Hereditary Spastic Paraplegia (HSP) represents a large group of clinically and genetically heterogeneous disorders linked to over 70 different loci and more than 60 recognized disease-causing genes. A heightened vulnerability to disruption of various cellular processes inherent to the unique function and morphology of corticospinal neurons may account, at least in part, for the genetic heterogeneity. Whole exome sequencing was utilized to identify candidate genetic variants in a four-generation Siberian kindred that includes nine individuals showing clinical features of HSP. Segregation of candidate variants within the family yielded a disease-associated mutation. Functional as well as in-silico structural analyses confirmed the selected candidate variant to be causative. Nine known patients had young-adult onset of bilateral slowly progressive lower-limb spasticity, weakness and hyperreflexia progressing over two-to-three decades to wheel-chair dependency. In the advanced stage of the disease, some patients also had distal wasting of lower leg muscles, pes cavus, mildly decreased vibratory sense in the ankles, and urinary urgency along with electrophysiological evidence of a mild distal motor/sensory axonopathy. Molecular analyses uncovered a missense c.2155C > T, p.R719W mutation in the highly conserved GTP-effector domain of dynamin 2. The mutant DNM2 co-segregated with HSP and affected endocytosis when expressed in HeLa cells. In-silico modeling indicated that this HSP-associated dynamin 2 mutation is located in a highly conserved bundle-signaling element of the protein while dynamin 2 mutations associated with other disorders are located in the stalk and PH domains; p.R719W potentially disrupts dynamin 2 assembly. This is the first report linking a mutation in dynamin 2 to a HSP phenotype. Dynamin 2 mutations have previously been associated with other phenotypes including two forms of Charcot-Marie-Tooth neuropathy and centronuclear myopathy. These strikingly different pathogenic effects may depend on structural relationships the mutations disrupt. Awareness of this distinct association between HSP and c.2155C > T, p.R719W mutation will facilitate ascertainment of additional DNM2 HSP families and will direct future research toward better understanding of cell biological processes involved in these partly overlapping clinical syndromes.

Extreme climatic conditions of the North with low temperatures and the traditional diet are responsible for development of a specific mechanisms of lipid metabolism among the indigenous peoples of the Sakha (Yakutia) Republic. The evolutionary patterns of lipid metabolism fixed in the genome in the form of polymorphic genetic markers are important for the development of regional healthcare programs for prevention of metabolic syndrome and cardiovascular diseases. The aim of the study was to analyze the characteristic features of lipid metabolism and metabolic disorders in the Yakut population. A systematic review of the results of studies of lipid profile parameters and key candidate genes involved in lipid metabolism among the indigenous inhabitants of Yakutia over the past 10 years was performed. The available evidence suggests that in indigenous inhabitants of Yakutia, the indicators of lipid metabolism are not a matter for concern. Participants of the most studies have a high concentrations of high-density lipoprotein cholesterol, low concentrations of triglycerides and low plasma atherogenic index, which are associated with physiological adaptation to environmental conditions. However, changes in dietary patterns including increased consumption of carbohydrates and lifestyle changes including reduced physical activity and abandonment of traditional activities have led to the spread of metabolic disorders in recent decades. Prevalence estimates for the metabolic syndrome in the indigenous inhabitants of Yakutia aged 20 years or older vary from 4.9 % in men to 49.4 % in women in the Arctic regions. We also discuss the mechanisms of lipid metabolism and the role of LepR, LPL, CETP, IL6, PON1 genes in the development of metabolic disorders in the Yakut population.

Forest plantations provide a wide range of products. Therefore, it is vital to ensure the sustainable growth and adequate management of forest resources. This study aims to examine the current challenges facing the forest industry, such as the depletion of forest resources, the increasing cost of wood processing products, and intensifying competition in the timber market (caused by the tropical wood supply). These challenges force the world’s leading forest countries to intensify forest cultivation, to consult forest industries in the Far East and to optimize the sustainable use of forest resources. It was found that current distribution of cutting practices threatens the forest ecosystem. The study suggests a scheme where 10–30% of forest area is clear-cut, 70–90% is selectively logged, and 20–35% is exposed to gradual felling. Factors, such as harvesting time, exhaust emissions, the loss of young trees, topsoil degradation, load on the soil surface, and the slope angle are essential for building mathematical models of forest sustainability. The intensity of wood transportation is also a critical factor influencing the above indicators. The study proposes a model for reorganizing regional wood harvesting companies to improve their profitability. The theoretical model is adapted to the Far Eastern context, but is suitable for use in other parts of the world.

Yakutia is one of the coldest permanently inhabited regions in the world, characterized by a subarctic climate with average January temperatures near −40 °C and the minimum below −60 °C. Recently, we demonstrated accelerated epigenetic aging of the Yakutian population in comparison to their Central Russian counterparts, residing in a considerably milder climate. In this paper, we analyzed these cohorts from the inflammaging perspective and addressed two hypotheses: a mismatch in the immunological profiles and accelerated inflammatory aging in Yakuts. We found that the levels of 17 cytokines displayed statistically significant differences in the mean values between the groups (with minimal p-value = 2.06 × 10⁻¹⁹), and 6 of them are among 10 SImAge markers. We demonstrated that five out of these six markers (PDGFB, CD40LG, VEGFA, PDGFA, and CXCL10) had higher mean levels in the Yakutian cohort, and therefore, due to their positive chronological age correlation, might indicate a trend toward accelerated inflammatory aging. At the same time, a statistically significant biological age acceleration difference between the two cohorts according to the inflammatory SImAge clock was not detected because they had similar levels of CXCL9, CCL22, and IL6, the top contributing biomarkers to SImAge. We introduced an explainable deep neural network to separate individual inflammatory profiles between the two groups, resulting in over 95% accuracy. The obtained results allow for hypothesizing the specificity of cytokine and chemokine profiles among people living in extremely cold climates, possibly reflecting the effects of long-term human (dis)adaptation to cold conditions related to inflammaging and the risk of developing a number of pathologies.

В статье приводятся результаты клинического и генетического исследования якутской семьи с наследственной спастической параплегией (НСП). Изучены заболевшие и здоровые члены семьи. Болезнь клинически характеризуется как прогрессирующая спастическая параплегия нижних конечностей в сочетании с далеко зашедшим случаем периферической нейропатии. Применены методы экзомного секвенирования всего генома, молекулярное моделирование динамина-2 и экспериментальное воспроизведение ключевых элементов патогенеза НСП. Генетический анализ выявил мутацию c.2155C> T, p.R719W в высоко устойчивом GTP-эффекторном домене гена динамин-2. В экспериментах на клетках HeLa показано, что мутантный динамин-2 подавляет процесс эндоцитоза. Моделирование in-silico определило, что выявленная мутация расположена в сигнальном комплексе динамина-2 и потенциально нарушает сборку и функциональные свойства белка. Тестирование этой мутации в других якутских семьях с НСП показало отрицательный результат, что еще раз подтверждает генетическую гетерогенность этой...