Browsing by Subject "ROLES"

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  • Ovaskainen, Otso; Somervuo, Panu; Finkelshtein, Dmitri (2020)
    Agent-based models are used to study complex phenomena in many fields of science. While simulating agent-based models is often straightforward, predicting their behaviour mathematically has remained a key challenge. Recently developed mathematical methods allow the prediction of the emerging spatial patterns for a general class of agent-based models, whereas the prediction of spatio-temporal pattern has been thus far achieved only for special cases. We present a general and mathematically rigorous methodology that allows deriving the spatio-temporal correlation structure for a general class of individual-based models. To do so, we define an auxiliary model, in which each agent type of the primary model expands to three types, called the original, the past and the new agents. In this way, the auxiliary model keeps track of both the initial and current state of the primary model, and hence the spatio-temporal correlations of the primary model can be derived from the spatial correlations of the auxiliary model. We illustrate the agreement between analytical predictions and agent-based simulations using two example models from theoretical ecology. In particular, we show that the methodology is able to correctly predict the dynamical behaviour of a host-parasite model that shows spatially localized oscillations.
  • NBCS Collaborators; ABCTB Investigators; kConFab Investigators; Morra, Anna; Escala-Garcia, Maria; Beesley, Jonathan; Muranen, Taru A.; Nevanlinna, Heli (2021)
    Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). Results Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.
  • Trela, Ewelina; Lan, Qiang; Myllymäki, Satu-Marja; Villeneuve, Clémentine; Lindström, Riitta; Kumar, Vinod; Wickström, Sara A.; Mikkola, Marja L. (2021)
    The mammary gland develops from the surface ectoderm during embryogenesis and proceeds through morphological phases defined as placode, hillock, bud, and bulb stages followed by branching morphogenesis. During this early morphogenesis, the mammary bud undergoes an invagination process where the thickened bud initially protrudes above the surface epithelium and then transforms to a bulb and sinks into the underlying mesenchyme. The signaling pathways regulating the early morphogenetic steps have been identified to some extent, but the underlying cellular mechanisms remain ill defined. Here, we use 3D and 4D confocal microscopy to show that the early growth of the mammary rudiment is accomplished by migration-driven cell influx, with minor contributions of cell hypertrophy and proliferation. We delineate a hitherto undescribed invagination mechanism driven by thin, elongated keratinocytes-ring cells-that form a contractile rim around the mammary bud and likely exert force via the actomyosin network. Furthermore, we show that conditional deletion of nonmuscle myosin IIA (NMIIA) impairs invagination, resulting in abnormal mammary bud shape.
  • Harjunpää, Katariina; Deppermann, Arnulf; Sorjonen, Marja-Leena (2021)
    Using video-recordings from one day of a theater project for young adults, this paper investigates how the meaning of novel verbal expressions is interactionally constituted and elaborated over the interactional history of a series of activities. We examine how the theater director introduces and instructs the group in the Chekhovian technique of acting, which is based on “imagining with the body,” and how the imaginary elements of the technique are “brought into existence” in the language of the instructions. By tracking shifts in the instructor’s use of the key expressions invisible/imaginary/inner body or movement through a series of exercises, we demonstrate how they are increasingly treated as real and perceivable bodily conduct. The analyses focus on the instructor’s attribution of factual and agentive properties to these expressions, and the changes that these properties undergo over the series of instructions. This case demonstrates the significance of longitudinal processes for the establishment of shared meaning in social interaction. The study thereby contributes to the field of interactional semantics and to longitudinal studies of social interaction.
