Amyloid as a natural product

Amyloid fibrils, such as those found in Alzheimer's and the gelsolin amyloid diseases, result from the misassembly of peptides produced by either normal or aberrant intracellular proteolytic processing. A paper in this issue by Marks and colleagues (Berson et al., 2003) demonstrates that intra-melanosome fibrils are formed through normal biological proteolytic processing of an integral membrane protein. The resulting peptide fragment assembles into fibrils promoting the formation of melanin pigment granules. These results, along with the observation that amyloid fibril formation by bacteria is highly orchestrated, suggest that fibril formation is an evolutionary conserved biological pathway used to generate natural product nanostructures

Induction of complement proteins in a mouse model for cerebral microvascular Aβ deposition

The deposition of amyloid β-protein (Aβ) in cerebral vasculature, known as cerebral amyloid angiopathy (CAA), is a common pathological feature of Alzheimer's disease and related disorders. In familial forms of CAA single mutations in the Aβ peptide have been linked to the increase of vascular Aβ deposits accompanied by a strong localized activation of glial cells and elevated expression of neuroinflammatory mediators including complement proteins. We have developed human amyloid-β precursor protein transgenic mice harboring two CAA Aβ mutations (Dutch E693Q and Iowa D694N) that mimic the prevalent cerebral microvascular Aβ deposition observed in those patients, and the Swedish mutations (K670N/M671L) to increase Aβ production. In these Tg-SwDI mice, we have reported predominant fibrillar Aβ along microvessels in the thalamic region and diffuse plaques in cortical region. Concurrently, activated microglia and reactive astrocytes have been detected primarily in association with fibrillar cerebral microvascular Aβ in this model. Here we show that three native complement components in classical and alternative complement pathways, C1q, C3, and C4, are elevated in Tg-SwDI mice in regions rich in fibrillar microvascular Aβ. Immunohistochemical staining of all three proteins was increased in thalamus, hippocampus, and subiculum, but not frontal cortex. Western blot analysis showed significant increases of all three proteins in the thalamic region (with hippocampus) as well as the cortical region, except C3 that was below detection level in cortex. Also, in the thalamic region (with hippocampus), C1q and C3 mRNAs were significantly up-regulated. These complement proteins appeared to be expressed largely by activated microglial cells associated with the fibrillar microvascular Aβ deposits. Our findings demonstrate that Tg-SwDI mice exhibit elevated complement protein expression in response to fibrillar vascular Aβ deposition that is observed in patients with familial CAA

Reshaping graduate outcomes of science students – The contribution of undergraduate research experiences

Today’s science graduates require substantially different skills compared to yesterday’s graduates given the changing nature of modern science. As higher education institutions struggle to reform curricula and pedagogy, undergraduate research experiences (UREs) are increasingly being incorporated to enhance undergraduate science curricula. This study is situated within a traditional Bachelor of Science degree that offers students some voluntary opportunities to participate in UREs. This study explores two graduating science cohorts (n=272), comparing those who did and did not participate in UREs. A survey investigated student perceptions (importance, confidence and improvements) of five graduate outcomes in the context of science: writing skills, communication skills, quantitative skills (QS), teamwork skills and content knowledge. Cross-tabs and a linear discriminant analysis were used to investigate perception change between the two groups. The notable differences in perception scores in this study were consistently higher in QS, perhaps indicative of UREs emphasising the need for such skills in science or from students gaining increased confidence as a result of utilising QS within an authentic context. Our results reveal little difference in other student outcome areas, which raises questions around the role of UREs as a broad strategy for enhancing the achievement of graduate outcomes in science. This study is limited to a single institution and is focused on specific graduate outcomes, so only limited conclusions can be drawn. However, further research to determine the graduate outcomes gained from UREs would benefit the sector, particularly science disciplines, in the changing focus of government policy on student learning outcomes

A Conserved Chromatin Architecture Marks and Maintains the Restricted Germ Cell Lineage in Worms and Flies

AbstractIn C. elegans, mRNA production is initially repressed in the embryonic germline by a protein unique to C. elegans germ cells, PIE-1. PIE-1 is degraded upon the birth of the germ cell precursors, Z2 and Z3. We have identified a chromatin-based mechanism that succeeds PIE-1 repression in these cells. A subset of nucleosomal histone modifications, methylated lysine 4 on histone H3 (H3meK4) and acetylated lysine 8 on histone H4 (H4acetylK8), are globally lost and the DNA appears more condensed. This coincides with PIE-1 degradation and requires that germline identity is not disrupted. Drosophila pole cell chromatin also lacks H3meK4, indicating that a unique chromatin architecture is a conserved feature of embryonic germ cells. Regulation of the germline-specific chromatin architecture requires functional nanos activity in both organisms. These results indicate that genome-wide repression via a nanos-regulated, germ cell-specific chromatin organization is a conserved feature of germline maintenance during embryogenesis