Publications by authors named "Elena Osipova"

28 Publications

  • Page 1 of 1

Serotherapy-Free Regimen Improves Non-Relapse Mortality and Immune Recovery Among the Recipients of αβ TCell-Depleted Haploidentical Grafts: Retrospective Study in Childhood Leukemia.

Transplant Cell Ther 2021 Apr 14;27(4):330.e1-330.e9. Epub 2021 Jan 14.

Department of Hematopoietic Stem Cell Transplantation, Dmitriy Rogachev National Medical Center Of Pediatric Hematology, Oncology And Immunology, Moscow, Russia. Electronic address:

Depletion of αβ T cells from the graft prevents graft-versus-host disease (GVHD) and improves the outcome of hematopoietic stem cell transplantation (HSCT) from haploidentical donors. Delayed recovery of adaptive immunity remains a problem, which can be approached by adoptive T-cell transfer. In a randomized trial, we have assessed the safety and efficacy of low-dose memory (CD45RA-depleted) donor lymphocytes (mDLI) after HSCT with αβ T-cell depletion. Antithymocyte globulin (ATG) is viewed as an essential component of preparative regimen, critical for both prevention of graft failure and GVHD. Variable pharmacokinetics of ATG may significantly affect lymphocyte subpopulations after HSCT. To uncover the potential of mDLI, we replaced rabbit ATG with tocilizumab and abatacept. Here we compare post hoc the immune recovery and the key clinical outcomes, including nonrelapse mortality (NRM), overall- and event-free survival (OS and EFS), between the cohort enrolled in the prospective randomized trial and a historical cohort, comprised of patients grafted with a conventional ATG-based HSCT with αβ T cell depletion. A cohort of 149 children was enrolled in the prospective trial and 108 patients were selected as historical controls from a prospectively populated database. Patient population was comprised of children with high-risk hematologic malignancies, with more than 90% represented by acute leukemia. Median age at enrollment was 8.8 years. In the prospective cohort 91% of the donors were haploidentical parents, whereas in the historical cohort 72% of the donors were haploidentical. Conditioning was based on either 12Gy total body irradiation or treosulfan. Thiotepa, fludarabine, bortezomib, and rituximab were used as additional agents. Patients in the historical cohort received rabbit ATG at 5 mg/kg total dose, while prospective cohort patients received tocilizumab at 8 mg /kg on day -1 and abatacept at 10 mg/kg on days 0, 7, 14, and 28. Patients in the prospective trial cohort were randomized 1:1 to receive mDLI starting on day 0, whereas 69% of historical cohort patients received mDLI after engraftment, as part of previous trials. Primary engraftment rate was 99% in the prospective cohort and 98% in the historical cohort. The incidence of grade II-IV aGVHD was 13% in the prospective cohort and 16 % in the control group. Chronic GVHD developed among 13% (historical) and 7% (prospective) cohorts (P = .07). The incidence of cytomegalovirus viremia was 51% in the prospective cohort arm and 54% in the historical control arm (p = ns). Overall, in the prospective cohort 2-year NRM was 2%, incidence of relapse was 25%, EFS was 71%, and OS was 80%, whereas in the historical cohort 2-year NRM was 13%, incidence of relapse was 19%, EFS was 67%, and OS was 76%, difference non-significant for relapse and survival. NRM was significantly improved in the ATG-free cohort (P = .002). Recovery of both αβ- and γδ- T cells was significantly improved at days +30 and +60 after HSCT in recipients of ATG-free preparative regimens, as well as recovery of naïve T cells. Among the recipients of αβ T-cell-depleted grafts, replacement of ATG with nonlymphodepleting abatacept and tocilizumab immunomodulation did not compromise engraftment and GVHD control and was associated with significantly lower NRM and better immune recovery early after HSCT.
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http://dx.doi.org/10.1016/j.jtct.2021.01.010DOI Listing
April 2021

Rhizosphere Bacterium sp. P1Y Metabolizes Abscisic Acid to Form Dehydrovomifoliol.

Biomolecules 2021 Feb 25;11(3). Epub 2021 Feb 25.

Kazan Institute of Biochemistry and Biophysics, Federal Research Center "Kazan Scientific Center of the RAS", Lobachevsky Street, 2/31, 420111 Kazan, Tatarstan Republic, Russia.

The phytohormone abscisic acid (ABA) plays an important role in plant growth and in response to abiotic stress factors. At the same time, its accumulation in soil can negatively affect seed germination, inhibit root growth and increase plant sensitivity to pathogens. ABA is an inert compound resistant to spontaneous hydrolysis and its biological transformation is scarcely understood. Recently, the strain sp. P1Y was described as a rhizosphere bacterium assimilating ABA as a sole carbon source in batch culture and affecting ABA concentrations in plant roots. In this work, the intermediate product of ABA decomposition by this bacterium was isolated and purified by preparative HPLC techniques. Proof that this compound belongs to ABA derivatives was carried out by measuring the molar radioactivity of the conversion products of this phytohormone labeled with tritium. The chemical structure of this compound was determined by instrumental techniques including high-resolution mass spectrometry, NMR spectrometry, FTIR and UV spectroscopies. As a result, the metabolite was identified as ()-4-hydroxy-3,5,5-trimethyl-4-[()-3-oxobut-1-enyl]cyclohex-2-en-1-one (dehydrovomifoliol). Based on the data obtained, it was concluded that the pathway of bacterial degradation and assimilation of ABA begins with a gradual shortening of the acyl part of the molecule.
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http://dx.doi.org/10.3390/biom11030345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996341PMC
February 2021

Safety and efficacy of the low-dose memory (CD45RA-depleted) donor lymphocyte infusion in recipients of αβ T cell-depleted haploidentical grafts: results of a prospective randomized trial in high-risk childhood leukemia.

