Aβ42 Mutants with Different Aggregation Profiles Induce Distinct Pathologies in Drosophila

Aggregation of the amyloid-β-42 (Aβ42) peptide in the brain parenchyma is a pathological hallmark of Alzheimer's disease (AD), and the prevention of Aβ aggregation has been proposed as a therapeutic intervention in AD. However, recent reports indicate that Aβ can form several different prefibrillar and fibrillar aggregates and that each aggregate may confer different pathogenic effects, suggesting that manipulation of Aβ42 aggregation may not only quantitatively but also qualitatively modify brain pathology. Here, we compare the pathogenicity of human Aβ42 mutants with differing tendencies to aggregate. We examined the aggregation-prone, EOFAD-related Arctic mutation (Aβ42Arc) and an artificial mutation (Aβ42art) that is known to suppress aggregation and toxicity of Aβ42 in vitro. In the Drosophila brain, Aβ42Arc formed more oligomers and deposits than did wild type Aβ42, while Aβ42art formed fewer oligomers and deposits. The severity of locomotor dysfunction and premature death positively correlated with the aggregation tendencies of Aβ peptides. Surprisingly, however, Aβ42art caused earlier onset of memory defects than Aβ42. More remarkably, each Aβ induced qualitatively different pathologies. Aβ42Arc caused greater neuron loss than did Aβ42, while Aβ42art flies showed the strongest neurite degeneration. This pattern of degeneration coincides with the distribution of Thioflavin S-stained Aβ aggregates: Aβ42Arc formed large deposits in the cell body, Aβ42art accumulated preferentially in the neurites, while Aβ42 accumulated in both locations. Our results demonstrate that manipulation of the aggregation propensity of Aβ42 does not simply change the level of toxicity, but can also result in qualitative shifts in the pathology induced in vivo

Pushing Lines Helps: Efficient Universal Centralised Transformations for Programmable Matter

In this paper, we study a discrete system of entities residing on a two-dimensional square grid. Each entity is modelled as a node occupying a distinct cell of the grid. The set of all $n$ nodes forms initially a connected shape $A$. Entities are equipped with a linear-strength pushing mechanism that can push a whole line of entities, from 1 to $n$, in parallel in a single time-step. A target connected shape $B$ is also provided and the goal is to \emph{transform} $A$ into $B$ via a sequence of line movements. Existing models based on local movement of individual nodes, such as rotating or sliding a single node, can be shown to be special cases of the present model, therefore their (inefficient, $\Theta(n^2)$) \emph{universal transformations} carry over. Our main goal is to investigate whether the parallelism inherent in this new type of movement can be exploited for efficient, i.e., sub-quadratic worst-case, transformations. As a first step towards this, we restrict attention solely to centralised transformations and leave the distributed case as a direction for future research. Our results are positive. By focusing on the apparently hard instance of transforming a diagonal $A$ into a straight line $B$, we first obtain transformations of time $O(n\sqrt{n})$ without and with preserving the connectivity of the shape throughout the transformation. Then, we further improve by providing two $O(n\log n)$-time transformations for this problem. By building upon these ideas, we first manage to develop an $O(n\sqrt{n})$-time universal transformation. Our main result is then an $O(n \log n)$-time universal transformation. We leave as an interesting open problem a suspected $\Omega(n\log n)$-time lower bound.Comment: 40 pages, 27 figure

Selective Release of MicroRNA Species from Normal and Malignant Mammary Epithelial Cells

MicroRNAs (miRNAs) in body fluids are candidate diagnostics for a variety of conditions and diseases, including breast cancer. One premise for using extracellular miRNAs to diagnose disease is the notion that the abundance of the miRNAs in body fluids reflects their abundance in the abnormal cells causing the disease. As a result, the search for such diagnostics in body fluids has focused on miRNAs that are abundant in the cells of origin. Here we report that released miRNAs do not necessarily reflect the abundance of miRNA in the cell of origin. We find that release of miRNAs from cells into blood, milk and ductal fluids is selective and that the selection of released miRNAs may correlate with malignancy. In particular, the bulk of miR-451 and miR-1246 produced by malignant mammary epithelial cells was released, but the majority of these miRNAs produced by non-malignant mammary epithelial cells was retained. Our findings suggest the existence of a cellular selection mechanism for miRNA release and indicate that the extracellular and cellular miRNA profiles differ. This selective release of miRNAs is an important consideration for the identification of circulating miRNAs as biomarkers of disease