The potential of antisense oligonucleotide therapies for inherited childhood lung diseases

Antisense oligonucleotides are an emerging therapeutic option to treat diseases with known genetic origin. In the age of personalised medicines, antisense oligonucleotides can sometimes be designed to target and bypass or overcome a patient’s genetic mutation, in particular those lesions that compromise normal pre-mRNA processing. Antisense oligonucleotides can alter gene expression through a variety of mechanisms as determined by the chemistry and antisense oligomer design. Through targeting the pre-mRNA, antisense oligonucleotides can alter splicing and induce a specific spliceoform or disrupt the reading frame, target an RNA transcript for degradation through RNaseH activation, block ribosome initiation of protein translation or disrupt miRNA function. The recent accelerated approval of eteplirsen (renamed Exondys 51™) by the Food and Drug Administration, for the treatment of Duchenne muscular dystrophy, and nusinersen, for the treatment of spinal muscular atrophy, herald a new and exciting era in splice-switching antisense oligonucleotide applications to treat inherited diseases. This review considers the potential of antisense oligonucleotides to treat inherited lung diseases of childhood with a focus on cystic fibrosis and disorders of surfactant protein metabolism

Investigating the implications of CFTR exon skipping using a Cftr exon 9 deleted mouse model

Introduction: Severity and disease progression in people with Cystic Fibrosis (CF) is typically dependent on their genotype. One potential therapeutic strategy for people with specific mutations is exon skipping with antisense oligonucleotides (AO). CFTR exon 9 is an in-frame exon and hence the exclusion of this exon would excise only 31 amino acids but not alter the reading frame of the remaining mRNA. Splice mutations 1209 + 1 G > C and 1209 + 2 T > G were documented to cause CFTR exon 9 skipping and these variants were reported to manifest as a milder CF disease, therefore exon 9 skipping could be beneficial for people with class I mutations that affect exon 9 such as p.Trp401X. While the impact of exon 9 skipping on gene expression and cellular pathways can be studied in cells in vitro, trace amount of full-length normal or mutated material could confound the evaluation. To overcome this limitation, the impact of CFTR exon 9 skipping on disease phenotype and severity is more effectively evaluated in a small animal model. It was hypothesised that antisense oligonucleotide-mediated skipping this particular exon could result in a “mild mouse CF phenotype”. Methods: Cftr exon 9 deleted mice were generated using homologous recombination. Survival of homozygous (CftrΔ9/Δ9) and heterozygous (CftrΔ9/+) mice was compared to that of other CF mouse models, and lung and intestinal organ histology examined for any pathologies. Primary airway epithelial cells (pAECs) were harvested from CftrΔ9/Δ9 mice and cultured at the Air Liquid Interface for CFTR functional assessment using Ussing Chamber analysis. Results: A CftrΔ9/Δ9 mouse model presented with intestinal obstructions, and at time of weaning (21 days). CftrΔ9/Δ9 mice had a survival rate of 83% that dropped to 38% by day 50. Histological sections of the small intestine from CftrΔ9/Δ9 mice showed more goblet cells and mucus accumulation than samples from the CftrΔ9/+ littermates. Airway epithelial cell cultures established from CftrΔ9/Δ9 mice were not responsive to forskolin stimulation. Summary: The effect of Cftr exon 9 deletion on Cftr function was assessed and it was determined that the encoded Cftr isoform did not result in a milder “mouse CF disease phenotype,” suggesting that Cftr exon 9 is not dispensable, although further investigation in human CF pAECs would be required to confirm this observation

Современные тенденции на рынке слияний и поглощений

В статье рассмотрены ключевые тенденции развития рынка сделок слияния и поглощений на современном этапе

Neuroelectronic Systems: Binding Neurons to Electric Circuits

This paper is devoted to description of a new type of information system based on interaction of biological neurons and electronic components – neuroelectronic (NE) system. Main features and components, like neural network sensor, of NE are briefly put into consideration followed with an example of electric interaction between neural network of a snail Lymnaea Stagnalis neurons and electronic MOSFET sensor

ДИФФЕРЕНЦИАЛЬНАЯ РЕГУЛЯЦИЯ ПРОДУКЦИИ АКТИВНЫХ ФОРМ КИСЛОРОДА И МЕХАНИЗМОВ ГИБЕЛИ ОПУХОЛЕВЫХ КЛЕТОК ПАРА-БЕНЗОХИНОНАМИ

It is established that thymoquinone (2-isopropyl-5-methyl-1,4-benzoquinone) and 1,4-benzoquinone regulate the intracellular reactive oxygen species (ROS) production and induce the death of tumor cells by different mechanisms. It is shown that the toxic action of 1,4-benzoquinone is associated with the inhibition of electron transfer in the mitochondrial respiratory chain and with the development of cellular oxidative stress. Thymoquinone initiating a lower level of ROS production in comparison with 1,4-benzoquinone is more toxic to tumor cells. It is established that thymoquinone-induced ROS are involved in the redox signaling processes that lead to the opening of mitochondrial transition pores of high permeability and the activation of the programmed death of cells.Установлено, что тимохинон (2-изопропил-5-метил-1,4-бензохинон) и 1,4-бензохинон регулируют внутриклеточную продукцию активных форм кислорода (АФК) и индуцируют гибель опухолевых клеток по различным механизмам. Показано, что токсическое действие 1,4- бензохинона связано с ингибированием переноса электронов в митохондриальной дыхательной цепи и развитием клеточного окислительного стресса. Тимохинон, инициирующий выход АФК более низкий в сравнении с 1,4-бензохиноном, является более токсичным для опухолевых клеток. Обнаружено, что образующиеся при действии тимохинона АФК являются участниками редокс-сигнальных процессов, ведущих к формированию митохондриальных пор высокой проницаемости и запуску программируемой гибели клеток

