Genetics of T cell co-stimulatory receptors -CD28, CTLA4, ICOS and PDCD1 in immunity and transplantation

Co-stimulatory signals are essential for the activation of naïve T cells and productive immune response. Naïve T cells receive first, antigen-specific signal through T cell receptor. Co-stimulatory receptors provide the second signal which can be either activating or inhibitory. The balance between signals determines the outcome of an immune response. CD28 is crucial for T cell activation; whereas cytotoxic T lymphocyte associated antigen 4 (CTLA4) mediates critical inhibitory signal. Inducible co-stimulator (ICOS) augments cytokine expression and plays role in immunoglobulin class switching. Programmed cell death 1 (PDCD1) acts as negative regulator of T cell proliferation and cytokine responses. The co-stimulatory receptor pathways are potentially involved in self-tolerance and thus, they provide a promising therapeutic strategy for autoimmune diseases and transplantation. The genes encoding CD28, CTLA4 and ICOS are located adjacently in the chromosome region 2q33. The PDCD1 gene maps further, to the region 2q37. CTLA4 and PDCD1 are associated with the risk of a few autoimmune diseases. There is strong linkage disequilibrium (LD) on the 2q33 region; the whole gene of CD28 exists in its own LD block but CTLA4 and the 5' part of ICOS are within a same LD block. The 3' part of ICOS and PDCD1 are in their own separate LD blocks. Extended haplotypes covering the 2q33 region can be identified. This study focuses on immune related conditions like coeliac disease (CD) which is a chronic inflammatory disease with autoimmune features. Immunoglobulin A deficiency (IgAD) belongs to the group of primary antibody deficiencies characterised by reduced levels of immunoglobulins. IgAD co-occurs often with coeliac disease. Renal transplantation is needed in the end stage kidney diseases. Transplantation causes strong immune response which is tried to suppress with drugs. All these conditions are multifactorial with complex genetic background and multiple environmental factors affecting the outcome. We have screened ICOS for polymorphisms by sequencing the exon regions. We detected 11 new variants and determined their frequencies in Finnish population. We have measured linkage disequilibrium on the 2q33 region in Finnish as well as other European populations and observed conserved haplotypes. We analysed genetic association and linkage of the co-stimulatory receptor gene region aiming to study if it is a common risk locus for immune diseases. The 2q33 region was replicated to be linked to coeliac disease in Finnish population and CTLA4-ICOS haplotypes were found to be associated with CD and IgAD being the first non-HLA risk locus common for CD and immunodeficiencies. We also showed association between ICOS and the outcome of kidney transplantation. Our results suggest new evidence for CTLA4-ICOS gene region to be involved in susceptibility of coeliac disease. The earlier published contradictory association results can be explained by involvement of both CTLA4 and ICOS in disease susceptibility. The pattern of variants acting together rather than a single polymorphism may confer the disease risk. These genes may predispose also to immunodeficiencies as well as decreased graft survival and delayed graft function. Consequently, the present study indicates that like the well established HLA locus, the co-stimulatory receptor genes predispose to variety of immune disorders.

A model for doped-oxide-source diffusion with a chemical reaction at the silicon-silicon dioxide interface

A mathematical model for doped-oxide-source diffusion is proposed. In this model the concept of segregation of impurity at the silicon-silicon dioxide is used and also a constant of “rate limitation” is introduced through a chemical reaction at the interface.

