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  • Roine, Ulrika; Roine, Timo; Salmi, Juha; Nieminen-von Wendt, Taina; Tani, Pekka; Leppämäki, Sami; Rintahaka, Pertti; Caeyenberghs, Karen; Leemans, Alexander; Sams, Mikko (BioMed Central, 2015)
    Abstract Background Recent brain imaging findings suggest that there are widely distributed abnormalities affecting the brain connectivity in individuals with autism spectrum disorder (ASD). Using graph theoretical analysis, it is possible to investigate both global and local properties of brain’s wiring diagram, i.e., the connectome. Methods We acquired diffusion-weighted magnetic resonance imaging data from 14 adult males with high-functioning ASD and 19 age-, gender-, and IQ-matched controls. As with diffusion tensor imaging-based tractography, it is not possible to detect complex (e.g., crossing) fiber configurations, present in 60–90 % of white matter voxels; we performed constrained spherical deconvolution-based whole brain tractography. Unweighted and weighted structural brain networks were then reconstructed from these tractography data and analyzed with graph theoretical measures. Results In subjects with ASD, global efficiency was significantly decreased both in the unweighted and the weighted networks, normalized characteristic path length was significantly increased in the unweighted networks, and strength was significantly decreased in the weighted networks. In the local analyses, betweenness centrality of the right caudate was significantly increased in the weighted networks, and the strength of the right superior temporal pole was significantly decreased in the unweighted networks in subjects with ASD. Conclusions Our findings provide new insights into understanding ASD by showing that the integration of structural brain networks is decreased and that there are abnormalities in the connectivity of the right caudate and right superior temporal pole in subjects with ASD.
  • Palviainen, Mari J; Junnikkala, Sami; Raekallio, Marja; Meri, Seppo; Vainio, Outi (BioMed Central, 2015)
    Abstract Background Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammatory pain in humans and animals. An overdose of an NSAID is nephrotoxic and can lead to acute kidney injury (AKI). Complement activation occurs in several types of renal disorders with proteinuria. The aim of this study was to investigate whether complement system becomes activated in kidneys after a high dose of NSAID. Kidney tissue and urine samples were collected from six sheep with ketoprofen-induced AKI and from six healthy control sheep. The localization of complement proteins in kidney tissue was carried out using immunohistochemical stainings, and excretion of C3 was tested by immunoblotting. Results The complement system was found to become activated in the kidney tissue as demonstrated by positive immunostaining for C1q, C3c, C4c, C5, C9 and factor H and by Western blotting analysis of C3 activation products in urine samples in sheep with AKI. Conclusions Our results thus suggest that the alternative complement pathway is activated, and it may contribute to the acute tubular injury seen in the kidneys of NSAID-induced AKI sheep. Inhibition of complement activation may serve as potential therapeutic target for intervention in drug-induced AKI.
  • Palviainen, Mari J; Junnikkala, Sami; Raekallio, Marja; Meri, Seppo; Vainio, Outi (BioMed Central, 2015)
    Abstract Background Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammatory pain in humans and animals. An overdose of an NSAID is nephrotoxic and can lead to acute kidney injury (AKI). Complement activation occurs in several types of renal disorders with proteinuria. The aim of this study was to investigate whether complement system becomes activated in kidneys after a high dose of NSAID. Kidney tissue and urine samples were collected from six sheep with ketoprofen-induced AKI and from six healthy control sheep. The localization of complement proteins in kidney tissue was carried out using immunohistochemical stainings, and excretion of C3 was tested by immunoblotting. Results The complement system was found to become activated in the kidney tissue as demonstrated by positive immunostaining for C1q, C3c, C4c, C5, C9 and factor H and by Western blotting analysis of C3 activation products in urine samples in sheep with AKI. Conclusions Our results thus suggest that the alternative complement pathway is activated, and it may contribute to the acute tubular injury seen in the kidneys of NSAID-induced AKI sheep. Inhibition of complement activation may serve as potential therapeutic target for intervention in drug-induced AKI.
