Multi-Year Monitoring of the Tick–Pathogen System in Natural Foci of Tick-Borne Encephalitis in the Suburbs of Irkutsk

Entomological Review - The state of the natural foci of tick-borne encephalitis (TBE) was monitored during 15 seasons (2005–2019) in several key plots within a popular recreational and...     

Isolation of flagellin antigens of salmonellae by the method of ultracentrifugation and their use for preparation of erythrocytic H-diagnostic agents]

Flagellar preparations were obtained from 6 salmonellae strains by differential ultracentrifugation; they were characterized by morphological, immunochemical, and serological tests. The results of investigations showed that the preparations possessed high serological activity; somatic antigen admixture was insignificant. Flagellins extracted from the flagellae were used to prepare erythrocytic H-diagnostic agents. The results of their use in the examination of sera of healthy persons, and of those suffering from typhoid fever and salmonellosis indicated the expediency of using passive H-hemagglutination for diagnostic purposes.     

A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma

Herein, we have identified cross-talk between the Hippo and fibroblast growth factor receptor (FGFR) oncogenic signaling pathways in cholangiocarcinoma (CCA). Yes-associated protein (YAP) nuclear localization and up-regulation of canonical target genes was observed in CCA cell lines and a patient-derived xenograft (PDX). Expression of FGFR1, -2, and -4 was identified in human CCA cell lines, driven, in part, by YAP coactivation of TBX5. In turn, FGFR signaling in a cell line with minimal basal YAP expression induced its cellular protein expression and nuclear localization. Treatment of YAP-positive CCA cell lines with BGJ398, a pan-FGFR inhibitor, resulted in a decrease in YAP activation. FGFR activation of YAP appears to be driven largely by FGF5 activation of FGFR2, as siRNA silencing of this ligand or receptor, respectively, inhibited YAP nuclear localization. BGJ398 treatment of YAP-expressing cells induced cell death due to Mcl-1 depletion. In a YAP-associated mouse model of CCA, expression of FGFR 1, 2, and 4 was also significantly increased. Accordingly, BGJ398 treatment was tumor-suppressive in this model and in a YAP-positive PDX model. These preclinical data suggest not only that the YAP and Hippo signaling pathways culminate in an Mcl-1-regulated tumor survival pathway but also that nuclear YAP expression may be a biomarker to employ in FGFR-directed therapy.     

Improvement of the serological diagnosis of food poisoning]

A possibility was shown of improvement of serological diagnosis of salmonelloses with the aid of polyvalent (complex) and group salmonellosis stable formalinized erythrocytic diagnostic agents. The use of the mentioned preparations for titration of antibodies of different immunochemical nature in the sera of patients suffering from food toxicoinfections permitted to confirm the clinical diagnosis of salmonellosis in about 30% of cases.     

Identification of the Spectrum of Pathogens in Ixodid Ticks from Natural Co-Infection Foci of the Baikal Region

Entomological Review - Ixodid ticks from different regions of the Baikal Region were examined for the presence of transmissive pathogens during 5 seasons (2013–2017). Frequency of occurrence...     

Study of the fractions and fibrinolytic activity of fungal mannan

Characteristics of the fraction composition of extracellular mannan produced by Rhodotorula rubra are presented. Various lots of the polysaccharide mainly contained two fractions similar by their chemical structures and differing in the solution relative viscosity. HPLC was used for determining the molecular weight of the samples. In the isolated fractions it differed 3-5 fold. Relationship between the fibrinolytic activity of the polysaccharide and its molecular weight was revealed. The samples of mannan with the molecular weight of 400-500 kD had the highest capacity for lowering the fibrinogen blood levels in rats. The polysaccharide with the molecular weight of less than 100 kD had practically no fibrinolytic activity.     

Defects in mitochondrial dynamics and metabolomic signatures of evolving energetic stress in mouse models of familial Alzheimer's disease

Background

The identification of early mechanisms underlying Alzheimer''s Disease (AD) and associated biomarkers could advance development of new therapies and improve monitoring and predicting of AD progression. Mitochondrial dysfunction has been suggested to underlie AD pathophysiology, however, no comprehensive study exists that evaluates the effect of different familial AD (FAD) mutations on mitochondrial function, dynamics, and brain energetics.

Methods and Findings

We characterized early mitochondrial dysfunction and metabolomic signatures of energetic stress in three commonly used transgenic mouse models of FAD. Assessment of mitochondrial motility, distribution, dynamics, morphology, and metabolomic profiling revealed the specific effect of each FAD mutation on the development of mitochondrial stress and dysfunction. Inhibition of mitochondrial trafficking was characteristic for embryonic neurons from mice expressing mutant human presenilin 1, PS1(M146L) and the double mutation of human amyloid precursor protein APP(Tg2576) and PS1(M146L) contributing to the increased susceptibility of neurons to excitotoxic cell death. Significant changes in mitochondrial morphology were detected in APP and APP/PS1 mice. All three FAD models demonstrated a loss of the integrity of synaptic mitochondria and energy production. Metabolomic profiling revealed mutation-specific changes in the levels of metabolites reflecting altered energy metabolism and mitochondrial dysfunction in brains of FAD mice. Metabolic biomarkers adequately reflected gender differences similar to that reported for AD patients and correlated well with the biomarkers currently used for diagnosis in humans.

Conclusions

Mutation-specific alterations in mitochondrial dynamics, morphology and function in FAD mice occurred prior to the onset of memory and neurological phenotype and before the formation of amyloid deposits. Metabolomic signatures of mitochondrial stress and altered energy metabolism indicated alterations in nucleotide, Krebs cycle, energy transfer, carbohydrate, neurotransmitter, and amino acid metabolic pathways. Mitochondrial dysfunction, therefore, is an underlying event in AD progression, and FAD mouse models provide valuable tools to study early molecular mechanisms implicated in AD.