Mice with chronic GSH deficit display phenotypical anomalies that resemble key aspects of schizophrenia

ABSTRACTSchizophrenia is a major psychiatric disorder occurring with a prevalence of 1% in the worldwide population. It develops progressively with psychosis onset in late adolescence or earlyadulthood. The disorder can take many different facets and has a highly diffuse anddistributed neuropathology including deficits in major neurotransmitter systems,myelination, stress regulation, and metabolism. The delayed onset and the heterogeneouspathology suggest that schizophrenia is a developmental disease that arises from interplayof genetic and environmental factors during sensitive periods. Redox dysregulation due to animbalance between pro-oxidants and antioxidant defence mechanisms is among the riskfactors for schizophrenia. Glutathione (GSH) is the major cellular redox regulator andantioxidant. Levels of GSH are decreased in cerebrospinal fluid, prefrontal cortex and postmortemstriatum of schizophrenia patients. Moreover, polymorphisms of the key GSHsynthesizingenzyme, glutamate-cysteine ligase, modifier (GCLM) subunit, are associatedwith the disease, suggesting that GSH deficit is of genetic origin. Here we used miceknockout (KO) for the GCLM gene, which display chronic GSH deficit (~70 to 80% decrease)to investigate the direct link between redox dysregulation and schizophrenia. Accordingly,we evaluated whether GCLM KO compared to normal wildtype mice display behavioralchanges that relate to schizophrenia symptoms and whether their brains showmorphological, functional or metabolic alterations that resemble those in patients.Moreover, we exposed pubertal GCLM mice to repeated mild stress and measured theirhormonal and behavioral stress reactivity. Our data show that chronic GSH deficit isassociated with altered emotion- and stress-related behaviors, deficient prepulse inhibition,pronounced amphetamine-induced hyperlocomotion but normal spatial learning andworking memory. These changes represent important schizophrenia endophenotypes.Moreover, this particular pattern of change indicates impairment of the ventralhippocampus (VH) and related circuitry as opposed to the dorsal hippocampus (DH), which isimplicated in spatial information processing. This is consistent with a selective deficit ofparvalbumin positive interneurons and gamma oscillation in the VH but not DH. Increasedlevels of circulating stress hormones in KO mice following pubertal stress corroborate VHdysfunction as it is involved in negative feedback control of the stress response. VHstructural and functional deficits are frequently found in the schizophrenic brain. Metabolicevaluation of the developing GCLM KO anterior cortex using in vivo magnetic resonancespectroscopy revealed elevated glutamine (Gln), glutamate (Glu), Gln/Glu and N-acetylaspartate(NAA) during the pre-pubertal period. Similar changes are reported in earlyschizophrenia. Overall, we observe phenotypic anomalies in GSH deficient GCLM KO micethat correspond to major schizophrenia endophenotypes. This supports an important rolefor redox dysregulation in schizophrenia and validates the GCLM KO mouse as model for thedisease. Moreover, our results indicate that puberty may be a sensitive period for redoxsensitivechanges highliting the importance of early intervention. Gln, Gln/Glu, Glu and NAAmay qualify as early metabolic biomarkers to identify young at-risk individuals. Since chronictreatment with NAC normalized most metabolic changes in GCLM KO mice, NAC may be oneadjunct treatment of choice for early intervention in patients.RESUMELa schizophrénie est une maladie psychiatrique majeure avec une prévalence de 1% dans