Mind what you say-general and specific mechanisms for monitoring in speech production

For most people, speech production is relatively effortless and error-free. Yet it has long been recognized that we need some type of control over what we are currently saying and what we plan to say. Precisely how we monitor our internal and external speech has been a topic of research interest for several decades. The predominant approach in psycholinguistics has assumed monitoring of both is accomplished via systems responsible for comprehending others' speech. This special topic aimed to broaden the field, firstly by examining proposals that speech production might also engage more general systems, such as those involved in action monitoring. A second aim was to examine proposals for a production-specific, internal monitor. Both aims require that we also specify the nature of the representations subject to monitoring.

The effect of graphene oxide and its oxidized debris on the cure chemistry and interphase structure of epoxy nanocomposites

The influence of graphene oxide (GO) and its surface oxidized debris (OD) on the cure chemistry of an amine cured epoxy resin has been investigated by Fourier Transform Infrared Emission Spectroscopy (FT-IES) and Differential Scanning Calorimetry (DSC). Spectral analysis of IR radiation emitted at the cure temperature from thin films of diglycidyl ether of bisphenol A epoxy resin (DGEBA) and 4,4'-diaminodiphenylmethane (DDM) curing agent with and without GO allowed the cure kinetics of the interphase between the bulk resin and GO to be monitored in real time, by measuring both the consumption of primary (1°) amine and epoxy groups, formation of ether groups as well as computing the profiles for formation of secondary (2°) and tertiary (3°) amines. OD was isolated from as-produced GO (aGO) by a simple autoclave method to give OD-free autoclaved GO (acGO). It has been found that the presence of OD on the GO prevents active sites on GO surfaces fully catalysing and participating in the reaction of DGEBA with DDM, which results in slower reaction and a lower crosslink density of the three-dimensional networks in the aGO-resin interphase compared to the acGO-resin interphase. We also determined that OD itself promoted DGEBA homopolymerization. A DSC study further confirmed that the aGO nanocomposite exhibited lower Tg while acGO nanocomposite showed higher Tg compared to neat resin because of the difference in crosslink densities of the matrix around the different GOs.

A preconditioned numerical solver for stiff nonlinear reaction-diffusion equations with fractional Laplacians that avoids dense matrices

The numerical solution of fractional partial differential equations poses significant computational challenges in regard to efficiency as a result of the spatial nonlocality of the fractional differential operators. The dense coefficient matrices that arise from spatial discretisation of these operators mean that even one-dimensional problems can be difficult to solve using standard methods on grids comprising thousands of nodes or more. In this work we address this issue of efficiency for one-dimensional, nonlinear space-fractional reaction–diffusion equations with fractional Laplacian operators. We apply variable-order, variable-stepsize backward differentiation formulas in a Jacobian-free Newton–Krylov framework to advance the solution in time. A key advantage of this approach is the elimination of any requirement to form the dense matrix representation of the fractional Laplacian operator. We show how a banded approximation to this matrix, which can be formed and factorised efficiently, can be used as part of an effective preconditioner that accelerates convergence of the Krylov subspace iterative solver. Our approach also captures the full contribution from the nonlinear reaction term in the preconditioner, which is crucial for problems that exhibit stiff reactions. Numerical examples are presented to illustrate the overall effectiveness of the solver.

Genomewide screens in ankylosing spondylitis

Efforts to identify genes other than HLA-B27 in AS have been driven by the strength of the evidence from genetic epidemiology studies indicating that HLA-B27, although a major gene in AS, is clearly not the only significant gene operating. This is the case for both genetic determinants of disease-susceptibility and phenotypic characteristics such as disease severity and associated disease features. In this chapter the genetic epidemiology of AS and the gene-mapping studies performed to date will be reviewed and the future direction of research in this field discussed.

Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors

Introduction: Ankylosing spondylitis (AS) is unique in its pathology where inflammation commences at the entheses before progressing to an osteoproliferative phenotype generating excessive bone formation that can result in joint fusion. The underlying mechanisms of this progression are poorly understood. Recent work has suggested that changes in Wnt signalling, a key bone regulatory pathway, may contribute to joint ankylosis in AS. Using the proteoglycan-induced spondylitis (PGISp) mouse model which displays spondylitis and eventual joint fusion following an initial inflammatory stimulus, we have characterised the structural and molecular changes that underlie disease progression. Methods: PGISp mice were characterised 12 weeks after initiation of inflammation using histology, immunohistochemistry (IHC) and expression profiling. Results: Inflammation initiated at the periphery of the intervertebral discs progressing to disc destruction followed by massively excessive cartilage and bone matrix formation, as demonstrated by toluidine blue staining and IHC for collagen type I and osteocalcin, leading to syndesmophyte formation. Expression levels of DKK1 and SOST, Wnt signalling inhibitors highly expressed in joints, were reduced by 49% and 63% respectively in the spine PGISp compared with control mice (P < 0.05) with SOST inhibition confirmed by IHC. Microarray profiling showed genes involved in inflammation and immune-regulation were altered. Further, a number of genes specifically involved in bone regulation including other members of the Wnt pathway were also dysregulated. Conclusions: This study implicates the Wnt pathway as a likely mediator of the mechanism by which inflammation induces bony ankylosis in spondyloarthritis, raising the potential that therapies targeting this pathway may be effective in preventing this process.

Altered immunoglobulin E diversity and regulation of allergic inflammation in asthma

The clinical efficacy of anti-immunoglobulin E (IgE) therapy indicates a central role for IgE in perpetuation of allergic inflammatory diseases. Omalizumab is now uti- lized in treatment of a wide variety of allergic conditions including severe asthma, allergic rhinitis, atopic dermati- tis, food allergy and urticaria either alone or adjunct with other therapies such as steroid administration or allergen- specific immunotherapy [1, 2]. Current research activity is focused on the cellular and molecular mechanisms by which IgE influences the immunopathogenesis of allergic disease [3]. Increased knowledge of how IgE exerts its effects will underpin effective clinical use of anti-IgE treatment. In this issue Kerzel et al. [4] investigate the effects of altered antibo dy repertoire on the outcomes of an experimental model of allergic asthma.

VH gene usage in immunoglobulin E responses of seasonal rhinitis patients allergic to grass pollen is oligoclonal and antigen driven

Background: IgE is the pivotal-specific effector molecule of allergic reactions yet it remains unclear whether the elevated production of IgE in atopic individuals is due to superantigen activation of B cell populations, increased antibody class switching to IgE or oligoclonal allergen-driven IgE responses. Objectives: To increase our understanding of the mechanisms driving IgE responses in allergic disease we examined immunoglobulin variable regions of IgE heavy chain transcripts from three patients with seasonal rhinitis due to grass pollen allergy. Methods: Variable domain of heavy chain-epsilon constant domain 1 cDNAs were amplified from peripheral blood using a two-step semi-nested PCR, cloned and sequenced. Results: The VH gene family usage in subject A was broadly based, but there were two clusters of sequences using genes VH 3-9 and 3-11 with unusually low levels of somatic mutations, 0-3%. Subject B repeatedly used VH 1-69 and subject C repeatedly used VH 1-02, 1-46 and 5a genes. Most clones were highly mutated being only 86-95% homologous to their germline VH gene counterparts and somatic mutations were more abundant at the complementarity determining rather than framework regions. Multiple sequence alignment revealed both repeated use of particular VH genes as well as clonal relatedness among clusters of IgE transcripts. Conclusion: In contrast to previous studies we observed no preferred VH gene common to IgE transcripts of the three subjects allergic to grass pollen. Moreover, most of the VH gene characteristics of the IgE transcripts were consistent with oligoclonal antigen-driven IgE responses.

