A TRIBUTE TO ELENA KORNEVA, A PIONEER OF NEUROIMMUNE BIOLOGY, ON HER 85 th BIRTHDAY

Abstract


The scientific carrier of Elena Korneva is presented, who dedicated her life for research on Immuno-Physiology, as she likes to call her field. PubMed reports 102 papers over 52 years. We can safely assume that her total production, including those works, which are not reported by PubMed might be over 200-250 papers, books and book chapters. We discuss a total of 70 papers, as for many papers only the titles were available to us. Of this 70 papers 55 were reported by PubMed between 1962 and 2009. In addition we have collected 14 papers and one book which were not reported by PubMed. These are book chapters and journal articles. Her research subjects vary a great deal, but everything has to do with Immuno-Physiology. The first paper we discuss establishes that the hypothalamus regulates immune function [1]. This knowledge that the Neuroendocrine and Immunes Systems interact never was neglected in her papers. Here we list the various fields of her investigations and put the reference numbers in brackets to help the reader. Neuroimmune interaction [References No.: 1, 5-12]; Glucocorticoids [13-15]; Cytokines [13-25]; Defensins [26, 27, 55]; Signal Transduction [29-31]; Stress [31-37]; Cholinergic immunoregulation [38, 39]; Opioid peptides [40]; Thymus [41]; Pineal gland [42]; Natural killer (NK) cells [43]; Anesthesia [44]; Nonspecific resistance [45]; Autoimmunity [46, 47]; Chronic fatigue syndrome (CFS) [48]. Orexin and immunity [49-52]; History of Neuroimmune Biology [54]; Concluding remarks to NIB 6 [55]; Immune response in the CNS [56]. Signal Transduction by IL-1 and IL-2 [57, 58]. c-Fos gene and Il-2 expression in the brain [59]; Signaling mechanisms in stress [60]. Orexin in the CNS and in immune organs [61, 62]. Neuroimmune pathology of stress [63]. As we may see Korneva covered just about any subjects belonging to Immuno-Physiology. She is a leader, not a follower, so all of the papers present new discoveries, new aspects of various areas of the subject matter she investigated. Considering this fact and also the work that could not be reported here makes her a truly outstanding scientist, which has been appreciated by various institutions. She received numerous medals and awards and fulfilled leading positions for a lifetime.

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INTRUDUCTION. Eighty five years have passed and she is till working. I remember meeting her in Italy when Nicola Fabris organized an International meting on Neuroimmune Biology. On that meeting Korneva came to me to say hello, as she knew my name from the literature, and this is how we met. This was in the late 1970-ies. In those days there were few people in the field, like Hans Selye, who developed the stress concept, Filipp, G, and Andor Szetivanyi, who discovered that the hypothalamus regulates immune function, Miklos Jancso discovered neurogenic inflammation, Robert Ader discovered Pavlovian conditioning of immune reactions and created the term Psychoneuroimmunology, Hugo Besedovsky developed the concept of cytokines and later worked mostly on the HPA axis in Immunity, the role of pituitary gland and immune function was discovered in my laboratory. Elena A. Korneva and L. M. Khai described that hypothalamic lesions regulated antibody formation in laboratory animals [1]. With this work they joined the team of old timers who worked on Neuroimmune Interaction. We could ask the question why Russia and Hungary is the birth place of Neuroimmune Biology (NIB)? Well in Russia Pavlov’s fame never faded. I saw the laboratory of Pavlov in St. Petersburg in 2009, it was there exactly like it was 100 years ago (Fig. 1). It was preserved for the educations of future generations. Pavlov put his dogs in an insulated chamber so no other stimulus could get to them only the ones, he delivered. This indicates how much he appreciated the power of the central nervous system, which has to do with everything. With this methodology he discovered conditioned neural reflexes, nowadays it is called «pavlovian conditioning». This was a good environment for Neuroimmune Biology to develop in Russia. In fact Pavlov’s students did work on the idea of NIB, but this work never got to be popular worldwide [56]. Hans Selye was Austro-Hungarian, as his mother was Austrian. His work on stress has been and still is of high esteem word wide. I learnt from Selye that the HPA axis mediates stress when I worked with him. When I got to be a staff member at the University of Manitoba, we asked the question what else the pituitary gland is doing to the Immune System? This is how pituitary immunoregulation was discovered. So Pavlov, his students and Korneva, were Russian and worked on the central nervous system. Selye, Filipp, Szentivanyi, Jancso and us (Berczi I. and Nagy, Eva) were Hungarians. People like Fabris were early to join the field which became a new discipline, and now we call it Neuroimmune Biology. Figure 1. In Pavlov’s laboratory. From left to right: Istvan Berczi, wife, Maria Eugenia Quintanar Stephano, Dr. V. M. Klimenko the Head of Department of Physiology (Pavlov’s Department) of the Institute of Experimental Medicine. So we got acquainted on that meeting and kept our friendship alive all the years till now. She invited me to meetings in St. Petersburg and I asked her to edit a book in my series of Neuroimmune Biology. She did so [55]. When I had trouble getting authors for my book on Stress and Immunity, she helped me out with 4 manuscripts [62-66]. And so we kept our friendship, helping each other for a long time until now. In addition she contributed regularly to Neurimmune Biology, and to Advances in Neuroimmune Biology which was much appreciated by me [please see the references]. Fifty years have elapsed since she wrote that ground braking paper and she is till working to this date. It beca МЕДИЦИНСКИЙ АКАДЕМИЧЕСКИЙ ЖУРНАЛ, 2014 г., ТОМ 14, № 4 21 me so natural for me that she is there if I need a good friend for some project she is ready to help. Well now it is time to turn our attention back and see what has been achieved by Dr. E. A. Korneva as she is cited in the literature. She provided me a list of papers for 10 years. Nobody asks for more than 5 years of papers these days, the rest is considered obsolete. This is a big mistake with the current generation. Most young scientists are not aware of the ever lasting values of key achievements in science, such as Korneva‘s work and achievements... So, to get things right I had to ask the question, what about 50 years of achievements?. What about her life time contribution? I consulted PubMed, and I found 102 papers listed from 1962 till 2011. Now in my case the papers listed in Pub Med amounts to around 40% of my publications, so in her case in maybe over 250 or so the total out put of papers. This is remarkable indeed. In any case her life time achievement is very significant. Her field is really