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This paper delves into the critical issues of individual health, environmental health, and public health, which are all interconnected in the complex web of food security in emerging countries. Leveraging data from the top 10 countries with the lowest climate index values according to the Numbeo ranking, this article introduces a groundbreaking deep learning algorithm. This algorithm has the potential to revolutionize agricultural productivity and food security in the face of climate change, filling the gap in research on deep learning in agriculture. By enabling intelligent management, this algorithm could boost yields in agriculture, rendering it less dependent on climatic factors and ensuring the effectiveness of digital modernization. Furthermore, we explore the promising benefits of restoring ancient irrigation systems to elevate productivity levels. Our study provides definitive insights into deep learning techniques for yield prediction and productivity enhancement, offering a beacon of hope for the future of food security in emerging economies.

About 90% of the apartment buildings that constitute Armenia's housing stock were built before 1990. After the devastating 1988 Spitak earthquake, the seismic conditions in the country were revised and these buildings no longer meet current seismic standards. About half of Armenia's population lives in these buildings, so the reliability, cost-effectiveness and durability of these structures are extremely important for the country. In addition, a number of other causes contribute to the deterioration of the technical condition of the housing fund over time: exogenous geological phenomena, physical and mechanical properties of the soil, the service life of the housing fund, non-compliance with operating conditions, bombardment, etc. The houses built in the Republic of Artsakh are relatively new, but during the September 27, 2020 war unleashed by Azerbaijan, more than a thousand houses were bombarded. They are no longer suitable for use. Following from the above, it is worth to note that in Armenia, as well as in Artsakh, there is a great demand for the reconstruction of the housing stock. In recent years, mainly monolithic, sometimes stone buildings have been constructed in Armenia and Artsakh. Large-panel buildings are almost completely excluded from construction projects. The reason for this is the low energy efficiency of these buildings. However, there are now new high-performance thermal insulation materials that can easily solve this problem. The purpose of the article is to show the feasibility and advantages of constructing large-panel buildings as an effective way to replenish the housing stock in Artsakh and Armenia.

This paper aims to describe the work-for-hire regime in Russia and provide the readers with practical information on the due formalization of relations between a company and its employees with regard to the intellectual property (hereinafter ‘IP’) that they create. We have reviewed recent high-profile cases (e.g. Rambler v NGINX, Mr. Mamichev v Interveeam LLC and Veeam Software, Laboratory Kaspersky v Cybersecurity Solutions) that reveal the most common problems related to the work-for-hire regime. Based on our analysis of the applicable legislation, court practice and doctrine, we have given some practical tips and recommendations on how to avoid widespread challenges concerning works for hire in Russia.

For Armenia, the main criterion of reliability and durability of buildings is the level of their seismic resistance. The experience of the 1988 Spitak devastating earthquake showed that the only type of apartment buildings that did not collapse and did not cause any loss of life or material damage were large paneled houses, which were designed for lower levels of seismic impact. In spite of the undeniable fact of high seismic stability and effective technical and economic indicators given in the article, further, due to low heat-insulating indicators of applied wall protection panels and limited spans up to 6m, the construction of such buildings in the republic was gradually reduced and has already undeservedly reached almost complete cessation. In this regard, it should be noted that at present there are already a lot of highly effective thermal insulation materials and technologies that allow to easily solve this problem of external walls and get large paneled buildings with a high level of energy saving. As for the limitation of spans, it cannot be considered a decisive factor, because spans up to 6m are quite acceptable for the construction of social apartment buildings. 80% of the population has a strong demand for such housing. The country has an acute shortage of affordable, high-seismic safe houses and this is especially acute now in the Spitak earthquake zone, where after more than 30 years, many still live in temporary houses. We believe that the construction of large-panel buildings would have solved this problem long ago. From all given it is possible to conclude that modernization according to achievements of a science and revival of large-panel housing construction for republic has quite reasonable technical-economic and town-planning basis.

Low-temperature thermochronological data for the Eurasian foreland north of the Bitlis–Zagros suture zone suggest that the tectonic stresses related to the Arabian collision during mid-Miocene time were transmitted efficiently over large distances, focusing preferentially at rheological discontinuities. Since the late Middle Miocene a new tectonic regime has been active as the westwards translation of Anatolia is accommodating most of the Arabia–Eurasia convergence, thus precluding the efficient transfer of stress northwards. Apatite fission-track data from the central Lesser Caucasus show that a portion of this orogen underwent a discrete phase of cooling/exhumation at 18–12 Ma (late Early–early Middle Miocene) as a result of the structural reactivation of a segment of the Late Cretaceous–Palaeogene Sevan–Akera suture zone. This inference contradicts the notion that the post-collisional history of the study area was dominated by strike-slip tectonics with relatively minor dip-slip components. Reactivation and exhumation was focused along those segments of the suture zone at high angles to the inferred collisional stress field; the remaining areas were not exhumed enough to expose a new apatite partial annealing zone and thus retained the thermochronological record of a phase of Late Cretaceous cooling/exhumation associated with ophiolite obduction and the following continental collision along the suture zone.

This paper is focused on petrological and geochemical data obtained on a series of Middle and Upper Eocene magmatic rocks from the Lesser Caucasus of Armenia in order to elucidate magma sources and geodynamic processes. Middle–Upper Eocene magmatism is present in two main zones: the Amasia–Sevan–Hakari suture zone (ASHSZ) and the so-called South Armenian Microplate (SAM). Volcanic rocks from both places range from basalt to rhyolite and mostly display a calc-alkaline character. Trace element patterns from the SAM and ASHSZ samples show mobile-elements enrichment (Rb, Ba, Th) together with strong negative high field strength elements (Nb, Ta, Hf, Zr) anomalies. The (La/Sm)Nratio yields very close values for both areas. Conversely, the (La/Yb)Nratio is, on average, significantly higher for SAM than for ASHSZ, suggesting the presence of residual garnet at the source of the SAM volcanic rocks. Nevertheless, trace elements suggest partial melting from phlogopite- and amphibole-bearing spinel lherzolitic mantle sources.Neodymium and strontium isotopes yield εNd(40Ma)and 87Sr/86Sr(40Ma)ratios ranging, respectively, from –0.3 to +6.6 and from 0.70314 to 0.70531 for SAM samples, and from +3.4 to +6.8 and from 0.70393 to 0.70433 for ASHSZ samples. Initial Pb/Pb isotopic ratios yield close values for both areas but with slightly higher and more homogeneous 207Pb/204Pb and 208Pb/204Pb ratios for SAM samples. Such features concur with a more pronounced slab-component contribution in the frontal part of the volcanic belt, that is, in the SAM domain. No significant crustal contamination has been detected in the studied Eocene magmatic rocks from both the ASHSZ and SAM.Considering geodynamic and geochemical constraints, we propose that this magmatism is connected with a north-dipping Southern Neotethys subduction, in an extensional (back-arc) environment of orogenic belts. The Arabia–Eurasia collision and the closure of the Neotethys Ocean may have occurred after this magmatic event.

