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排序方式: 共有353条查询结果,搜索用时 31 毫秒
101.
María Ángeles Tormo-Más Jorge Donderis María García-Caballer Aaron Alt Ignacio Mir-Sanchis Alberto Marina José R. Penadés 《Molecular cell》2013,49(5):947-958
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103.
William Stokes Geetha Srinivas Richard McFarland Jodie Kulpa-Eddy Warren Casey Angela Walker Hans Draayer Randy Sebring Karen Brown Elisabeth Balks Catrina Stirling Eric Klaasen Richard Hill Byron Rippke Kevin Ruby David Alt Suman Mukhopadhyay Hajime Kojima Brett Jones 《Biologicals》2013,41(5):279-294
Routine potency testing of Leptospira vaccines is mostly conducted using a vaccination–challenge test that involves large numbers of hamsters and unrelieved pain and distress. NICEATM, ICCVAM, and their international partners organized a workshop to review the state of the science of alternative methods that might replace, reduce, and refine the use of animals for veterinary Leptospira vaccine potency testing and to identify ways to advance improved alternative methods. Vaccine manufacturers were encouraged to initiate or continue product-specific validation using in vitro enzyme-linked immunosorbent assays as replacements for potency testing of four common Leptospira serogroups. Participants discussed the potential for eliminating the back-titration procedure in the hamster challenge assay, which could reduce animal use by 50% for each individual potency test. Further animal reduction may also be possible by using cryopreserved Leptospira stock to replace continual passaging through hamsters. Serology assays were identified as a way to further reduce and refine animal use but should be considered only after attempting in vitro assays. Workshop participants encouraged consideration of analgesics and use of earlier humane endpoints when the hamster vaccination–challenge potency assay is used. International harmonization of alternative potency methods was recommended to avoid duplicative potency testing to meet regionally different requirements. 相似文献
104.
Emilie Rass Gurushankar Chandramouly Shan Zha Frederick W. Alt Anyong Xie 《The Journal of biological chemistry》2013,288(10):7086-7095
Ataxia telangiectasia mutated (ATM) is activated upon DNA double strand breaks (DSBs) and phosphorylates numerous DSB response proteins, including histone H2AX on serine 139 (Ser-139) to form γ-H2AX. Through interaction with MDC1, γ-H2AX promotes DSB repair by homologous recombination (HR). H2AX Ser-139 can also be phosphorylated by DNA-dependent protein kinase catalytic subunit and ataxia telangiectasia- and Rad3-related kinase. Thus, we tested whether ATM functions in HR, particularly that controlled by γ-H2AX, by comparing HR occurring at the euchromatic ROSA26 locus between mouse embryonic stem cells lacking either ATM, H2AX, or both. We show here that loss of ATM does not impair HR, including H2AX-dependent HR, but confers sensitivity to inhibition of poly(ADP-ribose) polymerases. Loss of ATM or H2AX has independent contributions to cellular sensitivity to ionizing radiation. The ATM-independent HR function of H2AX requires both Ser-139 phosphorylation and γ-H2AX/MDC1 interaction. Our data suggest that ATM is dispensable for HR, including that controlled by H2AX, in the context of euchromatin, excluding the implication of such an HR function in genomic instability, hypersensitivity to DNA damage, and poly(ADP-ribose) polymerase inhibition associated with ATM deficiency. 相似文献
105.
Thaqif El Khassawna Wolfgang B?cker Parameswari Govindarajan Nathalie Schliefke Britta Hürter Marian Kampschulte Gudrun Schlewitz Volker Alt Katrin Susanne Lips Miriam Faulenbach Henriette M?llmann Daniel Zahner Lutz Dürselen Anita Ignatius Natali Bauer Sabine Wenisch Alexander Claus Langheinrich Reinhard Schnettler Christian Heiss 《PloS one》2013,8(8)
Many postmenopausal women have vitamin D and calcium deficiency. Therefore, vitamin D and calcium supplementation is recommended for all patients with osteopenia and osteoporosis. We used an experimental rat model to test the hypothesis that induction of osteoporosis is more efficiently achieved in peripheral bone through combining ovariectomy with a unique multi-deficiencies diet (vitamin D depletion and deficient calcium, vitamin K and phosphorus). 14-week-old Sprague-Dawley rats served as controls to examine the initial bone status. 11 rats were bilaterally ovariectomized (OVX) and fed with multi-deficiencies diet. Three months later the treated group and the Sham group (n = 8) were euthanized. Bone biomechanical competence of the diaphyseal bone was examined on both, tibia and femur. Image analysis was performed on tibia via µCT, and on femur via histological analysis. Lower torsional stiffness indicated inferior mechanical competence of the tibia in 3 month OVX+Diet. Proximal metaphyseal region of the tibia showed a diminished bone tissue portion to total tissue in the µCT despite the increased total area as evaluated in both µCT and histology. Cortical bone showed higher porosity and smaller cross sectional thickness of the tibial diaphysis in the OVX+Diet rats. A lower ALP positive area and elevated serum level of RANKL exhibited the unbalanced cellular interaction in bone remodeling in the OVX+Diet rat after 3 month of treatment. Interestingly, more adipose tissue area in bone marrow indicated an effect of bone loss similar to that observed in osteoporotic patients. Nonetheless, the presence of osteoid and elevated serum level of PTH, BGP and Opn suggest the development of osteomalacia rather than an osteoporosis. As the treatment and fracture management of both osteoporotic and osteomalacia patients are clinically overlapping, this study provides a preclinical animal model to be utilized in local supplementation of minerals, drugs and growth factors in future fracture healing studies. 相似文献
106.
