The role of complement in retinal ganglion cell loss in glaucoma

Glaucoma is an umbrella term for a number of related optic neuropathies which have the common pathology of a progressive, irreversible vision loss associated with atrophy of retinal ganglion cells. Together, the various forms of glaucoma constitute the second leading cause of vision loss in the developed world. Current therapies for the treatment of glaucoma focus on alleviating the primary risk factor, an elevation in intraocular pressure. These treatments are effective at mitigating the progression of vision loss however they cannot recover vision and do not completely halt vision loss, limiting their use as treatments. To better understand the biology underlying the loss of retinal ganglion cells in glaucoma, I have examined the role of complement in retinal ganglion cell loss. Complement is a network of cross-reacting serine proteases which form part of the humoral immune system and are primarily responsible for clearance of apoptotic cells and defence against pathogens. To understand the role played by complement in glaucoma I used an inducible model of glaucoma to establish the complement activation occurs in the glaucomatous retina. I then used the inhibitor of the classical complement cascade, C1 inhibitor to protect the dendrites and cell bodies of retinal ganglion cells and found that this protection did not prevent axonal degeneration. Using in vitro and in vivo animal models of complement deficiency I established that deficiency in complement components C3 and C6 which are further down the cascade, exacerbates damage suffered in hypertensive glaucoma. This study adds to the existing evidence that the role of complement in central nervous system degeneration is a complex, multifactorial process, with elements of the complement system being variously protective and damaging. It does, however, add hope to the prospect of developing a treatment for glaucomatous optic neuropathy based on manipulation of the complement system

A novel method for the induction of experimental glaucoma using magnetic microspheres

Purpose. The development of a method for the sustained elevation of intraocular pressure in experimental glaucoma based on the anterior chamber injection of paramagnetic microbeads. Methods. Unilateral glaucoma was induced in adult male Norwegian Brown rats by the injection of paramagnetic polystyrene microspheres. A handheld 0.45 Tesla magnet was used to draw the beads into the iridocorneal angle to impede aqueous drainage via the trabecular meshwork. Results. Elevated intraocular pressures (IOPs) were induced in 61 rats, resulting in a mean elevation of 5.8 mm Hg ± 1.0 (SEM) relative to the contralateral control eye. The mean duration of sustained IOP elevation (defined as >5 mm Hg relative to the control eye for at least 7 consecutive days) after a single injection was 12.8 days ± 0.9 (SEM, maximum duration 27 days). In all eyes, the visual axis remained clear from the time of injection, with minimal inflammation after injection. Retinal ganglion cell loss was determined in 21 animals (mean integral IOP, 194.5 mm Hg days ± 87.5 [SEM]) as 36.4% ± 2.4 (SEM) compared with the contralateral, untreated eye. Conclusions. The use of paramagnetic microbeads for the occlusion of the iridocorneal angle produces a sustained elevation of IOP with fewer injections and avoids the risk of visual axis occlusion. It represents a simple and effective method for the induction of experimental glaucoma

Assessing movement of the California sea cucumber Parastichopus californicus in response to organically enriched areas typical of aquaculture sites

Funding was provided by Fisheries and Oceans Canada’s Aquaculture Collaborative Research and Development Program, Viking Bay Ventures and the Klahoose Shellfish Limited Partnership.An increasing global demand for sea cucumbers has led to interest in benthic ranching of the California sea cucumber Parastichopus californicus beneath existing aquaculture sites in British Columbia, Canada, where high levels of total organic matter (TOM) are typical. The objective of the present study was to investigate movement of P. californicus in relation to areas of increased organic content to assess the feasibility of sea cucumber ranching beneath existing aquaculture sites. A laboratory experiment using adult sea cucumbers showed that P. californicus changed their foraging behaviour based on available amounts of TOM, moving more randomly in high-TOM (~8.0%) areas and more directly in low-TOM (~1.4%) ones. They also moved more rapidly in areas with high TOM than in those with low TOM. As long as animals were exposed to high TOM, they did not abandon random movement. Because of this behaviour, aquaculture tenures may retain a population of cultured individuals, but could also attract wild individuals from the surrounding area.Publisher PDFPeer reviewe

Final report on LDRD project : outstanding challenges for AlGaInN MOCVD.