Complimentary collaborations: Teachers and researchers co-developing best practices in art education

Australia is currently experiencing a huge cultural shift as it moves from a State-based curriculum, to a national education system. The Australian State-based bodies that currently manage teacher registration, teacher education course accreditation, curriculum frameworks and syllabi are often complex organisations that hold conflicting ideologies about education and teaching. The development of a centralised system, complete with a single accreditation body and a national curriculum can be seen as a reaction to this complexity. At the time of writing, the Australian Curriculum is being rolled out in staggered phases across the states and territories of Australia. Phase one has been implemented, introducing English, Mathematics, History and Science. Subsequent phases (Humanities and Social Sciences, the Arts, Technologies, Health and Physical Education, Languages, and year 9-10 work studies) are intended to follow. Forcing an educational shift of this magnitude is no simple task; not least because the States and Territories have and continue to demonstrate varying levels of resistance to winding down their own curricula in favour of new content with its unfamiliar expectations and organisations. The full implementation process is currently far from over, and far from being fully resolved. The Federal Government has initiated a number of strategies to progress the implementation, such as the development of the Australian Institute for Teaching and School Leadership (AITSL) to aid professional educators to implement the new curriculum. AITSL worked with professional and peak specialist bodies to develop Illustrations of Practice (hereafter IoP) for teachers to access and utilise. This paper tells of the building of one IoP, where a graduate teacher and a university lecturer collaborated to construct ideas and strategies to deliver visual arts lessons to early childhood students in a low Socio- Economic Status [SES] regional setting and discusses the experience in terms of its potential for professional learning in art education.

Co-distribution and co-infection of chikungunya and dengue viruses

BACKGROUND Chikungunya and dengue infections are spatio-temporally related. The current review aims to determine the geographic limits of chikungunya, dengue and the principal mosquito vectors for both viruses and to synthesise current epidemiological understanding of their co-distribution. METHODS Three biomedical databases (PubMed, Scopus and Web of Science) were searched from their inception until May 2015 for studies that reported concurrent detection of chikungunya and dengue viruses in the same patient. Additionally, data from WHO, CDC and Healthmap alerts were extracted to create up-to-date global distribution maps for both dengue and chikungunya. RESULTS Evidence for chikungunya-dengue co-infection has been found in Angola, Gabon, India, Madagascar, Malaysia, Myanmar, Nigeria, Saint Martin, Singapore, Sri Lanka, Tanzania, Thailand and Yemen; these constitute only 13 out of the 98 countries/territories where both chikungunya and dengue epidemic/endemic transmission have been reported. CONCLUSIONS Understanding the true extent of chikungunya-dengue co-infection is hampered by current diagnosis largely based on their similar symptoms. Heightened awareness of chikungunya among the public and public health practitioners in the advent of the ongoing outbreak in the Americas can be expected to improve diagnostic rigour. Maps generated from the newly compiled lists of the geographic distribution of both pathogens and vectors represent the current geographical limits of chikungunya and dengue, as well as the countries/territories at risk of future incursion by both viruses. These describe regions of co-endemicity in which lab-based diagnosis of suspected cases is of higher priority.

Co-Signaling by Neurotrophic Factors and the Extracellular Matrix for Axonal Growth and Neuronal Survival

