Scn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndrome

Dravet syndrome is a severe epileptic encephalopathy caused primarily by haploinsufficiency of the SCN1A gene. Repetitive seizures can lead to endurable and untreatable neurological deficits. Whether this severe pathology is reversible after symptom onset remains unknown. To address this question, we generated a Scn1a conditional knock-in mouse model (Scn1a Stop/+) in which Scn1a expression can be re-activated on-demand during the mouse lifetime. Scn1a gene disruption leads to the development of seizures, often associated with sudden unexpected death in epilepsy (SUDEP) and behavioral alterations including hyperactivity, social interaction deficits and cognitive impairment starting from the second/third week of age. However, we showed that Scn1a gene re-activation when symptoms were already manifested (P30) led to a complete rescue of both spontaneous and thermic inducible seizures, marked amelioration of behavioral abnormalities and normalization of hippocampal fast-spiking interneuron firing. We also identified dramatic gene expression alterations, including those associated with astrogliosis in Dravet syndrome mice, that, accordingly, were rescued by Scn1a gene expression normalization at P30. Interestingly, regaining of Nav1.1 physiological level rescued seizures also in adult Dravet syndrome mice (P90) after months of repetitive attacks. Overall, these findings represent a solid proof-of-concept highlighting that disease phenotype reversibility can be achieved when Scn1a gene activity is efficiently reconstituted in brain cells.

The Effect of Aerobic Exercise on Deteriorating VO2max and Diminished Mitochondrial Biogenesis During Aging

Aging seems to be inevitable and gradual loss of physical activity is associated with frailty and many age-related disorders. Exercise is the way of keeping a healthy life and delaying aging process. Deterioration in pulmonary vital capacity is inevitable, and mitochondrial biogenesis also diminishes with aging. Regular aerobic exercise alleviates the diminishing vital capacity while increasing mitochondrial biogenesis in aging. Peroxisome proliferator-activated receptor c coactivator 1 alpha (PGC-1a), which is the master regulator of mitochondrial biogenesis, is activated by reactive oxygen species (ROS). Exercise-induced lactate leads to formation of ROS and synthesis of nitric oxide (NO) at physiological level. PGC1a regulation by NO seems to be controversial. Over the physiological limit of ROS and NO has toxic effects in cellular environment with reduced antioxidant activities in aging. Overall, exercise seems to be beneficial option to alleviate reduction rate of vital capacity and to enhance mitochondrial biogenesis via lactate-induced ROS formation. Keywords: Aging, Exercise, Maximum oxygen consumption rate, Lungs vital capacity, Mitochondria Biogenesis.

Impact of dietary supplements based on L-carnitine on free-radical processes in model systems

Introduction. According to the results of numerous studies and meta-analyses, the effectiveness of male infertility therapy with micronutrients-antioxidants in various variants remains low, especially concerning the increase in live-birth rates and the incidence of clinical pregnancy. This may be due to both the empirical nature of such therapy with an imbalance of ejaculate redox systems, and an overdose of individual ingredients of antioxidant complexes.Purpose of the study. To evaluate the antioxidant activity of complex preparation based on L-carnitine for the treatment of male infertility in an experimental model system.Materials and methods. The dietary supplements «AndroDoz®» («Nizhfarm» JSC, Russian Federation) and «Proxeed® plus» (Sigma-Tau Pharmaceuticals Inc., Italy) were tested. The antioxidant properties of the preparations were determined in vitro by recording chemiluminescence in model systems generating reactive oxygen species using the «LKB-Wallac 1256 chemiluminometer» (Wallac Oy/PerkinElmer®, Finland). Chemiluminescence was evaluated by the light sum and the maximum amplitude of the glow, the antioxidant activity in the biological environment was studied when adding drugs to chicken yolk lipids similar to blood lipoprotein complexes.Results. The introduction of «AndroDoz®» and «Proxeed® plus» into the incubation medium in an amount comparable to the physiological level of L-carnitine in seminal plasma, inhibited the luminescence of the model system. At the same time, if «Proxeed® plus» almost completely inhibited the formation of radicals, then an equivalent dose of «AndroDoz®» reduced the intensity of chemiluminescence by 60%. Approximately in the same proportions, the preparations suppressed the intensity of lipid peroxidation processes in a model system with lipoprotein complexes similar to blood lipids, that is, the antioxidant activity was preserved in the biological environment. A decrease in the value of the chemiluminescence light sum was also found against the background of the use of these dietary supplements, which may indicate their protective effect on biological membranes, including subcellular structures of spermatozoa.Conclusion. The combined dietary supplements used in the study have a high antioxidant potential. The preparation «Proxeed® plus» can completely suppress the processes of lipoperoxidation with the possible development of a deficiency of free radicals that provide vital processes. The preparation «AndroDoz®» has a milder effect on free-radical phenomena probably due to a lower content of active ingredients and a balanced composition, which reduces the risk of complications in the form of an «antioxidant paradox» or reductive stress.