The AlGaInN material system is used for virtually all advanced solid state lighting and short wavelength optoelectronic devices. Although metal-organic chemical vapor deposition (MOCVD) has proven to be the workhorse deposition technique, several outstanding scientific and technical challenges remain, which hinder progress and keep RD&A costs high. The three most significant MOCVD challenges are: (1) Accurate temperature measurement; (2) Reliable and reproducible p-doping (Mg); and (3) Low dislocation density GaN material. To address challenge (1) we designed and tested (on reactor mockup) a multiwafer, dual wavelength, emissivity-correcting pyrometer (ECP) for AlGaInN MOCVD. This system simultaneously measures the reflectance (at 405 and 550 nm) and emissivity-corrected temperature for each individual wafer, with the platen signal entirely rejected. To address challenge (2) we measured the MgCp{sub 2} + NH{sub 3} adduct condensation phase diagram from 65-115 C, at typical MOCVD concentrations. Results indicate that it requires temperatures of 80-100 C in order to prevent MgCp{sub 2} + NH{sub 3} adduct condensation. Modification and testing of our research reactor will not be complete until FY2005. A new commercial Veeco reactor was installed in early FY2004, and after qualification growth experiments were conducted to improve the GaN quality using a delayed recovery technique, which addresses challenge (3). Using a delayed recovery technique, the dislocation densities determined from x-ray diffraction were reduced from 2 x 10{sup 9} cm{sup -2} to 4 x 10{sup 8} cm{sup -2}. We have also developed a model to simulate reflectance waveforms for GaN growth on sapphire

Nanofabrication of tunable nanowire lasers via electron and ion-beam based techniques.

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Teaching Access, or Freedom of Information Law

Based on the author\u27s experience developing and administering the course and materials, this article provides an introduction and resources to teach a graduate journalism or professional law school course on access to government, commonly called freedom of information law , which may be constructed as a capstone course in law school. The appendices provide supporting material and references

Evolutionary history of human colitis-associated colorectal cancer

Objective: IBD confers an increased lifetime risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) is molecularly distinct from sporadic CRC (S-CRC). Here we have dissected the evolutionary history of CA-CRC using multiregion sequencing. Design: Exome sequencing was performed on fresh-frozen multiple regions of carcinoma, adjacent non-cancerous mucosa and blood from 12 patients with CA-CRC (n=55 exomes), and key variants were validated with orthogonal methods. Genome-wide copy number profiling was performed using single nucleotide polymorphism arrays and low-pass whole genome sequencing on archival non-dysplastic mucosa (n=9), low-grade dysplasia (LGD; n=30), high-grade dysplasia (HGD; n=13), mixed LGD/HGD (n=7) and CA-CRC (n=19). Phylogenetic trees were reconstructed, and evolutionary analysis used to reveal the temporal sequence of events leading to CA-CRC. Results: 10/12 tumours were microsatellite stable with a median mutation burden of 3.0 single nucleotide alterations (SNA) per Mb, ~20% higher than S-CRC (2.5 SNAs/Mb), and consistent with elevated ageing-associated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CA-CRC, indicating a precancer mutational field. CA-CRCs were often near triploid (40%) or near tetraploid (20%) and phylogenetic analysis revealed that copy number alterations (CNAs) began to accrue in non-dysplastic bowel, but the LGD/HGD transition often involved a punctuated ‘catastrophic’ CNA increase. Conclusions: Evolutionary genomic analysis revealed precancer clones bearing extensive SNAs and CNAs, with progression to cancer involving a dramatic accrual of CNAs at HGD. Detection of the cancerised field is an encouraging prospect for surveillance, but punctuated evolution may limit the window for early detection

You Are What You Eat: Within-Subject Increases in Fruit and Vegetable Consumption Confer Beneficial Skin-Color Changes

R Whitehead was funded by an ESRC Studentship.Background: Fruit and vegetable consumption and ingestion of carotenoids have been found to be associated with human skin-color (yellowness) in a recent cross-sectional study. This carotenoid-based coloration contributes beneficially to the appearance of health in humans and is held to be a sexually selected cue of condition in other species. Methodology and Principal Findings: Here we investigate the effects of fruit and vegetable consumption on skin-color longitudinally to determine the magnitude and duration of diet change required to change skin-color perceptibly. Diet and skin-color were recorded at baseline and after three and six weeks, in a group of 35 individuals who were without makeup, self-tanning agents and/or recent intensive UV exposure. Six-week changes in fruit and vegetable consumption were significantly correlated with changes in skin redness and yellowness over this period, and diet-linked skin reflectance changes were significantly associated with the spectral absorption of carotenoids and not melanin. We also used psychophysical methods to investigate the minimum color change required to confer perceptibly healthier and more attractive skin-coloration. Modest dietary changes are required to enhance apparent health (2.91 portions per day) and attractiveness (3.30 portions). Conclusions: Increased fruit and vegetable consumption confers measurable and perceptibly beneficial effects on Caucasian skin appearance within six weeks. This effect could potentially be used as a motivational tool in dietary intervention.Publisher PDFPeer reviewe