Genetic factors of obesity and eating disorders: Copy number variations (CNV) involving SH2B1

Context : It is now clearly shown that genetic factors in association with environment play a key role in obesity and eating disorders. This project studies the clinical symptoms and molecular abnormalities in patients carrying a strong hereditary predisposition to obesity and eating behavior disorders. We have previously published the association between the 16:29.5-30.1 deletion and a very penetrant form of morbid obesity and macrocephaly. We have also demonstrated the association between the reciprocal 16:29.5-30.1 duplication and underweight and small head circumference. These 2 studies demonstrate that gene dosage of one or several genes in this region regulates BMI as well as brain growth. At present, there are no data pointing towards particular candidate genes. We are currently investigating a second non-overlapping recurrent CNV encompassing SH2B1, upstream of the aforementioned rearrangement. SNPs in this gene have been associated with BMI in GWAS studies and mice models confirmed this association. Bokuchova et al have reported an association between deletions encompassing this gene and severe early onset obesity, as well as insulin resistance. We are currently collecting and analyzing data to fully characterize the phenotype and the transcriptional patterns associated with this rearrangement. Aims : 1. Identify carriers of any CNVs in the greater 16p11.2 region (between 16:28MB and 32MB) in the EGG consortium. 2. Perform association studies between SNPs in the greater 16p11.2 region (16:28-32MB) and anthropometric measures with adjusted "locus-wide significance", to identify or prioritize candidate genes potentially driving the association observed in patients with the CNVs (and thus worthy of further validation and sequencing). 3. Explore associations between GSV genome-wide and brain volume. 4. Explore relationship between brain volumes (whole brain and regional for those who underwent brain MRI), head circumference and BMI. 5. Extrapolate this procedure to other regions covered by the Metabochip. Methods : - Examine and collect clinical informations, as well as molecular informations in these patients. - Analysis of MRI data in children and adults with BMI > 2SD. Compare changes to MRI data obtained in patients with monogenic forms of obesity (data from Lausanne study) and to underweight (BMI<-2SD) individuals from EGG. - Test whether opposite extremes of the phenotypic distribution may be highly informative Expected results : This is a highly focused study, pertaining to approximately 1 0/00 of the human genome. Yet it is clear that if successful, the lessons learned from this study could be extrapolated to other segments of the genome and would need validation and replication by additional studies. Altogether they will contribute to further explore the missing heritability and point to etiologic genes and pathways underlying these important health burdens.

Combined approaches in large vestibular schwannomas: surgical and radiosurgical perspective

Purpose: The management of vestibular schwanommas (VS) is challenging, with microsurgery remaining the main treatment option. Planned subtotal resection is now being increasingly considered to reduce the risk of neurological deficits following complete resection. The residual part of the tumor can then be treated with Gamma Knife surgery (GKS) to achieve long-term growth control. Methods: This case series of 11 patients documents early results with planned subtotal resection followed by GKS in Lausanne University Hospital, between July 2010 and March 2012. We analyzed clinical symptoms and signs for all cases, as well as MRI and audiograms. Results: Mean age in this series was 50.3 years (range 24.1-73.4). Two patients (18.2%) had a stereotactic fractionated radiotherapy, which had failed to ensure tumor control, before the microsurgical intervention. The lesions were solid in 9 cases (81.8%), and mixed (solid and cystic) in 2 patients (18.2%). Presurgical tumor volume was of a mean of 18.5 cm3 (range 9.7-34.9 cm3). The mean duration between microsurgery and GKS was 10.5 months (range 4-22.8). The mean tumor volume at the time of GKS treatment was 4.9 cm3 (range 0.5- 12.8). A mean number of 20.7 isocenters was used (range 8-31). Nine patients received 12 Gy and 2 patients with 11 Gy at the periphery (at the 50% prescription isodose). We did not have any major complications in our series. Postoperative status showed no facial nerve deficits. Four patients with useful pre-operative hearing underwent surgery aiming to preserve the cochlear nerve function. Of these patients, the patient who had Gardner-Robertson (GR) class 1 before surgery, remained in GR class 1. Two patients improved after surgery, one changing from GR 5 to GR 3 and the other with slight improvement, remaining in the same GR 3 class. Mean follow-up after surgery was 15.4 months (range 4-31.2). One patient, who presented with secondary trigeminal neuralgia before surgery, had transitory facial hypoesthesia following surgery. No other neurological deficits were encountered. Following GKS, the patients had a mean follow-up of 5.33 months (range 1-13). No new neurological deficits were encountered. Conclusions: Our data suggest that planned subtotal resection followed by GKS has an excellent clinical outcome with respect to preservation of cranial nerves, and other neurological functions, and a good possibility of recovery of many of the pre-operative cranial nerve dysfunctions

