Sexually dimorphic interplay between anxiety-related phenotype and fear memory extinction

Ability to efficiently extinguish fear memories is critical for individual well-being, and extinction impairments are commonly observed in a variety of neuropsychiatric conditions. Efficient extinction is also a critical component of exposure therapy, the most widely utilized form of treatment for anxiety and trauma/stressor-related disorders. While individual as well as sex-related differences in extinction are recognized, their neurobiological underpinnings remain unclear. To examine neurobehavioral and molecular features that may contribute to the efficacy of fear memory extinction in genetically similar subjects raised in the same conditions, extinction learning was analyzed in the cohorts of inbred wild-type male and female mice. We showed that unlike memory acquisition, anxiety status of the animals appeared to significantly influence extinction. Interestingly, the effect was sex-specific: the level of anxiety-related behavior inversely correlated with extinction efficacy in male mice only. Significant difference in hippocampal expression of anxiolytic Corticotropin Releasing Hormone Receptor 2 (CRHR2) between the male, but not female animals differing in extinction efficacy, suggests that CRHR2 may serve as a key factor underlying sexually dimorphic interplay between anxiety and fear memory extinction. Our results emphasize the need for tailoring treatment strategies for anxiety and fear-related disorders in accordance with the patient sex and identify specific neurobehavioral and molecular features potentially important for such adjustments.Significance StatementFear memory extinction is a gradual diminishment of fear due to the learning that previously fearful context is now safe. Impaired or inefficient extinction has long been associated with anxiety and trauma/stressor-related disorders. Despite strong interest in therapeutic extinction enhancement, the progress has been limited due to insufficient understanding of the mechanisms regulating extinction efficacy and, especially, their sex-related features. This study showed notable sex differences in relation between fear memory extinction and anxiety-related behavior and identified likely molecular underpinnings of such differences. These findings should significantly improve our understanding of neurobehavioral and molecular factors regulating extinction. Furthermore, they could contribute to novel strategies of extinction augmentation and predictive assessments of extinction efficacy in accordance with the subject’s sex.

THE PROCESS OF RELIGIOLIZATION IN MODERN KAZAKHSTAN: SPECIFICS AND TRENDS

Kazakhstan as the middle country of Eurasia experiences deterministic influences on the course of a number of societal processes including religious ones. Sovereign development turned out to be synchronized with deideologization which replaced it with re-deideologization, the transformation of ideological identity. The dilemma of secularity / religiosity is manifested ambivalently, the number of explicit and non-obvious supporters of the transition to religious statehood is increasing. Religiosity appears to be procedural rather than spontaneously functioning. The risks associated with the loss of intellectual potential, distancing from the traditions of ethno-confessional identity, the growing influence of quasi-religious archaization, decrease in national competitiveness are increasing. Religiolization of Kazakhstani society is a new trend, manifests itself as a tendency for the interaction of non-religious and religious content of life, has an impact on the development of society, the state and dynamics of changes in human capital. Systematic interdisciplinary studies of the process reveal its philosophical, sociological, political, religious, psychological and legal dimensions. Accordingly, the processes of religiolization can be effectively studied through monitoring, analysis, reconstruction, conceptualization, modeling, predictive assessments and the development of scientific and practical recommendations for actors of state and political administration. The article examines the concepts of the process of religiolization of the Kazakhstani society with a focus on the political dimension.

Real-world overall survival (OS) and time to therapy discontinuation (TTD) of patients (pts) with mCRPC treated with second-generation novel hormonal therapies (NHT) associated with tissue-based comprehensive genomic profiling (CGP).

