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  • Pirie, Ailith; Guo, Qi; Kraft, Peter; Canisius, Sander; Eccles, Diana M; Rahman, Nazneen; Nevanlinna, Heli; Chen, Constance; Khan, Sofia; Tyrer, Jonathan; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Michailidou, Kyriaki; Lush, Michael; Dunning, Alison M; Shah, Mitul; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Lambrechts, Dieter; Weltens, Caroline; Leunen, Karin; van Ongeval, Chantal; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Blomqvist, Carl; Aittomäki, Kristiina; Fagerholm, Rainer; Muranen, Taru A; Olsen, Janet E; Hallberg, Emily; Vachon, Celine; Knight, Julia A; Glendon, Gord; Mulligan, Anna M; Broeks, Annegien; Cornelissen, Sten; Haiman, Christopher A; Henderson, Brian E; Schumacher, Frederick; Le Marchand, Loic; Hopper, John L; Tsimiklis, Helen; Apicella, Carmel; Southey, Melissa C; Cross, Simon S; Reed, Malcolm W; Giles, Graham G; Milne, Roger L; McLean, Catriona; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John W; van den Ouweland, Ans M; Marme, Federick; Schneeweiss, Andreas; Yang, Rongxi; Burwinkel, Barbara; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Brenner, Hermann; Butterbach, Katja; Holleczek, Bernd; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Li, Jingmei; Brand, Judith S; Humphreys, Keith; Devilee, Peter; Tollenaar, Robert A; Seynaeve, Caroline; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Ficarazzi, Filomena; Beckmann, Matthias W; Hein, Alexander; Ekici, Arif B; Balleine, Rosemary; Phillips, Kelly-Anne; Benitez, Javier; Zamora, M P; Perez, Jose I A; Menéndez, Primitiva; Jakubowska, Anna; Lubinski, Jan; Gronwald, Jacek; Durda, Katarzyna; Hamann, Ute; Kabisch, Maria; Ulmer, Hans U; Rüdiger, Thomas; Margolin, Sara; Kristensen, Vessela; Nord, Siljie; Evans, D G; Abraham, Jean; Earl, Helena; Poole, Christopher J; Hiller, Louise; Dunn, Janet A; Bowden, Sarah; Yang, Rose; Campa, Daniele; Diver, W R; Gapstur, Susan M; Gaudet, Mia M; Hankinson, Susan; Hoover, Robert N; Hüsing, Anika; Kaaks, Rudolf; Machiela, Mitchell J; Willett, Walter; Barrdahl, Myrto; Canzian, Federico; Chin, Suet-Feung; Caldas, Carlos; Hunter, David J; Lindstrom, Sara; Garcia-Closas, Montserrat; Couch, Fergus J; Chenevix-Trench, Georgia; Mannermaa, Arto; Andrulis, Irene L; Hall, Per; Chang-Claude, Jenny; Easton, Douglas F; Bojesen, Stig E; Cox, Angela; Fasching, Peter A; Pharoah, Paul D; Schmidt, Marjanka K (BioMed Central, 2015)
    Abstract Introduction Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium. Methods A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect. Results Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease. Conclusions Although no variants reached genome-wide significance (P <5 x 10−8), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.
