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Highly pathogenic avian influenza A(H5N1) virus was detected in dead seals on Tyuleniy Island in eastern Russia, in the Sea of Okhotsk. Viruses isolated from dead northern fur seals belong to clade 2.3.4.4b and are closely related to viruses detected predominantly in the Russian Far East and Japan in 2022–2023.

A time continuous statistical model of chirp signal observed against the background of stationary Gaussian noise is considered in the paper. Asymptotic normality of the LSE for parameters of such a sinusoidal regression model is obtained.

APOBEC/AID cytidine deaminases play an important role in innate immunity and antiviral defenses and were shown to suppress hepatitis B virus (HBV) replication by deaminating and destroying the major form of HBV genome, covalently closed circular DNA (cccDNA), without toxicity to the infected cells. However, developing anti-HBV therapeutics based on APOBEC/AID is complicated by the lack of tools for activating and controlling their expression. Here, we developed a CRISPR-activation-based approach (CRISPRa) to induce APOBEC/AID transient overexpression (>4–800,000-fold increase in mRNA levels). Using this new strategy, we were able to control APOBEC/AID expression and monitor their effects on HBV replication, mutation, and cellular toxicity. CRISPRa prominently reduced HBV replication (∼90%–99% decline of viral intermediates), deaminated and destroyed cccDNA, but induced mutagenesis in cancer-related genes. By coupling CRISPRa with attenuated sgRNA technology, we demonstrate that APOBEC/AID activation can be precisely controlled, eliminating off-site mutagenesis in virus-containing cells while preserving prominent antiviral activity. This study untangles the differences in the effects of physiologically expressed APOBEC/AID on HBV replication and cellular genome, provides insights into the molecular mechanisms of HBV cccDNA mutagenesis, repair, and degradation, and, finally, presents a strategy for a tunable control of APOBEC/AID expression and for suppressing HBV replication without toxicity.

A multivariate trigonometric regression model is considered. In the paper strong consistency of the least squares estimator for amplitudes and angular frequencies is obtained for such a multivariate model on the assumption that the random noise is a homogeneous or homogeneous and isotropic Gaussian, specifically, strongly dependent random field on ${\mathbb{R}^{M}},M\ge 3$.

CRISPR-Cas9 systems can directly target the hepatitis B virus (HBV) major genomic form, covalently closed circular DNA (cccDNA), for decay and demonstrate remarkable anti-HBV activity. Here, we demonstrate that CRISPR-Cas9-mediated inactivation of HBV cccDNA, frequently regarded as the “holy grail” of viral persistence, is not sufficient for curing infection. Instead, HBV replication rapidly rebounds because of de novo formation of HBV cccDNA from its precursor, HBV relaxed circular DNA (rcDNA). However, depleting HBV rcDNA before CRISPR-Cas9 ribonucleoprotein (RNP) delivery prevents viral rebound and promotes resolution of HBV infection. These findings provide the groundwork for developing approaches for a virological cure of HBV infection by a single dose of short-lived CRISPR-Cas9 RNPs. Blocking cccDNA replenishment and re-establishment from rcDNA conversion is critical for completely clearing the virus from infected cells by site-specific nucleases. The latter can be achieved by widely used reverse transcriptase inhibitors.

Author Juris Jansons requested his exclusion from the authors of the original publication [...]

A time continuous statistical model of multiple chirp signal observed against the background of strongly-dependent stationary Gaussian noise is considered in the paper. Strong consistency of the least squares estimates for such a trigonometric regression model parameters is proved.

The high incidence of epithelial malignancies in HIV-1 infected individuals is associated with co-infection with oncogenic viruses, such as high-risk human papillomaviruses (HR HPVs), mostly HPV16. The molecular mechanisms underlying the HIV-1-associated increase in epithelial malignancies are not fully understood. A collaboration between HIV-1 and HR HPVs in the malignant transformation of epithelial cells has long been anticipated. Here, we delineated the effects of HIV-1 reverse transcriptase on the in vitro and in vivo properties of HPV16-infected cervical cancer cells. A human cervical carcinoma cell line infected with HPV16 (Ca Ski) was made to express HIV-1 reverse transcriptase (RT) by lentiviral transduction. The levels of the mRNA of the E6 isoforms and of the factors characteristic to the epithelial/mesenchymal transition were assessed by real-time RT-PCR. The parameters of glycolysis and mitochondrial respiration were determined using Seahorse technology. RT expressing Ca Ski subclones were assessed for the capacity to form tumors in nude mice. RT expression increased the expression of the E6*I isoform, modulated the expression of E-CADHERIN and VIMENTIN, indicating the presence of a hybrid epithelial/mesenchymal phenotype, enhanced glycolysis, and inhibited mitochondrial respiration. In addition, the expression of RT induced phenotypic alterations impacting cell motility, clonogenic activity, and the capacity of Ca Ski cells to form tumors in nude mice. These findings suggest that HIV-RT, a multifunctional protein, affects HPV16-induced oncogenesis, which is achieved through modulation of the expression of the E6 oncoprotein. These results highlight a complex interplay between HIV antigens and HPV oncoproteins potentiating the malignant transformation of epithelial cells.

Background & Aims: Chronic HCV infection causes cellular stress, fibrosis and predisposes to hepatocarcinogenesis. Mitochondria play key roles in orchestrating stress responses by regulating bioenergetics, inflammation and apoptosis. To better understand the role of mitochondria in the viral life cycle and disease progression of chronic hepatitis C, we studied morphological and functional mitochondrial alterations induced by HCV using productively infected hepatoma cells and patient livers. Methods: Biochemical and imaging assays were used to assess localization of cellular and viral proteins and mitochondrial functions in cell cultures and liver biopsies. Cyclophilin D (CypD) knockout was performed using CRISPR/Cas9 technology. Viral replication was quantified by quantitative reverse-transcription PCR and western blotting. Results: Several HCV proteins were found to associate with mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), the points of contact between the ER and mitochondria. Downregulation of CypD, which is known to disrupt MAM integrity, reduced viral replication, suggesting that MAMs play an important role in the viral life cycle. This process was rescued by ectopic CypD expression. Furthermore, HCV proteins were found to associate with voltage dependent anion channel 1 (VDAC1) at MAMs and to reduce VDAC1 protein levels at MAMs in vitro and in patient biopsies. This association did not affect MAM-associated functions in glucose homeostasis and Ca2+ signaling. Conclusions: HCV proteins associate specifically with MAMs and MAMs play an important role in viral replication. The association between viral proteins and MAMs did not impact Ca2+ signaling between the ER and mitochondria or glucose homeostasis. Whether additional functions of MAMs and/or VDAC are impacted by HCV and contribute to the associated pathology remains to be assessed. Impact and implications: Hepatitis C virus infects the liver, where it causes inflammation, cell damage and increases the long-term risk of liver cancer. We show that several HCV proteins interact with mitochondria in liver cells and alter the composition of mitochondrial subdomains. Importantly, HCV requires the architecture of these mitochondrial subdomains to remain intact for efficient viral replication.

