Evaluation of APD and SiPM Matrices as Sensors for Monolithic PET Detector Block

Gamma detectors based on monolithic scintillator blocks coupled to APDs matrices have proved to be a good alternative to pixelated ones for PET scanners. They provide comparable spatial resolution, improve the sensitivity and make easier the mechanical design of the system. In this study we evaluate by means of Geant4-based simulations the possibility of replacing the APDs by SiPMs. Several commercial matrices of light sensors coupled to LYSO:Ce monolithic blocks have been simulated and compared. Regarding the spatial resolution and linearity of the detector, SiPMs with high photo detection efficiency could become an advantageous replacement for the APDs

Medidas autosemejantes en el plano, momentos y matrices de Hessenberg

La tesis MEDIDAS AUTOSEMEJANTES EN EL PLANO, MOMENTOS Y MATRICES DE HESSENBERG se enmarca entre las áreas de la teoría geométrica de la medida, la teoría de polinomios ortogonales y la teoría de operadores. La memoria aborda el estudio de medidas con soporte acotado en el plano complejo vistas con la óptica de las matrices infinitas de momentos y de Hessenberg asociadas a estas medidas que en la teoría de los polinomios ortogonales las representan. En particular se centra en el estudio de las medidas autosemejantes que son las medidas de equilibrio definidas por un sistema de funciones iteradas (SFI). Los conjuntos autosemejantes son conjuntos que tienen la propiedad geométrica de descomponerse en unión de piezas semejantes al conjunto total. Estas piezas pueden solaparse o no, cuando el solapamiento es pequeño la teoría de Hutchinson [Hut81] funciona bien, pero cuando no existen restricciones falla. El problema del solapamiento consiste en controlar la medida de este solapamiento. Un ejemplo de la complejidad de este problema se plantea con las convoluciones infinitas de distribuciones de Bernoulli, que han resultado ser un ejemplo de medidas autosemejantes en el caso real. En 1935 Jessen y A. Wintner [JW35] ya se planteaba este problema, lejos de ser sencillo ha sido estudiado durante más de setenta y cinco años y siguen sin resolverse las principales cuestiones planteadas ya por A. Garsia [Gar62] en 1962. El interés que ha despertado este problema así como la complejidad del mismo está demostrado por las numerosas publicaciones que abordan cuestiones relacionadas con este problema ver por ejemplo [JW35], [Erd39], [PS96], [Ma00], [Ma96], [Sol98], [Mat95], [PS96], [Sim05],[JKS07] [JKS11]. En el primer capítulo comenzamos introduciendo con detalle las medidas autosemejante en el plano complejo y los sistemas de funciones iteradas, así como los conceptos de la teoría de la medida necesarios para describirlos. A continuación se introducen las herramientas necesarias de teoría de polinomios ortogonales, matrices infinitas y operadores que se van a usar. En el segundo y tercer capítulo trasladamos las propiedades geométricas de las medidas autosemejantes a las matrices de momentos y de Hessenberg, respectivamente. A partir de estos resultados se describen algoritmos para calcular estas matrices a partir del SFI correspondiente. Concretamente, se obtienen fórmulas explícitas y algoritmos de aproximación para los momentos y matrices de momentos de medidas fractales, a partir de un teorema del punto fijo para las matrices. Además utilizando técnicas de la teoría de operadores, se han extendido al plano complejo los resultados que G. Mantica [Ma00, Ma96] obtenía en el caso real. Este resultado es la base para definir un algoritmo estable de aproximación de la matriz de Hessenberg asociada a una medida fractal u obtener secciones finitas exactas de matrices Hessenberg asociadas a una suma de medidas. En el último capítulo, se consideran medidas, μ, más generales y se estudia el comportamiento asintótico de los autovalores de una matriz hermitiana de momentos y su impacto en las propiedades de la medida asociada. En el resultado central se demuestra que si los polinomios asociados son densos en L2(μ) entonces necesariamente el autovalor mínimo de las secciones finitas de la matriz de momentos de la medida tiende a cero. ABSTRACT The Thesis work “Self-similar Measures on the Plane, Moments and Hessenberg Matrices” is framed among the geometric measure theory, orthogonal polynomials and operator theory. The work studies measures with compact support on the complex plane from the point of view of the associated infinite moments and Hessenberg matrices representing them in the theory of orthogonal polynomials. More precisely, it concentrates on the study of the self-similar measures that are equilibrium measures in a iterated functions system. Self-similar sets have the geometric property of being decomposable in a union of similar pieces to the complete set. These pieces can overlap. If the overlapping is small, Hutchinson’s theory [Hut81] works well, however, when it has no restrictions, the theory does not hold. The overlapping problem consists in controlling the measure of the overlap. The complexity of this problem is exemplified in the infinite convolutions of Bernoulli’s distributions, that are an example of self-similar measures in the real case. As early as 1935 [JW35], Jessen and Wintner posed this problem, that far from being simple, has been studied during more than 75 years. The main cuestiones posed by Garsia in 1962 [Gar62] remain unsolved. The interest in this problem, together with its complexity, is demonstrated by the number of publications that over the years have dealt with it. See, for example, [JW35], [Erd39], [PS96], [Ma00], [Ma96], [Sol98], [Mat95], [PS96], [Sim05], [JKS07] [JKS11]. In the first chapter, we will start with a detailed introduction to the self-similar measurements in the complex plane and to the iterated functions systems, also including the concepts of measure theory needed to describe them. Next, we introduce the necessary tools from orthogonal polynomials, infinite matrices and operators. In the second and third chapter we will translate the geometric properties of selfsimilar measures to the moments and Hessenberg matrices. From these results, we will describe algorithms to calculate these matrices from the corresponding iterated functions systems. To be precise, we obtain explicit formulas and approximation algorithms for the moments and moment matrices of fractal measures from a new fixed point theorem for matrices. Moreover, using techniques from operator theory, we extend to the complex plane the real case results obtained by Mantica [Ma00, Ma96]. This result is the base to define a stable algorithm that approximates the Hessenberg matrix associated to a fractal measure and obtains exact finite sections of Hessenberg matrices associated to a sum of measurements. In the last chapter, we consider more general measures, μ, and study the asymptotic behaviour of the eigenvalues of a hermitian matrix of moments, together with its impact on the properties of the associated measure. In the main result we demonstrate that, if the associated polynomials are dense in L2(μ), then necessarily follows that the minimum eigenvalue of the finite sections of the moments matrix goes to zero.