  • Tudor-Locke, Catrine; Mire, Emily F; Dentro, Kara N; Barreira, Tiago V; Schuna, John M; Zhao, Pei; Tremblay, Mark S; Standage, Martyn; Sarmiento, Olga L; Onywera, Vincent; Olds, Tim; Matsudo, Victor; Maia, José; Maher, Carol; Lambert, Estelle V; Kurpad, Anura; Kuriyan, Rebecca; Hu, Gang; Fogelholm, Mikael; Chaput, Jean-Philippe; Church, Timothy S; Katzmarzyk, Peter T (BioMed Central, 2015)
    Abstract Background We present a model for reporting accelerometer paradata (process-related data produced from survey administration) collected in the International Study of Childhood Obesity Lifestyle and the Environment (ISCOLE), a multi-national investigation of >7000 children (averaging 10.5 years of age) sampled from 12 different developed and developing countries and five continents. Methods ISCOLE employed a 24-hr waist worn 7-day protocol using the ActiGraph GT3X+. Checklists, flow charts, and systematic data queries documented accelerometer paradata from enrollment to data collection and treatment. Paradata included counts of consented and eligible participants, accelerometers distributed for initial and additional monitoring (site specific decisions in the face of initial monitoring failure), inadequate data (e.g., lost/malfunction, insufficient wear time), and averages for waking wear time, valid days of data, participants with valid data (≥4 valid days of data, including 1 weekend day), and minutes with implausibly high values (≥20,000 activity counts/min). Results Of 7806 consented participants, 7372 were deemed eligible to participate, 7314 accelerometers were distributed for initial monitoring and another 106 for additional monitoring. 414 accelerometer data files were inadequate (primarily due to insufficient wear time). Only 29 accelerometers were lost during the implementation of ISCOLE worldwide. The final locked data file consisted of 6553 participant files (90.0% relative to number of participants who completed monitoring) with valid waking wear time, averaging 6.5 valid days and 888.4 minutes/day (14.8 hours). We documented 4762 minutes with implausibly high activity count values from 695 unique participants (9.4% of eligible participants and <0.01% of all minutes). Conclusions Detailed accelerometer paradata is useful for standardizing communication, facilitating study management, improving the representative qualities of surveys, tracking study endpoint attainment, comparing studies, and ultimately anticipating and controlling costs. Trial registration NCT01722500
  • Ma, Li; Piirainen, Sami; Kulesskaya, Natalia; Rauvala, Heikki; Tian, Li (BioMed Central, 2015)
    Abstract Background Social deficit is one of the core symptoms of neuropsychiatric diseases, in which immune genes play an important role. Although a few immune genes have been shown to regulate social and emotional behaviors, how immune gene network(s) may jointly regulate sociability has not been investigated so far. Methods To decipher the potential immune-mediated mechanisms underlying social behavior, we first studied the brain microarray data of eight inbred mouse strains with known variations in social behavior and retrieved the differentially expressed immune genes. We then made a protein-protein interaction analysis of them to find the major networks and explored the potential association of these genes with the behavior and brain morphology in the mouse phenome database. To validate the expression and function of the candidate immune genes, we selected the C57BL/6 J and DBA/2 J strains among the eight inbred strains, compared their social behaviors in resident-intruder and 3-chambered social tests and the mRNA levels of these genes, and analyzed the correlations of these genes with the social behaviors. Results A group of immune genes were differentially expressed in the brains of these mouse strains. The representative C57BL/6 J and DBA/2 J strains displayed significant differences in social behaviors, DBA/2 J mice being less active in social dominance and social interaction than C57BL/6 J mice. The mRNA levels of H2-d1 in the prefrontal cortex, hippocampus, and hypothalamus and C1qb in the hippocampus of the DBA/2 J strain were significantly down-regulated as compared to those in the C57BL/6 J strain. In contrast, Polr3b in the hippocampus and Tnfsf13b in the prefrontal cortex of the DBA/2 J strain were up-regulated. Furthermore, C1qb, Cx3cl1, H2-d1, H2-k1, Polr3b, and Tnfsf13b were predicted to be associated with various behavioral and brain morphological features across the eight inbred strains. Importantly, the C1qb mRNA level was confirmed to be significantly correlated with the sociability in DBA/2 J but not in C57BL/6 J mice. Conclusions Our study provided evidence on the association of immune gene network(s) with the brain development and behavior in animals and revealed neurobiological functions of novel brain immune genes that may contribute to social deficiency in animal models of neuropsychiatric disorders.
  • Määttä, Suvi; Lehto, Reetta; Nislin, Mari; Ray, Carola; Erkkola, Maijaliisa; Sajaniemi, Nina; Roos, Eva (BioMed Central, 2015)
    Abstract Background Effective interventions that target socioeconomic status (SES) differences to avoid the potential widening of inequalities in health are needed. Children at preschool age is a valuable intervention target since sedentary behaviors, physical activity (PA), dietary behaviors, and sleep habits, jointly called the energy balance-related behaviors (EBRBs), are established in early childhood and tend to persist later in life. The interventions are most effective, when they focus on evidence-based factors. One potential factor associated with EBRBs and SES is children’s stress regulation, which receives special attention in this study. Based on the socioecological approach, the combinations of multiple levels (e.g. individual, environmental, societal) of analysis and diverse methodologies (e.g. surveys, observations, biological measurements) are used to assess the healthfulness of environments (e.g. social, physical, learning, policy) in preschool and family settings. The intervention aimed to diminish SES differences in EBRBs is then conducted in the preschool setting. Methods/design The DAGIS study is divided into two phases. The first phase comprises focus group interviews and a cross-sectional survey. Parents and preschool personnel in low SES neighborhoods participated in interviews about children’s sedentary behaviors, dietary behaviors, and PA in 2014. In the cross-sectional survey beginning in autumn 2015, preschools will be recruited from a random sample of preschools in 3–5 municipalities in Southern Finland. A total of 800 children will wear an accelerometer for seven days. Children’s hair and saliva samples will be taken. Parents and preschool personnel will complete questionnaires on EBRBs, social and physical environments and SES factors. The quality of preschool environment is also observed. In the second phase, an intervention targeting to narrowing SES differences in EBRBs is conducted. The effects of the intervention will be evaluated in randomised controlled trial. The implementation of the intervention will also be evaluated. Conclusion If effective, this unique preschool-based study will be able to narrow the SES differences in preschool children’s EBRBs. This study is anticipated to identify the most important modifiable factors in preschool and family environmental settings associated with children’s EBRBs, especially in children from low SES backgrounds. Trial registration ISRCTN57165350 (January, 8th, 2015).
