2,101 research outputs found

    SAF-A mutants disrupt chromatin structure through dominant negative effects on RNAs associated with chromatin

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    Here we provide a brief review of relevant background before presenting results of our investigation into the interplay between scaffold attachment factor A (SAF-A), chromatin-associated RNAs, and DNA condensation. SAF-A, also termed heterogenous nuclear protein U (hnRNP U), is a ubiquitous nuclear scaffold protein that was implicated in XIST RNA localization to the inactive X-chromosome (Xi) but also reported to maintain open DNA packaging in euchromatin. Here we use several means to perturb SAF-A and examine potential impacts on the broad association of RNAs on euchromatin, and on chromatin compaction. SAF-A has an N-terminal DNA binding domain and C-terminal RNA binding domain, and a prominent model has been that the protein provides a single-molecule bridge between XIST RNA and chromatin. Here analysis of the impact of SAF-A on broad RNA-chromatin interactions indicate greater biological complexity. We focus on SAF-A\u27s role with repeat-rich C0T-1 hnRNA (repeat-rich heterogeneous nuclear RNA), shown recently to comprise mostly intronic sequences of pre-mRNAs and diverse long non-coding RNAs (lncRNAs). Our results show that SAF-A mutants cause dramatic changes to cytological chromatin condensation through dominant negative effects on C0T-1 RNA\u27s association with euchromatin, and likely other nuclear scaffold factors. In contrast, depletion of SAF-A by RNA interference (RNAi) had no discernible impact on C0T-1 RNA, nor did it cause similarly marked chromatin changes as did three different SAF-A mutations. Overall results support the concept that repeat-rich, chromatin-associated RNAs interact with multiple RNA binding proteins (RBPs) in a complex dynamic meshwork that is integral to larger-scale chromatin architecture and collectively influences cytological-scale DNA condensation

    New Barriers to Participation: Application of New Mexico's Voter Identification Law

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    In democratic societies there is a tension between maximizing ballot access and minimizing voter fraud. Since the 2000 presidential election, this tension has been central to discussions about election reform, at the national and local level. We examine this tension by focusing on the implementation of voter identification laws in one state that has experienced significant issues in recent elections, and that is now implementing significant attempts at election reform: New Mexico. We hypothesized that Hispanic voters were more likely to show some form of identification than other types of voters. Using a voter data set from New Mexico’s First Congressional District in the 2006 election, we find that Hispanic, male and Election Day voters were more likely to show some form of identification than non-Hispanic, female and early voters. In addition, using an overlapping study of Bernalillo County 2006 poll workers, we find no evidence that certain groups of poll workers were more likely to ask for voter identification. Our findings suggest that broad voter identification laws, which may be applied unequally, may be perceived as discriminatory

    PCV23: VARIATION IN COSTS OF TREATING HYPERCHOLESTEROLEMIC PATIENTS IN FRANCE

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    The evolution of male ornamentation has long been the focus of sexual selection studies. However, evidence is accumulating that sexually selected traits can also be lost, although the process is ill-understood. In male fairy-wrens (Malurus spp.), early molt into the seasonal breeding plumage is critical for obtaining extra-pair paternity (EPP), which reaches very high levels in these socially monogamous songbirds. A notable exception is the purple-crowned fairy-wren, Malurus coronatus, which, like its congeners, breeds cooperatively, but where EPP is very rare. Nevertheless, males develop a conspicuous seasonal breeding plumage at highly variable times. Based on 6 years of molt data collected for 137 individuals, we investigated the adaptive significance of pre-breeding molt timing as a sexual signal under (near) genetic monogamy. Molt timing varied between and within individuals with age and climate: molt was completed earlier in older males and after wetter years. Despite its potential to act as a sexual signal of male quality, fitness benefits and costs of early molt appear limited: molt timing did not correlate with 1) the likelihood of gaining a breeding position; 2) female mate preference (EPP/cuckoldry, divorce); 3) female reproductive investment (breeding timing, clutch size, number of clutches); 4) breeding performance (hatching success, fledging success, fledgling survival, annual reproductive success); and 5) male survival. However, although molt timing did not predict which subordinates would become breeders, breeders molted earlier than subordinates. The lack of EPP in this species might imply relaxed sexual selection on early molt with potential to lead to trait disappearance

    Cosmological Constraints on Dissipative Models of Inflation

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    (Abridged) We study dissipative inflation in the regime where the dissipative term takes a specific form, \Gamma=\Gamma(\phi), analyzing two models in the weak and strong dissipative regimes with a SUSY breaking potential. After developing intuition about the predictions from these models through analytic approximations, we compute the predicted cosmological observables through full numerical evolution of the equations of motion, relating the mass scale and scale of dissipation to the characteristic amplitude and shape of the primordial power spectrum. We then use Markov Chain Monte Carlo techniques to constrain a subset of the models with cosmological data from the cosmic microwave background (WMAP three-year data) and large scale structure (SDSS Luminous Red Galaxy power spectrum). We find that the posterior distributions of the dissipative parameters are highly non-Gaussian and their allowed ranges agree well with the expectations obtained using analytic approximations. In the weak regime, only the mass scale is tightly constrained; conversely, in the strong regime, only the dissipative coefficient is tightly constrained. A lower limit is seen on the inflation scale: a sub-Planckian inflaton is disfavoured by the data. In both weak and strong regimes, we reconstruct the limits on the primordial power spectrum and show that these models prefer a {\it red} spectrum, with no significant running of the index. We calculate the reheat temperature and show that the gravitino problem can be overcome with large dissipation, which in turn leads to large levels of non-Gaussianity: if dissipative inflation is to evade the gravitino problem, the predicted level of non-Gaussianity might be seen by the Planck satellite.Comment: 14 pages, 9 figures, Accepted by JCAP without text changes, References adde

