Search Results (21)

Background/Objective: Genetic factors contribute significantly to Parkinson’s disease (PD), especially in cases with early onset or positive family history. However, previous investigations of the genetic landscape in PD populations were mainly based on targeted genotyping. The aim of this study was to investigate the prevalence of pathogenic variants in known PD-associated genes in a series of Swedish PD patients. Methods: We performed whole-exome sequencing on 285 PD probands from southern Sweden. Our series was enriched for patients with early disease onset or positive family history. We focused on 44 genes previously linked to PD. Results: We identified a CHCHD2 p.(Phe84LeufsTer6) frameshift variant in two unrelated patients and report the first PD case of Swedish ancestry carrying the VPS35 p.(Asp620Asn) variant. Additionally, in one patient each, we found an SNCA duplication, an SNCA p.(Ala53Thr) variant, and a LRRK2 p.(Gly2019Ser) variant. Thus, only 2.1% (n = 6) of patients in this series had Mendelian monogenic PD forms. In addition, forty-three patients carried variants in GBA1, including T369M, which may lack disease-association in our population (n = 12); E326K (n = 22), which is classified as a PD risk variant; as well as N370S (n = 3), R329H (n = 3), S107L (n = 1), and L444P (n = 1), with one patient harboring both T369M and E326K. Pathogenic variants in ARSA, ATP7B, and PRKN genes were also detected in heterozygote form, but their role in PD remains uncertain. Conclusions: Monogenic forms of PD are rare in southern Sweden, even among the familial and early-onset PD patients that were overrepresented in our study. Our findings highlight the genetic diversity in Swedish PD patients and identify key variants for further functional and clinical studies. Full article

The effects of proline co-solvent on helix folding are explored through the single discrete coordinate of the number of helical hydrogen bonds. The analysis is based on multi-microsecond length molecular dynamics simulations of alanine-based helix-forming peptides, (ALA)n, of length n = 4, 8, 15 and 21 residues, in an aqueous solution with 2 M concentration of proline. The effects of addition of proline on the free energy landscape for helix folding were analyzed using the graph-based Dijkstra algorithm, Optimal Dimensionality Reduction kinetic coarse graining, committor functions, as well as through the diffusion of the helix boundary. Viewed at a sufficiently long time-scale, helix folding in the coarse-grained hydrogen bond space follows a consecutive mechanism, with well-defined initiation and propagation phases, and an interesting set of intermediates. Proline addition slows down the folding relaxation of all four peptides, increases helix content and induces subtle mechanistic changes compared to pure water solvation. A general trend is for transition state shift towards earlier stages of folding in proline relative to water. For ALA5 and ALA8 direct folding is dominant. In ALA8 and ALA15 multiple pathways appear possible. For ALA21 a simple mechanism emerges, with a single path from helix to coil through a set of intermediates. Overall, this work provides new insights into effects of proline co-solvent on helix folding, complementary to more standard approaches based on three-dimensional molecular structures. Full article

The vigorous development of urban air mobility (UAM) is reshaping the urban travel landscape, but it also poses severe challenges to the safe and efficient operation of dense and complex airspace. Potential conflicts between flight plans have become a core bottleneck restricting its development. Traditional flight plan adjustment and management methods often rely on deterministic trajectory predictions, ignoring the inherent temporal uncertainties in actual operations, which may lead to the underestimation of potential risks. Meanwhile, existing global optimization strategies often face issues of inefficiency and overly broad adjustment scopes when dealing with large-scale plan conflicts. To address these challenges, this study proposes an innovative flight plan conflict management framework. First, by introducing a probabilistic model of flight time errors, a new conflict detection mechanism based on confidence intervals is constructed, significantly enhancing the ability to foresee non-obvious conflict risks. Furthermore, based on complex network theory, the framework accurately identifies a small number of “critical flight plans” that play a core role in the conflict network, revealing their key impact on chain reactions of conflicts. On this basis, a phased optimization strategy is adopted, prioritizing the adjustment of spatiotemporal parameters (departure time and speed) for these critical plans to systematically resolve most conflicts. Subsequently, only fine-tuning the speeds of non-critical plans is required to address remaining local conflicts, thereby minimizing interference with the overall operational order. Simulation results demonstrate that this framework not only significantly improves the comprehensiveness of conflict detection but also effectively reduces the total number of conflicts. Additionally, the proposed phased artificial lemming algorithm (ALA) outperforms traditional optimization algorithms in terms of solution quality. This work provides an important theoretical foundation and a practically valuable solution for developing robust and efficient UAM dynamic scheduling systems, holding promise to support the safe and orderly operation of large-scale urban air traffic in the future. Full article

