Articles from BioMed Central


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  • Davidsson, Pär; Broberg, Martin; Kariola, Tarja; Sipari, Nina; Pirhonen, Minna; Palva, E. T (BioMed Central, 2017)
    Abstract Background Oligogalacturonides (OGs) are important components of damage-associated molecular pattern (DAMP) signaling and influence growth regulation in plants. Recent studies have focused on the impact of long OGs (degree of polymerization (DP) from 10–15), demonstrating the induction of plant defense signaling resulting in enhanced defenses to necrotrophic pathogens. To clarify the role of trimers (trimeric OGs, DP3) in DAMP signaling and their impact on plant growth regulation, we performed a transcriptomic analysis through the RNA sequencing of Arabidopsis thaliana exposed to trimers. Results The transcriptomic data from trimer-treated Arabidopsis seedlings indicate a clear activation of genes involved in defense signaling, phytohormone signaling and a down-regulation of genes involved in processes related to growth regulation and development. This is further accompanied with improved defenses against necrotrophic pathogens triggered by the trimer treatment, indicating that short OGs have a clear impact on plant responses, similar to those described for long OGs. Conclusions Our results demonstrate that trimers are indeed active elicitors of plant defenses. This is clearly indicated by the up-regulation of genes associated with plant defense signaling, accompanied with improved defenses against necrotrophic pathogens. Moreover, trimers simultaneously trigger a clear down-regulation of genes and gene sets associated with growth and development, leading to stunted seedling growth in Arabidopsis.
  • Puolakkainen, Tero; Ma, Hongqian; Kainulainen, Heikki; Pasternack, Arja; Rantalainen, Timo; Ritvos, Olli; Heikinheimo, Kristiina; Hulmi, Juha J; Kiviranta, Riku (BioMed Central, 2017)
    Abstract Background Inhibition of activin/myostatin pathway has emerged as a novel approach to increase muscle mass and bone strength. Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that leads to progressive muscle degeneration and also high incidence of fractures. The aim of our study was to test whether inhibition of activin receptor IIB ligands with or without exercise could improve bone strength in the mdx mouse model for DMD. Methods Thirty-two mdx mice were divided to running and non-running groups and to receive either PBS control or soluble activin type IIB-receptor (ActRIIB-Fc) once weekly for 7 weeks. Results Treatment of mdx mice with ActRIIB-Fc resulted in significantly increased body and muscle weights in both sedentary and exercising mice. Femoral μCT analysis showed increased bone volume and trabecular number (BV/TV +80%, Tb.N +70%, P < 0.05) in both ActRIIB-Fc treated groups. Running also resulted in increased bone volume and trabecular number in PBS-treated mice. However, there was no significant difference in trabecular bone structure or volumetric bone mineral density between the ActRIIB-Fc and ActRIIB-Fc-R indicating that running did not further improve bone structure in ActRIIB-Fc-treated mice. ActRIIB-Fc increased bone mass also in vertebrae (BV/TV +20%, Tb.N +30%, P < 0.05) but the effects were more modest. The number of osteoclasts was decreased in histological analysis and the expression of several osteoblast marker genes was increased in ActRIIB-Fc treated mice suggesting decreased bone resorption and increased bone formation in these mice. Increased bone mass in femurs translated into enhanced bone strength in biomechanical testing as the maximum force and stiffness were significantly elevated in ActRIIB-Fc-treated mice. Conclusions Our results indicate that treatment of mdx mice with the soluble ActRIIB-Fc results in a robust increase in bone mass, without any additive effect by voluntary running. Thus ActRIIB-Fc could be an attractive option in the treatment of musculoskeletal disorders.