  • Ye, Lingling; Wang, Xin; Lyu, Munan; Siligato, Riccardo; Eswaran, Gugan; Vainio, Leo; Blomster, Tiina; Zhang, Jing; Mähönen, Ari Pekka (2021)
    During primary growth, plant tissues increase their length, and as these tissues mature, they initiate secondary growth to increase thickness.(1) It is not known what activates this transition to secondary growth. Cytokinins are key plant hormones regulating vascular development during both primary and secondary growth. During primary growth of Arabidopsis roots, cytokinins promote procambial cell proliferation(2,3) and vascular patterning together with the hormone auxin.(4-7) In the absence of cytokinins, secondary growth fails to initiate.(8) Enhanced cytokinin levels, in turn, promote secondary growth.(8,9) Despite the importance of cytokinins, little is known about the downstream signaling events in this process. Here, we show that cytokinins and a few downstream LATERAL ORGAN BOUNDARIES DOMAIN (LBD) family of transcription factors are rate limiting components in activating and further promoting secondary growth in Arabidopsis roots. Cytokinins directly activate transcription of two homologous LBD genes, LBD3 and LBD4. Two other homologous LBDs, LBD1 and LBD11, are induced only after prolonged cytokinin treatment. Our genetic studies revealed a two stage mechanism downstream of cytokinin signaling: while LBD3 and LBD4 regulate activation of secondary growth, LBD1, LBD3, LBD4, and LBD11 together promote further radial growth and maintenance of cambial stem cells. LBD overexpression promoted rapid cell growth followed by accelerated cell divisions, thus leading to enhanced secondary growth. Finally, we show that LBDs rapidly inhibit cytokinin signaling. Together, our data suggest that the cambium-promoting LBDs negatively feed back into cytokinin signaling to keep root secondary growth in balance.
  • Sanz-Navarro, Maria; Delgado, Irene; Torres, Miguel; Mustonen, Tuija; Michon, Frederic; Rice, David P. (2019)
    MEIS1 is a key developmental regulator of several organs and participates in stem cell maintenance in different niches. However, despite the murine continuously growing incisor being a well described model for the study of adult stem cells, Meis1 has not been investigated in a dental context. Here, we uncover that Meis1 expression in the tooth is confined to the epithelial compartment. Its expression arises during morphogenesis and becomes restricted to the mouse incisor epithelial stem cell niche, the labial cervical loop. Meis1 is specifically expressed by Sox2(+) stem cells, which give rise to all dental epithelial cell lineages. Also, we have found that Meis1 in the incisor is coexpressed with potential binding partner Pbx1 during both embryonic and adult stages. Interestingly, Meis2 is present in different areas of the forming tooth and it is not expressed by dental epithelial stem cells, suggesting different roles for these two largely homologous genes. Additionally, we have established the expression patterns of Meis1 and Meis2 during tongue, hair, salivary gland and palate formation. Finally, analysis of Meis1-null allele mice indicated that, similarly, to SOX2, MEIS1 is not essential for tooth initiation, but might have a role during adult incisor renewal.
  • He, Siwen; Soininen, Janne; Chen, Kai; Wang, Beixin (2020)
    Metacommunity theory provides a useful framework to describe the underlying factors (e.g., environmental and dispersal-related factors) influencing community structure. The strength of these factors may vary depending on the properties of the region studied (e.g., environmental heterogeneity and spatial location) and considered biological groups. Here, we examined environmental and dispersal-related controls of stream macroinvertebrates and diatoms in three regions in China using the distance-decay relationship analysis. We performed analyses for the whole stream network and separately for two stream network locations (headwater and downstream sites) to test the network position hypothesis (NPH), which states that the strength of environmental and dispersal-related controls varies between headwater and downstream communities. Community dissimilarities were significantly related to environmental distances, but not geographical distances. These results suggest that communities are structured strongly by environmental filtering, but weakly by dispersal-related factors such as dispersal limitation. More importantly, we found that, at the whole network scale, environmental control was the highest in the regions with highest environmental heterogeneity. Results further showed that the influence of environmental control was strong in both headwaters and downstream sites, whereas spatial control was generally weak in all sites. This suggests a lack of consistent support for the NPH in our studied stream networks. Moreover, we found that local-scale variables relative to basin-scale variables better explained community dissimilarities for diatoms than for macroinvertebrates. This indicates that diatoms and macroinvertebrates responded to environment at different scales. Collectively, these results suggest that the importance of drivers behind the metacommunity assembly varied among regions with different level of environmental heterogeneity and between organism groups, potentially indicating context dependency among stream systems and taxa.