  • Haukkala, Ari; Konttinen, Hanna; Hankonen, Nelli; Perola, Markus; Kääriäinen, Helena; Salomaa, Veikko (BioMed Central, 2015)
    Abstract Background The role and meaning of genetic information has grown considerably in the recent decades. We examined changes in causal beliefs about morbidity as well as the associations between causal beliefs, health behaviors and obesity, and health outcome beliefs from 1982 to 2002. Methods In five population-based risk-factor surveys (the FINRISK Studies) of individuals aged 25 to 64 years conducted from 1982 to 2002 (n = 37,503), respondents chose the most important cause of morbidity from a list of ten alternatives. Health outcome beliefs were assessed with two items. Physical inactivity and smoking status were based on self-reports and obesity was based on measured height and weight. Results The prevalence of those who endorse genetic factors as the most important cause of morbidity increased from 4% in 1982 to 10% in 1992 and remained at that level until 2002. During the study period, lack of exercise and overweight increased, whereas inappropriate diet and stress diminished as causal beliefs about morbidity. Smokers and physically inactive were more likely to endorse genetic than behavioral causes of morbidity, whereas obese respondents were more likely to choose overweight over genetic causes of morbidity. Those who endorse genetic factors as the most important cause had more pessimistic outcome beliefs about health behavior changes, but these outcome beliefs became more positive in all causal belief groups during the study period. Conclusion Despite increased public discussion of genomics, the relative proportion of those who endorse genetic factors as the most important cause of morbidity has remained low. However, within this group beliefs about benefits of health behavior changes have become more positive. This could indicate that increase in genomic health information does not lead to more negative appraisals of efficacy of lifestyle changes.
  • Katajisto, Pekka; Doehla, Julia; Chaffer, Christine L.; Pentinmikko, Nalle; Marjanovic, Nemanja; Iqbal, Md Sharif; Zoncu, Roberto; Chen, Walter; Weinberg, Robert A.; Sabatini, David M. (AAAS, American Association for the Advancement of Science, 2015)
    By dividing asymmetrically, stem cells can generate two daughter cells with distinct fates. However, evidence is limited in mammalian systems for the selective apportioning of subcellular contents between daughters. We followed the fates of old and young organelles during the division of human mammary stemlike cells and found that such cells apportion aged mitochondria asymmetrically between daughter cells. Daughter cells that received fewer old mitochondria maintained stem cell traits. Inhibition of mitochondrial fission disrupted both the age-dependent subcellular localization and segregation of mitochondria and caused loss of stem cell properties in the progeny cells. Hence, mechanisms exist for mammalian stemlike cells to asymmetrically sort aged and young mitochondria, and these are important for maintaining stemness properties.
