Evaluation of matricellular proteins as potential therapeutics for the treatment of human chronic skin wounds

There is currently an unmet need for treatments to enhance healing of human chronic skin wounds. Previously, therapy development has focused on growth factors and physical matrices, often resulting in disappointing clinical outcomes. In this thesis, we approached chronic skin wound treatment with a focus on fibrosis and matricellular proteins. Fibrosis is a pathological condition where tissue repair continues, unchecked, resulting in excess contraction, matrix accumulation and fibrogenic growth factor activity; features critically reduced in chronic skin wounds. Identifying factors that promote fibrosis may offer new therapeutic targets for use in chronic skin wounds. Two such factors are the matricellular proteins periostin and CCN2. As a group, matricellular proteins have established roles in acute wound healing; facilitating growth factor signaling, matrix production and contraction. However, as of yet, matricellular proteins represent an uninvestigated resource for modulating chronic skin wound healing. The objective of this thesis was to determine the potential of periostin and CCN2 as therapeutics for accelerating skin wound healing. Periostin is up-regulated during skin healing but its function was unknown. Using periostin knockout mice, we observed a delay in fullthickness excisional wound closure in the absence of periostin. This delay was attributed to a lack of myofibroblast differentiation, central to wound contraction, both in vivo and in vitro. Next we examined the expression patterns of periostin and CCN2 in tissue samples from human chronic skin wounds. Within these wounds CCN2 was not induced and periostin was decreased. These expression patterns were likely due to the environment of the wounds since fibroblasts cultured from wound tissue expressed periostin and CCN2, responded to TGFβ, proliferated and contracted collagen gels; consistent with a fibrotic phenotype. Using a mouse model of impaired diabetic skin healing, we found that delivery of recombinant periostin or CCN2 accelerated wound healing. The mechanisms through which periostin and CCN2 delivery influenced wound healing were distinct, and combination of the two treatments produced synergistic outcomes. These findings represent the first report of using matricellular proteins to enhance healing of diabetic skin wounds in an animal model, with an aim to improve healing of human chronic skin wounds

Immersion microscopy based on photonic crystal materials

Theoretical model of the enhanced optical resolution of the surface plasmon immersion microscope is developed, which is based on the optics of surface plasmon Bloch waves in the tightly bound approximation. It is shown that a similar resolution enhancement may occur in a more general case of an immersion microscope based on photonic crystal materials with either positive or negative effective refractive index. Both signs of the effective refractive index have been observed in our experiments with surface plasmon immersion microscope, which is also shown to be capable of individual virus imaging.Comment: 23 pages, 10 figure

Black Holes in Einstein-Aether Theory

We study black hole solutions in general relativity coupled to a unit timelike vector field dubbed the "aether". To be causally isolated a black hole interior must trap matter fields as well as all aether and metric modes. The theory possesses spin-0, spin-1, and spin-2 modes whose speeds depend on four coupling coefficients. We find that the full three-parameter family of local spherically symmetric static solutions is always regular at a metric horizon, but only a two-parameter subset is regular at a spin-0 horizon. Asymptotic flatness imposes another condition, leaving a one-parameter family of regular black holes. These solutions are compared to the Schwarzschild solution using numerical integration for a special class of coupling coefficients. They are very close to Schwarzschild outside the horizon for a wide range of couplings, and have a spacelike singularity inside, but differ inside quantitatively. Some quantities constructed from the metric and aether oscillate in the interior as the singularity is approached. The aether is at rest at spatial infinity and flows into the black hole, but differs significantly from the the 4-velocity of freely-falling geodesics.Comment: 22 pages, 6 figures; v2: minor editing; v3: corrected overall sign in twist formula and an error in the equation for the aether stress tensor. Results unchanged since correct form was used in calculations; v4: corrected minor typ

Synchronization and Control in Intrinsic and Designed Computation: An Information-Theoretic Analysis of Competing Models of Stochastic Computation

We adapt tools from information theory to analyze how an observer comes to synchronize with the hidden states of a finitary, stationary stochastic process. We show that synchronization is determined by both the process's internal organization and by an observer's model of it. We analyze these components using the convergence of state-block and block-state entropies, comparing them to the previously known convergence properties of the Shannon block entropy. Along the way, we introduce a hierarchy of information quantifiers as derivatives and integrals of these entropies, which parallels a similar hierarchy introduced for block entropy. We also draw out the duality between synchronization properties and a process's controllability. The tools lead to a new classification of a process's alternative representations in terms of minimality, synchronizability, and unifilarity.Comment: 25 pages, 13 figures, 1 tabl