Maximal safe surgical resection is the gold standard in brain tumor surgery. Fluorescence-guided surgery (FGS) is one of many intraoperative techniques that have been designed with the intention of accomplishing this goal. 5-aminolevulinic acid (5-ALA) is one of the main fluorophores that facilitates FGS in neurosurgical oncology. Multiple different types of brain tumors can take in and metabolize 5-ALA into protoporphyrin IX (PpIX) through the mitochondria heme biosynthesis pathway. PpIX then selectively accumulates in brain tumor cells due to decreased ferrochelatase activity and emits red fluorescence (630–720 nm) when excited with blue light (375–440 nm). This mechanism allows neurosurgeons to better visualize tumor burden and increase extent of resection while preserving non-cancerous brain parenchyma and, specifically, eloquent white matter tracts, if combined with mapping techniques, thereby minimizing morbidity while improving survival. While 5-ALA use is well established in the treatment of high-grade gliomas, its applicability in recurrent high-grade and non-enhancing IDH-mutant low-grade gliomas, as well as non-glial tumors, is less established or limited by certain features of their cellular and molecular biology. This review aims to discuss the current landscape of 5-ALA utility across the diverse range of brain tumors, practical considerations that optimize its current use in neurosurgery, modern clinical limitations of 5-ALA, and how its application can be expanded by combining its use with other techniques that overcome current limitations. Full article

Proinsulin has three distinct regions: the well-folded A- and B-chains and the dynamic disordered C-peptide. The highly conserved B-chain is a hotspot for diabetes-associated mutations, including the severe loss-of-function R(B22)Q mutation linked to childhood-onset diabetes. Here, we explore R(B22)’s role in proinsulin stability using AlphaFold-predicted structures and metadynamics simulations to achieve enhanced sampling of the free energy landscape. Our results show that R(B22) stabilizes proinsulin by interacting with N86. Substituting R(B22) with E or Q disrupts this interaction, increasing conformational flexibility. The R(B22)Q variant exhibits a flattened free energy landscape, favoring unfolded states. Additional substitutions, including Gly, Ala, Lys, Tyr, Asp, and Phe, destabilize proinsulin to varying extents by weakening hydrogen bonding. Disrupting the R(B22)–N86 interaction broadly reduces inter-chain contacts, raising the risk of aggregation-prone states. Given the link between R(B22) mutations and diabetes, our study provides crucial molecular insights into proinsulin instability. These findings highlight the role of key inter-domain (A-Chain–B-chain, B-Chain–C-peptide, and A-Chain–C-peptide) interactions in maintaining protein structures and the implications this has for understanding disease-associated proinsulin variants. Full article

Small intermountain river basins are most suitable for developing new methods to estimate water balance due to their well-defined catchment boundaries, relatively rapid runoff processes, and accessible landscapes for study. In general terms, dissecting the hydrograph of a small mountain river requires calibration of the flow model against multi-year data sets, including (a) glacier mass balance and snow water content, (b) radiation balance calculation, (c) estimation of the groundwater contribution, and (d) water discharge measurements. The minimum primary data set is limited to the precipitation and temperature distributions at the catchment. This approach postulates that the conditions for the formation of all components of river flow are known in advance. It is reduced to calculating the dynamic balance between precipitation (input part) and runoff, ablation, and evaporation (output part). In practice, accurately accounting for the inflow and outflow components of the balance, as well as the impact of regulating reservoirs, can be a challenging task that requires significant effort and expense, even for the extensively researched catchments. Our studies indicate the potential benefits of an approach based on one-time, but detailed, observations of stable isotope composition, temperature, and water chemistry, in addition to standard datasets. This paper presents the results of the 2022–2023 work conducted in the basin of the small mountain river Ala-Archa, located on the northern slope of the Kyrgyz Range in Tien-Shan, which was chosen as an example due to its well-studied nature. Our approach could identify previously unknown factors of flow formation and assess the time and effectiveness of work in similar conditions. Full article