Equidistribution of Fekete Points on the Sphere

Fekete points are the points that maximize a Vandermonde-type determinant that appears in the polynomial Lagrange interpolation formula. They are well suited points for interpolation formulas and numerical integration. We prove the asymptotic equidistribution of Fekete points in the sphere. The way we proceed is by showing their connection to other arrays of points, the so-called Marcinkiewicz-Zygmund arrays and interpolating arrays, that have been studied recently.

Maintenance and construction outsourcing in a public-owned electricity network company

Euroopan sähkösektori on ollut viimeisen vuosikymmenen suurten mullistusten kourissa. Sähkömarkkinoiden avautumisen jälkeen monopoliliiketoimintaa harjoittavien sähköyhtiöiden on ollut pakko parantaa tuottavuuttaan. Ratkaisuksi tähän on etsitty apua huolto- ja rakennustoimintojen ulkoistamisella. Ulkoistaminen on kuitenkin uusi menetelmä tällä sektorilla. Tämän tutkielman tavoitteena on selvittää syyt, jotka tanskalaisella sähköverkkoyhtiöllä oli huolto- ja rakennustoimintojen ulkoistamiseen, sekä löytää siitä saatavat hyödyt ja siihen sisältyvät riskit. Tutkimus suoritetaan käyttäen apuna kirjallisuutta, saatavilla olevia due diligence-, sekä muita raportteja ja analyysejä, sekä tapausta koskettavien tahojen haastatteluja.Lisäksi sähköverkkoalan asiantuntijoiden kanssa käytyjä konsultointia käytetäänselvitykseen. Tutkimus osoittaa, että perimmäiset ajurit huolto- ja rakennustoimintojen ulkoistamiseen tulivat lainmuutosten ja vapautuneiden sähkömarkkinoiden asettamista paineista. Kunnallisessa organisaatiossa parantaa tehokkuutta ulkoistamalla jotain toimintoja yksityisomisteiselle palvelun tuottajalle. Muut ulkoistamisesta odotetut hyödyt olivat alentuneet kustannukset, virtaviivaisempi organisaation ja sähköverkkoyhtiön tehottomista osista eroon pääseminen ennen sen myymistä.

On the differential evolution algorithm and its appliation to training radial basis function networks

The parameter setting of a differential evolution algorithm must meet several requirements: efficiency, effectiveness, and reliability. Problems vary. The solution of a particular problem can be represented in different ways. An algorithm most efficient in dealing with a particular representation may be less efficient in dealing with other representations. The development of differential evolution-based methods contributes substantially to research on evolutionary computing and global optimization in general. The objective of this study is to investigatethe differential evolution algorithm, the intelligent adjustment of its controlparameters, and its application. In the thesis, the differential evolution algorithm is first examined using different parameter settings and test functions. Fuzzy control is then employed to make control parameters adaptive based on an optimization process and expert knowledge. The developed algorithms are applied to training radial basis function networks for function approximation with possible variables including centers, widths, and weights of basis functions and both having control parameters kept fixed and adjusted by fuzzy controller. After the influence of control variables on the performance of the differential evolution algorithm was explored, an adaptive version of the differential evolution algorithm was developed and the differential evolution-based radial basis function network training approaches were proposed. Experimental results showed that the performance of the differential evolution algorithm is sensitive to parameter setting, and the best setting was found to be problem dependent. The fuzzy adaptive differential evolution algorithm releases the user load of parameter setting and performs better than those using all fixedparameters. Differential evolution-based approaches are effective for training Gaussian radial basis function networks.

