Membrane Permeabilization by Oligomeric α-Synuclein: In Search of the Mechanism

Background: \ud The question of how the aggregation of the neuronal protein α-synuclein contributes to neuronal toxicity in Parkinson's disease has been the subject of intensive research over the past decade. Recently, attention has shifted from the amyloid fibrils to soluble oligomeric intermediates in the α-synuclein aggregation process. These oligomers are hypothesized to be cytotoxic and to permeabilize cellular membranes, possibly by forming pore-like complexes in the bilayer. Although the subject of α-synuclein oligomer-membrane interactions has attracted much attention, there is only limited evidence that supports the pore formation by α-synuclein oligomers. In addition the existing data are contradictory.\ud \ud Methodology/Principal Findings:\ud Here we have studied the mechanism of lipid bilayer disruption by a well-characterized α-synuclein oligomer species in detail using a number of in vitro bilayer systems and assays. Dye efflux from vesicles induced by oligomeric α-synuclein was found to be a fast all-or-none process. Individual vesicles swiftly lose their contents but overall vesicle morphology remains unaltered. A newly developed assay based on a dextran-coupled dye showed that non-equilibrium processes dominate the disruption of the vesicles. The membrane is highly permeable to solute influx directly after oligomer addition, after which membrane integrity is partly restored. The permeabilization of the membrane is possibly related to the intrinsic instability of the bilayer. Vesicles composed of negatively charged lipids, which are generally used for measuring α-synuclein-lipid interactions, were unstable to protein adsorption in general.\ud \ud Conclusions/Significance:\ud The dye efflux from negatively charged vesicles upon addition of α-synuclein has been hypothesized to occur through the formation of oligomeric membrane pores. However, our results show that the dye efflux characteristics are consistent with bilayer defects caused by membrane instability. These data shed new insights into potential mechanisms of toxicity of oligomeric α-synuclein species

Computational approaches for modeling human intestinal absorption and permeability

Human intestinal absorption (HIA) is an important roadblock in the formulation of new drug substances. Computational models are needed for the rapid estimation of this property. The measurements are determined via in vivo experiments or in vitro permeability studies. We present several computational models that are able to predict the absorption of drugs by the human intestine and the permeability through human Caco-2 cells. The training and prediction sets were derived from literature sources and carefully examined to eliminate compounds that are actively transported. We compare our results to models derived by other methods and find that the statistical quality is similar. We believe that models derived from both sources of experimental data would provide greater consistency in predictions. The performance of several QSPR models that we investigated to predict outside the training set for either experimental property clearly indicates that caution should be exercised while applying any of the models for quantitative predictions. However, we are able to show that the qualitative predictions can be obtained with close to a 70% success rate

Cephalopod-omics: emerging fields and technologies in cephalopod biology

Few animal groups can claim the level of wonder that cephalopods instill in the minds of researchers and the general public. Much of cephalopod biology, however, remains unexplored: the largest invertebrate brain, difficult husbandry conditions, complex (meta-)genomes, among many other things, have hindered progress in addressing key questions. However, recent technological advancements in sequencing, imaging, and genetic manipulation have opened new avenues for exploring the biology of these extraordinary animals. The cephalopod molecular biology community is thus experiencing a large influx of researchers, emerging from different fields, accelerating the pace of research in this clade. In the first post-pandemic event at the Cephalopod International Advisory Council (CIAC) conference in April 2022, over 40 participants from all over the world met and discussed key challenges and perspectives for current cephalopod molecular biology and evolution. Our particular focus was on the fields of comparative and regulatory genomics, gene manipulation, single cell transcriptomics, metagenomics and microbial interactions. This article is a result of this joint effort, summarizing the latest insights from these emerging fields, their bottlenecks and potential solutions. The article highlights the interdisciplinary nature of the cephalopod -omics community and provides an emphasis on continuous consolidation of efforts and collaboration in this rapidly evolving field

The new early-maturing winter bread wheat variety ‘Zhavoronok’

There has been presented the characteristics of the new early-maturing winter bread wheat variety ‘Zhavoronok’ according to economically valuable traits and properties. The development of early-maturing grain crop varieties is one of the main issues of grain production. The combination of a relatively short vegetation period with high productivity in one genotype helps to solve a number of agricultural concerns. This allows using techniques more systematic, reducing the intensity of harvesting and yield loss significantly, which occur when cultivating simultaneously maturing varieties on large areas. The purpose of the current study was to evaluate the new early-maturing winter bread wheat variety ‘Zhavoronok’ on the basis of a set of economically valuable traits. The study was carried out in 2015–2019 with such forecrops as maize for grain, weedfree fallow, peas and sunflower. In the department of winter wheat breeding and seed production of the FSBSI Agricultural Research Center “Donskoy” a lot of work is being done on winter wheat breeding, and one of the important directions is the development of early-maturing varieties. The winter bread wheat variety ‘Zhavoronok’ has been included in the State List of Breeding Achievements of the Russian Federation since 2020 and approved for use the North Caucasus and Nizhne-Volga regions. According to the length of the growing period, it belongs to the early-maturing group. Its high and stable productivity with various forecrops is explained by a complex of positive economically valuable traits and properties, such as high productivity of a head, resistance to lodging and brown rust, high frost resistance (the same as that of the variety ‘Don 107’). The variety ‘Zhavoronok’ is capable of producing good yields and full grain in arid years, its early maturity allows it to ‘escape’ drought, disease and other unfavorable conditions.</jats:p

The new early-maturing winter bread wheat variety ‘Zhavoronok’

There has been presented the characteristics of the new early-maturing winter bread wheat variety ‘Zhavoronok’ according to economically valuable traits and properties. The development of early-maturing grain crop varieties is one of the main issues of grain production. The combination of a relatively short vegetation period with high productivity in one genotype helps to solve a number of agricultural concerns. This allows using techniques more systematic, reducing the intensity of harvesting and yield loss significantly, which occur when cultivating simultaneously maturing varieties on large areas. The purpose of the current study was to evaluate the new early-maturing winter bread wheat variety ‘Zhavoronok’ on the basis of a set of economically valuable traits. The study was carried out in 2015–2019 with such forecrops as maize for grain, weedfree fallow, peas and sunflower. In the department of winter wheat breeding and seed production of the FSBSI Agricultural Research Center “Donskoy” a lot of work is being done on winter wheat breeding, and one of the important directions is the development of early-maturing varieties. The winter bread wheat variety ‘Zhavoronok’ has been included in the State List of Breeding Achievements of the Russian Federation since 2020 and approved for use the North Caucasus and Nizhne-Volga regions. According to the length of the growing period, it belongs to the early-maturing group. Its high and stable productivity with various forecrops is explained by a complex of positive economically valuable traits and properties, such as high productivity of a head, resistance to lodging and brown rust, high frost resistance (the same as that of the variety ‘Don 107’). The variety ‘Zhavoronok’ is capable of producing good yields and full grain in arid years, its early maturity allows it to ‘escape’ drought, disease and other unfavorable conditions