Development of a topical bacteriophage gel targeting Cutibacterium acnes for acne prone skin and results of a phase 1 cosmetic randomized clinical trial.

Background: Topical antibiotics are frequently used to treat acne vulgaris. Their prolonged use, often for longer durations than recommended, has led to antibiotic resistance in Cutibacterium acnes (C. acnes), a bacterium implicated in acne pathophysiology. Bacteriophage (phage), which specifically target C. acnes by a different mechanism of action and do not harm potentially beneficial bacteria, may offer an alternative approach for improvement of the appearance of acne prone skin. Objectives: To identify and characterize C. acnes targeting phage, carry out a comprehensive preclinical safety evaluation of phages selected for further development and examine their safety, tolerability and ability to target facial C. acnes when applied topically in a cosmetic clinical study including participants with mild-to-moderate acne. Methods: Phages were isolated by conventional microbiological methods also used to examine their breadth of host range on different C. acnes strains and specificity to this bacterial species. Safety assessment of three selected phages was carried out by complete genomic analysis to assure the absence of undesired sequences and by ex vivo models employed to evaluate the safety, irritability and potential systemic bioavailability of phage applied topically. A randomized, controlled clinical study assessed safety, tolerability and efficacy in targeting facial C. acnes. Results: Wide host range phages that also target antibiotic resistant C. acnes were identified. Their genomes were shown to be free of undesired genes. The three-phage cocktail, BX001, was not irritant to human skin or ocular tissues in ex vivo models and did not permeate through human epidermis. In a cosmetic clinical study, topically applied BX001 was safe and well tolerated and reduced the facial burden of C. acnes. Conclusions: Combined in silico and ex vivo approaches successfully predicted the observed safety and efficacy of C. acnes targeting phage when these were topically administered in a well-controlled cosmetic clinical study.

Open field behavior and the state of the thymus and adrenal glands in rats after exposure to stress and elevation of blood level of autoantibodies to dopamine and glutamate.

Blood level of autoantibodies to dopamine and glutamate in rats increased in 4 weeks after exposure to stress. Under these conditions, active animals demonstrated decreased motor and exploratory activity in the open field, while in passive animals, only the number of explored objects decreased. The increase in blood level of autoantibodies to dopamine and glutamate in rats exposed to stress was followed by an increase in the adrenal gland weight in active animals and thymus weight in passive animals. The increased blood level of autoantibodies to dopamine and glutamate in rats exposed to stress reflects the development of the long-term stress-induced response.

[Geometrical images of coherent interrelations of biopotentials of EEG different frequency ranges in dynamics of humans goal-directed behavior].

Spatial organization of teta, alfa, beta-1, beta-2 in EEG potentials in humans who quickly an with a high accuracy performed task to learn and reproduce on PC monitor a definite sequence o accuracy performed task to learn and reproduce on PC monitor a definite sequence of circles wer studied. It was found that geometric images of coherent interrelations of teta, alfa, beta-1, beta-2 in EEG potentials were dynamically changed on the different stages of goal-directed the humans activity. The studies give the grounds to consider dynamically changed geometrical images of coherent links of different EEG potentials as an objective index of external projection of intracerebral processes of system architectonics of goal-directed behavior on brain cortex.

[The informative mechanisms of systemic organization of psychic activity].

In this review on the basis of functional systems theory developed by P. Anokhin theoretical approaches to informative mechanisms of systemic organization of psychic activity are presented. Author formulates the conception on discrete system quantums of psychic and behavioral activity from needs to its satisfaction and develops its informative equivalents. It was shown that informative equivalents of needs and its satisfaction are reflected in structures of action acceptors in the form of dynamic informative images. On the basis of acceptors of results of action informative systemic quantums are developed which constantly control its manifestation in behavioral systemic quantums. Informative systemic quantums are extracted in advance by predominate motivations and are associated with negative emotions of needs and positive emotions of their satisfaction. The content of this review confirms I.P. Pavlov's foresight on possible confluence of material and idealistic processes in psychic human activity.

Ultrasonic vocalization of rats in various motivational and emotional states.

We studied the specific features of ultrasonic vocalization of Wistar rats in various motivational and emotional states. No significant changes were found in ultrasonic vocalization of rats during experimental food motivation and after the satisfaction of food requirements. The state of thirst and satisfaction of water requirements in animals were associated with an increase in the mean frequency of ultrasound and dominance of ultrasonic waves of a higher frequency. The formation of a negative emotional state in rats after immobilization with simultaneous electrocutaneous stimulation was accompanied by a decrease in the total duration of ultrasonic vocalization and shift in the power spectrum of ultrasound towards the dominant frequencies of 20-30, 40-50, and 80-90 kHz. During the post-stress period, the maximum power of ultrasonic waves approached the baseline (30-40 kHz). Our results indicate that the formation of various motivational and emotional states in rats is characterized by specific patterns of ultrasonic vocalization. Therefore, the parameters of ultrasonic vocalization can serve as an objective criteria for the subjective state of a living organism.

