T-cell epitope prediction and immune complex simulation using molecular dynamics:state of the art and persisting challenges

Atomistic Molecular Dynamics provides powerful and flexible tools for the prediction and analysis of molecular and macromolecular systems. Specifically, it provides a means by which we can measure theoretically that which cannot be measured experimentally: the dynamic time-evolution of complex systems comprising atoms and molecules. It is particularly suitable for the simulation and analysis of the otherwise inaccessible details of MHC-peptide interaction and, on a larger scale, the simulation of the immune synapse. Progress has been relatively tentative yet the emergence of truly high-performance computing and the development of coarse-grained simulation now offers us the hope of accurately predicting thermodynamic parameters and of simulating not merely a handful of proteins but larger, longer simulations comprising thousands of protein molecules and the cellular scale structures they form. We exemplify this within the context of immunoinformatics.

Glutamatergic input-output properties of thalamic astrocytes

Astrocytes in the somatosensory ventrobasal (VB) thalamus of rats respond to glutamatergic synaptic input with metabotropic glutamate receptor (mGluR) mediated intracellular calcium ([Ca²?](i)) elevations. Astrocytes in the VB thalamus also release the gliotransmitter (GT) glutamate in a Ca²?-dependent manner. The tripartite synapse hypothesis posits that astrocytic [Ca²?](i) elevations resulting from synaptic input releases gliotransmitters that then feedback to modify the synapse. Understanding the dynamics of this process and the conditions under which it occurs are therefore important steps in elucidating the potential roles and impact of GT release in particular brain activities. In this study, we investigated the relationship between VB thalamus afferent synaptic input and astrocytic glutamate release by recording N-methyl-D-aspartate (NMDA) receptor-mediated slow inward currents (SICs) elicited in neighboring neurons. We found that Lemniscal or cortical afferent stimulation, which can elicit astrocytic [Ca²?](i) elevations, do not typically result in the generation of SICs in thalamocortical (TC) neurons. Rather, we find that the spontaneous emergence of SICs is largely resistant to acute afferent input. The frequency of SICs, however, is correlated to long-lasting afferent activity. In contrast to short-term stimulus-evoked GT release effects reported in other brain areas, astrocytes in the VB thalamus do not express a straightforward input-output relationship for SIC generation but exhibit integrative characteristics.

Proteomic analysis of a noninvasive human model of acute inflammation and its resolution:the twenty-one day gingivitis model

The 21-day experimental gingivitis model, an established noninvasive model of inflammation in response to increasing bacterial accumulation in humans, is designed to enable the study of both the induction and resolution of inflammation. Here, we have analyzed gingival crevicular fluid, an oral fluid comprising a serum transudate and tissue exudates, by LC-MS/MS using Fourier transform ion cyclotron resonance mass spectrometry and iTRAQ isobaric mass tags, to establish meta-proteomic profiles of inflammation-induced changes in proteins in healthy young volunteers. Across the course of experimentally induced gingivitis, we identified 16 bacterial and 186 human proteins. Although abundances of the bacterial proteins identified did not vary temporally, Fusobacterium outer membrane proteins were detected. Fusobacterium species have previously been associated with periodontal health or disease. The human proteins identified spanned a wide range of compartments (both extracellular and intracellular) and functions, including serum proteins, proteins displaying antibacterial properties, and proteins with functions associated with cellular transcription, DNA binding, the cytoskeleton, cell adhesion, and cilia. PolySNAP3 clustering software was used in a multilayered analytical approach. Clusters of proteins that associated with changes to the clinical parameters included neuronal and synapse associated proteins.

