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601.
Par proteins establish discrete intracellular spatial domains to polarize many different cell types. In the single-cell embryo of the nematode worm Caenorhabditis elegans, the segregation of Par proteins is crucial for proper division and cell fate specification. Actomyosin-based cortical flows drive the initial formation of anterior and posterior Par domains, but cortical actin is not required for the maintenance of these domains. Here we develop a model of interactions between the Par proteins that includes both mutual inhibition and PAR-3 oligomerization. We show that this model gives rise to a bistable switch mechanism, allowing the Par proteins to occupy distinct anterior and posterior domains seen in the early C. elegans embryo, independent of dynamics or asymmetries in the actin cortex. The model predicts a sharp loss of cortical Par protein asymmetries during gradual depletion of the Par protein PAR-6, and we confirm this prediction experimentally. Together, these results suggest both mutual inhibition and PAR-3 oligomerization are sufficient to maintain distinct Par protein domains in the early C. elegans embryo. 相似文献
602.
Ceniz Zihni Peter M.G. Munro Ahmed Elbediwy Nicholas H. Keep Stephen J. Terry John Harris Maria S. Balda Karl Matter 《The Journal of cell biology》2014,204(1):111-127
Epithelial cells develop morphologically characteristic apical domains that are bordered by tight junctions, the apical–lateral border. Cdc42 and its effector complex Par6–atypical protein kinase c (aPKC) regulate multiple steps during epithelial differentiation, but the mechanisms that mediate process-specific activation of Cdc42 to drive apical morphogenesis and activate the transition from junction formation to apical differentiation are poorly understood. Using a small interfering RNA screen, we identify Dbl3 as a guanine nucleotide exchange factor that is recruited by ezrin to the apical membrane, that is enriched at a marginal zone apical to tight junctions, and that drives spatially restricted Cdc42 activation, promoting apical differentiation. Dbl3 depletion did not affect junction formation but did affect epithelial morphogenesis and brush border formation. Conversely, expression of active Dbl3 drove process-specific activation of the Par6–aPKC pathway, stimulating the transition from junction formation to apical differentiation and domain expansion, as well as the positioning of tight junctions. Thus, Dbl3 drives Cdc42 signaling at the apical margin to regulate morphogenesis, apical–lateral border positioning, and apical differentiation. 相似文献
603.
604.
Margherita Bertuzzi Markus Schrettl Laura Alcazar-Fuoli Timothy C. Cairns Alberto Mu?oz Louise A. Walker Susanne Herbst Maryam Safari Angela M. Cheverton Dan Chen Hong Liu Shinobu Saijo Natalie D. Fedorova Darius Armstrong-James Carol A. Munro Nick D. Read Scott G. Filler Eduardo A. Espeso William C. Nierman Hubertus Haas Elaine M. Bignell 《PLoS pathogens》2014,10(10)
605.
Yoni Gavish Hadar Kedem Irit Messika Carmit Cohen Evelyn Toh Daniel Munro Qunfeng Dong Clay Fuqua Keith Clay Hadas Hawlena 《PloS one》2014,9(10)
Relationships between host and microbial diversity have important ecological and applied implications. Theory predicts that these relationships will depend on the spatio-temporal scale of the analysis and the niche breadth of the organisms in question, but representative data on host-microbial community assemblage in nature is lacking. We employed a natural gradient of rodent species richness and quantified bacterial communities in rodent blood at several hierarchical spatial scales to test the hypothesis that associations between host and microbial species diversity will be positive in communities dominated by organisms with broad niches sampled at large scales. Following pyrosequencing of rodent blood samples, bacterial communities were found to be comprised primarily of broad niche lineages. These communities exhibited positive correlations between host diversity, microbial diversity and the likelihood for rare pathogens at the regional scale but not at finer scales. These findings demonstrate how microbial diversity is affected by host diversity at different spatial scales and suggest that the relationships between host diversity and overall disease risk are not always negative, as the dilution hypothesis predicts. 相似文献
606.
Association of Dietary Factors with Presence and Severity of Tinnitus in a Middle-Aged UK Population
Abby McCormack Mark Edmondson-Jones Duane Mellor Piers Dawes Kevin J. Munro David R. Moore Heather Fortnum 《PloS one》2014,9(12)
Objective
The impact of dietary factors on tinnitus has received limited research attention, despite being a considerable concern among people with tinnitus and clinicians. The objective was to examine the link between dietary factors and presence and severity of tinnitus.Design
This study used the UK Biobank resource, a large cross-sectional study of adults aged 40–69. 171,722 eligible participants were asked questions specific to tinnitus (defined as noises such as ringing or buzzing in the head or ears). Dietary factors included portions of fruit and vegetables per day, weekly fish consumption (oily and non-oily), bread type, cups of caffeinated coffee per day, and avoidance of dairy, eggs, wheat and sugar. We controlled for lifestyle, noise exposure, hearing, personality and comorbidity factors.Results
Persistent tinnitus, defined as present at least a lot of the time, was elevated with increased: (i) fruit/vegetable intake (OR = 1.01 per portion/day), (ii) bread (wholemeal/wholegrain, OR = 1.07; other bread, 1.20) and (iii) dairy avoidance (OR = 1.27). Persistent tinnitus was reduced with: (i) fish consumption (non-oily, OR = 0.91; oily, 0.95), (ii) egg avoidance (OR = 0.87) and (iii) caffeinated coffee consumption (OR = 0.99 per cup/day). Reports of “bothersome” tinnitus (moderate-severe handicap) increased with wholemeal/wholegrain bread intake (OR = 0.86). Reports of less frequent transient tinnitus increased with dairy avoidance (OR = 1.18) and decreased with caffeinated coffee (OR = 0.98 per cup/day) and brown bread (OR = 0.94).Conclusions
This is the first population study to report the association between dietary factors and tinnitus. Although individually dietary associations are mostly modest, particular changes in diet, such as switching between foodstuffs, may result in stronger associations. These findings offer insights into possible dietary associations with tinnitus, and this may be useful when discussing management options in combination with other lifestyle changes and therapies. 相似文献607.
