COGNITIVE MODELS OF THE BARBARITY TRIGGER

Статья представляет предварительный анализ категориального языка варваристики в контексте взаимодействия цивилизации и варварства. На протяжении истории варварство претерпевало серьезную мутацию, меняя семантику, но сохраняя матрицу своей «материнской» стадиальной лексики. Выработан особый лексикон агрессивных злонамеренных действий, характеризующих или нарастание варварства, или его изживание. Некоторые термины и понятия продолжают употребляться метафорически и методологически, скорее ориентируя, нежели определяя. В статье рассматривается особая деструктивная роль стимулов, толчков, порождающих всплески варварства, что актуализировало необходимость ввести в варваристику новое понятие — «триггер» варварства. Подобная исследовательская задача ставится в исторической науке впервые. Триггер рассматривается в качестве действия, ставшего толчком для сущностного изменения, решающего поворота, скачка или стремительного перехода из одного функционального состояния в другое. Исследовательская стратегия статьи определена когнитивным подходом конкретно-исторического анализа проявления триггеров варварства в широком географическом и хронологическом контексте. Это позволяет обратить внимание на «пороховые погреба» варварства тлеющего, скрытого и скрываемого, на механизм, инструментарий и формы проявления триггеров. Постановка проблемы вызвана необходимостью поиска новых методологий в разработке более глобальной проблемы — цивилизация vs. варварство в условиях современного цивилизационного кризиса, на пороге кардинальных изменений представлений о природе варвара и варварства, которое развивается и эволюционирует быстрее, чем его исследование и осмысление. The article presents a preliminary analysis of the categorical language of barbarism in the context of the interaction of civilization and barbarism. Throughout history, barbarism has undergone a severe mutation, changing semantics, but still retaining the matrix of its «maternal» stadium vocabulary. A unique lexicon of aggressive, malicious actions has been developed, characterizing either the growth of barbarism or its elimination. Some terms and concepts continue to be used metaphorically and methodologically, orienting rather than defining. The article considers the special destructive role of stimuli and shocks that generate bursts of barbarism, which actualized the need to introduce a new concept into barbarism — the «trigger» of barbarism. Such a research task is being set in historical science for the first time. A trigger is considered an action that has become the impetus for an essential change, a decisive turn, a leap, or a rapid transition from one functional state to another. The research strategy of the article is determined by the cognitive approach of a concrete historical analysis of the manifestation of barbarism triggers in a broad geographical and chronological context. This allows us to pay attention to the «powder cellars» of smoldering, hidden and concealed barbarism, to the mechanism, tools and forms of manifestation of triggers. The problem statement is caused by the need to search for new methodologies in the development of a more global problem - civilization vs. barbarism in the conditions of the modern civilizational crisis, on the threshold of cardinal changes in the ideas about the nature of the barbarian and barbarism, that develops and evolves faster than the research and comprehension.

Protocol for ethyl methanesulphonate (EMS) mutagenesis application in rice

Background: Non-transgenic chemical mutagen application, particularly ethyl methanesulfonate (EMS), is an important tool to create mutations and gain a new genetic makeup for plants. It is useful to obtain a sufficient number of mutant plants instead of working with a severe mutation in a few plants. EMS dose and exposure period have been previously studied in several crops; however, EMS used to create point mutations in presoaked rice seeds has not been sufficiently studied and there is no standard protocol for such treatment. The aim of this study is to establish a standard protocol for EMS mutagenesis application in rice. Methods: Two studies were conducted to evaluate the effect of four durations of rice seed presoaking (0, 6, 12, and 24 hours), four EMS concentration doses (0.0%, 0.5%, 1.0%, and 2.0%), and four EMS exposure periods (6, 12, 24, and 48 hours). Germination rate, plumula and radicle length, seedling survival, LD50 (Lethal Dose) determination, shoot length, root length and fresh seedling weight were evaluated. Results: Results showed that a 12-hour presoaking duration, 0.5% EMS dose, and six hours of EMS exposure were the best practices for the optimum number of mutant plants. Conclusions: In light of both this study and the literature, a standard application protocol was established. This application protocol, detailed in this article, contains the following guidelines: (1) Presoaking: 12 hours, (2) EMS application: 0.5% dose EMS and six hours, (3) Final washing: six hours, (4) Drying: 72 hours at 38°C. A user-friendly protocol has been presented for utilization by researchers.

