Control of the mutagenicity of a new immunomodulator

New immunostimulator STP, peptide isolated from the cultivation medium of Streptococcus species producer strain TOM-1606 by chromatographic purification, was controlled for mutagenicity. The preparation, introduced into mice in doses of 6.7 X 10(2) - 6.7 X 10(4) micrograms/kg, i.e. exceeding the stimulating dose 1000-fold, did not induce the appearance of micronuclei in polychromatophilic erythrocytes of the marrow, the fixation of the material being made 24, 48 and 72 hours after the injection. In Ames' test on Salmonella typhimurium strains TA 98 and TA 100 neither native STP, nor STP activated with the microsomal fraction of rat liver enzymes did not increase the frequency of reversions to histidine independence. The absence of mutagenic properties in STP was demonstrated by the parallel pronounced genotoxic action of a number of known mutagens used as positive controls.     

Postsynaptic factors control the duration of synaptic enhancement in area CA1 of the hippocampus.

In area of CA1 of the hippocampus, at least two phases of long-term potentiation (LTP) can be isolated: an early decremental component referred to as short-term potentiation (STP), which precedes a long-lasting, nondecremental component commonly considered to be stable LTP. Utilizing the hippocampal slice preparation, experiments were performed to determine the physiological factors controlling the conversion of STP to LTP. The duration of NMDA receptor-dependent synaptic enhancement was influenced by several factors, including the degree of postsynaptic NMDA receptor activation and the magnitude and timing of postsynaptic membrane depolarization during synaptic transmission. It was possible to convert STP to LTP by manipulations that increased the influx of calcium into the postsynaptic cell. These results demonstrate that NMDA receptor activation can result in distinct forms of synaptic potentiation and imply that the magnitude of postsynaptic calcium increase is a critical variable controlling the duration of synaptic enhancement.     

Immunomodulating therapy with myelopid in experimental Salmonella infection

The influence of myelopid on immunological characteristics in experimental Salmonella infection has been studied. This preparation has been found to produce a pronounced effect on the characteristics of immune response: it increases the number of T- and B-lymphocytes in the blood and the lymphoid organs. The indirect rosette-formation test has shown that myelopid facilitates earlier and more rapid binding and elimination of the antigen (S. typhimurium) from the body. Under the influence of myelopid the release of antigen-binding lymphocytes from the thymus to the peripheral lymphoid organs becomes more intensive.     

Short-term plasticity at primary afferent synapse in rat spinal dorsal horn and its biological function

Short-term plasticity (STP) is an important element of information processing in neuronal networks. As the first synaptic relay between primary afferent fibers (PAFs) and central neurons, primary afferent synapses in spinal dorsal horn (DH) are essential to the initial processing of somatosensory information. In this research, we examined the STP between Adelta-PAFs and spinal DH neurons by patch-clamp recording. Our results showed that depression dominated the STP at primary afferent synapses. The curves of STP had no significant changes in the presence of bicuculline, CTZ or AP-5. Lowering extracellular Ca(2+) concentration ([Ca(2+)](o)) from 2.4 to 0.8 mM reduced the depression of synaptic responses at all stimulus rates, while raising [Ca(2+)](o) from 2.4 to 4.0 mM increased the synaptic depression. Increasing the bath temperature from 24 to 32 degrees C clearly reduced the depression of all responses. These results indicate that the observed STP is of presynaptic origin and depends on transmitter release. By fitting the experimental data recorded under different conditions, a model of STP was used to quantitatively characterize the observed STP and to analyze the possible mechanisms underlying the effects of [Ca(2+)](o) and temperature. Furthermore, using a model neuron receiving synaptic inputs, we found that with this form of STP, postsynaptic DH neurons could detect rate changes in both rapidly- and slowly-firing afferents with equal sensitivity. The present study links the intrinsic STP properties of primary afferent synapses with their role in processing neural information, and provides a basis for further research on the STP in spinal DH and its biological function under in vivo conditions.     