lapopulation. Son développement est progressif, les premières psychoses apparaissant àl'adolescence ou au début de l'âge adulte. La maladie a plusieurs présentations et uneneuropathologie étendue, qui inclut des déficits neurochimiques, métaboliques, de lamyélination et de la régulation du stress. L'émergence tardive et l'hétérogénéité de lapathologie suggèrent que la schizophrénie est une maladie développementale, favorisée pardes facteurs génétiques et environnementaux durant des périodes sensibles. La dérégulationrédox, due à un déséquilibre entre facteurs pro-oxidantes et défenses anti-oxidantes,constitue un facteur de risque. Le glutathion (GSH) est le principal régulateur rédox et antioxidantdes cellules, ses taux sont diminués dans le liquide céphalorachidien, le cortexpréfrontal et le striatum de patients. De plus, des variations du gène codant la sous-unitémodulatrice (GCLM) de la glutamate-cystéine ligase, enzyme de synthèse du GSH, sontassociés la maladie, suggérant que le déficit observé chez les patients est d'originegénétique. Nous avons donc utilisé des souris ayant une délétion du gène GCLM (KO), quiont un déficit chronique en GSH (70-80%), afin d'étudier le lien entre une dérégulation rédoxet la schizophrénie. Nous avons évalué si ces souris présentent des altérationscomportementales analogues aux symptômes de la maladie, et des modificationsstructurelles, fonctionnelles et métaboliques au niveau du cerveau, ressemblant à celles despatients. De plus, nous avons soumis les souris à des stresses modérés durant la puberté,puis mesuré les réponses hormonales et comportementales. Les animaux présentent undéficit pré-attentionnel du traitement des informations moto-sensorielles, un déficit pourcertains apprentissages, une réponse accrue à l'amphétamine, mais leurs mémoires spatialeet de travail sont préservées. Ces atteintes comportementales sont analogues à certainsendophénotypes de la schizophrénie. De plus, ces changements comportementaux sontlargement expliqués par une perturbation morphologique et fonctionnelle de l'hippocampeventral (HV). Ainsi, nous avons observé un déficit sélectif des interneurones immunoréactifsà la parvalbumine et une désynchronisation neuronale dans l'HV. L'hippocampe dorsal,impliqué dans l'orientation spatiale, demeure en revanche intact. L'augmentationd'hormones de stress dans le sang des souris KO suite à un stress prépubertal soutien aussil'hypothèse d'une dysfonction de l'HV, connu pour moduler ce type de réponse. Des déficitsstructurels et fonctionnels dans l'hippocampe antérieur (ventral) ont d'ailleurs été rapportéschez des patients schizophrènes. Par de résonance magnétique, nous avons également suivile profil métabolique du le cortex antérieur au cours du développement postnatal des sourisKO. Ces mesures ont révélé des taux élevés de glutamine (Gln), glutamate (Glu), du ratioGln/Glu, et de N-acétyl-aspartate (NAA) durant la période prépubertale. Des altérationssimilaires sont décrites chez les patients durant la phase précoce. Nous avons donc révélédes anomalies phénotypiques chez les souris GCLM KO qui reflètent certainsendophénotypes de la schizophrénie. Nos résultats appuient donc le rôle d'une dérégulationrédox dans l'émergence de la maladie et le potentiel des souris KO comme modèle. De plus,cette étude met en évidence la puberté comme période particulièrement sensible à unedérégulation rédox, renforçant l'importance d'une intervention thérapeutique précoce. Dansce cadre, Gln, Gln/Glu, Glu and NAA seraient des biomarqueurs clés pour identifier de jeunesindividus à risque. De part son efficacité dans notre modèle, NAC pourrait être unesubstance de choix dans le traitement précoce des patients.

