108 research outputs found
Cell-Type Specific Translational Profiling in Huntington\u27s Disease Mouse Models
Medium spiny neurons (MSNs) are among the most vulnerable cell populations in Huntington’s Disease (HD). Within this population, striatopallidal MSNs are more vulnerable than striatonigral MSNs, which may explain the typical progression in HD of chorea to hypokinesis. The biological basis for this differential vulnerability is unknown, although differences in transcriptional dysfunction caused by mutant huntingtin (mhtt) have been proposed as a possible mechanism. In order to determine the differences in gene expression caused by mhtt in these two populations, we selectively isolated translated mRNAs from striatopallidal and striatonigral MSNs in the R6-2 and YAC128 HD mouse models at pre- and post-symptomatic time points using the BACTRAP technique (Heiman et al, 2008). We re-characterized the behavioral phenotype of the HD model mice on the D1 and D2 TRAP backgrounds and found many changes in the translated mRNA profiles of these two classes of medium spiny neurons, including known changes in the literature as well as novel pathways. One novel pathway was sphingosine-1-phosphate (S1P) signaling. Because the S1P-receptor G-protein coupled receptor 6 (GPR6) is enriched in striatopallidal cells, we hypothesized that changes in this pathway might play a role in striatopallidal medium spiny neuron vulnerability. Using mass spectrometry, we have shown that S1P levels, as well as other complex sphingolipid species, are decreased in the striatum of R6-2 mice early in disease progression. We have preliminary evidence to suggest Sphk2 and Sgpl1, the enzymes responsible for the production and degradation of S1P, are altered in HD mouse models in patterns that might explain the changes in S1P levels. We have shown that S1P can have pro-survival effects in an in vitro model of striatal origin. Together, these results implicate alterations in S1P signaling in the pathogenesis of Huntington’s Disease and offer an approach for moving from clinical observations of a disease toward the beginning of a mechanistic understanding of the underlying causes of specific cell vulnerability in other diseases
Disparate associations of a functional promoter polymorphism in PCK1 with carotid wall ultrasound traits
Background and Purpose - Cytosolic phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32), encoded by PCK1, catalyzes the first committed step in gluconeogenesis. We previously showed that a -232C\u3eG promoter polymorphism within a cis-acting element required for basal and cAMP-mediated PCK1 gene transcription results in loss of negative regulation by insulin, contributing to worsened metabolic control in the context of insulin resistance. We hypothesized that this polymorphism would be associated with carotid atherosclerosis in a sample of 150 aboriginal Canadians. Methods - Dependent variables were 2 distinct carotid traits, namely intima-media thickness (IMT) assessed using B-mode ultrasound and total carotid plaque volume (TPV) assessed using 3D ultrasound. Results - Multivariate analysis showed significant but opposite associations of PCK1 genotype with these traits. Specifically, subjects with the PCK1-232G/G genotype had more carotid IMT (0.80±0.02 versus 0.73±0.03 mm; P=0.007) but less TPV (0.10±0.09 versus 0.38±0.13; P=0.03) than subjects with other genotypes. Conclusions - The findings connect the key enzyme in gluconeogenesis with atherosclerosis. The meaning of the opposing associations of PCK1 genotype with IMT and TPV is unclear; more work is required to confirm whether these might be distinct quantitative traits with different biological determinants. © 2005 American Heart Association, Inc
Genetic variation in PPARG encoding peroxisome proliferator-activated receptor γ associated with carotid atherosclerosis
Background and Purpose-Peroxisome proliferator-activated receptor γ is a crucial molecule in atherogenesis because it is associated with metabolic risk factors such as obesity and diabetes and also plays a key role in subcellular metabolism of arterial wall macrophage foam cells. Genetic variation in PPARG has been associated with metabolic and cardiovascular end points. Methods-We investigated the relationship between 2 common PPARG polymorphisms, namely P12A and c.1431C\u3eT, and carotid atherosclerosis in a sample of 161 Canadian aboriginal people. Dependent variables were carotid intima media thickness (IMT), assessed using B-mode ultrasonography, and total carotid plaque volume (TPV), assessed using 3D ultrasound. Results-Using multivariate analysis, we found that subjects with ≥ 1 PPARG A12 allele had less carotid IMT than others (0.72±0.03 versus 0.80±0.02 mm; P=0.0045), with no between-genotype difference in TPV. In contrast, subjects with the PPARG c.1431T allele had greater TPV than others (124±18.4 versus 65.1±23.7 mm3; P=0.0079), with no between-genotype difference in IMT. Conclusions-The findings show an association between PPARG genotypes and carotid arterial phenotypes, and further reflect the prevailing view that the PPARG A12 allele protects against deleterious phenotypes. Also, whereas IMT and TPV are somewhat correlated with each other, they might also represent distinct traits with discrete determinants representing different stages of atherogenesis
Identifying therapeutic targets by combining transcriptional data with ordinal clinical measurements
The immense and growing repositories of transcriptional data may contain critical insights for developing new therapies. Current approaches to mining these data largely rely on binary classifications of disease vs. control, and are not able to incorporate measures of disease severity. We report an analytical approach to integrate ordinal clinical information with transcriptomics. We apply this method to public data for a large cohort of Huntington's disease patients and controls, identifying and prioritizing phenotype-associated genes. We verify the role of a high-ranked gene in dysregulation of sphingolipid metabolism in the disease and demonstrate that inhibiting the enzyme, sphingosine-1-phosphate lyase 1 (SPL), has neuroprotective effects in Huntington's disease models. Finally, we show that one consequence of inhibiting SPL is intracellular inhibition of histone deacetylases, thus linking our observations in sphingolipid metabolism to a well-characterized Huntington's disease pathway. Our approach is easily applied to any data with ordinal clinical measurements, and may deepen our understanding of disease processes
A comparison of ultrasound measurements to assess carotid atherosclerosis development in subjects with and without type 2 diabetes
BACKGROUND: Subjects with type 2 diabetes are at an increased risk of vascular complications. The use of carotid ultrasound remains an attractive, non-invasive method to monitor atherosclerotic disease progression and/or response to treatment in patients with type 2 diabetes, with intima-media thickness routinely used as the gold standard to detect pathology. However, alternative measurements, such as plaque area or volume, may represent a potentially more powerful approach. Thus, the objective of this study was to compare the traditional intima-media thickness measurement against the novel total plaque volume measurement in analyzing carotid atherosclerosis development in individuals with type 2 diabetes. METHODS: The case-control study included 49 Oji-Cree adults with diabetes or impaired glucose tolerance, aged 21–69, and 49 sex- and age-matched normoglycemic subjects. At baseline, metabolic variables were measured, including body mass index, waist circumference, total cholesterol:high density lipoprotein ratio, plasma triglycerides, plasma glucose, and serum insulin. Carotid ultrasound measurements, 7 years later, assessed carotid arterial intima-media thickness and total plaque volume. RESULTS: At baseline, the two groups were well matched for smoking habits, hypertension, body mass index, and waist circumference. Differences were noted in baseline measurements of total cholesterol:high density lipoprotein (P = 0.0006), plasma triglycerides (P < 0.0001) and fasting glucose (P < 0.0001). After seven years, carotid ultrasound scans revealed that total plaque volume measurements (P = 0.037), but not intima-media thickness measurements, were higher in subjects with diabetes/impaired glucose tolerance compared to the normoglycemic controls. Correlation between intima-media thickness and total plaque volume was moderate. Based on our study findings, to achieve power levels >0.70 when comparing intima-media thickness measurements for diabetics versus non-diabetics, thousands of study subjects are required. For comparing total plaque volume measurements, only hundreds of study subjects are required. CONCLUSION: The development of atherosclerotic plaque is greater in subjects with diabetes/impaired glucose tolerance. Total plaque volume appears to capture the atherosclerotic disease burden more effectively in subjects with type 2 diabetes, and would be an appropriate outcome measure for studies aimed at changing the diabetic milieu
Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation
The mechanisms by which mutant huntingtin (mHTT) leads to neuronal cell death in Huntington’s disease (HD) are not fully understood. To gain new molecular insights, we used single nuclear RNA sequencing (snRNA-seq) and translating ribosome affinity purification (TRAP) to conduct transcriptomic analyses of caudate/putamen (striatal) cell type-specific gene expression changes in human HD and mouse models of HD. In striatal spiny projection neurons, the most vulnerable cell type in HD, we observe a release of mitochondrial RNA (mtRNA) (a potent mitochondrial-derived innate immunogen) and a concomitant upregulation of innate immune signaling in spiny projection neurons. Further, we observe that the released mtRNAs can directly bind to the innate immune sensor protein kinase R (PKR). We highlight the importance of studying cell type-specific gene expression dysregulation in HD pathogenesis and reveal that the activation of innate immune signaling in the most vulnerable HD neurons provides a novel framework to understand the basis of mHTT toxicity and raises new therapeutic opportunities
Relationship of the metabolic syndrome to carotid ultrasound traits
BACKGROUND: The metabolic syndrome is associated with increased vascular disease risk. We evaluated two carotid ultrasound measurements, namely intima media thickness and total plaque volume, in a Canadian Oji-Cree population with a high metabolic syndrome prevalence rate. METHODS: As part of the Sandy Lake Complications Prevalence and Risk Factor Study, 166 Oji-Cree subjects (baseline metabolic syndrome prevalence, 44.0%, according to the National Cholesterol Education Program Adult Treatment Panel III guidelines) were examined using a high-resolution duplex ultrasound scanner. RESULTS: Image analysis showed that mean intima media thickness was elevated in subjects with the metabolic syndrome (818 ± 18 vs 746 ± 20 μm), as was total plaque volume (125 ± 26 vs 77.3 ± 17.0 mm(3)). However, after adjustment for age and sex, the differences were significant only for intima media thickness (P = 0.039). Furthermore, a significant trend towards increased intima media thickness was observed with increasing numbers of metabolic syndrome components: mean intima media thickness was highest among individuals with all five metabolic syndrome components compared to those with none (866 ± 55 vs 619 ± 23 μm, P = 0.0014). A similar, but non-significant trend was observed for total plaque volume. CONCLUSION: This is the first study of the relationship between the metabolic syndrome and two distinct carotid ultrasound traits measured in the same individuals. The results suggest that standard intima media thickness measurement shows a more consistent and stronger association with the metabolic syndrome than does total plaque volume
The case for the continued use of the genus name Mimulus for all monkeyflowers
The genus Mimulus is a well-studied group of plant species, which has for decades allowed researchers to address a wide array of fundamental questions in biology (Wu & al. 2008; Twyford & al. 2015). Linnaeus named the type species of Mimulus (ringens L.), while Darwin (1876) used Mimulus (luteus L.) to answer key research questions. The incredible phenotypic diversity of this group has made it the focus of ecological and evolutionary study since the mid-20th century, initiated by the influential work of Clausen, Keck, and Hiesey as well as their students and collaborators (Clausen & Hiesey 1958; Hiesey & al. 1971, Vickery 1952, 1978). Research has continued on this group of diverse taxa throughout the 20th and into the 21st century (Bradshaw & al. 1995; Schemske & Bradshaw 1999; Wu & al. 2008; Twyford & al. 2015; Yuan 2019), and Mimulus guttatus was one of the first non-model plants to be selected for full genome sequencing (Hellsten & al. 2013). Mimulus has played a key role in advancing our general understanding of the evolution of pollinator shifts (Bradshaw & Schemske 2003; Cooley & al. 2011; Byers & al. 2014), adaptation (Lowry & Willis 2010; Kooyers & al. 2015; Peterson & al. 2016; Ferris & Willis 2018; Troth & al. 2018), speciation (Ramsey & al. 2003; Wright & al. 2013; Sobel & Streisfeld 2015; Zuellig & Sweigart 2018), meiotic drive (Fishman & Saunders 2008), polyploidy (Vallejo-Marín 2012; Vallejo-Marín & al. 2015), range limits (Angert 2009; Sexton et al. 2011; Grossenbacher & al. 2014; Sheth & Angert 2014), circadian rhythms (Greenham & al. 2017), genetic