Neurotrophic factors (NTFs) and the extracellular matrix (ECM) are important regulators of axonal growth and neuronal survival in mammalian nervous system. Understanding of the mechanisms of this regulation is crucial for the development of posttraumatic therapies and drug intervention in the injured nervous system. NTFs act as soluble, target-derived extracellular regulatory molecules for a wide range of physiological functions including axonal guidance and the regulation of programmed cell death in the nervous system. The ECM determines cell adhesion and regulates multiple physiological functions via short range cell-matrix interactions. The present work focuses on the mechanisms of the action of NTFs and the ECM on axonal growth and survival of cultured sensory neurons from dorsal root ganglia (DRG). We first examined signaling mechanisms of the action of the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) on axonal growth. GDNF, neurturin (NRTN) and artemin (ART) but not persephin (PSPN) promoted axonal initiation in cultured DRG neurons from young adult mice. This effect required Src family kinase (SFK) activity. In neurons from GFRalpha2-deficient mice, NRTN did not significantly promote axonal initiation. GDNF and NRTN induced extensive lamellipodia formation on neuronal somata and growth cones. This study suggested that GDNF, NRTN and ARTN may serve as stimulators of nerve regeneration under posttraumatic conditions. Consequently we studied the convergence of signaling pathways induced by NTFs and the ECM molecule laminin in the intracellular signaling network that regulates axonal growth. We demonstrated that co-stimulation of DRG neurons with NTFs (GDNF, NRTN or nerve growth factor (NGF)) and laminin leads to axonal growth that requires activation of SFKs. A different, SFK-independent signaling pathway evoked axonal growth on laminin in the absence of the NTFs. In contrast, axonal branching was regulated by SFKs both in the presence and in the absence of NGF. We proposed and experimentally verified a Boolean model of the signaling network triggered by NTFs and laminin. Our results put forward an approach for predictable, Boolean logics-driven pharmacological manipulation of a complex signaling network. Finally we found that N-syndecan, the receptor for the ECM component HB-GAM was required for the survival of neonatal sensory neurons in vitro. We demonstrated massive cell death of cultured DRG neurons from mice deficient in the N-syndecan gene as compared to wild type controls. Importantly, this cell death could not be prevented by NGF the neurotrophin which activates multiple anti-apoptotic cascades in DRG neurons. The survival deficit was observed during first postnatal week. By contrast, DRG neurons from young adult N-syndecan knock-out mice exhibited normal survival. This study identifies a completely new syndecan-dependent type of signaling that regulates cell death in neurons.

Ruthenium(II)-CO complexes of N-[(2-pyridyl)methyliden]-alpha(or beta)-aminonaphthalene: Synthesis, spectral studies, crystal structure, redox properties and DFT calculation

The characterization and properties of trans-(X)-[RuX2(CO)(2)(alpha/beta-NaiPy)] (1, 2) (alpha-NaiPy (a), beta-NaiPy (b); X = Cl (1), I (2)) are described in this work. The structures are confirmed by single crystal X-ray diffraction studies. Reaction of these compounds with Me3NO in MeCN has isolated monocarbonyl trans-(X)-RuX2(CO)(MeCN)(alpha/beta-NaiPy)] (3, 4). The complexes show intense emission properties. Quantum yields of 1 and 2 (phi= 0.02-0.08) are higher than 3 and 4 (phi = 0.006-0.015). Voltammogram shows higher Ru(III)/Ru(II) (1.3-1.5 V) potential of 1 and 2 than that of 3 and 4 (0.8-0.9 V) that may be due to coordination of two pi-acidic CO groups in former. The electronic spectra and redox properties of the complexes are compared with the results obtained by density functional theory (DFT) and time-dependent density functional theory (TD-DFT) using polarizable continuum model (CPCM).

Co(II) and Cr(III) complexes of formate-formamide mixed ligands: synthesis, structures, single crystal-to-single crystal transformation and magnetic behaviour

Solvothermal treatment of an equimolar mixture of Co(NO3)(2)center dot 6H(2)O, HCONH2 and NaN3 in MeOH at 100 degrees C yielded a three-dimensional NaCl type network Co(HCOO)(2)(HCONH2)(2) center dot HCONH2 (1a) containing formamides in the pores of the structure. Solvated pink 1a undergoes single crystal-to-single crystal (SCSC) transformation at 215 degrees C to form the desolvated dark brown product Co(HCOO)(2)-( HCONH2)(2) (1b) with the retention of the original framework. Reversible single crystal-to-single crystal transformation of 1b (brown) to 1a (pink) in the presence of excess formamide was also established at room temperature. The coordination environment around Co(II) in both 1a and 1b is octahedral with a CoN2O4 coordination composition. A similar reaction replacing Co(II) by Cr(III) produced a heterometallic 3D extended network Na[Cr(HCOO)(4)(HCONH2)(2)]center dot 2H(2)O (2a) at 100 degrees C. An increase in reaction temperature to 150 degrees C produced a simple mononuclear complex Cr(HCOO)(3)(HCONH2)(3) center dot 3H(2)O (2b). Variable temperature magnetic studies revealed the presence of a canting phenomena in both 1a and 1b, and hysteresis loop in the field dependent magnetisation plot at 2 K whereas complex 2a is simply paramagnetic in nature.