Physiology and treats her subject matter as Immuno-Physiology [3]. A career spent on immuno-phy-siology. Korneva’s major papers cited by PubMed: Neuroimmune Interaction. Wistar rats (intact, sham operated and cortex or hypothalamic lesions). In the groups of sham-operated and cortex-lesioned rats spleen weights increased 7 days after operation. This was due to increase of the red pulp weight. The white pulp compartment’s ratio was not affected. Lesioning of the posterior hypothalamic area prevented these effects of the operation. Coagulation of the lateral hypothalamic area causes a significant decrease of the weight of spleen primary follicules which contain IgM+IgD+-bearing B-lymphocytes exerting characteristics of circulating pool of B-lymphocytes [5]. Changes in the levels of dopamine, norepinephrine, serotonin and their metabolites in the hypothalamic structures closely related to neurohumoral regulation of immunogenesis. The findings suggest that the monoami-nergic systems of the brain are widely involved in the body’s response to antigen, which may lead to the conclusion that there are numerous modes of entering information from the immune to the nervous system [6]. Inhibition or stimulation of IL-2 gene expression in lymphoid cells depends on the nature of the stressors. Restrain stress (RS) or antigenic stimuli induce c-fos and IL-2 gene expression in definite structures of the brain. The dynamics of this process are time dependent. The partial correlation between c-fos and IL-2 mRNA expression in localization in brain structure and time dependence was shown [7]. 'There was no increase in c-fos mRNA positive cells in the hypothalamus at 30 min. after tetanus toxoid (TT) injection. Elevation of the c-fos mRNA positive cells occurred in the hypothalamic’ posterior (PHA), lateral (LHA), anterior (AHA), areas dorsomedial (DMH), and ventromedial (VMH) nuclei within 2 hours of TT administration. In 6 hours the c-fos mRNA positive cells number decreased in PHA, LHA, DMH. There was no response to TT in arqua-te and supraoptic hypothalamic nuclei [8]. In Sprague-Dawley rats the number of c-fos mRNA-positive cells in all the hypothalamic structures was insignificant 30 min after injections of tetanus toxoid. c-fos mRNA-positive cells were seen in the posterior, lateral, and anterior hypothalamic fields and in the dorsomedial and ventromedial hypothalamic nuclei 2 h after injections of tetanus toxoid [9]. In situ hybridization on paraffin sections of the rat brain showed that synthetic peptides Vilon, Epithalon, and Cortagen modulated the expression of IL-2 gene in vivo in cells of some hypothalamic structures depending on the terms and routes of administration [10]. In rats c-Fos-positive cells 2 h after administration of lipopolysaccharide were seen in the following hypothalamic structures: AHN, PVH, LHA, VMH, DMH, and PH. After electrical pain stimulation, the number of c-Fos-positive cells increased in these same hypothalamic structures (AHN, PVH, LHA, VMH, DMH, and PH). The combination of electrical pain stimulation and lipopolysaccharide administration led to a decrease in the extent of activation in hypothalamic structures AHN, PVH, LHA, and VMH [11]. Hypothalamic orexin neurons react to injection of LPS in animals [12]. Glucocorticoids. Glucocorticoids regulate immune function. Antigen acts on cellular and molecular levels. Changes in glycocorticoid binding sites and cyclo-nuc-leotides levels occure. Glucocorticoids, and the neuroen-dorine system jointly regulate individual clones of immunocompetent cells to generate an immune response [13]. Correlations between endogenous glucocorticoid levels and intensity of humoral and cell-mediated immune responses were studied in different experimental sets. Changes of cyclic nucleotide levels in spleen lymphocytes induced by antigen were shown to depend on the intensity of hormonal shifts. The major significance of the intensity of hormonal changes and the sensitivity of cell populations to hormones for the final hormonal influence, is emphasized [14]. IL-1 was shown to increase the plasma level of corticosterone in rats by ip administration. It also produced a direct effect on the secretion of adrenal cells without enhancing ACTH stimulating action. IL-1 action on the hypothalamic-pituitary-adrenocortical system is implemented through its influence on neurons of the 22 МЕДИЦИНСКИЙ АКАДЕМИЧЕСКИЙ ЖУРНАЛ, 2014 г., ТОМ 14, № 4 cerebral hypothalamic areas secreting the corticotrophin releasing hormone [15]. Cytokines. Pure human interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6), both of natural origin, were found to cause fever in rabbits when injected into the PO/AH region of the brain. The threshold dose required for this effect was between 0,4 and 4 U, equivalent to 0,04 to 0,4 ng for IL-1beta, and around 50 U, equivalent to 0,05 ng for IL-6. From this it was estimated that this area of the brain responds to a local concentration of approximately 1 ng/ml of these cytokines, a level which can easily be reached after intravenous administration of threshold pyrogenic doses of either cytokine. The observation supports the view that fever induced by systemic endogenous production of IL-1 and IL-6 is due to a direct effect on the thermoregulatory center and may not require production of mediators, such as prostaglandins, at sites distant from the center [16]. LPS induced fever, released defensins and initiated IL-1 production. Thus, defensins may be involved in thermoregulation and may influence IL-1 secretion [17]. Deletion from human recombinant IL-1, serine, asparagine and aspartic acid (positions 52-54), significantly reduced functions. The resulting molecule (SND) acted on the immune system, as an IL-1 antagonist [18]. Sphingomyelin is involved in Interleukin 1 beta (IL-1) signaling in membrane fraction P2 of murine brain. IL-1 beta activated dose-dependently nSMase in P2 fraction of the brain cortex. Brain cortex membranes from mice deficient in the type I IL-1 receptor and of IL-1 receptor antagonist inhibited this response [19]. Injection of 5% mustard in vegetable oil, an injection of vegetable oil and needle prick was applied into leg gastrocnemius muscle of rats. Expression of c-fos-like proteins was shown after the injection (within 2 h) in the spinal cord structures, the maximum quantity of the labeled cells was found in the I and II sacral segments (in the superficial lamina of the gray matter of the dorsal horns in the ipsila-teral side), the minimum in the IV and V lumbar segments (in the intermediate zone of the gray matter at the level of the central canal). c-fos immunoreactivity appeared mostly in the contralateral side of the hypothalamus, therefore maybe in our investigation the mechanism of sensory stimuli mostly results in the changes that have been obtained. The information of applied stimulus arrived in the spinal cord, and it was transmitted to the brain where it activated certain brain structures inducing c-fos and IL-2 gene