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  • Koskinen, Lotta L E; Seppälä, Eija H; Belanger, Janelle M; Arumilli, Meharji; Hakosalo, Osmo; Jokinen, Päivi; Nevalainen, Elisa M; Viitmaa, Ranno; Jokinen, Tarja S; Oberbauer, Anita M; Lohi, Hannes (BioMed Central, 2015)
    Abstract Background Idiopathic epilepsy is a common neurological disease in human and domestic dogs but relatively few risk genes have been identified to date. The seizure characteristics, including focal and generalised seizures, are similar between the two species, with gene discovery facilitated by the reduced genetic heterogeneity of purebred dogs. We have recently identified a risk locus for idiopathic epilepsy in the Belgian Shepherd breed on a 4.4 megabase region on CFA37. Results We have expanded a previous study replicating the association with a combined analysis of 157 cases and 179 controls in three additional breeds: Schipperke, Finnish Spitz and Beagle (pc = 2.9e–07, pGWAS = 1.74E-02). A targeted resequencing of the 4.4 megabase region in twelve Belgian Shepherd cases and twelve controls with opposite haplotypes identified 37 case-specific variants within the ADAM23 gene. Twenty-seven variants were validated in 285 cases and 355 controls from four breeds, resulting in a strong replication of the ADAM23 locus (praw = 2.76e–15) and the identification of a common 28 kb-risk haplotype in all four breeds. Risk haplotype was present in frequencies of 0.49–0.7 in the breeds, suggesting that ADAM23 is a low penetrance risk gene for canine epilepsy. Conclusions These results implicate ADAM23 in common canine idiopathic epilepsy, although the causative variant remains yet to be identified. ADAM23 plays a role in synaptic transmission and interacts with known epilepsy genes, LGI1 and LGI2, and should be considered as a candidate gene for human epilepsies.
  • Liu, Chengyu; Louhimo, Riku; Laakso, Marko; Lehtonen, Rainer; Hautaniemi, Sampsa (BioMed Central, 2015)
    Abstract Background Histologically similar tumors even from the same anatomical position may still show high variability at molecular level hindering analysis of genome-wide data. Leveling the analysis to a gene regulatory network instead of focusing on single genes has been suggested to overcome the heterogeneity issue although the majority of the network methods require large datasets. Network methods that are able to function at a single sample level are needed to overcome the heterogeneity and sample size issues. Methods We present a novel network method, Differentially Expressed Regulation Analysis (DERA) that integrates expression data to biological network information at a single sample level. The sample-specific networks are subsequently used to discover samples with similar molecular functions by identification of regulations that are shared between samples or are specific for a subgroup. Results We applied DERA to identify key regulations in triple negative breast cancer (TNBC), which is characterized by lack of estrogen receptor, progesterone receptor and HER2 expression and has poorer prognosis than the other breast cancer subtypes. DERA identified 110 core regulations consisting of 28 disconnected subnetworks for TNBC. These subnetworks are related to oncogenic activity, proliferation, cancer survival, invasiveness and metastasis. Our analysis further revealed 31 regulations specific for TNBC as compared to the other breast cancer subtypes and thus form a basis for understanding TNBC. We also applied DERA to high-grade serous ovarian cancer (HGS-OvCa) data and identified several common regulations between HGS-OvCa and TNBC. The performance of DERA was compared to two pathway analysis methods GSEA and SPIA and our results shows better reproducibility and higher sensitivity in a small sample set. Conclusions We present a novel method called DERA to identify subnetworks that are similarly active for a group of samples. DERA was applied to breast cancer and ovarian cancer data showing our method is able to identify reliable and potentially important regulations with high reproducibility. R package is available at .
