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61.
Aswin Mangerich Harry Scherthan Jörg Diefenbach Ulrich Kloz Franciscus van der Hoeven Sascha Beneke Alexander Bürkle 《Transgenic research》2009,18(2):261-279
Here we report an approach to generate a knock-in mouse model using an ‘ends-out’ gene replacement vector to substitute the
murine Parp-1 (mParp-1) coding sequence (32 kb) with its human orthologous sequence (46 kb). Unexpectedly, examination of mutant ES cell clones
and mice revealed that site-specific homologous recombination was mimicked in three independently generated ES cell clones
by bidirectional extension of the vector homology arms using the endogenous mParp-1-flanking sequences as templates. This was followed by adjacent integration of the targeting vector, thus leaving the endogenous
mParp-1 locus functional. A related phenomenon termed ‘ectopic gene targeting’ has so far only been described for ‘ends-in’ integration-type
vectors in non-ES cell gene targeting. We provide reliable techniques to detect such ectopic gene targeting which represents
an unexpected caveat in mouse genetic engineering that should be considered in the design and validation strategy of future
gene knock-in approaches.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
62.
Annemarie W Oldenbeuving Paul LM de Kort Ben PW Jansen L Jaap Kappelle Gerwin Roks 《BMC neurology》2008,8(1):34
Background
Delirium is a common disorder in the early phase of stroke. Given the presumed cholinergic deficiency in delirium, we tested treatment with the acetylcholinesterase inhibitor rivastigmine.Methods
This pilot study was performed within an epidemiological study. In 527 consecutive stroke patients presence of delirium was assessed during the first week with the confusion assessment method. Severity was scored with the delirium rating scale (DRS). Sixty-two patients developed a delirium in the acute phase of stroke. Only patients with a severe and persistent delirium (defined as a DRS of 12 or more for more than 24 hours) were enrolled in the present study. In total 26 fulfilled these criteria of whom 17 were treated with orally administered rivastigmine with a total dose between 3 and 12 mg a day. Eight patients could not be treated because of dysphagia and one because of early discharge.Results
No major side effects were recorded. In 16 patients there was a considerable decrease in severity of delirium. The mean DRS declined from 14.8 on day one to 8.5 after therapy and 5.6 after tapering. The mean duration of delirium was 6.7 days (range; 2–17).Conclusion
Rivastigmine is safe in stroke patients with delirium even after rapid titration. In the majority of patients the delirium improved after treatment. A randomized controlled trial is needed to establish the usefulness of rivastigmine in delirium after stroke.Trial registration
Nederlands Trial Register NTR139563.
S Chhabra R Narang LR Krishnan S Vasisht DP Agarwal LM Srivastava SC Manchanda N Das 《BMC genetics》2002,3(1):9-6
Background
A close association between Sst I polymorphism in the 3' untranslated region of the apolipoproteinC3 (APOC3 ) gene and levels of plasma triglycerides (TG) had been reported by different investigators. Hypertriglyceridemia(HTG) is a known risk factor for coronary artery disease (CAD) in the context of Asian Indians. We conducted a study on the relationship between APOC3 SstI polymorphism (S1S1, S1S2 and S2S2 genotypes) and plasma TG levels in a group of 139 male healthy volunteers from Northern India. 相似文献64.
W. Reuben Kaufman B. Duff Sloley Roger J. Tatchell Geoff L. Zbitnew Thomas J. Diefenbach Jeffrey I. Goldberg 《Experimental & applied acarology》1999,23(3):251-265
Dopamine (DA) content of the salivary glands in partially fed female and fed male ticks, Amblyomma hebraeum Koch (Acari: Ixodidae), was measured by high-performance liquid chromatography with electrochemical detection or by a radioenzymatic assay for catecholamines following experimental treatment. Some glands were held in vitro for up to 3 days. Other preparations (backless explants) allowed one side to be surgically denervated, the contralateral side serving as control. Normal ticks were sampled for up to 4 days post-removal from the host (rabbits). In the backless explants, there was little if any difference in DA content between denervated and control sides, even after 4 days in vitro, indicating that unilateral denervation did not eliminate the major salivary gland pool of DA. High doses of reserpine (333 g per g body weight) and 6-hydroxydopamine (1000 g per g body weight) did not significantly reduce the DA content of the salivary gland, also suggesting that only a minor component of the DA pool is within axons innervating the salivary gland. A dispersed population of cells rich in tyrosine hydroxylase immunoreactivity (an enzyme marker for catecholamine-synthesizing cells) was found in close association with the granular acini. This further suggests that the major DA pool in the salivary gland may be in cells other than the dopaminergic nerves arising from the central nervous system. © Rapid Science Ltd. 1998 相似文献
65.
