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41.
Lei P Ayton S Finkelstein DI Spoerri L Ciccotosto GD Wright DK Wong BX Adlard PA Cherny RA Lam LQ Roberts BR Volitakis I Egan GF McLean CA Cappai R Duce JA Bush AI 《Nature medicine》2012,18(2):291-295
The microtubule-associated protein tau has risk alleles for both Alzheimer's disease and Parkinson's disease and mutations that cause brain degenerative diseases termed tauopathies. Aggregated tau forms neurofibrillary tangles in these pathologies, but little is certain about the function of tau or its mode of involvement in pathogenesis. Neuronal iron accumulation has been observed pathologically in the cortex in Alzheimer's disease, the substantia nigra (SN) in Parkinson's disease and various brain regions in the tauopathies. Here we report that tau-knockout mice develop age-dependent brain atrophy, iron accumulation and SN neuronal loss, with concomitant cognitive deficits and parkinsonism. These changes are prevented by oral treatment with a moderate iron chelator, clioquinol. Amyloid precursor protein (APP) ferroxidase activity couples with surface ferroportin to export iron, but its activity is inhibited in Alzheimer's disease, thereby causing neuronal iron accumulation. In primary neuronal culture, we found loss of tau also causes iron retention, by decreasing surface trafficking of APP. Soluble tau levels fall in affected brain regions in Alzheimer's disease and tauopathies, and we found a similar decrease of soluble tau in the SN in both Parkinson's disease and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. These data suggest that the loss of soluble tau could contribute to toxic neuronal iron accumulation in Alzheimer's disease, Parkinson's disease and tauopathies, and that it can be rescued pharmacologically. 相似文献
42.
Blaine D. Griffen John M. Drake 《Proceedings. Biological sciences / The Royal Society》2009,276(1677):4363-4371
Ecological theory suggests that several demographic factors influence metapopulation extinction risk, including synchrony in population size between subpopulations, metapopulation size and the magnitude of fluctuations in population size. Theoretically, each of these is influenced by the rate of migration between subpopulations. Here we report on an experiment where we manipulated migration rate within metapopulations of the freshwater zooplankton Daphnia magna to examine how migration influenced each of these demographic variables, and subsequent effects on metapopulation extinction. In addition, our experimental procedures introduced unplanned but controlled differences between metapopulations in light intensity, enabling us to examine the relative influences of environmental and demographic factors. We found that increasing migration rate increased subpopulation synchrony. We failed to detect effects of migration on population size and fluctuations in population size at the metapopulation or subpopulation level, however. In contrast, light intensity did not influence synchrony, but was positively correlated with population size and negatively correlated with population fluctuation. Finally, synchrony did not influence time to extinction, while population size and the magnitude of fluctuations did. We conclude that environmental factors had a greater influence on extinction risk than demographic factors, and that metapopulation size and fluctuation were more important to extinction risk than metapopulation synchrony. 相似文献
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44.
Chromosomal engineering was used to localize the deoxyerythronolide B synthase (DEBS) genes and propionyl-CoA carboxylase (PCC) genes to the BAP1 Escherichia coli chromosome creating the new strain YW9. YW9 then featured a plasmid-free heterologous pathway for the production of the polyketide product 6-deoxyerythronolide B (6dEB, a precursor to the antibiotic erythromycin) highlighted by the successful chromosomal integration of five genes total and three DEBS genes each approximately 10 kb in length. The new strain was tested for small-scale 6dEB biosynthesis and compared to 6dEB production from plasmid-derived gene expression at 22, 30, and 37 degrees C. YW9 produced 6dEB at each temperature tested; whereas, the current plasmid-based system could only produce 6dEB at 22 and 30 degrees C. As determined by MS analysis, average production levels for YW9 were 0.47 (22 degrees C), 0.52 (30 degrees C), and 0.11 (37 degrees C)mg/L. 相似文献
45.
Metabolic rates provide an estimate of the cost of living for different organisms that can readily be compared across species to provide an estimate of their relative requirements for survival. As such, metabolic rates have been measured for decades on a wide range of organisms. Here, we review published estimates of metabolic rates for brachyuran crabs, a ubiquitous and ecologically and economically important group of consumers. Consistent with ecological theory and results in many other groups of animals, and after controlling for phylogenetic relationships, crab metabolic rates scale with body mass with a scaling exponent of 0.65. Similarly, as with other groups of poikilotherms, crab metabolic rates increase strongly with temperature, with a Q10 of 1.26. Additionally, we found that metabolic rates were correlated with ecological niche, varying with both the diet strategy and the habitat occupied. These results help clarify the relative risk to crabs from environmental changes that impose metabolic stress, including climate change and the proliferation of hypoxic zones. 相似文献
46.
