Self-Templated Nucleation in Peptide and Protein aggregation

Peptides and proteins exhibit a common tendency to assemble into highly ordered fibrillar aggregates, whose formation proceeds in a nucleation-dependent manner that is often preceded by the formation of disordered oligomeric assemblies. This process has received much attention because disordered oligomeric aggregates have been associated with neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Here we describe a self-templated nucleation mechanism that determines the transition between the initial condensation of polypeptide chains into disordered assemblies and their reordering into fibrillar structures. The results that we present show that at the molecular level this transition is due to the ability of polypeptide chains to reorder within oligomers into fibrillar assemblies whose surfaces act as templates that stabilise the disordered assemblies.Comment: 4 pages, 3 figure

Planare Graphen und ihre Dualgraphen auf Zylinderoberflächen

In this thesis, we investigates plane drawings of undirected and directed graphs on cylinder surfaces. In the case of undirected graphs, the vertices are positioned on a line that is parallel to the cylinder’s axis and the edge curves must not intersect this line. We show that a plane drawing is possible if and only if the graph is a double-ended queue (deque) graph, i. e., the vertices of the graph can be processed according to a linear order and the edges correspond to items in the deque inserted and removed at their end vertices. A surprising consequence resulting from these observations is that the deque characterizes planar graphs with a Hamiltonian path. This result extends the known characterization of planar graphs with a Hamiltonian cycle by two stacks. By these insights, we also obtain a new characterization of queue graphs and their duals. We also consider the complexity of deciding whether a graph is a deque graph and prove that it is NP-complete. By introducing a split operation, we obtain the splittable deque and show that it characterizes planarity. For the proof, we devise an algorithm that uses the splittable deque to test whether a rotation system is planar. In the case of directed graphs, we study upward plane drawings where the edge curves follow the direction of the cylinder’s axis (standing upward planarity; SUP) or they wind around the axis (rolling upward planarity; RUP). We characterize RUP graphs by means of their duals and show that RUP and SUP swap their roles when considering a graph and its dual. There is a physical interpretation underlying this characterization: A SUP graph is to its RUP dual graph as electric current passing through a conductor to the magnetic field surrounding the conductor. Whereas testing whether a graph is RUP is NP-hard in general [Bra14], for directed graphs without sources and sink, we develop a linear-time recognition algorithm that is based on our dual graph characterization of RUP graphs.Die Arbeit beschäftigt sich mit planaren Zeichnungen ungerichteter und gerichteter Graphen auf Zylinderoberflächen. Im ungerichteten Fall werden Zeichnungen betrachtet, bei denen die Knoten auf einer Linie parallel zur Zylinderachse positioniert werden und die Kanten diese Linie nicht schneiden dürfen. Es kann gezeigt werden, dass eine planare Zeichnung genau dann möglich ist, wenn die Kanten des Graphen in einer double-ended queue (Deque) verarbeitet werden können. Ebenso lassen sich dadurch Queue, Stack und Doppelstack charakterisieren. Eine überraschende Konsequenz aus diesen Erkenntnissen ist, dass die Deque genau die planaren Graphen mit Hamiltonpfad charakterisiert. Dies erweitert die bereits bekannte Charakterisierung planarer Graphen mit Hamiltonkreis durch den Doppelstack. Im gerichteten Fall müssen die Kantenkurven entweder in Richtung der Zylinderachse verlaufen (SUP-Graphen) oder sich um die Achse herumbewegen (RUP-Graphen). Die Arbeit charakterisiert RUP-Graphen und zeigt, dass RUP und SUP ihre Rollen tauschen, wenn man Graph und Dualgraph betrachtet. Der SUP-Graph verhält sich dabei zum RUP-Graphen wie elektrischer Strom durch einen Leiter zum induzierten Magnetfeld. Ausgehend von dieser Charakterisierung ist es möglich einen Linearzeit-Algorithmus zu entwickeln, der entscheidet ob ein gerichteter Graph ohne Quellen und Senken ein RUP-Graph ist, während der allgemeine Fall NP-hart ist [Bra14]

Formula SAE cooling system design and optimization

Using a systems engineering approach to engine cooling design we will develop a cooling system that will provide reliable powertrain operation under all vehicle operating conditions. This will include vehicle operation from a cold start to full throttle. Our vehicle will be capable of completing a 16 mile race without overheating. Customer requirements and expectations, business and project requirements, and external requirements will all be identified in the systems partitioning phase of our project. This will allow our team to properly identify all external factors that need to be taken into consideration for our design. Ideal function, control factors, noise factors, side effects, and potential failure modes coupled with external requirements will allow for most optimal design to be attained. During our testing procedure (see Appendix N) we will utilize a Land and Sea Dynamometer to simulate an appropriate vehicle load. A system of fans, and heaters will also be used to simulate various driving and ambient conditions. A grid of sensors will be placed at various locations on the engine (see Figures 1-3) to acquire all data needed for design. After all relevant information is obtained we will make the proper correlations between any relevant fields of data. This analysis will allow our team to properly size the radiator / fan unit, water pump, header tank, swirl pot, hose diameters, clamps, and overflow. The principles of heat transfer, fluid dynamics, and thermodynamics will be applied