ATP concentration in the cingulum bundle of rats during stimulation of the ventromedial hypothalamus.

We measured the concentration of ATP in the posterior cingulum bundle of Sprague-Dawley rats during electrical stimulation of the negative emotiogenic zone in the ventromedial hypothalamus. Electrostimulation of the ventromedial hypothalamus in animals was accompanied by an increase in systolic and diastolic blood pressure, which illustrates the autonomic response to this treatment. Variations in BP of rats were followed by an increase in ATP content in the posterior cingulum bundle. After stimulation of the ventromedial hypothalamus, ATP concentration in the cingulum bundle reached the maximum levels of 1.3±0.3 µM (n=4) and 1.67±0.43 µM (n=10) and remained high for 42.6±7.5 sec. The enhanced release of ATP in the cingulate region of the brain is probably related to the involvement of this structure into emotional reactions. ATP plays a role of the major energy source and signal molecule, which provides the adequate biochemical and physiological processes and cell-to-cell interaction in CNS upon the exposure to negative emotiogenic factors.

[Holographic construction of integrative cerebration].

The theoretical concept concerning informational aspects of systemic cerebration was proved based on the theory of functional systems formulated by P.K. Anokhin. It has been postulated that informational models of discrete informational systemoquantum in the form of holographic images of mentality were constructed. They are constructed for the dynamics of formation of functional systems of cerebral architectonics, which determine behavior and mentality on morphofunctional structures of acceptors of the outcome of action. The successive steps of formation of informational systemoquamtums of action outcome acceptors are presented. The leading role of the dominant motivations in building and rapid retrieval of informational systemoquamtums of mentality from the memory was underlined.

[Characteristics of serum albumin in patients with intracerebral hemorrhagic stroke].

Authors studied the influence of the psychoemotional stress preceding the stroke on the dynamics of neurological symptoms (Glasgo coma scale, Scandinavian stroke scale and Barthel index) and on the conformational changes of albumin in 59 patients with intracerebral hemorrhage due to arterial hypertension. The psychoemotional stress was associated with less favorable clinical course and outcome of intracerebral hemorrhage. Conformational properties of albumin were changed in all patients with intracerebral hemorrhage compared to controls. Psychoemotional stress preceding stroke aggravated changes in albumin molecule.

Dizocilpine and cycloheximide prevent inhibition of c-Fos gene expression by delta sleep-inducing peptide in the paraventricular nucleus of the hypothalamus in rats with different resistance to emotional stress.

The effects of the non-competitive NMDA-receptor blocker MK-801 (dizocilpine) and the protein synthesis inhibitor cycloheximide on the delta sleep-inducing peptide (DSIP) inhibition of c-Fos immediate early gene expression were studied in the parvocellular subdivision of the hypothalamic paraventricular nucleus (pPVN) of male Wistar rats with either high or low resistance to emotional stress, predicted from differences in their open-field behaviour. The experiments show that intraperitoneal (i.p.) DSIP injection (60 nmol/kg) decreased the number of Fos-immunoreactive (Fos-IR) cells in the pPVN, activated by immobilization. The NMDA-receptor antagonist dizocilpine (MK-801) (90 nmol i.c.v.) prevented the inhibition of c-Fos expression by DSIP in the pPVN of rats predisposed to emotional stress. The protein synthesis inhibitor cycloheximide (210 nmol i.c.v.) prevented the inhibition of c-Fos expression by DSIP in the pPVN of rats that were resistant to emotional stress. The experiments indicate that the DSIP effect on c-Fos gene expression might be mediated by NMDA-receptors. DSIP may induce production of some protein transcription factors, transmitting a signal from membrane NMDA-receptors to the nucleus.

[Immune links in the system organization of behaviour].

The work is devoted to the research of immune mechanisms in self-control of various functional systems of homeostatic and behavioral levels. Distinction of immune mechanisms in rats with different prognostic stress-resistance is established. Immunization of rats by conjugates of various neuromediators with bovine serum albumin selectively changes the animals stress-resistance. Participation cytokines in reactions of a brain's separate neurons and their interaction with a leading neuromediator - norepinephrine is established. Individual changes of pro- and anti-inflammatory cytokines in blood serum are shown in rats with different stress-resistance. There are revealed features of morphological distinctions of immunogenic structures small intestine fabrics in animals with various behavioral activity in the "Open field" test.