  • Kaunomäki, Jenni; Jokela, Markus; Kontio, Raija; Laiho, Tero; Sailas, Eila; Lindberg, Nina (BioMed Central, 2017)
    Abstract Background Patient aggression and violence against staff members and other patients are common concerns in psychiatric units. Many structured clinical risk assessment tools have recently been developed. Despite their superiority to unaided clinical judgments, staff has shown ambivalent views towards them. A constant worry of staff is that the results of risk assessments would not be used. The aims of the present study were to investigate what were the interventions applied by the staff of a psychiatric admission ward after a high risk patient had been identified, how frequently these interventions were used and how effective they were. Methods The data were collected in a naturalistic setting during a 6-month period in a Finnish psychiatric admission ward with a total of 331 patients with a mean age of 42.9 years (SD 17.39) suffering mostly from mood, schizophrenia-related and substance use disorders. The total number of treatment days was 2399. The staff assessed the patients daily with the Dynamic Appraisal of Situational Aggression (DASA), which is a structured violence risk assessment considering the upcoming 24 h. The interventions in order to reduce the risk of violence following a high DASA total score (≥4) were collected from the patients’ medical files. Inductive content analysis was used. Results There were a total of 64 patients with 217 observations of high DASA total score. In 91.2% of cases, at least one intervention aiming to reduce the violence risk was used. Pro re nata (PRN)-medication, seclusion and focused discussions with a nurse were the most frequently used interventions. Non-coercive and non-pharmacological interventions like daily activities associated significantly with the decrease of perceived risk of violence. Conclusion In most cases, a high score in violence risk assessment led to interventions aiming to reduce the risk. Unfortunately, the most frequently used methods were psychopharmacological or coercive. It is hoped that the findings will encourage the staff to use their imagination when choosing violence risk reducing intervention techniques.
  • Ylivinkka, Irene; Sihto, Harri; Tynninen, Olli; Hu, Yizhou; Laakso, Aki; Kivisaari, Riku; Laakkonen, Pirjo; Keski-Oja, Jorma; Hyytiäinen, Marko (BioMed Central, 2017)
    Abstract Background Glioblastoma is an untreatable brain cancer. The tumors contain a population of stem-like cells which are highly invasive and resistant to therapies. These cells are the main reason for the lethality of glioblastoma. Extracellular guidance molecule netrin-1 promotes the invasiveness and survival of various cancer cell types. We have previously found that netrin-1 activates Notch signaling, and Notch signaling associates with cell stemness. Therefore, we have here investigated the effects of netrin-1 on glioblastoma pathogenesis and glioblastoma cell stemness. Methods Glioma tissue microarrays were stained with immunohistochemistry and the results were used to evaluate the association between netrin-1 and survival of glioma patients. The localization of netrin-1 was analyzed utilizing fresh frozen glioblastoma tissues. The glioma cell invasion was investigated using ex vivo glioma tissue cultures and newly established primary cell cultures in 3D in vitro invasion assays. Intracranial mouse xenograft models were utilized to investigate the effects of netrin-1 on glioblastoma growth and invasion in vivo. Results Netrin-1 expression associated with poor patient prognosis in grade II-III gliomas. In addition, its expression correlated with the stem-like cell marker nestin. Netrin-1 overexpression in cultured cells led to increased formation of stem-like cell spheroids. In glioblastoma tumor biopsies netrin-1 localized to hypoxic tumor areas known to be rich in the stem-like cells. In xenograft mouse models netrin-1 expression altered the phenotype of non-invasive glioblastoma cells into diffusively invading and increased the expression of glioma stem-like cell markers. Furthermore, a distinct invasion pattern where netrin-1 positive cells were following the invasive stem-like cells was detected both in mouse models and ex vivo human glioblastoma tissue cultures. Inhibition of netrin-1 signaling targeted especially the stem-like cells and inhibited their infiltrative growth. Conclusions Our findings describe netrin-1 as an important regulator of glioblastoma cell stemness and motility. Netrin-1 activates Notch signaling in glioblastoma cells resulting in subsequent gain of stemness and enhanced invasiveness of these cells. Moreover, inhibition of netrin-1 signaling may offer a way to target stem-like cells.
