Chronic Methamphetamine Administration Causes Differential Regulation of Transcription Factors in the Rat Midbrain

Methamphetamine (METH) is an addictive and neurotoxic psychostimulant widely abused in the USA and throughout the world. When administered in large doses, METH can cause depletion of striatal dopamine terminals, with preservation of midbrain dopaminergic neurons. Because alterations in the expression of transcription factors that regulate the development of dopaminergic neurons might be involved in protecting these neurons after toxic insults, we tested the possibility that their expression might be affected by toxic doses of METH in the adult brain. Male Sprague-Dawley rats pretreated with saline or increasing doses of METH were challenged with toxic doses of the drug and euthanized two weeks later. Animals that received toxic METH challenges showed decreases in dopamine levels and reductions in tyrosine hydroxylase protein concentration in the striatum. METH pretreatment protected against loss of striatal dopamine and tyrosine hydroxylase. In contrast, METH challenges caused decreases in dopamine transporters in both saline- and METH-pretreated animals. Interestingly, METH challenges elicited increases in dopamine transporter mRNA levels in the midbrain in the presence but not in the absence of METH pretreatment. Moreover, toxic METH doses caused decreases in the expression of the dopamine developmental factors, Shh, Lmx1b, and Nurr1, but not in the levels of Otx2 and Pitx3, in saline-pretreated rats. METH pretreatment followed by METH challenges also decreased Nurr1 but increased Otx2 and Pitx3 expression in the midbrain. These findings suggest that, in adult animals, toxic doses of METH can differentially influence the expression of transcription factors involved in the developmental regulation of dopamine neurons. The combined increases in Otx2 and Pitx3 expression after METH preconditioning might represent, in part, some of the mechanisms that served to protect against METH-induced striatal dopamine depletion observed after METH preconditioning

Analysis of results of questioning of students in organization and conduct on exam department of infectious diseases and clinical immunology

Self-evaluation of educational activity of the department is used as an important component of summarizing and planning process. Surveyfeedbackis a method to the consumers of the educational process. The results of the survey of students on the organization of the exam on the discipline.Самооценка учебной деятельности кафедры используется как важный компонент подведения итогов и планирования процесса. Анкетирование является методом обратной связи с потребителями учебного процесса. В работе представлены результаты анкетирования студентов по вопросам организации экзамена по дисциплине

Methamphetamine Preconditioning Alters Midbrain Transcriptional Responses to Methamphetamine-Induced Injury in the Rat Striatum

Methamphetamine (METH) is an illicit drug which is neurotoxic to the mammalian brain. Numerous studies have revealed significant decreases in dopamine and serotonin levels in the brains of animals exposed to moderate-to-large METH doses given within short intervals of time. In contrast, repeated injections of small nontoxic doses of the drug followed by a challenge with toxic METH doses afford significant protection against monoamine depletion. The present study was undertaken to test the possibility that repeated injections of the drug might be accompanied by transcriptional changes involved in rendering the nigrostriatal dopaminergic system refractory to METH toxicity. Our results confirm that METH preconditioning can provide significant protection against METH-induced striatal dopamine depletion. In addition, the presence and absence of METH preconditioning were associated with substantial differences in the identity of the genes whose expression was affected by a toxic METH challenge. Quantitative PCR confirmed METH-induced changes in genes of interest and identified additional genes that were differentially impacted by the toxic METH challenge in the presence of METH preconditioning. These genes include small heat shock 27 kD 27 protein 2 (HspB2), thyrotropin-releasing hormone (TRH), brain derived neurotrophic factor (BDNF), c-fos, and some encoding antioxidant proteins including CuZn superoxide dismutase (CuZnSOD), glutathione peroxidase (GPx)-1, and heme oxygenase-1 (Hmox-1). These observations are consistent, in part, with the transcriptional alterations reported in models of lethal ischemic injuries which are preceded by ischemic or pharmacological preconditioning. Our findings suggest that multiple molecular pathways might work in tandem to protect the nigrostriatal dopaminergic pathway against the deleterious effects of the toxic psychostimulant. Further analysis of the molecular and cellular pathways regulated by these genes should help to provide some insight into the neuroadaptive potentials of the brain when repeatedly exposed to drugs of abuse

Описание клинической картины и оценка функциональной активности канала CFTR у пациента с комплексным аллелем [S466X; R1070Q]