Bacillus anthracis is the bacterium responsible for causing the zoonotic disease called anthrax. The disease presents itself in different forms like gastrointestinal, inhalation, and cutaneous. Bacterial spores are tremendously adaptable, can persist for extended periods and occasionally endanger human health. The Anthrax Toxin Receptor-2 (ANTXR2) gene acts as membrane receptor and facilitates the entry of the anthrax toxin into host cells. Additionally, mutations in the ANTXR2 gene have been linked to various autoimmune diseases, including Hyaline Fibromatosis Syndrome (HFS), Ankylosing Spondylitis (AS), Juvenile Hyaline Fibromatosis (JHF), and Infantile Systemic Hyalinosis (ISH). This study delves into the genetic landscape of ANTXR2, aiming to comprehend its associations with diverse disorders, elucidate the impacts of its mutations, and pinpoint minimal non-pathogenic mutations capable of reducing the binding affinity of the ANTXR2 gene with the protective antigen. Recognizing the pivotal role of single-nucleotide polymorphisms (SNPs) in shaping genetic diversity, we conducted computational analyses to discern highly deleterious and tolerated non-synonymous SNPs (nsSNPs) in the ANTXR2 gene. The Mutpred2 server determined that the Arg465Trp alteration in the ANTXR2 gene leads to altered DNA binding (p = 0.22) with a probability of a deleterious mutation of 0.808; notably, among the identified deleterious SNPs, rs368288611 (Arg465Trp) stands out due to its significant impact on altering the DNA-binding ability of ANTXR2. We propose these SNPs as potential candidates for hypertension linked to the ANTXR2 gene, which is implicated in blood pressure regulation. Noteworthy among the tolerated substitutions is rs200536829 (Ala33Ser), recognized as less pathogenic; this highlights its potential as a valuable biomarker, potentially reducing side effects on the host while also reducing binding with the protective antigen protein. Investigating these SNPs holds the potential to correlate with several autoimmune disorders and mitigate the impact of anthrax disease in humans. Full article

Erythropoietic protoporphyria (EPP) is a genetic disorder stemming from reduced ferrochelatase expression, the final enzyme in the pathway of heme biosynthesis. A closely related condition, X-linked protoporphyria (XLP), bears similar clinical features although it arises from the heightened activity of δ-aminolevulinic acid synthase 2 (ALAS2), the first and normally rate-controlling enzyme in heme biosynthesis in developing red blood cells. Both of these abnormalities result in the buildup of protoporphyrin IX, leading to excruciating light sensitivity and, in a minority of cases, potentially fatal liver complications. Traditionally, managing EPP and XLP involved sun avoidance. However, the emergence of innovative therapies, such as dersimelagon, is reshaping the therapeutic landscape for these conditions. In this review, we summarize salient features of the properties of dersimelagon, shedding light on its potential role in advancing our understanding of treatment options for EPP and XLP. Full article

Inherited retinal diseases (IRDs) constitute a prevalent group of inherited ocular disorders characterized by marked genetic diversity alongside moderate clinical variability. Among these, ABCA4-related eye pathology stands as a prominent form affecting the retina. In this study, we conducted an in-depth analysis of 96 patients harboring ABCA4 variants in the European part of Russia. Notably, the complex allele c.[1622T>C;3113C>T] (p.Leu541Pro;Ala1038Val, or L541P;A1038V) and the variant c.5882G>A (p.Gly1961Glu or G1961E) emerged as primary contributors to this ocular pathology within this population. Additionally, we elucidated distinct disease progression characteristics associated with the G1961E variant. Furthermore, our investigation revealed that patients with loss-of-function variants in ABCA4 were more inclined to develop phenotypes distinct from Stargardt disease. These findings provide crucial insights into the genetic and clinical landscape of ABCA4-related retinal dystrophies in this specific population. Full article