Cellular mechanisms underlying the regulation of dendritic development by hepatocyte growth factor.

Acquisition of a mature dendritic morphology is critical for neural information processing. In particular, hepatocyte growth factor (HGF) controls dendritic arborization during brain development. However, the cellular mechanisms underlying the effects of HGF on dendritic growth remain elusive. Here, we show that HGF increases dendritic length and branching of rat cortical neurons through activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Activation of MAPK by HGF leads to the rapid and transient phosphorylation of cAMP response element-binding protein (CREB), a key step necessary for the control of dendritic development by HGF. In addition to CREB phosphorylation, regulation of dendritic growth by HGF requires the interaction between CREB and CREB-regulated transcription coactivator 1 (CRTC1), as expression of a mutated form of CREB unable to bind CRTC1 completely abolished the effects of HGF on dendritic morphology. Treatment of cortical neurons with HGF in combination with brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family that regulates dendritic development via similar mechanisms, showed additive effects on MAPK activation, CREB phosphorylation and dendritic growth. Collectively, these results support the conclusion that regulation of cortical dendritic morphology by HGF is mediated by activation of the MAPK pathway, phosphorylation of CREB and interaction of CREB with CRTC1.

Multi-slice three-dimensional myocardial strain tensor quantification using zHARP.

In this article we propose a novel method for calculating cardiac 3-D strain. The method requires the acquisition of myocardial short-axis (SA) slices only and produces the 3-D strain tensor at every point within every pair of slices. Three-dimensional displacement is calculated from SA slices using zHARP which is then used for calculating the local displacement gradient and thus the local strain tensor. There are three main advantages of this method. First, the 3-D strain tensor is calculated for every pixel without interpolation; this is unprecedented in cardiac MR imaging. Second, this method is fast, in part because there is no need to acquire long-axis (LA) slices. Third, the method is accurate because the 3-D displacement components are acquired simultaneously and therefore reduces motion artifacts without the need for registration. This article presents the theory of computing 3-D strain from two slices using zHARP, the imaging protocol, and both phantom and in-vivo validation.

Using Pareto optimality to explore the topology and dynamics of the human connectome.

Graph theory has provided a key mathematical framework to analyse the architecture of human brain networks. This architecture embodies an inherently complex relationship between connection topology, the spatial arrangement of network elements, and the resulting network cost and functional performance. An exploration of these interacting factors and driving forces may reveal salient network features that are critically important for shaping and constraining the brain's topological organization and its evolvability. Several studies have pointed to an economic balance between network cost and network efficiency with networks organized in an 'economical' small-world favouring high communication efficiency at a low wiring cost. In this study, we define and explore a network morphospace in order to characterize different aspects of communication efficiency in human brain networks. Using a multi-objective evolutionary approach that approximates a Pareto-optimal set within the morphospace, we investigate the capacity of anatomical brain networks to evolve towards topologies that exhibit optimal information processing features while preserving network cost. This approach allows us to investigate network topologies that emerge under specific selection pressures, thus providing some insight into the selectional forces that may have shaped the network architecture of existing human brains.

Spektrikuvien tiivistäminen itseorganisoituvan kartan avulla.

Vuosi vuodelta kasvava tietokoneiden prosessointikyky on mahdollistanut harmaataso- ja RGB-värikuvia tarkempien spektrikuvien käsittelyn järjellisessä ajassa ilman suuria kustannuksia. Ongelmana on kuitenkin, ettei talletus- ja tiedonsiirtomedia ole kehittynyt prosessointikyvyn vauhdissa. Ratkaisu tähän ongelmaan on spektrikuvien tiivistäminen talletuksen ja tiedonsiirron ajaksi. Tässä työssä esitellään menetelmä, jossa spektrikuva tiivistetään kahdessa vaiheessa: ensin ryhmittelemällä itseorganisoituvan kartan (SOM) avulla ja toisessa vaiheessa jatketaan tiivistämistä perinteisin menetelmin. Saadut tiivistyssuhteet ovat merkittäviä vääristymän pysyessä siedettävänä. Työ on tehty Lappeenrannan teknillisen korkeakoulun Tietotekniikan osaston Tietojenkäsittelytekniikan tutkimuslaboratoriossa osana laajempaa kuvantiivistyksen tutkimushanketta.

Hämeenlinnan Energian kaukolämpö- ja maakaasuverkoston suunnittelu- ja kunnossapitoympäristön kehittäminen tietojärjestelmien avulla