Can a natural singing voice be enhanced through digital processing? Implications of voice training and vocology in singers

Introduction. The traditional way of facilitating a good singing voice has been achieved through rigorous voice training. In the modern days, however, there are some aspects of the singing voice that can be enhanced through digital processing. Although in the past, the frequency or intensity manipulations had to be achieved through the various singing techniques of the singer, technology today allows the singing voice to be enhanced from the instruments within recording studios. In essence, the traditional voice pedagogy and the evolution of digital audio processing both strive to achieve a better quality of the singing voice, but with different methods. Nevertheless, the major aspects of how the singing voice can be manipulated are not communicated among the professionals in each field. Objective. This paper offers insights as to how the quality of the singing voice can be changed physiologically through the traditional ways of voice training, and also digitally through various instruments that are now available in recording studios. Reflection. The ways in which singers train their voice must be mediated with the audio technology that is available today. Although there are aspects in which the digital technology can aid the singer’s voice, there remain areas in which the singers must train their singing system in a physiological level to produce a better singing voice.

Exposure assessment using biomonitoring

Complex studies were performed combining macroscopic and biochemical analyzes of selected biomonitors, exposed in exposure systems outdoor with mixtures of pollutants as well as controlled exposure with certain concentrations of pollutants in fumigation chambers. In this study, the following plant species were used as bioindicators: Nicotiana tabacum, Petunia hybrida, Ricinus comunis, Trifolium pretense. The exposure plant samples were compared with control samples of biomonitors maintained under standardized conditions in the climate chamber. Classical methods of biochemistry combined with those of exposure biomonitoring have led to the completion of knowledge about the ways of action of plants to pollution. The analysis of some of the antioxidant compounds that are representing a structural class of chemicals (enzymes) with a wide range of biological functions, with the role of free radical inhibition, was performed. Many of the constituent compounds in certain cell types, also called active compounds, in this case, polyphenols are present in the body of some plant species. Polyphenol's presence in organisms, that are not usually present or are in normal quantities, is caused by stress, (pollution being a stress factor). Large amounts of polyphenols in plants are also given by the presence of pollutants in the environment. Through these extensive combined studies, it has been demonstrated that pollution can be a degenerative factor at the biochemical and physiological level, at the plant tissue level, with irreversible effects.

Current Role of Nanotechnology Used in Food Processing Industry to Control Food Additives and Exploring Their Biochemical Mechanisms

Background: With the advent of food additives centuries ago, the human race has found ways to improve and maintain the safety of utility, augment the taste, color, texture, nutritional value, and appearance of the food. Since the 19th century, when the science behind food spoilage was discerned, the use of food additives in food preservation has been increasing worldwide and at a fast pace to get along with modern lifestyles. Although food additives are thought to be used to benefit the food market, some of them are found to be associated with several health issues at an alarming rate. Studies are still going on regarding the mechanisms by which food additives affect public health. Therefore, an attempt has been made to find out the remedies by exploiting technologies that may convey new properties of food additives that can only enhance the quality of food without having any systemic side effects. Thus, this review focuses on the applications of nanotechnology in the production of nano-food additives and evaluates its success regarding reduction in the health-related hazards collaterally maintaining the food nutrient value. Methodology: Ahorough literature study was performed using scientific databases like PubMed, Science Direct, Scopus, Web of Science for determining the design of the study, and each article was checked for citation and referred to formulate the present review article. Conclusion: Nanotechnology can be applied in the food processing industry to control the unregulated use of food additives and to intervene in the biochemical mechanisms at a cellular and physiological level for the ensuring safety of food products. The prospective of nano-additive of chemical origin could be useful to reduce risks of hazards related to human health that are caused majorly due to the invasion of food contaminants (either intentional or non-intentional) into food, though this area still needs scientific validation. Therefore, this review provides comprehensive knowledge on different facets of food contaminants and also serves as a platform of ideas for encountering health risk problems about the design of improved versions of nano-additives.