  • Gel'man, Vladimir (Russian Analytical Digest, 2015)
  • Ahola, Tero; Karlin, David G (BioMed Central, 2015)
    Abstract Background Members of the alphavirus supergroup include human pathogens such as chikungunya virus, hepatitis E virus and rubella virus. They encode a capping enzyme with methyltransferase-guanylyltransferase (MTase-GTase) activity, which is an attractive drug target owing to its unique mechanism. However, its experimental study has proven very difficult. Results We examined over 50 genera of viruses by sequence analyses. Earlier studies showed that the MTase-GTase contains a “Core” region conserved in sequence. We show that it is followed by a long extension, which we termed “Iceberg” region, whose secondary structure, but not sequence, is strikingly conserved throughout the alphavirus supergroup. Sequence analyses strongly suggest that the minimal capping domain corresponds to the Core and Iceberg regions combined, which is supported by earlier experimental data. The Iceberg region contains all known membrane association sites that contribute to the assembly of viral replication factories. We predict that it may also contain an overlooked, widely conserved membrane-binding amphipathic helix. Unexpectedly, we detected a sequence homolog of the alphavirus MTase-GTase in taxa related to nodaviruses and to chronic bee paralysis virus. The presence of a capping enzyme in nodaviruses is biologically consistent, since they have capped genomes but replicate in the cytoplasm, where no cellular capping enzyme is present. The putative MTase-GTase domain of nodaviruses also contains membrane-binding sites that may drive the assembly of viral replication factories, revealing an unsuspected parallel with the alphavirus supergroup. Conclusions Our work will guide the functional analysis of the alphaviral MTase-GTase and the production of domains for structure determination. The identification of a homologous domain in a simple model system, nodaviruses, which replicate in numerous eukaryotic cell systems (yeast, flies, worms, mammals, and plants), can further help crack the function and structure of the enzyme. Reviewers This article was reviewed by Valerian Dolja, Eugene Koonin and Sebastian Maurer-Stroh.
  • Caburet, Sandrine; Anttonen, Mikko; Todeschini, Anne-Laure; Unkila-Kallio, Leila; Mestivier, Denis; Butzow, Ralf; Veitia, Reiner A (BioMed Central, 2015)
    Abstract Background Ovarian granulosa cell tumors (GCTs) are the most frequent sex cord-stromal tumors. Several studies have shown that a somatic mutation leading to a C134W substitution in the transcription factor FOXL2 appears in more than 95% of adult-type GCTs. Its pervasive presence suggests that FOXL2 is the main cancer driver gene. However, other mutations and genomic changes might also contribute to tumor formation and/or progression. Methods We have performed a combined comparative genomic hybridization and transcriptomic analyses of 10 adult-type GCTs to obtain a picture of the genomic landscape of this cancer type and to identify new candidate co-driver genes. Results Our results, along with a review of previous molecular studies, show the existence of highly recurrent chromosomal imbalances (especially, trisomy 14 and monosomy 22) and preferential co-occurrences (i.e. trisomy 14/monosomy 22 and trisomy 7/monosomy 16q). In-depth analyses showed the presence of recurrently broken, amplified/duplicated or deleted genes. Many of these genes, such as AKT1, RUNX1 and LIMA1, are known to be involved in cancer and related processes. Further genomic explorations suggest that they are functionally related. Conclusions Our combined analysis identifies potential candidate genes, whose alterations might contribute to adult-type GCT formation/progression together with the recurrent FOXL2 somatic mutation.
  • Sumanen, Hilla; Pietiläinen, Olli; Lahti, Jouni; Lahelma, Eero; Rahkonen, Ossi (BioMed Central, 2015)
    Abstract Background A low socioeconomic position (SEP) is consistently associated with ill health, sickness absence (SA) and permanent disability, but studies among young employees are lacking. We examined the interrelationships between education, occupational class and income as determinants of SA among 25-34-year-old employees. We also examined, whether the association between SEP and SA varied over time in 2002–2007 and 2008–2013. Methods The analyses covered young, 25-34-year-old women and men employed by the City of Helsinki over the time periods 2002–2007 and 2008–2013. Four-level education and occupational class classifications were used, as well as income quartiles. The outcome measure was the number of annual SA days. Results Education had the strongest and most consistent independent association with SA among women and men in both periods under study. Occupational class had weaker independent and less consistent association with SA. Income had an independent association with SA, which strengthened over time among the men. The interrelationships between the SEP indicators and SA were partly explained by prior or mediated through subsequent SEP indicators. Socioeconomic differences followed only partially a gradient for occupational class and also for income among men. Conclusions Preventive measures to reduce the risk of SA should be considered, especially among young employees with a basic or lower-secondary education.
