Dynamic changes in heparan sulfate during muscle differentiation and ageing regulate myoblast cell fate and FGF2 signalling

Satellite cells (SCs) are skeletal muscle stem cells residing quiescent around healthy muscle fibres. In response to injury or disease SCs activate, proliferate and eventually differentiate and fuse to one another to form new muscle fibres, or to existing damaged fibres to repair them. The sulfated polysaccharide heparan sulfate (HS) is a highly variable biomolecule known to play key roles in the regulation of cell fate decisions, though the changes that muscle HS undergoes during SC differentiation are unknown. Here we show that the sulfation levels of HS increase during SC differentiation; more specifically, we observe an increase in 6-O and 2-O-sulfation in N-acetylated disaccharides. Interestingly, a specific increase in 6-O sulfation is also observed in the heparanome of ageing muscle, which we show leads to promotion of FGF2 signalling and satellite cell proliferation, suggesting a role for the heparanome dynamics in age-associated loss of quiescence. Addition of HS mimetics to differentiating SC cultures results in differential effects: an oversulfated HS mimetic increases differentiation and inhibits FGF2 signalling, a known major promoter of SC proliferation and inhibitor of differentiation. In contrast, FGF2 signalling is promoted by an N-acetylated HS mimetic, which inhibits differentiation and promotes SC expansion. We conclude that the heparanome of SCs is dynamically regulated during muscle differentiation and ageing, and that such changes might account for some of the phenotypes and signalling events that are associated with these processes

Learning, Social Intelligence and the Turing Test - why an "out-of-the-box" Turing Machine will not pass the Turing Test

The Turing Test (TT) checks for human intelligence, rather than any putative general intelligence. It involves repeated interaction requiring learning in the form of adaption to the human conversation partner. It is a macro-level post-hoc test in contrast to the definition of a Turing Machine (TM), which is a prior micro-level definition. This raises the question of whether learning is just another computational process, i.e. can be implemented as a TM. Here we argue that learning or adaption is fundamentally different from computation, though it does involve processes that can be seen as computations. To illustrate this difference we compare (a) designing a TM and (b) learning a TM, defining them for the purpose of the argument. We show that there is a well-defined sequence of problems which are not effectively designable but are learnable, in the form of the bounded halting problem. Some characteristics of human intelligence are reviewed including it's: interactive nature, learning abilities, imitative tendencies, linguistic ability and context-dependency. A story that explains some of these is the Social Intelligence Hypothesis. If this is broadly correct, this points to the necessity of a considerable period of acculturation (social learning in context) if an artificial intelligence is to pass the TT. Whilst it is always possible to 'compile' the results of learning into a TM, this would not be a designed TM and would not be able to continually adapt (pass future TTs). We conclude three things, namely that: a purely "designed" TM will never pass the TT; that there is no such thing as a general intelligence since it necessary involves learning; and that learning/adaption and computation should be clearly distinguished.Comment: 10 pages, invited talk at Turing Centenary Conference CiE 2012, special session on "The Turing Test and Thinking Machines

The potential for circular dichroism as an additional facile and sensitive method of monitoring low-molecular-weight heparins and heparinoids

The ultraviolet circular dichroism (CD) spectra of commercial low-molecular-weight heparins, heparinoids and other anticoagulant preparations have been recorded between 180 and 260 nm. Principal component analysis of the spectra allowed their differentiation into a number of groups related to the means of their production reflecting the structural changes introduced by each process. The findings suggest that CD provides a complementary technique for the rapid analysis of heparin preparations

Shape recognition: convexities, concavities and things in between.

Visual objects are effortlessly recognized from their outlines, largely irrespective of viewpoint. Previous studies have drawn different conclusions regarding the importance to shape recognition of specific shape features such as convexities and concavities. However, most studies employed familiar objects, or shapes without curves, and did not measure shape recognition across changes in scale and position. We present a novel set of random shapes with well-defined convexities, concavities and inflections (intermediate points), segmented to isolate each feature type. Observers matched the segmented reference shapes to one of two subsequently presented whole-contour shapes (target or distractor) that were re-scaled and re-positioned. For very short segment lengths, performance was significantly higher for convexities than for concavities or intermediate points and for convexities remained constant with increasing segment length. For concavities and intermediate points, performance improved with increasing segment length, reaching convexity performance only for long segments. No significant differences between concavities and intermediates were found. These results show for the first time that closed curvilinear shapes are encoded using the positions of convexities, rather than concavities or intermediate regions. A shape-template model with no free parameters gave an excellent account of the data