  • Kovalchuk, Andriy; Raffaello, Tommaso; Jaber, Emad; Keriö, Susanna; Ghimire, Rajendra; Lorenz, W W; Dean, Jeffrey F; Holopainen, Jarmo K; Asiegbu, Fred O (BioMed Central, 2015)
    Abstract Background During their lifetime, conifer trees are exposed to numerous herbivorous insects. To protect themselves against pests, trees have developed a broad repertoire of protective mechanisms. Many of the plant’s defence reactions are activated upon an insect attack, and the underlying regulatory mechanisms are not entirely understood yet, in particular in conifer trees. Here, we present the results of our studies on the transcriptional response and the volatile compounds production of Scots pine (Pinus sylvestris) upon the large pine weevil (Hylobius abietis) feeding. Results Transcriptional response of Scots pine to the weevil attack was investigated using a novel customised 36.4 K Pinus taeda microarray. The weevil feeding caused large-scale changes in the pine transcriptome. In total, 774 genes were significantly up-regulated more than 4-fold (p ≤ 0.05), whereas 64 genes were significantly down-regulated more than 4-fold. Among the up-regulated genes, we could identify genes involved in signal perception, signalling pathways, transcriptional regulation, plant hormone homeostasis, secondary metabolism and defence responses. The weevil feeding on stem bark of pine significantly increased the total emission of volatile organic compounds from the undamaged stem bark area. The emission levels of monoterpenes and sesquiterpenes were also increased. Interestingly, we could not observe any correlation between the increased production of the terpenoid compounds and expression levels of the terpene synthase-encoding genes. Conclusions The obtained data provide an important insight into the transcriptional response of conifer trees to insect herbivory and illustrate the massive changes in the host transcriptome upon insect attacks. Moreover, many of the induced pathways are common between conifers and angiosperms. The presented results are the first ones obtained by the use of a microarray platform with an extended coverage of pine transcriptome (36.4 K cDNA elements). The platform will further facilitate the identification of resistance markers with the direct relevance for conifer tree breeding.
  • Kovalchuk, Andriy; Raffaello, Tommaso; Jaber, Emad; Keriö, Susanna; Ghimire, Rajendra; Lorenz, W W; Dean, Jeffrey F; Holopainen, Jarmo K; Asiegbu, Fred O (BioMed Central, 2015)
    Abstract Background During their lifetime, conifer trees are exposed to numerous herbivorous insects. To protect themselves against pests, trees have developed a broad repertoire of protective mechanisms. Many of the plant’s defence reactions are activated upon an insect attack, and the underlying regulatory mechanisms are not entirely understood yet, in particular in conifer trees. Here, we present the results of our studies on the transcriptional response and the volatile compounds production of Scots pine (Pinus sylvestris) upon the large pine weevil (Hylobius abietis) feeding. Results Transcriptional response of Scots pine to the weevil attack was investigated using a novel customised 36.4 K Pinus taeda microarray. The weevil feeding caused large-scale changes in the pine transcriptome. In total, 774 genes were significantly up-regulated more than 4-fold (p ≤ 0.05), whereas 64 genes were significantly down-regulated more than 4-fold. Among the up-regulated genes, we could identify genes involved in signal perception, signalling pathways, transcriptional regulation, plant hormone homeostasis, secondary metabolism and defence responses. The weevil feeding on stem bark of pine significantly increased the total emission of volatile organic compounds from the undamaged stem bark area. The emission levels of monoterpenes and sesquiterpenes were also increased. Interestingly, we could not observe any correlation between the increased production of the terpenoid compounds and expression levels of the terpene synthase-encoding genes. Conclusions The obtained data provide an important insight into the transcriptional response of conifer trees to insect herbivory and illustrate the massive changes in the host transcriptome upon insect attacks. Moreover, many of the induced pathways are common between conifers and angiosperms. The presented results are the first ones obtained by the use of a microarray platform with an extended coverage of pine transcriptome (36.4 K cDNA elements). The platform will further facilitate the identification of resistance markers with the direct relevance for conifer tree breeding.
