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The Trace Amine-Associated Receptor 1 (TAAR1) is one of the six functional receptors belonging to the family of monoamine-related G protein-coupled receptors (TAAR1-TAAR9) found in humans. However, the exact biological mechanisms of TAAR1 central and peripheral action remain to be fully understood. TAAR1 is widely expressed in the prefrontal cortex and several limbic regions, interplaying with the dopamine system to modulate the reward circuitry. Recent clinical trials suggest the efficacy of TAAR1 agonists as potential novel antipsychotic agents. Here, we characterize behavioral and neurochemical phenotypes of TAAR1 knockout mice, focusing on aggression and self-grooming behavior that both strongly depend on the monoaminergic signaling and cortico-striatal and cortico-limbic circuits. Overall, we report increased aggression in these knockout mice in the resident-intruder test, accompanied by reduced self-grooming behavior in the novelty-induced grooming test, and by higher cortical serotonin (5-HT) tissue levels. Further studies are necessary to explore whether TAAR1-based therapies can become potential novel treatments for a wide range of neuropsychiatric disorders associated with aggression.
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Genética Comportamental , Receptores Acoplados a Proteínas G , Serotonina , Animais , Camundongos , Agressão/fisiologia , Asseio Animal/fisiologia , Camundongos Knockout , Córtex Pré-Frontal/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Serotonina/metabolismoRESUMO
Trace amine-associated receptors (TAARs) are a group of G protein-coupled receptors that are expressed in the olfactory epithelium, central nervous system, and periphery. TAAR family generally consists of nine types of receptors (TAAR1-9), which can detect biogenic amines. During the last 5 years, the TAAR5 receptor became one of the most intriguing receptors in this subfamily. Recent studies revealed that TAAR5 is involved not only in sensing socially relevant odors but also in the regulation of dopamine and serotonin transmission, emotional regulation, and adult neurogenesis by providing significant input from the olfactory system to the limbic brain areas. Such results indicate that future antagonistic TAAR5-based therapies may have high pharmacological potential in the field of neuropsychiatric disorders. TAAR5 is known to be expressed in leucocytes as well. To evaluate potential hematological side effects of such future treatments we analyzed several hematological parameters in mice lacking TAAR5. In these mutants, we observed minor but significant changes in the osmotic fragility test of erythrocytes and hematocrit levels. At the same time, analysis of other parameters including complete blood count and reticulocyte levels showed no significant alterations in TAAR5 knockout mice. Thus, TAAR5 gene knockout leads to minor negative changes in the erythropoiesis or eryptosis processes, and further research in that field is needed. The impact of TAAR5 deficiency on other hematological parameters seems minimal. Such negative, albeit minor, effects of TAAR5 deficiency should be taken into account during future TAAR5-based therapy development.
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Aminas Biogênicas/metabolismo , Eritrócitos/metabolismo , Fragilidade Osmótica/genética , Receptores Acoplados a Proteínas G/genética , Animais , Sistema Nervoso Central/metabolismo , Técnicas de Inativação de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucosa Olfatória/metabolismoRESUMO
In the last two decades, interest has grown significantly in the investigation of the role of trace amines and their receptors in mammalian physiology and pathology. Trace amine-associated receptor 9 (TAAR9) is one of the least studied members of this receptor family with unidentified endogenous ligands and an unknown role in the central nervous system and periphery. In this study, we generated two new TAAR9 knockout (TAAR9-KO) rat strains by CRISPR-Cas9 technology as in vivo models to evaluate the role of TAAR9 in mammalian physiology. In these mutant rats, we performed a comparative analysis of a number of hematological and biochemical parameters in the blood. Particularly, we carried out a complete blood count, erythrocyte osmotic fragility test, and screening of a panel of basic biochemical parameters. No significant alterations in any of the hematological and most biochemical parameters were found between mutant and WT rats. However, biochemical studies revealed a significant decrease in total and low-density lipoprotein cholesterol levels in the blood of both strains of TAAR9-KO rats. Such role of TAAR9 in cholesterol regulation not only brings a new understanding of mechanisms and biological pathways of lipid exchange but also provides a new potential drug target for disorders involving cholesterol-related pathology, such as atherosclerosis.