Diffusion and Creep in Silica-Doped Tetragonal Zirconia

Silica segregation at two grain junctions or in amorphous triple junction pockets can influence creep by altering the grain-boundary diffusion coefficient. Although the addition of silica to superplastic yttria-stabilized tetragonal zirconia enhances ductility, differences in reported creep parameters have limited critical identification of rate controlling mechanisms. The present study on a pure 3 mol% yttria-stabilized tetragonal zirconia (3YTZ) and 3YTZ with 0.39 or 3.9 wt% silica involved a detailed characterization of creep over a wide range of experimental conditions and also tracer diffusion measurements. The data broadly show transitions in creep stress exponents from n∼1 to ∼2 to ∼3 with a decrease in the stress. The data at high stresses are consistent with Coble diffusion creep, and creep at lower stresses is attributed to interface-controlled diffusion creep. Measurements indicated that silica does not have any significant influence on grain boundary or lattice diffusion, and this is consistent with the observation that 3YTZ and 3YTZ with 0.39% or 3.9% silica exhibit essentially identical creep behavior in the Coble creep regime. Silica influences the interface control process so that the transitions in stress exponents are pushed to lower stresses with an increase in silica content.

Topological close packed mu phase formation and the determination of diffusion parameters in the Co-Mo system

The study on the formation and growth of topological close packed (TCP) compounds is important to understand the performance of turbine blades in jet engine applications. These deleterious phases grow mainly by diffusion process in the superalloy substrate. Significant volume change was found because of growth of the p phase in Co-Mo system. Growth kinetics of this phase and different diffusion parameters, like interdiffusion, intrinsic and tracer diffusion coefficients are calculated. Further the activation energy, which provides an idea about the mechanism, is determined. Moreover, the interdiffusion coefficient in Co(Mo) solid solution and impurity diffusion coefficient of Mo in Co are determined.

Ultrasonic degradation of poly(methyl methacrylate-co-alkyl acrylate) copolymers

The copolymers, poly(methyl methacrylate-co-methyl acrylate) (PMMAMA), poly(methyl methacrylate-co-ethyl acrylate) (PMMAEA) and poly(methyl methacrylate-co-butyl acrylate) (PMMABA), of different compositions were synthesized and characterized. The effect of alkyl acrylate content, alkyl group substituents and solvents on the ultrasonic degradation of these copolymers was studied. A model based on continuous distribution kinetics was used to study the kinetics of degradation. The rate coefficients were obtained by fitting the experimental data with the model. The linear dependence of the rate coefficients on the logarithm of the vapor pressure of the solvent indicated that vapor pressure is the crucial parameter that controls the degradation process. The rate of degradation increases with an increase in the alkyl acrylate content. At any particular copolymer composition, the rate of degradation follows the order: PMMAMA > PMMAEA > PMMABA. It was observed that the degradation rate coefficient varies linearly with the mole percentage of the alkyl acrylate in the copolymer.

Synthesis, Structure, and Properties of Boron- and Nitrogen-Doped Graphene

Boron- and nitrogen-doped graphenes are are prepared by the arc discharge between carbon electrodes or by the transformation of nanodiamond under appropriate atmospheres. Using a combination of experiment and theories based on first principles, systematic changes in the carrier-concentration and electronic structure of the doped graphenes are demonstrated. Stiffening of the G-band mode and intensification of the defect-related D-band in the Raman spectra are also observed.