  • Chong, Sun-Li; Derba-Maceluch, Marta; Koutaniemi, Sanna; Gómez, Leonardo D; McQueen-Mason, Simon J; Tenkanen, Maija; Mellerowicz, Ewa J (BioMed Central, 2015)
    Abstract Background Expressing microbial polysaccharide-modifying enzymes in plants is an attractive approach to custom tailor plant lignocellulose and to study the importance of wall structures to plant development. Expression of α-glucuronidases in plants to modify the structures of glucuronoxylans has not been yet attempted. Glycoside hydrolase (GH) family 115 α-glucuronidases cleave the internal α-D-(4-O-methyl)glucopyranosyluronic acid ((Me)GlcA) from xylans or xylooligosaccharides. In this work, a GH115 α-glucuronidase from Schizophyllum commune, ScAGU115, was expressed in Arabidopsis thaliana and targeted to apoplast. The transgene effects on native xylans’ structures, plant development, and lignocellulose saccharification were evaluated and compared to those of knocked out glucuronyltransferases AtGUX1 and AtGUX2. Results The ScAGU115 extracted from cell walls of Arabidopsis was active on the internally substituted aldopentaouronic acid (XUXX). The transgenic plants did not show any change in growth or in lignocellulose saccharification. The cell wall (Me)GlcA and other non-cellulosic sugars, as well as the lignin content, remained unchanged. In contrast, the gux1gux2 double mutant showed a 70% decrease in (Me)GlcA to xylose molar ratio, and, interestingly, a 60% increase in the xylose content. Whereas ScAGU115-expressing plants exhibited a decreased signal in native secondary walls from the monoclonal antibody UX1 that recognizes (Me)GlcA on non-acetylated xylan, the signal was not affected after wall deacetylation. In contrast, gux1gux2 mutant was lacking UX1 signals in both native and deacetylated cell walls. This indicates that acetyl substitution on the xylopyranosyl residue carrying (Me)GlcA or on the neighboring xylopyranosyl residues may restrict post-synthetic modification of xylans by ScAGU115 in planta. Conclusions Active GH115 α-glucuronidase has been produced for the first time in plants. The cell wall–targeted ScAGU115 was shown to affect those glucuronate substitutions of xylan, which are accessible to UX1 antibody and constitute a small fraction in Arabidopsis, whereas majority of (Me)GlcA substitutions were resistant, most likely due to the shielding by acetyl groups. Plants expressing ScAGU115 did not show any defects under laboratory conditions indicating that the UX1 epitope of xylan is not essential under these conditions. Moreover the removal of the UX1 xylan epitope does not affect lignocellulose saccharification.
  • Chong, Sun-Li; Derba-Maceluch, Marta; Koutaniemi, Sanna; Gómez, Leonardo D; McQueen-Mason, Simon J; Tenkanen, Maija; Mellerowicz, Ewa J (BioMed Central, 2015)
    Abstract Background Expressing microbial polysaccharide-modifying enzymes in plants is an attractive approach to custom tailor plant lignocellulose and to study the importance of wall structures to plant development. Expression of α-glucuronidases in plants to modify the structures of glucuronoxylans has not been yet attempted. Glycoside hydrolase (GH) family 115 α-glucuronidases cleave the internal α-D-(4-O-methyl)glucopyranosyluronic acid ((Me)GlcA) from xylans or xylooligosaccharides. In this work, a GH115 α-glucuronidase from Schizophyllum commune, ScAGU115, was expressed in Arabidopsis thaliana and targeted to apoplast. The transgene effects on native xylans’ structures, plant development, and lignocellulose saccharification were evaluated and compared to those of knocked out glucuronyltransferases AtGUX1 and AtGUX2. Results The ScAGU115 extracted from cell walls of Arabidopsis was active on the internally substituted aldopentaouronic acid (XUXX). The transgenic plants did not show any change in growth or in lignocellulose saccharification. The cell wall (Me)GlcA and other non-cellulosic sugars, as well as the lignin content, remained unchanged. In contrast, the gux1gux2 double mutant showed a 70% decrease in (Me)GlcA to xylose molar ratio, and, interestingly, a 60% increase in the xylose content. Whereas ScAGU115-expressing plants exhibited a decreased signal in native secondary walls from the monoclonal antibody UX1 that recognizes (Me)GlcA on non-acetylated xylan, the signal was not affected after wall deacetylation. In contrast, gux1gux2 mutant was lacking UX1 signals in both native and deacetylated cell walls. This indicates that acetyl substitution on the xylopyranosyl residue carrying (Me)GlcA or on the neighboring xylopyranosyl residues may restrict post-synthetic modification of xylans by ScAGU115 in planta. Conclusions Active GH115 α-glucuronidase has been produced for the first time in plants. The cell wall–targeted ScAGU115 was shown to affect those glucuronate substitutions of xylan, which are accessible to UX1 antibody and constitute a small fraction in Arabidopsis, whereas majority of (Me)GlcA substitutions were resistant, most likely due to the shielding by acetyl groups. Plants expressing ScAGU115 did not show any defects under laboratory conditions indicating that the UX1 epitope of xylan is not essential under these conditions. Moreover the removal of the UX1 xylan epitope does not affect lignocellulose saccharification.