  • Kaur, Sippy; Lotsari, Johanna E; Al-Sohaily, Sam; Warusavitarne, Janindra; Kohonen-Corish, Maija R; Peltomäki, Päivi (BioMed Central, 2015)
    Abstract Background Altered expression of microRNAs (miRNAs) commonly accompanies colorectal (CRC) and endometrial carcinoma (EC) development, but the underlying mechanisms and clinicopathological correlations remain to be clarified. We focused on epigenetic mechanisms and aimed to explore if DNA methylation patterns in tumors depend on DNA mismatch repair (MMR) status, sporadic vs. Lynch-associated disease, and geographic origin (Finland vs. Australia). Treatment of cancer cell lines with demethylating agents revealed 109 significantly upregulated miRNAs. Seven met our stringent criteria for possible methylation-sensitive miRNAs and were used to screen patient specimens (205 CRCs and 36 ECs) by methylation-specific multiplex ligation-dependent probe amplification. Results Three miRNAs (129-2, 345, and 132) with low methylation levels in normal tissue and frequent hypermethylation in tumors were of particular interest. Hypermethylation of miR-345 and miR-132 associated with MMR deficiency in CRC regardless of geographic origin, and hypermethylation of miR-132 distinguished sporadic MMR-deficient CRC from Lynch-CRC. Finally, hypermethylation of miRNAs stratified 49 endometrial hyperplasias into low-methylator (simple hyperplasia) and high-methylator groups (complex hyperplasia with or without atypia) and suggested that miR-129-2 methylation in particular could serve as a marker of progression in early endometrial tumorigenesis. Conclusions Our study identifies miR-345 and miR-132 as novel differentially methylated miRNAs in CRC, thereby facilitating sub-classification of CRC and links miR-129-2 methylation to early endometrial tumorigenesis.
  • Zhang, Yanlei; Ning, Feng; Sun, Jianping; Pang, Zengchang; Wang, Xiaoyong; Kapur, Anil; Sintonen, Harri; Qiao, Qing (BioMed Central, 2015)
    Abstract Background Screening for type 2 diabetes helps detect previously unknown diabetes and identify people with pre-diabetes, but the adverse impact of such screening on individuals labelled as pre-diabetes or classified as normal, is less known. In this study the health-related quality of life (HRQoL), depression and lifestyle changes in a rural Chinese population are assessed three years after a screening program. Methods A total of 647 (39.1%) individuals with pre-diabetes and 1009 (60.9%) individuals with normoglycaemia from a population-based diabetes screening program in 2009 were re-examined in 2012–2013. Changes at the end of 3 years in HRQoL, depression, BMI, weight, frequency of physical activity and vegetable intake were assessed. Results In men with normoglycaemia the mean (SD) 15D scores were 0.974 (0.04) at baseline and 0.973 (0.05) at follow-up; and 0.971 (0.05) and 0.966 (0.06) for men with pre-diabetes. In women the scores were 0.973 (0.05) and 0.963 (0.06) for normoglycaemia and 0.959 (0.06) and 0.954 (0.07) for pre-diabetes, respectively. Compared to baseline, the HRQoL was slightly lower at 3 years in all groups but the change was not considered to be clinically important, and was only statistically significant for women with normoglycaemia (p < 0.05). The depression score was slightly elevated in women, but not in men. No significant changes in BMI were noticed, but weight increased slightly in the normoglycemia group (p < 0.05). Screening had a significant positive impact on physical activity and vegetable intake. Conclusions This population-based diabetes screening program generated long-term positive changes toward a healthy lifestyle as measured by physical activity and vegetable intake for all the participants without adverse effects on the HRQoL and depression.