The safety of a new chemical typhoid preparation containing a complex of Vi and K antigens in tests of its acute and chronic toxicity]

Acute and chronic toxicity of a new chemical typhoid preparation containing the complex of surface Vi- and K-antigens has been studied. The study has revealed that the preparation, when introduced subcutaneously and intravenously in immunizing doses in a single injection or in multiple injections, produces no toxic effect on the organs and tissues of experimental animals. In experiments of chronic toxicity the microscopic study has shown pronounced hyperplasia of the lymphoid system with enhanced macrophage reaction in the spleen, thymus, mesenteric lymph nodes and Peyer's patches in the small intestine.     

Experimental study of the immunological activity of a preparation made from the antigenic complexes of opportunistic microorganisms administered by different routes

The data obtained in the experimental study of the humoral factors of local and systemic immunity, as well as the morphofunctional changes of internal organs, after multiple subcutaneous and aerosol immunization with the combined preparation of Proteus, Staphylococcus, Klebsiella pneumoniae and Escherichia coli antigens (preparation nC-4) are presented. The subcutaneous and aerosol administration of preparation nC-4 has been found to induce an increase in the levels of antibodies to all components of the preparation in the blood serum and in respiratory tract secretions. The introduction of the preparation through the respiratory tract resulted in an earlier intensive accumulation of specific antibodies and IgA in respiratory tract secretions. The results of the quantitative cytological study of respiratory tract secretions and the morphofunctional changes of the lymphoid tissue associated with the lungs are indicative of an important role played by cell-mediated immunity factors in the formation of local postvaccinal immunity.     

A highly potent and safe pyrrolopyridine-based allosteric HIV-1 integrase inhibitor targeting host LEDGF/p75-integrase interaction site

Allosteric integrase inhibitors (ALLINIs) are a class of experimental anti-HIV agents that target the noncatalytic sites of the viral integrase (IN) and interfere with the IN-viral RNA interaction during viral maturation. Here, we report a highly potent and safe pyrrolopyridine-based ALLINI, STP0404, displaying picomolar IC₅₀ in human PBMCs with a >24,000 therapeutic index against HIV-1. X-ray structural and biochemical analyses revealed that STP0404 binds to the host LEDGF/p75 protein binding pocket of the IN dimer, which induces aberrant IN oligomerization and blocks the IN-RNA interaction. Consequently, STP0404 inhibits proper localization of HIV-1 RNA genomes in viral particles during viral maturation. Y99H and A128T mutations at the LEDGF/p75 binding pocket render resistance to STP0404. Extensive in vivo pharmacological and toxicity investigations demonstrate that STP0404 harbors outstanding therapeutic and safety properties. Overall, STP0404 is a potent and first-in-class ALLINI that targets LEDGF/p75 binding site and has advanced to a human trial.     

Short Term Depression Unmasks the Ghost Frequency

Short Term Plasticity (STP) has been shown to exist extensively in synapses throughout the brain. Its function is more or less clear in the sense that it alters the probability of synaptic transmission at short time scales. However, it is still unclear what effect STP has on the dynamics of neural networks. We show, using a novel dynamic STP model, that Short Term Depression (STD) can affect the phase of frequency coded input such that small networks can perform temporal signal summation and determination with high accuracy. We show that this property of STD can readily solve the problem of the ghost frequency, the perceived pitch of a harmonic complex in absence of the base frequency. Additionally, we demonstrate that this property can explain dynamics in larger networks. By means of two models, one of chopper neurons in the Ventral Cochlear Nucleus and one of a cortical microcircuit with inhibitory Martinotti neurons, it is shown that the dynamics in these microcircuits can reliably be reproduced using STP. Our model of STP gives important insights into the potential roles of STP in self-regulation of cortical activity and long-range afferent input in neuronal microcircuits.     

