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)

Mitochondrial dynamics–fusion, fission, movement, and mitophagy–in neurodegenerative diseases

Neurons are metabolically active cells with high energy demands at locations distant from the cell body. As a result, these cells are particularly dependent on mitochondrial function, as reflected by the observation that diseases of mitochondrial dysfunction often have a neurodegenerative component. Recent discoveries have highlighted that neurons are reliant particularly on the dynamic properties of mitochondria. Mitochondria are dynamic organelles by several criteria. They engage in repeated cycles of fusion and fission, which serve to intermix the lipids and contents of a population of mitochondria. In addition, mitochondria are actively recruited to subcellular sites, such as the axonal and dendritic processes of neurons. Finally, the quality of a mitochondrial population is maintained through mitophagy, a form of autophagy in which defective mitochondria are selectively degraded. We review the general features of mitochondrial dynamics, incorporating recent findings on mitochondrial fusion, fission, transport and mitophagy. Defects in these key features are associated with neurodegenerative disease. Charcot-Marie-Tooth type 2A, a peripheral neuropathy, and dominant optic atrophy, an inherited optic neuropathy, result from a primary deficiency of mitochondrial fusion. Moreover, several major neurodegenerative diseases—including Parkinson's, Alzheimer's and Huntington's disease—involve disruption of mitochondrial dynamics. Remarkably, in several disease models, the manipulation of mitochondrial fusion or fission can partially rescue disease phenotypes. We review how mitochondrial dynamics is altered in these neurodegenerative diseases and discuss the reciprocal interactions between mitochondrial fusion, fission, transport and mitophagy

Pregnancy, childbirth and perinatal outcomes in isthmic-cervical insufficiency, depending on the method of delivery

Introduction. Isthmic-cervical insufficiency (ICI) continues to be one of the main causes of miscarriage and premature birth (PB), contributing to the growth of reproductive losses and directly affecting the indicators of perinatal morbidity and mortality.Objective of the study – to study the features of the course of pregnancy, childbirth and perinatal outcomes in ICI, depending on the method of delivery.Material and methods. A retrospective analysis of birth histories (n = 144) with a diagnosis of Isthmic-cervical insufficiency was carried out, for the period from 2015 to 2020. 102 pregnant women who delivered through the natural birth canal (70.8%) made up group 1, and 42 women whose births ended with cesarean section (29.2%) made up group 2. The control groups included patients with a singleton uncomplicated pregnancy, which ended with an emergency delivery through the natural birth canal (group 3 – n = 96) and by caesarean section (group 4 – n = 58). Anamnestic data, peculiarities of the course of pregnancy, childbirth and perinatal outcomes were studied in detail. Statistical analysis was carried out using the programs Excel MS Office Professional and STATISTICA 7.0.Results and discussion. ICI is more common in repeat-bearing women with a male fetus (p < 0.001), with a burdened obstetric and gynecological history, concomitant extragenital pathology, over the age of 30 years. In PB, conservative management of the birth act prevails against the background of ICI (70.8%) (p >< 0.001). The choice of delivery method in ICI determines the gestation period, fetal condition, the occurrence of urgent obstetric complications and premature rupture of fetal membranes. With ICI, the birth of children in a state of asphyxia prevails (p >< 0.001). With operative delivery, the probability of diagnosing mild asphyxia (1.3 times) and respiratory distress syndrome (2 times) increases. With conservative management of childbirth against the background of ICI in newborns, the frequency of grade I cerebral ischemia increases significantly (by 5 times) (p >< 0.001). Conclusion. The results of the study once again confirmed the significant importance of the ICI in the implementation of PB, which dictates the need for further study of this problem to improve the quality of care for pregnant women and improve perinatal outcomes. >< 0.001), with a burdened obstetric and gynecological history, concomitant extragenital pathology, over the age of 30 years. In PB, conservative management of the birth act prevails against the background of ICI (70.8%) (p < 0.001). The choice of delivery method in ICI determines the gestation period, fetal condition, the occurrence of urgent obstetric complications and premature rupture of fetal membranes. With ICI, the birth of children in a state of asphyxia prevails (p >< 0.001). With operative delivery, the probability of diagnosing mild asphyxia (1.3 times) and respiratory distress syndrome (2 times) increases. With conservative management of childbirth against the background of ICI in newborns, the frequency of grade I cerebral ischemia increases significantly (by 5 times) (p >< 0.001). Conclusion. The results of the study once again confirmed the significant importance of the ICI in the implementation of PB, which dictates the need for further study of this problem to improve the quality of care for pregnant women and improve perinatal outcomes.>< 0.001). The choice of delivery method in ICI determines the gestation period, fetal condition, the occurrence of urgent obstetric complications and premature rupture of fetal membranes. With ICI, the birth of children in a state of asphyxia prevails (p < 0.001). With operative delivery, the probability of diagnosing mild asphyxia (1.3 times) and respiratory distress syndrome (2 times) increases. With conservative management of childbirth against the background of ICI in newborns, the frequency of grade I cerebral ischemia increases significantly (by 5 times) (p >< 0.001). Conclusion. The results of the study once again confirmed the significant importance of the ICI in the implementation of PB, which dictates the need for further study of this problem to improve the quality of care for pregnant women and improve perinatal outcomes.><  0.001). With operative delivery, the probability of diagnosing mild asphyxia (1.3 times) and respiratory distress syndrome (2 times) increases. With conservative management of childbirth against the background of ICI in newborns, the frequency of grade I cerebral ischemia increases significantly (by 5 times) (p < 0.001). Conclusion. The results of the study once again confirmed the significant importance of the ICI in the implementation of PB, which dictates the need for further study of this problem to improve the quality of care for pregnant women and improve perinatal outcomes.>< 0.001).Conclusion. The results of the study once again confirmed the significant importance of the ICI in the implementation of PB, which dictates the need for further study of this problem to improve the quality of care for pregnant women and improve perinatal outcomes

