Linking micellar phases to peptide supramolecular hydrogels

Supramolecular peptide solutions and hydrogels are pathway-dependent multi-scale structured materials. This Thesis investigates three major aspects that impact on the self-assembly pathway. Firstly, the importance of the kinetics is investigated in the dipeptide gelators self-assembly pathway. Second, a proposed gelator-solvent phase diagram suggested a worm-like phase and an entangled worm-like micellar phase for N-protected dipeptide gelators. Thirdly, some links between hydrogel network structure and gelator solution phase properties were identified over multiple length scales for a particular class of peptide-based low molecular weight gelators (LMWG). These links allows some predictions to be made on the mechanical properties of peptide hydrogels triggered by salts based on the solution phase properties. A new method based on carbon dioxide acidification of specific gelator solutions formed unusual membrane hydrogels. This unusual heterogeneous hydrogel formation occured when the gelator’s apparent pKa was a pH unit close to the final pH and the starting gelator solution did not have a high viscous solution at the high pH (typically above pH 10.5). This membrane hydrogel phase had similar viscoelastic properties to the intermediary transition state previously found with pH-switch methods in bulk hydrogel formation (from high to low pH). The carbon dioxide method was also capable of forming bulk hydrogels for gelators with apparent pKa significantly above the final pH. This method was thoroughly investigated with 6-bromo-2-naphthalene-alanine-valine (BrNapAV). This research also focused on the first detailed phase diagram of an individual gelator solution phase, in this case of 2-naphthalene-diphenylalanine (2NapFF), an N-protected dipeptides over three orders of magnitude in concentration and between temperatures of 15 °C and 45 °C. The solution phase of 2NapFF was found to go through a range of micellar transformations with an increase in concentration from free-surfactant, spherical aggregate phase, worm-like micellar phase and packed worm-like micellar phase. The critical micellar concentrations (cmc’s), at which phase transitions occur, and the minimum gelator concentrations (mgc) with calcium nitrate salt solutions were found for 2NapFF. The common trends in the 2NapFF solution phase were extended to a library of 17 gelators. It was found that the 2NapFF peptide hydrogel phase is structurally connected to the corresponding solution phase. This allows prediction of the final properties of the Calcium-hydrogels (Ca-hydrogels) from the starting conditions of the corresponding peptide surfactant solutions, based on consideration of the solution phase diagram and self-assembly process. These results showed that the 2NapFF solutions could form Ca-hydrogels in a concentration from 0.02 wt% to 1.0 wt%, corresponding to three orders of magnitude in complex modulus. It was also found that the presence of worm like micelles in the solution phase was linked to mechanically stronger Ca-hydrogels. The gelation by addition of the calcium salt shifted the worm-like micellar concentration region and changed the microstructure to increase packing. The concentration was found to correlate with the mechanical properties with an exponential function with a 1.99 coefficient, typical for cross-linked networks and biopolymer gels. Finally, four types of microscopy techniques were used to conduct a structural analysis on multiple length scales with: optical microscopy, scanning electron microscopy, confocal microscopy and atomic force microscopy. A new open-source fibre tracking software was used on microscopy images and the structural parameters obtained were characterised by: fibre and worm diameter, bundle diameter, persistence length, contour length, nematic order, and type of fibre. These results suggest that microscopy interpretation of hierarchical structured materials has to be done for a specific length scale image, only relate to the features of length scale covered from the size that image to the resolution of the image. The Ca-hydrogel nanofibres in between a concentration of 0.01 and 1.0 wt% had the main nanofibre width of 20.5 ± 4.3 nm measured by SEM. There were also detectable fibres with an extended width from tenths of nanometres to few micrometres. Laser Scanning Confocal Microscopy (LSCM) measurements allowed a microstructural snapshot of the Ca-hydrogels. Additionally, LSCM identified that in solution phase no correlation is observable between the microstructure (persistence length of the fibre bundles) and the complex modulus G*, while for the Ca-hydrogel phase, the persistence length of the nanofibre bundles increases with the increase G*. The worm-like structures were found to be highly oriented in the solution phase across concentrations from 0.1 wt% to 1.0 wt%. In the Ca-hydrogel phase, the degree or oriented structures increased from 0.05 wt% to 1.0 wt%

