In vivo adenine base editing corrects newborn murine model of Hurler syndrome

Mucopolysaccharidosis type I (MPS I) is a severe disease caused by loss-of-function mutations variants in the α-L-iduronidase (IDUA) gene. In vivo genome editing represents a promising strategy to correct IDUA mutations, and has the potential to permanently restore IDUA function over the lifespan of the patients. Here, we used adenine base editing to directly convert A>G (TAG>TGG) in newborn murine model harboring Idua-W392X mutation, which recapitulates the human condition and is analogous to the highly prevalent human W402X mutation. We engineered a split-intein dual-adeno-associated virus (AAV) 9 in vivo adenine base editor to circumvent the package size limit of AAV vectors. Intravenous injection of AAV9-base editor system into MPS I newborn mice led to sustained enzyme expression sufficient for correction of metabolic disease (GAGs substrate accumulation) and prevention of neurobehavioral deficits. We observed a reversion of the W392X mutation in 22.46 plus-or-minus sign 6.74% of hepatocytes, 11.18 plus-or-minus sign 5.25% of heart and 0.34 plus-or-minus sign 0.12% of brain, along with decreased GAGs storage in peripheral organs (liver, spleen, lung and kidney). Collectively, these data showed the promise of a base editing approach to precisely correct a common genetic cause of MPS I in vivo and could be broadly applicable to the treatment of a wide array of monogenic diseases.

PECULIARITIES OF ESTATE OF THE NATIONAL GEODESIC NETWORK IN THE CENTRAL REGION OF UKRAINE

A common feature of NGN in the central region of Ukraine is aging. The differences are determined by the peculiarities of fixing its points on the locallity place. The choice of a specific type of geodetic signal was determined by local physical and geographical features of the location of the point, such as: soil properties, depth of soil freezing, visibility conditions, etc. On the territory of Poltava and Kirovohrad regions there are 70 types of centers, benchmarks and brands, which are fixed points of the planimetric, altitude and gravimetric networks. At the same time, only 9 types significantly prevail of distribution: soil centers and benchmarks for areas with shallow (up to 1.5 m) seasonal soil freezing of types 1, 1op, 2, 2op, 146, 160 and 160 Late; wall benchmarks type 143 and wall beacons type 144. The peculiarity of the central region of Ukraine is the presence of points that are both points of the planimetric NGN 1, 2 and 3 classes, and altitude NGN I or II classes. Thus such points are fixed either by the ground centers, or ground benchmarks, or horizontal beacons. Because of the lack of geodetic information on a significant part of the points of the planned and altitude networks, the condition of the NGN of the central region of Ukraine cannot be considered satisfactory at present. For the requirements of monitoring, it is proposed to expand the content of maps of construction, survey and updating of geodetic points with data on the rights of ownership or use of land locations of points and their cadastral numbers. It is also necessary to update the data on those points in the central region of Ukraine, the inspection of which was realized before 2010. The indicator of admissibility of losses of points of NGN which should be defined separately for networks of 1, 2 and 3 classes is offered. If according to the results of the calculation the actual amount of points is less than the minimum allowable for the corresponding class, and the indicator of admissibility of losses of points has a minus sign, then the corresponding network does not meet the technical parameters. Loss of points in this case is not allowed, and lost points must be restored. The results of the calculation of this indicator for the central region of Ukraine indicate the need to restore 6 points of the planimetric network of the 2 class in the Kirovohrad region and the inadmissibility of further losses of points of this class.

Structural brain connectivity in children with developmental dyscalculia

Developmental dyscalculia (DD) is a neurodevelopmental disorder specific to arithmetic learning even with normal intelligence and age-appropriate education. Difficulties often persist from childhood through adulthood. Underlying neurobiological mechanisms of DD, however, are poorly understood. This study aimed to identify possible structural connectivity alterations in DD. We evaluated 10 children with pure DD (11.3 plus-or-minus sign 0.7 years) and 16 typically developing (TD) peers (11.2 plus-or-minus sign 0.6 years) using diffusion tensor imaging. We first assessed white matter microstructure with tract-based spatial statistics. Then we used probabilistic tractography to evaluate tract lengths and probabilistic connectivity maps in specific regions. At whole brain level, we found no significant microstructural differences in white matter between children with DD and TD peers. Also, seed-based connectivity probabilities did not differ between groups. However, we did find significant differences in regions-of-interest tracts which had previously been related to math ability in children. The major findings of our study were reduced white matter coherence and shorter tract lengths of the left superior longitudinal/arcuate fasciculus and left anterior thalamic radiation in the DD group. Furthermore, lower white matter coherence and shorter pathways corresponded with the lower math performance as a result of the correlation analyses. These results from regional analyses indicate that learning, memory and language-related pathways in the left hemisphere might underlie DD. Keywords: Mathematical learning disability, diffusion tensor imaging, superior longitudinal fasciculus, anterior thalamic radiation, probabilistic tractography, tract-based spatial statistics

On the protective role of the blood vessels in glaucomatous damage: a transversal study.