Bridging physiological and perceptual views of autism by means of sampling-based Bayesian inference

Theories for autism spectrum disorder (ASD) have been formulated at different levels: ranging from physiological observations to perceptual and behavioral descriptions. Understanding the physiological underpinnings of perceptual traits in ASD remains a significant challenge in the field. Here we show how a recurrent neural circuit model which was optimized to perform sampling-based inference and displays characteristic features of cortical dynamics can help bridge this gap. The model was able to establish a mechanistic link between two descriptive levels for ASD: a physiological level, in terms of inhibitory dysfunction, neural variability and oscillations, and a perceptual level, in terms of hypopriors in Bayesian computations. We took two parallel paths: inducing hypopriors in the probabilistic model, and an inhibitory dysfunction in the network model, which lead to consistent results in terms of the represented posteriors, providing support for the view that both descriptions might constitute two sides of the same coin.

Automatic Air Volume Control System for Ventilation of Two Patients Using a Single Ventilator: A Large Animal Model Study

The COVID-19 pandemic outbreak led to a global ventilator shortage. Hence, different strategies to use a single ventilator to support multiple patients are considered. A mechatronic system Ventil divides and automatically controls gas volume pumped through two channels and was successfully validated in independent lung ventilation. We used Ventil in a series of experiments on a large animal model to verify its usability for ventilation in two patients using a single ventilator. The results of investigations on 12 pigs showed that the physiological level of respiratory parameters was maintained for 24 hours. Application of Ventil did not lead to injuries in the lungs, as indicated by CT scan analysis. We conclude that ventilation using Ventil can be considered safe in patients subjected to deep sedation without spontaneous breathing efforts.

Effects of NP on some hematological and immunological indices in sarcoma TG180-bearing mice

Objective: Evaluate the effects of saponin-rich extracts from Panax notoginseng roots with steaming - NP (H) and without steaming - NP (O) on some hematological and immunological indices in sarcoma TG180-bearing mice. Methods: The mice were injected with Sarcoma TG180 cells in the thigh to cause tumors, then were oral administrated NP(O), NP(H), Letinan or normal saline from the 6th day to 22nd day since developed tumors. On the 22nd day, blood was taken for IL-2, TNF-α and hematological indicators, revealing and determining the relative weight of spleen and thymus. Results: NP(H) and NP(O) at both level of the doses of 300 mg/kg/day and 900 mg/kg/day increased red blood cell count, hemoglobin, hematocrit, adjusted white blood cell and platelet counts return to physiological level, increased blood IL-2 and TNF-α, increased relative weight of spleen and thymus. Conclusion: The saponin-rich extracts from Panax notoginseng roots had the effects of improving hematological index and enhancing immunity on sarcoma 180-bearing mice, in which the extract from steaming Panax notoginseng roots has a better effect compared with no-steaming Panax notoginseng roots ones.

A Role for Adipocytes and Adipose Stem Cells in the Breast Tumor Microenvironment and Regenerative Medicine

Obesity rates are climbing, representing a confounding and contributing factor to many disease states, including cancer. With respect to breast cancer, obesity plays a prominent role in the etiology of this disease, with certain subtypes such as triple-negative breast cancer having a strong correlation between obesity and poor outcomes. Therefore, it is critical to examine the obesity-related alterations to the normal stroma and the tumor microenvironment (TME). Adipocytes and adipose stem cells (ASCs) are major components of breast tissue stroma that have essential functions in both physiological and pathological states, including energy storage and metabolic homeostasis, physical support of breast epithelial cells, and directing inflammatory and wound healing responses through secreted factors. However, these processes can become dysregulated in both metabolic disorders, such as obesity and also in the context of breast cancer. Given the well-established obesity-neoplasia axis, it is critical to understand how interactions between different cell types in the tumor microenvironment, including adipocytes and ASCs, govern carcinogenesis, tumorigenesis, and ultimately metastasis. ASCs and adipocytes have multifactorial roles in cancer progression; however, due to the plastic nature of these cells, they also have a role in regenerative medicine, making them promising tools for tissue engineering. At the physiological level, the interactions between obesity and breast cancer have been examined; here, we will delineate the mechanisms that regulate ASCs and adipocytes in these different contexts through interactions between cancer cells, immune cells, and other cell types present in the tumor microenvironment. We will define the current state of understanding of how adipocytes and ASCs contribute to tumor progression through their role in the tumor microenvironment and how this is altered in the context of obesity. We will also introduce recent developments in utilizing adipocytes and ASCs in novel approaches to breast reconstruction and regenerative medicine.