Otitis media: recent advances in otitis media vaccine development and model systems

Otitis media is an inflammatory disorder of the middle ear caused by airways-associated bacterial or viral infections. It is one of the most common childhood infections as globally more than 80% of children are diagnosed with acute otitis media by 3 years of age and it is a common reason for doctor’s visits, antibiotics prescriptions, and surgery among children. Otitis media is a multifactorial disease with various genetic, immunologic, infectious, and environmental factors predisposing children to develop ear infections. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the most common culprits responsible for acute otitis media. Despite the massive global disease burden, the pathogenesis of otitis media is still unclear and requires extensive future research. Antibiotics are the preferred treatment to cure middle ear infections, however, the antimicrobial resistance rate of common middle ear pathogens has increased considerably over the years. At present, pneumococcal and influenza vaccines are administered as a preventive measure against otitis media, nevertheless, these vaccines are only beneficial in preventing carriage and/or disease caused by vaccine serotypes. Otitis media caused by non-vaccine serotype pneumococci, non-typeable H. influenza, and M. catarrhalis remain an important healthcare burden. The development of multi-species vaccines is an arduous process but is required to reduce the global burden of this disease. Many novel vaccines against S. pneumoniae, non-typeable H. influenza, and M. catarrhalis are in preclinical trials. It is anticipated that these vaccines will lower the disease burden and provide better protection against otitis media. To study disease pathology the rat, mouse, and chinchilla are commonly used to induce experimental acute otitis media to test new therapeutics, including antibiotics and vaccines. Each of these models has its advantages and disadvantages, yet there is still a need to develop an improved animal model providing a better correlated mechanistic understanding of human middle ear infections, thereby underpinning the development of more effective otitis media therapeutics. This review provides an updated summary of current vaccines against otitis media, various animal models of otitis media, their limitations, and some future insights in this field providing a springboard in the development of new animal models and novel vaccines for otitis media

Quantisation without Gauge Fixing: Avoiding Gribov Ambiguities through the Physical Projector

The quantisation of gauge invariant systems usually proceeds through some gauge fixing procedure of one type or another. Typically for most cases, such gauge fixings are plagued by Gribov ambiguities, while it is only for an admissible gauge fixing that the correct dynamical description of the system is represented, especially with regards to non perturbative phenomena. However, any gauge fixing procedure whatsoever may be avoided altogether, by using rather a recently proposed new approach based on the projection operator onto physical gauge invariant states only, which is necessarily free on any such issues. These different aspects of gauge invariant systems are explicitely analysed within a solvable U(1) gauge invariant quantum mechanical model related to the dimensional reduction of Yang-Mills theory.Comment: 22 pages, no figures, plain LaTeX fil

Measurements of Scintillation Efficiency and Pulse-Shape for Low Energy Recoils in Liquid Xenon

Results of observations of low energy nuclear and electron recoil events in liquid xenon scintillator detectors are given. The relative scintillation efficiency for nuclear recoils is 0.22 +/- 0.01 in the recoil energy range 40 keV - 70 keV. Under the assumption of a single dominant decay component to the scintillation pulse-shape the log-normal mean parameter T0 of the maximum likelihood estimator of the decay time constant for 6 keV < Eee < 30 keV nuclear recoil events is equal to 21.0 ns +/- 0.5 ns. It is observed that for electron recoils T0 rises slowly with energy, having a value ~ 30 ns at Eee ~ 15 keV. Electron and nuclear recoil pulse-shapes are found to be well fitted by single exponential functions although some evidence is found for a double exponential form for the nuclear recoil pulse-shape.Comment: 11 pages, including 5 encapsulated postscript figure

A synthetic genetic polymer with an uncharged backbone chemistry based on alkyl phosphonate nucleic acids

The physicochemical properties of nucleic acids are dominated by their highly charged phosphodiester backbone chemistry. The polyelectrolyte structure decouples information content (base sequence) from bulk properties such as solubility and has been proposed as a defining trait of all informational polymers. However, this conjecture has not been tested experimentally. Here, we describe the encoded synthesis of a genetic polymer with an uncharged backbone chemistry: alkyl-phosphonate nucleic acids (phNA), in which the canonical, negatively charged phosphodiester is replaced by an uncharged P-alkylphosphonodiester backbone. Using synthetic chemistry and polymerase engineering, we describe the enzymatic, DNA-templated synthesis of P-methyl- and P-ethyl-phNAs, and the directed evolution of specific streptavidin-binding phNA aptamer ligands directly from random-sequence, mixed P-methyl- / P-ethyl-phNA repertoires. Our results establish a first example of the DNA-templated enzymatic synthesis and evolution of an uncharged genetic polymer and provide a foundational methodology for their exploration as a source of novel, functional molecules

Pole structure of the Hamiltonian ζ\zeta-function for a singular potential

We study the pole structure of the $\zeta$-function associated to the Hamiltonian $H$ of a quantum mechanical particle living in the half-line $\mathbf{R}^+$, subject to the singular potential $g x^{-2}+x^2$. We show that $H$ admits nontrivial self-adjoint extensions (SAE) in a given range of values of the parameter $g$. The $\zeta$-functions of these operators present poles which depend on $g$ and, in general, do not coincide with half an integer (they can even be irrational). The corresponding residues depend on the SAE considered.Comment: 12 pages, 1 figure, RevTeX. References added. Version to appear in Jour. Phys. A: Math. Ge

The transition of adolescents with juvenile idiopathic arthritis or epilepsy from paediatric health-care services to adult health-care services: A scoping review of the literature and a synthesis of the evidence