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Aterosclerose/genética , Colesterol/sangue , Receptores Acoplados a Proteínas G/genética , Animais , Aterosclerose/sangue , Aterosclerose/patologia , Sistemas CRISPR-Cas , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Colesterol/genética , Modelos Animais de Doenças , Eritrócitos/metabolismo , Eritrócitos/patologia , Técnicas de Inativação de Genes , Humanos , Ligantes , Fragilidade Osmótica/genética , RatosRESUMO
In this work, Al-Mg intermetallic powders were characterized and obtained by melting, casting into a steel chill and subsequent mechanical activation in a planetary mill. The method for producing Al12Mg17 intermetallic powder is presented. The dispersity, morphology, chemical composition, and phase composition of the obtained powder materials were investigated. Certain thermodynamic properties of high-energy materials containing the Al-Mg powder after mechanical activation of various durations were investigated. The addition of the Al-Mg powders to the high-energy composition (synthetic rubber SKDM-80 + ammonium perchlorate AP + boron B) can significantly increase the burning rate by approximately 47% and the combustion heat by approximately 23% compared with the high-energy compositions without the Al-Mg powder. The addition of the Al12Mg17 powder obtained after 6 h of mechanical activation provides an increase in the burning rate by 8% (2.5 ± 0.1 mm/s for the mechanically activated Al12Mg17 powder and 2.3 ± 0.1 mm/s for the commercially available powder) and an increase in the combustion heat by 3% (7.4 ± 0.2 MJ/kg for the mechanically activated Al-Mg powder and 7.1 ± 0.2 MJ/kg for the commercially available powder). The possibility of using the Al-Mg intermetallic powders as the main component of pyrotechnic and special compositions is shown.
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Ligas/química , Alumínio/química , Magnésio/química , Pós/química , Dureza , Teste de Materiais , Tamanho da PartículaRESUMO
This paper presents the results of studies on AlMgB14-based ceramic coatings deposited on WC-Co hard alloy substrates using RF plasma sputtering. The aim of this work is to study the structure, phase composition, and mechanical properties of AlMgB14-based coatings depending on the sputtering mode. According to the results of the microstructural study, the bias voltage applied to the substrate during the sputtering process significantly contributed to the formation of the coating morphology. Based on the results of compositional and structural studies by energy dispersive X-ray spectroscopy, X-ray diffraction, and Raman spectroscopy, it was found that the coatings are composed of nanocrystalline B12 icosahedrons distributed in an amorphous matrix consisting of Al, Mg, B, and O elements. The nanohardness of the coatings varied from 24 GPa to 37 GPa. The maximum value of the hardness together with the lowest coefficient of friction (COF) equal to 0.12 and wear resistance of 7.5 × 10-5 mm3/N·m were obtained for the coating sputtered at a bias voltage of 100 V. Compared with the COF of the original hard alloy substrate, which is equal to 0.31, it can be concluded that the AlMgB14-based coatings could reduce the COF of WC-based hard alloys by more than two times. The hardness and tribological properties of the coatings obtained in this study are in good agreement with the properties of AlMgB14-based materials obtained by other methods reported in the literature.
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Digital light processing (DLP) or stereolithography is the most promising method of additive manufacturing (3D printing) of products based on high-energy materials due to, first of all, the absence of a high-temperature impact on the material. This paper presents research results of an ultraviolet (UV)-cured urethane methacrylate polymer containing 70 wt.% of high-energy solid powder based on ammonium salts, which is intended for digital light processing. Polymerization of the initial slurry is studied herein. It is shown that the addition of coarse powder transparency for the UV radiation to resin increases its curing depth. The thickness of the layer, which can polymerize, varies from 600 µm to 2 mm when the light power density ranges from 20 to 400 mJ/cm2, respectively. In DLP-based 3D printing, the obtained material density is 92% of the full density, while the compressive strength is 29 ± 3 MPa, and the ultimate tensile strength is 13 ± 1.3 MPa. The thermogravimetric analysis shows the decrease in the thermal decomposition temperature of UV-cured resin with high-energy additives compared to the thermal decomposition temperatures of the initial components separately. Thermal decomposition is accompanied by intensive heat generation. The burning rate of obtained samples grows from 0.74 to 3.68 mm/s, respectively, at the pressure growth from 0.1 to 4 MPa. Based on the results, it can be concluded that DLP-based 3D printing with the proposed UV photocurable resin is rather promising for the fabrication of multicomponent high-energy systems and complex profile parts produced therefrom.