Bone Marrow Transplant 2021 Feb 16. Epub 2021 Feb 16.

Department of Hematopoietic Stem Cell Transplantation, Dmitriy Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

Depletion of αβ T cells from the graft prevents graft-vs.-host disease (GVHD) and improves outcome of HSCT from haploidentical donors. In a randomized trial, we aimed to evaluate the safety and efficacy of low-dose memory (CD45RA-depleted) donor lymphocytes (mDLI) after HSCT with αβ T-cell depletion. A cohort of 149 children was enrolled, 76 were randomized to receive scheduled mDLI and 73 received standard care. Conditioning was based on either 12 Gy total body irradiation or treosulfan. Rabbit antithymocyte globulin was replaced by tocilizumab and abatacept. Primary end points were the incidence of acute GVHD grades II-IV and the incidence of cytomegalovirus (CMV) viremia. The incidence of grades II-IV aGVHD was 14% in the experimental arm and 12% in the control arm, p-0.8. The incidence of CMV viremia was 45% in the experimental arm and 55% in the control arm, p-0.4. Overall, in the total cohort 2-year NRM was 2%, cumulative incidence of relapse was 25%, event-free survival 71%, and overall survival 80%, without difference between the study arms. Memory DLI was associated with improved recovery of CMV-specific T-cell responses in a subcohort of CMV IgG seropositive recipients.
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http://dx.doi.org/10.1038/s41409-021-01232-xDOI Listing
February 2021

Circadian rhythms in zebrafish (Danio rerio) behaviour and the sources of their variability.

Biol Rev Camb Philos Soc 2021 Jun 17;96(3):785-797. Epub 2020 Dec 17.

I.D. Papanin Institute for Biology of Inland Waters Russian Academy of Sciences, Borok, Nekouz, Yaroslavl Oblast, 152742, Russia.

Over recent decades, changes in zebrafish (Danio rerio) behaviour have become popular quantitative indicators in biomedical studies. The circadian rhythms of behavioural processes in zebrafish are known to enable effective utilization of energy and resources, therefore attracting interest in zebrafish as a research model. This review covers a variety of circadian behaviours in this species, including diurnal rhythms of spawning, feeding, locomotor activity, shoaling, light/dark preference, and vertical position preference. Changes in circadian activity during zebrafish ontogeny are reviewed, including ageing-related alterations and chemically induced variations in rhythmicity patterns. Both exogenous and endogenous sources of inter-individual variability in zebrafish circadian behaviour are detailed. Additionally, we focus on different environmental factors with the potential to entrain circadian processes in zebrafish. This review describes two principal ways whereby diurnal behavioural rhythms can be entrained: (i) modulation of organismal physiological state, which can have masking or enhancing effects on behavioural endpoints related to endogenous circadian rhythms, and (ii) modulation of period and amplitude of the endogenous circadian rhythm due to competitive relationships between the primary and secondary zeitgebers. In addition, different peripheral oscillators in zebrafish can be entrained by diverse zeitgebers. This complicated orchestra of divergent influences may cause variability in zebrafish circadian behaviours, which should be given attention when planning behavioural studies.
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http://dx.doi.org/10.1111/brv.12678DOI Listing
June 2021

Rye Snow Mold-Associated Strains Inhabiting a Common Area: Variability in Genetics, Morphotype, Extracellular Enzymatic Activities, and Virulence.

J Fungi (Basel) 2020 Dec 3;6(4). Epub 2020 Dec 3.

Laboratory of Plant Infectious Diseases, FRC Kazan Scientific Center of RAS, ul. Lobachevskogo, 2/31, 420111 Kazan, Russia.

Snow mold is a severe plant disease caused by psychrophilic or psychrotolerant fungi, of which species are the most harmful. A clear understanding of biology has many gaps; the pathocomplex and its dynamic are poorly characterized, virulence factors are unknown, genome sequences are not available, and the criteria of plant snow mold resistance are not elucidated. Our study aimed to identify comprehensive characteristics of a local community of snow mold-causing species colonizing a particular crop culture. By using the next-generation sequencing (NGS) technique, we characterized fungal and bacterial communities of pink snow mold-affected winter rye () plants within a given geographical location shortly after snowmelt. Twenty-one strains of were isolated, classified on the basis of internal transcribed spacer 2 (ITS2) region, and characterized by morphology, synthesis of extracellular enzymes, and virulence. Several types of extracellular enzymatic activities, the level of which had no correlations with the degree of virulence, were revealed for species for the first time. Our study shows that genetically and phenotypically diverse strains simultaneously colonize winter rye plants within a common area, and each strain is likely to utilize its own, unique strategy to cause the disease using "a personal" pattern of extracellular enzymes.
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http://dx.doi.org/10.3390/jof6040335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761817PMC
December 2020

Regulatory encoding of quantitative variation in spatial activity of a enhancer.

Sci Adv 2020 Dec 2;6(49). Epub 2020 Dec 2.

Evolutionary Ecology, Ludwig-Maximilians Universität München, Fakultät für Biologie, Biozentrum, Grosshaderner Strasse 2, 82152 Planegg-Martinsried, Germany.

Developmental enhancers control the expression of genes prefiguring morphological patterns. The activity of an enhancer varies among cells of a tissue, but collectively, expression levels in individual cells constitute a spatial pattern of gene expression. How the spatial and quantitative regulatory information is encoded in an enhancer sequence is elusive. To link spatial pattern and activity levels of an enhancer, we used systematic mutations of the enhancer, active in developing wings, and tested their effect in a reporter assay. Moreover, we developed an analytic framework based on the comprehensive quantification of spatial reporter activity. We show that the quantitative enhancer activity results from densely packed regulatory information along the sequence, and that a complex interplay between activators and multiple tiers of repressors carves the spatial pattern. Our results shed light on how an enhancer reads and integrates trans-regulatory landscape information to encode a spatial quantitative pattern.
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http://dx.doi.org/10.1126/sciadv.abe2955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821883PMC
December 2020

T-cell tracking, safety, and effect of low-dose donor memory T-cell infusions after αβ T cell-depleted hematopoietic stem cell transplantation.