  • Akl, Elie A; Kahale, Lara A; Agarwal, Arnav; Al-Matari, Nada; Ebrahim, Shanil; Alexander, Paul E; Briel, Matthias; Brignardello-Petersen, Romina; Busse, Jason W; Diab, Batoul; Iorio, Alfonso; Kwong, Joey; Li, Ling; Lopes, Luciane C; Mustafa, Reem; Neumann, Ignacio; Tikkinen, Kari AO; Vandvik, Per O; Zhang, Yuqing; Alonso-Coello, Pablo; Guyatt, Gordon (BioMed Central Ltd, 2014)
    Abstract Background There is no consensus on how authors conducting meta-analysis should deal with trial participants with missing outcome data. The objectives of this study are to assess in Cochrane and non-Cochrane systematic reviews: (1) which categories of trial participants the systematic review authors consider as having missing participant data (MPD), (2) how trialists reported on participants with missing outcome data in trials, (3) whether systematic reviewer authors actually dealt with MPD in their meta-analyses of dichotomous outcomes consistently with their reported methods, and (4) the impact of different methods of dealing with MPD on pooled effect estimates in meta-analyses of dichotomous outcomes. Methods/Design We will conduct a methodological study of Cochrane and non-Cochrane systematic reviews. Eligible systematic reviews will include a group-level meta-analysis of a patient-important dichotomous efficacy outcome, with a statistically significant effect estimate. Teams of two reviewers will determine eligibility and subsequently extract information from each eligible systematic review in duplicate and independently, using standardized, pre-piloted forms. The teams will then use a similar process to extract information from the trials included in the meta-analyses of interest. We will assess first which categories of trial participants the systematic reviewers consider as having MPD. Second, we will assess how trialists reported on participants with missing outcome data in trials. Third, we will compare what systematic reviewers report having done, and what they actually did, in dealing with MPD in their meta-analysis. Fourth, we will conduct imputation studies to assess the effects of different methods of dealing with MPD on the pooled effect estimates of meta-analyses. We will specifically calculate for each method (1) the percentage of systematic reviews that lose statistical significance and (2) the mean change of effect estimates across systematic reviews. Discussion The impact of different methods of dealing with MPD on pooled effect estimates will help judge the associated risk of bias in systematic reviews. Our findings will inform recommendations regarding what assumptions for MPD should be used to test the robustness of meta-analytical results.
  • Tudor-Locke, Catrine; Barreira, Tiago V; Schuna, John M; Mire, Emily F; Chaput, Jean-Philippe; Fogelholm, Mikael; Hu, Gang; Kuriyan, Rebecca; Kurpad, Anura; Lambert, Estelle V; Maher, Carol; Maia, José; Matsudo, Victor; Olds, Tim; Onywera, Vincent; Sarmiento, Olga L; Standage, Martyn; Tremblay, Mark S; Zhao, Pei; Church, Timothy S; Katzmarzyk, Peter T (BioMed Central, 2015)
    Abstract Background We compared 24-hour waist-worn accelerometer wear time characteristics of 9–11 year old children in the International Study of Childhood Obesity, Lifestyle and the Environment (ISCOLE) to similarly aged U.S. children providing waking-hours waist-worn accelerometer data in the 2003–2006 National Health and Nutrition Examination Survey (NHANES). Methods Valid cases were defined as having ≥4 days with ≥10 hours of waking wear time in a 24-hour period, including one weekend day. Previously published algorithms for extracting total sleep episode time from 24-hour accelerometer data and for identifying wear time (in both the 24-hour and waking-hours protocols) were applied. The number of valid days obtained and a ratio (percent) of valid cases to the number of participants originally wearing an accelerometer were computed for both ISCOLE and NHANES. Given the two surveys’ discrepant sampling designs, wear time (minutes/day, hours/day) from U.S. ISCOLE was compared to NHANES using a meta-analytic approach. Wear time for the 11 additional countries participating in ISCOLE were graphically compared with NHANES. Results 491 U.S. ISCOLE children (9.92±0.03 years of age [M±SE]) and 586 NHANES children (10.43 ± 0.04 years of age) were deemed valid cases. The ratio of valid cases to the number of participants originally wearing an accelerometer was 76.7% in U.S. ISCOLE and 62.6% in NHANES. Wear time averaged 1357.0 ± 4.2 minutes per 24-hour day in ISCOLE. Waking wear time was 884.4 ± 2.2 minutes/day for U.S. ISCOLE children and 822.6 ± 4.3 minutes/day in NHANES children (difference = 61.8 minutes/day, p < 0.001). Wear time characteristics were consistently higher in all ISCOLE study sites compared to the NHANES protocol. Conclusions A 24-hour waist-worn accelerometry protocol implemented in U.S. children produced 22.6 out of 24 hours of possible wear time, and 61.8 more minutes/day of waking wear time than a similarly implemented and processed waking wear time waist-worn accelerometry protocol. Consistent results were obtained internationally. The 24-hour protocol may produce an important increase in wear time compliance that also provides an opportunity to study the total sleep episode time separate and distinct from physical activity and sedentary time detected during waking-hours. Trial registration NCT01722500 .