Diplomityössä selvitetään Hämeenlinnan Energian kaukolämpö- ja maakaasuverkoston suunnitteluun ja kunnossapitoon liittyvien tietojärjestelmien kehitysmahdollisuuksia. Käydään läpi olemassa olevat järjestelmät ja todetaan olevan tarpeen uudistaa verkostolaskenta- ja kunnossapito-ohjelmia. Mahdolliseksi uudeksi verkostolaskentaohjelmaksi rajataan Komartekin Flowra 32 tai Process Visionin lämpö Nexus. Kunnossapidon osalta Komartekin Lämpökunto tai Kunnondatan Visual Maint. Tehtyjen ohjelmavertailujen jälkeen työssä esitetään Hämeenlinnan Energian uudeksi verkostolaskentaohjelmaksi lämpö Nexus ja kunnossapito-ohjelmaksi Visual Maint. Ohjelmahankinnoille esitetään käyttöönottosuunnitelmat. Olemassa olevien tietojärjestelmien osalta esitetään vaihtoehtoja, joilla voidaan lisätä ohjelmista saatavaa hyötyä.

Education and Training in Forensic Intelligence: a New Challenge

From recent calls for positioning forensic scientists within the criminal justice system, but also policing and intelligence missions, this paper emphasizes the need for the development of educational and training programs in the area of forensic intelligence, It is argued that an imbalance exists between perceived and actual understanding of forensic intelligence by police and forensic science managers, and that this imbalance can only be overcome through education. The challenge for forensic intelligence education and training is therefore to devise programs that increase forensic intelligence awareness, firstly for managers to help prevent poor decisions on how to develop information processing. Two recent European courses are presented as examples of education offerings, along with lessons learned and suggested paths forward. It is concluded that the new focus on forensic intelligence could restore a pro-active approach to forensic science, better quantify its efficiency and let it get more involved in investigative and managerial decisions. A new educational challenge is opened to forensic science university programs around the world: to refocus criminal trace analysis on a more holistic security problem solving approach.

Developing and Applying Generative Market Intelligence within Multinational Companies

Tutkielman tarkoitus on kehittää monikansallisille yrityksille tuottavan markkinaälyn malli, jonka avulla yritykset pystyvät käsittelemään muuttuvasta ja globalisoituvasta markkinaympäristöstä aiheutuvaa epävarmuutta. Malli koostuu pääosin kolmesta käsitteestä: markkinainformaation prosessoinnista, markkinasuuntautuneisuudesta ja organisationaalisesta oppimisesta. Tutkimuksessa osoitetaan, kuinka näiden samanaikainen soveltaminen johtaa synergiaetuihin. Lähdeaineistona käytettiin alan kirjallisuutta. Lisäksi haastateltiin neljää johtajaa monikansallisista yrityksistä. Käytännössä markkinaälyn soveltamisen haasteet liittyvät lähinnä markkinainformaation prosessoinnin asenteellisiin ja psykologisiin aspekteihin. Ihmisten tulisi ymmärtää, että koko yritys hyötyy heidän halukkuudestaan tiedon tuottamiseen ja jakamiseen. Lisäksi tietoa itsessään voimavarana tulisi kunnioittaa

Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease.

The key information processing units within gene regulatory networks are enhancers. Enhancer activity is associated with the production of tissue-specific noncoding RNAs, yet the existence of such transcripts during cardiac development has not been established. Using an integrated genomic approach, we demonstrate that fetal cardiac enhancers generate long noncoding RNAs (lncRNAs) during cardiac differentiation and morphogenesis. Enhancer expression correlates with the emergence of active enhancer chromatin states, the initiation of RNA polymerase II at enhancer loci and expression of target genes. Orthologous human sequences are also transcribed in fetal human hearts and cardiac progenitor cells. Through a systematic bioinformatic analysis, we identified and characterized, for the first time, a catalog of lncRNAs that are expressed during embryonic stem cell differentiation into cardiomyocytes and associated with active cardiac enhancer sequences. RNA-sequencing demonstrates that many of these transcripts are polyadenylated, multi-exonic long noncoding RNAs. Moreover, knockdown of two enhancer-associated lncRNAs resulted in the specific downregulation of their predicted target genes. Interestingly, the reactivation of the fetal gene program, a hallmark of the stress response in the adult heart, is accompanied by increased expression of fetal cardiac enhancer transcripts. Altogether, these findings demonstrate that the activity of cardiac enhancers and expression of their target genes are associated with the production of enhancer-derived lncRNAs.