Bone Marrow Transplant 2021 Apr 17;56(4):900-908. Epub 2020 Nov 17.

Department of Hematopoietic Stem Cell Transplantation, Dmitriy Rogachev National Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

The delayed recovery of adaptive immunity underlies transplant-related mortality (TRM) after αβ T cell-depleted hematopoietic stem cell transplantation (HSCT). We tested the use of low-dose memory donor lymphocyte infusions (mDLIs) after engraftment of αβ T cell-depleted grafts.A cohort of 131 pediatric patients (median age 9 years) were grafted with αβ T cell-depleted products from either haplo (n = 79) or unrelated donors (n = 52). After engraftment, patients received mDLIs prepared by CD45RA depletion. Cell dose was escalated monthly from 25 × 10 to 100 × 10/kg (haplo) and from 100 × 10 to 300 × 10 /kg (MUD). In a subcohort of 16 patients, T-cell receptor (TCR) repertoire profiling with deep sequencing was used to track T-cell clones and to evaluate the contribution of mDLI to the immune repertoire.In total, 343 mDLIs were administered. The cumulative incidence (CI) of grades II and III de novo acute graft-versus-host disease (aGVHD) was 5% and 2%, respectively, and the CI of chronic graft-versus-host disease was 7%. Half of the patients with undetectable CMV-specific T cells before mDLI recovered CMV-specific T cells. TCR repertoire profiling confirmed that mDLI-derived T cells significantly contribute to the TCR repertoire up to 1 year after HSCT and include persistent, CMV-specific T-cell clones.
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http://dx.doi.org/10.1038/s41409-020-01128-2DOI Listing
April 2021

Quantification of NG2-positivity for the precise prediction of KMT2A gene rearrangements in childhood acute leukemia.

Genes Chromosomes Cancer 2021 Feb 20;60(2):88-99. Epub 2020 Nov 20.

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

It has long been known that there is a link between neuron glial antigen 2 (NG2) surface expression and KMT2A gene rearrangements in acute leukemia (AL). However, the exact levels of NG2 positivity that predict the presence of KMT2A rearrangement are not known. The current study focuses on a cohort of 505 pediatric AL patients who showed any level of positive NG2 expression (greater than 1% of cells) for whom comprehensive genetic data were available. NG2 expression was measured as either the percentage of positive cells or the number of molecules on the cell surface. KMT2A gene rearrangements were identified by FISH. The fusion partner was detected with RT-PCR, LDI-PCR or anchored multiplex PCR followed by high-throughput sequencing. KMT2A-positive samples comprised a substantial proportion of the NG2-positive cohort (180 of 505, 36%), with a total of 19 different types of translocation. Despite its occurrence in other AL genetic subgroups, NG2 expression was significantly increased in AL patients with KMT2A rearrangements in terms of both the cell percentage and number of molecules per cell. The threshold levels (TL) for NG2-positivity were established by ROC analysis of the whole cohort and separately for children less than 1 years old and older with lymphoblastic (ALL) and myeloid (AML) leukemia. The lowest TL was defined in infants with ALL (7%), while in older children, the threshold was higher (12%). In AML patients, the situation was reversed, with 28% NG2-positivity in infants and 14% in patients >1 year old. The defined TLs resulted in improved diagnostic performance compared to the conventional thresholds of 10% and 20% for all patient groups.
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http://dx.doi.org/10.1002/gcc.22915DOI Listing
February 2021

In vitro megakaryocyte culture from human bone marrow aspirates as a research and diagnostic tool.

Platelets 2020 Sep 16:1-8. Epub 2020 Sep 16.

Hematology Department, Brigham and Women's Hospital Division of Hematology and Harvard Medical School Department of Medicine, Boston, MA, USA.

Megakaryocytes (MKs) are relatively rare in bone marrow, comprising <0.05% of the nucleated cells, which makes direct isolation from human bone marrow impractical. As such, in vitro expansion of primary MKs from patient samples offers exciting fundamental and clinical opportunities. As most of the developed ex vivo methods require a substantial volume of biomaterial, they are not widely performed on young patients. Here we propose a simple, robust, and adapted method of primary human MK culture from 1 mL of bone marrow aspirate. Our technique uses a small volume of bone marrow per culture, uses straightforward isolation methods, and generates approximately 6 × 10 mature MKs per culture. The relative high cell purity and yield achieved by this technique, combined with efficient use of low volumes of bone marrow, make this approach suitable for diagnostic and basic research of human megakaryopoiesis.
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http://dx.doi.org/10.1080/09537104.2020.1817359DOI Listing
September 2020

Enhancer evolutionary co-option through shared chromatin accessibility input.

Proc Natl Acad Sci U S A 2020 08 10;117(34):20636-20644. Epub 2020 Aug 10.

