Mathematical modelling for topographically influenced cell migration and the modulating effect of Gap27 on connexin 43 cycling and 2-d scrape wound closure: applications to cutaneous wound healing

Cutaneous wounds represent a serious economic and health burden for many developed nations. In the U.K., around 2.2 million people a year receive wound care, absorbing roughly 4% of total annual NHS expenditure. Chronic cutaneous wounds in particular may possess poor prognoses. Diabetic foot ulcers, for example, carry a five-year mortality rate comparable to cancer. The prevalence of chronic wounds amongst developed nations is anticipated to rise further, with increasing incidence of conditions strongly associated with chronic wound aetiology, such as obesity and diabetes. A common feature among chronic wounds is the dysfunctional regulation of connexin proteins in cutaneous tissue, which ordinarily modulates in a carefully orchestrated manner post-injury to enable effective healing. Experimental studies targeted to the restoration of the typical spatio-temporal expression pattern of connexins post-injury have shown accelerated and improved healing outcomes across a range of in vitro, in vivo animal and ex vivo human models, and now clinical trials - with various connexin-targeted agents established as promising therapeutic candidates. Physical properties of the extracellular environment have long been known to regulate cellular behaviours. Cutaneous tissue presents a huge range of topographic configurations that cells must navigate in order to carry out reparative function during wound repair. Surface ‘topography’ has since been established in the experimental literature as a major regulator of cell migration behaviour. The capacity for topography to influence migration has been shown to have significant applications in biomaterial and bioimplant design and development, including advanced wound healing treatments like ‘skin substitutes’. In this thesis, we propose three new mathematical models pertaining to these applications. We derive a stochastic model for topographically influenced cell migration, based on a biased Ornstein-Uhlenbeck cell model. We use this model to probe the influence of linearly and randomly organised topographies on migration trajectory behaviour and how the gradual introduction of random perturbations to linear features changes this behaviour, with the intention to further understand how surface imperfections introduced by surface fabrication impact migration. We then derive a mathematical model for connexin 43 (Cx43) cycling dynamics and its dynamical modulation by connexin mimetic peptide Gap27, using mass action kinetics. We use this model to further understand how the introduction of Gap27 may function to affect Cx43-based species dynamics. Finally, we derive a mathematical model for Cx43-based cell-cell interaction influenced cell migration and its dynamical modulation by Gap27 within a two-dimensional computational model of a scrape wound. We use this model to investigate how Cx43 dynamics might affect cell migration behaviour and population invasion of a scrape wound and how Gap27 might modulate these cellular behaviours

Ascorbic acid oxidation: A potential cause of the elevated severity of atherosclerosis in diabetes mellitus?

AbstractThe exposure of mouse peritoneal macrophages to cholesterol linoleate-containing, artificial lipoproteins can lead to intracellular ceroid accumulation. This can be used as a model to study the role of oxidation in macrophage uptake of lipoproteins containing unsaturated fatty acids, considered by many as a primary event in atherosclerotic plaque formation. Our studies show that ascorbic acid can both inhibit and promote the formation of ceroid in such a model system. The transition metal copper (Cu(II)) further elevates ceroid accumulation and EDTA, a metal chelator, inhibits it. When trace levels of transition metals are present, low concentrations of ascorbic acid can elevate ceroid formation. This pro- and antioxidant characteristic of ascorbic acid was confirmed by monitoring the generation of oxidants by various concentrations of ascorbic acid, assessed by benzoic acid hydroxylation or the fragmentation of BSA. We discuss these observations in the context of an apparent increase in ascorbic acid oxidation and elevated severity of atherosclerosis in diabetes mellitus

Complementary and Alternative Medicine (CAM) Therapies as a Means of Advancing Patient-Centered Care for Veterans Receiving Palliative Care

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140336/1/acm.2014.5130.abstract.pd