    Strategic Planning for Local Tourism Destinations: An Analysis of Tourism

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    This paper reports on a study of the planning practices of local tourism destinations. The tourism plans of 30 local tourism destinations in Queensland, Australia were analyzed to determine the extent to which sustainability principles, namely strategic planning and stakeholder participation, were integrated into the planning process. Utilizing a tourism planning process evaluation instrument developed by Simpson (2001), it was found that local tourism destinations are not integrating sustainability principles in their planning processes

    Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells

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    Dicer, an enzyme involved in microRNA (miRNA) maturation, is required for proper cell differentiation and embryogenesis in mammals. Recent evidence indicates that Dicer and miRNA may also regulate tumorigenesis. To better characterize the role of miRNA in primary cell growth, we generated Dicer-conditional mice. Ablation of Dicer and loss of mature miRNAs in embryonic fibroblasts up-regulated p19Arf and p53 levels, inhibited cell proliferation, and induced a premature senescence phenotype that was also observed in vivo after Dicer ablation in the developing limb and in adult skin. Furthermore, deletion of the Ink4a/Arf or p53 locus could rescue fibroblasts from premature senescence induced by Dicer ablation. Although levels of Ras and Myc oncoproteins appeared unaltered, loss of Dicer resulted in increased DNA damage and p53 activity in these cells. These results reveal that loss of miRNA biogenesis activates a DNA damage checkpoint, up-regulates p19Arf-p53 signaling, and induces senescence in primary cells

    The impact of storage conditions on human stool 16S rRNA microbiome composition and diversity

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    Background: Multiple factors can influence stool sample integrity upon sample collection. Preservation of faecal samples for microbiome studies is therefore an important step, particularly in tropical regions where resources are limited and high temperatures may significantly influence microbiota profiles. Freezing is the accepted standard to preserve faecal samples however, cold chain methods are often unfeasible in fieldwork scenarios particularly in low and middle-income countries and alternatives are required. This study therefore aimed to address the impact of different preservative methods, time-to-freezing at ambient tropical temperatures, and stool heterogeneity on stool microbiome diversity and composition under real-life physical environments found in resource-limited fieldwork conditions. Methods: Inner and outer stool samples collected from one specimen obtained from three children were stored using different storage preservation methods (raw, ethanol and RNAlater) in a Ugandan field setting. Mixed stool was also stored using these techniques and frozen at different time-to-freezing intervals post-collection from 0–32 h. Metataxonomic profiling was used to profile samples, targeting the V1–V2 regions of 16S rRNA with samples run on a MiSeq platform. Reads were trimmed, combined and aligned to the Greengenes database. Microbial diversity and composition data were generated and analysed using Quantitative Insights Into Microbial Ecology and R software. Results: Child donor was the greatest predictor of microbiome variation between the stool samples, with all samples remaining identifiable to their child of origin despite the stool being stored under a variety of conditions. However, significant differences were observed in composition and diversity between preservation techniques, but intra-preservation technique variation was minimal for all preservation methods, and across the time-to-freezing range (0–32 h) used. Stool heterogeneity yielded no apparent microbiome differences. Conclusions: Stool collected in a fieldwork setting for comparative microbiome analyses should ideally be stored as consistently as possible using the same preservation method throughout

    Centriolar satellites expedite mother centriole remodeling to promote ciliogenesis

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    Centrosomes are orbited by centriolar satellites, dynamic multiprotein assemblies nucleated by Pericentriolar material 1 (PCM1). To study the requirement for centriolar satellites, we generated mice lacking PCM1, a crucial component of satellites. Pcm1−/− mice display partially penetrant perinatal lethality with survivors exhibiting hydrocephalus, oligospermia, and cerebellar hypoplasia, and variably expressive phenotypes such as hydronephrosis. As many of these phenotypes have been observed in human ciliopathies and satellites are implicated in cilia biology, we investigated whether cilia were affected. PCM1 was dispensable for ciliogenesis in many cell types, whereas Pcm1−/− multiciliated ependymal cells and human PCM1−/− retinal pigmented epithelial 1 (RPE1) cells showed reduced ciliogenesis. PCM1−/− RPE1 cells displayed reduced docking of the mother centriole to the ciliary vesicle and removal of CP110 and CEP97 from the distal mother centriole, indicating compromised early ciliogenesis. Similarly, Pcm1−/− ependymal cells exhibited reduced removal of CP110 from basal bodies in vivo. We propose that PCM1 and centriolar satellites facilitate efficient trafficking of proteins to and from centrioles, including the departure of CP110 and CEP97 to initiate ciliogenesis, and that the threshold to trigger ciliogenesis differs between cell types
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