Фотодинамическая терапия в лечении интраэпителиальных неоплазий шейки матки, вульвы и влагалища

In the present review the authors analyzed the effectiveness of treatment of intraepithelial neoplasia I-II-III of the cervix (CIN), vulva (VIN) and vagina (VaIN) using photodynamic therapy (PDT). PDT is a method based on exposure to light after preliminary introduction of a photosensitizer into the body with the formation of singlet oxygen, which has a cytotoxic effect. The results of research on the use of PDT with various photosensitizers in the complex of therapeutic measures in patients with CIN, VIN, VaIN are presented. These data on the effectiveness and safety of PDT, ease of use allow this medical technology to be attributed to one of the most promising areas in the treatment of pathological intraepithelial changes of the cervix, vulva and vagina. The presented information allows focusing the attention on the PDT method and informing doctors and researchers about the broad prospects for applying this treatment method in clinical practice.В обзоре литературы представлен анализ эффективности лечения интраэпителиальной неоплазии I-II-III степени шейки матки (CIN), вульвы (VIN) и влагалища (VaIN) с использованием фотодинамической терапии (ФДТ). ФДТ – метод, основанный на воздействии светом после предварительного введения в организм фотосенсибилизатора с образованием синглетного кислорода, оказывающего цитотоксический эффект. Представлены результаты исследований по использованию ФДТ с различными фотосенсибилизаторами в комплексе лечебных мероприятий у больных с CIN, VIN, VaIN. Приведенные данные об эффективности и безопасности ФДТ, простота применения позволяют данную медицинскую технологию отнести к числу наиболее перспективных направлений в лечении различной степени выраженности интраэпителиальных изменений шейки матки, вульвы и влагалища. Представленная информация позволит акцентировать внимание на ФДТ и информировать врачей и научных сотрудников о широких перспективах применения данного метода в клинической практике

