Alzheimer’s disease AdvaxCpG- adjuvanted MultiTEP-based dual and single vaccines induce high-titer antibodies against various forms of tau and Aβ pathological molecules

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Although β-amyloid (Aβ) may be the primary driver of Alzheimer's disease (AD) pathology, accumulation of pathological tau correlates with dementia in AD patients. Thus, the prevention/inhibition of AD may require vaccine/s targeting Aβ and tau simultaneously or sequentially. Since high antibody titers are required for AD vaccine efficacy, we have decided to generate vaccines, targeting Aβ (AV-1959R), Tau (AV-1980R) or Aβ/tau (AV-1953R) B cell epitopes, based on immunogenic MultiTEP platform and evaluate the immunogenicity of these vaccines formulated with Advax(CpG), delta inulin, Alhydrogel(®), Montanide-ISA51, Montanide-ISA720, MPLA-SM pharmaceutical grade adjuvants. Formulation of AV-1959R in Advax(CpG) induced the highest cellular and humoral immune responses in mice. The dual-epitope vaccine, AV-1953R, or the combination of AV-1959R and AV-1980R vaccines formulated with Advax(CpG) induced robust antibody responses against various forms of both, Aβ and tau pathological molecules. While anti-Aβ antibody titers after AV-1953R immunization were similar to that in mice vaccinated with AV-1959R or AV-1959R/AV-1980R combination, anti-tau titers were significantly lower after AV-1953R injection when compared to the AV-1980R or AV-1959R/AV-1980R. In silico 3D-modeling provided insight into the differences in immunogenicity of these vaccine constructs. In sum, AV-1959R and AV-1980R formulated with Advax(CpG) adjuvant were identified as promising immunogenic vaccines for ongoing pre-clinical assessment and future human clinical trials

Opportunities of x-ray imajing in ligament injuryes of ankle

X-ray study was performed in forty five patients with chronic ankle instability as a result of diagnostic errors or inadequate treatment. It has been revealed that a simple x-ray tests (particularly antero-posterior view of the intact ankle and injured ankle with and without weight bearing) allow to evaluate the acute and chronic ankle ligament injuries efficiently.Проведено рентгенологическое обследование 45 больных с посттравматической хронической нестабильностью голеностопного сустава. Определено, что хроническая нестабильность голеностопного сустава является результатом некачественной первичной диагностики и тактико-технических ошибок, допущенных в процессе лечения. Применение сравнительной рентгенографии голеностопного сустава и рентгенографии в нагрузке позволяет в подавляющем большинстве случаев (89,6%) получить объективные рентгенометрические показатели, свидетельствующие о наличии повреждения связок, не прибегая к дорогостоящим методам диагностики

Exploring the Caves of Armenia by the First Official U.S. Caving Expedition (2007-2013)

The first U.S. caving expedition to Armenia, the South Caucasus, by NSS cavers took place in August 2007. Subsequent expeditions took place in 2010, 2011, and 2013, with additional trips planned for the future. The goal is the exploration and photo-documentation of the caves of Armenia, and to increase awareness of its underground realms. Although, in the past, there had been a few known caving expeditions to Armenia, overall little information existed.  In addition, Armenia’s local caving community is small in number.  As a result, this topic was studied and the first official US caving expedition to Armenia was organized in 2007. During the first expedition, four of Armenia’s significant natural caves were explored in the province of Vayots Dzor: Mozrov Cave, Arjeri Cave (Cave of the Bears), Mageli Cave, and Karmir Cave (Red Cave). Man-made caves were also visited.  Subsequent trips to Armenia in 2010, 2011, and 2013 included (1) further exploration of Mozrov, Arjeri, and Mageli caves, (2) a cave trip to the neighboring independent Armenian Republic of Nagorno-Karabagh to explore Azokh Cave, and (3) the exploration of several caves in the northeast Armenian provinces of Tavush and Lori. Natural caves consisting of limestone, conglomerate, and lava were explored during these expeditions.  Also, a number of man-made caves were visited, some of which were used as churches in centuries past.  This article summarizes the four expeditions and discusses both the natural and man-made caves of Armenia. I beleive the article will be interesting to builders, gas pipelines and road engineers. In practice, it can be used by travel agencies and individual tourists, as well as by all lovers of underground monuments of nature and culture

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

Тіньова економіка та її вплив на проблему податкової злочинності

Давтян Л. Г. Тіньова економіка та її вплив на проблему податкової злочинності / Л. Г. Давтян // Новітні кримінально-правові дослідження – 2016 : зб. наук. пр. / відп. ред. О. В. Козаченко. – Миколаїв : Іліон, 2016. - С. 90-93

Суб'єктивний аспект податкових злочинів

Давтян Л. Г. Суб'єктивний аспект податкових злочинів / Л. Г. Давтян // Новітні кримінально-правові дослідження – 2015 : зб. наук. пр. / відп. ред. О. В. Козаченко. - Миколаїв : Іліон, 2015. - С. 193-196

Dimensionalities of Weak Solutions in Hydrogenic Systems

A close inspection on the 3D hydrogen atom Hamiltonian revealed formal eigenvectors often discarded in the literature. Although not in its domain, such eigenvectors belong to the Hilbert space, and so their time evolution is well defined. They are then related to the 1D and 2D hydrogen atoms and it is numerically found that they have continuous components, so that ionization can take place

mRNA Vaccine for Alzheimer’s Disease: Pilot Study

The escalating global healthcare challenge posed by Alzheimer's Disease (AD) and compounded by the lack of effective treatments emphasizes the urgent need for innovative approaches to combat this devastating disease. Currently, passive and active immunotherapies remain the most promising strategy for AD. FDA-approved lecanemab significantly reduces Aβ aggregates from the brains of early AD patients administered biweekly with this humanized monoclonal antibody. Although the clinical benefits noted in these trials have been modest, researchers have emphasized the importance of preventive immunotherapy. Importantly, data from immunotherapy studies have shown that antibody concentrations in the periphery of vaccinated people should be sufficient for targeting Aβ in the CNS. To generate relatively high concentrations of antibodies in vaccinated people at risk of AD, we generated a universal vaccine platform, MultiTEP, and, based on it, developed a DNA vaccine, AV-1959D, targeting pathological Aβ, completed IND enabling studies, and initiated a Phase I clinical trial with early AD volunteers. Our current pilot study combined our advanced MultiTEP technology with a novel mRNA approach to develop an mRNA vaccine encapsulated in lipid-based nanoparticles (LNPs), AV-1959LR. Here, we report our initial findings on the immunogenicity of 1959LR in mice and non-human primates, comparing it with the immunogenicity of its DNA counterpart, AV-1959D

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

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