Evaluation of the Polygenic Risk Score for Alzheimer's Disease in Russian Patients with Dementia Using a Low-Density Hydrogel Oligonucleotide Microarray.

The polygenic risk score (PRS), together with the ɛ4 allele of the APOE gene (APOE-ɛ4), has shown high potential for Alzheimer's disease (AD) risk prediction. The aim of this study was to validate the model of polygenic risk in Russian patients with dementia. A microarray-based assay was developed to identify 21 markers of polygenic risk and ɛ alleles of the APOE gene. This case-control study included 348 dementia patients and 519 cognitively normal volunteers. Cerebrospinal fluid (CSF) amyloid-ß (Aß) and tau protein levels were assessed in 57 dementia patients. PRS and APOE-ɛ4 were significant genetic risk factors for dementia. Adjusted for APOE-ɛ4, individuals with PRS corresponding to the fourth quartile had an increased risk of dementia compared to the first quartile (OR 1.85; p-value 0.002). The area under the curve (AUC) was 0.559 for the PRS model only, and the inclusion of APOE-ɛ4 improved the AUC to 0.604. PRS was positively correlated with tTau and pTau181 and inversely correlated with Aß42/Aß40 ratio. Carriers of APOE-ɛ4 had higher levels of tTau and pTau181 and lower levels of Aß42 and Aß42/Aß40. The developed assay can be part of a strategy for assessing individuals for AD risk, with the purpose of assisting primary preventive interventions.

Alteration of Blood Immune Biomarkers in MCI Patients with Different APOE Genotypes after Cognitive Training: A 1 Year Follow-Up Cohort Study.

Many studies aim to detect the early phase of dementia. One of the major ways to achieve this is to identify corresponding biomarkers, particularly immune blood biomarkers. The objective of this study was to identify such biomarkers in patients with mild cognitive impairment (MCI) in an experiment that included cognitive training. A group of patients with MCI diagnoses over the age of 65 participated in the study (n = 136). Measurements of cognitive functions (using the Mini-Mental State Examination scale and Montreal Cognitive Assessment) and determination of 27 serum biomarkers were performed twice: on the first visit and on the second visit, one year after the cognitive training. APOE genotypes were also determined. Concentrations of EGF (F = 17; p = 0.00007), Eotaxin (F = 7.17; p = 0.008), GRO (F = 13.42; p = 0.0004), IL-8 (F = 8.16; p = 0.005), MCP-1 (F = 13.46; p = 0.0001) and MDC (F = 5.93; p = 0.016) increased after the cognitive training in MCI patients. All these parameters except IL-8 demonstrated a weak correlation with other immune parameters and were poorly represented in the principal component analysis. Differences in concentrations of IP-10, FGF-2, TGFa and VEGF in patients with MCI were associated with APOE genotype. Therefore, the study identified several immune blood biomarkers that could potentially be associated with changes in cognitive function.

Distinct Traits of Structural and Regulatory Evolutional Conservation of Human Genes with Specific Focus on Major Cancer Molecular Pathways.

The evolution of protein-coding genes has both structural and regulatory components. The first can be assessed by measuring the ratio of non-synonymous to synonymous nucleotide substitutions. The second component can be measured as the normalized proportion of transposable elements that are used as regulatory elements. For the first time, we characterized in parallel the regulatory and structural evolutionary profiles for 10,890 human genes and 2972 molecular pathways. We observed a ~0.1 correlation between the structural and regulatory metrics at the gene level, which appeared much higher (~0.4) at the pathway level. We deposited the data in the publicly available database RetroSpect. We also analyzed the evolutionary dynamics of six cancer pathways of two major axes: Notch/WNT/Hedgehog and AKT/mTOR/EGFR. The Hedgehog pathway had both components slower, whereas the Akt pathway had clearly accelerated structural evolution. In particular, the major hub nodes Akt and beta-catenin showed both components strongly decreased, whereas two major regulators of Akt TCL1 and CTMP had outstandingly high evolutionary rates. We also noticed structural conservation of serine/threonine kinases and the genes related to guanosine metabolism in cancer signaling: GPCRs, G proteins, and small regulatory GTPases (Src, Rac, Ras); however, this was compensated by the accelerated regulatory evolution.

Suicide-Related Single Nucleotide Polymorphisms, rs4918918 and rs10903034: Association with Dementia in Older Adults.

Dementia has enormous implications for patients and the health care system. Genetic markers are promising for detecting the risk of cognitive impairment. We hypothesized that genetic variants associated with suicide risk might significantly increase the risk of cognitive decline because suicide in older adults is often a consequence of cognitive impairment. We investigated several single-nucleotide polymorphisms that were initially associated with suicide risk in dementia older adults and identified the APOE gene alleles. The study was performed with subjects over the age of 65: 112 patients with dementia and 146 healthy volunteers. The MMSE score was used to assess cognitive functions. Study participants were genotyped using real-time PCR (APOE: rs429358, rs7412; genes associated with suicide: rs9475195, rs7982251, rs2834789, rs358592, rs4918918, rs3781878, rs10903034, rs165774, rs16841143, rs11833579 rs10898553, rs7296262, rs3806263, and rs2462021). Genotype analysis revealed the significance of APOEε4, APOEε2, and rs4918918 (SORBS1) when comparing dementia and healthy control groups. The association of APOEε4, APOEε2, and rs10903034 (IFNLR1) with the overall MMSE score was indicated. The study found an association with dementia of rs4918918 (SORBS1) and rs10903034 (IFNLR1) previously associated with suicide and confirmed the association of APOEε4 and APOEε2 with dementia.