The Earth’s ionosphere experiences forcing from above and below and varies in different periods. We analyzed the dynamics of the ionospheric global and regional electron contents (GEC and REC) in solar cycles 23/24 (SC23/SC24) and the first part of solar cycle 25 (SC25). We considered several methodological issues for GEC calculations and created a tool to compute GEC and made it available through SIMuRG (System for Ionosphere Monitoring and Research from GNSS). The paper shows the asymmetry of GEC dynamics in different solar cycles. The mid-latitude summer evening anomaly disrupted the diurnal REC variation in the Siberian region under solar minima. The mean GEC showed similar dependence on the F10.7 index in SC25 and SC23/SC24. The difference in solar cycles could prevent reliable forecasting for GEC for the next solar cycle. Our model, based on a neural network, could predict GEC dynamics in SC25 accurately when we input the F10.7 index.

Beer ranks third in terms of consumption worldwide, and its technology is constantly being improved and perfected. The boom in craft brewing has led to the production of thousands of new types of beer, but most often without scientific justification of the technological decisions made. This paper discusses the approaches to the modeling of the composition of the malt mixture and the mode of lager beer production. A special cubic simplex-lattice design with two replications was used to model the mixture with three malt types: Pilsner, Caramel Pils and Caramel Munich type 2. Models for the main brewing characteristics, i.e., wort extract and color, as well as models for the biological parameters of the mash, i.e., phenolic compound content and antioxidant potential, were developed using different methods. Multi-objective optimization was carried out and a specific mixture was developed for the production of lager beer. The influence of acidulated malt, lactic acid and CaCl2 additions on the extract yield and malt mash filtration time were established through one-factor experiments. The extract and fermentable sugar yield during individual pauses in the mashing mode was studied with a view to its optimization.

During 2000–2022, a total of 69 of Russia’s 85 administrative regions reported 164,580 hemorrhagic fever with renal syndrome (HFRS) cases, with an annual average rate of 4.9 cases/100,000 population (105 popul.). European Russia reported 162,045 (98.5%) cases in 53/60 regions with 9.7 cases/105 popul. Asian Russia reported 2535 (1.5%) cases in 16/25 regions with 0.6 cases/105 popul. In the same period, Russia reported 668 (0.4%) fatal HFRS cases, and 4030 (2.4%) cases among children under the age of 14 years. Most HFRS cases occurred during autumn and winter. The incidence among rural residents was 6.7 per 105 popul., higher than the urban 4.4 per 105 popul.; however, among HFRS patients, rural and urban residents account for 35% and 65%, respectively. Six hantaviruses, causing HFRS of different clinical severity, were recognized as pathogens: Hantaan (HTNV) and Amur (AMUV) of Orthohantavirus hantanense species, Seoul (SEOV) of Orthohantavirus seoulense species, Puumala (PUUV) of Orthohantavirus puumalaense species, and Kurkino (KURV) and Sochi (SOCV) of Orthohantavirus dobravaense species, with the principal hosts Apodemus agrarius coreae, Apodemus peninsulae, Rattus norvegicus, Myodes glareolus, Apodemus agrarius agrarius, and Sylvaemus ponticus, respectively. It was found that 97.7% of HFRS cases are caused by PUUV, therefore, this virus plays the main role in the HFRS morbidity structure in Russia.

In a continuous time nonlinear regression model the residual correlogram is considered as an estimator of the stationary Gaussian random noise covariance function. For this estimator the functional central limit theorem is proved in the space of continuous functions. The result obtained shows that the limiting sample continuous Gaussian random process coincides with the limiting process in the central limit theorem for standard correlogram of the random noise in the specified regression model.

Knowledge about the distribution of living organisms on Earth is very important for many areas of biological science and understanding of the surrounding world. However, much of the existing distributional data are scattered throughout a multitude of sources, such as taxonomic publications, checklists and natural history collections. And often bring them together is difficult. A very successful attempt to solve this problem is the GBIF project, which allows a huge number of researchers to publish data in one place in a single standard. Our dataset represents a significant addition to the occurrences of amphibians in the Volga, Don riverine basins and adjacent territories.The dataset contains up-to-date information on amphibian occurrences in the Volga river basin and adjacent territories, located most part on the Russian plain of European Russia. Dataset is based on its own studies that were conducted in the years 1996-2020. The dataset consists of 4,627 incident records, all linked to geographical coordinates. A total of 13 amphibian species belonging to 9 genera and 6 families have been registered within the studied territory, although the distribution of amphibian species in this region of Russia has not yet been fully studied. This is especially relevant with the spread of cryptic species that can only be identified using molecular genetic research methods.The main purpose of publishing a database is to make our data available in the global biodiversity system to a wide range of users. The data can be used by researchers, as well as to help the authorities to manage their territory more efficiently.All occurrences are published in GBIF for the first time. Most of the data is stored in field diaries and we would like to make it available to everyone by adding it in the global biodiversity database (GBIF).

An important problem of modern Wi-Fis is the interferences caused by hidden stations active in the same area, or in multihop communications. All these issues significantly degrade the efficiency of the random channel access methods. Recent standardization and research activities are focused on solving coordination problems between various Wi-Fi devices. For example, the ongoing development of Wi-Fi 7 includes a coordinated schedule between the access points as a candidate solution. Consequently, Wi-Fi has many deterministic channel access mechanisms, which schedule channel time in a periodic manner well in advance and, thus, are utilized for streaming QoS sensitive data. However, both random traffic intensity and error-prone nature of the wireless channel complicate choosing such reservation parameters, i.e., the duration and the period of the reserved time intervals, that satisfy QoS requirements while minimizing channel time consumption. This paper introduces a general mathematical framework to solve the problem of choosing appropriate reservations parameters. The comparison of the analytical and simulation results show the high accuracy of the proposed framework. Finally, the paper gives an example of how to use the developed framework to maximize the network capacity.