INCORPORATION OF MAGNETIC NANOPARTICLES INTO MESOPOROUS CALCIUM CARBONATE MATRICES FOR BIOMEDICAL APPLICATIONS

In this work the formation of magnetically sensitive "core-shell" systems based on pre-synthesized vaterite microparticles and iron oxide nanoparticles was studied by two methods: physical sorption of nanoparticles from a suspension at room temperature, as well as freezing-induced loading.Работа выполнена при финансовой поддержке РНФ (проект № 21-74-10058)

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

Ubiquitous [Na+]i/[K+]i-Sensitive Transcriptome in Mammalian Cells: Evidence for Ca2+i-Independent Excitation-Transcription Coupling

Stimulus-dependent elevation of intracellular Ca2+ ([Ca2+]i) affects the expression of numerous genes – a phenomenon known as excitation-transcription coupling. Recently, we found that increases in [Na+]i trigger c-Fos expression via a novel Ca2+i-independent pathway. In the present study, we identified ubiquitous and tissue-specific [Na+]i/[K+]i-sensitive transcriptomes by comparative analysis of differentially expressed genes in vascular smooth muscle cells from rat aorta (RVSMC), the human adenocarcinoma cell line HeLa, and human umbilical vein endothelial cells (HUVEC). To augment [Na+]i and reduce [K+]i, cells were treated for 3 hrs with the Na+,K+-ATPase inhibitor ouabain or placed for the same time in the K+-free medium. Employing Affymetrix-based technology, we detected changes in expression levels of 684, 737 and 1839 transcripts in HeLa, HUVEC and RVSMC, respectively, that were highly correlated between two treatments (p<0.0001; R2>0.62). Among these Na+i/K+i-sensitive genes, 80 transcripts were common for all three types of cells. To establish if changes in gene expression are dependent on increases in [Ca2+]i, we performed identical experiments in Ca2+-free media supplemented with extracellular and intracellular Ca2+ chelators. Surprisingly, this procedure elevated rather than decreased the number of ubiquitous and cell-type specific Na+i/K+i-sensitive genes. Among the ubiquitous Na+i/K+i-sensitive genes whose expression was regulated independently of the presence of Ca2+ chelators by more than 3-fold, we discovered several transcription factors (Fos, Jun, Hes1, Nfkbia), interleukin-6, protein phosphatase 1 regulatory subunit, dual specificity phosphatase (Dusp8), prostaglandin-endoperoxide synthase 2, cyclin L1, whereas expression of metallopeptidase Adamts1, adrenomedulin, Dups1, Dusp10 and Dusp16 was detected exclusively in Ca2+-depleted cells. Overall, our findings indicate that Ca2+i-independent mechanisms of excitation-transcription coupling are involved in transcriptomic alterations triggered by elevation of the [Na+]i/[K+]i ratio. There results likely have profound implications for normal and pathological regulation of mammalian cells, including sustained excitation of neuronal cells, intensive exercise and ischemia-triggered disorders

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.

Genetic Ablation of PLA2G6 in Mice Leads to Cerebellar Atrophy Characterized by Purkinje Cell Loss and Glial Cell Activation

Infantile neuroaxonal dystrophy (INAD) is a progressive, autosomal recessive neurodegenerative disease characterized by axonal dystrophy, abnormal iron deposition and cerebellar atrophy. This disease was recently mapped to PLA2G6, which encodes group VI Ca2+-independent phospholipase A2 (iPLA2 or iPLA2β). Here we show that genetic ablation of PLA2G6 in mice (iPLA2β-/-) leads to the development of cerebellar atrophy by the age of 13 months. Atrophied cerebella exhibited significant loss of Purkinje cells, as well as reactive astrogliosis, the activation of microglial cells, and the pronounced up-regulation of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Moreover, glial cell activation and the elevation in TNF-α and IL-1β expression occurred before apparent cerebellar atrophy. Our findings indicate that the absence of PLA2G6 causes neuroinflammation and Purkinje cell loss and ultimately leads to cerebellar atrophy. Our study suggests that iPLA2β-/- mice are a valuable model for cerebellar atrophy in INAD and that early anti-inflammatory therapy may help slow the progression of cerebellar atrophy in this deadly neurodegenerative disease