expression. The most important conclusion is that the used stress induced not only c-fos gene but also IL-2 gene expression in the brain. The synthesis of both mRNA takes place in the same brain structures [20]. This peptide (Lys-Glu) is the shortest regulatory fragment promoting the transport of trans-acting factors into the nucleus. It can not be excluded that Lys-Glu is a structural component of trans-acting factor active centers, which are necessary for the activation of interleukin- 2 gene transcription in lymphocytes [21]. IL-1 beta signaling in the CNS is mediated by the IL-1 type I receptor and neutral sphingomyelinase, the initiating enzyme of the sphingomyelin cascade [22]. IL-1beta signals in the CNS is mediated by the IL-1 type I receptor and activation of neutral sphingomyelinase as the initiating enzyme of the sphingomyelin cascade in mouse cerebral cortex cells [23]. The synthetic peptides Vilon (Lys-Glu), Epithalon (Ala-Glu-Asp-Gly), and Cortagen (Ala-Glu-Asp-Pro) in vitro activated interleukin-2 mRNA synthesis in spleno-cytes from CBA mice in the absence of specific inducers. The intensity of interleukin-2 mRNA synthesis in spleno-cytes depended on the type, concentration, and duration of treatment with the peptides. Vilon and Epithalon were most potent, while Cortagen produced a less pronounced effect on interleukin-2 mRNA synthesis [24]. The number of hypothalamic IL-2-containing cells changed in rats receiving Vilon and Epithalon during mild stress (handling). The number of IL-2-positive cells in hypothalamic structures decreased 24 h after intramuscular injection of Epithalon and 2 h after intranasal administration of the test peptides. Adaptation of animals to experimental conditions prevented the decrease in the number of IL-2-positive cells in the supraoptic nucleus after intranasal administration of Epithalon. Parallel analysis of c-Fos protein expression during activation of the rat anterior hypothalamic cells, and expression of interleukin-2 (IL-2) after mild stress (handling) and adaptation to it, and intranasal administration of saline and the peptides Vilon (Lys-Glu) and Epithalon (Ala-Glu-Asp-Gly). The expression of cFos gene and IL-2 production were studied in the lateral (LHA) area, anterior (AHN), supraoptic (SO) and paraventricular (PVH) nuclei of Wistar rats. A negative correlation was found between the activation of cells and their IL-2 contents [25]. Defensin. The human neutrophil peptide defensin (0,1-40 micrograms/mL) did not promote platelet aggregation, but decreased platelet aggregation responses to ADF, collagen or thrombin, inhibited ATP levels, which was released during platelet aggregation and malondialdehyde production, induced by thrombin and collagen. Therefore defensin is an antagonist of platelet aggregation [26]. Defensins had corticostatic activity in vivo in stress- and ACTH-induced elevation of corticosterone. Also defensins abolished the immunosuppressive action of stress in animals. Thus defensins protect against stress [27]. МЕДИЦИНСКИЙ АКАДЕМИЧЕСКИЙ ЖУРНАЛ, 2014 г., ТОМ 14, № 4 23 Defensin, a peptide derived from human neutrophils, (0,01 microgram/mL - 100 micrograms/mL) caused a distinct dose dependent aggregation of normal donor monocytes. and increased the rate of monocyte aggregation, induced arachidonic acid or phorbol myristate acetate [28]. Signal Transduction. The sphingomyelin pathway of IL-1beta signal transduction is one of the principle signal mechanisms providing realization of most, if not all, biological effects of this cytokine. Sphingomyelinase (nSMase) catalyses the hydrolysis of membrane shin-gomyelin to the secondary cellular messenger ceramide. It has been established that IL-1beta operation in the CNS involves IL-1 type beta1 receptor and the shingo-myeline pathway of cytokine signal transduction into the cell. Type 1 IL-1 receptor is necessary. Change in nSMase activity in membranes of nerve and immunocompetent cells is the common link in the stress reaction of neuroendocrine and immune cells [29]. Modifications of serum glucocorticoids in mice induced changes in neutral sphingomyelinase activity in the Immune- and Nervous Systems. Thus, sphingomyelin regulates IL-1beta signaling, which might be useful to affect glucocorticoid mediated immunoregulation [30]. Endogenous glucocorticoids in mice induced changes in neutral sphingomyelinase activity in the immune and nervous systems. Thus, IL-1beta might be useful to treat abnormalities of glucocorticoid mediated immunoregulation [31]. Stress. It was shown that NMS increases the c-Fos positive cell quantity in the lateral hypothalamic area (LHA), ventro-medial (VMH), dorso-medial (DMH) hypothalamic nuclei and anterior hypothalamic area (AHN) by 116, 199, 101 and 157% respectively, in comparison with the c-Fos immunoreactive cell quantity in intact animals. EHF irradiation of the skin decreased the intensity of c-Fos-like proteins synthesis induced by NMS in the most of the investigated structures (LHA, VMH, DMH and AHA by 32,8, 29, 15 and 33%, resp.) [31]. IL-1 is released by various stress reactions from lymphoid target cells, and in turn IL-1 signals nerve tissue via the sphingomyelin pathway [32]. Rotation stress induced macrophage release of LAF with peak reactions in 0-1 h after termination of stress, followed by elevation of plasma IL-1alpha. Induction of LAF release was accompanied by a higher concentration of corticosterone (Cs) in the blood, most prominent at 0 and 0,5 h after termination of the stressful procedure, and recovering to normal values 1 h later [33]. Cold stress suppressed the response of peripheral blood lymphocytes to IL-1beta. IL-1beta administrated i.p. to rats before cooling was immunoprotective. Thus IL-1beta modulates immunological and neuroendocrine responses during stress [34]. Activation of c-fos gene expression has been shown in cells of the hypothalamus of rats after exposure to noxious mechanical stimulation (NMS) by itself and after NMS combined with EHF irradiation of the skin. The «stress» reaction of cells in specific hypothalamic structures has been shown to be decreased after EHF exposure of the skin [35]. The results provided conclusive evidence of Epithalon's stress-protective effect at the level of IL-1beta signal transduction via sphingomyelin pathway in the nerve tissue, as well as at the level of target thymocyte proliferation [36]. In rats c-Fos-positive cells 2 h after administration of lipopolysaccharide were seen in the following hypothalamic structures: AHN, PVH, LHA, VMH, DMH, and PH. After electrical pain stimulation, the number of c-Fos-positive cells increased in these same hypothalamic structures (AHN, PVH, LHA, VMH, DMH, and PH). The combination of electrical pain stimulation and lipopolysaccharide administration led to a decrease in the extent of activation in hypothalamic structures AHN, PVH, LHA, and VMH [37]. Cholinergic immunorerulation. Electrolytic lesions of the anterior hypothalamus increased significantly the