Technology selection and group decision support systems: Case studies on supporting strategic technology selection processes

The objective of the dissertation is to increase understanding and knowledge in the field where group decision support system (GDSS) and technology selection research overlap in the strategic sense. The purpose is to develop pragmatic, unique and competent management practices and processes for strategic technology assessment and selection from the whole company's point of view. The combination of the GDSS and technology selection is approached from the points of view of the core competence concept, the lead user -method, and different technology types. In this research the aim is to find out how the GDSS contributes to the technology selection process, what aspects should be considered when selecting technologies to be developed or acquired, and what advantages and restrictions the GDSS has in the selection processes. These research objectives are discussed on the basis of experiences and findings in real life selection meetings. The research has been mainly carried outwith constructive, case study research methods. The study contributes novel ideas to the present knowledge and prior literature on the GDSS and technology selection arena. Academic and pragmatic research has been conducted in four areas: 1) the potential benefits of the group support system with the lead user -method,where the need assessment process is positioned as information gathering for the selection of wireless technology development projects; 2) integrated technology selection and core competencies management processes both in theory and in practice; 3) potential benefits of the group decision support system in the technology selection processes of different technology types; and 4) linkages between technology selection and R&D project selection in innovative product development networks. New type of knowledge and understanding has been created on the practical utilization of the GDSS in technology selection decisions. The study demonstrates that technology selection requires close cooperation between differentdepartments, functions, and strategic business units in order to gather the best knowledge for the decision making. The GDSS is proved to be an effective way to promote communication and co-operation between the selectors. The constructs developed in this study have been tested in many industry fields, for example in information and communication, forest, telecommunication, metal, software, and miscellaneous industries, as well as in non-profit organizations. The pragmatic results in these organizations are some of the most relevant proofs that confirm the scientific contribution of the study, according to the principles of the constructive research approach.

Implementing a metasearch engine : Metalib and SFX

L'article presenta les característiques i funcionalitats principals de les eines MetaLib i SFX, programaris per a la gestió i accés als recursos electrònics. S'analitzen els programaris citant els diferents tipus de funcionalitats, i la gestió i el manteniment. El procés s'emmarca en l'experiència de la Universitat Oberta de Catalunya, membre del CBUC, i se n'expliquen la configuració, els reptes i les dificultats que es van produir durant la implementació dels sistemes.

The Impact of Catechol-O-Methyltransferase and Dopamine D4 Receptor Genotypes on Neurophysiological Markers of Performance Monitoring

Dynamic adaptations of one"s behavior by means of performance monitoring are a central function of the human executive system, that underlies considerable interindividual variation. Converging evidence from electrophysiological and neuroimaging studies in both animals and humans hints atthe importance ofthe dopaminergic system forthe regulation of performance monitoring. Here, we studied the impact of two polymorphisms affecting dopaminergic functioning in the prefrontal cortex [catechol-O-methyltransferase (COMT) Val108/158Met and dopamine D4 receptor (DRD4) single-nucleotide polymorphism (SNP)-521] on neurophysiological correlates of performance monitoring. We applied a modified version of a standard flanker task with an embedded stop-signal task to tap into the different functions involved, particularly error monitoring, conflict detection and inhibitory processes. Participants homozygous for the DRD4 T allele produced an increased error-related negativity after both choice errors and failed inhibitions compared with C-homozygotes. This was associated with pronounced compensatory behavior reflected in higher post-error slowing. No group differences were seen in the incompatibility N2, suggesting distinct effects of the DRD4 polymorphism on error monitoring processes. Additionally, participants homozygous for the COMTVal allele, with a thereby diminished prefrontal dopaminergic level, revealed increased prefrontal processing related to inhibitory functions, reflected in the enhanced stop-signal-related components N2 and P3a. The results extend previous findings from mainly behavioral and neuroimaging data on the relationship between dopaminergic genes and executive functions and present possible underlying mechanisms for the previously suggested association between these dopaminergic polymorphisms and psychiatric disorders as schizophrenia or attention deficit hyperactivity disorder.