142 Background: Robust biomarkers for personalization of NHT treatment decisions remains an unmet need. Most assessments of candidate biomarkers to predict NHT resistance have been conducted in clinical trials or academic centers, meriting additional validation in diverse community settings. We sought to correlate real-world outcomes on NHT with comprehensive genomic profiling (CGP)-reported alterations, hypothesizing that AR amplification ( ARamp) and deleterious genomic alterations (GAs) in BRCA2, PTEN, RB1, TP53 would correlate with worse outcomes on NHT. Methods: Following a prespecified analysis plan, pts were selected from Flatiron Health (FH)-Foundation Medicine (FMI) clinico-genomic database (CGDB), a nationwide deidentified electronic health record database linked to FMI CGP. Inclusion criteria: mCRPC diagnosis, treatment in FH network and CGP result between 1/1/11-3/30/20 where tissue collected prior to initiation of first line (1L) or second (2L) NHT (within 180 days for ARamp +/- comparison). A priori power analyses were conducted. Adjusted hazard ratios (aHR) from multivariable Cox proportional hazard models were utilized for TTD and OS comparisons from start of NHT including: GA groups, adjusted for age, line number, practice type, and left truncation. Results: Among 1626 evaluable pts, 397 received 1L (n = 287; 72%) or 2L (n = 110; 28%) NHT with majority treated in community setting (n = 297; 75%). Abiraterone (n = 242; 61%) and enzalutamide (n = 145; 39%) were most common NHTs. Incidence: ARamp (15%) and deleterious GA in TP53 (45%), PTEN (28%), RB1 (3%), and BRCA2 (8%). Cohort was strongly powered to assess TP53 & PTEN, moderately for ARamp & BRCA2, weakly for RB1. As hypothesized, ARamp correlated with worse TTD (aHR: 3.37 [1.26-9.0]) and OS (aHR: 4.92 [1.47-16.5]). BRCA2 GA correlated with improved OS (aHR: 0.41 [0.21-0.81]), but no differences in TTD (aHR: 1.25 [0.82-1.9]). RB1 GA had trends for worse OS (aHR: 2.0 [0.93-4.28]) and worse TTD (aHR – 1.41 [0.72-2.8]). TP53 GA had worse OS (aHR: 1.47 [1.1-2.0]), but no difference in TTD (aHR: 1.08 [0.85-1.4]), and PTEN GA did not correlate with TTD (aHR: 0.94 [0.72-1.2]) or OS (aHR: 1.01 [0.74-1.38]). Conclusions: ARamp is associated with worse TTD and OS in mCRPC pts treated with NHT in real-world, mostly community practice, consistent with prior academic center studies and trials data. Surprisingly, BRCA2 GA correlated with improved OS but not TTD. RB1 GA were directionally consistent with prior studies but underpowered. This study supports using CGP to inform decisions for escalation of non-NHT treatment use in conjunction with patient goals and predictive CGP biomarkers for other drugs. Additional biomarkers, multivariable models and, NHT vs taxane chemo predictive assessments will be reported at symposium.

Hydrogeological Earthquake Precursors: A Case Study From the Kamchatka Peninsula

The relevance of hydrogeological precursors (HGPs) study is justified by the need to obtain reliable information about the spatio-temporal manifestations and the relationships of HGPs with the parameters of subsequent earthquakes for seismic forecasting. In the review the data on repeated manifestations of HGPs before strong earthquakes obtained from long-term observations in five deep wells on the Kamchatka Peninsula (Far East of Russia) are presented. The analysis of the correlation of HGPs occurring in several wells is carried out in comparison with earthquake parameters characterizing both earthquake sources (magnitude, linear size of the source) and the impact of earthquakes in the area of wells (specific energy density in wave, intensity of shaking). It is shown that the manifestation of HGPs in several wells is observed before earthquakes with Mw = 6.6–7.8 at epicentral distances up to the first hundreds of km to observation wells in the near and intermediate zones of the sources with the ratio of the epicentral distances and the source sizes no more than 1–5. A feature of our study was the use of certain types of HGPs in water-level changes for predictive assessments of the strong earthquakes in the Kamchatka Peninsula. The review presents precursors in water-level changes detected in real time and the corresponding earthquake forecasts, which were recognized as successful according to the conclusions of the expert council on earthquake prediction.