Because of their high biocompatibility, biological barrier negotiation, and functionalization properties, biological nanoparticles have been actively investigated for many medical applications. Biological nanoparticles, including natural extracellular vesicles (EVs) and synthetic extracellular vesicle–mimetic nanovesicles (EMNVs), represent novel drug delivery vehicles that can accommodate different payloads. In this study, we investigated the physical, biological, and delivery properties of EVs and EMNVs and analyzed their ability to deliver the chemotherapeutic drug doxorubicin. EMNVs and EVs exhibit similar properties, but EMNVs are more effectively internalized, while EVs show higher intracellular doxorubicin release activity. In addition, these nanotherapeutics were investigated in combination with the FDA-approved drug hydroxychloroquine (HCQ). We demonstrate that HCQ-induced lysosome destabilization and could significantly increase nanoparticle internalization, doxorubicin release, and cytotoxicity. Altogether, these data demonstrate that, from the delivery standpoint in vitro, the internalization of EMNVs and EVs and their payload release were slightly different and both nanotherapeutics had comparable cytotoxic performance. However, the synthesis of EMNVs was significantly faster and cost-effective. In addition, we highlight the benefits of combining biological nanoparticles with the lysosome-destabilizing agent HCQ that increased both the internalization and the cytotoxic properties of the particles.

Red blood cells (RBCs) are the most numerous cells in the body and perform gas exchange between all tissues. During the infusion of cancer chemotherapeutic (CT) agents, blood cells are the first ones to encounter aggressive cytostatics. Erythrocyte dysfunction caused by direct cytotoxic damage might be a part of the problem of chemotherapy-induced anemia—one of the most frequent side effects. The aim of the current study is to evaluate the functional status of RBCs exposed to mono and combinations of widely used commercial pharmaceutical CT drugs with different action mechanisms: paclitaxel, carboplatin, cyclophosphamide, and doxorubicin, in vitro. Using laser diffraction, flow cytometry, and confocal microscopy, we show that paclitaxel, having a directed effect on cytoskeleton proteins, by itself and in combination with carboplatin, caused the most marked abnormalities—loss of control of volume regulation, resistance to osmotic load, and stomatocytosis. Direct simulations of RBCs’ microcirculation in microfluidic channels showed both the appearance of a subpopulation of cells with impaired velocity (slow damaged cells) and an increased number of cases of occlusions. In contrast to paclitaxel, such drugs as carboplatin, cyclophosphamide, and doxorubicin, whose main target in cancer cells is DNA, showed significantly less cytotoxicity to erythrocytes in short-term exposure. However, the combination of drugs had an additive effect. While the obtained results should be confirmed in in vivo models, one can envisioned that such data could be used for minimizing anemia side effects during cancer chemotherapy.

This paper aims to adapt the system justification scales (general, political, economic, and gender) for the Russian socio-cultural context and to carry out their psychometric analysis. In Study 1 (N = 450), the original items from four system justification scales on a Russian sample were tested. The results suggested that none of the original scales worked properly in Russia and all of them demonstrated weak fit indices. In Study 2 (N = 553), culturally specific grounds for system justification in the Russian context were highlighted and tested. The results of this study confirmed that all the adapted scales demonstrated a good fit to the data. In Study 3 (N = 1,011), the invariance of system justification scales and the convergent and discriminant validity of the scales was tested. The results confirmed that the general, political, and economic system justification scales demonstrated full invariance, while the gender system justification scale showed partial invariance for multigroup comparison. All the scales convergent and discriminant validity, which leads to consider them as an effective tool for measuring system justification in various types of social relationships in Russia. The role of socio-cultural characteristics in justifying the status quo is discussed.

Photonic-assisted receivers for instantaneous microwave frequency measurement are devices used to measure the instantaneous frequency and amplitude of one or more microwave signals in the optical range, typically used in radar systems. Increasingly higher demands are placed on frequency range, accuracy and resolution during the development of instantaneous microwave frequency measurement applications, and these demands can be satisfied by the creation of new devices and operating principles. To permit further development in this area, it is necessary to generalize the experience gained during the development of devices based on frequency and amplitude discriminators of resonance type, including advanced ones with the best performances. Thus, in this report, we provide an overview of all the basic types of approaches used for the realization of photonic-assisted receivers based on fiber Bragg gratings, integrated Fano and optical ring resonators, Brillouin gain spectrum, and so on. The principles of their operation, as well as their associated advantages, disadvantages, and existing solutions to identified problems, are examined in detail. The presented approaches could be of value and interest to those working in the field of microwave photonics and radar systems, as we propose an original method for choosing photonic-assisted receivers appropriate for the characterization of multiple frequency measurements.

The ongoing epidemic caused by SARS-CoV-2 infection led to the search for fundamentally new ways and means to combat inflammation and other pathologies caused by this virus. Using a cellular model of lipopolysaccharide (LPS)-induced sepsis (human promonocytes), we showed that both a hydrogen sulfide donor (sodium thiosulfate, STS) and a recombinant Heat shock protein 70 (rHsp70) effectively block all major inflammatory mediators when administrated before and after LPS challenge. The protective anti-inflammatory effect of rHsp70 and H2S was also confirmed in vivo using various animal models of pneumonia. Specifically, it was found that rHsp70 injections prevented the development of the acute respiratory distress syndrome in highly pathogenic pneumonia in mice, increased animal survival, and reduced the number of Programmed death-1 (PD-1)-positive T-lymphocytes in peripheral blood. Based on our model experiments we developed a combined two-phase therapeutic approach for the treatment of COVID-19 patients. This procedure includes the inhalation of hot helium–oxygen mixtures for induction of endogenous Hsp70 in the first phase and STS inhalation in the second phase. The use of this approach has yielded positive results in COVID-19 patients, reducing the area of lung lesions, restoring parameters of innate immunity and T-cell immune response against coronavirus infection, and preventing the development of pulmonary fibrosis and immune exhaustion syndrome.

Background and Aims: COVID-19 has infected more than 77 million people worldwide and impacted the lives of many more, with a particularly devastating impact on vulnerable populations, including people with substance use disorders (SUDs). Quarantines, travel bans, regulatory changes, social distancing, and “lockdown” measures have affected drug and alcohol supply chains and subsequently their availability, price, and use patterns, with possible downstream effects on presentations of SUDs and demand for treatment. Given the lack of multicentric epidemiologic studies, we conducted a rapid global survey within the International Society of Addiction Medicine (ISAM) network in order to understand the status of substance-use patterns during the current pandemic.Design: Cross-sectional survey.Setting: Worldwide.Participants: Starting on April 4, 2020 during a 5-week period, the survey received 185 responses from 77 countries.Measurements: To assess addiction medicine professionals' perceived changes in drug and alcohol supply, price, use pattern, and related complications during the COVID-19 pandemic.Findings: Participants reported (among who answered “decreased” or “increased”) a decrease in drug supply (69.0%) and at the same time an increase in price (95.3%) globally. With respect to changes in use patterns, an increase in alcohol (71.7%), cannabis (63.0%), prescription opioids (70.9%), and sedative/hypnotics (84.6%) use was reported, while the use of amphetamines (59.7%), cocaine (67.5%), and opiates (58.2%) was reported to decrease overall.Conclusions: The global report on changes in the availability, use patterns, and complications of alcohol and drugs during the COVID-19 pandemic should be considered in making new policies and in developing mitigating measures and guidelines during the current pandemic (and probable future ones) in order to minimize risks to people with SUD.