  • Miroshnikova, Yekaterina A; Cohen, Idan; Ezhkova, Elena; Wickström, Sara A (2019)
    The skin epidermis is a constantly renewing stratified epithelium that provides essential protective barrier functions throughout life. Epidermal stratification is governed by a step-wise differentiation program that requires precise spatiotemporal control of gene expression. How epidermal self-renewal and differentiation are regulated remains a fundamental open question. Cell-intrinsic and cell-extrinsic mechanisms that modify chromatin structure and interactions have been identified as key regulators of epidermal differentiation and stratification. Here, we will review the recent advances in our understanding of how chromatin modifiers, tissue-specific transcription factors, and force-induced nuclear remodeling processes function to shape chromatin and to control epidermal tissue development and homeostasis.
  • Evsyukov, Valentin; Domanskyi, Andrii; Bierhoff, Holger; Gispert, Suzana; Mustafa, Rasem; Schlaudraff, Falk; Liss, Birgit; Parlato, Rosanna (2017)
    Genetic mutations underlying neurodegenerative disorders impair ribosomal DNA (rDNA) transcription suggesting that nucleolar dysfunction could be a novel pathomechanism in polyglutamine diseases and in certain forms of amyotrophic lateral sclerosis/frontotemporal dementia. Here, we investigated nucleolar activity in pre-symptomatic digenic models of Parkinson's disease (PD) that model the multifactorial aetiology of this disease. To this end, we analysed a novel mouse model mildly overexpressing mutant human alpha-synuclein (hA53T-SNCA) in a PTEN-induced kinase 1 (PINK1/ PARK6) knockout background and mutant mice lacking both DJ-1 (also known as PARK7) and PINK1. We showed that overexpressed hA53T-SNCA localizes to the nucleolus. Moreover, these mutants show a progressive reduction of rDNA transcription linked to a reduced mouse lifespan. By contrast, rDNA transcription is preserved in DJ-1/PINK1 double knockout (DKO) mice. mRNA levels of the nucleolar transcription initiation factor 1A (TIF-IA, also known as RRN3) decrease in the substantia nigra of individuals with PD. Because loss of TIF-IA, as a tool to mimic nucleolar stress, increases oxidative stress and because DJ-1 and PINK1 mutations result in higher vulnerability to oxidative stress, we further explored the synergism between these PD-associated genes and impaired nucleolar function. By the conditional ablation of TIF-IA, we blocked ribosomal RNA (rRNA) synthesis in adult dopaminergic neurons in a DJ-1/PINK1 DKO background. However, the early phenotype of these triple knockout mice was similar to those mice exclusively lacking TIF-IA. These data sustain a model in which loss of DJ-1 and PINK1 does not impair nucleolar activity in a pre-symptomatic stage. This is the first study to analyse nucleolar function in digenic PD models. We can conclude that, at least in these models, the nucleolus is not as severely disrupted as previously shown in DA neurons from PD patients and neurotoxin-based PD mouse models. The results also show that the early increase in rDNA transcription and nucleolar integrity may represent specific homeostatic responses in these digenic pre-symptomatic PD models.
