Raphe-mediated signals control the hippocampal response to SRI antidepressants via miR-16

Serotonin reuptake inhibitor (SRI) antidepressants such as fluoxetine (Prozac), promote hippocampal neurogenesis. They also increase the levels of the bcl-2 protein, whose overexpression in transgenic mice enhances adult hippocampal neurogenesis. However, the mechanisms underlying SRI-mediated neurogenesis are unclear. Recently, we identified the microRNA miR-16 as an important effector of SRI antidepressant action in serotonergic raphe and noradrenergic locus coeruleus (LC). We show here that miR-16 mediates adult neurogenesis in the mouse hippocampus. Fluoxetine, acting on serotonergic raphe neurons, decreases the amount of miR-16 in the hippocampus, which in turn increases the levels of the serotonin transporter (SERT), the target of SRI, and that of bcl-2 and the number of cells positive for Doublecortin, a marker of neuronal maturation. Neutralization of miR-16 in the hippocampus further exerts an antidepressant-like effect in behavioral tests. The fluoxetine-induced hippocampal response is relayed, in part, by the neurotrophic factor S100β, secreted by raphe and acting via the LC. Fluoxetine-exposed serotonergic neurons also secrete brain-derived neurotrophic factor, Wnt2 and 15-Deoxy-delta12,14-prostaglandin J2. These molecules are unable to mimic on their own the action of fluoxetine and we show that they act synergistically to regulate miR-16 at the hippocampus. Of note, these signaling molecules are increased in the cerebrospinal fluid of depressed patients upon fluoxetine treatment. Thus, our results demonstrate that miR-16 mediates the action of fluoxetine by acting as a micromanager of hippocampal neurogenesis. They further clarify the signals and the pathways involved in the hippocampal response to fluoxetine, which may help refine therapeutic strategies to alleviate depressive disorders

MicroRNA Genes Derived from Repetitive Elements and Expanded by Segmental Duplication Events in Mammalian Genomes

MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene expression by targeting mRNAs for translation repression or mRNA degradation. Many miRNAs are being discovered and studied, but in most cases their origin, evolution and function remain unclear. Here, we characterized miRNAs derived from repetitive elements and miRNA families expanded by segmental duplication events in the human, rhesus and mouse genomes. We applied a comparative genomics approach combined with identifying miRNA paralogs in segmental duplication pair data in a genome-wide study to identify new homologs of human miRNAs in the rhesus and mouse genomes. Interestingly, using segmental duplication pair data, we provided credible computational evidence that two miRNA genes are located in the pseudoautosomal region of the human Y chromosome. We characterized all the miRNAs whether they were derived from repetitive elements or not and identified significant differences between the repeat-related miRNAs (RrmiRs) and non-repeat-derived miRNAs in (1) their location in protein-coding and intergenic regions in genomes, (2) the minimum free energy of their hairpin structures, and (3) their conservation in vertebrate genomes. We found some lineage-specific RrmiR families and three lineage-specific expansion families, and provided evidence indicating that some RrmiR families formed and expanded during evolutionary segmental duplication events. We also provided computational and experimental evidence for the functions of the conservative RrmiR families in the three species. Together, our results indicate that repetitive elements contribute to the origin of miRNAs, and large segmental duplication events could prompt the expansion of some miRNA families, including RrmiR families. Our study is a valuable contribution to the knowledge of evolution and function of non-coding region in genome

AMPK in Pathogens

During host–pathogen interactions, a complex web of events is crucial for the outcome of infection. Pathogen recognition triggers powerful cellular signaling events that is translated into the induction and maintenance of innate and adaptive host immunity against infection. In opposition, pathogens employ active mechanisms to manipulate host cell regulatory pathways toward their proliferation and survival. Among these, subversion of host cell energy metabolism by pathogens is currently recognized to play an important role in microbial growth and persistence. Extensive studies have documented the role of AMP-activated protein kinase (AMPK) signaling, a central cellular hub involved in the regulation of energy homeostasis, in host–pathogen interactions. Here, we highlight the most recent advances detailing how pathogens hijack cellular metabolism by suppressing or increasing the activity of the host energy sensor AMPK. We also address the role of lower eukaryote AMPK orthologues in the adaptive process to the host microenvironment and their contribution for pathogen survival, differentiation, and growth. Finally, we review the effects of pharmacological or genetic AMPK modulation on pathogen growth and persistence.CIHR -Canadian Institutes of Health Researc

