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161.
Corradi HR Corrigall AV Boix E Mohan CG Sturrock ED Meissner PN Acharya KR 《The Journal of biological chemistry》2006,281(50):38625-38633
Protoporphyrinogen IX oxidase, a monotopic membrane protein, which catalyzes the oxidation of protoporphyrinogen IX to protoporphyrin IX in the heme/chlorophyll biosynthetic pathway, is distributed widely throughout nature. Here we present the structure of protoporphyrinogen IX oxidase from Myxococcus xanthus, an enzyme with similar catalytic properties to human protoporphyrinogen IX oxidase that also binds the common plant herbicide, acifluorfen. In the native structure, the planar porphyrinogen substrate is mimicked by a Tween 20 molecule, tracing three sides of the macrocycle. In contrast, acifluorfen does not mimic the planarity of the substrate but is accommodated by the shape of the binding pocket and held in place by electrostatic and aromatic interactions. A hydrophobic patch surrounded by positively charged residues suggests the position of the membrane anchor, differing from the one proposed for the tobacco mitochondrial protoporphyrinogen oxidase. Interestingly, there is a discrepancy between the dimerization state of the protein in solution and in the crystal. Conserved structural features are discussed in relation to a number of South African variegate porphyria-causing mutations in the human enzyme. 相似文献
162.
Du W McMahon TJ Zhang ZS Stiber JA Meissner G Eu JP 《The Journal of biological chemistry》2006,281(40):30143-30151
Excitation-contraction (EC) coupling in striated muscles is mediated by the cardiac or skeletal muscle isoform of voltage-dependent L-type Ca(2+) channel (Ca(v)1.2 and Ca(v)1.1, respectively) that senses a depolarization of the cell membrane, and in response, activates its corresponding isoform of intracellular Ca(2+) release channel/ryanodine receptor (RyR) to release stored Ca(2+), thereby initiating muscle contraction. Specifically, in cardiac muscle following cell membrane depolarization, Ca(v)1.2 activates cardiac RyR (RyR2) through an influx of extracellular Ca(2+). In contrast, in skeletal muscle, Ca(v)1.1 activates skeletal muscle RyR (RyR1) through a direct physical coupling that negates the need for extracellular Ca(2+). Since airway smooth muscle (ASM) expresses Ca(v)1.2 and all three RyR isoforms, we examined whether a cardiac muscle type of EC coupling also mediates contraction in this tissue. We found that the sustained contractions of rat ASM preparations induced by depolarization with KCl were indeed partially reversed ( approximately 40%) by 200 mum ryanodine, thus indicating a functional coupling of L-type channels and RyRs in ASM. However, KCl still caused transient ASM contractions and stored Ca(2+) release in cultured ASM cells without extracellular Ca(2+). Further analyses of rat ASM indicated that this tissue expresses as many as four L-type channel isoforms, including Ca(v)1.1. Moreover, Ca(v)1.1 and RyR1 in rat ASM cells have a similar distribution near the cell membrane in rat ASM cells and thus may be directly coupled as in skeletal muscle. Collectively, our data implicate that EC-coupling mechanisms in striated muscles may also broadly transduce diverse smooth muscle functions. 相似文献
163.
Boubacar Coulibaly Augustin Zoungrana Frank P. Mockenhaupt R. Heiner Schirmer Christina Klose Ulrich Mansmann Peter E. Meissner Olaf Müller 《PloS one》2009,4(5)
Background
With the availability of new preventive and curative interventions, global malaria control has been strengthened significantly in recent years. Drugs effective in reducing malaria gametocytaemia might contribute to local elimination and possible long-term eradication. We here report on the effects of methylene blue (MB)-based malaria combination therapy on gametocytaemia during a randomised-controlled trial in Burkina Faso.Methods
An open-label randomised controlled phase II study in 180 children aged 6–10 years with uncomplicated falciparum malaria was conducted in Nouna, north-western Burkina Faso. Children were randomised to MB–artesunate (AS), MB–amodiaquine (AQ), and AS-AQ (local standard of care). Overall follow-up was for 28 days, follow-up for gametocytaemia was for 14 days.Findings
The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. Compared to AS-AQ, both MB-containing regimens were associated with significantly reduced gametocyte carrier rates during follow-up days 3, 7, and 14. This effect was seen both in patients with and without P. falciparum gametocytaemia at baseline.Interpretation
MB reveals pronounced gametocytocidal activity which appears to act against both existing and developing P. falciparum gametocytes. MB-based combination therapy thus has the potential to reduce transmission of P. falciparum malaria in endemic regions, which has important implications for future elimination and eradication strategies.Trial Registration
ClinicalTrials.gov NCT00354380相似文献164.
165.
