Fitting C2 Continuous Parametric Surfaces to Frontiers Delimiting Physiologic Structures

We present a technique to fit C2 continuous parametric surfaces to scattered geometric data points forming frontiers delimiting physiologic structures in segmented images. Such mathematical representation is interesting because it facilitates a large number of operations in modeling. While the fitting of C2 continuous parametric curves to scattered geometric data points is quite trivial, the fitting of C2 continuous parametric surfaces is not. The difficulty comes from the fact that each scattered data point should be assigned a unique parametric coordinate, and the fit is quite sensitive to their distribution on the parametric plane. We present a new approach where a polygonal (quadrilateral or triangular) surface is extracted from the segmented image. This surface is subsequently projected onto a parametric plane in a manner to ensure a one-to-one mapping. The resulting polygonal mesh is then regularized for area and edge length. Finally, from this point, surface fitting is relatively trivial. The novelty of our approach lies in the regularization of the polygonal mesh. Process performance is assessed with the reconstruction of a geometric model of mouse heart ventricles from a computerized tomography scan. Our results show an excellent reproduction of the geometric data with surfaces that are C2 continuous

Inverse Problems in data-driven multi-scale Systems Medicine: application to cancer physiology

Systems Medicine is an interdisciplinary framework involving reciprocal feedback between clinical investigation and mathematical modeling/analysis. Its aim is to improve the understanding of complex diseases by integrating knowledge and data across multiple levels of biological organization. This Thesis focuses on three inverse problems, arising from three kinds of data and related to cancer physiology, at different scales: tissues, cells, molecules. The general assumption of this piece of research is that cancer is associated toa path ological glucose consumption and, in fact, its functional behavior can be assessed by nuclear medicine experiments using [18F]-fluorodeoxyglucose (FDG) as a radioactive tracer mimicking the glucose properties. At tissue-scale, this Thesis considers the Positron Emission Tomography (PET) imaging technique, and deals with two distinct issues within compartmental analysis. First, this Thesis presents a compartmental approach, referred to as reference tissue model, for the estimation of FDG kinetics inside cancer tissues when the arterial blood input of the system is unknown. Then, this Thesis proposes an efficient and reliable method for recovering the compartmental kinetic parameters for each PET image pixel in the context of parametric imaging, exploiting information on the tissue physiology. Standard models in compartmental analysis assume that phosphorylation and dephosphorylation of FDG occur in the same intracellular cytosolic volume. Advances in cell biochemistry have shown that the appropriate location of dephosphorylation is the endoplasmic reticulum (ER). Therefore, at cell-scale, this Thesis formalizes a biochemically-driven compartmental model accounting for the specific role played by the ER, and applies it to the analysis of in vitro experiments on FDG uptake by cancer cell cultures obtained with a LigandTracer (LT) device. Finally, at molecule-scale, this Thesis provides a preliminary mathematical investigation of a chemical reaction network (CRN), represented by a huge Molecular Interaction Map (MIM), describing the biochemical interactions occurring between signaling proteins in specific pathways within a cancer cell. The main issue addressed in this case is the network parameterization problem, i.e. how to determine the reaction rate coefficients from protein concentration data

Functional and structural characterization of Aquifex aeolicus sulfide:quinone oxidoreductase