Jose A. Martinez-Perez Smriti Iyengar Harlan E. Shannon David Bleakman Andrew Alt David K. Clawson Brian M. Arnold Michael G. Bell Thomas J. Bleisch Ana M. Castaño Miriam Del Prado Esteban Dominguez Ana M. Escribano Sandra A. Filla Ken H. Ho Kevin J. Hudziak Carrie K. Jones Ana Mateo Paul L. Ornstein 《Bioorganic & medicinal chemistry letters》2013,23(23):6463-6466
We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models. 相似文献
107.
Shukla K Thomas AG Ferraris DV Hin N Sattler R Alt J Rojas C Slusher BS Tsukamoto T 《Bioorganic & medicinal chemistry letters》2011,21(20):6184-6187
A series of sulfasalazine analogs were synthesized and tested for their ability to block cystine-glutamate antiporter system xc? using L-[(14)C]cystine as a substrate. Replacement of sulfasalazine's diazo group with an alkyne group led to an equally potent inhibitor, 2-hydroxy-5-((4-(N-pyridin-2-ylsulfamoyl)phenyl)ethynyl)benzoic acid 6. Our SAR studies also revealed that the carboxylate group of sulfasalazine is essential for its inhibitory activity while the phenolic hydroxyl group is dispensable. Truncated analogs lacking an N-pyridin-2-ylsulfamoyl moiety were less potent than sulfasalazine, but may serve as more tractable templates because of their low molecular weight by applying a variety of fragment growing approaches. Given that sulfasalazine is rapidly metabolized through cleavage of the diazo bond, these analogs may possess a more desirable pharmacological profile as system xc- blockers, in particular, for in vivo studies. 相似文献
108.
109.
Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation 总被引:9,自引:1,他引:8
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Lombard DB Alt FW Cheng HL Bunkenborg J Streeper RS Mostoslavsky R Kim J Yancopoulos G Valenzuela D Murphy A Yang Y Chen Y Hirschey MD Bronson RT Haigis M Guarente LP Farese RV Weissman S Verdin E Schwer B 《Molecular and cellular biology》2007,27(24):8807-8814
Homologs of the Saccharomyces cerevisiae Sir2 protein, sirtuins, promote longevity in many organisms. Studies of the sirtuin SIRT3 have so far been limited to cell culture systems. Here, we investigate the localization and function of SIRT3 in vivo. We show that endogenous mouse SIRT3 is a soluble mitochondrial protein. To address the function and relevance of SIRT3 in the regulation of energy metabolism, we generated and phenotypically characterized SIRT3 knockout mice. SIRT3-deficient animals exhibit striking mitochondrial protein hyperacetylation, suggesting that SIRT3 is a major mitochondrial deacetylase. In contrast, no mitochondrial hyperacetylation was detectable in mice lacking the two other mitochondrial sirtuins, SIRT4 and SIRT5. Surprisingly, despite this biochemical phenotype, SIRT3-deficient mice are metabolically unremarkable under basal conditions and show normal adaptive thermogenesis, a process previously suggested to involve SIRT3. Overall, our results extend the recent finding of lysine acetylation of mitochondrial proteins and demonstrate that SIRT3 has evolved to control reversible lysine acetylation in this organelle. 相似文献
110.
Sadat S Gehmert S Song YH Yen Y Bai X Gaiser S Klein H Alt E 《Biochemical and biophysical research communications》2007,363(3):674-679
Emerging evidence suggests that adipose tissue-derived stem cells (ASCs) can be used for the treatment of ischemic heart diseases. However, the mechanisms underlying their therapeutic effects have not been clearly defined. In this study cytokines released by ASCs were detected by ELISA and pro-angiogenic effects were assessed by tube formation assay. To define the anti-apoptotic effect of ASCs, neonatal rat cardiomyocytes were subjected to hypoxia condition in a co-culture system. Our data show that ASCs secrete significant amounts of VEGF (810.65 ± 56.92 pg/μg DNA) and IGF-I (328.33 ± 22.7 pg/μg DNA). Cardiomyocytes apoptosis was significantly prevented by ASCs and 62.5% of the anti-apoptotic effect was mediated by IGF-I and 34.2% by VEGF. ASCs promoted endothelial cell tube formation by secreting VEGF. In conclusion we demonstrated that ASCs have a marked impact on anti-apoptosis and angiogenesis and helps to explain data of stem cells benefit without transdifferentiation. 相似文献