cardiologists to complete the WOEST (What is the Optimal antiplatElet & Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary StenTing) survey 2018. In this questionnaire, we presented a patient with a non-ST-elevation myocardial infarction (NSTEMI) and an elective PCI case.ResultsThe results were based on 118 completed questionnaires (response rate 69.4%). In the case of the AF patient with NSTEMI, most cardiologists indicated they would initiate dual antiplatelet therapy (acetylsalicylic acid and clopidogrel) and continue non-vitamin K antagonist oral anticoagulant (NOAC) therapy at admission and during coronary angiography/PCI. At discharge, 70.3% would prescribe triple antithrombotic therapy (oral anticoagulation, acetylsalicylic acid and clopidogrel), mostly for 1 month. One year after NSTEMI, 83.1% would cancel the antiplatelet therapy and prescribe NOAC monotherapy. For the AF patient undergoing elective PCI, 51.7% would start dual antiplatelet therapy prior to the procedure and 52.5% would discontinue NOAC therapy prior to the PCI. At discharge, 55.1% would start triple antithrombotic therapy. Furthermore, 25.4% responded they routinely prescribe a reduced dose of NOAC after discharge. One year after PCI, 89.0% would continue NOAC monotherapy.ConclusionThe WOEST survey demonstrated heterogeneity in antithrombotic management strategies among interventional cardiologists. This observed variety mirrors the heterogeneity of the many guidelines and consensus documents. Further research is needed to guide patient-tailored medicine for AF patients undergoing PCI.Electronic supplementary materialThe online version of this article (10.1007/s12471-020-01500-3) contains supplementary material, which is available to authorized users. 相似文献
58.
Margarida Gama Carvalho Claúdia Moreira Joana F. M. F. Cardoso Geert-Jan A. Brummer Piet van Gaever Henk W. van der Veer 《Marine Biology Research》2017,13(7):764-773
The shanny Lipophrys pholis is an intertidal fish commonly found in Portuguese coastal waters. Spawning takes place from early autumn to mid spring, after which demersal eggs hatch and larvae disperse along the coast. Two to three months later, young juveniles return to the tide pools to settle. However, information on fish movement, habitat connectivity and population structure is scarce for this species. One hundred and twenty early juveniles (16–35?mm) were collected in April 2014 from six rocky beaches along the western and south Portuguese coasts (Agudela, Cabo do Mundo, Boa Nova, Peniche, Sines and Olhos de Água). δ18O and δ13C were determined by isotope-ratio mass spectrometry. Data were analysed to determine whether isotopic signatures could be used to assess the degree of separation between individuals collected from different locations. Mean δ13C and δ18O values ranged from ?0.02‰ to 1.14‰ and ?7.77‰ to ?6.62‰, respectively. Both seawater temperature and salinity caused differences in otolith δ18O among the four main sampling areas. The variation among areas in δ13C was most likely related to slight differences in the diet, growth and metabolism of fish. The distinct isotopic signatures, at least for the northern and central areas, suggested low levels of connectivity across large spatial scales during the juvenile stage. Furthermore, similar isotopic signatures within the same area indicated some degree of larval oceanic retention at short spatial scales. This study suggests that stable isotope records in otoliths could provide information about the home residency, movements and habitat connectivity of intertidal fishes. 相似文献
59.
Britas Klemens Eriksson Tjisse van der Heide Johan van de Koppel Theunis Piersma Henk W. van der Veer Han Olff 《Ecosystems》2010,13(5):752-764
Shallow soft-sediment systems are mostly dominated by species that, by strongly affecting sediment dynamics, modify their
local environment. Such ecosystem engineering species can have either sediment-stabilizing or sediment-destabilizing effects
on tidal flats. They interplay with abiotic forcing conditions (wind, tide, nutrient inputs) in driving the community structure
and generating spatial heterogeneity, determining the composition of different communities of associated species, and thereby
affecting the channelling of energy through different compartments in the food web. This suggests that, depending on local
species composition, tidal flats may have conspicuously different geomorphology and biological functions under similar external
conditions. Here we use a historical reconstruction of benthic production in the Wadden Sea to construct a framework for the
relationships between human impacts, ecosystem engineering and sediment dynamics. We propose that increased sediment disturbances
by human exploitation interfere with biological controls of sediment dynamics, and thereby have shifted the dominant compartments
of both primary and secondary production in the Wadden Sea, transforming the intertidal from an internally regulated and spatially
heterogeneous, to an externally regulated and spatially homogenous system. This framework contributes to the general understanding
of the interaction between biological and environmental control of ecosystem functioning, and suggests a general framework
for predicting effects of human impacts on soft-bottom ecosystems. 相似文献
60.