The Khoy region (NW Iran) is important in the clarification of the structural framework of the alpine belt between the Taurides, the Lesser Caucasus and the NW Iran belt. The area is well-known for these ophiolitic units. We present here new stratigraphic and structural data that can be used to reconstruct the tectonic evolution of this region and then try to establish connections between these belts. According to new dates from nannoplankton assemblages, the obducted ophiolite of the Khoy complex was thrust over a sheared Campanian olistostrome and lenses of amphibolite are included within the contact. The obduction event is also marked by erosion of the ophiolitic unit and the deposition of conglomerates, shales, sandstones and siltstones. Poorly extended Paleocene detrital deposits cover the Campanian–Maastrichtian rocks. The Eocene formations characterize a basin filled with volcanogenic and sedimentary layers. The Middle and Upper Eocene series unconformably overlie the ophiolites and their cover of Campanian–Maastrichtian and Paleocene deposits. This corresponds to a syn-orogenic basin formed after the collision between Eurasia and the Taurides–Anatolides–South Armenian microplate. The Oligocene–Miocene Qom Formation with basal conglomerates unconformably covers all the earlier formations, including the Palaeozoic formations, indicating intense shortening before its deposition. Compressional deformation continued and is manifested by numerous folds, mainly west-dipping thrusts and reverse faults cutting the Qom Formation, and by recent NW–SE dextral strike-slip faults. This illustrates the continuous shortening and uplift (with intense erosion) resulting from the advanced stage of the collision between Arabia and Eurasia. The structural location of the tectonic units suggests that the Khoy Gondwana-related basement was part of the South Armenian Block and that the Khoy allochthonous ophiolites were obducted on it from the Amasia–Stepanavan–Sevan–Hakari suture zone.

Two new and relatively well-preserved radiolarian faunas were extracted from blocks included in the Cretaceous ophiolitic méééélange unit that crops out in the Erakh area south of Yerevan, Armenia. One of these radiolarian assemblages was extracted from cherts that are in stratigraphic contact with variolitic lavas. This radiolarian assemblage suggests a late Aalenian to middle Bajocian age (Unitary Association Zones 2–3) based on the co-occurrence of the species Parasaturnalis diplocyclis(Yao) and Transhsuum hisuikyoense(Isozaki & Matsuda). A second radiolarian assemblage was obtained from a block, several metres thick, of alternating pelagic limestones and cherts. It was characterized by the co-occurrence of the species Hemicryptocapsa capitaTan and Dicerosaturnalis dicranacanthos(Squinabol). The presence of these two species within the same assemblage correlates with Unitary Association Zone 17 and these samples are therefore assigned to the late Valanginian. These results suggest that submarine volcanic activity took place during the late Aalenian–middle Bajocian interval and that mixed carbonate and siliceous ooze accumulated during the late Valanginian. Previous biochronological data on Radiolaria from the Erakh mééééélange and the Vedi ophiolite are reviewed and their implications for the geodynamic and palaeoenvironmental evolution of the Tethyan ocean in Armenia are discussed.

The AGAPEPAEPAQPGVY proline-rich peptide (PRP-1) was isolated from neurosecretory granules of the bovine neurohypophysis; it is produced by N. supraopticus and N. paraventricularis. It has been shown that PRP-1 has many potentially beneficial biological effects, including immunoregulatory, hematopoietic, antimicrobial, and antineurodegenerative properties. Here we showed that PRP increased colony-forming cell (CFC) proliferation in rat bone marrow (BM) cells in vivo. In PRP-treated rat BM, the CFU number at day 7 and day 14 was considerably increased in comparison with untreated rat BM and no difference was found at day 21 and day 28. The related peptide [arg8]vasopressin did not reveal CFC proliferation. PRP failed to farther increase CFC proliferation in vitro in BM obtained from PRP-treated or untreated rats. After 3–4 days of human BM stromal cell cultivation in the presence of 2–20 μg/ml PRP the appearance of cells expressing CD15, CD10, CD11a, CD11b, CD3, CD4, and CD16 surface antigens did not differ from the untreated cells. PRP increased the appearance of CD14-positive cells upon 3–4-day incubation with both adult and fetal BM stromal cells. Our results suggest a previously undescribed role for the hypothalamic peptide within neurosecretory hypothalamus–bone marrow humoral axis, because PRP enhances BM colony-forming cell proliferation and stromal cell differentiation.

The following results are proved:there exists an integrable function such that any subsequence of the Ces[?] ro means of negative order of the Fourier series of this function diverges almost everywhere; the values of an arbitrary integrable function can be changed on a set (independent of this function) of arbitrarily small measure so that the Fourier series with respect to both the Franklin system and the Haar system of the 'modified' function will be absolutely convergent almost everywhere on [ 0,1 ]; there exists a continuous function which features an unremovable absolute divergence. Bibliography: 47 titles.