  • Salmiheimo, Aino N. E.; Mustonen, Harri K.; Vainionpaa, Sanna A. A.; Shen, Zhanlong; Kemppainen, Esko A. J.; Seppanen, Hanna E.; Puolakkainen, Pauli A. (2016)
    Recent studies suggest that pro-inflammatory type M1 macrophages inhibit tumor progression and that anti-inflammatory M2 macrophages enhance it. The aim of this study was to examine the interaction of type M1 and M2 macrophages with pancreatic cancer cells. We studied the migration rate of fluorescein stained pancreatic cancer cells on Matrigel cultured alone or with Granulocyte- Macrophage Colony Stimulating Factor (GM-CSF) differentiated macrophages or with Macrophage Colony Stimulating Factor (M-CSF) differentiated macrophages, skewing the phenotype towards pro- and anti-inflammatory direction, respectively. Macrophage differentiation was assessed with flow cytometry and the cytokine secretion in cell cultures with cytokine array. Both GM-CSF and M-CSF differentiated macrophages increased the migration rate of primary pancreatic adenocarcinoma cell line (MiaPaCa-2) and metastatic cell line (HPAF-II). Stimulation with IL6 or IL4+ LPS reversed the macrophages' increasing effect on the migration rate of Mi-aPaCa-2 completely and partly of HPAF-II. Co-culture with MiaPaCa-2 reduced the inflammatory cytokine secretion of GM-CSF differentiated macrophages. Co-culture of macrophages with pancreatic cancer cells seem to change the inflammatory cytokine profile of GM-CSF differentiated macrophages and this might explain why also GM-CSF differentiated macrophages promoted the invasion. Adding IL6 or IL4+ LPS to the cell culture with MiaPaCa-2 and GM-CSF or M-CSF differentiated macrophages increased the secretion of inflammatory cytokines and this could contribute to the reversion of the macrophage induced increase of cancer cell migration rate.
  • Saraswat, Mayank; Joenväärä, Sakari; Tohmola, Tiialotta; Sutinen, Eva; Vartiainen, Ville; Koli, Katri; Myllärniemi, Marjukka; Renkonen, Risto (2020)
    Idiopathic pulmonary fibrosis (IPF) is a lung parenchymal disease of unknown cause usually occurring in older adults. It is a chronic and progressive condition with poor prognosis and diagnosis is largely clinical. Currently, there exist few biomarkers that can predict patient outcome or response to therapies. Together with lack of markers, the need for novel markers for the detection and monitoring of IPF, is paramount. We have performed label-free plasma proteomics of thirty six individuals, 17 of which had confirmed IPF. Proteomics data was analyzed by volcano plot, hierarchical clustering, Partial-least square discriminant analysis (PLS-DA) and Ingenuity pathway analysis. Univariate and multivariate statistical analysis overlap identified haptoglobin-related protein as a possible marker of IPF when compared to control samples (Area under the curve 0.851, ROC-analysis). LXR/RXR activation and complement activation pathways were enriched in t-test significant proteins and oxidative regulators, complement proteins and protease inhibitors were enriched in PLS-DA significant proteins. Our pilot study points towards aberrations in complement activation and oxidative damage in IPF patients and provides haptoglobin-related protein as a new candidate biomarker of IPF.
  • Mohlin, Sofie; Kunttas, Ezgi; Persson, Camilla U.; Abdel-Haq, Reem; Castillo, Aldo; Murko, Christina; Bronner, Marianne E.; Kerosuo, Laura (2019)
    Neural crest cells have broad migratory and differentiative ability that differs according to their axial level of origin. However, their transient nature has limited understanding of their stem cell and self-renewal properties. While an in vitro culture method has made it possible to maintain cranial neural crest cells as self-renewing multipotent crestospheres (Kerosuo et al., 2015), these same conditions failed to preserve trunk neural crest in a stem-like state. Here we optimize culture conditions for maintenance of avian trunk crestospheres, comprised of both neural crest stem and progenitor cells. Our trunk-derived crestospheres are multipotent and display self-renewal capacity over several weeks. Trunk crestospheres display elevated expression of neural crest cell markers as compared to those characteristic of ventrolateral neural tube or mesodermal fates. Moreover, trunk crestospheres express increased levels of trunk neural crest-enriched markers as compared to cranial crestospheres. Finally, we use lentiviral transduction as a tool to manipulate gene expression in trunk crestospheres. Taken together, this method enables long-term in vitro maintenance and manipulation of multipotent trunk neural crest cells in a premigratory stem or early progenitor state. Trunk crestospheres are a valuable resource for probing mechanisms underlying neural crest sternness and lineage decisions as well as accompanying diseases.
