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31.
Geert Zegels Geert AA Van Raemdonck Edmond P Coen Wiebren AA Tjalma Xaveer WM Van Ostade 《Proteome science》2009,7(1):17-16
Background
Cervical-vaginal fluid (CVF) plays an important role in the prevention of gynecological infections, although little is known about the contribution of CVF proteins to the immunity of the lower female genital tract. In order to analyze the protein composition of human CVF, we used CVF samples that are routinely collected during colposcopy, but are usually discarded. Since these samples are available in large quantities we aimed to analyze their usefulness for proteomics experiments. The samples were analyzed using different prefractionation techniques (ultrafiltration and C4(RP)-LC protein separation) followed by C18(RP)-LC peptide separation and identification by MALDI-TOF-TOF mass spectrometry. To determine the reproducibility of this proteomics platform we analyzed three technical replicates. Using spectral counting, protein abundances were estimated in a semiquantitative way. We also compared the results obtained in this study with those from previous studies derived from patients with different physiological conditions in order to determine an overlapping protein set. 相似文献32.
Yingying Lu Shichen Dong Baixia Hao Chang Li Kaiyuan Zhu Wenjing Guo Qian Wang King-Ho Cheung Connie WM Wong Wu-Tian Wu Huss Markus Jianbo Yue 《Autophagy》2014,10(11):1895-1905
Autophagy is a catabolic lysosomal degradation process essential for cellular homeostasis and cell survival. Dysfunctional autophagy has been associated with a wide range of human diseases, e.g., cancer and neurodegenerative diseases. A large number of small molecules that modulate autophagy have been widely used to dissect this process and some of them, e.g., chloroquine (CQ), might be ultimately applied to treat a variety of autophagy-associated human diseases. Here we found that vacuolin-1 potently and reversibly inhibited the fusion between autophagosomes and lysosomes in mammalian cells, thereby inducing the accumulation of autophagosomes. Interestingly, vacuolin-1 was less toxic but at least 10-fold more potent in inhibiting autophagy compared with CQ. Vacuolin-1 treatment also blocked the fusion between endosomes and lysosomes, resulting in a defect in general endosomal-lysosomal degradation. Treatment of cells with vacuolin-1 alkalinized lysosomal pH and decreased lysosomal Ca2+ content. Besides marginally inhibiting vacuolar ATPase activity, vacuolin-1 treatment markedly activated RAB5A GTPase activity. Expression of a dominant negative mutant of RAB5A or RAB5A knockdown significantly inhibited vacuolin-1-induced autophagosome-lysosome fusion blockage, whereas expression of a constitutive active form of RAB5A suppressed autophagosome-lysosome fusion. These data suggest that vacuolin-1 activates RAB5A to block autophagosome-lysosome fusion. Vacuolin-1 and its analogs present a novel class of drug that can potently and reversibly modulate autophagy. 相似文献
33.
Fredrick M Mobegi Sacha AFT van Hijum Peter Burghout Hester J Bootsma Stefan PW de Vries Christa E van der Gaast-de Jongh Elles Simonetti Jeroen D Langereis Peter WM Hermans Marien I de Jonge Aldert Zomer 《BMC genomics》2014,15(1)
Background
Bacterial respiratory tract infections, mainly caused by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are among the leading causes of global mortality and morbidity. Increased resistance of these pathogens to existing antibiotics necessitates the search for novel targets to develop potent antimicrobials.Result
Here, we report a proof of concept study for the reliable identification of potential drug targets in these human respiratory pathogens by combining high-density transposon mutagenesis, high-throughput sequencing, and integrative genomics. Approximately 20% of all genes in these three species were essential for growth and viability, including 128 essential and conserved genes, part of 47 metabolic pathways. By comparing these essential genes to the human genome, and a database of genes from commensal human gut microbiota, we identified and excluded potential drug targets in respiratory tract pathogens that will have off-target effects in the host, or disrupt the natural host microbiota. We propose 249 potential drug targets, 67 of which are targets for 75 FDA-approved antimicrobials and 35 other researched small molecule inhibitors. Two out of four selected novel targets were experimentally validated, proofing the concept.Conclusion
Here we have pioneered an attempt in systematically combining the power of high-density transposon mutagenesis, high-throughput sequencing, and integrative genomics to discover potential drug targets at genome-scale. By circumventing the time-consuming and expensive laboratory screens traditionally used to select potential drug targets, our approach provides an attractive alternative that could accelerate the much needed discovery of novel antimicrobials.Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-958) contains supplementary material, which is available to authorized users. 相似文献34.
WM. G. Moore 《The Western journal of medicine》1921,19(9):362-363
35.
Michael G Anderson Richard T Libby Mao Mao Ioan M Cosma Larry A Wilson Richard S Smith Simon WM John 《BMC biology》2006,4(1):20-11
Background
DBA/2J (D2) mice develop an age-related form of glaucoma. Their eyes progressively develop iris pigment dispersion and iris atrophy followed by increased intraocular pressure (IOP) and glaucomatous optic nerve damage. Mutant alleles of the Gpnmb and Tyrp1 genes are necessary for the iris disease, but it is unknown whether alleles of other D2 gene(s) are necessary for the distinct later stages of disease. We initiated a study of congenic strains to further define the genetic requirements and disease mechanisms of the D2 glaucoma. 相似文献36.
W M Hendrikx 《Zeitschrift für Parasitenkunde (Berlin, Germany)》1983,69(1):119-126
The oral, percutaneous and subcutaneous routes of infection of Oswaldocruzia filiformis were investigated in amphibia. Tadpoles of Bufo bufo and Rana temporaria can be infected with O. filiformis when kept temporarily in a suspension of infective larvae in water. Larval stages and subadults were found in tadpoles. All stages of the parasite, including egg-producing females, were found after metamorphosis of the host. However, under natural circumstances infection of tadpoles seems unlikely. Oral infections in metamorphosed hosts of both species were successful in 97.5% of the host animals used. The first eggs appeared 29 days after infection in the faeces. The oral route seems to be normal for O. filiformis in amphibia. Experiments on percutaneous infections did not reveal actual penetration of larvae in or through the skin nor a subsequent migration through host tissues. Sometimes a few larvae were found in the stomach and intestine, but in these particular cases the experimental conditions did not totally exclude the possibility of oral infections. Consequently, the percutaneous route of infection is not plausible for O. filiformis. Subcutaneous inoculation of infective larvae seems to be a possible way of establishing experimental infections. Erratic localisation of the parasite in the enlarged gall bladder of the host was observed. 相似文献
37.
WM. F. Stein M. Dorthy Beck Arthur C. Hollister Jr. Earl Mortenson 《The Western journal of medicine》1951,75(2):94-97
The procedures used in the organization and operation of a special study on diarrheal diseases involving federal, state, and local agencies are outlined. The integration of such a project into a local routine program is discussed and the possible benefits derived by the various agencies are briefly evaluated. 相似文献
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