Perceptions of harm and addiction among dual users of cigarettes and e-cigarettes

Background: Tobacco harm perceptions are important factors in why individuals may initiate, substitute, and/or engage in dual or poly-tobacco use patterns. Identifying correlates of these perceptions is important for understanding why these cognitions may exist and help provide intervention targets. The purpose of the current study was to examine perceptions of harm and addiction among a sample of cigarette and electronic cigarette (e-cigarette) users and examine whether these perceptions differ by demographics, other substance use, and tobacco use history. Methods: The current sample consisted of 29 individuals who consented to participate in a clinical laboratory study of dual cigarette and e-cigarette users during 2015-2016. Screening data for this secondary analysis included demographics, substance use, other tobacco use history, and perceptions of harm and addiction. Perception items asked about the health risk level for cigarettes and e-cigarettes and the level of harm compared to regular cigarettes and likelihood of addiction for variety of tobacco products (e.g., e-cigarettes, snus, nicotine replacement therapies [NRT]). Descriptive statistics followed by independent T-tests were used to explore differences in perception items by demographics, other substance use, and tobacco use history (p Results: The sample’s mean age was 39 years, and a majority were White males. Half of the sample completed some college or higher. Past 30-day alcohol use (55%) and ever trying marijuana (62%) were prevalent, and most were not concurrently using other tobacco products (79%). A majority (78%) reported that cigarettes were at least somewhat risky to health, while only 48% reported the equivalent for e-cigarettes. Participants rated most tobacco products as about same harm level or higher compared to regular cigarettes except for roll-your-own cigarettes, e-cigarettes, and NRT. All participants perceived regular cigarettes and chewing tobacco as having at least a moderate addiction risk. E-cigarettes and NRT had the lowest addiction risk ratings. Only perceptions of snus addiction risk differed by gender with males reporting higher ratings. By race, ratings for addiction risk for e-cigarettes and NRT differed significantly with Whites reporting lower ratings. Lifetime marijuana users had significantly higher harm perception ratings for e-cigarettes. Perceived addiction risk for regular cigarettes and e-cigarettes was significantly lower among those who used other tobacco products. Discussion: Among this sample, perceptions of harm and addiction were lower for e-cigarettes and NRT relative to regular cigarettes and other tobacco products. There were few perceptions that differed by demographics and other substance/tobacco use history. Dual users who used other tobacco products were more likely to perceive lower risks for cigarettes and e-cigarettes. This association may be because lower addiction perceptions drive greater tobacco use or alternative. Current findings support future investigation of harm and addiction perceptions particularly among individuals who use more than one tobacco product. Funding: This research was supported by an Internal Grant from Virginia Commonwealth University’s School of Nursing and the National Cancer Institute of the National Institutes of Health under Award Number R21CA184634 and the Center for Tobacco Products of the U.S. Food and Drug Administration. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Food and Drug Administration.https://scholarscompass.vcu.edu/uresposters/1235/thumbnail.jp

Shape-Tension Coupling Produces Nematic Order in an Epithelium Vertex Model

We study the vertex model for epithelial tissue mechanics extended to include coupling between the cell shapes and tensions in cell-cell junctions. This coupling represents an active force which drives the system out of equilibrium and leads to the formation of nematic order interspersed with prominent, long-lived +1 defects. The defects in the nematic ordering are coupled to the shape of the cell tiling, affecting cell areas and coordinations. This intricate interplay between cell shape, size, and coordination provides a possible mechanism by which tissues could spontaneously develop long-range polarity through local mechanical forces without resorting to long-range chemical patterning

From Dry to Wet Vertex Model Dynamics:Generating Sustained Flows

Complex tissue flows in epithelia are driven by intra- and inter-cellular processes that generate, maintain, and coordinate mechanical forces. There has been growing evidence that cell shape anisotropy, manifested as nematic order, plays an important role in this process. Here we extend a nematic vertex model by replacing substrate friction with internal viscous dissipation, of relevance to epithelia not supported by a substrate or the extracellular matrix, such as many early-stage embryos. When coupled to cell shape anisotropy, the internal viscous dissipation allows for long-range velocity correlations and thus enables the spontaneous emergence of flows with a large degree of spatiotemporal organisation. We demonstrate sustained flow in epithelial sheets confined to a channel, thus providing a link between the dynamical behaviour of continuum active nematics and the cell-level vertex model of tissue dynamics.<br/

From Dry to Wet Vertex Model Dynamics:Generating Sustained Flows

Complex tissue flows in epithelia are driven by intra- and inter-cellular processes that generate, maintain, and coordinate mechanical forces. There has been growing evidence that cell shape anisotropy, manifested as nematic order, plays an important role in this process. Here we extend a nematic vertex model by replacing substrate friction with internal viscous dissipation, of relevance to epithelia not supported by a substrate or the extracellular matrix, such as many early-stage embryos. When coupled to cell shape anisotropy, the internal viscous dissipation allows for long-range velocity correlations and thus enables the spontaneous emergence of flows with a large degree of spatiotemporal organisation. We demonstrate sustained flow in epithelial sheets confined to a channel, thus providing a link between the dynamical behaviour of continuum active nematics and the cell-level vertex model of tissue dynamics.<br/

Standardized, systemic phenotypic analysis reveals kidney dysfunction as main alteration of Kctd1 I27N mutant mice