  • Ahvenainen, Patrik; Dixon, Patrick G; Kallonen, Aki; Suhonen, Heikki; Gibson, Lorna J; Svedström, Kirsi (BioMed Central, 2017)
    Abstract Background Biological materials have a complex, hierarchical structure, with vital structural features present at all size scales, from the nanoscale to the macroscale. A method that can connect information at multiple length scales has great potential to reveal novel information. This article presents one such method with an application to the bamboo culm wall. Moso (Phyllostachys edulis) bamboo is a commercially important bamboo species. At the cellular level, bamboo culm wall consists of vascular bundles embedded in a parenchyma cell tissue matrix. The microfibril angle (MFA) in the bamboo cell wall is related to its macroscopic longitudinal stiffness and strength and can be determined at the nanoscale with wide-angle X-ray scattering (WAXS). Combining WAXS with X-ray microtomography (XMT) allows tissue-specific study of the bamboo culm without invasive chemical treatment. Results The scattering contribution of the fiber and parenchyma cells were separated with spatially-localized WAXS. The fiber component was dominated by a high degree of orientation corresponding to small MFAs (mean MFA 11°). The parenchyma component showed significantly lower degree of orientation with a maximum at larger angles (mean MFA 65°). The fiber ratio, the volume of cell wall in the fibers relative to the overall volume of cell wall, was determined by fitting the scattering intensities with these two components. The fiber ratio was also determined from the XMT data and similar fiber ratios were obtained from the two methods, one connected to the cellular level and one to the nanoscale. X-ray diffraction tomography was also done to study the differences in microfibril orientation between fibers and the parenchyma and further connect the microscale to the nanoscale. Conclusions The spatially-localized WAXS yields biologically relevant, tissue-specific information. With the custom-made bench-top set-up presented, diffraction contrast information can be obtained from plant tissue (1) from regions-of-interest, (2) as a function of distance (line scan), or (3) with two-dimensional or three-dimensional tomography. This nanoscale information is connected to the cellular level features.
  • Ballo, Haitham; Tarkia, Miikka; Haavisto, Matti; Stark, Christoffer; Strandberg, Marjatta; Vähäsilta, Tommi; Saunavaara, Virva; Tolvanen, Tuula; Teräs, Mika; Hynninen, Ville-Veikko; Savunen, Timo; Roivainen, Anne; Knuuti, Juhani; Saraste, Antti (BioMed Central, 2017)
    Abstract Background We evaluated echocardiographic area-length methods to measure left ventricle (LV) volumes and ejection fraction (EF) in parasternal short axis views in comparison with cardiac computed tomography (CT) in pigs with chronic myocardial infarction (MI). Methods Male farm pigs with surgical occlusion of the left anterior descending coronary artery (n = 9) or sham operation (n = 5) had transthoracic echocardiography and cardiac-CT 3 months after surgery. We measured length of the LV in parasternal long axis view, and both systolic and diastolic LV areas in parasternal short axis views at the level of mitral valve, papillary muscles and apex. Volumes and EF of the LV were calculated using Simpson’s method of discs (tri-plane area) or Cylinder-hemiellipsoid method (single plane area). Results The pigs with coronary occlusion had anterior MI scars and reduced EF (average EF 42 ± 10%) by CT. Measurements of LV volumes and EF were reproducible by echocardiography. Compared with CT, end-diastolic volume (EDV) measured by echocardiography showed good correlation and agreement using either Simpson’s method (r = 0.90; mean difference −2, 95% CI −47 to 43 mL) or Cylinder-hemiellipsoid method (r = 0.94; mean difference 3, 95% CI −44 to 49 mL). Furthermore, End-systolic volume (ESV) measured by echocardiography showed also good correlation and agreement using either Simpson’s method (r = 0.94; mean difference 12 ml, 95% CI: −16 to 40) or Cylinder-hemiellipsoid method (r = 0.97; mean difference:13 ml, 95% CI: −8 to 33). EF was underestimated using either Simpson’s method (r = 0.78; mean difference −6, 95% CI −11 to 1%) or Cylinder-hemiellipsoid method (r = 0.74; mean difference −4, 95% CI–10 to 2%). Conclusion Our results indicate that measurement of LV volumes may be accurate, but EF is underestimated using either three or single parasternal short axis planes by echocardiography in a large animal model of chronic MI.