In the Lesser Caucasus and NE Anatolia, three domains are distinguished from south to north: (1) Gondwanian-derived continental terranes represented by the South Armenian Block (SAB) and the Tauride–Anatolide Platform (TAP), (2) scattered outcrops of Mesozoic ophiolites, obducted during the Upper Cretaceous times, marking the northern Neotethys suture, and (3) the Eurasian plate, represented by the Eastern Pontides and the Somkheto-Karabagh Arc. At several locations along the northern Neotethyan suture, slivers of preserved unmetamorphozed relics of now-disappeared Northern Neotethys oceanic domain (ophiolite bodies) are obducted over the northern edge of the passive SAB and TAP margins to the south. There is evidence for thrusting of the suture zone ophiolites towards the north; however, we ascribe this to retro-thrusting and accretion onto the active Eurasian margin during the latter stages of obduction. Geodynamic reconstructions of the Lesser Caucasus feature two north dipping subduction zones: (1) one under the Eurasian margin and (2) farther south, an intra-oceanic subduction leading to ophiolite emplacement above the northern margin of SAB. We extend our model for the Lesser Caucasus to NE Anatolia by proposing that the ophiolites of these zones originate from the same oceanic domain, emplaced during a common obduction event. This would correspond to the obduction of non-metamorphic oceanic domain along a lateral distance of more than 500 km and overthrust up to 80 km of passive continental margin. We infer that the missing volcanic arc, formed above the intra-oceanic subduction, was dragged under the obducting ophiolite through scaling by faulting and tectonic erosion. In this scenario part of the blueschists of Stepanavan, the garnet amphibolites of Amasia and the metamorphic arc complex of Erzincan correspond to this missing volcanic arc. Distal outcrops of this exceptional object were preserved from latter collision, concentrated along the suture zones.

Crush-syndrom (CS) was characterized by Bywaters E.G.L. in 1941 after London blitz. The soft tissues is followed by acute hemodynamic shock, myoglobinuria, acute renal insufficiency, and lethal endotoxicity. Data of CS pathogenesis study has shown that the largest changes in Crush occur during decompression and are accompanied by acute alteration of brain protein synthesis and strong morphological changes of brain structures. The period of decompression might be characterized by the proteolytic breakdown of the myoglobine and formation of toxic peptides. In our current work we have identified four newly formed peptides in the brain of the animals subjected to the experimental muscle tissue injury. Our investigations related with the CS experimental model have demonstrated that during the 2-hours compression protein synthesis was decreased in cytosol (32,7) and mitochondria (49), after 5-h compression there were registered non-significant changes in the level of protein synthesis. Intraperitoneal administration of Proline-rich peptide, ((PRP), 1 mcg/100g weight of rats), originating from proteolysis of C-terminal glycoprotein a neurophysin II along with vasopressin and oxytocin and transferring from the hypothalamus to the neurohypophysis by axonal transport, initiates activation of the protein synthesis in all studied cellular subcomponents of brain cells. The positive effect of the peptide is conditioned, most probably, by activation of the immune system and adaptation mechanisms, including mobilization of endogen-protective mechanisms of the organism.

In the Lesser Caucasus three main domains are distinguished from SW to NE: (1) the autochthonous South Armenian Block (SAB), a Gondwana-derived terrane; (2) the ophiolitic Sevan–Akera suture zone; and (3) the Eurasian plate. Based on our field work, new stratigraphical, petrological, geochemical and geochronological data combined with previous data we present new insights on the subduction, obduction and collision processes recorded in the Lesser Caucasus. Two subductions are clearly identified, one related to the Neotethys subduction beneath the Eurasian margin and one intra-oceanic (SSZ) responsible for the opening of a back-arc basin which corresponds to the ophiolites of the Lesser Caucasus. The obduction occurred during the Late Coniacian to Santonian and is responsible for the widespread ophiolitic nappe outcrop in front of the suture zone. Following the subduction of oceanic lithosphere remnants under Eurasia, the collision of the SAB with Eurasia started during the Paleocene, producing 1) folding of ophiolites, arc and Upper Cretaceous formations (Transcaucasus massif to Karabakh); 2) thrusting toward SW; and 3) a foreland basin in front of the belt. Upper–Middle Eocene series unconformably cover the three domains. From Eocene to Miocene as a result of the Arabian plate collision with the SAB to the South, southward propagation of shortening featured by folding and thrusting occurred all along the belt. These deformations are sealed by a thick sequence of unconformable Miocene to Quaternary clastic and volcanic rocks of debated origin.

Similar geological, petrological, geochemical and age features are found in various Armenian ophiolitic massifs (Sevan, Stepanavan and Vedi). These data argue for the presence of a single large ophiolite unit obducted on the South Armenian Block (SAB). Lherzolite Ophiolite type rock assemblages evidence a Lower–Middle Jurassic slow-spreading rate. The lavas and gabbros have a hybrid geochemical composition intermediate between arc and Mid Ocean Ridge Basalt (MORB) signatures which suggest they were probably formed in a back-arc basin. This oceanic sequence is overlain by pillowed alkaline lavas emplaced in marine conditions. Their geochemical composition is similar to plateau-lavas. Finally, this thickened oceanic crust is overlain by Upper Cretaceous calc-alkaline lavas likely formed in a supra-subduction zone environment. The age of the ophiolite is constrained by 40Ar/39Ar dating experiments provided a magmatic crystallization age of 178.7±2.6 Ma, and further evidence of greenschist facies crystallization during hydrothermal alteration until c. 155 Ma. Thus, top-to-the-south obduction likely initiated along the margin of the back-arc domain, directly south of the Vedi oceanic crust, and was transported as a whole on the SAB in the Coniacian times (88–87 Ma). Final closure of the basin is Late Cretaceous in age (73–71 Ma) as dated by metamorphic rocks.

In order to improve our understanding of the palaeogeographic and geodynamic evolution of the Tethyan realms preserved in the Lesser Caucasus we here review the existing data for the sedimentary cover of ophiolites preserved in Armenia. Particular attention is given to those dated sedimentary rocks that are in direct genetic contact with ophiolitic lavas, as they provide constraints for submarine oceanic activity. The oldest available ages come from the Sevan–Akera suture zone that point to a Late Triassic oceanization. Data from both the Sevan and Vedi ophiolites provide evidence for Middle Jurassic (Bajocian) submarine activity, that continued until at least the Late Jurassic (Mid/Late Oxfordian to Late Kimmeridgian/Early Tithonian), as dated recently in Stepanavan and in this study for the Vedi ophiolite.

