Multiple steps of prion strain adaptation to a new host.

The transmission of prions across species is a critical aspect of their dissemination among mammalian hosts, including humans. This process often necessitates strain adaptation. In this study, we sought to investigate the mechanisms underlying prion adaptation while mitigating biases associated with the history of cross-species transmission of natural prion strains.

Multiple steps of prion strain adaptation to a new host.

The transmission of prions across species is a critical aspect of their dissemination among mammalian hosts, including humans. This process often necessitates strain adaptation. In this study, we sought to investigate the mechanisms underlying prion adaptation while mitigating biases associated with the history of cross-species transmission of natural prion strains.

Amyloid Precursor Protein Changes Arrangement in a Membrane and Its Structure Depending on the Cholesterol Content.

One of the hallmarks of Alzheimer's disease (AD) is the accumulation of amyloid beta (Aβ) peptides in the brain. The processing of amyloid precursor protein (APP) into Aβ is dependent on the location of APP in the membrane, membrane lipid composition and, possibly, presence of lipid rafts. In this study, we used atomic force microscopy (AFM) to investigate the interaction between transmembrane fragment APP (corresponding to Aβ) and its amyloidogenic mutant L723P with membranes combining liquid-ordered and liquid-disordered lipid phases.

The Role of Genetic Variants in the Long Non-Coding RNA Genes and in the Pathogenesis of Childhood Obesity.

Long non-coding RNAs (lncRNAs) play important roles in the maintenance of metabolic homeostasis. Recently, many studies have suggested that lncRNAs, such as Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) and Imprinted Maternally Expressed Transcript (H19), might participate in the pathogenesis of metabolic disorders such as obesity. We conducted a case-control study with 150 Russian children and adolescents aged between 5 and 17 years old in order to assess the statistical association between the single nucleotide polymorphisms (SNPs) rs3200401 in and rs217727 in , and the risk of developing obesity in this population.

Diversity of Structural, Dynamic, and Environmental Effects Explain a Distinctive Functional Role of Transmembrane Domains in the Insulin Receptor Subfamily.

Human InsR, IGF1R, and IRR receptor tyrosine kinases (RTK) of the insulin receptor subfamily play an important role in signaling pathways for a wide range of physiological processes and are directly associated with many pathologies, including neurodegenerative diseases. The disulfide-linked dimeric structure of these receptors is unique among RTKs. Sharing high sequence and structure homology, the receptors differ dramatically in their localization, expression, and functions.

Computer-aided Evaluation of Polyvalent Medications' Pharmacological Potential. Multiphytoadaptogen as a Case Study.

Many human diseases including cancer, degenerative and autoimmune disorders, diabetes and others are multifactorial. Pharmaceutical agents acting on a single target do not provide their efficient curation. Multitargeted drugs exhibiting pleiotropic pharmacological effects have certain advantages due to the normalization of the complex pathological processes of different etiology.

Aβ plaques do not protect against HSV-1 infection in a mouse model of familial Alzheimer's disease, and HSV-1 does not induce Aβ pathology in a model of late onset Alzheimer's disease.

The possibility that the etiology of late onset Alzheimer's disease is linked to viral infections of the CNS has been actively debated in recent years. According to the antiviral protection hypothesis, viral pathogens trigger aggregation of Aβ peptides that are produced as a defense mechanism in response to infection to entrap and neutralize pathogens. To test the causative relationship between viral infection and Aβ aggregation, the current study examined whether Aβ plaques protect the mouse brain against Herpes Simplex Virus 1 (HSV-1) infection introduced via a physiological route and whether HSV-1 infection triggers formation of Aβ plaques in a mouse model of late-onset AD that does not develop Aβ pathology spontaneously.

Kinetics and Energetics of Intramolecular Electron Transfer in Single-Point Labeled TUPS-Cytochrome Derivatives.

Electron transfer within and between proteins is a fundamental biological phenomenon, in which efficiency depends on several physical parameters. We have engineered a number of horse heart cytochrome single-point mutants with cysteine substitutions at various positions of the protein surface. To these cysteines, as well as to several native lysine side chains, the photoinduced redox label 8-thiouredopyrene-1,3,6-trisulfonate (TUPS) was covalently attached.