muscarinic antagonist, [3H] quinuclidinyl benzilate ([3H]QNB) -specific binding in thymocytes 7 days after neurosurgery. Lesions of other hypothalamic structures (area preoptica medialis, area hypothalamica posterior) or sensomotor cortex had no effect. Lymphocytes isolated from rat spleen or peripheral blood were not affected. Both T-cell-dependent (sheep red blood cells) and T-cell-independent (Vi antigen of Salmonella typhi) antigens induced a significant increase in [3H]QNB-specific binding in spleen lymphocytes while peripheral blood lymphocytes did not change. A different pattern of lymphocyte m-AchR expression found in various lymphoid tissues after immunization or brain lesions suggests a local involvement of cholinergic mechanisms in neuroimmune interaction [38]. Peroral administration of phosphor-organic pesticide antio (phormothion) 1/100 and 1/20 LD50 induced the dose-dependent inhibition of splenocyte acetylcholine-esterase activity after 2 months of treatment. It is suggested that the immunosuppressive action of pesticide is manifested by interfering with cholinergic mediation that regulates lymphoid cell function [39] Opioid peptides. Rabbits and mice were injected with the opioid analog, leu-enkephalin-dalargin (D) or naloxone. Injection of D with IL-I to mice decreased (x1,5) C-reactive protein (CRP) as compared to controls. Naloxone injected with saline or D prior to IL-1, prevented IL-1-induced rise in CRP level and of the pyrogenic IL-1 induced anti-nociceptive impulses on the 24 МЕДИЦИНСКИЙ АКАДЕМИЧЕСКИЙ ЖУРНАЛ, 2014 г., ТОМ 14, № 4 CNS of rabbits. Thus opioids inhibit cytokine induced inflammatory mediators at the level of cell receptors [40]. Thymus. Immunomodulating effects of synthetic peptides Vilon (Lys-Glu), Epithalon (Ala-Glu-Asp-Gly), and Cortagen (Ala-Glu-Asp-Pro) and possible involvement of the sphingomyelin signal transduction pathway in their effects in mouse thymocytes were studied. Vilon produced the most potent comitogenic effect on thymocyte proliferation and modulated comitogenic activity of interleukin-1b. Epithalon was less potent, while Cortagen produced no such effects. Vilon produced a more pronounced stimulatory effect on sphingomyelinase activity in mouse thymocyte membranes compared to Epithalon and Cortagen [41]. A stereotactic electrolytic lesion of the anterior hypothalamic area in mice produces a rapid involution of the thymus and a reduction of lymphocytes in the peripheral blood. This effect on the thymus and blood lymphoid compartment can be prevented by postoperational administration of thyrotropin -releasing hormone (TRH) or melatonin. These activities of TRH or melatonin are antagonized by the opioid receptor blocker naltrexone. They do not seem to depend on stimulation of the thyroid gland or of the endogenous opioid system but rather on a direct activity of TRH on thymic targets or binding sites on lymphocytes [42]. Natural killer (NK) cells. The effect of cyclophosphamide-containing drug, Cytoxan, on activation of hypothalamic neurons involved in the regulation of natural killer cell activity in the spleen and changes in cytotoxicity of these cells. Administration of Cytoxan in a dose of 60 mg/kg increased the number of c-Fos-positive cells in the ventromedial hypothalamus and lateral hypothalamic area and reduced interferon-alpha-induced cytotoxic activity of natural killer cells [43]. Anesthesia. Synthesis of c-Fos-like proteins occurred only in the spinal cord in conditions of constant 1,5% halothane anesthesia. The pattern of brain structures reacting to mechanical pain stimulation with expression of c-Fos-like protein was identified. This type of stimulation was shown to induce increases in the quantity of c-Fos-positive cells in the lateral hypothalamic area (LHA), the ventromedial (VMH) and dorso-medial (DMH) hypothalamic nuclei, and in the ventral hypothalamic area (AHA) by 116%, 167%, 101%, and 157% respectively. Skin irradiation with UHF currents decreased the intensity of mechanical pain stimulation-induced synthesis of c-Fos-like protein in most structures (LHA, VMH, DMN, and AHA by 32,8%, 29%, 15%, and 33% respectively. Only induction halothane anesthesia allowed identification of hypothalamic structures reacting to mechanical pain stimulation and the modifying effects of irradiating the skin with UHF currents on the intensity of these reactions [44]. The inhibitory stimulus also activates c-Fos in inhibitory nuclei of the hypothalamus!!! Nonspecific resistance. The authors studied the level of proteins in the acute phase of inflammation and the level of glucocorticoid hormones, the leukocyte composition, the functional activity of the peripheral blood phagocytes, and the body temperature in rabbits under normal conditions and in subcutaneous turpentine injection in transcranial electric stimulation in the analgesia regimen. Changes of the studied parameters and activation of the mechanisms of the organism’s nonspecific resistance occurred on a model of aseptic inflammation [45]. Autoimmunity. Monkeys (Macaca mulatta), both sexes were repeatedly immunized with a complex of glial antigens of the homologous brain demonstrated abnormalities of hormonal functions after 1 to 5 weeks. These abnormalities were marked by a decrease in the total serum tyroxi-ne (after 1 week) and a rise in the concentration of 11-hyd-roxycorticosteroids (11-OHCS) that occurred after 5 weeks. The changes in tyroxine level were more stable than those in the concentration of 11-OHCS. The immunized animals manifested changes in the disc electrophoregram of the serum. Application of stress resulted in a consistent elevation of the concentration of 11-OHCS and in temporary changes in the number and intensity of individual fractions of serum proteins. The fractional composition of serum proteins was different in control and experimental monkeys [46]. Adaptive-transfer of experimental autoimmune encephalomyelitis is an inflammatory neurodegenerative disease which is induced by injection of activated encep-halitogenic T-cells. Encephalitogenic T-cells ultimately migrate through spleen and parathymic lymph nodes regardless of the start point of cells migration after i.p. and i.v. injection [47]. Chronic fatigue syndrome (CFS). In chronic fatigue syndrome (CFS) interaction between the immune and neuroendocrine systems is disturbed. A similar syndrome may be induced in animals by injecting double-stranded RNA of poly I-C. Cytotoxic and proliferative activities of splenocytes was disturbed during CSF development. Neutral sphingomyelinase (nSMase) - the key enzyme of the sphingomyelin cascade - in membranes of cells in brain cortex, was expressed on the 3d day after Poly I : C administration to rats. Poly I:C disturbed HPA axis functions which led to decreased corticosterone concentrations [48]. Orexin and immunity. Orexin mRNA A and B and their receptors; connections between orexin neurons and neurons from different structures of the brain and spinal cord and the participation