3,5-Dimethyladamantan-1-amine Restores Short-term Synaptic Plasticity by Changing Function of Excitatory Amino Acid Transporters in Mouse Model of Spinocerebellar Ataxia Type 1

Introduction. Memantine is an agent that used for treatment of Alzheimer's type dementia. Memantine considerably reduces the effects of neurodegeneration, may potentially slow down the neurodegenerative changes in the cerebellum and may act as treatment of choice for spinocerebellar ataxia type 1 (SCA 1). Our objective was to study molecular mechanisms of the short-term synaptic plasticity improvement associated with long-term memantine use in SCA 1 transgenic mice. Materials and methods. The experiments were performed on 12-week-old CD1 mice. We created a mouse model of cerebellar astrogliosis after expression of mutant ataxin-1 (ATXN1[Q85]) in the Bergmann glia (BG). To model the astrocyte-mediated neurodegeneration in the cerebellum, the mice were injected with LVV GFAP-Flag-ATXN1[Q85] lentiviral vector (LVV) constructs intracortically. Some of the mice received 0.35 mg/kg memantine dissolved in drink water once daily for 9 weeks. The control animals were administered LVV GFAP-ATXN1[Q2]-Flag. Changes of the excitatory postsynaptic currents amplitudes from Purkinje cells (PC) were recorded by patch clamp. Expression of anti-EAAT1 in the cerebellar cortex was assessed using immunohistochemistry. Results. The reactive glia of the cerebellar cortex in SCA1 mice is characterized by a decrease in the immunoreactivity of anti-EAAT1, while chronic memantine use restores this capacity. The decay time of the excitatory postsynaptic current amplitude in the parallel fiber-Purkinje cell (PF-PC) synapses of the SCA1 mice is considerably longer, which indicates the slowing of glutamate reuptake and EAAT1 dysfunction. The prolonged presence of increased neurotransmitter levels in the synaptic cleft facilitates activation of the mGluR1 signaling and restoration of mGluR1-dependent synaptic plasticity in Purkinje cells of the SCA1 mice. Conclusions. The slowing of neurotransmitter reuptake associated with long-term memantine treatment improves mGluR1-dependent short-term synaptic plasticity of the Purkinje cells in the SCA1 mice. Restoration of synaptic plasticity in these animals may underlie partial reduction of ataxic syndrome

Coverage with timely administered vaccination against hepatitis b virus and its influence on the prevalence of HBV infection in the regions of different endemicity

Funding Information: Funding: This research was funded by grant of the Russian Science Foundation (ID-20-15-00148). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Universal hepatitis B vaccination of newborns was implemented in Russia starting from 1998. From 1998 to 2019, the incidence of acute hepatitis B reduced from 43.8 to 0.57 cases per 100,000 population. Here, we assessed the timely coverage of newborns with the birth dose (HepB-BD), second dose (HepB-2nd), and three vaccine doses (HepB3) in two remote regions of Russia with low (Belgorod Oblast) and high (Yakutia) levels of hepatitis B virus (HBV) endemicity. Vaccination data were obtained from the medical records of 1000 children in Yakutia and 2182 children in Belgorod Oblast. Sera of healthy volunteers from Belgorod Oblast (n = 1754) and Yakutia (n = 1072) across all age groups were tested for serological markers of HBV to assess the infection prevalence and herd immunity. Average HepB-BD coverage was 99.2% in Yakutia and 89.4% in Belgorod Oblast (p < 0.0001) and in both regions varied significantly, from 66% to 100%, between medical centers. The principal reason for the absence of HepB-BD was parent refusal, which accounted for 63.5% of cases of non-vaccination (83/123). While timely HepB-2nd coverage was only 55.4%–64.7%: HepB3 coverage by the age of one year exceeded 90% in both study regions. HBV surface antigen (HBsAg) prevalence in the 1998–2019 birth cohort was 0.2% (95% CI: 0.01–1.3%) in Belgorod Oblast and 3.2% (95% CI: 1.9–5.2%) in Yakutia. The proportion of persons testing negative for both antibodies to HBsAg (anti-HBs) and antibodies to HBV core antigen (anti-HBc) in the 1998–2019 birth cohort was 26.2% (125/481) in Belgorod Oblast and 32.3% (162/501) in Yakutia. We also assessed the knowledge of and attitude towards vaccination among 782 students and teachers of both medical and non-medical specialties from Belgorod State University. Only 60% of medical students knew that hepatitis B is a vaccine-preventable disease. Both medical and nonmedical students, 37.8% and 31.3%, respectively, expressed concerns about safety and actual necessity of vaccination. These data indicate the need to introduce a vaccine delivery audit system, improve medical education with respect to vaccination strategies and policies, and reinforce public knowledge on the benefits of vaccination.Peer reviewe