On the mathematical modeling of wound healing angiogenesis in skin as a reaction-transport process

Over the last 30 years, numerous research groups have attempted to provide mathematical descriptions of the skin wound healing process. The development of theoretical models of the interlinked processes that underlie the healing mechanism has yielded considerable insight into aspects of this critical phenomenon that remain difficult to investigate empirically. In particular, the mathematical modeling of angiogenesis, i.e., capillary sprout growth, has offered new paradigms for the understanding of this highly complex and crucial step in the healing pathway. With the recent advances in imaging and cell tracking, the time is now ripe for an appraisal of the utility and importance of mathematical modeling in wound healing angiogenesis research. The purpose of this review is to pedagogically elucidate the conceptual principles that have underpinned the development of mathematical descriptions of wound healing angiogenesis, specifically those that have utilized a continuum reaction-transport framework, and highlight the contribution that such models have made toward the advancement of research in this field. We aim to draw attention to the common assumptions made when developing models of this nature, thereby bringing into focus the advantages and limitations of this approach. A deeper integration of mathematical modeling techniques into the practice of wound healing angiogenesis research promises new perspectives for advancing our knowledge in this area. To this end we detail several open problems related to the understanding of wound healing angiogenesis, and outline how these issues could be addressed through closer cross-disciplinary collaboration.

A polymerase chain reaction-based method for isolating clones from a complimentary DNA library in sheep

The sheep (Ovis aries) is favored by many musculoskeletal tissue engineering groups as a large animal model because of its docile temperament and ease of husbandry. The size and weight of sheep are comparable to humans, which allows for the use of implants and fixation devices used in human clinical practice. The construction of a complimentary DNA (cDNA) library can capture the expression of genes in both a tissue- and time-specific manner. cDNA libraries have been a consistent source of gene discovery ever since the technology became commonplace more than three decades ago. Here, we describe the construction of a cDNA library using cells derived from sheep bones based on the pBluescript cDNA kit. Thirty clones were picked at random and sequenced. This led to the identification of a novel gene, C12orf29, which our initial experiments indicate is involved in skeletal biology. We also describe a polymerase chain reaction-based cDNA clone isolation method that allows the isolation of genes of interest from a cDNA library pool. The techniques outlined here can be applied in-house by smaller tissue engineering groups to generate tools for biomolecular research for large preclinical animal studies and highlights the power of standard cDNA library protocols to uncover novel genes.

Pathogens penetrating the central nervous system: Infection pathways and the cellular and molecular mechanisms of invasion

The brain is well protected against microbial invasion by cellular barriers, such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). In addition, cells within the central nervous system (CNS) are capable of producing an immune response against invading pathogens. Nonetheless, a range of pathogenic microbes make their way to the CNS, and the resulting infections can cause significant morbidity and mortality. Bacteria, amoebae, fungi, and viruses are capable of CNS invasion, with the latter using axonal transport as a common route of infection. In this review, we compare the mechanisms by which bacterial pathogens reach the CNS and infect the brain. In particular, we focus on recent data regarding mechanisms of bacterial translocation from the nasal mucosa to the brain, which represents a little explored pathway of bacterial invasion but has been proposed as being particularly important in explaining how infection with Burkholderia pseudomallei can result in melioidosis encephalomyelitis.

Fourier spectral methods for fractional-in-space reaction-diffusion equations

Fractional differential equations are becoming increasingly used as a powerful modelling approach for understanding the many aspects of nonlocality and spatial heterogeneity. However, the numerical approximation of these models is demanding and imposes a number of computational constraints. In this paper, we introduce Fourier spectral methods as an attractive and easy-to-code alternative for the integration of fractional-in-space reaction-diffusion equations described by the fractional Laplacian in bounded rectangular domains ofRn. The main advantages of the proposed schemes is that they yield a fully diagonal representation of the fractional operator, with increased accuracy and efficiency when compared to low-order counterparts, and a completely straightforward extension to two and three spatial dimensions. Our approach is illustrated by solving several problems of practical interest, including the fractional Allen–Cahn, FitzHugh–Nagumo and Gray–Scott models, together with an analysis of the properties of these systems in terms of the fractional power of the underlying Laplacian operator.