Web Software Engineering - value added approach

Taking the maximum advantage of technological innovations and the investment in them is of key importance for businesses. The IT industry offers a wide range of innovative high-technology solutions to manage information processing and distribution. However for end-user businesses to make informed decisions in this area is challenging. The aim of this research is to identify the key differences in principal solutions, and what the selection criteria should be for those involved. Existing methodologies for software development are classified, and some key criteria are described to help IT system developers and users determine what are the most important factors in system selection, development and deployment. Statistical data is researched and analysed, a theoretical basis is developed and reviewed, key issues from case studies are identified and generalized to be presented along with the conclusions in the current study. The results give a good basis for corporate consideration and provide overall support to the key decisions in developing web-based software. The conclusion is that new web developments should be considered the stakeholders as an evolution of existing business systems, but they should then pay particular attention to the new advantages that web-based software offers in terms of standardised interfaces and procedures, universal deployment opportunities, and a range of other benefits the study highlights.

Financial Modeling to Support Organizational Control

Tutkimus tarkastelee taloudellisia mallintamismahdollisuuksia metsäteollisuuden liiketoimintayksikössä. Tavoitteena on suunnitella ja luoda taloudellinen malli liiketoimintayksikölle, jonka avulla sen tuloksen analysoiminen ja ennustaminen on mahdollista. Tutkimusta tarkastellaan konstruktiivisen tutkimusmenetelmän avulla. Teoreettinen viitekehys tarkastelee olemassa olevan informaation muotoilemista keskittyen tiedon jalostamisen tarpeisiin, päätöksenteon asettamiin vaatimuksiin sekä mallintamiseen. Toiseksi, teoria esittää informaatiolle asetettavia vaatimuksia organisatorisen ohjauksen näkökulmasta.Empiirinen tieto kerätään osallistuvan havainnoinnin avulla hyödyntäen epävirallisia keskusteluja, tietojärjestelmiä ja laskentatoimen dokumentteja. Tulokset osoittavat, että liikevoiton ennustaminen mallin avulla on vaikeaa, koska taustalla vaikuttavien muuttujien määrä on suuri. Tästä johtuen malli täytyykin rakentaa niin, että se tarkastelee liikevoittoa niin yksityiskohtaisella tasolla kuin mahdollista. Testauksessa mallin tarkkuus osoittautui sitä paremmaksi, mitä tarkemmalla tasolla ennustaminen tapahtui. Lisäksi testaus osoitti, että malli on käyttökelpoinen liiketoiminnan ohjauksessa lyhyellä aikavälillä. Näin se luo myös pohjan pitkän aikavälin ennustamiselle.

Call for uniform neuropsychological assessment after aneurysmal subarachnoid hemorrhage: Swiss recommendations.

BACKGROUND: In a high proportion of patients with favorable outcome after aneurysmal subarachnoid hemorrhage (aSAH), neuropsychological deficits, depression, anxiety, and fatigue are responsible for the inability to return to their regular premorbid life and pursue their professional careers. These problems often remain unrecognized, as no recommendations concerning a standardized comprehensive assessment have yet found entry into clinical routines. METHODS: To establish a nationwide standard concerning a comprehensive assessment after aSAH, representatives of all neuropsychological and neurosurgical departments of those eight Swiss centers treating acute aSAH have agreed on a common protocol. In addition, a battery of questionnaires and neuropsychological tests was selected, optimally suited to the deficits found most prevalent in aSAH patients that was available in different languages and standardized. RESULTS: We propose a baseline inpatient neuropsychological screening using the Montreal Cognitive Assessment (MoCA) between days 14 and 28 after aSAH. In an outpatient setting at 3 and 12 months after bleeding, we recommend a neuropsychological examination, testing all relevant domains including attention, speed of information processing, executive functions, verbal and visual learning/memory, language, visuo-perceptual abilities, and premorbid intelligence. In addition, a detailed assessment capturing anxiety, depression, fatigue, symptoms of frontal lobe affection, and quality of life should be performed. CONCLUSIONS: This standardized neuropsychological assessment will lead to a more comprehensive assessment of the patient, facilitate the detection and subsequent treatment of previously unrecognized but relevant impairments, and help to determine the incidence, characteristics, modifiable risk factors, and the clinical course of these impairments after aSAH.