  • Koski, M.; Naukkarinen, H. (BioMed Central, 2017)
    Abstract Background Obesity has a multifaceted etiology that involves genetic, biological and behavioral factors, body growth, eating habits, energy expenditure and the function of adipose tissue. The present study aimed to expand upon knowledge about the relationships among obesity, emotions and eating habits in severely obese individuals using a case-control method. Methods The subject group consisted of 112 individuals (81 females and 31 males) receiving a permanent disability pension primarily for obesity. The control subjects were randomly selected from the same area and were receiving a disability pension for a different primary illness. The controls were matched with the subjects by the place of residence, sex, age, the time since the pension was granted and occupation. Psychiatric interviews were conducted on all participants. The results were analyzed using the chi-squared test (χ2-test) and the percent distribution. The subject and control groups were compared using the t-test for paired variables. Conditional logistic regression analysis was also conducted. Results The emotional state of eating was significantly associated with quarrels and feelings of loneliness. The subjects suffered from night eating syndrome, which was associated with an increased risk of early retirement. Binge eating syndrome was observed more frequently in the study group. The subjects reported feeling increased hunger compared with the controls. A significant percentage of the subjects had a body mass index of ≥ 40. No differences in eating habits were observed between the groups. Conclusion This study provides information on the relationship between emotions and eating habits in obesity, which is a rarely studied topic. We believe that our study provides a novel and necessary overview of the associations among severe obesity, emotions and eating habits.
  • Immonen, Isa A M; Karikoski, Ninja; Mykkänen, Anna; Niemelä, Tytti; Junnila, Jouni; Tulamo, Riitta-Mari (BioMed Central, 2017)
    Abstract Background Surgical treatment of colic is expensive and complications may occur. Information on the prognosis and the use of the horse after surgery for colic is important for surgeons and owners. Current literature on return to athletic function after celiotomy is limited. The present study reviewed surgical cases of the Veterinary Teaching Hospital, Helsinki, Finland for 2006–2012. The aim was to follow the population of horses of different breeds for surgical findings, postsurgical complications, long-term recovery and prognosis. The findings and their influence on survival, return to previous or intended use and performance were assessed. Results Most of the operated horses (82.6%; 195/236) recovered from anesthesia and 74.9% (146/195) were discharged. The total follow-up time was 8 years and 10 months and the median survival time 79.2 months. Age of the horse, location of the abdominal lesion (small vs. large intestine), incidence of postoperative colic, surgical site infection, incisional hernia or convalescence time after surgery, did not significantly affect the probability of performing in the previous or intended discipline after the surgery. A majority of the discharged horses (83.7%) was able to perform in the previous or intended discipline and 78.5% regained their former or higher level of performance. Operated horses had 0.18 colic episodes per horse-year during the long-term follow-up. The incidence of colic was 20.0% within the first year after surgery. Horses operated for large intestinal colic were 3.3-fold more prone to suffer postoperative colic than horses operated for small intestinal colic. The majority of the owners (96.3%) were satisfied with the veterinary care and nearly all (98.5%) evaluated the recovery after the colic surgery to be satisfactory or above. Conclusions If the horse survives to discharge, prognosis for long-term survival and return to previous level of sporting activity and performance was good after colic surgery in a population of horses of different breeds. None of the factors studied were found to decrease the probability of performing in the same or intended discipline after surgery. The majority of horses were able to return to their previous activity and perform satisfactorily for several years after surgery.
  • Sumanen, Hilla; Pietiläinen, Olli; Lahelma, Eero; Rahkonen, Ossi (BioMed Central, 2017)
    Abstract Background Mental disorders are common diagnostic causes for longer sickness absence and disability retirement in OECD-countries. Short sickness absence spells are also common, and neither trivial for health and work ability. We studied how prior short sickness absence spells and days are associated with subsequent longer sickness absence due to mental disorders in two age-groups of municipal employees during a 2-, 5- and 9-year follow-up. Methods The analyses covered 20–34 and 35–49-year-old employees of the City of Helsinki in 2004. Those with prior ≥14 day sickness absence in 2002, 2003 or 2004 were excluded. Women and men were pooled together. Short, 1–13-day sickness absence spells and days were calculated per the actual time of employment during 2004. Logistic regression analysis was used to calculate odds ratios (OR) and their 95% confidence intervals (CI) for the subsequent long (≥14 days) sickness absence due to mental disorders during three follow-ups. Results The risk for long sickness absence due to mental disorders increased with increasing amount of short sickness absence spells and days. 3 or more short sickness absence spells and 8–14 sickness absence days from short spells in 2004 were strongly associated with subsequent long sickness absence in all three follow-ups. The associations were strongest for the 2-year follow-up; the younger employees tended to have higher risks than the older ones. Conclusions Three spells or 8 days of short sickness absence per year constitutes a high risk for subsequent long sickness absence due to mental disorders and preventive measures should be considered.
