The use of intermediate inserts for CO 2 laser welding of steel AISI 321 and a Grade 2 titanium alloy

The paper studies the structure, chemical and phase compositions, hardness and strength of welded joints obtained in AISI 321 steel and Grade 2 titanium alloy sheets by CO 2 continuous laser with the use of intermediate Cu, Ni and Ag-Cu-Zn alloy inserts. It is demonstrated that the maximum strength of welded joints is achieved by the welding conditions enabling one to form multiphase structures with intermetallics in the material of a weld, rather than only those based on solid solutions. © 2018 Author(s)

ROLE OF IL-4, IL-6, IL-8, IL-10 CYTOKINES IN THE IMMUNOPATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Chronic obstructive pulmonary disease (COPD) is socially significant disease. COPD is based on chronic inflammatory process of respiratory tract, which determines steady progression of the bronchial obstruction. Studies of the role of cytokines in immune pathogenesis of COPD are of crucial importance. The biological mediators determine local, systemic inflammation, and pathophysiological effects of extra-systemic pathological manifestations. In this work, we studied spontaneous and induced production of IL-4, IL-6, IL-8, IL-10 cytokines by blood leukocytes from the patients with moderate and severe chronic obstructive pulmonary disease, beyond the exacerbation phase. It is shown that the evident role in formation of the inflammatory process in COPD belongs to the IL-6, IL-8. We have found a significant increase in both spontaneous and induced production of IL-6 and IL-8 (p < 0.05) in the patients. Induced production of cytokines strongly suggests the reserve capabilities of immunocompetent cells in response to the pathogenic factor. Neutrophilic type of inflammation, manifesting as activation of granulocytes, mostly, neutrophils, in response to toxic agents (in particular, smoking) and bacterial pathogens, is primarily associated with IL-6 and IL-8. These results reflect the type and intensity of respiratory tract inflammation in patients with chronic obstructive pulmonary disease and its persistent course.High levels of the studied cytokines confirm their role in bronchial remodeling and contribute to irreversibility of bronchial obstruction in this disorder. The relationship between spontaneous and induced production of the studied cytokines and the clinical indices of the disease course has been shown. Statistically significant increase between frequency of COPD recurrences (more than 2 times pro year, p < 0.05), and low FEV1 values (p < 0.05) were observed in patients with high values of spontaneous and induced production of IL-6 and IL-8. It may be associated with persistent course of neutrophilic inflammation of respiratory tract and progressive bronchial obstruction. IL-6 and IL-8 significantly contribute to pathogenetic mechanisms, determining the clinical course of COPD and may serve as markers of severity in this disorder. Certainly, the immune mechanisms of pathological inflammation in COPD are complex and multifaceted. Studies of clinical significance of induced cytokine production will help the physician when determining type and duration of treatment. Personalized approach to the therapy of patients with COPD depends on the phenotype of pathology, pattern, severity and intensity of inflammation

Synthesis and tribological properties of new fluoro-containing oligomers

Oligomers based on (polyfluoroalkyl)methyl oxiranes and thiiranes was first synthesized by the cationic polymerization in the presence of boron trifluoride etherate. Molecular weights of the products were defined by cryoscopic method. It was found that synthesized oligomers can be used as additives to industrial lubricants and sulfur oligomers are of the greatest positive tribological effect. © Pleiades Publishing, Ltd., 2013

Assessment of Epizootiological-Epidemiological Situation on Natural Focal Infections in Aleksandrovsk-Sakhalin Territory of the Sakhalin Region