Long term association of the cytokine receptor gp130 and the Janus kinase Jak1 revealed by FRAP analysis 总被引:3,自引:0,他引:3
Giese B Au-Yeung CK Herrmann A Diefenbach S Haan C Küster A Wortmann SB Roderburg C Heinrich PC Behrmann I Müller-Newen G 《The Journal of biological chemistry》2003,278(40):39205-39213
Signal transduction through cytokine receptors is mediated mainly by non-covalently associated Jak tyrosine kinases. By confocal microscopy, the cytokine receptor gp130 and Jak1, fused with either yellow (YFP) or cyan (CFP) fluorescent protein, were found to be colocalized predominantly at intracellular vesicular structures and at the plasma membrane. Quantitative fluorescence recovery after photobleaching (FRAP) analysis at the plasma membrane revealed equal mobilities for gp130-YFP and Jak1-YFP. Thus, Jak1-YFP diffuses like a transmembrane protein indicating that membrane-bound Jak1 does not exchange rapidly with cytosolic Jaks. Applying a novel dual-color FRAP approach we found that immobilization of gp130-CFP by a pair of monoclonal antibodies led to a corresponding immobilization of co-transfected Jak1-YFP. We conclude from these findings that Jak1, once bound to a gp130 molecule, does not exchange between different receptors at the plasma membrane neither via the cytoplasmic compartment nor via a membrane-associated state. 相似文献
66.
Cutting edge: tumor rejection mediated by NKG2D receptor-ligand interaction is dependent upon perforin 总被引:13,自引:0,他引:13
Hayakawa Y Kelly JM Westwood JA Darcy PK Diefenbach A Raulet D Smyth MJ 《Journal of immunology (Baltimore, Md. : 1950)》2002,169(10):5377-5381
We have investigated the primary immunity generated in vivo by MHC class I-deficient and -competent tumor cell lines that expressed the NKG2D ligand retinoic acid early inducible-1 (Rae-1) beta. Rae-1beta expression on class I-deficient RMA-S lymphoma cells enhanced primary NK cell-mediated tumor rejection in vivo, whereas RMA-Rae-1beta tumor cells were rejected by a combination of NK cells and CD8(+) T cells. Rae-1beta expression stimulated NK cell cytotoxicity and IFN-gamma secretion in vitro, but not proliferation. Surprisingly, only NK cell perforin-mediated cytotoxicity, but not production of IFN-gamma, was critical for the rejection of Rae-1beta-expressing tumor cells in vivo. This distinct requirement for perforin activity contrasts with the NK cell-mediated rejection of MHC class I-deficient RMA-S tumor cells expressing other activating ligands such as CD70 and CD80. Thus, these results indicated that NKG2D acted as a natural cytotoxicity receptor to stimulate perforin-mediated elimination of ligand-expressing tumor cells. 相似文献
67.
Although genomics techniques such as DNA microarrays have been widely used in virology, much more limited use has been made of proteomics. Although difficult, proteomics can greatly contribute to an understanding of virus-cell interactions, including the ternary structure of viral receptors at the cell surface, post-translational modifications and isoforms of critical viral and cellular proteins and even to the structure of viruses. Proteomics techniques also offer the potential for discovering markers for diagnostic and prognostic tests of viral infections in vivo. This review describes the use of several proteomic approaches for the analysis of HIV-cellular receptor interactions, the molecular mechanisms of transport of herpes simplex virus within neurons, and the structure of the tegument of herpes simplex virus. 相似文献
68.