Background: The coronavirus disease 2019 (COVID-19) pandemic has impacted people with substance use disorders (SUDs) worldwide, and healthcare systems have reorganized their services in response to the pandemic.Methods: One week after the announcement of the COVID-19 as a pandemic, in a global survey, 177 addiction medicine professionals described COVID-19-related health responses in their own 77 countries in terms of SUD treatment and harm reduction services. The health responses were categorized around (1) managerial measures and systems, (2) logistics, (3) service providers, and (4) vulnerable groups.Results: Respondents from over 88% of countries reported that core medical and psychiatric care for SUDs had continued; however, only 56% of countries reported having had any business continuity plan, and 37.5% of countries reported shortages of methadone or buprenorphine supplies. Participants of 41% of countries reported partial discontinuation of harm-reduction services such as needle and syringe programs and condom distribution. Fifty-seven percent of overdose prevention interventions and 81% of outreach services were also negatively impacted.Conclusions: Participants reported that SUD treatment and harm-reduction services had been significantly impacted globally early during the COVID-19 pandemic. Based on our findings, we highlight several issues and complications resulting from the pandemic concerning people with SUDs that should be tackled more efficiently during the future waves or similar pandemics. The issues and potential strategies comprise the following: (1) helping policymakers to generate business continuity plans, (2) maintaining the use of evidence-based interventions for people with SUDs, (3) being prepared for adequate medication supplies, (4) integrating harm reduction programs with other treatment modalities, and (5) having specific considerations for vulnerable groups such as immigrants and refugees.

IntroductionThe Electronic Health Record (EHR) has become an integral component of healthcare delivery. Survey based studies have estimated that physicians spend 4-6 hours of their workday devoted to EHR. Our study was designed to use computer software to objectively obtain time spent on EHR.MethodsWe recorded EHR time for 248 physiciansover 2 time intervals. EHR active use was defined as more than 15 keystrokes, or 3 mouse clicks, or 1700 "mouse miles" per minute. We recorded total time and % of work hours spent on EHR, and differences in those based on seniority. Physicians reported duty hours using a standardized toolkit.ResultsPhysicians spent 3.8 (±2) hours on EHR daily, which accounted for 37% (±17%), 41% (±14%), and 45% (±12%) of their day for all clinicians, residents, and interns, respectively. With the progression of training, there was a reduction in EHR time (all p values ConclusionsPhysicians spend close to 40% of their work day on EHR, with interns spending the most time. There is a significant reduction in time spent on EHR with training and greater experience, although the overall amount of time spent on EHR remained high.

E-cigarette, or vaping, product use–associated lung injury (EVALI) outbreak was linked to vitamin E acetate (VEA) used as a solvent for tetrahydrocannabinol (THC). Several studies were conducted to assess the products of VEA (and THC/VEA mixtures) thermal degradation as a result of vaporizing/aerosolizing from a traditional type (coil—cotton wick) and ceramic type coil vape pens. The particle size distribution (PSD) of VEA aerosol and the temperature VEA and THC/VEA mixtures are heated to were also measured for a few types of traditional and ceramic vape pens. The current study assessed the PSD of the aerosol generated from THC, VEA, and a number of THC/VEA mixtures using a dab-type vape pen under two different temperature settings and two puffing flow rates. Thermal degradation of THC, VEA, and THC/VEA mixtures were also assessed, and coil temperature was measured. Results showed the dependence of the PSD upon the chemical content of the aerosolized mixture as well as upon the puffing flow rate. Minimal thermal degradation was observed. Flaws in the vape pen’s design, which most likely affected results, were detected. The suitability of VEA, THC, and THC/VEA mixtures with certain types of vape pens was discussed.

The results of the detailed sedimentological study and bed-by-bed collecting of fossils from the Borschovo section exposing the upper Givetian–lower Frasnian boundary beds are discussed. The succession consists of sandstones alternating with argillaceous and clayey packages that contain vertebrate and plant remains in the upper part. The grain size, sedimentary structures and cross-bed orientation considerably differ in the Oredezh Beds and the Staritsa Beds. Fine- to coarse-grained cross-stratified sandstones of the Oredezh Beds most probably are fluvial deposits, whereas the sandstones of the Staritsa Beds yielding tidal structures that show variable directions of the cross-bedding were accumulated in a tidally influenced or even tidally dominated environment. The Oredezh Beds in the study area lack fossils; however, sedimentary features allow correlation with the Sietiņi Formation corresponding to the lower part of the Gauja Regional Stage. The age of the Staritsa Beds is defined based on the distribution of vertebrate taxa as corresponding to the Amata Regional Stage. Probably, the deposits from the Borschovo locality represent the most complete section of the Staritsa Beds, including its lowermost part. Rather good preservation of some thin and fragile fish bones, buried together with large-sized quartz grains, and wide taxonomical diversity, are characteristic of the Borschovo locality, which is not common for the vertebrate localities of the Main Devonian Field corresponding to the Amata Regional Stage.

A microarray-based assay to detect IgG and IgM antibodies against betacoronaviruses (SARS-CoV-2, SARS, MERS, OC43, and HKU1), other respiratory viruses and type I interferons (IFN-Is) was developed. This multiplex assay was applied to track antibody cross-reactivity due to previous contact with similar viruses and to identify antibodies against IFN-Is as the markers for severe COVID-19. In total, 278 serum samples from convalescent plasma donors, COVID-19 patients in the intensive care unit (ICU) and patients who recovered from mild/moderate COVID-19, vaccine recipients, prepandemic and pandemic patients with autoimmune endocrine disorders, and a heterogeneous prepandemic cohort including healthy individuals and chronically ill patients were analyzed. The anti-SARS-CoV-2 microarray results agreed well with the ELISA results. Regarding ICU patients, autoantibodies against IFN-Is were detected in 10.5% of samples, and 10.5% of samples were found to simultaneously contain IgM antibodies against more than two different viruses. Cross-reactivity between IgG against the SARS-CoV-2 nucleocapsid and IgG against the OC43 and HKU1 spike proteins was observed, resulting in positive signals for the SARS-CoV-2 nucleocapsid in prepandemic samples from patients with autoimmune endocrine disorders. The presence of IgG against the SARS-CoV-2 nucleocapsid in the absence of IgG against the SARS-CoV-2 spike RBD should be interpreted with caution.

