The molecular view of mechanical stress of brain cells, local translation, and neurodegenerative diseases

The assumption that chronic mechanical stress in brain cells stemming from intracranial hypertension, arterial hypertension, or mechanical injury is a risk factor for neurodegenerative diseases was put forward in the 1990s and has since been supported. However, the molecular mechanisms that underlie the way from cell exposure to mechanical stress to disturbances in synaptic plasticity followed by changes in behavior, cognition, and memory are still poorly understood. Here we review (1) the current knowledge of molecular mechanisms regulating local translation and the actin cytoskeleton state at an activated synapse, where they play a key role in the formation of various sorts of synaptic plasticity and long-term memory, and (2) possible pathways of mechanical stress intervention. The roles of the mTOR (mammalian target of rapamycin) signaling pathway; the RNA-binding FMRP protein; the CYFIP1 protein, interacting with FMRP; the family of small GTPases; and the WAVE regulatory complex in the regulation of translation initiation and actin cytoskeleton rearrangements in dendritic spines of the activated synapse are discussed. Evidence is provided that chronic mechanical stress may result in aberrant activation of mTOR signaling and the WAVE regulatory complex via the YAP/TAZ system, the key sensor of mechanical signals, and influence the associated pathways regulating the formation of F actin filaments and the dendritic spine structure. These consequences may be a risk factor for various neurological conditions, including autistic spectrum disorders and epileptic encephalopathy. In further consideration of the role of the local translation system in the development of neuropsychic and neurodegenerative diseases, an original hypothesis was put forward that one of the possible causes of synaptopathies is impaired proteome stability associated with mTOR hyperactivity and formation of complex dynamic modes of de novo protein synthesis in response to synapse-stimulating factors, including chronic mechanical stress

Causes of global extinctions in the history of life: facts and hypotheses

Paleontologists define global extinctions on Earth as a loss of about three-quarters of plant and animal species over a relatively short period of time. At least five global extinctions are documented in the Phanerozoic fossil record (~500-million-year period): ~65, 200, 260, 380, and 440 million years ago. In addition, there is evidence of global extinctions in earlier periods of life on Earth – during the Late Cambrian (~500 million years ago) and Ediacaran periods (more than 540 million years ago). There is still no common opinion on the causes of their occurrence. The current study is a systematized review of the data on recorded extinctions of complex life forms on Earth from the moment of their occurrence during the Ediacaran period to the modern period. The review discusses possible causes for mass extinctions in the light of the influence of abiogenic factors, planetary or astronomical, and the consequences of their actions. We evaluate the pros and cons of the hypothesis on the presence of periodicity in the extinction of Phanerozoic marine biota. Strong evidence that allows us to hypothesize that additional mechanisms associated with various internal biotic factors are responsible for the emergence of extinctions in the evolution of complex life forms is discussed. Developing the idea of the internal causes of periodicity and discontinuity in evolution, we propose our own original hypothesis, according to which the bistability phenomenon underlies the complex dynamics of the biota development, which is manifested in the form of global extinctions. The bistability phenomenon arises only in ecosystems with predominant sexual reproduction. Our hypothesis suggests that even in the absence of global abiotic catastrophes, extinctions of biota would occur anyway. However, our hypothesis does not exclude the possibility that in different periods of the Earth’s history the biota was subjected to powerful external influences that had a significant impact on its further development, which is reflected in the Earth’s fossil record

ON THE EQUIVALENCE OF DELAYED ARGUMENTS AND TRANSFER EQUATIONS FOR MODELING DYNAMIC SYSTEMS

Development and improvement of mathematical methods used in modeling biological systems represents a topical issue of mathematical biology. In this paper, we considered a general form of a system of first-order delayed differential equations, traditionally used for describing the function of biological systems of different hierarchical levels. The main feature of this class of models is that some inherent processes (for example, elongation of DNA, RNA, and protein synthesis) are described in a subtle form and can be explicitly specified only through delayed arguments. In this paper, we propose an algorithm for rewriting systems with constant delayed arguments in an equivalent form that represents a system of partial differential equations with transfer equations. The algorithm is universal, since it does not impose any special conditions on the form of the right-hand parts of systems with delayed arguments. The proposed method is a multivariant algorithm. That is, based on one system of differential equations with delayed arguments, the algorithm allows writing out a number of special systems of partial differential equations, which are equivalent to the original system with delayed argument in the entire solution set. The results obtained indicate that delayed arguments and transfer equations are equivalent mathematical tools for describing all types of dynamic processes of energy and/or matter transfer in biological, chemical, and physical systems, indicating a deep-level similarity between properties of dynamic systems, regardless of their origin. At the same time, those processes that are subtle when retarded argument is used can be explicitly described in the form of transfer equations using systems of partial differential equations. This property is extremely important for the modeling of molecular genetic systems in which processes of DNA, RNA, and protein synthesis proceed at variable rates and need to be considered in certain problems, what can easily be done in models constructed using the mathematical tool of partial derivatives

