Engineered tissue models for drug development: the lung as a paradigm

Poster presented at Biomedical Technology Showcase 2006, Philadelphia, PA. Retrieved 18 Aug 2006 from http://www.biomed.drexel.edu/new04/Content/Biomed_Tech_Showcase/Poster_Presentations/Lelkes_6.pdf.There is an un-met clinical and technological need for developing high-fidelity tissue models for high-throughput drug discovery. Tissue engineering is a viable means for engineering functional tissue equivalents, which hold the promise of revolutionizing the pharmacological industry by providing novel venues for high throughput drug testing. Working at the interface between applied developmental biology/medicine and tissue engineering we propose to generate such functional tissue equivalents, using the distal lung as our prime paradigm. With such model tissue we will demonstrate physiological responses, induce pathological conditions, and test therapeutics in disease models, such as pulmonary hypertension and emphysema

In Vitro Cell Culture Infectivity Assay for Human Noroviruses

A 3-dimensional organoid human small intestinal epithelium model was used

Comparisons of depression, anxiety, well-being, and perceptions of the built environment amongst adults seeking social, intermediate and market-rent accommodation in the former London Olympic Athletes' Village.

The Examining Neighbourhood Activities in Built Living Environments in London (ENABLE London) study provides a unique opportunity to examine differences in mental health and well-being amongst adults seeking social, intermediate (affordable rent), and market-rent housing in a purpose built neighbourhood (East Village, the former London 2012 Olympic Athletes' Village), specifically designed to encourage positive health behaviours. Multi-level logistic regression models examined baseline differences in levels of depression, anxiety and well-being across the housing groups. Compared with the intermediate group, those seeking social housing were more likely to be depressed, anxious and had poorer well-being after adjustment for demographic and health status variables. Further adjustments for neighbourhood perceptions suggest that compared with the intermediate group, perceived neighbourhood characteristics may be an important determinant of depression amongst those seeking social housing, and lower levels of happiness the previous day amongst those seeking market-rent housing. These findings add to the extensive literature on inequalities in health, and provide a strong basis for future longitudinal work that will examine change in depression, anxiety and well-being after moving into East Village, where those seeking social housing potentially have the most to gain

Fibulin-5, an integrin-binding matricellular protein: its function in development and disease

Interactions between the extracellular matrix (ECM) and cells are critical in embryonic development, tissue homeostasis, physiological remodeling, and tumorigenesis. Matricellular proteins, a group of ECM components, mediate cell-ECM interactions. One such molecule, Fibulin-5 is a 66-kDa glycoprotein secreted by various cell types, including vascular smooth muscle cells (SMCs), fibroblasts, and endothelial cells. Fibulin-5 contributes to the formation of elastic fibers by binding to structural components including tropoelastin and fibrillin-1, and to cross-linking enzymes, aiding elastic fiber assembly. Mice deficient in the fibulin-5 gene (Fbln5) exhibit systemic elastic fiber defects with manifestations of loose skin, tortuous aorta, emphysematous lung and genital prolapse. Although Fbln5 expression is down-regulated after birth, following the completion of elastic fiber formation, expression is reactivated upon tissue injury, affecting diverse cellular functions independent of its elastogenic function. Fibulin-5 contains an evolutionally conserved arginine-glycine-aspartic acid (RGD) motif in the N-terminal region, which mediates binding to a subset of integrins, including α5β1, αvβ3, and αvβ5. Fibulin-5 enhances substrate attachment of endothelial cells, while inhibiting migration and proliferation in a cell type- and context-dependent manner. The antagonistic function of fibulin-5 in angiogenesis has been demonstrated in vitro and in vivo; fibulin-5 may block angiogenesis by inducing the anti-angiogenic molecule thrompospondin-1, by antagonizing VEGF165-mediated signaling, and/or by antagonizing fibronectin-mediated signaling through directly binding and blocking the α5β1 fibronectin receptor. The overall effect of fibulin-5 on tumor growth depends on the balance between the inhibitory property of fibulin-5 on angiogenesis and the direct effect of fibulin-5 on proliferation and migration of tumor cells. However, the effect of tumor-derived versus host microenvironment-derived fibulin-5 remains to be evaluated

Born to be Happy? The Etiology of Subjective Well-Being

Subjective Wellbeing (SWB) can be assessed with distinct measures that have been hypothesized to represent different domains of SWB. The current study assessed SWB with four different measures in a genetically informative sample of adolescent twins and their siblings aged 13–28 years (N = 5,024 subjects from 2,157 families). Multivariate genetic modeling was applied to the data to explore the etiology of individual differences in SWB measures and the association among them. Developmental trends and sex differences were examined for mean levels and the variance-covariance structure. Mean SWB levels were equal in men and women. A small negative effect of age on mean levels of SWB was found. Individual differences in SWB were accounted for by additive and non-additive genetic influences, and non-shared environment. The broad-sense heritabilities were estimated between 40 and 50%. The clustering of the four different measures (quality of life in general, satisfaction with life, quality of life at present, and subjective happiness) was explained by an underlying additive genetic factor and an underlying non-additive genetic factor. The effect of these latent genetic factors on the phenotypes was not moderated by either age or sex

The Human Polyoma JC Virus Agnoprotein Acts as a Viroporin

Virus infections can result in a range of cellular injuries and commonly this involves both the plasma and intracellular membranes, resulting in enhanced permeability. Viroporins are a group of proteins that interact with plasma membranes modifying permeability and can promote the release of viral particles. While these proteins are not essential for virus replication, their activity certainly promotes virus growth. Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease resulting from lytic infection of oligodendrocytes by the polyomavirus JC virus (JCV). The genome of JCV encodes six major proteins including a small auxiliary protein known as agnoprotein. Studies on other polyomavirus agnoproteins have suggested that the protein may contribute to viral propagation at various stages in the replication cycle, including transcription, translation, processing of late viral proteins, assembly of virions, and viral propagation. Previous studies from our and other laboratories have indicated that JCV agnoprotein plays an important, although as yet incompletely understood role in the propagation of JCV. Here, we demonstrate that agnoprotein possesses properties commonly associated with viroporins. Our findings demonstrate that: (i) A deletion mutant of agnoprotein is defective in virion release and viral propagation; (ii) Agnoprotein localizes to the ER early in infection, but is also found at the plasma membrane late in infection; (iii) Agnoprotein is an integral membrane protein and forms homo-oligomers; (iv) Agnoprotein enhances permeability of cells to the translation inhibitor hygromycin B; (v) Agnoprotein induces the influx of extracellular Ca2+; (vi) The basic residues at amino acid positions 8 and 9 of agnoprotein key are determinants of the viroporin activity. The viroporin-like properties of agnoprotein result in increased membrane permeability and alterations in intracellular Ca2+ homeostasis leading to membrane dysfunction and enhancement of virus release