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This article presents the results of studies of the features of the development of thermoelastic martensitic transformations during cooling/heating in the free state and under load of Ti50Ni49.7-XNbXMo0.3 alloys (X = 0.5, 1.0 and 1.5 at% Nb) with shape memory effects. Using X-ray diffraction analysis, it was found that all the alloys studied at room temperature contained a multiphase mixture consisting of intermetallic compounds with the TiNi (B2, B19'), Ni56Ti29Nb15, and Ti2Ni compositions. Scanning electron microscopy was used to study the microstructure of TiNi (Nb,Mo) alloys and it was found that the distribution of fine Ni56Ti29Nb15 particles in the matrix depends significantly on the concentration of the alloying element. A correlation was established between changes in the structural-phase state in TiNi (Nb,Mo) alloys and the occurrence of the B2âB19' martensitic transition in the free state and under load. Based on physical and mechanical studies, the temperature ranges of the martensitic transformations (MT) in the free state and under load were established. Based on the thermodynamic description of the MT and the analysis of the characteristic temperatures of the MT, it was found that the MT mechanism is strongly dependent on the concentration of the alloying element.
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Trace amines and their receptors are a family of G protein-coupled receptors widely distributed in the central nervous system and periphery. The trace amine-associated receptor 1 (TAAR1) plays a significant role as a therapeutic target for schizophrenia, depression, diabetes, and obesity. In this study, TAAR1 knockout mice and WT groups were tested in conditions of a high-fructose diet. The consumption of a high-fructose diet may be due to the influence on the metabolism processes by dopamine in the brain, neuromotor function, and level of anxiety of TAAR1 knockout mice. During a comparative analysis of behavioral, biochemical, and morphological parameters, significant differences were found between liver and biochemical parameters, the regulation of protein metabolism (AST/ALT ratio, creatine kinase activity, urea), and alterations in behavior. An elevated plus maze analysis showed the influence of fructose and genetic factors on the level of anxiety. A new marker of the grooming microstructure (depression ratio) was tested, which showed high efficiency as a marker of depression-like behavioral changes and a possible association with dopamine-dependent regulation of protein metabolism. These results confirm a possible association of the TAAR1 gene knockout with an increase in catabolic reaction levels by AST/ALT-dependent and possible dopamine-mediated protein metabolism regulation and depression-like behavior.
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A mathematical model of the pulse generation of decontaminating aerosols utilizing the energy of high-energy materials (HEM) is proposed with account for the physical and chemical properties of the atomized substance, HEM characteristics, and gas generator parameters. Such a model is needed to counter the environmental hazards, process emissions, and terrorist attacks with hazardous and dangerous aerosols. Another aspect of the problem is the danger of biological aerosols carrying viral or microbial particles that are spread naturally or induced using biological weapons. In many cases, the mission is not only to neutralize aerosol particles in indoor air and on surfaces but also to do it quickly. In this regard, an attractive option is the pulse method for generating special aerosols aimed at quickly, within a few seconds, creating a cloud of particles that will interact with hazardous aerosol particles and decontaminate them. HEM energy is proposed to be used for the pulse generation of such aerosols. It is important not only to atomize the decontaminating aerosol quickly and evenly in space but also to preserve the useful physical and chemical properties of the particles. To test the regimes and methods of pulse generation, an adequate mathematical model of the process is required, which is proposed in this manuscript.
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In this work, the structure, phase composition, hardness and tensile strength of the AlMgB14-based material obtained by spark plasma sintering (SPS) were investigated. According to the XRD results, the spark plasma sintered material contains 94 wt% AlMgB14 phase and 6 wt% spinel MgAl2O4. Analysis of the SEM images showed that the obtained AlMgB14 sample has a dense structure; the relative density of the sample is 98.6%. The average microhardness of the spark plasma sintered (SPSed) sample is 29 ± 0.88 GPa. According to the results of the Brazilian test, the tensile strength of AlMgB14 is 56 MPa. The fracture is characterized by a single straight tensile crack that divides the sample along the compression line into two halves. The type of fracture in the AlMgB14 sample can be characterized as a cleavage fracture due to crack growth occurring in accordance with the transcrystalline fracture. The tensile strength of the obtained material is in good agreement with the tensile strength of boride and oxide ceramics studied in other works.