The presence of pathogenic variants in the CFTR gene causes cystic fibrosis (CF) through various molecular mechanisms that affect the formation and functional activity of the CFTR chloride channel. An important factor affecting the phenotypic manifestations of CF and the effectiveness of targeted therapy is the presence of complex alleles with > 2 consecutive mutations per 1 allele, or in the cis position. The influence of complex alleles on the manifestations of CF has not been sufficiently studied globally due to the small number of studies.The aim of the study was to investigate the influence of the complex allele [S466X; R1070Q] on the phenotypic manifestations of CF and the effectiveness of targeted therapy in a model of intestinal organoids from a patient with [S466X; R1070Q]/CFTRdele2,3 genotype.Methods. We used medical history data, intestinal current measurement, intestinal organoid method, and forskolin test.Results. The progressive nature of the disease with a clear degradation of lung function was established. The ICM method showed absent chloride channel function. The tests on the culture of organoids obtained from the intestinal tissue indicated a complete loss of the chloride channel function. In addition, the complex allele [S466X; R1070Q] was insensitive to all targeted drugs tested.Conclusion. The complex allele [S466X; R1070Q] causes a complete loss of the functional CFTR protein and is not sensitive to any of the approved targeted drugs.Наличие патогенных вариантов в гене CFTR вызывает муковисцидоз (МВ) посредством различных молекулярных механизмов, оказывающих влияние на образование и функциональную активность хлорного канала CFTR. Важным фактором, влияющим на фенотипические проявления МВ и эффективность таргетной терапии, является наличие комплексных аллелей — > 2 последовательных мутаций на 1-м аллеле, или в цис-положении. Влияние комплексных аллелей на проявления МВ в мире изучено недостаточно из-за небольшого количества проведенных исследований.Целью исследования явилось изучение влияния комплексного аллеля [S466X; R1070Q] на фенотипические проявления МВ и эффективность таргетной терапии на модели кишечных органоидов у пациента с генотипом [S466X; R1070Q]/CFTRdele2,3.Материалы и методы. Использовались данные истории болезни пациента, метод определения разницы кишечных потенциалов (ОРКП), метод кишечных органоидов, форсколиновый тест.Результаты. Установлен прогрессирующий характер заболевания с явной деградацией легочной функции. При использовании метода ОРКП показано отсутствие функции хлорного канала. Проведенные на полученной из ткани кишечника культуре органоидов тесты свидетельствуют о полной утрате функции хлорного канала. Кроме того, комплексный аллель [S466X; R1070Q] оказался нечувствительным ко всем протестированным таргетным препаратам.Заключение. Установлено, что комплексный аллель [S466X; R1070Q] вызывает полную утрату функционального белка CFTR и нечувствителен к действию ни одного из зарегистрированных таргетных препаратов

Advances in Social Media Research:Past, Present and Future

Social media comprises communication websites that facilitate relationship forming between users from diverse backgrounds, resulting in a rich social structure. User generated content encourages inquiry and decision-making. Given the relevance of social media to various stakeholders, it has received significant attention from researchers of various fields, including information systems. There exists no comprehensive review that integrates and synthesises the findings of literature on social media. This study discusses the findings of 132 papers (in selected IS journals) on social media and social networking published between 1997 and 2017. Most papers reviewed here examine the behavioural side of social media, investigate the aspect of reviews and recommendations, and study its integration for organizational purposes. Furthermore, many studies have investigated the viability of online communities/social media as a marketing medium, while others have explored various aspects of social media, including the risks associated with its use, the value that it creates, and the negative stigma attached to it within workplaces. The use of social media for information sharing during critical events as well as for seeking and/or rendering help has also been investigated in prior research. Other contexts include political and public administration, and the comparison between traditional and social media. Overall, our study identifies multiple emergent themes in the existing corpus, thereby furthering our understanding of advances in social media research. The integrated view of the extant literature that our study presents can help avoid duplication by future researchers, whilst offering fruitful lines of enquiry to help shape research for this emerging field

Neurotrophic actions of dopamine on the development of a serotonergic feeding circuit in Drosophila melanogaster

<p>Abstract</p> <p>Background</p> <p>In the fruit fly, <it>Drosophila melanogaster</it>, serotonin functions both as a neurotransmitter to regulate larval feeding, and in the development of the stomatogastric feeding circuit. There is an inverse relationship between neuronal serotonin levels during late embryogenesis and the complexity of the serotonergic fibers projecting from the larval brain to the foregut, which correlate with perturbations in feeding, the functional output of the circuit. Dopamine does not modulate larval feeding, and dopaminergic fibers do not innervate the larval foregut. Since dopamine can function in central nervous system development, separate from its role as a neurotransmitter, the role of neuronal dopamine was assessed on the development, and mature function, of the 5-HT larval feeding circuit.</p> <p>Results</p> <p>Both decreased and increased neuronal dopamine levels in late embryogenesis during development of this circuit result in depressed levels of larval feeding. Perturbations in neuronal dopamine during this developmental period also result in greater branch complexity of the serotonergic fibers innervating the gut, as well as increased size and number of the serotonin-containing vesicles along the neurite length. This neurotrophic action for dopamine is modulated by the D₂dopamine receptor expressed during late embryogenesis in central 5-HT neurons. Animals carrying transgenic RNAi constructs to knock down both dopamine and serotonin synthesis in the central nervous system display normal feeding and fiber architecture. However, disparate levels of neuronal dopamine and serotonin during development of the circuit result in abnormal gut fiber architecture and feeding behavior.</p> <p>Conclusions</p> <p>These results suggest that dopamine can exert a direct trophic influence on the development of a specific neural circuit, and that dopamine and serotonin may interact with each other to generate the neural architecture necessary for normal function of the circuit.</p