Heliospheric modulation of cosmic rays during the neutron monitor era:calibration using PAMELA data for 2006–2010

Abstract A new reconstruction of the heliospheric modulation potential for galactic cosmic rays is presented for the neutron monitor era, since 1951. The new reconstruction is based on an updated methodology in comparison to previous reconstructions: (1) the use of the new-generation neutron monitor yield function; (2) the use of the new model of the local interstellar spectrum, employing in particular direct data from the distant missions; and (3) the calibration of the neutron monitor responses to direct measurements of the cosmic ray spectrum performed by the Payload for Antimatter Matter Exploration and Light-nuclei Astrophysics (PAMELA) spaceborne spectrometer over 47 time intervals during 2006–2010. The reconstruction is based on data from six standard NM64-type neutron monitors (Apatity, Inuvik, Kergulen, Moscow, Newark, and Oulu) since 1965 and two International Geophysical Year-type ground-based detectors (Climax and Mount Washington) for 1951–1964. The new reconstruction, along with the estimated uncertainties is tabulated in the paper. The presented series forms a benchmark record of the cosmic ray variability (in the energy range between 1 and 30 GeV) for the last 60 years and can be used in long-term studies in the fields of solar, heliospheric, and solar-terrestrial physics.Plain Language Summary Solar magnetic activity modulates the flux of energetic galactic cosmic rays bombarding Earth. A newly revised method for a quantitative assessment of the cosmic ray modulation parameter using data from the ground-based network of neutron monitors is presented. The new reconstruction employs a calibration of the ground-based data to the spaceborne direct measurements during a period of 2006–2010. The presented reconstructions form a benchmark record of the cosmic ray variability (in the energy range between 1 and 30 GeV) for the last 60 years and can be used in long-term studies in the field of solar, heliospheric, and solar-terrestrial physics

An anisotropic cosmic-ray enhancement event on 07-June-2015:a possible origin

Abstract A usual event, called anisotropic cosmic-ray enhancement (ACRE), was observed as a small increase (≤5%) in the count rates of polar neutron monitors during 12–9 UT on 07 June 2015. The enhancement was highly anisotropic, as detected only by neutron monitors with asymptotic directions in the southwest quadrant in geocentric solar ecliptic (GSE) coordinates. The estimated rigidity of the corresponding particles is ≤1 GV. No associated detectable increase was found in the space-borne data from the Geostationary Operational Environmental Satellite (GOES), the Energetic and Relativistic Nuclei and Electron (ERNE) on board the Solar and Heliospheric Observatory (SOHO), or the Payload for Antimatter Matter Exploration and Light-nuclei Astrophysics (PAMELA) instruments, whose sensitivity was not sufficient to detect the event. No solar energetic particles were present during that time interval. The heliospheric conditions were slightly disturbed, so that the interplanetary magnetic field strength gradually increased during the event, followed by an increase of the solar wind speed after the event. It is proposed that the event was related to a crossing of the boundary layer between two regions with different heliospheric parameters, with a strong gradient of low-rigidity (&lt;1 GV) particles. It was apparently similar to another cosmic-ray enhancement (e.g., on 22 June 2015) that is thought to have been caused by the local anisotropy of Forbush decreases, with the difference that in our case, the interplanetary disturbance was not observed at Earth, but passed by southward for this event

Impact of Universal Hepatitis B Vaccination on Prevalence, Infection-Associated Morbidity and Mortality, and Circulation of Immune Escape Variants in Russia.

