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21.
Spinal muscular atrophy is a neurodegenerative disease caused by mutations of the SMN1 gene. The homologous SMN2 gene is unable to complement SMN1 because of a crucial mutation in an exonic splicing enhancer, leading to alternative splicing and exclusion of exon 7. Two recent papers show that the defect in splicing of exon 7 of SMN2 is specifically corrected by small synthetic effectors. These new and specific approaches have potential in the treatment of diseases caused by defective splicing. 相似文献
22.
Thomas van den Akker Jogchum Beltman Joey Leyten Beatrice Mwagomba Tarek Meguid Jelle Stekelenburg Jos van Roosmalen 《PloS one》2013,8(1)
Introduction
WHO proposes a set of organ-failure based criteria for maternal near miss. Our objective was to evaluate what implementation of these criteria would mean for the analysis of a cohort of 386 women in Thyolo District, Malawi, who sustained severe acute maternal morbidity according to disease-based criteria.Methods and Findings
A WHO Maternal Near Miss (MNM) Tool, created to compare disease-, intervention- and organ-failure based criteria for maternal near miss, was completed for each woman, based on a review of all available medical records. Using disease-based criteria developed for the local setting, 341 (88%) of the 386 women fulfilled the WHO disease-based criteria provided by the WHO MNM Tool, 179 (46%) fulfilled the intervention-based criteria, and only 85 (22%) the suggested organ-failure based criteria.Conclusions
In this low-resource setting, application of these organ-failure based criteria that require relatively sophisticated laboratory and clinical monitoring underestimates the occurrence of maternal near miss. Therefore, these criteria and the suggested WHO approach may not be suited to compare maternal near miss across all settings. 相似文献23.
van den Akker E Reijnen M Korving J Brouwer A Meijlink F Deschamps J 《Mechanisms of development》1999,89(1-2):103-114
Hoxb8 mutant mice were generated by inserting the lacZ coding sequence in frame with the first exon of Hoxb8. These mice express a fusion protein with a functional beta-galactosidase activity instead of Hoxb8. Mutant embryos were analyzed for anatomical changes. The results indicate that Hoxb8 is not an indispensable regulator of A-P patterning in the forelimb, unlike suggested by our Hoxb8 gain of function experiments (Charité J, DeGraaff W, Shen S, Deschamps J. Cell 1994;78:589-601). The null mutant phenotypic traits include degeneration of the second spinal ganglion (C2), an abnormality opposite to the alteration in the gain of function transgenic mice. Subtle changes in the thoracic part of the vertebral column were observed as well. Adult homozygous mutants exhibit an abnormal clasping reflex of the limbs. 相似文献
24.
Zähringer U Lindner B Knirel YA van den Akker WM Hiestand R Heine H Dehio C 《The Journal of biological chemistry》2004,279(20):21046-21054
The facultative intracellular pathogen Bartonella henselae is responsible for a broad range of clinical manifestations, including the formation of vascular tumors as a result of increased proliferation and survival of colonized endothelial cells. This remarkable interaction with endotoxin-sensitive endothelial cells and the apparent lack of septic shock are considered to be due to a reduced endotoxic activity of the B. henselae lipopolysaccharide. Here, we show that B. henselae ATCC 49882(T) produces a deep-rough-type lipopolysaccharide devoid of O-chain and report on its complete structure and Toll-like receptor-dependent biological activity. The major short-chain lipopolysaccharide was studied by chemical analyses, electrospray ionization, and matrix-assisted laser desorption/ionization mass spectrometry, as well as by NMR spectroscopy after alkaline deacylation. The carbohydrate portion of the lipopolysaccharide consists of a branched trisaccharide containing a glucose residue attached to position 5 of an alpha-(2-->4)-linked 3-deoxy-d-manno-oct-2-ulosonic acid disaccharide. Lipid A is a pentaacylated beta-(1'-->6)-linked 2,3-diamino-2,3-dideoxy-glucose disaccharide 1,4'-bisphosphate with two amide-linked residues each of 3-hydroxydodecanoic and 3-hydroxyhexadecanoic acids and one residue of either 25-hydroxyhexacosanoic or 27-hydroxyoctacosanoic acid that is O-linked to the acyl group at position 2'. The lipopolysaccharide studied activated Toll-like receptor 4 signaling only to a low extent (1,000-10,000-fold lower compared with that of Salmonella enterica sv. Friedenau) and did not activate Toll-like receptor 2. Some unusual structural features of the B. henselae lipopolysaccharide, including the presence of a long-chain fatty acid, which are shared by the lipopolysaccharides of other bacteria causing chronic intracellular infections (e.g. Legionella and Chlamydia), may provide the molecular basis for low endotoxic potency. 相似文献
25.