Molecular mechanisms of autism as a form of synaptic dysfunction

Autism spectrum disorders are a separate group of defects with a very high genetic component. Genetic screening has identified hundreds of mutations and other genetic variations associated with autism, and bioinformatic analysis of signaling pathways and gene networks has led to understanding that many of these mutational changes are involved in the functioning of synapses. A synapse is a site of electrochemical communication between neurons and an essential subunit for learning and memory. Interneuronal communicative relationships are plastic. The most prominent forms of synaptic plasticity are accompanied by changes in protein biosynthesis, both in neuron body and in dendrites. Protein biosynthesis or translation is a carefully regulated process, with a central role played by mTOR (mammalian or mechanistic target of rapamycin). Normally mTOR-regulated translation is slightly inhibited, and in most cases mutational damage to at least one of the links of the mTOR signaling pathway, increases translation and leads to impaired synaptic plasticity and behavior. Deregulation of the local translation in dendrites is connected with the following monogenic autism spectrum disorders: neurofibromatosis type 1, Noonan syndrome, Costello syndrome, Cowden syndrome, tuberous sclerosis, fragile X chromosome, syndrome, and Rett syndrome. The review considers the most important mutations leading to monogenic autism, as well as the possibility of a mechanism-based treatment of certain disorders of the autism spectrum

Rational metabolic engineering of <i>Corynebacterium glutamicum</i> to create a producer of L-valine

L-Valine is one of the nine amino acids that cannot be synthesized de novo by higher organisms and must come from food. This amino acid not only serves as a building block for proteins, but also regulates protein and energy metabolism and participates in neurotransmission. L-Valine is used in the food and pharmaceutical industries, medicine and cosmetics, but primarily as an animal feed additive. Adding L-valine to feed, alone or mixed with other essential amino acids, allows for feeds with lower crude protein content, increases the quality and quantity of pig meat and broiler chicken meat, as well as improves reproductive functions of farm animals. Despite the fact that the market for L-valine is constantly growing, this amino acid is not yet produced in our country. In modern conditions, the creation of strains-producers and organization of L-valine production are especially relevant for Russia. One of the basic microorganisms most commonly used for the creation of amino acid producers, along with Escherichia coli, is the soil bacterium Corynebacterium glutamicum. This review is devoted to the analysis of the main strategies for the development of L- valine producers based on C. glutamicum. Various aspects of L-valine biosynthesis in C. glutamicum are reviewed: process biochemistry, stoichiometry and regulation, enzymes and their corresponding genes, export and import systems, and the relationship of L-valine biosynthesis with central cell metabolism. Key genetic elements for the creation of C. glutamicum-based strains-producers are identified. The use of metabolic engineering to enhance L-valine biosynthesis reactions and to reduce the formation of byproducts is described. The prospects for improving strains in terms of their productivity and technological characteristics are shown. The information presented in the review can be used in the production of producers of other amino acids with a branched side chain, namely L-leucine and L-isoleucine, as well as D-pantothenate

Computer analysis of regulation of hepatocarcinoma marker genes hypermethylated by HCV proteins

Hepatitis C virus (HCV) is a risk factor that leads to hepatocellular carcinoma (HCC) development. Epigenetic changes are known to play an important role in the molecular genetic mechanisms of virus-induced oncogenesis. Aber rant DNA methylation is a mediator of epigenetic changes that are closely associated with the HCC pathogenesis and considered a biomarker for its early diagnosis. The ANDSystem software package was used to reconstruct and evaluate the statistical significance of the pathways HCV could potentially use to regulate 32 hypermethylated genes in HCC, including both oncosuppressor and protumorigenic ones identified by genome-wide analysis of DNA methylation. The reconstructed pathways included those affecting protein-protein interactions (PPI), gene expression, protein activity, stability, and transport regulations, the expression regulation pathways being statistically significant. It has been shown that 8 out of 10 HCV proteins were involved in these pathways, the HCV NS3 protein being implicated in the largest number of regulatory pathways. NS3 was associated with the regulation of 5 tumor-suppressor genes, which may be the evidence of its central role in HCC pathogenesis. Analysis of the reconstructed pathways has demonstrated that following the transcription factor inhibition caused by binding to viral proteins, the expression of a number of oncosuppressors (WT1, MGMT, SOCS1, P53) was suppressed, while the expression of others (RASF1, RUNX3, WIF1, DAPK1) was activated. Thus, the performed gene-network reconstruction has shown that HCV proteins can influence not only the methylation status of oncosuppressor genes, but also their transcriptional regulation. The results obtained can be used in the search for pharmacological targets to develop new drugs against HCV-induced HCC

The Transcription Factor Ultraspiracle Influences Honey Bee Social Behavior and Behavior-Related Gene Expression

Behavior is among the most dynamic animal phenotypes, modulated by a variety of internal and external stimuli. Behavioral differences are associated with large-scale changes in gene expression, but little is known about how these changes are regulated. Here we show how a transcription factor (TF), ultraspiracle (usp; the insect homolog of the Retinoid X Receptor), working in complex transcriptional networks, can regulate behavioral plasticity and associated changes in gene expression. We first show that RNAi knockdown of USP in honey bee abdominal fat bodies delayed the transition from working in the hive (primarily “nursing” brood) to foraging outside. We then demonstrate through transcriptomics experiments that USP induced many maturation-related transcriptional changes in the fat bodies by mediating transcriptional responses to juvenile hormone. These maturation-related transcriptional responses to USP occurred without changes in USP's genomic binding sites, as revealed by ChIP–chip. Instead, behaviorally related gene expression is likely determined by combinatorial interactions between USP and other TFs whose cis-regulatory motifs were enriched at USP's binding sites. Many modules of JH– and maturation-related genes were co-regulated in both the fat body and brain, predicting that usp and cofactors influence shared transcriptional networks in both of these maturation-related tissues. Our findings demonstrate how “single gene effects” on behavioral plasticity can involve complex transcriptional networks, in both brain and peripheral tissues