Coordinate based random effect size meta-analysis of neuroimaging studies

Low power in neuroimaging studies can make them difficult to interpret, and Coordinate based meta-analysis (CBMA) may go some way to mitigating this issue. CBMA has been used in many analyses to detect where published functional MRI or voxel-based morphometry studies testing similar hypotheses report significant summary results (coordinates) consistently. Only the reported coordinates and possibly t statistics are analysed, and statistical significance of clusters is determined by coordinate density. Here a method of performing coordinate based random effect size meta-analysis and meta-regression is introduced. The algorithm (ClusterZ) analyses both coordinates and reported t statistic or Z score, standardised by the number of subjects. Statistical significance is determined not by coordinate density, but by a random effects meta-analyses of reported effects performed cluster-wise using standard statistical methods and taking account of censoring inherent in the published summary results. Type 1 error control is achieved using the false cluster discovery rate (FCDR), which is based on the false discovery rate. This controls both the family wise error rate under the null hypothesis that coordinates are randomly drawn from a standard stereotaxic space, and the proportion of significant clusters that are expected under the null. Such control is necessary to avoid propagating and even amplifying the very issues motivating the meta-analysis in the first place. ClusterZ is demonstrated on both numerically simulated data and on real data from reports of grey matter loss in multiple sclerosis (MS) and syndromes suggestive of MS, and of painful stimulus in healthy controls. The software implementation is available to download and use freely

Generic Mechanism of Emergence of Amyloid Protofilaments from Disordered Oligomeric aggregates

The presence of oligomeric aggregates, which is often observed during the process of amyloid formation, has recently attracted much attention since it has been associated with neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. We provide a description of a sequence-indepedent mechanism by which polypeptide chains aggregate by forming metastable oligomeric intermediate states prior to converting into fibrillar structures. Our results illustrate how the formation of ordered arrays of hydrogen bonds drives the formation of beta-sheets within the disordered oligomeric aggregates that form early under the effect of hydrophobic forces. Initially individual beta-sheets form with random orientations, which subsequently tend to align into protofilaments as their lengths increases. Our results suggest that amyloid aggregation represents an example of the Ostwald step rule of first order phase transitions by showing that ordered cross-beta structures emerge preferentially from disordered compact dynamical intermediate assemblies.Comment: 14 pages, 4 figure

Functional reorganisation in chronic pain and neural correlates of pain sensitisation

© 2016 Published by Elsevier Ltd. Maladaptive mechanisms of pain processing in chronic pain conditions (CP) are poorly understood. We used coordinate based meta-analysis of 266 fMRI pain studies to study functional brain reorganisation in CP and experimental models of hyperalgesia.The pattern of nociceptive brain activation was similar in CP, hyperalgesia and normalgesia in controls. However, elevated likelihood of activation was detected in the left putamen, left frontal gyrus and right insula in CP comparing stimuli of the most painful vs. other site. Meta-analysis of contrast maps showed no difference between CP, controls, mood conditions. In contrast, experimental hyperalgesia induced stronger activation in the bilateral insula, left cingulate and right frontal gyrus.Activation likelihood maps support a shared neural pain signature of cutaneous nociception in CP and controls. We also present a double dissociation between neural correlates of transient and persistent pain sensitisation with general increased activation intensity but unchanged pattern in experimental hyperalgesia and, by contrast, focally increased activation likelihood, but unchanged intensity, in CP when stimulated at the most painful body part

Lesion topography and microscopic white matter tract damage contribute to cognitive impairment in symptomatic carotid artery disease

Purpose: To investigate associations between neuroimaging markers of cerebrovascular disease, including lesion topography and extent and severity of strategic and global cerebral tissue injury, and cognition in carotid artery disease (CAD). Materials and Methods: All participants gave written informed consent to undergo brain magnetic resonance imaging and the Addenbrooke’s Cognitive Examination–Revised. One hundred eight patients with symptomatic CAD but no dementia were included, and a score less than 82 represented cognitive impairment. Group comparison and interrelations between global cognitive and fluency performance, lesion topography, and ultrastructural damage were assessed with voxel-based statistics. Associations between cognition, medial temporal lobe atrophy (MTA), lesion volumes, and global white matter ultrastructural damage indexed as increased mean diffusivity were tested with regression analysis by controlling for age. Diagnostic accuracy of imaging markers selected from a multivariate prediction model was tested with receiver operating characteristic analysis. Results: Cognitively impaired patients (n = 53 [49.1%], classified as having probable vascular cognitive disorder) were older than nonimpaired patients (P = .027) and had more frequent MTA (P<.001), more cortical infarctions (P = .016), and larger volumes of acute (P = .028) and chronic (P = .009) subcortical ischemic lesions. Lesion volumes did not correlate with global cognitive performance (lacunar infarctions, P = .060; acute lesions, P = .088; chronic subcortical ischemic lesions, P = .085). In contrast, cognitive performance correlated with presence of chronic ischemic lesions within the interhemispheric tracts and thalamic radiation (P< .05, false discovery rate corrected). Skeleton mean diffusivity showed the closest correlation with cognition (R2 = 0.311, P< .001) and promising diagnostic accuracy for vascular cognitive disorder (area under the curve, 0.82 [95% confidence interval: 0.75, 0.90]). Findings were confirmed in subjects with a low risk of preclinical Alzheimer disease indexed by the absence of MTA (n = 85). Conclusion: Subcortical white matter ischemic lesion locations and severity of ultrastructural tract damage contribute to cognitive impairment in symptomatic CAD, which suggests that subcortical disconnection within large-scale cognitive neural networks is a key mechanism of vascular cognitive disorder