Objective of the work was to carry out complex assessment of the current state of epizootic activity and epidemiological significance of the infectious disease natural foci in the Aleksandrovsk-Sakhalin territory of the Sakhalin Region. Trapped were 56 samples of small mammals in July, 2010; collected were 180 specimens of taiga tick imago, caught were 1000 specimens of mosquitoes. 223 samples of blood sera were taken from residents of the region. All the field data were tested to detect specific antibodies, antigens and genetic material of agents. Based on the results of epizootiological investigations, serological and molecular-genetic assays, demonstrated was the occurence of natural foci of leptospirosis, tularemia, tick-borne encephalitis, borreliosis, rickettsiosis, human granulocytic anaplasmosis, human monocytic ehrlichiosis, West Nile fever, Inco fever, Batai and Geto fevers, as well as HFRS with varying degree of activity manifestation in the territory of the region. Isolated was tick-borne encephalitis virus from mosquitoes

Epidemiological Situation on Natural Focal Infectious Diseases of Bacterial and Viral Etiology in 2012 in the Territory of Siberia and Far East, and Prognosis for 2013

Analyzed is the incidence rate as regards natural focal infections of bacterial and viral etiology. Displayed is the data on the performed laboratory diagnostics of these infections in the territory of Siberia and Far East in 2012 and forecast of the epidemiological situation development in 2013. Analysis is carried out based on the data received by the Reference Center for surveillance over natural focal infections at the Irkutsk Research Anti-Plague Institute, from Rospotrebnadzor Institutions of Siberian, Far-Eastern and Ural Federal districts, as well as reviews and prognoses on the current state of natural foci of infections available from Altay, Tuva, Chita, Khabarovsk and Primorsk plague control stations

Evaluating the SERCA2 and VEGF mRNAs as Potential Molecular Biomarkers of the Onset and Progression in Huntington's Disease

Abnormalities of intracellular Ca2+ homeostasis and signalling as well as the down-regulation of neurotrophic factors in several areas of the central nervous system and in peripheral tissues are hallmarks of Huntington\u2019s disease (HD). As there is no therapy for this hereditary, neurodegenerative fatal disease, further effort should be made to slow the progression of neurodegeneration in patients through the definition of early therapeutic interventions. For this purpose, molecular biomarker(s) for monitoring disease onset and/or progression and response to treatment need to be identified. In the attempt to contribute to the research of peripheral candidate biomarkers in HD, we adopted a multiplex real-time PCR approach to analyse the mRNA level of targeted genes involved in the control of cellular calcium homeostasis and in neuroprotection. For this purpose we recruited a total of 110 subjects possessing the HD mutation at different clinical stages of the disease and 54 sex- and agematched controls. This study provides evidence of reduced transcript levels of sarco-endoplasmic reticulum-associated ATP2A2 calcium pump (SERCA2) and vascular endothelial growth factor (VEGF) in peripheral blood mononuclear cells (PBMCs) of manifest and premanifest HD subjects. Our results provide a potentially new candidate molecular biomarker for monitoring the progression of this disease and contribute to understanding some early events that might have a role in triggering cellular dysfunctions in HD

Defects in Mitochondrial Dynamics and Metabolomic Signatures of Evolving Energetic Stress in Mouse Models of Familial Alzheimer's Disease

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.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.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

High-Content Chemical and RNAi Screens for Suppressors of Neurotoxicity in a Huntington's Disease Model

To identify Huntington's Disease therapeutics, we conducted high-content small molecule and RNAi suppressor screens using a Drosophila primary neural culture Huntingtin model. Drosophila primary neurons offer a sensitive readout for neurotoxicty, as their neurites develop dysmorphic features in the presence of mutant polyglutamine-expanded Huntingtin compared to nonpathogenic Huntingtin. By tracking the subcellular distribution of mRFP-tagged pathogenic Huntingtin and assaying neurite branch morphology via live-imaging, we identified suppressors that could reduce Huntingtin aggregation and/or prevent the formation of dystrophic neurites. The custom algorithms we used to quantify neurite morphologies in complex cultures provide a useful tool for future high-content screening approaches focused on neurodegenerative disease models. Compounds previously found to be effective aggregation inhibitors in mammalian systems were also effective in Drosophila primary cultures, suggesting translational capacity between these models. However, we did not observe a direct correlation between the ability of a compound or gene knockdown to suppress aggregate formation and its ability to rescue dysmorphic neurites. Only a subset of aggregation inhibitors could revert dysmorphic cellular profiles. We identified lkb1, an upstream kinase in the mTOR/Insulin pathway, and four novel drugs, Camptothecin, OH-Camptothecin, 18β-Glycyrrhetinic acid, and Carbenoxolone, that were strong suppressors of mutant Huntingtin-induced neurotoxicity. Huntingtin neurotoxicity suppressors identified through our screen also restored viability in an in vivo Drosophila Huntington's Disease model, making them attractive candidates for further therapeutic evaluation.National Institutes of Health (U.S.) (grant R01 EB007042)National Institutes of Health (U.S.

Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Nature America for personal use, not for redistribution. The definitive version was published in Nature Neuroscience 12 (2009): 864-871, doi:10.1038/nn.2346.Selected vulnerability of neurons in Huntington’s disease (HD) suggests alterations in a cellular process particularly critical for neuronal function. Supporting this idea, pathogenic Htt (polyQ-Htt) inhibits fast axonal transport (FAT) in various cellular and animal HD models (mouse and squid), but the molecular basis of this effect remains unknown. Here we show that polyQ-Htt inhibits FAT through a mechanism involving activation of axonal JNK. Accordingly, increased activation of JNK was observed in vivo in cellular and animal HD models. Additional experiments indicate that polyQ-Htt effects on FAT are mediated by the neuron-specific JNK3, and not ubiquitously expressed JNK1, providing a molecular basis for neuron-specific pathology in HD. Mass spectrometry identified a residue in the kinesin-1 motor domain phosphorylated by JNK3, and this modification reduces kinesin-1 binding to microtubules. These data identify JNK3 as a critical mediator of polyQ-Htt toxicity and provides a molecular basis for polyQ-Htt-induced inhibition of FAT.This work was supported by 2007/2008 MBL summer fellowship to GM; an HDSA grant to GM; NIH grants MH066179 to GB; and ALSA, Muscular Dystrophy Association, and NIH (NS23868, NS23320, NS41170) grants to STB

Loss of Caveolin-1 Accelerates Neurodegeneration and Aging

The aged brain exhibits a loss in gray matter and a decrease in spines and synaptic densities that may represent a sequela for neurodegenerative diseases such as Alzheimer's. Membrane/lipid rafts (MLR), discrete regions of the plasmalemma enriched in cholesterol, glycosphingolipids, and sphingomyelin, are essential for the development and stabilization of synapses. Caveolin-1 (Cav-1), a cholesterol binding protein organizes synaptic signaling components within MLR. It is unknown whether loss of synapses is dependent on an age-related loss of Cav-1 expression and whether this has implications for neurodegenerative diseases such as Alzheimer's disease.We analyzed brains from young (Yg, 3-6 months), middle age (Md, 12 months), aged (Ag, >18 months), and young Cav-1 KO mice and show that localization of PSD-95, NR2A, NR2B, TrkBR, AMPAR, and Cav-1 to MLR is decreased in aged hippocampi. Young Cav-1 KO mice showed signs of premature neuronal aging and degeneration. Hippocampi synaptosomes from Cav-1 KO mice showed reduced PSD-95, NR2A, NR2B, and Cav-1, an inability to be protected against cerebral ischemia-reperfusion injury compared to young WT mice, increased Aβ, P-Tau, and astrogliosis, decreased cerebrovascular volume compared to young WT mice. As with aged hippocampi, Cav-1 KO brains showed significantly reduced synapses. Neuron-targeted re-expression of Cav-1 in Cav-1 KO neurons in vitro decreased Aβ expression.Therefore, Cav-1 represents a novel control point for healthy neuronal aging and loss of Cav-1 represents a non-mutational model for Alzheimer's disease