  • Lassila, Riitta; Campbell, Robert (2019)
    Take home messages To understand the main interplay between coagulation system and inflammation and to recognize the key invasive infectious agents causing typical abnormalities in activation of blood platelets, coagulation and fibrinolysis. To capture, monitor and follow-up the clinical and laboratory phenotype and the management related to the pathophysiology of inflammation.
  • Isakova, Elena P.; Matushkina, Irina N.; Popova, Tatyana N.; Dergacheva, Darya; Gessler, Natalya N.; Klein, Olga; Semenikhina, Anastasya; Deryabina, Yulia; La Porta, Nicola; Saris, Nils-Eric L. (2020)
    In this study, we evaluated the metabolic profile of the aerobic microorganism of Endomyces magnusii with a complete respiration chain and well-developed mitochondria system during long-lasting cultivation. The yeast was grown in batches using glycerol and glucose as the sole carbon source for a week. The profile included the cellular biological and chemical parameters, which determined the redox status of the yeast cells. We studied the activities of the antioxidant systems (catalases and superoxide dismutases), glutathione system enzymes (glutathione peroxidase and reductase), aconitase, as well as the main enzymes maintaining NADPH levels in the cells (glucose-6-phosphate dehydrogenase and NADP(+)-isocitrate dehydrogenase) during aging of Endomyces magnusii on two kinds of substrates. We also investigated the dynamics of change in oxidized and reduced glutathione, conjugated dienes, and reactive oxidative species in the cells at different growth stages, including the deep stationary stages. Our results revealed a similar trend in the changes in the activity of all the enzymes tested, which increased 2-4-fold upon aging. The yeast cytosol had a very high reduced glutathione content, 22 times than that of Saccharomyces cerevisiae, and remained unchanged during growth, whereas there was a 7.5-fold increase in the reduced glutathione-to-oxidized glutathione ratio. The much higher level of reactive oxidative species was observed in the cells in the late and deep stationary phases, especially in the cells using glycerol. Cell aging of the culture grown on glycerol, which promotes active oxidative phosphorylation in the mitochondria, facilitated the functioning of powerful antioxidant systems (catalases, superoxide dismutases, and glutathione system enzymes) induced by reactive oxidative species. Moreover, it stimulated NADPH synthesis, regulating the cytosolic reduced glutathione level, which in turn determines the redox potential of the yeast cell during the early aging process.
  • Ylösmäki, Erkko; Lavilla Alonso, Sergio; Jäämaa, Sari Susanna; Vaha-Koskela, Markus; af Hällström, Taija Maria; Hemminki, Akseli; Arola, Johanna; Mäkisalo, Heikki; Saksela, Kalle (2013)
  • Orav, Ester; Dowavic, Ilona; Huupponen, Johanna; Taira, Tomi; Lauri, Sari (2019)
    Kainate type ionotropic glutamate receptors (KARs) are expressed in hippocampal interneurons and regulate interneuron excitability and GABAergic transmission. Neuropilin tolloid-like proteins (NETO1 and NETO2) act as KAR auxiliary subunits; however, their significance for various functions of KARs in GABAergic interneurons is not fully understood. Here we show that NETO1, but not NETO2, is necessary for dendritic delivery of KAR subunits and, consequently, for formation of KAR-containing synapses in cultured GABAergic neurons. Accordingly, electrophysiological analysis of neonatal CA3 stratum radiatum interneurons revealed impaired postsynaptic and metabotropic KAR signaling in Neto1 knockouts, while a subpopulation of ionotropic KARs in the somatodendritic compartment remained functional. Loss of NETO1/KAR signaling had no significant effect on development of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA)-receptor-mediated glutamatergic transmission in CA3 interneurons, contrasting the synaptogenic role proposed for KARs in principal cells. Furthermore, loss of NETO1 had no effect on excitability and characteristic spontaneous network bursts in the immature CA3 circuitry. However, we find that NETO1 is critical for kainate-dependent modulation of network bursts and GABAergic transmission in the hippocampus already during the first week of life. Our results provide the first description of NETO1-dependent subcellular targeting of KAR subunits in GABAergic neurons and indicate that endogenous NETO1 is required for formation of KAR-containing synapses in interneurons. Since aberrant KAR-mediated excitability is implicated in certain forms of epilepsy, NETO1 represents a potential therapeutic target for treatment of both adult and early life seizures.