Fakultät für Biologie, Biozentrum, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany

The diversity of forms in multicellular organisms originates largely from the spatial redeployment of developmental genes [S. B. Carroll, 134, 25-36 (2008)]. Several scenarios can explain the emergence of -regulatory elements that govern novel aspects of a gene expression pattern [M. Rebeiz, M. Tsiantis, 45, 115-123 (2017)]. One scenario, enhancer co-option, holds that a DNA sequence producing an ancestral regulatory activity also becomes the template for a new regulatory activity, sharing regulatory information. While enhancer co-option might fuel morphological diversification, it has rarely been documented [W. J. Glassford et al., 34, 520-531 (2015)]. Moreover, if two regulatory activities are borne from the same sequence, their modularity, considered a defining feature of enhancers [J. Banerji, L. Olson, W. Schaffner, 33, 729-740 (1983)], might be affected by pleiotropy. Sequence overlap may thereby play a determinant role in enhancer function and evolution. Here, we investigated this problem with two regulatory activities of the gene , the novel enhancer and the ancestral enhancer. We used precise and comprehensive quantification of each activity in wings to systematically map their sequences along the locus. We show that the enhancer has co-opted the sequences of the enhancer. We also identified a pleiotropic site necessary for DNA accessibility of a shared regulatory region. While the evolutionary steps leading to the derived activity are still unknown, such pleiotropy suggests that enhancer accessibility could be one of the molecular mechanisms seeding evolutionary co-option.
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http://dx.doi.org/10.1073/pnas.2004003117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456186PMC
August 2020

Steric and Electronic Effect of Cp-Substituents on the Structure of the Ruthenocene Based Pincer Palladium Borohydrides.

Molecules 2020 May 9;25(9). Epub 2020 May 9.

A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilova Str., Moscow 119991, Russia.

Ruthenocene-based PCP pincer ligands were used to synthesize novel pincer palladium chloride Rc[PCP]PdCl () and two novel palladium tetrahydroborates Rc[PCP]Pd(BH) () and Rc[PCP]Pd(BH) (), where Rc[PCP] = κ-{2,5-(tBuPCH)CH}Ru(Cp) (Cp = CMeCF), and Rc*[PCP] = κ-{2,5-(tBuPCH)CH}Ru(Cp*) (Cp* = CMe). These coordination compounds were characterized by X-ray, NMR and FTIR techniques. Analysis of the X-ray data shows that an increase of the steric bulk of non-metalated cyclopentadienyl ring in and relative to non-substituted Rc[PCP]Pd(BH) analogue (; where Rc[PCP] = κ-{2,5-(tBuPCH)CH}Ru(Cp), Cp = CH) pushes palladium atom from the middle plane of the metalated Cp ring in the direction opposite to the ruthenium atom. This displacement increases in the order < < following the order of the Cp-ring steric volume increase. The analysis of both X-ray and IR data suggests that BH ligand in both palladium tetrahydroborates and has the mixed coordination mode η. The strength of the BH bond with palladium atom increases in the order Rc[PCP]Pd(BH) < Rc*[PCP]Pd(BH) < Rc[PCP]Pd(BH) that appears to be affected by both steric and electronic properties of the ruthenocene moiety.
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http://dx.doi.org/10.3390/molecules25092236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248887PMC
May 2020

Hypercapnia potentiates HIF-1α activation in the brain of rats exposed to intermittent hypoxia.

Respir Physiol Neurobiol 2020 07 17;278:103442. Epub 2020 Apr 17.

National Medical Research Center named after V.A. Almazov, 197341, Akkuratova st., 2, St. Petersburg, Russia.

The mechanisms and signalling pathways of the neuroprotective effect of hypercapnia and its combination with hypoxia are poorly understood. The study aims to test the hypothesis about the potentiating effect of hypercapnia on hypoxia adaptation systems directly related to hypoxia-induced factor 1α (HIF-1α). In this study we assessed HIF-1α content in hippocampal extracts and astrocytes obtained from Wistar male rats exposed to different respiratory conditions (7- or 15-fold of hypoxia and/or hypercapnia). In addition, HIF-1α content in astrocytes was assessed in in vitro model of chemical hypoxia as well as in the cerebral cortex after photothrombotic damage of this brain region. This study indicates increased levels of HIF1α in hippocampal extracts, astrocytes, and in cells of the near-stroke region of the cerebral cortex in rats exposed to hypoxia and hypercapnic hypoxia, but not hypercapnia alone. In in vitro study, hypercapnia facilitates the effects of acute chemical hypoxia observed in astrocytes. Thus, hypercapnia does not increase the level of transcription factor HIF-1α. However, the combined effects of hypercapnia and hypoxia in in vitro simulations of acute chemical hypoxia potentiate the accumulation of HIF-1α.
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http://dx.doi.org/10.1016/j.resp.2020.103442DOI Listing
July 2020

The Influence of Changes in Magnetic Variations and Light-Dark Cycle on Life-History Traits of Daphnia magna.

Bioelectromagnetics 2020 Jul 15;41(5):338-347. Epub 2020 Apr 15.

I.D. Papanin Institute for Biology of Inland Waters Russian Academy of Sciences, Borok, Russia.

Day-night cycle is the main zeitgeber (time giver) for biological circadian rhythms. Recently, it was suggested that natural diurnal geomagnetic variation may also be utilized by organisms for the synchronization of these rhythms. In this study, life-history traits in Daphnia magna were evaluated after short-term and multigenerational exposure to 16 h day/8 h night cycle, 32 h day/16 h night cycle, diurnal geomagnetic variation of 24 h, simulated magnetic variation of 48 h, and combinations of these conditions. With short-term exposure, the lighting mode substantially influenced the brood to brood period and the lifespan in daphnids. The brood to brood period, brood size, and body length of crustaceans similarly depended on the lighting mode during the multigenerational exposure. At the same time, an interaction of lighting mode and magnetic variations affected to a lesser extent brood to brood period, brood size, and newborn's body length. The influence of simulated diurnal variation on life-history traits in daphnids appeared distinctly as effects of synchronization between periods of lighting mode and magnetic variations during the multigenerational exposure. Newborn's body length significantly depended on the lighting regime when the periods of both studied zeitgebers were unsynchronized, or on the interaction of light regime with magnetic variations when the periods were synchronized. These results confirm the hypothesis that diurnal geomagnetic variation is an additional zeitgeber for biological circadian rhythms. Possible mechanisms for these observed effects are discussed. Bioelectromagnetics. © 2020 Bioelectromagnetics Society.
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http://dx.doi.org/10.1002/bem.22264DOI Listing
July 2020

The response of Daphnia magna Straus to long-term exposure to simulated geomagnetic storms.