Strategy Change in Vibrissal Active Sensing during Rat Locomotion

During exploration, rats and other small mammals make rhythmic back-and-forth sweeps of their long facial whiskers (macrovibrissae) [1, 2 and 3]. These “whisking” movements are modulated by head movement [4] and by vibrissal sensory input [5 and 6] and hence are often considered “active” in the Gibsonian sense of being purposive and information seeking [7 and 8]. An important hallmark of active sensing is the modification of the control strategy according to context [9]. Using a task in which rats were trained to run circuits for food, we tested the hypothesis that whisker control, as measured by high-speed videography, changes with contextual variables such as environment familiarity, risk of collision, and availability of visual cues. In novel environments, functionally blind rats moved at slow speeds and performed broad whisker sweeps. With greater familiarity, however, they moved more rapidly, protracted their whiskers further, and showed decreased whisking amplitude. These findings indicate a strategy change from using the vibrissae to explore nearby surfaces to using them primarily for “look ahead.” In environments with increased risk of collision, functionally blind animals moved more slowly but protracted their whiskers further. Sighted animals also showed changes in whisker control strategy with increased familiarity, but these changes were different to those of the functionally blind strain. Sighted animals also changed their vibrissal behavior when visual cues were subsequently removed (by being placed in darkness). These contextual influences provide strong evidence of active control and demonstrate that the vibrissal system provides an accessible model of purposive behavior in mammals

Haemodynamic effects of a prehospital emergency anaesthesia protocol consisting of fentanyl, ketamine and rocuronium in patients with trauma:a retrospective analysis of data from a Helicopter Emergency Medical Service

OBJECTIVES: Prehospital rapid sequence induction (RSI) of anaesthesia is an intervention with significant associated risk. In this study, we aimed to investigate the haemodynamic response over time of a prehospital RSI protocol of fentanyl, ketamine and rocuronium in a heterogeneous population of trauma patients. DESIGN, SETTING AND PARTICIPANT: We performed a retrospective study of all trauma patients who received a prehospital RSI for trauma by a physician staffed Helicopter Emergency Medical Service in the UK between 1 June 2018 and 1 February 2020. PRIMARY OUTCOME MEASURE: Primary outcome was defined as the incidence of clinically relevant hypotensive (systolic blood pressure (SBP) or mean arterial pressure (MAP) >20% below baseline, with an absolute SBP 20% above baseline) episodes in the first 10 minutes post-RSI. RESULTS: In total, 322 patients were included. 204 patients (63%) received a full-dose induction of 3 μg/kg fentanyl, 2 mg/kg ketamine and 1 mg/kg rocuronium, whereas 128 patients (37%) received a reduced-dose induction. Blood pressures decreased on average 12 mm Hg (95% CI 7 to 16) in the full-dose group and 6 mm Hg (95% CI 1 to 11) in the reduced-dose group, p=0.10). A hypotensive episode (mean SBP drop 53 mm Hg) was noted in 29 patients: 17 (8.3%) receiving a full dose and 12 (10.2%) receiving a reduced-dose induction, p=0.69. The blood pressure nadir was recorded on average 6–8 min after RSI. A hypertensive episode was present in 22 patients (6.8%). The highest blood pressures were recorded in the first 3 min after RSI. CONCLUSION: Prehospital induction of anaesthesia for trauma with fentanyl, ketamine and rocuronium is not related to a significant change in haemodynamics in most patients. However, a (delayed) hypotensive response with a significant drop in SBP should be anticipated in a minority of patients irrespective of the dose regimen chosen

Naive Bayes novelty detection for a moving robot with whiskers

Novelty detection would be a useful ability for any autonomous robot that seeks to categorize a new environment or notice unexpected changes in its present one. A biomimetic robot (SCRATCHbot) inspired by the rat whisker system was here used to examine the performance of a novelty detection algorithm based on a 'naive' implementation of Bayes rule. Naive Bayes algorithms are known to be both efficient and effective, and also have links with proposed neural mechanisms for decision making. To examine novelty detection, the robot first used its whiskers to sense an empty floor, after which it was tested with a textured strip placed in its path. Given only its experience of the familiar situation, the robot was able to distinguish the novel event and localize it in time. Performance increased with the number of whiskers, indicating benefits from integrating over multiple streams of information. Considering the generality of the algorithm, we suggest that such novelty detection could have widespread applicability as a trigger to react to important features in the robot's environment. © 2010 IEEE