of the orexin neuron system in the functional regulation are discussed [49]. Injection of cyclophosphamide (40 mg/kg) or EHF-irradiation of the skin decreased the staining of orexin- МЕДИЦИНСКИЙ АКАДЕМИЧЕСКИЙ ЖУРНАЛ, 2014 г., ТОМ 14, № 4 25 containing neurons, which was most pronounced in the subfornical region of the lateral hypothalamic area (LHAs). A redistribution of orexin from the perinuclear space to the processes of these cells took place, which occurs after the activation and the expression of the c-fos-gene. c-Fos protein was expressed in most neurons with minimum content of orexin, i.e. activation of these neurons correlated with the redistribution of orexins caused by skin EHF-irradiation and injection of cyclophosphamide (CPA) [50]. Orexin is a hypothalamic peptide, a neurotransmitter described in 1998. The brain respond to antigenic challenge by activating preproorexin and orexin containing neurons, which suggest that the orexin system participates in immune defense [51]. Orexin neurons react to injection of LPS in animals [52]. Localization of orexin receptors in various CNS structures and in peripheral organs mediates regulation of different physiological functions by orexins. Low concentration of orexins in peripheral blood and orexin-con-taining cells in ganglions and internal organs suggests a possibility to activate orexin-sensitive cells distantly, paracrinely or autocrinely [53]. Major contributions which are not listed in PubMed. Defensins. Defensins are antimicrobial cationic peptides with a cysteine-stabilized amphipathic structure. These substances are normally localized in phagocytes (neutrophil, monocyte/macrophage) and in the epithelial cells of mucous membranes and skin. Some defensins are released into the blood during the course of infection, inflammation and stress. Defensin functions not only as endogenous animal antibiotic molecules, killing microbial cells and enveloped viruses, but also as physiological regulators. Defensins are implicated in the regulation of endocytosis, chemotaxis, mast cell degranulation and inflammation. Moreover, these molecules are modulators of hemostasis and neuroendocrine-immune interaction. Defensins lower the stress-induced elevation of corticosteroid levels in the blood, and abolish the stress-induced inhibition of the humoral immune response. These facts support the hypothesis that defen-sins are antibacterial peptides with a broad spectrum of biological activity [54]. I was the Editor the Book series, Neuroimmune Biology in 2008 and planned a volume on Cytokines and the Brain to be published in this book series. After some consultation I felt that this volume though challenging, it is a good idea. The research interest of Elena Korneva from Russia an of Christopher Phelps from the USA were right to edit this volume. The work was going very well and success seemed obvious when Phelps suddenly died, so Elena had to finish the work with my assistance. All of the sudden she became an expert book Editor, she did jus fine on this job. I prepared a shortened version of her closing remarks for the book, so the reader would see what was the significance of this volume [55]. Concluding remarks to NIB 6. Neuroimmune Biology investigates the role of the Nervous and Endocrine Systems in the regulation of Immune System. Numerous mechanisms are involved. Cytokines in brain Physiology and Pathophysiology has only been considered recently. «Cytokines and the brain» is one of the first books addressing this comprehensive research area. Well-known scientists are dealing with the basic and applied aspects of these multifaceted problems. The blood-brain-barrier (BBB)-cytokine interactions are important for physiological neuroimmune interactions. Cytokine-BBB interactions are not static, they respond to physiological and pathological events. IL-1, IL-3, IL-6, IL-8, TNF (and others) are transported. Cytokine transport/release is selective. These mechanisms might change under pathologic conditions, which is of special importance. Important progress has been made in the role of cytokines in neuronal interaction, including the regulation of synaptic functions. Many cytokines are shown as signaling molecules for neurons of the CNS. Each cytokine can influence many cell types and exert many different effects, while acting by autocrine, paracrine or endocrine mechanisms. TNF regulates synaptic plasticity in regions of the brain associated with learning and memory. IL-1, depending on its concentration, can either promote or inhibit synaptic plasticity. IL-6 predominantly plays a protective role. It improves the survival of neurons, and attenuates pain signals. Interferons and chemokines are also involved. Disorders play a role in the development of many neurological diseases. Cytokine receptors of brain cells, the role of the receptors, the significance of their density and affinity for neuronal functions, etc. are discussed. Immunostimulation and inhibition can be elicited at will during various forms of stress, which results in increased blood glucocorticoids and IL-1. The localization of cytokine receptors in different brain structures indicates the function of brain neurons and brain nuclei. IL-1a and IL-1 receptors play an important role in coordinating HPA reactions during stress. CRF is participating in modulating IL-1 receptor affinity under stress. Stromal elements contribute to the regulation of brain cells in a major way. This volume of NIB gives insights to changes in the functional activity of neurons as influenced by cytokines, and to their effects on some CNS functions, including 26 МЕДИЦИНСКИЙ АКАДЕМИЧЕСКИЙ ЖУРНАЛ, 2014 г., ТОМ 14, № 4 sleep, feeding behavior, memory, and involvement in biological defense system, cytokine effects on animal behavior and the role of lateralization of cytokine production. Sex hormones, in particular estrogen, have a role in brain tissue regeneration and brain functional recovery, and involved with cytokines. Estrogen and the cytokines stimulated by sex hormones may be useful for optimization of treatment of patients receiving stem cells therapy. «Cytokines and Brain in stress and Pathology» a chapter of this book indicates that investigations into the roles and mechanisms of cytokine involvement in brain functions are very promising [56]. Signal Transduction By IL-1 and IL-2. Cytokines play an important role in the communication of neuroendocrine and immune systems. It is of special interest how the cytokine signals are transmitted in nerve and immunocompetent cells. Interleukin-1 beta (IL-1beta) is one of the key cytokines that regulate host defense. And it is an important mediator of neuroimmune interaction. However, the pathways of signal transduction by IL-1beta have not been fully elucidated. Over thee last decade a new sphingomyelin signal transduction pathway has been described for IL-1beta, tumor necrosis factor-alpha and interferon-gamma. This pathway is initiated by the membrane bound enzyme, neutral