Hybrid vehicles are now more common in response to increasing global warming. The hybridization of energy sources and energy storage units enables improving the sustainability, reliability, and robustness of power systems. To reach the objective of zero emissions, a proton exchange membrane hydrogen fuel-cell was utilized as an energy source. The aim of this research was to create an accurate optimal sizing procedure for determining the nominal rating of the necessary sources. We modeled the fuel cell and the battery pack using data from real experimental results to create the generic database. Then, we added data on the mission profile, system constraints, and the minimization target function. The mission profile was then analyzed by the sizing algorithm to determine optional minimum and maximum fuel cell ratings. Analyzing the optional solutions using the vehicle real time energy management system controller resulted in a set of solutions for each available rated fuel cell, and the optimal compatible battery in the revealed band successfully accomplished the route of the driving cycle within the system limitations. Finally, the Pareto curve represented the optimal finding of the sizing procedure. Ultimately, in contrast to previous works that utilize gross manufacturer data in the sizing procedure, the main research contribution and novelty of this research is the very accurate sizing results, which draw on real experimental-based fuel-cell and battery sizing models. Moreover, the actual vehicle real time energy management system controllers were used in the sizing procedure.

Abstract Background In multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), inflammation is perpetuated by both infiltrating leukocytes and astrocytes. Recent work implicated SUR1-TRPM4 channels, expressed mostly by astrocytes, in murine EAE. We tested the hypothesis that pharmacological inhibition of SUR1 during the chronic phase of EAE would be beneficial. Methods EAE was induced in mice using myelin oligodendrocyte glycoprotein (MOG) 35–55. Glibenclamide (10 μg/day) was administered beginning 12 or 24 days later. The effects of treatment were determined by clinical scoring and tissue examination. Drug within EAE lesions was identified using bodipy-glibenclamide. The role of SUR1-TRPM4 in primary astrocytes was characterized using patch clamp and qPCR. Demyelinating lesions from MS patients were studied by immunolabeling and immunoFRET. Results Administering glibenclamide beginning 24 days after MOG35–55 immunization, well after clinical symptoms had plateaued, improved clinical scores, reduced myelin loss, inflammation (CD45, CD20, CD3, p65), and reactive astrocytosis, improved macrophage phenotype (CD163), and decreased expression of tumor necrosis factor (TNF), B-cell activating factor (BAFF), chemokine (C-C motif) ligand 2 (CCL2) and nitric oxide synthase 2 (NOS2) in lumbar spinal cord white matter. Glibenclamide accumulated within EAE lesions, and had no effect on leukocyte sequestration. In primary astrocyte cultures, activation by TNF plus IFNγ induced de novo expression of SUR1-TRPM4 channels and upregulated Tnf, Baff, Ccl2, and Nos2 mRNA, with glibenclamide blockade of SUR1-TRPM4 reducing these mRNA increases. In demyelinating lesions from MS patients, astrocytes co-expressed SUR1-TRPM4 and BAFF, CCL2, and NOS2. Conclusions SUR1-TRPM4 may be a druggable target for disease modification in MS.

A series of 15 benzene-fused hexahydropyrrolo[1,2-b]isoquinolonic acids with substantial degree of steric encumbrance has been prepared via a novel variant of the Castagnoli–Cushman reaction of homophthalic anhydride (HPA) and various indolenines. The employment of a special kind of a cyclic imine component reaction allowed, for the first time, isolating a Mannich-type adduct between HPA and an imine component which has been postulated but never obtained in similar reactions.

Purpose. To develop the fuzzy model of distribution of excess regenerative energy in traction and external power supply systems allowing to exercise effective operation of the power equipment. Relevance. For effective distribution of excess regenerative energy in systems of electric transport, as well as for systems equipped with stationary stores of energy and inverting traction substations with regulators of output voltage it is necessary to solve a number of the problems with high degree of uncertainty demanding taking into account a set of random factors such as the modes of power lines and traction loadings. These factors have to be considered in operation for choosing the rational modes of energy stores, inverters and regulators of voltage on buses of substations to provide the rational conditions for energy regeneration on electric transport. Scientific novelty. The control system of energy storage devices, inverters and traction substation output voltage regulators, designed on the basis of fuzzy logic, can provide the necessary conditions for the regeneration on electric transport on sections with a shortage of traction power consumption and allows to optimize the distribution of excess braking energy of transport vehicles. It is achieved by determining the rational relationship between the components of the excess current of regeneration in real time, which can ensure a minimum of power losses of regenerative energy in traction and external power supply systems. Practical importance. The use of the developed approach is effective under the conditions of incomplete information received by measurement systems and on the basis of additional studies it can allow to minimize rated capacity of stores, inverters and traction substation output voltage regulators that could reduce the costs of modernization of existing sections and electrification of new electric transport systems.

It is shown that in any metric compact space X there exists a countable closed subset F whose upper capacitarian dimension dimBF is equal to any preassigned non-negative number not exceeding the upper capacitarian dimension of X. A similar assertion is proved for the upper order of the metric approximation ord(ξ) of maximal linked systems. Namely, for any number a satisfying the inequalities 0 a dimBX there exists ξ ∈ λ(X) for which ord(ξ) = a and supp(ξ) = X.

Global polio eradication requires both safe and effective vaccines, and safe production processes. Sabin oral poliomyelitis vaccine (OPV) strains can evolve to virulent viruses and result in poliomyelitis outbreaks, and conventional inactivated poliomyelitis vaccine (Salk-IPV) production includes accumulation of large stocks of neurovirulent wild polioviruses. Therefore, IPV based on attenuated OPV strains seems a viable option. To increase the global supply of affordable inactivated vaccine in the still not-polio free world we developed an IPV made from the Sabin strains–PoliovacSin. Clinical trials included participants 18–60 years of age. A phase I single-center, randomized, double-blind placebo-controlled clinical trial included 60 participants, who received one dose of PoliovacSin or Placebo. A phase II multicenter, randomized, double-blind, comparative clinical trial included 200 participants, who received one dose of PoliovacSin or Imovax Polio. All vaccinations were well tolerated, and PoliovacSin had a comparable safety profile to the Placebo or the reference Imovax Polio preparations. A significant increase in neutralizing antibody levels to polioviruses types 1–3 (Sabin and wild) was observed in PoliovacSin and Imovax Polio vaccinated groups. Therefore, clinical trials confirmed good tolerability, low reactogenicity, and high safety profile of the PoliovacSin and its pronounced immunogenic properties. The preparation was approved for clinical trials involving infants.

Abstract Infantile soft tissue tumors of the head are very rare and the majority of them are myofibromas. The authors present the case of a 1-day-old boy with a scalp tumor with several distinct histopathological features including myofibroma, hemangiopericytoma, and fibrosarcoma consistent with the diagnosis of composite infantile myofibromatosis. Genetic testing was negative for trisomy 17, translocation (12; 15), FUS, and ETV6 translocations. Despite the ominous histopathological features, the clinical course was benign. The authors review here available literature concerning current concepts of making the diagnosis of composite infantile myofibromatosis and discuss treatment options.