Spinal locomotion in cats following spinal cord injury : a prospective study

Research Areas: Agriculture ; Veterinary SciencesThis article aimed to evaluate the safety and efficacy of intensive neurorehabilitation in paraplegic cats, with no deep pain perception (grade 0 on the modified Frankel scale), with more than three months of injury. Nine cats, admitted to the Arrábida Veterinary Hospital/Arrábida Animal Rehabilitation Center (CRAA), were subjected to a 12-week intensive functional neurorehabilitation protocol, based on ground and underwater treadmill locomotor training, electrostimulation, and kinesiotherapy exercises, aiming to obtain a faster recovery to ambulation and a modulated locomotor pattern of flexion/extension. Of the nine cats that were admitted in this study, 56% (n = 5) recovered from ambulation, 44% of which (4/9) did so through functional spinal locomotion by reflexes, while one achieved this through the recovery of deep pain perception. These results suggest that intensive neurorehabilitation can play an important role in ambulation recovery, allowing for a better quality of life and well-being, which may lead to a reduction in the number of euthanasia procedures performed on paraplegic animals.info:eu-repo/semantics/publishedVersio

Learning to segment when experts disagree

Recent years have seen an increasing use of supervised learning methods for segmentation tasks. However, the predictive performance of these algorithms depend on the quality of labels, especially in medical image domain, where both the annotation cost and inter-observer variability are high. In a typical annotation collection process, different clinical experts provide their estimates of the “true” segmentation labels under the influence of their levels of expertise and biases. Treating these noisy labels blindly as the ground truth can adversely affect the performance of supervised segmentation models. In this work, we present a neural network architecture for jointly learning, from noisy observations alone, both the reliability of individual annotators and the true segmentation label distributions. The separation of the annotators’ characteristics and true segmentation label is achieved by encouraging the estimated annotators to be maximally unreliable while achieving high fidelity with the training data. Our method can also be viewed as a translation of STAPLE, an established label aggregation framework proposed in Warfield et al. [1] to the supervised learning paradigm. We demonstrate first on a generic segmentation task using MNIST data and then adapt for usage with MRI scans of multiple sclerosis (MS) patients for lesion labelling. Our method shows considerable improvement over the relevant baselines on both datasets in terms of segmentation accuracy and estimation of annotator reliability, particularly when only a single label is available per image. An open-source implementation of our approach can be found at https://github.com/UCLBrain/MSLS

Fake supersymmetry versus Hamilton-Jacobi

We explain when the first-order Hamilton-Jacobi equations for black holes (and domain walls) in (gauged) supergravity, reduce to the usual first-order equations derived from a fake superpotential. This turns out to be equivalent to the vanishing of a newly found constant of motion and we illustrate this with various examples. We show that fake supersymmetry is a necessary condition for having physically sensible extremal black hole solutions. We furthermore observe that small black holes become scaling solutions near the horizon. When combined with fake supersymmetry, this leads to a precise extension of the attractor mechanism to small black holes: The attractor solution is such that the scalars move on specific curves, determined by the black hole charges, that are purely geodesic, although there is a non-zero potential.Comment: 20 pages, v2: Typos corrected, references adde

Kerr-AdS and its Near-horizon Geometry: Perturbations and the Kerr/CFT Correspondence