In 1881, Louis Pasteur described the Bacillus anthracis vaccine, which plays an important role for the treatment and prophylaxis of anthrax. Currently, treatment for anthrax infection involves the use of several different antibiotics, used in combination with vaccines, which possess potential virulence in white mice and guinea pigs. We discovered several new immunomodulators cytokines (polypeptides) produced by the neurosecretory cells of hypothalamus, some of which can be used as drugs for the treatment and prophylaxis of the anthrax. The proline-rich polypeptides, which consist from 10 to 15 amino acids and four proline residues, are of the special interest; one of them (PRP-1), which consist of 15 amino acids and has the following primary structure ALa-GLy-ALa-Pro-GLu-Pro-Ala-GLu-Pro-Ala-GLn-Pro-GLy-Val-Tyr (AGAPEPAEPAQPGVY) possesses antibacterial activity, and a new proline-rich peptide described by Galoyan and called Gx-NH2. Both were tested for treatment against the anthrax bacillus or anthrax strain N55 vaccine in guinea pigs and mice in vivo, and in vitro preparations. The results of experiments show that these hypothalamic neurosecretory cytokines have a strong prophylaxis and therapeutic properties towards animals infected by episodic strain of anthrax and anthrax vaccine N55. The conventional concepts concerning the function of hypothalamic neurosecretion and hypothalamic mechanisms of adaptation have to be reconsidered.

Abstract We investigated the action of the new hypothalamic proline-rich peptide (PRP-1), normally produced by neurosecretory cells of hypothalamic nuclei (NPV and NSO), 3 and 4 weeks following rat sciatic nerve transection. The impulse activity flow of interneurons (IN) and motoneurons (MN) on stimulation of mixed (n. ischiadicus), flexor (n. gastrocnemius – G) and extensor (n. peroneus communis – P) nerves of both injured and symmetric intact sides of spinal cord (SC) was recorded in rats with daily administration of PRP-1 (for a period of 3 weeks) and without it (control). On the injured side of SC in control, there were no responses of IN and MN on ipsilateral G and P stimulation, while responses were elicited on contralateral nerve stimulation. The neuron responses on the intact side of SC were revealed in a reverse ratio. Thus, there were no effects upon stimulation of the injured nerve distal stump in the control because of the absence of fusion between transected nerve stumps. This was also testified by the atrophy of the distal stump and the absence of motor activity of the affected limb. In PRP-1-treated animals, the responses of SC IN and MN in postaxotomy 3 weeks on the injured side of SC at ipsilateral nerve stimulation and on the intact side at contralateral nerve stimulation were recorded because of the obvious fusion of the severed nerve stumps. The histochemical data confirmed the electrophysiological findings. Complete coalescence of transected fibers together with restoration of the motor activity of the affected limb provided evidence for reinnervation on the injured side. Thus, it may be concluded that PRP-1 promotes nerve regeneration and may be used clinically to improve the outcome of peripheral nerve primary repair.

Abstract The purpose of the present study was to evaluate the neuroprotective action of proline-rich peptide-1 (PRP-1) produced by hypothalamic nuclei cells (nuclei paraventricularis and supraopticus) following lateral hemisection of spinal cord (SC). The dynamics of rehabilitative shifts were investigated at various periods of postoperative survival (1–2, 3, and 4 weeks), both with administration of PRP-1 and without it (control). We registered evoked spike flow activity in both interneurons and motoneurons of the same segment of transected and symmetric intact sides of SC and below it on the stimulation of mixed (n. ischiadicus), flexor (n. gastrocnemius) and extensor (n. peroneus communis) nerves. In the control group (administration of 0.9% saline as placebo), no significant decrease of post-stimulus activity of neurons was observed on the transected side by the 2nd week. This activity strongly decreased by week 3 postaxotomy, with some increase on the intact side, possibly of compensatory origin. No shifts occurred by the 4th week. Regardless of the period of administration, PRP-1 increased neuronal activity on the transected side, with the same activation levels on both SC sides. These data were confirmed by histochemical investigation. PRP-1 administration, both daily and every other day, for a period of 2–3 weeks led to prevention of scar formation and promotion of the re-growth of white matter nerve fibers in the damaged area. It also resulted in prevention of neuroglial elements degeneration and reduction in gliosis expression in the lesion supporting neuronal survival. Thus, PRP-1 achieved protection against “tissue stress”, which was also confirmed by the registration of activity on the level of transection and restoration of the motor activity on the injured side. The obtained data propose the possibility of PRP-1 application in clinical practice for prevention of neurodegeneration of traumatic origin.

Abstract The AGAPEPAEPAQPGVY proline-rich polypeptide (PRP) was isolated from neurosecretory granules of the bovine neurohypophysis; it is produced by N. supraopticus and N. paraventricularis. PRP possesses immune-modulating activity, preventing the death of Gram-negative bacteria-infected mice. Here we show that PRP does not affect human peripheral blood neutrophlis and monocytes phagocytosis but dramatically enhances spontaneous or fMLP- and PMA-induced, and also phagocytosis-dependent, oxidative burst. We demonstrated the regulatory role of PRP on the oxidative burst induction of normal and relapsing inflammatory disease (Behcet’s disease and familial Mediterranean fever) neutrophils and monocytes. Our results suggest a previously undescribed role for the hypothalamic peptide within primary activated neutrophils and monocytes, since we provide evidence that PRP can differentially regulate both chemotaxis- and phagocytosis-dependent oxidative burst in normal and inflammatory disease effector cells.

The damaging effect of aluminum ions (Al3+) on the organism is widely investigated in clinics and experiments that indicate its role as a participant in the synthesis of precursors for amyloid proteins and as a potential agent in the ethiology of Alzheimer's disease. It has been shown that Al produces neurotoxic effects. We established that AlCl3produces degenerative changes in the ultrastructure of Hasserian neurinoma cells in vitroand in L929fibroblast cells. Proline-rich peptide-1 (PRP-1) isolated from neurosecretory granules of bovine neurohypophysis is a potent antineurodegenerative agent against spinal cord hemisection and crush syndrome–induced neurodegeneration of brain and spinal cord neurons. PRP-1 is one of the neurotrophic brain factors. By electron microscopic study of the rat hippocampus and other tissues, we succeeded in visualizing the epithelioprotectory effect of PRP-1, contributing as a powerful agent in removal of aluminum accumulation in different tissues in experimental aluminum neurotoxicosis.