Characterization of PARP6 Function in Knockout Mice and Patients with Developmental Delay

PARP6, a member of a family of enzymes (17 in humans) known as poly-ADP-ribose polymerases (PARPs), is a neuronally enriched PARP. While previous studies from our group show that Parp6 is a regulator of dendrite morphogenesis in rat hippocampal neurons, its function in the nervous system in vivo is poorly understood. Here, we describe the generation of a Parp6 loss-of-function mouse model for examining the function of Parp6 during neurodevelopment in vivo. Using CRISPR-Cas9 mutagenesis, we generated a mouse line that expressed a Parp6 truncated variant (Parp6TR) in place of Parp6WT. Unlike Parp6WT, Parp6TR is devoid of catalytic activity. Homozygous Parp6TR do not exhibit obvious neuromorphological defects during development, but nevertheless die perinatally. This suggests that Parp6 catalytic activity is important for postnatal survival. We also report PARP6 mutations in six patients with several neurodevelopmental disorders, including microencephaly, intellectual disabilities, and epilepsy. The most severe mutation in PARP6 (C563R) results in the loss of catalytic activity. Expression of Parp6C563R in hippocampal neurons decreases dendrite morphogenesis. To gain further insight into PARP6 function in neurons we also performed a BioID proximity labeling experiment in hippocampal neurons and identified several microtubule-binding proteins (e.g., MAP-2) using proteomics. Taken together, our results suggest that PARP6 is an essential microtubule-regulatory gene in mice, and that the loss of PARP6 catalytic activity has detrimental effects on neuronal function in humans.

Protocol for ethyl methanesulphonate (EMS) mutagenesis application in rice

Background: Non-transgenic chemical mutagen application, particularly ethyl methanesulfonate (EMS), is an important tool to create mutations and gain a new genetic makeup for plants. It is useful to obtain a sufficient number of mutant plants instead of working with a severe mutation in a few plants. EMS dose and exposure period have been previously studied in several crops; however, EMS used to create point mutations in presoaked rice seeds has not been sufficiently studied and there is no standard protocol for such treatment. The aim of this study is to establish a standard protocol for EMS mutagenesis application in rice. Methods: Two studies were conducted to evaluate the effect of four durations of rice seed presoaking (0, 6, 12, and 24 hours), four EMS concentration doses (0.0%, 0.5%, 1.0%, and 2.0%), and four EMS exposure periods (6, 12, 24, and 48 hours). Germination rate, plumula and radicle length, seedling survival, shoot length, root length and fresh seedling weight were evaluated. Results: Results showed that a 12-hour presoaking duration, 0.5% EMS dose, and six hours of EMS exposure were the best practices for the optimum number of mutant plants. Conclusions: In light of both this study and the literature, a standard application protocol was established. This application protocol, detailed in this article, contains the following guidelines: (1) Presoaking: 12 hours, (2) EMS application: 0.5% dose EMS and six hours, (3) Final washing: six hours, (4) Drying: 72 hours at 38°C. A user-friendly protocol has been presented for utilization by researchers.

Phenotypic Spectrum of α-Dystroglycanopathies Associated With the c.919T>a Variant in the FKRP Gene in Humans and Mice

Mutations in the fukutin-related protein gene, FKRP, are the most frequent single cause of α-dystroglycanopathy. Rare FKRP mutations are clinically not well characterized. Here, we review the phenotype associated with the rare c.919T>A mutation in FKRP in humans and mice. We describe clinical and paraclinical findings in 6 patients, 2 homozygous, and 4-compound heterozygous for c.919T>A, and compare findings with a mouse model we generated, which is homozygous for the same mutation. In patients, the mutation at the homozygous state is associated with a severe congenital muscular dystrophy phenotype invariably characterized by severe multisystem disease and early death. Compound heterozygous patients have a severe limb-girdle muscular dystrophy phenotype, loss of ambulation before age 20 and respiratory insufficiency. In contrast, mice homozygous for the same mutation show no symptoms or signs of muscle disease. Evidence therefore defines the FKRP c.919T>A as a very severe mutation in humans. The huge discrepancy between phenotypes in humans and mice suggests that differences in protein folding/processing exist between human and mouse Fkrp. This emphasizes the need for more detailed structural analyses of FKRP and shows the challenges of developing appropriate animal models of dystroglycanopathies that mimic the disease course in humans.

Phenotype-genotype correlations in patients with inherited ABCA4-associated retinal diseases

Целью исследования было охарактеризовать клинико-генетические корреляции у пациентов с ABCA4-ассоциированными наследственными заболеваниями сетчатки (НЗС). Распространенная «мягкая» мутация АВСА4:p.G1961E была обнаружена у 20 из 54 больных, наблюдающихся с НЗС и имеющих, по крайней мере, одну мутацию в гене АВСА4. У 8 пациентов p.G1961E выявлена в компаунд-гетерозиготном состоянии с комплексной миссенс-мутацией p.[L541P;A1038V], у 6 - с другими миссенс-мутациями (p.N1805D; p.R1640W; p.P1088T; p.L541P; p.P1380L; p.R1640Q). В нашей выборке у пациентов с длительностью заболевания от 9 лет мутация p.G1961E в 81% случаев ассоциирована с лёгким течением НЗС, даже при наличии второй тяжелой мутации, и является предиктором более легкого течения заболевания, в соответствии с базовой моделью клинико-генетических корреляций при АВСА4-ассоциированных заболеваниях. The aim of this study was to characterize phenotype-genotype correlations in patients with ABCA4-associated IRDs. By NGS, we have identified the widespread “mild” ABCA4 mutation p.G1961E in 20 of 54 IRD patients with at least one mutation in the ABCA4 gene. In 8 patients, p.G1961E was in combination with a complex missense mutation p. [L541P; A1038V], in six - in combination with other missense mutations (p.N1805D; p.R1640W; p. P1088T; p.L541P; p.P1380L; p.R1640Q). In 81% of our patients with a disease course of 9 years or more, the p.G1961E mutation is associated with mild disease, even in the presence of a second severe mutation, and is a predictor of a milder phenotype, in accordance with the basic model of phenotype-genotype correlations in ABCA4-associated diseases.

