Electrically conductive polyimides containing silver trifluoroacetylacetonate

Polyimides with enhanced electrical conductivity are produced by adding a silver ion-containing additive to the polyamic acid resin formed by the condensation of an aromatic dianhydride with an aromatic diamine. After thermal treatment the resulting polyimides had surface conductivities in the range of 1.7.times.10.sup.-3 4.5 .OMEGA..sup.-1 making them useful in low the electronics industry as flexible, electrically conductive polymeric films and coatings

Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control.

Approximately half the mammalian genome is composed of repetitive sequences, and accumulating evidence suggests that some may have an impact on genome function. Here, we characterized a large array class of repeats of long-interspersed elements (LINE-1). Although widely distributed in mammals, locations of such arrays are species specific. Using targeted deletion, we asked whether a 170-kb LINE-1 array located at a mouse imprinted domain might function as a modulator of local transcriptional control. The LINE-1 array is lamina associated in differentiated ES cells consistent with its AT-richness, and although imprinting occurs both proximally and distally to the array, active LINE-1 transcripts within the tract are biallelically expressed. Upon deletion of the array, no perturbation of imprinting was observed, and abnormal phenotypes were not detected in maternal or paternal heterozygous or homozygous mutant mice. The array does not shield nonimprinted genes in the vicinity from local imprinting control. Reduced neural expression of protein-coding genes observed upon paternal transmission of the deletion is likely due to the removal of a brain-specific enhancer embedded within the LINE array. Our findings suggest that presence of a 170-kb LINE-1 array reflects the tolerance of the site for repeat insertion rather than an important genomic function in normal development

Distinct Effects of Two HIV-1 Capsid Assembly Inhibitor Families That Bind the Same Site within the N-Terminal Domain of the Viral CA Protein

The emergence of resistance to existing classes of antiretroviral drugs necessitates finding new HIV-1 targets for drug discovery. The viral capsid (CA) protein represents one such potential new target. CA is sufficient to form mature HIV-1 capsids in vitro, and extensive structure-function and mutational analyses of CA have shown that the proper assembly, morphology, and stability of the mature capsid core are essential for the infectivity of HIV-1 virions. Here we describe the development of an in vitro capsid assembly assay based on the association of CA-NC subunits on immobilized oligonucleotides. This assay was used to screen a compound library, yielding several different families of compounds that inhibited capsid assembly. Optimization of two chemical series, termed the benzodiazepines (BD) and the benzimidazoles (BM), resulted in compounds with potent antiviral activity against wild-type and drug-resistant HIV-1. Nuclear magnetic resonance (NMR) spectroscopic and X-ray crystallographic analyses showed that both series of inhibitors bound to the N-terminal domain of CA. These inhibitors induce the formation of a pocket that overlaps with the binding site for the previously reported CAP inhibitors but is expanded significantly by these new, more potent CA inhibitors. Virus release and electron microscopic (EM) studies showed that the BD compounds prevented virion release, whereas the BM compounds inhibited the formation of the mature capsid. Passage of virus in the presence of the inhibitors selected for resistance mutations that mapped to highly conserved residues surrounding the inhibitor binding pocket, but also to the C-terminal domain of CA. The resistance mutations selected by the two series differed, consistent with differences in their interactions within the pocket, and most also impaired virus replicative capacity. Resistance mutations had two modes of action, either directly impacting inhibitor binding affinity or apparently increasing the overall stability of the viral capsid without affecting inhibitor binding. These studies demonstrate that CA is a viable antiviral target and demonstrate that inhibitors that bind within the same site on CA can have distinct binding modes and mechanisms of action

Who Decides and Why it Matters: Institutions, Differentiation and Northern Rural Higher Education

The purpose of this research was to study the impact of institutional forces on higher education policy processes. The project involved a case study analysis of the alignment between intention and perceived impact, focused specifically on the implementation of higher education differentiation policy within two of Canada’s provincial norths (Northern Alberta and Northern Ontario). These provinces were chosen because they represent two of the largest jurisdictions in Canada by population, and because they have both implemented differentiation policy frameworks within the last decade and a half. The research was undertaken within a theoretical framework that combined elements of new institutionalism (North, 1990; DiMaggio Powell, 1991; Thelen, 1999; Peters, 2012; Lowndes Roberts, 2013; Scott, 2014), strategic reaction theory (Oliver 1991), pragmatism (Allison Pomeroy, 2000; Duemer Zebidi, 2009; Anderson Shattuck, 2012; Kaye, 2013), and power (Foucault, 1980; Mills, 2003). Through examination of the ways in which similar policy goals were implemented in Northern and Rural Central Alberta, and in Northern Ontario, it was possible to identify institutional forces that impacted the policy process in each jurisdiction. The central argument of this study was that, in order to improve alignment between policy intentions and policy outcomes, policy makers (political decision makers) and policy implementers (organizational decision makers) must take these institutional forces into account at every stage in the higher education policy process.Ph.D

Association between anxiety and cognitive decline in community-dwelling older adults

