Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic mice.

BackgroundAlzheimer disease (AD) is characterized by the accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau, which together lead to neurodegeneration and cognitive decline. Current therapeutic approaches have primarily aimed to reduce pathological aggregates of either Aβ or tau, yet phase 3 clinical trials of these approaches have thus far failed to delay disease progression in humans. Strong preclinical evidence indicates that these two abnormally aggregated proteins interact synergistically to drive downstream neurodegeneration. Therefore, combinatorial therapies that concurrently target both Aβ and tau might be needed for effective disease modification.MethodsA combinatorial vaccination approach was designed to concurrently target both Aβ and tau pathologies. Tau22/5xFAD (T5x) bigenic mice that develop both pathological Aβ and tau aggregates were injected intramuscularly with a mixture of two MultiTEP epitope vaccines: AV-1959R and AV-1980R, targeting Aβ and tau, respectively, and formulated in AdvaxCpG, a potent polysaccharide adjuvant. Antibody responses of vaccinated animals were measured by ELISA, and neuropathological changes were determined in brain homogenates of vaccinated and control mice using ELISA and Meso Scale Discovery (MSD) multiplex assays.ResultsT5x mice immunized with a mixture of Aβ- and tau-targeting vaccines generated high Aβ- and tau-specific antibody titers that recognized senile plaques and neurofibrillary tangles/neuropil threads in human AD brain sections. Production of these antibodies in turn led to significant reductions in the levels of soluble and insoluble total tau, and hyperphosphorylated tau as well as insoluble Aβ42, within the brains of bigenic T5x mice.ConclusionsAV-1959R and AV-1980R formulated with AdvaxCpG adjuvant are immunogenic and therapeutically potent vaccines that in combination can effectively reduce both of the hallmark pathologies of AD in bigenic mice. Taken together, these findings warrant further development of this vaccine technology for ultimate testing in human AD

The Coulomb-Oscillator Relation on n-Dimensional Spheres and Hyperboloids

In this paper we establish a relation between Coulomb and oscillator systems on $n$-dimensional spheres and hyperboloids for $n\geq 2$. We show that, as in Euclidean space, the quasiradial equation for the $n+1$ dimensional Coulomb problem coincides with the $2n$-dimensional quasiradial oscillator equation on spheres and hyperboloids. Using the solution of the Schr\"odinger equation for the oscillator system, we construct the energy spectrum and wave functions for the Coulomb problem.Comment: 15 pages, LaTe

3D Oscillator and Coulomb Systems reduced from Kahler spaces

We define the oscillator and Coulomb systems on four-dimensional spaces with U(2)-invariant Kahler metric and perform their Hamiltonian reduction to the three-dimensional oscillator and Coulomb systems specified by the presence of Dirac monopoles. We find the Kahler spaces with conic singularity, where the oscillator and Coulomb systems on three-dimensional sphere and two-sheet hyperboloid are originated. Then we construct the superintegrable oscillator system on three-dimensional sphere and hyperboloid, coupled to monopole, and find their four-dimensional origins. In the latter case the metric of configuration space is non-Kahler one. Finally, we extend these results to the family of Kahler spaces with conic singularities.Comment: To the memory of Professor Valery Ter-Antonyan, 11 page

Effect of CPAP therapy on left atrial remodeling in patients with paroxysmal atrial fibrillation and obstructive sleep apnea undergoing pulmonary vein isolation

Aim. To study the isolated effect of obstructive sleep apnea (OSA) on left atrial (LA) remodeling in patients with paroxysmal atrial fibrillation (AF) who underwent pulmonary vein (PV) ablation and concomitant severe and moderate OSA.Material and methods. A subanalysis of echocardiographic data was performed in 50 patients with paroxysmal AF and moderate/severe OSA who underwent PV isolation and were followed up for 12 months (main group, 33; control group, 17). The clinical efficacy of catheter ablation was assessed after the end of the threemonth blind period. The following echocardiographic parameters were included in the subanalysis: anterior-posterior LA dimension, LA volume, LA volume index (LAVI), and pulmonary artery systolic pressure (PASP).Results. After 12 months, the control group showed a significant increase in the anterior-posterior LA dimension (40,5 (40-42) mm vs 42 (40-45) mm, p=0,037), LA volume (68,5 (58-74,5) ml vs 69 (63-89) ml, p=0,006), LAVI (35,0 (29-37) ml/m2 vs 35,5 (32-41,5) ml/m2, p=0,005) and PASP (27 (25-30) vs 30 (29-33), p=0,004). Intragroup analysis of patients not receiving continuous positive airway pressure (CPAP) therapy and without recurrent AF did not reveal significant changes in LA size (anterior-posterior LA dimension — 40 (40-42) mm vs 40 (40- 41) mm, p=0,317; LA volume — 63 (58-71) ml vs 64 (61-69) ml, p=0,509; LAVI — 32 (29-36) ml/m2 vs 33 (31-34) ml2, p=0,509).Conclusion. In patients with paroxysmal AF and concomitant moderate to severe OSA who underwent AF catheter treatment, the absence of CPAP therapy is not associated with a significant increase in the linear and volume LA dimensions in the absence of AF recurrence