  • 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).
  • Mikonranta, Lauri; Mappes, Johanna; Kaukoniitty, Minna; Freitak, Dalial (BioMed Central Ltd, 2014)
    Abstract Background Previous exposure to a pathogen can help organisms cope with recurring infection. This is widely recognised in vertebrates, but increasing occasions are also being reported in invertebrates where this phenomenon is referred to as immune priming. However, the mechanisms that allow acquired pathogen resistance in insects remain largely unknown. Results We studied the priming of bacterial resistance in the larvae of the tiger moth, Parasemia plantaginis using two gram-negative bacteria, a pathogenic Serratia marcescens and a non-pathogenic control, Escherichia coli. A sublethal oral dose of S. marcescens provided the larvae with effective protection against an otherwise lethal septic infection with the same pathogen five days later. At the same time, we assessed three anti-bacterial defence mechanisms from the larvae that had been primarily exposed to the bacteria via contaminated host plant. Results showed that S. marcescens had induced a higher amount of reactive oxygen species (ROS) in the larval haemolymph, possibly protecting the host from the recurring infection. Conclusions Our study supports the growing evidence of immune priming in insects. It shows that activation of the protective mechanism requires a specific induction, rather than a sheer exposure to any gram-negative bacteria. The findings indicate that systemic pathogen recognition happens via the gut, and suggest that persistent loitering of immune elicitors or anti-microbial molecules are a possible mechanism for the observed prophylaxis. The self-harming effects of ROS molecules are well known, which indicates a potential cost of increased resistance. Together these findings could have important implications on the ecological and epidemiological processes affecting insect and pathogen populations.
  • Laurila, Kirsti; Autio, Reija; Kong, Lingjia; Närvä, Elisa; Hussein, Samer; Otonkoski, Timo; Lahesmaa, Riitta; Lähdesmäki, Harri (BioMed Central Ltd, 2014)
    Abstract Background Human genomic variations, including single nucleotide polymorphisms (SNPs) and copy number variations (CNVs), are associated with several phenotypic traits varying from mild features to hereditary diseases. Several genome-wide studies have reported genomic variants that correlate with gene expression levels in various tissue and cell types. Results We studied human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) measuring the SNPs and CNVs with Affymetrix SNP 6 microarrays and expression values with Affymetrix Exon microarrays. We computed the linear relationships between SNPs and expression levels of exons, transcripts and genes, and the associations between gene CNVs and gene expression levels. Further, for a few of the resulted genes, the expression value was associated with both CNVs and SNPs. Our results revealed altogether 217 genes and 584 SNPs whose genomic alterations affect the transcriptome in the same cells. We analyzed the enriched pathways and gene ontologies within these groups of genes, and found out that the terms related to alternative splicing and development were enriched. Conclusions Our results revealed that in the human pluripotent stem cells, the expression values of several genes, transcripts and exons were affected due to the genomic variation.
  • 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.
  • Lappalainen, Anu K; Vaittinen, Elina; Junnila, Jouni; Laitinen-Vapaavuori, Outi (BioMed Central Ltd, 2014)
    Abstract Background Intervertebral disc disease (IDD) is a very common neurological disease, Dachshunds being the breed most often affected. In this breed, IDD has a hereditary background and is associated with intervertebral disc calcification (IDC), an indicator of severe intervertebral disc degeneration. In Finland, spinal radiography is used, when screening for IDC before breeding Dachshunds. We evaluated the association between IDC and IDD in Finnish Dachshunds radiographically screened for IDC. A questionnaire was sent to owners of 193 radiographically screened Dachshunds aged at least ten years. Clinical signs indicative of IDD were compared with IDC grade (grade 0&#8201;=&#8201;no calcifications, grade 1&#8201;=&#8201;1 &#8211; 2 calcifications, grade 2&#8201;=&#8201;3 &#8211; 4 calcifications and grade 3&#8201;=&#8201;5 or more calcifications) and with age at the time of the radiographic examination. The diagnosis of IDD was confirmed by a veterinarian. Results IDD was common in the study population with 31% of dogs being affected. IDD and IDC were clearly connected (P&#8201;&lt;&#8201;0.001); IDD was rare in dogs with no calcifications (grade 0) and common in dogs with severe IDC (grade 3). The IDC grade was strongly positively associated with frequency of back pain periods (P&#8201;&lt;&#8201;0.001), and dogs with IDC grade 3 had frequent periods of pain. Reluctance to jump onto a sofa had a strong positive association with back pain. No association existed between age of the dog at the time of the radiographic examination and clinical signs indicative of IDD. Conclusions Radiographically detected IDC and IDD are common in Finnish Dachshunds and are strongly associated with one another. Spinal radiography is an appropriate screening tool for breeders attempting to diminish IDC and IDD in Dachshunds. A breeding program that screens dogs and selects against IDC can be expected to reduce the occurrence of IDD in future. Twenty-four to 48&#160;months of age is a suitable age for screening.