sphyngomyelinase (nSMase), which was shown to play a key role in the sphyngomyelin cascade. Recent studies have demonstrated that IL-1 receptor subtype 1 and an accessory protein are involved in the activation of nSMase by IL-1beta. In turn nSMase activation initiates intracellular signaling by the sphyngo-myelin pathway in nerve cells. It was suggested that the pathway for transmission for IL-1 beta signal into nerve cells, astrocytes and immunocompetent cells are similar and include the activation of nSMase. Further experiments suggested that IL-1beta is involved in the stress reaction and that cytokine signaling through the sphyngomyelin pathway play a role in the stress response of both nerve and immune cells. The data reviewed in this paper provide compelling evidence that glucocorticoid hormones and short immunomodulatory peptides are able to modify the spyngomyelin pathway of IL-1 beta signaling in cells of both the neuroendocrine and immune systems [57]. c-Fos gene and IL-2 expression in the brain. This article summarizes the expression of immediate-early genes (IEG): c-fos gene, encoding one of the interleukin-2 (IL-2) cytokine transcriptional factors - c-Fos, and IL-2 genes in brain cells. The main molecular features and tissue-specific differences of IL-2 and IL-2 receptors in the brain are discussed. The expression of c-fos and IL-2 genes in CNS neurons has been shown after different stressor stimuli. An application of these stimuli activates the processes of IEG expression in the cells of hypothalamic structures. Antigen injection leads to activation of c-fos and IL-2 genes in the cells of hypothalamic nuclei and areas of rat brain. The definite temporospatial pattern of activation of hypothalamic structures in response to antigen was noted, which is not equal to one induced by other stressors. The IEG expression in immune and nervous system cells can be modified by using short synthetic immuno-modulating peptides. Definite physical factors, like EHF skin irradiation, modulate (mostly decrease) stress induced stimulation of IEG genes expression in hypothalamic neurons. The JAK-STAT and Ras-MAPK signal transduction pathways mediate IL-2 gene expression in lymphocytes and in nervous cells [58]. Immune response in the CNS. Chemo-attrac-tant cytokines participate in the CNS not only in pathological situations but also in physiological functions. They influence neural and glial cells proliferation and migration during the process of CNS development. Molecules of the major and minor histocompatibility complexes are present in neurons. Neurons produce cytokines, and their repertoire being quite extended. Immunocompetent cells, including T-lymphocytes, can enter the brain under pathological conditions. Antigen presentation to brain tissue does not elicit an adaptive immune response, but rather evokes reactions, including cytokine production, as a part of innate immune response. IL-1ß is present in the normal brain, and its expression increases upon parenteral administration of LPS. IL-1ß regulates neuronal survival and contributes to the realization of the neuroendocrine response to stress, the latter being brought about by IL-1ß expression in the neuroendocrine nuclei of the hypothalamus. De novo IL-1ß synthesis in the blood-brain barrier upon infections contributes to behavioral responses to infections. Especially interesting are the data about IL-1ß involvement in normal brain physiology. Cytokines of astrocytes stimulate neurons and their synaptic integration. Astroglia also produce cytokines and influence the development of neural diseases and neuroimmune interactions, IL- 1β and IFN-α stimulate the electrical activity of the efferent nerves of the spleen and reduce NK-cell activity. These cytokines produced in the brain and may be key factors of stress-induced immunosuppression. The sympathoadrenal system and norepinephrine interact with the nervous and immune systems during inflammation. Norepinephrine is released by lymphocytes in the modulation of immunological processes. IL-2 is involved in the mediation of brain responses to stressors and to antigenic stimuli. The IL-2 gene is expressed at a low level in brain neurons and glial cells under normal conditions. Increases in IL-2 mRNA occur under stress or after antigenic stimulation, which may be modulated by therapeutic drugs. МЕДИЦИНСКИЙ АКАДЕМИЧЕСКИЙ ЖУРНАЛ, 2014 г., ТОМ 14, № 4 27 Some of the inflammatory cells in the CNS and PNS promote repair and reduce the extent of damage of nerve cells after insult and injury. This information may serve for the development of novel therapeutic approaches for neurological diseases. The development of autoimmune pathological processes in the brain particularly, in the case of multiple sclerosis, is associated with increased blood and brain levels of proinflammatory cytokines (IL-1, IL-2. TNF-α, and interferons). This book helps the development of Physiology and Pathophysiology of the Central Nervous System. Brain cytokines represent a novel and important area of Neuroimmune Biology. There is a lot to be discovered yet in this area [59]. History of Neuroimmune Biology. In the literature, the research field under consideration is designated with several names including Immunophysiology, Neuro immuno modulation, Psychoneuroimmunology, and the most general one, Neuroimmune Biology. They all are used as synonyms although each one stresses a specific aspect. The term «Neuroimmunomodulation» emphasizes that the Neuroendocrine System and the Immune Systems forms a systemic regulatory circuitry which regulates the entire host organism. The term «Psychoneuroimmunology» highlights the role of the psychic and neural factors in the development of immunological processes, and the terms «Immunophysiology» and «Neuroimmune Biology» define the whole issue in the most general way as studies of interaction of the neuroendocrine and the immune systems. Ultimately it is biology, what we are dealing with. The subject of this discipline includes both, the external (e.g. neural, endocrine or other humoral) mechanisms that control the functions of the immune system and the role of immune mechanisms in the functioning of the neuroendocrine system. At the present-time biomedical science features an unprecedented progress in Neuroimmune Biology manifested as an avalanche of new data, organization of new laboratories, publication of new journals and allocation of ever increasing funds to research in this field. A reason for so high activity is probably not only the desire to decipher blank spots still present in our knowledge but, also, the promise of making medical use of the new information so obtained. Here a brief history of this exciting field of scientific enquiry is presented [60]. Neural response to stress and antigen. The specificity of central nervous system (CNS) response to different destabilizing stimuli is discussed. Hypothalamic neurons are involved in brain reactions to various stimulants. The effects of stress and