Neuronal pentraxins mediate synaptic refinement in the developing visual system

Peer reviewedPublisher PD

A Splicing Mutation in Slc4a5 Results in Retinal Detachment and Retinal Pigment Epithelium Dysfunction

Fluid and solute transporters of the retinal pigment epithelium (RPE) are core components of the outer blood-retinal barrier. Characterizing these transporters and their role in retinal homeostasis may provide insights into ocular function and disease. Here, we describe RPE defects in tvrm77 mice, which exhibit hypopigmented patches in the central retina. Mapping and nucleotide sequencing of tvrm77 mice revealed a disrupted 5\u27 splice donor sequence in Slc4a5, a sodium bicarbonate cotransporter gene. Slc4a5 expression was reduced 19.7-fold in tvrm77 RPE relative to controls, and alternative splice variants were detected. SLC4A5 was localized to the Golgi apparatus of cultured human RPE cells and in apical and basal membranes. Fundus imaging, optical coherence tomography, microscopy, and electroretinography (ERG) of tvrm77 mice revealed retinal detachment, hypopigmented patches corresponding to neovascular lesions, and retinal folds. Detachment worsened and outer nuclear layer thickness decreased with age. ERG a- and b-wave response amplitudes were initially normal but declined in older mice. The direct current ERG fast oscillation and light peak were reduced in amplitude at all ages, whereas other RPE-associated responses were unaffected. These results link a new Slc4a5 mutation to subretinal fluid accumulation and altered light-evoked RPE electrophysiological responses, suggesting that SLC4A5 functions at the outer blood-retinal barrier

Cigarette smoke extract profoundly suppresses TNFα-mediated proinflammatory gene expression through upregulation of ATF3 in human coronary artery endothelial cells

Endothelial dysfunction caused by the combined action of disturbed flow, inflammatory mediators and oxidants derived from cigarette smoke is known to promote coronary atherosclerosis and increase the likelihood of myocardial infarctions and strokes. Conversely, laminar flow protects against endothelial dysfunction, at least in the initial phases of atherogenesis. We studied the effects of TNFα and cigarette smoke extract on human coronary artery endothelial cells under oscillatory, normal laminar and elevated laminar shear stress for a period of 72 hours. We found, firstly, that laminar flow fails to overcome the inflammatory effects of TNFα under these conditions but that cigarette smoke induces an anti-oxidant response that appears to reduce endothelial inflammation. Elevated laminar flow, TNFα and cigarette smoke extract synergise to induce expression of the transcriptional regulator activating transcription factor 3 (ATF3), which we show by adenovirus driven overexpression, decreases inflammatory gene expression independently of activation of nuclear factor-κB. Our results illustrate the importance of studying endothelial dysfunction in vitro over prolonged periods. They also identify ATF3 as an important protective factor against endothelial dysfunction. Modulation of ATF3 expression may represent a novel approach to modulate proinflammatory gene expression and open new therapeutic avenues to treat proinflammatory diseases

A 32 kb Critical Region Excluding Y402H in CFH Mediates Risk for Age-Related Macular Degeneration

Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N = 293) and AMD cases (White N = 4210 Indian = 134; Malay = 140) and controls (White N = 3229; Indian = 117; Malay = 2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI = [2.51, 3.01]; p = 8.31×10−109); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p = 3.52×10−9) and by 15.57-fold (P = 0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in ΔCNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number

Love it or hate it: students' responses to the experience of virtual worlds

Effective experiential learning within virtual worlds requires students to engage with the virtual world, not only as active learners but also as embodied actors, fully immersed in the world, with a developed inworld identity and body image. These elements are one source of the added value that immersive virtual worlds bring to the educational experience, but can also be a source of anxiety and resistance for many students. In order to move forward with teaching and learning in virtual worlds, it is important that educators seek to understand these reactions and, furthermore, develop strategies to address them. This paper will describe the range of responses displayed by students to virtual worlds, drawn from evidence collated during the authors’ seven years collective experience of teaching in virtual worlds. The responses can be attributed to a variety of cultural and value-based attitudes held by students to technology in general and to virtual worlds in particular. In addition, the authors note the potential existence of an “embodiment tendency” which may be the basis of an innate engagement with, or failure to connect with, virtual worlds. Drawing on particular cases, and evidenced by students’ testimonies, the authors will set out a typology of students’ responses, both positive and negative. They will describe a framework proposal of strategies for engaging with these responses, and discuss the ethical implications that students’ negative opinions raise for educators making use of immersive virtual worlds

Virtual worlds and identity

Virtual worlds in their graphical forms have been used since the mid-1980s (Yakal 1986, p.32), primarily for social networking. They are computer-generated environments in which participants adopt an avatar to interact with each other and with the virtual environment around them. The word "avatar" in this sense means "a graphical representation of a user within the environment which is under his or her direct control" (Allbeck and Badler 2002, p.313). It is derived from the Sanskrit avatârah, a compound of ava, ("down"), and tarati, ("he crosses"). It means therefore "the crossing down" and traditionally refers to the incarnation of a deity within the physical world (Isdale et al. 2002, p.530). Taking on the form of an avatar within a virtual world is thus a literacy of crossing down from the real into the digital. The word has been used in this context since it was employed by Farmer and Morningstar in an immersive virtual world called Habitat in 1985 (Britt 2003), the first platform that enabled tens of thousands of users to participate in creating aspects of the environment around them, chat with other users, play games and engage in governance of their emerging community

Love it or hate it: students’ responses to the experience of virtual worlds

[About the book] Virtual worlds are computer-generated three-dimensional worlds in which participants adopt digital personae, called avatars, to interact with others. One of the strengths of virtual worlds as platforms is that they can provide engaging and authentic experiences for participants, enabling simulations of different environments, opportunities to roleplay different activities, and facilitating creativity and imagination. This volume focuses on this use of virtual worlds for providing experiential learning in particular. Some of the questions the volume aims to answer are: To what extent can the experiences of virtual worlds be considered "real"? What types of experiential learning are virtual worlds effective at providing and how can learning design make best use of their potential?; How do different types of learners respond to virtual worlds? How can virtual worlds develop leadership skills? How are courtship rituals and multiracial identity expressed in virtual worlds and what does this reveal about learning? What is the future of experiential learning in virtual worlds