A Histone Deacetylase (HDAC) Inhibitor with Pleiotropic In Vitro Anti-Toxoplasma and Anti-Plasmodium Activities Controls Acute and Chronic Toxoplasma Infection in Mice

Toxoplasmosis is a highly prevalent human disease, and virulent strains of this parasite emerge from wild biotopes. Here, we report on the potential of a histone deacetylase (HDAC) inhibitor we previously synthesized, named JF363, to act in vitro against a large panel of Toxoplasma strains, as well as against the liver and blood stages of Plasmodium parasites, the causative agents of malaria. In vivo administration of the drug significantly increases the survival of mice during the acute phase of infection by T. gondii, thus delaying its spreading. We further provide evidence of the compound’s efficiency in controlling the formation of cysts in the brain of T. gondii-infected mice. A convincing docking of the JF363 compound in the active site of the five annotated ME49 T. gondii HDACs was performed by extensive sequence–structure comparison modeling. The resulting complexes show a similar mode of binding in the five paralogous structures and a quite similar prediction of affinities in the micromolar range. Altogether, these results pave the way for further development of this compound to treat acute and chronic toxoplasmosis. It also shows promise for the future development of anti-Plasmodium therapeutic interventions.     

Evaluation of atrial septal defects with 4D flow MRI—multilevel and inter-reader reproducibility for quantification of shunt severity

Purpose

With the hypothesis that 4D flow can be used in evaluation of cardiac shunts, we seek to evaluate the multilevel and interreader reproducibility of measurements of the blood flow, shunt fraction and shunt volume in patients with atrial septum defect (ASD) in practice at multiple clinical sites.

Materials and methods

Four-dimensional flow MRI examinations were performed at four institutions across Europe and the US. Twenty-nine patients (mean age, 43 years; 11 male) were included in the study. Flow measurements were performed at three levels (valve, main artery and periphery) in both the pulmonary and systemic circulation by two independent readers and compared against stroke volumes from 4D flow anatomic data. Further, the shunt ratio (Q_p/Q_s) was calculated. Additionally, shunt volume was quantified at the atrial level by tracking the atrial septum.

Results

Measurements of the pulmonary blood flow at multiple levels correlate well whether measuring at the valve, main pulmonary artery or branch pulmonary arteries (r = 0.885–0.886). Measurements of the systemic blood flow show excellent correlation, whether measuring at the valve, ascending aorta or sum of flow from the superior vena cava (SVC) and descending aorta (r = 0.974–0.991). Intraclass agreement between the two observers for the flow measurements varies between 0.96 and 0.99. Compared with stroke volume, pulmonic flow is underestimated with 0.26 l/min at the main pulmonary artery level, and systemic flow is overestimated with 0.16 l/min at the ascending aorta level. Direct measurements of ASD flow are feasible in 20 of 29 (69%) patients.

Conclusion

Blood flow and shunt quantification measured at multiple levels and performed by different readers are reproducible and consistent with 4D flow MRI.

     

Visual search for a tilted target: tests of spatial uncertainty models

We report that spatial cueing of a parafoveal target in the presence of distractors enhances orientational acuity for that target. When no distractors were present, orientation thresholds were in the range 1-4 degrees. For long exposure times, distractors increased threshold by the amount predicted from a winner-takes-all spatial uncertainty model. For short (100-msec) exposures followed by a random dot mask, the rise in threshold with distractors was considerably greater than that predicted from spatial uncertainty. For brief exposures the effect of distractors was greater when the target and distractors were spatially crowded rather than widely spaced. Adding a tilt to the distractors in the opposite direction to the target increased thresholds still further. Cueing the target with a spatial pointer decreased the effect of distractors, even when they were crowded. We suggest that when attention cannot be appropriately focused, discrimination is carried out by a relatively coarse texture analyser, which averages over several elements, and that focused attention permits the analysis of the target over a smaller area of space.     

Applying SVMs and weight-based factor analysis to unsupervised adaptation for speaker verification

This paper presents an extended study on the implementation of support vector machine (SVM) based speaker verification in systems that employ continuous progressive model adaptation using the weight-based factor analysis model. The weight-based factor analysis model compensates for session variations in unsupervised scenarios by incorporating trial confidence measures in the general statistics used in the inter-session variability modelling process. Employing weight-based factor analysis in Gaussian mixture models (GMMs) was recently found to provide significant performance gains to unsupervised classification. Further improvements in performance were found through the integration of SVM-based classification in the system by means of GMM supervectors.This study focuses particularly on the way in which a client is represented in the SVM kernel space using single and multiple target supervectors. Experimental results indicate that training client SVMs using a single target supervector maximises performance while exhibiting a certain robustness to the inclusion of impostor training data in the model. Furthermore, the inclusion of low-scoring target trials in the adaptation process is investigated where they were found to significantly aid performance.     

Evolutionary design of discrete controllers for hybrid mechatronic systems

This paper investigates the issue of evolutionary design of controllers for hybrid mechatronic systems. Finite State Automaton (FSA) is selected as the representation for a discrete controller due to its interpretability, fast execution speed and natural extension to a statechart, which is very popular in industrial applications. A case study of a two-tank system is used to demonstrate that the proposed evolutionary approach can lead to a successful design of an FSA controller for the hybrid mechatronic system, represented by a hybrid bond graph. Generalisation of the evolved FSA controller to unknown control targets is also tested. Further, a comparison with another type of controller, a lookahead controller, is conducted, with advantages and disadvantages of each discussed. The comparison sheds light on which type of controller representation is a better choice to use in various stages of the evolutionary design of controllers for hybrid mechatronic systems. Finally, some important future research directions are pointed out, leading to the major work of the succeeding part of the research.     