We investigate linear perturbations of spin-s fields in the Kerr-AdS black hole and in its near-horizon geometry (NHEK-AdS), using the Teukolsky master equation and the Hertz potential. In the NHEK-AdS geometry we solve the associated angular equation numerically and the radial equation exactly. Having these explicit solutions at hand, we search for linear mode instabilities. We do not find any (non-)axisymmetric instabilities with outgoing boundary conditions. This is in agreement with a recent conjecture relating the linearized stability properties of the full geometry with those of its near-horizon geometry. Moreover, we find that the asymptotic behaviour of the metric perturbations in NHEK-AdS violates the fall-off conditions imposed in the formulation of the Kerr/CFT correspondence (the only exception being the axisymmetric sector of perturbations).Comment: 26 pages. 4 figures. v2: references added. matches published versio

A non-linear VAD for noisy environments

This paper deals with non-linear transformations for improving the performance of an entropy-based voice activity detector (VAD). The idea to use a non-linear transformation has already been applied in the field of speech linear prediction, or linear predictive coding (LPC), based on source separation techniques, where a score function is added to classical equations in order to take into account the true distribution of the signal. We explore the possibility of estimating the entropy of frames after calculating its score function, instead of using original frames. We observe that if the signal is clean, the estimated entropy is essentially the same; if the signal is noisy, however, the frames transformed using the score function may give entropy that is different in voiced frames as compared to nonvoiced ones. Experimental evidence is given to show that this fact enables voice activity detection under high noise, where the simple entropy method fails

Holography at an Extremal De Sitter Horizon

Rotating maximal black holes in four-dimensional de Sitter space, for which the outer event horizon coincides with the cosmological horizon, have an infinite near-horizon region described by the rotating Nariai metric. We show that the asymptotic symmetry group at the spacelike future boundary of the near-horizon region contains a Virasoro algebra with a real, positive central charge. This is evidence that quantum gravity in a rotating Nariai background is dual to a two-dimensional Euclidean conformal field theory. These results are related to the Kerr/CFT correspondence for extremal black holes, but have two key differences: one of the black hole event horizons has been traded for the cosmological horizon, and the near-horizon geometry is a fiber over dS_2 rather than AdS_2.Comment: 15 page

Germline heterozygous DDX41 variants in a subset of familial myelodysplasia and acute myeloid leukemia

The Brazilian National Council for Scientific and Technological Development), Bloodwise, Children with Cancer and MRC (Medical Research Council, UK)

Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis

Financial support provided by The Medical Research Council-MR/K000292/1, Children with Cancer- 2013/144 and Blood Wise-14032 (AJW, LC, SC, AE, TV, HT and ID). KMG is supported by the National Institute for Health Research through the NIHR Southampton Biomedical Research Centre

Branch Mode Selection during Early Lung Development

Many organs of higher organisms, such as the vascular system, lung, kidney, pancreas, liver and glands, are heavily branched structures. The branching process during lung development has been studied in great detail and is remarkably stereotyped. The branched tree is generated by the sequential, non-random use of three geometrically simple modes of branching (domain branching, planar and orthogonal bifurcation). While many regulatory components and local interactions have been defined an integrated understanding of the regulatory network that controls the branching process is lacking. We have developed a deterministic, spatio-temporal differential-equation based model of the core signaling network that governs lung branching morphogenesis. The model focuses on the two key signaling factors that have been identified in experiments, fibroblast growth factor (FGF10) and sonic hedgehog (SHH) as well as the SHH receptor patched (Ptc). We show that the reported biochemical interactions give rise to a Schnakenberg-type Turing patterning mechanisms that allows us to reproduce experimental observations in wildtype and mutant mice. The kinetic parameters as well as the domain shape are based on experimental data where available. The developed model is robust to small absolute and large relative changes in the parameter values. At the same time there is a strong regulatory potential in that the switching between branching modes can be achieved by targeted changes in the parameter values. We note that the sequence of different branching events may also be the result of different growth speeds: fast growth triggers lateral branching while slow growth favours bifurcations in our model. We conclude that the FGF10-SHH-Ptc1 module is sufficient to generate pattern that correspond to the observed branching modesComment: Initially published at PLoS Comput Bio