Le premier objectif de cette étude consiste à déterminer si l’anxiété (clinique ou sous-clinique), chez les aînés, est associée au déclin cognitif sur une période d’un an. Le deuxième objectif est de vérifier l’existence de différences entre les hommes et les femmes quant à l’association entre l’anxiété et le déclin cognitif. Un échantillon populationnel de 1942 participants, âgés entre 65 et 96 ans, a été évalué à l’entrée dans l’étude (T0) et un an plus tard (T1). L’anxiété a été identifiée sur la base d’une entrevue semi-structurée et le fonctionnement cognitif a été évalué avec le Mini-Mental State Examination. Les résultats révèlent que la présence d’un trouble anxieux ne prédit pas le déclin cognitif chez les hommes et les femmes. L’anxiété sous-clinique prédit un déclin cognitif, mais chez les femmes seulement. Par ailleurs, chez les hommes, la présence de symptômes appartenant à plus d’un trouble anxieux prédit un déclin cognitif. Chez les femmes, le déclin est prédit par la présence de symptômes appartenant à un seul trouble anxieux. Ces résultats illustrent le rôle de l’anxiété dans le déclin cognitif des personnes âgées vivant dans la population générale.The present study was conducted to determine whether anxiety among community-dwelling elders is associated with cognitive decline over a period of one year as well as to verify whether there are sex differences in the association between anxiety and cognitive decline. Participants (n=1942) were community-dwelling adults aged 65–96 years assessed at study entry (T0) and one year later (T1). Anxiety was identified with a semi-structured interview and cognitive functioning was assessed using the Mini-Mental State Examination. Results revealed that the presence of a clinically significant anxiety disorder did not predict cognitive decline in men and women. Subclinical anxiety symptoms predicted cognitive decline in women only. Moreover, for men, the presence of symptoms from at least two anxiety disorders predicted cognitive decline. For women, cognitive decline was predicted by the presence of symptoms from one anxiety disorder only. Overall, the results illustrate the role of anxiety in cognitive decline in community-dwelling older adults

Biphenylsulfonacetic Acid Inhibitors of the Human Papillomavirus Type 6 E1 Helicase Inhibit ATP Hydrolysis by an Allosteric Mechanism Involving Tyrosine 486

Human papillomaviruses (HPVs) are the causative agents of benign and malignant lesions of the epithelium. Despite their high prevalence, there is currently no antiviral drug for the treatment of HPV-induced lesions. The ATPase and helicase activities of the highly conserved E1 protein of HPV are essential for viral DNA replication and pathogenesis and hence are considered valid antiviral targets. We recently described novel biphenylsulfonacetic acid inhibitors of the ATPase activity of E1 from HPV type 6 (HPV6). Based on kinetics and mutagenesis studies, we now report that these compounds act by an allosteric mechanism. They are hyperbolic competitive inhibitors of the ATPase activity of HPV6 E1 and also inhibit its helicase activity. Compounds in this series can also inhibit the ATPase activity of the closely related enzyme from HPV11; however, the most potent inhibitors of HPV6 E1 are significantly less active against the type 11 protein. We identified a single critical residue in HPV6 E1, Tyr-486, substituted by a cysteine in HPV11, which is primarily responsible for this difference in inhibitor potency. Interestingly, HPV18 E1, which also has a tyrosine at this position, could be inhibited by biphenylsulfonacetic acid derivatives, thereby raising the possibility that this class of inhibitors could be optimized as antiviral agents against multiple HPV types. These studies implicate Tyr-486 as a key residue for inhibitor binding and define an allosteric pocket on HPV E1 that can be exploited for future drug discovery efforts

Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control.

Approximately half the mammalian genome is composed of repetitive sequences, and accumulating evidence suggests that some may have an impact on genome function. Here, we characterized a large array class of repeats of long-interspersed elements (LINE-1). Although widely distributed in mammals, locations of such arrays are species specific. Using targeted deletion, we asked whether a 170-kb LINE-1 array located at a mouse imprinted domain might function as a modulator of local transcriptional control. The LINE-1 array is lamina associated in differentiated ES cells consistent with its AT-richness, and although imprinting occurs both proximally and distally to the array, active LINE-1 transcripts within the tract are biallelically expressed. Upon deletion of the array, no perturbation of imprinting was observed, and abnormal phenotypes were not detected in maternal or paternal heterozygous or homozygous mutant mice. The array does not shield nonimprinted genes in the vicinity from local imprinting control. Reduced neural expression of protein-coding genes observed upon paternal transmission of the deletion is likely due to the removal of a brain-specific enhancer embedded within the LINE array. Our findings suggest that presence of a 170-kb LINE-1 array reflects the tolerance of the site for repeat insertion rather than an important genomic function in normal development

Genomic matrix attachment region and chromosome conformation capture quantitative real time PCR assays identify novel putative regulatory elements at the imprinted Dlk1/Gtl2 locus

We previously showed that genomic imprinting regulates matrix attachment region activities at the mouse Igf2 (insulin-like growth factor 2) locus and that these activities are functionally linked to neighboring differentially methylated regions (DMRs). Here, we investigate the similarly structured Dlk1/Gtl2 imprinted domain and show that in the mouse liver, the G/C-rich intergenic germ line-derived DMR, a sequence involved in domain-wide imprinting, is highly retained within the nuclear matrix fraction exclusively on the methylated paternal copy, reflecting its differential function on that chromosome. Therefore, not only "classical" A/T-rich matrix attachment region (MAR) sequences but also other important regulatory DNA elements (such as DMRs) can be recovered from genomic MAR assays following a high salt treatment. Interestingly, the recovery of one A/T-rich sequence (MAR4) from the "nuclear matrix" fraction is strongly correlated with gene expression. We show that this element possesses an intrinsic activity that favors transcription, and using chromosome conformation capture quantitative real time PCR assays, we demonstrate that the MAR4 interacts with the intergenic germ line-derived DMR specifically on the paternal allele but not with the Dlk1/Gtl2 promoters. Altogether, our findings shed a new light on gene regulation at this locus