Using fNIRS to Verify Trust in Highly Automated Driving

Trust in automation is crucial for the safe and appropriate adoption of automated driving technology. Current research methods to measure trust mainly rely on subjective scales, with several intrinsic limitations. This empirical experiment proposes a novel method to measure trust objectively, using functional near-infrared spectroscopy (fNIRS). Through manipulating participants’ expectations regarding driving automation credibility, we have induced and successfully measured opposing levels of trust in automation. Most notably, our results evidence two separate yet interrelated cortical mechanisms for trust and distrust. Trust is demonstrably linked to decreased monitoring and working memory, whereas distrust is event-related and strongly tied to affective (or emotional) mechanisms. This paper evidence that trust in automation and situation awareness are strongly interrelated during driving automation usage. Our findings are crucial for developing future driver state monitoring technology that mitigates the impact of inappropriate reliance, or over trust, in automated driving systems

Magnetic light

In this paper we report on the observation of novel and highly unusual magnetic state of light. It appears that in small holes light quanta behave as small magnets so that light propagation through such holes may be affected by magnetic field. When arrays of such holes are made, magnetic light of the individual holes forms novel and highly unusual two-dimensional magnetic light material. Magnetic light may soon become a great new tool for quantum communication and computing.Comment: Submitted to Phys.Rev.Lett., 3 figure

Obtaining material identification with cosmic ray radiography

The passage of muons through matter is mostly affected by their Coulomb interactions with electrons and nuclei. The muon interactions with electrons lead to continuous energy loss and stopping of muons, while their scattering off nuclei lead to angular 'diffusion'. By measuring both the number of stopped muons and angular changes in muon trajectories we can estimate density and identify materials. Here we demonstrate the material identification using data taken at Los Alamos with the Mini Muon Tracker.Comment: 10 pages, 9 figures, Accepted to AIP Advance

T. brucei cathepsin-L increases arrhythmogenic sarcoplasmic reticulum-mediated calcium release in rat cardiomyocytes

Aims: African trypanosomiasis, caused by Trypanosoma brucei species, leads to both neurological and cardiac dysfunction and can be fatal if untreated. While the neurological-related pathogenesis is well studied, the cardiac pathogenesis remains unknown. The current study exposed isolated ventricular cardiomyocytes and adult rat hearts to T. brucei to test whether trypanosomes can alter cardiac function independent of a systemic inflammatory/immune response. Methods and results: Using confocal imaging, T. brucei and T. brucei culture media (supernatant) caused an increased frequency of arrhythmogenic spontaneous diastolic sarcoplasmic reticulum (SR)-mediated Ca2+ release (Ca2+ waves) in isolated adult rat ventricular cardiomyocytes. Studies utilising inhibitors, recombinant protein and RNAi all demonstrated that this altered SR function was due to T. brucei cathepsin-L (TbCatL). Separate experiments revealed that TbCatL induced a 10–15% increase of SERCA activity but reduced SR Ca2+ content, suggesting a concomitant increased SR-mediated Ca2+ leak. This conclusion was supported by data demonstrating that TbCatL increased Ca2+ wave frequency. These effects were abolished by autocamtide-2-related inhibitory peptide, highlighting a role for CaMKII in the TbCatL action on SR function. Isolated Langendorff perfused whole heart experiments confirmed that supernatant caused an increased number of arrhythmic events. Conclusion: These data demonstrate for the first time that African trypanosomes alter cardiac function independent of a systemic immune response, via a mechanism involving extracellular cathepsin-L-mediated changes in SR function

Antecedent hypertension and heart failure after myocardial infarction

AbstractObjectivesWe sought to assess the relationship of antecedent hypertension to neurohormones, ventricular remodeling and clinical heart failure (HF) after myocardial infarction (MI).BackgroundHeart failure is a probable contributor to the increased mortality observed after MI in those with antecedent hypertension. Hence, neurohormonal activation, adverse ventricular remodeling and a higher incidence of clinical HF may be expected in this group. However, no previous report has documented serial postinfarction neurohumoral status, serial left ventricular imaging and clinical outcomes over prolonged follow-up in a broad spectrum of patients with and without antecedent hypertension.MethodsInpatient events were documented in 1,093 consecutive patients (436 hypertensive and 657 normotensive) with acute MI. In 68% (282 hypertensive, 465 normotensive) serial neurohormonal sampling and radionuclide ventriculography were performed one to four days and three to five months after infarction. Clinical outcomes were recorded over a mean follow-up of two years.ResultsPlasma neurohormones were significantly higher in hypertensives than in normotensives one to four days and three to five months after infarction. From similar initial values, left ventricular volumes increased significantly in hypertensives, compared with normotensives. Left ventricular ejection fraction rose significantly in normotensive but not hypertensive patients. Together with higher inpatient (8.1% vs. 4.4%, p < 0.002) and post-discharge mortality (9.5% vs. 5.5%, p = 0.043), hypertensive patients incurred more inpatient HF (33% vs. 24%, p < 0.001) and more late HF requiring readmission to hospital (12.4% vs. 5.5%, p < 0.001). Antecedent hypertension predicted late HF in patients >64 years of age with neurohormonal activation and early left ventricular dilation.ConclusionsAntecedent hypertension interacts with age, neurohumoral activation and early ventricular remodeling to confer greater risk of HF after MI