Assessment of the severity of chronic sinusitis in children with cystic fibrosis using the Lund-Mackay Score depending on genotype

Introduction. Chronic sinusitis affects most patients with cystic fibrosis (CF). The Lund-Mackay (LM) scale is an objective tool allowing for easy assessment of the severity of lesions in sinuses observed in computed tomography (CT). The link between clinical picture, image results and CFTR gene mutations is not well evaluated. Aim. To specify the correlation of the severity of lesions found in computed tomography and the CFTR gene mutation type causing an underlying disease in children with cystic fibrosis. Material and methods. Data of the children with cystic fibrosis who underwent CT between 2016-2018 at the Department of Paediatric Otolaryngology of the Medical University of Warsaw was analysed. The following factors were taken into account: age, sex and CFTR gene mutation type. Each CT was assessed using the basic and modified Lund-Mackay Score (LMS and MLMS). The study was retrospective. Results. 34 children, 16 girls and 18 boys aged between 3 and 17 years (median age ? 10 years), were enrolled to the study at the time of CT. LMS median was 17 (range 2-23), and MLMS ? 18 (range 2-24), and their difference was statistically significant. 16 patients were F508del homozygous. Severe CFTR mutation in both alleles was observed in 28 patients, and mild mutation was found in at least one allele in 6 patients. LMS median in the group of patients with severe mutation was 17.5, and in the group of patients with mild mutation ? 14.5. MLMS median was 18 and 14.5, respectively. The difference was statistically significant for both LMS and MLMS. No statistically significant correlation was found between the LMS and MLMS results and sex. The weak positive correlation between LMS and MLMS and patient’s age was not statistically significant. Hypoplasia or aplasia of one or more paranasal sinuses was observed in 11 children (32%). Conclusions. The score on the modified Lund-Mackay scale is higher than the score on the basic LMS scale in children with cystic fibrosis. The group of patients with a severe CFTR gene mutation has higher scores for both LMS and MLMS than the group with a mild mutation. Due to frequent sinus aplasia in children with cystic fibrosis, the use of the modified Lund-Mackay scale allows for error avoidance when comparing CT results of different patients.

Carriers of a Classic CYP21A2 Mutation Have Reduced Mortality: A Population-Based National Cohort Study

Context Congenital adrenal hyperplasia (CAH) is a common monogenic recessive disorder. It has been suggested that CYP21A2 deficiency is common because carriers may have a survival advantage, 1 in 15,000 in most populations. Carriers of CYP21A2 mutations typically do not have clinical symptoms but have a defined phenotype with a more prompt cortisol response to ACTH. Objective We investigated whether the mortality was lower, and determined the cause of death in carriers and population controls. Design A total of 1143 obligate carriers of a CYP21A2 mutation (561 men) were identified from the Swedish National CAH Registry, encompassing >700 patients and the Multi-Generation Registry to identify their parents. The mortality and cause of death were identified through the Swedish Cause of Death Registry. The hazard ratios (HRs) and 95% CIs were calculated. The results were compared with controls from the general population, matched for sex and age. Results The overall mortality was lower in carriers of a CYP21A2 mutation compared with the controls (HR 0.79; 95% CI, 0.678 to 0.917; P = 0.002). The difference was more marked among carriers of a more severe mutation. Infection as the cause of death was significantly lower (HR 0.65; 95% CI, 0.48 to 0.87; P < 0.01), particularly for death in pneumonia (HR 0.22; 95% CI, 0.06 to 0.88; P = 0.03). The lower overall mortality among women compared with men in the general population was confirmed among both carriers and controls. Conclusion Obligate CYP21A2 carriers of a classic mutation had a reduced mortality. Specifically, a possible reduced mortality due to pneumonia was seen.

Developing a diagnostic test to identify the selected mutation within the CFTR gene that determines the onset of cystic fibrosis

Cystic fibrosis is one of the most common genetic diseases among Caucasians due to its prevalence. Modern methods of molecular diagnostics and treatment of the disease allow to prolong the life of patients. In order to apply the appropriate treatment, the genetic basis of this disease should, however, first be known. The most common and the most severe mutation present in the CFTR gene (60-70% of cases) takes the form of an allele. This is responsible for the deletion of phenylalanine in position 508 (Δ508) of the CFTR protein. Determination of mutations in the CFTR gene using molecular techniques makes it possible to identify the causes of the disease in people who do not show the characteristic symptoms of cystic fibrosis.