  • Lokki, A I; Järvelä, Irma; Israelsson, Elisabeth; Maiga, Bakary; Troye-Blomberg, Marita; Dolo, Amagana; Doumbo, Ogobara K; Meri, Seppo; Holmberg, Ville (BioMed Central Ltd, 2011)
    Abstract Background Fulani are a widely spread African ethnic group characterized by lower susceptibility to Plasmodium falciparum, clinical malaria morbidity and higher rate of lactase persistence compared to sympatric tribes. Lactase non-persistence, often called lactose intolerance, is the normal condition where lactase activity in the intestinal wall declines after weaning. Lactase persistence, common in Europe, and in certain African people with traditions of raising cattle, is caused by polymorphisms in the enhancer region approximately 14 kb upstream of the lactase gene. Methods To evaluate the relationship between malaria and lactase persistence genotypes, a 400 bp region surrounding the main European C/T-13910 polymorphism upstream of the lactase gene was sequenced. DNA samples used in the study originated from 162 Fulani and 79 Dogon individuals from Mali. Results Among 79 Dogon only one heterozygote of the lactase enhancer polymorphism was detected, whereas all others were homozygous for the ancestral C allele. Among the Fulani, the main European polymorphism at locus C/T-13910 was by far the most common polymorphism, with an allele frequency of 37%. Three other single-nucleotide polymorphisms were found with allele frequencies of 3.7%, 1.9% and 0.6% each. The novel DNA polymorphism T/C-13906 was seen in six heterozygous Fulani. Among the Fulani with lactase non-persistence CC genotypes at the C/T-13910 locus, 24% had malaria parasites detectable by microscopy compared to 18% for lactase persistent genotypes (P = 0.29). Pooling the lactase enhancer polymorphisms to a common presumptive genotype gave 28% microscopy positives for non-persistent and 17% for others (P = 0.11). Conclusions Plasmodium falciparum parasitaemia in asymptomatic Fulani is more common in individuals with lactase non-persistence genotypes, but this difference is not statistically significant. The potential immunoprotective properties of dietary cow milk as a reason for the partial malaria resistance of Fulani warrant further investigation.
  • Tanislav, Christian; Grittner, Ulrike; Misselwitz, Bjoern; Jungehuelsing, Gerhard Jan; Enzinger, Christian; von Sarnowski, Bettina; Putaala, Jukka; Kaps, Manfred; Kropp, Peter; Rolfs, Arndt; Tatlisumak, Turgut; Fazekas, Franz; Kolodny, Edwin; Norrving, Bo (BioMed Central Ltd, 2014)
    Abstract Background Translating knowledge derived from medical research into the clinical setting is dependent on the representativeness of included patients. Therefore we compared baseline data of patients included in a recent large study addressing young stroke in comparison to a large representative stroke registry. Methods We analysed baseline data of 5023 patients (age 18-55&#160;years) with an acute cerebrovascular event included in the sifap1 (Stroke in Young Fabry Patients) study. For comparison 17007 stroke patients (age 18-55&#160;years) documented (2004-2010) in a statutory stroke registry of the Institute of Quality Assurance Hesse of the Federal State of Hesse (GQH), Germany. Results Among 17007 juvenile (18-55&#160;years) patients identified in the GQH registry 15997 had an ischaemic stroke or TIA (91%) or an intracranial haemorrhage (9%). In sifap1 5023 subjects were included. Sex distribution was comparable (men: 59% sifap1 versus 60.5% GQH) whereas age differed between the groups: median age was 46&#160;years in sifap1 versus 49&#160;years in GQH. Slightly higher percentages for diabetes mellitus and hypertension in the GQH registry were noted. There were no differences in stroke severity as assessed by NIHSS (median 3) and mRS (median 2). In patients with ischaemic stroke or TIA (n&#8201;=&#8201;4467 sifap1; n&#8201;=&#8201;14522 GQH) higher rates of strokes due to small artery occlusion and atherosclerosis occurred in older age groups; cardioembolism and strokes of other determined cause occurred more frequently in younger patients. Conclusions The comparison of baseline characteristics between the sifap1 study and the GQH registry revealed differences mainly determined by age.
