Acetylation of c-Myc at Lysine 148 Protects Neurons After Ischemia.

This study focuses on understanding the role of c-Myc, a cancer-associated transcription factor, in the penumbra following ischemic stroke. While its involvement in cell death and survival is recognized, its post-translational modifications, particularly acetylation, remain understudied in ischemia models. Investigating these modifications could have significant clinical implications for controlling c-Myc activity in the central nervous system. Although previous studies on c-Myc acetylation have been limited to non-neuronal cells, our research examines its expression in perifocal cells during stroke recovery to explore regulatory mechanisms via acetylation. We found that in peri-infarct neurons, c-Myc is upregulated with acetylation at K148 but not K323 during the acute phase of stroke, with SIRT2 deacetylase primarily affecting K148 acetylation. Molecular dynamics simulations suggest that lysine 148 plays a crucial role in stabilizing c-Myc spatial structure. Increased acetylation at K148 reduces c-Myc compaction, potentially limiting its nuclear penetration, promoting calpain-mediated cleavage, and decreasing nuclear localization. Additionally, cytoplasmic acetylation at K148 may alter c-Myc's interaction with unidentified proteins, potentially influencing its pro-apoptotic effects and promoting cytoplasmic accumulation. Targeting SIRT2 with selective inhibitors could be a promising avenue for future stroke therapy strategies.

Acetylation of p53 in the Cerebral Cortex after Photothrombotic Stroke.

p53 expression and acetylation are crucial for the survival and death of neurons in penumbra. At the same time, the outcome of ischemia for penumbra cells depends largely on the histone acetylation status, but the effect of histone acetyltransferases and deacetylases on non-histone proteins like p53 is largely understudied. With combined in silico and in vitro approach, we have identified enzymes capable of acetylation/deacetylation, distribution, stability, and pro-apoptotic activity of p53 in ischemic penumbra in the course of post-stroke recovery, and also detected involved loci of acetylation in p53. The dynamic regulation of the acetylation of p53 at lysine 320 is controlled by acetyltransferase PCAF and histone deacetylases HDAC1 and HDAC6. The in silico simulation have made it possible to suggest the acetylation of p53 at lysine 320 acetylation may facilitate the shuttling of p53 between the nucleus and cytoplasm in penumbra neurons. Acetylation of p53 at lysine 320 is more preferable than acetylation at lysine 373 and probably promotes survival and repair of penumbra neurons after stroke. Strategies to increase p53 acetylation at lysine 320 via increasing PCAF activity, inhibiting HDAC1 or HDAC6, inhibiting p53, or a combination of these interventions may have therapeutic benefits for stroke recovery and would be promising for neuroprotective therapy of stroke.

[Indirect molecular genetic predisposition factors to increased thrombosis in sufferers with mechanical lower limb trauma]. / Nepryamye molekulyarno-geneticheskie faktory predraspolozhennosti k povyshennomu tromboobrazovaniyu u poterpevshikh s mekhanicheskoi travmoi nizhnikh konechnostei.

THE AIM OF THE STUDY: Was to selectively determine the occurrence frequency of polymorphic alleles in candidate genes of hereditary predisposition to increased thrombosis (T) in persons with mechanical trauma of musculoskeletal system (MS), who died from pulmonary artery thromboembolia (PATE). A total of 48 deaths from PATE cases of sufferers with MS trauma. The character of single nucleotide polymorphisms carriage (SNPC) in 13 candidate genes of hereditary predisposition to increased T (in genes, responsible for the synthesis of plasma proteins of the hemostatic system, platelet factors affecting tension of vessel wall and folate cycle) was determined. It has been established that the most common «mutant¼ alleles are found in PAI-1 -675 5G/4G, MTHFR 677 CT and MTRR 66AG genes, and in 87.8, 53.85 and 75.0% of the analysed cases, respectively. The consideration of SNP carriage character in the genes of predisposition to increased T is required for the full expert judgement on the causality between a mechanical trauma and PATE.

[Forensic expert evaluation problems of early and late complications of interventional methods of treating coronary heart disease (systematic literature review)].

