Mice with ablated adult brain neurogenesis are not impaired in antidepressant response to chronic fluoxetine

The neurogenesis hypothesis of major depression has two main facets. One states that the illness results from decreased neurogenesis while the other claims that the very functioning of antidepressants depends on increased neurogenesis. In order to verify the latter, we have used cyclin D2 knockout mice (cD2 KO mice), known to have virtually no adult brain neurogenesis, and we demonstrate that these mice successfully respond to chronic fluoxetine. After unpredictable chronic mild stress, mutant mice showed depression-like behavior in forced swim test, which was eliminated with chronic fluoxetine treatment, despite its lack of impact on adult hippocampal neurogenesis in cD2 KO mice. Our results suggest that new neurons are not indispensable for the action of antidepressants such as fluoxetine. Using forced swim test and tail suspension test, we also did not observe depression-like behavior in control cD2 KO mice, which argues against the link between decreased adult brain neurogenesis and major depression

State-of-the-art methods for exposure-health studies: Results from the exposome data challenge event

The exposome recognizes that individuals are exposed simultaneously to a multitude of different environmental factors and takes a holistic approach to the discovery of etiological factors for disease. However, challenges arise when trying to quantify the health effects of complex exposure mixtures. Analytical challenges include dealing with high dimensionality, studying the combined effects of these exposures and their interactions, integrating causal pathways, and integrating high-throughput omics layers. To tackle these challenges, the Barcelona Institute for Global Health (ISGlobal) held a data challenge event open to researchers from all over the world and from all expertises. Analysts had a chance to compete and apply state-of-the-art methods on a common partially simulated exposome dataset (based on real case data from the HELIX project) with multiple correlated exposure variables (P > 100 exposure variables) arising from general and personal environments at different time points, biological molecular data (multi-omics: DNA methylation, gene expression, proteins, metabolomics) and multiple clinical phenotypes in 1301 mother–child pairs. Most of the methods presented included feature selection or feature reduction to deal with the high dimensionality of the exposome dataset. Several approaches explicitly searched for combined effects of exposures and/or their interactions using linear index models or response surface methods, including Bayesian methods. Other methods dealt with the multi-omics dataset in mediation analyses using multiple-step approaches. Here we discuss features of the statistical models used and provide the data and codes used, so that analysts have examples of implementation and can learn how to use these methods. Overall, the exposome data challenge presented a unique opportunity for researchers from different disciplines to create and share state-of-the-art analytical methods, setting a new standard for open science in the exposome and environmental health field

Selected problems in Sabahattin Ali's novel "Madonna in a fur coat"

Sabahattin Ali jest jednym z czołowych twórców literatury tureckiej. Jest autorem kilku powieści, opowiadań a także poezji. Żył w czasach reform i przemian ustrojowych w Turcji w pierwszej połowie XX wieku. W swoich utworach często poruszał tematy kontrowersyjne a także dokonywał krytyki rządu. Tematem niniejszej pracy dyplomowej są wybrane problemy poruszane w powieści Sabahattina Alego pod tytułem „Madonna w futrze”. Akcja powieści osadzona jest w międzywojennych Niemczech. Opowiada o miłości Turka Raifa Efendiego do Niemki Marii Puder. Oprócz tematyki miłosnej, przedstawiona została także problematyka samotności, z którą zmagają się główni bohaterowie. Ukazane zostały również trudne relacje rodzinne, które miały wpływ na dalsze życie głównego bohatera. W pracy przedstawiony został także życiorys autora, jego twórczość oraz tajemnicza i przedwczesna śmierć.Sabahattin Ali is one of the leading authors of Turkish literature. He is the author of several novels, short stories and poetry. Sabahattin Ali lived in times of reforms and systemic transformations in Turkey in the first half of the 20th century. In his works, he often touched upon controversial topics and criticized the government. The subject of this diploma thesis are selected problems raised in Sabahattin Ali's novel "Madonna in a fur coat". The action of the novel is set in interwar Germany. It tells about the love of Turk Raif Efendi for the German woman Maria Puder. In addition to the love theme, the problem of loneliness, which the main characters struggle with, is also presented. Difficult family relationships that had an impact on the main character's further life were also shown. The author's biography, his work as well as mysterious and premature death are also presented in this thesis

The inception, activity and eradication of so-called the Pruszków Mafia in the light of the activity of the Polish law enforcement authorities.