Modulation of the dynamics of cerebellar Purkinje cells through the interaction of excitatory and inhibitory feedforward pathways

The dynamics of cerebellar neuronal networks is controlled by the underlying building blocks of neurons and synapses between them. For which, the computation of Purkinje cells (PCs), the only output cells of the cerebellar cortex, is implemented through various types of neural pathways interactively routing excitation and inhibition converged to PCs. Such tuning of excitation and inhibition, coming from the gating of specific pathways as well as short-term plasticity (STP) of the synapses, plays a dominant role in controlling the PC dynamics in terms of firing rate and spike timing. PCs receive cascade feedforward inputs from two major neural pathways: the first one is the feedforward excitatory pathway from granule cells (GCs) to PCs; the second one is the feedforward inhibition pathway from GCs, via molecular layer interneurons (MLIs), to PCs. The GC-PC pathway, together with short-term dynamics of excitatory synapses, has been a focus over past decades, whereas recent experimental evidence shows that MLIs also greatly contribute to controlling PC activity. Therefore, it is expected that the diversity of excitation gated by STP of GC-PC synapses, modulated by strong inhibition from MLI-PC synapses, can promote the computation performed by PCs. However, it remains unclear how these two neural pathways are interacted to modulate PC dynamics. Here using a computational model of PC network installed with these two neural pathways, we addressed this question to investigate the change of PC firing dynamics at the level of single cell and network. We show that the nonlinear characteristics of excitatory STP dynamics can significantly modulate PC spiking dynamics mediated by inhibition. The changes in PC firing rate, firing phase, and temporal spike pattern, are strongly modulated by these two factors in different ways. MLIs mainly contribute to variable delays in the postsynaptic action potentials of PCs while modulated by excitation STP. Notably, the diversity of synchronization and pause response in the PC network is governed not only by the balance of excitation and inhibition, but also by the synaptic STP, depending on input burst patterns. Especially, the pause response shown in the PC network can only emerge with the interaction of both pathways. Together with other recent findings, our results show that the interaction of feedforward pathways of excitation and inhibition, incorporated with synaptic short-term dynamics, can dramatically regulate the PC activities that consequently change the network dynamics of the cerebellar circuit.     

DNA strand transfer protein beta from yeast mitotic cells differs from strand transfer protein alpha from meiotic cells

We have purified to homogeneity an activity from mitotic cell extracts of the yeast Saccharomyces cerevisiae, which promotes the transfer of a strand from a duplex linear DNA molecule to a complementary circular single strand. This activity does not require any nucleotide cofactor and is greatly stimulated by yeast single-stranded DNA-binding protein. It consists of a single polypeptide of an apparent molecular mass of 180 kDa as determined by SDS-polyacrylamide gel electrophoresis. This activity, which we call DNA strand transfer protein beta (STP beta), has reaction properties similar to those of DNA strand transfer protein alpha (STP alpha) purified from crude extracts of yeast meiotic cells (Sugino, A., Nitiss, J., and Resnick, M. A. (1988) Proc. Natl. Acad. Sci. U.S.A. 85, 3683-3687). However, STP beta differs from STP alpha in its molecular weight and column chromatographic behavior as well as by immunological comparison. Furthermore, the STP beta polypeptide remains in cells in which the STP alpha gene has been disrupted. Thus, we conclude the STP beta activity is encoded by a gene different from that for STP alpha. Although STP beta was isolated from mitotic cells, the amount of STP beta increases severalfold during meiosis. STP beta also appears to differ in molecular weight from similar activities described by other groups and may be an intact form of their activities.     

The neuroprotective adenosine-activated signal transduction pathway involves activation of phospholipase C

We have demonstrated before that exposure of neuronal cultures to poisoning by iodoacetic acid (IAA) followed by "reperfusion" (IAA-R insult), results in severe cytotoxicity, which could be markedly attenuated by prior activation of the adenosine A1 receptors. We also have demonstrated that adenosine activates a signal transduction pathway (STP), which involves activation of PKC epsilon and opening of KATP channels. Here, we provide proof for the involvement also of phospholipase C (PLC) in the neuronal protective adenosine-activated STP. R-PIA, a specific A1 adenosine receptor agonist, was found to enhance neuronal PLC activity and protect against the IAA-R insult. The PLC inhibitor U73122, abrogated both R-PIA-induced effects. These results demonstrate that activation of PLC is a vital step in the neuronal protective adenosine-induced STP.     

Effect of a high-polymer, metal-containing biostimulator on the immunological reactivity of the body of experimental animals]

"Phodomos", a biostimulator of the "Biomos" group of metal complexes, considerably increases (2-3-fold) antibody production and the phagocytic ability of micro- and macrophages in experimental animals. The preparation has no essential influence on the ability of the bone marrow stem cells for colony formation in the body of irradiated animals.     