Purpose: To corroborate whether vessels on the surface of the optic nerve head can provide protection against the loss of underlying axons in subjects with manifest glaucoma. Methods: In this pilot study, thirty-six glaucomatous eyes with a perimetric defect in the Bjerrum area were included. The retinal nerve fiber layer (RNFL) thickness was measured in each of the sectors of the clock-hour map obtained by Cirrus HD-OCT considering the presence or absence of blood vessels. These sectors were related with their corresponding areas of the retina examined in the visual field using a mathematical model of the retina introduced by Jansonius, in order to determine the values of threshold sensitivity in those areas in the presence or absence of vessels. Results: We corroborated the protective role of the blood vessel for peripapillary RNFL thickness of clock-hour 12 despite obtaining a p-value (p = 0.023; w = 228.5) close to the acceptance zone (p ≥ 0.05). The mean plus-or-minus sign standard deviation with vessel and without vessel were 70.95 plus-or-minus sign 24.35 and 88.46 plus-or-minus sign 23.96, respectively. No differences were found between the mean values of threshold sensitivity to the presence or absence of blood vessels in each of the sectors considered. Conclusions: Our findings do not allow us to affirm that there is an association between the presence of a vessel and protection against glaucomatous damage in subjects with an advanced manifestation of the disease. In the future, more extensive studies are needed to study this relationship in subjects with early glaucoma. Key words: astrocytes, visual field, primary open-angle glaucoma, aqueous humor, blood vessel.

ANALYSIS OF TECHNICAL-TACTICAL ACTIONS OF CENTRAL MIDFIELDERS

The observations were held in 2020-2021 during the competitive matches of the Champions League and Euro league Cups and European countries (England, Spain, Germany, Italy). The observations were made by analyzing the videos and TV broadcasting, during which T. Mueller ("Bavaria"), K. De Bruyne ("Manchester City"), B. Fernandez ("Manchester United"), L. Modric ("Real"), H. Mkhitaryan ("Roma") were observed in 4 matches each. During the research, we developed a viewing card, including all the technical and tactical actions used during the game. When studying them, the accuracy of the action was marked by plus (+) or minus (-) sign.

Regional segment in the news content of the central television of Ukraine

The article reviews the news content of all-Ukrainian television media. It was found out that the news information on Ukrainian television is represented by the following thematic segments: socio-political / military, criminal, social, cultural and artistic, emergency materials. In consideration of the significant number of materials with the negative contextual connotation (socio-political, social, criminal) television media potentially form both negative internal and external images of the country as a whole and the local image of its regions. The general trends in the formation of the media image of a particular region are determined on the example of the coverage of Sumy events by rating TV channels. It was established that information about the region is presented in the vast majority of materials of criminal subjects and negative news from the socio-political and social spheres, which results in the formation of an image of the territory with a «minus» sign.

CALMNESS/INDIFFERENCE, OR NUANCES OF EVALUATIVE INTERPRETATIONS

В статье семантика безразличия представлена в непосредственной связи с понятиями оценка и ценности. В центре внимания оказывается, во-первых, субъект оценки – человек, считающий необходимым засвидетельствовать свое безразличное отношение к объекту: безразличие рассматривается как состояние субъекта (семантика состояния). Во-вторых, сам субъект и носитель такого состояния представлен как объект оценки со стороны социума. Показано семантическое развитие слова равнодушие, значение которого трансформировалось с точки зрения оценочно-коннотативных свойств: от нейтральной оценки до негативной. Тексты художественной литературы свидетельствуют о том, что бездействие в момент, когда необходимо действие, – это поступок со знаком минус. Аксиогенный общественный ориентир – неравнодушие. The article presents the semantics of indifference in direct connection with the concepts of assessment and values. The focus is, firstly, on the subject of assessment – a person who considers it necessary to attest to his indifference to the object: indifference is presented as a state of the subject (semantics of the state). Secondly, the subject as the bearer of such a state is presented as an object of assessment by society. The semantic development of the word «indifference» is shown, the meaning of which has been transformed from the point of view of evaluative-connotative properties: from a neutral assessment to a negative one. The texts of fiction indicate that inaction at the moment when action is needed is an act with a minus sign. An axiogenic social reference is indifference.

Different adrenal response of critically ill neonates; An Egyptian model

Background: Adequate adrenocortical function is essential for survival of critically ill neonates. Although most of them display elevated plasma cortisol concentrations, which reflects activation of the hypothalamic pituitary adrenal axis (HPA), yet; adrenocortical insufficiency is seen in septic shock. Objectives: Evaluate the HPA response in critically ill neonates with shock. Subjects:this prospective observational study included a total of 60 neonates divided into 3 groups;(A)30 critical ill neonates with septic shock on inotropic support, (B)15 patients with sepsis who did not need inotropic support and(C) control group(n=15). Methods: Adrenal functions were evaluated by taking a single diurnal ACTH reading and two readings for serum cortisol level (diurnal and nocturnal). Results: Gram negative organism was more prevalent among the patients; 53%, 63% in groups A and B respectively. Group A showed Significant statistical hypotension before vasopressor drug administration (p<0.001) as compared to both groups. Group A showed Significant statistical improvement of blood pressure after vasopressor drug administration (p<0.001) as compared to both groups B, C. Serum cortisol was significantly higher in group A(57.21 plus-or-minus sign 24.31) and B (48.01 plus-or-minus sign 18.27 ), while it was lower in group C(19.57plus-or-minus sign 16.05 ) . A highly statistically significant rise of serum cortisol level( p=0.000) and ACTH(p=0.000) in group A when was compared to the other two groupsConclusion: This study introduced a new pattern of serum cortisol response in neonates ranging from very high cortisol level to a near normal values; highlighting a state of glucocorticoid resistance in neonates and relative adrenal insufficiency.