  • Morales, Luis O.; Shapiguzov, Alexey; Safronov, Omid; Leppälä, Johanna; Vaahtera, Lauri; Yarmolinsky, Dmitry; Kollist, Hannes; Brosche, Mikael (2021)
    Tropospheric ozone (O-3) is a major air pollutant that decreases yield of important crops worldwide. Despite long-lasting research of its negative effects on plants, there are many gaps in our knowledge on how plants respond to O-3. In this study, we used natural variation in the model plant Arabidopsis (Arabidopsis thaliana) to characterize molecular and physiological mechanisms underlying O-3 sensitivity. A key parameter in models for O-3 damage is stomatal uptake. Here we show that the extent of O-3 damage in the sensitive Arabidopsis accession Shahdara (Sha) does not correspond with O-3 uptake, pointing toward stomata-independent mechanisms for the development of O-3 damage. We compared tolerant (Col-0) versus sensitive accessions (Sha, Cvi-0) in assays related to photosynthesis, cell death, antioxidants, and transcriptional regulation. Acute O-3 exposure increased cell death, development of lesions in the leaves, and decreased photosynthesis in sensitive accessions. In both Sha and Cvi-0, O-3-induced lesions were associated with decreased maximal chlorophyll fluorescence and low quantum yield of electron transfer from Photosystem II to plastoquinone. However, O-3-induced repression of photosynthesis in these two O-3-sensitive accessions developed in different ways. We demonstrate that O-3 sensitivity in Arabidopsis is influenced by genetic diversity given that Sha and Cvi-0 developed accession-specific transcriptional responses to O-3. Our findings advance the understanding of plant responses to O-3 and set a framework for future studies to characterize molecular and physiological mechanisms allowing plants to respond to high O-3 levels in the atmosphere as a result of high air pollution and climate change.
  • Yan, Yan; Stoddard, Frederick L.; Neugart, Susanne; Sadras, Victor O.; Lindfors, Anders; Morales, Luis Orlando; Aphalo, Pedro J. (2019)
    Blue light and UV radiation shape a plant's morphology and development, but accession-dependent responses under natural conditions are unclear. Here we tested the hypothesis that two faba bean (Vicia faba L.) accessions adapted to different latitudes and altitudes vary in their responses to solar blue and UV light. We measured growth, physiological traits, phenolic profiles and expression of associated genes in a factorial experiment combining two accessions (Aurora, a Swedish cultivar adapted to high latitude and low altitude; ILB938, from the Andean region of Colombia and Ecuador, adapted to low latitude and high altitude) and four filter treatments created with plastic sheets: 1. transparent as control; 2. attenuated short UV (290-350 nm); 3. attenuated UV (290-400 nm); 4. attenuated blue and UV light. In both accessions, the exclusion of blue and UV light increased plant height and leaf area, and decreased transcript abundance of ELONGATED HYPOCOTYL 5 (HY5) and TYROSINE AMINOTRANSFERASE 3 (TAT3). Blue light and short UV induced the accumulation of epidermal and whole-leaf flavonoids, mainly quercetins, and the responses in the two accessions were through different glycosides. Filter treatments did not affect kaempferol concentration, but there were more tri-glycosides in Aurora and di-glycosides in ILB938. Furthermore, fewer quercetin glycosides were identified in ILB938. The transcript abundance was consistently higher in Aurora than in ILB938 for all seven investigated genes: HY5, TAT3, CHALCONE SYNTHASE (CHS), CHALCONE ISOMERASE (CHI), DON-GLUCOSYLTRANSFERASE 1 (DOGT1), ABA INSENSITIVE 2 (ABI2), AUXIN-INDUCIBLE 2-27 (IAA5). The two largest differences in transcript abundance between the two accessions across treatments were 132-fold in CHS and 30-fold in DOGT1 which may explain the accession-dependent glycosylation patterns. Our findings suggest that agronomic selection for adaptation to high altitude may favour phenotypes with particular adaptations to the light environment, including solar UV and blue light.