Positive Effect of Cognitive Training in Older Adults with Different APOE Genotypes and COVID-19 History: A 1-Year Follow-Up Cohort Study.

(1) Background: Older people suffer from cognitive decline; several risk factors contribute to greater cognitive decline. We used acquired (COVID-19 infection) and non-modifiable (presence of APOE rs429358 and rs7412 polymorphisms) factors to study the progression of subjective cognitive impairment while observing patients for one year. Cognitive training was used as a protective factor. (2) Methods: Two groups of subjects over the age of 65 participated in the study: group with subjective cognitive decline receiving cognitive training and individuals who did not complain of cognitive decline without receiving cognitive training (comparison group). On the first visit, the concentration of antibodies to COVID-19 and APOE genotype was measured. At the first and last point (1 year later) the Mini-Mental State Examination scale and the Hospital Anxiety and Depression Scale were performed. (3) Results: COVID-19 infection did not affect cognitive function. A significant role of cognitive training in improving cognitive functions was revealed. Older adults with APOE-ε4 genotype showed no positive effect of cognitive training. (4) Conclusions: Future research should focus on cognitive dysfunction after COVID-19 in long-term follow-up. Attention to the factors discussed in our article, but not limited to them, are useful for a personalized approach to maintaining the cognitive health of older adults.

Porosity Formation in Thin Welded Joints of Al-MG-LI Alloys.

This work is about the study of the correlation of pore formation in welded joints of Al-MG-LI alloy with zirconium additives with the state of the base metal, thermal vacuum treatment, and welding technologies MIG and EBW. Metallographic analysis has been carried out, the phase composition of the alloy and weld metal has been investigated, and thermal cycles of welding have been calculated, allowing to estimate the residence time of metal in the alloying zone and weld metal in the liquid state. The nature of the allocation of strengthening fine-dispersed phases in the welded joints of the alloy has been determined. The regularity and character of pore formation in welded joints depending on the applicable thermal vacuum treatment (TVT) and welding technology have been revealed. It was established that TVT with subsequent hardening and aging has no effect on the phase composition of the alloy. However, this type of treatment contributes to the formation of a more homogeneous and uniform nature of the separation of fine-dispersed strengthening phases. It was revealed that the MIG technology (metal with and without TVT) is characterized by a large length of the fusion zone, the high residence time of metal in the fusion zone and weld metal in the liquid state, and the formation of pores. Phase formation in the temperature range of the beginning and end of the alloy crystallization occurs not only in the weld at the final stage of crystallization but also in the fusion zone, which may induce pore formation, whereas EBW welding shows the opposite trend and no pores. It was found that EBW technology prevents pore formation and makes it possible to obtain welded joints of 1420 Al alloys of the required quality.

Targeted Lipidomic Analysis of Aqueous Humor Reveals Signaling Lipid-Mediated Pathways in Primary Open-Angle Glaucoma.

Primary open-angle glaucoma (POAG) is characterized by degeneration of retinal ganglion cells associated with an increase in intraocular pressure (IOP) due to hindered aqueous humor (AH) drainage through the trabecular meshwork and uveoscleral pathway. Polyunsaturated fatty acids and oxylipins are signaling lipids regulating neuroinflammation, neuronal survival and AH outflow. Among them, prostaglandins have been previously implicated in glaucoma and employed for its treatment. This study addressed the role of signaling lipids in glaucoma by determining their changes in AH accompanying IOP growth and progression of the disease. Eye liquids were collected from patients with POAG of different stages and cataract patients without glaucoma. Lipids were identified and quantified by UPLC-MS/MS. The compounds discriminating glaucoma groups were recognized using ANCOVA and PLS-DA statistic approaches and their biosynthetic pathways were predicted by bioinformatics. Among 22 signaling lipids identified in AH, stage/IOP-dependent alterations in glaucoma were provided by a small set of mediators, including 12,13-DiHOME, 9- and 13-HODE/KODE, arachidonic acid and lyso-PAF. These observations correlated with the expression of cytochromes P450 (CYPs) and phospholipases A2 in the ocular tissues. Interestingly, tear fluid exhibited similar lipidomic alterations in POAG. Overall, POAG may involve arachidonic acid/PAF-dependent pathways and oxidative stress as evidenced from an increase in its markers, KODEs and 12,13-DiHOME. The latter is a product of CYPs, one of which, CYP1B1, is known as POAG and primary congenital glaucoma-associated gene. These data provide novel targets for glaucoma treatment. Oxylipin content of tear fluid may have diagnostic value in POAG.