Life Sci Space Res (Amst) 2019 May 25;21:83-88. Epub 2019 Apr 25.

Papanin Institute for Biology of Inland Waters, Russian Academy of Sciences, 152742 Yaroslavl Oblast, Borok, Russia.

The capability of Daphnia magna to adapt to artificial low-frequency magnetic fields via a maternal effect has been demonstrated previously. The current study assessed the possibility of a maternal effect in response to simulated natural geomagnetic fluctuations. D. magna lines were exposed to simulated geomagnetic storms for two, five, and eight sequential generations. Evaluations were conducted on the 3rd, 6th, and 9th generations of daphnids from experimental and control lines in order to determine the period required for the formation of an adaptive maternal effect. The evaluations showed that larger offspring were produced when maturation and reproduction occurred under the same conditions as those in which the Daphnia had lived in for generations. These observations suggest a manifestation of an adaptive maternal effect occurs in response to long-term exposure to simulated geomagnetic storms. Ecological relevance of geomagnetic storms to natural populations of daphnids is discussed.
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http://dx.doi.org/10.1016/j.lssr.2019.04.004DOI Listing
May 2019

Designing Blood-Brain Barrier Models Reproducing Alterations in Brain Aging.

Front Aging Neurosci 2018 6;10:234. Epub 2018 Aug 6.

Department of Biochemistry, Medical, Pharmaceutical & Toxicological Chemistry, Krasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky, Krasnoyarsk, Russia.

Blood-brain barrier (BBB) modeling is a huge area of research covering study of intercellular communications and development of BBB, establishment of specific properties that provide controlled permeability of the barrier. Current approaches in designing new BBB models include development of new (bio) scaffolds supporting barriergenesis/angiogenesis and BBB integrity; use of methods enabling modulation of BBB permeability; application of modern analytical techniques for screening the transfer of metabolites, bio-macromolecules, selected drug candidates and drug delivery systems; establishment of 3D models; application of microfluidic technologies; reconstruction of microphysiological systems with the barrier constituents. Acceptance of idea that BBB models should resemble real functional activity of the barrier in different periods of ontogenesis and in different (patho) physiological conditions leads to proposal that establishment of BBB model with alterations specific for aging brain is one of current challenges in neurosciences and bioengineering. Vascular dysfunction in the aging brain often associates with leaky BBB, alterations in perivascular microenvironment, neuroinflammation, perturbed neuronal and astroglial activity within the neurovascular unit, impairments in neurogenic niches where microvascular scaffold plays a key regulatory role. The review article is focused on aging-related alterations in BBB and current approaches to development of "aging" BBB models .
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http://dx.doi.org/10.3389/fnagi.2018.00234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6088457PMC
August 2018

The inhibitory effect of LPS on the expression of GPR81 lactate receptor in blood-brain barrier model in vitro.

J Neuroinflammation 2018 Jul 4;15(1):196. Epub 2018 Jul 4.

Research Institute of Molecular Medicine and Pathobiochemistry, Krasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky, Krasnoyarsk, Russia.

Background: Lipopolysaccharide (LPS) is one of the main constituents of the cell wall of gram-negative bacteria. As an endotoxin, LPS induces neuroinflammation, which is associated with the blood-brain barrier impairment. Lactate is a metabolite with some significant physiological functions within the neurovascular unit/blood-brain barrier (BBB). Accumulation of extracellular and cerebrospinal fluid lactate is a specific feature of bacterial meningitis. However, the role of lactate production, transport, and sensing by lactate receptors GPR81 in the pathogenesis of bacterial neuroinflammation is still unknown.

Methods: In this study, we analyzed effects of LPS on the expression of GPR81 and MCT-1 and proliferation of cerebral endothelial cells in the BBB model in vitro. We used molecular profiling methods to measure the expression of GPR81, MCT-1, IL-1β, and Ki67 in the cerebral endothelium after treatment with different concentrations of LPS followed by measuring the level of extracellular lactate, transendothelial electric resistance, and permeability of the endothelial cell layer.

Results: Our findings showed that exposure to LPS results in neuroinflammatory changes associated with decreased expression of GPR81 and MCT-1 in endothelial cells, as well as overproduction of IL-1β and elevation of lactate concentrations in the extracellular space in a dose-dependent manner. LPS treatment reduced JAM tight junction protein expression in cerebral endothelial cells and altered BBB structural integrity in vitro.

Conclusion: The impairment of lactate reception and transport might contribute to the alterations of BBB structural and functional integrity caused by LPS-mediated neuroinflammation.
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http://dx.doi.org/10.1186/s12974-018-1233-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030740PMC
July 2018

Gliotransmitters and cytokines in the control of blood-brain barrier permeability.

Rev Neurosci 2018 07;29(5):567-591

Research Institute of Molecular Medicine and Pathobiochemistry, Krasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky, P. Zheleznyaka str., 1, Krasnoyarsk 660022, Russia.

The contribution of astrocytes and microglia to the regulation of neuroplasticity or neurovascular unit (NVU) is based on the coordinated secretion of gliotransmitters and cytokines and the release and uptake of metabolites. Blood-brain barrier (BBB) integrity and angiogenesis are influenced by perivascular cells contacting with the abluminal side of brain microvessel endothelial cells (pericytes, astrocytes) or by immune cells existing (microglia) or invading the NVU (macrophages) under pathologic conditions. The release of gliotransmitters or cytokines by activated astroglial and microglial cells is provided by distinct mechanisms, affects intercellular communication, and results in the establishment of microenvironment controlling BBB permeability and neuroinflammation. Glial glutamate transporters and connexin and pannexin hemichannels working in the tight functional coupling with the purinergic system serve as promising molecular targets for manipulating the intercellular communications that control BBB permeability in brain pathologies associated with excessive angiogenesis, cerebrovascular remodeling, and BBB-mediated neuroinflammation. Substantial progress in deciphering the molecular mechanisms underlying the (patho)physiology of perivascular glia provides promising approaches to novel clinically relevant therapies for brain disorders. The present review summarizes the current understandings on the secretory machinery expressed in glial cells (glutamate transporters, connexin and pannexin hemichannels, exocytosis mechanisms, membrane-derived microvesicles, and inflammasomes) and the role of secreted gliotransmitters and cytokines in the regulation of NVU and BBB permeability in (patho)physiologic conditions.
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http://dx.doi.org/10.1515/revneuro-2017-0092DOI Listing
July 2018

Low-dose donor memory T-cell infusion after TCR alpha/beta depleted unrelated and haploidentical transplantation: results of a pilot trial.