Modelado de Cadenas Cinemáticas mediante Matrices de Desplazamiento. Una alternativa al método de Denavit-Hartenberg

En este trabajo se presenta un método para el modelado de cadenas cinemáticas de robots que salva las dificultades asociadas a la elección de los sistemas de coordenadas y obtención de los parámetros de Denavit-Hartenberg. El método propuesto parte del conocimiento de la posición y orientación del extremo del robot en su configuración de reposo, para ir obteniendo en qué se transforman éstas tras los sucesivos movimientos de sus grados de libertad en secuencia descendente, desde el más alejado al más cercano a su base. Los movimientos son calculados en base a las Matrices de Desplazamiento, que permiten conocer en que se transforma un punto cuando éste es desplazado (trasladado o rotado) con respecto a un eje que no pasa por el origen. A diferencia del método de Denavit-Hartenberg, que precisa ubicar para cada eslabón el origen y las direcciones de los vectores directores de los sistemas de referencia asociados, el método basado en las Matrices de Desplazamiento precisa solo identificar el eje de cada articulación, lo que le hace más simple e intuitivo que aquel. La obtención de las Matrices de Desplazamiento y con ellas del Modelo Cinemático Directo a partir de los ejes de la articulación, puede hacerse mediante algunas simples operaciones, fácilmente programables.