This work presents the first complete structure of the membrane protein sulfide:quinone oxidoreductase (SQR), obtained by X-ray crystallography. Its description is complemented by the results of biochemical and functional experiments. SQRs are ubiquitous flavoprotein disulfide reductases (FDRs), present in all domains of life, including in humans. Their physiological role extends from sulfide detoxification to sulfide-dependent respiration and photosynthesis (in archaea and bacteria), to heavy metal tolerance (in yeast) and possibly to sulfide signalling (in higher eukaryotes). Until now understanding the function of SQRs was difficult because of the poor level of sequence conservation in this enzyme family, the limited functional characterization available and the absence of any structural data. SQR was identified in the native membranes of the hyperthermophilic bacterium Aquifex aeolicus by peptide mass fingerprinting (PMF) and by a spectrophotometric activity assay. The protein was solubilized in the detergent dodecyl-beta-D-maltoside (DDM) and purified to homogeneity in a functionally active state. It binds one FAD molecule per protein monomer and FAD is its only cofactor. Its structure was determined in the “as-purified”, substrate-bound and inhibitor-bound forms at resolutions of 2.3, 2.0 and 2.9 Å, respectively. It is composed of two Rossmann-fold domains and of one membrane-attachment region. Despite the overall monomeric architecture being similar to that of FDRs, the structure reveals properties that had not been observed in FDRs until now and that have strong implications for the SQR catalytic mechanism. Surprisingly, A. aeolicus SQR is trimeric in the crystal structure and in solution, as determined by density-matched analytical ultracentrifugation, cross-linking and single particle electron microscopy. The trimer creates an appropriate surface for binding lipids and thus ensures that SQR exclusively reduces hydrophobic quinones. SQR inserts to a depth of about 12 Å into the membrane as an integral monotopic membrane protein. The interaction is mediated by an amphipathic helix-turn-helix tripodal motif and two lipid clamps. A channel in the membrane-binding domain extends towards the si-side of FAD and represents the quinone-binding site. The quinone ring is sandwiched between the conserved amino acids Phe 385 and Ile 346 and is possibly protonated upon reduction via Glu 318, Lys 382 and/or neighboring solvent molecules. Sulfide polymerization occurs on the re-side of FAD, where the highly conserved Cys 156 and Cys 347 appear to be covalently bound to the putative product of the reaction, a polysulfur chain which takes the form of an S8 ring in some monomers. Finally, the structure shows that FAD is covalently connected to the protein in an unprecedented way, via a putative disulfide bridge between the 8-methyl group of the isoalloxazine moiety and Cys 124. The high resolution insight into the protein and all unexpected structural observations presented in this work suggest that the catalytic mechanism of SQRs is significantly different from that of FDRs. In agreement with the structural and functional data, two reaction schemes are proposed for A. aeolicus SQR. They both provide a detailed description of how sulfide and quinones reach and bind the active site, how electrons are transferred from sulfide to quinone via FAD and how the elongating polysulfur product is attached to the polypeptide and is finally released. The two hypotheses differ in defining the structure of the covalent protein-FAD intermediate that forms during the reaction cycle and whose identity still remains experimentally undetermined. Remarkably, the structure of the active site and the FAD-binding mode of A. aeolicus SQR are not conserved in another SQR structure which also became available recently, that of the archaeon Acidianus ambivalens. The variability in SQRs suggests that not all of these enzymes follow the same catalytic mechanism, despite having been considered homologous. Consequently, the currently available but contradictory sequence-based classifications of the SQR family were revised. A structure-based alignment calculated on the increasing number of available sequences allowed to define new SQR groups and their characteristic sequence fingerprints in agreement with the reported structural and functional data. In conclusion, the results obtained in this work offer for the first time a detailed look into the intriguing but complicated reactions catalysed by SQRs and provide a stimulus for further genetic, biochemical and structural investigation.Diese Arbeit stellt die erste vollständige Röntgenkristallstruktur des Membranproteins Sulfid:Chinon Oxidoreduktase (SQR) vor. Die Beschreibung der Struktur, wird durch die biochemische und funktionelle Charakterisierung des Enzyms ergänzt. SQRs sind ubiquitäre Flavoprotein-Disulfid-Reduktasen (FDRs), die in allen Domänen des Lebens, darunter auch im Menschen, vertreten sind. Ihre physiologische Funktion reicht von der Sulfidentgiftung bis hin zur sulfidabhängigen Atmung und Photosynthese (in Archaea und Bakterien), zur Schwermetalltoleranz (in Hefen) und vermutlich zur sulfidabhängigen Signalübertragung (in höheren Eukaryoten). Bis heute war es schwierig, die Funktion der SQRs zu verstehen, da diese Familie eine geringe Sequenzidentität aufweist, nur wenig funktionell charakterisiert war und keine strukturellen Daten zur Verfügung standen. Die SQR wurde in den Plasmamembranen des hyperthermophilen Bakteriums Aquifex aeolicus durch einen Peptidmassen Fingerabdruck (PMF) und einen spektrophotometrischen Aktivitätstest identifiziert. Das Protein wurde mit dem Detergenz Dodecyl-β-D-maltosid (DDM) solubilisiert und in aktiver Form bis zur Homogenität gereinigt. Jedes Monomer bindet ein FAD Molekül, welches der einzige Cofaktor ist. Die Struktur der SQR wurde in der „wie-gereinigten“, der Substrat-gebundenen und der Inhibitor-gebundenen Form mit einer Auflösung von 2,3, 2,0 bzw. 2,9 Å bestimmt. Sie besteht aus zwei Rossmann-Domänen und einer Membrankontaktregion. Obwohl die Architektur des Monomers derjenigen von FDRs ähnelt, zeigt die Struktur Merkmale, die bisher noch nicht beobachtet wurden, jedoch groβe Auswirkungen auf den katalytischen Mechanismus der SQRs haben. Die SQR von A. aeolicus liegt überraschenderweise im Kristall als Trimer vor, was durch analytische Ultrazentrifugation (AUC), Crosslinking und Einzelpartikelanalyse auch als native Form in Lösung bestätigt wurde. Das Trimer erzeugt eine passende Oberfläche für die Bindung an die Membran und stellt dadurch sicher, dass die SQR ausschließlich membranassoziierte Chinone reduziert. Die SQR sitzt als integrales monotopisches Membranprotein bis zu einer Tiefe von etwa 12 Å in der Membran. Die Interaktion wird durch zwei amphipatische Helices und zwei spezifische Lipid-Bindestellen vermittelt. Ein Kanal, der von der Membranbindedomäne zur si-Seite des FAD reicht, repräsentiert die Chinon-Bindestelle. Der Chinon-Ring ist zwischen den zwei konservierten Aminosäuren Phe 385 und Ile 346 gebunden und wird nach der Reduktion vermutlich von Glu 318, Lys 382 und/oder den in der Nähe lokalisierten Wassermolekülen protoniert. Die Sulfid-Polymerisierung hingegen geschieht auf der re-Seite des FAD. Hier sind die hoch konservierten Aminosäuren Cys 156 und Cys 347 kovalent an eine Polyschwefelkette gebunden, die in manchen Monomeren die Form eines S8 Rings annimmt und vermutlich das Produkt der Reaktion ist. Schließlich zeigt die Struktur eine ungewöhnliche kovalente Bindung der 8-Methylgruppe von FAD zu Cys 124, welche vermutlich eine Disulfidbrücke darstellt. Der detaillierte Einblick in das Protein und alle unerwarteten strukturellen Beobachtungen, die hier in dieser Arbeit gezeigt werden, deuten auf einen katalytischen Mechanismus der SQRs hin, der sich signifikant zu dem der anderen FDRs unterscheidet. In Übereinstimmung mit den strukturellen und funktionellen Daten werden zwei Reaktionsmechanismen für SQRs vorgeschlagen. Beide erklären wie Sulfid und Chinon in das aktive Zentrum gelangen und binden, wie Elektronen vom Sulfid über FAD zum Chinon übertragen werden und wie das Polyschwefelprodukt, das an die Polypeptidkette gebunden ist, verlängert und schließlich abgegeben wird. Der Unterschied beider Hypothesen liegt in dem kovalenten Protein-FAD Intermediat, das sich während des Reaktionszyklus bildet und dessen Struktur experimentell noch nicht bestimmt wurde. Interessanterweise zeigt die Struktur der SQR von Acidianus ambivalens, welche seit kurzem auch zur Verfügung steht, Unterschiede im aktiven Zentrum und in der FAD-Bindestelle zur SQR von A. aeolicus. Diese Variabilität der SQRs deutet darauf hin, dass nicht alle diese Enzyme dem gleichen katalytischen Mechanismus folgen, obwohl sie bisher als homolog betrachtet wurden. Folglich, wurden die verfügbaren aber widersprüchlichen sequenzbasierten Klassifizierungen der SQR Familie wieder aufgegriffen. Da die entscheidenden Sequenzabschnitte nun bekannt waren, erfolgte die Einteilung der Gruppen durch einen strukturbasierten Abgleich der steigenden Anzahl an verfügbaren Sequenzen und wurde mit den vorhandenen strukturellen und funktionellen Daten in Einklang gebracht. Diese Arbeit liefert erstmals einen tieferen Einblick in den faszinierenden aber komplexen Reaktionen, die SQRs katalysieren, und bietet eine Grundlage für weitere genetische, biochemische und strukturelle Untersuchungen