Variations in the Peritrophic Matrix Composition of Heparan Sulphate from the Tsetse Fly, Glossina morsitans morsitans

Tsetse flies are the principal insect vectors of African trypanosomes—sleeping sickness in humans and Nagana in cattle. One of the tsetse fly species, Glossina morsitans morsitans, is host to the parasite, Trypanosoma brucei, a major cause of African trypanosomiasis. Precise details of the life cycle have yet to be established, but the parasite life cycle involves crossing the insect peritrophic matrix (PM). The PM consists of the polysaccharide chitin, several hundred proteins, and both glycosamino- and galactosaminoglycan (GAG) polysaccharides. Owing to the technical challenges of detecting small amounts of GAG polysaccharides, their conclusive identification and composition have not been possible until now. Following removal of PMs from the insects and the application of heparinases (bacterial lyase enzymes that are specific for heparan sulphate (HS) GAG polysaccharides), dot blots with a HS-specific antibody showed heparan sulphate proteoglycans (HSPGs) to be present, consistent with Glossina morsitans morsitans genome analysis, as well as the likely expression of the HSPGs syndecan and perlecan. Exhaustive HS digestion with heparinases, fluorescent labeling of the resulting disaccharides with BODIPY fluorophore, and separation by strong anion exchange chromatography then demonstrated the presence of HS for the first time and provided the disaccharide composition. There were no significant differences in the type of disaccharide species present between genders or between ages (24 vs. 48 h post emergence), although the HS from female flies was more heavily sulphated overall. Significant differences, which may relate to differences in infection between genders or ages, were evident, however, in overall levels of 2-O-sulphation between sexes and, for females, between 24 and 48 h post-emergence, implying a change in expression or activity for the 2-O-sulphotransferase enzyme. The presence of significant quantities of disaccharides containing the monosaccharide GlcNAc6S contrasts with previous findings in Drosophila melanogaster and suggests subtle differences in HS fine structure between species of the Diptera

Chemotherapy-Response Monitoring of Breast Cancer Patients Using Quantitative Ultrasound-Based Intra-Tumour Heterogeneities

© 2017 The Author(s). Anti-cancer therapies including chemotherapy aim to induce tumour cell death. Cell death introduces alterations in cell morphology and tissue micro-structures that cause measurable changes in tissue echogenicity. This study investigated the effectiveness of quantitative ultrasound (QUS) parametric imaging to characterize intra-tumour heterogeneity and monitor the pathological response of breast cancer to chemotherapy in a large cohort of patients (n = 100). Results demonstrated that QUS imaging can non-invasively monitor pathological response and outcome of breast cancer patients to chemotherapy early following treatment initiation. Specifically, QUS biomarkers quantifying spatial heterogeneities in size, concentration and spacing of acoustic scatterers could predict treatment responses of patients with cross-validated accuracies of 82 ± 0.7%, 86 ± 0.7% and 85 ± 0.9% and areas under the receiver operating characteristic (ROC) curve of 0.75 ± 0.1, 0.80 ± 0.1 and 0.89 ± 0.1 at 1, 4 and 8 weeks after the start of treatment, respectively. The patients classified as responders and non-responders using QUS biomarkers demonstrated significantly different survivals, in good agreement with clinical and pathological endpoints. The results form a basis for using early predictive information on survival-linked patient response to facilitate adapting standard anti-cancer treatments on an individual patient basis

Strategies for Supporting College Students Experiencing Grief

Grief and loss are a shared human experience. However, lacking cultural awareness of the impact of grief and insufficient social support can make managing the loss of a loved one very challenging for students. One strategy to support students who experience loss during college is the development of a course that addresses content related to the experience within supportive academic relationships. This presentation will explore research findings about student experiences of grief on college campuses and evidence-based practices for the development and implementation of an academic course on grief

Grief Off-The-Clock: Supporting Hospice Professionals Through Personal Loss

Working with clients who die can have a major impact on the way professionals address their own grief. Daily exposure to the possibility of death alters the process of mourning and can leave professionals feeling disconnected from family and friends during times of grief. This presentation will look at the challenges that hospice workers, clergy members, social workers and other professionals face when they experience grief in their own lives. Evidence-based strategies for supporting professionals in their grief will also be explored