  • Pausch, Hubert; Venhoranta, Heli; Wurmser, Christine; Hakala, Kalle; Iso-Touru, Terhi; Sironen, Anu; Vingborg, Rikke K; Lohi, Hannes; Söderquist, Lennart; Fries, Ruedi; Andersson, Magnus (BioMed Central, 2016)
    Abstract Background Artificial insemination is widely used in many cattle breeding programs. Semen samples of breeding bulls are collected and closely examined immediately after collection at artificial insemination centers. Only ejaculates without anomalous findings are retained for artificial insemination. Although morphological aberrations of the spermatozoa are a frequent reason for discarding ejaculates, the genetic determinants underlying poor semen quality are scarcely understood. Results A tail stump sperm defect was observed in three bulls of the Swedish Red cattle breed. The spermatozoa of affected bulls were immotile because of severely disorganized tails indicating disturbed spermatogenesis. We genotyped three affected bulls and 18 unaffected male half-sibs at 46,035 SNPs and performed homozygosity mapping to map the fertility disorder to an 8.42 Mb interval on bovine chromosome 13. The analysis of whole-genome re-sequencing data of an affected bull and 300 unaffected animals from eleven cattle breeds other than Swedish Red revealed a 1 bp deletion (Chr13: 24,301,425 bp, ss1815612719) in the eleventh exon of the armadillo repeat containing 3-encoding gene (ARMC3) that was compatible with the supposed recessive mode of inheritance. The deletion is expected to alter the reading frame and to induce premature translation termination (p.A451fs26). The mutated protein is shortened by 401 amino acids (46 %) and lacks domains that are likely essential for normal protein function. Conclusions We report the phenotypic and genetic characterization of a sterilizing tail stump sperm defect in the Swedish Red cattle breed. Exploiting high-density genotypes and massive re-sequencing data enabled us to identify the most likely causal mutation for the fertility disorder in bovine ARMC3. Our results provide the basis for monitoring the mutated variant in the Swedish Red cattle population and for the early identification of infertile animals.
  • 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.
  • 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.
  • Kaurilind, Eve; Xu, Enjun; Brosché, Mikael (BioMed Central, 2015)
    Abstract Background To survive in a changing environment plants constantly monitor their surroundings. In response to several stresses and during photorespiration plants use reactive oxygen species as signaling molecules. The Arabidopsis thaliana catalase2 (cat2) mutant lacks a peroxisomal catalase and under photorespiratory conditions accumulates H2O2, which leads to activation of cell death. Methods A cat2 double mutant collection was generated through crossing and scored for cell death in different assays. Selected double mutants were further analyzed for photosynthetic performance and H2O2 accumulation. Results We used a targeted mutant analysis with more than 50 cat2 double mutants to investigate the role of stress hormones and other defense regulators in H2O2-mediated cell death. Several transcription factors (AS1, MYB30, MYC2, WRKY70), cell death regulators (RCD1, DND1) and hormone regulators (AXR1, ERA1, SID2, EDS1, SGT1b) were essential for execution of cell death in cat2. Genetic loci required for cell death in cat2 was compared with regulators of cell death in spontaneous lesion mimic mutants and led to the identification of a core set of plant cell death regulators. Analysis of gene expression data from cat2 and plants undergoing cell death revealed similar gene expression profiles, further supporting the existence of a common program for regulation of plant cell death. Conclusions Our results provide a genetic framework for further study on the role of H2O2 in regulation of cell death. The hormones salicylic acid, jasmonic acid and auxin, as well as their interaction, are crucial determinants of cell death regulation.
  • Kaurilind, Eve; Xu, Enjun; Brosché, Mikael (BioMed Central, 2015)
    Abstract Background To survive in a changing environment plants constantly monitor their surroundings. In response to several stresses and during photorespiration plants use reactive oxygen species as signaling molecules. The Arabidopsis thaliana catalase2 (cat2) mutant lacks a peroxisomal catalase and under photorespiratory conditions accumulates H2O2, which leads to activation of cell death. Methods A cat2 double mutant collection was generated through crossing and scored for cell death in different assays. Selected double mutants were further analyzed for photosynthetic performance and H2O2 accumulation. Results We used a targeted mutant analysis with more than 50 cat2 double mutants to investigate the role of stress hormones and other defense regulators in H2O2-mediated cell death. Several transcription factors (AS1, MYB30, MYC2, WRKY70), cell death regulators (RCD1, DND1) and hormone regulators (AXR1, ERA1, SID2, EDS1, SGT1b) were essential for execution of cell death in cat2. Genetic loci required for cell death in cat2 was compared with regulators of cell death in spontaneous lesion mimic mutants and led to the identification of a core set of plant cell death regulators. Analysis of gene expression data from cat2 and plants undergoing cell death revealed similar gene expression profiles, further supporting the existence of a common program for regulation of plant cell death. Conclusions Our results provide a genetic framework for further study on the role of H2O2 in regulation of cell death. The hormones salicylic acid, jasmonic acid and auxin, as well as their interaction, are crucial determinants of cell death regulation.