Bone Marrow Transplant 2018 03 21;53(3):264-273. Epub 2017 Dec 21.

Department of Hematopoietic Stem Cell Transplantation, Dmitriy Rogachev National Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

Recovery of immunity is delayed in recipients of T-depleted grafts. Adoptive transfer of memory T-cells may improve immune response to common pathogens. A cohort of 53 patients with malignant (n = 36) and non-malignant conditions (n = 17) received TCR alpha/beta depleted grafts from haploidentical (n = 25) or MUD (n = 28) donors. Donor lymphocytes were depleted of CD45RA-positive cells. At a median of 48 days after transplantation, patients received DLI at 25 × 10/kg CD3 cells from haploidentical or 100 × 10/kg CD3 from MUD donors. Up to 3 doses of donor lymphocytes were administered at monthly intervals, escalating to 100 × 10/kg in haploidentical transplants and 300 × 10/kg in MUD transplants. At a median follow-up of 23 months, the cumulative incidence of de novo acute GVHD after DLI is 2% (1 of 43), while the rate of reactivation of preexisting aGVHD was 50% (5 of 10). The transplant-related mortality is 6%. The overall survival rates are 80% and 88% in malignant and non-malignant conditions, respectively. Among patients with absent CMV-specific immune reactivity at baseline (n = 31) expansion of CMV-specific T-cells was demonstrated in 20 (64.5%) within 100 days. Infusions of low dose donor memory T-lymphocytes are safe and constitute a simple measure to prevent infections in the setting of alpha/beta T cell-depleted transplantation.
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http://dx.doi.org/10.1038/s41409-017-0035-yDOI Listing
March 2018

Polyphenol oxidase from Pectobacterium atrosepticum: identification and cloning of gene and characteristics of the enzyme.

J Basic Microbiol 2017 Dec 25;57(12):998-1009. Epub 2017 Oct 25.

Kazan Institute of Biochemistry and Biophysics, Kazan Science Centre, Russian Academy of Sciences, Kazan, Russia.

In the present study, we attempted to elucidate if the harmful phytopathogenic bacteria of Pectobacterium genus (P. atrosepticum) possess the enzymes for oxidation of phenolic compounds. Polyphenol oxidase (laccase) activity was revealed in P. atrosepticum cell lysates. Using bioinformatic analysis, an ORF encoding a putative copper-containing polyphenol oxidase of 241 amino acids with a predicted molecular mass of 25.9 kDa was found. This protein (named Pal1) shares significant level of identity with laccases of a new type described for several bacterial species. Cloning and expression of the pal1 gene and the analysis of corresponding recombinant protein confirmed that Pal1 possessed laccase activity. The recombinant Pal1 protein was characterized in terms of substrate specificity, kinetic parameters, pH and temperature optimum, sensitivity to inhibitors and metal content. Pal1 demonstrated alkali- and thermo-tolerance. The kinetic parameters K and kcat for 2,6-dimethoxyphenol were 0.353 ± 0.062 mM and 98.79 ± 4.9 s , respectively. The protein displayed high tolerance to sodium azide, sodium fluoride, NaCl, SDS and cinnamic acid. The transcript level of the pal1 gene in P. atrosepticum was shown to be induced by plant-derived phenolic compound (ferulic acid) and copper sulfate.
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http://dx.doi.org/10.1002/jobm.201700413DOI Listing
December 2017

Gaps and opportunities for the World Heritage Convention to contribute to global wilderness conservation.

Conserv Biol 2018 02 6;32(1):116-126. Epub 2017 Dec 6.

School of Earth and Environmental Sciences, University of Queensland, St Lucia QLD 4072, Australia.

Wilderness areas are ecologically intact landscapes predominantly free of human uses, especially industrial-scale activities that result in substantial biophysical disturbance. This definition does not exclude land and resource use by local communities who depend on such areas for subsistence and bio-cultural connections. Wilderness areas are important for biodiversity conservation and sustain key ecological processes and ecosystem services that underpin planetary life-support systems. Despite these widely recognized benefits and values of wilderness, they are insufficiently protected and are consequently being rapidly eroded. There are increasing calls for multilateral environmental agreements to make a greater and more systematic contribution to wilderness conservation before it is too late. We created a global map of remaining terrestrial wilderness following the established last-of-the-wild method, which identifies the 10% of areas with the lowest human pressure within each of Earth's 62 biogeographic realms and identifies the 10 largest contiguous areas and all contiguous areas >10,000 km . We used our map to assess wilderness coverage by the World Heritage Convention and to identify gaps in coverage. We then identified large nationally designated protected areas with good wilderness coverage within these gaps. One-quarter of natural and mixed (i.e., sites of both natural and cultural value) World Heritage Sites (WHS) contained wilderness (total of 545,307 km ), which is approximately 1.8% of the world's wilderness extent. Many WHS had excellent wilderness coverage, for example, the Okavango Delta in Botswana (11,914 km ) and the Central Suriname Nature Reserve (16,029 km ). However, 22 (35%) of the world's terrestrial biorealms had no wilderness representation within WHS. We identified 840 protected areas of >500 km that were predominantly wilderness (>50% of their area) and represented 18 of the 22 missing biorealms. These areas offer a starting point for assessing the potential for the designation of new WHSs that could help increase wilderness representation on the World Heritage list. We urge the World Heritage Convention to ensure that the ecological integrity and outstanding universal value of existing WHS with wilderness values are preserved.
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http://dx.doi.org/10.1111/cobi.12976DOI Listing
February 2018

Global Gene Expression Analysis of Cross-Protected Phenotype of Pectobacterium atrosepticum.