Degradation of 3-Chlorobenzoate under Low-Oxygen Conditions in Pure and Mixed Cultures of the Anoxygenic Photoheterotroph Rhodopseudomonas palustris DCP3 and an Aerobic Alcaligenes Species 总被引:2,自引:0,他引:2 下载免费PDF全文
Janneke Krooneman Sytske van den Akker Teresa M. Pedro Gomes Larry J. Forney Jan C. Gottschal 《Applied microbiology》1999,65(1):131-137
The presence or absence of molecular oxygen has been shown to play a crucial role in the degradability of haloaromatic compounds. In the present study, it was shown that anaerobic phototrophic 3-chlorobenzoate (3CBA) metabolism by Rhodopseudomonas palustris DCP3 is oxygen tolerant up to a concentration of 3 μM O2. Simultaneous oxidation of an additional carbon source permitted light-dependent anaerobic 3CBA degradation at oxygen input levels which, in the absence of such an additional compound, would result in inhibition of light-dependent dehalogenation. Experiments under the same experimental conditions with strain DCP3 in coculture with an aerobic 3CBA-utilizing heterotroph, Alcaligenes sp. strain L6, revealed that light-dependent dehalogenation of 3CBA did not occur. Under both oxygen limitation (O2 < 0.1 μM) and low oxygen concentrations (3 μM O2), all the 3CBA was metabolized by the aerobic heterotroph. These data suggest that biodegradation of (halo)aromatics by photoheterotrophic bacteria such as R. palustris DCP3 may be restricted to anoxic photic environments. 相似文献
26.
Elizabeth A. Rodkey Marisa L. Winkler Christopher R. Bethel Sundar Ram Reddy Pagadala John D. Buynak Robert A. Bonomo Focco van den Akker 《PloS one》2014,9(1)
β-Lactamases are the major reason β-lactam resistance is seen in Gram-negative bacteria. To combat this resistance mechanism, β-lactamase inhibitors are currently being developed. Presently, there are only three that are in clinical use (clavulanate, sulbactam and tazobactam). In order to address this important medical need, we explored a new inhibition strategy that takes advantage of a long-lived inhibitory trans-enamine intermediate. SA2-13 was previously synthesized and shown to have a lower k
react than tazobactam. We investigated here the importance of the carboxyl linker length and composition by synthesizing three analogs of SA2-13 (PSR-4-157, PSR-4-155, and PSR-3-226). All SA2-13 analogs yielded higher turnover numbers and k
react compared to SA2-13. We next demonstrated using protein crystallography that increasing the linker length by one carbon allowed for better capture of a trans-enamine intermediate; in contrast, this trans-enamine intermediate did not occur when the C2 linker length was decreased by one carbon. If the linker was altered by both shortening it and changing the carboxyl moiety into a neutral amide moiety, the stable trans-enamine intermediate in wt SHV-1 did not form; this intermediate could only be observed when a deacylation deficient E166A variant was studied. We subsequently studied SA2-13 against a relatively recently discovered inhibitor-resistant (IR) variant of SHV-1, SHV K234R. Despite the alteration in the mechanism of resistance due to the K→R change in this variant, SA2-13 was effective at inhibiting this IR enzyme and formed a trans-enamine inhibitory intermediate similar to the intermediate seen in the wt SHV-1 structure. Taken together, our data reveals that the C2 side chain linker length and composition profoundly affect the formation of the trans-enamine intermediate of penam sulfones. We also show that the design of SA2-13 derivatives offers promise against IR SHV β-lactamases that possess the K234R substitution. 相似文献
27.
F. van den Akker J.C. Deddens P.A. Doevendans J.P.G. Sluijter 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
After myocardial infarction (MI) a local inflammatory reaction clears the damaged myocardium from dead cells and matrix debris at the onset of scar formation. The intensity and duration of this inflammatory reaction are intimately linked to post-infarct remodeling and cardiac dysfunction. Strikingly, treatment with standard anti-inflammatory drugs worsens clinical outcome, suggesting a dual role of inflammation in the cardiac response to injury. Cardiac stem cell therapy with different stem or progenitor cells, e.g. mesenchymal stem cells (MSC), was recently found to have beneficial effects, mostly related to paracrine actions. One of the suggested paracrine effects of cell therapy is modulation of the immune system.Scope of review
MSC are reported to interact with several cells of the immune system and could therefore be an excellent means to reduce detrimental inflammatory reactions and promote the switch to the healing phase upon cardiac injury. This review focuses on the potential use of MSC therapy for post-MI inflammation. To understand the effects MSC might have on the post-MI heart the cellular and molecular changes in the myocardium after MI need to be understood.Major conclusions
By studying the general pathways involved in immunomodulation, and examining the interactions with cell types important for post-MI inflammation, it becomes clear that MSC treatment might provide a new therapeutic opportunity to improve cardiac outcome after acute injury.General significance
Using stem cells to target the post-MI inflammation is a novel therapy which could have considerable clinical implications. This article is part of a Special Issue entitled Biochemistry of Stem Cells. 相似文献28.
A metagenetic approach to determine the diversity and distribution of cyst nematodes at the level of the country,the field and the individual 下载免费PDF全文
29.
Chatterjee-Kishore M van Den Akker F Stark GR 《The Journal of biological chemistry》2000,275(27):20406-20411
The LMP2 gene, which encodes a protein required for efficient presentation of viral antigens, requires both unphosphorylated Stat1 and IRF1 for basal expression. LMP2 expression is down-regulated by the adenovirus protein E1A, which binds to Stat1 and CBP/p300, and by the mutant E1A protein RG2, which binds to Stat1 but not to CBP/p300, but not by the mutant protein Delta2-36, which does not bind to either Stat1 or CBP/p300. Stat1 and IRF1 associate in untreated cells and bind as a complex to the overlapping ICS-2/GAS element of the LMP2 promoter. E1A interferes with the formation of this complex by occupying domains of Stat1 that bind to IRF1. These results reveal how adenovirus infection attenuates LMP2 expression, thereby interfering with the presentation of viral antigens. 相似文献
30.