The current rate and magnitude of temperature rise in the Arctic are disproportionately high compared to global averages. Along with other natural and anthropogenic disturbances, this warming has caused widespread permafrost degradation and soil subsidence, resulting in the formation of thermokarst (thaw) lakes in areas of ice-rich permafrost. These lakes are hotspots of greenhouse gas emissions (CO₂ and CH₄), but with substantial spatial and temporal heterogeneity across Arctic and sub-Arctic regions. In Central Yakutia (Eastern Siberia, Russia), nearly half of the landscape has been affected by thermokarst processes since the early Holocene, resulting in the formation of more than 10,000 partly drained lake depressions (alas lakes). It is not yet clear how recent changes in temperature and precipitation will affect existing lakes and the formation of new thermokarst lakes. A multi-decadal remote sensing analysis of lake formation and development was conducted for two large study areas (~1200 km² each) in Central Yakutia. Mask Region-Based Convolutional Neural Networks (R-CNN) instance segmentation was used to semi-automate lake detection in Satellite pour l’Observation de la Terre (SPOT) and declassified US military (CORONA) images (1967–2019). Using these techniques, we quantified changes in lake surface area for three different lake types (unconnected alas lake, connected alas lake, and recent thermokarst lake) since the 1960s. Our results indicate that unconnected alas lakes are the dominant lake type, both in the number of lakes and total surface area coverage. Unconnected alas lakes appear to be more susceptible to changes in precipitation compared to the other two lake types. The majority of recent thermokarst lakes form within 1 km of observable human disturbance and their surface area is directly related to air temperature increases. These results suggest that climate change and human disturbances are having a strong impact on the landscape and hydrology of Central Yakutia. This will likely affect regional and global carbon cycles, with implications for positive feedback scenarios in a continued climate warming situation. Full article

Alas landscapes are unique ecosystems, which are dynamic, geochemically closed thermokarst landforms of the permafrost zone. Alases have a limited capacity in their active layer, and specific conditions for soil, flora and fauna formation. A comprehensive study of alas landscape functionswas carried out in Central Yakutia from 1988 to the present time using conventional methods of geobotany, zoology, entomology, etc. This paper presents long-term observations of lake fluctuation cycles and changes in the spatial structure of meadow spaces. The dynamics of the spatial structure lead to significant fluctuations in the productivity of alas phytocenoses. It was revealed that wet and normal alas meadows have the highest vegetation productivity. The long-term course of their productivity tends to decrease, which shows the influence of anthropogenic pressure since the main haymaking areas are located in these meadows. With sharp fluctuations in interannual weather conditions, which determine the microclimatic and soil characteristics of grass growth, the productivity of the edge phytocenoses tends to increase. The productivity of the steppe phytocenoses of the alas remains practically at the same level. Over the years of observation, the economic capacity of alas pastures and hayfields was calculated. Additionally, the paper presents the important role of fauna within closed alas ecosystems, which directly affects the functioning of alas landscapes and is directly involved in soil formation and the circulation of matter and energy. Full article

Using small molecules to inhibit the PD-1/PD-L1 pathway is an important approach in cancer immunotherapy. Natural compounds such as capsaicin, zucapsaicin, 6-gingerol and curcumin have been proposed to have anticancer immunologic functions by downregulating the PD-L1 expression. PD-L1 dimerization promoted by small molecules was recently reported to be a potential mechanism to inhibit the PD-1/PD-L1 pathway. To clarify the molecular mechanism of such compounds on PD-L1 dimerization, molecular docking and molecular dynamics simulations were performed. The results evidenced that these compounds could inhibit PD-1/PD-L1 interactions by directly targeting PD-L1 dimerization. Binding free energy calculations showed that capsaicin, zucapsaicin, 6-gingerol and curcumin have strong binding ability with the PD-L1 dimer, where the affinities of them follow the trend of zucapsaicin > capsaicin > 6-gingerol ≈ curcumin. Analysis by residue energy decomposition, contact numbers and nonbonded interactions revealed that these compounds have a tight interaction with the C-sheet, F-sheet and G-sheet fragments of the PD-L1 dimer, which were also involved in the interactions with PD-1. Moreover, non-polar interactions between these compounds and the key residues Ile54, Tyr56, Met115 and Ala121 play a key role in stabilizing the protein–ligand complexes in solution, in which the 4′-hydroxy-3′-methoxyphenyl group and the carbonyl group of zucapsaicin, capsaicin, 6-ginger and curcumin were significant for the complexation of small molecules with the PD-L1 dimer. The conformational variations of these complexes were further analyzed by free energy landscape (FEL) and principal component analysis (PCA) and showed that these small molecules could make the structure of dimers more stable. This work provides a mechanism insight for food-derived small molecules blocking the PD-1/PD-L1 pathway via directly targeting the PD-L1 dimerization and offers theoretical guidance to discover more effective small molecular drugs in cancer immunotherapy. Full article