Double diffusive Marangoni convection flow of electrically conducting fluid in a square cavity with chemical reaction

Double diffusive Marangoni convection flow of viscous incompressible electrically conducting fluid in a square cavity is studied in this paper by taking into consideration of the effect of applied magnetic field in arbitrary direction and the chemical reaction. The governing equations are solved numerically by using alternate direct implicit (ADI) method together with the successive over relaxation (SOR) technique. The flow pattern with the effect of governing parameters, namely the buoyancy ratio W, diffusocapillary ratio w, and the Hartmann number Ha, is investigated. It is revealed from the numerical simulations that the average Nusselt number decreases; whereas the average Sherwood number increases as the orientation of magnetic field is shifted from horizontal to vertical. Moreover, the effect of buoyancy due to species concentration on the flow is stronger than the one due to thermal buoyancy. The increase in diffusocapillary parameter, w caus

Proteogenomics of selective susceptibility to endotoxin using circulating acute phase biomarkers and bioassay development in sheep: a review

Scientists have injected endotoxin into animals to investigate and understand various pathologies and novel therapies for several decades. Recent observations have shown that there is selective susceptibility to Escherichia coli lipopolysaccharide (LPS) endotoxin in sheep, despite having similar breed characteristics. The reason behind this difference is unknown, and has prompted studies aiming to explain the variation by proteogenomic characterisation of circulating acute phase biomarkers. It is hypothesised that genetic trait, biochemical, immunological and inflammation marker patterns contribute in defining and predicting mammalian response to LPS. This review discusses the effects of endotoxin and host responses, genetic basis of innate defences, activation of the acute phase response (APR) following experimental LPS challenge, and the current approaches employed in detecting novel biomarkers including acute phase proteins (APP) and micro-ribonucleic acids (miRNAs) in serum or plasma. miRNAs are novel targets for elucidating molecular mechanisms of disease because of their differential expression during pathological, and in healthy states. Changes in miRNA profiles during a disease challenge may be reflected in plasma. Studies show that gel-based two-dimensional electrophoresis (2-DE) coupled with either matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) or liquid chromatography-mass spectrometry (LC-MS/MS) are currently the most used methods for proteome characterisation. Further evidence suggests that proteomic investigations are preferentially shifting from 2-DE to non-gel based LC-MS/MS coupled with data extraction by sequential window acquisition of all theoretical fragment-ion spectra (SWATH) approaches that are able to identify a wider range of proteins. Enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), and most recently proteomic methods have been used to quantify low abundance proteins such as cytokines. qRT-PCR and next generation sequencing (NGS) are used for the characterisation of miRNA. Proteogenomic approaches for detecting APP and novel miRNA profiling are essential in understanding the selective resistance to endotoxin in sheep. The results of these methods could help in understanding similar pathology in humans. It might also be helpful in the development of physiological and diagnostic screening assays for determining experimental inclusion and endpoints, and in clinical trials in future

Unimolecular reaction chemistry of a charge-tagged beta-hydroxyperoxyl radical

β-Hydroxyperoxyl radicals are formed during atmospheric oxidation of unsaturated volatile organic compounds such as isoprene. They are intermediates in the combustion of alcohols. In these environments the unimolecular isomerization and decomposition of β-hydroxyperoxyl radicals may be of importance, either through chemical or thermal activation. We have used ion-trap mass spectrometry to generate the distonic charge-tagged β-hydroxyalkyl radical anion, ˙CH2C(OH)(CH3)CH2C(O)O−, and investigated its subsequent reaction with O2 in the gas phase under conditions that are devoid of complicating radical–radical reactions. Quantum chemical calculations and master equation/RRKM theory modeling are used to rationalize the results and discern a reaction mechanism. Reaction is found to proceed via initial hydrogen abstraction from the γ-methylene group and from the β-hydroxyl group, with both reaction channels eventually forming isobaric product ions due to loss of either ˙OH + HCHO or ˙OH + CO2. Isotope labeling studies confirm that a 1,5-hydrogen shift from the β-hydroxyl functionality results in a hydroperoxyalkoxyl radical intermediate that can undergo further unimolecular dissociations. Furthermore, this study confirms that the facile decomposition of β-hydroxyperoxyl radicals can yield ˙OH in the gas phase.

A stochastic exponential Euler scheme for simulation of stiff biochemical reaction systems

In order to simulate stiff biochemical reaction systems, an explicit exponential Euler scheme is derived for multidimensional, non-commutative stochastic differential equations with a semilinear drift term. The scheme is of strong order one half and A-stable in mean square. The combination with this and the projection method shows good performance in numerical experiments dealing with an alternative formulation of the chemical Langevin equation for a human ether a-go-go related gene ion channel mode