Endothelial dysfunction is recognized as one of the leading factors in the pathogenesis of diseases of the central nervous system of various etiologies. Numerous studies have shown the role of hyperhomocysteinemia in the development of endothelial dysfunction and the prothrombogenic state. The most important condition in the development of multiple sclerosis (MS) is a dysregulation of the blood-brain barrier (BBB) and transendothelial leukocyte migration. It has been proven that homocysteine also contributes to the damage of neurons by the mechanism of excitotoxicity and the induction of the apoptosis of neurons. These processes can be one of the factors of neurodegenerative brain damage, which plays a leading role in the progression of MS. This review describes the pleiotropic effect of homocysteine on these processes and its role in MS pathogenesis.

Minerals from mantle xenoliths in the Zapolyarnaya pipe in the Upper Muna field, Russia and from mineral separates from other large diamondiferous kimberlite pipes in this field (Deimos, Novinka and Komsomolskaya-Magnitnaya) were studied with EPMA and LA-ICP-MS. All pipes contain very high proportions of sub-calcic garnets. Zapolyarnaya contains mainly dunitic xenoliths with veinlets of garnets, phlogopites and Fe-rich pyroxenes similar in composition to those from sheared peridotites. PT estimates for the clinopyroxenes trace the convective inflection of the geotherm (40–45 mW·m−2) to 8 GPa, inflected at 6 GPa and overlapping with PT estimates for ilmenites derived from protokimberlites. The Upper Muna mantle lithosphere includes dunite channels from 8 to 2 GPa, which were favorable for melt movement. The primary layering deduced from the fluctuations of CaO in garnets was smoothed by the refertilization events, which formed additional pyroxenes. Clinopyroxenes from the Novinka and Komsomolskaya-Magnitnaya pipes show a more linear geotherm and three branches in the P-Fe# plot from the lithosphere base to the Moho, suggesting several episodes of pervasive melt percolation. Clinopyroxenes from Zapolyarnaya are divided into four groups according to thermobarometry and trace element patterns, which show a stepwise increase of REE and incompatible elements. Lower pressure groups including dunitic garnets have elevated REE with peaks in Rb, Th, Nb, Sr, Zr, and U, suggesting mixing of the parental protokimberlitic melts with partially melted metasomatic veins of ancient subduction origin. At least two stages of melt percolation formed the inclined PT paths: (1) an ancient garnet semi-advective geotherm (35–45 mW·m−2) formed by volatile-rich melts during the major late Archean event of lithosphere growth; and (2) a hotter megacrystic PT path (Cpx-Ilm) formed by feeding systems for kimberlite eruptions (40–45 mW·m−2). Ilmenite PT estimates trace three separate PT trajectories, suggesting a multistage process associated with metasomatism and formation of the Cpx-Phl veinlets in dunites. Heating associated with intrusions of protokimberlite caused reactivation of the mantle metasomatites rich in H2O and alkali metals and possibly favored the growth of large megacrystalline diamonds.

This work is devoted to studying the accumulation of hydrogen in titanium coatings to use a completely new concept of hydrogen accumulators based on a system of easily replaceable cartridges. Modern hydrogen accumulators based on magnesium powder have several problems associated with uneven heating during hydrogen desorption. Increasing the efficiency of hydrogen accumulators and the possibility of their reuse and/or repair remains a topical problem. For the analysis of the microstructure of the received titanium coatings, scanning electron microscopy (SEM) was used, the structural-phase state was studied using x-ray diffraction (XRD) analysis. The coatings were hydrogenation by gas-phase saturation at 450–550 °C. Increased film thickness reduced the storage capacity of coatings. Besides hydrogenation at 450 °C, 20 µm of titanium coatings accumulated 3.96 wt.%, while 80 µm of coatings accumulated 3.98 wt.%. The chemical composition of the coatings before and after the hydrogenation was controlled using glow-discharge optical emission spectroscopy.

Telomerase reverse transcriptase (TERT) is a classic tumor-associated antigen overexpressed in majority of tumors. Several TERT-based cancer vaccines are currently in clinical trials, but immune correlates of their antitumor activity remain largely unknown. Here, we characterized fine specificity and lytic potential of immune response against rat TERT in mice. BALB/c mice were primed with plasmids encoding expression-optimized hemagglutinin-tagged or nontagged TERT or empty vector and boosted with same DNA mixed with plasmid encoding firefly luciferase (Luc DNA). Injections were followed by electroporation. Photon emission from booster sites was assessed by in vivo bioluminescent imaging. Two weeks post boost, mice were sacrificed and assessed for IFN-γ, interleukin-2 (IL-2), and tumor necrosis factor alpha (TNF-α) production by T-cells upon their stimulation with TERT peptides and for anti-TERT antibodies. All TERT DNA-immunized mice developed cellular and antibody response against epitopes at the N-terminus and reverse transcriptase domain (rtTERT) of TERT. Photon emission from mice boosted with TERT/TERT-HA+Luc DNA was 100 times lower than from vector+Luc DNA-boosted controls. Bioluminescence loss correlated with percent of IFN-γ/IL-2/TNF-α producing CD8+ and CD4+ T-cells specific to rtTERT, indicating immune clearance of TERT/Luc-coexpressing cells. We made murine adenocarcinoma 4T1luc2 cells to express rtTERT by lentiviral transduction. Expression of rtTERT significantly reduced the capacity of 4T1luc2 to form tumors and metastasize in mice, while not affecting in vitro growth. Mice which rejected the tumors developed T-cell response against rtTERT and low/no response to the autoepitope of TERT. This advances rtTERT as key component of TERT-based therapeutic vaccines against cancer.

Sphingomyelins (SMs) are a class of relevant bioactive molecules that act as key modulators of different cellular processes, such as growth arrest, exosome formation, and the inflammatory response influenced by many environmental conditions, leading to pyroptosis, a form of programmed cell death due to Caspase-1 involvement. To study liver pyroptosis and hepatic SM metabolism via both lysosomal acid SMase (aSMase) and endoplasmic reticulum/nucleus neutral SMase (nSMase) during the exposure of mice to radiation and to ascertain if this process can be modulated by protective molecules, we used an experimental design (previously used by us) to evaluate the effects of both ionizing radiation and a specific protective molecule (rMnSOD) in the brain in collaboration with the Joint Institute for Nuclear Research, Dubna (Russia). As shown by the Caspase-1 immunostaining of the liver sections, the radiation resulted in the loss of the normal cell structure alongside a progressive and dose-dependent increase of the labelling, treatment, and pretreatment with rMnSOD, which had a significant protective effect on the livers. SM metabolic analyses, performed on aSMase and nSMase gene expression, as well as protein content and activity, proved that rMnSOD was able to significantly reduce radiation-induced damage by playing both a protective role via aSMase and a preventive role via nSMase.