D A Parfitt M Aguila C H McCulley D Bevilacqua H F Mendes D Athanasiou S S Novoselov N Kanuga P M Munro P J Coffey B Kalmar L Greensmith M E Cheetham 《Cell death & disease》2014,5(5):e1236
Retinitis pigmentosa (RP) is a group of inherited diseases that cause blindness due to the progressive death of rod and cone photoreceptors in the retina. There are currently no effective treatments for RP. Inherited mutations in rhodopsin, the light-sensing protein of rod photoreceptor cells, are the most common cause of autosomal-dominant RP. The majority of mutations in rhodopsin, including the common P23H substitution, lead to protein misfolding, which is a feature in many neurodegenerative disorders. Previous studies have shown that upregulating molecular chaperone expression can delay disease progression in models of neurodegeneration. Here, we have explored the potential of the heat-shock protein co-inducer arimoclomol to ameliorate rhodopsin RP. In a cell model of P23H rod opsin RP, arimoclomol reduced P23H rod opsin aggregation and improved viability of mutant rhodopsin-expressing cells. In P23H rhodopsin transgenic rat models, pharmacological potentiation of the stress response with arimoclomol improved electroretinogram responses and prolonged photoreceptor survival, as assessed by measuring outer nuclear layer thickness in the retina. Furthermore, treated animal retinae showed improved photoreceptor outer segment structure and reduced rhodopsin aggregation compared with vehicle-treated controls. The heat-shock response (HSR) was activated in P23H retinae, and this was enhanced with arimoclomol treatment. Furthermore, the unfolded protein response (UPR), which is induced in P23H transgenic rats, was also enhanced in the retinae of arimoclomol-treated animals, suggesting that arimoclomol can potentiate the UPR as well as the HSR. These data suggest that pharmacological enhancement of cellular stress responses may be a potential treatment for rhodopsin RP and that arimoclomol could benefit diseases where ER stress is a factor. 相似文献
608.
Kimberly L. Weirich Samantha Stam Edwin Munro Margaret L. Gardel 《Biophysical journal》2021,120(10):1957-1970
The actin cytoskeleton is a soft, structural material that underlies biological processes such as cell division, motility, and cargo transport. The cross-linked actin filaments self-organize into a myriad of architectures, from disordered meshworks to ordered bundles, which are hypothesized to control the actomyosin force generation that regulates cell migration, shape, and adhesion. Here, we use fluorescence microscopy and simulations to investigate how actin bundle architectures with varying polarity, spacing, and rigidity impact myosin II dynamics and force generation. Microscopy reveals that mixed-polarity bundles formed by rigid cross-linkers support slow, bidirectional myosin II filament motion, punctuated by periods of stalled motion. Simulations reveal that these locations of stalled myosin motion correspond to sustained, high forces in regions of balanced actin filament polarity. By contrast, mixed-polarity bundles formed by compliant, large cross-linkers support fast, bidirectional motion with no traps. Simulations indicate that trap duration is directly related to force magnitude and that the observed increased velocity corresponds to lower forces resulting from both the increased bundle compliance and filament spacing. Our results indicate that the microstructures of actin assemblies regulate the dynamics and magnitude of myosin II forces, highlighting the importance of architecture and mechanics in regulating forces in biological materials. 相似文献
609.
Abstract During the course of natural product screening, two actinomycete strains, designated 3828E and 3913E, were isolated from soil collected in the Phillipines and New Zealand, respectively. Strain 3828E released without induction an actinophage. The host isolate was chemotaxonomically identical to members of the revised genus Microtetraspora having both wall chemotype III, sugar pattern B and phospholipid pattern PIV. On the basis of cultural and morphological characteristics, the isolate was most similar to Microtetraspora salmonea . Strain 3913E shared the same chemotaxonomic characteristics as strain 3828E; however, morphological examination revealed the presence of spores arranged distinctively as pairs along aerial hyphae. On this basis, strain 3913E was classified as a member of the genus Microbispora . When re-infected into the soil it had been isolated from, actinophage were recovered that specifically attacked strain 3931E. The presence of phage from both maduromycetes was confirmed by transmission electron microscopy. Neither phage was able to attack a range of other actinomycetes. We believe this to be the first reported isolation of actinophage that attack species of the genera Microtetraspora and Microbispora . 相似文献
610.
Escherichia coli are the most common etiological agents of urinary tract infections (UTIs). Uropathogenic E. coli (UPECs) produce specific toxins including the cytotoxic necrotizing factor-1 (CNF1) and the alpha-hemolysin (alpha-Hly). CNF1 triggers, through Rho protein activation, a specific gene response of host cells, which results in the production for instance of interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and the macrophage inflammatory protein-3alpha (MIP-3alpha). The alpha hemolysin alpha-Hly also triggers the production of inflammatory mediators. Cnf1 is always associated with alpha-hly in a pathogenicity island conserved among UPECs. Using two complementary approaches we have investigated whether alpha-hly and cnf1 bearing UPECs are associated with a specific type of UTI both in term of pathology and host response. Here we report that UPECs bearing alpha-hly/cnf1 have a prevalence of 50% in UPECs isolated from hemorrhagic UTIs, as compared to 30% in the overall UPEC population. In addition, we observed that MCP-1, and IL-8 to a lower extent, is produced in urine at higher concentrations in UTIs caused by UPECs carrying alpha-hly/cnf1. 相似文献