antigenic stimulation on the hypothalamus are reviewed. Previously it was known that the brain responds specifically to various patterns of stimuli, which depends on the nature and intensity of the stimulus. Antigens have a special place amongst the stimuli applied to the brain. The effects of antigen depend on their biochemical nature though they also are considered to be stress factors [61]. Signaling mechanisms in stress. The comparative role of Interleukin-1a/Interleukin-1ß (IL-1a/IL-1ß) production, blood levels and ligand-receptor interactions of IL-1b with its immune and nerve target cells was analyzed. We also investigated intracellular signal transduction via the sphingomyelin pathway during the development of stress reaction. In mice stress of different durations and intensities induced increased concentrations of glucocorti-cois and of IL-1a/IL-1ß in blood. Thymocytes and lymphocytes responded to the concomitant actions of IL-1a, which correlated with changes in the humoral immune response. These events coincided with stress-induced changes in the activity of neutral-sphingomyelinase, the key enzyme of the sphingomyelin cascade, in membrane fractions of mouse cerebral cortex and of thymocytes. It is indicated that the function of immune and nerve cells is changed. Lymphocyte and thymocyte proliferation and cytotoxic activity of splenic natural killer (NK) cells, the intensity of cytokine signal transduction in the cells of the immune and neuroendocrine system, indicate immune and neuralimmune responses to stress [62]. Orexin in the CNS and in immune organs. The number of orexin containing neurons is relatively law. They are located in the hypothalamus mostly in the LHA, but projections extend into brain and spinal cord neurons. A wide range of cells express orexin receptors. The orexin system regulates a variety of functions. The presence of orexin containing cells and their receptors in peripheral organs (spleen, liver, gut, etc.) is a recent finding. Since low levels of orexins were found in the blood and cerebrospinal fluid, there is reason to believe that orexin may fulfill humoral regulatory functions. It may be concluded on the basis of current evidence that orexin containing neurons respond to antigenic stimulation of the host, and that the CNS also responds to this antigen. It mast be stressed that only designated neurons respond to antigenic stimulation. Combined results indicate that there are changes both in synthesis and utilization of neurons during physiological function. It must be taken into consideration that utilization is intense, and that the level of orexin neurons is law, even if the level of preproorexin is significantly increased, Thus orexin neurons regulate immune function [63]. Orexin-containing neurons and neurotransmitters of orexin A and B were shown to be involved in brain res 28 МЕДИЦИНСКИЙ АКАДЕМИЧЕСКИЙ ЖУРНАЛ, 2014 г., ТОМ 14, № 4 ponse to stress. Here we review new experimental data about the involvement of orexin neurons in brain reactions to stressors (hunger, hypoglycemia, immobilization, pain, etc.). Recent evidence shows that the release of orexin A and B affect the secretion of the hypothalamic-pituitary-adrenal axis hormones in response to stressors. Hypothalamic orexin-containing neurons depend for activation on applied stimulation. The patterns of morphological and functional changes of ore-xin-containing neurons, which are localized in various hypothalamic structures, were analyzed after various stressors (eg. restraint stress, cold stress, antigen application). The analysis of the literature and our own data suggest functional identity of populations of orexin-con-taining neurons in the perifornical part of hypothalamus. The reactions of orexin-sensitive cells of the hypothalamus, midbrain, medulla, spinal cord and immune organs to antigen injections in different doses reflect changes in the function of orexinergic cells. These data indicate the participation of orexin system in brain reaction to various kinds of stressors [64]. Multiple sclerosis (MS) patients frequently complain of fatigue and sleep disturbances and orexin is a neuropeptide known to play crucial role in sleep/wakefulness regulation and in many other physiological functions. Hypothalamic orexin neurons were studied during adoptive transfer to rats of experimental autoimmune encephalomyelitis (EAE). Though the total quantity of ore-xin-positive cells was decreased in EAE animals, differential counts of these neurons revealed discrete hypothalamic zone responses. Three possible variants could be distinguished: reduction of orexin-positive neurons quantity with no changes in their RTD (DMHa, LHAd, LHAvm); increase of RTD with no alterations in quantity (more medial hypothalamic structures); quantity was reduced and RTD was increased (in more lateral hypothalamic structures). The preproorexin gene expression in hypothalamic cells of EAE animals was slightly increased, indicating the possible increase of orexin synthesis. EAE induction decreased orexin neurons and synthesis and utilization was increased. Hypothalamic orexinergic neurons participate in CNS response to EAE, which could be important for understanding the pathology of multiple sclerosis [65]. Neuroimmune pathology of stress. These preparations of peptides and nucleotides are known to be effective modulators of the immune and neuroendocrine systems. Here we discuss a new concept, which suggests that endogenous short peptides and their synthetic analogues, bind to specific sequences of nucleotides in DNA. These site specific peptide-DNA interactions modulate cellular genetic functions and form the basis of molecular-genetics of stress-protective short synthetic peptides. Protective action of nucleotide preparations on impaired functions of the immune and neuroendocrine systems was shown. It seems that these effects are based on the ability of nucleotides to penetrate cells and subsequently splitting into nucleotides, which, after release by the cells, bind to purinergic P2 receptors. These results indicate that short peptides and DNA preparations are capable of correcting stress-induced impairment on neuroimmune function. Multiple sclerosis (MS) patients frequently complain of fatigue and sleep disturbances and orexin is a neuropeptide known to play crucial role in sleep/wakefulness regulation and in many other physiological functions. Hypothalamic orexin neurons were studied during adoptive transfer to rats of experimental autoimmune encephalomyelitis (EAE). Though the total quantity of ore-xin-positive cells was decreased in EAE animals, differential counts of these neurons revealed discrete hypothalamic zone responses. Three possible variants could be distinguished: reduction of orexin-positive neurons quantity with no changes in their RTD (DMHa, LHAd, LHAvm); increase of RTD with no alterations in quantity (more medial hypothalamic structures); quantity was reduced and RTD was increased (in more lateral hypothalamic structures). The preproorexin gene expression in hypothalamic cells of EAE animals was slightly increased, indicating the possible increase of orexin synthesis. EAE induction decreased orexin neurons and synthesis and utilization was increased. Hypothalamic orexinergic neurons participate in CNS response to EAE, which could be important for understanding the pathology of multiple sclerosis [66]. Orexin containing and orexin sensitive neurons regulate brain responses to antigen. LPS injection alters the orexin contents of neurons, affects the intensity of preproorexin gene expression and of orexin receptor gene expression [67]. CONCLUDING REMARKS. Positions held (from Kornev’s CV). 