  • Tommiska, Johanna; Sorensen, Kaspar; Aksglaede, Lise; Koivu, Rosanna; Puhakka, Lea; Juul, Anders; Raivio, Taneli (BioMed Central Ltd, 2011)
    Abstract Background Pubertal timing is a strongly heritable trait, but no single puberty gene has been identified. Thus, the genetic background of idiopathic central precocious puberty (ICPP) is poorly understood. Overall, the genetic modulation of pubertal onset most likely arises from the additive effect of multiple genes, but also monogenic causes of ICPP probably exist, as cases of familial ICPP have been reported. Mutations in KISS1 and KISSR, coding for kisspeptin and its receptor, involved in GnRH secretion and puberty onset, have been suggested causative for monogenic ICPP. Variation in LIN28B was associated with timing of puberty in genome-wide association (GWA) studies. LIN28B is a human ortholog of the gene that controls, through microRNAs, developmental timing in C. elegans. In addition, Lin28a transgenic mice manifest the puberty phenotypes identified in the human GWAS. Thus, both LIN28B and LIN28A may have a role in pubertal development and are good candidate genes for monogenic ICPP. Methods Thirty girls with ICPP were included in the study. ICPP was defined by pubertal onset before 8 yrs of age, and a pubertal LH response to GnRH testing. The coding regions of LIN28B, LIN28A, KISS1, and KISS1R were sequenced. The missense change in LIN28B was also screened in 132 control subjects. Results No rare variants were detected in KISS1 or KISS1R in the 30 subjects with ICPP. In LIN28B, one missense change, His199Arg, was found in one subject with ICPP. However, this variant was also detected in one of the 132 controls. No variation in LIN28A was found. Conclusions We did not find any evidence that mutations in LIN28B or LIN28A would underlie ICPP. In addition, we confirmed that mutations in KISS1 and KISS1R are not a common cause for ICPP.
  • Raj, R; Kivisaari, R; Siironen, J; SkrifVars, M (BioMed Central Ltd, 2014)
  • Rodger, Marc A; Langlois, Nicole J; de Vries, Johanna IP; Rey, Évelyne; Gris, Jean-Christophe; Martinelli, Ida; Schleussner, Ekkehard; Ramsay, Timothy; Mallick, Ranjeeta; Skidmore, Becky; Middeldorp, Saskia; Bates, Shannon; Petroff, David; Bezemer, Dick; van Hoorn, Marion E; Abheiden, Carolien NH; Perna, Annalisa; de Jong, Paulien; Kaaja, Risto (BioMed Central Ltd, 2014)
    Abstract Background Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and the small-for-gestational age newborn. They are leading causes of maternal, fetal, and neonatal morbidity and mortality in developed nations. Women who have experienced these complications are at an elevated risk of recurrence in subsequent pregnancies. However, despite decades of research no effective strategies to prevent recurrence have been identified, until recently. We completed a pooled summary-based meta-analysis that strongly suggests that low-molecular-weight heparin reduces the risk of recurrent placenta-mediated complications. The proposed individual patient data meta-analysis builds on this successful collaboration. The project is called AFFIRM, An individual patient data meta-analysis oF low-molecular-weight heparin For prevention of placenta-medIated pRegnancy coMplications. Methods/Design We conducted a systematic review to identify randomized controlled trials with a low-molecular-weight heparin intervention for the prevention of recurrent placenta-mediated pregnancy complications. Investigators and statisticians representing eight trials met to discuss the outcomes and analysis plan for an individual patient data meta-analysis. An additional trial has since been added for a total of nine eligible trials. The primary analyses from the original trials will be replicated for quality assurance prior to recoding the data from each trial and combining it into a common dataset for analysis. Using the anonymized combined data we will conduct logistic regression and subgroup analyses aimed at identifying which women with previous pregnancy complications benefit most from treatment with low-molecular-weight heparin during pregnancy. Discussion The goal of the proposed individual patient data meta-analysis is a thorough estimation of treatment effects in patients with prior individual placenta-mediated pregnancy complications and exploration of which complications are specifically prevented by low-molecular-weight heparin. Systematic review registration PROSPERO (International Prospective Registry of Systematic Reviews) 23 December 2013, CRD42013006249