Po zmianach ustrojowych jakie nastąpiły po 1989 roku społeczeństwo polskie zmagało się z wieloma problemami natury społecznej, gospodarczej i ekonomicznej. Chaos jaki zapanował w nowopowstałej III Rzeczpospolitej Polskiej sprzyjał rozwojowi zorganizowanych grup przestępczych, między innymi tzw. mafii pruszkowskiej. Tematem niniejszej pracy jest analiza problematyki zorganizowanych grup przestępczych na przykładzie tzw. mafii pruszkowskiej, skupiając się na utworzeniu, działalności i rozbiciu grupy. W pracy ukazana została kwestia działalności polskich organów ścigania w świetle formowania oraz aktywnego działania opisywanej grupy przestępczej. Poruszona została także kwestia instytucji świadka koronnego, której wprowadzenie do polskiego systemu prawnego miało związek ze wzrostem przestępczości zorganizowanej w kraju. W pracy przedstawiona została także zasadność przyznania statusu świadka Jarosławowi Sokołowskiemu ps. "Masa", byłemu członkowi gangu pruszkowskiego, którego współpraca z polskimi organami ścigania doprowadziła do rozbicia tzw. mafii pruszkowskiej.After the changes in the state system that took place after 1989, Polish society struggled with many problems of a social and economic nature. The chaos that prevailed in the newly established Third Republic of Poland was conducive to the development of organized crime groups, including the so-called the Pruszków Mafia. The subject of this thesis is an analysis of the problems of organized crime groups on the example of the so-called the Pruszków Mafia, focusing on the inception, activities, and the ending of the group with its eradication. In the thesis there was shown the issue of the activity of Polish law enforcement authorities in the light of the formation and active operation of the described criminal group. The issue of the institution of the crown witness was also raised, the inclusion of which into the Polish legal system was related to the growth of organized crime in the country. The legitimacy of granting the status of a crown witness to Jarosław Sokołowski "Masa", a former member of the Pruszków gang, whose cooperation with the Polish law enforcement authorities led to the breakup of the so-called the Pruszków Mafia

Prenatal exposure to environmental contaminants and child behaviour in the HELIX european cohorts

The focus of this study was to assess the associations between prenatal exposure to a wide range of environmental chemicals, including some that have been identified as neurodevelopmental disruptors, and child externalising and internalising behaviour between three and seven years of age in the European HELIX cohorts.El objetivo de este estudio fue evaluar las asociaciones entre la exposición prenatal a una amplia gama de productos químicos ambientales, incluidos algunos que han sido identificados como disruptores del desarrollo neurológico, y el comportamiento de externalización e internalización infantil entre los tres y siete años en las cohorts HELIX europeas.L'objectiu d'aquest estudi va ser avaluar les associacions entre l'exposició prenatal a una àmplia gamma de productes químics ambientals, incloent-hi alguns que s'han identificat com a disruptors del desenvolupament neurològic i el comportament d'externalització i internalització dels menors entre els tres i els set anys d'edat en les cohorts HELIX europee

The influence of cyclin D2 gene knockout on the hippocampus-dependent behavior in mice

<p>Better understanding of mechanisms underlying hippocampal functioning is crucial for prevention and treatment of brain dysfunctions based on altered hippocampus structure, integrity or connectivity with other brain areas. Adult hippocampal neurogenesis is proposed to be one of such mechanisms and recently it has become a subject of intense research. Adult neurogenesis means generation, differentiation, maturation and integration of new neurons into existing neuronal networks of adult animals, including humans. The exact function of this process remains elusive, although it has been suggested to play a role in learning and memory as well as in etiology and treatment of anxiety and mood disorders.<br>In the present study, we employed cyclin D2 gene knockout mice (cD2 KO), showing almost complete reduction of adult brain neurogenesis in the dentate gyrus. This deficit was already shown not to alter hippocampal-dependent learning ability and memory formation. Since cD2 KO mice transferred to a novel genetic background (c57BL/6) were used, the model had to be first characterized. Therefore, the first part of the study describes behavioral phenotyping and validation of cyclin D2 KO model necessary to identify possible alterations which could interfere with further hippocampus- and adult neurogenesis-dependent tasks. Although cD2 KO mice did not show impairment in accelerating rotarod test, they were hyperactive in the open field and automated motility chamber and showed increased exploration tendency in IntelliCage. Mutant mice showed also alterations in rodent-specific tasks: they were building none or poorer nests and were digging less robustly than control mice. All features described so far were previously observed in animals with hippocampal lesions. Nevertheless, cyclin D2 gene knockout neither altered the hippocampal-dependent learning ability nor the memory formation.<br>In the second part of the study emotional phenotype of cD2 KO mice, i.e. their initial level of anxiety and depressive-like behavior were characterized. Naïve cD2 KOs showed reduced anxiety and elevated levels of exploratory behavior when compared to their control wild-type littermates (WT). They spent more time in open parts of the elevated zero maze, paid more visits and traveled longer distance in the compartment with novel juvenile mouse in the sociability test, and buried less marbles and showed decreased latency to feed in the novelty suppressed feeding test (NSF). On the other hand, none of the tests revealed increased level of initial depressive-like behavior in cD2 KO animals. Moreover, naïve cD2 KO showed even shorter immobility time in forced swimming (FST) and tail suspension (TST) tests when compared to control animals. Interestingly, the difference observed for mutant mice was elevated, when they were subjected to acute stressor prior to the behavioral testing.<br>In the last part of the study cD2 KO mice were subjected to unpredictable chronic mild stress to induce depressive-like behavior, and then chronically administered with fluoxetine - a selective serotonin reuptake inhibitor showing antidepressive effects. In WT mice chronic stress caused decrease in the adult brain neurogenesis reversible by fluoxetine treatment. In cD2 KO mice, neither stress nor antidepressant administration affected the neurogenesis. Except for this difference, mutant animals displayed similar response to chronic stress as WT mice, i.e, showed decreased body weight gain and increased latency to feed in NSF, performed less grooming, and stayed immobile for longer time in FST and TST. The effect observed in the two latter tests was reversed by chronic fluoxetine treatment, irrespectively from animals’ genotype.<br>The results presented herein suggest that cyclin D2 gene knockout, irrespectively of the genetic background, caused impairment of adult hippocampal neurogenesis without influencing learning abilities. Moreover, morphological abnormalities of hippocampal formation or impairment of the adult brain neurogenesis (or both) altered activity and some hippocampal-<br>9<br>dependent behaviors as well as decreased levels of anxiety in mutant mice. Additionally, although it seems that missing adult brain neurogenesis in cD2 KO mice did not contribute to depression onset, it is possible that new neurons may play role in regulation of behavioral response following acute stress. Finally, present study does not support the hypothesis that new neurons are necessary for antidepressant action of fluoxetine.</p> <p> </p