  • Ajao, Charmaine; Andersson, Maria; Teplova, Vera V; Nagy, Szabolcs; Gahmberg, Carl G.; Andersson, Leif C.; Hautaniemi, Maria; Kakasi, Balazs; Roivainen, Merja; Salkinoja-Salonen, Mirja Sinikka (Elsevier, 2015)
    Effects of triclosan (5-chloro-2’-(2,4-dichlorophenoxy)phenol) on mammalian cells were investigated using human peripheral blood mono nuclear cells (PBMC), keratinocytes (HaCaT), porcine spermatozoa and kidney tubular epithelial cells (PK-15), murine pancreatic islets (MIN-6) and neuroblastoma cells (MNA) as targets. We show that triclosan (1 – 10 μg ml-1) depolarised the mitochondria, upshifted the rate of glucose consumption in PMBC, HaCaT, PK-15 and MNA, and subsequently induced metabolic acidosis. Triclosan induced a regression of insulin producing pancreatic islets into tiny pycnotic cells and necrotic death. Short exposure to low concentrations of triclosan (30 min, ≤ 1 μg / ml) paralysed the high amplitude tail beating and progressive motility of spermatozoa, within 30 min exposure, depolarized the spermatozoan mitochondria and hyperpolarised the acrosome region of the sperm head and the flagellar fibrous sheath (distal part of the flagellum). Experiments with isolated rat liver mitochondria showed that triclosan impaired oxidative phosphorylation, downshifted ATP synthesis, uncoupled respiration and provoked excessive oxygen uptake. These exposure concentrations are 100 - 1000 fold lower that those permitted in consumer goods. The mitochondriotoxic mechanism of triclosan differs from that of valinomycin, cereulide and the enniatins by not involving potassium ionophoric activity.
  • Ollikainen, Miina; Ismail, Khadeeja; Gervin, Kristina; Kyllönen, Anjuska; Hakkarainen, Antti; Lundbom, Jesper; Järvinen, Elina A; Harris, Jennifer R; Lundbom, Nina; Rissanen, Aila; Lyle, Robert; Pietiläinen, Kirsi H; Kaprio, Jaakko (BioMed Central, 2015)
    Abstract Background The current epidemic of obesity and associated diseases calls for swift actions to better understand the mechanisms by which genetics and environmental factors affect metabolic health in humans. Monozygotic (MZ) twin pairs showing discordance for obesity suggest that epigenetic influences represent one such mechanism. We studied genome-wide leukocyte DNA methylation variation in 30 clinically healthy young adult MZ twin pairs discordant for body mass index (BMI; average within-pair BMI difference: 5.4 ± 2.0 kg/m2). Results There were no differentially methylated cytosine-guanine (CpG) sites between the co-twins discordant for BMI. However, stratification of the twin pairs based on the level of liver fat accumulation revealed two epigenetically highly different groups. Significant DNA methylation differences (n = 1,236 CpG sites (CpGs)) between the co-twins were only observed if the heavier co-twins had excessive liver fat (n = 13 twin pairs). This unhealthy pattern of obesity was coupled with insulin resistance and low-grade inflammation. The differentially methylated CpGs included 23 genes known to be associated with obesity, liver fat, type 2 diabetes mellitus (T2DM) and metabolic syndrome, and potential novel metabolic genes. Differentially methylated CpG sites were overrepresented at promoters, insulators, and heterochromatic and repressed regions. Based on predictions by overlapping histone marks, repressed and weakly transcribed sites were significantly more often hypomethylated, whereas sites with strong enhancers and active promoters were hypermethylated. Further, significant clustering of differentially methylated genes in vitamin, amino acid, fatty acid, sulfur, and renin-angiotensin metabolism pathways was observed. Conclusions The methylome in leukocytes is altered in obesity associated with metabolic disturbances, and our findings indicate several novel candidate genes and pathways in obesity and obesity-related complications.
    Idäntutkimus-lehden 1/2015 pääkirjoitus
  • Montovan, Kathryn J.; Couchoux, Christelle; Jones, Laura E.; Reeve, Hudson K.; van Nouhuys, Saskya (UNIVERSITY OF CHICAGO PRESS, 2015)
    When there is conspicuous underexploitation of a limited resource, it is worth asking, what mechanisms allow presumably valuable resources to be left unused? Evolutionary biologists have generated a wide variety of hypotheses to explain this, ranging from interdemic group selection to selfishly prudent individual restraint. We consider a situation in which, despite high intraspecific competition, individuals leave most of a key resource unexploited. The parasitic wasp that does this finds virtually all host egg clusters in a landscape but parasitizes only about a third of the eggs in each and then leaves a deterrent mark around the cluster. We first test—and reject—a series of system-specific simple constraints that might limit full host exploitation, such as asynchronous maturation of host eggs. We then consider classical hypotheses for the evolution of restraint. Prudent predation and bet-hedging fail as explanations because the wasp lives as a large, well-mixed population. Additionally, we find no individual benefits to the parasitoid of developing in a sparsely parasitized host nest.However, an optimal foragingmodel, including empirically measured costs of superparasitism and hyperparasitism, can explain through individual selection both the consistently low rate of parasitism and deterrent marking.