Background: Increased levels of blood plasma urea were used as phenotypic parameter for establishing novel mouse models for kidney diseases on the genetic background of C3H inbred mice in the phenotype-driven Munich ENU mouse mutagenesis project. The phenotypically dominant mutant line HST014 was established and further analyzed. Methods: Analysis of the causative mutation as well as the standardized, systemic phenotypic analysis of the mutant line was carried out. Results: The causative mutation was detected in the potassium channel tetramerization domain containing 1 (Kctd1) gene which leads to the amino acid exchange Kctd1 I27N thereby affecting the functional BTB domain of the protein. This line is the first mouse model harboring a Kctd1 mutation. Kctd1 I27N homozygous mutant mice die perinatally. Standardized, systemic phenotypic analysis of Kctd1 I27N heterozygous mutants was carried out in the German Mouse Clinic (GMC). Systematic morphological investigation of the external physical appearance did not detect the specific alterations that are described in KCTD1 mutant human patients affected by the scalp-ear-nipple (SEN) syndrome. The main pathological phenotype of the Kctd1 I27N heterozygous mutant mice consists of kidney dysfunction and secondary effects thereof, without gross additional primary alterations in the other phenotypic parameters analyzed. Genome-wide transcriptome profiling analysis at the age of 4 months revealed about 100 differentially expressed genes (DEGs) in kidneys of Kctd1 I27N heterozygous mutants as compared to wild-type controls. Conclusions: In summary, the main alteration of the Kctd1 I27N heterozygous mutants consists in kidney dysfunction. Additional analyses in 9–21 week-old heterozygous mutants revealed only few minor effects

Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells

High attrition rates of novel anti-cancer drugs highlight the need for improved models to predict toxicity. Although polo-like kinase 1 (Plk1) inhibitors are attractive candidates for drug development, the role of Plk1 in primary cells remains widely unexplored. Therefore, we evaluated the utility of an RNA interference-based model to assess responses to an inducible knockdown (iKD) of Plk1 in adult mice. Here we show that Plk1 silencing can be achieved in several organs, although adverse events are rare. We compared responses in Plk1-iKD mice with those in primary cells kept under controlled culture conditions. In contrast to the addiction of many cancer cell lines to the non-oncogene Plk1, the primary cells' proliferation, spindle assembly and apoptosis exhibit only a low dependency on Plk1. Responses to Plk1-depletion, both in cultured primary cells and in our iKD-mouse model, correspond well and thus provide the basis for using validated iKD mice in predicting responses to therapeutic interventions

Claudin-12 is not required for blood-brain barrier tight junction function

Background The blood-brain barrier (BBB) ensures central nervous system (CNS) homeostasis by strictly controlling the passage of molecules and solutes from the bloodstream into the CNS. Complex and continuous tight junctions (TJs) between brain endothelial cells block uncontrolled paracellular diffusion of molecules across the BBB, with claudin-5 being its dominant TJs protein. However, claudin-5 deficient mice still display ultrastructurally normal TJs, suggesting the contribution of other claudins or tight-junction associated proteins in establishing BBB junctional complexes. Expression of claudin-12 at the BBB has been reported, however the exact function and subcellular localization of this atypical claudin remains unknown. Methods We created claudin-12-lacZ-knock-in C57BL/6J mice to explore expression of claudin-12 and its role in establishing BBB TJs function during health and neuroinflammation. We furthermore performed a broad standardized phenotypic check-up of the mouse mutant. Results Making use of the lacZ reporter allele, we found claudin-12 to be broadly expressed in numerous organs. In the CNS, expression of claudin-12 was detected in many cell types with very low expression in brain endothelium. Claudin-12(lacZ/lacZ) C57BL/6J mice lacking claudin-12 expression displayed an intact BBB and did not show any signs of BBB dysfunction or aggravated neuroinflammation in an animal model for multiple sclerosis. Determining the precise localization of claudin-12 at the BBB was prohibited by the fact that available anti-claudin-12 antibodies showed comparable detection and staining patterns in tissues from wild-type and claudin-12(lacZ/lacZ) C57BL/6J mice. Conclusions Our present study thus shows that claudin-12 is not essential in establishing or maintaining BBB TJs integrity. Claudin-12 is rather expressed in cells that typically lack TJs suggesting that claudin-12 plays a role other than forming classical TJs. At the same time, in depth phenotypic screening of clinically relevant organ functions of claudin-12(lacZ/lacZ) C57BL/6J mice suggested the involvement of claudin-12 in some neurological but, more prominently, in cardiovascular functions

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

A comprehensive and comparative phenotypic analysis of the collaborative founder strains identifies new and known phenotypes.

The collaborative cross (CC) is a large panel of mouse-inbred lines derived from eight founder strains (NOD/ShiLtJ, NZO/HILtJ, A/J, C57BL/6J, 129S1/SvImJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Here, we performed a comprehensive and comparative phenotyping screening to identify phenotypic differences and similarities between the eight founder strains. In total, more than 300 parameters including allergy, behavior, cardiovascular, clinical blood chemistry, dysmorphology, bone and cartilage, energy metabolism, eye and vision, immunology, lung function, neurology, nociception, and pathology were analyzed; in most traits from sixteen females and sixteen males. We identified over 270 parameters that were significantly different between strains. This study highlights the value of the founder and CC strains for phenotype-genotype associations of many genetic traits that are highly relevant to human diseases. All data described here are publicly available from the mouse phenome database for analyses and downloads

Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria

Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria (MMAuria), present unique challenges to energetic homeostasis by disrupting energy producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut) type MMAuria. We found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared to littermate controls, along with a relative reduction in lean mass but increase in fat mass. Brown adipose tissue showed a process of whitening, in line with lower body surface temperature and lesser ability to cope with cold challenge. Mutant mice had dysregulated plasma glucose, delayed glucose clearance and a lesser ability to regulate energy sources when switching from the fed to fasted state, while liver investigations indicated metabolite accumulation and altered expression of peroxisome proliferator-activated receptor and Fgf21-controlled pathways. Together, these indicate hypometabolism, energetic inflexibility and increased stores at the expense of active tissue as energy shortage consequences