The optical vector analyzer is a device used to measure the magnitude, phase responses, and other parameters of optical devices. There have been increasingly higher demands placed on optical vector analyzers during the development of optical technologies, which are satisfied by the creation of new devices and their operating principles. For further development in this area, it is necessary to generalize the experience gained during the development of optical vector analyzers. Thus, in this report, we provide an overview of all the basic types of approaches used for the realization of optical vector analyzers, including the advanced ones with the best performances. The principles of their working, as well as their associated advantages, disadvantages, and existing solutions to the identified problems, are examined in detail. The presented approaches could be of value and interest to those working in the field of laser dynamics and optical devices, as we propose one use of the optical vector analyzer as being the characterization of Fano resonance structures.

The fungus, Alternaria sonchi is considered to be a potential agent for the biocontrol of perennial sowthistle (Sonchus arvensis). A new chlorinated xanthone, methyl 8-hydroxy-3-methyl-4-chloro-9-oxo-9H-xanthene-1-carboxylate (1) and a new benzophenone derivative, 5-chloromoniliphenone (2), were isolated together with eleven structurally related compounds (3−13) from the solid culture of the fungus, which is used for the production of bioherbicidal inoculum of A. sonchi. Their structures were determined by spectroscopic (mostly by NMR and MS) methods. Alternethanoxins A and B, which were reported in A. sonchi earlier, were re-identified as moniliphenone and pinselin, respectively. The isolated compounds were tested for phytotoxic, antimicrobial, insecticidal, cytotoxic and esterase-inhibition activities. They did not demonstrate high phytotoxicity (lesions up to 2.5 mm in diameter/length at a concentration of 2 mg/mL) when tested on leaf disks/segments of perennial sowthistle (Sonchus arvensis) and couch grass (Elytrigia repens). They did not possess acute toxicity to Paramecium caudatum, and showed moderate to low cytotoxicity (IC50 > 25 µg/mL) for U937 and K562 tumor cell lines. However, chloromonilicin and methyl 3,8-dihydroxy-6-methyl-4-chloro-9-oxo-9H-xanthene-1-carboxylate (4) were shown to have antimicrobial properties with MIC 0.5−5 µg/disc. Compound 4 and chloromonilinic acid B were found to have contact insecticidal activity to wheat aphid (Schizaphis graminum) at 1 mg/mL. Compounds 2 and methyl 3,8-dihydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate displayed selective carboxylesterase inhibition activity at concentration of 100 µg/mL. Therefore, the waste solid substrate for production of A. sonchi spores can be re-utilized for the isolation of a number of valuable natural products.

Background/objectivesPrevious studies have demonstrated that in acute coronary syndrome (ACS), plaque destabilization and vessel inflammation, represented by vessel edema, often occur simultaneously in multiple coronaries, as well as extend to the cerebrovascular system. Our aim was to determine whether the inflammatory vascular processes occurring within the coronaries during ACS extend simultaneously to the descending aorta.MethodsWe prospectively enrolled 111 patients (56 ACS patients and 55 non-ACS patients with known coronary artery disease) to undergo cardiac magnetic resonance of the thoracic aortic wall at presentation and at three-month follow-up. The primary outcome was change in aortic wall area (AWA) and maximal aortic wall thickness (AWT) from baseline to three-month follow-up. Secondary outcomes were baseline and follow-up differences in AWA and AWT, and changes in C-reactive protein (CRP).ResultsThere was a significant reduction in mean AWA (p = 0.01) and AWT (p = 0.01) between index and follow up scans in ACS group, with no significant changes in non ACS group (both p>0.1) and no difference between ACS and non-ACS groups (p = 0.22). There was no significant difference in AWA and AWT at baseline (p>0.36) and follow-up (p>0.2) between groups. There was a significant reduction in CRP in both groups (pConclusionsThere was a reduction in aortic wall size, aortic wall area, and aortic wall thickness in patients presenting with ACS, and no change in non-ACS patients. There were no interval between-group differences in these measurements. We observed a reduction in C-reactive protein in both groups, with higher reduction noted in ACS patients.

BACKGROUND:Hemorrhagic transformation is a major complication of ischemic stroke, is linked to matrix metalloproteinase-9 (MMP-9), and is exacerbated by tissue plasminogen activator (tPA). Cerebral ischemia/reperfusion is characterized by SUR1-TRPM4 (sulfonylurea receptor 1-transient receptor potential melastatin 4) channel upregulation in microvascular endothelium. In humans and rodents with cerebral ischemia/reperfusion (I/R), the SUR1 antagonist, glibenclamide, reduces hemorrhagic transformation and plasma MMP-9, but the mechanism is unknown. We hypothesized that tPA induces protease activated receptor 1 (PAR1)-mediated, Ca2+-dependent phasic secretion of MMP-9 from activated brain endothelium, and that SUR1-TRPM4 is required for this process. METHODS:Cerebral I/R, of 2 and 4 hours duration, respectively, was obtained using conventional middle cerebral artery occlusion. Immunolabeling was used to quantify p65 nuclear translocation. Murine and human brain endothelial cells (BEC) were studied in vitro, without and with NF-κB activation, using immunoblot, zymography and ELISA, patch clamp electrophysiology, and calcium imaging. Genetic and pharmacological manipulations were used to identify signaling pathways. RESULTS:Cerebral I/R caused prominent nuclear translocation of p65 in microvascular endothelium. NF-κB-activation of BEC caused de novo expression of SUR1-TRPM4 channels. In NF-κB-activated BEC: (i) tPA caused opening of SUR1-TRPM4 channels in a plasmin-, PAR1-, TRPC3- and Ca2+-dependent manner; (ii) tPA caused PAR1-dependent secretion of MMP-9; (iii) tonic secretion of MMP-9 by activated BEC was not influenced by SUR1 inhibition; (iv) phasic secretion of MMP-9 induced by tPA or the PAR1-agonist, TFLLR, required functional SUR1-TRPM4 channels, with inhibition of SUR1 decreasing tPA-induced MMP-9 secretion. CONCLUSIONS:tPA induces PAR1-mediated, SUR1-TRPM4-dependent, phasic secretion of MMP-9 from activated brain endothelium.