Evaluating the reinforcement of inorganic fullerene-like nanoparticles in thermoplastic matrices by depth-sensing indentation

The reinforcing effect of inorganic fullerene-like tungsten disulfide (IF-WS2) nanoparticles in two different polymer matrices, isotactic polypropylene (iPP) and polyphenylene sulfide (PPS), has been investigated by means of dynamic depth-sensing indentation. The hardness and elastic modulus enhancement upon filler addition is analyzed in terms of two main contributions: changes in the polymer matrix nanostructure and intrinsic properties of the filler including matrix-particle load transfer. It is found that the latter mainly determines the overall mechanical improvement, whereas the nanostructural changes induced in the polymer matrix only contribute to a minor extent. Important differences are suggested between the mechanisms of deformation in the two nanocomposites, resulting in a moderate mechanical enhancement in case of iPP (20% for a filler loading of 1%), and a remarkable hardness increase in case of PPS (60% for the same filler content). The nature of the polymer amorphous phase, whether in the glassy or rubbery state, seems to play here an important role. Finally, nanoindentation and dynamic mechanical analysis measurements are compared and discussed in terms of the different directionality of the stresses applied.

Differential elimination by differential specialization of Sylvester style matrices

Differential resultant formulas are defined, for a system $\cP$ of $n$ ordinary Laurent differential polynomials in $n-1$ differential variables. These are determinants of coefficient matrices of an extended system of polynomials obtained from $\cP$ through derivations and multiplications by Laurent monomials. To start, through derivations, a system $\ps(\cP)$ of $L$ polynomials in $L-1$ algebraic variables is obtained, which is non sparse in the order of derivation. This enables the use of existing formulas for the computation of algebraic resultants, of the multivariate sparse algebraic polynomials in $\ps(\cP)$, to obtain polynomials in the differential elimination ideal generated by $\cP$. The formulas obtained are multiples of the sparse differential resultant defined by Li, Yuan and Gao, and provide order and degree bounds in terms of mixed volumes in the generic case.

Activating mutations in the extracellular domain of the fibroblast growth factor receptor 2 function by disruption of the disulfide bond in the third immunoglobulin-like domain

Multiple human skeletal and craniosynostosis disorders, including Crouzon, Pfeiffer, Jackson–Weiss, and Apert syndromes, result from numerous point mutations in the extracellular region of fibroblast growth factor receptor 2 (FGFR2). Many of these mutations create a free cysteine residue that potentially leads to abnormal disulfide bond formation and receptor activation; however, for noncysteine mutations, the mechanism of receptor activation remains unclear. We examined the effect of two of these mutations, W290G and T341P, on receptor dimerization and activation. These mutations resulted in cellular transformation when expressed as FGFR2/Neu chimeric receptors. Additionally, in full-length FGFR2, the mutations induced receptor dimerization and elevated levels of tyrosine kinase activity. Interestingly, transformation by the chimeric receptors, dimerization, and enhanced kinase activity were all abolished if either the W290G or the T341P mutation was expressed in conjunction with mutations that eliminate the disulfide bond in the third immunoglobulin-like domain (Ig-3). These results demonstrate a requirement for the Ig-3 cysteine residues in the activation of FGFR2 by noncysteine mutations. Molecular modeling also reveals that noncysteine mutations may activate FGFR2 by altering the conformation of the Ig-3 domain near the disulfide bond, preventing the formation of an intramolecular bond. This allows the unbonded cysteine residues to participate in intermolecular disulfide bonding, resulting in constitutive activation of the receptor.