The objective of this immunohistochemical research was to reveal the distribution of a proline-rich peptide-1 (PRP-1) in various brain structures of intact and trauma-injured rats and to identify the mechanisms of promotion of neuronal recovery processes following PRP-1 treatment. PRP-1, produced by bovine hypothalamic magnocellular cells and consisting of 15 amino acid residues, is a fragment of neurophysin vasopressin associated glycoprotein isolated from bovine neurohypophysis neurosecretory granules. PRP-1-immunoreactivity (PRP-1-IR) was detected in the brain of intact rats in the neurons of paraventricular (PVN) and supraoptic (SON) nuclei in the hypothalamus, in almost all cell groups in the medulla oblongata, in Purkinje and some cerebellar nuclei cells, and in nerve fibers. At 3 weeks after hemisection of the spinal cord (SC) an asymmetry of PRP-1 localization in the PVN and SON was observed: no PRP-1-IR was exhibited at the affected sides of both nuclei. Daily intramuscular administration of PRP-1 for 3 weeks significantly increased the number of PRP-1–immunoreactive (PRP-1-Ir) varicose nerve fibers, and cells in PVN and SON and in cell groups of the limbic system and brain stem. Tanycytes in the median eminence and covering ependyma also demonstrated strong PRP-1-IR. PRP-1 treatment also activated neuropeptide Y-IR (NPY-IR) in nerve fibers and immunophilin fragment-IR (IphF-IR) in lymphocytes and nerve cells. A strong increase of PRP-1-IR was observed in the PVN and SON of SC-injured rats following the treatment with another PRP (PRP-3). Preliminary physiological data demonstrate that PRP-3 is more “aggressive” in the recovery processes than PRP-1. Based on the findings regarding PRP action on neurons survival, axons regeneration, and the number of IphF-Ir lymphocytes and NPY-Ir nerve fibers, PRP is suggested to act as a neuroprotector, functioning as a putative neurotransmitter and immunomodulator.

Neurotrophins are molecules that regulate neuronal survival, nervous system plasticity, and many other physiological functions of neuronal and glial cells. Here we studied the physiological action of a novel neurosecretory polypeptide proline-rich polypeptide (PRP), isolated from bovine neurohypophysis neurosecretory granules, on voltage-gated Ca currents and spike firing activity of retinal ganglion cells. PRP reversibly increased high voltage–activated L-type Ca current, but was without effect on low voltage–activated T-type current. PRP also increased the spike after hyperpolarization and reduced the frequency of spike firing, most likely by affecting a Ca-dependent potassium current.

The distribution of the protein-carrier of one of the coronary dilatatory glycopeptides, neurohormone “G” (PCG) in rat heart was examined by immunohistochemistry. PCG-immunoreactive nerve fibers and varicosities were found around cardiac ganglion cells and in close topographical contact with coronary vessels and capillaries of the heart. The anatomical localization of the PCG-containing neuronal fibers was similar that of calcitonin gene-related peptide (CGRP) and neuropeptide Y (NPY); however, the intensity of the stainings were different. In contrast to NPY immunostainings, cardiac ganglion cells did not show any PCG immunoreactivity. Some of the small, SIF cell-like NPY immunopositive neurons were also immunostained to PCG. In the atrial cardiomyocytes, only ANP exhibited fairly intensive immunoreactivity. Fourteen days after vagotomy, no considerable changes were found in the distribution of PCG and other neuropeptides investigated in cardiac neurons and nerve fibers. The presence of PCG in cardiac neuronal elements suggests a possible role of this peptide in cardiovascular regulations.

The effect of hypothalamic proline-rich polypeptide (PRP) against Pseudomonas aeruginosainfection in BALB/c mice with leukopenia was investigated. Mice were treated with cyclophosphamide (CPA) and were then injected with PRP 24 h after CPA treatment. The lethal doses of P. aeruginosawere injected to mice when the number of peripheral blood leukocytes reached a nadir on day 5 after CPA administration. The administration of PRP significantly increased the survival of infected mice, and had a pronounced protective effect during the period of development of the infection. The number of bacteria in internal organs of PRP-treated mice was significantly lower than that in control mice. In PRP-treated mice, the neutrophil levels in peripheral blood started to increase 7 days after CPA administration and were consistently higher, and they were more mature than those in controls. Our results may indicate the ability of PRP to stimulate recovery of myelopoiesis and enhance mature neutrophil function.

Previously by immunohistochemical technique the distribution of immunophilin 1–15 fragment (IphF) isolated from bovine hypothalamus was examined in various tissues (heart, lung), including immune system organs (spleen and thymus) of intact rats. IphF-like immunoreactivity (IphF-LI) was revealed in several cell types: lymphocytes, monocytes, macrophages and mast cells. In the present study the immunohistochemical localization of IphF was examined in intact rat and frog brains. In rat brain several cell groups concentrated particularly in the supraoptic nucleus (SON) of hypothalamus, medulla oblongata (reticular formation, olives, hypoglossal and facial motor nuclei) and cerebellum (lateral cerebellar nucleus) demonstrated IphF-LI. In frog hypothalamus (SON) the same working dilution (1:5000) of IphF-antiserum revealed very strong immunoreactivity. In the paraventricular nucleus (PVN) IphF-LI varicosities were scattered around the immunonegative cells. The second cell groups showing IphF-LI in the frog brain were gliocytes (mainly the astrocytes). Besides, IphF distribution was investigated in rats subjected to hemisection of spinal cord (SC) with and without administration of proline-rich polypeptide (PRP). PRP was isolated from bovine neurohypophysis neurosecretory granules, produced by magnocellular nuclei of hypothalamus. Hemisection of SC led to changes of IphF distribution in the hypothalamus. In PRP treated animals IphF showed no immunoreactivity. PRP is suggested to act as a neurotransmitter and neuroregulator.

A study of separate and combined actions of cobra venom (CV) and a new hypothalamic proline-rich polypeptide (PRP) isolated from magnocellular cells (NPV and NSO) on intoxication-and trauma, induced neuronal injury (during 3-4 weeks after hemisection with and without PRP treatment) was carried out. The registration of background and evoked impulse activity flow, changes in spinal cord (SC) inter- and motoneurons, responding to flexor, extensor, and mixed nerve stimulation in both acute and chronic experimental neurodegeneration was performed. The facilitating effect of PRP on the abovementioned neurons was revealed. High doses of CV that evoked the neurodegenerative changes demonstrated an inhibitory effect. In this case PRP treatment both before and after intoxication restored electrical neuronal activity to baseline level and higher. These results are evidence of protective action of PRP. The low doses of CV induced a facilitating effect. The combination of CV and PRP displayed an additive facilitating effect; in a number of cases the repeated administration of CV led to decrease of significant PRP effect till baseline level (for example, the inhibition after primary response prior to secondary late discharge). Greater liability of the secondary early and late long-time discharges of poststimulus responses, differently expressed in various neuron types of SC to chemical influences is of interest. PRP-induced inhibition of the paroxysmal activity related with CV action is also very interesting. Morpho-functional experiments with SC injury demonstrated the abolition of difference in the background and evoked SC neuronal activity below the section and on intact symmetric side after daily PRP administration for 3 weeks. PRP hindered the scar formation and activated neuroglia proliferation; it promoted white matter element growth, hampered the degeneration of cellular elements, and protected against tissue stress. Our results favor the combined use of PRP and CV in clinical practice for the treatment of neurodegeneration of toxic and traumatic origin, as well as specific neurodegenerative diseases such as Alzheimer's.