Modern Telemetry

Telemetry is based on knowledge of various disciplines like Electronics, Measurement, Control and Communication along with their combination. This fact leads to a need of studying and understanding of these principles before the usage of Telemetry on selected problem solving. Spending time is however many times returned in form of obtained data or knowledge which telemetry system can provide. Usage of telemetry can be found in many areas from military through biomedical to real medical applications. Modern way to create a wireless sensors remotely connected to central system with artificial intelligence provide many new, sometimes unusual ways to get a knowledge about remote objects behaviour. This book is intended to present some new up to date accesses to telemetry problems solving by use of new sensors conceptions, new wireless transfer or communication techniques, data collection or processing techniques as well as several real use case scenarios describing model examples. Most of book chapters deals with many real cases of telemetry issues which can be used as a cookbooks for your own telemetry related problems

Study on open science: The general state of the play in Open Science principles and practices at European life sciences institutes

Nowadays, open science is a hot topic on all levels and also is one of the priorities of the European Research Area. Components that are commonly associated with open science are open access, open data, open methodology, open source, open peer review, open science policies and citizen science. Open science may a great potential to connect and influence the practices of researchers, funding institutions and the public. In this paper, we evaluate the level of openness based on public surveys at four European life sciences institute

Augmentation of Brain Function: Facts, Fiction and Controversy. Volume III: From Clinical Applications to Ethical Issues and Futuristic Ideas

The final volume in this tripartite series on Brain Augmentation is entitled “From Clinical Applications to Ethical Issues and Futuristic Ideas”. Many of the articles within this volume deal with translational efforts taking the results of experiments on laboratory animals and applying them to humans. In many cases, these interventions are intended to help people with disabilities in such a way so as to either restore or extend brain function. Traditionally, therapies in brain augmentation have included electrical and pharmacological techniques. In contrast, some of the techniques discussed in this volume add specificity by targeting select neural populations. This approach opens the door to where and how to promote the best interventions. Along the way, results have empowered the medical profession by expanding their understanding of brain function. Articles in this volume relate novel clinical solutions for a host of neurological and psychiatric conditions such as stroke, Parkinson’s disease, Huntington’s disease, epilepsy, dementia, Alzheimer’s disease, autism spectrum disorders (ASD), traumatic brain injury, and disorders of consciousness. In disease, symptoms and signs denote a departure from normal function. Brain augmentation has now been used to target both the core symptoms that provide specificity in the diagnosis of a disease, as well as other constitutional symptoms that may greatly handicap the individual. The volume provides a report on the use of repetitive transcranial magnetic stimulation (rTMS) in ASD with reported improvements of core deficits (i.e., executive functions). TMS in this regard departs from the present-day trend towards symptomatic treatment that leaves unaltered the root cause of the condition. In diseases, such as schizophrenia, brain augmentation approaches hold promise to avoid lengthy pharmacological interventions that are usually riddled with side effects or those with limiting returns as in the case of Parkinson’s disease. Brain stimulation can also be used to treat auditory verbal hallucination, visuospatial (hemispatial) neglect, and pain in patients suffering from multiple sclerosis. The brain acts as a telecommunication transceiver wherein different bandwidth of frequencies (brainwave oscillations) transmit information. Their baseline levels correlate with certain behavioral states. The proper integration of brain oscillations provides for the phenomenon of binding and central coherence. Brain augmentation may foster the normalization of brain oscillations in nervous system disorders. These techniques hold the promise of being applied remotely (under the supervision of medical personnel), thus overcoming the obstacle of travel in order to obtain healthcare. At present, traditional thinking would argue the possibility of synergism among different modalities of brain augmentation as a way of increasing their overall effectiveness and improving therapeutic selectivity. Thinking outside of the box would also provide for the implementation of brain-to-brain interfaces where techniques, proper to artificial intelligence, could allow us to surpass the limits of natural selection or enable communications between several individual brains sharing memories, or even a global brain capable of self-organization. Not all brains are created equal. Brain stimulation studies suggest large individual variability in response that may affect overall recovery/treatment, or modify desired effects of a given intervention. The subject’s age, gender, hormonal levels may affect an individual’s cortical excitability. In addition, this volume discusses the role of social interactions in the operations of augmenting technologies. Finally, augmenting methods could be applied to modulate consciousness, even though its neural mechanisms are poorly understood. Finally, this volume should be taken as a debate on social, moral and ethical issues on neurotechnologies. Brain enhancement may transform the individual into someone or something else. These techniques bypass the usual routes of accommodation to environmental exigencies that exalted our personal fortitude: learning, exercising, and diet. This will allow humans to preselect desired characteristics and realize consequent rewards without having to overcome adversity through more laborious means. The concern is that humans may be playing God, and the possibility of an expanding gap in social equity where brain enhancements may be selectively available to the wealthier individuals. These issues are discussed by a number of articles in this volume. Also discussed are the relationship between the diminishment and enhancement following the application of brain-augmenting technologies, the problem of “mind control” with BMI technologies, free will the duty to use cognitive enhancers in high-responsibility professions, determining the population of people in need of brain enhancement, informed public policy, cognitive biases, and the hype caused by the development of brain- augmenting approaches