Rotational isomerism about the Ca-CO bond in proline derivatives. 1H and 13C NMR studies of benzyloxycarbonyl-Pro-N-methylamide and pivaloyl-Pro-N-methylamide

The 270 MHz 1H n.m.r. spectrum of benzyloxycarbonyl-Pro-N-methylamide in CDCl3 is exchange broadened at 293° K. Spectral lines due to two species are frozen out at 253° K and a dynamically averaged spectrum is obtained at 323° K. A selective broadening of the Cβ and Cγ resonances in the 13C n.m.r. spectrum is observed at 253° K, with a splitting of the Cβ and Cγ resonances into a pair of lines of unequal intensity. A similar broadening of Cβ and Cγ peaks is also detected in pivaloyl-Pro-N-methylamide where cis-trans interconversion about the imide bond is precluded by the bulky t-butyl group. The rate process is thus attributed to rotation about the Cα-CO bond (ψ) and a barrier (ΔG#) of 14kcal mol-1 is estimated. 13C n.m.r. data for pivaloyl-Pro-N-methylamide in a number of solvents is presented and the differences in the Cβ and Cγ chemical shifts are interpreted in terms of rotational isomerism about the Cα-CO bond.

Novel synthesis of superparamagnetic Ni-Co-B nanoparticles and their effect on superconductor properties of MgB2

A new procedure for the preparation of amorphous Ni-Co-B nanoparticles is reported, with a detailed investigation of their morphology by X-ray diffraction and transmission electron microscopy, as well as their magnetic properties. Many factors, such as chemical composition, anisotropy, size and shape of the particles, were controlled through chemical synthesis, resulting in the control of morphological and magnetic properties of the nanoparticles. Controlling pH values with ethylenediamine and using sodium dodecyl sulfate surfactant lowered the size of the nanoparticles to below 10 nm. Such a small structure and chemical disorder in nanocrystalline materials lead to magnetic properties that are different from those in their bulk-sized counterparts. The obtained nanoparticles can be used for different purposes, from pharmaceutical applications to implementations in different materials technology. The focus of this research is the synthesis of Ni-Co-B nanoparticles in a new way and studying the reaction of Ni-Co-B nanoparticles with Mg and B precursors and their effect on MgB2 properties. New nanostructures are formed in the reaction of Ni-Co-B nanoparticles with Mg: Mg2Ni, Co2Mg and possibly Mg2Co.

Zr4+ doping in Li4Ti5O12 anode for lithium-ion batteries: Open Li+ diffusion paths through structural imperfection

One-dimensional nanomaterials have short Li+ diffusion paths and promising structural stability, which results in a long cycle life during Li+ insertion and extraction processes in lithium rechargeable batteries. In this study, we fabricated one-dimensional spinel Li 4Ti5O12 (LTO) nanofibers using an electrospinning technique and studied the Zr4+ doping effect on the lattice, electronic structure, and resultant electrochemical properties of Li-ion batteries (LIBs). Accommodating a small fraction of Zr4+ ions in the Ti4+ sites of the LTO structure gave rise to enhanced LIB performance, which was due to structural distortion through an increase in the average lattice constant and thereby enlarged Li+ diffusion paths rather than changes to the electronic structure. Insulating ZrO2 nanoparticles present between the LTO grains due to the low Zr4+ solubility had a negative effect on the Li+ extraction capacity, however. These results could provide key design elements for LTO anodes based on atomic level insights that can pave the way to an optimal protocol to achieve particular functionalities. Distorted lattice: Zr4+ is doped into a 1 D spinel Li4Ti5O12 (LTO) nanostructure and the resulting electrochemical properties are explored through a combined theoretical and experimental investigation. The improved electrochemical performance resulting from incorporation of Zr4+ in the LTO is due to lattice distortion and, thereby, enlarged Li+ diffusion paths rather than to a change in the electronic structure.

A novel ionic diffusion strategy to fabricate high-performance anode-supported solid oxide fuel cells (SOFCs) with proton-conducting Y-doped BaZrO3 films

A stable Y-doped BaZrO3 electrolyte film, which showed a good performance in proton-conducting SOFCs, was successfully fabricated using a novel ionic diffusion strategy.