Testing and Monitoring Mill Connection Messages

Tarve tälle työlle on noussut sanomapalvelinsoveluksissa (servers) esiintyvistä ongelmista. Sanomapalvelinsovelluksia käytetään lähettämään ja vastaanottamaan sanomia paperiteollisuuden myynnin ja jakelun järjestelmässä maantieteellisesti erillään olevista paperiteollisuuden tehtaista. Sanomapalvelinsovelusten kunnollinen toimivuus on tärkeää koko järjestelmän toimivuuden kannalta, koska nämä palvelimet käsittelevät päivittäin tuhansia sanomia, jotka sisältävät merkityksellistä järjestelmätietoa. Tässä työssä on tutkittu mahdollisia toteutustekniikoita ja näihin tutkimuksiin pohjautuen toteutettu työkalut sanomapalvelinsovellusten testaukseen ja valvontaan. Sovellus-arkkituuritekniikoita tutkittaessa tutkimus rajattiin 3-tasoarkkitehtuuritekniikkaan, erityisesti TUXEDOTM -järjestelmätekniikkaan, koska toteutettavaa sovellusta käytetään hajautetussa sovellusympäristössä. Sovellusasiakkaan (client) toteutusta varten tutkittiin ja vertailtiin XML-tekniikkaa ja Microsoft Visual C++ -tekniikkaa käytettynä Tieto-Enatorin Phobos Interaktiivisen C++ -luokkakirjaston kanssa. XML-tekniikoita sekä Visual C++ ja Phobos-luokkakirjasto –tekniikkaa tutkittiin niiltä osin, mitä tarvittiin sanomamerkkijonojen katseluun. XML-tietokantatekniikoita tutkittiin mahdollisena vaihtoehtona tietokanta ja sovelluspalvelintekniikalle. Työn ensimmäisenä tavoitteena oli toteuttaa työkalu sanomapalvelinsovellusten testaamiseen. Toisena tavoitteena oli toteuttaa työkalu sanomien sisällön oikeellisuuden valvontaan. Kolmantena tavoitteena oli analysoida olemassaolevaa sanomavirheiden valvontasovellusta ja kehittää sitä eteenpäin. Diplomityön tuloksena toteutettiin sovellus sanomapalvelinsovellusten testaamiseen ja valvontaan. Tutkituista asiakassovelustekniikoista valittiin toteutus-tekniikaksi MS Visual C++ käytettynä Phobos Interaktiivisen C++ luokkakirjaston kanssa tekniikan tunnettavuuden vuoksi. 3-taso TUXEDOTM-tekniikka valittiin sovelluksen arkkitehtuuriksi. Lisäksi löydettiin parannuksia olemassa oleviin sanoma-virheiden valvontatoimintoihin. Tutkitut toteutustekniikat ovat yleisiä ja niitä voidaan käyttää, kun toteutetaan samanlaisia sovelluksia samanlaisiin sovellusympäristöihin.

Serum anticholinergic activity and postoperative cognitive dysfunction in elderly parients