Pregnancy exposure to phthalates and synthetic phenols and placental DNA methylation in the SEPAGES cohort

The aim of the present work will be to assess the association between pregnancy phthalates and phenols other than triclosan and DNA methylation of placental genes. We will follow two complementary approaches: 1) Candidate approach: to explore whether associations observed in the EDEN cohort between pregnancy phthalates and phenols other than triclosan and DNA methylation of placental genes can be replicated in the SEPAGES cohort with improved exposure assessment; 2) Exploratory epigenome-wide association study (EWAS) and differentially methylated regions (DMRs) analysis to identify potential new genomic locations affected by phthalates and phenols exposure

Transient alteration of the vestibular calyceal junction and synapse in response to chronic ototoxic insult in rats

Ototoxicity is known to cause permanent loss of vestibule function through degeneration of sensory hair cells (HCs). However, functional recovery has been reported during washout after chronic ototoxicity, although the mechanisms underlying this reversible dysfunction are unknown. Here, we study this question in rats chronically exposed to the ototoxic compound 3,3′-iminodipropionitrile (IDPN). Pronounced alterations in vestibular function appeared before significant loss of HCs or stereociliary coalescence became evident by ultrastructural analyses. This early dysfunction was fully reversible if the exposure was terminated promptly. In cristae and utricles, the distinct junctions formed between type I HCs (HCI) and calyx endings were completely dismantled at these early stages of reversible dysfunction, and completely rebuilt during washout. Immunohistochemical observations revealed loss and recovery of the junction proteins CASPR1 and tenascin-C and RT-PCR indicated that their loss was not due to decreased gene expression. KCNQ4 was mislocalized during intoxication and recovered control-like localization after washout. At early stages of the intoxication, the calyces could be classified as showing intact or lost junctions, indicating that calyceal junction dismantlement is triggered on a calyx-by-calyx basis. Chronic toxicity also altered the presence of ribeye, PSD-95 and GluA2 puncta in the calyces. These synaptic alterations varied between the two types of calyx endings (formed by calyx-only or dimorphic afferents) and some persisted at the end of the washout period. The present data reveal new forms of plasticity of the calyx endings in adult mammals, including a robust capacity for rebuilding the calyceal junction. These findings contribute to a better understanding of the phenomena involved in progressive vestibular dysfunction and its potential recovery during and after ototoxic exposure

Adult neurogenesis and depression

<p>Adult neurogenesis (ANGE) is a process of generating new neurons in the brains of adult mammals, including humans. It takes place, e.g., in the subgranular zone of the dentate gyrus in the hippocampal formation. The function of the new neurons is not fully explained; however, they are considered to play an important role in learning and memory processes. There is also evidence that ANGE can mediate the response of hippocampal<br>formation to stress, preventing the onset of depression. Besides, newly-generated neurons seem to play an important role in therapeutic action of antidepressants (AD). Results from animal models and human studies, confirming and questioning the hypothesis of a key connection between depression and ANGE, are presented.<br>It is not clear whether the suppression of the production of new neurons influences the pathogenesis of depression and it seems that some other factors are more important. However, it is likely that the level of ANGE is important in treatment of at least some forms of depression. Several experiments, using animal models, have shown that AD, mood stabilizers or other depression therapies increase the level of ANGE. Also, blocking the generation of new neurons abolishes their therapeutic effect. Nevertheless, some recent publications question the significance of ANGE in AD action. The discrepancies described herein,<br>concerning the significance of ANGE in aetiology and treatment of depression, may reflect the complexity of the depressive disorder. This complexity is manifested by the different response (or no response) to various AD and other depression therapies in human patients.</p> <p> </p

Quantitative analysis of fluorescent image : from descriptive to computational microscopy

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