  • Laaksonen, Sauli; Oksanen, Antti; Julmi, Jérôme; Zweifel, Claudio; Fredriksson-Ahomaa, Maria; Stephan, Roger (BioMed Central, 2017)
    Abstract Background Various food-producing animals were recognized in recent years as healthy carriers of bacterial pathogens causing human illness. In northern Fennoscandia, the husbandry of semi-domesticated reindeer (Rangifer tarandus tarandus) is a traditional livelihood and meat is the main product. This study determined the presence of selected foodborne pathogens, methicillin-resistant Staphylococcus aureus (MRSA), and extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae in healthy semi-domesticated reindeer at slaughter in northern Finland and Norway. Results All 470 reindeer fecal samples tested negative for Salmonella spp., whereas L. monocytogenes was detected in 3%, Yersinia spp. in 10%, and Shiga toxins genes (stx1 and/or stx2) in 33% of the samples. Listeria monocytogenes isolates belonged to the serotype 1/2a (14/15) and 4b, Yersinia spp. were identified mainly as Y. kristensenii (30/46) and Y. enterocolitica (8/46), and stx2 predominated among the Shiga toxin genes (stx2 alone or in combination with stx1 was found in 25% of the samples). With regard to the frequency and distribution of stx1/stx2, striking differences were evident among the 10 different areas of origin. Hence, reindeer could constitute a reservoir for Shiga toxin-producing E. coli (STEC), but strain isolation and characterization is required for verification purposes and to assess the potential human pathogenicity of strains. On the other hand, the favorable antibiotic resistance profiles (only 5% of 95 E. coli isolates were resistant to one or more of the tested antibiotics) and the absence of MRSA and ESBL-producing Enterobacteriaceae (when applying selective methods) suggest only a limited risk of transmission to humans. Conclusions Healthy semi-domesticated reindeer in northern Finland and Norway can be carriers of certain bacterial foodborne pathogens. Strict compliance with good hygiene practices during any step of slaughter (in particular during dehiding and evisceration) is therefore of central importance to avoid carcass contamination and to prevent foodborne pathogens from entering the food chain.
  • Zhu, Duolong; Fu, Yuxin; Liu, Fulu; Xu, Haijin; Saris, Per E J; Qiao, Mingqiang (BioMed Central, 2017)
    Abstract Background The implementation of novel chassis organisms to be used as microbial cell factories in industrial applications is an intensive research field. Lactococcus lactis, which is one of the most extensively studied model organisms, exhibits superior ability to be used as engineered host for fermentation of desirable products. However, few studies have reported about genome reduction of L. lactis as a clean background for functional genomic studies and a model chassis for desirable product fermentation. Results Four large nonessential DNA regions accounting for 2.83% in L. lactis NZ9000 (L. lactis 9 k) genome (2,530,294 bp) were deleted using the Cre-loxP deletion system as the first steps toward a minimized genome in this study. The mutants were compared with the parental strain in several physiological traits and evaluated as microbial cell factories for heterologous protein production (intracellular and secretory expression) with the red fluorescent protein (RFP) and the bacteriocin leucocin C (LecC) as reporters. The four mutants grew faster, yielded enhanced biomass, achieved increased adenosine triphosphate content, and diminished maintenance demands compared with the wild strain in the two media tested. In particular, L. lactis 9 k-4 with the largest deletion was identified as the optimum candidate host for recombinant protein production. With nisin induction, not only the transcriptional efficiency but also the production levels of the expressed reporters were approximately three- to fourfold improved compared with the wild strain. The expression of lecC gene controlled with strong constitutive promoters P5 and P8 in L. lactis 9 k-4 was also improved significantly. Conclusions The genome-streamlined L. lactis 9 k-4 outcompeted the parental strain in several physiological traits assessed. Moreover, L. lactis 9 k-4 exhibited good properties as platform organism for protein production. In future works, the genome of L. lactis will be maximally reduced by using our specific design to provide an even more clean background for functional genomics studies than L. lactis 9 k-4 constructed in this study. Furthermore, an improved background will be potentially available for use in biotechology.