Extracellular HIV-1 virus protein R causes a large inward current and cell death in cultured hippocampal neurons: Implications for AIDS pathology

The small HIV-1 accessory protein Vpr (virus protein R) is a multifunctional protein that is present in the serum and cerebrospinal fluid of AIDS patients. We previously showed that Vpr can form cation-selective ion channels across planar lipid bilayers, introducing the possibility that, if incorporated into the membranes of living cells, Vpr might form ion channels and consequently perturb the maintained ionic gradient. In this study, we demonstrate, by a variety of approaches, that Vpr added extracellularly to intact cells does indeed form ion channels. We use confocal laser scanning microscopy to examine the subcellular localization of fluorescently labeled Vpr. Plasmalemma depolarization and damage are examined using the anionic potential-sensitive dye bis(1,3-dibutylbarbituric acid) trimethine oxonol and propidium iodide (PI), respectively, and the effect of Vpr on whole-cell current is demonstrated directly by using the patch-clamp technique. We show that recombinant purified extracellular Vpr associates with the plasmalemma of hippocampal neurons to cause a large inward cation current and depolarization of the plasmalemma, eventually resulting in cell death. Thus, we demonstrate a physiological action of extracellular Vpr and present its mechanistic basis. These findings may have important implications for neuropathologies in AIDS patients who possess significant amounts of Vpr in the cerebrospinal fluid.

Tyrosine phosphorylation of paxillin and focal adhesion kinase by activation of muscarinic m3 receptors is dependent on integrin engagement by the extracellular matrix

The G protein-coupled m1 and m3 muscarinic acetylcholine receptors increase tyrosine phosphorylation of several proteins, including the focal adhesion-associated proteins paxillin and focal adhesion kinase (FAK), but the mechanism is not understood. Activation of integrins during adhesion of cells to extracellular matrix, or stimulation of quiescent cell monolayers with G protein-coupled receptor ligands including bradykinin, bombesin, endothelin, vasopressin, and lysophosphatidic acid, also induces tyrosine phosphorylation of paxillin and FAK and formation of focal adhesions. These effects are generally independent of protein kinase C but are inhibited by agents that prevent cytoskeletal assembly or block activation of the small molecular weight G protein Rho. This report demonstrates that tyrosine phosphorylation of paxillin and FAK elicited by stimulation of muscarinic m3 receptors with the acetylcholine analog carbachol is inhibited by soluble peptides containing the arginine–glycine–aspartate motif (the recognition site for integrins found in adhesion proteins such as fibronectin) but is unaffected by peptides containing the inactive sequence arginine–glycine–glutamate. Tyrosine phosphorylation elicited by carbachol, but not by cell adhesion to fibronectin, is reduced by the protein kinase C inhibitor GF 109203X. The response to carbachol is dependent on the presence of fibronectin. Moreover, immunofluorescence studies show that carbachol treatment induces formation of stress fibers and focal adhesions. These results suggest that muscarinic receptor stimulation activates integrins via a protein kinase C-dependent mechanism. The activated integrins transmit a signal into the cell’s interior leading to tyrosine phosphorylation of paxillin and FAK. This represents a novel mechanism for regulation of tyrosine phosphorylation by muscarinic receptors.

Extracellular enveloped vaccinia virus is resistant to complement because of incorporation of host complement control proteins into its envelope

Vaccinia virus (VV) produces two antigenically and structurally distinct infectious virions, intracellular mature virus (IMV) and extracellular enveloped virus (EEV). Here we have investigated the resistance of EEV and IMV to neutralization by complement in the absence of immune antibodies. When EEV is challenged with complement from the same species as the cells used to grow the virus, EEV is resistant to neutralization by complement, whereas IMV is not. EEV resistance was not a result of EEV protein B5R, despite its similarity to proteins of the regulators of complement activation (RCA) family, or to any of the other EEV proteins tested (A34R, A36R, and A56R gene products). EEV was sensitive to complement when the virus was grown in one species and challenged with complement from a different species, suggesting that complement resistance might be mediated by host RCA incorporated into the EEV outer envelope. This hypothesis was confirmed by several observations: (i) immunoblot analysis revealed that cellular membrane proteins CD46, CD55, CD59, CD71, CD81, and major histocompatibility complex class I antigen were detected in purified EEV but not IMV; (ii) immunoelectron microscopy revealed cellular RCA on the surface of EEV retained on the cell surface; and (iii) EEV derived from rat cells expressing the human RCA CD55 or CD55 and CD59 were more resistant to human complement than EEV derived from control rat cells that expressed neither CD55 nor CD59. These data justify further analysis of the roles of these (and possible other) cellular proteins in EEV biology.