En face OCT imaging for the assessment of glaucoma

Glaucoma is a leading cause of irreversible vision loss globally, and demands early and accurate diagnosis. OCT has become a key investigative technique in glaucoma, and, although it provides invaluable clinical support, detection of early glaucoma remains imperfect. Recent OCT developments enabled direct assessment of retinal nerve fibre bundle (RNFB) reflectance in en face OCT images. The technique has considerable potential in the assessment of glaucoma, yet it has limited clinical usability due to an incomplete understanding of RNFB features in healthy and glaucoma eyes and the lack of accepted methods to identify reflectance defects. This thesis aimed to better understand characteristics of RNFB reflectance in en face OCT imaging and to develop objective methods to extract defects in this domain. Structural and functional measures of glaucoma changes were collected in eyes with established glaucoma and age-similar controls. Results showed that the healthy configuration of RNFB varies across the retina and between different eyes. We developed a method for automated and objective examination of reflectivity changes in en face images. This method considers individual anatomy and varying RNFB configuration, and found more abnormalities than previous approaches. Measures of en face reflectance and conventional retinal nerve fibre layer thickness were strongly related. The agreement between changes of reflectance and visual function was moderate-to-good, and both testing domains presented concordant abnormalities in all tested eyes. Following further minimisation of artefacts in en face images, direct use of reflectance analysis or its combination with perimetry appear viable and with significant potential for clinical examination of glaucoma

Factors Influencing Customer Satisfaction towards E-shopping in Malaysia

Online shopping or e-shopping has changed the world of business and quite a few people have decided to work with these features. What their primary concerns precisely and the responses from the globalisation are the competency of incorporation while doing their businesses. E-shopping has also increased substantially in Malaysia in recent years. The rapid increase in the e-commerce industry in Malaysia has created the demand to emphasize on how to increase customer satisfaction while operating in the e-retailing environment. It is very important that customers are satisfied with the website, or else, they would not return. Therefore, a crucial fact to look into is that companies must ensure that their customers are satisfied with their purchases that are really essential from the ecommerce’s point of view. With is in mind, this study aimed at investigating customer satisfaction towards e-shopping in Malaysia. A total of 400 questionnaires were distributed among students randomly selected from various public and private universities located within Klang valley area. Total 369 questionnaires were returned, out of which 341 questionnaires were found usable for further analysis. Finally, SEM was employed to test the hypotheses. This study found that customer satisfaction towards e-shopping in Malaysia is to a great extent influenced by ease of use, trust, design of the website, online security and e-service quality. Finally, recommendations and future study direction is provided. Keywords: E-shopping, Customer satisfaction, Trust, Online security, E-service quality, Malaysia