  • Tolppanen, Heli; Rivas-Lasarte, Mercedes; Lassus, Johan; Sans-Roselló, Jordi; Hartmann, Oliver; Lindholm, Matias; Arrigo, Mattia; Tarvasmäki, Tuukka; Köber, Lars; Thiele, Holger; Pulkki, Kari; Spinar, Jindrich; Parissis, John; Banaszewski, Marek; Silva-Cardoso, Jose; Carubelli, Valentina; Sionis, Alessandro; Harjola, Veli-Pekka; Mebazaa, Alexandre (Springer Paris, 2017)
    Abstract Background The clinical CardShock risk score, including baseline lactate levels, was recently shown to facilitate risk stratification in patients with cardiogenic shock (CS). As based on baseline parameters, however, it may not reflect the change in mortality risk in response to initial therapies. Adrenomedullin is a prognostic biomarker in several cardiovascular diseases and was recently shown to associate with hemodynamic instability in patients with septic shock. The aim of our study was to evaluate the prognostic value and association with hemodynamic parameters of bioactive adrenomedullin (bio-ADM) in patients with CS. Methods CardShock was a prospective, observational, European multinational cohort study of CS. In this sub-analysis, serial plasma bio-ADM and arterial blood lactate measurements were collected from 178 patients during the first 10 days after detection of CS. Results Both bio-ADM and lactate were higher in 90-day non-survivors compared to survivors at all time points (P < 0.05 for all). Lactate showed good prognostic value during the initial 24 h (AUC 0.78 at admission and 0.76 at 24 h). Subsequently, lactate returned normal (≤2 mmol/L) in most patients regardless of later outcome with lower prognostic value. By contrast, bio-ADM showed increasing prognostic value from 48 h and beyond (AUC 0.71 at 48 h and 0.80 at 5–10 days). Serial measurements of either bio-ADM or lactate were independent of and provided added value to CardShock risk score (P < 0.001 for both). Ninety-day mortality was more than double higher in patients with high levels of bio-ADM (>55.7 pg/mL) at 48 h compared to those with low bio-ADM levels (49.1 vs. 22.6%, P = 0.001). High levels of bio-ADM were associated with impaired cardiac index, mean arterial pressure, central venous pressure, and systolic pulmonary artery pressure during the study period. Furthermore, high levels of bio-ADM at 48 to 96 h were related to persistently impaired cardiac and end-organ function. Conclusions Bio-ADM is a valuable prognosticator and marker of impaired hemodynamics in CS patients. High levels of bio-ADM may show shock refractoriness and developing end-organ dysfunction and thus help to guide therapeutic approach in patients with CS. Study identifier of CardShock study NCT01374867 at
  • Nemery, Elodie; Gabriel, Annick; Cassart, Dominique; Bayrou, Calixte; Piret, Joëlle; Antoine, Nadine; Nilsson, Monika; Steinwall, Lars; Jacobson, Inger; Martins, Ângela; Carvalho, Carla; Viegas, Inês; Marcellin-Little, Denis J; Harrysson, Ola L A; Crimi, Christopher S; Levine, David; Calatayud, María; Resano, María; Mucha, Marion; Virac, Ivonne; Lang, Cornelia; Wittek, Kathleen; Tichy, Alexander; Bockstahler, Barbara; Randy Walker, J.; Swogger, Āren; Gibson, Tavis; Ryan, Janice; Gilligan, Chris; Haulcomb, Katie; Norris, Leigh A; Powers, Matt; Pugh, Tracy; Purkey, Seth; Pulkkinen, Hanna; Lappalainen, Anu; Laitinen-Vapaavuori, Outi; Hyytiäinen, Heli; Essner, Ann; Sjöström, Rita; Zetterberg, Lena; Hellström, Karin; Gustås, Pia; Högberg, Hans; Hielm-Björkman, Anna; Orrfors, Charlotte; Sundelin, Gunnevi; Gonçalves, Luísa; Niza-Ribeiro, João; Millis, Darryl L; de Matos, Augusto J; Teeling, Marinette; Ross, Kate; Geddes, Victoria; Carstens, Ann; Kriel, Tineka; du Toit, Karien; Pauw, Jeanette; Martindale, Gillian; Mylo, Kristine; van den Berg, Sybrand S; Ogasawara, Morito; Noguchi, Hiromi; Minami, Takeo; Zdeb, Krzysztof; Baumgart, Urszula; Ribeiro, Ana M; Palas, Ricardo; Capelão, Martinho; Speciani, Mila; De Luca, Alessandra; Anzolin, Elisa; Pirinen, Nina; Pastell, Matti; Mykkänen, Anna; Jokisalo, Jonna; Niinistö, Kati; Hänninen, Laura; McGowan, Catherine; Holt, Alexandria; Subirats, Marta; Perez, Maria; Hernández, Tatiana; Gutierrez-Cepeda, Luna; Cediel, Rafael; Román, Javier