Over the past three decades, industry sponsored research expanded in the United States. Financial incentives can lead to potential conflicts of interest (COI) resulting in underreporting of negative study results.We hypothesized that over the three decades, there would be an increase in: a) reporting of conflict of interest and source of funding; b) percentage of randomized control trials c) number of patients per study and d) industry funding.Original articles published in three calendar years (1988, 1998, and 2008) in The Lancet, New England Journal of Medicine and Journal of American Medical Association were collected.Studies were reviewed and investigational design categorized as prospective and retrospective clinical trials. Prospective trials were categorized into randomized or non-randomized and single-center or multi-center trials. Retrospective trials were categorized as registries, meta-analyses and other studies, mostly comprising of case reports or series. Study outcomes were categorized as positive or negative depending on whether the pre-specified hypothesis was met. Financial disclosures were researched for financial relationships and profit status, and accordingly categorized as government, non-profit or industry sponsored. Studies were assessed for reporting COI.1,671 original articles were included in this analysis. Total number of published studies decreased by 17% from 1988 to 2008. Over 20 year period, the proportion of prospective randomized trials increased from 22 to 46% (p < 0.0001); whereas the proportion of prospective non-randomized trials decreased from 59% to 27% (p < 0.001). There was an increase in the percentage of prospective randomized multi-center trials from 11% to 41% (p < 0.001). Conversely, there was a reduction in non-randomized single-center trials from 47% to 10% (p < 0.001). Proportion of government funded studies remained constant, whereas industry funded studies more than doubled (17% to 40%; p < 0.0001). The number of studies with negative results more than doubled (10% to 22%; p

Reverse transcriptase (RT) is a key enzyme in viral replication and susceptibility to ART and a crucial target of immunotherapy against drug-resistant HIV-1. RT induces oxidative stress which undermines the attempts to make it immunogenic. We hypothesized that artificial secretion may reduce the stress and make RT more immunogenic. Inactivated multidrug-resistant RT (RT1.14opt-in) was N-terminally fused to the signal providing secretion of NS1 protein of TBEV (Ld) generating optimized inactivated Ld-carrying enzyme RT1.14oil. Promotion of secretion prohibited proteasomal degradation increasing the half-life and content of RT1.14oil in cells and cell culture medium, drastically reduced the residual polymerase activity, and downmodulated oxidative stress. BALB/c mice were DNA-immunized with RT1.14opt-in or parental RT1.14oil by intradermal injections with electroporation. Fluorospot and ELISA tests revealed that RT1.14opt-in and RT1.14oil induced IFN-γ/IL-2, RT1.14opt-in induced granzyme B, and RT1.14oil induced perforin production. Perforin secretion correlated with coproduction of IFN-γ and IL-2 (R=0,97). Both DNA immunogens induced strong anti-RT antibody response. Ld peptide was not immunogenic. Thus, Ld-driven secretion inferred little change to RT performance in DNA immunization. Positive outcome was the abrogation of polymerase activity increasing safety of RT-based DNA vaccines. Identification of the molecular determinants of low cellular immunogenicity of RT requires further studies.

BACKGROUND:Right Atrial Volume Index (RAVI) measured by echocardiography is an independent predictor of morbidity in patients with heart failure (HF) with reduced ejection fraction (HFrEF). The aim of this study is to evaluate the predictive value of RAVI assessed by cardiac magnetic resonance (CMR) for all-cause mortality in patients with HFrEF and to assess its additive contribution to the validated Meta-Analysis Global Group in Chronic heart failure (MAGGIC) score. METHODS AND RESULTS:We identified 243 patients (mean age 60 ± 15; 33% women) with left ventricular ejection fraction (LVEF) ≤ 35% measured by CMR. Right atrial volume was calculated based on area in two- and four -chamber views using validated equation, followed by indexing to body surface area. MAGGIC score was calculated using online calculator. During mean period of 2.4 years 33 patients (14%) died. The mean RAVI was 53 ± 26 ml/m2; significantly larger in patients with than without an event (78.7±29 ml/m2 vs. 48±22 ml/m2, p

New teeth belonging to Karksiodus mirus Ivanov & Märss (Chondrichthyes) were found together with putative chondrichthyan scales in five new localities of the Leningrad Region, northwestern Russia, within the Aruküla and Burtnieki regional stages, Givetian, Middle Devonian. The teeth exhibit variability in the number of cusps, angles between the lateral cusps, base curvature, length of lateral parts and the prominence of the wall of the transversal basal canal. Karksiodus tooth material collected from these sites suggests that this taxon possesses an heterodont dentition and a specific, complex vascularization system affecting the dental base and the crown. Enameloid tissue seems to be absent, thus the surface striations on the cusps are presumably made up by orthodentine. The fish fauna from these localities is listed.

Studies on the relationship between reactive oxygen species (ROS)/manganese superoxide dismutase (MnSOD) and sphingomyelinase (SMase) are controversial. It has been demonstrated that SMase increases the intracellular ROS level and induces gene expression for MnSOD protein. On the other hand, some authors showed that ROS modulate the activation of SMase. The human recombinant manganese superoxide dismutase (rMnSOD) exerting a radioprotective effect on normal cells, qualifies as a possible pharmaceutical tool to prevent and/or cure damages derived from accidental exposure to ionizing radiation. This study aimed to identify neutral SMase (nSMase) as novel molecule connecting rMnSOD to its radiation protective effects. We used a new, and to this date, unique, experimental model to assess the effect of both radiation and rMnSOD in the brain of mice, within a collaborative project among Italian research groups and the Joint Institute for Nuclear Research, Dubna (Russia). Mice were exposed to a set of minor γ radiation and neutrons and a spectrum of neutrons, simulating the radiation levels to which cosmonauts will be exposed during deep-space, long-term missions. Groups of mice were treated or not-treated (controls) with daily subcutaneous injections of rMnSOD during a period of 10 days. An additional group of mice was also pretreated with rMnSOD for three days before irradiation, as a model for preventive measures. We demonstrate that rMnSOD significantly protects the midbrain cells from radiation-induced damage, inducing a strong upregulation of nSMase gene and protein expression. Pretreatment with rMnSOD before irradiation protects the brain with a value of very high nSMase activity, indicating that high levels of activity might be sufficient to exert the rMnSOD preventive role. In conclusion, the protective effect of rMnSOD from radiation-induced brain damage may require nSMase enzyme.

Teeth of a new elasmobranch Karksiodus mirus gen. et sp. nov. were discovered on two levels in the sandstones of the Karksi outcrop (South Estonia), corresponding to the Härma Beds, lower part of the Burtnieki Regional Stage (Givetian, Middle Devonian). These teeth differ from all known Palaeozoic elasmobranch teeth in the presence of a unique wide transversal tube-shaped basal canal, in very fine and dense striation of cusps and in an arched base without well-developed extensions. The order and family of this taxon are notspecified.