  • Kahanpää, Jere; Zatwarnicki, Tadeusz (Pensoft Publishers, 2015)
    The recent checklist of the Ephydridae of Finland by Zatwarnicki and Kahanpää (2014) mentioned 13 ephydrid species as new for Finland without further details. This paper presents detailed records for those species and a few other species of interest. Four species are recorded for the first time from Russia. junior synonym of Trimerina microchaeta Trimerina in distincta Krivosheina, 2004 is herein considered as a new Hendel, 1932, syn. nov.
  • Tiittula, Liisa (KAINUUN SANOMAT, 2015)
  • Kurra, Venla; Vehmas, Tuija; Eräranta, Arttu; Jokihaara, Jarkko; Pirttiniemi, Päivi; Ruskoaho, Heikki; Tokola, Heikki; Niemelä, Onni; Mustonen, Jukka; Pörsti, Ilkka (BioMed Central, 2015)
    Abstract Background Recent studies suggest a causal role for increased plasma uric acid in the progression of chronic renal insufficiency (CRI). However, uric acid also functions as an antioxidant with possible beneficial effects. Methods We investigated the influence of hyperuricemia on mesenteric arterial tone (main and second order branch) and morphology in experimental CRI. Forty-four Sprague–Dawley rats were 5/6 nephrectomized (NX) or Sham-operated and fed 2.0% oxonic acid or control diet for 9 weeks. Results Oxonic acid feeding elevated plasma uric acid levels 2.4 and 3.6-fold in the NX and Sham groups, respectively. Plasma creatinine and urea were elevated 2-fold and blood pressure increased by 10 mmHg in NX rats, while hyperuricemia did not significantly influence these variables. Right and left ventricular weight, and atrial and B-type natriuretic peptide mRNA content were increased in NX rats, but were not affected by hyperuricemia. In the mesenteric artery, hyperuricemia did not influence vasoconstrictor responses in vitro to norepinephrine or potassium chloride. The small arteries of NX rats featured hypertrophic remodeling independent of uric acid levels: wall to lumen ratio, wall thickness and cross-sectional area were increased without changes in lumen diameter. In the main branch, vasorelaxations to acetylcholine were impaired in NX rats, but were not affected by hyperuricemia. In contrast, relaxations to the large-conductance Ca2+-activated K+-channel (BKCa) opener NS-1619 were reduced by oxonic acid feeding, whereas responses to nitroprusside were not affected. Conclusions Experimental hyperuricemia did not influence cardiac load or vascular remodeling, but impaired BKCa -mediated vasorelaxation in experimental CRI.
  • Acevedo, Nathalie; Reinius, Lovisa E; Vitezic, Morana; Fortino, Vittorio; Söderhäll, Cilla; Honkanen, Hanna; Veijola, Riitta; Simell, Olli; Toppari, Jorma; Ilonen, Jorma; Knip, Mikael; Scheynius, Annika; Hyöty, Heikki; Greco, Dario; Kere, Juha (BioMed Central, 2015)
    Abstract Background Age-related changes in DNA methylation occurring in blood leukocytes during early childhood may reflect epigenetic maturation. We hypothesized that some of these changes involve gene networks of critical relevance in leukocyte biology and conducted a prospective study to elucidate the dynamics of DNA methylation. Serial blood samples were collected at 3, 6, 12, 24, 36, 48 and 60 months after birth in ten healthy girls born in Finland and participating in the Type 1 Diabetes Prediction and Prevention Study. DNA methylation was measured using the HumanMethylation450 BeadChip. Results After filtering for the presence of polymorphisms and cell-lineage-specific signatures, 794 CpG sites showed significant DNA methylation differences as a function of age in all children (41.6% age-methylated and 58.4% age-demethylated, Bonferroni-corrected P value <0.01). Age-methylated CpGs were more frequently located in gene bodies and within +5 to +50 kilobases (kb) of transcription start sites (TSS) and enriched in developmental, neuronal and plasma membrane genes. Age-demethylated CpGs were associated to promoters and DNAse-I hypersensitivity sites, located within −5 to +5 kb of the nearest TSS and enriched in genes related to immunity, antigen presentation, the polycomb-group protein complex and cytoplasm. Conclusions This study reveals that susceptibility loci for complex inflammatory diseases (for example, IRF5, NOD2, and PTGER4) and genes encoding histone modifiers and chromatin remodeling factors (for example, HDAC4, KDM2A, KDM2B, JARID2, ARID3A, and SMARCD3) undergo DNA methylation changes in leukocytes during early childhood. These results open new perspectives to understand leukocyte maturation and provide a catalogue of CpG sites that may need to be corrected for age effects when performing DNA methylation studies in children.
