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121.
New germline mutations in the human retinoblastoma gene are known to arise preferentially on paternally derived chromosomes,
but the magnitude of that bias has not been measured. We evaluated 49 cases with a new germline mutation and found that in
40 cases (82%) the mutation arose on the paternally derived allele. We also evaluated 48 cases likely to have a somatic initial
mutation; in this group the initial mutation arose on paternal or maternal chromosomes with approximately equal frequency.
There was no statistically significant difference in the average age of fathers of children with new paternal germline mutations
from the average age of fathers of children with new maternal germline mutations or somatic initial mutations. Combining the
data with that from previous reports from other groups, the proportion of new germline mutations arising on a paternally derived
allele is 85% (based on 72 cases; 95% confidence interval = 76–93%). This number can be useful in the genetic counseling of
some families with retinoblastoma.
Received: 18 December 1996 / Accepted: 30 April 1997 相似文献
122.
Active site alanine mutations convert deubiquitinases into high‐affinity ubiquitin‐binding proteins
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Marie E Morrow Michael T Morgan Marcello Clerici Katerina Growkova Ming Yan David Komander Titia K Sixma Michal Simicek Cynthia Wolberger 《EMBO reports》2018,19(10)
A common strategy for exploring the biological roles of deubiquitinating enzymes (DUBs) in different pathways is to study the effects of replacing the wild‐type DUB with a catalytically inactive mutant in cells. We report here that a commonly studied DUB mutation, in which the catalytic cysteine is replaced with alanine, can dramatically increase the affinity of some DUBs for ubiquitin. Overexpression of these tight‐binding mutants thus has the potential to sequester cellular pools of monoubiquitin and ubiquitin chains. As a result, cells expressing these mutants may display unpredictable dominant negative physiological effects that are not related to loss of DUB activity. The structure of the SAGA DUB module bound to free ubiquitin reveals the structural basis for the 30‐fold higher affinity of Ubp8C146A for ubiquitin. We show that an alternative option, substituting the active site cysteine with arginine, can inactivate DUBs while also decreasing the affinity for ubiquitin. 相似文献
123.
Mark A. Seefeld Hong Lin Joerg Holenz Dave Downie Brian Donovan Tingting Fu Kishore Pasikanti Wei Zhen Matthew Cato Khuram W. Chaudhary Pat Brady Tania Bakshi Dwight Morrow Sridharan Rajagopal Swapan Kumar Samanta Naveena Madhyastha Bharathi Mohan Kuppusamy Robert W. Dougherty Yasuji Matsuoka 《Bioorganic & medicinal chemistry letters》2018,28(23-24):3793-3797
Neuronal voltage-gated potassium channels, KV7s, are the molecular mediators of the M current and regulate membrane excitability in the central and peripheral neuronal systems. Herein, we report novel small molecule KV7 openers that demonstrate anti-seizure activities in electroshock and pentylenetetrazol-induced seizure models without influencing Rotarod readouts in mice. The anti-seizure activity was determined to be proportional to the unbound concentration in the brain. KV7 channels are also expressed in the bladder smooth muscle (detrusor) and activation of these channels may cause localized undesired effects. Therefore, the impact of individual KV7 isoforms was investigated in human detrusor tissue using a panel of KV7 openers with distinct activity profiles among KV7 isoforms. KCNQ4 and KCNQ5 mRNA were highly expressed in detrusor tissue, yet a compound that has significantly reduced activity on homomeric KV7.4 did not reduce detrusor contraction. This may suggest that the homomeric KV7.4 channel plays a less significant role in bladder contraction and further investigation is needed. 相似文献
124.
Reduction of the partial pressure of carbon dioxide in the arterial blood by mechanical hyperventilation (Pco2 25-30 mm Hg; Po2 100-150 mm Hg) may be beneficial in cases of severe head injury. To evaluate its efficacy and establish prognostic guidelines intracranial pressure, radiocirculograms, and cerebrospinal fluid (C.S.F.) lactate levels were studied in 31 patients. In survivors intracranial pressure fell and cerebral blood flow improved with treatment. A C.S.F. lactate greater than 55 mg/100 ml was associated with a poor prognosis. Selection of patients was based on clinical judgement, and adults with signs of extensive brain damage were excluded. The importance of an adequate airway and resuscitation is stressed before a final decision is made. The object of treatment is to improve the quality of survival and the criteria measured may aid in the distinction between patients with a potential for good recovery and those capable only of a vegetative existence. Many associated factors as well as hypocapnia reduce intracranial pressure, and these are discussed. We believe that hyperventilation may improve some head injuries, and further study is indicated. 相似文献
125.