  • Reichhardt, M. P.; Holmskov, U.; Meri, S. (2017)
    It is becoming increasingly clear that the connections between our immune system and the microbiota colonizing us have a tremendous impact on human health. A number of innate molecular defence mechanisms cooperate to selectively target unwanted microorganisms at the mucosal surfaces. Amongst others these include the complement system, IgA and the SALSA molecule. The salivary scavenger and agglutinin (SALSA), also known as deleted in malignant brain tumors 1 (DMBT1), salivary agglutinin (SAG) or gp340 is a multifunctional molecule with important functions in innate immunity, inflammation and epithelial homeostasis. The SALSA protein is expressed at most mucosal surfaces, where it is one of the most abundant proteins. In the fetal meconium and infant intestine it may constitute even up to 10% of the total protein amount. SALSA is found either directly associated with the epithelial surface or secreted into the lining fluids. In the fluid-phase SALSA interacts with a number of bacterial and viral organisms, as well as with endogenous ligands, including IgA, lactoferrin, surfactant proteins and complement components. While complement has been shown to impact the mucosal environment, this remains an area of limited research. The multiple interactions of the SALSA molecule provide a scaffold, where this potent defence system may engage in cooperative microbial clearance together with corresponding mucosal host ligands. With its high abundance, and multiple effects on both host and microbes, the SALSA molecule is a key player in maintaining the immunological balance at the mucosal surfaces. This is further supported by observations linking the expression of different SALSA isoforms to the development of chronic inflammatory conditions, such as Crohn's disease and ulcerative colitis. This review describes the latest advances in understanding functions of SALSA and its different isoforms. Recently recognized functions are related to complement activation and regulation, endothelial development and epithelial homeostasis. In addition, we suggest mechanisms how SALSA regulates inflammation at the mucosal surfaces.
  • Morgunova, Ekaterina; Yin, Yimeng; Jolma, Arttu; Dave, Kashyap; Schmierer, Bernhard; Popov, Alexander; Eremina, Nadejda; Nilsson, Lennart; Taipale, Jussi (2015)
    The mammalian cell cycle is controlled by the E2F family of transcription factors. Typical E2Fs bind to DNA as heterodimers with the related dimerization partner (DP) proteins, whereas the atypical E2Fs, E2F7 and E2F8 contain two DNA-binding domains (DBDs) and act as repressors. To understand the mechanism of repression, we have resolved the structure of E2F8 in complex with DNA at atomic resolution. We find that the first and second DBDs of E2F8 resemble the DBDs of typical E2F and DP proteins, respectively. Using molecular dynamics simulations, biochemical affinity measurements and chromatin immunoprecipitation, we further show that both atypical and typical E2Fs bind to similar DNA sequences in vitro and in vivo. Our results represent the first crystal structure of an E2F protein with two DBDs, and reveal the mechanism by which atypical E2Fs can repress canonical E2F target genes and exert their negative influence on cell cycle progression.