BACKGROUND: Cerebral cholinergic transmission plays a key role in cognitive function, and anticholinergic drugs administered during the perioperative phase are a hypothetical cause of postoperative cognitive dysfunction (POCD). We hypothesized that a perioperative increase in serum anticholinergic activity (SAA) is associated with POCD in elderly patients. METHODS: Seventy-nine patients aged >65 years undergoing elective major surgery under stan- dardized general anesthesia (thiopental, sevoflurane, fentanyl, and atracurium) were investi- gated. Cognitive functions were assessed preoperatively and 7 days postoperatively using the extended version of the CERAD-Neuropsychological Assessment Battery. POCD was defined as a postoperative decline >1 z-score in at least 2 test variables. SAA was measured preop- eratively and 7 days postoperatively at the time of cognitive testing. Hodges-Lehmann median differences and their 95% confidence intervals were calculated for between-group comparisons. RESULTS: Of the patients who completed the study, 46% developed POCD. Patients with POCD were slightly older and less educated than patients without POCD. There were no relevant differences between patients with and without POCD regarding gender, demographically cor- rected baseline cognitive functions, and duration of anesthesia. There were no large differences between patients with and without POCD regarding SAA preoperatively (pmol/mL, median [inter- quartile range]/median difference [95% CI], P; 1.14 [0.72, 2.37] vs 1.13 [0.68, 1.68]/0.12 [−0.31, 0.57], P = 0.56), SAA 7 days postoperatively (1.32 [0.68, 2.59] vs 0.97 [0.65, 1.83]/0.25 [−0.26, 0.81], P = 0.37), or changes in SAA (0.08 [−0.50, 0.70] vs −0.02 [−0.53, 0.41]/0.1 [−0.31, 0.52], P = 0.62). There was no significant relationship between changes in SAA and changes in cognitive function (Spearman rank correlation coefficient preoperatively of 0.03 [95% CI, −0.21, 0.26] and postoperatively of −0.002 [95% CI, −0.24, 0.23]). CONCLUSIONS: In this panel of patients with low baseline SAA and clinically insignificant periopera- tive anticholinergic burden, although a relationship cannot be excluded in some patients, our analysis suggests that POCD is probably not a substantial consequence of anticholinergic medications admin- istered perioperatively but rather due to other mechanisms.

The Armc10/SVH gene: Genome context, regulation of mitochondrial dynamics and protection against Aβ-induced mitochondrial fragmentation

Mitochondrial function and dynamics are essential for neurotransmission, neural function and neuronal viability. Recently, we showed that the eutherian-specific Armcx gene cluster (Armcx1-6 genes), located in the X chromosome, encodes for a new family of proteins that localise to mitochondria, regulating mitochondrial trafficking. The Armcx gene cluster evolved by retrotransposition of the Armc10 gene mRNA, which is present in all vertebrates and is considered to be the ancestor gene. Here we investigate the genomic organisation, mitochondrial functions and putative neuroprotective role of the Armc10 ancestor gene. The genomic context of the Armc10 locus shows considerable syntenic conservation among vertebrates, and sequence comparisons and CHIP-data suggest the presence of at least three conserved enhancers. We also show that the Armc10 protein localises to mitochondria and that it is highly expressed in the brain. Furthermore, we show that Armc10 levels regulate mitochondrial trafficking in neurons, but not mitochondrial aggregation, by controlling the number of moving mitochondria. We further demonstrate that the Armc10 protein interacts with the KIF5/Miro1-2/Trak2 trafficking complex. Finally, we show that overexpression of Armc10 in neurons prevents A beta-induced mitochondrial fission and neuronal death. Our data suggest both conserved and differential roles of the Armc10/Armcx gene family in regulating mitochondrial dynamics in neurons, and underscore a protective effect of the Armc10 gene against A beta-induced toxicity. Overall, our findings support a further degree of regulation of mitochondrial dynamics in the brain of more evolved mammals.

The Armc10/SVH gene: Genome context, regulation of mitochondrial dynamics and protection against Aβ-induced mitochondrial fragmentation

Mitochondrial function and dynamics are essential for neurotransmission, neural function and neuronal viability. Recently, we showed that the eutherian-specific Armcx gene cluster (Armcx1-6 genes), located in the X chromosome, encodes for a new family of proteins that localise to mitochondria, regulating mitochondrial trafficking. The Armcx gene cluster evolved by retrotransposition of the Armc10 gene mRNA, which is present in all vertebrates and is considered to be the ancestor gene. Here we investigate the genomic organisation, mitochondrial functions and putative neuroprotective role of the Armc10 ancestor gene. The genomic context of the Armc10 locus shows considerable syntenic conservation among vertebrates, and sequence comparisons and CHIP-data suggest the presence of at least three conserved enhancers. We also show that the Armc10 protein localises to mitochondria and that it is highly expressed in the brain. Furthermore, we show that Armc10 levels regulate mitochondrial trafficking in neurons, but not mitochondrial aggregation, by controlling the number of moving mitochondria. We further demonstrate that the Armc10 protein interacts with the KIF5/Miro1-2/Trak2 trafficking complex. Finally, we show that overexpression of Armc10 in neurons prevents A beta-induced mitochondrial fission and neuronal death. Our data suggest both conserved and differential roles of the Armc10/Armcx gene family in regulating mitochondrial dynamics in neurons, and underscore a protective effect of the Armc10 gene against A beta-induced toxicity. Overall, our findings support a further degree of regulation of mitochondrial dynamics in the brain of more evolved mammals.