PLoS One 2017 12;12(1):e0169536. Epub 2017 Jan 12.

Department of Microbiology and Plant Pathology, University of Pretoria, Pretoria, South Africa.

The ability to adapt to adverse conditions permits many bacterial species to be virtually ubiquitous and survive in a variety of ecological niches. This ability is of particular importance for many plant pathogenic bacteria that should be able to exist, except for their host plants, in different environments e.g. soil, water, insect-vectors etc. Under some of these conditions, bacteria encounter absence of nutrients and persist, acquiring new properties related to resistance to a variety of stress factors (cross-protection). Although many studies describe the phenomenon of cross-protection and several regulatory components that induce the formation of resistant cells were elucidated, the global comparison of the physiology of cross-protected phenotype and growing cells has not been performed. In our study, we took advantage of RNA-Seq technology to gain better insights into the physiology of cross-protected cells on the example of a harmful phytopathogen, Pectobacterium atrosepticum (Pba) that causes crop losses all over the world. The success of this bacterium in plant colonization is related to both its virulence potential and ability to persist effectively under various stress conditions (including nutrient deprivation) retaining the ability to infect plants afterwards. In our previous studies, we showed Pba to be advanced in applying different adaptive strategies that led to manifestation of cell resistance to multiple stress factors. In the present study, we determined the period necessary for the formation of cross-protected Pba phenotype under starvation conditions, and compare the transcriptome profiles of non-adapted growing cells and of adapted cells after the cross-protective effect has reached the maximal level. The obtained data were verified using qRT-PCR. Genes that were expressed differentially (DEGs) in two cell types were classified into functional groups and categories using different approaches. As a result, we portrayed physiological features that distinguish cross-protected phenotype from the growing cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169536PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5230779PMC
August 2017

Structure of Scots pine defensin 1 by spectroscopic methods and computational modeling.

Int J Biol Macromol 2016 Mar 11;84:142-52. Epub 2015 Dec 11.

Department of Physics and Optical Science and Center for Biomedical Engineering and Science, University of North Carolina, Charlotte, NC, USA. Electronic address:

Defensins are part of the innate immune system in plants with activity against a broad range of pathogens, including bacteria, fungi and viruses. Several defensins from conifers, including Scots pine defensin 1 (Pinus sylvestris defensin 1, (PsDef1)) have shown a strong antifungal activity, however structural and physico-chemical properties of the family, needed for establishing the structure-dynamics-function relationships, remain poorly characterized. We use several spectroscopic and computational methods to characterize the structure, dynamics, and oligomeric state of PsDef1. The three-dimensional structure was modeled by comparative modeling using several programs (Geno3D, SWISS-MODEL, I-TASSER, Phyre(2), and FUGUE) and verified by circular dichroism (CD) and infrared (FTIR) spectroscopy. Furthermore, FTIR data indicates that the structure of PsDef1 is highly resistant to high temperatures. NMR diffusion experiments show that defensin exists in solution in the equilibrium between monomers and dimers. Four types of dimers were constructed using the HADDOCK program and compared to the known dimer structures of other plant defensins. Gaussian network model was used to characterize the internal dynamics of PsDef1 in monomer and dimer states. PsDef1 is a typical representative of P. sylvestris defensins and hence the results of this study are applicable to other members of the family.
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http://dx.doi.org/10.1016/j.ijbiomac.2015.12.011DOI Listing
March 2016

Influence of magnetic field on zebrafish activity and orientation in a plus maze.

Behav Processes 2016 Jan 14;122:80-6. Epub 2015 Nov 14.

I.D Papanin Institute for Biology of Inland Waters, Russian Academy of Sciences, 152742 Borok, Russian Federation. Electronic address:

We describe an impact of the geomagnetic field (GMF) and its modification on zebrafish's orientation and locomotor activity in a plus maze with four arms oriented to the north, east, south and west. Zebrafish's directional preferences were bimodal in GMF: they visited two arms oriented in opposed directions (east-west) most frequently. This bimodal preference remained stable for same individuals across experiments divided by several days. When the horizontal GMF component was turned 90° clockwise, the preference accordingly shifted by 90° to arms oriented to the north and south. Other modifications of GMF (reversal of both vertical and horizontal GMF components; reversal of vertical component only; and reversal of horizontal component only) did not exert any discernible effect on the orientation of zebrafish. The 90° turn of horizontal component also resulted in a significant increase of fish's locomotor activity in comparison with the natural GMF. This increase became even more pronounced when the horizontal component was repeatedly turned by 90° and back with 1min interval between turns. Our results show that GMF and its variations should be taken into account when interpreting zebrafish's directional preferences and locomotor activity in mazes and other experimental devices.
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http://dx.doi.org/10.1016/j.beproc.2015.11.009DOI Listing
January 2016

The response of Daphnia magna Straus to the long-term action of low-frequency magnetic fields.

Ecotoxicol Environ Saf 2013 Oct 11;96:213-9. Epub 2013 Jul 11.

I.D. Papanin Institute for Biology of Inland Waters, Russian Academy of Sciences, Borok, Nekouz, Yaroslavl Oblast 152742, Russia.