  • Stenroos, Antti J; Handolin, Lauri E (BioMed Central Ltd, 2014)
    Abstract Background Alpine skiing is one of the most popular winter sports in the world. Nevertheless, it has always been associated with a high risk of injury. There are however, only a few studies that have examined the risk of injury of competitive skiers, especially of the junior ski racers. Methods The inclusion criterion was an injury in alpine skiing resulting in a pause in training longer than one week. Athletes of all ages were included. The study period was from the start of the season of 2008&#8211;2009 to end of the season of 2009&#8211;2010 (two years). Results The average annual number of ski racers in Finland was 661. There were 61 injuries (36 males with a median age of 14&#160;years, 25 females with a median age of 14) fulfilling the inclusion criteria. Ligamentous knee injury was the most frequent (17) and lower leg fracture the second common (16) injury, respectively. There was a female dominance in the ACL injuries. Only one major abdominal injury and no major head injuries were observed. The overall training pause was 26&#160;weeks after the ACL injury and 17&#160;weeks after the lower leg fracture, respectively. Conclusion The most common and most disabling injuries affect the knee and the lower leg. The high number of lower leg and ACL injuries is alarming. A continuous and careful monitoring of injuries needs to be established to assess this trend. A systematic review of injuries is the appropriate way to monitor the effects of changes made in terms of safety. The present retrospective two-year pilot study forms a base for a continuous alpine ski injury survey in Finland.
  • 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 ClinicalTrials.gov: NCT01722500
  • 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 ClinicalTrials.gov: NCT01722500
  • Cao, Tianjian; Hyytiäinen, Kari; Hurttala, Henna; Valsta, Lauri; Vanclay, Jerome K (Beijing Forestry University, 2015)
    Abstract Background Bioenergy is re-shaping opportunities and imperatives of forest management. This study demonstrates, through a case study in Scots pine (Pinus sylvestris L.), how forest bioenergy policies affect stand management strategies. Methods Optimization studies were examined for 15 Scots pine stands of different initial stand densities, site types, and temperature sum regions in Finland. Stand development was modelled using the PipeQual stand simulator coupled with the simulation-optimization tool OptiFor Bioenergy to assess three forest bioenergy policies on energy wood harvest from early thinnings. Results The optimal solutions maximizing bare land value indicate that conventional forest management regimes remain optimal for sparse stands. Energy harvests occurred only when profitable, led to lower financial returns. A forest bioenergy policy which included compulsory energy wood harvesting was optimal for denser stands. At a higher interest rate (4 %), increasing energy wood price postponed energy wood harvesting. In addition, our results show that early thinning somewhat reduced wood quality for stands in fertile sites. For less fertile sites, the changes were insignificant. Conclusions A constraint of profitable energy wood harvest is not rational. It is optimal to carry out the first thinning with a flexible forest bioenergy policy depending on stand density.
  • Sobral-Leite, Marcelo; Wesseling, Jelle; Smit, Vincent T H B M; Nevanlinna, Heli; van Miltenburg, Martine H; Sanders, Joyce; Hofland, Ingrid; Blows, Fiona M; Coulson, Penny; Patrycja, Gazinska; Schellens, Jan H M; Fagerholm, Rainer; Heikkilä, Päivi; Aittomäki, Kristiina; Blomqvist, Carl; Provenzano, Elena; Ali, Hamid R; Figueroa, Jonine; Sherman, Mark; Lissowska, Jolanta; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Phillips, Kelly-Anne; Couch, Fergus J; Olson, Janet E; Vachon, Celine; Visscher, Daniel; Brenner, Hermann; Butterbach, Katja; Arndt, Volker; Holleczek, Bernd; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John W M; van Deurzen, Carolien H M; van de Water, Bob; Broeks, Annegien; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Easton, Douglas F; Pharoah, Paul D P; García-Closas, Montserrat; de Graauw, Marjo; Schmidt, Marjanka K (BioMed Central, 2015)
    Abstract Background Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model. Results The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05–1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91–1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17–2.45). Conclusions ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.