Fast and Rigorous Computation of Gene and Pathway Scores from SNP-Based Summary Statistics.

Integrating single nucleotide polymorphism (SNP) p-values from genome-wide association studies (GWAS) across genes and pathways is a strategy to improve statistical power and gain biological insight. Here, we present Pascal (Pathway scoring algorithm), a powerful tool for computing gene and pathway scores from SNP-phenotype association summary statistics. For gene score computation, we implemented analytic and efficient numerical solutions to calculate test statistics. We examined in particular the sum and the maximum of chi-squared statistics, which measure the strongest and the average association signals per gene, respectively. For pathway scoring, we use a modified Fisher method, which offers not only significant power improvement over more traditional enrichment strategies, but also eliminates the problem of arbitrary threshold selection inherent in any binary membership based pathway enrichment approach. We demonstrate the marked increase in power by analyzing summary statistics from dozens of large meta-studies for various traits. Our extensive testing indicates that our method not only excels in rigorous type I error control, but also results in more biologically meaningful discoveries.

Associations of Urinary Uromodulin with Clinical Characteristics and Markers of Tubular Function in the General Population.

BACKGROUND AND OBJECTIVES: Allelic variants in UMOD, the gene coding for uromodulin, are associated with rare tubulointerstitial kidney disorders and risk of CKD and hypertension in the general population. The factors associated with uromodulin excretion in the normal population remain largely unknown, and were therefore explored in this study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Urinary uromodulin excretion was measured using a validated ELISA in two population-based cohorts that included more than 6500 individuals. The Swiss Kidney Project on Genes in Hypertension study (SKIPOGH) included 817 adults (mean age±SD, 45±17 years) who underwent renal ultrasonography and performed a 24-hour urine collection. The Cohorte Lausannoise study included 5706 adults (mean age, 53±11 years) with fresh spot morning urine samples. We calculated eGFRs using the CKD-Epidemiology Collaboration formula and by 24-hour creatinine clearance. RESULTS: In both studies, positive associations were found between uromodulin and urinary sodium, chloride, and potassium excretion and osmolality. In SKIPOGH, 24-hour uromodulin excretion (median, 41 [interquartile range, 29-57] mg/24 h) was positively associated with kidney length and volume and with creatinine excretion and urine volume. It was negatively associated with age and diabetes. Both spot uromodulin concentration and 24-hour uromodulin excretion were linearly and positively associated (multivariate analyses) with eGFR<90 ml/min per 1.73 m(2). CONCLUSION: Age, creatinine excretion, diabetes, and urinary volume are independent clinical correlates of urinary uromodulin excretion. The associations of uromodulin excretion with markers of tubular functions and kidney dimensions suggest that it may reflect tubule activity in the general population.

¿Pueden contribuir los métodos visuales a avanzar hacia una investigación inclusiva? Un estudio sobre inclusión sociolaboral con personas con Trastorno Mental Grave (TMG) = Can visual methods help to go forward inclusive research? A study about social and labor inclusion with people with Severe Mental Illness (SMI)

En este artículo se pretende mostrar cómo la utilización de métodos visuales en la investigación contribuye a potenciar la participación activa de las personas con TMG. Se utiliza como ejemplo un estudio de caso de corte cualitativo que incorpora tres actividades de componente visual (el dibujo “el río de la vida”, las fotografías y el dibujo de proyección de futuro) para favorecer la reflexión narrada que, sobre sus experiencias y vivencias, desarrollan cinco personas con TMG. El uso de las fotografías y dibujos en este estudio permite afirmar que estas estrategias se han mostrado válidas para acceder, en la medida que los participantes han querido, a esferas de vida personales en trayectorias vitales determinadas por la enfermedad mental