A Structural Model of the Pore-Forming Region of the Skeletal Muscle Ryanodine Receptor (RyR1) 下载免费PDF全文
Srinivas Ramachandran Adrian W. R. Serohijos Le Xu Gerhard Meissner Nikolay V. Dokholyan 《PLoS computational biology》2009,5(4)
Ryanodine receptors (RyRs) are ion channels that regulate muscle contraction by releasing calcium ions from intracellular stores into the cytoplasm. Mutations in skeletal muscle RyR (RyR1) give rise to congenital diseases such as central core disease. The absence of high-resolution structures of RyR1 has limited our understanding of channel function and disease mechanisms at the molecular level. Here, we report a structural model of the pore-forming region of RyR1. Molecular dynamics simulations show high ion binding to putative pore residues D4899, E4900, D4938, and D4945, which are experimentally known to be critical for channel conductance and selectivity. We also observe preferential localization of Ca2+ over K+ in the selectivity filter of RyR1. Simulations of RyR1-D4899Q mutant show a loss of preference to Ca2+ in the selectivity filter as seen experimentally. Electrophysiological experiments on a central core disease mutant, RyR1-G4898R, show constitutively open channels that conduct K+ but not Ca2+. Our simulations with G4898R likewise show a decrease in the preference of Ca2+ over K+ in the selectivity filter. Together, the computational and experimental results shed light on ion conductance and selectivity of RyR1 at an atomistic level. 相似文献
166.
Purushothaman Sumithra Cathrin P. Britto Muthukalingan Krishnan 《Cell and tissue research》2010,339(2):349-358
Cell death is a scheduled event during animal development and tissue turnover. Here, we affirm the presence of two major pathways of programmed cell death (PCD), viz. apoptotic and autophagic cell death, in the disintegrated pupal perivisceral (PV) fat body during pupal-adult metamorphosis. The acridine orange (a vital stain for apoptosis) staining pattern and DNA fragmentation assay have revealed the exact day (6th day of the pupal stage) of disintegration in the PV fat body as represented by chromatin condensation and DNA laddering. Electron microscopy and scanning electron microscopy have demonstrated the presence of cytoplasmic budding and giant autophagic vacuoles and the low numbers of mitochondria, all of which are attributes of autophagic cell death. Immunoblot analysis of proteosomal subunits 20S and 26S has established the involvement of proteolytic activity during PCD of PV tissue. Lysosomal participation during the PCD of PV tissues has been confirmed by the elevated level of the marker enzyme, acid phosphatase, which is distinct on day 6 of the pupal period. The results of the present study have thus ascertained the co-existence of both autophagic and apoptotic cell death in PV fat body tissue. 相似文献
167.
168.
A robust animal model for “hypothesis-testing/mechanistic” research in human immunology and immuno-pathology should meet the
following criteria. First, it has well-studied hemato-lymphoid organs and target cells similar to those of humans. Second,
the human pathogens establish infection and lead to relevant diseases. Third, it is genetically inbred and can be manipulated
via genetic, immunological and pharmacological means. Many human-tropic pathogens such as HIV-1 fail to infect murine cells
due to the blocks at multiple steps of their life cycle. The mouse with a reconstituted human immune system and other human
target organs is a good candidate. A number of human-mouse chimeric models with human immune cells have been developed in
the past 20 years, but most with only limited success due to the selective engraftment of xeno-reactive human T cells in hu-PBL-SCID
mice or the lack of significant human immune responses in the SCID-hu Thy/Liv mouse. This review summarizes the current understanding
of HIV-1 immuno-pathogenesis in human patients and in SIV-infected primate models. It also reviews the recent progress in
the development of humanized mouse models with a functional human immune system, especially the recent progress in the immunodeficient
mice that carry a defective gammaC gene. NOD/SCID/gammaC−/− (NOG or NSG) or the Rag2−/−gammaC−/− double knockout (DKO) mice, which lack NK as well as T and B cells (NTB-null mice), have been used to reconstitute a functional
human immune system in central and peripheral lymphoid organs with human CD34+ HSC. These NTB-hu HSC humanized models have been used to investigate HIV-1 infection, immuno-pathogenesis and therapeutic
interventions. Such models, with further improvements, will contribute to study human immunology, human-tropic pathogens as
well as human stem cell biology in the tissue development and function in vivo. 相似文献
169.
170.
Holger Rupp Jörg Rinklebe Sebastian Bolze Ralph Meissner 《Ecological Engineering》2010,36(10):1439-1447
The Elbe River, Germany, has received heavy metals and arsenic from the discharge of urban industrial, and agricultural effluent. During periods of inundation, these contaminants were transported with water into floodplain ecosystems, where they settled and accumulated predominantly in depressions and low-lying terraces. Markedly elevated arsenic concentration in soil solution during floods exceeded the inspection value of 10 μg L?1 of the German soil protection ordinance. Highly variable hydrological conditions in floodplains can affect the dynamics of pollutants. The study of processes controlling the dynamics of pollutants is challenging because the results are required to answer both scientific and practical questions regarding protection of groundwater and plants, sustainable management of floodplains or explain the fate of environmentally harmful substances.Our experiments in small groundwater lysimeter and biogeochemical microcosms tended to yield similar results regarding the functional relationships among the investigated site parameters. But the results of the field experiments, carried out at a floodplain site of the middle course of the Elbe River, Germany, are often characterized by complex and varying factors. Whereas arsenic tended to be mobilized during flooding due to decreasing redox potential (EH), chromium showed the opposite trend, with peak concentrations at the highest EH values. Our approach at three different spatiotemporally scale levels, ranging from 23 days (microcosms) to two-and-a-half years (field soil hydrological facility) allows us to overcome process interferences observed in field studies. 相似文献