  • Laurenne, Nina; Tuominen, Jouni; Saarenmaa, Hannu; Hyvönen, Eero (BioMed Central, 2014)
    Abstract Background The scientific names of plants and animals play a major role in Life Sciences as information is indexed, integrated, and searched using scientific names. The main problem with names is their ambiguous nature, because more than one name may point to the same taxon and multiple taxa may share the same name. In addition, scientific names change over time, which makes them open to various interpretations. Applying machine-understandable semantics to these names enables efficient processing of biological content in information systems. The first step is to use unique persistent identifiers instead of name strings when referring to taxa. The most commonly used identifiers are Life Science Identifiers (LSID), which are traditionally used in relational databases, and more recently HTTP URIs, which are applied on the Semantic Web by Linked Data applications. Results We introduce two models for expressing taxonomic information in the form of species checklists. First, we show how species checklists are presented in a relational database system using LSIDs. Then, in order to gain a more detailed representation of taxonomic information, we introduce meta-ontology TaxMeOn to model the same content as Semantic Web ontologies where taxa are identified using HTTP URIs. We also explore how changes in scientific names can be managed over time. Conclusions The use of HTTP URIs is preferable for presenting the taxonomic information of species checklists. An HTTP URI identifies a taxon and operates as a web address from which additional information about the taxon can be located, unlike LSID. This enables the integration of biological data from different sources on the web using Linked Data principles and prevents the formation of information silos. The Linked Data approach allows a user to assemble information and evaluate the complexity of taxonomical data based on conflicting views of taxonomic classifications. Using HTTP URIs and Semantic Web technologies also facilitate the representation of the semantics of biological data, and in this way, the creation of more “intelligent” biological applications and services.
  • Moilanen, Ulla; Kellock, Miriam; Várnai, Anikó; Andberg, Martina; Viikari, Liisa (BioMed Central Ltd, 2014)
    Abstract Background The recalcitrance of softwood to enzymatic hydrolysis is one of the major bottlenecks hindering its profitable use as a raw material for platform sugars. In softwood, the guaiacyl-type lignin is especially problematic, since it is known to bind hydrolytic enzymes non-specifically, rendering them inactive towards cellulose. One approach to improve hydrolysis yields is the modification of lignin and of cellulose structures by laccase-mediator treatments (LMTs). Results LMTs were studied to improve the hydrolysis of steam pre-treated spruce (SPS). Three mediators with three distinct reaction mechanisms (ABTS, HBT, and TEMPO) and one natural mediator (AS, that is, acetosyringone) were tested. Of the studied LMTs, laccase-ABTS treatment improved the degree of hydrolysis by 54%, while acetosyringone and TEMPO increased the hydrolysis yield by 49% and 36%, respectively. On the other hand, laccase-HBT treatment improved the degree of hydrolysis only by 22%, which was in the same order of magnitude as the increase induced by laccase treatment without added mediators (19%). The improvements were due to lignin modification that led to reduced adsorption of endoglucanase Cel5A and cellobiohydrolase Cel7A on lignin. TEMPO was the only mediator that modified cellulose structure by oxidizing hydroxyls at the C6 position to carbonyls and partially further to carboxyls. Oxidation of the reducing end C1 carbonyls was also observed. In contrast to lignin modification, oxidation of cellulose impaired enzymatic hydrolysis. Conclusions LMTs, in general, improved the enzymatic hydrolysis of SPS. The mechanism of the improvement was shown to be based on reduced adsorption of the main cellulases on SPS lignin rather than cellulose oxidation. In fact, at higher mediator concentrations the advantage of lignin modification in enzymatic saccharification was overcome by the negative effect of cellulose oxidation. For future applications, it would be beneficial to be able to understand and modify the binding properties of lignin in order to decrease unspecific enzyme binding and thus to increase the mobility, action, and recyclability of the hydrolytic enzymes.