We exposed Daphnia magna Straus to an extra-low-frequency magnetic field (ELF MF) for several sequential generations to study its affect on size and number of nonviable individuals in Daphnia offspring produced. The lines of D. magna were subjected to ELF MF over three months. The abundance, wet biomass, and morphometric parameters were measured for adults, first brood, and second brood over eight generations. Then, in order to find a maternal effect in the experimental lines of D. magna, separate tests were performed with the control and experimental lines. The number of nonviable offspring in the first five broods and newborns' body lengths in the first five broods were evaluated. The exposure of D. magna to ELF MF led to decreases in size and the biomass and changes in generalized variance of the measured morphometric parameters of Daphnids compared with the control. Daphnids from the experimental lines produced more viable and larger offspring in conditions of ELF MF action as compared with the control. These findings assess the impacts of magnetic fields influenced by anthropogenic factors on Daphnia and possibly the effects of laboratory equipment emitting ELF MF on Daphnia in experimental settings.
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http://dx.doi.org/10.1016/j.ecoenv.2013.06.012DOI Listing
October 2013

Structure-function relationship in the CYP74 family: conversion of divinyl ether synthases into allene oxide synthases by site-directed mutagenesis.

FEBS Lett 2013 Aug 2;587(16):2552-8. Epub 2013 Jul 2.

Kazan Institute of Biochemistry and Biophysics, Russian Academy of Sciences, P.O. Box 30, Kazan 420111, Russia.

Non-classical P450s of CYP74 family control several enzymatic conversions of fatty acid hydroperoxides to bioactive oxylipins in plants, some invertebrates and bacteria. The family includes two dehydrases, namely allene oxide synthase (AOS) and divinyl ether synthase (DES), and two isomerases, hydroperoxide lyase (HPL) and epoxyalcohol synthase. To study the interconversion of different CYP74 enzymes, we prepared the mutant forms V379F and E292G of tobacco (CYP74D3) and flax (CYP74B16) divinyl ether synthases (DESs), respectively. In contrast to the wild type (WT) enzymes, both mutant forms lacked DES activity. Instead, they produced the typical AOS products, α-ketols and (in the case of the flax DES mutant) 12-oxo-10,15-phytodienoic acid. This is the first demonstration of DES into AOS conversions caused by single point mutations.
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http://dx.doi.org/10.1016/j.febslet.2013.06.030DOI Listing
August 2013

The response of European Daphnia magna Straus and Australian Daphnia carinata King to changes in geomagnetic field.

Electromagn Biol Med 2013 Mar 15;32(1):30-9. Epub 2013 Jan 15.

I. D. Papanin Institute for Biology of Inland Waters, Russian Academy of Sciences, Borok, Russia.

This study investigates the effects of lifelong exposure to reversed geomagnetic and zero geomagnetic fields (the latter means absence of geomagnetic field) on the life history of Daphnia carinata King from Australia and Daphnia magna Straus from Europe. Considerable deviation in the geomagnetic field from the usual strength, leads to a decrease in daphnia size and life span. Reduced brood sizes and increased body length of neonates are observed in D. magna exposed to unusual magnetic background. The most apparent effects are induced by zero geomagnetic field in both species of Daphnia. A delay in the first reproduction in zero geomagnetic field is observed only in D. magna. No adaptive maternal effects to reversed geomagnetic field are found in a line of D. magna maintained in these magnetic conditions for eight generations. Integrally, the responses of D. magna to unusual geomagnetic conditions are more extensive than that in D. carinata. We suggest that the mechanism of the effects of geomagnetic field reversal on Daphnia may be related to differences in the pattern of distribution of the particles that have a magnetic moment, or to moving charged organic molecules owing to a change in combined outcome and orientation of the geomagnetic field and Earth's gravitational field. The possibility of modulation of self-oscillating processes with changes in geomagnetic field is also discussed.
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http://dx.doi.org/10.3109/15368378.2012.700291DOI Listing
March 2013

Late Myelosuppressive Action of Programmed Chemotherapy in Acute Lymphoblastic Leukemia in Children.

Russ J Immunol 2000 Dec;5(4):391-398

Research Institute of Pediatric Hematology, Moscow, Russia.

The capability of peripheral blood leukocytes and bone marrow cells to spontaneous apoptosis was studied in 36 children with ALL remission at various periods after polychemotherapy withdrawal. The enhancement of apoptotic activity has been revealed to be the universal mechanism of delayed effect of antileukemic chemotherapy for all the compartments of hemopoiesis, including granulocyte/macrophage precursors. The expression of this phenomenon is decreasing with the time period elapsed after treatment withdrawal. However, approximation analysis shows that the recovery of normal values of blood cell apoptosis occurs not earlier than 8 years after therapy withdrawal. Therein, in should be noted that the numbers of leukocytes don't differ from normal values at all the periods of observation. The growth of proliferative potential for precursor cells and the increased proportion of proliferating granulocyte pool of bone marrow are shown to be the probable mechanisms contributing to compensation of enhanced ability of blood cells to apoptosis.
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December 2000

Kinetics of Apoptosis of Peripheral Blood Leukocytes in Normal State and in Children Recovered from Acute Lymphoblastic Leukemia.

Russ J Immunol 2000 Oct;5(3):301-306

Research Institute of Pediatric Hematology, Moscow, Russia.

The original method is proposed for the study of apoptosis kinetics in cell populations by determination of apoptotic cell accumulation during the day's incubation in serum free medium. We have studied the features of this process for peripheral blood granulocytes and lymphocytes from healthy children. High sensitivity of the proposed method has been shown for the estimation of apoptosis, taking for illustration the analysis of delayed chemotherapy influence on blood cells in children, recovered from acute limphoblastic leukemia (ALL). In children with ALL, the delayed myelosuppressive effect of antileukemic therapy has been proved to be not only in relation to the increase of blood cell ability to spontaneous apoptosis, but also to induce the certain impairments in the kinetics of this process.
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October 2000