The T4 gene 32 protein, which binds to single-stranded but not duplex DNA, forms a specifically located denaturation loop in covalently closed circular simian virus 40 (SV40) DNA. Cleavage of the SV40 DNA-gene 32 protein complex with a restriction endonuclease from Hemophilus parainfluenzae shows the loop center to be at 0.46 on the SV40 DNA map. This is within one of the regions of SV40 DNA cleaved preferentially by the single-strand-specific nuclease S(1). 相似文献
126.
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128.
In the present study, quids from La Cueva de los Muertos Chiquitos (CMC) were subjected to ELISA tests for 2 protozoan parasites, Toxoplasma gondii (n=45) and Trypanosoma cruzi (n=43). The people who occupied CMC, the Loma San Gabriel, lived throughout much of present-day Durango and Zacatecas in Mexico. The known pathoecology of these people puts them into at-risk categories for the transmission of T. gondii and T. cruzi. Human antibodies created in response to these 2 parasites can be detected in modern saliva using ELISA kits intended for use with human serum. For these reasons, quids were reconstituted and subjected to ELISA testing. All test wells yielded negative results. These results could be a factor of improper methods because there is no precedence for this work in the existing literature. The results could equally be a simple matter of parasite absence among those people who occupied CMC. A final consideration is the taphonomy of human antibodies and whether or not ELISA is a sufficient method for recovering antibodies from archaeological contexts. An additional ELISA test targeting secretory IgA (sIgA) was conducted to further examine the failure to detect parasite-induced antibodies from quids. Herein, the methods used for quid preparation and ELISA procedures are described so that they can be further developed by future researchers. The results are discussed in light of the potential future of quid analysis. 相似文献
129.
Tsan Liu Arnold Stern L. Jackson Roberts Jason D. Morrow MD 《Journal of biomedical science》1999,6(4):226-235
The isoprostanes (IsoPs) are a unique series of prostaglandin-like compounds formed in vivo from the free radical-catalyzed peroxidation of arachidonic acid. This review summarizes our current knowledge regarding these compounds. Novel aspects of the biochemistry and bioactivity of IsoPs are detailed and methods by which these compounds are analyzed are discussed. A considerable portion of this review deals with the utility of measuring IsoPs as markers of oxidant injury in human diseases particularly in association with risk factors that predispose to atherosclerosis, a condition in which excessive oxidative stress has been causally implicated. 相似文献
130.
Functional characterization of apolipoprotein E isoforms overexpressed in Escherichia coli. 总被引:3,自引:0,他引:3
Apolipoprotein (apo) E plays an important role in lipid metabolism, and the major isoforms of apoE (apoE2, apoE3, and apoE4) have significantly different metabolic effects. Apolipoprotein E4 is associated with a higher risk of both heart disease and Alzheimer's disease (AD). Patients homozygous for apolipoprotein E2 are predisposed to type III hyperlipoproteinemia, and apoE2 may be protective against AD. Structure/function studies have proved to be a useful tool in understanding how the different apoE isoforms result in different pathological consequences. As these studies continue, it is essential to have a reliable method to produce large quantities of apoE and mutants of apoE. We describe here a method of apoE production in Escherichia coli strain BL21(DE3). The cDNA from apoE isoforms was inserted into a pET32a vector with a T7 promoter and a fusion partner (thioredoxin). The T7 promoter results in high expression of an easily purified His-tagged fusion protein. A thrombin recognition site was positioned in the expression vector so that only two novel amino acids (Gly-Ser) are added to the amino terminus of apoE following the removal of thioredoxin. Approximately 20 mg of apoE is obtained from a 1-liter culture. The major isoforms of apoE produced with this system were extensively characterized for their ability to bind the low-density lipoprotein (LDL) receptor, for their characteristic lipid association preferences, and for their stability as measured by guanidine denaturation. The recombinant proteins behaved identically to plasma-derived apoE isoforms. 相似文献