The empirical assessment of agency accountability: A regime approach and an application to the German Bundesnetzagentur

Regulation has in many cases been delegated to independent agencies, which has led to the question of how democratic accountability of these agencies is ensured. There are few empirical approaches to agency accountability. We offer such an approach, resting upon three propositions. First, we scrutinize agency accountability both de jure (accountability is ensured by formal rights of accountability 'fora' to receive information and impose consequences) and de facto (the capability of fora to use these rights depends on resources and decision costs that affect the credibility of their sanctioning capacity). Second, accountability must be evaluated separately at political, operational and managerial levels. And third, at each level accountability is enacted by a system of several (partially) interdependent fora, forming together an accountability regime. The proposed framework is applied to the case of the German Bundesnetzagentur's accountability regime, which shows its suitability for empirical purposes. Regulatory agencies are often considered as independent, yet accountable. This article provides a realistic framework for the study of accountability 'regimes' in which they are embedded. It emphasizes the need to identify the various actors (accountability fora) to which agencies are formally accountable (parliamentary committees, auditing bodies, courts, and so on) and to consider possible relationships between them. It argues that formal accountability 'on paper', as defined in official documents, does not fully account for de facto accountability, which depends on the resources possessed by the fora (mainly information-processing and decision-making capacities) and the credibility of their sanctioning capacities. The article applies this framework to the German Bundesnetzagentur.

Social Cognition and Behavior in Relationship Context

Social information processing (SIP; Crick & Dodge, 1994) and social-cognitive learning theories have been often used to understand children’s problem behaviors, such as aggression. According to these theories, children’s thinking guides their subsequent behaviors. Although most of us agree that social behavior and underlying thought processes are context-dependent, personality and social development researchers have usually engaged in searching for stable patterns of dispositions and behaviors, ignoring (or treating as error) the variance across different situations and relationship types. This, however, can result in erroneous conclusions and question the interpretation of previous findings. Four studies were conducted to explore the influence of relationship context on children’s social-cognitive evaluations and behavior. Samples were fourth to sixth graders from Estonia and Finland. Social cognitions were assessed by presenting children with hypothetical vignettes where the previously identified relationship partner’s behavior had a negative consequence for the child (Studies I, II, and IV), followed by questions measuring different social-cognitive processes (e.g., hostile attributions, behavioral strategies, outcome expectations and self-efficacy beliefs for aggression). In addition, in Studies II and IV, children provided information about their behavior within a specific relationship context. In Study III, an affective priming paradigm was employed where participants were presented with a short display of photographs of children’s liked and disliked classmates, and unknown peers. The results of this thesis suggest that children’s thinking and behavior are largely influenced by the affective valence of the relationship. Moreover, cognitions guide behavior within the relationship. The current findings offer a fruitful avenue for studying the heterogeneity of peer interactions.

Maturation and Functional Integration of New Granule Cells into the Adult Hippocampus.

The adult hippocampus generates functional dentate granule cells (GCs) that release glutamate onto target cells in the hilus and cornus ammonis (CA)3 region, and receive glutamatergic and γ-aminobutyric acid (GABA)ergic inputs that tightly control their spiking activity. The slow and sequential development of their excitatory and inhibitory inputs makes them particularly relevant for information processing. Although they are still immature, new neurons are recruited by afferent activity and display increased excitability, enhanced activity-dependent plasticity of their input and output connections, and a high rate of synaptogenesis. Once fully mature, new GCs show all the hallmarks of neurons generated during development. In this review, we focus on how developing neurons remodel the adult dentate gyrus and discuss key aspects that illustrate the potential of neurogenesis as a mechanism for circuit plasticity and function.