1965-69, head sci. organizing dept., 1969-75, head lab. Neuroimmunology, 1975, head dept. gen. pathology and pathophysiology, 1982-2014; scientific consultant 2014, prof. pathophysiology St. Petersburg (Russia) State U. Sch. Medicine, St. Petersburg, Russia, 1997, Chair of All USSR Commn. On Physiol. Mechanisms of Host Resistance, 1982-90; mem. State Highest Attestation Commn. Medals, Prizes and Distinctions (From CV). Recipient Pres. award, ISNM, 1990, Gold medal, Russian Immunology Soc., Internat. Soc. Immunorehabilitation, 2004, Laureate prince P. Oldenburgsky prize, Inst. Exptl. Medicine, 2009. Mem. Internat. Soc. NeuroImmunoModulation (cofounder, bd. dirs., Presdl. citation 1990), Fund of МЕДИЦИНСКИЙ АКАДЕМИЧЕСКИЙ ЖУРНАЛ, 2014 г., ТОМ 14, № 4 29 Psychoneuroimmunology(hon.dir.), Internat.Rsch. Soc. Psychoneuroimmunology (co-founder, bd. dirs. 1993-95), Internat. Soc. Immunorehab. (hon.), NY Acad. Scis., Internat. Soc. Neuroscis., Immunological Soc. (pres. St. Petersburg br. 1985), Nat. Sci. Soc. For Neuroimmunology, NeuroImmunomodulation (pres. 1992), Internat.Soc. Pathophysiology, Acad. Med. Sci. USSR (corr. 1986), Russion Acad. Med. Sci. (academician 1996,chmn. Neuroimmunophysiology problem com. of sci. coun. of exptl. and applied physiology, 1990, Disting Scientist of Russia award 2000), Japanese Soc. Pathophisiology (hon.), Inst. Exptl.Medicine (hon.). Democrat. Avocations: painting, theatre, hunting forest mushrooms. Books, book chapters and Editorial work. 1. 1985-90. Author: Evolution of Reflex Regulation of Cardiac Activity, 1965 (in Russian), 2. Neurohumoral maintenance of immune homeostasis, 1978, 3. The regulation of defense functions of the body, 1982, 4. Hormones and Immune Systems, 1986; 5. Interaction of nervous and immune systems. Molecular and cellular aspects / St. Petersburg / Nauka / 2012, p. 173. 6. editor: Handbook of Immunophysiology, 1993; 7. co-editor Cytokines and the Brain, Neuroimmune Biology Elsevier 2008. 8. Editor; Brain, Behavior and Immunity.1986-98. 9. Editor; Internat. Jour. Neuroimmunomodulation, 1993-2000. Korneva’s letter to me describing the early history of Immuno-Physiology. Dated 11/11/2014. «I’m sending you the draft of my last talk on the forum, «Actual problems of fundamental medicine» in Ekaterinburg. This lecture gave a short history of neuroimmunophysiology development. «As it is known that S. Metalnikov is the founder of Neuroimmunophysiology (1925). Since that time some investigations have performed similar studies in different labs, but mostly not systematically, some of them successful, but not always. In 1957 in Saint-Petersburg, Institute for Experimental Medicine, Academician D. Biryukov, physiologist, initiated the beginning of this field. Academician V. Ioffe accepted this suggestion and the experiments of this project was started: H. Korneva and L. Khai were asked to do this project. After 3 years of work it become clear that the only possible explanation of our experimental results is to conclude that all the immune responses we observed were dependent on CNS action. We destroyed hypothalamic structures carefully, so the size of lesion was very small. To our surprise, intensive inhibition or intensive increase of antibody production was observed after operation on AHP. Surely, these experiments indicted the beginning of new foundations of biological sciences. By the 1960-s similar investigations were developed in many scientific centers in USSR. Little bit later a very different and emotional discussion took place in our country. Academician A. Ado initiated the commission to stop these investigations and our lab was to be closed. This situation was very dangerous, especially if you keep in mind the difficult events in physiology and genetics in our country. Two persons saved the lab and the development of this field: academician N. Bekhtereva, the director of IEM, physiologist, and academician R. Petrov, he was the main immunologist in USSR. These actions were of historically important. But the discussions were prolonged, and they were still dangerous. It is likely that process of developing neuroimmunophysiology in other countries was not easy either. The physiologists accepted this new field easily, because for them the body was the whole organism. But immunologists at that time were working mostly with the cells or reactions in vitro. At that very time I was invited to Stanford to give a lectures (1967), but of course it was not permitted to go, and professor George Solomon Figure 2. Elena A. Korneva chairing a presentation in the Immunophysiology Meeting in St. Petersburg, 2009. came to our lab. As he ruled later, in his last book, «I visited Elena Korneva to find out if the results are a matter of truth and not the next soviet propaganda». George spent in our lab for two weeks, learned the techniques and documents and sent us his pupil - Margaret Kemeny. Later on they published the article, 30 МЕДИЦИНСКИЙ АКАДЕМИЧЕСКИЙ ЖУРНАЛ, 2014 г., ТОМ 14, № 4 which has been done using our model and this stopped the discussion. Professor Ado accepted this direction as a real one openly in some conferences. The number of labs working in the world in that time was very limited. And all of the people working in the world in this field were invited to first international symposium which took place in Institute for Experimental Medicine in 1978. We couldn’t invite only three persons - Istvan Berczi, Filipp, G, and Andor Szentivanyi - because they emigrated from Hungary and on one hand it was not easy to find them, but more importantly our government would not allow them to come. It was necessary to mention all foreign guests of this symposium, because later on they became the first persons of this direction (G. Solomon (USA), B. Ader (USA), W. Pierpaoli (Switzerland), B. Jankovich (Yugoslavia), N. Spector (USA), H. Besedovsky (Switzerland)). Most of them met each other for the first time, «found» each other and began to organise international societies and journals. Very best wishes, Elena Korneva»

About the authors

Istvan Berczi

University of Manitoba; Universidad Autónoma de Aguascalientes

Email: Berczii@ms.umanitoba.ca
Department of Immunology; Departamento de Fisiologia y Farmacologia, Centro de Ciencias Basicas

References

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