AlldEnantiomeric Peptide D3 Designed for Alzheimer's Disease Treatment Dynamically Interacts with Membrane-Bound Amyloid-β Precursors.

Alzheimer's disease (AD) is a severe neurodegenerative pathology with no effective treatment known. Toxic amyloid-β peptide (Aβ) oligomers play a crucial role in AD pathogenesis. AlldEnantiomeric peptide D3 and its derivatives were developed to disassemble and destroy cytotoxic Aβ aggregates.

Association of SNPs in Lipid Metabolism Gene Single Nucleotide Polymorphism with the Risk of Obesity in Children.

Obesity is one of the most common metabolic disorders in the world, which develops due to an imbalance in energy consumption and expenditure, and both genetic and environmental factors are of great importance. We investigated the potential interactions of single nucleotide polymorphisms that might contribute to the development of polygenic obesity in children. The study involved 367 children and adolescents of both sexes aged from 4 to 18 years.

[Possibilities of in silico estimations for the development of pharmaceutical composition phytoladaptogene cytotoxic for bladder cancer cells].

Based on the prediction of biological activity spectra for several secondary metabolites of medicinal plants using the PASS computer program and validation in vitro of the predictions results the priority direction of the pharmaceutical composition Phytoladaptogene (PLA) development was determined. PLA is a complex of structurally diverse small organic compounds including biologically active substances of phytoadaptogenes (ginsenosides from Panax ginseng, rhodionin from Rhodiola rosea and others) compiled considering previously developed pharmaceutical compositions. Two variants of the pharmaceutical composition were studied: - the major and minor variants included 22 and 13 compounds, respectively.

Alzheimer's disease-associated β-amyloid does not protect against herpes simplex virus 1 infection in the mouse brain.

Alzheimer's disease (AD) is a devastating fatal neurodegenerative disease. An alternative to the amyloid cascade hypothesis is that a viral infection is key to the etiology of late-onset AD, with β-amyloid (Aβ) peptides playing a protective role. In the current study, young 5XFAD mice that overexpress mutant human amyloid precursor protein with the Swedish, Florida, and London familial AD mutations were infected with one of two strains of herpes simplex virus 1 (HSV-1), 17syn+ and McKrae, at three different doses.

Familial L723P Mutation Can Shift the Distribution between the Alternative APP Transmembrane Domain Cleavage Cascades by Local Unfolding of the Ε-Cleavage Site Suggesting a Straightforward Mechanism of Alzheimer's Disease Pathogenesis.

Alzheimer's disease is an age-related pathology associated with accumulation of amyloid-β peptides, products of enzymatic cleavage of amyloid-β precursor protein (APP) by secretases. Several familial mutations causing early onset of the disease have been identified in the APP transmembrane (TM) domain. The mutations influence production of amyloid-β, but the molecular mechanisms of this effect are unclear.

Probing the effect of membrane contents on transmembrane protein-protein interaction using solution NMR and computer simulations.

The interaction between the secondary structure elements is the key process, determining the spatial structure and activity of a membrane protein. Transmembrane (TM) helix-helix interaction is known to be especially important for the function of so-called type I or bitopic membrane proteins. In the present work, we present the approach to study the helix-helix interaction in the TM domains of membrane proteins in various lipid environment using solution NMR spectroscopy and phospholipid bicelles.

Atomistic mechanism of the constitutive activation of PDGFRA via its transmembrane domain.

Single-point mutations in the transmembrane (TM) region of receptor tyrosine kinases (RTKs) can lead to abnormal ligand-independent activation. We use a combination of computational modeling, NMR spectroscopy and cell experiments to analyze in detail the mechanism of how TM domains contribute to the activation of wild-type (WT) PDGFRA and its oncogenic V536E mutant. Using a computational framework, we scan all positions in PDGFRA TM helix for identification of potential functional mutations for the WT and the mutant and reveal the relationship between the receptor activity and TM dimerization via different interfaces.