The number of publications on the investigation of crush syndrome (CS) pathogenesis at traumatic toxicosis is rather limited. The influence of some pharmacological preparations on the development of CS pathogenesis is not very well clarified. Proline-rich peptide (PRP) is a fragment of a glycopeptide comprising the carboxyterminus of the neurohypophyseal vasopressin-neurophysin precursor isolated from the bovine neurohypophysis neurosecretory granules. The polypeptide possesses stimulating activity on differentiation and proliferation of T-lymphocytes and Interleukin-2 (Il-2) biosynthesis. The experimental model of CS of white rats was induced by 2-h of compression followed by 2, 24, and 48-h of decompression of femoral muscle tissue. The influence of PRP on [14C]glucose utilization was investigated in brain, heart, and kidney tissues. The level of [14C]glucose utilization decreased in brain during compression followed by 2-h and 24-h of decompression, while it increased under the influence of PRP at all decompression periods. The influence of PRP on the myocardium and kidneys differs, depending on its nature and on the periods of decompression.

The comparative study has been carried out on hypothalamic neurohormone (proline-rich polypeptides-PRP) and synthetic glucocorticoid dexamethasone (DEX) protective properties at the systemic (i/m) administration. Both background and evoked electrical activity (on n.ischiadicus stimulation) of single neurons in the lumbo-sacral part (laminae II–VI and VII–VIII by Rexed) and field potentials (FP) of spinal cord were recorded during acute experiments on intact spinal rats, subjected to Vipera Raddei (VR) venom intoxication, and chronic spinal cord trauma (hemisection). The action of PRP was characterized by the pronounced activation of the background activity (BA) with adaptive effect, depending on dose and initial level of BA, by results of the statistical analysis. A high effect is received from comparatively small doses. For comparison it was used strong glucocorticoid DEX, possessing single-directed but less expressed excitative action on investigated spinal cord neurons. The initial increase of BA frequency with subsequent depression was the typical symptom of venom influence. A protective effect of preliminary PRP injection is revealed on the succeeding VR venom influence. Use of PRP and DEX causes the increase of reduced activity of neurons on the injury side of animals with spinal cord hemisection. It provides the possibility of the therapeutic utilization. It was revealed considerably more expressed PRP action on neurodegenerative process connected to spinal cord injury (in comparison with DEX). The influence of hormones was compared in identical conditions of experiments on non-injured (control) and injured sides. Taking into consideration revealed protection characteristic of PRP and also the ability of snake venom to stabilize and to prolong its action combined with these preparations, the assumption is made on prospective use of the specified combination in clinical practice.

The aim of this review is not so much to show the problem of neuroendocrine, neurophysiologic, and neurochemical mechanisms of the immune system regulation of the organism by brain (there is a great deal of literature about it), as to solve the problem of whether the brain itself is an immune organ, and also to define cellular, neurochemical, and immunological properties of the brain for its immune defense when the blood-brain barrier is not damaged in spite of the penetration of the infection to brain. The accumulated literary data on CNS interaction with the immune system, expression of several cytokines and their receptors in the neurons of human brain culture, in astrocytes and microglia, all testify to the existence of a brain immune system. Recently studies appeared on the expression of major histocompatibility complex in brain neurons. It does not exclude the possibility of expression of immunoglobulins (or immunoglobulin-like proteins) in brain cells. Data obtained by us on the biosynthesis of a number of known interleukins and new cytokines in neurosecretory neurons of hypothalamus (N.Paraventricularis and N.Supraopticus) demonstrate that neuroendocrine nuclei of the hypothalamus are the center for neuroendocrine and immune systems of brain.

In the course of the study of the primary structures and molecular mechanisms of action of immunologically active compounds of the nervous system we have isolated from the soluble fraction of total bovine brain two heat-stable proteins. The purification procedure was mainly based on DEAE-Servacel ion-exchange chromatography and reversed-phase HPLC. The proteins were identified by the N-terminal Edman microsequence analysis and database searching as macrophage migration inhibitory factor (MIF). The N-terminal sequences for MIF1 and MIF2 were found to be identical. According to mass spectral analysis, the molecular masses for MIF1 and MIF2 were determined respectively as 12,369.21 and 12,299.7 Da. In addition, we have also isolated a third peptide having the same N-terminal sequence and Mr 9,496.2 that seems to be a proteolytic fragment of MIF. Using p-hydroxyphenylpyruvate as a substrate, we have not revealed tautomerase activity of either MIF1 or MIF2. As both the immunologic and enzymatic activities were reported to be expressed by the oligomeric structure of MIF, we suggest that the present study may give additional information on MIF in terms of structural properties of this protein. A comparatively simple purification procedure is presented that may be widely used for simultaneous isolation in one run of MIF isoforms.

The action of PRP is characterized by the pronounced activation of the background activity (BA) of the brain spinal cord, and the degree of the activity depends on BA initial level. The typical peculiarity of Vipera raddei venom influence is the initial increase in frequency of BA with subsequent depression. A preliminary injection of PRP has a protective effect at subsequent influence of venom. In animals with hemisection the PRP increases the decreased activity of neurons on injury side. Taking into consideration the protective peculiarities of PRP in the relationship to snake venom and the possibility of the latter to stabilize and prolong the action of drugs (in the case of PRP) combined with them, it is supposed that the mentioned use of the combination in clinical practice will be perspective. The data obtained testify the PRP to be a neuroprotector against many toxic compounds formed in organism (glutamate, ceramid, beta-amyloid neurotoxisity, etc.). Investigations in this aspect are still in the process.