Muistisairauksia potevien ihmisten fyysinen kuntoutus

Tämän toiminnallisen opinnäytetyön tarkoituksena oli järjestää liikuntatuokio muistisairauksia poteville ihmisille. Tavoitteena oli antaa asukkaille ja henkilökunnalle ohjeita oikeanlaiseen kuntouttavaan liikuntaan muistisairauksia potevia ihmisiä ajatellen. Tämän lisäksi kokosimme henkilökunnalle kuvallisen kansion sekä teoriatietoa, jotta he voisivat myöhemmin hyödyntää suunnittelemiamme liikuntaharjoitteita. Opinnäytetyön tilaajana oli yksityinen hoitokoti Villa Fredrika. Tapahtuma toteutettiin 16.5.2013 yksityisessä hoitokodissa Villa Fredrikassa Hyvinkäällä. Osallistujia oli yhteensä 21, iältään 75-91-vuotiaita. Kolme osallistujista oli pyörätuolissa. Ryhmä jaettiin viiteen osaan ohjaamisen helpottamiseksi. Kullekin ryhmälle oli varattu aikaa noin 30 minuuttia. Kokonaisuudessaan tilaisuus kesti noin 5 tuntia. Liikuntatuokioon olimme valinneet kolme pääteemaa, lihaskunto-, tasapaino- ja kestävyysharjoitukset. Lisäksi lopussa pidimme rentoutushetken. Tilaisuuden onnistumista arvioimme kyselylomakkeella, jotka täytettiin yhdessä osallistujien kanssa heti kunkin ryhmän jälkeen. Myös osa henkilökunnasta täytti kyselyn. Arviointilomakkeet asukkaille ja henkilökunnalle olivat hieman erilaiset. Kyselylomake oli kvantitatiivinen eli määrällinen. Tuloksia tarkastellen toimintapäivä oli onnistunut hyvin sekä ohjauksen että liikunnan osalta.People with memory disorders and their physical rehabilitation The purpose of the thesis was to organize an exercise event to people with memory disorders. The objective was to give directions for right rehabilitative exercise to the residents and staff. In addition, we made a graphical folder of exercise for the staff to be used later. The study was commissioned by the private nursing home Villa Fredrika. The event took place on 16th of May 2013 in the private nursing home Villa Fredrika in Hyvinkää. Overall 21 residents took part in the event. They were aged 75-91. Three of them were in wheel chairs. The group was divided in five to make tutoring easier. Every group took time about 30 minutes. In the exercise event we had chosen three main themes, muscle, balance and durability exercises. At the end we had a relaxation moment. The success of the event was assessed with by a questionnaire which was filled together with the participants right after each group. Also part of the staff filled it. The questionnaires of the staff and the residents were different. The study was quantitative. The result showed, that the day was a success as well as guidance and physical activity

Melatonin ameliorates hippocampal nitric oxide production and large conductance calcium-activated potassium channel activity in chronic intermittent hypoxia

Melatonin protects against hippocampal injury induced by intermittent hypoxia (IH). IH-induced oxidative stress is associated with decreases in constitutive production of nitric oxide (NO) and in the activity of large conductance calcium-activated potassium (BK) channels in hippocampal neurons. We tested the hypothesis that administration of melatonin alleviates the NO deficit and impaired BK channel activity in the hippocampus of IH rats. Sprague-Dawley rats were injected with melatonin (10 mg/kg, i.p.) or vehicle before daily IH exposure for 8 hr for 7 days. The NO and intracellular calcium ([Ca2+]i) levels in the CA1 region of hippocampal slices were measured by electrochemical microsenor and spectrofluorometry, respectively. The activity of BK channels was recorded by patch-clamping electrophysiology in dissociated CA1 neurons. Malondialdehyde levels were increased in the hippocampus of hypoxic rats and were lowered by the melatonin treatment. Levels of NO under resting and hypoxic conditions, and the protein expression of neuronal NO synthase (nNOS) were significantly reduced in the CA1 neurons of hypoxic animals compared with the normoxic controls. These deficits were mitigated in the melatonin-treated hypoxic rats with an improved [Ca 2+]i response to acute hypoxia. The open probability of BK channels was decreased in the hypoxic rats and was partially restored in the melatonin-treated animals, without alterations in the expression of channel subunits and unitary conductance. Acute treatment of melatonin had no significant effects on the BK channel activity or on the [Ca2+] i response to hypoxia. Collectively, these results suggest that melatonin ameliorates the constitutive NO production and BK channel activity via an antioxidant mechanism against an IH-induced down-regulation of nNOS expression in hippocampal neurons. © 2007 The Authors.link_to_subscribed_fulltex