Modeling the Emergence of Whisker Direction Maps in Rat Barrel Cortex

Based on measuring responses to rat whiskers as they are mechanically stimulated, one recent study suggests that barrel-related areas in layer 2/3 rat primary somatosensory cortex (S1) contain a pinwheel map of whisker motion directions. Because this map is reminiscent of topographic organization for visual direction in primary visual cortex (V1) of higher mammals, we asked whether the S1 pinwheels could be explained by an input-driven developmental process as is often suggested for V1. We developed a computational model to capture how whisker stimuli are conveyed to supragranular S1, and simulate lateral cortical interactions using an established self-organizing algorithm. Inputs to the model each represent the deflection of a subset of 25 whiskers as they are contacted by a moving stimulus object. The subset of deflected whiskers corresponds with the shape of the stimulus, and the deflection direction corresponds with the movement direction of the stimulus. If these two features of the inputs are correlated during the training of the model, a somatotopically aligned map of direction emerges for each whisker in S1. Predictions of the model that are immediately testable include (1) that somatotopic pinwheel maps of whisker direction exist in adult layer 2/3 barrel cortex for every large whisker on the rat's face, even peripheral whiskers; and (2) in the adult, neurons with similar directional tuning are interconnected by a network of horizontal connections, spanning distances of many whisker representations. We also propose specific experiments for testing the predictions of the model by manipulating patterns of whisker inputs experienced during early development. The results suggest that similar intracortical mechanisms guide the development of primate V1 and rat S1

Hypocrea jecorina CEL6A protein engineering

The complex technology of converting lignocellulose to fuels such as ethanol has advanced rapidly over the past few years, and enzymes are a critical component of this technology. The production of effective enzyme systems at cost structures that facilitate commercial processes has been the focus of research for many years. Towards this end, the H. jecorina cellobiohydrolases, CEL7A and CEL6A, have been the subject of protein engineering at Genencor. Our first rounds of cellobiohydrolase engineering were directed towards improving the thermostability of both of these enzymes and produced variants of CEL7A and CEL6A with apparent melting temperatures above 70°C, placing their stability on par with that of H. jecorina CEL5A (EG2) and CEL3A (BGL1). We have now moved towards improving CEL6A- and CEL7A-specific performance in the context of a complete enzyme system under industrially relevant conditions. Achievement of these goals required development of new screening strategies and tools. We discuss these advances along with some results, focusing mainly on engineering of CEL6A

Re-ordering connections: UK healthcare workers' experiences of emotion management during the COVID-19 pandemic

This paper examines the impact of disruptions to the organisation and delivery of healthcare services and efforts to re-order care through emotion management during the COVID-19 pandemic in the UK. Framing care as an affective practice, studying healthcare workers' (HCWs) experiences enables better understanding of how interactions between staff, patients and families changed as a result of the pandemic. Using a rapid qualitative research methodology, we conducted interviews with frontline HCWs in two London hospitals during the peak of the first wave of the pandemic and sourced public accounts of HCWs' experiences of the pandemic from social media (YouTube and Twitter). We conducted framework analysis to identify key factors disrupting caring interactions. Fear of infection and the barriers of physical distancing acted to separate staff from patients and families, requiring new affective practices to repair connections. Witnessing suffering was distressing for staff, and providing a 'good death' for patients and communicating care to families was harder. In addition to caring for patients and families, HCWs cared for each other. Infection control measures were important for limiting the spread of COVID-19 but disrupted connections that were integral to care, generating new work to re-order interactions

Storage capacity of a constructive learning algorithm

Upper and lower bounds for the typical storage capacity of a constructive algorithm, the Tilinglike Learning Algorithm for the Parity Machine [M. Biehl and M. Opper, Phys. Rev. A {\bf 44} 6888 (1991)], are determined in the asymptotic limit of large training set sizes. The properties of a perceptron with threshold, learning a training set of patterns having a biased distribution of targets, needed as an intermediate step in the capacity calculation, are determined analytically. The lower bound for the capacity, determined with a cavity method, is proportional to the number of hidden units. The upper bound, obtained with the hypothesis of replica symmetry, is close to the one predicted by Mitchinson and Durbin [Biol. Cyber. {\bf 60} 345 (1989)].Comment: 13 pages, 1 figur