  • Sobral-Leite, Marcelo; Wesseling, Jelle; Smit, Vincent T H B M; Nevanlinna, Heli; van Miltenburg, Martine H; Sanders, Joyce; Hofland, Ingrid; Blows, Fiona M; Coulson, Penny; Patrycja, Gazinska; Schellens, Jan H M; Fagerholm, Rainer; Heikkilä, Päivi; Aittomäki, Kristiina; Blomqvist, Carl; Provenzano, Elena; Ali, Hamid R; Figueroa, Jonine; Sherman, Mark; Lissowska, Jolanta; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Phillips, Kelly-Anne; Couch, Fergus J; Olson, Janet E; Vachon, Celine; Visscher, Daniel; Brenner, Hermann; Butterbach, Katja; Arndt, Volker; Holleczek, Bernd; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John W M; van Deurzen, Carolien H M; van de Water, Bob; Broeks, Annegien; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Easton, Douglas F; Pharoah, Paul D P; García-Closas, Montserrat; de Graauw, Marjo; Schmidt, Marjanka K (BioMed Central, 2015)
    Abstract Background Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model. Results The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05–1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91–1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17–2.45). Conclusions ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.
  • Sobral-Leite, Marcelo; Wesseling, Jelle; Smit, Vincent T H B M; Nevanlinna, Heli; van Miltenburg, Martine H; Sanders, Joyce; Hofland, Ingrid; Blows, Fiona M; Coulson, Penny; Patrycja, Gazinska; Schellens, Jan H M; Fagerholm, Rainer; Heikkilä, Päivi; Aittomäki, Kristiina; Blomqvist, Carl; Provenzano, Elena; Ali, Hamid R; Figueroa, Jonine; Sherman, Mark; Lissowska, Jolanta; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Phillips, Kelly-Anne; Couch, Fergus J; Olson, Janet E; Vachon, Celine; Visscher, Daniel; Brenner, Hermann; Butterbach, Katja; Arndt, Volker; Holleczek, Bernd; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John W M; van Deurzen, Carolien H M; van de Water, Bob; Broeks, Annegien; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Easton, Douglas F; Pharoah, Paul D P; García-Closas, Montserrat; de Graauw, Marjo; Schmidt, Marjanka K (BioMed Central, 2015)
    Abstract Background Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model. Results The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05–1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91–1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17–2.45). Conclusions ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.
  • Kort, Remco; Westerik, Nieke; Mariela Serrano, L.; Douillard, François P; Gottstein, Willi; Mukisa, Ivan M; Tuijn, Coosje J; Basten, Lisa; Hafkamp, Bert; Meijer, Wilco C; Teusink, Bas; de Vos, Willem M; Reid, Gregor; Sybesma, Wilbert (BioMed Central, 2015)
    Abstract Background The lactic acid bacterium Lactobacillus rhamnosus GG is the most studied probiotic bacterium with proven health benefits upon oral intake, including the alleviation of diarrhea. The mission of the Yoba for Life foundation is to provide impoverished communities in Africa increased access to Lactobacillus rhamnosus GG under the name Lactobacillus rhamnosus yoba 2012, world’s first generic probiotic strain. We have been able to overcome the strain’s limitations to grow in food matrices like milk, by formulating a dried starter consortium with Streptococcus thermophilus that enables the propagation of both strains in milk and other food matrices. The affordable seed culture is used by people in resource-poor communities. Results We used S. thermophilus C106 as an adjuvant culture for the propagation of L. rhamnosus yoba 2012 in a variety of fermented foods up to concentrations, because of its endogenous proteolytic activity, ability to degrade lactose and other synergistic effects. Subsequently, L. rhamnosus could reach final titers of 1E+09 CFU ml−1, which is sufficient to comply with the recommended daily dose for probiotics. The specific metabolic interactions between the two strains were derived from the full genome sequences of L. rhamnosus GG and S. thermophilus C106. The piliation of the L. rhamnosus yoba 2012, required for epithelial adhesion and inflammatory signaling in the human host, was stable during growth in milk for two rounds of fermentation. Sachets prepared with the two strains, yoba 2012 and C106, retained viability for at least 2 years. Conclusions A stable dried seed culture has been developed which facilitates local and low-cost production of a wide range of fermented foods that subsequently act as delivery vehicles for beneficial bacteria to communities in east Africa.