In CA3 pyramidal cells of guinea pig hippocampal slices, picrotoxin (50 μM) elicited spontaneous, rhythmically recurring epileptiform bursts 285–435 ms in duration. The addition of (S)-3,5-dihydroxyphenylglycine (DHPG, 50 μM, 90 min application), a selective group I metabotropic glutamate receptor (mGluR) agonist, resulted in a rapid-onset transient increase in burst frequency. This was followed by a slowly progressive increase in burst duration, with bursts reaching 1.5–3.8 s in duration at 90 min of DHPG application. The potentiation of epileptiform burst duration persisted at least 2 h after agonist removal. To determine whetherN-methyl-D-aspartate (NMDA) receptor activation participates in the mGluR-induced potentiation of epileptiform bursts, experiments were carried out in the presence ofd-2-amino-5-phosphonovaleric acid (APV, 50–100 μM), an NMDA receptor antagonist. Application of DHPG in the presence of APV resulted in a significantly enhanced transient increase in burst frequency. Nevertheless, when compared with the control described above, there was no significant alteration in the rate of development of the burst prolongation nor its persistence after washout. In other experiments, application of APV in the presence of fully developed mGluR-induced potentiated bursts (after 90 min washout of DHPG) resulted in no significant change in either burst frequency or duration. The data reveal that both induction and maintenance of group I mGluR-mediated potentiation of epileptiform discharges are NMDA receptor-independent processes, suggesting that epileptogenesis, when induced by group I mGluR activation, may occur and be sustained in the absence of NMDA receptor activation.

Evidence is presented that multiple forms of cyclic nucleotide phophodiesterase (PDE) activity chromatographically separated from the soluble fraction of bovine hypothalamus are co-eluted with multiple forms of 5'-nucleotidase (5'N) activity. The enzymes could not be resolved from each other by anion-exchange chromatography on DEAE-TSK; by affinity chromatography on phenyl-, blue-, concanavalin A-, 5' AMP-sepharose, cAMP-silica gel; or by gel filtration on sephacryl S-200. The catalytic activities were found to be associated with the tetrameric, dimeric, and monomeric forms of the enzymes. The molecular weights determined by gel filtration or by SDS-gel electrophoresis were 220, 114, and 57 kDa, respectively. Kinetic analysis revealed that the first-order rate constant for 5' AMP hydrolysis measured in the reactions: cAMP?5'AMP?adenosine was 100 times higher than that in the reaction: 5'AMP?adenosine. Thus, functional interrelation between PDE and 5'N was expressed in drastic acceleration of the consecutive reactions: cAMP ?5'AMP?adenosine. The results confirm the conclusion about the existence of a multienzyme system involving PDE and 5'N or of a single bifunctional enzyme in brain tissue.

Neurohormone “C” (NC) is a glycopeptide isolated from bovine hypothalamus, which inhibits Ca-calmodulin (CaM)-dependent cAMP and cGMP phosphodiesterase (PDE) and is a regulator of Ca in the cell. Distribution of [45Ca]CaCl2 in the mitochondria and reticulum (SR) of heart and brain mitochondria and changes of Ca-binding proteins in these organelles under NC influence have been studied in the myocardium before and after isoproterenol-induced necrosis. Intraperitoneal administration of 80–100 mU of PDE inhibitory activity of NC to rats did not cause any noticeable changes in the protein content of intracellular organelles, but altered the affinity of certain proteins to45Ca2+. This property of NC was especially noticable after isoproterenol necrosis. Necrotic injury of the myocardium induced Ca2+ storage in the mitochondria and SR of brain, and decreased the Ca2+ concentration in myocardial mitochondria. NC injection to the animals with necrosis was followed by Ca2+ release from all the studied organelles.

Cathespin B has been purified 750-fold to apparent homogeneity from human and bovine brain cortex using ammonium sulfate fractionation (30–70%), chromatography on Sephadex G-100, CM-Sephadex C-50, and concanavalin A-Sepharose. Enzyme was assayed fluorometrically at pH 4.0 with pyridoxyl-hemoglobin in the presence of 1 mM DTT and 1 mM EDTA. Properties of the enzyme from the two sources proved to be similar. On disc PAGE the purified preparation produced two bands associated with proteinase activity that are due to existence of two multiple forms of brain cathepsin B with pI 6.1 and 6.8. The enzyme is completely inactivated by thiol-blocking reagents, leupeptin, E-64, and demands thiol compounds for its ultimate activity. Z-Phe-Ala-CHN2 is a potent inhibitor of the enzyme (K2nd=1280 M-1s-1) in contrast to Z-Phe-Phe-CHN2 (K2nd=264 M-1s-1). pH optimum in the reaction of hydrolysis of Pxy-Hb is 4.0–6.0,KM(app.) =10-5 M. Cathepsin B splits azocasein: pH optimum 5.0–6.0,KM(app.)=2.2·10-5 M, but inclusion of urea in the incubation medium depresses the azocaseinolytic activity of the enzyme 1.5-fold. It does not split Lys-NNap, Arg-NMec and is not inhibited by bestatin. The specific activity of brain cathepsin B with Z-Arg-Arg-NNapOMe at pH 6.0 is 10-fold higher than with Bz-Arg-NNap, Z-Gly-Gly-Arg-NNap is a poor substrate. With Z-Arg-Arg-NMec and Bz-Phe-Val-Arg-NMec the specific acitivity is 80 and 35%, respectively of that with Z-Phe-Arg-NMec.

The action of three previously isolated electrophoretically homogeneous brain proteinases—cathepsin B (EC 3.4.22.1), cathepsin D (EC 3.4.23.5), and high-molecular-weight aspartic proteinase (Mr=90K; EC 3.4.23.-)—on human angiotensins I and II has been investigated. The products of enzymatic hydrolysis have been identified by thin-layer chromatography on Silufol plates using authentic standards and by N-terminal amino acid residue analysis using a dansyl chloride method. Cathepsin D and high-molecular-weight aspartic proteinase did not split angiotensin I or angiotensin II. Cathepsin B hydrolyzed angiotensin I via a dipeptidyl carboxypeptidase mechanism removing His-Leu to form angiotensin II, and it degraded angiotensin II as an endopeptidase at the Val3-Tyr4 bond. Cathepsin B did not split off His-Leu from Z-Phe-His-Leu. Brain cathepsin B may have a role in the generation and degradation of angiotensin II in physiological conditions.