Astrocyte plasticity:implications for synaptic and neuronal activity

Astrocytes are increasingly implicated in a range of functions in the brain, many of which were previously ascribed to neurons. Much of the prevailing interest centers on the role of astrocytes in the modulation of synaptic transmission and their involvement in the induction of forms of plasticity such as long-term potentiation and long-term depression. However, there is also an increasing realization that astrocytes themselves can undergo plasticity. This plasticity may be manifest as changes in protein expression which may modify calcium activity within the cells, changes in morphology that affect the environment of the synapse and the extracellular space, or changes in gap junction astrocyte coupling that modify the transfer of ions and metabolites through astrocyte networks. Plasticity in the way that astrocytes release gliotransmitters can also have direct effects on synaptic activity and neuronal excitability. Astrocyte plasticity can potentially have profound effects on neuronal network activity and be recruited in pathological conditions. An emerging principle of astrocyte plasticity is that it is often induced by neuronal activity, reinforcing our emerging understanding of the working brain as a constant interaction between neurons and glial cells. © The Author(s) 2013.

Respiratory monitoring using fibre long period grating sensors

We demonstrate the use of a series of in-line fibre long period grating curvature sensors on a garment, used to monitor the thoracic and abdominal volumetric tidal movements of a human subject. These results are used to obtain volumetric tidal changes of the human torso showing reasonable agreement with a spirometer used simultaneously to record the volume at the mouth during breathing. The curvature sensors are based upon long period gratings written in a progressive three layered fibre that are insensitive to refractive index changes. The sensor platform consists of the long period grating laid upon a carbon fibre ribbon, which is encapsulated in a low temperature curing silicone rubber.

Application of long period gratings sensors to respiratory function monitoring

A series of in-line curvature sensors on a garment are used to monitor the thoracic and abdominal movements of a human during respiration. These results are used to obtain volumetric tidal changes of the human torso showing reasonable agreement with a spirometer used simultaneously to record the volume at the mouth during breathing. The curvature sensors are based upon long period gratings written in a progressive three layered fibre that are insensitive to refractive index changes. The sensor platform consists of the long period grating laid upon a carbon fibre ribbon, which is encapsulated in a low temperature curing silicone rubber. An array of sensors is also used to reconstruct the shape changes of a resuscitation manikin during simulated respiration. The data for reconstruction is obtained by two methods of multiplexing and interrogation: firstly using the transmission spectral profile of the LPG's attenuation bands measured using an optical spectrum analyser; secondly using a derivative spectroscopy technique.

The Cascade Orthogonal Neural Network

In the paper new non-conventional growing neural network is proposed. It coincides with the Cascade- Correlation Learning Architecture structurally, but uses ortho-neurons as basic structure units, which can be adjusted using linear tuning procedures. As compared with conventional approximating neural networks proposed approach allows significantly to reduce time required for weight coefficients adjustment and the training dataset size.

Self-Learning Fuzzy Spiking Neural Network as a Nonlinear Pulse-Position Threshold Detection Dynamic System Based on Second-Order Critically Damped Response Units

Architecture and learning algorithm of self-learning spiking neural network in fuzzy clustering task are outlined. Fuzzy receptive neurons for pulse-position transformation of input data are considered. It is proposed to treat a spiking neural network in terms of classical automatic control theory apparatus based on the Laplace transform. It is shown that synapse functioning can be easily modeled by a second order damped response unit. Spiking neuron soma is presented as a threshold detection unit. Thus, the proposed fuzzy spiking neural network is an analog-digital nonlinear pulse-position dynamic system. It is demonstrated how fuzzy probabilistic and possibilistic clustering approaches can be implemented on the base of the presented spiking neural network.

Application of long-period-grating sensors to respiratory plethysmography

A series of in-line curvature sensors on a garment are used to monitor the thoracic and abdominal movements of a human during respiration. These results are used to obtain volumetric tidal changes of the human torso in agreement with a spirometer used simultaneously at the mouth. The curvature sensors are based on long-period gratings (LPGs) written in a progressive three-layered fiber to render the LPGs insensitive to the refractive index external to the fiber. A curvature sensor consists of the fiber long-period grating laid on a carbon fiber ribbon, which is then encapsulated in a low-temperature curing silicone rubber. The sensors have a spectral sensitivity to curvature, dλ/dR from ∼7-nm m to ∼9-nm m. The interrogation technique is borrowed from derivative spectroscopy and monitors the changes in the transmission spectral profile of the LPG's attenuation band due to curvature. The multiplexing of the sensors is achieved by spectrally matching a series of distributed feedback (DFB) lasers to the LPGs. The versatility of this sensing garment is confirmed by it being used on six other human subjects covering a wide range of body mass indices. Just six fully functional sensors are required to obtain a volumetric error of around 6%. © 2007 Society of Photo-Optical Instrumentation Engineers.