  • Krogius-Kurikka, Lotta; Lyra, Anna; Malinen, Erja; Aarnikunnas, Johannes; Tuimala, Jarno; Paulin, Lars; Mäkivuokko, Harri; Kajander, Kajsa; Palva, Airi (BioMed Central Ltd, 2009)
    Abstract Background A growing amount of scientific evidence suggests that microbes are involved in the aetiology of irritable bowel syndrome (IBS), and the gastrointestinal (GI) microbiota of individuals suffering from diarrhoea-predominant IBS (IBS-D) is distinguishable from other IBS-subtypes. In our study, the GI microbiota of IBS-D patients was evaluated and compared with healthy controls (HC) by using a high-resolution sequencing method. The method allowed microbial community analysis on all levels of microbial genomic guanine plus cytosine (G+C) content, including high G+C bacteria. Methods The collective faecal microbiota composition of ten IBS-D patients was analysed by examining sequences obtained using percent G+C (%G+C) -based profiling and fractioning combined with 16S rRNA gene clone library sequencing of 3267 clones. The IBS-D library was compared with an analogous healthy-control library of 23 subjects. Real-time PCR analysis was used to identify phylotypes belonging to the class Gammaproteobacteria and the order Coriobacteriales. Results Significant differences were found between clone libraries of IBS-D patients and controls. The microbial communities of IBS-D patients were enriched in Proteobacteria and Firmicutes, but reduced in the number of Actinobacteria and Bacteroidetes compared to control. In particular, 16S rDNA sequences belonging to the family Lachnospiraceae within the phylum Firmicutes were in greater abundance in the IBS-D clone library. Conclusions In the microbiota of IBS-D sufferers, notable differences were detected among the prominent bacterial phyla (Firmicutes, Actinobacteria, Bacteroidetes, and Proteobacteria) localized within the GI tract.
  • Karhu, Lasse; Turku, Ainoleena; Xhaard, Henri (BioMed Central, 2015)
    Abstract Background Interactions between the orexin peptides and their cognate OX1 and OX2 receptors remain poorly characterized. Site-directed mutagenesis studies on orexin peptides and receptors have indicated amino acids important for ligand binding and receptor activation. However, a better understanding of specific pairwise interactions would benefit small molecule discovery. Results We constructed a set of three-dimensional models of the orexin 1 receptor based on the 3D-structures of the orexin 2 receptor (released while this manuscript was under review), neurotensin receptor 1 and chemokine receptor CXCR4, conducted an exhaustive docking of orexin-A16–33 peptide fragment with ZDOCK and RDOCK, and analyzed a total of 4301 complexes through multidimensional scaling and clustering. The best docking poses reveal two alternative binding modes, where the C-terminus of the peptide lies deep in the binding pocket, on average about 5–6 Å above Tyr6.48 and close to Gln3.32. The binding modes differ in the about 100° rotation of the peptide; the peptide His26 faces either the receptor’s fifth transmembrane helix or the seventh helix. Both binding modes are well in line with previous mutation studies and partake in hydrogen bonding similar to suvorexant. Conclusions We present two binding modes for orexin-A into orexin 1 receptor, which help rationalize previous results from site-directed mutagenesis studies. The binding modes should serve small molecule discovery, and offer insights into the mechanism of receptor activation.