Second Hopf map and Yang-Coulomb system on 5d (pseudo)sphere

Using the second Hopf map, we perform the reduction of the eight-dimensional (pseudo)spherical (Higgs)oscillator to a five-dimensional system interacting with a Yang monopole. Then, using a standard trick, we obtain, from the latter system, the pseudospherical and spherical generalizations of the Yang-Coulomb system (the five dimensional analog of MICZ-Kepler system). We present the whole set of its constants of motions, including the hidden symmetry generators given by the analog of Runge-Lenz vector. In the same way, starting from the eight-dimensional anisotropic inharmonic Higgs oscillator, we construct the integrable (pseudo)spherical generalization of the Yang-Coulomb system with the Stark term.Comment: 10 pages, PACS: 03.65.-w, 02.30.Ik, 14.80.H

Casimir energy in the Fulling--Rindler vacuum

The Casimir energy is evaluated for massless scalar fields under Dirichlet or Neumann boundary conditions, and for the electromagnetic field with perfect conductor boundary conditions on one and two infinite parallel plates moving by uniform proper acceleration through the Fulling--Rindler vacuum in an arbitrary number of spacetime dimension. For the geometry of a single plate the both regions of the right Rindler wedge, (i) on the right (RR region) and (ii) on the left (RL region) of the plate are considered. The zeta function technique is used, in combination with contour integral representations. The Casimir energies for separate RR and RL regions contain pole and finite contributions. For an infinitely thin plate taking RR and RL regions together, in odd spatial dimensions the pole parts cancel and the Casimir energy for the whole Rindler wedge is finite. In $d=3$ spatial dimensions the total Casimir energy for a single plate is negative for Dirichlet scalar and positive for Neumann scalar and the electromagnetic field. The total Casimir energy for two plates geometry is presented in the form of a sum of the Casimir energies for separate plates plus an additional interference term. The latter is negative for all values of the plates separation for both Dirichlet and Neumann scalars, and for the electromagnetic field.Comment: 28 pages, 4 figures, references added, typos corrected, accepted for publication in Phys. Rev.

The immunological potency and therapeutic potential of a prototype dual vaccine against influenza and Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Numerous pre-clinical studies and clinical trials demonstrated that induction of antibodies to the β-amyloid peptide of 42 residues (Aβ₄₂) elicits therapeutic effects in Alzheimer's disease (AD). However, an active vaccination strategy based on full length Aβ₄₂is currently hampered by elicitation of T cell pathological autoreactivity. We attempt to improve vaccine efficacy by creating a novel chimeric flu vaccine expressing the small immunodominant B cell epitope of Aβ₄₂. We hypothesized that in elderly people with pre-existing memory Th cells specific to influenza this dual vaccine will simultaneously boost anti-influenza immunity and induce production of therapeutically active anti-Aβ antibodies.</p> <p>Methods</p> <p>Plasmid-based reverse genetics system was used for the rescue of recombinant influenza virus containing immunodominant B cell epitopes of Aβ₄₂(Aβ_1-7/10).</p> <p>Results</p> <p>Two chimeric flu viruses expressing either 7 or 10 aa of Aβ₄₂(flu-Aβ_1-7or flu-Aβ_1-10) were generated and tested in mice as conventional inactivated vaccines. We demonstrated that this dual vaccine induced therapeutically potent anti-Aβ antibodies and anti-influenza antibodies in mice.</p> <p>Conclusion</p> <p>We suggest that this strategy might be beneficial for treatment of AD patients as well as for prevention of development of AD pathology in pre-symptomatic individuals while concurrently boosting immunity against influenza.</p

Anisotropic inharmonic Higgs oscillator and related (MICZ-)Kepler-like systems

We propose the integrable (pseudo)spherical generalization of the four-dimensional anisotropic oscillator with additional nonlinear potential. Performing its Kustaanheimo-Stiefel transformation we then obtain the pseudospherical generalization of the MICZ-Kepler system with linear and $\cos\theta$ potential terms. We also present the generalization of the parabolic coordinates, in which this system admits the separation of variables. Finally, we get the spherical analog of the presented MICZ-Kepler-like system.Comment: 7 page

Large aperture vibrating wire monitor with two mechanically coupled wires for beam halo measurements

Development of a new type of vibrating wire monitor (VWM), which has two mechanically coupled wires (vibrating and target), is presented. The new monitor has a much larger aperture size than the previous model of the VWM, and thus allows us to measure transverse beam halos more effectively. A prototype of such a large aperture VWM with a target wire length of 60 mm was designed, manufactured, and bench-tested. Initial beam measurements have been performed at the Fermilab High Intensity Neutrino Source facility, and key results are presented.open1

Quantum oscillator as 1D anyon

It is shown that in one spatial dimension the quantum oscillator is dual to the charged particle situated in the field described by the superposition of Coulomb and Calogero-Sutherland potentials.Comment: 9 pages, LaTe