Displacing the optic nerve into the telencephalon in adult Rana pipiensinduces a projection to olfactory cortex. We have examined the topographic organization of this projection anatomically by injecting a mixture of biotin dextran (BDA) with 3H‐amino acids into the affected eye immediately after making cuts across defined sectors of the nerve fiber layer to trace the complementary patterns of anterograde migration of BDA and 3H label in the cut and intact retinal axons, respectively. Fibers from the temporal side of the optic disc terminated in an oblique band along the posterior two‐thirds or more of the ectopic projection field. In contrast, fibers arising in the nasal retina terminated in a parallel strip occupying the anterior one‐third or less of the field. Varying the location of the cuts within each hemiretina did not reveal any further organization along the nasotemporal or dorsoventral axes of the retina. The retinal location of the cells involved in this projection was further studied with injections of wheat germ agglutinin conjugated to horseradish peroxidase into the olfactory cortex. Ganglion cells labeled by retrograde transport were found throughout the retina, but they were much more numerous on the temporal side, having a mean spatial density 3.7‐7.4 times greater in the temporal hemiretina, whereas the overall ganglion cell density (labeled plus unlabeled) was roughly the same in the two halves of the retina. These data provide an example of a permanent projection in which the overall representation of the retina, though nontopological, is polarized in one axis (nasotemporal) and, therefore, compartmentally organized. J. Comp. Neurol. 383:415‐427, 1997. © 1997 Wiley‐Liss, Inc.

We previously reported the presence of a group of coronary dilatatory protein-carriers of the cardioactive neurohormones and precursors of bioactive compounds in the hypothalamus of some animals.

Recently, five glycopeptides with coronaro-constrictory properties were isolated from bovine hypothalamus [(1988) Neurochemistry (USSR) 7, 519-524]. Calmodulin has been recognized in our laboratory as a target protein for the neuropeptides isolated from hypothalamus. The results of indirect enzyme-linked immunosorbent assay have shown that the new hypothalamic neuropeptides antagonize with the monospecific anti-calmodulin antibody for Calmodulin binding although they are not fragments of Calmodulin. The inhibitory potency of the peptides is dependent on their concentration and the length of the polypeptide chain. Four out of five peptides are effective in nM concentration range. Ca 2+stimulates the binding of peptides to calmodulin; however, immunocomplex can be formed in the absence of Ca 2+as well. The effects of trifluoperazine and peptides on the calmodulin/antibody interaction are not additive, suggesting the cooperativity between the binding sites on calmodulin. Under physiological conditions the presence of the peptides could produce distinct conformers of calmodulin which may exhibit altered potency for stimulation/inhibition of target enzymes.

In a continuing study of the physiological role of protein breakdown in the hypothalamus, acid proteinase from bovine hypothalamus was purified about 1000-fold. The molecular weight of the enzyme was approximately 50,000. Maximal activity against hemoglobin was obtained at pH 3.2–3.5; serum albumin was split much more slowly. Hypothalamus acid proteinase was partially inhibited by ß-phenyl pyruvate, or benzethonium Cl, and was completely inhibited by low concentrations of pepstatin. This proteinase splits somatostatin, substance P, and analogs of substance P. The probable sites of enzyme action on these peptides were determined by the end group dansyl technique. The enzyme, most likely cathepsin D, may play an important role in the formation and breakdown of peptide hormones in the hypothalamus.

In the course of the study of structure-functional properties and molecular mechanisms of neuropeptides and of low molecular weight proteins of the central nervous system we succeeded in isolating from the soluble fraction of bovine hypothalamus a protein having Mr 11897.3, according to mass spectral analysis. The purification procedure was mainly based on reversed phase HPLC. As the N-terminus of the molecule was found to be blocked, we have subjected it to CNBr degradation. By Edman microsequence analysis of the peptide fragments and by data base searching the isolated substance was identified as parvalbumin alpha (PRVA)—one of the calcium-binding proteins. However, its primary structure was found not to be identical to that of the known PRVAs from other sources. One of the features of PRVA is its stability. Being subjected to an exhausting purification procedure it retains its complete structure. As neuropeptides and low molecular weight proteins are found to be polyfunctional, a central question concerns the biological role of PRVAs in terms of “where and when” they express their action.

A new experimental method is proposed for measuring the refractive indices of liquids based on mode line measurements. The experimental setup consists of a dielectric substrate in which a rectangular hollow is formed containing the concerned liquid. This is covered by a trapezium-shaped prism. The liquid, confined between both basin walls and the prism, forms a wavegude. Thus, the refractive index of the liquid can be determined by measuring the propagating modes in the structure. Using this technique, the refractive indices of liquids can be measured to an accuracy of the order of 1×10-4.

Studying the influence of brain cathepsin D (EC 3.4.23.5) and high molecular weight (HMW) aspartic endopeptidase (EC 3.4.23.‐) on the processing of hypothalamic calmodulin‐binding coronaro‐constrictory peptide factors from the β‐chain of globin it was found that only HMW aspartic endopeptidase generates the fragment 31–40 of the β‐chain of bovine hemoglobin (Hb) by cleavage of the Leu30‐Leu31and Phe40‐Phe41bonds. Digestion of the β‐chain of globin was performed at 37°C at an enzyme/substrate ratio of 1:80 at pH 3.5 using different times of incubation (from 4 h to 10 h). The resulting peptides were separated by reversed‐phase high‐performance liquid chromatography (HPLC) and then identified by amino acid analysis and Edman degradation. The differences in specificity and activity of these two brain aspartic proteinases could be explained by their different structural features. Our finding provides evidence for a different biological function of these two enzymes. Data obtained give us reason to suppose that HMW aspartic proteinase probably can participate in the processing of the coronaro‐constrictory peptide in vivo by limited proteolysis of Hb or Hb‐like protein.

A fragment (11–19) of thymosin ß4 was found to stimulate phosphodiesterase activity even in the absence of calcium and calmodulin. Half-maximal enzyme activation occurred with 10 nM peptide, and was further increased by phospholipids such as phosphatidylserine. The mechanism of stimulation is an increase in the Vmax of cAMP degradation without a substantial change in the Km for the substrate. In the presence of calcium ions and calmodulin the peptide was also stimulatory.