METHODS:6,217 sera samples collected from volunteers in six epidemiologically different regions of Russia were tested for serological and molecular markers of HBV infection. A mathematical model developed by the U.S. Centers for Disease Control and Prevention was used to estimate the effect of vaccination and birth dose coverage on the incidence of HB and adverse outcomes of infection. RESULTS:Prevalence of HBsAg in the study population varied from 1.2% to 8.2%; anti-HBc detection rates were 13.0-46.2%. HBsAg detection rates in epidemiologically significant cohorts were 0.6-10.5% in women of childbearing age; 0-2.4% in children ≤5 years old; 1.9-8.1% in adults ≥30 years old. Mathematical modeling demonstrated that the current 96.1-99.6% level of birth dose coverage increased the effectiveness of vaccination 10-21 times compared to 50% and 0% birth dose coverage scenarios. HBV DNA was detected in 63 sera samples. The frequency of amino acid substitutions in HBsAg was 38% (24/63). Only in 3% (2/63) the mutations were within the a-determinant of HBsAg (M133T and G145S, one case each). None of the identified mutations eluded HBsAg detection, since all these samples tested positive for HBsAg by commercial ELISA. CONCLUSION:Despite a significant decline in acute HB incidence after the introduction of universal vaccination, many undiagnosed potential sources of infection remain. Low prevalence of HBV immune escape variants is a favorable predictor of vaccine effectiveness in the future

Analysis of Ground-Level Enhancements:strong events are hard

Abstract Ground Level Enhancements (GLEs) recorded by neutron monitor detectors are characterized by a variety of energy spectra of solar energetic particles (SEP), which vary between soft (as in August 1972) and hard (February 1956) ones. The aim of this work is to investigate the statistical relation between the hardness of the energy spectra and the event-integrated intensity. We calculated the event-integrated omnidirectional fluence of protons above 30 MeV (F₃₀) and above 200 MeV (F₂₀₀) using energy spectra reconstructed from both ground-based and space-borne data. The ratio of the F₃₀-to-F₂₀₀ fluences is considered as an index of the hardness of the events spectra. The main results of this study is that all strong events (with the event-integrated intensity greater than 100%*hr) are characterized by a hard or very hard spectrum, while weak and moderate events do not show any clear pattern between the hardness and the intensity of the event

Amino acid substitutions within HBsAg in HBV strains isolated in Russia.

<p>Amino acid substitutions within HBsAg in HBV strains isolated in Russia.</p

Prevalence of anti-HBc in different age groups in six regions of Russia.

<p>In the age groups <1 the rate of anti-HBc positivity was significantly higher in Tyva Republic compared to Moscow region, Sverdlovsk region, and Khabarovsk region. In the age groups 1–7 and 8–14 anti-HBc prevalence was significantly higher in Sakha Republic (Yakutia) compared to other regions. In the age groups 15–19, 20–29, 30–39, 40–49, 50–59, and > 60 years anti-HBc rates were significantly higher in Tyva Republic and Sakha Republic (Yakutia).</p

Prevalence of HBsAg in epidemiologically significant cohorts.

<p>These groups are considered to be epidemiologically significant as rates of HBV chronicity depend on the age of infection. In the perinatal infection chronicity of HBV infection occurs in 90% of cases, infection in early childhood—in 30% of cases, infection at the age of 5 years—6% [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0157161#pone.0157161.ref006" target="_blank">6</a>]. Data on the prevalence of HBsAg in these groups needed to work with a mathematical model.</p

Sampling territories (shaded on the map), HBV vaccination coverage of newborn children in 2008, the number of sampled sera.

<p>Vaccination against hepatitis B includes three doses of vaccine. The first dose is administered to newborns in maternity wards in the first 24 hours after birth, the second dose in 1 month, and the third in 6 months.</p