Colorings with few Colors: Counting, Enumeration and Combinatorial Bounds

Edge coloring, total coloring and L(2,1)-labeling are well-studied NP-hard graph problems. Even the versions asking whether a graph has a coloring with few colors or a labeling with few labels remain NP-hard on graphs of small maximum degree. This paper studies enumeration and counting problems on edge colorings, total colorings and L(2,1)-labelings of graphs. One part deals with the enumeration of all edge 3-colorings, all total 4-colorings and all L(2,1)-labelings of span 5 of a given connected cubic graph. Branching algorithms to solve these enumeration problems are established. They imply upper bounds on the maximum number of edge 3-colorings, total 4-colorings and L(2,1)-labelings of span 5 in any n-vertex connected cubic graphs. Corresponding combinatorial lower bounds are also provided. The other part of the paper studies dynamic programming algorithms solving counting problems. On one hand, algorithms to count the number of edge k-colorings and total k-colorings for graphs of bounded pathwidth are given. On the other hand, an algorithm to count the number of L(2,1)-labelings of span 4 for graphs of maximum degree three are given.     

An expert system for choosing the best combination of options in a general purpose program for Automated Design Synthesis

An expert system called EXADS has been developed to aid users of the Automated Design Synthesis (ADS) general purpose optimization program. ADS has approximately 100 combinations of strategy, optimizer, and one-dimensional search options from which to choose. It is difficult for a nonexpert to make this choice. This expert system aids the user in choosing the best combination of options based on the users knowledge of the problem and the expert knowledge stored in the knowledge base. The knowledge base is divided into three categories; constrained problems, unconstrained problems, and constrained problems being treated as unconstrained problems. The inference engine and rules are written in LISP, contains about 200 rules, and executes on DEC-VAX (with Franz-LISP) and IBM PC (with IQ-LISP) computers.     

Delivering scalable video with QoS to the home

User satisfaction is a key factor in the success of novel multimedia services. Yet, to enable service providers and network operators to control and maximize the quality (QoS, QoE) of delivered video streams, quite some challenges remain. In this paper, we particularly focus on three of them. First of all, objectively measuring video quality requires appropriate quality metrics and methods of assessing them in a real-time fashion. Secondly, the recent Scalable Video Coding (SVC) format opens opportunities for adapting video to the available (network) resources, yet the appropriate configuration of video encoding as well as real-time streaming adaptation are largely unaddressed research areas. Thirdly, while bandwidth reservation mechanisms in access/core networks do exist, service providers lack a means for guaranteeing QoS in the increasingly complex home networks (which they are not in full control of). In this paper we offer a broad view on these interrelated issues, by presenting the developments originating in a Flemish research project (including proof-of-concept demonstrations). From a developmental perspective, we propose an architecture combining a real-time video quality monitoring platform, on-the-fly adaptation (optimizing the video quality) and QoS reservation in a heterogeneous home network based on UPnP QoS?v3. From a research perspective, we propose a new subjective test procedure that revealed user preference for temporal scalability over quality scalability. In addition, an extensive study on optimizing HD SVC encoding in IPTV scenarios with fluctuating bandwidth showed that under certain bandwidth constraints (prohibiting sufficient fidelity) spatial scalability is a better option than quality scalability.     

A knowledge-based approach to automatic detection of the spinal cord in CT images

Accurate planning of radiation therapy entails the definition of treatment volumes and a clear delimitation of normal tissue of which unnecessary exposure should be prevented. The spinal cord is a radiosensitive organ, which should be precisely identified because an overexposure to radiation may lead to undesired complications for the patient such as neuronal disfunction or paralysis. In this paper, a knowledge-based approach to identifying the spinal cord in computed tomography images of the thorax is presented. The approach relies on a knowledge-base which consists of a so-called anatomical structures map (ASM) and a task-oriented architecture called the plan solver. The ASM contains a frame-like knowledge representation of the macro-anatomy in the human thorax. The plan solver is responsible for determining the position, orientation and size of the structures of interest to radiation therapy. The plan solver relies on a number of image processing operators. Some are so-called atomic (e.g., thresholding and snakes) whereas others are composite. The whole system has been implemented on a standard PC. Experiments performed on the image material from 23 patients show that the approach results in a reliable recognition of the spinal cord (92% accuracy) and the spinal canal (85% accuracy). The lamina is more problematic to locate correctly (accuracy 72%). The position of the outer thorax is always determined correctly.     

Characterization and role of an elastomeric interphase on carbon fibers reinforcing an epoxy matrix

Oxidized carbon fibers were coated using an on-line filament winding process with an elastomeric adduct crosslinkable and compatible with an epoxy matrix. The coating and modifications of the epoxy network were studied by dynamic mechanical measurements. Assuming that apparent activation energies of the secondary relaxation β_e of the epoxy network and main relaxation α_a of adduct are very different, it is possible at low frequencies to separate the two peaks. The composite material can be described as a three phase system: an epoxy network as matrix, carbon fibers, and a soft interlayer. The mechanical behavior of unidirectional composite materials studied by impact and bending tests is strongly dependent on the presence and the thickness of the coating at the carbon fiber surface.