Structural basis of the signal transduction via transmembrane domain of the human growth hormone receptor.

Background: Prior studies of the human growth hormone receptor (GHR) revealed a distinct role of spatial rearrangements of its dimeric transmembrane domain in signal transduction across membrane. Detailed structural information obtained in the present study allowed elucidating the bases of such rearrangement and provided novel insights into receptor functioning.

Methods: We investigated the dimerization of recombinant TMD fragment GHR by means of high-resolution NMR in DPC micelles and molecular dynamics in explicit POPC membrane.

Determination of apple juice authenticity using gas chromatography-mass spectrometry, volt-ampere and new conductometric methods.

Background: Organoleptic properties and positive health effect on consumers both justify the importance of determining apple juice authenticity with respect to retail and wholesale trade networks worldwide.

Results: Adulteration of apple juice through dilution with water, as well as with ascorbic acid, has been determined. It has been demonstrated that polarization curves of a platinum electrode in apple juice are useful for undeclared antioxidant determination, as a result of the movement of the polarization curve to the left, by 200 mV, when ascorbic acid was added.

Effect of Phytoadaptogen Administration during Early Ontogeny on Lifespan and Somatic Status of CBA Mice with High Incidence of Tumors.

We studied the influence of nontoxic phytoadaptogen complex on the lifespan and somatic status (body weight, coat state, and motor activity) of CBA mice predisposed to spontaneous hepatomas. Administration of the complex phytoadaptogen during the first month of postnatal ontogeny increased mean animal lifespan by 17.1% (p<0.

NMR relaxation parameters of methyl groups as a tool to map the interfaces of helix-helix interactions in membrane proteins.

In the case of soluble proteins, chemical shift mapping is used to identify the intermolecular interfaces when the NOE-based calculations of spatial structure of the molecular assembly are impossible or impracticable. However, the reliability of the membrane protein interface mapping based on chemical shifts or other relevant parameters was never assessed. In the present work, we investigate the predictive power of various NMR parameters that can be used for mapping of helix-helix interfaces in dimeric TM domains.

The Conformation of the Epidermal Growth Factor Receptor Transmembrane Domain Dimer Dynamically Adapts to the Local Membrane Environment.

The epidermal growth factor receptor (EGFR) family is an important class of receptor tyrosine kinases, mediating a variety of cellular responses in normal biological processes and in pathological states of multicellular organisms. Different modes of dimerization of the human EGFR transmembrane domain (TMD) in different membrane mimetics recently prompted us to propose a novel signal transduction mechanism based on protein-lipid interaction. However, the experimental evidence for it was originally obtained with slightly different TMD fragments used in the two different mimetics, compromising the validity of the comparison.

Conformational transitions and interactions underlying the function of membrane embedded receptor protein kinases.

Among membrane receptors, the single-span receptor protein kinases occupy a broad but specific functional niche determined by distinctive features of the underlying transmembrane signaling mechanisms that are briefly overviewed on the basis of some of the most representative examples, followed by a more detailed discussion of several hierarchical levels of organization and interactions involved. All these levels, including single-molecule interactions (e.g.

New Insights into Molecular Organization of Human Neuraminidase-1: Transmembrane Topology and Dimerization Ability.

Neuraminidase 1 (NEU1) is a lysosomal sialidase catalyzing the removal of terminal sialic acids from sialyloconjugates. A plasma membrane-bound NEU1 modulating a plethora of receptors by desialylation, has been consistently documented from the last ten years. Despite a growing interest of the scientific community to NEU1, its membrane organization is not understood and current structural and biochemical data cannot account for such membrane localization.

Morphological Studies of Hepatocellular Carcinomas in Male CBA Mice with High Liability to Cancer under the Effect of Phytoadaptogen.

Treatment of CBA mice predisposed to cancer with a complex phytoadaptogen in the therapeutic and preventive modes led to the appearance of moderate and low-differentiation hepato-cellular carcinomas infiltrated by leukocytes. Destructive signs were detected in tumor tissue.