recombination (Hellsten & al. 2013), mating systems (Fenster & Ritland 1994; Dudash & Carr 1998; Brandvain & al. 2014) and developmental biology (Moody & al. 1999; Baker & al. 2011, 2012; Yuan 2019). This combination of a rich history of study coupled with sustained modern research activity is unparalleled among angiosperms. Across many interested parties, the name Mimulus therefore takes on tremendous biological significance and is recognizable not only by botanists, but also by zoologists, horticulturalists, naturalists, and members of the biomedical community. Names associated with a taxonomic group of this prominence should have substantial inertia, and disruptive name changes should be avoided. As members of the Mimulus community, we advocate retaining the genus name Mimulus to describe all monkeyflowers. This is despite recent nomenclature changes that have led to a renaming of most monkeyflower species to other genera.Additional co-authors: Jannice Friedman, Dena L Grossenbacher, Liza M Holeski, Christopher T Ivey, Kathleen M Kay, Vanessa A Koelling, Nicholas J Kooyers, Courtney J Murren, Christopher D Muir, Thomas C Nelson, Megan L Peterson, Joshua R Puzey, Michael C Rotter, Jeffrey R Seemann, Jason P Sexton, Seema N Sheth, Matthew A Streisfeld, Andrea L Sweigart, Alex D Twyford, John H Willis, Kevin M Wright, Carrie A Wu, Yao-Wu Yua
Retreat into scientism, paradoxes of transparency, and corruption in education
Um dos sintomas da razão indolente (SANTOS, 2006) é o recuo ao cientificismo, o qual tem sido, particularmente, acentuado nas políticas, cada vez mais hegemônicas, de avaliação, de prestação de contas e de responsabilização. Por isso, um dos objetivos deste texto é o de colocar em causa este aparente consenso
cientificista (ou este consenso supostamente transideológico) e fazer uma breve incursão exploratória ao que aqui se designa de paradoxos da transparência. Considera-se que esses paradoxos traduzem a existência de tensões e contradições relativas a uma dimensão central dos discursos políticos e educacionais contemporâneos. Com isso, o artigo pretende dar continuidade a uma linha de pesquisa que tem procurado sublinhar a relevância da necessidade de complexificar e dar maior rigor teórico-conceptual à accountability em educação. Finalmente, tentando abrir caminho para o desenvolvimento de novas articulações e análises, chama-se a atenção para a corrupção na educação cuja complexidade ainda é insuficientemente
conhecida e pesquisada, nomeadamente, nas suas relações com as problemáticas da transparência e da accountability. Admite-se que as práticas de corrupção em educação, em muitas situações, são (paradoxalmente) induzidas pela necessidade de dar resposta à governação baseada nos números, nos rankings e nas (supostas) evidências, anulando completamente as expectativas legítimas em torno da transparência dos processos educacionais e das decisões políticas.One symptom of “indolent reason” (SANTOS, 2006) is the retreat into scientism, which is especially marked in the increasingly hegemonic policies surrounding assessment, reporting and accountability. As such, one of the aims of this paper is to call into question this apparent consensus on scientism (a supposedly trans-ideological
consensus), and briefly explore what we define as the paradoxes of transparency. These paradoxes are found to reveal the existence of tensions and contradictions concerning a central aspect of current political and educational discourse. In doing so, the article seeks to continue a line of study which has aimed to emphasize the significance of the need for a more complex, and theoretically and conceptually rigorous understanding of accountability in education. Finally, in an attempt to pave the way for further discussion and analysis, attention is drawn to corruption in education, the complex nature of which remains insufficiently understood and studied,
notably in terms of its relationship with the problems of transparency and accountability. It is acknowledged that practices of corruption within education are, in many situations, (paradoxically) caused by the need to answer to a system of governance based on numbers, league tables, and (supposed) truths, completely nullifying legitimate expectations about the transparency of educational processes and policy decisions.Trabalho financiado por Fundos Nacionais através da FCT – Fundação para a Ciência e a Tecnologia – no âmbito do Projeto PEst-OE/CED/UI1661/2014.info:eu-repo/semantics/publishedVersio
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