The Potential Role of a Self-Management Intervention for Ulcerative Colitis: A Brief Report From the Ulcerative Colitis Hypnotherapy Trial

Inflammatory bowel diseases (IBD) are chronic inflammatory illnesses marked by unpredictable disease flares, which occur spontaneously and/or in response to external triggers, especially personal health behaviors. Behavioral triggers of flare may be responsive to disease self-management programs. We report on interim findings of a randomized controlled trial of gut-directed hypnotherapy (HYP, n = 19) versus active attention control (CON, n = 17) for quiescent ulcerative colitis (UC). To date, 43 participants have enrolled; after 5 discontinuations (1 in HYP) and 2 exclusions due to excessive missing data, 36 were included in this preliminary analysis. Aim 1 was to determine the feasibility and acceptability of HYP in UC. This was achieved, demonstrated by a reasonable recruitment rate at our outpatient tertiary care clinic (20%), high retention rate (88% total), and our representative IBD sample, which is reflected by an equal distribution of gender, an age range between 21 and 69, recruitment of ethnic minorities (~20%), and disease duration ranging from 1.5 to 35 years. Aim 2 was to estimate effect sizes on key clinical outcomes for use in future trials. Effect sizes (group × time at 20 weeks) were small to medium for IBD self-efficacy (.34), Inflammatory Bowel Disease Questionnaire (IBDQ) total score (.41), IBDQ bowel (.50), and systemic health (.48). Between-group effects were observed for the IBDQ bowel health subscale (HYP > CON; p = .05) at 20 weeks and the Short Form 12 Health Survey Version 2 (SF-12v2) physical component (HYP > CON; p < .05) at posttreatment and 20 weeks. This study supports future clinical trials testing gut-directed HYP as a relapse prevention tool for IBD

Gut-directed hypnotherapy significantly augments clinical remission in quiescent ulcerative colitis

Psychotherapy is not routinely recommended for in ulcerative colitis (UC). Gut-directed hypnotherapy (HYP) has been linked to improved function in the gastrointestinal tract and may operate through immune-mediated pathways in chronic diseases

ПОВЫШЕНИЕ ИНФОРМАТИВНОСТИ РАСЧЕТНЫХ ОЦЕНОК НАДЕЖНОСТИ БОРТОВОЙ АППАРАТУРЫ МАЛОГАБАРИТНЫХ КОСМИЧЕСКИХ АППАРАТОВ

An increase in the informative content of the calculated values of the reliability measure (RM) of objects, whose reliability is ensured by the redundancy of structural elements, is considered in the article. The increase of the informative content is ensured using the interval estimates of the RM. In the normal reliability calculation, the calculated value of the object’s RM is unambiguous, and for an interval reliability estimate, the value range is obtained, which can be quite appreciated as the increase in the informative content. The choice of on-board equipment for small spacecrafts as an object of research in this work is determined as follows: at present, the vast majority of spacecrafts can be classified as small spacecrafts; since the reliability of small spacecrafts is high, it is necessary to use redundancy; the Belarusian spacecraft for remote sen-sing of the Earth belongs to the category of small spacecrafts. As a result of research, the formulas for calculation of interval estimation results are established for the linear and nonlinear dependence of the object’s RM on the RM of its elements. Structural reliability schemes (SSR) are used as an object (system) reliability model, which includes blocks of elements without redundancy (simple) and blocks with different-type redundancy (complex). The object’s RM is a reliability measure determined by its SSR. Therefore, for an interval estimation of the object’s RM to be obtained, the interval estimates of the RM of its blocks must be made. RM interval estimates of simple and complex SSR blocks are obtained in the article. Complex blocks were considered as a set of parallel circuits provi- ding: continuous redundancy for all loaded circuits; non-continuous redundancy of loaded and unloaded circuits; standby redun-dancy; redundancy by voting. The formulas for interval estimation of the object’s RM represented by the SSR and the example of using the methodology on the component part of a real on-board information system are given in the article. The boundary values of the interval estimates of the example can be taken as optimistic and pessimistic estimates.Рассматривается вопрос повышения информативности расчетных значений показателей надежности (ПН) объектов (надежность которых обеспечивается путем резервирования структурных элементов) за счет использования их интервальных оценок. При обычном расчете надежности значение ПН объекта является однозначной величиной, а при интервальной оценке получается диапазон значений, что вполне можно считать повышением информативности. Выбор объектом исследований бортовой аппаратуры (БА) малогабаритных космических аппаратов (МКА) обусловлен следующим: в настоящее время подавляющее большинство космических аппаратов относятся к категории МКА; для МКА предъявляются высокие требования к надежности, что приводит к необходимости использования резервирования; Белорусский космический аппарат дистанционного зондирования Земли (БКА) относится к категории МКА. В ходе исследования установлены формулы вычисления результатов интервальной оценки при линейной и нелинейной зависимости ПН объекта от ПН его элементов. В качестве модели надежности объекта (системы) использовались структурные схемы надежности (ССН), в состав которых входят блоки из элементов без резервирования (простые) и с различными видами резервирования (сложные). Показатель надежности объекта устанавливается по его ССН, поэтому для получения его интервальной оценки необходимо определить интервальные оценки ПН его блоков. Получены интервальные оценки ПН простых и сложных блоков ССН. Сложные блоки рассматривались как совокупность параллельных цепей, обеспечивающих постоянное резервирование при всех нагруженных цепях, непостоянное резервирование нагруженных и ненагруженных цепей, резервирование замещением и голосованием. Приведены формулы интервальной оценки ПН объекта, представленного ССН, и пример использования методики на составной части реальной бортовой аппаратуры МКА – бортовой информационной системе, при этом граничные значения интервальных оценок можно принимать как оптимистические и пессимистические