  • Arnulfo, Gabriele; Narizzano, Massimo; Cardinale, Francesco; Fato, Marco M; Palva, Jaakko M (BioMed Central, 2015)
    Abstract Background Invasive monitoring of brain activity by means of intracerebral electrodes is widely practiced to improve pre-surgical seizure onset zone localization in patients with medically refractory seizures. Stereo-Electroencephalography (SEEG) is mainly used to localize the epileptogenic zone and a precise knowledge of the location of the electrodes is expected to facilitate the recordings interpretation and the planning of resective surgery. However, the localization of intracerebral electrodes on post-implant acquisitions is usually time-consuming (i.e., manual segmentation), it requires advanced 3D visualization tools, and it needs the supervision of trained medical doctors in order to minimize the errors. In this paper we propose an automated segmentation algorithm specifically designed to segment SEEG contacts from a thresholded post-implant Cone-Beam CT volume (0.4 mm, 0.4 mm, 0.8 mm). The algorithm relies on the planned position of target and entry points for each electrode as a first estimation of electrode axis. We implemented the proposed algorithm into DEETO, an open source C++ prototype based on ITK library. Results We tested our implementation on a cohort of 28 subjects in total. The experimental analysis, carried out over a subset of 12 subjects (35 multilead electrodes; 200 contacts) manually segmented by experts, show that the algorithm: (i) is faster than manual segmentation (i.e., less than 1s/subject versus a few hours) (ii) is reliable, with an error of 0.5 mm ± 0.06 mm, and (iii) it accurately maps SEEG implants to their anatomical regions improving the interpretability of electrophysiological traces for both clinical and research studies. Moreover, using the 28-subject cohort we show here that the algorithm is also robust (error < 0.005 mm) against deep-brain displacements (< 12 mm) of the implanted electrode shaft from those planned before surgery. Conclusions Our method represents, to the best of our knowledge, the first automatic algorithm for the segmentation of SEEG electrodes. The method can be used to accurately identify the neuroanatomical loci of SEEG electrode contacts by a non-expert in a fast and reliable manner.
  • Guo, Baocheng; DeFaveri, Jacquelin; Sotelo, Graciela; Nair, Abhilash; Merilä, Juha (BioMed Central, 2015)
    Abstract Background The degree of genetic differentiation among populations experiencing high levels of gene flow is expected to be low for neutral genomic sites, but substantial divergence can occur in sites subject to directional selection. Studies of highly mobile marine fish populations provide an opportunity to investigate this kind of heterogeneous genomic differentiation, but most studies to this effect have focused on a relatively low number of genetic markers and/or few populations. Hence, the patterns and extent of genomic divergence in high-gene-flow marine fish populations remain poorly understood. Results We here investigated genome-wide patterns of genetic variability and differentiation in ten marine populations of three-spined stickleback (Gasterosteus aculeatus) distributed across a steep salinity and temperature gradient in the Baltic Sea, by utilizing >30,000 single nucleotide polymorphisms obtained with a pooled RAD-seq approach. We found that genetic diversity and differentiation varied widely across the genome, and identified numerous fairly narrow genomic regions exhibiting signatures of both divergent and balancing selection. Evidence was uncovered for substantial genetic differentiation associated with both salinity and temperature gradients, and many candidate genes associated with local adaptation in the Baltic Sea were identified. Conclusions The patterns of genetic diversity and differentiation, as well as candidate genes associated with adaptation, in Baltic Sea sticklebacks were similar to those observed in earlier comparisons between marine and freshwater populations, suggesting that similar processes may be driving adaptation to brackish and freshwater environments. Taken together, our results provide strong evidence for heterogenic genomic divergence driven by local adaptation in the face of gene flow along an environmental gradient in the post-glacially formed Baltic Sea.