Vegetation and soils of the North Taiga zone were studied in natural and thermokarst-disturbed areas of Yana-Adycha interfluve (northeastern Yakutia). Soil research includes a description and physicochemical analysis of samples. The objects of study were selected taking into account the landscape diversity of the area experiencing permafrost melting due to pyrogenic factors under global climate change: young thermokarst and taiga untouched by fires and within the thermokarst basin of early Holocene. It was determined that the permafrost melting is accompanied by the transformation of homogeneous soil cover. After a forest fire, thawing depth increases and occurs redistribution of moisture and water-soluble matters. As a result, on the drier tops of byllars, the formation of albic material under the organogenic horizon is observed in the calcic cambic cryosol, which indicates a fairly fast transformation rate. In depressions, the forest is not recovered. In the mature alas, the vegetation and soil cover has a belt structure, represented by a combination of cryosols, stagnosols, and gleysols. In contrast to the soils of the Central Yakutia alases, there are almost no signs of lacustrine redeposition of soil, which indicates a difference in the processes of alas formation in different parts of the cryolitozone. Full article

Among the reasons for soil degradation, runoff-induced erosion causes the greatest damage to agriculture in European Russia. One of the effective tools for regulating soil erosion is changing the structure of sown areas and the composition of crops with a focus on soil conservation and rehabilitation land use. The aim of this paper is to present the results of the impact of the program on river-basin nature management and the adaptive landscape agriculture system (ALAS) on changes in soil losses due to storm erosion in one of the agriculturally most developed and, at the same time, most eroded administrative regions of European Russia—Belgorod Oblast. In this study, the calculation of potential soil washout was carried out for three cropland models: (1) The maximum erosion potential of the territory, expressed in terms of soil washout from bare (clean) fallow areas; (2) soil washout, considering the actual structure of sown areas over the past 10 years; and (3) soil washout, considering the full implementation of projects for the erosion-control organization of cropland within the framework of ALAS. The calculation of erosion-induced soil losses was carried out according to the USLE model adapted to regional environmental conditions, while the C-factor values were set separately for each model. For model 1, the average soil loss is 11.3 t/ha per year; for model 2, it is 3.5 t/ha per year; and for model 3, it is 2.2 t/ha per year. It was found that the current programs for the biologization of agriculture and the contour-reclamation organization of cropland would have a noticeable erosion-control effect. It is noteworthy that the greatest efficiency was modeled for areas with unfavorable relief conditions, with up to 40% reduction in soil losses as compared to actual ones. Full article

In cancer immunotherapy, an emerging approach is to block the interactions of programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) using small-molecule inhibitors. The food-derived polyphenols curcumin (CC), resveratrol (RSV) and epigallocatechin gallate (EGCG) have anticancer immunologic functions, which, recently, have been proposed to act via the downregulation of PD-L1 expression. However, it remains unclear whether they can directly target PD-L1 dimerization and, thus, interrupt the PD-1/PD-L1 pathway. To elucidate the molecular mechanism of such compounds on PD-L1 dimerization, molecular docking and nanosecond molecular dynamics simulations were performed. Binding free energy calculations show that the affinities of CC, RSV and EGCG to the PD-L1 dimer follow a trend of CC > RSV > EGCG. Hence, CC is the most effective inhibitor of the PD-1/PD-L1 pathway. Analysis on contact numbers, nonbonded interactions and residue energy decomposition indicate that such compounds mainly interact with the C-, F- and G-sheet fragments of the PD-L1 dimer, which are involved in interactions with PD-1. More importantly, nonpolar interactions between these compounds and the key residues Ile54, Tyr56, Met115, Ala121 and Tyr123 play a dominant role in binding. Free energy landscape and secondary structure analyses further demonstrate that such compounds can stably interact with the binding domain of the PD-L1 dimer. The results provide evidence that CC, RSV and EGCG can inhibit PD-1/PD-L1 interactions by directly targeting PD-L1 dimerization. This provides a novel approach to discovering food-derived small-molecule inhibitors of the PD-1/PD-L1 pathway with potential applications in cancer immunotherapy. Full article