The Helicobacter pylori adhesin protein HopQ exploits the dimer interface of human CEACAMs to facilitate translocation of the oncoprotein CagA 下载免费PDF全文
Daniel A Bonsor Qing Zhao Barbara Schmidinger Evelyn Weiss Jingheng Wang Daniel Deredge Robert Beadenkopf Blaine Dow Wolfgang Fischer Dorothy Beckett Patrick L Wintrode Rainer Haas Eric J Sundberg 《The EMBO journal》2018,37(13)
Helicobacter pylori infects half of the world's population, and strains that encode the cag type IV secretion system for injection of the oncoprotein CagA into host gastric epithelial cells are associated with elevated levels of cancer. CagA translocation into host cells is dependent on interactions between the H. pylori adhesin protein HopQ and human CEACAMs. Here, we present high‐resolution structures of several HopQ‐CEACAM complexes and CEACAMs in their monomeric and dimeric forms establishing that HopQ uses a coupled folding and binding mechanism to engage the canonical CEACAM dimerization interface for CEACAM recognition. By combining mutagenesis with biophysical and functional analyses, we show that the modes of CEACAM recognition by HopQ and CEACAMs themselves are starkly different. Our data describe precise molecular mechanisms by which microbes exploit host CEACAMs for infection and enable future development of novel oncoprotein translocation inhibitors and H. pylori‐specific antimicrobial agents. 相似文献
47.
48.
Anneleen Daemen Obi L Griffith Laura M Heiser Nicholas J Wang Oana M Enache Zachary Sanborn Francois Pepin Steffen Durinck James E Korkola Malachi Griffith Joe S Hur Nam Huh Jongsuk Chung Leslie Cope Mary Jo Fackler Christopher Umbricht Saraswati Sukumar Pankaj Seth Vikas P Sukhatme Lakshmi R Jakkula Yiling Lu Gordon B Mills Raymond J Cho Eric A Collisson Laura J van’t Veer Paul T Spellman Joe W Gray 《Genome biology》2013,14(10):R110
49.
Scanlan BJ Tuft B Elfrey JE Smith A Zhao A Morimoto M Chmielinska JJ Tejero-Taldo MI Mak IuT Weglicki WB Shea-Donohue T 《Molecular and cellular biochemistry》2007,306(1-2):59-69
The aim of this study was to determine the effect of magnesium deficiency on small intestinal morphology and function. Rats
were assigned to 4 groups and placed on magnesium sufficient or deficient diet for 1 or 3 weeks. Infiltration of neutrophils
and mucosal injury were assessed in stained sections of small intestine. Magnesium deficiency alone induced a significant
increase in neutrophil infiltration and increased vascular ICAM-1 expression, in the absence of changes in mucosal injury
or expression of proinflammatory mediators. Magnesium deficiency was associated with hyposecretory epithelial cell responses
and vascular macromolecular leak in the small intestine and lung, which was attributed partly to reduced expression of NOS-3.
To determine the effect of hypomagnesmia on the intestinal responses to a known oxidative stress, groups of rats were randomized
to either sham operation or superior mesenteric artery occlusion for 10 (non-injurious) or 30 (injurious) minutes followed
by a 1- or 4-hour reperfusion period. In response to mesenteric ischemia/reperfusion, deficient rats showed exaggerated PMN
influx, but similar mucosal injury. Intestinal ischemia in sufficient animals induced vascular macromolecular leak in the
small intestine and lung at 4 hours of reperfusion, with levels similar to those observed in untreated deficient rats. Acute
magnesium repletion of deficient rats 24 h before surgery attenuated the exaggerated inflammation in deficient rats. These
data show that magnesium deficiency induced a subclinical inflammation in the small intestine in the absence of mucosal injury,
but with significant functional changes in local and remote organs and increased sensitivity to oxidative stress.
The opinions contained herein are those of the authors and are not to be construed as official policy or reflecting the views
of the Department of Defense 相似文献
50.
BALB/c mice injected intravenously with a single, sub-lethal dose of Nocardia asteroides GUH-2 develop several levodopa responsive movement disorders. These included head-shake, stooped posture, bradykinesia, and hesitation to forward movement (6). The changes in monoamine levels in the brain of these mice were determined. There was a significant loss of dopamine with greatly increased dopamine turnover in the neostriatum 7 to 29 days after infection. These effects were specific for dopaminergic neurons since minimal changes were found in neostriatal norepinephrine and serotonin even though serotonin turnover was increased. Changes in monoamine metabolism were not limited to the neostriatum. There were reduced levels of serotonin and norepinephrine with increased serotonin turnover in the cerebellum. One year after infection, dopamine metabolism had returned to near normal levels, but many of the movement disorders persisted. Specific changes in neurochemistry did not always appear to correspond with these impairments. Nevertheless, these data are similar to those reported in MPTP treated BALB/c mice. 相似文献