The impact of the Miami Cuban exile's political culture on the 1996 fiscal crisis of the city of Miami

The purpose of this study was to determine if the political culture of the Miami Cuban exile community was a significant factor in creating the environment that led to the 1996 fiscal crisis of the City of Miami. The study performed an ethnographic case study that utilized a triangulation strategy which included both qualitative and quantitative methods. Focus groups were conducted to ascertain qualitative and quantitative data as to differences among ethnic and generational groups regarding notions of governance, public administration practices, and overall political values and core beliefs. Quantitative data was obtained through a five year and seven month review of newspaper articles from two periodicals based in Miami-Dade County. A review was also conducted of secondary data in audit and management reports, blue ribbon commission studies, Certified Public Manager (CPM) enrollment, and legal case decisions to examine the administrative practices of the City of Miami leading up to and subsequent to its fiscal crisis. The study found that a political subculture of caudillismo was present in Cuban exile core areas of Miami that appears to have had an influence on the administrative practices and notions of governance that led to the fiscal crisis. The author concludes that an imported foreign political culture has imposed itself as a subculture in core areas of the exile community and that the operationalization of this subculture has manifested itself in non-mainstream notions of governance and public administration practices. ^

Making the grade: The perceived impact of Florida's A+ Plan on the learning environment of one elementary school

The purpose of this study was to ascertain the perceptions of educators at one elementary school regarding the changes in the teaching and learning environment and their related effects following the implementation of Florida's A+ high-stakes accountability system. This study also assessed whether these changes were identified by participants as meaningful and enduring, in terms of the definition by Lieberman and Miller (1999). Twenty-one educators, including 17 teachers and four administrators, at Blue Ribbon Elementary school were interviewed. Data were inductively coded and categorized into four major themes: (a) teaching and learning environment consistency, (b) changes in the teaching and learning environment since the implementation of A+, (c) effects of the changes, and (d) significant and enduring change. Findings fell into three categories (a) identified changes since A+ implementation, (b) effects of changes, and (c) what participants believed was significant and long term change, which included those characteristics of the school that had been identified as consistent in the teaching and learning environment. Statements of the participants explained their perceptions about what instructional decisions where made in response to the A+ Plan including the modification of curriculum, the addition or omission of subject matter taught, and the positive or negative impact these decisions had on the teaching and learning environment. It was found that study participants felt all changes and their effects were a direct result of the A+ Plan and viewed many of the changes as being neither significant nor long term Analysis of the educators' perceptions of the changes they experienced revealed the overall feeling that the changes were not indicative of what was necessary to make a school successful. For the participants, the changes lacked the characteristics that they had described as vital in what constituted success. This led to the conclusion that, by Lieberman and Miller's definition, the majority of changes and effects that were implemented at the school as a result of the mandated A+ Plan, were not meaningful and enduring for effective school reform. ^

Making the grade : the perceived impact on Florida's A+ plan on the learning environment of one elementary school