Components of the Increment Dynamics of Early and Late Wood of Quercus robur Stem in the Upland Oak Forest of the Southern Forest-Steppе

The stem radial increment contains information on the tree growth, development, and condition. The early and late wood increment has essential features. The increment dynamics contains monotonous and cyclic components. Retrospective and predictive assessments of growth and development of a tree and a stand based on the patterns of radial increment are possible. The purpose of the article is to analyze the properties of the components and their contribution to the increment dynamics of oak early and late wood, depending on the favorability of growth period and the crown development. The research object was the artificial upland oak forest of the first quality class (pure in composition). Two periods of growth were considered: 1st – favorable (1968–1996) and 2nd – unfavourable (1997–2014). We studied three groups of oak, each group of 10 trees. The groups were distinguished by the development of crown (original classification) and its dynamics. The stem cores were taken at a height of 1.3 m from the southeast side. Indicators of radial increment were defined in the images of cores scanned at 1200 dpi resolution. Three components of the dynamics were identified: a long-term trend and cyclic components with 12- and 2–5-year cycles. The variability of cyclic components of the dynamics of early wood increment was more than twice lower, than that of the late wood. The contribution of the component with 2–5-year cyclicity to the dynamics of early and late wood increment prevails during the favorable period of growth. The contribution of the component with 12-year cyclicity increases during the unfavorable period and the more, the less developed the crowns. The transition of the radial increment to a lower level occurred during the minimum of the component with 12-year cyclicity. There is no significant correlation between early and late wood increment of the component with 2–5-year cyclicity, which makes the major contribution to their ratio. The correlation between early and late wood increment of other components is closer during the unfavorable period and with a decline in crown development. The correlation between the early and late wood increment of the previous year is closer than that of the same year.

ANALYSIS OF PROSPECTIVE DIRECTIONS FOR DEVELOPMENT OF SYSTEMS USING REFLECTION OR SECONDARY RADIATION OF ACOUSTIC WAVES

In this work, to identify promising areas for the development of electronic systems using reflection or secondary radiation of acoustic waves, a patent analysis method is used based on the formation of time series of US patents and comparison between different technical solutions for the number of patents registered in specific subgroups of the International Patent Classification (IPC), and the dynamics of their issuance in the interval 2010–2019. The use of the IPC allows an effective search and classification of any technical solution, a retrospective analysis, as well as the formation of predictive assessments of the development of technologies, involving open resources of various patent offices. As a result of the study, data were obtained that suggest that all systems using the reflection of acoustic waves have been successfully developing for the past ten years. The most promising among them are systems using reflection of acoustic waves and systems specially designed for special applications. Among systems with reflection of acoustic waves, the most promising systems are systems for determining the location of a target by measuring only range using transmissions of intermittent pulse-modulated signals.

Factors and forecast assessments of innovative development of transport infrastructure

Introduction. Due to the introduction of the euro integration vector of the Ukrainian economy development, the modernization and adaptation of the transport infrastructure to the EU standards should take place. For ensuring the efficient operation of transport infrastructure, it is necessary to develop a new, more efficient management model in the form of a national innovative transport HUB. The purpose of the paper is the offering of mechanism for the innovative development of transport infrastructure based on factor and forecast estimates. Results. The proposed mechanism of the state regulation of development of national innovative transport HUB is to transform the impact of the environment as the main source of innovation change, which simultaneously serves as a source of resources that infrastructure as an open system uses at the input of its activities to ensure the expected result. The possibility of implementing the proposed mechanism of the state regulation of development of the national innovative transport HUB was analyzed on the basis of the results of activities of individual entities that are part of the transport infrastructure of the Kyiv region. Conclusion. The simulation results prove that the developed simulation model of innovative behavior of the transport infrastructure objects has considerable potential for explaining the peculiarities of the innovative behavior of the transport infrastructure objects of the Kyiv region, identifying and implementing priority innovative projects. Factor and predictive assessments of the innovative development of transport infrastructure of the Kyiv region, allows to evaluate the impact on the innovative behavior of certain factors, including the degree of development of elements of innovative infrastructure and the effectiveness of measures for state regulation of innovative activity of transport infrastructure objects in the coordinates of two-dimensional matrix “Efficiency-Reliability”.