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It is known that the presence of oxygen phases in hard materials leads to an undesirable decrease in the mechanical properties. In materials based on AlMgB14, the main oxygen impurity is spinel MgAl2O4; it significantly reduces the hardness of AlMgB14 and its formation during sintering is inevitable. In this work, the ultra-hard spark plasma sintered (SPSed) AlMgB14-TiB2 composite material was fabricated from the AlMgB14-TiB2 precursor obtained by self-propagating high-temperature synthesis (SHS). Due to the high synthesis temperatures, the main oxygen phase in the obtained composite was Al4B2O9 instead of spinel MgAl2O4. It was found that the obtained composite has excellent mechanical properties. The maximum hardness of the sample is 44.1 GPa. The presence of oxygen in the form of the Al4B2O9 phase led to unexpected results: the friction coefficient of the obtained AlMgB14-TiB2 composite under dry conditions against the Al2O3 counter-specimen is approximately four times lower than the friction coefficient of pure ceramic AlMgB14 (0.18 against 0.7, respectively). Based on the observed results, it was found that the Al4B2O9 particles formed during the SHS are responsible for the low friction coefficient. The quantum chemical calculations showed that the elastic moduli of Al4B2O9 are significantly smaller than the elastic moduli of AlMgB14 and TiB2. Thus, during sliding, Al4B2O9 particles are squeezed out onto the composite surface, form the lubricating layer and reduce the friction coefficient.
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In this work, composite materials were obtained by spark plasma sintering of an Al12Mg17-B-Si powder mixture. The structure, phase composition, and mechanical properties of the obtained composites were studied. It was found that various compounds based on B12 icosahedrons, such as AlB12, B4Si, and B6Si, are formed during spark plasma sintering. Based on the SEM images and results of XRD analysis of the obtained specimens, a probable scheme for the formation of the phase composition of composite materials during spark plasma sintering was proposed. An increase in the Al12Mg17-B powder content in the initial mixture from 30 to 70 wt% leads to an increase in hardness from 16.55 to 21.24 GPa and a decrease in the friction coefficient and wear rate from 0.56 to 0.32 and 13.60 to 5.60 10-5 mm-3/(N/m), respectively.
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Trace amine-associated receptors (TAAR1-TAAR9) are a family of G-protein-coupled monoaminergic receptors which might have great pharmacological potential. It has now been well established that TAAR1 plays an important role in the central nervous system. Interestingly, deletion of TAAR9 in rats leads to alterations in the periphery. Previously, we found that knockout of TAAR9 in rats (TAAR9-KO rats) decreased low-density lipoprotein cholesterol levels in the blood. TAAR9 was also identified in intestinal tissues, and it is known that it responds to polyamines. To elucidate the role of TAAR9 in the intestinal epithelium, we analyzed TAAR9-co-expressed gene clusters in public data for cecum samples. As identified by gene ontology enrichment analysis, in the intestine, TAAR9 is co-expressed with genes involved in intestinal mucosa homeostasis and function, including cell organization, differentiation, and death. Additionally, TAAR9 was co-expressed with genes implicated in dopamine signaling, which may suggest a role for this receptor in the regulation of peripheral dopaminergic transmission. To further investigate how TAAR9 might be involved in colonic mucosal homeostasis, we analyzed the fecal microbiome composition in TAAR9-KO rats and their wild-type littermates. We identified a significant difference in the number of observed taxa between the microbiome of TAAR9-KO and wild-type rats. In TAAR9-KO rats, the gut microbial community became more variable compared with the wild-type rats. Furthermore, it was found that the family Saccharimonadaceae, which is one of the top 10 most abundant families in TAAR9-KO rat feces, is almost completely absent in wild-type animal fecal samples. Taken together, these data indicate a role of TAAR9 in intestinal function.