This article focuses on current concepts of ischemic heart disease, its interventional treatment, pathomorphology of early and late postoperative complications, and forensic aspects in evaluation of restenosis of a stented blood vessel.

Morphometric Parameters of the Lung Tissue in Isolated Musculoskeletal Injuries under Conditions of Moderate Hyperhomocysteinemia.

The combination of inherited and acquired factors of increased thrombosis complicates establishing the cause-effect relationships between mechanical injury and death during forensic medical examination. Morphometric parameters of the lung tissue and pulmonary vessels in isolated mechanical trauma under conditions of moderate hyperhomocysteinemia were studied in an experiment on laboratory animals. A regularity in changes of the morphometry parameters of the pulmonary vessels was found. Morphometric changes in the wall of pulmonary parenchyma veins can be used as an additional marker to assess the causal relationship between isolated mechanical injury and fatal complication in the form of pulmonary embolism.

Model of Moderate Hyperhomocisteinemia Associated with Mechanical Injury: Dynamics of Morphometric Parameters of Microcirculatory Vessels.

A model of moderate hyperhomocysteinemia associated with mechanical injury of the musculoskeletal system was developed and experimentally substantiated. The adequacy of this model for studies of morphological and functional regularities is verified. This model can be used for the development of a new concept of evaluation of thrombotic complications of mechanical injury.

[Molecular genetic basis of sudden cardiac death in the young with cardiomyopathy of various origins]. / Molekuliarno-geneticheskie osnovy vnezapnoi serdechnoi smerti lits molodogo vozrasta s kardiomiopatiei razlichnogo geneza.

This paper provides a review of the modern literature devoted to the problem of forensic medical interpretation of the molecular genetic research of the young who died suddenly. The authors attempted to draw a parallel between the morphological markers of different variants of cardiomyopathy as the most common disease in sudden death at a young age and the association with genetic mutations in the genes responsible for the synthesis of sarcomer proteins, desmos and membrane channels. Based on the results of the analysis, further research is proposed to improve the accuracy of forensic diagnosis in cases of young deaths.

Detection of nucleotide sequences capable of forming non-canonical DNA structures: Application of automata theory.

In this study, we develop a program that allows us to reveal DNA receptors, i.e. nucleotide sequences that may form more than one non-canonical structure. The data obtained may be analysed either experimentally or using DNA banks, and refers to the coding, non-coding or promotor region of the gene. These results provide a better understanding of the role that non-canonical structures play in pathological modifications of the genetic apparatus, resulting in tumour formation or inherited disease. They also reveal the effect of single nucleotide polymorphisms on gene expression, indicate so-called "risk regions" in which the substitution of a single nucleotide may lead to increased formation of non-canonical structures, and elucidate the epigenetic mechanisms of microorganism adaptation.

[The evaluation of stability of blood stains immobilized on the FHA cards during their prolonged storage].

We have studied the samples of dry blood immobilized on the FTA cards following a 15-year period of their storage at room temperature. The DNA preparations were obtained based on the protocol recommended by the manufacturer including washing up with the FTA reactant and in parallel by means of complete extraction with the use of robotic stations. The preparations were compared in terms of the content of amplificationally active DNA and the effectiveness of typing STR-loci of chromosomal DNA. The complete genetic profile was derived only from 41 (82%) of the 50 FTA cards with immobilized blood samples available for the investigation that had been treated with the FTA reactant and stored during 15 years at room temperature. In 9 (18%) cases, incomplete genetic profiles were obtained that were characterized by the absence of PCR-products, as well as missing of true alleles and the presence of pseudoalleles. Such poor results are supposed to be attributable to the occurrence of the residual inhibitors of DNA-polymerase activity due to the incomplete purification of the samples. This disadvantage was overcome by the application of robotic stations for the total DNA extraction. This approach made it possible to obtain the acceptable genetic profiles for each blood samples stored at the FTA cards during 15 years. Nevertheless, even these preparations exhibited the reduced matrix activity of high molecular weight SRT-loci. This observation suggests that long-term storage of dry blood samples on FTA cards at room temperature does not guarantee the absence of degradation of their DNA.