Self-assembly of fibronectin into fibrillar networks underneath dipalmitoyl phosphatidylcholine monolayers: Role of lipid matrix and tensile forces

The cell-mediated assembly of fibronectin (Fn) into fibrillar matrices is a complex multistep process that is incompletely understood because of the chemical complexity of the extracellular matrix and a lack of experimental control over molecular interactions and dynamic events. We have identified conditions under which Fn assembles into extended fibrillar networks after adsorption to a dipalmitoyl phosphatidylcholine (DPPC) monolayer in contact with physiological buffer. We propose a sequential model for the Fn assembly pathway, which involves the orientation of Fn underneath the lipid monolayer by insertion into the liquid expanded (LE) phase of DPPC. Attractive interactions between these surface-anchored proteins and the liquid condensed (LC) domains leads to Fn enrichment at domain edges. Spontaneous self-assembly into fibrillar networks, however, occurs only after expansion of the DPPC monolayer from the LC phase though the LC/LE phase coexistence. Upon monolayer expansion, the domain boundaries move apart while attractive interactions among Fn molecules and between Fn and domain edges produce a tensile force on the proteins that initiates fibril assembly. The resulting fibrils have been characterized in situ by using fluorescence and light-scattering microscopy. We have found striking similarities between fibrils produced under DPPC monolayers and those found on cellular surfaces, including their assembly pathways.

Constitutive and impaired signaling of leptin receptors containing the Gln → Pro extracellular domain fatty mutation

Leptin (OB), an adipocyte-secreted circulating hormone, and its receptor (OB-R) are key components of an endocrine loop that regulates mammalian body weight. In this report we have analyzed signal transduction activities of OB-R containing the fatty mutation [OB-R(fa)], a single amino acid substitution at position 269 (Gln → Pro) in the OB-R extracellular domain that results in the obese phenotype of the fatty rat. We find that this mutant receptor exhibits both ligand-independent transcriptional activation via interleukin 6 and hematopoietin receptor response elements and ligand-independent activation of signal transducer and activator of transcription (STAT) proteins 1 and 3. However, OB-R(fa) is unable to constitutively activate STAT5B and is highly impaired for ligand induced activation of STAT5B compared with OB-R(wt). Introduction of the fatty mutation into a OB-R/G-CSF-R chimera generates a receptor with constitutive character that is similar but distinct from that of OB-R(fa). Constitutive mutant OB-R(fa) receptor signaling is repressed by coexpression of OB-R(wt). The implications of an extracellular domain amino acid substitution generating a cytokine receptor with a partially constitutive phenotype are discussed both in terms of the mechanism of OB-R triggering and the biology of the fatty rat.

A peptide derived from an extracellular domain selectively inhibits receptor internalization: Target sequences on insulin and insulin-like growth factor 1 receptors

Certain peptides derived from the α1 domain of the major histocompatibility class I antigen complex (MHC-I) inhibit receptor internalization, increasing the steady-state number of active receptors on the cell surface and thereby enhancing the sensitivity to hormones and other agonists. These peptides self-assemble, and they also bind to MHC-I at the same site from which they are derived, suggesting that they could bind to receptor sites with significant sequence similarity. Receptors affected by MHC-I peptides do, indeed, have such sequence similarity, as illustrated here by insulin receptor (IR) and insulin-like growth factor-1 receptor. A synthetic peptide with sequence identical to a certain extracellular receptor domain binds to that receptor in a ligand-dependent manner and inhibits receptor internalization. Moreover, each such peptide is selective for its cognate receptor. An antibody to the IR peptide not only binds to IR and competes with the peptide but also inhibits insulin-dependent internalization of IR. These observations, and binding studies with deletion mutants of IR, indicate that the sequence QILKELEESSF encoded by exon 10 plays a key role in IR internalization. Our results illustrate a principle for identifying receptor-specific sites of importance for receptor internalization, and for enhancing sensitivity to hormones and other agonists.