STP (the substance produced by a strain of Streptococcus sp. Thom-1606) as a stimulant of the nonspecific resistance of the macroorganism

Preparation STP, a new immunostimulating agent, is a substance produced by Streptococcus strain sp. Thom-1606 and capable of enhancing the nonspecific activity of the body as shown in animal experiments. The optimal dose-time parameters of the administration of the immunostimulator have been established by the method of the mathematical planning of experiments. As a result, the survival of all animals used in the experiment has been achieved. Mouse peritoneal macrophages have been found to form the population of target cells whose phagocytic activity is enhanced under the effect of the immunostimulating agent STP.     

Cyclic nucleotides in the dynamic development of shock caused by the murine toxin of Yersinia pestis

The authors have studied the effect of Y. pestis "mouse" toxin (LD50), injected intravenously to rats, on cAMP and cGMP content in the tissues of different organs (the lungs, liver, heart, spleen, kidneys, small intestine) and in the blood in the course of the development of toxinfection shock. The effect of Y. pestis "mouse" toxin on cyclic nucleotide content in the organs of experimental animals is determined by the sum of oppositely directed effects produced by the thermostable and thermolabile fractions of the toxin. Its thermostable fraction, when introduced in the dose used in the experiments, did not kill the animals. The most pronounced changes in the cyclic nucleotide content have been detected in the lungs which appear to be the main target organ for Y. pestis "mouse" toxin.     

Effect of the substances "Ammivit" and "cerloplasmin" on lipid peroxidation products level and of antioxidant system indicators under irradiation

It has been shown, that the total X-ray irradiation in the dozes of 0.5 and 1 Gy influences on the content of lipid peroxidation products and enzymatic activity of antioxidant system in rat spleen and thymus cells. The influence of preparations "AMMIVIT" and "Ceruloplasmin" on these processes is investigated also. So, the animals feeding by the vitamin concentrate "AMMIVIT" have lead to increase of MDA level (a final product of lipid peroxidation) and the overactivity of some antioxidant enzymes in rat spleen and thymus cells. Injection of the preparation "Ceruloplasmin" to experimental animals up 1 hour before the irradiation has normalized LPO intensity and activity of AO enzymes.     

A computational view of short-term plasticity and its implications for E-I balance

Short-term plasticity (STP) and excitatory-inhibitory balance (EI balance) are both ubiquitous building blocks of brain circuits across the animal kingdom. The synapses involved in EI are also subject to short-term plasticity, and several experimental studies have shown that their effects overlap. Recent computational and theoretical work has begun to highlight the functional implications of the intersection of these motifs. The findings are nuanced: while there are general computational themes, such as pattern tuning, normalization, and gating, much of the richness of these interactions comes from region- and modality specific tuning of STP properties. Together these findings point towards the STP-EI balance combination as being a versatile and highly efficient neural building block for a wide range of pattern-specific responses.     

Induction and propagation of transient synchronous activity in neural networks endowed with short-term plasticity

Transient, task related synchronous activity within neural populations has been recognized as the substrate of temporal coding in the brain. The mechanisms underlying inducing and propagation of transient synchronous activity are still unknown, and we propose that short-term plasticity (STP) of neural circuits may serve as a supplemental mechanism therein. By computational modeling, we showed that short-term facilitation greatly increases the reactivation rate of population spikes and decreases the latency of response to reactivation stimuli in local recurrent neural networks. Meanwhile, the timing of population spike reactivation is controlled by the memory effect of STP, and it is mediated primarily by the facilitation time constant. Furthermore, we demonstrated that synaptic facilitation dramatically enhances synchrony propagation in feedforward neural networks and that response timing mediated by synaptic facilitation offers a scheme for information routing. In addition, we verified that synaptic strengthening of intralayer or interlayer coupling enhances synchrony propagation, and we verified that other factors such as the delay of synaptic transmission and the mode of synaptic connectivity are also involved in regulating synchronous activity propagation. Overall, our results highlight the functional role of STP in regulating the inducing and propagation of transient synchronous activity, and they may inspire testable hypotheses for future experimental studies.