Young people with long-term health conditions (LTCs) can face challenges when making the transition to adult health services. This paper sought to identify studies that assess and explore transitional care for young people with LTCs. Two conditions were used as exemplars: juvenile idiopathic arthritis (JIA) and epilepsy. A scoping review of the literature was conducted by using search terms to search for papers in English between 2001 and 2016 concerning transitional care on four databases. Qualitative papers were reviewed and synthesized using thematic analysis. Quantitative papers using health outcomes were also synthesized. Twenty-eight papers were selected for review. Despite the wealth of literature concerning aspects of transitional care that are key to a successful transition for young people with JIA or epilepsy, there is a paucity of outcomes that define ‘successful’ transition and consequently a lack of reliable research evaluating the effectiveness of transitional care interventions to support young people moving to adult health services

Extensive Anti-CoA Immunostaining in Alzheimer’s Disease and Covalent Modification of Tau by a Key Cellular Metabolite Coenzyme A

Alzheimer’s disease (AD) is a neurodegenerative disorder, accounting for at least two-thirds of dementia cases. A combination of genetic, epigenetic and environmental triggers is widely accepted to be responsible for the onset and development of AD. Accumulating evidence shows that oxidative stress and dysregulation of energy metabolism play an important role in AD pathogenesis, leading to neuronal dysfunction and death. Redox-induced protein modifications have been reported in the brain of AD patients, indicating excessive oxidative damage. Coenzyme A (CoA) is essential for diverse metabolic pathways, regulation of gene expression and biosynthesis of neurotransmitters. Dysregulation of CoA biosynthesis in animal models and inborn mutations in human genes involved in the CoA biosynthetic pathway have been associated with neurodegeneration. Recent studies have uncovered the antioxidant function of CoA, involving covalent protein modification by this cofactor (CoAlation) in cellular response to oxidative or metabolic stress. Protein CoAlation has been shown to both modulate the activity of modified proteins and protect cysteine residues from irreversible overoxidation. In this study, immunohistochemistry analysis with highly specific anti-CoA monoclonal antibody was used to reveal protein CoAlation across numerous neurodegenerative diseases, which appeared particularly frequent in AD. Furthermore, protein CoAlation consistently co-localized with tau-positive neurofibrillary tangles, underpinning one of the key pathological hallmarks of AD. Double immunihistochemical staining with tau and CoA antibodies in AD brain tissue revealed co-localization of the two immunoreactive signals. Further, recombinant 2N3R and 2N4R tau isoforms were found to be CoAlated in vitro and the site of CoAlation mapped by mass spectrometry to conserved cysteine 322, located in the microtubule binding region. We also report the reversible H_{2}O_{2}-induced dimerization of recombinant 2N3R, which is inhibited by CoAlation. Moreover, CoAlation of transiently expressed 2N4R tau was observed in diamide-treated HEK293/Pank1β cells. Taken together, this study demonstrates for the first time extensive anti-CoA immunoreactivity in AD brain samples, which occurs in structures resembling neurofibrillary tangles and neuropil threads. Covalent modification of recombinant tau at cysteine 322 suggests that CoAlation may play an important role in protecting redox-sensitive tau cysteine from irreversible overoxidation and may modulate its acetyltransferase activity and functional interactions

Path Integral Approach for Superintegrable Potentials on Spaces of Non-constant Curvature: II. Darboux Spaces DIII and DIV

This is the second paper on the path integral approach of superintegrable systems on Darboux spaces, spaces of non-constant curvature. We analyze in the spaces \DIII and \DIV five respectively four superintegrable potentials, which were first given by Kalnins et al. We are able to evaluate the path integral in most of the separating coordinate systems, leading to expressions for the Green functions, the discrete and continuous wave-functions, and the discrete energy-spectra. In some cases, however, the discrete spectrum cannot be stated explicitly, because it is determined by a higher order polynomial equation. We show that also the free motion in Darboux space of type III can contain bound states, provided the boundary conditions are appropriate. We state the energy spectrum and the wave-functions, respectively

Exact expression for the diffusion propagator in a family of time-dependent anharmonic potentials

We have obtained the exact expression of the diffusion propagator in the time-dependent anharmonic potential $V(x,t)={1/2}a(t)x^2+b\ln x$. The underlying Euclidean metric of the problem allows us to obtain analytical solutions for a whole family of the elastic parameter a(t), exploiting the relation between the path integral representation of the short time propagator and the modified Bessel functions. We have also analyzed the conditions for the appearance of a non-zero flow of particles through the infinite barrier located at the origin (b<0).Comment: RevTex, 19 pgs. Accepted in Physical Review

Quantum singular oscillator as a model of two-ion trap: an amplification of transition probabilities due to small time variations of the binding potential

Following the paper by M. Combescure [Ann. Phys. (NY) 204, 113 (1990)], we apply the quantum singular time dependent oscillator model to describe the relative one dimensional motion of two ions in a trap. We argue that the model can be justified for low energy excited states with the quantum numbers $n\ll n_{max}\sim 100$, provided that the dimensionless constant characterizing the strength of the repulsive potential is large enough, $g_*\sim 10^5$. Time dependent Gaussian-like wave packets generalizing odd coherent states of the harmonic oscillator, and excitation number eigenstates are constructed. We show that the relative motion of the ions, in contradistinction to its center of mass counterpart, is extremely sensitive to the time dependence of the binding harmonic potential, since the large value of $g_*$ results in a significant amplification of the transition probabilities between energy eigenstate even for slow time variations of the frequency.Comment: 19 pages, LaTeX, 5 eps-figures, to appear on Phys. Rev. A, one reference correcte