Effects of extracellular Ca2+ concentration on hair-bundle stiffness and gating-spring integrity in hair cells

When a hair cell is stimulated by positive deflection of its hair bundle, increased tension in gating springs opens transduction channels, permitting cations to enter stereocilia and depolarize the cell. Ca2+ is thought to be required in mechanoelectrical transduction, for exposure of hair bundles to Ca2+ chelators eliminates responsiveness by disrupting tip links, filamentous interstereociliary connections that probably are the gating springs. Ca2+ also participates in adaptation to stimuli by controlling the activity of a molecular motor that sets gating-spring tension. Using a flexible glass fiber to measure hair-bundle stiffness, we investigated the effect of Ca2+ concentration on stiffness before and after the disruption of gating springs. The stiffness of intact hair bundles depended nonmonotonically on the extracellular Ca2+ concentration; the maximal stiffness of ≈1200 μN⋅m−1 occurred when bundles were bathed in solutions containing 250 μM Ca2+, approximately the concentration found in frog endolymph. For cells exposed to solutions with sufficient chelator capacity to reduce the Ca2+ concentration below ≈100 nM, hair-bundle stiffness fell to ≈200 μN⋅m−1 and no longer exhibited Ca2+-dependent changes. Because cells so treated lost mechanoelectrical transduction, we attribute the reduction in bundle stiffness to tip-link disruption. The results indicate that gating springs are not linearly elastic; instead, they stiffen with increased strain, which rises with adaptation-motor activity at the physiological extracellular Ca2+ concentration.

Proteinase inhibitors I and II from potatoes specifically block UV-induced activator protein-1 activation through a pathway that is independent of extracellular signal-regulated kinases, c-Jun N-terminal kinases, and P38 kinase

Solar UV irradiation is the causal factor for the increasing incidence of human skin carcinomas. The activation of the transcription factor activator protein-1 (AP-1) has been shown to be responsible for the tumor promoter action of UV light in mammalian cells. We demonstrate that proteinase inhibitor I (Inh I) and II (Inh II) from potato tubers, when applied to mouse epidermal JB6 cells, block UV-induced AP-1 activation. The inhibition appears to be specific for UV-induced signal transduction for AP-1 activation, because these inhibitors did not block UV-induced p53 activation nor did they exhibit any significant influence on epidermal growth factor-induced AP-1 transactivation. Furthermore, the inhibition of UV-induced AP-1 activity occurs through a pathway that is independent of extracellular signal-regulated kinases and c-Jun N-terminal kinases as well as P38 kinases. Considering the important role of AP-1 in tumor promotion, it is possible that blocking UV-induced AP-1 activity by Inh I or Inh II may be functionally linked to irradiation-induced cell transformation.

An extracellular signaling component in propagation of astrocytic calcium waves

Focally evoked calcium waves in astrocyte cultures have been thought to propagate by gap-junction-mediated intercellular passage of chemical signal(s). In contrast to this mechanism we observed isolated astrocytes, which had no physical contact with other astrocytes in the culture, participating in a calcium wave. This observation requires an extracellular route of astrocyte signaling. To directly test for extracellular signaling we made cell-free lanes 10–300 μm wide in confluent cultures by deleting astrocytes with a glass pipette. After 4–8 hr of recovery, regions of confluent astrocytes separated by lanes devoid of cells were easily located. Electrical stimulation was used to initiate calcium waves. Waves crossed narrow (<120 μm) cell-free lanes in 15 of 36 cases, but failed to cross lanes wider than 120 μm in eight of eight cases. The probability of crossing narrow lanes was not correlated with the distance from the stimulation site, suggesting that cells along the path of the calcium wave release the extracellular messenger(s). Calculated velocity across the acellular lanes was not significantly different from velocity through regions of confluent astrocytes. Focal superfusion altered both the extent and the direction of calcium waves in confluent regions. These data indicate that extracellular signals may play a role in astrocyte–astrocyte communication in situ.