METHODS OF EVALUATION OF SANITARY-ECOLOGICAL CONDITION OF TERRITORIES

Introduction. On the basis of monitoring data for 2005-2017, the analysis of the ecological and hygienic situation in the territory of the Bryansk region was carried out and the integral index of pollution of territories was derived. Ranking of territories was carried out taking into account pollution of air, water, food by chemical and radioactive substances. Material and methods. Monitoring of environmental pollution, method of expert estimations, the coefficient of concordance, integral index of pollution. Results. The study identified anthropogenic pollutants of the areas, the most disadvantaged areas, and relatively clean areas. The degree of pollution of each territory was established on the basis of an integral index. The proposed method for ecological and hygienic ranking of territories allowed systematically assessing the state of the environment. Conclusion. According to the results of the research, it can be confirmed that the main sources of impact on the environment of the region are vehicles and construction enterprises, as well as the consequences of the Chernobyl disaster. Risk assessment for public health was carried out taking into account the real risk of human exposure to ecotoxicants coming from all objects of the environment, using the method of expert assessments and an integral index assessing the total pollution and taking into account the level of pollution of air, water, food chemicals, and radioactive substances. New approaches to the ecological and hygienic characteristics of the territories can be recommended for a comprehensive assessment of the environment, the development of predictive assessments of the negative impact of man-made environmental pollution on public health, management of risk factors for the development of environmentally-dependent pathology in the population in areas with different levels of man-made pollution.

Environmental Regulation of the Heart: The Role of Non-Coding RNA and Epigenetics in Influencing Mitochondrial and Cellular Health

The mitochondrion, a small but ubiquitously distributed organelle in the cell, continues to be the focus of many disease pathogeneses, tissue and organ dysfunctions, and other morbidities that occur throughout the body. The purpose of this work was to understand how cardiac mitochondrion are altered in disease and pathological states, specifically in their adaptation to environmentally stimulated regulatory networks, such as epigenetic modifications and promotion/inhibition of non-coding RNAs. Acute stress to mitochondrial regulation (inhalation toxicology) as well as chronic (type 2 diabetes mellitus) was examined. Using a FVB transgenic microRNA-378a mouse knockout model, the cardiovascular impact derived from altering the innate microRNA-378a response following acute nano-TiO2 inhalation exposure was evaluated. In atrial tissue from 50 patients (30 non-diabetic and 20 type 2 diabetic) physiological, biochemical, genomic, and epigenomic factors were assessed using machine learning algorithms in an attempt to better predict the pathogenesis of the disease in the heart. Next-generation sequencing was performed on human patient and FVB mouse mitochondrial and cytoplasmic non-coding RNA populations, along with polynucleotide phosphorylase (PNPase) crosslinking immunoprecipitation (CLIP). Ultimately, the work summarized in the preceding experiments highlights how multiple pathological insults, whether chronic or acute, can influence the underlying molecular, regulatory networks in the heart. While overt cardiovascular and mitochondrial dysfunction follow insult, an emphasis on epigenetic control and non-coding RNA regulation may prove to be primary axes for therapeutic intervention. As we continue to pursue more informed and predictive assessments of cardiovascular dysfunction, the mitochondrion remains at the heart of the issue.

Comparison of Measurement-Based Methodologies to Apportion Secondary Organic Carbon (SOC) in PM2.5: A Review of Recent Studies

Secondary organic aerosol (SOA) is known to account for a major fraction of airborne particulate matter, with significant impacts on air quality and climate at the global scale. Despite the substantial amount of research studies achieved during these last decades, the source apportionment of the SOA fraction remains difficult due to the complexity of the physicochemical processes involved. The selection and use of appropriate approaches are a major challenge for the atmospheric science community. Several methodologies are nowadays available to perform quantitative and/or predictive assessments of the SOA amount and composition. This review summarizes the current knowledge on the most commonly used approaches to evaluate secondary organic carbon (SOC) contents: elemental carbon (EC) tracer method, chemical mass balance (CMB), SOA tracer method, radiocarbon (14C) measurement and positive matrix factorization (PMF). The principles, limitations, challenges and good practices of each of these methodologies are discussed in the present article. Based on a comprehensive—although not exhaustive—review of research papers published during the last decade (2006–2016), SOC estimates obtained using these methodologies are also summarized for different regions across the world. Conclusions of some studies which are directly comparing the performances of different methodologies are then specifically discussed. An overall picture of SOC contributions and concentrations obtained worldwide for urban sites under similar conditions (i.e., geographical and seasonal ones) is also proposed here. Finally, further needs to improve SOC apportionment methodologies are also identified and discussed.