L; Boström, Anna F; Savolainen, Lotta; Lappalainen, Anu K; Stadig, Sarah; Lundström, Linda; Bergh, Anna; Ley, Charles; Olsén, Lena; Ingvast-Larsson, Carina; Diniz, Renata; Nicolau, Cristina; Gamundi, Antonio; Akaarir, Mourad; Roberts, Elizabeth; McLennan, Leander; Cartildge, Helen C; Evans, Lucy K M; Baugh, Stephen; Stenfeldt, Pernilla; Ericson, Cajsa; Söderberg, Linnéa; Sjöström, Lennart; Colborne, Robert; Byström, Anna; Drum, Marti; de Swarte, Marie; Morandi, Federica; Guevara, José; Hickey, Dawn; Camp, Ellen; Dickson, Rachel (BioMed Central, 2016)
  • Heinävaara, Otte; Leppä-aho, Janne; Corander, Jukka; Honkela, Antti (BioMed Central, 2016)
    Abstract Background Various ℓ 1-penalised estimation methods such as graphical lasso and CLIME are widely used for sparse precision matrix estimation and learning of undirected network structure from data. Many of these methods have been shown to be consistent under various quantitative assumptions about the underlying true covariance matrix. Intuitively, these conditions are related to situations where the penalty term will dominate the optimisation. Results We explore the consistency of ℓ 1-based methods for a class of bipartite graphs motivated by the structure of models commonly used for gene regulatory networks. We show that all ℓ 1-based methods fail dramatically for models with nearly linear dependencies between the variables. We also study the consistency on models derived from real gene expression data and note that the assumptions needed for consistency never hold even for modest sized gene networks and ℓ 1-based methods also become unreliable in practice for larger networks. Conclusions Our results demonstrate that ℓ 1-penalised undirected network structure learning methods are unable to reliably learn many sparse bipartite graph structures, which arise often in gene expression data. Users of such methods should be aware of the consistency criteria of the methods and check if they are likely to be met in their application of interest.
  • Mishra, Pashupati P; Medlar, Alan; Holm, Liisa; Törönen, Petri (BioMed Central, 2016)
    Abstract Background Competitive gene set analysis is a standard exploratory tool for gene expression data. Permutation-based competitive gene set analysis methods are preferable to parametric ones because the latter make strong statistical assumptions which are not always met. For permutation-based methods, we permute samples, as opposed to genes, as doing so preserves the inter-gene correlation structure. Unfortunately, up until now, sample permutation-based methods have required a minimum of six replicates per sample group. Results We propose a new permutation-based competitive gene set analysis method for multi-group gene expression data with as few as three replicates per group. The method is based on advanced sample permutation technique that utilizes all groups within a data set for pairwise comparisons. We present a comprehensive evaluation of different permutation techniques, using multiple data sets and contrast the performance of our method, mGSZm, with other state of the art methods. We show that mGSZm is robust, and that, despite only using less than six replicates, we are able to consistently identify a high proportion of the top ranked gene sets from the analysis of a substantially larger data set. Further, we highlight other methods where performance is highly variable and appears dependent on the underlying data set being analyzed. Conclusions Our results demonstrate that robust gene set analysis of multi-group gene expression data is permissible with as few as three replicates. In doing so, we have extended the applicability of such approaches to resource constrained experiments where additional data generation is prohibitively difficult or expensive. An R package implementing the proposed method and supplementary materials are available from the website .