Intermediate certification organization for the discipline «infectious diseases in children in implementation of the requirements of the competence-based approach

The article describes the results of the course exam for the discipline «infectious diseases of children» for students of the course 6 pediatric faculty. Examination conditions conform to real clinical practice physician pediatriciandistrict, which would be university graduates. Examiner assessed the degree of development of competences, in which participates the staff of the Department of infectious diseases and Clinical Immunology.В статье приведены результаты курсового экзамена по дисциплине «Инфекционные болезни у детей» для студентов 6 курса педиатрического факультета. Условия проведения экзамена соответствовали реальной клинической практике врача педиатра-участкового, в которой окажутся выпускники университета. Экзаменатор оценивал степень освоения компетенций, в формировании которых принимает участие коллектив кафедры инфекционных болезней и клинической иммунологии

Clinical, hormonal and molecular-genetic characteristics of monogenic diabetes mellitus associated with the mutations in the <i>INS</i> gene

Background: Currently more than 50 mutations of the INS gene are known to affect the various stages of insulin biosynthesis in the beta cells of the pancreas. However only individual cases of diabetes mellitus (DM) associated with heterozygous mutations in the coding region of the INS gene were reported in Russian Federation. We report a group of patients with a clinical manifestation of DM caused by mutations in both coding and non-coding regions of the INS gene. The patients with a mutation in the intron of the INS gene are reported for the first time in Russian FederationMaterials and methods: 60 patients with an isolated course of neonatal DM (NDM), 52 patients with a manifestation of DM at the age of 7–12 months and the absence of the main autoimmune markers of type 1 DM, 650 patients with the MODY phenotype were included in the study. NGS technology was used for molecular genetic research. Author’s panel of primers (Custom DNA Panel) was used for multiplex PCR and sequencing using Ion Ampliseq™ technology. The author’s panel “­Diabetes Mellitus” included 28 genes (13 candidate genes of MODY and other genes associated with DM).Results: 13 heterozygous mutations were identified in 16 probands and 9 relatives. The majority of mutations were detected in patients with PNDM (18.75%) and in patients with an onset of DM at the age of 7–12 months (9.6%). Mutations in the INS gene were detected in 2 patients (0.3%) in the group with the MODY phenotype. Mutations in the INS gene were not detected in patients with transient NDM (TNDM). Analysis of clinical data in patients with PND and onset of diabetes at the age of 7–12 months did not show significant differences in the course of the disease. The clinical characteristics of the cases of MODY10 and diabetes caused by a mutation in the intron of the INS gene are reported in details.Conclusion: The role of INS gene mutations in NDM, MODY, and DM with an onset at the age of 7–12 months was analyzed in a large group of patients. The clinical characteristics of DM due to a mutation in the intron of the INS gene are reported for the first time in the Russian Federation

Differential effects of prenatal and postnatal expressions of mutant human DISC1 on neurobehavioral phenotypes in transgenic mice: evidence for neurodevelopmental origin of major psychiatric disorders

Strong genetic evidence implicates mutations and polymorphisms in the gene Disrupted-In-Schizophrenia-1 (DISC1) as risk factors for both schizophrenia and mood disorders. Recent studies have shown that DISC1 has important functions in both brain development and adult brain function. We have described earlier a transgenic mouse model of inducible expression of mutant human DISC1 (hDISC1) that acts in a dominant-negative manner to induce the marked neurobehavioral abnormalities. To gain insight into the roles of DISC1 at various stages of neurodevelopment, we examined the effects of mutant hDISC1 expressed during (1) only prenatal period, (2) only postnatal period, or (3) both periods. All periods of expression similarly led to decreased levels of cortical dopamine (DA) and fewer parvalbumin-positive neurons in the cortex. Combined prenatal and postnatal expression produced increased aggression and enhanced response to psychostimulants in male mice along with increased linear density of dendritic spines on neurons of the dentate gyrus of the hippocampus, and lower levels of endogenous DISC1 and LIS1. Prenatal expression only resulted in smaller brain volume, whereas selective postnatal expression gave rise to decreased social behavior in male mice and depression-like responses in female mice as well as enlarged lateral ventricles and decreased DA content in the hippocampus of female mice, and decreased level of endogenous DISC1. Our data show that mutant hDISC1 exerts differential effects on neurobehavioral phenotypes, depending on the stage of development at which the protein is expressed. The multiple and diverse abnormalities detected in mutant DISC1 mice are reminiscent of findings in major mental diseases