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Dopamina , Microbioma Gastrointestinal , Receptores Acoplados a Proteínas G , Animais , Ratos , Sistema Nervoso Central/metabolismo , Dopamina/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Técnicas de Inativação de Genes , Fezes/microbiologiaRESUMO
It is known that the trace amine-associated receptor 1 (TAAR1) receptor is involved in limbic brain functions by regulating dopamine transmission and putative reward circuitry. Moreover, other TAARs are expressed in the olfactory system of all studied vertebrate species, sensing innate socially-relevant odors, including pheromones. Therefore, one can assume that TAARs may play a role in rodent social and sexual behavior. A comparative behavioral and biochemical analysis of TAAR1 knockout (TAAR1-KO) and wild-type mice is also important for the preliminary evaluation of the potential side effects of future TAAR1-based therapies. In our studies, we adapted a sexual incentive motivation test for mice to evaluate the sexual behavior of TAAR1-KO and wild-type mice. Previously, similar methods were primarily applied to rats. Furthermore, we measured testosterone and other biochemical parameters in the blood. As a result, we found only minimal alterations in all of the studied parameters. Thus, the lack of TAAR1 does not significantly affect sexual motivation and routine lipid and metabolic blood biochemical parameters, suggesting that future TAAR1-based therapies should have a favorable safety profile.
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In this work, the process for obtaining aluminum nitride in the combustion mode of co-flow filtration of a nitrogen-argon mixture was investigated. The combustion of granules consisting of aluminum and aluminum nitride as an inert diluent was studied under conditions of co-current filtration in a flow of nitrogen and a nitrogen-argon mixture in the range of a specific flow rate of 1.5-5.0 cm3/(sâcm2). It was found that the specific flow rate of the gas mixture and the amount of argon in the nitrogen-argon mixture had a significant effect on the rate and the temperature of combustion. The structure and phase composition of the synthesis products were studied. The maximum achieved yield of the AlN phase was 95 wt.%. Moreover, this method is energy efficient and allows the production of metal nitrides without the use of high-pressure reactors.
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AlMgB14-TiB2 composite materials were fabricated by self-propagating high-temperature synthesis (SHS) followed by spark plasma sintering of the obtained SHS products. It was found that, during the SHS, the AlMgB14 phase is formed at a donor (Ti + 2B) to acceptor (Al12Mg17-B) mass ratio of 3:7 and 4:6, respectively. The specimen sintered from the SHS powder with the donor:acceptor mass ratio of 5:5 at a temperature of 1470 °C has a uniform skeletal structure. The average hardness of the obtained specimen is 30.1 GPa.
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The paper explores the influence of planetary milling on the temperature and velocity of Al-Ti-B powder mixture combustion and also on the structure and phase composition of the reaction products. It is found that the time increase of planetary milling modifies the structure of the powder particles, improves the density of compacted specimens, and increases the temperature and velocity of their combustion. These time dependences are extreme, with maximum values during 180 s planetary milling. Experiments show that the reaction products consist of an aluminum matrix with uniformly distributed particles of titanium diboride of not over 1 µm in size. The average particle size changes with the increase in the time of the planetary milling of the initial powder mixture.
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Among the ground-breaking achievements of the International Conference on Population and Development (ICPD) was its call to place adolescent sexual and reproductive health (ASRH) on global health and development agendas. This article reviews progress made in low- and middle-income countries in the 25 years since the ICPD in six areas central to ASRH-adolescent pregnancy, HIV, child marriage, violence against women and girls, female genital mutilation, and menstrual hygiene and health. It also examines the ICPD's contribution to the progress made. The article presents epidemiologic levels and trends; political, research, programmatic and social responses; and factors that helped or hindered progress. To do so, it draws on research evidence and programmatic experience and the expertise and experiences of a wide number of individuals, including youth leaders, in numerous countries and organizations. Overall, looking across the six health topics over a 25-year trajectory, there has been great progress at the global and regional levels in putting adolescent health, and especially adolescent sexual and reproductive health and rights, higher on the agenda, raising investment in this area, building the epidemiologic and evidence-base, and setting norms to guide investment and action. At the national level, too, there has been progress in formulating laws and policies, developing strategies and programs and executing them, and engaging communities and societies in moving the agenda forward. Still, progress has been uneven across issues and geography. Furthermore, it has raced ahead sometimes and has stalled at others. The ICPD's Plan of Action contributed to the progress made in ASRH not just because of its bold call in 1994 but also because it provided a springboard for advocacy, investment, action, and research that remains important to this day.