Application of Dynamic Beam Positioning for Creating Specified Structures and Properties of Welded Joints in Electron-Beam Welding.

The application of electron beam sweep makes it possible to carry out multifocal and multi-beam welding, as well as combine the welding process with local heating or subsequent heat treatment, which is important when preparing products from thermally-hardened materials. This paper presents a method of electron beam welding (EBW) with dynamic beam positioning and its experimental-calculation results regarding the formation of structures and properties of heat-resistant steel welded joints (grade of steel 20Cr3MoWV). The application of electron beam oscillations in welding makes it possible to change the shape and dimensions of welding pool. It also affects the crystallization and formation of a primary structure. It has been established that EBW with dynamic beam positioning increases the weld metal residence time and the thermal effect zone above the critical A3 point, increases cooling time and considerably reduces instantaneous cooling rates as compared to welding without beam sweep. Also, the difference between cooling rates in the depth of a welded joint considerably reduces the degree of structural non-uniformity. A bainitic-martensitic structure is formed in the weld metal and the thermal effect zone throughout the whole depth of fusion. As a result of this structure, the level of mechanical properties of a welded joint produced from EBW with dynamic electron beam positioning approaches that of parent metal to a greater extent than in the case of welding by a static beam. As a consequence, welding of heat-resistant steels reduces the degree of non-uniformity of mechanical properties in the depth of welded joints, as well as decreases the level of hardening of a welded joint in relation to parent metal.

Comparative lipidomic analysis of inflammatory mediators in the aqueous humor and tear fluid of humans and rabbits.

INTRODUCTION: Ocular inflammation is a key pathogenic factor in most blindness-causing visual disorders. It can manifest in the aqueous humor (AH) and tear fluid (TF) as alterations in polyunsaturated fatty acids (PUFAs) and their metabolites, oxylipins, lipid mediators, which are biosynthesized via enzymatic pathways involving lipoxygenase, cyclooxygenase or cytochrome P450 monooxygenase and specifically regulate inflammation and resolution pathways. OBJECTIVES: This study aimed to establish the baseline patterns of PUFAs and oxylipins in AH and TF by their comprehensive lipidomic identification and profiling in humans in the absence of ocular inflammation and comparatively analyze these compounds in the eye liquids of rabbits, the species often employed in investigative ophthalmology. METHODS: Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used for qualitative and quantitative characterization of lipid compounds in the analyzed samples. RESULTS: A total of 28 lipid compounds were identified, including phospholipid derivatives and PUFAs, as well as 22 oxylipins. Whereas the PUFAs included arachidonic, docosahexaenoic and eicosapentaenoic acids, the oxylipins were derived mainly from arachidonic, linoleic and α-linolenic acids. Remarkably, although the concentration of oxylipins in AH was lower compared to TF, these liquids showed pronounced similarity in their lipid profiles, which additionally exhibited noticeable interspecies concordance. CONCLUSION: The revealed correlations confirm the feasibility of rabbit models for investigating pathogenesis and trialing therapies of human eye disorders. The identified metabolite patterns suggest enzymatic mechanisms of oxylipin generation in AH and TF and might be used as a reference in ocular inflammation studies.

Ecotoxicological effects of traffic-related pollutants in roadside soils of Moscow.

The objective of this research is to find correlations between traffic-related contaminants in the roadside soils and their ecotoxicity. The study was conducted in Moscow in the vicinity of a highway of 125 000 vehicles per day. The topsoils (0-3 cm depth) were sampled perpendicular to the road at 1-, 6-, 10-, 18- and 50-m distances from the roadbed. Total petroleum hydrocarbons (TPH), polycyclic aromatic hydrocarbons (PAH), heavy metals (HM) in total and phyto-available forms, and deicing salts (DS) were determined. A battery of soil-contacting organisms was tested: phytotoxicity of rye (H. vulgare L.) and garden cress (L. sativum L.); E. foetida earthworm growth rate and mortality; basal and substrate-induced respiration activity, nitrogen fixation and the denitrification activity of the soil microbial complex. To determine the possible risk to aquatic ecosystems, the algal toxicity test (S. quadricauda) was provided. Correlations between "chemical" data and intensity of "biological" effects were analyzed. Concentrations of most contaminants declined to the background values with distance from the road increase. However, the toxicity of roadside soils was obtained for all examined organisms within the whole 50 m zone. Live organisms exhibited different sensitivities to roadside soils pollution. The intensity of inhibition effects decreased in order: higher plants > earthworms and microorganisms > algae. The risk for aquatic ecosystems was assessed as low. Higher plants toxicity correlated with TPH, PAH, some HM, and DS; earthworm toxicity correlated with TPH, some PAH, HM, and DS; microorganism toxicity correlated with TPH and DS; algae had no observed correlations with contaminants. TPH and DS were general ecotoxicants affecting all organisms. Higher plants may be considered the PAH indicators and earthworms as HM indicators. A set of higher plants and earthworms may be recommended as the reduced test-battery of relevant organisms for cost-effective assessment of the toxicity of roadside soils.