Increased use of stable isotope analysis to examine food-web dynamics, migration, transfer of nutrients, and behavior will likely result in expansion of stable isotope studies investigating human-induced global changes. Recent elevation of atmospheric CO2 concentration, related primarily to fossil fuel combustion, has reduced atmospheric CO2 δ13C (13C/12C), and this change in isotopic baseline has, in turn, reduced plant and animal tissue δ13C of terrestrial and aquatic organisms. Such depletion in CO2 δ13C and its effects on tissue δ13C may introduce bias into δ13C investigations, and if this variation is not controlled, may confound interpretation of results obtained from tissue samples collected over a temporal span. To control for this source of variation, we used a high-precision record of atmospheric CO2 δ13C from ice cores and direct atmospheric measurements to model modern change in CO2 δ13C. From this model, we estimated a correction factor that controls for atmospheric change; this correction reduces bias associated with changes in atmospheric isotopic baseline and facilitates comparison of tissue δ13C collected over multiple years. To exemplify the importance of accounting for atmospheric CO2 δ13C depletion, we applied the correction to a dataset of collagen δ13C obtained from mountain lion (Puma concolor) bone samples collected in California between 1893 and 1995. Before correction, in three of four ecoregions collagen δ13C decreased significantly concurrent with depletion of atmospheric CO2 δ13C (n ≥ 32, P ≤ 0.01). Application of the correction to collagen δ13C data removed trends from regions demonstrating significant declines, and measurement error associated with the correction did not add substantial variation to adjusted estimates. Controlling for long-term atmospheric variation and correcting tissue samples for changes in isotopic baseline facilitate analysis of samples that span a large temporal range. 相似文献
69.
Diefenbach RJ Diefenbach E Douglas MW Cunningham AL 《Biochemical and biophysical research communications》2004,319(3):987-992
The conventional microtubule-dependent motor protein kinesin consists of heavy and light chains both of which have been documented to bind a variety of potential linker or cargo proteins. In this study we employed a yeast two-hybrid assay to identify additional binding partners of the kinesin heavy chain isoform KIF5B. A human brain cDNA library was screened with a bait corresponding to amino acid residues 814-963 of human KIF5B. This screen identified the ribosome receptor, p180, as a KIF5B-binding protein. The sites of interaction are residues 1294-1413 of p180 and the C-terminal half of the cargo binding-domain of KIF5B (residues 867-907). The KIF5B-binding site in p180 is homologous to the previously determined KIF5B-binding site in kinectin. The interacting regions of p180 and KIF5B consist almost entirely of heptad repeats, suggesting the interaction is a coiled-coil. A role for the kinesin/p180 interaction may include mRNA localization and/or transport of endoplasmic reticulum-derived vesicles. 相似文献
70.
Determination of interactions between tegument proteins of herpes simplex virus type 1 总被引:5,自引:0,他引:5 下载免费PDF全文
Vittone V Diefenbach E Triffett D Douglas MW Cunningham AL Diefenbach RJ 《Journal of virology》2005,79(15):9566-9571
The aim of this study was to elucidate protein-protein interactions between tegument proteins of herpes simplex virus type 1 (HSV-1). To do so, we have cloned and expressed in the LexA yeast (Saccharomyces cerevisiae) two-hybrid system, 13 of the 21 currently known tegument proteins of HSV-1. These included the tegument proteins essential for replication in cell lines, UL17, UL36, UL37, UL48, and UL49, and the nonessential tegument proteins US11, UL11, UL14, UL16, UL21, UL41, UL46, and UL47. A total of 104 combinations were screened in the yeast two-hybrid assay, with 9 interactions identified. These included: UL11-UL16, UL36-UL37, UL36-UL48, UL46-UL48, UL47-UL48, and UL48-UL49. The remaining interactions consisted of self-associations that were observed for US11, UL37, and UL49. The interactions UL36-UL37, UL36-UL48, UL37-UL37, UL46-UL48, and UL47-UL48 have not been previously reported for HSV-1. The interaction of UL46-UL48 was verified using an in vitro pull-down assay. The interactions of UL36-UL37 and UL37-UL37 were verified with a coimmunoprecipitation assay. Knowledge of HSV-1 tegument protein-protein interactions will provide insights into the pathways of tegument assembly, and the identified interactions are potential targets for new antiviral drugs. 相似文献