The purpose of this study was to ascertain the perceptions of educators at one elementary school regarding the changes in the teaching and learning environment and their related effects following the implementation of Florida's A+ high-stakes accountability system. This study also assessed whether these changes were identified by participants as meaningful and enduring, in terms of the definition by Lieberman and Miller (1999). Twenty-one educators, including 17 teachers and four administrators, at Blue Ribbon Elementary school were interviewed. Data were inductively coded and categorized into four major themes: (a) teaching and learning environment consistency, (b) changes in the teaching and learning environment since the implementation of A+, (c) effects of the changes, and (d) significant and enduring change. Findings fell into three categories (a) identified changes since A+ implementation, (b) effects of changes, and (c) what participants believed was significant and long term change, which included those characteristics of the school that had been identified as consistent in the teaching and learning environment. Statements of the participants explained their perceptions about what instructional decisions where made in response to the A+ Plan including the modification of curriculum, the addition or omission of subject matter taught, and the positive or negative impact these decisions had on the teaching and learning environment. It was found that study participants felt all changes and their effects were a direct result of the A+ Plan and viewed many of the changes as being neither significant nor long term Analysis of the educators' perceptions of the changes they experienced revealed the overall feeling that the changes were not indicative of what was necessary to make a school successful. For the participants, the changes lacked the characteristics that they had described as vital in what constituted success. This led to the conclusion that, by Lieberman and Miller's definition, the majority of changes and effects that were implemented at the school as a result of the mandated A+ Plan, were not meaningful and enduring for effective school reform.

Peptide-induced coalescence of bicellar lipid assemblies: sensitivity to anionic lipid and peptide properties

Bicellar lipid mixture dispersions progressively coalesce to larger structures on warming. This phase behaviour is particularly sensitive to interactions that perturb bilayer properties. In this study, ²H NMR was used to study the perturbation of bicellar lipid mixtures by two peptides (SP-B₆₃₋₇₈, a lung surfactant protein fragment and Magainin 2, an antimicrobial peptide) which are structurally similar. Particular attention was paid to the relation between peptide-induced perturbation and lipid composition. In bicellar dispersions containing only zwitterionic lipids (DMPC-d₅₄/DMPC/DHPC (3:1:1)) both peptides had little to no effect on the temperature at which coalescence to larger structures occurred. Conversely, in mixtures containing anionic lipids (DMPC-d₅₄/DMPG/DHPC (3:1:1)), both peptides modified bicellar phase behaviour. In mixtures containing SP-B₆₃₋₇₈, the presence of peptide decreased the temperature of the ribbon-like to extended lamellar phase transition. The addition of Magainin 2 to DMPCd₅₄/ DMPG/DHPC (3:1:1) mixtures, in contrast, increased the temperature of this transition and yielded a series of spectra resembling DMPC/DHPC (4:1) mixtures. Additional studies of lipid dispersions containing deuterated anionic lipids were done to determine whether the observed perturbation involved a peptide-induced separation of zwitterionic and anionic lipids. Comparison of DMPC/DMPG-d₅₄/DHPC (3:1:1) and DMPC-d₅₄/DMPG/DHPC (3:1:1) mixtures showed that DMPC and DMPG occupy similar environments in the presence of SP-B₆₃₋₇₈, but different lipid environments in the presence of Magainin 2. This might reflect the promotion of anionic lipid clustering by Magainin 2. These results demonstrate the variability of mechanisms of peptide-induced perturbation and suggest that lipid composition is an important factor in the peptide-induced perturbation of lipid structures.

Generic helical edge states due to Rashba spin-orbit coupling in a topological insulator

We study the helical edge states of a two-dimensional topological insulator without axial spin symmetry due to the Rashba spin-orbit interaction. Lack of axial spin symmetry can lead to so-called generic helical edge states, which have energy-dependent spin orientation. This opens the possibility of inelastic backscattering and thereby nonquantized transport. Here we find analytically the new dispersion relations and the energy dependent spin orientation of the generic helical edge states in the presence of Rashba spin-orbit coupling within the Bernevig-Hughes-Zhang model, for both a single isolated edge and for a finite width ribbon. In the single-edge case, we analytically quantify the energy dependence of the spin orientation, which turns out to be weak for a realistic HgTe quantum well. Nevertheless, finite size effects combined with Rashba spin-orbit coupling result in two avoided crossings in the energy dispersions, where the spin orientation variation of the edge states is very significantly increased for realistic parameters. Finally, our analytical results are found to compare well to a numerical tight-binding regularization of the model.

Kinase C substrates and synaptic plasticity in Aplysia

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.