[Geometric imaging of coherent interrelationships of electroencephalogram α-rhythm in dynamics of system effective human activity].

In subjects performing tasks quickly and precisely, geometric imaging of coherent connections among the EEG alpha-range potentials dynamically changed and turned out to be specific for each of the intended activity's stages. In the subjects performing tasks slowly and with errors, in different stages of effective human activity, a stability of the geometric image was observed. The revealed geometric imaging changing in different stages of effective activity seems to reflect a multi-level organization of the action results acceptor.

[From molecules and genes to functional systems].

The advantages of system approach in understanding of functions of the whole organism are polemically substantiated. Modem analytical investigations in the field of molecular-cellular biology are critically viewed. It is shown that the results of analytical researches should be considered as components of different functional systems of the organism.

[The information theory of brain systemic activity].

Information equivalents of initial requirements and their satisfaction are shown to induce formation of discrete information systemoquanta of psychic activity on morphofunctional structures of the action result acceptor in the course of build-up of cerebral archtectonics of the functional systems governing the behaviour and psychic activity. Consecutive stages of induction of information systemoquanta of action result acceptors are described. Predominant motivations are supposed to play the leading role in the psychic activity through their involvement in the induction of information systemoquanta and their retrieval from memory. The role of emotions in the subjective information estimation of systemic cerebral activity is considered. It is argued that parameters of achievement of adaptive results by a subject are imprinted on acceptor structures via reverse afferentation in the form of specific information images. Enrichment of action results acceptors with information and extraction of information systemoquanta by prevailing motivations are believed to make up the basis of consciousness and thinking. The hypothesis of holographic organization of acceptors of the results of systemic brain action is considered.

Involvement of cingulate cortex in the formation of defensive behavior in rats.

Changes in behavior patterns in rats during electric stimulation of the ventromedial hypothalamus (the center of defensive behavior) and cingulate cortex were studied. Electric stimulation of the frontomedial cingulate cortex reduced the latency for anxiety and escape reactions during electric stimulation of the ventromedial hypothalamus. Electrolytic destruction of the frontomedial cingulate cortex substantially increased the threshold of escape behavior during stimulation of the ventromedial hypothalamus. These findings demonstrate the involvement of the frontomedial cingulate cortex into the development of defensive (anxiety and escape) behavior in rats.

Specific features of molecular postsynaptic excitation processes of different sensory modalities in edible snail neurons.

Stimulations of different sensory modalities result in selective activation of second messengers and genes controlled by them in defensive behavior command neurons (LPl-1 and RPl-1) in edible snail. Excitation induced by stimulation of chemoreceptors of snail head results in cAMP accumulation in command neurons and induction of associated transcriptional factors of immediate early gene C/EBP, whereas regulating mechanisms of another sensory input mediating excitation after tactile head stimulation, involve protein kinase C and associated transcriptional factor SRF. These findings reflect specific features of postsynaptic processes providing excitation of different sensory modalities converging to defensive behavior command neurons in edible snails.

[Results and perspectives of functional systems theory development].

This paper illustrates the leading role of the theory of functional systems in understanding physiology of the integral organism and summarizes results of its development by P.K. Anokhin's scientific school. New principles of functional system organization in living organisms are postulated and prospects of further research in this field are outlined.

[Assessment of cardiorespiratory functions in patients receiving suggestive psychotherapy].

It is shown that suggestive psychotherapy based on verbal suggestions provides a tool for individual correction of the patient's functional state. It reduces sympathetic and promotes parasympathetic influences, decreases high initial level of psychoemotional tension, and normalizes relationship between cardiac and respiratory rhythms. Also, suggestive psychotherapy has beneficial effect on the psychological sphere and subjective feeling of well-being, reduces anxiety, strengthens the sense of confidence and hope for a cure.

[Emotional stress in the development of experimental hemorrhagic stroke in rats with different resistance to stress].

Individual behavioral characteristics of rats in the open-field test reflect their resistance to emotional stress and determine the severity of neurological disorders during intracerebral hemorrhage. Stress-resistant rats are characterized by a more rapid restoration of neurological status and disappearance of locomotor and coordination disturbances on day 7 after unilateral hemorrhage stroke in the caudate nucleus as compared to stress-predisposed animals. After hemorrhage stroke in the caudate nucleus, changes in vessels and neurons of the contralateral sensorimotor cortex were more pronounced in stress-predisposed passive rats than in stress-resistant active animals. The newly formed capillaries were not seen in stress-predisposed specimens. To day 7 of post stress hemorrhage stroke in the caudate nucleus, signs of the involvement of compensatory mechanisms in the contralateral sensorimotor cortex appeared in stress-resistant but not in stress-predisposed rats. This finding suggests the possibility of restoration of structure and normal functioning of neurons.